IHAST2 Operations Manual.doc

Created 4/12/23 IHAST 2 Operations Manual

Table of Contents

Chapter I. Introduction I-1

I. A History and Background of the Problem.........................................................................I-1

I.A.1. Surgical Outcome....................................................................................................I-1

I.A.2. Intraoperative Protective Efforts.............................................................................I-2

I.A.3. This Trial.................................................................................................................I-3

I. B Trial Development...........................................................................................................I-3

Chapter II. Protocol Overview (Brief) II-1

Chapter III. Organizational Structure and Personnel III-1

III. A Steering Committee..................................................................................................III-1

III. B Advisory Committee.................................................................................................III-2

III. C Clinical Coordinating Center (CCC)........................................................................III-2

III. D Data Management Center (DMC).............................................................................III-2

III. E Physician Protocol Monitor (PPM)...........................................................................III-3

III. F Physician Safety Monitor (PSM)..............................................................................III-3

III. G NIH Protocol Safety Monitoring Committee (NIH PSMB).....................................III-4

III. H University of Iowa Division of Sponsored Programs...............................................III-4

Chapter IV. Participating Centers IV-1

IV. A Requirements for Participation.................................................................................IV-1

IV.A.1. Minimum Case Load.............................................................................................IV-1

IV.A.2. Selection Bias and Demographics........................................................................IV-1

IV.A.3. Principal Investigator and Co-Investigator Agreements.......................................IV-2

IV.A.4. Institutional Agreements.......................................................................................IV-2

a) Consortium Agreements................................................................................................IV-2

b) Financial Subcontract....................................................................................................IV-3

c) Human Studies Approval..............................................................................................IV-4

IV.A.5. Organizational Meeting Attendance......................................................................IV-5

IV.A.6. Subsequent Yearly Meetings.................................................................................IV-5

IV.A.7. Centers Recruited Later........................................................................................IV-6

IV.A.8. On-site Audits.......................................................................................................IV-6

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IV.A.9. Local Documentation............................................................................................IV-6

a) Operations Manual........................................................................................................IV-6

b) Case Report Forms/Patient Notebooks.........................................................................IV-6

c) Site Regulatory Binder..................................................................................................IV-7

IV. B Personnel Required, Duties and Certification Requirements...................................IV-7

IV.B.1. Local Principal Investigator (PI)...........................................................................IV-7

IV.B.2. Local Co-Investigator...........................................................................................IV-9

IV.B.3. Anesthesiologists..................................................................................................IV-9

a) Protocol.........................................................................................................................IV-9

b) Blinding.........................................................................................................................IV-9

c) Data Collection.............................................................................................................IV-9

d) Certification................................................................................................................IV-10

IV.B.4. Neurosurgeons.....................................................................................................IV-11

a) Recruitment/Notification............................................................................................IV-11

b) Protocol.......................................................................................................................IV-11

c) Data Collection...........................................................................................................IV-11

d) Certification................................................................................................................IV-11

IV.B.5. Study Coordinators.............................................................................................IV-12

a) Responsibilities...........................................................................................................IV-12

b) Certification................................................................................................................IV-14

IV.B.6. Neurologic Examiners........................................................................................IV-15

a) Responsibilities...........................................................................................................IV-15

b) Examiner Selection and Blinding...............................................................................IV-15

c) Certification................................................................................................................IV-16

IV.B.7. Neuropsychologic Examiners.............................................................................IV-17

a) Certification................................................................................................................IV-17

IV. C Funding...................................................................................................................IV-17

IV.C.1. General................................................................................................................IV-17

IV.C.2. Start Up Funds....................................................................................................IV-18

a) Local Human Studies Committee approval................................................................IV-18

b) Consortium arrangement completion..........................................................................IV-18

c) Financial Subcontract completion...............................................................................IV-18

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d) Organizational meeting attendence.............................................................................IV-18

IV.C.3. “Practice” Patients..............................................................................................IV-18

IV.C.4. Initial 10 Patients................................................................................................IV-18

IV.C.5. Subsequent Patients............................................................................................IV-19

IV.C.6. General Payment Schedule.................................................................................IV-19

IV.C.7. Payment Procedures............................................................................................IV-19

IV.C.8. Local Institutional Overhead/Indirect Costs.......................................................IV-20

Chapter V. Patient Assessment Instruments and Training V-1

V. A WFNS1 and GCS............................................................................................................V-1

a) Training and Certification..............................................................................................V-2

V. B Rankin Disability Score2,3...............................................................................................V-3


V. C NIHSS4,5,6,7......................................................................................................................V-3


V. D Barthel's Activities of Daily Living (ADL)8,9.................................................................V-5


V. E Mini-Mental State Exam (MMSE).................................................................................V-5


V. F Neuropsychologic Testing Battery.................................................................................V-6

V.F.1. Benton Visual Retention Test (BVRT)...................................................................V-6

V.F.2. Controlled Oral Word Association (COWA)..........................................................V-7

V.F.3. Complex Figure Test (CFT)...................................................................................V-7

V.F.4. Grooved Pegboard (GP).........................................................................................V-7

V.F.5. Trail Making Test (TMT).......................................................................................V-7


V. G Glasgow Outcome Score (GOS)....................................................................................V-7


V. H Summary........................................................................................................................V-9

Chapter VI. Enrollment and Randomization Procedures VI-1

VI. A Randomization Scheme............................................................................................VI-1

VI.A.1. What Constitutes Randomization?.......................................................................VI-2

VI.A.2. Envelopes, Patient Notebooks, and Other CRF’s.................................................VI-2

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VI.A.3. Brown or White?..................................................................................................VI-3

VI. B Eligibility Assessments.............................................................................................VI-3

VI.B.1. Enrollment Criteria...............................................................................................VI-3

a) Inclusion Criteria..........................................................................................................VI-3

b) Exclusion Criteria.........................................................................................................VI-4

c) Procedural Criteria........................................................................................................VI-4

VI. C Enrollment Telephone Call.......................................................................................VI-4

VI.C.1. Enrollment Call Instructions.................................................................................VI-4

a) Calling the automated telephone randomization system..............................................VI-5

b) Tips for success with the system:.................................................................................VI-5

c) Telephone Scripts.........................................................................................................VI-5

VI.C.2. Enrollment Call Problems....................................................................................VI-8

a) PCC is not yet approved to commence patient enrollment..........................................VI-9

b) Individual making the call is not yet certified..............................................................VI-9

c) Incorrect Menu Choice.................................................................................................VI-9

d) Entry indicates that a patient does not meet enrollment criteria...................................VI-9

e) Incorrect date entry......................................................................................................VI-9

f) Incorrect interval between SAH and surgery..............................................................VI-10

VI.C.3. Practice Obtaining a Randomization Assignment..............................................VI-10

VI. D Study Packets..........................................................................................................VI-10

VI. E 24-hour Patient Randomization Status Call...........................................................VI-11

Chapter VII. Reporting and Data Submission VII-1

VII. A Organization of Data Collection Materials.............................................................VII-1

VII.A.1. Patient Notebooks...............................................................................................VII-1

VII.A.2. Screening and Eligibility Forms..........................................................................VII-1

VII.A.3. Study Packets......................................................................................................VII-1

a) Access to Envelopes, Patient Notebooks, and Other CRF’s.......................................VII-2

VII.A.4. PCC Correction Report Forms............................................................................VII-3

VII.A.5. Site Regulatory Binder........................................................................................VII-4

VII.A.6. Patient Log Binder..............................................................................................VII-4

VII. B Distribution of Materials.........................................................................................VII-5

VII. C General Guidelines for Completing Case Report Forms........................................VII-5

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VII.C.1. Once Randomized, Data Collection Continues...................................................VII-5

VII.C.2. Recording Data on Case Report Forms...............................................................VII-6

a) Zero-fill.......................................................................................................................VII-6

b) Dates............................................................................................................................VII-6

c) Daily Post-op Screen and Medications (tabular forms)..............................................VII-7

d) Correcting Mistakes....................................................................................................VII-7

e) Correcting TEMPERATURE Forms...........................................................................VII-8

VII.C.3. Header Information.............................................................................................VII-8

a) Patient ID.....................................................................................................................VII-9

b) Center Identification Number......................................................................................VII-9

c) Patient Log Number....................................................................................................VII-9

d) Date……...................................................................................................................VII-10

e) Time...........................................................................................................................VII-10

VII.C.4. Footer Information............................................................................................VII-10

a) Initials of Person Completing the Form....................................................................VII-10

b) Signature....................................................................................................................VII-11

c) Certification Number.................................................................................................VII-11

d) Form Completion Date..............................................................................................VII-11

VII.C.5. Types of Data Collection Item...........................................................................VII-11

a) Example with No-Yes................................................................................................VII-11

b) Example with No-Probable-Definite data.................................................................VII-12

c) Lists - Example with No-Yes options........................................................................VII-12

d) Lists - Example with No-Probable-Definite..............................................................VII-12

e) Lists - Example with categorical data.......................................................................VII-12

f) Unknown or Questionable Items...............................................................................VII-13

g) Tabular Forms...........................................................................................................VII-13

VII. D Case Report Forms to be Completed by StudyCoordinator..................................VII-14

VII. E Case Report Forms to be Completed by Certified IHAST2 physicians...............VII-14

VII. F Case Report Forms to be completed by Neurologic Examiners...........................VII-15

VII. G Case Report Forms to be completed by Neuropsychologists................................VII-15

VII. H DMC Reports to PCC, CCC, etc...........................................................................VII-15

VII.H.1. No Patient Randomization Status Call..............................................................VII-15

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VII.H.2. IHAST2 Patient Calendar..................................................................................VII-15

VII.H.3. Weekly Patient Summary Report......................................................................VII-16

VII.H.4. Data Edit Reports..............................................................................................VII-16

VII.H.5. Update Newsletter.............................................................................................VII-16

VII. I Data Submission/Collection..................................................................................VII-16

VII. J Task Personnel Spreadsheet..................................................................................VII-18

VII. K How to ship Case Report Forms to the DMC.......................................................VII-20

VII. L The IHAST2 Data Management System...............................................................VII-20

VII.L.1. Overview...........................................................................................................VII-20

VII.L.2. Data Quality Assurance.....................................................................................VII-21

VII.L.3. The Data Edit Report.........................................................................................VII-21

VII.L.4. On-Site Audits...................................................................................................VII-22

VII. M Communication.....................................................................................................VII-23

Chapter VIII.Detailed Protocol VIII-1

VIII. A Overview................................................................................................................VIII-1

VIII. B Patient Recruitment/Study Activation....................................................................VIII-1

VIII. C Initial Assessment/Patient Eligibility.....................................................................VIII-1

VIII. D Specific Eligibility criteria.....................................................................................VIII-2

a) Comment: Medical Contraindications......................................................................VIII-2

VIII.D.1. Consent and Enrollment.....................................................................................VIII-3

a) Enrollment Questions.................................................................................................VIII-4

b) Enrollment Follow-up................................................................................................VIII-4

VIII. E Preoperative Assessments......................................................................................VIII-5

VIII. F Anesthetic Management.........................................................................................VIII-5

VIII.F.1. Equipment Required..........................................................................................VIII-5

VIII.F.2. CRFs/Materials for the Anesthesiologist...........................................................VIII-6

VIII.F.3. Room Conditions prior to Patient arrival to the Operating Room.....................VIII-7

a) Room Temperature.....................................................................................................VIII-7

b) Water Mattress...........................................................................................................VIII-7

c) Temperature Devices/Displays..................................................................................VIII-7

VIII.F.4. Monitoring.........................................................................................................VIII-8

a) Required Monitoring..................................................................................................VIII-8

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b) Other Monitoring.......................................................................................................VIII-8

VIII.F.5. Intraoperative Anesthetic Agents.......................................................................VIII-8

VIII.F.6. Basic Protocol....................................................................................................VIII-9

a) Blinding......................................................................................................................VIII-9

b) Prior to Induction of Anesthesia..............................................................................VIII-10

c) Induction and Maintenance of Anesthesia...............................................................VIII-10

d) Temperature Monitor and Blanket Placement..........................................................VIII-11

e) Initial Intraoperative Temperature............................................................................VIII-11

f) Post-clip Temperature Management........................................................................VIII-12

g) End of Surgery.........................................................................................................VIII-13

h) Other Intraoperative Surgical and Anesthetic Management....................................VIII-14

VIII.F.7. Neurosurgical Management.............................................................................VIII-14

a) Patient Selection.......................................................................................................VIII-15

b) Blinding....................................................................................................................VIII-15

c) Temperature Guess...................................................................................................VIII-15

d) Intraoperative Protective Agents..............................................................................VIII-15

e) Other drugs...............................................................................................................VIII-16

f) Temporary Clipping.................................................................................................VIII-16

VIII.F.8. Postoperative Care/0-2-hours...........................................................................VIII-16

VIII.F.9. Intraoperative & Early Postoperative Intercurrent Events..............................VIII-16

VIII.F.10.Early postoperative NIHSS..............................................................................VIII-17

VIII.F.11.Postoperative Care/Later..................................................................................VIII-17

VIII.F.12.Daily Assessments...........................................................................................VIII-17

VIII.F.13.Intercurrent Events...........................................................................................VIII-18

a) Severe/Indicator IEs.................................................................................................VIII-18

b) Routine IEs...............................................................................................................VIII-18

VIII.F.14.Postoperative Neurologic Assessments............................................................VIII-19

VIII.F.15.Discharge.........................................................................................................VIII-19

VIII.F.16.Post-Discharge Follow-up...............................................................................VIII-20

a) Interim Contacts.......................................................................................................VIII-20

b) Three-month Follow-up...........................................................................................VIII-20

c) Follow-up Difficulties..............................................................................................VIII-21

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Chapter IX. Data Forms/Completion Instructions IX-1

IX. A Screening Form.........................................................................................................IX-1

IX.A.1. Overview:.............................................................................................................IX-1

IX.A.2. Data Items.............................................................................................................IX-1

IX. B Eligibility Form........................................................................................................IX-2

IX.B.1. Overview:.............................................................................................................IX-2

IX.B.2. Data Items.............................................................................................................IX-3

IX. C Contact Form............................................................................................................IX-8

IX.C.1. Overview:.............................................................................................................IX-8

IX.C.2. Data Items.............................................................................................................IX-9

IX. D Pre-SAH History Form.............................................................................................IX-9

IX.D.1. Overview:.............................................................................................................IX-9

IX.D.2. Data Items...........................................................................................................IX-10

a) Section A. Neurologic History Prior to Current SAH...............................................IX-10

b) Section B. Cardiovascular History Prior to Current SAH.........................................IX-12

c) Section C. Respiratory History Prior to Current SAH...............................................IX-15

d) Section D. Coagulation Disorders Prior to Current SAH..........................................IX-16

e) Section E. Other Disorders Prior to Current SAH.....................................................IX-17

IX. E Post-Admit Screen..................................................................................................IX-19

IX.E.1. Overview:...........................................................................................................IX-19

a) Section A. Neurology.................................................................................................IX-20

b) Section B. Other Events..............................................................................................IX-23

IX. F Neurosurgeon..........................................................................................................IX-27

IX.F.1. Overview:...........................................................................................................IX-27

IX.F.2. Data Items...........................................................................................................IX-27

IX. G Anesthesiologist......................................................................................................IX-30

IX.G.1. Overview:...........................................................................................................IX-30

IX.G.2. Data Items...........................................................................................................IX-31

a) Section A. Patient Eligibility.....................................................................................IX-31

b) Section B. Physical Examination Prior to Induction.................................................IX-32

c) Section C. Induction...................................................................................................IX-34

d) Section D. Randomization..........................................................................................IX-37

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e) Section E. Conditions at Definitive Clip Placement*.................................................IX-37

f) Section F. Intraoperative Fluids.................................................................................IX-39

g) Section G. Events occurring during the first 0-2 hours after leaving the operating roomIX-40

h) Section H. Perioperative Events................................................................................IX-41

IX. H Temperature............................................................................................................IX-49

IX.H.1. Overview:...........................................................................................................IX-49

IX.H.2. Data Items...........................................................................................................IX-49

IX. I Daily Post-Op Screen.................................................................................................IX-52

IX.I.1. Overview:...........................................................................................................IX-52

IX. J Intercurrent Events.....................................................................................................IX-59

IX.J.1. Overview:...........................................................................................................IX-59

IX.J.2. Data Items...........................................................................................................IX-60

IX. K IE Definitions.........................................................................................................IX-63

IX. L Contact Follow-up Form........................................................................................IX-63

IX. M Outcome Follow-up................................................................................................IX-66

IX. N 3-Month Visit..........................................................................................................IX-67

IX. O Death/Patient Withdrawal.......................................................................................IX-68

IX.O.1. Overview:...........................................................................................................IX-68

IX. P NIHSS.....................................................................................................................IX-70

IX.P.1. Overview............................................................................................................IX-70

IX.P.2. Certification........................................................................................................IX-71

Special Situations...................................................................................................................IX-79

Coma IX-79

Persons Who Refuse to Cooperate.................................................................................IX-79

IX. Q Neuropsychology Forms and Test Performance.....................................................IX-80

IX.Q.1. Overview............................................................................................................IX-80

IX.Q.2. Data Items...........................................................................................................IX-80

a) Benton Visual Retention Test (BVRT).......................................................................IX-80

b) Controlled Oral Word Association (COWA)..............................................................IX-81

c) Complex Figure Test (CFT)........................................................................................IX-82

d) Grooved Pegboard Test...............................................................................................IX-82

e) Trail Making Test........................................................................................................IX-83

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IX. R Medications............................................................................................................IX-85

IX.R.1. Overview............................................................................................................IX-85

IX. S DETAILED IE DEFINITIONS..............................................................................IX-90

Chapter X. The First Two “Practice” patients X-1

X.A.1. Overview................................................................................................................X-1

X.A.2. Procedure...............................................................................................................X-1

Chapter XI. Appendices XI-1

XI. A UI Contact Information............................................................................................XI-1

XI. B Participating Centers Contact Information...............................................................XI-1

XI. C Pilot Trial Publication...............................................................................................XI-1

XI. D The University of Iowa IRB documents...................................................................XI-1

XI. E Consortium letter template......................................................................................XI-1

XI. F NIH Subcontract template........................................................................................XI-1

XI. G DMC Forms..............................................................................................................XI-1

a) No Patient Randomization Status Call.........................................................................XI-1

b) IHAST2 Patient Calendar.............................................................................................XI-1

c) Weekly Patient Summary Report..................................................................................XI-1

d) Data Edit Report (DER)...............................................................................................XI-1

e) PCC Correction Report.................................................................................................XI-1

f) Script for Interval Contacts...........................................................................................XI-1

g) IHAST2 Comment Entry System.................................................................................XI-1

XI.G.2. GOS/Rankin Testing Vignettes.............................................................................XI-1

XI.G.3. Case Report Forms...............................................................................................XI-2

a) SCREENING................................................................................................................XI-2

b) ELIGIBILITY...............................................................................................................XI-2

c) CONTACT....................................................................................................................XI-2

d) NIH STROKE SCALE.................................................................................................XI-2

e) PRE-SAH HISTORY...................................................................................................XI-2

f) POST-ADMIT SCREEN..............................................................................................XI-2

g) ANESTHESIOLOGIST...............................................................................................XI-2

h) NEUROSURGEON......................................................................................................XI-2

i) TEMPERATURE-H.....................................................................................................XI-2

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j) TEMPERATURE-N.....................................................................................................XI-2

k) DAILY POST-OP SCREEN.........................................................................................XI-2

l) DPS SUPPLEMENT....................................................................................................XI-2

m) CONTACT FOLLOW-UP....................................................................................XI-2

n) OUTCOME FOLLOW-UP...........................................................................................XI-2

o) NEUROPSYCHOLOGY FORMS...............................................................................XI-2

p) MEDICATIONS...........................................................................................................XI-3

q) INTERCURRENT EVENTS.......................................................................................XI-3

r) IE SUPPLEMENT........................................................................................................XI-3

s) DEATH/PATIENT WITHDRAWAL............................................................................XI-3

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CHAPTER I. INTRODUCTION

Welcome to IHAST2!

This is a large multi-center, prospective, randomized, partially blinded clinical trial, designed to determine whether mild intraoperative hypothermia results in improved neurologic outcome in patients with an acute subarachnoid hemorrhage (SAH), undergoing an open craniotomy to clip their aneurysms. To the best of our knowledge, this is the only NIH funded trial to examine the impact of an intraoperative intervention on neurologic outcome following any neurosurgical procedure. It is certainly the largest trial of its kind yet undertaken.

In this manual we have tried to cover all aspects of trial design and organization, participant and participating center requirements, training, eligibility rules, enrollment procedures, study protocols, form completion, data submission, etc. There is an enormous amount of material here. We strongly urge you to make this manual available to everyone in your PCC who will be involved - and to encourage him or her to read at least those portions that pertain to their activities. If you have questions, we ask that you first refer to the Table of Contents, or try searching for the relevant terms on the electronic version of the manual when it becomes available. However, please don’t hesitate to contact the Clinical Coordinating Center (CCC) or Data Management Center (DMC) at Iowa with any and all questions that you may have—at any time.

I. A HISTORY AND BACKGROUND OF THE PROBLEM

While alternative therapies are being evaluated, the definitive “solution” to aneurysmal SAH remains surgical obliteration of the aneurysm via open craniotomy. Unfortunately, surgery remains an imperfect therapy. Although it can prevent recurrent bleeding, it does not reverse the consequences of the original hemorrhage. More importantly, surgery performed in these patients is not benign, and may result in additional morbidity and mortality.

I.A.1. Surgical Outcome

The long term outcome of patients who undergo surgery to clip ruptured intracranial aneurysms has not changed a great deal in the last decade, in spite of the introduction of nimodipine and improvements in surgical and anesthetic techniques. Among patients with SAH, between 55% and 65% of patients will be classified as having a “Good Outcome” by the Glasgow Outcome Scale (GOS=1) when examined three months after admission. Since poor grade patients often do not undergo surgery (and do poorly regardless), it is reasonable to assume that outcomes in the surgical subgroups will be somewhat better than noted above. Unfortunately, only the 1990 Cooperative Trial report provided specific outcome results for patients who actually underwent surgery (2922 patients, 68% GOS=1).

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Of course, these results imply that 30-45% of SAH patients either die or suffer neurologic disabilities severe enough to reduce their quality of life. The results may be even worse than this since cognitive abnormalities are common, even among patients with GOS scores =1. Most of these suboptimal outcomes are the direct result of the initial SAH and its complications. Nevertheless, a certain fraction of the adverse outcomes may be related to surgery itself, either due to a direct neurologic injury (e.g., misplaced aneurysm clips, prolonged temporary clipping, retraction, dissection, induced vasospasm, hemorrhage, etc.), or due to surgically/anesthetically-induced exacerbation of underlying damage (a so-called “secondary injury”). For example, in the European Tirilazad trial, 28% of patients with admission World Federation of Neurologic Surgeons (WFNS) scores of I-III had poor outcomes (GOS=3-5). More importantly (and of greater relevance to this proposal), a certain fraction of patients develop new postoperative neurologic deficits. In the Cooperative Trial, approximately one-third of all surgical patients had a decline in neurologic status immediately (1-2 days) following surgery - even in patients who were neurologically normal preoperatively.

The fact that good-grade patients suffer poor outcomes, or that new neurologic deficits appear postoperatively, supports our contention that surgery and anesthesia per se may lead to dysfunction. It is tempting to conclude that these estimates of surgery-related injuries are too high, or that the deficits stem from the disease itself (e.g., vasospasm). Superficially, support for this view comes from patients undergoing elective surgery for unruptured aneurysms. Presumably, any postoperative deficit in such patients must be surgically related. In 1994, King et al., reported a meta-analysis of elective surgery performed in 733 patients (from 28 published reports). They noted an overall combined morbidity/mortality rate of only ≈5%, a rate much lower than for SAH patients. Unfortunately, this review almost certainly deals with selectively reported results and underestimates the true incidence, particularly the incidence of less severe deficits. It is also likely that the excellent results reported by some surgeons - while perhaps reflecting what can be achieved - do not necessarily reflect “community wide” results.

The limited reliability of such data resulted in the NIH-funded “International Study of Unruptured Intracranial Aneurysms”. The results of this epidemiological study indicate that overall 30 day surgical mortality and morbidity is between 12 and 17% (95% confidence interval). In our own pilot trial (see Appendix), 22% of the patients with unruptured aneurysms suffered some degree of morbidity or mortality. This is very similar to the results recently reported by Khanna et al., who noted that 22% of 172 patients undergoing surgery for unruptured aneurysms suffered either a mild or severe neurologic deficit; 2% of patients died (5 of 172).

I.A.2. Intraoperative Protective Efforts

The most evident “acknowledgment” of the potential for surgery to result in direct neurologic complications is the effort expended by neurosurgeons and anesthesiologists to “protect” the brain during surgery. Unfortunately, in spite of these efforts, an extensive review of the literature fails to reveal even a single controlled trial of any form of intraoperative protective modality. Many protective interventions have been advocated, and even employed in an uncontrolled fashion. These include barbiturates, etomidate, propofol, isoflurane, desflurane, high-dose mannitol, vitamin E (and other antioxidants) - and of course, hypothermia.

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Hypothermia is clearly the oldest protective modality to be employed clinically. There is no question that deep hypothermia (T<20oC) can protect the brain against prolonged periods of complete ischemia (circulatory arrest). However, this degree of deep hypothermia requires the use of complete anticoagulation and cardiopulmonary bypass, making its widespread use in routine aneurysm surgery impractical. More recently, studies have shown that much smaller reductions in brain temperature (32-35oC) also have protective value in experimental animals subjected to both global and focal ischemic insults.

Enthusiasm for the use of mild hypothermia during surgery has grown. There are several reasons. First, the animal data mentioned above is reasonably unambiguous. Second, several clinical studies examining the impact of mild hypothermia (T>30oC) on ICP and outcome following head trauma have been modestly positive - although the definitive, multi-center trial of hypothermia in trauma failed to demonstrate any benefit (Guy Clifton M.D., personal communication). Third, unlike deep hypothermia, mild hypothermic temperatures are easily achieved, particularly in anesthetized patients; in fact, a 1.5-2oC drop in temperature is “normal” under general anesthesia unless actively prevented. This makes it easy to employ “hypothermia by default”.

I.A.3. This Trial

The decision to examine the protective effects of hypothermia during aneurysm surgery was made only after extensive consideration and discussions with numerous anesthesiologists and neurosurgeons. There are two major reasons to pursue this investigation.

First, laboratory data demonstrating the protective efficacy of mild hypothermia in the face of multiple different insults suggests that this modality is the one “most likely to succeed”. By contrast, barbiturate therapy, while consistently beneficial during focal ischemia, has not proven useful in the face of other insults (e.g., global ischemia, hypoxia, trauma).

Second, this method is already in widespread use “by default”, in spite of the lack of demonstrated clinical benefit; some centers even believe that maintaining normothermia is unethical. We believe that this application of an unproven therapy is unwise. It either assumes that mild hypothermia works in humans, or, at the very least, it is harmless. The problem is that efficacy has not been shown. Moreover, there is clear evidence that hypothermia need not be risk free. Hypothermia is known to inhibit normal coagulation and to increase perioperative blood loss during hip surgery. Hypothermia can increase the risk of ventricular dysrhythmias and is associated with an increased incidence of postoperative myocardial ischemia, which may occur long after body temperature has been normalized. Hypothermia also impairs the immune response and results in an increase in surgical wound infections following “dirty” surgery (e.g., colon resections). Lastly, hypothermia can delay emergence from anesthesia, can markedly increase metabolic demands even when shivering is prevented, and can be followed by “rebound hyperthermia.”

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For these reasons, we believe that it is appropriate to undertake a prospective trial of mild intraoperative hypothermia during aneurysm surgery. Without the knowledge derived from such a trial, patients will either, a) continue to be subjected to a therapy with unknown risk/benefit characteristics - which may in fact be detrimental, or b) be denied a valuable intervention which can be delivered easily and very inexpensively with readily available equipment.

I. B TRIAL DEVELOPMENT

IHAST2 has been a long time in development. The project grew out of a series of discussions held among members of the Society for Neurosurgical Anesthesia and Critical Care (SNACC) as long ago as 1991. The decision to focus on hypothermia in patients with SAH was made at a small research meeting of neuroanesthesiologists held in 1992. This, in turn, lead to the design and execution of a small (114-patient) randomized, prospective pilot trial that was conducted at five clinical centers between 1994 and 1997 (and which was published in January 1999, see Appendix). This pilot trial was designated as IHAST1. This lead to the formal preparation of a grant to NIH which was submitted in June 1998 and which was approved for funding in January, 1999. Actual organization of IHAST2 began in the fall of 1998, and commenced “full time” in April, 1999.

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CHAPTER II. PROTOCOL OVERVIEW (BRIEF)

Title: Intraoperative Hypothermia for Aneurysm Surgery Trial, Part 2 (also known as IHAST2).

Principal Investigator: Michael M. Todd, M.D.

Institution: University of Iowa (UI) College of Medicine.

Biostatisticians: Robert F. Woolson, Ph.D., William R. Clarke Ph.D., (Director, UI Data Management Center-DMC).

Epidemiologist: James C. Torner, Ph.D.

Project phase or primary methodology: Randomized, prospective, partially blinded clinical trial.

Target disease: Acute aneurysmal subarachnoid hemorrhage (surgical patients).

Intervention: Mild intraoperative cooling (core temperature 33°C) with immediate post-clip rewarming.

Number of patients to be enrolled: 1000 (power analysis indicates ≈ 920 completed patients needed).

Number of clinical centers: Approximately 30

Primary hypothesis: Mild hypothermia limited to the intraoperative period in patients undergoing craniotomies for the clipping of intracranial aneurysms will improve neurologic outcome at three months as quantitated by Glasgow Outcome Scale score (GOS) as compared with outcome in patients remaining normothermic during surgery.

Secondary hypotheses: Mild hypothermia will also improve outcome as assessed by other neurologic or neuropsychologic measures, and will beneficially influence hospital course, including:

At three months: NIH Stroke Score, Barthel Index (Activities of Daily Living), Rankin Disability Score, Mini-Mental State Exam (MMSE) and five-test neuropsychology battery.

In hospital: Duration of intubation/ventilation, duration of ICU care, duration of hospitalization, discharge destination, other intercurrent events and intensity of therapy.

Patient selection criteria: Adult, non-obese, non-pregnant WFNS Grade I, II or III patients with SAH scheduled to undergo craniotomies for aneurysm clipping within 14 days of SAH. No contraindications to cooling, pre-SAH Rankin scores of 0 or 1, nimodipine therapy planned.

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Description of pre-randomization procedures or process: Patients will be examined to verify eligibility. After consent is obtained, the DMC will be contacted and the color of a sealed envelope containing the temperature group assignment will be provided. This envelope will not be opened until after the induction of general anesthesia – and the patient will not be considered randomized and entered until the envelope is opened.

Precise treatment dose description for protocol: In hypothermic patients, core temperature will be reduced to a target of 33oC, using water mattresses, forced air cooling and cold intravenous fluids. Cooling will begin after the induction of anesthesia in the operating room, and rewarming will commence immediately after the aneurysm is clipped. Normothermia will be restored within two hours after patient arrival in the postoperative care area.

Plan for follow-up: Patients will be examined daily for 14 days postoperatively, or until discharge from hospital. They will be seen again at ≈six weeks after surgery, with an extensive, final evaluation to be completed at three months following surgery.

Extent and type of blinding/masking: The Anesthesiologist in the O.R. cannot be blinded. However, every effort will be made to ensure that the operating surgeon remains blinded. The individual responsible for all neurologic outcome assessments, both in the hospital and at three months postoperatively, will be completely blinded, as will the Local Study Coordinator.

Endpoints and outcomes: Primary outcome will be Glasgow Outcome Score at three months. Secondary outcomes will include NIH Stroke Score, employment status, place of residence, Rankin Disability Scale, Barthel's Activities of Daily Living Scale, and Neuropsychology.

Statistical design and sample size calculations: The trial is designed to achieve a power of 0.90 and alpha=0.05 (two-sided) to detect an improvement of 10% (absolute) in the number of patients with a Glasgow Outcome Score =1 (Good Outcome) (i.e., from 65% in the control (normothermia) group to 75% in the treatment group). Patient entry will be randomized with stratification by center and by interval between SAH and surgery (0-7 and 8-14 days). This will be done only to ensure equal distributions of normothermic and hypothermic patients within each center and within each interval subgroup (i.e., no restriction on the number of patients in each subgroup).

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Proposed safety and efficacy monitoring boundaries: The NIH Patient Safety & Monitoring Board (PSMB) will have final say over boundaries. We intend to monitor primary efficacy (GOS at three months) with the Lan & DeMets interim monitoring procedure, using an alpha-spending function approach with O’Brien-Fleming boundaries. Two formal efficacy analyses are planned after entry (through three-month follow-up) of 300 and 600 patients. With these boundaries, the significance level required for the first interim analysis is 0.00052; for the second it is 0.01429. Safety analysis will involve comparison of adverse events between treatment groups by body system and specific COSTART term. Interim analysis for safety will examine all adverse event comparisons; those with P<0.05 will be flagged for the attention of the PSMB. Local safety monitoring will be done on an ongoing basis by the Local Safety Monitor (Harold P. Adams, Jr., M.D.), reviewing mortality and serious IEs. Regular safety analysis by the local monitor will be reported to the PSMB.

Patient accrual plan: First patient to be entered late in 1999. Thereafter, target accrual rate is 30 patients per month. Sufficient PCC’s will be recruited to maintain this accrual rate.

Ethical and consent considerations: Since no form of intraoperative management has ever been evaluated, there do not appear to be any evident ethical concerns regarding randomization; both normothermia and hypothermia are used by personal preference by many teams (no PCC has an established temperature monitoring protocol). There are theoretical risks to cooling, and several studies have demonstrated some increase in the incidence of myocardial ischemia and dysrhythmias, and in the incidence of wound infections. However, these data were not obtained in a neurosurgical setting, and available data in this population (including in our own pilot study) have failed to demonstrate any risk to moderate hypothermia limited to the intraoperative period. Regarding consent; study consent will be obtained from either the patient or the next of kin/consenting person. Specifically, consent will be obtained from the same individual who signed the surgical consent document.

Participating pharmaceutical or device manufacturing company: Augustine Medical Inc., Prairie View, Minnesota (will provide forced air cooling equipment only). Mallinckrodt Medical, St. Louis, Missouri will provide combined esophageal stethoscope/thermistors and cables.

PAYMENT: $3,000 per completed patient, paid in two $1500 increments (first after discharge data filed and verified, second after final three-month data filed and verified.) $10,000 advance payment prior to initiation (charged against the first 10 patients in each center). Travel funds for one meeting per year (Local PI and Study Coordinator).

AUDITS: Intraoperative records will be audited by the Physician Protocol Monitor (PPM - blinded as to outcome). All data forms and patient records will be subjected to two onsight data audits. The first audit will take place as soon after enrollment of the first patient as possible, but before the end of the first year. The second audit will occur sometime in the second or third year.

Funding agencies: National Institutes of Health (NIH), National Institute of Neurologic Disease and Stroke (NINDS)

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CHAPTER III. ORGANIZATIONAL STRUCTURE AND PERSONNEL

There is a complex organizational/administrative structure to a trial of this magnitude. This structure is shown graphically below, and is described in detail in the paragraphs that follow.

III. A STEERING COMMITTEE

Overall responsibility for the trial rests with the “Steering Committee”, chaired by Dr. Todd, and made up of the primary individuals of the Clinical Coordinating Center (CCC) and the Data Management Center (DMC) as well as Drs. Matthew Howard, III (UI Neurosurgery), Patricia Davis (UI Neurology) and Dan Tranel (UI Neurology-Neuropsychology). All decisions regarding, a) protocol changes, b) continued participation of PCC’s, c) expenditures, case report forms (CRF’s) and Operations Manual development, etc., are vested in the Steering Committee. Individual Steering Committee members will also be available to the Physician Safety Monitor (Harold P. Adams, Jr., M.D.) to assist in the assessment of safety issues related to their specific specialties (anesthesiology, neurosurgery, neurology, or neuropsychology).

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Data Management Center (University of Iowa)

Participating Centers

Sub

mis

sion

Verif

icat

ionS

ubmission

Verification

Physician Protocol Monitor

Verification

Physician Safety Monitor

Verified IE’s

Steering Committee

Todd (PI and Chair), Hindman, Woolson,

Torner, Clarke, Tranel, Howard, Davis

Advisory Committee

Loftus, Gelb Schubert, Clifton

NIH Protocol Safety & Monitoring Committee

William Young, Chair

Intercurrent Event Reports

Case Report Forms

Anesthesia & PACU Records

Audits Enrollment & Verification 319-353-4708

Other Committees (To be Named) Publications

Concurrent Studies

IE Summaries

Clinical Coordinating Center (University of Iowa)


III. B ADVISORY COMMITTEE

The “outside” Advisory Committee is chaired by Dr. Loftus (University of Oklahoma, Neurosurgery) and also includes Drs. Gelb (University of Western Ontario, Anesthesiology), Schubert (Cleveland Clinic, Anesthesiology) and Clifton (University of Texas, Houston, Neurosurgery). The primary role of this group is to provide consultative services regarding protocols, protocol changes, CRF development, etc., to the Steering Committee.

III. C CLINICAL COORDINATING CENTER (CCC)

The CCC, chaired by Dr. Todd, is made up of two physicians (Drs. Todd and Hindman), three clinical coordinators (Ms. Weeks, Mrs. McAllister and Ms. Moss) and a secretary (Mrs. Janan Winn). This group will be the primary liaison with PCCs, will answer any protocol, eligibility and enrollment questions, and will receive and evaluate any emergently submitted “INTERCURRENT EVENTS (IE)” forms, with the primary goal being to ensure that all information needed to “define” the circumstances surrounding the IE is adequately collected. If any certified individual at any PCC has any questions regarding the conduct of the trial or regarding an individual patient, these should be directed to the CCC. Personnel at the CCC will be available “on-call” 24 hours-per-day.

In addition, the CCC will be responsible for the performance of on-site audits of PCCs. Plans call for each center to be visited twice during the period of the study, once during the first 12 months, and one additional time during the following three years.

Note that all members of the CCC will remain blinded regarding the temperature assignment of individual patients and will not receive information regarding outcomes until the time of on-site audits. In particular, they will have access to submitted CRFs only when these forms are “closed.” Ongoing group-related outcome information will not be provided to the CCC until the study is completed.

III. D DATA MANAGEMENT CENTER (DMC)

The DMC, chaired by Dr. William Clarke, is made up of a center coordinator (Mrs. Wichman), a database analyst (Mr. Reardon), a systems analyst (Mr. Peters), a biostatistician (Mr. Hansen), and a research assistant III (Ms. Anderson), responsible for all data entry and analysis. The DMC, in conjunction with the CCC, Steering and Advisory Committees developed the CRFs, the Operations Manual, the automated telephone enrollment system, RANDOMIZATION ENVELOPES, etc., and will construct and maintain the database, receive, enter and oversee the quality of all patient data, and perform interim and final outcome analysis. They will also provide regular “blinded” reports to the Physician Safety Monitor (PSM) (identified only by “Group A vs. Group B”) and additional outcome and safety information to the NIH Protocol Safety and Monitoring Board (NIH PSMB). They will provide “completed” CRFs to the CCC at the time of planned on-site audits.

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III. E PHYSICIAN PROTOCOL MONITOR (PPM)

It is critical that members of the CCC remain blinded as to temperature assignment at all times. This blinding will be maintained even at the time of on-site audits. However, it is necessary to have a knowledgeable individual audit the actual intraoperative conduct of the study. This individual is the Physician Protocol Monitor (PPM). The PPM – David S. Warner, M.D, - who will receive “immediate” unblinded copies of the intraoperative records (local hospital anesthesia records, early (0-2 hours) postoperative records) as well as copies of the ANESTHESIOLOGIST and TEMPERATURE forms. The TEMPERATURE form, and your local hospital anesthesia and recovery records (in sealed envelopes), will each be sent to the DMC at the time of the 48-hour postoperative data submission. The DMC will, in turn, forward the needed documents to the PPM.

It is the PPM’s responsibility to verify that the assigned protocols have been followed, to direct necessary questions regarding management (i.e., patient safety, intercurrent events) to the local investigators, and to provide feedback to the PCCs in the event of protocol violations/deviations in individual patients. If the PPM questions the patient’s eligibility or intercurrent event(s), then the DMC will include these in the Data Edit Reports (DERs) that will be sent by email within 24 hours to the PCC and resolved in their usual manner (see Chapter VII.L.3 of the IHAST2 Operations Manual for details).

The CCC and Steering Committee will never see individual PPM protocol reviews. When four new patients for a center are entered into the database, two summaries of the PPM reviews will be prepared by the DMC. One summary will contain data from the four newest patients from the specified center. The second summary will contain data from all patients from the specified center. These summaries will be reviewed by the Director of the DMC, the Physician Safety Monitor, the PSMB, the Steering Committee, and the CCC. The CCC will also receive notification when inconsistencies are found by the PPM between reported serious intercurrent events and the local hospital anesthesia and/or early recovery records. In response to the PPM-derived information and DMC summaries, the Steering Committee will be empowered to notify PCCs of persistent/recurring protocol problems and, if not corrected, to drop a center from the study.

III. F PHYSICIAN SAFETY MONITOR (PSM)

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It is critical that patients enrolled in this trial not be subjected to any inordinate risks. This requires early detection of any “disproportionate” morbidity in one group, or excess morbidity relative to published information concerning this disease and its treatment. The Physician Safety Monitor (PSM) – Harold P. Adams, Jr., M.D. - is the primary person responsible for ensuring the safety of the trial. His source of information will be regular summary reports of IEs provided by the DMC. While he will remain “strictly” blinded as to group assignment, he will be provided with group-related information (Group A vs. Group B) without identifying which is the hypothermic group. His task is to detect and evaluate evidence that suggests a disproportionate number of adverse events occurring in one group, events that may indicate a disproportionate risk of injury in one specific group. He may draw on the expertise of others on the Steering Committee as needed to assist in determining the likelihood that reported events are related to group assignment rather than to the disease itself or surgery (as distinct from hypothermia or normothermia). The PSM will also communicate regularly with the NIH PSMB.

III. G NIH PROTOCOL SAFETY MONITORING COMMITTEE (NIH PSMB)

The PSMB is a committee appointed by NIH, consisting of anesthesiologists, neurosurgeons, neurologists, statisticians, etc. with appropriate expertise in SAH and clinical trials. The committee is chaired by Dr. William Young, Dept. of Anesthesia, University of California, San Francisco. The PSMB has oversight responsibilities. After communications with the PI and Steering Committee, it has the power to temporarily or permanently halt patient enrollment if, in their view, patient safety is compromised (e.g., excess morbidity/mortality in one of the two study groups). Alternatively, it may stop the trial if continuation is unwarranted based on information provided at one of the two interim analysis (after ≈300 and 600 patients). Such a “stop” may result from either the demonstration of efficacy (a significant difference between the groups) or futility (i.e., continued enrollment of patients cannot result in a statistical difference between the groups). The PSMB may also mandate changes in the study protocol, and will approve protocol changes recommended by the Steering Committee.

III. H UNIVERSITY OF IOWA DIVISION OF SPONSORED PROGRAMS

Financial administration of the trial will be vested in the UI Division of Sponsored Programs. This office will be the primary liaison with the NIH Grants Management Office.

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CHAPTER IV. PARTICIPATING CENTERS

IV. A REQUIREMENTS FOR PARTICIPATION

IV.A.1.Minimum Case Load

Our overall goal is to enroll approximately 30 patients per month for 30 - 34 months, or until a total of 1000 patients have been studied. To achieve this goal, we have set a target of one patient per PCC per month. We realize that caseloads at individual PCC’s will vary; some PCC’s will contribute far more than this, others will contribute fewer. What is critical is that all PCC’s enroll as many eligible patients as possible, at a consistent pace over the duration of the study.

There are reasons for these “requirements”. It is very difficult to assess “quality” of care at a given center if very few patients are enrolled. A center which contributes only one or two patients to the study may be a serious detriment. Conversely, even if a center contributes only five to 10 well-managed patients over the duration of the study, their contribution would be quite valuable. Hence we do not intend to implement rigid “minimum criteria” except for one. Any center, which fails to enroll its first eligible patient within four months after being notified that all requirements for “startup” have been met, will be dropped from the study. PCC’s, which enroll patients at a rate less than five patients per year, will be considered “on probation” and their caseload and patient selection activities will be carefully reviewed by the Steering Committee.

Theoretically, the trial could also be biased by too much data coming from too few centers (i.e., too great a fraction of the total patient numbers coming from two or three institutions).

IV.A.2.Selection Bias and Demographics

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There are other enrollment issues. Our intention is to have the study sample represent the overall “population” of patients undergoing surgery for aneurysm clipping, within the limits set out by the protocol (acute SAH, WFNS Grades I, II or III, etc.). If a center were to “selectively” enroll only certain patients and exclude others (e.g., exclude patients whom the local study physicians “believe” would benefit from hypothermia and hence should not be subjected to the “risk” of being randomized to normothermia, and thus enroll only patients in whom the physicians believe that temperature management “doesn’t matter”), the study sample could be seriously skewed and unrepresentative. For this reason, we need to carefully monitor the total relevant surgical caseload (including patients with unruptured aneurysms). This is the primary reason that we ask all PCC’s to complete the initial SCREENING form for all patients undergoing craniotomies for aneurysm clipping, and to complete the ELIGIBILITY form for all surgical patients with aneurysmal SAH. Data from these forms will provide an accurate measure of the “denominator” of the study, (i.e., the total number of patients, eligible or not, who undergo surgery at the PCC’s). If it is apparent that only a small and potentially “selected” sample of patients are being enrolled at a given center, it may be necessary to review a center’s continued participation. Examples of potential “selection bias” would include a very high “failure to consent” rate, or a large proportion of patients who the surgeon and/or anesthesiologist “decline to enroll”, or a large number of patients excluded for “Procedural Criteria” (e.g., lack of a Study Coordinator, lack of certified personnel, etc.).

Our intent is not to “micromanage” the activities of PCC’s, and we definitely do not wish to exclude PCC’s whose caseload is unavoidably low, but which make every effort to recruit, enroll and successfully manage as many patients as possible. However, “reluctant” participation can be fatally damaging to the trial.

IV.A.3.Principal Investigator and Co-Investigator Agreements

This trial demands a close cooperative working relationship between anesthesiologists and neurosurgeons. For a center to participate, both a Local Principal Investigator (Local PI) and a Local Co-Investigator (Local Co-PI) must be identified. One of these individuals must be an anesthesiologist, the other a neurosurgeon (although the specific role played by which specialist is irrelevant; the Local PI can be either an anesthesiologist or neurosurgeon). Both individuals must acknowledge in writing that they understand the basic goals of the study and that they agree to accept the conditions set forth in the protocol, commensurate with the safety of individual patients.

The Local PI will be the primary “official” contact person for the CCC and DMC (although most day-to-day communications will be via the Study Coordinator). The Local PI will also be responsible for supervising the activities of the Local Study Coordinator. Together with the Co-PI and Study Coordinator, the PI will be responsible for educating other participating anesthesiologists, neurosurgeons, coordinators, neurologic examiners etc., and for ensuring that only “certified” anesthesiologists, neurosurgeons, coordinators and neurologic examiners are involved in the specific operative care and follow-up of enrolled patients (certification procedures will be described below). If protocol or data-related difficulties are noted by the DMC, the PPM or others, the Local PI will be the primary individual contacted to aid in resolving any problems.

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The PI, Co-PI and Study Coordinator must develop the local mechanisms by which patients scheduled to undergo operative aneurysm clipping are brought to the attention of study personnel. This system must allow identification of surgical patients with unruptured and ruptured aneurysms (patients without and with SAH), as well as patients with SAH who may be ineligible. Who calls whom is of little consequence – but some reasonably systematic procedure needs to be implemented.

In addition to such administrative responsibility, it is assumed that the PI, Co-PI and Study Coordinator will meet on a regular basis to review the PCC’s activities, such as training, patient recruitment, data form completion, follow-up examinations etc., as well as for maintaining communication with other participating physicians and support staff.

The Local Co-PI will be responsible for local trial management in the absence of the PI.

IV.A.4.Institutional Agreements

a) Consortium Agreements

Consortium Agreement – A consortium agreement between each PCC and the UI is a requirement by the NIH. The following is a description of this agreement.

The UI, as the direct and primary recipient of NIH grant funds, is accountable to the NIH for the performance of the project, the quality of data submitted, the appropriate expenditure of grant funds by all parties, etc. In general, the requirements that apply to the UI also apply to the consortium participant(s).

Under consortium agreements:

The award will be made to the UI and Dr. Michael M. Todd, Principal Investigator, even though institutions other than the UI will carry out portions of the planned programmatic activity.

The UI must perform a substantive role in the conduct of the planned research and not merely serve as a conduit of funds to other institutions.

Whether proposed at the application stage or subsequent to award, the following information must be provided to NIH for review and approval:

A list of all proposed performance sites both at the UI and at the consortium participant(s) sites;

Complete application budget pages (for the first year and each future year of support requested) for each consortium participant.

The following statement or a similar statement, accompanied by the signatures of the authorized institutional officials (or equivalent) of the UI and consortium participants must be provided to NIH for review and approval:

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“The appropriate programmatic and administrative personnel of each organization involved in this grant application are aware of the NIH consortium agreement policy and are prepared to establish the necessary inter-institutional agreement(s) consistent with that policy.”

The agreement must be signed by an administrative official of your institution, such as your Vice President of Research, or the equivalent, and must be addressed to our Vice President of Research, Dr. David J. Skorton. See Appendix for a copy of the consortium agreement template.

b) Financial Subcontract

A copy of the subcontract template is provided in the Appendix.

Following is a brief explanation of the NIH Subcontract and the contents. The grantee (UI) must enter into a formal written agreement with each consortium participant. This agreement includes the negotiated arrangements for meeting the scientific, administrative, financial, and reporting requirements of the grant, including those necessary to ensure compliance with all applicable Federal regulations and policies and facilitate a smoothly functioning collaborative venture. At a minimum, this agreement must include:

Identification of the PI and individuals responsible for the research activity at each consortium participant along with their roles and responsibilities;

Procedures for directing and monitoring the research effort;

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Procedures to be followed in reimbursing each consortium participant for its effort, including dollar ceiling, method and schedule of reimbursement, type of supporting documentation required, and procedures for review and approval of expenditures of grant funds at each organization;

If different from those of the grantee, a determination of policies to be followed in such areas as travel reimbursement and salaries and fringe benefits. The policies of the consortium participant may be used as long as they meet NIH requirements;

Incorporation of those generally applicable requirements included in Part II of this policy statement and provisions indicating the intent of each consortium participant to comply, including submission of applicable assurances (see “Public Policy Requirements and Objectives”).

A provision addressing ownership and disposition of data produced under the consortium agreement;

A provision making the inventions and patent policy (see “Administrative Requirements Availability of Research Results: Publications and Intellectual Property Rights, Including Unique Research Resources”) applicable to each consortium participant and it’s employees in order to ensure that the rights of the parties to the consortium agreement are protected and that the grantee can fulfill its responsibilities to NIH. The grantee should also obtain appropriate patent agreements from all persons who perform any part of the work under the grant and may be reasonably expected to make inventions, and agreements to govern disposition of rights to inventions resulting from screening compounds synthesized under the grant; and

As appropriate, provisions regarding property, program income, publications, reporting, and audit necessary for the grantee to fulfill its obligations to NIH.

Negotiations regarding Subcontracts will take place between the UI Sponsored Programs office and appropriate individuals at each PCC.

c) Human Studies Approval

Participation of any PCC is dependent on approval of the protocol by a local Institutional Review Board (IRB) recognized by NIH, and which operates in a fashion compatible with US governmental rules for the protection of research subjects. The fundamental responsibility of an IRB is to assure that all ethical issues have been fully addressed in the protection of human subjects who volunteer to participate in research studies. The IRB is charged with the protection of human subjects in research, regardless of whether the research is subject to Federal regulation and regardless of sponsorship. IRBs must consider: the risks to the subjects, the anticipated benefits to the subjects and/or others, the importance of the knowledge that may be gained, and the informed consent process to be employed.

Each PCC must have a protocol approved by their local IRB. Since the UI is the recipient of this NIH grant, the NIH requires that each PCC provide a copy of their institution’s IRB approval. The UI Principal Investigator (Dr. Todd) must review the documents from each PCC to be sure they meet the guidelines of the initial grant submitted for funding. This includes the Study Protocol, Patient Summary and Informed Consent.

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Each center’s IRB application should be based on the application already approved by the UI, with whatever modifications are required locally. A copy of the UI IRB documents can be found in the Appendix. Certain specific components of that application are required for participation. Specifically, each PCC’s Patient Summary and Informed Consent must contain material covering the following items:

Standard of care (hypothermia, normothermia or at the discretion of the Anesthesiologist/Neurosurgeon) by which patients will be managed if they elect not to participate.

A statement to the effect: “Records of all participation in this research will be maintained and kept confidential to the extent permitted by law or when ordered by a court of law. However, absolute confidentiality cannot be guaranteed. This is a large research study involving many patients at many different hospitals around the world. The study is being managed by the UI, and the PCC will retain a copy of the data collected. In addition, your medical records may be “audited” by someone from CCC to ensure accurate recording of information.”

A statement to the effect: “The results of the study will be reported to the US Public Health Service/National Institutes of Health who are sponsoring this research. Representatives of the NIH may inspect and copy study records relating to this research study. These records may also be inspected by other Federal government regulatory agencies. In this event, some identifying information may be reviewed or retained by the government agencies.”

A statement to the effect: “In the event of any report or publication from this study, the identity of participants will not be disclosed.”

Comment: No supplementary studies should be included in the primary IRB application or documents. Any supplementary studies which are approved by the Concurrent Studies Committee must be handled as a supplementary application/consent.

Ethics Committee/IRB approval will be usually given for a year and then the PCC will go through an annual review process. Some institutions will be given approval for a longer period of time, maybe several years. At the end of the approved time each center is responsible for submitting their continual annual review documents to their local review boards. Coordinators at the UI will be following up to be sure each PCC is reapproved and a continued annual review document must be sent to the the UI.

IV.A.5.Organizational Meeting Attendance

The startup investigator’s meeting is set for September 24-26, 1999. It will be held at The Westin O’Hare Hotel in Park Ridge, Illinois (just outside Chicago). The meeting is critical to ensure that everyone understands all aspects of the study and that we are all working “from the same game-plan”. Center-to-Center consistency is the key to the success of this project. Each PCC should send two individuals, preferably the Local Principal Investigator and the Local Study Coordinator. Everyone should consider this meeting to be “mandatory”. Members from the Advisory Committee, the CCC and the DMC will be attending.

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IV.A.6.Subsequent Yearly Meetings

Subsequent annual meetings will usually be held in conjunction with the annual American Society of Anesthesiologists meeting in October. Two representative from each PCC will attend to receive updates (typically the Local PI and Study Coordinator), and communicate information that will facilitate consistent and correct performance of the IHAST2 protocol.

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IV.A.7.Centers Recruited Later

PCC’s that join the study after the initial organizational meeting are required to meet with the CCC and the DMC in Iowa City. The purpose of the meeting is to provide the Study Coordinator and PI with instruction/training prior to participation in the study. This meeting will be arranged only after a consortium agreement, IRB approval and a subcontract are received from the prospective center.

IV.A.8.On-site Audits

Site audits are performed to ensure compliance to the trial protocol, correct data collection, and to assist PCC’s with questions. Each PCC will be audited on at least two occasions during the trial period. The first audit will occur once within the first 6-12 months after enrollment of the first patient, and again prior to completion of data collection within the IHAST2 trial (by April 2003). The audit will involve two areas: the patient notebooks and the Site Regulatory Binder.

To initiate the audit process, the Local Study Coordinator will be contacted approximately one month prior to the audit. At this time, the audit, which will take approximately two days, will be arranged. At one week prior to the audit date, the PCC Study Coordinator will be given the identification numbers of two-to-four patients randomly chosen for review and any other patients whose records that the CCC/DMC believes need to be reviewed. The Study Coordinator must arrange to have the patient charts available for the auditor on the day of the visit. The auditor will bring copies of the relevant CRF’s that have been sent to the DMC, and compare these with the copies contained in the PCC’s files, and also compare these forms with data from the patients chart. In addition, the PCC Study Coordinator must provide the Site Regulatory Binder for review.

IV.A.9.Local Documentation

a) Operations Manual

Each PCC will need an updated copy of this Operations Manual. Periodic updates will be provided as changes/modifications occur. The earlier versions of the relevant sections should be replaced with these updates.

b) Case Report Forms/Patient Notebooks

The PCC’s copies of all completed CRF’s should be retained in clearly labeled, patient-specific binders. Randomly selected patient notebooks will be audited in conjunction with the patients’ medical record to determine completeness and consistency between the two documents.

To maintain blinding of the auditors, anesthesia records, as well as the TEMPERATURE and ANESTHESIOLOGIST forms will not be audited during the site visit and should removed from the patient’s chart and patient notebook. Copies of all anesthesia records will be forwarded to the DMC (along with other submitted records). All anesthesia records will be audited by the PPM.

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c) Site Regulatory Binder

Each PCC must retain a “Site Regulatory Binder” that contains certain important paperwork and documentation. The purpose of this binder is to provide a central source to store material not kept in the individual patient notebooks. This binder will be reviewed during on-site audits. The specific contents of this binder can be found in Chapter VII.A.5.

IV. B PERSONNEL REQUIRED, DUTIES AND CERTIFICATION REQUIREMENTS

IV.B.1.Local Principal Investigator (PI)

At each PCC, the Local PI is responsible for the overall conduct of the trial. The PI must be either a neurosurgeon or an anesthesiologist. In addition, a Co-PI, must also be designated. If the PI is a neurosurgeon, the Co-PI must be an anesthesiologist, and vice versa. The PI will be the primary communication person between each PCC and the CCC and DMC. The PI will be the local resource regarding all elements of the trial. Accordingly, the Local PI must be completely familiar with eligibility requirements, intraoperative protocols, and postoperative evaluations.

The Local PI will be responsible for communication with the local human studies committee (or IRB). The Local PI will maintain local IRB approval for patient participation in IHAST2. Updated copies of the local Patient Information Summary, local Consent Form, and local IRB approval documentation are to be maintained at each PCC. Updated copies of each of these documents are also to be sent to the CCC on a timely basis.

The Local PI is responsible for maintaining a Patient Log Binder that will record the age, gender, and ethnicity of all patients undergoing cerebral aneurysm surgery, regardless of study eligibility and/or participation (i.e., the log contains the canary copy of all SCREENING and ELIGIBILITY forms). This log is necessary to establish the overall surgical experience of a given PCC (cases per year). Accordingly, the Local PI will be responsible for establishing a system whereby all patients undergoing intracranial aneurysm surgery are screened, and all patients undergoing surgery for a ruptured intracranial aneurysm are evaluated for study eligibility in a timely manner prior to surgery. The specific contents of this binder can be found in Chapter VII.A.6.

The Local PI is responsible for ensuring that all IHAST2 study materials are accurate, completed on a timely basis, and submitted to the DMC on schedule. The Local PI (or Co-PI) will be responsible for providing a written narrative describing the circumstances surrounding any patient death.

The Local PI will be responsible for organizing personnel required to conduct the trial. As a practical matter, there are five functional roles to be fulfilled for each patient enrolled into IHAST2:

1) Neurosurgeon(s);

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2) Anesthesiologist(s);

3) Study Coordinator(s);

4) Neurologic Examiner(s);

5) Neuropsychology Examiner.

In each PCC, the Local PI will need to establish a system to ensure that each of these roles are continuously “covered” (24 hours-per-day, 7 days-per-week).

Comment: In some instances, an individual may serve more than one role. However, in no instance may any person who is performing any postoperative outcome evaluation have been present during surgery, been in contact with the patient in the first two hours after surgery, or be aware of patient group assignment or intraoperative temperatures).

All patients enrolled in IHAST2 must have their intraoperative care provided by a neurosurgeon and Anesthesiologist who are certified to participate in IHAST2. Consequently, in each PCC, the Local PI will need to organize teams of participating neurosurgeons and anesthesiologists continuously “on call”, so that all consenting patients may be enrolled and randomized, regardless of the time of day.

The Local PI is responsible for designating a Study Coordinator, who will be largely responsible for pre- and postoperative patient evaluations, as well as data entry in the case report books. Given the vital role of the Study Coordinator in this trial, a “back-up” person must be available to ensure the Study Coordinator's role is fulfilled (by an appropriate IHAST2 participant) whenever the usual Study Coordinator is not available.

The Neurologic Examiner is a person blinded to patient group assignment who is certified to perform NIH Stroke Scale (NIHSS) examinations at defined intervals before and after surgery. The Neurologic Examiner may not be involved in the daily care of the patient. Because NIHSS exams are critical to the trial, none of these exams can be missed (see comment below). Hence, once again, a 24 hour-per-day call system, and a “back-up” person must exist to ensure this role is continuously fulfilled. Although it is greatly preferred that postoperative NIHSS exams (3 to 6-, 24-, and 72- hours after surgery; and at discharge) be performed by a designated Neurologic Examiner, the Local Study Coordinator may perform these exams if necessary, so long as s/he is not aware of patient group assignment or perioperative temperature data. The final 3 month (12 week) NIHSS examination must be performed only by a certified Neurologic Examiner—no other IHAST2 participant may perform this exam.

Comment: If the patient has received pharmacologic agents (sedatives, hypnotics, anesthetics) which have resulted in a state of anesthesia, or a level of sedation that substantively impairs the patient’s ability to meaningfully cooperate with this exam; or the patient is pharmacologically paralyzed (neuromuscular blocker), then the NIHSS exam need not be performed for that time interval. Please see Chapter IX.P for further instruction.

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Finally, at each PCC, provisions must be made for administration of the neuropsychology test battery at the final, three-month, postoperative evaluation. This battery must be administered by a Neuropsychology Examiner who has been certified by the CCC. Preferably, the Neuropsychology Examiner will be either a Neuropsychologist (M.D. or Ph.D.) or a professional Neuropsychology technician. If such a person does not exist at a given PCC, arrangements must be made via the CCC.

The Local PI is responsible for local financial management. The Local PI will establish the salary and/or reimbursement rates for all participating personnel. The Local PI and the local administration (Sponsored Programs) will negotiate the institutional indirect cost rate (if any).

IV.B.2.Local Co-Investigator

The Local Co-PI must be either a neurosurgeon or an anesthesiologist. If the PI is an anesthesiologist, the Co-PI must be a neurosurgeon, and vice versa. The role of the Local Co-PI is to assist the Local PI in all elements of the trial and to assume the role of PI whenever the PI is not available. Accordingly, the Local Co-PI must be completely familiar with the responsibilities of the PI, as described above.

IV.B.3.Anesthesiologists

a) Protocol

To be randomized, patients enrolled in IHAST2 must obtain their intraoperative anesthetic care by an anesthesiologist who is certified to participate in IHAST2 (see below for certification process). A patient whose anesthesia and temperature management is performed by an uncertified anesthesiologist may be classified as an enrollment error and protocol violation (and hence, payment may be jeopardized).

When the patient arrives at the operating room, the Anesthesiologist will determine whether the patient is still eligible (WFNS score, general medical condition) and will characterize the patient’s condition immediately prior to surgery. The Anesthesiologist is responsible for providing anesthetic and cardiovascular management in accordance with protocol. The Anesthesiologist is responsible for managing the patient’s temperature in accordance with protocol.

Only the Anesthesiologist caring for the patient during their primary aneurysm surgery may open the assigned RANDOMIZATION ENVELOPE; no exceptions, ever.

b) Blinding

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The Anesthesiologist is responsible for maintaining the blind. Only the Anesthesiologist caring for the patient during their primary aneurysm surgery may know the patient’s group assignment and intraoperative temperature data, which is recorded on the TEMPERATURE form. Only the Anesthesiologist caring for the patient during their primary aneurysm surgery may complete the TEMPERATURE form, which is sealed in an envelope at the end of the case; no exceptions, ever. The Anesthesiologist is not to reveal temperature information to anyone, including other anesthesiologists not participating in the case. Similarly, the Neurosurgeon, Local Study Coordinator, and Neurologic and Neuropsychology Examiner(s) are not to learn of the patient’s group (temperature) assignment and/or any intraoperative temperature data.

There is only one exception: The Anesthesiologist may inform the Neurosurgeon of the patient’s group assignment and/or temperature only for immediate intraoperative safety reasons. However, in this instance, no one else may know: the Local Study Coordinator and Neurologic Examiner(s) are still not to be informed regarding patient temperature.

c) Data Collection

The Anesthesiologist is responsible for characterizing the patient’s condition at the time of aneurysm clipping (mean arterial pressure, glucose, etc.) and recording this information on the ANESTHESIOLOGIST form. The Anesthesiologist is responsible for postoperative warming (if needed) and continued management of any temperature-related or anesthetic-related problems that extend into the postoperative period.

The Anesthesiologist is responsible for characterizing key events occurring during surgery, and for the first two hours after the patient leaves the operating room. Accordingly, only the Anesthesiologist who cared for the patient during their primary aneurysm surgery may complete the ANESTHESIOLOGIST form. If, during surgery, or the first two hours after surgery, events occur that warrant completion of an INTERCURRENT EVENTS (IE) form, it is strongly recommended that the IE form(s) be completed only by the Anesthesiologist. However, the Local Study Coordinator may assist in completion of the IE forms so long as the Coordinator is not informed of patient group assignment or intraoperative temperatures.

The Anesthesiologist is responsible for providing “blinded” copies of the intraoperative anesthesia record and early (0-2-hours) postoperative recovery or critical care records to the Study Coordinator for submission to the DMC. These copies are to be provided to the Study Coordinator in the used Study Packet that contained the assigned RANDOMIZATION ENVELOPE. This is done to help prevent the Study Coordinator from accidentally learning of the patient’s intraoperative and early (0-2-hours) postoperative temperatures. The Anesthesiologist should use the large Study Packet containing the assigned RANDOMIZATION ENVELOPE to place and seal the local hospital anesthesia record and early (0-2 hour) postoperative data.

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Certified anesthesiologists may also assist in all other IHAST2 functions, according to local needs and customs. In many instances, local PCC’s may wish to have an anesthesiologist complete, or assist in, the ELIGIBILITY, PRE-SAH, and POST-ADMIT SCREEN evaluations, given that these evaluations essentially constitute a routine preoperative anesthetic evaluation. If needed, anesthesiologists may perform postoperative outcome evaluations (DAILY POST-OP SCREEN, MEDICATIONS, NIHSS), as long as they: 1) have the qualifications (certification) to perform the necessary examinations; 2) did not care for the patient in the O.R. during the primary aneurysm surgery; 3) were not in the presence of the patient for the first two hours after the primary aneurysm surgery; and 4) are not aware of patient group assignment or intraoperative temperature data.

d) Certification

Certification as a participating anesthesiologist is a straightforward procedure. Prior to January 1, 2001, each PCC was provided with written educational (protocol summary, summary of responsibilities, forms and instructions for their completion, GCS/WFNS CD) and testing (Anesthesiologist and GCS/WFNS exams) materials for participating Anesthesiologists. Effective January 1, 2001, all educational and testing materials for participating Anesthesiologists are available via the IHAST2 website. The required certification exams (Anesthesiologist and GCS/WFNS) are taken and scored on line.

Following successful completion of these tests, each anesthesiologist will be assigned a “certification number” by the CCC via email. This certification number must be listed on each case report form completed by the certified individual.

Additional: If an anesthesiologist intends to be involved in other aspects of patient assessment, additional certifications will be needed. For example, if an anesthesiologist is going to use the NIHSS, certification will be needed (see Neurologic Examiners section below). Similarly, certification in the performance of the Glasgow Outcome Score may also be required.

IV.B.4.Neurosurgeons

Participating Neurosurgeons will have four major roles in IHAST2:

a) Recruitment/Notification

Because most patients with SAH are admitted to a neurosurgical service, or require a neurosurgical consult shortly after admission, we anticipate that the recruitment, notification and enrollment process will typically start with a neurosurgeon (or neurosurgical resident) who will contact the Local Study Coordinator or Local PI. The mechanism for such notification will be set up jointly by the Local PI, Local CoPI, the Local Study Coordinator and the Departments of Anesthesia and Neurosurgery. The Neurosurgeon should also notify the Local Study Coordinator when surgery is planned in patients with unruptured aneurysms, since a small amount of information regarding these patients will be tracked by the trial.

b) Protocol

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All cranitomies for aneurysm clipping in enrolled patients must be performed by neurosurgeons who have been certified by the CCC. Therefore, eligibility is dependent on the availability and involvement of such a certified surgeon. A patient whose surgery is performed by an uncertified surgeon may be classified as an enrollment error and protocol violation (and hence payment may be jeopardized). Each participating surgeon must demonstrate his/her awareness of the protocols involved and restrictions imposed by the trial.

In most PCC’s, the operating Neurosurgeon is responsible for postoperative care of SAH patients. While there are no detailed “protocol” issues in such postoperative care (all postoperative care is as per local routine), it is critical that the Neurosurgeon make every effort to keep the Local PI and Local Study Coordinator informed about important events in the clinical course of the patients recovery. Patients will be seen frequently by the Local Study Coordinator, but s/he will be encouraged to contact the operating Neurosurgeon on a regular basis to ensure that a complete picture of the postoperative period is obtained.

The success of IHAST2 is absolutely dependent on obtaining adequate follow-up of the patients. This includes a mandatory clinic visit at three months following surgery. Since such visits will most commonly be handled by the Neurosurgeon’s office or the Neurosurgical clinic, it is critical that the Neurosurgeon understand the need for such follow-up, and do everything possible to facilitate a patient's return to clinic for this visit. In addition, the Neurosurgeon should ensure that the Study Coordinator is notified in the event of an unexpected medical event occurring in an enrolled patient (e.g., an emergency room visit for a postoperative seizure), assuming that such an event has been brought to the Neurosurgeon’s attention.

c) Data Collection

The Neurosurgeon must complete the NEUROSURGEON form upon completion of surgery.

d) Certification

Neurosurgical certification is a straightforward procedure. Prior to January 1, 2001, each PCC was provided with written educational (protocol summary, summary of responsibilities, forms and instructions for their completion) and testing (Neurosurgeon exam) materials for participating Neurosurgeons. Effective January 1, 2001, all educational and testing materials for participating Neurosurgeons are available via the IHAST2 website. The required certification exam is taken and scored on line

Upon successful completion of these tests, each neurosurgeon will be assigned a “certification number” by the CCC via email. This certification number must be listed on each case report form completed by the certified individual.

IV.B.5.Study Coordinators

a) Responsibilities

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Study Coordinators, perhaps more than any other individual, are the “organizational backbone” of this study. The Study Coordinator must have a thorough understanding of the overall trial design and organization, the randomization process, exclusion/inclusion/eligibility criteria, all forms contained in the patient notebooks and how they are to be completed, the schedule of necessary visits and examinations needed for all patients, etc. In addition, the Study Coordinator must communicate with the CCC and DMC, as well as with all other local personnel involved in the trial. Distribution of study materials to the appropriate individuals, including the Anesthesiologist, Neurosurgeon, Neurologic Examiner and Neuropsychology Examiner is also the Study Coordinators responsibility. In most cases, the Study Coordinator will be responsible for maintaining all needed documentation, including the patient notebooks, the Site Regulatory Binder, etc. Finally, the Study Coordinator must be familiar with and certified to perform a variety of patient assessments.

A list of Study Coordinator responsibilities, in an order typically encountered in the management of any study patient, follows:

To be available for notification, by the Neurosurgeon, Anesthesiologist or other individual, upon the admission and scheduling of a possible study patient.

Upon notification, the Study Coordinator will gather the needed materials, including the patient notebook, pregnancy test, Information Summary and Consent documents, etc. The Study Coordinator will then see the patient, complete the SCREENING form, and if appropriate, the ELIGIBILITY form. Completion of these forms and the determination of eligibility will require that the Study Coordinator be certified in the assessment of the GCS, WFNS and the Rankin scales. In addition, a pregnancy test must be performed on any pre-menopausal female, regardless of methods of contraception (unless prior hysterectomy or tubal ligation).

If the patient is deemed eligible to participate in the study, consent will be obtained from either the patient, legal next of kin, or consenting person, whichever individual is deemed qualified to sign the consent for surgery. Note that in some institutions, consent may be obtained by a certified anesthesiologist or neurosurgeon.

Either the Study Coordinator or Anesthesiologist will contact the DMC telephone enrollment number to obtain an appropriate Study Packet number (Patient ID number) and RANDOMIZATION ENVELOPE color (the RANDOMIZATION ENVELOPE number is the same as Study Packet number). This call must be made no more that two hours prior to the start of surgery.

Once consent has been obtained, the CONTACT form should be completed. The primary purpose of this form is to facilitate later patient contact for follow-up evaluations.

Conduct an NIHSS examination of the patient.

Complete PRE-SAH HISTORY and POST-ADMIT SCREEN forms. Information can be obtained from the patient, the medical record, a person living with the patient or a person not living with the patient. In the event that the information is obtained from someone other than the patient, that person should be listed on the CONTACT form. Note that in some cases, these forms may be completed by a certified anesthesiologist or neurosurgeon. These forms also need not be completed prior to the start of surgery, but should be completed no later than 24 hours after surgery.

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Distribute NEUROSURGEON and ANESTHESIOLOGIST forms to the appropriate individuals, and provide the assigned (number and color) RANDOMIZATION ENVELOPE and all other needed Study Packet materials to the Anesthesiologist responsible for the patient.

Comment: As part of our efforts to maintain the Study Coordinators “blinded” status, the Coordinator must not enter the operating room, and can play no role in the completion of the TEMPERATURE form.

Upon completion of surgery, the Anesthesiologist will notify the Study Coordinator. However, the Coordinator must make no effort to see the patient until at least two hours have elapsed. Again, the purpose of this delay is to aid in maintaining the blind; if the Coordinator were to enter the PACU or SICU while a hypothermic patient was being rewarmed, blinding would be lost.

After the requisite delay, the Study Coordinator will visit the patient and perform the 3 to 6-hour postoperative NIHSS (note that this examination can be completed by the Neurologic Examiner if desired).


The Study Coordinator should notify the Neurologic Examiner that a patient has been enrolled, and provide the Examiner with a schedule for the required postoperative examinations.

The Study Coordinator will be responsible for completion of all DAILY POST-OP SCREEN and MEDICATION forms through day 14 and then at discharge. [Note: if the patient is discharged on or before day 14, the DAILY POST-OP SCREEN form should be completed through “discharge minus 1” followed by the Discharge column.] Information will be obtained from patient examination, patient charts, physician or nursing staff.

If the patient remains hospitalized longer than 14 days it is essential that the Study Coordinator is constantly aware of the patient’s status. This will ensure that no critical events are missed including discharge.

Comment: It is very easy, when the hospital stay is prolonged, to inadvertently “miss” the day of discharge unless close contact with the patient and care team is maintained. This error would make accurate completion of the Discharge column of the DAILY POST-OP SCREEN form impossible, and would result in a failure to notify the Neurologic Examiner to complete the discharge NIHSS examination – which would result in a serious loss of data.

The Study Coordinator will complete INTERCURRENT EVENTS forms as needed, occasionally preoperatively but, most commonly, postoperatively and following discharge. IEs may be apparent upon examination of the patient, patient charts, or through contact with the physician or nursing staff. The intercurrent events list is found in the patient notebook under Intercurrent Events.

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Comment: Underlined IEs in this list, or any other serious complication/event must be reported promptly to the CCC.

The Study Coordinator will contact the patient or family by telephone at ≈three weeks, six weeks and nine weeks after the completion of surgery. [In some cases, the patients may still be hospitalized at three weeks, in which case a personal visit should be made instead. Similarly, some patients may be scheduled to return to clinic at some interim point (e.g., at six weeks) in which case the patient may be seen in person rather than be contacted by phone.] The primary purpose of these calls is to “maintain contact” with the patient, to ensure that the patients returns for the final three-month follow-up exam. No paperwork is required for the three and nine-week calls, but a CONTACT FOLLOW-UP and OUTCOME FOLLOW-UP form will be completed at six weeks.

The Study Coordinator will ensure that both the Neurologic Examininer and Neuropsychology Examiner are scheduled to see the patient at the three-month visit. S/he will also complete a CONTACT FOLLOW-UP form at the time of the three-month follow-up visit and provide the three-month OUTCOME FOLLOW-UP form to the Neurologic Examiner and the neuropsychology materials to the Neuropsychology Evaluator.

Data Submission: See Chapter VII of the Operations Manual.

b) Certification

Each Study Coordinator must be certified by the CCC and DMC. Given the key role that the Study Coordinator plays in the success of the study, this certification procedure will require a personal meeting between the Study Coordinator and CCC/DMC personnel, either at the time of a large organization meeting, or in Iowa City. Prior to January 1, 2001, each PCC was provided with written educational (protocol summary, summary of responsibilities, forms and instructions for their completion, GCS/WFNS CD, and an NIH Stroke Scale videotape) and testing (Study Coordinator, GCS/WFNS, GOS/Rankin, and NIHSS exams) materials for participating Study Coordinators. Effective January 1, 2001, except for the NIH Stroke Scale, all educational and testing materials for participating Study Coordinators are available via the IHAST2 website. The required certification exams (Study Coordinator, GCS/WFNS, and GOS/Rankin) are taken and scored on line. A videotape demonstrating the performance and scoring of the NIH Stroke Scale, along with two “testing” videotapes and copies of the NIHSS form to be used for testing will be provided to each PCC. The first videotape is viewed for training purposes. The second tape shows five patients who are to be scored on the appropriate forms, and the forms sent to the CCC for scoring.

Upon successful completion of these four tests, each Study Coordinator will be assigned a “certification number” by the CCC via email. This certification number must be listed on each case report form completed by the certified individual.

Comment: There is a third tape in the NIHSS set. This tape contains an added five patients to be scored, and is to be viewed approximately six (6) months after taking the test on the second tape. Another set of forms should be completed and forwarded to the CCC. If a follow-up exam has not been submitted within the requisite time, the Study Coordinator will be contacted by the DMC.

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IV.B.6.Neurologic Examiners

a) Responsibilities

Neurologic Examiners for IHAST2 play a critical role. This individual(s) is responsible for the final three-month outcome assessments of the GOS, Rankin, Barthel’s, the NIHSS, and, in some PCC’s, the Neuropsychology battery. NO OTHER IHAST2 PERSONNEL MAY PERFORM THE FINAL OUTCOME ASSESSMENTS. In addition, the Neurologic Examiner may be responsible for the NIHSS scores recorded at 24 and 72 hours after surgery, and again at the time of hospital discharge. In fact, this is preferred.


The Neurologic Examiner can be a nurse, a physician (any specialty, resident or staff) or a technician. The examiner must be trained and certified in the performance of the critical outcome measurements.

b) Examiner Selection and Blinding

It is critical that the Neurologic Examiner will have no contact with or knowledge of study patients other than that derived through the examinations performed. This means that the examiner may not be routinely involved in the surgical, anesthetic or ICU care of SAH patients. The examiner should not make any effort to review the chart of patients prior to or after the various examinations, should refrain from asking any questions of the Study Coordinator or discussing study patient-related matters with the Coordinator, the PI, CoPI, anesthesiologists or neurosurgeons directly responsible for intraoperative care of study patients. The examiner must NOT have access to any of the CRF’s, other than those needed to record his/her assigned examinations.

Adequate blinding of the Neurologic Examiner is absolutely critical to the validity of this trial. We recognize that different PCC’s will find it appropriate to use different kinds of individuals as Neurologic Examiners. The goal is that such Examiners should be at considerable “distance” from the care of patients undergoing surgery for aneurysmal SAH, and have minimal chance of discovering critical aspects of specific patient management (e.g., group assignment, intraoperative temperature).

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The Neurologic Examiner should not be a member of the regular IHAST2 clinical care team. In other words, neither Local Study Coordinator, Local PI, nor Local CoPI can serve as a Neurologic Examiner (Note: ONLY IF NECESSARY, the Study Coordinator may perform some duties involving neurologic assessment. Specifically, NIHSS exams at 3 to 6-, 24-, and 72- hours after surgery, and at discharge may be performed by a blinded Study Coordinator.) However, this is distinct from the activities of the Neurologic Examiner, who is the ONLY person who may perform the final outcome determinations (NIHSS, Glasgow Outcome Score, Rankin, Barthel) at three months.

The examiner should not be a clinically active neurosurgeon or neuroanesthesiologist.

Ideally, the examiner should not be a neurosurgeon or anesthesiologist.

Examples of preferred examiners

A neurology faculty, fellow or resident not routinely involved in the care of SAH patients (ideal).

An Emergency Room physician not routinely involved in the care of SAH patients (ideal).

A neurology nurse not routinely involved in the care of SAH patients (ideal).

A surgical or anesthesia faculty or fellow with no routine involvement in the care of SAH patients (acceptable).

A neurosurgical or neuroanesthesia fellow with no clinical commitments at the time the examination are performed and no prior knowledge of specific study patients (e.g., working solely in the laboratory) (acceptable).

Example of In appropriate NE’s:

The Neuroanesthesia group consists of three individuals (A, B, C), all of whom are certified to participate in IHAST2. Anesthesiologist A agrees to perform neurologic outcome assessments for patients cared for by Anesthesiologist B and C, while Anesthesiologist B, agreess to evaluate patients cared for by Anesthesiologists A and C, etc. Given the small size of the group and the involvement of all three invididuals in IHAST2, the changes of inadvertent unblinding is too great. A similar inappropriate example would involve neurosurgeons.

c) Certification

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All Neurologic Examiners must be trained in and certified to perform several neurologic tests. These include: 1) the Glasgow Outcome Scale, 2) the NIHSS, and 3) the Rankin Disability Scale. In certain PCC’s, this person may also need to obtain certification in the performance of the MMSE and the neuropsychology battery. Information regarding training and certification procedures can be found in Chapter V., below. Prior to January 1, 2001, each PCC was provided with written educational (protocol summary, summary of responsibilities, forms and instructions for their completion, and an NIH Stroke Scale videotape) and testing (GOS/Rankin, and NIHSS exams) materials for participating Neurologic Examiners. Effective January 1, 2001, except for the NIH Stroke Scale, educational and testing materials for participating Neurologic Examiners are available via the IHAST2 website. One of the two required certification exams, specifically, the GOS/Rankin exam, is taken and scored on line. A videotape demonstrating the performance and scoring of the NIH Stroke Scale, along with two “testing” videotaopes and copies of the NIHSS form to be used for testing will be provided to each PCC. The first videotape is viewed for training purposes. The second tape shows five patients who are to be scored on the appropriate forms, and the forms sent to the CCC for scoring.

Upon successful completion of these tests, each Neurologic Examiner will be assigned a “certification number” by the CCC via email. This certification number must be listed on each case report form completed by the certified individual.

Comment: There is a third tape in the NIHSS set. This tape contains an added five patients to be scored, and is to be viewed approximately six (6) months after taking the test on the second tape. Another set of forms should be completed and forwarded to the CCC. If a follow-up exam has not been submitted within the requisite time, the Neurologic Examiner will be contacted by the DMC.

IV.B.7.Neuropsychologic Examiners

The neuropsychology examinations must be administered in a consistent fashion. In general, we anticipate that most PCC’s will have access to a Ph.D. or M.D. neuropsychologist and/or professional neuropsychology technicians. The tests being used are quite “standard” and will be completely familiar to such persons. If such individuals can be identified, no further “certification” will be required.

We also realize that in some PCC’s, professional neuropsychology personnel may not be available. In this case, some other individual will need to be trained and certified. This process will be handled on an individual basis by Drs. Tranel and/or Anderson.

A detailed description of the neuropsych battery and its administration can be found in Chapter IX.Q.

a) Certification

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Certification of neuropsychology examiners will be handled by Drs. Tranel/Anderson of the UI Department of Neurology/Neuropsychology. Each PCC must designate one or more individuals to serve in this role. Each such individual will be asked to submit a current curriculum vitae/resume. This will be reviewed by Drs. Tranel or Anderson. If the individual is deemed to be experienced in the administration of the appropriate tests, a certification number will be issued. This certification number must be included on all forms submitted to the DMC.

If an experienced neuropsychologist or neuropsych technician is not available, specific training and certification of a designated individual will be arranged for by Drs. Tranel or Anderson.

IV. C FUNDING

IV.C.1.General

Two practice patients must be studied at each PCC before formal enrollment and randomization of IHAST2 patients may begin. PCC’s will be paid $1000 for each of these two practice patients (see Chapter X below).

PCC’s will be paid a total of $3000 per successfully randomized and managed patient. However, the schedule of payments will differ for the first 10 actual study patients.

IV.C.2.Start Up Funds

In general, payment is provided ONLY after completion of all data forms. However, we also realize that in many cases, some funds are needed before enrollment of the first patient, principally to aid in securing the services of a Local Study Coordinator. We, therefore, intend to provide an initial $10,000 to each approved PCC, contingent on the following requirements:

a) Local Human Studies Committee approval

b) Consortium arrangement completion

c) Financial Subcontract completion

d) Organizational meeting attendence

This initial $10,000 will then be “deducted” from the fee paid for each of the first 10 patients enrolled in the study (at a rate of $1000 per patient). In other words, separate per patient payments of $2000 each will be provided for the first 10 patients, with $3000 each provided for all subsequent patients.

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NOTE: In the event that the $10,000 startup funds are paid to a PCC, but no actual patients are enrolled within four months of a PCC being notified that it is ready to begin, it may be necessary to “drop” a center from the project. In such an event, repayment of the start up funds will be required. Similarly, if less than 10 patients are enrolled by a given PCC before completion of the study, any “unused” funds may need to be returned.

IV.C.3.“Practice” Patients

Before patients can be enrolled and randomized, each PCC must demonstrate its ability to carry out the hypothermic protocol in two “practice” patients. Details regarding these studies can be found in Chapter X. Each PCC will be paid a total of $2000 for these two patients ($1000 each) upon submission of the required (limited) CRF’s.

IV.C.4.Initial 10 Patients

Once the two “practice” patients have been satisfactorily entered, PCC’s may begin to recruit, enroll and randomize patients into the formal trial. Reimbursement for the first 10 randomized patients will be $2000 each, divided into two payments, according to the schedule noted in Item 6 below.

IV.C.5.Subsequent Patients

For all patients after the initial 10, a total of $3000 will be paid, divided into two payments of $1500 each. The schedule of payments is noted in Item 6 below.

IV.C.6.General Payment Schedule

To be eligible for the initial payment, submission and verification by the DMC, of completeness of the following CRF’s, must take place:

SCREENING and ELIGIBILITY forms

PRE-SAH HISTORY and POST-ADMIT SCREEN forms

Preoperative NIHSS form

ANESTHESIOLOGIST and NEUROSURGEON forms

TEMPERATURE form, and copies of the anesthesia record, and PACU/ICU nursing records for the first two postoperative hours. Note: the anesthesiologist recovery records must be placed in the Study Packet and sealed, without being reviewed/read by the Study Coordinator.

NIHSS forms completed at 3 to 6-hours, 24-hours, 72-hours postoperatively, and upon discharge

DAILY POST-OP SCREEN form

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All appropriate INTERCURRENT EVENTS forms completed prior to discharge

MEDICATIONS form completed through the time of discharge

To be eligible for final payment, submission and verification by the DMC of completeness of the following post-discharge follow-up forms, must occur:

CONTACT FOLLOW-UP and OUTCOME FOLLOW-UP forms for the six-week and three-month visits, appropriate INTERCURRENT EVENTS forms, as well as the final NIHSS and Neuropsychology forms.

In the event a patient dies at any time before the end of the three-month follow-up evaluation (including deaths occurring in the hospital prior to discharge), final payment will be made when all appropriate DEATH/PATIENT WITHDRAWAL forms are submitted and verified.

IV.C.7.Payment Procedures

Once the subcontract is completed between the UI and your institution, and a blank invoice is submitted to the CCC, the CCC will be able to initiate the first payment.

Payments include: 1) An initial $10,000.00 for start-up costs; 2) $1,000.00 each for the first two practice patients; 3) $1,000.00 ($1,500.00 after the tenth patient) upon receipt of all forms through discharge of patient from the hospital; and 4) $1,000.00 ($1,500.00 after the tenth patient) upon receipt of forms through the final three-month patient visit. For further explanation of the payment schedule, you may refer to your subcontract, Exhibit A, or call the CCC.

The first payment of $10,000 will be sent after necessary administrative tasks are complete. 1) A consortium agreement as well as a subcontract between the University of Iowa and your institution must first be completed. 2) Local Human Studies Committee approval, including an approved consent document, must be attained. 3) Both an Investigator and Coordinator must attend either the initial organizational meeting in Chicago (September 1999) or a subsequent meeting held in Iowa City. Subsequent payments will be initiated by the CCC at the end of each month in which submission of all appropriate data to the DMC has occurred for a patient (either the case report forms submitted at discharge, or those submitted at the final three-month follow-up).

For information regarding payment procedures, contact the CCC.

IV.C.8.Local Institutional Overhead/Indirect Costs

No added funds will be provided for institutional overhead fees. Any overhead charged by PCCs must be paid from the $3000 per patient fee. As a general rule, no more than 25% of the per patient fee should be paid to the institution as overhead.

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CHAPTER V. PATIENT ASSESSMENT INSTRUMENTS AND TRAINING

Other than issues related to blinding and to compliance with the protocol, the most important items in this trial are the neurologic assessment instruments needed to assess patient eligibility, to track their perioperative course, and to measure long-term neurologic outcome. To ensure the validity of collected data, each test must be performed by an individual certified in their performance by the CCC. The materials below will briefly describe each test, and define the mechanisms needed to achieve certification.

V. A WFNS1 AND GCS

Many different “scales” have been developed over the years to characterize the preoperative condition of patients with SAH. Perhaps the best known of these is the Hunt and Hess scale described first in 1968. These scales were initially designed to improve communications among neurosurgeons and neurologists, but have subsequently been shown to correlate with patient cerebral physiology (e.g., cerebral blood flow, ICP, autoregulation, etc.) and to have some utility in predicting ultimate outcome. In general, these scales assign numbers of I through V to patients, with a score of I representing a neurologically normal individual, and a score of V representing a severely damaged/moribund patient. Note that the scales are meaningful (and have been validated) ONLY in patients with SAH, although some assign scores of 0 to patients with unruptured aneurysms.

We have chosen to use the scoring system developed by the World Federation of Neurologic Surgeons (WFNS), which was first reported in 1988. This system has now been used in multiple trials related to SAH, including the International Cooperative Trial, trials of nimodipine, nicardipine and tirilazad. This scoring system is based on the GCS (which is in worldwide use by both nurses and physicians).

The GCS is described below:

Eye Opening Best Motor Best Verbal

4 = Spontaneous 6 = Obeys 5 = Oriented

3 = To Speech 5 = Localizes 4 = Confused

2 = To Pain 4 = Withdraws 3 = Inappropriate Words

1 = None 3 = Abnormal Flexion (decorticate) 2 = Incomprehensible

99 = Untestable 2 = Extension (decerebrate) 1 = None

1 = None 99 = Untestable

99 = Untestable

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The total GCS is the sum of the subcategory scores. A normal individual has a GCS = 15 (4 + 6 + 5). A deeply comatose individual has a GCS=3 (1+1+1) which is the lowest score possible.

This scoring system does not provide quantitative information related to focal deficits. If a patient is hemiplegic, but obeys commands with the non-plegic side, their “best motor score” is still 6. Nevertheless, after SAH, focal motor deficits are known to be predictive of outcome; patients with focal deficits do worse than patients without such deficits.

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The WFNS attempts to include some measure of such focal neurologic deficit:

WFNS Score = I: GCS of 15, no motor deficits

WFNS Score = II: GCS 13-14, no motor deficits

WFNS Score = III: GCS 13-14, any motor deficit or aphasia

WFNS Score = IV: GCS 7-12, with or without motor deficit

WFNS Score = V: GCS 3-6, with or without motor deficit

WFNS Score = 99 GCS not testable

It is rare, but possible, to have a patient with a motor deficit (which is not covered by the above scale) who has a GCS = 15 . In this case, the patient is considered to have a WFNS Score = I. Since patients with “poor” WFNS scores do not do well regardless of therapy, we have elected to restrict this trial to patients with immediate preoperative WFNS scores of I, II or III. (Note: Since it is often difficult to accurately determine a patient’s “Best Verbal” score when the trachea is intubated, we have decided to exclude patients who are endotracheally intubated at the time of assessment of study eligibility).

Also, WFNS scores may change rapidly. A patient admitted to the Emergency Room with a WFNS = V may rapidly improve, even to a WFNS score of I. Similarly, patients may deteriorate. For this reason, the trial mandates that patients have a WFNS = I, II or III at the time of enrollment, AND that a score of I, II or III still be present prior to the induction of anesthesia. The score may change - but it must not fall to IV or V.

The GCS will also be used as part of the postoperative daily screening process to quantitate neurologic function postoperatively.

In the postoperative phase, if the patient is intubated or has a tracheostomy, written answers to the orientation questions may be tried or the patient may be able to mouth the words. If this is untestable despite all these efforts, the GCS score cannot be assigned, and the patient should receive a score of 99.

a) Training and Certification

A WFNS score will be assigned at the time eligibility is determined and prior to the induction of general anesthesia. The Local Study Coordinator, the PI and each participating anesthesiologist must be certified in the WFNS and GCS.

Each PCC will be provided with a CD-ROM containing examples of patients with various GCS and WFNS scales. Prior to January 1, 2001, each PCC was also provided with written (paper-based) educational and testing materials for the GCS and WFNS scales. Effective January 1, 2001, all educational and testing materials for the GCS and WFNS are available via the IHAST2 website. The GCS/WFNS certification exam is taken and scored on line.

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V. B RANKIN DISABILITY SCORE2,3

The Rankin Score is a 6-point scale intended to define the degree of a patient’s functional disability. While originally intended to assess neurologic disability, it also applies to patients disabled by other disease (e.g., arthritis, heart failure, etc). The score is listed below:

Rankin = 0 No symptoms at all

Rankin = 1 No significant disability despite symptoms; able to carry out all usual duties and activities

Rankin = 2 Slight disability unable to carry out all normal activities but able to look after own affairs without assistance

Rankin = 3 Moderate disability requiring some help but able to walk without assistance

Rankin = 4 Moderately severe disability unable to walk without assistance, and unable to attend to own bodily needs without assistance

Rankin = 5 Severe disability bedridden, incontinent and requiring constant nursing care and attention

4


The Rankin Disability Score will be used twice in this study. First, a Rankin Score that reflects the patients functional status prior to the SAH will be assigned based on interviews with the patient or next of kin. Eligibility will be restricted to patients with Pre-SAH Rankin scores of 0 or 1. The purpose of this is to exclude patients who have been severely disabled either as a result of a prior neurologic insult or some other serious disease. We believe that such serious pre-intervention disability will complicate and confuse our efforts to ascertain whether hypothermia influences outcome. Second, a Rankin Disability Score will be assigned at the time of the 6-week and 3-month postoperative Outcome Follow-up.


A Rankin score will be assigned at the time of eligibility determination, again at the time of the 6-week and 3-month postoperative OUTCOME FOLLOW-UP exam. The Local Study Coordinator, the PI and the Neurologic Examiner must be certified in the use of the Rankin Score.

The scale is “self-evident” and no formal training is needed.. Prior to January 1, 2001, each PCC was provided with written (paper-based) testing materials for the Rankin scale (combined GOS/Rankin test). Effective January 1, 2001, all educational and testing materials for the Rankin scale are available via the IHAST2 website. The combined GOS/Rankin certification exam is taken and scored on line.

V. C NIHSS4,5,6,7

The NIHSS is a quantitative neurologic examination developed for use following strokes of various etiologies. It has not been formally used to follow patients with SAH, but has been exceptionally well validated in other circumstances. Specifically, it is easily performed by non-neurologists, detects changes in neurologic status well, and has excellent inter-rater reliability. The scale consists of 11 items. Normal performance in any area receives a score of zero; hence a completely normal patient will have a cumulative score of 0. Worst case scores for individual items range from 2 to 4, with a maximum score in a devastated individual being 42. Details on the performance of this scale can be found in Chapter IX later in this Manual.

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Item Score Worst Case

1a. Level of Consciousness 0-3 Reflex Only or Unresponsive

1b. Level of Consciousness Questions 0-2 Answers Neither Question

1c. Level of Consciousness Commands 0-2 Performs Neither Task Correctly

2. Best Gaze 0-2 Forced Deviation/Total Gaze Paresis

3. Vision/Visual Fields 0-3 Bilat Hemianopia or Blind

4. Facial Palsy 0-3 Complete Paralysis One or Both Sides.

5a. Motor - Left Arm 0-4 No Movement

5b. Motor - Right Arm 0-4 No Movement

6a. Motor - Left Leg 0-4 No Movement

6b. Motor - Right Leg 0-4 No Movement

7. Limb Ataxia 0-2 Present Both Limbs

8. Sensory 0-2 Severe to Total Sensory Loss (or Coma or Unresponsive)

9. Best Language 0-3 Mute, Global Aphasia

10. Dysarthria 0-2 Severe, Slurred, Unintelligible

11. Extinction/Inattention 0-2 Profound Hemi-inattention

Max Score = 42 (severely damaged)

Min Score = 0 ( normal)


A score will be assigned preoperatively, at 3-6 hours after the patient arrives in the PACU/SICU directly from the O.R., at 24 and 72 hours after surgery, at discharge, and finally at the 3-month follow-up exam. The Local Study Coordinator and the Neurologic Examiner must be certified in the performance of this test. In addition, given the importance of this test, we would like each Local PI to be certified as well.

Each PCC will be provided with a series of two videotapes. The first tape is for training. When this is completed, each individual will then watch the testing tape. This test demonstrates the performance of the exam in five patients with varying degrees of dysfunction. During a viewing of this tape the candidate will complete a standard test form for each individual. These forms will be submitted to and scored by the CCC.

Six weeks after this initial test, each PCC will be sent a third videotape for “confirmatory” testing. Each previously certified individual will need to watch this supplementary tape and provide written scores for the included patients.

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V. D BARTHEL'S ACTIVITIES OF DAILY LIVING (ADL)8,9

The Barthel's ADL scale is intended to evaluate day to day “self-care” issues in a patient who has suffered a stroke. It is a scale that reflects dysfunction that is not necessarily evident on the NIHSS or Rankin Disability Scale. In addition, the score can be determined by telephone interview. The score is noted below:

Bowels 0 = incontinent (or needs enemas); 5 = occasional accident; 10 = continent

Bladder 0 = incontinent or catheterized and unable to manage; 5 = occasional accident; 10 = continent

Grooming 0 = needs help with personal care; 5 = independent face/hair/teeth/shaving

Toilet Use 0 = dependent; 5 = needs some help but can do some things alone; 10 = independent

Feeding 0 = unable; 5 = needs help cutting, spreading butter, etc.; 10 = independent (food provided in reach)

Transfer 0 = unable/no sitting balance; 5 = major help (1-2 people); 10 = minor help; 15 = independent

Mobility 0 = Immobile; 5 = wheel chair independent; 10 = walks with help of one person; 15 = independent

Dressing 0 = dependent; 5 = needs help but does approximately half unaided; 10 = independent

Stairs 0 = unable; 5 = needs help; 10 = independent

Bathing 0 = dependent; 5 = independent

7


Max Score = 100 (normal)

Min Score = 0 (severely damaged)


The Barthel's score will be determined at the time of the 6-week and 3-month postoperative FOLLOW-UP OUTCOME exam.

The scale is “self-evident” and no formal training is needed.

V. E MINI-MENTAL STATE EXAM (MMSE)

The MMSE is a very old, simple screening test to assess cognitive status. We have elected to use this test for two reasons. First, abnormalities in the MMSE have been noted in as many as 15% of patients undergoing intracranial surgery for the repair of unruptured aneurysms, and hence we believe that it may be a sensitive test of surgical injury. In addition, the test can be administered by telephone by relatively unsophisticated individuals. It hence provides a “backup” to the more elaborate neuropsychologic test battery (Chapter V.F. below) in the event that a face-to-face visit at three months is not possible. The exam to be used in a face-to-face interview as follows:

Item Component(s) Score

Time Name: year, season, month, date, day 5

Place Name: state, county, city, building, floor 5

Registration Subject repeats: “apple, table, penny” 3

Attention Spell “WORLD” backward 5

Recall Recall: “apple, table, penny” 3

Naming Name: “pencil, watch” 2

Repitition Repeat: “No if’s, and’s, or but’s” 1

Written command “Close your eyes” 1

3-step command Take a piece of paper in your right hand, fold it in half, and put it on the floor

3

Writing construction Write any complete sentence 1

Drawing Draw two five sided figures 1

8


Total 0-30


This test will only be administered at the time of the 3-month follow-up, and will be performed (ideally) by the individual responsible for the neuropsychologic battery. These are intended to be administered by a professional neuropsychologist or neuropsychology technician - individuals who are already familiar with these highly standardized tests. If such individuals are available, no formal training and certification will be needed. In the event that such individuals are not available in a given PCC, they will be administered by the Neurologic Examiner. The training and certification of this individual will be the responsibility of Dr. Daniel Tranel and/or Dr. Steven Anderson of the UI Department of Neurology/Division of Neuropsychology. If a face-to-face 3-month visit proves impossible, the tests can be administered over the telephone, probably by the Study Coordinator. Hence the Coordinator will need to be certified in its use. As stated above, certification of this individual will be the responsibility of Dr. Daniel Tranel and/or Dr. Steven Anderson of the UI Department of Neurology/Division of Neuropsychology.

V. F NEUROPSYCHOLOGIC TESTING BATTERY

SAH can result in both gross neurologic dysfunction as well as more subtle cognitive deficits. It is know that as many as 50% of patients who appear to have otherwise recovered well (e.g., a GOS = 1, Chapter V. G below) may have detectable cognitive abnormalities. Therefore, to improve the “sensitivity” of our outcome assessment, we have selected a battery of five neuropsychologic tests to be administered to all patients at the time of their 3-month final follow-up. The five tests to be used and the cognitive domains covered by each are:

V.F.1. Benton Visual Retention Test (BVRT)

The BVRT assesses attention and anterograde memory. A series of 10 geometric figures of increasing complexity is presented to the patient. Each figure is individually displayed for 10 seconds and then removed. Immediately after each figure is removed, the patient is required to draw the figure from memory. Drawings are scored for accuracy and various types of errors (e.g., perseverations).

V.F.2. Controlled Oral Word Association (COWA)

COWA requires the generation of as many words as possible which begin with a certain letter, within a one minute time limit. This subtest from the Multilingual Aphasia Examination has been normed in all major languages. Three letters are used, with total test time of just over three minutes. COWA is sensitive to virtually any impairment of language.

V.F.3. Complex Figure Test (CFT)

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The CFT places demands on visuospacial and visuoconstructional abilities by requiring the patient to copy a complex geometric figure. Response time is recorded, and an extensive scoring system allows quantification of accuracy of reproduction.

V.F.4. Grooved Pegboard (GP)

This test measures speeded visuomotor coordination, while placing few demands on higher order cognitive abilities. Each hand is tested separately. The patient is required to pick up small metal pegs, rotate each one to match the orientation of grooved target holes, and place them in the holes. The time to completion is the primary dependent measure.

V.F.5. Trail Making Test (TMT)

The TMT places demands on executive functions by requiring the patient to simultaneously track two different types of information (a series of numbers and a series of letters), and to alternate responses between the two sets of information. Accurate performance depends on the ability to shift cognitive set and maintain information “on line” while performing a separate cognitive task (working memory).


These tests will be used only at the three month evaluation. They are intended to be administered by a professional neuropsychologist or neuropsychology technician - individuals who are already familiar with these highly standardized tests. If such individuals are available, no formal training and certification will be needed. In the event that such individuals are not available in a given PCC, they will be administered by the Neurologic Examiner. The training and certification of this individual will be the responsibility of Drs. Daniel Tranel and/or Steven Anderson of the UI Department of Neurology/Division of Neuropsychology.

V. G GLASGOW OUTCOME SCORE (GOS)

The Glasgow Outcome Score is a simple five-point scale originally designed to assess long-term outcome following head trauma. However, it has now been used to assess outcome following many neurologic insults - and is the only outcome measure to date demonstrated to “respond” to therapeutic interventions in patients with SAH. The GOS is our “Primary Outcome Variable” (i.e., the outcome variable upon which all sample size calculations are based and upon which the fundamental conclusion regarding the efficacy of hypothermia will be based). The scoring system follows:

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GOS = 1, Good Recovery Capacity to resume normal occupational and social activities, although there may be minor physical or mental deficits or symptoms.

GOS = 2, Moderate Disability Independent and can resume almost all activities of daily living. Disabled to the extent that they can not participate in a variety of social and work activities.

GOS = 3, Severe Disability No longer capable of engaging in most previous personal, social or work activities. Limited communication skills and have abnormal behavioral or emotional responses. Typically are partially or totally dependent on assistance from others in daily living.

GOS = 4, Persistent Vegetative State Not aware of surroundings or purposely responsive to stimuli.

GOS = 5, Dead Obvious


A GOS score will be assigned at the 6-week and 3-month OUTCOME FOLLOW-UP evaluation. The Study Coordinator, the PI and the Neurologic Examiner must be certified in this exam. The scale is “self-evident” and no formal training is needed. Prior to January 1, 2001, each PCC was provided with written (paper-based) testing materials for the GOS (combined GOS/Rankin test). Effective January 1, 2001, all educational and testing materials for the GOS are available via the IHAST2 website. The combined GOS/Rankin certification exam is taken and scored on line. In addition, effective January 1, 2001, all Study Coordinators and Neurologic Examiners must be annually recertified on the GOS. The GOS recertifiction exam is available via the IHAST2 website.

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V. H SUMMARY

Summary: Patient Assessment Instruments for which certification is necessary

Test StudyCoordinator

Local PI Anesthesiologist Neurosurgeon Neurologic Examiner

Neuropsych. Examiner

WFNS/GCS X X X optional

Rankin/GOS X X optional optional X

NIHSS X (X) X

MMSE (X) [X] X

Neuropsych Battery

(X) [X] X

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Comment. The WFNS and Rankin scores are required to determine patient eligibility; hence both the Study Coordinator and Local PI (and any other physicians involved in enrolling patients) need to be certified for the these tests. In addition, the Local PI should be familiar with the other tests (indicated by the (X) notation). Under most circumstances, the neuropsychologic battery will be administered by a professional neuropsychologist or neuropsychology technician. However, in the event that such a person is not available, we anticipate that the Neurologic Examiner will need to be certified in the administration of this battery, as indicated by the [X] notation above.

References1Drake, C. G. (1988). “Report of World Federation of Neurological Surgeons Committee on a universal subarachnoid hemorrhage grading scale.” J. Neurosurg. 68: 985-986.

2Rankin, J. (1957). “Cerebral vascular accidents in patients over the age of 60. 2. Prognosis.” Scott Med J 2: 200-215.

3van Swieten, J. C., P. J. Koudstaal, et al. (1988). “Interobserver agreement for the assessment of handicap in stroke patients.” Stroke 19: 604-607.

4Brott, T., H. P. Adams, Jr., et al. (1989). “Measurements of acute cerebral infarction: a clinical examination scale .” Stroke 20(7): 864-70.

5Lyden, P., T. Brott, et al. (1994). “Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group.” Stroke 25(11): 2220-6.

6Muir, K. W., C. J. Weir, et al. (1996). “Comparison of neurological scales and scoring systems for acute stroke prognosis.” Stroke 27(10): 1817-20.

7Goldstein, L. B. and G. P. Samsa (1997). “Reliability of the National Institutes of Health Stroke Scale. Extension to non-neurologists in the context of a clinical trial.” Stroke 28(2): 307-10.8Mahoney, F. I. and D. W. Barthel (1965). “Functional Evaluation: the Barthel Index.” Maryland State Medical Journal 14: 61-64.9Wade, D. T. and C. Collin (1988). “The Barthel ADL index: a standard measure of physical disability.” Int Disabil Studies 10: 64-67.

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CHAPTER VI. ENROLLMENT AND RANDOMIZATION PROCEDURES

VI. A RANDOMIZATION SCHEME

Overview of the randomization process

Patients in IHAST2 will be randomized using a central randomization facility at the DMC. Randomization will be stratified by study center and time from onset of SAH to planned surgery. Patients will be assigned to either hypothermia or normothermia using the method of permuted blocks. This will make it impossible for anyone to accurately predict the next treatment assignment at any PCC.

At the beginning of the study, each PCC will receive a box containing Study Packets for their first 30 patients. The Study Packet is a large (10 x 13 in.) envelope which is pre-labeled with an IHAST2 patient identification (PID) number. The PID number on the outside of the Study Packet envelope must correspond to the PID number assigned to the patient by the phone enrollment system. The Study Packet envelope contains the following items:

a. One (1) (9 x 12 in.) sealed white RANDOMIZATION ENVELOPE pre-labeled with the same PID number.

b. One (1) (9 x 12 in.) sealed brown RANDOMIZATION ENVELOPE pre-labeled with the same PID number.

c. Two (2) white (6.5 x 9.5 in.) unsealed envelopes pre-labeled with the same PID number.

d. Eight (8) white (0.5 x 1.75 in.) adhesive labels pre-labeled with the same PID number.

Except for one of the RANDOMIZATION ENVELOPES (the one which is NOT to be opened), the Anesthesiologist will need the entire Study Packet—including the Study Packet envelope itself (see below). Because the Anesthesiologist should only be provided with the sealed RANDOMIZATION ENVELOPE that matches the color and PID assigned to the patient by the phone enrollment system, the other (unassigned) RANDOMIZATION ENVELOPE should be removed from the Study Packet before it is given to the Anesthesiologist. The unopened Randomization Envelope may be kept in the Patient Notebook until returned to the DMC.

The assigned RANDOMIZATION ENVELOPE contains a TEMPERATURE form which indicates the temperature group to which the patient has been randomized. Except for the local hospital anesthesia record, this TEMPERATURE form is the only place where intraoperative temperature data for IHAST2 is to be recorded. TEMPERATURE forms (therefore treatment assignments) will be randomly assigned to the brown and white envelopes so that it will be impossible for anyone outside the DMC to know which assignment is in which envelope.

The two white (6.5 x 9.5 in) unsealed envelopes will be used by the Anesthesiologist to place the completed TEMPERATURE forms. On the outside of these envelopes are instructions telling the Anesthesiologist into which of these envelopes the two copies of the completed TEMPERATURE form (upper white original and lower canary-colored copy) are to be placed and sealed at the end of surgery. After these two envelopes are sealed, they are to be returned to the Local Study Coordinator (the sooner the better) and never opened.

1


In order to enroll a patient and obtain a planned randomization assignment the PCC will have to call the automated telephone system at the DMC. A detailed description of how to access and use the automated randomization system follows (Chapter VI.C). Only certified investigators and Study Coordinators will be able to access the system. The enrollment call will ask for the caller’s certification number, the date of the SAH, and the planned date of surgery. Using this information, the system will determine the appropriate treatment assignment and determine which of the two RANDOMIZATION ENVELOPES (white or brown) contains the TEMPERATURE form for that assignment. The caller will be supplied with the Patient ID number and the color of the RANDOMIZATION ENVELOPE that the Anesthesiologist should open to obtain the treatment assigment for the current patient..

A patient is not randomized until the RANDOMIZATION ENVELOPE is opened. The study Anesthesiologist should only take to the operating room the RANDOMIZATION ENVELOPE whose color was specified by the enrollment call and the remainder of the materials provided in the assigned Study Packet. (The UNassigned RANDOMIZATION ENVELOPE should be removed from the Study Packet) If, between the time of the enrollment call and the beginning of surgery, the patient becomes ineligible, then the assigned RANDOMIZATION ENVELOPE should not be opened and the patient will not be considered randomized. Neither the white nor the brown RANDOMIZATION ENVELOPE with that Patient ID will ever be used in the study and neither should be opened. If a patient is not randomized then the unopened RANDOMIZATION ENVELOPES should be placed in the patient notebook with the assigned Patient ID. The unopened envelopes should not be opened or used in any way. Both unopened RANDOMIZATION ENVELOPES should be sent to the DMC on the last working day of the month.

Regardless of whether or not the patient is randomized (the RANDOMIZATION ENVELOPE is opened) the PCC must call the automated telephone system to confirm whether or not the RANDOMIZATION ENVELOPE was opened. The telephone system will use this information to inform the DMC whether or not a patient has been randomized. If the DMC does not receive a confirmation call within one working day of the randomization call, a report will be sent to the PCC to determine the status of that patient and to remind the PCC that the confirmation call must be completed.

The automated telephone system will not provide a caller with a Patient ID and RANDOMIZATION ENVELOPE color if it cannot confirm that a patient is eligible. This means that the patient satisfies all inclusion criteria and does not satisfy any exclusion criterion. If a patient cannot be confirmed as eligible then the automated telephone system will suggest that the caller contact the CCC and will terminate the call.

VI.A.1. What Constitutes Randomization?

Once a RANDOMIZATION ENVELOPE is opened, the patient is considered randomized. Even if the patient dies or withdraws before the planned craniotomy is begun, s/he must still be reported to the DMC as having been randomized, by making a confirmation call. Once a patient has been randomized, the DMC will expect to receive data on the patient through the 3-month follow-up.

VI.A.2. Envelopes, Patient Notebooks, and Other CRF’s

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The Study Coordinator should ensure that the IHAST2 Study Packets (which contain the RANDOMIZATION ENVELOPES), patient notebooks and SCREENING and ELIGIBILITY forms are available at all times to investigating physicians in the trial. Patients may be enrolled at any time, including nights and weekends. Since the color of the RANDOMIZATION ENVELOPE is determined by the DMC at the time the enrollment phone call is made, the Study Packets (which contain the RANDOMIZATION ENVELOPES), patient notebooks, and SCREENING and ELIGIBILITY forms should be readily available to every investigating physician. In particular, the study Anesthesiologist who is responsible for the case must have access to the Study Packets and the SCREENING, ELIGIBILITY, PRE-SAH HISTORY, POST-ADMIT SCREEN, preoperative and 3 to 6-hour postoperative NIHSS, NEUROSURGEON, and ANESTHESIOLOGIST forms.

VI.A.3. Brown or White?

After the investigating physician or Study Coordinator has determined that a patient is eligible for the study and informed consent has been obtained, s/he should call the DMC and follow the voice menu options (see Chapter VI.C). If the automated telephone system confirms that the patient is eligible, the system will provide the caller with patient's IHAST2 Patient ID number (same as the Study Packet number) and the color of the RANDOMIZATION ENVELOPE that contains the treatment assigned to that patient, either brown or white. The study Anesthesiologist must have the assigned Study Packet and RANDOMIZATION ENVELOPE available in the operating room so that it can be opened to obtain the patient's assigned treatment. Inside of the RANDOMIZATION ENVELOPE will be a TEMPERATURE form that will indicate which protocol, normothermia or hypothermia, which the Anesthesiologist should follow.

VI. B ELIGIBILITY ASSESSMENTS

All patients who have had an acute SAH with angiographically verified aneurysm should be screened for this trial. The randomly assigned thermal management during the scheduled surgery must be scheduled within 24 hours of the patient assessment for study; therefore familiarity with all inclusion and exclusion criteria is extremely important.

In order to screen patients for IHAST2, a neurological exam must be completed. If the physician has any questions concerning eligibility, please call Julie Weeks, CCC Center Coordinator, at 319-356-0461. A CCC physician, Dr. Mike Todd or Dr. Brad Hindman, will also be available to answer questions 24 hours a day and may be reached at (319) 384-7116.

VI.B.1. Enrollment Criteria

See Chapter 8 for a detailed description of each of these criteria. In brief:

a) Inclusion Criteria

1. Age 18 or older.

2. Aneurysm verified by imaging methods.

3


3. Initial SAH (proven by CT or lumbar puncture)within 14 days prior to surgery without intervening discharge.

4. Planned open craniotomy within 24 hours of patient assessment for study.

5. Pre-SAH Rankin disability score of 0 or 1.

4


6. A full course of nimodipine is planned.

7. WFNS score of I, II, or III assessed within 12 hours prior to surgery.

b) Exclusion Criteria

1. Endotracheally intubated at the time of WFNS score.

2. Body Mass Index (BMI) > 35 kg/m2.

3. Pregnant or positive or indeterminant pregnany test.

4. Prior craniotomy for aneurysm clipping within one year prior to current SAH.

5. Planned second craniotomy within three months after surgery for this SAH.

6. Aneurysm to be clipped has been previously coiled or treated by other endovascular procedure.

7. Previously randomized in IHAST2 (envelope opened).

8. Currently enrolled in other clinical or therapeutic trial.

9. History of cold-related disease (cryglobulinemia, Raynaud’s, sickle-cell).

10. Severe medical or psychiatric illness, or active life-threatening disease.

11. Other contraindication to protocol anesthetic.

c) Procedural Criteria

1. Certified IHAST2 study personnel available to carry out protocol.

2. Patient available for 3-month evaluation.

3. Appropriate language translator available if needed for all evaluations.

4. Surgeon and Anesthesiologist agree to proceed.

5. Patient agrees to participation in this trial or if unable to give informed consent, next-of-kin or consenting person gives consent.

VI. C ENROLLMENT TELEPHONE CALL

As mentioned above, the assigned surgery must be scheduled within 24 hours of the assessment of the patient's eligibility. Thus, once consent has been obtained and eligibility for this study is determined, the certified physician or PCC Study Coordinator should call the DMC at 319-353-4708 to enroll the patient in the study.

VI.C.1. Enrollment Call Instructions

The automated telephone randomization system at the DMC has four functions.

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Function 1 is used to confirm the eligibility of a patient and to supply the Patient ID number and temperature treatment assignment (envelope color).

Function 2 is used to confirm that a patient who has been assigned an ID number has or has not been randomized.

Function 3 is used to obtain the Patient ID number and temperature treatment assignment (envelope color) through an override code obtained from a physician at the CCC.

Function 4 is used to obtain contact information for the CCC.

Use of each function is discussed in detail in the following:

All information that the caller will need to supply the automated telephone randomization system during the call is found on the patient's ELIGIBILITY form. The caller should have completed the ELIGIBILITY form and have it with her/him when making the enrollment call. In particular, on page 3 there is a place to record the Patient ID number and the color of the envelope to open to obtain the appropriate treatment assignment. All responses to the phone system are numeric and are entered by pressing the appropriate number keys on a touch tone keypad. All responses should be completed by pressing the # key. In the following descriptions the messages you will hear from the telephone system are given in bold type.

a) Calling the automated telephone randomization system

When it is determined that a patient is eligible for randomization then a certified investigator or certified Study Coordinator should call 319-353-4708 to access the automated telephone randomization system.

b) Tips for success with the system:

Listen carefully to each question and respond accordingly.

Each answer should be followed by pressing #.

Dates must be in the format mmddyyyy containing eight digits and leading zeros where necessary.

c) Telephone Scripts

When the caller is connected to the automated telephone randomization system s/he will hear the following message:

Hello, you have reached the IHAST2 patient registration system. Please enter your 5-digit certification number, followed by the # key.

Comment: When an investigator or Study Coordinator is certified to participate in IHAST2 s/he is assigned a five-digit certification number, which is made up of the two-digit PCC number and a three-digit CCC-assigned number.

After pressing the # key, you must confirm your answer following this message:

You entered (XXXXX). Press the # key to accept or the * key to try again.

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If the certification number is found in the database, you will then hear the statements below:

Press 1 and the # key to begin the IHAST2 eligibility program.

Press 2 and the # key to record patient randomization status.

Press 3 and the # key if you are calling with an override number.

Press 4 and the # key if you would like contact information for the Clinical Coordinating Center.

Press the * to end this call.

Select the Menu Item appropriate to your call.

(1) MENU 1 - ENROLLMENT

If all inclusion criteria in section A, items 1 through 7 are checked yes, press 1, followed by the # key. If any of these items is checked no, press 0, followed by the # key.

Provide the appropriate response.

From inclusion criteria item 3, enter the SAH date in the form month, day and 4-digit year including leading zeros, followed by the # key.



You entered (XXXXXXXX). Press the # key to accept or the * key to try again.

Comment: The caller should enter a valid date in the form of mmddyyyy containing eight digits. Please enter leading zeros for days or months that are less than 10. For example, for March 4, 2001 please enter 03042001#.

From inclusion criteria item 4, enter the planned surgery date in the form month, day and 4-digit year including leading zeros, followed by the # key.




If all exclusion criteria in section B, items 1 through 11 are checked no, press 0, followed by the # key. If any items are check yes, then press 1, followed by the # key.


If all procedural criteria in section C, items 1 through 5 are answered yes, press 1, followed by the # key. If any of these items are checked no, then press 0, followed by the # key.


All criteria have been met for this patient.

This patient's study ID number is XXXXX.

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Please use the brown envelope. Again this patient's study ID number is XXXXX. Please use the brown envelope.

or

Please use the white envelope. Again this patient's study ID number is XXXXX. Please use the white envelope.

To repeat the study ID number and randomization envelope color, press 1, followed by the # key. Press only the # key to continue.

If the caller presses any other key and the # key, s/he will hear the following message:

You have successfully completed the IHAST2 enrollment process. Thank you for calling the Data Management Center.

Comment: The caller should carefully enter the Patient ID number (in the form XX-XXX) and envelope color on the last page of the patient's ELIGIBILITY form. Also enter the Patient ID number in the Header of the SCREENING and ELIGIBILITY forms.

(2) MENU 2 –PATIENT RANDOMIZATION STATUS

Because it is possible to obtain a Patient ID number and envelope color for a patient that is not subsequently randomized (e.g., due to a change in eligiblity status before arrival in the O.R.), the DMC must be notified within 24 hours of the original enrollment call whether or not the patient was actually randomized.

When 2 is entered on the access menu the caller will hear the following message:

Please enter the patient's 5-digit study identification number, followed by the # key.



You entered (XXXXX). Press the # key to accept or the * key to try again.

Was the randomization envelope opened for this patient? Press 1 for yes, 0 for no, followed by the # key.

If the caller responds yes (1) then s/he will hear the following message:

You responded that the randomization envelope was opened. Press 1 if that is correct, or 0 if you need to change your response. Press the # key when completed.

If the caller presses no (0), s/he will get the following message:

You responded that the randomization envelope was not opened. Press 1 if that is correct, or 0 if you need to change your response. Press the # key when completed.

Once the caller has successfully provided the required information then s/he will hear the following message:

You have successfully completed the IHAST2 confirmation process. Thank you for calling the Data Management Center.

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(3) MENU 3 – OVERRIDE CODE

In rare and exceptional circumstances the physicians at the CCC will provide an investigator with a code that will allow her/him to obtain a randomization assignment without using menu 1 above. After selecting option 3 from the main menu the caller will hear the following message:

Enter the override code followed by the # key.

Provide the appropriate information


You entered (XXX). Press the # key to accept or the * key to try again.

Comment: The override code numbers will be constructed so that the automated telephone randomization system will be able to verify that the code was indeed supplied by one of the CCC investigators.

From inclusion criteria item 3, enter the SAH date in the form month, day and 4-digit year including leading zeros, followed by the # key.




If a valid SAH date is entered then the caller will hear the following message:

From inclusion criteria item 4, enter the planned surgery date in the form month, day and 4-digit year including leading zeros, followed by the # key.




After valid SAH and planned surgery dates are entered the caller will hear the following:

All criteria have been met for this patient.

This patient's study ID number is XXXXX.

Please use the brown envelope. Again this patient's study ID number is XXXXX. Please use the brown envelope.

or

Please use the white envelope. Again this patient's study ID number is XXXXX. Please use the white envelope.

To repeat the study ID number and randomization envelope color, press 1, followed by the # key. Press only the # key to continue.

If the caller presses any other key and the # key, s/he will hear the following message:

You have successfully completed the IHAST2 enrollment process. Thank you for calling the Data Management Center.

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(4) MENU 4 – ADDITIONAL HELP

Occasionally, an investigator will need to talk to the physicians at the CCC. By pressing 4 on the access menu s/he will hear the following:

If you need to talk to a physician at the CCC, call 319-384-7116. Thank you for calling the Data Management Center.

VI.C.2. Enrollment Call Problems

The scripts above are presented “as if” all entries were correct and without difficulty. However, the system does have an extensive series of checks to ensure that approved persons and PCC’s are entering information, and that data are entered correctly. The following are examples of how the system will deal with various problems.

a) PCC is not yet approved to commence patient enrollment.

The certification number you gave is not valid. Please enter your 5-digit certification number again, followed by the # key.

If an invalid number is entered twice, the telephone call will be terminated.

Comment: It is possible for an individual to have a valid certification number, but for the PCC to not yet be approved to begin patient entry (e.g., due to the lack of another certified key individual).

b) Individual making the call is not yet certified

The certification number you gave is not valid. Please enter your 5-digit certification number again, followed by the # key.

If an invalid number is entered twice, the telephone call will be terminated.

c) Incorrect Menu Choice

In many cases, you will be asked to enter a number, such as 0 or 1, or 1, 2, 3 or 4. If you enter a number other than one of the possible entries, you will hear:

The answer you gave was invalid. Please listen to the question completely and answer as directed.

d) Entry indicates that a patient does not meet enrollment criteria

If during enrollment, you are asked to answer certain questions relative to eligibility criteria and an incorrect answer is entered, you will hear:

The value you entered does not meet criteria for patient enrollment. Please listen to the question completely and answer as directed.

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The phone system will then repeat the original message. If an unacceptable answer is again entered, then the system will terminate after the caller hears the following message:

The patient did not meet all criteria for randomization and was not assigned a study Patient ID number. If you need to talk to a physician at the CCC, call 319-384-7116. Otherwise, please hang up and retry your call. Thank you for calling the Data Management Center.

e) Incorrect date entry

All dates must be entered as 8-digit numbers, in the form mmddyyyy. If you enter a number that does not meet this format, you will hear a response similar to the following”

The SAH date you entered is not valid. Please listen to the question completely and answer as directed.

f) Incorrect interval between SAH and surgery

You will be asked to enter the date of SAH and the date of planned surgery. In order to be eligible, a patient must have surgery within 14 days of the SAH. If the difference in days between the date of the call and the date of the SAH is greater then 14 days then the caller will hear the following message:

The days between SAH date and today’s date are not within 14 days. These dates do not fall within protocol guidelines. Please listen to the question completely and answer as directed.

The telephone system allows three attempts to enter a valid SAH date. After three unsuccessful attempts the system terminates the call.

VI.C.3. Practice Obtaining a Randomization Assignment

The automated telephone system provides a way for the user to practice with the automated telephone randomization system. The user can access menu items 1 and 2 without actually randomizing a patient or generating data in the DMC database. In order to do this the user must enter the certification number 99999. The call will proceed as if it were a real call but the call will not generate a real randomization and the system will provide a bogus Patient ID number and envelope color.

VI. D STUDY PACKETS

Thirty sets of Study Packets containing sealed RANDOMIZATION ENVELOPES will be placed in a box and sent to each PCC at the beginning of the study. Each Study Packet is a large (10 x 13 in.) envelope which is pre-labeled with an IHAST2 patient identification (PID) number. The PID number on the outside of the Study Packet envelope must correspond to the PID number assigned to the patient by the phone enrollment system. The Study Packet envelope contains the following items:

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The assigned RANDOMIZATION ENVELOPE contains a TEMPERATURE form which indicates the temperature group to which the patient has been randomized. This TEMPERATURE form is the only place where intraoperative temperature data for IHAST2 is to be recorded. TEMPERATURE forms (therefore treatment assignments) will be randomly assigned to the brown and white envelopes so that it will be impossible for anyone outside the DMC to know which assignment is in which envelope.

The two white (6.5 x 9.5 in) unsealed envelopes will be used by the Anesthesiologist to place the completed TEMPERATURE forms. On the outside of these envelopes are instructions telling the Anesthesiologist into which of these envelopes the two copies of the completed TEMPERATURE form (upper white original and lower canary-colored copy) are to be placed and sealed at the end of surgery. After these two envelopes are sealed, they are to be returned to the Local Study Coordinator (the sooner the better) and never opened. One of these envelopes will indicate, "return white original to the DMC" and the other will indicate "return canary copy to patient's notebook." The envelope marked "return white original to the DMC" should be included in the 48-hour submission to the DMC. The other envelope should be placed in the patient's notebook.

The eight (8) white (0.5 x 1.75 in.) adhesive labels pre-labeled with the same PID number are used to label photocopies of the local hospital anesthesia record and early (0-2 h) recovery records. Patient identifiers (name, social security number) are to be removed or obscured on these records. These photocopies are provided to the Study Coordinator in the original Study Packet which bears the PID.

VI. E 24-HOUR PATIENT RANDOMIZATION STATUS CALL

No more than 24 hours after the completion of surgery, the PCC Study Coordinator or a certified physician at the PCC must notify the DMC either that the patient was actually randomized (the envelope was opened) or that the patient was not randomized. This is done via the automated telephone system. Call 319-353-4708, provide the requested certification numbers, select menu item 2 and answer accordingly.

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CHAPTER VII. REPORTING AND DATA SUBMISSION

VII. A ORGANIZATION OF DATA COLLECTION MATERIALS

VII.A.1. Patient Notebooks

Each PCC is supplied with at least five (5) patient notebooks at a time which contain most (See section on SCREENING and ELIGIBILITY forms) of the CRF’s necessary for a single randomized patient in the IHAST2 trial. The notebook is organized by form name, with each divider section clearly labeled. The CRF’s are placed in the notebook to reflect their evaluation time period.

The MEDICATIONS form and the DAILY POST-OP SCREEN are in a grid-like (spreadsheet) format. Data for these forms will be captured over a specified period of time from weeks to months.

The neuropsychology battery forms are placed together in a folder in each notebook. Each folder is provided with a checklist of instructions for the PCC Study Coordinator to remove and use as a guide, if desired. This folder with its contents should be given to the neuropsychologist at the three-month follow-up.

The DEATH/PATIENT WITHDRAWAL form is located at the back of the notebook.

VII.A.2. Screening and Eligibility Forms

Each PCC is supplied with 50 SCREENING and 50 ELIGIBILITY forms. The forms are placed in manila folders clearly labeled with the appropriate form name. The PCC Study Coordinator should place these forms where both the PCC Study Coordinator and PCC physicians can easily access them. A SCREENING and ELIGIBILITY form needs to be completed for any patient with a subarachnoid hemorrhage and scheduled for clipping of an intracranial aneurysm within 24 hours regardless of eligibility status.

VII.A.3. Study Packets

Thirty sets of Study Packets containing sealed RANDOMIZATION ENVELOPES will be placed in a box and sent to each PCC at the beginning of the study. Each Study Packet is a large (10 x 13 in.) envelope which is pre-labeled with an IHAST2 patient identification (PID) number. The PID number on the outside of the Study Packet envelope must correspond to the PID number assigned to the patient by the phone enrollment system. The Study Packet envelope contains the following items:



1





The assigned RANDOMIZATION ENVELOPE contains a TEMPERATURE form which indicates the temperature group to which the patient has been randomized. This TEMPERATURE form is the only place where intraoperative temperature data for IHAST2 is to be recorded. TEMPERATURE forms (therefore treatment assignments) will be randomly assigned to the brown and white envelopes so that it will be impossible for anyone outside the DMC to know which assignment is in which envelope.

The two white (6.5 x 9.5 in) unsealed envelopes will be used by the Anesthesiologist to place the completed TEMPERATURE forms. On the outside of these envelopes are instructions telling the Anesthesiologist into which of these envelopes the two copies of the completed TEMPERATURE form (upper white original and lower canary-colored copy) are to be placed and sealed at the end of surgery. After these two envelopes are sealed, they are to be returned to the Local Study Coordinator (the sooner the better) and never opened. One of these envelopes will indicate, "return white original to the DMC" and the other will indicate "return canary copy to patient's notebook." The envelope marked "return white original to the DMC" should be included in the 48-hour submission to the DMC. The other envelope should be placed in the patient's notebook.

The eight (8) white (0.5 x 1.75 in.) adhesive labels pre-labeled with the same PID number are used to label photocopies of the local hospital anesthesia record and early (0-2 h) recovery records. Patient identifiers (name, social security number) are to be removed or obscured on these records. These photocopies are provided to the Study Coordinator in the original Study Packet which bears the PID.

a) Access to Envelopes, Patient Notebooks, and Other CRF’s

The Study Coordinator should ensure that the IHAST2 Study Packets (which contain the RANDOMIZATION ENVELOPES), patient notebooks and SCREENING and ELIGIBILITY forms are available at all times to investigating physicians in the trial. Patients may be enrolled at any time, including nights and weekends. Since the color of the RANDOMIZATION ENVELOPE is determined by the DMC at the time the enrollment phone call is made, the Study Packets (which contain the RANDOMIZATION ENVELOPES), patient notebooks, and SCREENING and ELIGIBILITY forms should be readily available to every investigating physician. In particular, the study Anesthesiologist who is responsible for the case must have access to the Study Packets and the following forms:

SCREENING

ELIGIBILITY

2


PRE-SAH HISTORY

POST-ADMIT SCREEN

PRE-OP AND 3 TO 6-HOUR NIH STROKE SCALE

NEUROSURGEON

ANESTHESIOLOGIST

VII.A.4. PCC Correction Report Forms

Each PCC will be supplied with 25 PCC CORRECTION REPORT forms (See Chapter VII.L.3). The PCC CORRECTION REPORT forms are to be used when personnel at the PCC find an error at any one time on a CRF which has already been sent to the DMC. Below are the steps you should follow to complete this form:

Item 1. Name of form being corrected. Write in the name of the CRF found in the upper right side on the first page of the CRF.

Item 2. Complete all applicable header information below. Applicable means list only the header variables from that particular CRF and leave all other header fields in Item 2 blank. For example, on the CONTACT FOLLOW-UP CRF, Patient ID number and Date of follow-up would be answered since they are applicable to the CONTACT FOLLOW-UP CRF, but Center ID number, Log number, and Time of exam or onset would be left blank since they are not applicable to this particular CRF.

Item 3. Indicate which field(s) you wish to correct below, the old value, and the new correct value. Field to be corrected should be a few words describing the field; Old value is the erred value; New correct value is the correct value; and Comments provides one line to briefly describe why an error occurred. For example, on the CONTACT FOLLOW-UP CRF, suppose while completing the 3-month follow-up you find additional medical records showing that on the 6-week follow-up an incorrect response was marked. On page 2, item #10, a ‘no’ for “in the time since last contact, has the patient been readmitted to an acute care hospital?” was marked and it should have been a ‘yes.’ Below is how you might fill out Item 3:

3


Item #10 (page 2) Field to be corrected

0 Old value

1 New correct value

Additional medical records found Comments

Comments should be brief, simply describing how the error occured (e.g., transcription error, updated or additional records found later, calculation error, etc.). Lengthy explanations are not necessary. If you find you need more room to write, however, than the Comments line allows, attach a sheet of paper behind the original white copy with identical information from Items 1-3 plus your comments concerning that particular field.

There are two sections available, allowing for two incorrect fields, per PCC CORRECTION REPORT form. If you have more than two errors that need to be corrected, you must fill out another PCC CORRECTION REPORT form with identical information in Items 1 and 2.

Sign your name at the bottom of the CRF, write in your certification number and the date you completed the form.

Return the white original of the PCC CORRECTION REPORT form, and a xerox copy of the corrected CRF and send both to the DMC. If you have more than one page of PCC CORRECTION REPORT form for a given CRF, attach the multiple sheets together before sending it. The canary-colored copy of the PCC CORRECTION REPORT form is for you to keep in your files.

VII.A.5. Site Regulatory Binder

The purpose of the Site Regulatory Binder is to provide a central source to store material and is also used for auditing purposes. This is what should be kept in the binder:

Regulatory Binder Instructions

CCC-DMC Contact Information (telephone numbers, pagers, mail, email addresses, etc.)

Participation form

IRB approval and Approved Consent form: This should include ALL IRB documents, including former versions, modifications and the most recently updated/approved version

Subcontract between your center and the UI

Copy of your Consortium Agreement

Letters describing updates to the Operations Manual (actual updated sections of the manual should be placed in the Operations Manual itself)

Newsletters and Safety Reports: The CCC and DMC will publish and distribute a regular “Newsletter” containing news regarding the progress of the study, as well as an updated summary of various intercurrent events that have been reported to the DMC

Records of completed on-site audits

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Correspondence

VII.A.6. Patient Log Binder

Since it is important to keep a record of all patients who undergo surgery for aneurysm clipping, regardless of eligibility, each PCC must maintain a Patient Log. This consists of a numbered list of every patient that undergoes open aneurysm clipping, along with a notation regarding whether or not they were enrolled. Each entry should be given a sequential number – and the Patient ID # of enrolled patients should be included when appropriate. The collected SCREENING and ELIGIBILITY forms should be used to help compile this list. The following is a list of materials that should go in this binder:

Patient Log spreadsheet

SCREENING form (canary copy) for all non-enrolled patients who have undergone a craniotomy to clip an aneurysm, regardless of whether a subarachnoid bleed has occurred.

ELIGIBILITY form (canary copy) for all non-enrolled patients with SAH.

Note that the white originals of the SCREENING and/or ELIGIBILITY forms for all non-enrolled patients must be sent to the DMC on the last working day of each month.

VII. B DISTRIBUTION OF MATERIALS

The DMC plans to ship the following at the beginning of the IHAST2 trial:

5 or 10 patient notebooks

30 Study Packets containing RANDOMIZATION ENVELOPES

50 SCREENING forms

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50 ELIGIBILITY forms

25 PCC CORRECTION REPORT forms

One Site Regulatory Binder

One Patient Log Binder

The DMC will send each PCC at least five (5) patient notebooks at a time. The DMC will send you another five (5) or 10 patient notebooks when the number of patients randomized at your center shows that you have about half of the supplied notebooks left.

Some CRF’s may never be used from one patient's notebook (e.g., an INTERCURRENT EVENTS form). If you need extras for a different patient, unused forms may be removed from an earlier patient's notebook.

The DMC will also ship 50 SCREENING and 50 ELIGIBILITY forms at a time. The DMC will send you an additional 50 SCREENING and/or 50 ELIGIBILITY forms when the number of forms for your center shows you have only 10 of either one left. Please notify the DMC if you are running low.

Twenty-five PCC CORRECTION REPORT forms will be sent to each PCC at a time. The DMC will send you additional forms at each PCC request.

Each PCC will receive a box of 30 Study Packets containing two RANDOMIZATION ENVELOPES, two (2) small white envelopes and a set of eight (8) white labels that have the same Patient ID numbers printed on them. The DMC will send you another set of 10 Study Packets when the number of patient enrollments for your center shows you have only five (5) Study Packets left.

Each PCC will receive one Site Regulatory Binder shipped at the beginning of the IHAST2 trial.

Each PCC will receive one Patient Log Binder at the beginning of the IHAST2 trial.

If you are running short of a particular CRF or patient notebooks, please notify the DMC at 319-353-5978.

VII. C GENERAL GUIDELINES FOR COMPLETING CASE REPORT FORMS

VII.C.1. Once Randomized, Data Collection Continues

It is important to remember that once a patient is randomized, all assessments must continue as scheduled, and all CRF’s must be completed. If it is discovered that the patient was misrandomized, all assessments must continue, whether or not the aneurysm surgery continues. A three-month follow-up must also be done.

If the patient refuses follow-up or dies, complete all forms up to the time of refusal or death including a DEATH/PATIENT WITHDRAWAL form and all associated INTERCURRENT EVENTS forms.

VII.C.2. Recording Data on Case Report Forms

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Forms must be completed in blue or black ink. Remember that as you are writing you are making a copy that will remain in the patient's notebook. Please press firmly so that the copy will be legible.

The patient's name should appear in full only on the IHAST2 CONTACT sheet that the PCC keeps for their records. The DMC cannot receive any personal identifiers except the Center ID, the Patient’s ID and Patient Log number.

Most forms have boxes to be checked - either an "X" or a check mark is appropriate. The small numbers next to each box are used in data entry to indicate which response was checked.

For “Specify” or “Other” a box may be provided for written answers. This information will be entered into the database so answers need to be printed legibly so that the key entry person can easily read them. Illegible entries will result in follow-up calls and correspondence that will take your valuable time. Please help us avoid this.

Every question on every form must be completed unless a question instructs you to answer subsequent questions based on a particular condition (see Chapter VII C.5 for examples).

a) Zero-fill

Whenever a series of blanks are available for an answer, fill all spaces. This is partly because the computer requires all allocated spaces to be entered. This is also because we may not always know what you mean for an answer.

1. Example of incorrect way – data entry system looks for five numbers not three

__ __ 1 0 0 ml Total crystalloid (isotonic, hypotonic, or hypertonic)

2. Another example of incorrect way – is this 100 or 10,000?

1 0 0 __ __ ml Total crystalloid (isotonic, hypotonic, or hypertonic)

3. Example of correct way – zero fill

0 0 1 0 0 ml Total crystalloid (isotonic, hypotonic, or hypertonic)

b) Dates

All dates must be entered using the month, day, year format. All entries are numeric. The data system will not recognize dates entered with the months spelled-out or abbreviated. Because of Y2K, we are asking that you enter the full year.

For example the date field will be coded as __ __/ __ __/ __ __ __ __

For March 1, 2000 you should enter 03/01/2000

Remember that the leading zeros are required.

7


The PRE-SAH HISTORY form asks for the dates of events that may have occurred some time before the current SAH. Please make every attempt to provide an accurate date. If this is not possible then do the best you can to approximate the date. In any case, please fill out the full date field. If it is impossible to obtain a valid approximation to the date then please fill in the blanks with zeros, i.e. 00/00/2000 and write to the side of the field telling us why you were unable to obtain a plausible value for that date.

c) Daily Post-op Screen and Medications (tabular forms)

The DAILY POST-OP SCREEN records the patient's postoperative condition for the first 14 days following surgery and at discharge. The MEDICATIONS form covers the same period but includes columns to record pre-sah and post-admit (but pre-operation) medications. Both forms are set up in a grid-like (spreadsheet) manner where each column represents a separate time frame and each row represents a new question for the DAILY POST-OP SCREEN or a different medication for the MEDICATIONS form. If the answer to a question or medication use is a ‘yes,’ place an ‘X’ in the box pertaining to the answer in the column for that time frame (see Chapter VII. C. 5). Otherwise, leave the space blank.

d) Correcting Mistakes

Correct a mistake by drawing a single horizontal line through the incorrect response and checking or writing in the correct response. Initial and date the correction. In addition, initial and date any questions answered later, i.e. after the original form was completed and submitted to the DMC. Any incorrect response must be clearly readable; do not use whiteout. For example, suppose blood glucose on the Anesthesiologist form is recorded as follows:

Blood glucose at definitive

clip placement ( + 20 minutes).*

2 5 0 . 0 X 1 - mg/dL 2 - mmol/L

If the correct blood glucose is 265, the correction would look like this:



265.0 mw 1/8/2000

2 5 0 . 0 X 1 - mg/dL 2 - mmol/L

8


If mg/dL was checked incorrectly, and the blood glucose was in mmol/L, the correction would appear as follows:

9




147.0 mw 1/8/2000

2 5 0 . 0

mw 1/8/2000

X 1 - mg/dL x 2 - mmol/L

10


If the correction turns out to be incorrect, and the blood glucose really was in mg/dL, draw a single line through the correction, and record and circle the new correct response, thus:

11




147.0 mw 1/8/2000

2 5 0 . 0 mw 1/10/2000

mw 1/10/2000 mw 1/8/2000

X 1 - mg/dL x 2 - mmol/L

12


e) Correcting TEMPERATURE Forms

Blinding must be maintained. Necessary changes will be requested of the Study Coordinator by Mr. Rick Peters at the DMC. To maintain blinding, give the envelope containing the canary-colored copy of the TEMPERATURE form to the attending local anesthesiologist.

The coordinator should instruct the anesthesiologist to do the following:

Make the requested changes following usual correction procedures, including initialing and dating each correction.

The anesthesiologist (or someone not associated with the study) should make a photocopy of the corrected form copy and send or FAX the photocopy to Mr. Peters.

The anesthesiologist should then put the corrected canary-colored form copy back in the white envelope or a new envelope with the PID written on it, seal it, and return it to the Study Coordinator to place back into the Patient’s Notebook.

If a Data Edit Report is received by the anesthesiologist for other problems with the TEMPERATURE form, s/he should contact the Local Study Coordinator to obtain the envelope containing the copy of the form and follow the above steps for correction.

VII.C.3. Header Information

At the top of each CRF is a boxed area containing several items of information, called the header. The purpose of the header is to provide information unique to each patient so that duplicate information is not entered into the database. The header must be filled out correctly on each page of the CRF. This is so that if pages of forms get separated, it will be possible to put the pages back together correctly.

a) Patient ID

The Patient ID number is assigned consecutively within each PCC by the DMC. It appears on a label attached to the RANDOMIZATION ENVELOPE and will also be given to you at the time of the enrollment call. The physician or Study Coordinator should peel off this label and place it on the spine of the patient notebook. S/he should also record the Patient ID number at the top of every page of every form s/he fills out.

IHAST2 Patient ID numbers identify patients from the various PCC hospitals. The structure of the Patient ID is as follows:

aa-bbb

aa = PCC identification number

bbb = consecutive patient number at each hospital

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The Study Coordinator should check that the "bbb" section of the ID number on the provided label is the next consecutive number for IHAST2 patients at that hospital. If the label does not show the next consecutive number, the Study Coordinator should notify the DMC at 319-353-5978 of the ID number(s) which was (were) skipped. (Remember that if a patient is enrolled but not randomized that the patient notebook for that patient's assigned ID number will never be used).

Note that for the SCREENING and ELIGIBILITY forms, if a person does not meet criteria for the IHAST2 study, Patient ID should be left blank. Once a patient number is assigned by the DMC automated telephone system it can never be used again. Thus if a patient number is assigned but the patient is not actually randomized (the assigned envelope is not opened) then that number and the patient notebook with that number will not be used in the IHAST2. Please keep the patient notebook with the rest of your notebooks. Please note on the front of the unused notebook that the patient number was assigned but the patient was not actually randomized. This will avoid confusion during the CCC monitoring visits.

b) Center Identification Number

This is a two-digit number assigned specifically to each PCC by the CCC.

c) Patient Log Number

You have been asked to maintain a Patient Log of every patient scheduled to undergo an open craniotomy for clipping an intracranial aneurysm. You will be supplied with a suggested blank log form. There is a space on that form for you to record a sequence number for each patient (a number that counts these patients seen at your hospital during the course of the study). On the SCREENING and ELIGIBILITY forms we call this the log number. When a patient is entered into the study then this number becomes meaningless to us. However, it may be important that the CCC or DMC is able to discuss a nonrandomized patient with someone at your center. We will use this number to help you identify individual patients.

Entries into the Patient Log should be made within 24 hours prior to surgery. In some cases this may not be possible. However, log entries should not be made far in advance of surgery (e.g., when notified that someone will have surgery to clip an unruptured aneurysm two weeks in the future) or long after surgery.

The SCREENING and ELIGIBILITY forms allow for four digits for the log number. This is in case an active hospital will see more than 999 patients during the course of this study. We are asking that you enter this number on the SCREENING and ELIGIBILITY forms so that if the CCC has a question then you will be able to easily identify the patient.

d) Date

The date in the header reflects the date the assessment is performed or, in the case of intercurrent events, the date of the occurrence or onset of the primary intercurrent event. Even if a form is completed after the fact, the form date should be the date of the exam, not the date the form is completed!

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Date in the header, as well as a date required in the body of a form, is always recorded in the format mm/dd/yyyy (e.g., March 5, 2000 = 03/05/2000). The computer requires that a date be entered as 03/05/2000. In order to avoid mistakes and unnecessary misunderstandings please always write in the leading zeros in every date field. (e.g., 03/05/2000 not 3_/5_/00__).

e) Time

The time in the header reflects the time the assessment is performed or, in the case of intercurrent events, the time of onset or occurrence of the primary intercurrent event. Even if a form is completed after the fact, the form time should be the time of the exam or event, not the time that the form is completed!

Time in the header, as well as any time required in the body of a form, is always recorded based on a 24-hour clock (e.g., 8:15 a.m.= 0815; 2:30 p.m. = 1430; one minute before midnight (11:59 p.m. = 2359; midnight = 0000; 12:01 a.m. = 0001). Thus, the range is from 0000 to 2359.

VII.C.4. Footer Information

At the bottom of each CRF is an area containing several items of information, called the footer. The purpose of the footer is to identify information pertaining to the person who filled out the form and when the form was filled out. The footer must be filled out correctly on each page of the CRF.

a) Initials of Person Completing the Form

The initials of the person who completes the form is required at the bottom of every page of every form excluding the last page where a signature is required. The initials should be in the format of first, middle, last. If there is no middle name, put the initials for the first and last name together. If there are two middle names, put the initials for the first name, the first middle name, and the last name together. Rule of thumb is to take the initial for the first name to show up in each position.

Example for John William Smith would be JWS

Example for John Smith (w/o a middle name) would be JS

Example for John Alan William Smith (two middle names) would be JAS

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b) Signature

The signature of the person who is responsible for the data being recorded and/or who completes the form is required on the last page of every form.

c) Certification Number

Prior to beginning the trial, the Study Coordinator and physicians who evaluate IHAST2 patients are assigned a certification number by the CCC. The certification number of the individual who completes the form and/or is responsible for the data being recorded should be placed here.

d) Form Completion Date

The date in the footer on the last page of every form reflects the date the form is completed. The date in the footer, as well as a date required in the body of a form, is always recorded in the format mm/dd/yyyy (e.g., January 1, 2000 = 01/01/2000). The computer requires that a date be entered as 01/01/2000. In order to avoid mistakes and unnecessary misunderstandings please always write in the leading zeros in every date field. (e.g., 01/01/2000 not 1_/1_/00__).

VII.C.5. Types of Data Collection Item

a) Example with No-Yes

Do not fill out the date if you check No.

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b) Example with No-Probable-Definite data.

Only fill out follow-up questions if you check response 1 (Probable) or 2 (Definite).

If a list of items appears with column headings (e.g., no, yes, unknown), every item in the list must have an answer. This also allows multiple items to be selected for a particular question.

c) Lists - Example with No-Yes options.

How was contact made?

No Yes

0 1 Telephone?

0 1 Hospital or clinic visit?

d) Lists - Example with No-Probable-Definite

No Probable Definite

0 1 2 Prior history of epilepsy?

0 1 2 Prior history of cognitive or psychiatric disease?

Note: Answer all items

e) Lists - Example with categorical data

Which follow-up is this?

1 6 week

2 3 month

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Note: Answer only one item

f) Unknown or Questionable Items

In general, every item on a form must have a response unless specifically instructed on the form not to answer the item(s). If an answer is "unknown,” leave the answer missing and write off to the side why the answer is missing. For example:

No Yes

0 1 Physical therapy since last contact? No records available and patient doesn’t remember

g) Tabular Forms

MEDICATION form. Place X’s in boxes where medications of the designated category have been administered since the previous days evaluation. If a medication in a given category has not been given, leave box blank.

Postoperative Daily

MEDICATION CLASS

PRE-

SAH

POST-

ADMIT 24h 48h 72h 4 5

Analgesics(opioids, NSAIDS, acetaminophen)

X X X X X

Anesthetics (thiopental, etomidate, pentobarbitol)

Sedative or Anxiolytic (benzodiazapine, etc)

X X

Anticonvulsants (phenytoin, phenobarbitol)

X X X X X

Antiemetics (odansetron, metoclopramide)

X X X

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DAILY POST-OP SCREEN form: Place X’s in boxes where the answer to any question is yes.

Post-operative Daily Screen

24h 48h 72h 4 5 6

1. What is today’s GCS?1 | 1 1 | 2 1 | 5 1 | 5 1 | 5 0 | 8

2. Did patient meet criteria for DIND or clinically symptomatic vasospasm?

X

3. Is the patient currently in an intensive care environment?

X X X

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VII. D CASE REPORT FORMS TO BE COMPLETED BY STUDYCOORDINATOR

Form Pre-oper-ative

Intra-oper-ative

3-6-

Hour

24-

Hour

48-

Hour

72-

Hour

Day

4-14

D/C 6 Wk. 3 Mo.

SCREENING X

ELIGIBILITY X

CONTACT X

PRE-SAH HISTORY X

POST-ADMIT SCREEN X

NIHSS X X (X) (X) (X)

MEDICATIONS X X X X X

DAILY POST-OP SCREEN X X X X X

CONTACT FOLLOW-UP X X

OUTCOME FOLLOW-UP X

INTERCURRENT EVENTS

As indicated and appropriate

DEATH/PATIENT WITHDRAWAL

As indicated and appropriate

(X) Although it is greatly preferred that the Neurologic Examiner perform the 24-hour, 72-hour, and discharge NIHSS exams, this may be done by the Local Study Coordinator if s/he remains blinded to group assignment.

For a complete summary of who can fill out each form, please refer to the Task Personnel spreadsheet in Chapter VII.J.

VII. E CASE REPORT FORMS TO BE COMPLETED BY CERTIFIED IHAST2 PHYSICIANS

NEUROSURGEON form – to be completed by the operating neurosurgeon only, at the time of surgery.

ANESTHESIOLOGIST form – to be completed by the attending anesthesiologist only, at the time of surgery

TEMPERATURE form – to be completed by attending anesthesiologist only, at the time of surgery

In addition, either the Neurosurgeon or Anesthesiologist MAY complete all preoperative forms as well, as per local arrangement.


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VII. F CASE REPORT FORMS TO BE COMPLETED BY NEUROLOGIC EXAMINERS

NIHSS at 24 hours, 72 hours, discharge and 3 months (although not recommended, if necessary, the 24 hours, 72 hours and discharge forms may be completed by the Local Study Coordinator if s/he is not aware of temperature group assignment).

OUTCOME FOLLOW-UP at three months.

In addition, the Neurologic Examiner MAY complete the pre-op and 3 to 6-hour post-op NIHSS forms, as per local arrangement.


VII. G CASE REPORT FORMS TO BE COMPLETED BY NEUROPSYCHOLOGISTS

BENTON VISUAL RETENTION

CONTROLLED ORAL WORD ASSOCIATION

COMPLEX FIGURE TEST

GROOVED PEGBOARD TEST

TRAIL MAKING A AND B TEST

MINI MENTAL STATE EXAM

All of the tests are performed at the three-month follow-up.

VII. H DMC REPORTS TO PCC, CCC, ETC.

VII.H.1. No Patient Randomization Status Call

If the 24-hour patient randomization status call is not made to the DMC for an enrolled patient, then a report (See Appendix) is sent via e-mail to the PCC Study Coordinator. Note that the call must be made even if the envelope was not opened. If there is some reason why a call cannot be made, please contact the DMC at 319-353-5978.

VII.H.2. IHAST2 Patient Calendar

Once the patient randomization call is made to the DMC confirming the patient was randomized, a 3-month Patient Calendar report (See Appendix) is produced and sent via e-mail to the PCC Study Coordinator. This patient calendar lists when the 6-week and three-month follow-up contact should occur based on the enrollment call. It also lists out the names of the CRFs, the dates they should be filled out, and the dates they are due at the DMC.

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VII.H.3. Weekly Patient Summary Report

This report (See Appendix) will be sent to each PCC Study Coordinator via e-mail so it arrives by early Monday each week. This memo lists the number of enrolled patients for the PCC, patients for whom no data has been received, appointments that need to be scheduled, CRFs and DER questions that need to be completed, and patient(s) for whom a randomization status call has not been made.

VII.H.4. Data Edit Reports

The Data Edit Reports (DERs) allow the DMC to question the PCC about the validity of data they have submitted. A report of the entered CRFs will be generated twice each week and sent to the PCC by email. The contents of the DERs are explained in detail in Chapter VII.L.3.

VII.H.5. Update Newsletter

The Update newsletter is posted on the IHAST2 website at http://ctsdmc.public-health.uiowa.edu/ihast2/, and each PCC will be notified via email when a new Update newsletter has been posted. You must have an IHAST2 certification number to access the Update newsletter. This newsletter will be produced at least on a quarterly basis. Among other things, the newsletter will discuss scientific issues concerning the study, patient enrollment and study compliance, upcoming events, updates to the IND Safety Reports, and data management issues.

VII. I DATA SUBMISSION/COLLECTION

Data should be sent to the DMC at three time points in each patient's follow-up period. These three points are: a) Within 48 hours after the completion of surgery, b) within seven (7) days of hospital discharge, and c) within 30 days after the final three-month follow-up examination. In addition, page 6 of the ANESTHESIOLOGIST form and IE forms involving Severe or “Indicator” events should be faxed immediately to the CCC. For patients not enrolled in IHAST2, accumulated SCREENING and ELIGIBILITY forms should be submitted on the last working day of the month to the DMC. For patients enrolled but not randomized (randomization envelope was not opened), SCREENING and ELIGIBILITY forms should be completed. Also, the header, items A.1, A.2, A.3 (if applicable) and the footer on page 1 and the header and footer on page 6 of the ANESTHESIOLOGIST form should be completed. If A.3 is applicable, please provide a brief explanation of why the patient was not randomized in the space provided. Within 48 hours, these forms should be returned along with the Study Packet containing both UNopened RANDOMIZATION ENVELOPES. Finally, the CONTACT forms should never be sent to the DMC or CCC.

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Submission Intervals

Form48-hour post-op

14-days post-op or

D/C3-month Immediately

Monthly (not case linked) Never

SCREENING X

SCREENING (ineligible pts) X

SCREENING (enrolled but not randomized pts)

X

ELIGIBILITY X

ELIGIBILITY (ineligible pts) X

ELIGIBILITY (enrolled but not randomized pts)

X

CONTACT X

PRE-SAH X

POST-ADMIT SCREEN X

NIHSS (pre-op, 3 to 6-hr, 24-hr)

X

ANESTHESIOLOGIST (include with the 48-hour postoperative submission, the anesthesia record and 0-2 hr critical care/recovery records)

SECTIONS A-H, p. 1-6 X

SECTION H, p. 6 (Fax) X

ANESTHESIOLOGIST (enrolled but not randomized pts) PAGES 1 & 6 ONLY

X

TEMPERATURE X

NEUROSURGEON X

DAILY POST-OP SCREEN X

MEDICATIONS X

NIHSS (72-hr, D/C) X

CONTACT FOLLOW-UP (6-week and 3-month)

X

OUTCOME FOLLOW-UP (6-week and 3-month)

X

NIHSS (3-month) X

NEUROPSYCHOLOGY X

INTERCURRENT EVENTS

Routine X (only if resolved)

X X

Severe/Indicators Immediately FAX to the CCC, Paper Copy to DMC with next scheduled submission


Immediately FAX to the CCC, Follow-up Paper Copy to DMC

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VII. J TASK PERSONNEL SPREADSHEET

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Form Name or Task Who will USUALLY complete it

Who MAY complete it

SCREENING SC Any certified IHAST2 participant may complete this form. Usually a certified -NS or -AN will complete this form if certified-SC is not available.

ELIGIBILITY SC or -AN Any certified IHAST2 participant who is qualified to make Rankin, GCS, and WFNS assessments. Any certified -NS, -AN, or -NE may also complete this form if they are Rankin, GCS, and WFNS qualified. (All certified-ANs are GCS and WFNS qualified).

NIHSS (Pre-op) SC or -NE Any certified IHAST2 participant who is qualified to make NIHSS assessments. Any certified -NS or -AN may also do this assessment if they are also NIHSS qualified.

CONTACT SC Any certified IHAST2 participant may complete this form. Usually a certified -NS or -AN will complete this form if certified-SC not available.

PRE-SAH HISTORY

SC or -AN Any certified IHAST2 participant. Usually this form would be completed by the certified-SC or-AN. However any certified -NS or -NE may also do this.

POST-ADMIT SCREEN

SC or -AN Any certified IHAST2 participant. Usually this form would be completed by the certified-SC or-AN. However any certified -NS or -NE may also do this.

Enrollment call SC or -AN Any certified IHAST2 participant. Usually this call would be completed by the certified-SC or-AN. However any certified -NS or -NE may also do this.

NEUROSURGEON NS only Only the certified-NS who performs the primary aneurysm surgery may complete the form. All certified- NS are to have completed the Neurosurgeon qualification exam.

ANESTHESIOLOGIST

AN only Only the certified-AN who cares for the patient during the primary aneurysm surgery may complete the form. All certified-ANs are required to be GCS and WFNS qualified, and to have completed the Anesthesiologist's qualification exam.

TEMPERATURE AN only Only the certified-AN who cares for the patient during the primary aneurysm surgery may complete the form. Once completed, it is sealed in an envelope and may not be seen by anyone.

NIHSS (3h to 6h Postop)

SC If the primary SC is not available, the first choice for an alternate would be the -NE or another SC. If these are not available, a -NS or -AN may also do this if they are NIHSS qualified AND were not present during the operation nor in the presence of the patient for the first 0-2 hours after leaving the operating room AND are not aware of patient group assignment or intraoperative temperature.

Form Name or Task Who will USUALLY

Who MAY complete it

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complete it

Randomization Status call

SC Any certified IHAST2 participant; usually a certified -NS or -AN if certified-SC not available.

DAILY POST-OP SCREEN

SC Any certified IHAST2 participant who is qualified to make GCS assessments. If the certified-SC is not available, any certified -NS or -AN may also do this if they are GCS qualified AND were not present during the operation nor in the presence of the patient for the first 0-2 hours after leaving the operating room AND are not aware of patient group assignment or intraoperative temperature.

INTERCURRENT EVENTS

SC Any certified IHAST2 participant. If the certified-SC is not available, any certified -NS or -AN may also do this if they were not present during the operation nor in the presence of the patient for the first 0-2 hours after leaving the operating room AND are not aware of patient group assignment or intraoperative temperature. EXCEPTION: The certified-AN caring for the patient during the primary aneurysm surgery should complete all IE forms pertaining to intraoperative and/or early postoperative (0-2 h) events (page 6 of the ANESTHESIOLOGIST form).

MEDICATIONS SC Any certified IHAST2 participant. If the certified-SC is not available, any certified -NS or -AN may also do this if they were not present during the operation nor in the presence of the patient for the first 0-2 hours after leaving the operating room AND are not aware of patient group assignment or intraoperative temperature.

NIHSS (24, 72h & Discharge)

SC or -NE If the primary SC is not available, the first choice for an alternate would be the -NE or another SC. If these are not available, a -NS or -AN may also do this if they are NIHSS qualified AND were not present during the operation nor in the presence of the patient for the first 0-2 hours after leaving the operating room AND are not aware of patient group assignment or intraoperative temperature.

CONTACT FOLLOW-UP (6wk)

SC Any certified IHAST2 participant. If the certified-SC is not available, any certified -NS or -AN may also do this if they were not present during the operation nor in the presence of the patient for the first 0-2 hours after leaving the operating room AND are not aware of patient group assignment or intraoperative temperature.

OUTCOME FOLLOW-UP (6wk)

SC Any IHAST2 participant who is qualified to make Barthel's, Rankin, and GOS assessments. If the certified-SC is not available, any certified -NS or -AN may also do this if they are Barthel's, Rankin, and GOS qualified AND were not present during the operation nor in the presence of the patient for the first 0-2 hours after leaving the operating room AND are not aware of the patient's temperature group or intraoperative temperature.

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Form Name or Task Who will USUALLY complete it

Who MAY complete it

CONTACT FOLLOW-UP (3mo)

SC Any certified IHAST2 participant. If the certified-SC is not available, any certified -NS or -AN may also do this if they were not present during the operation nor in the presence of the patient for the first 0-2 hours after leaving the operating room AND are not aware of patient group assignment or intraoperative temperature.

OUTCOME FOLLOW-UP (3mo)

NE only Only the certified-NE may perform this exam.

NIHSS(3 months) NE only Only the certified-NE may perform this exam.

NEUROPSYCH (3mo)

NPE Any certified IHAST2 participant who is qualified to administer neuropsychologic tests. This person CANNOT have been present during the operation nor in the presence of the patient for the first 0-2 hours after leaving the operating room AND must NOT be aware of the patient's temperature group or intraoperative temperature. The SC may NOT perform this evaluation. These tests may be administered by the 3-month NE if he/she is qualified to administer these tests, but they must be under the supervision of the coordinating NPE.


SC and Local PI

Usually this form would be initiated by the certified-SC. However, the local PI and/or Co-PI (certified-NS or -AN) are required to complete the narrative section.

Legend: SC = Study Coordinator; AN=Anesthesiologist; NE=Neurologic Examiner; NS=Neurosurgeon; NPE=Neuropsych Examiner. Items in ALL CAPS/BOLD refer to forms in the Patient Notebook.

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VII. K HOW TO SHIP CASE REPORT FORMS TO THE DMC

For each phase, you will need to send the appropriate CRFs to the DMC. Place the CRFs in a 10” x 12” (or 2.56 x 3.05 cm) envelope, put the pre-addressed labels on the envelope addressed to the DMC that was provided to you at the beginning of the IHAST2 study, and Fed/Ex or mail it to us right away.

VII. L THE IHAST2 DATA MANAGEMENT SYSTEM

VII.L.1. Overview

The IHAST2 data processing system has been developed to ensure the efficient, accurate, and secure processing of study data. All data entry, data editing, and data analysis will be run on systems at the DMC. The database system runs on Microsoft SQL Server that is located in a locked and protected room. The system is backed-up every night and weekly copies of the back-ups are maintained off-site.

The data system supports data entry, data editing, error correction, report generation, and data analysis. The database system also supports multi-level editing processes that are designed to detect invalid values through range and value checks, logical consistency checks within forms, and logical consistency checks between forms.

The data system is based on paper CRF’s with central key entry. Each CRF is printed on carbonless (NCR) paper that provides an original (white) copy to be sent to the DMC and a canary copy to be stored in the official patient notebooks. Submission schedules and submission processes were discussed in previous parts of this section. Every change to any value on any form in the database is recorded by an "audit trail" system that allows us to track any change to any data item any time during the study.

A patient is entered into the study when the automated telephone randomization system provides a Patient ID number and envelope color to the PCC. If the DMC does not receive a randomization status call within 24 hours the PCC will be contacted to see why the call has not happened. Once a patient is confirmed as having been randomized then s/he is entered into the IHAST2 database. In order to successfully complete the planned intention-to-treat analysis all forms on all randomized patients must be included in the database.

VII.L.2. Data Quality Assurance

All forms will be logged into the system as soon as they are received at the DMC. Data will be entered and double entry verified at the DMC. In order to control key entry mistakes, the data entry system will perform validity and range checks on every data item. However, if an invalid value has been entered as it is on the form then the value will be entered into the database. Errors will be identified and corrected in the data editing process.

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The IHAST2 data quality assurance system (Query system) will question the local PCC concerning impossible, unusual, or inconsistent values. We have invested considerable time in developing and testing edit criteria that will identify impossible and incorrect values. Please note that many of these queries, particularly those concerning unusually high or low values, will result in the PCC confirming that the original value is valid. However, in order to eliminate invalid values, some valid values will be queried. Edit criteria will be "tuned" as the study goes along so that we can avoid unnecessary queries and minimize the load on the PCC Coordinators.

As soon as a form is entered into the database, the query system edits all values on the form. This edit process includes range and impossible value checks. It also examines values for consistency within a form and across forms. If a data value "fails" an edit criterion then a query is entered into the systems question table. The database question table will identify the exact form and item that generated the exception and will include an informative message that should help the DMC and PCC resolve the query.

VII.L.3. The Data Edit Report

Twice weekly, the DMC will generate a Data Edit Report (DER) of the entered CRFs for each PCC. The DER will list all queries for that PCC that have been generated since the last report. Because we do not want to generate confusion by including the same query on two DERs, unresolved queries from previous reports will not be included in a new report. Similarly, while it is possible for one value to generate many questions, the DER will not contain more than one query for any data value. If a value is in question, no intra- or inter-form logic checks using that value will be performed.

The DER report (See Appendix) will list each specific data value that is being questioned and a message that will describe why the item is being questioned. These reports will be e-mailed to the PCCs. The report will provide a blank space for the Study Coordinator to state that the value is correct as it is on the form or incorrect and needs to be changed.

As soon as possible, but within two weeks of receiving the DER, the Local PCC Study Coordinator should resolve all of the questions in a DER. For each question on the DER, s/he should mark either that the value is correct or incorrect. It is vital that the database at the DMC agrees with the CRFs in the patient notebooks. All corrections should be recorded on the PCC copy of the CRF, and all changes should be initialed and dated on the form by the person making the correction. The Study Coordinator should make sure that all changes are clearly entered, initialed, and dated. The Study Coordinator should then make a photocopy of each page of any form that contains a corrected value and send the copies along with the completed DER to the DMC.

Occasionally, a PCC Study Coordinator or other staff member will discover a problem that the Query system has not identified. When this happens, the PCC Study Coordinator should fill out a PCC CORRECTION REPORT (see Chapter VII.A.4). S/he should indicate the exact form and value that needs to be changed and provide the corrected value. S/he should include a photocopy of the corrected form with the original (white) copy of the PCC CORRECTION REPORT when s/he sends it back to the DMC.

30


If the PCC Study Coordinator has any questions about a query or how to resolve the query, s/he should e-mail Michelle Wichman or Diane Anderson at [email protected] or phone the DMC at 319-353-5978. DMC staff may also call a Local PCC Study Coordinator if they have questions that can be resolved over the telephone.

The DMC will log and process all DERs as soon as they are returned. DMC staff will mark values that are confirmed as valid values and inactivate the associated error messages in the Query system. Staff will also enter all corrections using the data system's Question Manager. A change in any value could cause inconsistencies with other values that have already been entered. Also, no logical checks are performed on a value that has already generated a query. Therefore, it is necessary to re-edit any form where a correction has been made. Newly created queries will be included in the next DER for the PCC.

VII.L.4. On-Site Audits

The data quality assurance system includes more than just the Query and Question Manager systems. The on-site audits are an important part of the system. During each audit, data from the database for randomly selected patients at the PCC will be compared to what is recorded on the copy of the CRF at the PCC. If the system works, the database should reflect what is on the PCC copy of the forms. If the monitor finds significant disagreement then the DMC will work with the PCC to determine why the discrepancies are occurring. This could lead to an on-site audit from the DMC and a complete review of all data at the PCC.

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mailto:[email protected]


VII. M COMMUNICATION

E-mail

Best way for PCC to ask questions to the DMC or CCC (DMC will be sending reports this way)

DMC email address is [email protected]

CCC email address is [email protected]

Phone

For longer, more complicated questions from PCC to the DMC or CCC

DMC will use this when immediate answers are needed

DMC phone number is 319-353-5978

CCC phone number is 319-356-0461

Fax

Page 6 of the ANESTHESIOLOGIST form must be faxed to the CCC by the Study Coordinator

CCC fax number is 319-384-8072

DMC fax number is 319-335-6535

Mail/FedEx

All forms to be sent to DMC by mail from PCC

DMC will send patient notebooks and updates to the notebooks and/or Operations Manual through mail media

Send forms to:

Data Management Center

2215 Westlawn Building

Department of Biostatistics

University of Iowa

Iowa City, Iowa 52242

Internet

Comment fields on CRF’s will be entered via web-based data entry system (See Appendix).

DMC web address is http://ctsdmc.public-health.uiowa.edu/ihast2/comment/

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http://ctsdmc.public-health.uiowa.edu/ihast2/comment/




If you have medical or patient eligibility questions, please refer them to Dr. Todd or Dr Hindman at 319-384-7116. If you have questions on how to fill out the forms, when forms are due, and how to correct data on a form please refer them to Michelle Wichman or Diane Anderson at 319-353-5978.

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CHAPTER VIII. DETAILED PROTOCOL

VIII. A OVERVIEW

This is a multicenter, prospective, randomized (and stratified), partially blinded clinical trial intended to assess the impact of intraoperative mild hypothermia on neurologic outcome in adult patients with recent subarachnoid hemorrhage (SAH) undergoing open craniotomies for clipping/occlusion of an intracranial aneurysm. Intraoperative anesthetic management will be standardized, with temperature management performed with surface cooling/warming methods. Postoperative care will be conducted as per standards within each PCC, but will be followed/documented daily for 14 days and/or until discharge. Patients will be followed by telephone contact and clinic visits until a final visit and examination at three months after surgery. The primary outcome variable is Glasgow Outcome Score (GOS) at three months, with secondary outcome variables being place of residence, employment status, NIH Stroke Score, Rankin Disability Score, Barthel’s Activities of Daily Living Score, and a battery of neuropsychological tests.

VIII. B PATIENT RECRUITMENT/STUDY ACTIVATION

Each PCC will be responsible for establishing its own procedures for ensuring that study personnel are notified promptly of ALL patients scheduled to undergo any open procedure for the clipping of an intracranial aneurysm. Notification must not be selectively based on “presumed eligibility (or ineligibility).” [In other words, “this patient doesn’t look eligible, I don’t think I’ll call anyone.....”] Ideally, study personnel should be notified of everyone scheduled to undergo surgery - and the decision regarding eligibility should be made after such notification. In most cases, notification will come from a member of the neurosurgical team, but can come from anyone.

Since these patients may be admitted or undergo surgery at any time of the day or night, some form of 24 hour-per-day “call system” must be in place.

VIII. C INITIAL ASSESSMENT/PATIENT ELIGIBILITY

Upon notification, the initial determination to be made is whether or not the patient has suffered a subarachnoid hemorrhage (SAH) within no more than 14 days prior to the date of planned surgery.

If the patient has NOT suffered a SAH, but is scheduled to undergo surgery for an unruptured aneurysm, only the initial SCREENING form need be completed and sent to the DMC. No other information will be collected on such patients. Details regarding the completion of the SCREENING form can be found in Chapter IX.A of this manual.

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If the patient has suffered a SAH within the designated time frame, the patient must be personally evaluated by a certified IHAST2 participant, most commonly the Study Coordinator or Investigator (Neurosurgeon or Anesthesiologist). All information on the ELIGIBILITY form must be completed on all patients with a proven SAH, regardless of whether or not they are deemed eligible for entry into the trial. Patient eligibility criteria are listed below:

VIII. D SPECIFIC ELIGIBILITY CRITERIA

Adult (age >18 yrs) patients must be scheduled to undergo an open craniotomy to clip an angiographically demonstrable intracranial aneurysm. They must have suffered a subarachnoid hemorrhage (proven by CT or lumbar puncture) no more than 14 days before surgery, during the same hospitalization (i.e., patients cannot be discharged and readmitted for elective surgery).

Patients must have a World Federation of Neurologic Surgeons (WFNS) Score of I, II or III, as assessed no more than 12hrs before surgery, and verified on arrival in the O.R.. We will exclude WFNS Grade IV and V patients, to avoid “diluting” the patient population with individuals who are unlikely to have a detectable benefit from the trial intervention.

Patients must have a baseline, pre-SAH Rankin disability score of 0 or 1, as determined by history obtained from the patient or family. We wish to exclude patients with serious pre-SAH disabilities (e.g., related to a prior stroke) which would complicate our assessment of changes related to the primary SAH and surgery. Note that a Rankin score of 2 or greater need not be due to neurologic disease; a patient with a Rankin score of 3 due to debilitating arthritis is “equally ineligible” as one with a similar score due to an old stroke.

Patients must not be endotracheally intubated at the time of their presurgical assessment. The presence of an endotracheal tube makes it very difficult to perform an accurate preoperative assessment, in particular to assign a NIH Stroke Score. [Some patients are intubated before or immediately after hospital admission. If early surgery is planned, patients are often sedated and the ET-tube left in place, rather than extubate the patient only to reinsert the tube a few hours later in the O.R.]

Patients must not have a body-mass-index (BMI, equal to weight in kg divided by the square of the height in meters: W/H2) greater than 35 kg/m2. Based on the pilot trial, obese patients cannot be cooled within a reasonable time frame, using the methods available. Cooling of such obese patients may be possible with more “invasive” measures (cold IV fluids, iced gastric lavage, extracorporeal heat exchangers etc.). However, we would prefer at this time to define the benefit of cooling before subjecting obese patients to additional risks that accompany such efforts.

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Patients must not suffer from any disorder that, in the opinion of a local participating physician (either neurosurgeon or anesthesiologist) constitutes a contraindication to cooling (e.g., cryoglobulinemia or severe Raynaud’s disease) or to the protocol anesthetic (e.g., a history). Exclusion by the operating surgeon or Anesthesiologist for other reasons, (e.g., severe heart disease, severe obstructive lung disease, allergies/, pre-existing severe psychiatric disease, etc.) must be justified on the ELIGIBILITY form by the local principal investigator.

a) Comment: Medical Contraindications

Comment: There are no “absolute” medical contraindications to participation, except perhaps a clear history of malignant hyperthermia that would make performance of the designated anesthetic impossible. The simple presence of ischemic heart disease, occlusive cerebrovascular disease, congestive failure, Raynaud’s disease, COPD, etc. does not immediately make a patient ineligible. Decisions in this area must be made by the local physicians, based on their best judgments. We anticipate that this may vary from PCC to PCC and from patient to patient, and may be based on sometimes poorly describable factors. For example, one patient with a history of ischemic heart disease may be deemed suitable for trial enrollment by a given physician, while another patient with a similar history, may be deemed ineligible by another physician. Similarly, one patient with COPD may be deemed eligible, while another patient with both COPD and renal failure may be judged ineligible. We urge local physicians to use their best judgment, but attempt to be consistent. On one hand, casual exclusion of patients for minor medical disorders may result in a PCC being dropped from the study. On the other hand, repeated inclusion of patients in whom major questions are present regarding suitability may also result in questions being asked and/or a PCC being dropped. In most cases, the decision to exclude a patient should be based on a judgment that randomization to the hypothermic group would represent an unacceptable risk. Note: if a patient were deemed medically ineligible, but then undergoes surgery with hypothermia “outside” the trial, we would probably judge this as a serious error on the part of the investigators.

Patients must have nimodipine therapy planned for the postoperative period (although patient-related circumstances, e.g., hypotension, may result in this decision being changed after administration of one or more doses).

Patients must not be enrolled in any other trial of a pharmacologic agent intended to influence neurologic outcome after SAH.

Appropriate, certified study personnel must be available to manage surgery and anesthesia, and to provide postoperative follow-up. In addition, the patient should be “available” for such follow-up. In other words, if a patient were otherwise eligible, but it was anticipated that the patient would return to Saudi Arabia after surgery and hence not be available for the three-month postoperative exam, they should not be enrolled.

IRB - approved, witnessed written consent must be obtained from either the patient or his/her next of kin, or consenting person, before trial entry.

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Comment: Patient conditions often change rapidly after an SAH. Many patients, on admission, may be deemed ineligible, for example due to a poor WFNS score. However, if conditions improve, such a patient may become eligible. Note, however, than in no circumstances should surgery be delayed solely for the purpose of allowing a patient to “improve” and hence become eligible.

Comment: If you are uncertain about whether some characteristic of a given patient renders them ineligible, please contact a physician-investigator or coordinator at the CCC. Someone will be “on-call” 24 hours-per-day to answer your questions. Note that this call should not be made concerning “medical exclusions” (i.e., issues discussed in section D.a. above); these medical decisions can only be made by Local PI.

VIII.D.1. Consent and Enrollment

When all eligibility criteria have been verified, written informed consent must be obtained from either the patient or from legal next of kin or consenting person. Consent should be obtained from whichever individual was deemed qualified to sign the consent for surgery.

After consent is obtained, the Study Coordinator or other certified individual (neurosurgeon or anesthesiologist) must call the computerized randomization system located at the DMC. This call must be made no more than two hours prior to the time of planned surgery. The computerized system will be active 24 hours per day, and can be reached via a designated, dedicated phone line. The caller should have their individual certification number and the completed ELIGIBILITY form immediately available when s/he initiates the enrollment call. For additional information, please see Chapter VI of this manual.

When the telephone is answered, the caller will be asked a series of questions designed to identify the caller, the PCC from which the call is placed, and to verify patient eligibility. If appropriate responses are obtained, the number and color of the assigned RANDOMIZATION ENVELOPE (kept in a Study Packet with the same number) will be provided. This number and color must be recorded on page 3 of the ELIGIBILITY form.

IMPORTANT: The assigned RANDOMIZATION ENVELOPE MUST NOT be opened at this time, but simply provided to the certified Anesthesiologist who will be responsible for the patients intraoperative care. The Anesthesiologist also MUST NOT open the RANDOMIZATION ENVELOPE until after anesthesia has been induced.

a) Enrollment Questions

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IMPORTANT: If, at the time the enrollment call is made, the computerized system “refuses” to issue an envelope number, and if you believe that the patient is indeed eligible, you will be given the pager number or telephone number of one of the Iowa physician-investigators (most commonly Dr. Todd or Dr. Hindman). In such an event, you should immediately dial that number and speak with the physician-investigator. If they agree that the patient is indeed eligible, they will provide you with an “override code.” The DMC enrollment number should again be called and the override code entered. The system will then issue you an envelope number/color. Similarly, if you suspect in advance that the system will refuse to permit enrollment (e.g., if the answer to one of the eligibility questions is “no” but you believe that this should not render the patient ineligible), you may contact the physician-investigator BEFORE making the call to the enrollment system.

Once eligibility has been ascertained, the enrollment call made, and an envelope number and color has been assigned, the Study Coordinator should complete the CONTACT form. Detailed information on the completion of this form can be found in Chapter IX.C of this manual.

b) Enrollment Follow-up

Comment: The date and time of the enrollment call will be logged by the DMC computer. This will trigger a monitoring process. Specifically, all PCC’s will be required to again contact the computerized system no later than 24 hours after this initial call to verify that the assigned RANDOMIZATION ENVELOPE has been opened, and that the patient has indeed been randomized. If this call is not received, the DMC will contact the Local Study Coordinator to inquire as to the patient’s status. This second call will also trigger a series of email/FAX reminders sent from the DMC to the PCC. These reminders are intended to aid the Local Study Coordinator in ensuring that postoperative exams, form submissions, assessments, clinic visits, etc., are performed on schedule.

For additional information on the randomization and enrollment process, please see Chapter VI of this manual.

VIII. E PREOPERATIVE ASSESSMENTS

After consent is obtained, you should then proceed to complete the preoperative assessment questions contained in the PRE-SAH HISTORY and POST-ADMIT SCREEN forms. The information on these forms should be obtained from whatever sources possible; the patient, a family member, a close friend, other medical records, etc.

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The PRE-SAH HISTORY form is equivalent to a “Past Medical History” and deals only with the patient’s medical history prior to the SAH, which resulted in the current hospital admission. Note that while the questions on this form cover most aspects of the medical history, some items may not be asked. The questions are designed to cover issues that we believe may represent significant variables that may influence either neurologic outcome (e.g., a history of prior stroke, prior neurosurgical procedures, etc.), or which may have bearing on certain perioperative complications (e.g., a history of coronary artery disease, respiratory disease, coagulation disorders, infectious diseases, etc.). If you believe that the form “omits” an appropriate question dealing with a disorder/event/procedure of major medical importance for a given patient, please enter this information using the web-based comment system provided by the DMC (See Appendix).

**Detailed directions for completion of the PRE-SAH HISTORY form can be found in Chapter IX-D of this manual.

The POST-ADMIT SCREEN form is designed to characterize events surrounding the actual SAH, and to capture medical/surgical events which occur between the time of the SAH and the primary neurosurgical procedure (the craniotomy to clip the patient’s aneurysm).

**Detailed directions for completion of the POST-ADMIT SCREEN form can be found in Chapter IX.E of this manual.

These two forms should ideally be completed before the start of surgery. However, we realize that this may not always be possible. However, since the forms MUST be completed and submitted to the DMC within 48 hours of surgery, the forms should be completed as quickly as possible following surgery. Since several important items on these forms may need to be obtained from either the patient or close relative, and since the patient may be incapacitated immediately after surgery or since relatives may not be readily available, preoperative completion should be the goal.

In addition to the above, the Study Coordinator should perform an appropriate examination and complete a preoperative NIHSS.

VIII. F ANESTHETIC MANAGEMENT

VIII.F.1. Equipment Required

Bair Hugger® cooling/warming air blanket (“whole body” size)

PolarAir® Forced Air Cooling/Warming Unit -to be provided by Augustine Medical Inc.

Cooling/Warming water mattress with temperature control unit. This mattress is to be on the O.R. bed, under the patient, pre-warmed to 37°C, and covered by at least one sheet.

Cold (4°C, refrigerated) saline or lactated Ringer’s solution (2 liters)

Combination esophageal stethoscope/thermister (Mallinckrodt XL probe) - to be provided by Mallinckrodt Medical

Interfacing cable/device to permit use of above esophageal thermister with local temperature monitoring device(s) - to be provided by Mallinckrodt Medical

A second thermister/temperature measurement probe

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Intravenous fluid warming device(s)

Inspired gas heater/humidifier

Thermometer to measure sublingual or tympanic temperature before induction

VIII.F.2. CRFs/Materials for the Anesthesiologist

The Anesthesiologist will need entire Study Packet (with the unassigned RANDOMIZATION ENVELOPE removed).

While in the O.R., the Anesthesiologist must have:

a) One (1) ANESTHESIOLOGIST form (6 pages).

b) The one (1) sealed RANDOMIZATION ENVELOPE which matches the PID and color assigned to the patient. The contents of the RANDOMIZATION ENVELOPE are to be seen only by the Anesthesiologist.

The RANDOMIZATION ENVELOPE, whose color is provided by the automated randomization system, must not be opened until, 1) after it has been determined that the patient is still eligible upon arrival in the O.R. (i.e., WFNS is still I, II, or III)), and 2) after anesthetic induction and patient positioning are complete.

The RANDOMIZATION ENVELOPE contains a TEMPERATURE form that indicates the temperature group to which the patient has been randomized, and is the only place where intraoperative temperature data for IHAST2 is to be recorded except the local hospital anesthesia record.

c) Two (2) white (6.5 x 9.5 in.) unsealed envelopes pre-labeled with the PID number.

On the outside of these envelopes are instructions telling the Anesthesiologist into which of these envelopes the two copies of the completed TEMPERATURE form (upper white original and lower canary-colored copy) are to be placed and sealed at the end of surgery. (The blue paper inside each envelope is to reduce transparency—just leave it in). After these two envelopes are sealed, they are to be returned to the Local Study Coordinator (the sooner the better).

Paperwork the Anesthesiologist Needs after Leaving the O.R.:

a) The same ANESTHESIOLOGIST form that was used in the O.R.

This is needed in order to record early postoperative patient status (section G) as well as Intercurrent Events that take place over the first two hours after surgery (section H (page 6) of the ANESTHESIOLOGIST form). Once sections G and H are completed (~two hours after surgery), the ANESTHESIOLOGIST form may be returned to the Local Study Coordinator (the sooner the better). Section H is faxed to the CCC; Sections A- G (the entire form) is mailed to the DMC as part of the 48-hour postoperative shipment.

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b) The white (0.5 x 1.75 in.) adhesive labels which are pre-labeled with the PID number.

These labels are to be affixed to photocopies of the local hospital anesthesia record and early (first two hours) postoperative ICU (or recovery) records. Any data on these records which are specific to the patient (e.g., name, local hospital identification number, social security number, birth date, etc.) are to be removed or covered up. Any unused labels may be discarded.

c) The Study Packet envelope. The Study Packet envelope is used to place photocopies of the local hospital anesthesia record and 0-2 hour postoperative recovery or critical care records.

After these items are in place, the Study Packet envelope is sealed. Once sealed, it is to be returned to the Local Study Coordinator (the sooner the better). To preserve “blinding” the Local Study Coordinator is not to view the local hospital anesthesia record or early postoperative data, ever.

d) After leaving the O.R., the Anesthesiologist may also need Intercurrent Event (IE) forms to complete/ It is preferred that the Anesthesiologist complete all IE forms triggered by responses to section H (page 6) of the ANESTHESIOLOGIST form. However, the Local Study Coordinator may assist in completion of these forms provided that s/he remains unaware of patient group assignment and temperature data.

VIII.F.3. Room Conditions prior to Patient arrival to the Operating Room

a) Room Temperature

Room temperature at 20-22°C. - Manipulation of room temperature is NOT part of the protocol. In fact, to facilitate blinding of temperature group assignment, room temperature should not be changed during the case. Hence, prior to patient arrival in the O.R., choose a room temperature that is likely to be acceptable for the duration of the case and do not change it. In most PCC’s, a room temperature of 20-22°C (68-72°F) will be acceptable. It is not necessary to conceal O.R. room temperature because it does not change.

b) Water Mattress

The cooling/warming water mattress should be on the bed prior to patient arrival (see above) and prewarmed to 37°C. A uniform (warm) starting temperature for the water mattress is necessary for patient comfort and facilitates blinding of subsequent temperature group assignment.

c) Temperature Devices/Displays

Temperature displays on the water mattress control unit and forced air cooling device (Polar Air), and all temperature monitors must be concealed to prevent anyone other than the Anesthesiologist from seeing the settings/results. Tape, paper, cardboard, would all be acceptable means of concealing temperature displays.

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VIII.F.4. Monitoring

a) Required Monitoring

Pulse oximetry

End-tidal carbon dioxide

Electrocardiogram (lead V5 or CM5 must be monitored, other leads may be monitored at the discretion of each PCC)

Blood pressure cuff (manual or automated)

Continuous arterial blood pressure via direct arterial cannulation

Esophageal temperature via esophageal stethoscope/thermistor

Comment: Proper depth of placement of the esophageal stethoscope/thermister is the point where heart sounds are heard most loudly (retrocardiac esophagus). In most cases, this should be when the stethoscope is inserted ~20 cm beyond the patient’s teeth.

Secondary temperature monitoring (nasopharyngeal, rectal, tympanic, other)

b) Other Monitoring

No other monitors are required for this study.

With the exception of ventriculostomy catheters, monitoring devices that penetrate the substance of the brain, such as needle thermistors or blood gas/pH electrodes are NOT permitted.

All other monitors (e.g., central venous pressure catheters, PA catheters, retrograde jugular catheters, electrophysiologic monitors, etc.) may be used as per local routines and/or the discretion of the attending Neurosurgeon or Anesthesiologist.

Comment: The choice of monitoring MUST NOT be made on the basis of temperature group assignment. For example, a pulmonary artery catheter or jugular venous catheter should not be placed simply because a patient was randomized to hypothermia. Therefore, unless the patient’s medical condition changes in such a way as to require some additional monitoring technique, all monitoring devices are to be chosen and in place prior to opening the RANDOMIZATION ENVELOPE.

VIII.F.5. Intraoperative Anesthetic Agents

Prior to induction of anesthesia, small doses of sedatives (e.g., midazolam) and/or opioids (e.g., fentanyl) are permitted in order to reduce patient anxiety and/or facilitate placement of monitors.

General anesthesia with endotracheal intubation will be used in all cases.

Anesthesia will be induced with either thiopental or etomidate but no other agent.

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Comment: On occasion, a patient may require an awake intubation, due to a difficult airway. Routine local procedures for such an intubation are acceptable. However, once the endotracheal tube is in place, anesthesia must be induced with only thiopental or etomidate.

Anesthesia will be maintained with a “balanced” anesthetic technique comprised of variable amounts of a volatile anesthetic, an opioid, and nitrous oxide.

Volatile anesthetics will be limited to either isoflurane or desflurane only; no other volatile agent may be used.

Opioids administered during surgery will be limited to fentanyl, sufentanil, or remifentanil; No other opioid may be used other than for a small dose of morphine just prior to completion of the case. There are no restrictions on postoperative opioid selection or use.

Nitrous oxide use is optional but, if used, is to be administered in concentrations not to exceed 72%.

Anesthetics should be administered in such a manner that endotracheal extubation should be possible at completion of surgery, provided the patient is normothermic (or nearly normothermic) and there are no other medical or surgical indications for continued endotracheal intubation.

There is no restriction on the choice and/or use of muscle relaxants at any time.

VIII.F.6. Basic Protocol

a) Blinding

Comment: Blinding Issues. Perhaps no other factor (except perhaps for correct determination of patient eligibility and completing the three-month follow-up exam) is as important as maintaining blinding regarding group assignment and actual intraoperative temperatures. UNBLINDING CAN DESTROY THE VALIDITY OF THIS STUDY!!!

The RANDOMIZATION ENVELOPE must not be opened until 1) after it has been determined that the patient is still eligible at the time of arrival in the OR, and 2) after the induction of anesthesia and completion of patient positioning for surgery. Furthermore, the contents of the RANDOMIZATION ENVELOPE (TEMPERATURE form) and all aspects of intraoperative temperature management are to be known only to the Anesthesiologist. Neither the Neurosurgeon, the Local Study Coordinator nor the Neurologic Examiner is to know the patients group assignment or their intraoperative or recovery area temperatures. The TEMPERATURE form, which contains this information, must be placed in the provided envelopes and sealed before the patient arrives in the recovery area.

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The Neurosurgeon is not to ask and, if s/he does ask, is not to be informed of the temperature group assignment or the patients actual temperature unless, in the judgment of either the Neurosurgeon or Anesthesiologist, the patients temperature management may be playing a critical and immediate role in a life-threatening intraoperative event(s). If, for safety reasons, the patient’s temperature management must deviate from protocol or from the assigned situation, please contact the CCC immediately. However, in no event is information regarding group assignment, actual temperatures or any protocol deviation, regardless of the reason, to be provided to the Local Study Coordinator or Neurologic Evaluator(s), or to any physician or nurse involved in the patient’s postoperative care. At no time during surgery or during the first two hours after surgery is the Local Study Coordinator or the Neurologic Examiner(s) permitted to be in the presence of the patient. Likewise, the Local Study Coordinator and Neurologic Evaluator(s) must not view the anesthesia record at any time.

b) Prior to Induction of Anesthesia

The patient will be placed on the O.R. table that has been prepared with a water mattress beneath the patient (prewarmed to 37oC) and O.R. temperature that been set between 20-22°C (see above)

The Anesthesiologist and/or Neurosurgeon will verify that there have been no changes in the WFNS score between enrollment and coming to the O.R. that have made the patient NOT eligible (page 1 of ANESTHESIOLOGIST form). To still be eligible, the patient must still have a WFNS score of I, II, or III upon arrival to the O.R. It does not matter if the patient’s WFNS score is different from that obtained during eligibility screening (better or worse) so long as it is still WFNS I, II, or III. If on arrival to the O.R. the patient’s WFNS score is either IV or V, the patient is no longer eligible for the study. In this case, do not open the RANDOMIZATION ENVELOPE. Record the reason(s) why the patient is no longer eligible on page 1 of the ANESTHESIOLOGIST form. The Anesthesiologist is to initial the bottom of page 1 and sign the bottom of page 6 of the ANESTHESIOLOGIST form and return the unopened RANDOMIZATION ENVELOPE and the unused forms to the Local Study Coordinator. Thereafter, care for the patient as you see fit, but the patient is not in the study. The DMC must be informed within 24 hours (sooner is better) that the patient did not enter the study.

If the patient is still eligible upon arrival to the O.R, the patient is considered still eligible for study entry – but the RANDOMIZATION ENVELOPE is still not to be opened. Before induction of anesthesia, a tympanic or sublingual temperature and other vital signs (respiratory rate, blood pressure, and oxygen saturation) will be recorded. Before induction, the patient’s electrocardiogram (lead V5 or CM5) will be characterized (rate, rhythm, ST segment, T wave).

As noted above, prior to induction of anesthesia, small doses of sedatives (e.g., midazolam) and/or opioids (e.g., fentanyl) are permitted in order to reduce patient anxiety and/or facilitate placement of monitors.

c) Induction and Maintenance of Anesthesia

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Anesthesia will be induced with either thiopental or etomidate in whatever dose is deemed appropriate by the attending Anesthesiologist.

All patients will be endotracheally intubated via whatever route and with whatever tube size is deemed appropriate by the attending Anesthesiologist.

Anesthesia will be maintained with a standardized “balanced” anesthetic which will include: 1) a volatile agent (either isoflurane or desflurane); 2) a synthetic opioid (fentanyl, sufentanil, or remifentanil) given either by repeated bolus or infusion; and 3) nitrous oxide in concentrations not to exceed 72%. Only nitrous oxide use is optional. There are no restrictions on the choice of paralytics, but no other anesthetic regimen or drugs will be permitted to induce or maintain anesthesia.

d) Temperature Monitor and Blanket Placement

Immediately after endotracheal intubation, a combined esophageal stethoscope/thermister [Mon-a-Therm Esophageal Stethoscope XL, Mallinckrodt Medical, St. Louis] will be inserted (see above). From this point, until the end of surgery, all information regarding body temperature (recorded only on the TEMPERATURE form and the local anesthesia record) will refer to data from this esophageal thermister.

In addition, a rectal, nasopharyngeal, tympanic (or other) temperature probe must also be inserted after intubation, to serve as a secondary “safety” backup.

As soon as possible after induction of anesthesia (typically after lumbar drain insertion and/or cranial pin placement), the patient will be covered with a forced air cooling/warming blanket. This air blanket should be applied over bare skin, without interposed sheets or blankets. The blanket should extend from the upper chest to the feet. Care must be taken to avoid limiting the internal airflow of this blanket by externally compressing the blanket by straps, tape, or other means. Care must also be taken to ensure that air cannot be blown onto the surgical field (taping the upper end of the blanket down over the patients shoulders will solve this problem). The air blanket will be connected to the Polar Air control unit, which will be set to deliver 37 oC air to all patients in both groups.

e) Initial Intraoperative Temperature

Temperature displays on the water mattress control unit and forced air cooling/warming device (Polar Air), as well as all other temperature monitor displays will be concealed to prevent anyone other than the Anesthesiologist from seeing the settings/results. After the cooling/warming air blanket is in place and the patient is finally positioned, the Anesthesiologist will open the RANDOMIZATION ENVELOPE, which contains the TEMPERATURE form.

This form may be seen ONLY by the Anesthesiologist caring for the patient.

The TEMPERATURE form will indicate the temperature group to which the patient has been assigned as either “Normothermia” or “Hypothermia.

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In patients randomized to the NORMOTHERMIA group, the temperature of the water mattress and forced air unit will be adjusted as needed to maintain esophageal temperature at a target of 36.5oC (acceptable range, 36-37oC) for the entire duration of surgery. Typically, the water mattress is set for 37.5°C and the Polar Air control unit is set for 38oC. Warming of all intravenous fluids (and/or blood) is required. Warming/humidification of inspired gases is required. Both esophageal temperature and “secondary” temperature at definitive clip placement (all aneurysms) are recorded ONLY on the TEMPERATURE form [and local anesthesia record]. (Other data collected at the time of final clip placement include clock time, mean arterial pressure, blood glucose, and the Neurosurgeon’s guess for group assignment. However, this data is recorded on page 4 the ANESTHESIOLOGIST form.)

In patients randomized to the HYPOTHERMIA group, the water mattress will be set to ≈10oC, and the Polar Air unit set on maximum cooling (10oC). Intravenous fluids and inspired gases are not to be warmed during the cooling phase. The goal is to achieve an esophageal temperature of 33.0oC (acceptable range 32.5-33.5oC) as rapidly as possible. If cooling is not complete prior to aneurysm clipping, surgery is not to be delayed in order to reach target temperature. However, an infusion of 7-14 ml/kg of ice cold (4 o) saline given as rapidly as possible via a peripheral I.V. catheter (not a central venous catheter) will quickly decrease core temperature ~0.5-1.0°C, and may be used at the discretion of the Anesthesiologist to achieve target temperature in slowly cooling patients.

To decrease the risk of hypothermia-induced arrhythmias, and to limit the risk of unblinding by somone seeing intraopertive blood gas records, alpha-stat blood gas management will be used in patients randomized to hypothermia. Accordingly, all blood gas management will refer to blood gas results obtained at 37.0°C. In other words, blood gases are NOT corrected to patient temperature. Thus, samples sent to the blood gas lab are to report patient temperature as 37.0°C, regardless of the patient’s actual (in vivo) temperature.

Usually, target temperature (33.0°C) will be achieved 30-60 minutes prior to final aneurysm clipping. Because of the physiology of surface cooling, patient core temperature will usually decrease an additional 0.3-0.5°C (over 30-45 minutes), after discontinuation of active cooling (“after-drop” phenomenon). Therefore, during cooling, once core temperature reaches ~33.5°C, active cooling should be stopped. The water mattress temperature should be reset to ~33°C, and the PolarAir control unit reset to 33°C. Because of “afterdrop,” in most cases, esophageal temperature will decrease at little more and stabilize at the target temperature (33.0°C). The goal is to maintain target esophageal temperature (33.0°C) until aneurysm clipping is complete. Both esophageal temperature and “secondary” temperature at final clip placement (all aneurysms) are recorded ONLY on the TEMPERATURE form [and local anesthesia record]. (Other data collected at the time of final clip placement include clock time, mean arterial pressure, blood glucose, and the Neurosurgeon’s guess for group assignment. However, this data is recorded on page 4 the ANESTHESIOLOGIST form.)

f) Post-clip Temperature Management

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Immediately after final clip placement, rewarming will begin in hypothermic patients. This will be accomplished by setting the water mattress to a temperature no greater than 40°C, and the forced air control unit on maximum (air temperature of 43°C). Heated humidifiers and fluid warmers are also be used during the warming phase. Room temperature is not to be changed. Rewarming should be accomplished as rapidly as possible with the goal of reestablishing normothermia by the end of surgery (dressing complete). Because of the physiology of surface rewarming, core temperature usually does not begin to increase for at least 30-60 minutes after rewarming procedures are begun. Therefore, once experience with surface cooling/warming has been obtained, AND when the Anesthesiologist is confident that final aneurysm clipping will occur within <15-20 minutes, the Anesthesiologist may elect to start rewarming procedures 15-20 prior to final clip placement, particularly when the patient’s temperature is less than 33.0°C.

g) End of Surgery

In both groups (Normothermia and Hypothermia), when surgery is complete anesthesia will be discontinued. The patient may be extubated at any time (in the O.R. or postoperative care area) at the discretion of the Anesthesiologist. However, it is recommended that patients should NOT be extubated whenever core temperature is less than 35.0-36.0°C. If continued endotracheal intubation is deemed necessary (for any reason) supplemental sedatives or hypnotics (e.g., midazolam, propofol) may be administered while the patient is still in the operating room.

To facilitate blinding, the forced airwarming blanket is to remain in place on all patients, regardless of group assignment or temperature for the first two hours after completion of surgery.

Upon completion of surgery, patient esophageal temperature will be recorded on the TEMPERATURE form. Thereafter, the underlying carbon copy of the TEMPERATURE form will be separated from the top copy. Each copy will be folded and each placed into a separate white (6.5 x 9.5 in.) envelope pre-labeled with the PID number (provided in the Study Packet) and sealed. On the outside of these envelopes are instructions telling the Anesthesiologist into which of these envelopes the two copies of the completed TEMPERATURE form (upper white original and lower canary-colored copy) are to be placed and sealed at the end of surgery. (The blue paper inside each envelope is to reduce transparency—just leave it in). After these two envelopes are sealed, they are to be returned to the Local Study Coordinator (the sooner the better).

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Comment: In general, it is recommended that all patients who are hypothermic (<35.5-36.0°C) upon arrival to the postoperative care area should undergo forced air warming until normothermia (>36.0-36.5°C) is re-established. Based on pilot trial data, as many as 40% of patients assigned to hypothermia will need to remain intubated, and/or sedated, and/or paralyzed for a period of time after the completion of surgery to complete rewarming. In general, it is recommended that, whenever short-term sedation is needed to facilitate rewarming or continued intubation, propofol may be used as the principle agent. Other sedatives, hypnotics, or opioids (e.g., midazolam, meperidine) may be used in the recovery area as needed. Nevertheless, in all circumstances, the goal will be to return the patient as quickly as possible to a state in which neurologic assessment and extubation are possible. To facilitate temperature and airway management, and to aid in the management of any immediate postoperative adverse events, the Anesthesiologist must remain directly involved in the patient’s care for at least the first two hours after completion of surgery. Based on pilot trial data, in all cases rewarming should be complete less than two hours after arrival in the postoperative recovery area.

As previously indicated, neither the Local Study Coordinator nor any Neurologic Evaluator is permitted to be in the presence of any study patient either during surgery or for the first two hours after surgery (after leaving the operating room). At 3 to 6 hours after arrival in the postoperative care area, a neurologic examination (NIHSS scale) will be performed by a certified examiner who will be unaware of group assignment. This examiner will refrain from obtaining any other postoperative information.

h) Other Intraoperative Surgical and Anesthetic Management

Surgery will proceed as per local routines. There are no restrictions on the use of fluids, steroids, mannitol or furosemide. Neurologic monitoring (electroencephalography, evoked potentials, retrograde jugular catheters) and techniques (lumbar drain) may also be used as per local routine. However, with the exception of ventriculostomy catheters, neurologic monitors which are placed into the substance of the brain (e.g., needle thermistors or blood gas electrodes) are NOT permitted in this study.

Induced hypotension or temporary clips may be used at the discretion of the operative team.

If induced hypotension is used (defined as mean arterial pressure ≤ 60 mm Hg for ≥15 consecutive minutes), only isoflurane, nitroprusside and/or ß-blocker (either alone or in any combination) may be used to accomplish this. If induced hypotension is used, item 13, of Section H (page 6) of the ANESTHESIOLOGIST form should be check as “Occurred in O.R.”

If temporary clips are used, temporary clip time will be recorded on the NEUROSURGEON form.

Although is not the Anesthesiologist’s responsibility to record temporary clip time on the ANESTHESIOLOGIST form, the Anesthesiologist may recorded this time on the local anesthesia record and provide this time to the Neurosurgeon at the end of the case.

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If the operative team deems that intraoperative pharmacologic brain protection is needed, this will be restricted to the administration of either thiopental or etomidate (no other agent) for as short a period as possible. In general, teams are not encouraged to use pharmacologic brain protection unless a specific indication exists. In general, it is recommended that teams use pharmacologic protection only when prolonged (>10 minutes) temporary clipping is anticipated or a temporary clip is left in place for >10 minutes (i.e., thiopental or etomidate may be started after the temporary clip is in place). The reason(s) for the use of thiopental and/or etomidate for pharmacologic brain protection and the cumulative dose administered must be entered into the ANESTHESIOLOGIST form (page 4).

Intraoperative blood loss and fluid balance will be recorded as follows:

Total estimated blood loss for the entire case.

Total urine output for the entire case.

Fluids administered for the entire case (crystalloids, colloids, and blood products).

VIII.F.7. Neurosurgical Management

There are very few “restrictions” placed on the intraoperative neurosurgical management of enrolled patients - and no restrictions placed on postoperative care. In fact, other than the need to complete the NEUROSURGEON form in the O.R. (typically at the end of the case), the Neurosurgeon should be able to complete these procedures as per his/her routine. The trial is also designed to minimize any delays in proceeding with surgery. For example, application of the aneurysm clip should not be delayed to permit achievement of target temperature (which would, of course, result in unblinding of the surgeon -see below). However, the following items are important:

a) Patient Selection

This trial is designed to be carried out in patients with carefully defined inclusion/exclusion criteria. If patients are inappropriately included or excluded, serious damage can be done to the trial. It is critical to avoid “selective” enrollment of patients, or “selective exclusion,” particularly when this decision is based on a desired to “select” temperature management. For example, patients should not be excluded because the Anesthesiologist and/or surgeon conclude “we really want to cool this patient.”

b) Blinding

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It is critical that the neurosurgical team remain blinded as to temperature assignment, at least during the procedure itself (we realize that blinding may be lost in the PACU/early SICU period). If patients in one group are managed differently than in the other, the entire validity of the trial will be compromised. For example, if a decision is made to administer pharmacologic protectants (e.g., thiopental) “because the patient is warm,” or alternatively the decision is made that “protection isn’t needed because the patient is already cold,” the resulting confounding variables may make the trial uninterpretable. For this reason, every effort will be made to conceal the temperature assignment from the neurosurgical team. Room temperatures will not be altered according to temperature assignments. All patients will be covered with a forced air warming/cooling blanket after positioning is complete. The same equipment will be used in both warm and cold patients - and the Polar Air cooling unit sounds the same whether in warming or cooling mode. Cooling will not start until after positioning is complete. All temperature monitors (including the displays on temperature control devices) will be “covered” or otherwise concealed from the Neurosurgeon. If asked, the Anesthesiologist will not provide information on the patient’s temperature (and we would sincerely request that you don’t ask).

Comment: There may be circumstances in which unblinding is required for patient safety reasons. If, for example, there is evidence or concern regarding hemorrhage or coagulation status, it may be necessary to prematurely rewarm hypothermic patients. In such cases, the decision should be made jointly by both the Neurosurgeon and Anesthesiologist, and this decision communicated to the CCC as quickly as possible after surgery.

c) Temperature Guess

Upon clipping of each aneurysm, the Anesthesiologist will ask the Neurosurgeon to “guess” as to the temperature assignment group.

d) Intraoperative Protective Agents

Pharmacologic protection is restricted to thiopental or etomidate. Propofol may not be used. In general, these drugs should only be administered when prolonged (e.g., >10min) temporary clipping of an intracranial vessel is required, although we recognized that other circumstances may arise. We strongly discourage the “routine” administration of protective agents to all patients (other than nimodipine), and continuous infusions of thiopental or etomidate (or propofol) throughout the procedure (or a large portion thereof) will be viewed as a major protocol violation.

e) Other drugs

There are no restrictions on the use of drugs such as dexamethasone, anticonvulsants, mannitol, furosemide, etc.

f) Temporary Clipping

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The decision to use temporary clipping or any other means of achieving vascular control is entirely at the discretion of the Neurosurgeon. However, the location of such clips and the duration of their application should be recorded on the NEUROSURGEON form.

VIII.F.8. Postoperative Care/0-2-hours

To facilitate temperature and airway management, and to aid in the management of any immediate postoperative adverse events, the Anesthesiologist will remain directly involved in the patient’s care for at least the first two hours after completion of surgery.

As described in Chapter VIII.F.6, the principal anesthetic management goals of the first two hours after completion of surgery will be:

Re-establishment and/or maintenance of systemic normothermia (≥36.0-36.5°C).

Rapid return of the patient to a state in which neurologic assessment can be performed.

Extubation of all patients in whom endotracheal intubation is no longer required.

Endotracheal intubation status at the time of arrival to the postoperative care area, and two hours later, will be recorded (ANESTHESIOLOGIST form).

VIII.F.9. Intraoperative & Early Postoperative Intercurrent Events

Intercurrent events (IEs) occurring during while the patient is in the operating room or during the first 0-2 hours after leaving the operating room will be noted by the Anesthesiologist using the checklist provided on the last page (Section H., page 6) of the ANESTHESIOLOGIST form. This page is to be faxed to the CCC within 24 hours after completion of surgery. Any and all items that apply are to be checked, even if “overlapping” or redundant.

The first 10 items of this checklist are considered to be critical or “indicator” events—events so serious that they must be reported to the CCC as soon as possible. These events are: 1) the need for cardiopulmonary resuscitation; 2) development of ventricular –tachycardia or –fibrillation; 3) development of myocardial -ischemia or –infarction; 4) development of cardiogenic shock; 5) the need for continuous vasopressor administration (≥15 min) to support the systemic circulation; 6) blood loss exceeding 1000 ml; 7) severe coagulopathy; 8) recurrent subarachnoid hemorrhage not due to surgical manipulation; 9) development of an epidural or subdural hemorrhage and 10) the need for previously unplanned (e.g., emergent) surgery. In each case, an IE form must be completed by the Anesthesiologist.

Items 11-24 of this checklist are also considered to be important events, but it is possible that some of these events may occur without any significant clinical impact on the patient. For this reason, IE forms are required only when, in the judgement of the Anesthesiologist, the event had a significant clinical impact on the patient. Some items deserve special comment.

Hypertension will be defined as MAP greater than 120 mm Hg for more than 15 minutes. If hypertension is present during or after surgery, the Anesthesiologist will classify it as: 1) INTENDED (item 11) (e.g., for aneurysm clipping) and/or 2) NOT INTENDED (item 12).

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Hypotension is defined as a mean arterial pressure (MAP) less than 60 mmHg for more than 15 minutes. If hypotension is present during or after surgery, the Anesthesiologist will classify it as: 1) INTENDED (item 13) (e.g., for aneurysm clipping) and/or 2) NOT INTENDED (item 14).

The Local Study Coordinator may assist the Anesthesiologist in completion of IE forms but may NOT be informed of: 1) the patient’s group assignment; 2) intraoperative temperatures; 3) patient temperature on arrival to the postoperative care area. Likewise, the Local Study Coordinator may NOT view the anesthesia record at any time over the entire course of the study.

VIII.F.10.Early postoperative NIHSS

After the patient has been rewarmed, but no earlier than three hours after arrival in the postoperative care area, the Study Coordinator should be contacted to assess and assign a NIHSS. Note that this exam can also be performed by the Neurologic Examiner. However, in no case should either the Coordinator or Examiner be allowed to visit the patient until normothermia has been restored and all rewarming efforts are complete. If this individual sees the patients while rewarming is in progress, blinding will be lost. It is preferrable to delay the exam than to risk unblinding.

VIII.F.11.Postoperative Care/Later

There are no protocol “rules” regarding postoperative care, but the care that is given must be carefully documented. The primary instrument for such monitoring is the DAILY POST-OP SCREEN form - see below.

VIII.F.12.Daily Assessments

The Local Study Coordinator or other designated individual should see each patient on a daily basis for a total of 14 days following surgery, or until discharge (or death) whichever comes first. Ideally, this visit should be made at a standardized, consistent time each day. The DAILY POST-OP SCREEN form is divided into columns, one for each of 14 days + discharge. Each column should be completed in turn. If a patient is discharged from the hospital seven days after surgery, the Study Coordinator should fill in the first six columns on the form, plus the Discharge column. If a patient is not discharged until the 21st postoperative day, all 14 columns on the DAILY POST-OP SCREEN form should be completed, plus the Discharge column (obviously completed at the time of Discharge).

We recognize that the Local Study Coordinator may not be personally able to see every patient every day, due to vacations, illness, etc. However, it is the responsibility of the Coordinator and the Local PI to ensure “backup coverage,” (i.e., to arrange for some certified individual to see the patient and complete the form). This can be any certified individual who was not involved in the intraoperative care of the patient. Such a person is not blinded with respect to the patients temperature assignment group, and cannot perform an unbiased evaluation.

Details regarding completion of the DAILY POST-OP SCREEN form can be found in Chapter IX.I and IX.K.

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Important Note: It is important that performing the daily evaluations and completing the DAILY POST-OP SCREEN be blinded as to group assignment. This means that the attending Anesthesiologist or anyone else involved in the intraoperative care, (e.g., an anesthesia resident or fellow, a neurosurgeon, etc.) cannot perform this evaluation. Similarly, since the attending Anesthesiologist who performed the case is not blinded (and cannot be), it is imperative that s/he refrains from discussing the case with the Study Coordinator or whoever is responsible for the posterative assessments.

VIII.F.13.Intercurrent Events

It is critical that important medical events, interventions and major diagnostic events are carefully recorded following surgery; these events represent an important part of the process of evaluating the impact of hypothermia. The primary mechanism for documenting such events is the DAILY POST-OP SCREEN form combined with the INTERCURRENT EVENTS form. Details concerning completion of these forms can be found in Chapter IX.I and IX.J.

a) Severe/Indicator IEs

Some IEs must be reported “emergently” to the CCC (i.e., by the next working day). The two types are classified as “ “Indicator Events” and “Severe IEs.”

“Indicator Events” are those that the literature suggests are most likely to be affected by intraoperative temperature management (major cardiovascular complications, bleeding, infection). Indicator Events are highlighted on the IE code list and in the IE definitions table (IX.S.). Using an INTERCURRENT EVENTS form, it is mandatory that all“Indicator Events” be promptly reported to the CCC, regardless of their judged severity (mild, moderate, severe, death)

“Severe IEs ” are those when event or procedure was either life-threatening, permanently disabling, or substantively prolonged in-patient hospitalization. Any and all IEs which are considered to be severe must be promptly reported to the CCC, even if it is not an “Indicator” IE, and even if all supporting information is not yet available.

b) Routine IEs

Other IEs, which are not Indicator Events, and which are not associated with serious patient morbidity are classified as “routine” and should be submitted at the times regular paper forms are sent to the DMC.

“Routine” IEs are classified as either “mild” or “moderate” based upon their net impact on the patient. Mild--the event or procedure was well tolerated by the patient and did not appear to substantially influence the patient's overall clinical course. Moderate--the event or procedure was sufficient to interfere with the patient's recovery. For most moderate events, some new treatment is necessary and/or the duration of hospitalization may be slightly prolonged because of the event.

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VIII.F.14.Postoperative Neurologic Assessments

A formal postoperative neurologic assessment, involving the performance of the NIHSS, must be performed at ≈3 to 6 hours following surgery, 24 and 72 hours after surgery, and then again on the day of discharge.


It is the responsibility of the Local Study Coordinator or physician investigator to ensure that these exams are performed on time. However, the DMC will provide weekly “reminders” to the Local Study Coordinator regarding exams that are “due” at various times.

Important Note: The validity of the postoperative NIHSS can be seriously compromised if the Neurologic Examiner becomes aware of the patient’s group assignment. Therefore, it is greatly preferred that NIHSS exams performed at 24-, and 72- hours after surgery, as well as the discharge NIHSS be performed by a designated Neurologic Examiner. In this circumstance, is critical that the neither the Study Coordinator nor any physician or other individual involved in the patient care discuss the patient’s care or clinical course with the Neurologic Examiner. Furthermore, the Neurologic Examiner should not, at any time, read or review any part of the patient’s medical record. However, if necessary, the 24-, and 72- hour and discharge NIHSS exams may be performed by the Local Study Coordinator, so long as the Coordinator remains blinded regarding temperature group assignment. Under no circumstance may the Local Study Coordinator perform any of the final 3-month neurologic outcome assessments.

VIII.F.15.Discharge

Using the DAILY POST-OP SCREEN form each patient is to be seen every day after the primary aneurysm surgery until either discharge from the hospital or postoperative day 14, whichever comes first. However, on the day of discharge from the hospital, (regardless of the duration of the hospital stay) the D/C (discharge) column of this form is to be completed. For example, if the patient is discharged on postoperative day 10, then columns for days 1-9 and the discharge column (day 10) must be completed. If the patient is discharged on day 21, then columns for days 1-14 and the discharge column (day 21) must be completed.

Even though a patient need not be seen every day beyond 14 days, it is critical that the Study Coordinator remains constantly aware of the patient’s status. It is very easy to “accidentally” discover that a patient has been discharged without the Study Coordinator’s knowledge IF constant contact has not been maintained. Since a NIHSS must be completed on the day of discharge, it is critical that the Study Coordinator knows of this impending discharge so that the Neurologic Examiner can be notified. Given these concerns, it is strongly recommended that the Study Coordinator visit every patient every day during hospitalization, even if no “form” needs to be completed.

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VIII.F.16.Post-Discharge Follow-up

a) Interim Contacts

Three “interim contacts” are required. The primary purpose of these contacts is to provide follow-up, to permit documentation of IEs (e.g., re-hospitalization, out-of hospital deaths, general functional status, etc.). In addition, such contacts serve as a means by which the Investigators can stay in contact with the patient, and thereby reinforce the need to return to the PCC for the three-month follow-up.

The general plan is that the patient or family will be contacted by telephone at three and nine weeks after surgery (NOT after discharge - all postoperative follow-up is timed from surgery), and seen in clinic at approximately six weeks. In most cases, we assume that the six-week clinic visit will be a regularly scheduled postoperative visit. However, in the event that such a clinic visit is not possible, telephone contact is sufficient.

Note that in some cases, a patient may still be in the hospital at the time of the three-week contact.

If contact is made by telephone, it must be conducted using a prepared script as a guideline. This interview includes question about place of residence, functional status (as assessed with some general questions as well as a Barthel’s Activities of Daily Living score). The person performing the interview is responsible for assigning a Glasgow Outcome Score based on the information obtained.

As noted, one purpose of this interview is to “maintain contact” and to remind the patient of the critical importance of returning to clinic for the final three-month examination. These contacts also represent an opportunity for helping the patient stay “invested” in the study, and to reinforce the investigators’ ongoing interest in their condition and care.

b) Three-month Follow-up

As noted before, there are three “critical” events in this trial, which, if violated, could cause irreparable damage to the validity of the trial. The first is enrollment of eligible individuals, the second is the maintenance of blinding, and the third is the final three-month follow-up exam. This trial is designed to assess the impact of hypothermia on “long-term outcome”; without this examination, we have no rigorous assessment of outcome. A failure to see a patient at three months (11-13 weeks postoperative is the “ideal” window) may render a great deal of work on this patient meaningless. Some information regarding outcome can be collected by telephone, or “pieced together” from data collected during the interim contacts, but this is clearly less than satisfactory. For example, it is impossible to perform a NIHSS or the neuropsychology battery by telephone.

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Other large neurologic outcome trials have demonstrated the feasibility of a 99%+ follow-up, and anything less than this can damage the validity of the trial. Absolutely every effort must be made to get the patient back to clinic at three months, even if the Neurosurgeon does not routinely see patients at this point. If absolutely necessary, the patient should be provided with a taxi ride, bus fare, hotel, airfare whatever is needed, etc. S/he must be constantly made aware of the importance of this visit.

c) Follow-up Difficulties

In the event that a patient absolutely cannot return to clinic, some alternative means of obtaining the needed outcome data must be used. These can include one or more of the following:

A visit to the patient in their home or other place of residence by the Neurologic Examiner, Study Coordinator and Neuropsychologic Examiner (or any one of these).

Arrangement for the patient to be evaluated at another PCC. For example, if a patient is studied in Los Angeles, but then moves to San Francisco, it is acceptable for the patient to be seen by examiners in San Francisco.

Arrangements for the patient to be examined by a non-participating neurologist who is familiar with the various outcome assessments (e.g., the NIHSS, the Barthel’s Activities of Daily Living Index, the Rankin Score and the Glasgow Outcome Score). It may be possible to provide detailed instructions to such an individual by telephone, fax, email, etc., if needed.

A telephone interview. It is possible to gather much of the needed information, including the Barthel’s Index, a Mini-Mental State Exam and GOS by phone, although the NIHSS and neuropsychologic battery cannot.

Delays in follow-up may also be unavoidable. For example, it may be impossible for a patient to be seen exactly at three months, but would be available at four or five months. In such cases, the patient should be seen even at this later date. A personal exam performed “late” is better than no exam at all or a telephone interview at three months.

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CHAPTER IX. DATA FORMS/COMPLETION INSTRUCTIONS

IX. A SCREENING FORM

IX.A.1. Overview:

Since surgical outcomes reflect the experience of the surgical team, we need to track the total aneurysm-related operative activities of each PCC. Hence it is necessary to maintain minimal records on ALL patients who undergo craniotomies for aneurysm clipping, regardless of participation in the project. The SCREENING form should be completed on ALL patients who undergo an open craniotomy for aneurysm clipping, regardless of whether or not they have suffered a subarachnoid hemorrhage (SAH) or whether or not they are eligible for enrollment.

A form does not need to be completed for patients undergoing "closed" procedures (e.g., aneurysm coiling) or for aneurysm patients undergoing craniotomies for purposes other than aneurysm obliteration.

The SCREENING form for non-eligible patients should be kept in the Patient Log binder. Note that the white originals of the SCREENING form for all non-eligible patients must be sent to the DMC on the last working day of each month.

IX.A.2. Data Items

Item 1. Gender: There are two choices, check one.

Comment: Self-explanatory

Item 2. Race: There are eight (8) possible choices, check only one.

North American Indian or Alaskan Native. Definition: A person having origins in any of the original peoples of North America, and who maintains cultural identification through tribal affiliation or community recognition.

Asian or Pacific Islander. Definition: A person having origins in any of the original peoples of the Far East, Southeast Asia, or the Pacific Islands. This area includes, for example, China, India, Japan, Korea, the Philippine Islands, and Samoa.

Black, not of Hispanic origin. Definition: A person having origins in any of the black racial groups of Africa.

Hispanic. Definition: A person of Mexican, Puerto Rican, Cuban, Central or South American, or other Spanish culture or origin, regardless of race

White, not of Hispanic origin. Definition: A person having origins in any of the original peoples of Europe, North Africa, or the Middle East.

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Indian/Pakistani. Definition: A person having origins in any of the original peoples of the Indian subcontinent.

Australian Aborigine. Definition: A person having origins among the aboriginal peoples of Australia.

Other or unknown. Definition: Any individual not covered by the preceding seven items. Please specify, if possible, in the space provided.

Comment: The NIH requires documentation regarding race to evaluate ethnic balance/minority inclusion in all funded trials. We fully recognize that these categories may not cover all possibilities, or that many individuals of mixed race/ethnicity may not fit easily into any category. When in doubt ask the patient, then do your best.

Item 3. Age: Enter the patient's age in years in the appropriate blanks.

Comment: It is the age the patient is “today.” So if a patient will turn age 18 the next day, s/he should still be recorded as age 17.

Item 4. Has this patient suffered an acute subarachnoid hemorrhage? There are two choices, check one.

Comment: An acute subarachnoid hemorrhage is defined as blood in the subarachnoid space, with the ictus occurring within the recent past (e.g., 30 days) prior to completion of this form. Note that this diagnosis should not be "speculative" but should be based solely on either CT/MRI evidence or by bloody or xanthrochromic CSF on lumbar puncture (LP). A patient with a history of sudden headache, but with negative CT/MRI and/or LP should be classified as "No".

No: If the answer to this question is "No" (i.e., the patient is undergoing surgery for an unruptured aneurysm) your record keeping activities with respect to this patient are completed. The completed SCREENING form should be filed in your local Patient log.

Yes: If the answer to this question is "Yes", the patient is potentially eligible for study. You should hence proceed to the ELIGIBILITY form.

IX. B ELIGIBILITY FORM

IX.B.1. Overview:

The SCREENING form needs to be completed for ALL patients undergoing craniotomies for aneurysm clipping (with or without SAH). Sections A and B of the ELIGIBILITY form must be filled out on ALL patients with SAH scheduled for clipping of an aneurysm, regardless of whether or not they are eligible for the study. This form should be filled out no more than 24 hours prior to the time of the scheduled surgery.

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The ELIGIBILITY form for non-eligible patients should be kept in the Patient Log binder. ALL ELEMENTS MUST BE COMPLETED REGARDLESS OF ELIGIBILITY STATUS. Note that the white originals of the ELIGIBILITY form for all non-eligible patients must be sent to the DMC on the last working day of each month.

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IX.B.2. Data Items

Section A: Inclusion Criteria

Item 1. Age 18 years or older? There are two choices, check one.

Comment: To be eligible for inclusion in the study, patients must be 18 years or older. This is defined as having had their 18th birthday. In other words, a patient that is 17 years 363 days old is NOT eligible for inclusion.

Item 2. Aneurysm verified by imaging methods? There are two choices, check one.

Comment: This item should be checked “YES”, only if the presence and location and approximate size of at least one intracranial aneurysm has been documented by an imaging technique such as angiography, MRI angiography, etc.

Item 3. Primary SAH (proven by CT or lumbar puncture) within 14 days prior to surgery without intervening discharge? There are two choices, check one.

If the answer is "Yes", please record the date on which they suffered their most recent hemorrhage in the space provided.

Comment: This is a study of acute SAH. To be eligible for inclusion in the study, patients must have suffered their SAH 14 or fewer days prior to the planned date of surgery. Primary SAH refers to the SAH which, because of severity of symptoms, directly leads to hospital admission and subsequently planned aneurysm surgery. "Warning leaks" (moderate headaches resulting from small aneurysmal hemorrhages in the days to weeks proceeding a major SAH, but which do not result in direct hospital admission) are not considered to be the primary SAH.

Item 4. Planned open craniotomy within 24 hours of patient assessment for study? There are two choices, check one.

If the answer is "Yes," please record the planned date of surgery in the space provided, even if this is the same as the date of form completion (found in the footer section of the form). Also provide an estimate of the planned starting time for this procedure in the space provided.

Comment: Example - If you are filling out this form at 1800 hours on the evening of July 22, and surgery is planned to commence at 0800 on the morning of July 23, then July 23rd, 0800 hours should be written into the appropriate blanks. Similarly, if the form is completed at 1800 hours on July 22 and surgery is planned to commence in one hour, then July 22, 1900 hours should be written into the appropriate blanks.

Item 5. Pre-SAH Rankin disability score of 0 or 1? There are two choices, check one.

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Comment: The Rankin score is an assessment of functional status/disability. Since we do not wish to enroll patients who were severely disabled prior to their SAH (a factor that would seriously complicate assessment of the impact of surgery per se), eligibility requires that patients have had a Rankin disability score of 0 or 1 prior to suffering the subarachnoid hemorrhage, which is the cause for their planned surgery (their “primary” SAH). The definitions for the various Rankin scores are provided. Please fill in the appropriate space. Note that in most cases this information will be obtained by patient/family interview. Again, this information pertains ONLY to the patient's condition prior to the current SAH, and should not be based on their current neurologic/functional status.

Item 6. A full course of nimodipine therapy is planned? There are two choices, check one.

Comment: Nimodipine is known to influence neurologic outcome following SAH. To avoid variability, nimodipine therapy must have been started or planned for patients to be eligible for enrollment.

Item 7. WFNS score of I, II, or III assessed within 12 hours prior to surgery? There are two choices, check one.

Also, provide the date and time (24-hour clock) when the WFNS score was assigned.

Comment: Patients with WFNS score of IV or V do very poorly after surgery, regardless of other therapy. To avoid obscuring the impact of hypothermia on outcome, we have elected NOT to enroll patients with such poor WFNS scores. WFNS scores often fluctuate. Hence, to be eligible, the patient must have a WFNS score of I, II or III as assessed no more than 12 hours prior to the time of planned surgery. A worksheet containing criteria for both the Glasgow Coma Score and the WFNS is provided. Please complete all items on this worksheet.

Note: A patient whose admitting WFNS score was IV may be eligible if, at the time of eligibility assessment, the score has improved to III or better. In other words, we are concerned only with WFNS scores recorded close to the time of actual surgery.

Section B: Exclusion Criteria

Item 1. Endotracheally intubated at the time of WFNS score? There are two choices, check one.

Comment: It is difficult to accurately assess the verbal component of the GCS in intubated patients. Hence patients who are endotracheally intubated at the time of the eligibility evaluation are NOT eligible for enrollment.

Item 2. BMI > 35 kg/m 2 ? There are two choices, check one.

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In addition, the patient's weight (kg), height (meters), and height2 (meters) should be entered in the appropriate spaces, along with their calculated body mass index (BMI). A nomogram (behind page 3 of the ELIGIBILITY form) has been provided for weight and height conversions.

Comment: With current technology, obese patients cannot be reliably cooled, at least within a reasonable time frame. As a result, obese patients (defined as having a body mass index of greater than 35 kg/m2) are not eligible.

Item 3. Woman known to be pregnant or to have a positive or indeterminate pregnancy test? There are two choices, check one.

Comment: Pregnant women are not eligible. In all premenopausal women a pregnancy test must be performed, using whatever test is standard in your institution. If this test is positive or if the test is indeterminate, check "Yes."

Item 4. Prior aneurysmal SAH and/or prior craniotomy for aneurysm clipping within 3 months prior to current SAH? There are two choices, check one.

Comment: Patients who have undergone a recent craniotomy for aneurysm clipping may be inordinately susceptible to perioperative injury. Hence patients who have undergone open clipping of ANY aneurysm (ruptured or not) within three months prior to the date of the planned current surgery are not eligible for enrollment.

Item 5. Planned second craniotomy within 3 months after surgery for this SAH? There are two choices, check one.

Comment: All enrolled patients will be carefully followed for three months after the planned surgery. Any intervening surgery could seriously complicate data assessment. We realize that some patients will require additional surgical procedures for many reasons. However, we do not wish to enroll patients in whom the surgeon already knows that a second craniotomy will be required (e.g., to clip a second aneurysm), and that procedure is scheduled to occur sooner than the three-month final follow-up date. Similarly, if a patient has a second aneurysm that the surgeon plans to coil within three months, the patient should not be enrolled.

Item 6. Aneurysm to be clipped has been previously coiled or treated by other endovascular procedure? There are two choices, check one.

Comment: Surgical procedures needed to clip a previously coiled aneurysm are quite different from routine. If the aneurysm scheduled to be clipped has been previously coiled, the patient is not eligible. Note, however, that this does not eliminate a patient in whom a different aneurysm has been previously coiled or treated with an endovascular procedure.

Item 7. Previously randomized in IHAST2 ( RANDOMIZATION ENVELOPE opened) ? There are two choices, check one.

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Comment: No patient may be enrolled in this study twice. Randomization occurs at the moment that the RANDOMIZATION ENVELOPE is opened. This would include any enrolled patient who has undergone a clipping, been followed for the full three-month period - and who then suffers a new SAH.

Item 8. Currently enrolled in other clinical or therapeutic trial? There are two choices, check one.

Comment: NIH rules (and good clinical practice) dictate that patients cannot be enrolled simultaneously in two trials. However, we recognize that various PCC’s may enroll patients in a parallel data collection study that does not involve any changes in protocol. If there are any doubts or questions, please contact the CCC.

Item 9. History of severe cold-related disease (cryoglobulinemia, Raynaud's, sickle cell)? There are two choices, check one.

Comment: There are no absolute medical exclusion criteria for this study. Hence, this item requires a judgment be made by the involved local physicians regarding the severity of the disorder. The key is that the physician assesses the relative risk of cooling for this specific patient. For example, a patient with very mild Raynaud's, with symptoms suffered only when exposed to sub-zero cold may be deemed eligible. Note: This decision must be made by the local physicians - it cannot be made by the CCC.

Item 10. Severe medical or psychiatric illness, or active life-threatening disease? There are two choices, check one.

Comment: There are no absolute medical exclusion criteria for this study. This item requires a judgment be made by the involved local physicians regarding the severity of the disorder. The key is that the physician assess the relative risk of cooling for this specific patient. For example, a patient with stable ischemic heart disease might be viewed as eligible, while a patient with unstable angina, a recent myocardial infarction, or severe congestive failure might be deemed ineligible. Similarly, a patient with well controlled schizophrenia may be deemed eligible, while another patient with more severe disease might be deemed ineligible. Note: This decision must be made by the local physicians - it cannot be made by the CCC.

Item 11. Other contraindications to the protocol anesthetic? There are two choices, check one.

Comment: There are no absolute medical exclusion criteria for this study. This item requires a judgment be made by the involved local physicians regarding the severity of the disorder. The key is that the physician assess the relative risk for this specific patient. For example, a patient with a history of malignant hyperthermia would probably be deemed ineligible, due to the mandated inclusion of isoflurane in the protocol. Conversely, a patient known to be allergic to thiopental might be included, since an alternative induction agent could be chosen (i.e., etomidate). Note: This decision must be made by the local physicians - it cannot be made by the CCC.

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If any question in section A is answered “NO,” or any question in section B is answered “YES,” then patient is NOT eligible. If NOT eligible, please sign form at bottom of page 2 and file in Patient Log binder. If patient IS eligible, continue with Section C.

Section C: Procedural Criteria

Comment: It is entirely possible for a patient to be medically eligible for inclusion, but for a variety of non-medial reasons, cannot be enrolled.

Item 1. Certified IHAST2 study personnel available to carry out the protocol? There are two choices, check one.

Comment: All aspects of the preoperative assessment, intraoperative care and postoperative follow-up assessments must be performed by individuals certified by the CCC (e.g., a certified Study Coordinator, a certified anesthesiologist, a certified neurosurgeon, a certified neurologic examiner, etc.). If such individuals are not available (e.g., if no certified anesthesiologist is available due to vacations), the patient should not be enrolled.

Item 2. Patient expected to be available for 3-month evaluation? There are two choices, check one.

Comment: It is critical that all patients be followed for the full three-month postoperative period. If you know in advance that a patient will be lost to follow-up (e.g., they plan to leave the country), they should not be enrolled. Note however that follow-up can be performed at another PCC. If, for example, surgery was performed in Vienna, Austria, but patient was planning to return after surgery to Los Angeles, California, follow-up at a PCC in Los Angeles would be possible and the patient may be deemed eligible.

Item 3. Appropriate language translators available if needed for all evaluations? There are two choices, check one.

Comment: To collect the needed information, the Local Study Coordinators, surgeons, anesthesiologists and neurologic examiners must be able to communicate with the patient (at least as well as the patient’s neurologic status permits). Language translation must be available if required.

Item 4. Surgeon and Anesthesiologist agree to proceed with IHAST2 protocols? There are two choices, check one.

Comment: There may be many reasons that a participating physician may choose not to enroll a patient or proceed with the protocol, even though a patient is otherwise eligible. It is important that we track such "drop outs."

Item 5. Written and witnessed informed consent obtained? There are two choices, check one.

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If "Yes" is checked, provide the date of consent.

Comment: Obviously only consented patients can be enrolled. If a patient declines consent, please check "No." However, detailed patient information can be collected only for consented patients.

If any question in section C is answered “NO,” then patient is NOT eligible. If NOT eligible, please sign form at bottom of this page and file in Patient Log binder. If patient IS eligible, continue with section D.

Section D: Patient Enrollment

If patient meets all inclusion criteria (all section A items are checked "Yes"), has no exclusionary conditions (all section B items are checked "No"), meets all procedural criteria (all section C items are checked "Yes") AND the SCREENING and ELIGIBILITY forms are completed, you are ready to proceed with obtaining the randomization information. This is done by contacting the DMC by telephone to enroll the patient and obtain the enrollment assignment.

THIS TELEPHONE CALL TO THE DMC SHOULD NOT BE MADE MORE THAN TWO HOURS PRIOR TO THE PLANNED TIME OF SURGERY.

To facilitate this telephone contact process, please have the completed ELIGIBILITY form immediately available during the enrollment call; you will be asked to enter certain data from this form at the time of the call. Also, make sure that you have your personal Certification Number available; it is critical that all individuals calling the DMC enrollment system be identifiable by this number. Note that non-certified persons cannot make this call. (For a discussion of the automated telephone randomization system see Chapter VI of the Operations Manual.)

The DMC automated telephone randomization system can be reached at the following number:

1-319-353-4708

At the conclusion of the enrollment call, you will be given a "Patient Identification (PID)" number as well as the color of the RANDOMIZATION ENVELOPE, which contains the assigned temperature group. Please record this information (PID and envelope color) on the form in the appropriate spaces.

DO NOT OPEN THE RANDOMIZATION ENVELOPE AT THIS TIME. The envelope is to be opened only by the study Anesthesiologist after induction of anesthesia.

IX. C CONTACT FORM

IX.C.1. Overview:

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This form is only for the internal use of the PCC’s. Since post-discharge follow-up is so critical to the success of this trial, it is important that information needed to contact the patient after discharge be carefully collected. To minimize the chances of losing a patient to follow-up, we strongly suggest that you collect the names, addresses, phone numbers, etc. for not only the subject, but also for any referring or local physician, for their next of kin (e.g., any individual who might have signed or co-signed the consent documents), and/or anyone else who is likely to know the patient’s whereabouts in the future.

There are confidentiality issues related to the collection of this data.

This form should be completed only for patients for whom a signed consent document has been obtained. This form should not be completed for patients without signed consent documents (collection of such data regarding non-consenting patients may constitute a violation of your IRB agreement).

Since PCC personnel will complete all follow-up, you should NOT send copies of this form to the DMC.

Do not collect names/addresses, etc. of individuals other than the patient without informing them of the reason for collecting this data. Serious difficulties might arise if an uninformed next door neighbor were contacted two months after discharge (perhaps because there was no answer at the patient’s home) - and complain to your local institution that "I never gave them permission to contact me" or "How did they get my phone number?" or "Why are they asking questions about my friend?"

IX.C.2. Data Items

Patient Information: Self-Evident.

Referring or Personal physician: Many patients have a family physician that is likely to know of their post-discharge condition or whereabouts.

Next of Kin (Or Consenting Person If Not Patient): Ideally, this would be an individual living with the patient (a spouse, child, parent, etc.) or other relative who will be familiar with their condition or whereabouts.

Person Likely to Know Outcome/Whereabouts of Patient in the Future: This could be a live-in partner, next door neighbor, close friend, etc.

IX. D PRE-SAH HISTORY FORM

IX.D.1. Overview:

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Any certified IHAST2 physician or Study Coordinator may complete this form. Usually, the Study Coordinator will complete this form. The purpose of the PRE-SAH HISTORY is to characterize the patient’s overall medical and neurological condition prior to the onset of their SAH. This information is necessary in order to establish study eligibility and, in enrolled patients, to identify those who may be at increased risk of perioperative complications. Information regarding the patient’s past medical history will likely come from a variety of sources: the patient, the patient’s family, “outside” physicians, records from your hospital, and records from other hospitals. Any and all sources of information may be used.

In general, the need for documentation of whether a given condition existed prior to the primary SAH need not exceed that which would ordinarily be necessary to adequately care for the patient before, during, and after their aneurysm surgery. For example, if the patient tells you that they are a diabetic, that is probably sufficient—It is not necessary to contact the local physician for results of a glucose tolerance test to prove that the patient is a diabetic. Alternatively, if the patient’s family tells you that “there is some problem with a heart valve,” that is not sufficient because some heart valve problems are inconsequential and others are serious. In this case, further information should be sought to learn exactly what type of valvular problem exists. Obviously, judgment is required in deciding how much “digging” and documentation are needed for characterize any given condition.

Largely because the patient’s past medical history is derived from many sources (both historical and objective) there will be varying degrees of confidence in whether a given condition truly exists. Accordingly, for each condition, we ask for your best judgment (based on your overall impression of the reliability of the data) as to whether a given condition is definitely present (“Definite”), probably present (“Probable”) or not present (“No”). To be “Definite ,” your confidence that the condition exists should exceed 90-95%. To be considered “Probable ,” your confidence that the condition exists should exceed 70% (but be less than 90-95%). Check “No ,” if your confidence that the condition exists is less than 70%. Our goal is specificity of diagnosis, not sensitivity. You need to judge the quality of the history, the historian, and other documentation to form your overall judgment. For example, if a lucid patient clearly tells you, “I had a heart attack two years ago and I have been taking nitrates and beta-blockers for my angina ever since,” we would consider this to be a “definite” prior history of abnormalities in coronary circulation (Section B, item1), even though formal documentation of coronary artery disease is lacking. If on the other hand, a patient tells you, “I have some chest pain now and then, but I haven’t seen a doctor about it,” this alone would not be sufficient to check either “probable” or “definite.”

Instruction box: All information pertains to events occurring or existing PRIOR TO THE CURRENT SAH.

IX.D.2. Data Items

a) Section A. Neurologic History Prior to Current SAH

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Comment: Because pre-existing neurologic disease or injury may affect the patient’s ability to recover from an aneurysmal SAH, it is important to characterize the patient’s baseline neurologic condition.

Item 1. Prior history of occlusive cerebrovascular disease?

There are three choices (No, Probable, Definite), check one.

Comment: Conditions in this category result in neurologic signs and symptoms because of a reduction of cerebral blood flow resulting from occlusive abnormalities in the cerebral vasculature (usually on the basis of atherosclerosis). Less common forms of occlusive cerebrovascular disease include Moyamoya disease and primary CNS vasculitities. Common manifestations may include transient or permanent focal motor (weakness) or sensory deficits (“numbness”), speech deficits, visual disturbances, or sudden transient loss of postural tone or consciousness (“drop attacks”). Such conditions include transient ischemic attacks (TIAs), reversible ischemic neurologic deficits (RINDs), ischemic cerebral infarction (“stroke”), and vertebrobasilar insufficiency (VBI). The only asymptomatic condition that is in this category is documented asymptomatic carotid stenosis.

If either Probable or Definite is checked, please indicate (No/Yes) whether the patient has a history of either Prior carotid endarterectomy (CEA) or carotid angioplasty, or Prior ischemic stroke. If the patient has had a prior ischemic stroke, please check “Yes” regardless of whether neurologic signs and symptoms have resolved by the time of the current SAH, and enter the date of the most recent stroke (month/day/year, in numeric fashion) in the space provided.

Item 2. Prior history of hemorrhagic cerebrovascular disease?


Comment: Conditions in this category result in neurologic signs and symptoms and are accompanied by intracranial bleeding. Such conditions include prior bleeding (subarachnoid or intraparenchymal) from cerebral aneurysms or arteriovenous malformations. Other causes of intracranial hemorrhage include primary hypertensive hemorrhages and hemorrhagic transformation of an ischemic stroke. Unruptured cerebral aneurysms or AVMs do not qualify because they have not bled.

If either Probable or Definite are checked, please indicate (No/Yes) whether the patient has a history of either: Prior aneurysmal subarchnoid or intracerebral hemorrhage (this is specific for cerebral aneurysms only), or Prior subarachnoid or intracerebral hemorrhage (from all other non- aneurysm causes) , or Prior cerebral aneurysm clipping or coiling. If the patient has had a prior aneurysmal hemorrhage, please enter the date of onset of the most hemorrhage (month/day/year, in numeric fashion) in the space provided. If the patient has undergone a prior cerebral aneurysm clipping or coiling, please enter the date of onset of the most recent procedure (month/day/year, in numeric fashion) in the space provided.

Item 3. Prior history of brain tumors, intracranial mass lesions and/or infection?


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Comment: Conditions in this category include conditions associated with mass lesions (brain tumors, intracranial cysts) and/or increased intracranial pressure (tumors, hydrocephalus) and/or central nervous system infections (meningitis, encephalitis)

If either Probable or Definite is checked, please indicate (No/Yes) whether the patient has a history of either: Brain tumor or other intracranial mass lesion, or Hydrocephalus, or Meningitis or encephalitis, or Previous craniotomy or other neurologic surgery (not noted in Item 2, above).

Item 4. Prior history of severe head trauma?

There are three choices (No, *Probable, *Definite), check one.

Comment: Conditions in this category should include only episodes of head trauma that were truly severe. Instances of head trauma that did not result in hospitalization do not qualify. Only when the patient was unconscious for >24 hours, or there is unequivocal documentation of trauma-related neurologic injury should “Definite” be checked. Head trauma which resulted in hospitalization, but did not lead to unconsciousness for >24 hours, should be checked as “Probable.”

Instruction box: *Probable: hospitalization for head trauma, with no data or limited period of unconsciousness. *Definite: unconscious for >24 hours.

Item 5. Prior history of epilepsy ( not including seizures associated with current illness )?


Comment: Conditions in this category are those where the patient exhibits transient neurologic dysfunction resulting from excessive abnormal electrical discharges of cerebral neurons. Seizures can either be generalized (i.e., tonic-clonic activity) or partial (simple partial if focal symptoms and no impairment of consciousness, and partial complex if consciousness altered). Febrile seizures in childhood do not qualify.

Item 6. Prior history of MAJOR cognitive or psychiatric disease?


Comment: Conditions where the patient has significant limitations or disabilities in cognition, emotional control, thought-disorders, or behavior. Such disorders would include severe impairment of orientation or memory, impulse control, major phobias, schizophrenia, or depression. Such disorders usually require hospitalization and/or chronic treatment.

Item 7. Prior history of other MAJOR neurologic disorder?


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Comment: If the patient has a prior history of some other major neurologic disorder which may influence the patient’s ability to regain full function after an aneurysmal subarachnoid hemorrhage, and this disorder is not appropriately characterized by Items A.1.-6., check Definite. If you believe that this represents critical information, comments should be filed via the IHAST2 web page.

b) Section B. Cardiovascular History Prior to Current SAH

Comment: Because some studies suggest intraoperative hypothermia may increase the risk of postoperative cardiovascular complications, it is necessary to characterize the patient’s pre-SAH cardiovascular status as completely as possible.

Item 1. Prior history of abnormalities in coronary circulation?


Comment: Conditions in this category are those which affect the coronary arteries and result in myocardial hypoperfusion (myocardial ischemia) and/or myocardial cell death (myocardial infarction) as a result of inadequate coronary artery blood flow. Usually, these conditions are due to coronary atherosclerosis, but coronary vasospastic conditions (e.g., variant or Prinzmetal’s angina) are also included. Classic angina (substernal chest pain) is perhaps the most obvious manifestation of this condition, but only some people with coronary disease have angina.

If either Probable or Definite is checked, please indicate (No/Yes) whether the patient has a history of either: Myocardial infarction (“heart attack”), or Angina, or Positive medical testing for myocardial ischemia, or Coronary artery surgery (“CABG”) or coronary angioplasty. If the patient has had a prior myocardial infarction, please enter the approximate date of onset of the most recent infarction (month/day/year, in numeric fashion) in the space provided. Positive medical testing for myocardial ischemia includes characteristic electrocardiographic, echocardiographic, or perfusion abnormalities with stress testing (exercise or pharmacologically induced), or demonstration of coronary artery disease with coronary angiography.

Item 2. Prior history of abnormalities in ventricular function?


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Comment: Conditions in this category are those in which either left or right ventricular systolic (pumping) function is impaired. Often, ventricular impairment is the result of myocardial damage from coronary artery disease, but primary diseases of the myocardium, pulmonary vasculature, or cardiac valves can lead to ventricular failure. With impaired left ventricular function, clinical signs and symptoms derive both from abnormally high left ventricular end diastolic pressure (resulting in translocation of fluid from the pulmonary capillaries into the pulmonary interstitial and/or alveolar spaces, “pulmonary edema”) and/or low systemic cardiac output. Signs and symptoms include elevated jugular venous pressure, peripheral edema, dyspnea at rest or on extertion, orthopnea, S3 gallop, rales and radiologic evidence of pulmonary congestion (increased pulmonary vascular markings and/or alveolar consolidation). Signs of low cardiac output may include relative hypotension; pallor or cool extremities; and impaired renal function. With right ventricular failure, elevated central venous pressures promote peripheral edema, liver enlargement, and ascites. Sometimes, medical therapy can largely eliminate these signs and symptoms--and patients are said to have “compensated” congestive failure. Even if well “compensated” at the time of onset of the SAH, these patients should be considered to have underlying ventricular dysfunction.

If either Probable or Definite is checked, please indicate (No/Yes) whether the patient has a history of either: Congestive heart failure or pulmonary edema or right heart failure, or documented left ventricular ejection fraction (LVEF <40%), or major wall motion abnormalities on echocardiogram, angiography or radionuclide scan.

Item 3. Prior history of major abnormalities in valvular function?

There are three choices (*No, Probable, Definite), check one.

Comment: Conditions in this category are those in which there is a major clinically significant abnormality of cardiac valvular function, (e.g., aortic stenosis or regurgitation, mitral stenosis or regurgitation, pulmonic stenosis, and possibly tricuspid regurgitation). Mitral Valve Prolapse qualifies only if the patient is has major symptoms (e.g., arrythmias, syncope, chest pain). Patients with a history of a “murmur” but who do not have a formal diagnosis and/ or have not undergone a formal evaluation do not quality. It is not necessary to specify the precise nature of the valvular abnormality.

Instruction box: *Patients with history of “murmur” but without other workup or diagnosis should be classified as “No”. *Patients with mitral valve prolapse by exam but without symptoms (arrhythmia, chest pain, etc.) should be classified as “No”.

If either Probable or Definite is checked, please indicate (No/Yes) whether the patient has a history of previous valvular surgery

Item 4. Prior history of rate or rhythm disturbances?

There are three choices (*No, Probable, Definite), check one.

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Comment: Conditions in this category are those in which there is a clinically significant abnormality of heart rate or rhythm. Patients with a history of only “palpitations,” “skipped-beats” or “irregular heart rate” and no other symptoms and/or no other documentation of a major cardiac rate or rhythm abnormality should be checked “No.”

Instruction box: *Patients with a history of “palpitations” but without other workup or formal diagnosis should be classified as “No.”

If either Probable or Definite are checked, please indicate (No/Yes) whether the patient has a history of either: atrial –fibrillation or –flutter, or other supraventricular dysrhythmia, or ventricular –fibrillation or tachycardia, or cardiac arrest, or bradycardia or sick sinus disorder, or has a Pacemaker or implanted defibrillator. Other supraventricular dysrhythmias include any clinically symptomatic abnormal rapid supraventricular rhythm such as paroxysmal atrial tachycardia (PAT), multifocal atrial tachycardia (MAT), paroxysmal supraventricular tachycardia (PSVT), AV nodal re-entrant tachycardias (like Wolff-Parkinson-White). It is not necessary to specify the type of abnormality.

Item 5. Prior history of peripheral vascular disease?


Comment: Conditions in this category are those in which there is clinically significant occlusive disease of the peripheral vasculature, usually on the basis of atherosclerosis. Carotid artery disease is not included in this category (because carotid disease is addressed in section A, Item 1.). Rare forms of non-atherosclerotic vascular occlusive disease are also included in this category.

If either Probable or Definite is checked, please indicate (No/Yes) whether the patient has a history of lower extremity claudication, ischemic ulcer or ischemic limb, or has undergone Abdominal aortic and/or peripheral vascular surgery or angioplasty.

Item 6. Prior history of hypertension?


Comment: Conditions in this category are those in which, either by history, or by objective criteria, the patient is considered to have an abnormally increased systemic arterial pressure (“hypertension”) prior to their aneurysmal SAH. Hypertension is considered to exist whenever either: 1) the diastolic blood pressure is greater than or equal to 90 mm Hg (12 kPa); or 2) mean arterial pressure (MAP) is greater than or equal to 120 mm Hg (16 kPa). Even if the patient is hypertensive after their aneurysmal SAH, if they have no history of hypertension before their SAH, then check “No.”

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If either Probable or Definite is checked, please classify the patient’s hypertension using one of three options. It is common for patients to have a history of hypertension, but with effective treatment (medication, diet, weight loss), to no longer meet the criteria for hypertension. Such patients are classified as 1-“Treated and Controlled”. It is also common for patients to be treated for hypertension but to remain hypertensive. These patients are classified as 2-“Treated and Uncontrolled”. Finally, some patients who have a history of hypertension have not received treatment. This last group is classified as 3-“Untreated.”

Item 7. Other prior MAJOR cardiovascular disorders not specified above?


Comment: If the patient has a prior history of some other major cardiovascular disorder which may influence the patient’s ability to regain full function after an aneurysmal subarachnoid hemorrhage, and this disorder is not appropriately characterized by Items B.1.-6., above, please check “Yes.”

c) Section C. Respiratory History Prior to Current SAH

Comment: Because pulmonary complications are relatively frequent after aneurysmal SAH, it is important to characterize the patient’s baseline pulmonary function.

Item 1. Prior history of smoking cigarettes?


Comment: Cigarette smoking is well established as a major risk factor for the development of aneurysmal SAH, whereas other tobacco use (pipe, cigar, etc.) is not. That is why we ask only for history of cigarette use.

If either Probable or Definite is checked, please indicate (No/Yes) to classify the patient’s smoking using one of two options. 1-“Current”: the patient was smoking up to the time of their aneurysmal SAH or quit smoking less than six months prior to their SAH. 2-“Former”: the patient quit smoking more than six months prior to their SAH.

Item 2. Prior history of clinical respiratory dysfunction?


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Comment: Conditions in this category are those which result in major functional limitation of respiratory function. Hence, if there is/was no major functional limitation associated with the condition, check “No.” For example, if a patient has a history of pneumonia that did not require hospitalization and resolved without chronic sequellae, check “No.” Similarly, mild-to-moderate asthma or a history of intermittent respiratory tract infections would probably not qualify so long as the patient had no major functional limitations and had not required hospitalization for these conditions. Any respiratory condition that leads to chronic hypoxemia or hypercarbia, or has required either hospitalization or chronic treatment would qualify.

If either Probable or Definite are checked, please indicate (No/Yes) whether the patient has a history of shortness of breath with daily activities, or Prior hospitalization for any respiratory disease, or Previously intubated for respiratory failure, or Home oxygen use or home CPAP (constant positive airway pressure).

Item 3. Prior history of chronic reactive or obstructive lung disease?


Comment: Conditions in this category are those associated with small airways disease such as asthma, chronic bronchitis, emphysema, and chronic obstructive pulmonary disease. In many instances, mild-to-moderate pulmonary conditions (conditions that do not result in major functional limitations’ “No” in Item 2, above), would be checked as “Probable” or “Definite” in this category. For example, well controlled chronic asthma.

Item 4. Prior history of thoracic surgery?


Comment: Any instance in which the patient has undergone any type of thoracic surgery qualifies under this category. Examples would include pulmonary lobectomy, pneumonectomy, bleb resection, pleurodesis, or mediastinal surgery.

Item 5. Other prior MAJOR lung disase or respiratory disorder?


Comment: If the patient has a prior history of some other major lung disease or respiratory disorder which may influence the patient’s ability to regain full function after an aneurysmal subarachnoid hemorrhage, and this disorder is not appropriately characterized by Items C.1.-4., above, please specify the condition in the space provided (e.g., cystic fibrosis, lung cancer).

d) Section D. Coagulation Disorders Prior to Current SAH

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Comment: Because some studies indicate intraoperative hypothermia may increase perioperative blood loss, it is necessary to establish whether the patient has any history of coagulation abnormalities.

Item 1. Prior history of deep vein thrombosis, thrombophlebitis, or pulmonary embolism?


Comment: Deep vein thrombosis and/or pulmonary embolism is a common occurrence after cerebral aneurysm surgery. Patients with a prior history suggestive of hypercoagulability, or an anatomic predisposition to deep vein thrombosis may be at increased risk.

Item 2. Prior history of bleeding or coagulation disorder?


Comment: Conditions in this category are those that predispose the patient to bleeding with trauma or surgery, i.e., major coagulopathies. Common examples would include hemophilia (factor VIII-Hemophilia A, or IX deficiency-Hemophilia B) or platelet function disorders (von Willebrand’s disease or Bernard-Soulier). However, sometimes coagulopathies exist without a formal diagnosis. Hence, if the patient (or family) relates a history of severe and unusual bleeding with surgery, trauma, or childbirth that cannot otherwise be explained by the circumstances, please check “Probable.”

If either Probable or Definite are checked, please indicate (No/Yes) whether the patient has a history of Severe bleeding with surgery, trauma or childbirth, or Hemophilia A or B, or Platelet disorder (e.g., von Willebrand’s), or Other type of illness that results in a propensity towards bleeding (e.g., thrombocyopenia)

e) Section E. Other Disorders Prior to Current SAH

Item 1. Diabetes Mellitus?


Comment: Diabetes mellitus refers to a group of disorders that result in hyperglycemia because of deficient pancreatic insulin production. If the patient only had diabetes during pregnancy (“gestational” diabetes) and has not required therapy after pregnancy, check “No.” If the patient’s diabetes is sufficiently mild as to require only dietary therapy or to have resolved with weight loss, check “Probable.” If the patient receives either oral hypoglycemic medications and/or insulin, check “Definite.”

Item 2. Renal Failure requiring hemodialysis or peritoneal dialysis?


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Comment: Although patients may have some degree of renal impairment, if the impairment is not sufficiently severe as to require either hemodialysis or peritoneal dialysis, check “No.”

Item 3. Current alcohol abuse or dependence?

There are three choices (No, Probable, Definite), check one, as it pertains to alcohol (ethanol).

The following definitions for substance Abuse and Dependence are derived from the “Diagnostic and Statistical Manual of Mental Disorders, 4th Edition”, published by the American Psychiatric Association.

Substance Abuse: A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following within a 12-month period:

Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home.

Recurrent substance use in situations in which it is physically hazardous (e.g., driving a car while impaired by the substance).

Recurrent substance-related legal problems.

Continued substance use despite having persistent or recurrent social or interpersonal problems caused by, or exacerbated by, the effects of the substance.

Substance Dependence: A cluster of cognitive, behavioral, and physiological symptoms indicating that an individual continues use of the substance despite significant substance-related problems. There is a pattern of repeated self-administration that usually results in tolerance and compulsive drug-taking behavior. Dependence is defined as the presence of three (or more) of the following conditions within a 12-month period:

Tolerance, as demonstrated by either: a) a need for markedly increased amounts of substance to achieve intoxication or desired effect, or b) markedly decreased effect with continued use of the same amount of substance.

Withdrawal, as demonstrated by either: a) characteristic withdrawal symptoms of the substance when not provided; or b) the same or a related drug is take to relieve or prevent withdrawal symptoms.

The substance is often taken in larger amounts, or over a longer period, than intended.

The individual has a persistent desire and/or unsuccessful efforts to decrease or control the use of the substance.

A great deal of the individual’s time is devoted to either obtaining, using, or recovering from the effect of the substance.

Important social or occupational activities are reduced because of the substance or its effect.

The individual continues to use the substance, despite knowledge of the negative effects of the substance on their life.

Item 4. Current cocaine, opioid, or amphetamines abuse or dependence?

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There are three choices (No, Probable, Definite), check one, as it pertains to cocaine, opioids, or amphetamines.

Please see definitions of abuse and dependence in Item 3 above. An opioid is a drug that acts via endogenous opioid receptors (e.g., heroin, opium, morphine, meperidine, fentanyl, oxycodone, etc.)

Item 5. History of hepatitis?

There are three choices (No, *Probable, Definite), check one.

Comment: The patient may have had any form of hepatitis (infectious agent, drug-induced, alcohol-related, etc.). If only a history of “jaundice” is obtained, without any other specific diagnosis, check “probable”, although this excludes neonatal jaundice.

Instruction box: *Check “probable” for a history of “jaundice” without more specific diagnosis.

Item 6. History of HIV or AIDS?


Comment: Indicate whether the patient has a history of being infected with the Human Immunodeficiency Virus (HIV, any type) or has Acquired Immunodeficiency Syndrome (AIDS).

Item 7. Known susceptibility to infection or immunologic compromise?


Comment: Conditions in this category are those which predispose the patient to infectious disease. Included are primary immunodeficiency diseases (Wiskott-Aldrich syndrome, Di George syndrome) and/or neurotrophil abnormalities (neutropenia or Chédiak-Higashi syndrome). Patients on immunosuppressive therapy (for example, patients who have had an organ transplant or who have a severe inflammatory condition) would also be included.

Item 8. History of recurrent or severe cutaneous infections requiring therapy?


Comment: Patients who have a history of recurrent or severe infections of the skin such as recurent impetigo, erysipelas, folliculitis, furuncles and carbundles (boils/abscesses).

Item 9. History of any malignancy not noted above (includes leukemia, lymphoma, etc.)?


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Last question. Have you checked probably or definite for items A7, B7, C5, or D2 (Other) or has there been any other MAJOR surgical procedures prior to the current SAH, or are they any additional comments you would like to add regarding the patient information on this form? There are two choices, check one.

No: There are no comments or additional information that you wish to communicate regarding the patient’s past medical history.

Yes: There are comments or additional information that you wish to communicate regarding the patient’s past medical history.

Instruction box: If yes, please go to web address http://ctsdmc.public-health.uiowa.edu/ihast2/comment/

Comment: Hand-written comments in page margins of this form cannot be recorded as data. If you have comments that you would like to make regarding any aspect of the patient’s past medical history, please file them at the web address above.

IX. E POST-ADMIT SCREEN

IX.E.1. Overview:

Any certified IHAST2 certified physician or Study Coordinator may complete this form. Usually, the Study Coordinator will complete this form. However, any certified -neurosurgeon or -anesthesiologist may also complete this form.

Items on this form refer to conditions and/or events occurring between the time of initial hospitalization for the primary subarachnoid hemorrhage and going to the operating room for the primary aneurysm surgery.

Initial hospitalization is considered to begin at the time when the patient presents to any hospital (emergency room or clinic) with the history, signs, and/or symptoms related to the primary subarachnoid hemorrhage, even if the patient is subsequently transferred to another hospital for care.

Primary subarachnoid hemorrhage refers to the subarachnoid hemorrhage which, because of severity of symptoms, directly leads to hospital admission and subsequently planned aneurysm surgery. "Warning leaks" (moderate headaches resulting from small aneurysmal hemorrhages in the days to weeks proceeding a major SAH, but which do not result in direct hospital admission) are not considered to be the primary subarachnoid hemorrhage.

Primary aneurysm surgery refers to cerebral aneurysm surgery that occurs as a direct result of the primary subarachnoid hemorrhage and which is intended to provide definitive therapy for the symptomatic (ruptured) aneurysm. Separate preparatory procedures in the days prior to definitive aneurysm surgery (e.g., clot evacuation and/or placement of a ventriculostomy) are not primary aneurysm surgery. Aneurysm surgery occurring at any time after completion of the primary aneurysm surgery is not characterized as primary aneurysm surgery. Rather, all subsequent aneurysm surgery would be considered to be "secondary" surgery.

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a) Section A. Neurology

Item 1. Date/Time of initial hospitalization (any hospital)

The Date (month, day, year) and Time of initial hospitalization is recorded in the space provided in numeric fashion. For example, five minutes after six o’clock in the morning of January 2, 2000 would be recorded as 01/02/2000 06:05. One minute after midnight on November 12, 2001 would be recorded as 11/12/2001 00:01. Note this may be different from the style used in many countries (e.g., most of Europe). Please be careful.

Comment: Initial hospitalization is considered to begin at the time the patient presents to any hospital (emergency room or clinic) with the signs and symptoms of the primary subarachnoid hemorrhage, even if the patient is subsequently transferred to another hospital for care. In many PCC’s, the patient will likely have first presented to another hospital.

Item 2. Was there loss of consciousness at the time of the primary SAH?

There are two choices, check one.

No: Best available information indicates the patient did not lose consciousness at the time of the primary SAH.

Yes: Best available information indicates the patient did lose consciousness at the time of the primary SAH.

Comment: Loss of consciousness at the time of the primary SAH may indicate that a relatively more severe initial neurologic insult has occurred as compared to when SAH occurs without a loss of consciousness.

Item 3. Level of consciousness at time of initial hospitalization (any hospital)?

There are four choices, check one.

Alert: Best available information indicates the patient was alert (conscious and aware of surroundings) at the time of initial presentation to the hospital (any hospital).

Drowsy: Best available information indicates the patient was drowsy (a depressed level of consciousness, somewhat aware of surroundings, but responsive to verbal stimuli) at the time of initial presentation to the hospital (any hospital).

Stuporous: Best available information indicates the patient was stuporous (very lethargic, barely aware of surroundings, but was somewhat rousable with potent stimuli) at the time of initial presentation to the hospital (any hospital).

Comatose: Best available information indicates the patient was comatose (unconsciousness from which the patient could not be roused even with potent stimuli) at the time of initial presentation to the hospital (any hospital).

Comment: Level of consciousness at presentation is an important independent prognostic factor in the setting of aneurysmal SAH.

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Item 4. Has the patient had a seizure or convulsion at the time of the primary SAH, or anytime after the initial hospitalization?


No: Best available information indicates the patient did not experience seizure at the time of the primary SAH, nor has the patient had a seizure in the interval between initial hospitalization and the primary aneurysm surgery.

Yes: Best available information indicates the patient did experience seizure at the time of the primary SAH, or the patient has had a seizure in the interval between initial hospitalization and the primary aneurysm surgery.

Item 5. Any major speech disorder noted at initial presentation or at any time after hospitalization, even if currently resolved?


No: Best available information indicates the patient did not have a major speech disorder (no substantial expressive or receptive aphasia) at the time of initial presentation, nor has the patient had any major speech disorder in the interval between initial hospitalization and the primary aneurysm surgery.

Yes: Best available information indicates the patient did have a major speech disorder (any substantial expressive or receptive aphasia) at the time of initial presentation, or the patient has (or has had) a major speech disorder in the interval between initial hospitalization and the primary aneurysm surgery. Check yes even if all symptoms of speech disorder have resolved prior to the primary aneurysm surgery.

Comment: The presence of a speech disorder prior to aneurysm surgery may increase the likelihood of postoperative speech disorder.

Item 6. Were any focal or lateralized motor deficits noted at initial presentation or any time after hospitalization, even if currently resolved?


No: Best available information indicates the patient did not have any focal or lateralized motor deficits at the time of initial presentation, nor has the patient had any such motor deficits in the interval between initial hospitalization and the primary aneurysm surgery.

Yes: Best available information indicates the patient did have a focal or lateralized motor deficit at the time of initial presentation, or the patient has (or has had) focal motor deficits in the interval between initial hospitalization and the primary aneurysm surgery. Check yes even if motor deficits were/are mild and/or have resolved prior to the primary aneurysm surgery.

If yes, please indicate which extremities were not ("No") and which extremities were ("Yes") affected by motor weakness:

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Right upper extremity

Right lower extremity

Left upper extremity

Left lower extremity

Comment: The presence of focal motor deficits prior to aneurysm surgery may increase the likelihood of postoperative motor deficits.

Item 7. Has the patient had a recurrent SAH or met the diagnostic criteria for DIND (or clinically symptomatic vasospasm) at any time since hospitalization, even if currently resolved?


No: The patient has not had a recurrent SAH nor met the diagnostic criteria for DIND in the interval between initial hospitalization and the primary aneurysm surgery.

Yes: The patient has either: 1) had a recurrent SAH; and/or 2) met the diagnostic criteria for DIND in the interval between initial hospitalization and the primary aneurysm surgery.

Instruction box: If yes, please complete an IE form (for recurrent SAH and/or DIND).

Comment: Both recurrent SAH and DIND are considered intercurrent events and require completion of IE forms. Both recurrent SAH and DIND have a bad prognosis. Because most patients undergo primary aneurysm surgery within the first few days after the primary SAH, very few patients in this trial will have had a recurrent SAH or developed DIND prior to aneurysm surgery. However, in some patients, early surgery may be deferred because of poor neurologic- and/or medical- condition. Such patients are more likely to experience a recurrent SAH and/or develop DIND. Nevertheless, it is possible for such patients to recover sufficiently to be eligible for this trial, so long as they do so within the 14-day interval between the primary SAH and primary aneurysm surgery.

b) Section B. Other Events

Item 1. Has the patient been endotracheally intubated or tracheostomized at any time since hospitalization (includes intubation on arrival)?


No: The patient has not been endotracheally intubated nor tracheostomized in the interval between initial hospitalization and the primary aneurysm surgery, nor was the patient intubated on initial presentation to the hospital.

Yes: The patient has been endotracheally intubated or tracheostomized at some time in the interval between initial hospitalization and the primary aneurysm surgery, or the patient was intubated on initial presentation to the hospital.

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Comment: Because patients who are endotracheally intubated at the time of the eligibility evaluation are not eligible to participate in IHAST2, if Item B.1. is checked "yes," this must mean that the patient was extubated at some time prior to the eligibility evaluation.

Item 2. Has the patient undergone any diagnostic or therapeutic procedure other than their initial, routine CT/MRI scan, cerebral angiogram, chest x-ray or electrocardiogram at any time since hospitalization?


No: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has not undergone any diagnostic or therapeutic procedure that was not entirely routine for patients with "uncomplicated" aneurysmal subarachnoid hemorrhage. Almost always, a CT or MRI scan, cerebral angiogram, chest x-ray, and electrocardiogram are obtained before aneurysm surgery, regardless of patient status.

Yes: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient underwent some diagnostic or therapeutic procedure that would not normally be considered to be part of the routine preoperative evaluation/preparation of an "uncomplicated" aneurysmal SAH patient.

Comment: Almost always, a CT or MRI scan, cerebral angiogram, chest x-ray, and electrocardiogram are obtained before aneurysm surgery in all patients, regardless of status. Almost always, if any other procedures are performed, they are performed because of conditions or events of major and immediate importance. For example: coronary angiography or bronchoscopy prior to primary aneurysm surgery would generally be considered to be non-routine procedures.

If yes, enter procedure codes (See IE Code list) in the spaces provided (up to ten codes).

If yes, were any of these procedures associated with an intercurrent event? There are two choices, check one.

No: Although one or more non-routine diagnostic or therapeutic procedures were performed prior to the primary aneurysm surgery, no definable intercurrent event was associated with the performance of the procedure(s).

*Yes: The performance of one or more non-routine diagnostic or therapeutic procedures prior to the primary aneurysm surgery was associated with more or more intercurrent events. In this circumstance, all appropriate IE forms should be completed.

Instruction box: *If yes, please complete an IE form (for all non-routine procedures and/or all associated events) and include related procedure code(s).

Item 3. Has the patient received any vasopressor or inotrope for 15 consecutive minutes or longer at any time between hospitalization for any reason?


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Comment: The duration of administration must be in consecutive minutes. Isolated or intermittent boluses of a vasopressor or inotrope do not qualify. For example, occasional boluses of ephedrine or phenylephrine (even if more than one bolus in a 15-minute period) do not qualify. If however, clinical circumstances require the continuous infusion of any vasopressor or inotrope for 15 consecutive minutes or longer, then the definition is met. Agents in this category include, but are not limited to: phenylephrine, phenylephrine, epinephrine, norepinephrine, dopamine, dobutamine, dopexamine, isoproterenol, methoxamine, amrinone, milrinone, etc. It is not necessary to specify the agent used.

No: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has not received any vasopressor or inotrope for ≥15 consecutive minutes.

Yes: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has received a vasopressor or inotrope for ≥15 consecutive minutes. Vasopressor administration is always considered to be an intercurrent event, although there are three different categories for vasopressor administration (see the IE list).

Item 4. Has any (major or minor) surgical procedure been performed since hospitalization?


No: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has not undergone any form of surgery (e.g., ventriculostomy, clot evacuation, etc.).

Yes: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has undergone some form of surgery.

Comment: Surgery is defined as any procedure performed by surgeon that requires the patient to go to the operating room. However, some “bedside” procedures, such as tracheostomy, ventriculostomy, or wound closure are also considered surgery. Dressing changes and/or line placement (central venous or arterial access) are not considered as “surgery” unless the procedure takes place in the operating room. Angiographic procedures are not considered surgery. In almost all instances, if a patient needs surgery before primary aneurysm clipping, the need for surgery is associated with an intercurrent event, such as rebleeding, symptomatic hydrocephalus, or other major non-neurosurgical problem. All surgeries other than the primary aneurysm surgery are considered intercurrent events.

Item 5. Has the patient developed as significant dysrhythmia or had evidence of myocardial ischemia or myocardial infarction at any time since hospitalization?

Comment: Arrhythmias are common in the setting of aneurysmal subarachnoid hemorrhage. Significant arrhythmias include: severe sinus bradycardia; acute atrial fibrillation or flutter; any of a variety of supraventricular tachydysrhythmias; 3rd-degree AV block (and some forms of 2nd-degree AV block); right- and left- bundle branch block; frequent ventricular premature contractions; ventricular tachycardia or fibrillation.

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In the setting of acute subarachnoid hemorrhage, electrocardiographic (ECG) abnormalities which ordinarily indicate myocardial ischemia or infarction are not, by themselves, reliable markers. Hence, the diagnosis of myocardial ischemia and/or infarction in the setting of acute SAH will require, in addition to appropriate ECG changes, at least one major, or two minor, supportive clinical and/or laboratory signs. Major signs include: 1) classic angina or the patient's anginal equivalent (with or without associated signs of nausea, diaphoresis, anxiety); 2) a new positive pyrophosphate scan; 3) significant stenosis of an appropriate coronary artery (angiography); 4) autopsy confirmation of acute myocardial ischemia or infarction. Minor signs include include: 1) a new and distinct increase in serum creatine kinase-MB (CKMB) or troponin levels; 2) associated acute hemodynamic instability; 3) associated acute pulmonary congestion (dyspnea, orthopena, rales, pulmonary edema); 4) a new and distinct regional wall motion abnormality.)


No: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has not developed any significant dysrhythmia nor had evidence of myocardial ischemia or myocardial infarction.

Yes: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has developed a significant dysrhythmia and/or has had evidence of myocardial ischemia or myocardial infarction. Such occurrences are considered intercurrent events (see the IE list).

Item 6. Has the patient had evidence of ventricular dysfunction (CHF, pulmonary edema, low cardiac output) at any time since hospitalization?

Comment: Any instance when clinical signs and/or symptoms point to abnormally high left ventricular end diastolic pressure, resulting in translocation of fluid from the pulmonary capillaries into the pulmonary interstitial and/or alveolar spaces ("hydrostatic" pulmonary edema). Signs and symptoms include rales, elevated jugular venous pressure, peripheral edema, dyspnea at rest or on extertion, orthopnea, S3 gallop, and radiologic evidence of pulmonary congestion (increased pulmonary vascular markings and/or alveolar consolidation). Although this can occur in patients with normal ventricular function, most often this is associated with compromised left ventricular function and diminished cardiac reserve. Signs of low cardiac output may include relative hypotension; pallor or cool extremities; oliguria; and/or low cardiac output measurements and/or marked wall motion or ejection abnormalities on echocardiographic examination.


No: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, patient has not had evidence of ventricular dysfunction (CHF, pulmonary edema, low cardiac output).

Yes: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, patient has had evidence of ventricular dysfunction (CHF, pulmonary edema, low cardiac output). Such occurrences are considered intercurrent events (see the IE list).

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Item 7. Has the patient had a fever (T 38.5 C), undergone microbiologic culturing or shown any other evidence of local or systemic infection at any time since hospitalization?

Comment: Since hypothermia may increase the risk of perioperative infection, it is important to characterize any infectious process that might be present prior to going to the operating room.


No: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has not had a fever, has not undergone culturing, nor has shown any sign of local or systemic infection. In other words, there has been no indication of infection.

Yes: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has either: had a fever (≥38.5°C); undergone microbiologic culturing (blood, sputum, surgical site, urine, CSF, etc.); or had other evidence of local or systemic infection (wound erythema; new infiltrates on chest x-ray; sepsis, etc.).

Item 8. Have any other respiratory, digestive, endocrine, urogenital, hematologic or other event occurred at any time since hospitalization (See IE Code list)?


No: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has not had any other respiratory (e.g., hypoxemia, bronchospasm); digestive (e.g., gastrointestinal hemorrhage); endocrine (e.g., hyperglycemia); urogenital, hematologic (e.g., deep venous thrombosis, coagulopathy); or other events, as delineated on the intercurrent events (IE) list.

Yes: In the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery, the patient has experienced some respiratory (e.g., hypoxemia, bronchospasm); digestive (e.g., gastrointestinal hemorrhage); endocrine (e.g., hyperglycemia); urogenital, hematologic (e.g., deep venous thrombosis, coagulopathy); or other event(s), as delineated on the intercurrent events (IE) list.

Instruction box: If yes to any question in items 3-8, please complete an IE form(s) (for all such events).

Last question. Are there additional comments you would like to add regarding patient information of this form?


No: There is no additional information that needs to be communicated regarding the patient’s condition in the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery.

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Yes: There is additional information that needs to be communicated regarding the patient’s condition in the interval between initial hospitalization and going to the operating room for the primary aneurysm surgery that is not adequately communicated by this form and/or associated IE forms.

Instruction box: If yes, please go to web address http://ctsdmc.public-health.uiowa.edu/ihast2/comment/. Additional comments may be recorded at this website.

Comment: Hand-written comments in page margins of this form cannot be recorded as data. If you have comments that you would like to make regarding any aspect of the patient’s course in the period from initial hospitalization to going to the operating room for the primary aneurysm surgery, please file them at the web address above.

IX. F NEUROSURGEON

IX.F.1.Overview:

All information recorded on this form MUST be filled out by the attending Neurosurgeon.

IX.F.2. Data Items

Section A: FIRST CT or MRI after SAH

Comment: Various characteristics of the SAH, a determined by the preoperative CT scan, are known to influence outcome. In an effort to adjust for such covariates, we need some information regarding the first scan performed on the patient after his/her SAH.

Item 1. Please define whether the first post-SAH scan was a CT or MRI.


Please provide the Date/Time of the scan in the space provided.

Comment: Note: if a patient had BOTH a CT and MRI scan performed, check CT, since all subsequent information should be based on a CT imaging. MRI should be checked only in the event that no CT scan was performed (i.e., only a MRI was done). If an initial CT scan was performed, followed by a MRI angiogram or other procedure, check CT.

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Item 2. What were the SAH blood characteristics?


If sub-item 4 is checked, answer both of the additional two items.

Comment: These four items represent the "Fisher Scale" and are typically based on CT imaging (not MRI).

Item 3. Other scan findings?

Please answer “Yes” or “No” to each item.

Comment: There are no firm "criteria" or definitions for these items. Use your best judgment. Also, since prior neurologic disease (existing prior to the current SAH) may play a role in outcome, we are very interested in the category of "remote neurologic injury."

Section B: Procedures or Events During Surgery

Item 1: Date of Surgery Month, day, year (e.g., 07/23/2000) is recorded in the space provided.

Item 2: Skin disorder, infection, or inflammation involving the surgical site?


Comment: A major potential complication of hypothermia is wound infection. Since prior infection or other skin disorder may predispose a patient to a postoperative wound infection, this information is needed (even though most surgeons would be reluctant to operate on any patient with an active scalp infection).

Item 3. Brain swelling at initial dural opening.

There are four choices, select one.

Comment: Brain swelling can influence the difficult of gaining access to the aneurysm. This score must be based on your best judgment. The primary determinant is whether or not some supplementary treatment is needed. If no treatment is needed, check the second (“slight”) box. Conversely, if the brain is severely swollen, special treatment is needed (e.g mannitol, furosemide, added hyperventilation, position change, etc.) AND you must wait for this treatment to be effective, check the last box, “severe.”

Item 4. Ease of aneurysm exposure


Comment: Again, this score must be based on your best judgment.

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Item 5. Were any of the following used during surgery?

There are five choices, each with a yes/no possibility.

Comment: Each item must be checked. In other words, if a lumbar drain was used but no other items, check "yes” for Lumbar drain, and "no" for all other items. No item should be left unchecked. In the event that the carotid artery was temporarily occluded in the neck, please note the duration of occlusion (minutes).

Item 6. Temporary occlusion of a major vessel.

There are two possibilities, check one.

If "yes" is checked, please refer to the subsequent items and check “yes” or “no” for each possible vessel. All items must be completed. For example, if the middle cerebral artery was temporarily clipped, this item should be check "yes" and all other vessels checked "no." Also, please record the duration of temporary occlusion of all vessels undergoing temporary occlusion.

Comment: Temporary clipping may play a role in defining postoperative neurologic dysfunction. It is critical that all vessels that were temporarily occluded by noted, along with the duration of occlusion.

Section C. Aneurysm Location Code and Treatment

At the top of the page are a series of 10 code numbers corresponding to the major locations for aneurysms around the circle of Willis. These code numbers are to be used in the first line of the subsequent table, to define the location of all aneurysms clipped/occluded. Space is provided to characterize the clipping of three aneurysms. They should be recorded in the order they were clipped. In other words, the column under "1st Aneurysm" should correspond to the first aneurysm which was clipped, "2nd Aneurysm" to the second aneurysm clipped, etc.

Line 1: Aneurysm Location Code: In the blank provided, enter the code number (from the top of the page) corresponding to the location of the clipped aneurysm. Also note whether it was located on the left or right side. For Anterior Communicating (code 07) and Vertebrobasilar (code 09) where location is midline, please code right or left side according to the side of the craniotomy.

Line 2: Largest angiographic diameter: In the blank provided, enter the largest diameter of the clipped aneurysm (in mm) as determined by the preoperative angiogram.

Line 3. Responsible for SAH? Was the aneurysm listed in Line 1 responsible for the SAH? There are three choices, check one.

Comment: We realize that in some cases, particularly with multiple aneurysms, it is not possible to determine with precision which aneurysm has ruptured. Use your best judgment.

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Comment: If surgery is unexpectedly aborted, prior to any attempt at aneurysm treatment, please complete Location Code, Angiographic Diameter, and Responsible for SAH for all aneurysms for which surgery had been planned.

Line 4: Thrombosed, larger than angio? There are two choices, check one. In the event "yes" is checked, please provide the estimated external diameter.

Comment: In the case of thick-walled aneurysms or aneurysm partially filled with clot, the external diameter of the aneurysm may be substantially larger than the portion filled with dye during angiography.

Line 5. Angiographic vasospasm in parent vessel? There are two choices, check one.

Comment: This determination should be based on inspection of the preoperative angiogram, not on direct inspection of the exposed vessel.

Line 6. Treatment. For each aneurysm, there are five choices, check “yes” or “no” for each item.

Comment: Multiple occlusion methods may be used for any given aneurysms (or, on occasion, occlusion may not be possible). Check each potential treatment as "yes" or "no". If an aneurysm is "routinely" clipped, check "yes" for "Clipped" and "no" for all other options.

Line 7. No. of permanent clips. Please enter a number in the space provided (from 0-9).

Line 8. Leak or rupture during surgery? There are two possibilities, check one.

Line 9. Were more than three aneurysms treated (clipped, wrapped, etc.)? There are two possibilities, check one.

Additional Comments: If added comments are needed, please enter these via the IHAST 2 website at http://ctsdmc.public-health.uiowa.edu/ihast2/comment/. Written comments can be given to the Study Coordinator for later entry.

IX. G ANESTHESIOLOGIST

IX.G.1. Overview:

This form is to be completed by the Anesthesiologist caring for the patient during their primary aneurysm surgery. No other IHAST2 participant may complete this form.

The Anesthesiologist is responsible for:

Determining whether or not the patient is still eligible for study entry when the patient presents to the operating room (Section A of this form).

Characterizing the patient's condition immediately prior to surgery (Section B of this form).

Providing anesthesia in accordance with protocol (Section C of this form).

Opening the RANDOMIZATION ENVELOPE and managing the patient's temperature in accordance with protocol (Section D of this form and TEMPERATURE form).

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Characterizing the patient's condition at the time of aneurysm clipping (Section E of this form).

Characterizing key events occurring during surgery, and for the first 0-2 hours after the patient leaves the operating room (Sections F, G, H of this form).

Instruction box: At the top of this form is a gray-shaded instruction box, which reminds the Anesthesiologist of the room conditions which are to exist prior to the patient entering the operating room: room temperature at 20-22°C; water mattress under patient at 37°C; temperature displays covered.

Comments

Room temperature at 20-22°C. Manipulation of operating room (O.R.) temperature is not part of the protocol. In fact, to facilitate blinding of temperature group assignment, room temperature should not be changed during the case. Hence, prior to patient arrival in the O.R., chose a room temperature that is likely to be acceptable for the duration of the case and do not change it. In most PCC’s, a room temperature of 20-22°C (68-72°F) will be acceptable. It is not necessary to conceal O.R. temperature because it does not change.

The cooling/warming water mattress should be on the bed prior to patient arrival (see above) and prewarmed to 37°C. A uniform (warm) starting temperature for the water mattress is necessary for patient comfort and facilitates blinding of subsequent temperature group assignment.

Temperature displays on the water mattress control unit and forced air control unit (Polar Air), and all temperature monitors must be concealed to prevent anyone other than the Anesthesiologist from seeing the settings or results. Tape, paper, cardboard, would all be acceptable means of concealing temperature displays.

IX.G.2. Data Items

a) Section A. Patient Eligibility

Item 1. Calculation of WFNS Score:

When the patient is brought to the operating room (O.R.), the attending Anesthesiologist must verify that there have been no changes in the World Federation of Neurologic Surgeons (WFNS) score that would make the patient no longer eligible. The WFNS score is determined by the Anesthesiologist.

The Glasgow Coma Scale (GCS) is the sum of scores from three components: 1) eye opening; 2) best motor response; and 3) best verbal response. Be aware that the best motor response may come from the side of the patient's body that is NOT affected by the SAH. The scores for each of the components (eye opening, motor, verbal) are recorded in the spaces provided, and the sum of these three scores is recorded in the space provided as the Total GCS.

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The WFNS Score is based on: 1) the patient's GCS score (above); and 2) the presence/absence of a major motor deficit (monoparesis, hemiparesis or hemiplegia) or aphasia. Any patient with a GCS ≤12 (regardless of motor/aphasia status) will not be eligible because they necessarily have a WFNS score of IV, or V. A patient having a motor deficit or aphasia will be eligible for randomization only if the GCS is ≥13 (this patient has a WFNS score of III). The WFNS score is recorded is the space provided. To still be eligible, the patient must still have a WFNS score of I, II, or III upon arrival to the O.R.

It does not matter if the patient’s WFNS score is different from that obtained during eligibility screening (better or worse) so long as it is still WFNS I, II, or III.

Item 2. Patient WFNS I, II, or III?


No: This means the patient's WFNS score is either IV or V. In this event, the patient is no longer eligible for the study. Do not open the RANDOMIZATION ENVELOPE . Do not record any other information because the patient is not in the study. Sign the bottom of page 6 of this form and return the unopened RANDOMIZATION ENVELOPE to your Local Study Coordinator. Thereafter, care for the patient as you see fit, but the patient is not in the study. The DMC must be informed within 24 hours (sooner is better) that the patient did not enter the study.

Instruction box: IF NO, DO NOT OPEN RANDOMIZATION ENVELOPE. Stop and sign form at bottom of page 6.

Yes: Continue form completion (i.e., go on to Item A.3).

Item 3. Is the patient otherwise still eligible?


No: Some new condition has arisen since the initial study evaluation and enrollment which now makes patient entry into the study inadvisable. Please note the reason for exclusion in the space provided. Do not open the RANDOMIZATION ENVELOPE . Do not record any other information because the patient is not in the study. Sign the bottom of page 6 of this form and return the unopened RANDOMIZATION ENVELOPE to your Local Study Coordinator. Thereafter, care for the patient as you see fit, but the patient is not in the study. The DMC must be informed within 24 hours (sooner is better) that the patient did not enter the study.

Instruction box: IF NO, DO NOT OPEN RANDOMIZATION ENVELOPE.

Stop and sign form at bottom of page 6.

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Comment: In general, such conditions should be serious and/or potentially independently life-threatening. Examples would include development of: severe congestive heart failure or unequivocal myocardial infarction; septic or cardiogenic shock; recurrent complex ventricular arrhythmias; disseminated intravascular coagulation; or severe psychiatric, psychosocial, or medico-legal issues. We respectfully ask investigators to use their best judgment so that minor and/or "normal" problems encountered in the care of patients with aneurysmal SAH do not result in patient exclusion. On the other hand, if, in good faith, local investigators feel an unusually serious problem exists, which makes entry into the study inadvisable, then they should exercise this option without reservation.

Yes: No new serious or immediately life-threatening medical, surgical, psycho-social condition has arisen since evaluation and registration that makes study entry (randomization) inadvisable. Continue form completion (i.e., go on to Section B).

b) Section B. Physical Examination Prior to Induction

Item 1. Vital Signs

Patient's temperature upon arrival in the O.R. (sublingual or tympanic): This temperature must be either a tympanic or sublingual temperature, and recorded in degrees centigrade in the space provided.

Respiratory Rate: recorded in breaths/minute in the space provided.

Oxygen saturation: This is obtained via pulse oximetry, and recorded as % oxyhemoglobin saturation in the space provided. (A oxyhemoglobin saturation obtained by arterial blood gas analysis is acceptable.) Indicate in the spaces provided whether the patient is breathing 1-room air or is receiving 2-supplemental O2. It is not necessary to record the inspired oxygen fraction (FiO2).

Blood Pressure (cuff or arterial line): Arterial blood pressure is recorded in mmHg in the space provided. This value may be from either a blood pressure cuff or arterial line (A-line). It is not necessary to indicate whether this is a cuff or A-line pressure.

Comment: Vital signs are recorded in order to assess whether any vital sign has any independent effect on outcome and/or any unique interaction with temperature management.

Item 2. Electrocardiogram

Instruction box: Lead V5 or CM5 must be monitored, but additional leads may also be monitored at local discretion.

a. Heart rate: The patient's ventricular heart rate in beats/minute is recorded in the space provided.

b. Rhythm: For each descriptor of cardiac rhythm, please indicate it's presence (Yes / No). Do not leave any item unmarked.

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Sinus Rhythm: Ventricular beats are triggered by and coupled with coordinated atrial activity originating largely or exclusively from the sinus node (P waves are present).

Atrial -fibrillation or -flutter: Atrial fibrillation: Electrocardiogram demonstrates a lack of clearly defined P-waves with an undulating baseline that may alternate between recognizable atrial activity or nearly a flat line. The ventricular response is irregular. Atrial flutter: Electrocardiogram demonstrates "sawtooth" atrial complexes (leads II, III, aVF) of constant morphology, polarity and cycle length with a rate from 240-340 bpm. The ventricular response rate to atrial flutter is frequently 2:1 or 4:1 and is regular.

Other supraventricular tachydysrhythmia: Any form of sustained abnormal rapid supraventricular rhythm. (Neither sinus tachycardia nor sinus bradycardia is included in this category.) Examples include premature atrial complexes, premature junctional complexes, paroxysmal atrial tachycardia (PAT), multifocal atrial tachycardia (MAT), paroxysmal supraventricular tachycardia (PSVT), AV nodal re-entrant tachycardias. It is not necessary to specify the type of abnormality.

Frequent premature ventricular contractions (PVCs) (≥5/min): Ectopic ventricular electrical activity is present (monomorphic, polymorphic, isolated, or with coupling) with a frequency of ≥5 PVCs per minute.

Atrio-Ventricular (AV) conduction abnormality: Abnormal conduction through the AV node including 1°, 2° (any form), or 3° AV block. It is not necessary to specify the type of abnormality.

Intraventricular conduction abnormality: Abnormal conduction through the His-Purkinje system as manifested as right bundle branch block (RBBB) or left bundle branch block (LBBB). It is not necessary to specify the type of abnormality. Left anterior hemiblock does not qualify.

Other: Any other clinically significant rhythm abnormality not specified above (e.g., Wolf-Parkinson-White Syndrome). If present (i.e., checked "yes"), please specify the abnormality in the space provided.

Did the patient require treatment for any form of arrhythmia prior to induction of anesthesia? There are two choices, check one.

No. The patient did not require treatment for any form of arrhythmia before induction of anesthesia. Treatment of mild to moderate sinus tachycardia (heart rate of 80-120) is not considered to constitute treatment for a major arrhythmia.

Yes. The patient did require treatment for a cardiac arrhythmia before induction of anesthesia. However, treatment of mild to moderate sinus tachycardia (heart rate of 80-120) is not considered to constitute treatment for a major arrhythmia.

c. Morphology: For each, please indicate it's presence (Yes) or absence (No) in any lead. Do not leave any item unmarked.

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ST segment elevation ≥1mm above isoelectric baseline in any lead?

ST segment depression ≥1mm below isoelectric baseline in any lead?

Abnormal T wave inversion in any lead?

Abnormal upright T wave in any lead?

Comment: The reason for characterizing the immediate preoperative electrocardiogram is to determine whether any electrocardiographic feature has any independent effect on outcome and/or interaction with temperature management.

c) Section C. Induction

Item 1. Date/Time of induction (of anesthesia)

The date (month, day, year) and time of induction of anesthesia will be recorded in the space provided in numeric fashion. For example, five minutes after six o’clock in the morning of January 2, 2000 would be recorded as 01/02/2000 06:05. One minute after midnight on November 12, 2001 would be recorded as 11/12/2001 00:01. Note this may be different from the style used in many countries (e.g., most of Europe). Please be careful.

Item 2. Induction agent There are two choices, check one.

1-Thiopental, or 2-Etomidate. According to protocol, no other agent is permitted. Specifically, propofol may not be used to induce anesthesia.

Comment: Prior to induction of anesthesia, small doses of sedatives (e.g., midazolam) and/or opioids (e.g., fentanyl) are permitted in order to reduce patient anxiety and/or facilitate placement of monitors. These are not considered induction agents.

The limitation of induction agents is intended only to help standardize anesthetic management as much as possible, while still providing some discretion for the Anesthesiologist. The exclusion of other induction agents (propofol, midazolam, etc.) is not intended to imply that either thiopental or etomidate are "better."

Item 3. Secondary core temperature monitoring site


Rectal

Nasopharyngeal

Tympanic

Other

If "Other" is checked, please record the site in the space provided.

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Comment: In addition to placement of the standard esophageal stethoscope/thermistor (primary temperature measurement) a secondary (safety) core temperature monitor is necessary in order to assure accurate temperature measurement and management.

Item 4. Anesthetic Agents

For each anesthetic agent listed, please indicate it's use (Yes) or non-use (No). Do not leave any item unmarked.

Isoflurane

Desflurane

Nitrous Oxide

Fentanyl

Sufentanil

Remifentanil

According to protocol, no other agents are permitted to maintain anesthesia during surgery. Prior to induction of anesthesia, small doses of sedatives (e.g., midazolam) and/or opioids (e.g., fentanyl) are permitted in order to reduce patient anxiety and/or facilitate placement of monitors. These are not considered maintenance agents.

Comment: According to protocol, anesthesia will be maintained with a standard “balanced” anesthetic which will include: a) a volatile agent (either isoflurane or desflurane); b) a synthetic opioid (either fentanyl, sufentanil, or remifentanil) given either by repeated bolus or infusion; and 3) nitrous oxide in concentrations not to exceed 72%. Only nitrous oxide use is optional.

There are no restrictions on the choice of paralytics, but no other anesthetic regimen or drugs will be permitted to maintain anesthesia. Specifically, neither sevoflurane, nor propofol or etomidate infusions may be used to maintain anesthesia. A short-term etomidate infusion may be used for the purposes of pharmacologic brain protection if temporary clips are used, but etomidate may not be used as the principal anesthetic for the case.

The limitation of agents to maintain anesthesia is intended only to help standardize anesthetic management as much as possible, while still providing some discretion for the Anesthesiologist. The exclusion of other agents/techniques is not intended to imply that "balanced" anesthesia is "better."

Item 5. Intraoperative Monitoring

For each of the monitoring modalities listed, please indicate it's use (Yes) or non-use (No). Do not leave any item unmarked.

Neurologic monitors to be recorded include:

Evoked potentials (any modality)

Electroencephalography (any variety)

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Retrograde jugular venous catheter

Intracranial pressure monitor (any type other than pre-existing ventriculostomy)

Central venous pressure only (no PA pressure)

CVP and pulmonary artery pressure (Swan Ganz)

Transesophageal echocardiography

Comment: Choice of monitoring modalities is entirely on the basis of local routines and/or the discretion of the attending Neurosurgeon or Anesthesiologist, with two conditions :

Condition 1: With the exception of ventriculostomy catheters, monitoring devices that penetrate the substance of the brain, such as needle thermistors or blood gas/pH electrodes are not permitted. Penetrating monitors are excluded because of a potential for increased risk of intraparenchymal (brain) hemorrhage.

Condition 2: Choice of monitoring MUST NOT be made on the basis of temperature group assignment. For example, a pulmonary artery catheter or jugular venous catheter may not be placed simply because a patient was randomized to hypothermia. Therefore, unless the patient's medical condition changes in such a way as to require some additional monitoring technique, all monitoring devices are to be chosen and in place prior to opening the RANDOMIZATION ENVELOPE.

d) Section D. Randomization

Instruction box: AFTER induction of anesthesia, AFTER patient positioning, and AFTER placement of the cooling/warming air blanket, open the RANDOMIZATION ENVELOPE and record all temperature data ONLY on the enclosed TEMPERATURE form.

Comment: The RANDOMIZATION ENVELOPE must not be opened until: 1) It has been determined that the patient is still eligible for study entry [WFNS score {A.2.}, medical condition {A.3.}]; 2) after induction of anesthesia; 3) after patient positioning for surgery; and 4) after placement of the cooling/warming blanket.

Comment: The contents of the RANDOMIZATION ENVELOPE (TEMPERATURE form and envelopes) and all aspects of intraoperative temperature management are to be known only to the Anesthesiologist caring for the patient during the primary aneurysm surgery. The TEMPERATURE form will indicate the temperature group to which the patient has been assigned and all intraoperative temperature data will be recorded on that form only.

e) Section E. Conditions at Definitive Clip Placement*

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Comment: *Because some aneurysms require multiple clips and/or a series of clip on-off-on sequences, record data at the time of placement of the final (or definitive) clip for each aneurysm in the sequence in which the aneurysms are clipped. However, not all aneurysms can be obliterated by clipping. Sometimes treatment consists of wrapping, clipping and wrapping, or, rarely, the aneurysm cannot be secured. In these latter circumstances, record data at the time when the treatment for each aneurysm is completed, whatever it is.

Item 1. Total number of aneurysms clipped/treated

Enter the total number of aneurysms clipped (or otherwise treated) in the space provided: 1, 2, 3, etc.

Item 2. There are six subitems

Time at definitive clip placement*: For each aneurysm clipped (or otherwise treated), enter the clock time (24 hour notation) at definitive clip placement in the space provided, in the sequence in which the aneurysms are clipped. Because some aneurysms require multiple clips and/or a series of clip applications, record the time of placement of the last (or definitive) clip for each aneurysm. *If the aneurysm is wrapped, clipped and wrapped, or the aneurysm cannot be secured, record the time when the treatment for each aneurysm (in sequence) is completed.

(Do not record temporary clip times here. Temporary clip times are to be recorded on the NEUROSURGEON form.)

Esophageal temperature, Secondary temperature: Note the Instruction Box “Record this data on TEMPERATURE form ONLY, not this form.” It is noted on this form only as a reminder.

Mean arterial pressure at definitive clip placement*: For each aneurysm clipped (or otherwise treated), record the mean arterial pressure (mmHg) at final definitive clip placement in the space provided, in the sequence in which the aneurysms are clipped. Because some aneurysms require multiple clips and/or a series of clip applications, record the time of placement of the final (or definitive) clip for each aneurysm. *If the aneurysm is wrapped, clipped and wrapped, or the aneurysm cannot be secured, record the time when the treatment for each aneurysm (in sequence) is completed.

Blood glucose at definitive clip placement*: For the first aneurysm clipped (or otherwise treated), record the blood glucose at final definitive clip placement in the space provided. *If the aneurysm is wrapped, clipped and wrapped, or the aneurysm cannot be secured, record blood glucose when the treatment for the first aneurysm is completed.

Using the check boxes, indicate the units in which blood glucose concentration is measured, either: 1-mg/dL or 2-mmol/L.

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Comment: Blood glucose is measured because temperature management may affect intraoperative blood glucose concentration and glucose concentration may affect neurologic outcome.

Arterial blood gas at definitive clip placement*: For the first aneurysm clipped (or otherwise treated), record the arterial blood gas at final definitive clip placement in the space provided. *If the aneurysm is wrapped, clipped and wrapped, or the aneurysm cannot be secured, record arterial blood gas when the treatment for the first aneurysm is completed.

Using the check boxes, indicate the units in which PO2 and PCO2 are measured, either: 1-mmHG or 2-kPa.

Surgeon's guess for group assignment after clipping*: After the first aneurysm is clipped (or otherwise treated), record the surgeon's guess for temperature group immediately after definitive clip placement (or other treatment) as either 1-Normothermia or 2-Hypothermia. *If the aneurysm is wrapped, clipped and wrapped, or the aneurysm cannot be secured, record arterial blood gas when the treatment for the first aneurysm is completed.

Comment: This question is not to be asked during clipping so as not to disturb the Neurosurgeon. However, we want to ask the Neurosurgeon this question as soon as possible after clipping--before the Neurosurgeon has the time, inclination, or opportunity to determine patient temperature.

Comment: It is important that the Neurosurgeon is not aware of the patient's temperature during surgery ("blinded”) so that intraoperative decisions are not made on the basis of

temperature. If blinding is maintained, it is anticipated that the use of temporary clips, induced hypotension, and supplemental pharmacologic "brain protection" will be equally distributed between the two temperature groups. If temporary clip time was longer and "brain protection" therapy was less frequent in hypothermic patients because neurosurgeons knew these patients were cold (and felt more "comfortable"), this bias would confound interpretation of the potential treatment effect of hypothermia. If blinding efforts are successful, neurosurgeons should not be able to guess patient temperature any better than random chance.

Instruction box: *If not clipped, when wrapping or other treatment done. As indicated by the * signs above, if clipping of the aneurysm is not possible, then record data when the treatment for each aneurysm is completed, whatever the treatment was (wrapped, clipped and wrapped, or the aneurysm could not be secured).

Item 3. Protective drugs used for clipping.


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No: Supplemental "neuroprotective" anesthetics (barbiturates, etomidate) were not given during the case, indicate this here as "No."

Yes: According to protocol, if the operative team decides that supplemental intraoperative pharmacologic brain protection is needed, this will be limited to the administration of either thiopental or etomidate (no other agent) for as short a period as possible. The total cumulative dose (mg) used for all aneurysms (excluding drug used to induce anesthesia at the start of the case) will be recorded in the spaces provided.

In addition, the reason for the use of this therapy will be recorded as one of three choices: 1-

Planned temporary clip time ≥10 minutes (anticipated that temporary clips would be applied ≥10 minutes); 2-Unplanned temporary clip time ≥10 minutes (although not anticipated beforehand, temporary clip exceeded 10 minutes); or 3-Other. If 3-Other is checked, please specify the reason in the space provided.

f) Section F. Intraoperative Fluids

The intraoperative period is defined as the interval between the time the patient arrives in the operating room and the time the patient leaves the operating room.

Item 1. Estimated blood loss for the entire case

Record the estimated blood loss for the entire case (in ml) in the space provided and be sure to use leading zeros. DO NOT LEAVE BLANK, if there is zero blood loss, enter 00000. If there was 200 mls of blood loss, enter 00200.

Instruction box: If ≥1,000 ml, please check appropriate box in Section H, item 6.

Item 2. Urine output for the entire case

Record the total urine output for the entire case (in ml) in the space provided and be sure to use leading zeros. DO NOT LEAVE BLANK, if there is zero urine output, enter 00000. If urine output is 1,200 mls, enter 01200.

Item 3. Intraoperative fluid administration

Total Crystalloids: In the space provided, record the total volume (in ml) of any intravenous crystalloid solution(s) administered to the patient during surgery. With the exception of mannitol, any and all forms of crystalloid are to be included, irrespective of whether the solution is hypotonic, isotonic, or hypertonic. It is not necessary to specify the type of crystalloid used. Use leading zeros. For example, if 3 liters of crystalloid are given, enter 03000 ml.

Total Mannitol: In the space provided, record the total volume (in ml) of mannitol administered to the patient. It is not necessary to specify the mannitol concentration. DO NOT LEAVE BLANK, if no mannitol is given enter 00000.

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Total Colloids: In the space provided, record the total volume (in ml) of any intravenous colloid solution(s) administered to the patient. Any and all forms of colloid are to be included (e.g., albumin, dextrans, gelatins, hetastarch or pentastarch). It is not necessary to specify the type or concentration of colloid used. DO NOT LEAVE BLANK, if none are given enter 00000.

Item 4. Intraoperative blood products (administered in the operating room)

Packed Red Cells: In the space provided, record the total number (in units) of Packed red blood cells (erythrocytes) administered to the patient during surgery. Typically, a unit of blood has a volume of 250-300 mls. DO NOT LEAVE BLANK, if no blood is given, enter 000. Use leading zeros. If 2 units of blood are given, enter 002.

Fresh Frozen Plasma or Cryoprecipitate: In the space provided, record the total volume (in mls) of Fresh frozen plasma or cryoprecipitate administered to the patient during surgery. DO NOT LEAVE BLANK, if none is given, enter 00000.

Platelets: In the space provided, record the total volume (in mls) of Platelets administered to the patient during surgery. DO NOT LEAVE BLANK, if none is given, enter 00000.

Other Blood Products: In the space provided, record the total volume of any Other blood product administered to the patient during surgery (e.g., whole blood, specific clotting factors, cell-saver). DO NOT LEAVE BLANK, if none is given, enter 00000. For any entry in this category please specify the product that was given in the blank space provided.

g) Section G. Events occurring during the first 0-2 hours after leaving the operating room

All events occurring between the time the patient leaves the operating room and up to two hours after surgery fall into this category, irrespective of the patient’s location.

Comment: To facilitate temperature and airway management, and to aid in the management of any immediate postoperative events, the Anesthesiologist will remain directly involved in the patient’s care for at least the first two hours after completion of surgery, irrespective of patient location.

Item 1. Arrival to postoperative care area (ICU, recovery room, etc .)

The date (month, day, year) and time when the patient arrived to the postoperative care area will be recorded in the space provided in numeric fashion. For example, five minutes after six o’clock in the morning of January 2, 2000 would be recorded as 01/02/2000 06:05. One minute after midnight on November 12, 2001 would be recorded as 11/12/2001 00:01. Note this may be different from the style used in many countries (e.g., most of Europe). Please be careful.

Comment: The postoperative care area may be a recovery room, post-anesthesia care unit, surgical intensive care unit, neurological or neurosurgical intensive care unit, or any area to which patients undergoing cerebral aneurysm clipping go after completion of surgery.

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Item 2. Intubated or tracheostomized on arrival to postoperative care area.


No: The patient is not endotracheally intubated nor has a tracheostomy when they arrive to the postoperative care area.

Yes: The patient is endotracheally intubated or has a trachostomy on arrival to the postoperative care area.

Comment: Even if the patient is extubated one minute after arrival to the postoperative care area, this item should be checked “Yes.”

Item 3. Was patient intubated or tracheostomized at two hours after leaving the operating room?

There are two choices, check one

No: The patient was not endotracheally intubated or tracheostomized two hours after surgery (after leaving the O.R.).

Yes: The patient is endotracheally intubated or tracheostomized two hours after surgery (after leaving the O.R.).

Comment: Even if the patient is extubated two hours and one minute after surgery, this item should be checked “Yes.”

Item 4. Patient's temperature two hours after leaving the operating room

In the space provided, record the patient's temperature (°C) two hours after the patient left the operating room. The temperature site from which this data is obtained must be either tympanic or sublingual.

h) Section H. Perioperative Events

Instruction box: PLEASE FAX THIS PAGE WITHIN 24 HOURS TO THE CCC AT 319-384-8072.

If any item (1-10) is checked as occurring, please complete an IE form(s).

For any item (11-24) checked as occurring, please complete an IE form(s) only if the event had a clinically significant effect.

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Comment: This checklist provides key information regarding intraoperative and immediate postoperative patient safety. Check all that apply, even if redundant. For example, a patient developed ventricular fibrillation, underwent cardiopulmonary resuscitation, was reintubated and resuscitated, and then had low cardiac output and ruled in for acute myocardial infarction, items 2, 1, 20, 4 or 18, and 3, respectively, should all be checked. "New" refers to the patient's condition on arrival to the operating room. For example, if a patient arrives to the operating room in atrial fibrillation and atrial fibrillation continues intraoperatively and postoperatively, then item 17 would be checked "Did not occur" with respect to atrial fibrillation. However, if a new arrhythmia occurred in addition to the atrial fibrillation (e.g., new left bundle branch block) then item 17 should be checked as occurring. For each question check all that apply, even if redundant.

Items 1-10 are considered to be critical or “indicator” events. An IE form must be completed by the Anesthesiologist for all such events and the CCC notified as soon as possible that such an event took place. Items 11-24 include other IEs. If, for items 11-24, the IE had no significant clinical impact on the patient’s clinical course, then an IE form does not need to be completed. If, for items 11-24, the IE did have a significant clinical impact on the patient, then an IE form should be completed.

Please indicate whether any of the events listed below: 1) Did not occur; 2) Occurred in the operating room (O.R.); or 3) Occurred during the first 0-2 hours after leaving the operating room (O.R.). DO NOT LEAVE ANY ITEM BLANK.

Item 1. Patient required cardiopulmonary resuscitation.

Cardiopulmonary resuscitation is any instance where open- or closed-chest manual cardiac compression is required. An IE form is required.

Item 2. Patient developed ventricular –tachycardia or –fibrillation.

Ventricular tachycardia is defined as any instance when there is a series of three or more consecutive wide complex (≥120 msec) beats at a rate ≥100 beats/minute, where the origin of electrical activation is the ventricle. The ventricular complexes can be monomorphic or polymorphic (Torsade de Pointes). With ventricular fibrillation (VF), the electrocardiogram reveals irregular and rapid oscilliations (250-400 bpm) of highly variable amplitude without identifiable QRS complexes or T waves. With VF, there is no coordinated ventricular contraction. As a result, immediate hemodynamic collapse always occurs. An IE form is required.

Item 3. Patient developed new signs or symptoms of myocardial ischemia or infarction.

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"New" refers to the patient's condition on arrival to the operating room. In the setting of acute subarachnoid hemorrhage, electrocardiographic (ECG) abnormalities which ordinarily indicate myocardial ischemia or infarction are not, by themselves, reliable markers. Hence, the diagnosis of myocardial ischemia and/or infarction in the setting of acute SAH will require, in addition to appropriate ECG changes, at least one major, or two minor, supportive clinical and/or laboratory signs. Major signs include: 1) classic angina or the patient's anginal equivalent (with or without associated signs of nausea, diaphoresis, anxiety); 2) a new positive pyrophosphate scan; 3) significant stenosis of an appropriate coronary artery (angiography); 4) autopsy confirmation of acute myocardial ischemia or infarction. Minor signs include: 1) a new and distinct increase in serum creatine kinase-MB (CKMB) or troponin levels; 2) associated acute hemodynamic instability; 3) associated acute pulmonary congestion (dyspnea, orthopnea, rales, pulmonary edema); 4) a new and distinct regional wall motion abnormality. An IE form is required.

Item 4. Patient developed cardiogenic shock.

Cardiogenic shock is defined as any instance where there is substantively decreased cardiac output (which is not due to hypovolemia or cardiac tamponade) associated with systemic hypoperfusion (increased lactate concentration, oliguria) and/or hypotension (MAP ≤60 mmHg). In the absence of inotropes, in cardiogenic shock cardiac index is usually less than 2.2 L/m2/min and/or mixed venous hemoglobin saturation is usually less than 65%. An IE form is required.

Item 5. Patient received a continuous infusion of a vasopressor or inotrope for 15 consecutive minutes or longer, to support the systemic circulation .

The duration of administration must be in consecutive minutes. Isolated or intermittent boluses of a vasopressor or inotrope do not qualify. For example, occasional boluses of ephedrine or phenylephrine (even if there is more than one bolus in a 15-minute period) do not qualify. If however, clinical circumstances require the continuous infusion of any vasopressor or inotrope for 15 consecutive minutes or longer, then the definition is met. Agents in this category include, but are not limited to: phenylephrine, epinephrine, norepinephrine, dopamine, dobutamine, isoproterenol, methoxamine, amrinone, milrinone, etc.

Comment: It is understood that vasopressors or inotropes may be given perioperatively for one or more different reasons. For example, these agents may be given to improve cerebral perfusion (IE code 241). However, when vasopressors or inotropes are given to treat hemodynamic or cardiovascular conditions such hypotension, low systemic vascular resistance, low cardiac output, or any form of cardiac failure, this is specifically coded on the IE form as Vasopressor or inotrope administration to support systemic circulation (code 240). An IE form is required.

Item 6. Blood loss of 1000 ml or greater (any cause).

If, in Section F, Item 1, the estimated blood loss for the entire case is 1000 ml or greater, check the “Occurred in the O.R.” box. If, during the first 0-2 hours after the patient left the O.R., severe bleeding occurred (≥1000 ml, any reason), please check the “Occurred 0-2 h after leaving O.R.” box. An IE form is required.

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Comment: Because of the devastating nature of major hemorrhagic complications in the setting of acute aneurysmal subarachnoid hemorrhage, and because of the potential of intraoperative hypothermia to increase these complications (hypothermic coagulopathy), any and all major bleeding complications (CNS or elsewhere) must be noted (Items 6- 10 of this Section).

Item 7. Patient had signs or symptoms of severe coagulopathy.

Even if the patient was coagulopathic on arrival to the O.R., if they were coagulopathic in the O.R. or postoperatively (0-2 hours), check the appropriate boxes. An IE form is required.

Comment: Signs and symptoms of severe coagulopathy include markedly abnormal preoperative, intraoperative or postoperative clotting studies (prothrombin time [PT], activated partial thromboplastin time [aPTT]), or evidence of disseminated intravascular coagulation [low fibrinogen and increased fibrin degradation products]. Non-CNS signs of coagulopathy could include bleeding from intravenous sites, spontaneous epistaxsis, or acute onset of clinically significant gastrointestinal or genitourinary bleeding. Extensive bruising and/or hematoma formation from angiography might also be a sign of coagulopathy. During surgery, signs of coagulopathy might include (in addition to the above) marked or unusual bleeding from wound edges, brain bleeding in response to retraction, or spontaneous brain bleeding. A platelet count less than 100,000/mm3 may be either an independent risk factor for bleeding, or a marker of major hemorrhage.

Comment: Because mild hypothermia can induce mild coagulopathy, and because recurrent intracranial hemorrhage, either before, during, or after aneurysm surgery is associated with major morbidity, it is important to determine whether or not intraoperative hypothermia substantially increases the risk of hemorrhagic complications. It is for this reason that the patient's pre-, intra- and postoperative coagulation status must be characterized.

Item 8. Patient had a recurrent subarachnoid hemorrhage not due to surgical manipulation .

Any instance when any subarachnoid hemorrhage occurs; either rebleeding from the previously ruptured aneurysm or bleeding from some other intracranial aneurysm; either during surgery or during the first 0-2 hours after the patient left the operating room. The only exception is aneurysmal bleeding caused by direct surgical manipulation of an aneurysm. Whenever there is a recurrent subarchnoid hemorrhage or aneurysmal rebleeding which is not a result of surgery, an IE form is required.

Item 9. Patient developed a new epidural or subdural hemorrhage.

"New" refers to the patient's condition on arrival to the operating room. Any instance when a new epidural or subdural hemorrhage occurs, either during surgery or during the first 0-2 hours after the patient left the operating room. Hemorrhage present prior to presenting to the O.R. for aneurysm surgery does not qualify. An IE form is required.

Item 10. Patient underwent other, previously unplanned (e.g., emergent) surgery.

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Comment: Almost always, if a patient needs additional, previously unplanned surgery in the first 0-2 hours after cerebral aneurysm surgery, this surgery is undertaken because there is a very serious problem. Usually, the problem is neurosurgical (e.g., acute intracranial hemorrhage). However, unanticipated non-neurosurgical problems so severe as to require emergent surgery immediately after aneurysm clipping are likely to be quite serious (acute abdomen, ischemic limb, emergent tracheostomy). We wish to follow all such events to determine if intraoperative temperature management influences the incidence or severity of such events. An IE form is required.

Item 11. HYPERtension-INTENDED (mean arterial pressure ≥120 mm Hg for 15 consecutive minutes or longer, which was clinically desired). Complete an IE form only if clinically significant.

Comment: This is the operational definition of hypertension in this trial. The duration of hypertension must be in consecutive minutes. For example, five separate three-minute periods of MAP ≥120 mmHg, separated by periods with MAP <120 mmHg would not constitute hypertension by this definition.

It is understood that, in some instances, hypertension may be clinically desired and intentionally induced during and after cerebral aneurysm surgery. For example, hypertension may be desired during temporary clipping to promote collateral blood flow. Induction of hypertension can occur either by active means (i.e., a vasopressor administration) or by passive means (i.e., "light" anesthesia). Irrespective of the means used to achieve it, if hypertension was the desired clinical result, hypertension is to be classified as "intentional." HYPERtension-Intended has a specific IE code (230). Complete an IE form only if clinically significant.

In other instances, hypertension may not be clinically desired, but might occur despite efforts to avoid it. Irrespective of cause, if achievement of hypertension was not the desired clinical result, hypertension is to be classified as "not intentional" (see Item 12 below).

Item 12. HYPERtension-NOT INTENDED (mean arterial pressure ≥120 mm Hg for 15 consecutive minutes or longer, which was not clinically desired ).

Comment: This is the operational definition of hypertension in this trial. The duration of hypertension must be in consecutive minutes. For example, five separate 3-minute periods of MAP ≥120 mmHg, separated by periods with MAP <120 mmHg would not constitute hypertension by this definition.

As discussed above (item 11), irrespective of cause, if achievement of hypertension was not the desired clinical result, hypertension is to be classified as "not intentional." HYPERtension-NOT Intended has a specific IE code (231). Complete an IE form only if clinically significant.

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Item 13. HYPOtension-INTENDED (mean arterial pressure ≤60 mm Hg for 15 consecutive minutes or longer, which was clinically desired).

Comment: This is the operational definition of hypotension in this trial. The duration of hypotension must be in consecutive minutes. For example, five separate three-minute periods of MAP ≤60 mmHg, separated by periods of time with MAP >60 mmHg would not constitute hypotension by this definition.

It is understood that, in some instances, hypotension may be clinically desired and intentionally induced during cerebral aneurysm surgery. For example, hypotension may be desired prior to and during permanent clip application. Induction of hypotension can occur either by active means (i.e., administration of vasodilators/anesthetics) or by passive means (i.e., blood pressure not actively supported). Irrespective of the means used to achieve it, if achievement of hypotension was the desired clinical result, hypotension is to be classified as "intentional." HYPOtension-Intended has a specific IE code (232). Complete an IE form only if clinically significant

In other instances, hypotension may not be clinically desired, but might occur despite efforts to avoid it. Irrespective of cause, if achievement of hypotension was not the desired clinical result, hypotension is to be classified as "not intentional” (see Item 14 below).

Item 14. HYPOtension-NOT INTENDED (mean arterial pressure ≤60 mm Hg for 15 consecutive minutes or longer, which was not clinically desired) .

Comment: This is the operational definition of hypotension in this trial. The duration of hypotension must be in consecutive minutes. For example, five separate 3-minute periods of MAP ≤60 mmHg, separated by periods of time with MAP >60 mmHg would not constitute hypotension by this definition.

As discussed above (Item 13), irrespective of cause, if achievement of hypotension was not the desired clinical result, hypotension is to be classified as "not intentional.") HYPOtension-NOT intended has a specific IE code (233). Complete an IE form only if clinically significant.

Item 15. Patient received a continuous infusion of a vasopressor or inotrope for 15 consecutive minutes or longer, to support the cerebral circulation. The duration of administration must be in consecutive minutes. Isolated or intermittent boluses of a vasopressor or inotrope do not qualify. For example, occasional boluses of ephedrine or phenylephrine (even if there is more than one bolus in a 15-minute period) do not qualify. If however, clinical circumstances require the continuous infusion of any vasopressor or inotrope for 15 consecutive minutes or longer, then the definition is met. Agents in this category include, but are not limited to: phenylephrine, epinephrine, norepinephrine, dopamine, dobutamine, isoproterenol, methoxamine, amrinone, milrinone, etc.

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Comment: It is understood that vasopressors or inotropes may be given perioperatively for one or more different reasons. As discussed in Item 5., these agents may be given to support the systemic circulation. However, these agents may also be given to improve cerebral perfusion. Intraoperatively, vasopressors or inotropes are often given during temporary clip application in an attempt to improve collateral circulation. Similarly, these agents may be given after surgery in an attempt to improve cerebral perfusion (most commonly to prevent or reverse a new or worsened neurologic deficit). Whenever vasopressors or inotropes are given with the specific intent of supporting or improving the cerebral circulation, this is specifically coded on the IE form as vasopressor or inotrope administration to support cerebral circulation (241). Complete an IE form only if clinically significant.

Item 16. Patient developed new signs or symptoms of neurologic injury or dysfunction (seizure; diabetes insipidus; intracranial hypertension; motor or speech deficit).

Comment: "New" refers to the patient's condition on arrival to the operating room. Because patients must arrive to the O.R. with a WFNS score of I, II, or III to be eligible, intraoperative conditions which would come into this category would include development of diabetes insipidus; new or exceptionally severe ("malignant") brain swelling; new or progressive abnormalities detected by neurologic monitoring (evoked potential abnormalities, marked jugular venous desaturation, intracranial hypertension). Postoperative conditions would include those just listed, in addition to deterioration in level of consciousness, seizures, development of a new focal motor deficit or aphasia. Complete an IE form only if clinically significant.

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Item 17. Patient developed new arrhythmia

Comment: "New" refers to the patient's condition on arrival to the operating room. Development of minor, infrequent, or clinically insignificant arrhythmias (such as occasional atrial or ventricular premature contractions, occasional transient junctional or wandering atrial pacemakers) should not be noted. Complete an IE form only if clinically significant. If the patient developed either ventricular –tachycardia or –fibrillation, this should be Item 2 above.

Item 18. Patient developed new signs or symptoms of ventricular dysfunction (CHF, pulmonary edema, low cardiac output

Comment: "New" refers to the patient's condition on arrival to the operating room. Any instance when clinical signs and/or symptoms point to abnormally high left ventricular end diastolic pressure, resulting in translocation of fluid from the pulmonary capillaries into the pulmonary interstitial and/or alveolar spaces ("hydrostatic" pulmonary edema). Signs and symptoms include rales, elevated jugular venous pressure, peripheral edema, dyspnea at rest or on exertion, orthopnea, S3 gallop, and radiologic evidence of pulmonary congestion (increased pulmonary vascular markings and/or alveolar consolidation). Although this can occur in patients with normal ventricular function, most often this is associated with compromised left ventricular function and diminished cardiac reserve. Signs of low cardiac output may include relative hypotension; pallor or cool extremities; oliguria; and/or low cardiac output measurements and/or marked wall motion or ejection abnormalities on echocardiographic examination. Complete an IE form only if clinically significant.

Item 19. Patient developed new signs or symptoms of respiratory dysfunction (hypoxemia, hypercarbia, bronchospasm, airway obstruction, respiratory arrest).

Comment: "New" refers to the patient's condition on arrival to the operating room. Hypoxemia is defined as any instance when the patient's arterial PO2 is ≤50 mmHg (or ≤6.7 kPa) or SaO2 is ≤85% [pulse oximetry] for any duration, for any reason. Hypercarbia is defined as any instance when the patient's arterial PCO2 is ≥50 mmHg (or ≥6.7 kPa) on two or more consecutive arterial blood gas measurements, irrespective of the interval between measurements, or the reason for its presence. Other signs and symptoms of respiratory dysfunction may include: dyspnea; orthopnea; tachypnea; apnea or respiratory arrest; evidence of small airway closure (“bronchospasm”) such as wheezing, or high inspiratory pressure or delayed expiration during mechanical ventilation. Airway obstruction may occur at any level of the tracheobronchial tree (small airways to pharnyx) and may occur through a variety of mechanisms including mucous plugs, severe bronchospasm, kinked endotracheal tube, laryngospasm or other peri-glottic obstructions. Finally, other (primarily lung) conditions which limit gas exchange such as pneumonia, ARDS, and pulmonary embolism are included in this category. Complete an IE form only if clinically significant. ("Hydrostatic" pulmonary edema, largely due to elevated left ventricular end-diastolic pressure, is classified under Item 18).

Item 20. Patient required re-intubation

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Comment: Check this item when: 1) The patient had been extubated (either in the operating room or in the recovery area); and 2) was subsequently re-intubated for any reason. Re-intubation can occur either in the operating room or recovery area. Re-intubation can occur for any reason: neurologic, airway management, etc. Complete an IE form only if clinically significant.

Item 21. Patient developed new major abnormality of sodium, potassium, or glucose. Complete an IE form only if clinically significant.

Comment: "New" refers to the patient's condition on arrival to the operating room. Sodium abnormalities include hyponatremia ([Na+] ≤125 mEq/L) or hypernatremia ([Na+] ≥155 mEq/L). Potassium abnormalities include hypokalemia ([K+] ≤2.0 mEq/L) or hyperkalemia ([K+] ≥6.0 mEq/L). Glucose abnormalities include hypoglycemia ([Glucose] ≤50 mg/dL or ≤ 2.8 mmol/L) or hyperglycemia ([Glucose] ≥400 mg/dL or ≥ 22 mmol/L).

Item 22. Patient developed new allergic or anaphylactic reaction

Comment: "New" refers to the patient's condition on arrival to the operating room. Check if the patient develops an anaphylactic, anaphylactoid, or marked idiosyncratic reaction to an administered medication, blood product, or in response to an environmental exposure (metal, latex, food allergen). The reaction should be clinically significant and should usually include classic allergic responses such as pruritis, hives or urticaria, cutaneous vasodilation ("flushing"), development of edema (peripheral or airway), peripheral vasodilation (hypotension), bronchospasm, and/or tachycardia, typically due to release of histamine, bradykinin, serotonin and/or complement fragments. Skin rashes, nausea, dysphoria, or other unexplained signs or symptoms associated with a medication, do not qualify unless systemic signs (above) are clearly present. . Complete an IE form only if clinically significant.

Item 23. Patient was anemic (hematocrit ≤24% or hemoglobin ≤ 8 mg/dL)

Even if the patient is anemic on arrival to the O.R., if they were anemic in the O.R. or for the first 0-2 hours after leaving the operating room for any reason, check “Yes.” Complete an IE form only if clinically significant.

Comment: Anemia is being followed for two reasons. First, although not firmly established, anemia to this degree probably has an independent adverse effect on neurologic outcome in the setting of an acute ischemic insult. Second, clinical circumstances that lead to this degree of anemia (e.g., severe intraoperative bleeding) may also have an independent adverse effect on neurologic outcome and/or indicate the presence of coagulopathy.

Item 24. During the first 0-2 hours after leaving the operating room, a head CT, MRI or cerebral angiogram was performed. Complete an IE form only if clinically significant.

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Comment: Often, if a patient needs a major diagnostic or therapeutic procedure in the first 0-2 hours after cerebral aneurysm surgery, there is a serious problem or concern. Most often, because of a new or worsened neurologic condition, the main neurosurgical concerns relate to the possibility of acute intracranial hemorrhage, acute vessel thrombosis, or misplaced aneurysm clip. We wish to track all such events to determine if intraoperative temperature management influences their incidence or severity.

Last question. Are there additional comments you would like to add regarding patient information on this form? There are two choices, check one.

No. There are no comments nor additional information that you wish to communicate regarding the intraoperative and/or immediate perioperative period.

Yes. There are comments or additional information that you wish to communicate regarding the intraoperative and/or immediate perioperative period.

Instruction box: If yes, please go to web address http://ctsdmc.public-health.uiowa.edu/ihast2/comment/

Comment: Hand-written comments in page margins of this form cannot be recorded as data. If you have comments you would like to make regarding any aspect of the patient’s course in the operating room or early postoperative phase (first two hours), please file them at the web address above.

IX. H TEMPERATURE

IX.H.1. Overview:

This form will indicate the temperature group to which the patient has been assigned and all intraoperative temperature data will be recorded on this form (and the local hospital anesthesia record) only. Only the Anesthesiologist caring for the patient during their primary aneurysm surgery may complete this form. The contents of the RANDOMIZATION ENVELOPE (TEMPERATURE form and envelopes) and all aspects of intraoperative temperature management are to be known only to the Anesthesiologist caring for the patient during the primary aneurysm surgery. The Neurosurgeon, Local Study Coordinator, and Neurologic Examiner(s) are not to learn of the patient's group (temperature) assignment and/or any intraoperative temperature data. The Neurosurgeon may learn of the patient's group assignment and/or temperature ONLY for immediate intraoperative safety reasons.

IX.H.2. Data Items

Item 1. Treatment Assignment

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The group to which the patient has been randomized, either HYPOTHERMIA or NORMOTHERMIA will be indicated in bold italicized capital letters at the top of this form.

Instruction Box: Immediately below the treatment assignment is a gray-shaded instruction box, which is a reminder for the target esophageal temperature for each group: Hypothermia (target esophageal temperature 33.0°C; acceptable range 32.5-33.5°C) or Normothermia (target esophageal temperature 36.5°C; acceptable range 36.0-37.0°C). Also included in the instruction box are reminders of how to induce hypothermia or maintain normothermia. HYPOTHERMIA: Water mattress at 10°C; Polar Air at maximum cooling (10°C); intravenous fluids not warmed; inspired gases not warmed. NORMOTHERMIA: Water mattress at 36-38°C; Polar Air at 38°C; intravenous fluids warmed; inspired gases warmed.

Item 2. Date/Time RANDOMIZATION ENVELOPE opened

The date (month, day, year) and time will be recorded in the space provided in numeric fashion. For example, five minutes after six o’clock in the morning of January 2, 2000 would be recorded as 01/02/2000 06:05. One minute after midnight on November 12, 2001 would be recorded as 11/12/2001 00:01.

Comment: Note this style of recording dates may be different from the style used in many countries (e.g., most of Europe). Please be careful.

Item 3. Temperatures at definitive clip placement*

For each aneurysm clipped (or otherwise treated), record both the esophageal temperature (°C) and secondary temperature at final definitive clip placement in the spaces provided, in the sequence in which the aneurysms are clipped (1st Aneurysm, 2nd Aneurysm, etc.). Because some aneurysms require multiple clips and/or a series of clip applications, record the time of placement of the final (or definitive) clip for each aneurysm. *If, instead of being clipped, the aneurysm is wrapped, clipped and wrapped, or the aneurysm cannot be secured, record the esophageal temperature when the treatment for each aneurysm (in sequence) is completed. Temperature information should be recorded on this form (and the local hospital anesthesia record) only . For each aneurysm clipped or otherwise treated, all other [non-temperature] information recorded at the time of definitive clip application (or other treatment) goes in section E of the ANESTHESIOLOGIST form.

Instruction Box: *If not clipped, when wrapping or other treatment done.

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Instruction Box: POST CLIP MANAGEMENT. The gray-shaded instruction box reminds the Anesthesiologist of how the patient's temperature is to be managed once the final aneurysm clip is in place or other forms of treatment are complete. Hypothermia, the instruction box will indicate: 1) the water mattress under the patient should be set at 40°C; 2) the Polar Air unit should be set to maximum warming (43°C); 3) intravenous fluids and inspired gases should be warmed; and 4) that the forced-air blanket should remain on the patient for two hours after leaving the operating room. (Probably 50% of the patients in the hypothermia group will require forced-air warming after leaving the operating room.) Normothermia: There is no change in thermal management, but the forced air blanket is to remain on the patient for the first two hours after leaving the operating room. Although patients in the normothermia group will probably not need warming after leaving the operating room, the forced-air blanket is left on the patient (without necessarily warming) to facilitate blinding.

Item 4. Did the patients' temperature management significantly deviate from protocol?

There are two choices, select one.

No: Intraoperative temperature management protocols and procedures were carried out in accordance with the patient's assigned temperature group, without any significant deviation.

Yes: Intraoperative temperature management protocols were not carried out in accordance with the patient's assigned temperature group (i.e., there were significant deviations from the assigned protocol). Four examples follow:

Example 1: A patient was randomized to NORMOTHERMIA but, at the time of clipping, esophageal temperature was 35°C because the Polar Air unit was not used, or was not set in accordance with protocol.

Example 2: A patient was randomized to HYPOTHERMIA but, at the time of clipping, esophageal temperature was 35°C because the Polar Air unit was not used, or was not set in accordance with protocol.

Example 3: A patient was randomized to NORMOTHERMIA, but some intraoperative catastrophe occurred and the Neurosurgeon and Anesthesiologist decided to induce hypothermia (in this case, Item 5 would also be checked "Yes").

Example 4: A patient was randomized to HYPOTHERMIA, but because of some event potentially related to hypothermia (e.g., severe persistent bradycardia or major coagulopathy), it was decided to reverse the hypothermia (i.e., rewarm the patient) before definitive clipping (in this case, Item 5 would also be checked "Yes”).

Item 5. Was surgeon informed of, or did surgeon learn of, the patient's temperature at any time during the operation? There are two choices, check one.

No. The surgeon was not informed of and did not learn of the patient's temperature at any time during the operation.

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Yes. The surgeon was either informed of, or learned of (either accidentally or intentionally) the patient's temperature at some time during the operation.

Comment: According to protocol, at no time before, during, or after surgery is the surgeon to know either: 1) the temperature group to which the patient was assigned; nor 2) the patient’s intraoperative temperature. The reason for "blinding" the Neurosurgeon is to eliminate bias in terms of choices of intraoperative surgical therapy and/or any influence on outcome evaluations. Accordingly, the Neurosurgeon is not to try to seek out this information, either directly (asking the Anesthesiologist) nor indirectly (looking at temperature monitors/displays or anesthesia record). If the Neurosurgeon should ask the Anesthesiologist for temperature-related information, the Anesthesiologist is not to reveal this information. The only exception to this rule is when, in the judgment of either the Neurosurgeon or Anesthesiologist, the patient's intraoperative thermal condition must be revealed in order to decide whether an immediate and potentially life-threatening intraoperative condition might be temperature related, and whether this might require a change in intraoperative thermal management. However, under no circumstances whatsoever is information regarding group assignment or ANY protocol deviation to be provided to the Local Study Coordinator, Neurologic Examiner(s) or to any other physician involved in postoperative care at any time.

Item 6. Esophageal temperature on completion of skin closure (last temperature in O.R.)

In the space provided, please record the patient's esophageal temperature (°C) at completion of surgery, either at skin closure or just before removal of the esophageal probe, whichever comes last. Like all other intraoperative temperature data, this temperature is not to be revealed to the Neurosurgeon.

Item 7. Other temperature-related comments?


No. There are no additional comments or data regarding the patient’s temperature in the operating room.

Yes. There are additional comments or data regarding the patient’s temperature in the operating room.

If yes, please record this information in the space provided.

Instruction box: When you have completed answering all of the above questions, the underlying carbon copy of this form is to be separated from the original. Each TEMPERATURE form is to be folded in half and each page is to be placed in separate pre-labeled envelopes that were included in the Study Packet. Each envelope is then sealed and returned to the Local Study Coordinator. Once sealed, these envelopes are never to be opened.

IX. I DAILY POST-OP SCREEN

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IX.I.1. Overview:

This form may be completed by any IHAST2 participant who is qualified to make Glasgow Coma Scale (GCS) assessments. Usually, this form will be completed by the Study Coordinator. However, any participating neurosurgeon or any participating anesthesiologist may also complete this form if they are GCS qualified and were not present during the operation nor in the presence of the patient for the first 0-2 hours after the patient left the operating room and are not aware of patient group assignment or intraoperative temperature(s).

This form is to be completed every day after the primary aneurysm surgery until either discharge from the hospital or postoperative day 14, whichever comes first. However, on the day of discharge from the hospital, (regardless of the duration of the hospital stay) the D/C (discharge) column of this form is to be completed.

The postoperative “clock” begins when the patient leaves the operating room after completion of the primary aneurysm surgery.

On the first postoperative visit (~24 hours after completion of the primary aneurysm surgery) refer to the patient’s condition in comparison to the patient's condition prior to going to the operating room. At all other postoperative visits, refer to the patient's condition in comparison to that which existed at the time of the previous post-op daily screening examination (approximately 24 hours earlier). Also, on the first postoperative visit, do not record intercurrent events occurring in the first 0-2 hours after the patient left the operating room--these events will be recorded by the Anesthesiologist. If the discharge visit occurs after postoperative day 15, include all intercurent events that have occurred in the interval between the last postoperative visit (day 14) and discharge.

Instruction box: IF THE ANSWER TO ANY OF THE QUESTIONS BELOW IS “YES”, PLACE AN “X” IN THE APPROPRIATE BOX. IF THE ANSWER IS “NO”, LEAVE THAT BOX BLANK. FOR ALL NEW INTERCURRENT EVENTS, PLEASE COMPLETE AN IE FORM(S). FOR CONTINUING EVENTS, MARK ALL APPROPRIATE BOXES, BUT A NEW IE FORM IS NOT NECESSARY.

Item 1. What is today's GCS?

Record the patient's GCS (Glasgow Coma Scale) each day in the space provided.

Comment: The GCS is the sum of scores from three components: 1) eye opening; 2) best motor response; and 3) best verbal response. Be aware that the best motor response may come from the side of the patient's body that is NOT affected by the SAH. The sum of these three scores is recorded in the space provided as the GCS. Note that if the GCS cannot be assessed (intubated or pharmacologically paralyzed) enter 99 as the score. The score of 99 will indicate ‘can’t evaluate.’

Item 2 . Did the patient meet criteria for DIND or clinically symptomatic vasospasm ?

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No: Since the last evaluation, the patient has not met the criteria for the diagnosis of delayed ischemic neurologic deficit (DIND) (or clinically symptomatic vasospasm). Leave the box blank.

Yes: Since the last evaluation, the patient has met the criteria for the diagnosis of delayed ischemic neurologic deficit (DIND) (or clinically symptomatic vasospasm). Place an “X” in the box. DIND is classified as an intercurrent event.

Comment: A common cause for delayed deterioration of the patient's neurologic status would be the development of DIND. Please see the Intercurrent Events section for diagnostic criteria for this condition.

Item 3. Is the patient currently in an intensive care environment?

No: The patient is not in an intensive care environment. Leave the box blank.

Yes: The patient is an intensive care environment. Place an “X” in the box.

Comment: An intensive care environment is defined as one where: 1) continuous invasive hemodynamic monitoring usually takes place; and/or 2) continuous mechanical ventilation usually takes place; and/or 3) the ratio of physicians and/or nurses per patient is significantly greater than units caring for uncomplicated post-surgical patients. A "recovery room" or "post-anesthesia care unit" is considered to be an intensive care environment.

If yes: Is this a readmission since the last evaluation?

No: Although the patient is an intensive care environment, the patient was in an intensive care environment at the last evaluation, without any intervening period of discharge from an intensive care environment. Leave the box blank.

Yes: The patient has been admitted to an intensive care environment since the last evaluation and, before that admission, the patient was not in an intensive care environment. Place an “X” in the box.

Comment: If the patient leaves an intensive care environment for a diagnostic or therapeutic procedure, or surgery, and returns to an intensive care environment, this does not constitute a discharge. On the first postoperative visit, 24 hours after completion of the primary aneurysm surgery, refer to the patient's location immediately prior to going to the operating room. If the patient was in an intensive care environment before surgery and went back to the ICU without admission to a non-intensive care environment, this question should be answered “no.”

Item 4. Is the patient currently endotracheally intubated or tracheostomized?

No: The patient is not endotracheally intubated nor has a tracheostomy. Leave the box blank.

Yes: The patient is either endotracheally intubated or has a tracheostomy. Place an “X” in the box.

If yes: Has the patient be reintubated or tracheostomized since the last evaluation?

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No: If the patient is currently intubated (or has a tracheostomy) and there has been no interval of extubation since the last evaluation. Leave the box blank.

Yes: The endotracheal tube or tracheostomy that is currently present has been placed since the last evaluation with some preceeding interval of extubation. Reintubation (or tracheostomy) is an intercurrent event. Place an “X” in the box.

Comment: If the patient has been continuously intubated since the time of the primary aneurysm surgery, without any interval of extubation, then answer "No” to the above question.

Item 5. Has any surgery (other than the primary clipping or treatment) been performed since the last evaluation?

No: The patient has not undergone any form of surgery (other than the primary aneurysm clipping) since the last evaluation. Leave the box blank.

Yes: The patient has undergone some form of surgery (other than the primary aneurysm clipping) since the last evaluation. Place an “X” in the box.

Comment Surgery is defined as any procedure performed by surgeon that requires the patient to return to the operating room. However, some “bedside” procedures, such as tracheostomy, ventriculostomy, or wound debridement are also considered surgery. Dressing changes and/or line placement (central venous or arterial access) are not considered as “surgery” unless the procedure takes place in the operating room. Angiographic procedures are not considered surgery. At the time of the first postoperative visit (24 hours after the primary aneurysm surgery) do not count the primary aneurysm surgery). In almost all instances, if a patient needs surgery after aneurysm clipping, the need for surgery is associated with an intercurrent event, such as rebleeding, symptomatic hydrocephalus, or other major non-neurosurgical problem.

Item 6. Have any blood products been administered since the last evaluation?

No: No blood products have been administered since the last evaluation. Leave the box blank.

Yes: Blood or blood products have been administered since the last evaluation. Place an “X” in the box.

Comment If, at any time during the patient's hospitalization, the patient receives a blood product, this is to be noted on an intercurrent event form (as well as any associated reasons for the blood product). However, blood received during the primary aneurysm surgery is not to be recorded on the DAILY POST-OP SCREEN because it is recorded by the Anesthesiologist. At the 24,- 48,- and 72- hour postoperative evaluations, blood product administration is recorded in detail in the next section (see below).

Item 7. Has the patient received any vasopressor or inotrope for 15 consecutive minutes or longer since the last evaluation?

No: The patient has not received any vasopressor or inotrope for ≥15 consecutive minutes since the last evaluation. Leave the box blank.

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Yes: The patient has received a vasopressor or inotrope for ≥15 consecutive minutes in the last 24 hours. Place an “X” in the box.

Comment: The duration of administration must be in consecutive minutes. Isolated or intermittent boluses of a vasopressor or inotrope do not qualify. For example, occasional boluses of ephedrine or phenylephrine (even if more than one bolus in a 15-minute period) do not qualify. If however, clinical circumstances require the continuous infusion of any vasopressor or inotrope for 15 consecutive minutes or longer, then the definition is met. Agents in this category include, but are not limited to: phenylephrine, phenylephrine, epinephrine, norepinephrine, dopamine, dobutamine, dopexamine, isoproterenol, methoxamine, amrinone, milrinone, etc. It is not necessary to specify the agent used.

Item 8. Has the patient developed a significant dysrhythmia or had evidence of myocardial ischemia or myocardial infarction since the last evaluation?

No: The patient has not developed a significant dysrhythmia nor had evidence of myocardial ischemia or myocardial infarction since the last evaluation. Leave the box blank.

Yes: The patient has developed a significant dysrhythmia and/or has had evidence of myocardial ischemia or myocardial infarction since the last evaluation. Place an “X” in the box.

Comment: Arrhythmias are common in the setting of aneurysmal subarachnoid hemorrhage. Significant arrhythmias include: severe sinus bradycardia; acute atrial fibrillation or flutter; any of a variety of supraventricular tachydysrhythmias; 3rd-degree AV block (and some forms of 2nd-degree AV block); right- and left- bundle branch block; frequent ventricular premature contractions; ventricular -tachycardia or -fibrillation.

Comment: In the setting of acute subarachnoid hemorrhage, electrocardiographic (ECG) abnormalities that ordinarily indicate myocardial ischemia or infarction are not, by themselves, reliable markers. Hence, the diagnosis of myocardial ischemia and/or infarction in the setting of acute SAH will require, in addition to appropriate ECG changes, at least one Major-, or two Minor-, -supportive clinical and/or laboratory signs. Major signs include: 1) classic angina or the patient's anginal equivalent (with or without associated signs of nausea, diaphoresis, anxiety); 2) a new positive pyrophosphate scan; 3) significant stenosis of an appropriate coronary artery (angiography); 4) autopsy confirmation of acute myocardial ischemia or infarction. Minor signs include include: 1) a new and distinct increase in serum creatine kinase-MB (CKMB) or troponin levels; 2) associated acute hemodynamic instability; 3) associated acute pulmonary congestion (dyspnea, orthopena, rales, pulmonary edema); 4) a new and distinct regional wall motion abnormality).

Item 9. Has the patient had evidence of ventricular dysfunction (CHF, pulmonary edema, low cardiac output) since the last evaluation?

No: The patient has not had evidence of ventricular dysfunction (CHF, pulmonary edema, low cardiac output) since the last evaluation. Leave the box blank.

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Yes: The patient has had evidence of ventricular dysfunction (CHF, pulmonary edema, low cardiac output) since the last evaluation. Place an “X” in the box

Comment: Any instance when clinical signs and/or symptoms point to abnormally high left ventricular end diastolic pressure, resulting in translocation of fluid from the pulmonary capillaries into the pulmonary interstitial and/or alveolar spaces ("hydrostatic" pulmonary edema). Signs and symptoms include rales, elevated jugular venous pressure, peripheral edema, dyspnea at rest or on exertion, orthopnea, S3 gallop, and radiologic evidence of pulmonary congestion (increased pulmonary vascular markings and/or alveolar consolidation). Although this can occur in patients with normal ventricular function, most often this is associated with compromised left ventricular function and diminished cardiac reserve. Signs of low cardiac output may include relative hypotension; pallor or cool extremities; oliguria; and/or low cardiac output measurements and/or marked wall motion or ejection abnormalities on echocardiographic examination.

Item 10. Has the patient had a fever (T 38.5 C), undergone microbiologic culturing or shown any other evidence of local or systemic infection since the last evaluation?

No: Since the last evaluation, the patient has not had a fever, has not undergone culturing, nor has shown any sign of local or systemic infection. In other words, there is no indication of infection. Leave the box blank.

Yes: Since the last evaluation, the patient has either: had a fever (T≥38.5°C); undergone microbiologic culturing (blood, sputum, surgical site, urine, CSF, etc.); or had other evidence of local or systemic infection (wound erythema; new infiltrates on chest x-ray; bacteremia; etc.). Place an “X’ in the box.

Item 11. Have any other respiratory, digestive, endocrine, urogenital, hematologic or other event occurred since the last evaluation (See IE list)?

No: The patient has not had any other respiratory (e.g., hypoxemia, bronchospasm); digestive (e.g., gastrointestinal hemorrhage); endocrine (e.g., hyperglycemia); urogenital, hematologic (e.g.,, deep venous thrombosis, coagulopathy); or other intercurrent events since the last evaluation. Leave the box blank.

Yes: The patient has had an intercurrent event which is listed under the respiratory, digestive, endocrine, urogenital, hematologic, or 'other' categories since the last evaluation. Place an “X” in the box.

Item 12. Are there additional comments you would like to add regarding patient information to this form? If yes, go to http://ctsdmc.public-health.uiowa.edu/ ihast2/comment/

Please enter additional information regarding the patient’s postoperative course that is not adequately indicated by this form and associated IE forms via the above website.

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Item 13. For any diagnostic or therapeutic procedures performed since the last evaluation (e.g., CT scan, echocardiogram, TCD, CXR, bronchoscopy, EKG) please enter procedure codes for the appropriate day below ( See IE Code list ):

No: The patient did not undergo any diagnostic or therapeutic procedures since the last evaluation. Leave the boxes blank.

Yes: The patient did undergo one or more diagnostic or therapeutic procedures since the last evaluation. In this instance, please enter the three-digit procedure codes (See IE Code list) in the spaces provided (up to five codes).

Comment: A diagnostic or therapeutic procedure is any procedure which is performed either to make a diagnosis or to treat a disease state. Examples include: electrocardiography, transcranial Doppler, any x-ray study, cardioversion, intubation, endoscopy, etc. Please see the IE list for a complete listing of all coded procedures. In general, routine daily blood chemistries (electrolytes, hemoglobin) are not considered to be a diagnostic or therapeutic procedure. In many instances, a diagnostic or therapeutic procedure is performed because of the presence of, or suspicion of, an intercurrent event. Hence, when a procedure is performed, please consider whether there are any associated IEs.

Daily Post-Op Screen Supplement: If a patient has more diagnostic or therapeutic procedures than you can list on the DAILY POST-OP SCREEN form, please complete the DPS (DAILY POST-OP SCREEN) SUPPLEMENT form. The Patient ID must match the corresponding DAILY POST-OP SCREEN form, and the Page Number should begin with 1. You may use as many DPS SUPPLEMENTs as needed for any single patient, numbering in succession beginning with 1.

POSTOPERATIVE FLUIDS

Instruction box: PLEASE COMPLETE AN IE FORM(S) FOR ANY POSTOPERATIVE BLOOD PRODUCT. Do NOT include intraoperative fluid or blood that was given during the primary aneurysm surgery (because these fluids are recorded by the Anesthesiologist).

At the 24-hour evaluation, include all fluids and blood administered since the patient left the operating room. At the 48- and 72- evaluations, include all fluids and blood administered since the last evaluation.

Item 1. Post-operative fluid administration since the last evaluation.

Total crystalloid: In the space provided, record the Total volume (in ml) of any intravenous crystalloid solution(s) administered since the last evaluation. Be sure to use leading zeros. With the exception of mannitol, any and all forms of crystalloid are to be included, irrespective of whether the solution is hypotonic, isotonic, or hypertonic.

Total mannitol: In the space provided, record the Total volume (ml) of mannitol administered to the patient since the last evaluation. Be sure to use leading zeros. It is not necessary to specify the mannitol concentration. DO NOT LEAVE BLANK. If no mannitol is given, enter 00000.

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Total colloid: In the space provided, record the Total volume (in ml) of any intravenous colloid solution(s) administered to the patient since the last evaluation. Be sure to use leading zeros. Any and all forms of colloid are to be included (e.g., albumin, dextrans, gelatins, hetastarch or pentastarch). It is not necessary to specify the type or concentration of colloid used. DO NOT LEAVE BLANK. If none are given, enter 00000.

Item 2. Postoperative blood products administered since the last evaluation.

Packed red blood cells: In the space provided, record the total number (in units) of packed red blood cells (erythrocytes) since the last evaluation. Be sure to use leading zeros. Typically, a unit of blood has a volume of 250-300 ml. DO NOT LEAVE BLANK. If no blood is given, enter 000.

Fresh frozen plasma or cryoprecipitate: In the space provided, record the total volume (in ml) of fresh frozen plasma or cryoprecipitate administered to the patient since the last evaluation. Be sure to use leading zeros. DO NOT LEAVE BLANK. If none is given, enter 00000.

Platelets: In the space provided, record the total volume (ml) of platelets administered to the patient since the last evaluation. Be sure to use leading zeros. DO NOT LEAVE BLANK. If none is given, enter 00000.

Other Blood Products: In the space provided, record the total volume of any other blood product administered to the patient since the last evaluation (e.g., whole blood, specific clotting factors, cell-saver). Be sure to use leading zeros. DO NOT LEAVE BLANK. If none is given, enter 00000.

DISCHARGE INFORMATION

Item 1. Date of discharge.

The date (month, day, year) of discharge from the hospital in which the primary aneurysm surgery took place will be recorded in the space provided in numeric fashion.

Item 2. Post discharge destination.

Please indicate where the patient will be going after discharge from the hospital. There are four choices, check one.

Other acute care hospital

Comment: In this instance, the patient is discharged from the hospital in which the primary aneurysm surgery took place, but is immediately transferred to another acute care hospital for additional in-hospital care. This type of transfer most commonly takes place between a medical center having a high-level neurosurgical service and a hospital with no (or a low-level) neurosurgical service, when the patient requires continued in-hospital care which is either recuperative or non-neurosurgical. In this instance, all reasonable efforts should be made to continue to monitor the patient's in-hospital course.

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Chronic care or rehabilitation facility

Comment: In this instance, the patient is discharged from the hospital in which the primary aneurysm surgery took place, but requires either chronic care or rehabilitative care. Chronic care is needed when a patient is so severely disabled that the patient cannot provide for his/her own basic needs (eating, bowel control, bathing, airway control) and the prospect for recovery to a level necessary for living in a domestic residence is poor (e.g., a patient in a persistent vegetative state). Rehabilitative care may be needed when a patient is mildly or moderately disabled at the time of discharge, but a finite period of rehabilitation in a specialized facility (equipment and personnel) is thought likely to restore function to a level necessary for living at a domestic residence.

Home or non-institutional residence (e.g., relative’s home)

Comment: In this instance, the patient is discharged from the hospital and returns either to their own home or the home of a family member, friend, or other care giver (a domestic residence). A patient may receive rehabilitation, either in the home or on an outpatient basis, but this location (home) is not a specialized facility (equipment/personnel).

Dead

Comment: In this instance, please complete a DEATH/PATIENT WITHDRAWAL form in addition to completing this form and all associated IE forms.

Instruction box: If dead, please complete PATIENT DEATH/WITHDRAWAL form.

IX. J INTERCURRENT EVENTS

IX.J.1. Overview:

This form may be completed by any IHAST2 participant. Usually this form will be completed by the Study Coordinator. However, any participating neurosurgeon or any participating anesthesiologist may also complete this form if: 1) they were not present during the operation nor in the presence of the patient for the first two hours after leaving the operating room; and 2) are not aware of patient group assignment or intraoperative temperature. The Anesthesiologist caring for the patient during surgery is to complete all IE forms pertaining to intraoperative and/or early postoperative (0-2 hours) events. Although the Study Coordinator may assist the Anesthesiologist in the completion of intraoperative and early postoperative IEs, the Study Coordinator must NOT be informed as to the patient’s temperature group assignment nor any perioperative temperature data.

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The purpose of this form is to characterize the severity of all clinically significant events associated with the patient’s subarachnoid hemorrhage, surgery, and postoperative course. In large measure, these events are tracked to monitor patient safety, to ensure that there is not excessive risk associated with assignment to either temperature group. Please note that all IEs that are characterized as being either “Severe” or leading to a patient’s DEATH must be promptly reported to the CCC, even if all supporting information is not available at the time. Likewise, it is mandatory that certain “Indicator Events” must also be promptly reported to the CCC, regardless of their severity. Indicator Events are those that the literature suggests are most likely to be affected by intraoperative temperature management (major cardiovascular complications, bleeding, infection). Indicator Events are highlighted on the IE code list.

IX.J.2. Data Items

Header. Please enter the date (mm/dd/yyyy) and time (0000-2359) of onset of the first primary IE listed in Item 2 (see details below).

Item 1. Describe event(s), sequellae, and supporting test results such as laboratory studies, radiology, etc. In the box provided, please provide a written narrative that provides a clear description of events in temporal sequence corresponding to the IEs and procedures coded in items 2 and 3. Please provide information to support all key diagnoses. Please see Chapter IX, Section S, of this Operations Manual, or the IHAST2 Intercurrent Events Codes & Definitions pocket notebook for definitions and diagnostic criteria for all IEs and procedures.

Item 2. Primary IE Code(s).

In the spaces provided (a. and b.), enter the three-digit code number(s) corresponding to one (or at most, two) primary IE(s). A primary IE is considered to be the principal, fundamental, or underlying problem or event. A primary IE is the key, central, or initiating event. Accordingly, most of the time, only a single IE code should be entered. It is understood that when multiple IEs occur within a short time period it may be difficult to know which IE was the primary IE. We ask that you use your best judgment. If you are certain there are more than two primary IEs occurring simultaneously, please complete additional IE forms for all other primary IEs.

Item 3. Clearly related and/or concurrent IE code(s).

In the spaces provided (a. through g.) enter the code numbers (up to seven codes) corresponding to IEs and/or procedures occurring either as a result of the primary IE, or occurring in such close association with the primary IE that they cannot be separated from it.

IE SUPPLEMENT: If you have more than seven codes in this section for a single patient, please use the IE SUPPLEMENT to list the additional codes. The Patient ID, Date of Onset, and Time of Onset of the IE SUPPLEMENT must match the corresponding INTERCURRENT EVENTS form.

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For each IE code entered in Items 2 and 3, please enter the Event Onset, Date of Onset, Maximum Event Severity, and resolution status, as described below. Exception: IE codes corresponding to procedures do not need either a severity rating nor an indication of resolution.

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Event Onset . There are five choices (1-5), check one.

1 =Between hospitalization and primary aneurysm surgery . The IE(s) coded in Items 2 and 3 had their onset in the interval between initial hospitalization for the primary subarachnoid hemorrhage (SAH) and going to the operating room for the primary aneurysm surgery. Initial hospitalization is considered to begin at the time when the patient presents to any hospital (emergency room or clinic) with the history, signs, and/or symptoms related to the primary subarachnoid hemorrhage, even if the patient is subsequently transferred to another hospital for care. Primary aneurysm surgery refers to cerebral aneurysm surgery that occurs as a direct result of the primary subarachnoid hemorrhage and which is intended to provide definitive therapy for the symptomatic (ruptured) aneurysm.

2 =Intraoperative . The IE(s) coded in Items 2 and 3 had their onset while the patient was in the operating room for the primary aneurysm surgery.

3 =First 0-2 hours after leaving the operating room . The IE(s) coded in Items 2 and 3 had their onset within the first two hours after leaving the operating room after the primary aneurysm surgery.

4 =Postoperative (>2 hours after leaving the operating room ). The IE(s) coded in Items 2 and 3 had their onset more than two hours after leaving the operating room after the primary aneurysm surgery.

5 =After discharge . The IE(s) coded in Items 2 and 3 had their onset after discharge from the hospital.

Comment: It is possible that a series of related IEs may have onsets in different intervals. For example, if a patient developed intraoperative myocardial ischemia (code 200) and then first experienced cardiogenic shock in the first 2 hours after surgery (code 210) and underwent cardiac catheterization on postoperative day 1 (code 291), the onsets would be 2 (intraop), 3 (first 2 h), and 4 (postop (>2 h)) respectively.

Date of Onset. For each IE code entered in items 2 and 3, please enter the corresponding date of onset using mm/dd/yyyy notation. Note, both the date and time of the primary IE (coded in Item 2.a.) should be recorded in the header of the form. For all other IEs coded on the form, only the date (but not the time) of onset is needed.

Comment: It is possible that a series of related IEs may have onsets on different dates. For example, a patient who developed delayed ischemic neurologic deficit (code 620) on postoperative day 4 might undergo cerebral angioplasty (code 698) to reduce vasospasm on postoperative day 6.

Maximum Event Severity. There are four choices (mild, moderate, severe, death); check one.

For each IE code, please indicate the maximum severity of that particular IE. Exception: IE codes corresponding to procedures do not need either a severity rating or indication of resolution. Event severity is defined as follows:

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Mild. The event that occurred was well tolerated by the patient and did not appear to substantially influence the patient's overall clinical course. If occurring after discharge from the hospital, "mild" events might warrant a phone call to the doctor but would likely not require a visit to the doctor, clinic, or emergency room.

Example 1: The patient has an episode of sinus bradycardia (heart rate <40, IE code 223) in the operating room, but blood pressure was acceptable and it spontaneously reversed. Example 2: The patient is diagnosed as having a urinary tract infection (IE code 700), but the patient is asymptomatic, and the infection quickly clears with antibiotics.

Moderate. The event that occurred was sufficient to interfere with the patient's recovery. Usually, some new treatment is necessary and/or the duration of hospitalization may be slightly prolonged because of the event. If occurring after discharge from the hospital, such events would be sufficient to warrant a visit to a physician, clinic, or emergency room, but probably not admission to an acute care hospital.

Example 1: Postoperatively, the patient develops new atrial fibrillation, but this is not associated with hypotension. The patient is started on medication and otherwise does well.

Example 2: Postoperatively, the patient is noted to be emotionally labile and distressed. A consulting Psychiatrist recommends starting anti-depressant medication and the patient improves markedly thereafter.

Severe. The event was either life-threatening, permanently disabling, or substantively prolonged in-patient hospitalization. Any and all IEs considered to be severe must be promptly reported to the CCC, even when all supporting information is not yet available. If occurring after discharge from the hospital, such events would be sufficient to warrant re-admission to an acute care hospital.

Example 1: Postoperatively, the patient develops marked symptoms of delayed ischemic neurologic deficit that, despite intensive therapy, results in permanent neurologic injury.

Example 2: Postoperatively, the patient has severe ventricular dysfunction, with cardiogenic shock and pulmonary edema. Vasopressors and inotropes are needed to restore normal hemodynamics.

Example 3: Postoperatively, the patient develops a severe pneumonia with hypoxemia and hypercarbia, and requires a tracheostomy for long-term ventilatory support.

Death. The event resulted in the patient’s death. Any and all IEs that result in a patient’s death must be promptly reported to the CCC, even when all supporting information is not yet available.

Has IE resolved? There are two choices (yes, no), check one.

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For each IE code, please indicate the whether or not that particular IE has resolved. An IE is considered to have resolved if symptoms have disappeared and/or treatment has been completed. Exception: IE codes corresponding to procedures do not need either a severity rating or indication of resolution.

For IEs with onset prior to discharge, please indicate whether or not the IE has resolved prior to discharge.

For IEs with onset after discharge, please indicate whether or not the IE has resolved by the time of the 3-month follow-up evaluation.

IX. K IE DEFINITIONS

To promote consistency among centers, all IEs have defined diagnostic criteria. In all instances possible, these criteria have been based on published guidelines, standards, or consensus statements. It is important that each PCC apply these criteria when diagnosing and reporting all IEs, but especially so for “Indicator” and “Severe” IEs. Please see chapter IX.S. for detailed IE definitions.

“Indicator” Events are those that the literature suggests are most likely to be affected by intraoperative temperature management (major cardiovascular complications, bleeding, infection). Indicator Events are highlighted on the IE code list and in the IE definitions table. Using an INTERCURRENT EVENTS form, it is mandatory that all“Indicator Events” be promptly reported to the CCC, regardless of their impact on the patient (mild, moderate, severe, death).

Please note that all IEs that are characterized as being either “Severe” or leading to a patient’s DEATH must be promptly reported to the CCC, even if they are not “Indicator” IE, and even if all supporting information is not available at the time at the time of the initial report

IX. L CONTACT FOLLOW-UP FORM

To assist each PCC, the DMC will e-mail a weekly list of the patients to be contacted for follow-up. Two follow-up contacts will be made with each patient. The first will occur via phone call at six weeks after the date of surgery. At this time, the Study Coordinator will contact the surviving patient, their next of kin, or another designated contact person. The second and final contact will occur three months following the date of surgery. This contact will occur within the clinic so that a Neuropsych Evaluation and Neurological Evaluation can be performed. Complete instructions for the postoperative contacts is covered in the following section. The Study Coordinator is responsible for completing a CONTACT FOLLOW-UP form at both contacts.

CONTACT INFORMATION

Item 1. Which follow-up is this?

There are two possible choices. Choose only one. If the visit/contact was made between five and seven weeks, check “6 weeks.” If the visit was made between 10 and 14 weeks, check “3 months.”

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Item 2. Was contact made?

Check one of the following two choices, yes or no. If no contact was made, fill in the number of times someone attempted to contact the patient.

Instruction Box: It is essential that contact be made at both six weeks and three months for data collection purposes. If contact is not possible, please contact the CCC immediately.

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Item 3: How was contact made?

Check the appropriate boxes that apply. If contact was made by telephone, check “yes” by telephone and if contact was not made, check “no” by telephone. If contact was made while the patient was at the clinic or hospital, check “yes” by this choice, and if not, check “no.”

Item 4. Who was your source of information?

Check any of the following that apply: Patient, Relative or individual living with patient, Relative or individual not in patient’s home, or Local treating physician. If information was obtained from someone “other” than the choices listed, fill in that person’s relationship to the participant. For example, "the patient's nurse in a skilled nursing facility."

Item 5. Where is the patient's current place of residence?

Check one of the following that best applies to the individual at the time of the contact.

If the patient is deceased, check "Dead” and do not answer any further questions. Sign your name at the end of the CONTACT FOLLOW-UP form, complete a DEATH/PATIENT WITHDRAWAL form, and place the forms in the patient notebook.

If the patient is living at home, in an acute care hospital, or in a chronic care or rehabilitation facility, check the appropriate box.

If you are unable to determine where the patient is living, check “Unknown.”

Item 6. What is the patient's current status?.

There are four choices. Choose the one choice that applies. This question refers to availability of the patient for follow-up.

If you are unable to determine whether the patient is alive or dead, check 1.

If the patient is alive but information is not available about the patient’s condition, check 2, and specify why this information is not available. Choice number 2 does not apply if the patient or legal guardian refuses to provide information about the patient’s condition.

If the patient or legal guardian refuses follow-up, check 3. If the patient, or an individual who knows about the patient, has agreed to the follow-up, check 4.

Note: If items 1,2 or 3 are checked, call the CCC at #319-356-0461. If the CCC approves, sign the form and place in the patient notebook.

Item 7. What is the patient's current work status?

There are three choices. Choose the one choice that applies.

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If the patient is employed or working full-time, check 1. Working may include self-employment, volunteer work, or previous work within the home.

If the patient is employed part-time or working part-time, check 2.

If the patient is not employed nor working or if the patient is employed but is still taking sick time, check 3.

Item 8. Has the patient returned to previous occupation and/or same level of performance? If the patient returned to his/her original position of employment/work or to a job requiring a similar level of skill that they held prior to the SAH, check “Yes.” For example, the patient may have returned to a different position because the position was not held for them. Also, if the patient was not working prior to the SAH and is still not working, check “Yes.” However, if the patient returned to a completely new job or a different position requiring a modified level of performance, check “No.” For example, if a patient returned to work in different position due to loss in ability to multi-task, loss of skill or physical impairment check “No.”

Item 9. Since the last contact, has the patient required any of the following (Physical Therapy, Occupational Therapy, Speech Therapy)?

Choose any of the three choices that apply and state how many visits, on average, per week that the patient attended therapy and the total number of weeks that the patient attended therapy. Round the number of visits per week to the closest integer. For example, if visits per week averaged 0.4, then the answer should be 00; if average visits equaled 1.6, the answer should be 02.

Please answer “yes” or “no” to questions 10-13 and fill out an IE form if the patient meets IHAST2 criteria for an IE.

Item 10. In the time since the last contact, has the patient been readmitted to an acute care hospital?

Item 11. In the time since the last contact, has the patient been seen in an emergency care setting?

Item 12. In the time since the last contact, has the patient been seen in a clinic for emergent or urgent reasons?

Item 13. In the time since the last contact, has the patient been seen in a non-neurology or non-neurosurgical clinic for any reason?

Last Item, Page 2: Are there additional comments you would like to add regarding patient information on this form?

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Check “Yes” or “No”. If “Yes” is checked, you must place your comments on the internet at http://ctsdmc.public-health.uiowa.edu/ihast2/comment/.

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IX. M OUTCOME FOLLOW-UP

This form is to be completed at six weeks and three months. If it is being completed as part of the three-month follow-up, it must be completed by a certified examiner who is unaware of group assignment. It should not be completed by the Study Coordinator. However, the Coordinator may complete the form at the six-week contact.

Item 1: Which follow-up is this.


BARTHEL’S ACTIVITIES OF DAILY LIVING

The Barthel’s ADL score is a 10 item, 100-point scale. Answers are best obtained by using a form "script," an example of which is found in the Appendix. Other information regarding the use or performance of this scale can be found in Chapter V, Section D.

RANKIN DISABILITY SCORE

The Rankin Disability Score is a six-point scale evaluating "global" disability. IMPORTANT NOTE: A patient’s disability need not be neurologic and it need not be related to their SAH. For example, a patient with severe arthritis or congestive heart failure is scored the same as a patient with disability due to a neurologic deficit. Disability may either be physical, neurologic, or cognitive.

In many cases a Rankin Disability Score can be derived from questions already asked on this form (e.g., employment, Barthel’s Index, etc.).

Details on the Rankin Disability Score can be found in Chapter V.B.

GLASGOW OUTCOME SCORE (GOS)

The GOS is a simple five-point scale. It can usually be derived from the questions already asked and answered on this form. Note that like the Rankin Disability Score, dysfunction need not be neurologic and it need not be related to their SAH. For example, a patient with severe arthritis or congestive heart failure is scored the same as a patient with disability due to a neurologic deficit. Disability may either be physical, neurologic or cognitive.

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IX. N 3-MONTH VISIT

An automatic reminder will be sent by the DMC three weeks prior to the day in which the three-month evaluation is to take place. The three-month visit should occur as close to three-month post-surgery as possible, (10-14 weeks is acceptable). The PCC Study Coordinator is responsible for arranging an appointment during which the patient will be seen by the Study Coordinator, the Neurologic Evaluator, and the Neurosychology Examiner. The Study Coordinator will need to provide both examiners with the appropriate material from the patient’s notebook. Following is a list of materials that the Study Coordinator will provide for the three-month visit.

Study Coordinator:

CONTACT FOLLOW-UP form. See instructions for CONTACT FOLLOW-UP above.

Neurologic Evaluator (The Study Coordinator may not perform the neurologic exam at the three-month follow-up):

OUTCOME FOLLOW-UP form which includes the Barthel’s Activities of Daily Living Scale, Rankin Disability Scale and Glasgow Outcome Score.

NIHSS Instructions

NIHSS form

Neuropsychology Examiner:

Benton Visual Retention Test

Controlled Oral Word Association

Complex Figure Test

Grooved Pegboard

Trail Making Test

Mini-Mental State Exam

In addition to the neurosych packet, sharp black lead pencils, a stopwatch, and a grooved pegboard are necessary for completing the neuropsychology exam. The Study Coordinator should check with the evaluator to make sure that the examiner will have these items. The Neuropsychologist will most likely have a grooved pegboard. However, contact the CCC if one is not available. Explanations for each exam and certification procedure for the examiners are found in Chapter V.

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IX. O DEATH/PATIENT WITHDRAWAL

IX.O.1. Overview:

Although usually this form will be initiated by the Study Coordinator, the Local PI, and/or Co-PI are required to complete the written narrative section.

For safety reasons, all deaths must be promptly reported to the CCC, even if all supporting formation is not fully available at the time of the initial report. In the event of a patient’s death, all appropriate IE forms must also be completed.

Patient withdrawal constitutes any instance when, after consent is obtained, either the patient, or the patient’s legal guardian, either withdraws consent or refuses further study participation before completion of the final three-month outcome assessments. Example 1: On arrival to the O.R., the patient insists that they be made hypothermic during surgery instead of having temperature determined by the randomization code. This constitutes a withdrawal of consent. Example 2: After discharge, the patient, or the person making decisions for the patient, refuses to permit the required follow-up contacts (six weeks and three months) during which outcome assessments are made. Because patient withdrawal is an extremely serious matter, this must be promptly reported to the CCC.

Instruction box: Please fax this page within 24 hours to the CCC at 319-384-8072.

Item 1. Reason for form completion.


Patient withdrawal (patient or legal guardian refuses any further participation in the study (See above).

Death. The patient dies in the interval between consent and the three-month outcome evaluation.

Item 2. Date of withdrawal or death.

Please enter the date of withdrawal or death in the space provided using numeric notation (month, day, year).

DEATH

Instruction box: If death, complete the next section (narrative, and Items 3 and 4).

Description of circumstances surrounding patient’s death. (Please include primary and secondary cause(s) of death.)

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In the space provided, the Local PI or Co-PI is to provide a written narrative that summarizes the patient’s death. We ask that a judgment be made as to the primary and (if any) secondary causes of death. These judgments may be made on the basis of any combination of clinical, laboratory, and pathological information that is considered appropriate. An autopsy is not required. IE codes need not be used. We are not seeking “blame,” only the pathophysiologic basis of the patient’s death.

Item 3. Location at time of death

There are five choices, check one.

Hospital (prior to initial discharge)

The patient died in the hospital without discharge to either home or to a rehabilitation or chronic care facility. If the patient is transferred (without discharge) to another acute care hospital and dies in the other acute care hospital, then this item should be checked.

Hospital (after readmission)

In this instance, the patient is discharged from the hospital (either to home or to a rehabilitation or chronic care facility) but requires readmission to an acute care hospital (any acute care hospital). During the subsequent admission, the patient dies in the hospital.

Home or non-institutional residence (e.g., home of a relative)

In this instance, the patient is discharged from the hospital and dies in their home or the home of a family member, friend, or other caregiver (a domestic residence). A patient may receive rehabilitation, either in the home or on an outpatient basis, but this location (home) is not a specialized facility.

Rehabilitation or chronic care facility

In this instance, the patient is discharged from the hospital and dies in a rehabilitation or chronic care facility (having specialized care, personnel, and/or equipment); not a domestic residence.

Other

In this instance, the patient is discharge from the hospital and dies in a location that is either unknown, or not adequately characterized by the above criteria (acute care hospital, home, specialized care facility).

Item 4. Was an autopsy performed?


No. The patient died but an autopsy was not performed.

Yes. The patient died and an autopsy was performed. If an autopsy was performed, please provide a copy of the final report as soon as possible to the CCC.

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Instruction box: Please provide a copy of the final autopsy report as soon as possible.

IX. P NIHSS

This form must be completed by a certified examiner who is unaware of patient group assignment. If the patient has received pharmacologic agents (sedatives, hypnotics, anesthetics) which have resulted in a state of anesthesia, or a level of sedation that substantively impairs the patient’s ability to meaningfully cooperate with this exam; or the patient is pharmacologically paralyzed (neuromuscular blocker), then on this page please write “The scheduled examination cannot be performed” followed with a brief explanation of why. Then skip to the bottom of page 3 and fill out the footer information only.

IX.P.1.Overview

The following material was taken (and modified slightly) from the NIHSS training materials for the NIH-sponsored tPA-stroke trial.

The NIH Stroke Scale is a standardized neurological examination intended to describe the neurological deficits found in large groups of stroke patients participating in treatment trials. These instructions reflect primary concern for reproducibility. The goal is to have multiple examiners at different sites rate patients similarly. It is possible to challenge the scale on sub-items, and competent neurologists will disagree over the "best" method for testing some items in individual patients. Nevertheless, our interest in reproducibility among many observers in a large multicenter study is paramount, and to this end, all examiners at all sites must use the scale uniformly. We recognize that for some examiners, this means that some testing may be one way for the study, and a different way in usual clinical practice. The consolation for this disparity is the knowledge that the reproducibility among examiners using this scale will (hopefully) be extremely high.

There are four general principals underlying the scale in its present form:

1. The most reproducible response is generally the first response. For example, on LOC questions, the patient is asked to state age and the current month. The patient who initially responds incorrectly, but later corrects himself, is scored as having given an incorrect response. This approach is critical, because we have no way of standardizing the myriad verbal and non-verbal cues that might be given to patients to promote a correction of an initially incorrect response.

2. It is not permissible to coach patients on any item unless specified in the instructions. This contradicts neurologic teaching, since we are generally interested in a patient's best possible performance. Again, standardization of coaching is not possible, and coaching must be avoided in the interest of reproducibility.

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3. Some items are scored only if definitely present. For example, ataxia is scored as absent in the patient with hemiplegia, because it is not definitely present at the time of examination. Although somewhat counterintuitive to some physicians, the item must be scored this way to avoid ambiguity and ensure reproducibility.

4. Most importantly, record what the patient does, not what you think the patient can do even if the findings appear contradictory. Many times a competent examiner forms an impression of the patient's level of function, but this impression must not influence scoring. Scoring should include prior deficits except for the sensory item (see instructions).

The patient's scores should be recorded immediately after the examination, and preferably each item should be coded as you go through the scale. This is especially necessary at baseline. If baseline results are recorded after the patient has received medication, the examiner may be influenced by the patient's response.

IX.P.2.Certification

Any investigator completing the NIH Stroke Scale for the trial must be certified.

Requirements for Certification:

1. Review of the NIH Stroke Scale Training Tape

2. Completion of NIH Stroke Scales for the five patients shown on the NIH

3. Stroke Scale Certification Tape- #1

4. Submission of the five completed forms to the Coordinating Center for review

5. Approval by the Coordinating Center

6. Retention of Certification

7. Completion of the NIH Stroke Scales on the six patients shown on the NIH Stroke Scale Certification Tape #2 (approximately six months after the initial certification).

8. Submission of the six completed forms to the Coordinating Center for review.

9. Approval by the Coordinating Center

The NIHSS is an 11-item test, generated from a highly standardized neurologic examination. A detailed description of the testing items follows:

Three items are used to assess the patient’s level of consciousness. It is vital that the items be asked in a standardized manner, as illustrated in the Stroke Scale training tape. Responses must be based on what the patient does first. Do not give credit if the patient corrects himself/herself and do not give any clues or coaching.

1A. LEVEL OF CONSCIOUSNESS:

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Instructions: The investigator must choose a response, even if a full evaluation is prevented by such obstacles as an endotracheal tube, language barrier, orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement (other than reflexive posturing) in response to noxious stimulation.

There are four possible scores, check one:

0 = Alert; keenly responsive.

1 = Not alert, but arousable by minor stimulation to obey, answer, or respond.

2 = Not alert, requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped).

3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, areflexic.

Comment: The investigator must choose a response, even if a full evaluation is prevented by such obstacles as an endotracheal tube, language barrier, orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement (other than reflexive posturing) in response to noxious stimulation.

1b. LOC QUESTIONS:

Instructions: The patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, language barrier or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues.

There are three possible scores, check one.

0 = Answers both questions correctly.

1 = Answers one question correctly.

2 = Answers neither question correctly.

Comment: The patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, language barrier, or any other problem, not secondary to aphasia, are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues.

1c. LOC COMMANDS:

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Instructions: The patient is asked to open and close the eyes and then to grip and release the nonparetic hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to them (pantomime) and score the result (i.e., follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored.


0 = Performs both tasks correctly.

1 = Performs one task correctly.

2 = Performs neither task correctly.

Comment: The patient is asked to open and close the eyes and then to grip and release the non-paretic hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made, but not completed, due to weakness. If the patient does not respond to command, the task should be demonstrated to them (pantomime) and score the result (i.e., follows none, one, or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored.

2. BEST GAZE:

Instructions: Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be scored but caloric testing is not done. If the patient has a conjugate deviation of the eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a patient has an isolated peripheral nerve paresis (CN III, IV or VI) score a 1. Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre-existing blindness or other disorder of visual acuity or fields should be tested with reflexive movements and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy.


0 = Normal.

1 = Partial gaze palsy. This score is given when gaze is abnormal in one or both eyes, but where forced deviation or total gaze paresis are not present.

2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic maneuver.

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Comment: Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be scored but caloric testing is not done. If the patient has a conjugate deviation of the eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a patient has an isolated peripheral nerve paresis (CN III, IV, or VI) score a 1. Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre-existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy.

3. VISUAL:

Instructions: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat as appropriate. Patient must be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia is found. If patient is blind from any cause score 3. Double simultaneous stimulation is performed at this point. If there is extinction patient receives a 1 and the results are also used to answer question 11.

There are four possible scores, check one.

0 = No visual loss.

1 = Partial hemianopia.

2 = Complete hemianopia.

3 = Bilateral hemianopia (blind including cortical blindness).

Comment: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat as appropriate. Patient must be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1 and the results are used to answer question 11.

4. FACIAL PALSY:

Instructions: Ask, or use pantomime to encourage the patient to show teeth or raise eyebrows and close eyes. Score symmetry of grimace in response to noxious stimuli in the poorly responsive or non-comprehending patient. If facial trauma/bandages, orotracheal tube, tape or other physical barrier obscures the face, these should be removed to the extent possible.


0 = Normal symmetrical movement.

1 = Minor paralysis (flattened nasolabial fold, asymmetry, on smiling).

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2 = Partial paralysis (total or near total paralysis of lower face).

3 = Complete paralysis of one or both sides (absence of facial movement in the upper and lower face).

Comment: Ask, or use pantomime, to encourage the patient to show teeth or raise eyebrows and close eyes. Score symmetry of grimace in response to noxious stimuli in the poorly responsive or non-comprehending patient. If facial trauma/bandages, orotracheal tube, tape, or other physical barrier obscures the face, these should be removed to the extent possible.

5 . MOTOR ARM:

Instructions (5-Motor Arm: 6-Motor Leg): Each limb is tested in turn, beginning with the non-paretic arm, if known. The limb is placed in the appropriate position: extend the arm (palm down) 90 degrees (if sitting) or 45 degrees (if supine) and the leg 30 degrees (always tested supine). Drift is scored if the arm falls before 10 seconds or the leg before 5 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime but not noxious stimulation. Only in the case of amputation or joint fusion at the shoulder or hip may the score be "9" and the examiner must clearly write the explanation for scoring as a "9."

For each subcomponent (5a. Left Arm, 5b. Right Arm) there are six possible scores, check one for each subcomponent.

0 = No drift, limb holds 90 (or 45) degrees for full 10 seconds.

1 = Drift, limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not hit bed or other support.

2 = Some effort against gravity, limb cannot get to or maintain (if cued) 90 (or 45) degrees drifts down to bed, but has some effort against gravity.

3 = No effort against gravity, limb falls.

4 = No movement.

9 = NO SCORE. Amputation, joint fusion, explain in box provided.

Comment: The limb is placed in the appropriate position: extend the arms (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in the case of amputation or joint fusion at the shoulder or hip may the score be "9" and the examiner must clearly write the explanation for scoring as a "9."

6. MOTOR LEG:

For each subcomponent (6a. Left Leg, 6b. Right Leg) there are six possible scores, check one for each subcomponent.

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0 = No drift, leg holds 30 degrees positions for full 5 seconds.

1 = Drift, leg falls by the end of the 5 second period, but does not hit bed.

2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity.

3 = No effort against gravity, leg falls to bed immediately.

4 = No movement.

9 = NO SCORE. Amputation, joint fusion, explain in box provided.

Comment: The limb is placed in the appropriate position: extend the leg 30 degrees (always tested supine). Drift is scored if the leg falls before five seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in the case of amputation or joint fusion at the shoulder or hip may the score be "9" and the examiner must clearly write the explanation for scoring as a "9."

7. LIMB ATAXIA:

Instructions: This item is aimed at finding evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, insure testing is done in the intact visual field. The finger-nose-finger and heel-shin tests are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient who cannot understand or is paralyzed. Although the use of untestable is discouraged, in the case of amputation, joint fusion or some fractures, the item may be scored "9," and the examiner must clearly write the explanation for not scoring. In case of blindness test by touching nose from extended arm position.

There are three main choices, check one. In the event of a score of 1 or 2, move to the break out boxes and score "Yes," "No" or "No Score" for each limb.

0 = Absent.

1 = Present in one limb.

2 = Present in two limbs.

If present in any limb (score above is 1 or 2), is ataxia in

Right arm

1 = Yes

2 = No

9 = NO SCORE. Amputation or joint fusion, explain in box provided.

Left arm

1 = Yes

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2 = No


Right leg

1 = Yes

2 = No


Left leg

1 = Yes

2 = No


Comment: This item is aimed at finding evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient who cannot understand or is paralyzed. Only in the case of amputation or joint fusion may the item be scored "9," and the examiner must clearly write the explanation for not scoring. In case of blindness, test by touching nose from extended arm position.

8. SENSORY:

Instructions: Sensation or grimace to pin prick when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. Only sensory loss attributed to stroke is scored as abnormal and the examiner should test as many body areas (arms (not hands), legs, trunk, face] as needed to accurately check for hemisensory loss. A score of 2, "severe or total," should only be given when. A severe or total loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will therefore probably score 1 or 0. The patient with brain stem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic score 2. Patients in coma (item la= 3) are arbitrarily given a 2 on this item.


0 = Normal; no sensory loss.

1 = Mild to moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial pain with pinprick but patient is aware s/he is being touched.

2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, and leg.

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Comment: Sensation or grimace to pin prick when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. Only sensory loss attributed to stroke is scored as abnormal and the examiner should test as many body areas [arms (not hands), legs, trunk, face] as needed to accurately check for hemisensory loss. A score of 2, "severe or total," should only be given when a severe or total loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brain stem stroke, who has bilateral loss of sensation, is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in coma (item 1a=3) are arbitrarily given a 2 on this item.

9. BEST LANGUAGE:

Instructions: A great deal of information about comprehension will be obtained during the preceding sections of the examination. The patient is asked to describe what is happening in the attached picture, to name the items on the attached naming sheet, and to read from the attached list of sentences. Be complete. Have the patient name all items on the naming sheet and read all phrases on the two reading sheets. Comprehension is judged from responses here as well as to all of the commands in the preceding general neurological exam. If visual loss interferes with the tests, ask the patient to identify objects placed in the hand, repeat, and produce speech. The intubated patient should be asked to write. The patient in coma (question la=3) will arbitrarily score 3 on this item. The examiner must choose a score in the patient with stupor or limited cooperation but a score of 3 should be used only if the patient is mute and follows no one step commands.


0 = No aphasia, normal.

1 = Mild to moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes conversation about provided material difficult or impossible. For example, in conversation about providing materials, examiner can identify picture or naming card from patient's response.

2 = Severe aphasia; all communication is through fragmentary expression; great need for inference, questioning, and guessing by the listener. Range of information that can be exchanged is limited; listener carries burden of communication from patient response.

3 = Mute, global aphasia; no usable speech or auditory comprehension.

Comment: A great deal of information about comprehension will be obtained during the preceding sections of the examination. The patient is asked to describe what is happening in the attached picture, to name the items on the attached naming sheet, and to read from the attached list of sentences. Comprehension is judged from responses here as well as to all of the commands in the preceding general neurological exam. If visual loss interferes with the tests, ask the patient to identify objects placed in the hand, repeat, and produce speech. The intubated patient should be asked to write. The patient in coma (question 1a=3) will arbitrarily score 3 on this item. The examiner must choose a score in the patient with stupor or limited cooperation, but a score of 3 should be used only if the patient is mute and follows no one step commands.

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10. DYSARTHRIA:

Instructions: If the patient is thought to be normal, an adequate sample of speech must be obtained by asking patient to read or repeat words from the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be rated. Only if the patient is intubated or has other physical barrier to producing speech, may the item be scored "9", and the examiner must clearly write an explanation for not scoring. Do not tell the patient why he/she is being tested.


0 = Normal.

1 = Mild to moderate; patient slurs at least some words and, at worst, can be understood with some difficulty.

2 = Severe; patient's speech is so slurred as to be unintelligible in the absence of or out of proportion to any dysphasia, or is mute/anarthric.

9 = NO SCORE. Intubated or other physical barrier, explain in box provided.

Comment: If patient is thought to be normal, an adequate sample of speech must be obtained by asking patient to read or repeat words from the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be rated. Only if the patient is intubated or has other physical barrier to producing speech, may the item be scored "9," and the examiner must clearly write an explanation for not scoring. Do not tell the patient why s/he is being tested.

11. EXTINCTION AND INATTENTION:

Instructions: Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to both sides, the score is normal. The presence of visual spatial neglect or anosagnosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable.


0 = No abnormality.

1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities.

2 = Profound hemi-inattention or hemi-inattention to more than one modality. Does not recognize own hand or orients to only one side of space.

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Comment: Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia, but does appear to attend to both sides, the score is normal. The presence of visual spatial neglect or anosagnosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable.

Special Situations

In some cases, scoring may be difficult. This is particularly true in comatose or uncooperative patients. The following comments should help.

Coma

A patient with a 3 on Item la (Level of Consciousness) is considered to be in a coma. A patient suspected to be in coma should be stimulated by rubbing on the chest or by using a painful stimulus. A 3 is scored only if the patient makes no movement (other than reflexive posturing) in response to the noxious stimulation. Patients who appear to be in coma and who score less than 3 must be tested on all items.

For patients scoring a 3 on Item la, the remaining items should be scored as follows:

Item lb (LOC Questions) - Score 2.

Item lc (LOC Commands) - Score 2.

Item 2 (Best Gaze) - Patient can be in coma and have gaze palsy that can be overcome by moving the head. Thus the oculocephalic maneuver must be done and the patient scored.

Item 3 (Visual) - Test using bilateral threat.

Item 4 (Facial Palsy) - Score 3.

Items 5 and 6 (Motor Arm and Leg) - This is interpreted as the voluntary ability to attain a posture. Score 4 for both arm and leg.

Item 7 (Limb Ataxia) - Scored only if present, out of proportion to weakness. Score 0.

Item 8 (Sensory) - Score 2 (arbitrary).

Item 9 (Best Language) - Score 3.

Item 10 (Dysarthria) - Score 2.

Item 11 (Extinction and inattention) - Coma implies loss of all cognitive abilities. Score 2.

Persons Who Refuse to Cooperate

In the event that a patient refuses to perform the tasks in the course of the examination resulting in an item untested, a detailed explanation must be clearly written on the form. All untested items will be reviewed by the medical monitor and discussed with the examiner if necessary.

Calculating a Score

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In computing a score, the following items should not be added to the total:

For Item 7 (Limb Ataxia) codes for affected sides (right and/or left arm and leg; 1 = yes, 2 = no, 9 = untestable).

Any 9's.

IX. Q NEUROPSYCHOLOGY FORMS AND TEST PERFORMANCE

IX.Q.1. Overview

The purpose of the neuropsychological evaluation in IHAST2 is to provide a standardized, quantitative index of cognition following surgery. The test battery is brief (less than 30 minutes) and can be administered in several languages. It is administered only once, at the three-month post-surgical follow-up. The battery is summarized in Chapter V.F above. Briefly, the tests and the areas tests are listed below:

Benton Visual Retention Test Attention and Memory

Controlled Oral Word Association Language (word finding) association

Complex Figure Test-copy Visuospatial abilities

Grooved Pegboard Visuomotor coordination

Trail Making Tests Part A and B Executive Function

Mini-Mental State Exam General

The neuropsychological tests should be administered by a clinical neuropsychologist or a trained neuropsychological technician, according to the instructions provided below. No scoring of the neuropsychological tests is to be conducted at the individual study centers. All raw data are to be returned to the DMC for blinded scoring.

If a patient does not attempt or complete any test in the battery, please indicate the reason for this on the patient response sheet. Also, if there are factors which inordinately affected test performance, please explain this in writing on the patient response sheet.

In addition to the neuropsychology tests, be sure to complete the questions regarding patient handedness and education.

IX.Q.2. Data Items

a) Benton Visual Retention Test (BVRT)

Materials: Response booklet (10 blank pages 8 ½” x 5 ½”) and a black lead pencil.

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Instructions to patient:

“I am going to show you a picture with one or more figures on it. You should look at it for 10 seconds. Then I will cover the picture and you are to draw what you saw. Make the drawing as much like the one of this page as you can.”

Begin timing for ten seconds then cover the design.

Before introducing Design 3 (the first to include two major figures and a peripheral minor figure), the examiner should say:

“BE SURE TO DRAW EVERYTHING YOU SEE.”

Occasionally, a patient will start the first design before the 10 seconds have elapsed. Stop him/her immediately and remind him/her to keep looking at the page. The examiner may make a comment such as:

“I KNOW THIS DESIGN IS AN EASY ONE, BUT THE OTHERS ARE HARDER, AND YOU SHOULD GET IN THE HABIT OF LOOKING AT THE DESIGN FOR THE FULL 10 SECONDS SO YOU HAVE YOUR BEST CHANCE OF REMEMBERING IT.”

b) Controlled Oral Word Association (COWA)

Materials: record sheet to enter patient’s responses, stop watch.


“I AM GOING TO SAY A LETTER OF THE ALPHABET AND YOU WILL HAVE ONE MINUTE TO SAY ALL THE WORDS YOU CAN THINK OF THAT BEGIN WITH THAT LETTER, AS QUICKLY AS YOU CAN. YOU CAN SAY ANY WORDS EXCEPT THOSE THAT BEGIN WITH A CAPITAL LETTER, SUCH AS THE NAMES OF PEOPLE OR PLACES. FOR EXAMPLE, IF I SAY “B,” YOU COULD SAY “BAT,” “BALL,” OR “BAKE,” BUT NOT “BETTY” OR “BURLINGTON.” ALSO, DO NOT USE THE SAME WORD OVER AND OVER WITH DIFFERENT ENDINGS, FOR EXAMPLE, IF YOU SAY “BUILD” DO NOT GO ON TO SAY “BUILDING,” “BUILT,” OR “BUILDER.” IF YOU SHOULD DRAW A BLANK, KEEP TRYING TO THINK OF WORDS UNTIL THE TIME LIMIT IS UP. ARE YOU READY? THE FIRST LETTER IS “C” GO AHEAD.

Begin timing for one minute, recording the patient’s responses on the record form.

If the patient is silent for 10 seconds, say something like “Words beginning with the letter C” to remind the patient of the task.

If the patient begins to generate improper responses (e.g., proper nouns, same root word with different endings, or words beginning with another letter) immediately correct them—as briefly as possible.

If the patient starts giving numbers as responses (usually 40, 41, 42, etc.) tell them

“NO MORE NUMBERS” as quickly as possible.

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Do not give credit for number responses after the first one.

c) Complex Figure Test (CFT)

Materials: a blank sheet of white, unlined 8 ½” x 11” paper and a black lead pencil.


“COPY THIS FIGURE AS ACCURATELY AS YOU CAN. THERE IS NO TIME LIMIT. MAKE AS ACCURATE A COPY AS YOU CAN.”

If the patient turns the stimulus design card on end while copying, turn the card to the correct orientation and say:

“THE PICTURE GOES THIS WAY.”

If the patient places the figure on its end again, say nothing and simply note the rotation. If the patient draws the figure on its end, without rotating the stimulus card, say nothing, but make a note of this rotation.

When the patient indicates that he or she is done, record the time in whole minutes and 10’s of seconds. If the patient appears to be finished, but has not said anything, ask them if they are finished before recording the time.

Discontinue after 10 minutes if the patient has not completed copying the figure.

d) Grooved Pegboard Test

Materials: Grooved Pegboard apparatus, stop watch.

Note: These instructions are for right-handers. If the patient is left-handed, he or she should use the left hand first, with all instructions below modified accordingly.

RIGHT HAND:

The pegboard is placed in mid-line with the patient so that the board is at the edge of the table with the peg dish closest to the patient and the peg tray farther away. The patient is to begin the test with the to-be-tested hand lying on the table next to the peg tray.


“THIS IS A PEGBOARD AND THESE ARE THE PEGS. ALL THE PEGS ARE THE SAME. IF YOU TURN THEM CORRECTLY, THEY FIT INTO THE HOLES. YOUR JOB IS TO PUT THE PEGS INTO THE HOLES LIKE THIS AS FAST AS YOU CAN.”

The examiner demonstrates the right-handed task by filling the first three holes of the top row from the patient’s left to right. Remove the pegs and place them back in the tray.

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“WHEN I SAY “GO,” FILL IN ALL THE HOLES USING ONLY YOUR RIGHT HAND. BEGIN HERE (point to the patient’s top row, left-most hole) AND WORK YOUR WAY ACROSS WITHOUT SKIPPING ANY HOLES. WHEN YOU FINISH ONE ROW, GO DOWN TO THE NEXT, WORKING FROM THIS SIDE TO THAT SIDE (pointing at 2nd row, left-most hole, over to right-most hole), UNTIL YOU HAVE FILLED IN ALL THE HOLES. PICK UP ONLY ONE PEG AT A TIME. WORK AS QUICKLY AS YOU CAN, BUT TRY NOT TO DROP ANY PEGS. READY, GO.

Begin timing as soon as you say “GO”.

Correct the patient IMMEDIATELY if they begin to pick up more than one peg at a time, skip a hole, or use the other hand.

Discontinue the test if the patient has not completed the first row within 60”.

LEFT HAND

After completing the test with the right hand, explain:

“THIS TIME YOU ARE TO USE YOUR LEFT HAND ONLY, AND WORK IN THIS DIRECTION (point to the top row, right-most hole, and move your hand across to the left-most hole, drop down to the second row and repeat). REMEMBER, PICK UP ONLY ONE PEG AT A TIME, WORK AS QUICKLY AS YOU CAN, AND TRY NOT TO DROP ANY PEGS. READY, GO.

Begin timing as soon as you say “GO”.

Discontinue the test if the patient has not completed the first row within 60”.

e) Trail Making Test

Materials: Trail Making Test form with Parts A and B, sharp black lead pencil.

Part A (Practice)


“ON THIS PAGE ARE SOME NUMBERS. BEGIN AT NUMBER 1 AND DRAW A LINE FROM 1 TO 2, 2 TO 3, 3 TO 4 AND SO ON, IN ORDER (point from 1 to 2 to 3 to 4), UNTIL YOU REACH THE END. DRAW THE LINES AS FAST AS YOU CAN. READY -- BEGIN.

If the patient is unable to perform the practice condition (i.e., makes more than two errors), do not administer the test. Otherwise, proceed to the next part.

Part A (Test)


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“THIS SHEET IS LIKE THE ONE YOU JUST DID, EXCEPT IT HAS MORE NUMBERS. AGAIN, BEGIN AT NUMBER 1 AND DRAW A LINE FROM 1 TO 2, 2 TO 3, 3 TO 4 AND SO ON, IN ORDER (point from 1 to 2 to 3 to 4), UNTIL YOU REACH THE END. DRAW THE LINES AS FAST AS YOU CAN. READY -- BEGIN.

Start timing as soon as the patient is told to begin. Remember to be alert for mistakes. If the patient makes an error, point it out immediately, return the patient to the last correct circle, and continue the test from that point. Do not stop timing.

Time limit: Unless the patient is within three circles of finishing, discontinue the test after 200”, or after four errors.

Part B (Practice)


“ON THIS PAGE ARE SOME NUMBERS AND LETTERS. BEGIN AT NUMBER 1 AND DRAW A LINE FROM 1 TO A, A TO 2, 2 TO B, B TO 3, 3 TO C, AND SO ON, IN ORDER (point from 1 to A to 2 to B to 3 to C), UNTIL YOU REACH THE END.

REMEMBER, FIRST YOU HAVE A NUMBER, THEN A LETTER, THEN A NUMBER, THEN A LETTER, AND SO ON. DRAW THE LINES AS FAST AS YOU CAN. READY -- BEGIN.

If the patient is unable to perform the practice condition (i.e., makes more than two errors, do not administer this part of the test.

Part B (Test)


“THIS SHEET IS LIKE THE ONE YOU JUST DID, EXCEPT IT HAS MORE NUMBERS AND LETTERS. AGAIN, BEGIN AT NUMBER 1 AND DRAW A LINE FROM 1 TO A, A TO 2, 2 TO B, B TO 3, 3 TO C AND SO ON, IN ORDER (point from 1 to A to 2 to B to 3 to C), UNTIL YOU REACH THE END. DRAW THE LINES AS FAST AS YOU CAN. READY -- BEGIN.

Time limit: Unless the patient is within three circles of finishing, discontinue the test after 400”, or after four errors.

After testing (Handedness, Grooved Peg Board Test, Trail Making), ask the patient the following question: Have you seen any of these tests before? If yes, which ones?

MINI-MENTAL STATE EXAM

Materials: MMSE scoring sheet, pencil

The MMSE is administered by reading verbatim the instructions and questions printed on the scoring sheet. The examiner records the subjects’ responses by checking the appropriate boxes on the left side of the scoring sheet.

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Please note:

Items 19 and 20: A sheet of paper with the sentence “CLOSE YOUR EYES” is attached to the MMSE scoring sheet. This is used for the reading task (Item 19), and then for the paper folding task (Item 20).

Item 22: The stimulus for the drawing task (2 intersecting pentagons) is provided on a separate piece of paper. The stimulus is in the upper half of the page, and the subject is to copy the figure using the bottom half of the page.

IX. R MEDICATIONS

IX.R.1. Overview

This form may be completed by any IHAST2 participant. Usually, this form will be completed by the Study Coordinator. However, any participating neurosurgeon or any participating anesthesiologist may also complete this form if they were not present during the operation nor in the presence of the patient for the first 0-2 hours after the patient left the operating room and are not aware of patient group assignment or intraoperative temperature(s).

The PRE-SAH and POST-ADMIT elements of this form should be completed prior to the patient going to the operating room for their primary aneurysm surgery. After surgery, data should be entered on this form every day until either discharge from the hospital or postoperative day (POD) 14, whichever comes first. Data should also be entered on this form on the day of discharge (D/C) from the hospital, regardless of the duration of the hospital stay.

PLEASE PLACE AN "X" IN A BOX WHEN THE PATIENT RECEIVED ANY MEDICATION CORRESPONDING TO THE CATEGORIES BELOW. NAME AND DOSE ARE NOT NEEDED.

PRE-SAH: Medications taken before the onset of the primary SAH.

POST-ADMIT: Medications between initial hospitalization and the primary aneurysm surgery.

24-hours: Medications between the time the patient left the O.R. and the 24-hour postoperative evaluation.

48-hours: Medications between the 24-hour postoperative evaluation and the 48-hour postoperative evaluation.

72-hours: Medications between the 48-hour postoperative evaluation and the 72-hour postoperative evaluation.

POD 4, 5, ...: Medications received in the 24-hours prior to evaluations on POD 4, 5, ....

D/C: Medications received between the last postoperative evaluation prior to discharge and the day of discharge

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Comment: For each medication category (rows in the table), please indicate when the patient received any medication in that category by placing an "X" in the appropriate box (columns in the table). On the first postoperative visit (24 hours after completion of the primary aneurysm surgery) include all medications administered after the patient leaves the operating room, but not during the primary aneurysm surgery. At all other postoperative visits (48 h, 72h, POD 4, 5,...) include all medications received by the patient since the last post-op daily screening examination, (including any intraoperative medications if the patient has any additional surgery). Because a medication can be used to treat more than one condition, it is important to categorize the medication in relation to the reason for its administration. For example, propranolol (a ß-adrenergic receptor blocker) can be used to treat hypertension, angina, migraine headaches, or even anxiety.

Analgesics (opioids, NSAIDs, aspirin, acetaminophen)

Comment: Drugs in this category are those given to treat pain. Opioids include all medications that act via opioid receptors, such as morphine, fentanyl, meperidine, etc. NSAIDs refer to nonsteroidal anti-inflammatory agents such as ibuprofen, ketorolac, etc.

Anesthetics (thiopental, etomidate, pentobarbital, propofol)

Comment: Drugs in this category are those given either to induce a state of general anesthesia, a state whether the patient is largely or entirely unresponsive to deeply painful or other noxious stimuli. Outside of the operating room, general anesthesia is sometimes induced for diagnostic or therapeutic procedures (e.g., cardioversion, cerebral angiographic procedures) or as a treatment for severe intracranial hypertension. If these agents are given only to induce sedation (i.e., the patient is still arousable), then these agents should be categorized as sedatives.

Sedative or Anxiolytic (benzodiazepine, propofol, butyrophenone)

Comment: Agents in this category are administered to either: induce sedation; reduce patient anxiety; or reduce patient agitation, disorientation, or combativeness. In all cases, these medications are intended to calm the patient, but not to significantly reduce the patient's level of consciousness. Benzodiazepines (e.g., midazolam, lorazepam) are frequently used for this purpose. In an intensive care environment, a constant infusion of propofol may also be used for this purpose. Sometimes agents with "anti-psychotic" properties are used for this purpose (e.g., haloperidol).

Anticonvulsants (phenytoin, phenobarbital)

Comment: Drugs in this category are those given specifically to prevent or treat central nervous system convulsive states (any condition commonly referred to as epilepsy). Because agents in this category can sometimes be given for other reasons, (e.g., anticonvulsants may be given to treat neuropathic pain, or phenytoin may be given to treat cardiac dysrhythmias) please be sure agents included in this category are being given as anticonvulsants.

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Antiemetics (ondansetron, metoclopramide)

Comment: Drugs in this category are those given specifically to prevent and/or treat nausea and/or vomiting.

Gastrointestinal Drugs (H 2 blocker, antacids)

Comment: Drugs in this category are those given specifically to prevent or treat any and all gastrointestinal conditions. In the setting of subarachnoid hemorrhage, agents to prevent or treat gastric "stress" ulcers are commonly given. Such agents include, but are not limited to: H2-receptor blockers (e.g., cimetidine, ranitidine); proton-pump inhibitors (e.g., omeprazole, lansoprazole); gastric barrier drugs (e.g., sucralfate) or even antacids. However, other gastrointestional agents such as medications to prevent or treat inflammatory bowel disease (e.g., sulfasalazine, azathioprine), pancreatic insufficiency (pancreatic enzymes), or hepatic failure (lactulose) are also included.

Anticoagulants, Antiplatelet, or Fibrinolytics (heparin, warfarin, ticlopidine, streptokinase)

Comment: Drugs in this category are those given specifically to inhibit some element of the blood coagulation process. Hence, in addition to heparin(s) (either intravenous or subcutaneous), hirudin, warfarin, or agents given in an attempt to decrease platelet adhesiveness, (low molecular weight dextran (dextran-40), aspirin, or other platelet antagonists (ticlopidine, abcixamab) come under this category. Also included are clot lytic agents such as streptokinase or tissue plasminogen activator.

Pro-coagulants ( -aminocaproic acid)

Comment: Drugs in this category are those given specifically to inhibit some element of the fibrinolytic process and/or promote blood clot formation and/or stability. Agents may include, but are not limited to: -aminocaproic acid; tranxemic acid; or vitamin K.

Antimicrobial (anti-bacterial, -viral, -fungal)

Comment: Drugs in this category are those given systemically (not topically) to either prevent or treat an infectious process (bacterial, viral, fungal, or parasitic).

Mannitol and/or Diuretics for neurologic reasons

Comment: This category is to note whenever mannitol and/or diuretics are given for the specific purpose of treating a neurologic condition. The most common neurologic conditions for which mannitol and/or diuretics are given are brain edema and/or increased intracranial pressure.

Glucocorticoid for neurologic reasons (dexamethasone)

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Comment: This category is to note whenever a glucocorticoid ("steroid") is given for the specific purpose of treating a neurologic condition. The most common neurologic conditions for which glucocorticoids are given are brain (vasogenic) edema and/or increased intracranial pressure. If glucocorticoids are given for other than neurologic reasons (e.g., rheumatoid arthritis, lung disease) do not include them in this category.

Nimodipine or Nicardipine for DIND (prevent or treat)

Comment: Nimodipine and nicardipine are calcium channel antagonists which are given specifically to prevent or treat delayed ischemic neurologic deficit (DIND). If other agents or techniques are used to treat DIND, do not include them in this category. Only nimodipine or nicardipine are listed in this category. If nimodipine or nicardipine are given for reasons other than DIND, do not include them in this category.

Antidysrhythmics (lidocaine, procainamide)

Comment: Drugs in this category are those given specifically to treat cardiac arrhythmias. Because agents in this category can sometimes be given for other reasons, (e.g., verapamil may be also be given to treat hypertension, or metoprolol may be given to treat angina, etc.) please be sure agents included in this category are being given as antidysrhythmics.

Antihypertensives (beta-blocker, Ca-antagonist, ACE inhibitor, vasodilator)

Comment: Drugs in this category are those given specifically to decrease systemic arterial pressure. Agents may include, but are not limited to: ß-adrenergic blockers (e.g., propranolol, metoprolol, labetolol); α-adrenergic blockers (e.g., prazosin, phentolaamine) calcium channel antagonists (e.g., nifedipine, verapamil, diltiazem); nitrates (e.g., nitroglycerine, nitroprusside); diuretics (e.g., furosemide, hydrochlorothiazide, spironolactone); angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, lisinopril) or angiotensin receptor antagonists (losartan); direct acting vasodilators (e.g., hydralazine); centrally acting adrenergic agents (e.g., clonidine).

Antipyretics (acetaminophen, aspirin, NSAID)

Comment: Drugs in this category are those given to prevent or treat a fever. Drugs in this class include acetaminophen (or any related drug, e.g., paracetoamol), aspirin (or any related salicylate), NSAIDs (nonsteroidal antiinflammatory agents, e.g., ibuprofen, ketorolac) or drugs sometimes used to facilitate patient cooling, such as chlorpromazine or diphenhydramine.

Vasopressor or inotrope (dopamine, phenylephrine, epinephrine)

Comment: Agents in this category are those which are given specifically to increase systemic arterial pressure and/or cardiac output. Please also note that vasopressor or inotrope administration require IE forms to be completed.

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There can be a number of different reasons for why clinicians may want to increase systemic arterial pressure and/or cardiac output. These medications may be given in an attempt to improve cerebral perfusion; most commonly to prevent or reverse a new or worsened neurologic deficit and/or to prevent or treat delayed ischemic neurologic deficit (DIND). In other instances, vasopressors or inotropes may be given to treat unwanted hemodynamic or cardiovascular conditions such hypotension, low systemic vascular resistance, low cardiac output, or other forms of cardiovascular insufficiency. However, irrespective of the reasons for their use, and irrespective of the duration of therapy, please list all agents given to increase systemic arterial pressure and/or cardiac output. Medications in this category would commonly include, but are not limited to: phenylephrine, ephedreine, epinephrine, norepinephrine, dopamine, dobutamine, dopexamine, isoproterenol, methoxamine, amrinone, milrinone.

Other Cardiovascular (nitroglycerine, digoxin)

Comment: Medications in this category are cardiovascular drugs which have not already been categorized as either antidysrhythmics, antihypertensives, or as a vasopresssor or inotrope. In general, agents in this category would be given to treat coronary artery disease (e.g., angina and related myocardial ischemic conditions) and/or ventricular dysfunction (e.g., congestive heart failure). Medications commonly used to treat coronary artery disease include ß-adrenergic blockers (e.g., propranolol, metoprolol, labetolol); calcium channel antagonists (e.g., nifedipine, verapamil, diltiazem); and nitrates (e.g., nitroglycerine, nitroprusside). Medications commonly used to treat ventricular dysfunction include diuretics (e.g., furosemide, hydrochlorothiazide, spironolactone); angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, lisinopril) or angiotensin receptor antagonists (e.g., losartan); and digitalis glycosides (e.g., digoxin).

Respiratory (inhaled bronchodilators, theophylline, glucocorticoid)

Comment: Agents in this category those used to treat respiratory disease, usually some form of small airway disease such as asthma or chronic obstructive pulmonary disease. Agents in this category include inhaled bronchodilators (e.g., albuterol, metaproterenol, ipratropium); inhaled steroids, inhaled cromolyn; intravenous aminophylline or oral theophylline; or leukotriene receptor antagonist (e.g., zafirlukast).

Endocrine (insulin, thyroid, DDAVP)

Comment: Agents in this category those used to treat endocrine disorders, such as insulin for diabetes mellitus, thyroid hormone replacement for hypothyroidism, propylthiouracil for hyperthyroidism, d-amino-arginine vasopressin (DDAVP) for diabetes insipidus.

Neuromuscular Blockers (pancuronium).

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Comment: Drugs in this category are those given specifically to pharmacologically induce motor paralysis. All agents in this category block the acetylcholine receptor at the neuromuscular junction, preventing neurally-mediated muscular contraction. These agents are used during surgery to relax musculature and/or prevent patient movement. Outside of the operating room, these agents are sometimes used in critical care settings to prevent unwanted patient movement and/or patient resistance to mechanical ventilation.

Colloids (albumin, hetastarch, dextran, polygeline)

Comment: Drugs in this category are macromolecules that act as colloids in the bloodstream, maintaining or increasing oncotic pressure. Most commonly, these agents are used to increase intravascular blood volume, although some are used to change blood rheology and/or coagulation. Agents in this category include albumin, plasma protein fraction, hetastarch, pentastarch, dextrans (both high- and low- molecular weight), and gelatins such as polygeline, Haemaccel, Gelofusin, etc.

Other Medications not listed above: Do not include vitamins, electrolytes, laxatives, nasal decongestants, and antidepressants.

Comment: For all other clinically significant medications that are not categorized above, please specify the name of the drugs (up to four) in the spaces provided. Please do not include medications that do not have a major impact on patient outcome. For example, please do not include items such as routine vitamins, dietary supplements, stool softeners, laxatives, skin lotions, electrolyte supplements, lipid lowering drugs, anti-depressants, anti-smoking agents, etc. In most cases, if an agent cannot be included in an existing category, do not list it under “Other Medications” unless it has had a clear and major impact on outcome.

IX. S DETAILED IE DEFINITIONS

In the following table, any event which is listed in BOLD CAPITAL LETTERS* is defined as an “Indicator” IE. All “Indicator” IEs must be promptly reported to the CCC, regardless of their severity (mild, moderate, severe, death).

INTERCURRENT EVENT CODES AND DEFINITIONS

Category-1 Code Event

Whole Body/General 100 SEPTIC SHOCK

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Definition/Criteria: Any instance when there is a confirmed microbial infection (with fever, tachycardia, neutrophilia or neutropenia, or ≥10% bands) with associated with organ dysfunction, and/or hypoperfusion (increased lactate concentration, oliguria) and/or hypotension (MAP ≤60 mmHg). In the presence of septic shock, hypotension is not readily reversed with fluid resuscitation. Inotropes and/or vasopressors are needed to maintain systemic blood pressure.

Reference: Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RMH, Sibbald WJ (The ACCP/SCCM Consensus Conference Committee): Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101:1644-55. Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine. Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Crit Care Med 1999; 27:639-660.


Whole Body/General 101 VASCULAR CATHETER-RELATED INFECTION

Definition/Criteria: Any instance when either A or B are present: A) Fever (≥38.5°C) and catheter tip colonization (≥1000 cfu/ml) and 1 of the following: pus at insertion site, or resolution of signs of infection after catheter removal and no other infectious site. B) Simultaneous recovery of the same organism (same species, same antibiotic susceptibility profile) from a catheter tip (regardless of concentration) and blood cultures.

Reference: Mimoz O, Pieroni L, Lawrence C, et al.: Prospective, randomized trial of two antiseptic solutions for prevention of central venous or arterial catheter colonization and infection in intensive care unit patients. Crit Care Med 1996; 24:18181-23. Timsit J-F, Sebille V, Farkas J-C, et al.: Effect of subcutaneous tunneling on internal jugular catheter-related sepsis in critically ill patients. A prospective randomized multicenter study. JAMA 1996; 276;1416-20.


Whole Body/General 102 BACTEREMIA

Definition/Criteria: Any instance when a blood culture is positive for bacteria and the organism is not considered to be a skin contaminant.


Whole Body/General 103 NON-NEUROLOGIC WOUND INFECTION

Definition/Criteria: Any instance when a wound infection (or other surgical site infection) is diagnosed that does not involve the surgical site used for the primary aneurysm surgery, nor is any form of central nervous system infection.


Whole Body/General 110 Fever

Definition/Criteria: Any instance when the patient's temperature is 38.5°C or greater, for any duration.


Whole Body/General 111 Allergic or anaphylactic reaction

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Definition/Criteria: Any instance when the patient develops an anaphylactic, anaphylactoid, or marked idiosyncratic reaction to an administered medication, blood product, or in response to an environmental exposure (metal, latex, food allergen). The reaction should be clinically significant and should include classic allergic responses such as pruritis, hives or urticaria, cutaneous vasodilation ("flushing"), development of edema (peripheral or airway), peripheral vasodilation (hypotension), bronchospasm, and/or tachycardia. Such responses are typically due to release of histamine, bradykinin, serotonin and/or complement fragments. Skin rashes, nausea, dysphoria, or other unexplained signs or symptoms, do not qualify unless systemic signs (above) are simultaneously present.


Whole Body/General 190 Angiographic complication (any type)

Definition/Criteria: Any instance when a clinically significant complication arises from any angiographic procedure. Please specify on the IE form the exact nature of the angiographic complication using additional IE codes.


Cardiovascular 200 MYOCARDIAL ISCHEMIA OR INFARCTION

Definition/Criteria: Any instance when there is myocardial hypoperfusion and/or myocardial cell death mediated by inadequate coronary artery blood flow, typically associated with atherosclerotic coronary artery disease. The diagnosis of myocardial ischemia and/or infarction in the setting of acute SAH will require, in addition to appropriate ECG changes, at least one major, or two minor, supportive clinical and/or laboratory signs. Major signs include: 1) classic angina or the patient's anginal equivalent (with or without associated signs of nausea, diaphoresis, anxiety); 2) a new positive pyrophosphate scan; 3) significant stenosis of an appropriate coronary artery (angiography); 4) autopsy confirmation of acute myocardial ischemia or infarction. Minor signs include: 1) a new and distinct increase in serum creatine kinase-MB (CKMB) or troponin levels 2) associated acute hemodynamic instability; 3) associated acute pulmonary congestion (dyspnea, orthopnea, rales, pulmonary edema); 4) a new and distinct regional wall motion abnormality.


Cardiovascular 210 CARDIOGENIC SHOCK

Definition/Criteria: Any instance when there is substantively decreased cardiac output (which is not due to hypovolemia or cardiac tamponade) associated with systemic hypoperfusion (increased lactate concentration, oliguria) and/or hypotension (MAP ≤60 mmHg). In the absence of inotropes, in cardiogenic shock cardiac index is usually less than 2.2 L/m2/min and/or mixed venous hemoglobin saturation is usually less than 65%. Whenever a continuous inotrope infusion is needed to maintain cardiac index > 2.2 L/m2/min, this is also cardiogenic shock. Note: This diagnosis requires measurement of cardiac output.

Reference: Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RMH, Sibbald WJ (The ACCP/SCCM Consensus Conference Committee): Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101:1644-55. Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine. Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Crit Care Med 1999; 27:639-660.


Cardiovascular 211 Congestive heart failure or pulmonary edema

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Definition/Criteria: Any instance when clinical signs and/or symptoms point to abnormally high left ventricular end diastolic pressure, resulting in translocation of fluid from the pulmonary capillaries into the pulmonary interstitial and/or alveolar spaces ("hydrostatic" pulmonary edema). Signs and symptoms include rales, elevated jugular venous pressure, peripheral edema, dyspnea at rest or on extertion, orthopnea, S3 gallop, and radiologic evidence of pulmonary congestion (increased pulmonary vascular markings and/or alveolar consolidation). Although this can occur in patients with normal ventricular function, most often this is associated with compromised left ventricular function and diminished cardiac reserve. Signs of low cardiac output may include relative hypotension; pallor or cool extremities; oliguria; and/or low cardiac output measurements and/or marked wall motion or ejection abnormalities on echocardiographic examination.

Reference: The Digitalis Investigation Group: The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336:525-33.


Cardiovascular 221 VENTRICULAR FIBRILLATION OR VENTRICULAR TACHYCARDIA

Definition/Criteria: Any instance when either ventricular fibrillation or ventricular tachycardia are present. Ventricular fibrillation (VF): Electrocardiogram reveals irregular and rapid oscillations (250-400 bpm) of highly variable amplitude without identifiable QRS complexes or T waves. With VF, there is no coordinated ventricular contraction. As a result, immediate hemodynamic collapse always occurs. Ventricular tachycardia: Any instance when there is series of 3 or more consecutive wide complex (≥120 msec) beats at a rate ≥100 beats/minute, where the origin of electrical activation is the ventricle. The ventricular complexes can be monomorphic or polymorphic (Torsade de Pointes).

Reference: Ch. 63: Textbook of Cardiovascular Medicine, Topol EJ (Ed), Lippincott-Raven, 1998.


Cardiovascular 222 Supraventricular dysrhythmia (Atrial-fibrillation or- flutter; other supraventricular tachydysrhythmia)

Definition/Criteria: Any instance when a supraventricular dysrhythmia is present. Atrial fibrillation: Electrocardiogram demonstrates a lack of clearly defined P-waves with an undulating baseline that may alternate between recognizable atrial activity or nearly a flat line. The ventricular response is irregular. Atrial flutter: Electrocardiogram demonstrates "sawtooth" atrial complexes (leads II, III, aVF) of constant morphology, polarity and cycle length with a rate from 240-340 bpm. The ventricular response rate to atrial flutter is frequently 2:1 or 4:1 and is regular. Other supraventricular tachydysrhythmia: Any form of sustained abnormal rapid supraventricular rhythm. Examples include premature atrial complexes, premature junctional complexes, paroxysmal atrial tachycardia (PAT), multifocal atrial tachycardia (MAT), paroxysmal supraventricular tachycardia (PSVT), AV nodal re-entrant tachycardias. It is not necessary to specify the type of abnormality.

Reference: Ch. 60, 61: Textbook of Cardiovascular Medicine, Topol EJ (Ed), Lippincott-Raven, 1998.


Cardiovascular 223 Sinus bradycardia

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Definition/Criteria: Any instance when the sinus node rate is equal to 40 beats/minute or less.


Cardiovascular 224 Conduction Blocks (Atrio-ventricular blocks, Bundle-branch blocks)

Definition/Criteria: Any instance when any form of AV nodal or complete bundle branch block exists. First-degree AV block: PR interval >0.2 s and each P wave is followed by a QRS complex. Second-degree AV block, either: Type I (Wenckebach): Progressive lengthening of the PR interval prior to a non-conducted P wave; Type II: Constant PR interval followed by sudden failure of a P wave to be conducted to the ventricle. Third-degree AV block: Dissociated P waves and QRS complexes, each firing at their own pacemaker rate. The atrial impulse is never conducted to the ventricles. Bundle Branch Block: supraventricular rhythm with a QRS duration ≥0.120 s and no Wolf-Parkinson-White pattern. Either right or left bundle branch block qualify. Left anterior hemiblock does not qualify.

Reference: Ch. 50, 56: Textbook of Cardiovascular Medicine, Topol EJ (Ed), Lippincott-Raven, 1998.


Cardiovascular 227 Other significant dysrhythmia (not 221,222,223,224)

Definition/Criteria: Any other clinically significant arrhythmia which is not adequately characterized by the arrhythmia criteria described above (not 221-224).


Cardiovascular 230 HYPERtension - Intended

Definition/Criteria: Any instance when mean arterial pressure (MAP) is ≥ 120 mmHg for 15 consecutive minutes (or longer), and this level of HYPERtension WAS clinically desired. Examples: 1) Induction of hypertension during temporary clipping; 2) Induction of hypertension in an attempt to reverse new and/or worse neurologic deficits.


Cardiovascular 231 HYPERtension - NOT Intended

Definition/Criteria: Any instance when mean arterial pressure (MAP) is ≥ 120 mmHg for 15 consecutive minutes (or longer), but this level of HYPERtension was NOT clinically desired.


Cardiovascular 232 HYPOtension – Intended

Definition/Criteria: Any instance when mean arterial pressure (MAP) is ≤ 60 mmHg for 15 consecutive minutes (or longer), and this level of HYPOtension WAS clinically desired. Examples: Induction of hypotension during the dissection and clipping phase of the aneurysm surgery, often referred to as "controlled" or "induced" or "deliberate" hypotension.


Cardiovascular 233 HYPOtension - NOT Intended

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Definition/Criteria: Any instance when mean arterial pressure (MAP) is ≤ 60 mmHg for 15 consecutive minutes (or longer), but this level of HYPOtension was NOT clinically desired.


Cardiovascular 240 VASOPRESSOR OR INOTROPE ADMINISTRATION TO SUPPORT SYSTEMIC CIRCULATION

Definition/Criteria: Any instance when any vasopressor or inotropic agent is continuously administered for 15 consecutive minutes (or longer) in order to support the systemic circulation. Examples: 1) vasopressor or inotrope administration to treat hypotension (local definition) low systemic vascular resistance, or shock; 2) vasopressor or inotrope administration to treat low cardiac output, cardiac or pulmonary failure.


Cardiovascular 241 Vasopressor or inotrope administration to support cerebral circulation

Definition/Criteria: Any instance when any vasopressor or inotropic agent is continuously administered for 15 consecutive minutes (or longer) in order to support the cerebral circulation. Examples: 1) vasopressor or inotrope administration to increase mean arterial pressure during temporary clipping; 2) vasopressor or inotrope administration in an attempt to prevent or reverse new and/or worse neurologic deficits.


Cardiovascular 242 Vasopressor or inotrope administration for other reasons (not 240 or 241)

Definition/Criteria: Any instance when any vasopressor or inotropic agent is continuously administered for 15 consecutive minutes (or longer) for reasons that do not fall into the two other "vasopress or inotrope" categories (not 240, 241). Example: "low-dose" dopamine infusion for "renal protection".


Cardiovascular 251 Other significant cardiovascular disorder or complication (not 200-242)

Definition/Criteria: Any other clinically significant cardiovascular disorder or complication which is not adequately characterized by the criteria above (not 200-242), e.g. pericardial tamponade.


Cardiovascular 290 CARDIOPULMONARY RESUSCITATION

Definition/Criteria: Any instance when open- or closed-chest manual cardiac compression is required.


Cardiovascular 291 CORONARY ANGIOGRAM

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Definition/Criteria: Any instance when any coronary angiogram is performed, regardless of specific technique.


Cardiovascular 292 CORONARY ANGIOPLASTY AND/OR INTRA-CORONARY STENT PLACEMENT

Definition/Criteria: Any instance when either coronary angioplasty is performed and/or an intracoronary vascular stent is placed.


Cardiovascular 293 CARDIAC SURGERY

Definition/Criteria: Any instance when the patient undergoes any form of cardiac surgery. Such procedures must occur in an operating room. This does NOT include angiographic procedures (see 291, 292 above)


Cardiovascular 294 Cardioversion or defibrillation

Definition/Criteria: Any instance when electrical current is directed to the heart, either directly (open chest) or indirectly (closed chest) to treat a cardiac rhythm abnormality.


Cardiovascular 295 Cardiac pacemaker placement

Definition/Criteria: Any instance when any cardiac pacemaker is placed, either internal or external, regardless of whether or not the pacemaker is, or is not, used.


Cardiovascular 296 Electrocardiogram

Definition/Criteria: Any instance when an electrocardiogram is performed, regardless of the reason for the examination.


Cardiovascular 297 Echocardiogram

Definition/Criteria: Any instance when an echocardiogram is performed (transthoracic or transesophageal), regardless of the reason for the examination.


Cardiovascular 298 Vascular surgery

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Definition/Criteria: Any instance when the patient undergoes any form of vascular surgery. Such procedures must occur in an operating room.


Cardiovascular 299 Other cardiovascular procedure, intervention, or surgery (not 290-298)

Definition/Criteria: Any instance when the patient undergoes any other clinically significant cardiovascular procedure, test, or intervention that does not fall into the above procedure categories (not 290-298), e.g. intra-aortic balloon pump, pulmonary angiogram).


Respiratory System 300 PNEUMONIA

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Definition/Criteria: Pneumonia must meet criteria specified in either A, B, or C:

A) Rales or dullness to percussion on physical examination of chest and 1 of the following:

a. new onset of purulent sputum or change in character of sputum

b. isolation of pathogen from specimen obtained by transtracheal aspirate, bronchial

brushing, or biopsy

c. organism isolated from blood culture

B) Chest radiographic examination shows new or progressive infiltrate, consolidation, cavitation, or pleural effusion and 1 of the following:

a. new onset of purulent sputum or change in character of sputum

b. isolation of pathogen from specimen obtained by transtracheal aspirate, bronchial

brushing, or biopsy

c. organism isolated from blood culture

d. isolation of virus or detection of viral antigen in respiratory secretions

e. diagnostic single antibody titer (IgM) or 4-fold increase in paired serum samples (IgG)

for pathogen

f. histopathologic evidence of pneumonia

C) Chest radiographic examination shows new infiltrate (segmental pattern, asymmetrical distribution and/or air bronchograms more specific) and

a. fever (≥38.0°C) and

b. leukocytosis (≥10,000 WBC/mm3) and

c. positive tracheobronchial cultures for pathogenic organisms

Reference: Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes MJ: CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16:128-40. Helling TS, Van Way C 3rd, Krantz S, Bertram K, Stewart A: The value of clinical judgment in the diagnosis of nosocomial pneumonia. Am J Surg 1996; 171:570-5.


Respiratory System 310 ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) AND/OR RESPIRATORY FAILURE

Definition/Criteria:

Acute Respiratory Distress Syndrome (ARDS) must fulfill all 5 of the following criteria:

1. Risk factors are present (at least one of the following: gastric aspiration, diffuse pulmonary infection,

near-drowning, sepsis syndrome, thoracic trauma, multiple transfusion).

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2. Acute onset

3. Bilateral [and/or diffuse] chest radiographic infiltrates

4. A pulmonary artery occlusion pressure of ≤18 mmHg or no evidence [clinical signs] of left atrial

hypertension [LV failure] or volume overload

5. Impaired oxygenation regardless of PEEP concentration with a PaO2/FiO2 ratio of ≤200 mmHg (≤27 kPa)

Reference: Bernard GR, et al.: The American-European consensus conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818-24. Luce JM: Acute lung injury and the acute respiratory distress syndrome. Critical Care Medicine. 26(2):369-76, 1998.

Respiratory Failure: EXCEPT for when the patient is under general anesthesia, any instance where both: a) a mechanical airway aid (e.g., endotracheal intubation, constant positive airway pressure (CPAP), or tracheostomy) and b) supplemental oxygen or ventilatory assistance, are required in order to maintain clinically adequate oxygenation or ventilation.


Respiratory System 311 Pulmonary Embolism

Definition/Criteria: Signs and symptoms of pulmonary embolism may include: acute onset of shortness of breath and pleuritic chest pain, tachycardia, rapid breathing, hemoptysis, hypoxemia, and hemodynamic collapse. In all patients (with or without confirmed deep venous thrombosis, see 810) either a "high-probability" V/Q scan or positive pulmonary angiogram is sufficient for diagnosis. Only in patients with confirmed deep venous thrombosis and overt clinical symptoms is an "intermediate probability" V/Q scan sufficient for diagnosis. In the absence of confirmed deep venous thrombosis, "intermediate- and low- probability" V/Q scans are not sufficient for diagnosis. A normal or near-normal ventilation-perfusion (V/Q) scan or pulmonary angiogram rules out the diagnosis of pulmonary embolism.

Reference: PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism: Results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA 1990; 263:2753.


Respiratory System 312 Severe Bronchospasm

Definition/Criteria: Any instance when either the patient's oxygenation or ventilation is significantly compromised because of either acute or chronic contraction of bronchial smooth muscle. Conditions in which this may occur include asthma, acute or chronic reactive airway diseases, chronic obstructive pulmonary disease, emphysema, and aspiration pneumonia. Typically, the patient's condition is improved with bronchodilator therapy (inhaled bronchodilators, aminophylline, etc.).


Respiratory System 313 Hypoxemia

Definition/Criteria: Any instance when the patient's arterial PO2 is ≤50 mmHg (or ≤6.7 kPa) or SaO2 is ≤85% [pulse oximetry] for any duration for any reason.


Respiratory System 314 Hypercarbia

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Definition/Criteria: Any instance when the patient's arterial PCO2 is ≥50 mmHg (or ≥6.7 kPa) on two or more consecutive arterial blood gas measurements, irrespective of the interval between measurements.


Respiratory System 316 Apnea or respiratory arrest

Definition/Criteria: Any instance when either oxygenation or ventilation is insufficient specifically because of an inadequate rate or volume of ventilation (either spontaneous or mechanically assisted). This is a problem of absence of ventilation. The functional status of the lungs, per se, does not enter into the diagnosis.


Respiratory System 317 Other significant airway or respiratory disorder or complication (not 300-316)

Definition/Criteria: Any other clinically significant airway or respiratory disorder or complication that is not adequately characterized by the criteria above (not 300-316), e.g., pneumothorax.


Respiratory System Pulmonary edema (see 211 above)


Respiratory System 390 Chest X-ray

Definition/Criteria: Any instance when the patient undergoes a chest x-ray, regardless of reason.


Respiratory System 391 Bronchoscopy

Definition/Criteria: Any instance when the patient undergoes bronchoscopy, regardless of reason.


Respiratory System 392 Endotracheal intubation

Definition/Criteria: EXCEPT for endotracheal intubation specifically for cerebral aneurysm surgery, ANY instance when the patient requires endotracheal intubation for ANY reason (neurologic, respiratory, other surgery,...) either before or after the primary aneurysm surgery.


Respiratory System 393 Tracheostomy

Definition/Criteria: Any instance when the patient undergoes any form of tracheotomy, either permanent or temporary, either via surgery or percutaneous technique.


Respiratory System 394 Thoracic surgery

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Definition/Criteria: Any instance when the patient undergoes any form of thoracic surgery. Such procedures must occur in an operating room.


Respiratory System 395 Thoracostomy or chest tube placement

Definition/Criteria: Any instance when the patient undergoes placement of a chest tube or other pleural drainage catheter.


Respiratory System 396 Other respiratory or thoracic procedure intervention, or surgery (not 390 – 395)

Definition/Criteria: Any instance when the patient undergoes any other clinically significant respiratory or thoracic procedure, intervention, or surgery that does not fall into the above procedure categories (not 390-395).


Digestive System 400 Hepatitis, jaundice, or liver failure

Definition/Criteria: Any instance when the patient is diagnosed as having either A, B, or C. A) Any form of hepatitis (due to an infectious agent, drug-induced, alcohol-related, etc.). B) Significantly elevated bilirubin (≥2 times upper normal range). C) Hepatic failure (elevated liver enzymes with encephalopathy, coagulopathy, low albumin, hypoglycemia, renal failure, ascites, hyponatremia, and sepsis).


Digestive System 401 Gastrointestinal tract bleeding

Definition/Criteria: Any instance when any of the following are present: hematemesis (patient vomits blood); gross blood or 'coffee grounds' material in a nasogastric aspirate; hematochezia (bloody feces) ; or melena (black tarry feces due to digested blood).

Reference: Cook DJ, et al.: Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med 1994; 330:377-81.


Digestive System 402 Other significant gastrointestinal disorder or complication (not 400, 401)

Definition/Criteria: Any other clinically significant gastrointestinal disorder or complication which is not adequately characterized by the criteria above (not 400, 401), e.g. cholecystitis.


Digestive System 490 Gastrointestinal endoscopy

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Definition/Criteria: Any instance when any gastrointestinal endoscopic procedure is performed (e.g. esophagoscopy, gastroscopy, small bowel endoscopy, sigmoidoscopy, colonoscopy, endoscopic retrograde cholangiography).


Digestive System 491 Gastrointestinal surgery

Definition/Criteria: Any instance when any gastrointestinal surgery is performed (e.g., appendectomy, cholecystectomy, bowel resection).


Digestive System 492 Other gastrointestinal procedure, intervention, or surgery (not 490, 491)

Definition/Criteria: EXCEPT for a nasogastric tube, any other clinically significant gastrointestinal procedure, intervention, or surgery that does not fall into the above procedure categories (not 490, 491).


Endocrine/Metabolic 500 Hypoglycemia

Definition/Criteria: Any instance when the patient's serum (or plasma) glucose concentration is ≤50 mg/dl (or ≤2.8 mmol/L) for any duration, for any reason.


Endocrine/Metabolic 501 Hyperglycemia

Definition/Criteria: Any instance when patient's serum (or plasma) glucose concentration is ≥400 mg/dl (or ≥22.2 mmol/L) for any duration, for any reason.


Endocrine/Metabolic 502 Diabetic ketoacidosis

Definition/Criteria: Any instance when the diagnosis of diabetic ketoacidosis is made. The patient must have diabetes mellitus with severe metabolic acidosis (increased anion gap), hyperglycemia, and elevated serum ketones; with or without altered mentation, elevated blood lactate, and hypotension.


Endocrine/Metabolic 503 Diabetes Insipidus

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Definition/Criteria: Any instance when the diagnosis of Diabetes Inspidus (DI) is made. DI is due to either to a decrease in the release of antidiuretic hormone (ADH) from the pituitary ("neurogenic DI"), or failure of the kidneys to respond to ADH ("nephrogenic DI"); both categories are included. In the absence of diuretic therapy, DI is diagnosed when the patient produces a large amount (usually >200 ml/h) of dilute urine (urine osmolality <250 mOsm/kg), resulting in intravascular volume depletion and progressively increasing serum (or plasma) sodium concentration and a hyperosmolar state (plasma osmolality >290 mOsm/kg). This condition is not reversed with fluid restriction.


Endocrine/Metabolic 504 Hyponatremia

Definition/Criteria: Any instance when the patient's serum (or plasma) sodium concentration is ≤125 mEq/L for any duration, for any reason.


Endocrine/Metabolic 505 Hypernatremia

Definition/Criteria: Any instance when patient's serum (or plasma) sodium concentration is ≥155 mEq/L for any duration, for any reason.


Endocrine/Metabolic 506 Hypokalemia

Definition/Criteria: Any instance when the patient's serum (or plasma) potassium concentration is ≤2.0 mEq/L for any duration, for any reason.


Endocrine/Metabolic 507 Hyperkalemia

Definition/Criteria: Any instance when the patient's serum (or plasma) potassium concentration is ≥6.0 mEq/L for any duration for any reason.


Endocrine/Metabolic 508 Other significant endocrine or electrolyte disorder or complication

Definition/Criteria: Any other clinically significant endocrine or electrolyte disorder that is not adequately characterized by the criteria above (not 500-507), e.g. myxedema coma, thyroid storm, symptomatic hypocalcemia.


Neurologic/ Neurosurgical 600 CRANIOTOMY INCISION INFECTION OR BONE-FLAP INFECTION

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Incision/Wound Infection: Infection occurs within 30 d after operation and infection involves only skin or subcutaneous tissue of the incision and at least 1 of the following:

a. Purulent drainage from the superficial incision

b. Diagnosis of superficial incision infection by the surgeon

c. Organisms isolated from an aseptically obtained culture of fluid [serous drainage] or tissue from the superficial incision

d. Superficial incision is deliberately opened by surgeon and at least 1 of the following are present: pain or tenderness, localized swelling, redness, or heat (unless the incision is culture-negative)

[Do not report stitch abscess-minimal inflammation and discharge confined to points of suture penetration]

Fascial/Muscle Flap or Bone Flap Infection: Infection occurs within 30 days after operation if no implant is left in place (or one year if implant is in place) and the infection appears to be related to the operation and involves deep soft tissues of the incision [galea, muscle flap, or bone flap] and at least 1 of the following:

a. Purulent drainage from the deep incision but not from the organ/space component of the surgical site,. i.e. no involvement of dura, subdural space or brain parenchyma.

b. Diagnosis of a deep incisional infection (galea, muscle flap, bone flap) by a surgeon or attending physician.

c. A deep incision spontaneously dehisces or is deliberately opened by a surgeon when the patient has at least 1 of the following: fever (>38C), localized pain or tenderness, (unless site is culture-negative).

d. An abscess or other evidence of infection involving the deep incision if found on direct examination, during reoperation, or by radiologic or histopathologic examination.

Reference: Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes MJ: CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16:128-40. Narotam PK, van Dellen JR, du Trevou MD, Gouws E: Operative sepsis in neurosurgery: a method of classifying surgical cases. Neurosurgery 1994; 34:409-16. Korinek AM: Risk factors for neurosurgical site infections after craniotomy: a prospective multicenter study of 2944 patients. The French Study Group of Neurosurgical Infections, the SEHP, and the C-CLIN Paris-Nord. Service Epidemiologie Hygiene et Prevention. Neurosurgery 1997; 41:1073-81. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR: Guideline for prevention of surgical site infection, 1999. Am J Infect Control 1999; 27:97-134.


Neurologic/ Neurosurgical 601 MENINGITIS OR VENTRICULITIS

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Meningitis or ventriculitis must meet at least 1 of the following criteria:

1. Organism isolated from a culture of CSF.

2. Diagnosis of meningitis or ventriculitis made by a surgeon and antimicrobial therapy instituted and at least 1 of the following present with no other recognized cause (fever, headache, stiff neck, meningeal signs, cranial nerve signs, or irritability) and at least 1 of the following:

a. Increased WBCs, elevated protein, and/or decreased glucose in CSF

b. Organism seen on gram stain of CSF

c. Organism isolated from blood culture

d. Positive antigen test on CSF, blood or urine

e. Diagnosistic single antibody titer (IgM) or 4-fold increase in paired serum samples (IgG) for pathogen

Reference: Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes MJ: CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16:128-40. Narotam PK. van Dellen JR. du Trevou MD. Gouws E: Operative sepsis in neurosurgery: a method of classifying surgical cases. Neurosurgery 1994; 34:409-16. Korinek AM: Risk factors for neurosurgical site infections after craniotomy: a prospective multicenter study of 2944 patients. The French Study Group of Neurosurgical Infections, the SEHP, and the C-CLIN Paris-Nord. Service Epidemiologie Hygiene et Prevention. Neurosurgery 1997; 41:1073-81. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR: Guideline for prevention of surgical site infection, 1999. Am J Infect Control 1999; 27:97-134.

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Neurologic/ Neurosurgical 602 BRAIN ABSCESS, OR EPIDURAL OR SUBDURAL INFECTION, OR ENCEPHALITIS

Definition/Criteria: Brain abscess, epidural or subdural infection, or encephalitis) must meet at least 1 of the following 3 criteria:

1. Organism isolated from culture of brain tissue, epidural, or subdural space

2. Abscess or evidence of intracranial infection seen during surgery or by histopathological examination

3. Diagnosis of intracranial infection made by surgeon and antimicrobial therapy instituted and at least 2 of the following are present with no other recognized cause (headache, dizziness, fever, localizing neurologic signs, changing level of consciousness or confusion) and at least 1 of the following:

a. Organism seen on microscopic exam of brain or abscess

b. Radiograhpic evidence of infection

c. Positive antigen test on blood or urine.

d. Diagnosistic single antibody titer (IgM) or 4-fold increase in paired serum samples (IgG) for

pathogen.

Reference: Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes MJ: CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16:128-40. Narotam PK. van Dellen JR. du Trevou MD. Gouws E: Operative sepsis in neurosurgery: a method of classifying surgical cases. Neurosurgery 1994; 34:409-16. Korinek AM: Risk factors for neurosurgical site infections after craniotomy: a prospective multicenter study of 2944 patients. The French Study Group of Neurosurgical Infections, the SEHP, and the C-CLIN Paris-Nord. Service Epidemiologie Hygiene et Prevention. Neurosurgery 1997; 41:1073-81. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR: Guideline for prevention of surgical site infection, 1999. Am J Infect Control 1999; 27:97-134.


Neurologic/ Neurosurgical 610 RECURRENT SUBARACHNOID HEMORRHAGE

Definition/Criteria: EXCEPT for the primary aneurysmal subarachnoid hemorrhage, ANY instance when any subarachnoid hemorrhage occurs for ANY reason except direct surgical manipulation.


Neurologic/ Neurosurgical 611 INTRAPARENCHYMAL (BRAIN) HEMORRHAGE

Definition/Criteria: EXCEPT for intraparenchymal hemorrhage associated with the primary aneurysmal subarachnoid hemorrhage (if any), ANY instance when any hemorrhage occurs in the substance of the brain for ANY reason at ANY time.


Neurologic/ Neurosurgical 612 EPIDURAL OR SUBDURAL HEMORRHAGE

Definition/Criteria: EXCEPT for sub- or epi-dural hemorrhage associated with the primary aneurysmal subarachnoid hemorrhage (if any), ANY instance when any hemorrhage occurs in either the subdural or epidural space.

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Neurologic/ Neurosurgical 620 Delayed ischemic neurologic deficit (DIND)

[Clinically symptomatic “vasospasm”]

Definition/Criteria: The clinical manifestations of Delayed Ischemic Neurologic Deficit (DIND) [or clinically symptomatic "vasospasm"] typically include alterations in consciousness such as drowsiness and disorientation, and/or focal neurologic deficits. DIND may be accompanied by increasing headache, meningismus, fever, and tachycardia. The time of onset of DIND is characteristic. DIND rarely occurs less than 3-5 days after aneurysm rupture. DIND most commonly occurs 7-10 days after aneursym rupture, and then typically resolves over the next 10-14 days. DIND is unlikely to have its onset more than 12-14 days after aneurysm rupture. DIND is caused by focal or global reductions in cerebral blood flow resulting from delayed narrowing ("vasospasm") of the major conducting arteries of the brain (e.g. middle cerebral, anterior cerebral).

The diagnosis of DIND is primarily based on the time of onset of the deficits (see above), the rate of development of the deficits (hours), the nature of the deficits (impaired orientation and decreased level of consciousness preceding focal deficits) and the exclusion of other potential causes of delayed neurologic deterioration including: aneurysm rebleeding, intracerebral hematoma, hydrocephalus, brain edema, seizures, metabolic disturbances (hypoxia, hyponatremia, hyper- or hypo-glycemia, drug intoxication), or angiographic or surgical complications. CT and/or MRI scanning, electroencephalography, and blood studies are used to rule out all of these latter possibilities. Neither cerebral angiography nor transcranial Doppler (TCD) studies are required to make the diagnosis of DIND. However, cerebral angiography is often performed to confirm the presence of vasospasm. TCD studies often reveal elevated cerebral blood flow velocities when vasospasm is present.

Treatment of DIND consists of prophylactic nimodipine, induction of hypertension and/or hypervolemia, and/or cerebral angioplasty.

Reference: Kassell NF, Sasaki T, Colohan ART, Nazar G: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 1985; 16:562-72. Awad IA, Carter LP, Spetzler RF, Jedina M, Williams FW Jr: Clinical vasospasm after subarachnoid hemorrhage: Response to hypervolemic hemodilution and arterial hypertension. Stroke 1987; 18: 365-72. Mayberg MR, Batjer HH, Dacey R, Diringer M, Haley EC, Heros RC, Sternau LL, Torner J, Adams HP, Feinberg W, Thies W: Guidelines for the management of aneurysmal subarachnoid hemorrhage. A statement for healthcare professionals from a special writing group of the stroke council, American Heart Association. Stroke 1994; 25: 2315-28. McGrath BJ, Guy J, Borel CO, Friedman AH, Warner DS: Perioperative management of aneurysmal subarachnoid hemorrhage: Part 2. Postoperative management. Anesth Analg 1995; 81: 1295-302. Miller JA, Dacey RG, Diringer MN: Safety of hypertensive hypervolemic therapy with phenylephrine in the treatment of delayed ischemic deficits after subarachnoid hemorrhage. Stroke 1995; 26: 2260-6.


Neurologic/ Neurosurgical 630 Hydrocephalus

Definition/Criteria: Any instance when intracranial cerebrospinal fluid (CSF) volume is considered to be abnormally large. Typically, the lateral ventricles are significantly larger than age-adjusted normal values (≥95% percentile).

Reference: van Gijn J, et al.: Acute hydrocephalus after aneurysmal subarachnoid hemorrhage. J Neurosurg 1985; 63:355-62.


Neurologic/ Neurosurgical 631 Seizure

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Definition/Criteria: Any instance where the patient exhibits signs and/or symptoms consistent with any form of central nervous system hyper-excitation state (epilepsy), either generalized (classic grand mal seizure with loss of consciousness and tonic/clonic movements) or partial (simple motor or sensory seizure, or complex partial seizure with alteration of consciousness).


Neurologic/ Neurosurgical 632 DELETED. See either code 636 (INTRACRANIAL HYPERTENSION) or code 637 (BRAIN SWELLING)


Neurologic/ Neurosurgical 633 CEREBRAL INFARCTION

Definition/Criteria: Any instance when cerebral infarction is diagnosed, using either clinical and/or radiologic criteria. Clinical criteria for cerebral infarction are based on the presence of focal and/or global neurologic deficits (sensory, motor, cranial nerve, or speech). Radiologic criteria (CT or MRI) for cerebral infarction are based on the presence of focal and/or global abnormalities in brain images that indicate regions which have lost viability.


Neurologic/ Neurosurgical 634 Neuropsychiatric disorder

Definition/Criteria: Any instance when the patient exhibits a clinically significant cognitive, emotional, behavioral, or psychiatric disorder that requires intervention (medication addition or removal, physical restraint, social service or psychiatry consultation).


Neurologic/ Neurosurgical 635 Other significant neurologic disorder or complication (not 600-634)

Definition/Criteria: Any other clinically significant nervous system disorder or complication that is not adequately characterized by the criteria above (not 600-634), e.g., major peripheral nerve injury.


Neurologic/ Neurosurgical 636 INTRACRANIAL HYPERTENSION

Definition/Criteria: Any instance when measured intracranial pressure is greater than 25mmHg (3.3kPa) for >15 consecutive minutes (or longer). This is an “indicator event” to be reported to the CCC within 24 h.


Neurologic/ Neurosurgical 637 BRAIN SWELLING

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Definition/Criteria: Any instance when either direct surgical observation or imaging studies (CT or MRI) indicate brain volume and/or water content (“brain edema”) are greater than normal, either focally or globally. On imaging studies, brain swelling will often be associated with effacement of the cortical sulci and/or shift of intracranial structures out of their normal anatomic position. This is an “indicator event” to be reported to the CCC within 24 h.


Neurologic/ Neurosurgical 690 REPEAT CRANIOTOMY

Definition/Criteria: EXCEPT for the craniotomy for cerebral aneurysm surgery, ANY instance when a craniotomy is needed for ANY reason.


Neurologic/ Neurosurgical 691 CRANIOTOMY WOUND OR BONE DEBRIDEMENT OR REMOVAL

Definition/Criteria: Any instance when either the craniotomy wound or bone flap is either surgically debrided or removed. In almost all circumstances, such procedures are done because of infection (600). However, if a bone flap is removed to reduce intracranial pressure because of brain swelling (637), please indicate this on the IE form.


Neurologic/ Neurosurgical 692 Placement of ventriculostomy, ventriculoperitoneal shunt or lumboperitoneal shunt

Definition/Criteria: EXCEPT for cerebrospinal fluid (CSF) drainage catheters inserted during the primary cerebral aneurysm surgery, any instance when any form of CSF drainage device is placed, either before or after the primary cerebral aneurysm surgery.


Neurologic/ Neurosurgical 693 Placement of an intracranial pressure (ICP) monitor that is NOT a ventriculostomy

Definition/Criteria: Any instance when an intracranial pressure (ICP) monitor is placed that is NOT a ventriculostomy (e.g. some form of intraparenchymal or peridural pressure transducer.


Neurologic/ Neurosurgical 694 Computed tomography (CT) or magnetic resonance imaging (MRI) of the head

Definition/Criteria: Any instance when either computed tomography (CT) or magnetic resonance (MR) techniques are used to obtain an image of the patient's intracranial contents (brain, CSF, etc.).


Neurologic/ Neurosurgical 695 Cerebral angiography

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Definition/Criteria: Any instance when the patient undergoes any form of cerebral angiography (i.e. imaging of cerebral vascular morphology).


Neurologic/ Neurosurgical 696 Transcranial Doppler (TCD)

Definition/Criteria: Any instance when the patient undergoes a transcranial Doppler examination, regardless of reason.


Neurologic/ Neurosurgical 697 Other Cerebral blood flow measurement (NOT TCD)

Definition/Criteria: Any procedure in which the patient's cerebral blood flow is determined (e.g., radioisotope clearance, CT- or MRI-based cerebral blood flow studies, or positron emission tomography).

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Neurologic/ Neurosurgical 698 Other nervous system procedure, intervention, or surgery

Definition/Criteria: Any instance when the patient undergoes any therapeutic cerebral angiographic procedure including cerebral angioplasty, intra-arterial papaverine administration, and/or cerebral aneurysm (or AVM) coiling or embolization.


Neurologic/ Neurosurgical 699 Other nervous system procedure, intervention, or surgery (not 690-698)

Definition/Criteria: Any other clinically significant nervous system procedure, intervention, or surgery that does not fall into the above procedure categories (not 690-698).


Urogenital 700 Urinary tract infection

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Definition/Criteria: Urinary tract infection includes symptomatic urinary tract infection, asymptomatic bacteriuria, and any other infection of the urinary tract.

Symptomatic urinary tract infection must meet one of the following (A or B):

A) Urine culture of ≥105 colonies/ml (with no more than 2 species of organisms) and 1 of the following: fever (>38°C), urgency, frequency, dysuria, suprapubic tenderness

B) Two of the following: fever (>38°C), urgency, frequency, dysuria, suprapubic tenderness and 1 of the following:

1. dipstick positive for leukocyte esterase and/or nitrate

2. pyuria (≥10 WBC/ml3 or ≥3 WBC/high-power field of unspun urine)

3. organism seen on gram stain of unspun urine

4. 2 urine cultures with repeated isolation of the same uropathogen with ≥102 colonies/ml in

nonvoided specimens

5. urine culture with ≤105 colonies/ml urine of single uropathogen in patient being treated with

appropriate antimicrobial therapy

6. physician’s diagnosis

7. physician institutes appropriate antimicrobial therapy.

Asymptomatic bacteriuria must meet one of the following (A or B):

A) An indwelling urinary catheter is present (or was present within 7 days before urine is cultured) and

1. urine culture of ≥105 CFU/ml with no more than 2 species of organisms, and

2. patient has no fever (>38°C), urgency, frequency, dysuria, or suprapubic tenderness

B) An indwelling urinary catheter is not present (nor has been present within 7 days) before the first of two urine cultures with ≥105 CUF/ml of the same organism with no more than two species of organisms, and

1. the patient has no fever (>38°C), urgency, frequency, dysuria, or suprapublic tenderness

Reference: Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes MJ: CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16:128-40.


Urogenital 710 Renal Insufficiency

Definition/Criteria: Any instance when the patient's blood urea nitrogen is 40 mg/dl (or greater) or patients blood creatinine is 2.1 mg/dl (or greater) for any duration.


Urogenital 711 Other significant urogenital disorder or complication (not700, 710)

Definition/Criteria: Any other clinically significant urogenital disorder or complication that is not adequately characterized by the criteria above (not 700, 710), e.g. kidney stones.


Urogenital 790 Hemodialysis or peritoneal dialysis

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Definition/Criteria: Any instance when the patient requires either hemodialysis or peritoneal dialysis for any reason for any duration.


Urogenital 791 Other urogenital procedure, intervention, or surgery

Definition/Criteria: EXCEPT bladder catheterization, any other clinically significant urogenital procedure, intervention, or surgery that does not fall into the above procedure categories (not 790), e.g. bladder cystoscopy.


Coagulation/ Hematologic 800 SEVERE HEMORRHAGE (≥1000 MLS IN ≤24 H)

Definition/Criteria: Any instance when bleeding from any source results in an estimated blood loss of 1000 ml or more over a time period of 24 hours or less.


Coagulation/ Hematologic 801 SEVERE COAGULOPATHY

Definition/Criteria: Any instance when signs and symptoms are consistent with severe coagulopathy. Signs and symptoms of severe coagulopathy include markedly abnormal pre-, intra-, or post-operative clotting studies (prothrombin time [PT], activated partial thromboplastin time [aPTT]), or evidence of disseminated intravascular coagulation [low fibrinogen and increased fibrin degradation products]. Non-CNS signs of coagulopathy include bleeding from intravenous sites, spontaneous epistaxis, or acute onset of clinically significant gastrointestinal or genitourinary bleeding. Extreme bruising and/or hematoma formation from angiography might also be a sign of coagulopathy. During surgery, signs of coagulopathy include (in addition to the above) marked or unusual bleeding from wound edges, brain bleeding in response to retraction, or spontaneous brain bleeding.


Coagulation/ Hematologic 810 Thrombophlebitis or deep venous thrombosis (DVT)

Definition/Criteria: Signs and symptoms of thrombophlebitis include tenderness and/or erythemia overlying venous structures ("red chord") with or without distal limb swelling. Because patients with aneurysmal SAH are at high risk of DVT, positive results on either impedance plethysmography, ultrasonography, or venography are sufficient for diagnosis of DVT.

Reference: Agnelli G, et al.: Enoxaparin plus compression stoking compared with compression stocking alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 1998; 339:80-5. Anand SS, Wells PS, Hunt D, et al.: Does this patient have deep vein thrombosis? JAMA 1998 279: 1094-9. Kearnon C: Noninvasive diagnosis for deep venous thrombosis. Ann Intern Med 1998; 128:663-7.


Coagulation/ Hematologic 820 Anemia

Definition/Criteria: Any instance when the patient's hematocrit is ≤24% (or hemoglobin concentration is ≤8.0 mg/dL) for any duration, for any reason.


Coagulation/ Hematologic 821 Neutropenia

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Definition/Criteria: Any instance when the patient's absolute neutrophil count ≤1,000 neutrophils/mm3, for any duration, for any reason


Coagulation/ Hematologic 822 Thrombocytopenia

Definition/Criteria: Any instance when the patient's platelet count is ≤100,000 platelets/mm3 for any duration, for any reason.


Coagulation/ Hematologic 823 Other significant coagulation or hematologic disorder or complication (not 800-822)

Definition/Criteria: Any other clinically significant coagulation or hematologic disorder or complication which is not adequately characterized by the criteria above (not 800-822).


Coagulation/ Hematologic 890 Packed red blood cell (PRBC) administration

Definition/Criteria: Any instance when the patient receives packed red blood cells (PRBCs) for any reason.


Coagulation/ Hematologic 891 Fresh frozen plasma (FFP) or cryoprecipitate administration

Definition/Criteria: Any instance when the patient receives either fresh frozen plasma (FFP) or cryoprecipitate for any reason.


Coagulation/ Hematologic 892 Platelet administration

Definition/Criteria: Any instance when the patient receives platelets for any reason.


Coagulation/ Hematologic 893 Other blood product administration (not PRBC, FFP, cryoprecipitate, or platelets)

Definition/Criteria: Any instance when the patient receives any other blood product (not RBC, FFP, cryoprecipitate, or platelets) for any reason.


Other/Unclassified 900 Other significant intercurrent event not listed above

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Definition/Criteria: Any other clinically significant intercurrent event which is not adequately characterized by any of the criteria above (100-111, 200-251, 300-317, 400-402, 500-508, 600-635, 700-711, 800-823).


Other/Unclassified 910 Other infection not listed above

Definition/Criteria: The diagnosis of “Other Infection” may be made whenever the patient has an infectious process with a microbial agent (bacterial, fungal, viral, parasitic, etc.) that is not accurately characterized by any other infection-related IE diagnosis, i.e. the process is NOT any of the following: 100 – Septic shock; 101 – Vascular catheter-related infection; 102 – Bacteremia; 103 – Non-neurologic wound infection; 300 – Pneumonia; 400 – Hepatitis (infectious); 600 – Craniotomy incision or bone-flap infection; 601 – Meningitis or ventriculitis; 602 – Brain abscess, epidural/subdural infection, encephalitis; 700 – Urinary tract infection. Examples of “other infection” include conjunctivitis, sinusitis, tooth abscess, prostatitis. Because of the extremely large number of possible “other infections,” standard diagnostic criteria for all possible conditions in this category cannot be specified. Therefore, the only criteria for diagnosis of “other infection” is a doctor’s clinical diagnosis, using whatever criteria he/she considers appropriate. However, the condition must be considered to be on the basis of a specific microbial agent or process, rather than other non-infectious inflammatory state such as rheumatoid arthritis or nonspecific vasculitis.


Other/Unclassified 990 Other significant diagnostic or therapeutic procedure not listed above

Definition/Criteria: Any other clinically system procedure, intervention, or surgery that does not fall into the above procedure categories (190, 290-299, 390-396, 490-492, 690-699, 790-791, 890-893).

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CHAPTER X. THE FIRST TWO “PRACTICE” PATIENTS

X.A.1. Overview

In any experiment, the toughest part is getting started. Part of the difficulty relates to inertia, but part is related to unfamiliarity with the protocol --“I’m not sure we understand how to do everything, so maybe we shouldn’t start.” In most experiments, this awkwardness results in “bad data” for the first couple of subjects; data which often needs to be discarded. The more complex the experiment, the greater the problem becomes.

Since one cannot casually discard data from a clinical trial like this, we want to give each PCC a chance to gain experience and expertise in the enrollment procedures, execution of the protocol (i.e., being able to cool and rewarm patients is most important, since everyone already knows how to keep patients warm), and CRF completion. To do this, each PCC will need to “study” two hypothermic patients BEFORE enrolling the first official, randomized individual. In essence, this is a “practice run” with a very brief follow-up (24 hours) – and essentially no penalties for error.

X.A.2. Procedure

Two “practice” patients must be studied. The two patients should be otherwise eligible to participate in IHAST2. Specifically they must meet all standard eligibility inclusion/exclusion criteria, and they must give consent using the standard, locally approved, IRB documents for IHAST2. However, it is permissible to inform these patients (prior to consent) that they will NOT be randomized, but will be intentionally cooled.

Once your center is certified to participate in the IHAST study, your center will receive the “go ahead” from the CCC. When you receive this notification you are to begin screening all patients for eligibility to participate in the study. This involves completing a SCREENING form on all patients scheduled to undergo an open craniotomy for the clipping of an intracranial aneurysm (with surgery planned within 48 hours), regardless of whether or not they are eligible. In addition, an ELIGIBILITY form will be completed if the patient has experienced a SAH, again, regardless of whether or not they are eligible. If the patient does not meet the eligibility criteria, please file their SCREENING and ELIBILITY forms in the Patient Log binder and then mail the white copy to the DMC on the last working day of the month.

When patient eligibility is verified and consent obtained, patients will be enrolled via the telephone system in a fashion similar to that described in Chapter VI.C, except that on the initial query, the number for enrollment of “Practice” Patients should be pressed. The DMC has constructed the telephone enrollment system such that the first two patients enrolled at each PCC will be considered “practice patients”, however assignment of RANDOMIZATION ENVELOPES will be done as per usual. Note that this process gives the DMC and CCC an opportunity to practice as well.

Also, remember that the patient randomization status call must be made within 24 hours after the completion of surgery.

1


The DMC will have shipped to you two “Practice” Patient Notebooks that contain all of the case report forms that you are required complete for these patients. Please complete all forms from the “Practice” Patient Notebook and store all originals there as well.

All preoperative examinations/assessments must be performed and CRFs completed. This includes the SCREENING, ELIGIBILITY, PRE-SAH HISTORY, POST-ADMIT SCREEN, and preoperative NIHSS.

All aspects of intraoperative anesthestic and surgical management must be performed and CRF’s completed, including the ANESTHESIOLOGIST, NEUROSURGEON, and TEMPERATURE forms.

The immediate postoperative care and data collection should be performed as per protocol standards. This includes performing the 3 to 6- hour postoperative NIHSS.

Finally, each patient should be seen at 24-hours post-op, and the first column of the DAILY POST-OP SCREEN and MEDICATION forms completed, along with any appropriate IEs. In addition, the designated Neurologic Examiner (or Study Coordinator) should perform a 24-hour NIHSS exam.


No follow-up is required on these “practice” patients after the 24-hour exam. There is no need to follow such individuals beyond this point, and there is no need to insist on a three-month follow-up visit. However, each PCC is to submit to the CCC a copy of the patient’s discharge summary labeled with the patient’s PID number and with other patient identifiers removed.

Upon completion of each “practice” patient, you will fax page 6 of the ANESTHESIOLOGIST form to the CCC and mail to the DMC the following: 1) photocopies of all the completed forms; 2) the sealed envelope containing the TEMPERATURE form from the opened RANDOMIZATION ENVELOPE; 3) the unopened RANDOMIZATION ENVELOPE; and 4) the Study Packet containing only the anesthesia record and 0-2 postoperative recovery or critical care records. You may fax to the DMC the originals of the completed forms (item 1) but items 2 through 4 listed above cannot be faxed and must be mailed to the DMC.

Once the DMC receives the “practice” patient forms, the forms will be reviewed and the PCC will receive, a listing of items on each form that need corrections, if any. The PCC will be asked to make corrections to the originals and fax the corrected originals or mail photocopies to the DMC for a second review. Upon completion of the two “practice” patients, the Clinical Coordinating Center and Data Management Center will review the forms. Once the review process is complete, your center will be informed that you may proceed with enrolling and randomizing “real” patients into the trial.

Each PCC will receive $1000 each for these two patients.

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CHAPTER XI. APPENDICES

XI. A UI CONTACT INFORMATION

XI. B PARTICIPATING CENTERS CONTACT INFORMATION

XI. C PILOT TRIAL PUBLICATION

XI. D THE UNIVERSITY OF IOWA IRB DOCUMENTS

XI. E CONSORTIUM LETTER TEMPLATE

XI. F NIH SUBCONTRACT TEMPLATE

XI. G DMC FORMS

a) No Patient Randomization Status Call

b) IHAST2 Patient Calendar

c) Weekly Patient Summary Report

d) Data Edit Report (DER)

e) PCC Correction Report

f) Script for Interval Contacts

g) IHAST2 Comment Entry System

XI.G.2. GOS/Rankin Testing Vignettes

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XI.G.3. Case Report Forms

a) SCREENING

b) ELIGIBILITY

c) CONTACT

d) NIH STROKE SCALE

e) PRE-SAH HISTORY

f) POST-ADMIT SCREEN

g) ANESTHESIOLOGIST

h) NEUROSURGEON

i) TEMPERATURE-H

j) TEMPERATURE-N

k) DAILY POST-OP SCREEN

l) DPS SUPPLEMENT

m) CONTACT FOLLOW-UP

n) OUTCOME FOLLOW-UP

o) NEUROPSYCHOLOGY FORMS

BENTON VISUAL RETENTION

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ORAL WORD

COMPLEX FIGURE TEST

GP/TMT

TRAIL MAKING Part A

TRAIL MAKING Part B

MMSE

p) MEDICATIONS

q) INTERCURRENT EVENTS

r) IE SUPPLEMENT

s) DEATH/PATIENT WITHDRAWAL

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IHAST2 Operations Manual.doc

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