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PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 1 of 16 Use most current version on IRB website and complete all sections
Example: Research Protocol Randomized Controlled Trial This protocol is being used as an example with permission from the author, Jamie Penk, MD. The
content in this protocol is to serve only as an example. Please download the most recent version of the
Advocate IRB Research Protocol Template (HRP_503) from their website
(http://www.advocatehealth.com/forms2) to write your own research protocol.
Principal Investigator: [Name, credentials]
Sub-Investigator(s): [Name, credentials] as appropriate
Research Coordinator: [Name, credentials] as appropriate
1) Protocol Title
'Continuous infusion versus bolus dosing for pain control after pediatric cardiothoracic surgery'
2) IRB Review History*
NA.
3) Objectives*
Pain control in the modern era of pediatric cardiothoracic surgery is evolving. In the
last decade many centers have moved toward an early extubation strategy in the post-
operative period. This is in contrast to earlier eras when positive pressure ventilation
and heavy sedation were the rule. This early extubation strategy has been the clinical
practice at Advocate Children’s Hospital-Oak Lawn for years.
The best way to achieve good pain control in patients who are not intubated and heavily
sedated has not been well studied. Practice at various centers is heterogeneous. Some
use continuous infusions of sedatives and analgesics and others use bolus dosing.
The purpose of this study is to test both of these pain treatment strategies and evaluate
the amount of analgesic medication administered and pain control in the first 24 hours
of the post-operative period.
The specific aims are to:
1) Evaluate the differences between groups in the total amount of analgesic
(morphine) and sedative (midazolam) medication administered between the groups.
2) Evaluate the difference in pain scores (i.e. average and maximum pain scores)
between groups.
3) Evaluate secondary outcomes between groups including length of stay in ICU and
total hospital length of stay, mortality and re-intubation rates.
Our hypothesis is that bolus dosing of analgesics and sedatives will result in the same
amount of pain control post-operatively while reducing the total use of these
medications.
4) Background*
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 2 of 16 Use most current version on IRB website and complete all sections
Prior data on this subject has been scarce. This is due to the shift in practice to early
extubation. The PI has experience with several pain and sedation strategies. In an ICU
fellowship the PI used bolus dosing for pain control after early extubation. The PI also
volunteers for International Children's Heart Foundation where early extubation is the rule.
Pain control is augmented with early and around the clock use of acetaminophen and ibuprofen
and little opiate or midazolam use is necessary. This practice has been shown to be beneficial
in previous studies by reducing opiate use (4). Especially when the bolus only strategy is
applied in the Pediatric Surgical Heart Unit (PSHU), these adjunctive medications are used to
augment pain control.
Previous studies related to pain control after cardiothoracic surgery are sparse in
pediatrics. An anesthesia study used a continuous infusion of levobupivacaine subcutaneously
into the surgical site and showed the treatment group required less morphine and midazolam
(1). This is a useful adjunctive medication, but is difficult to institute widely because of the
technical difficulties of using continuous subcutaneous infusions.
Adjunctive medications, acetaminophen and ketorolac, are more widely available and
likely to be used by other institutions. These medications will help limit our morphine and
midazolam requirements. It has been shown previously that when used in combination with
other analgesic dugs (multi-modal analgesia) NSAIDs decreased opioid consumption by 30-
40% (13, 14, 15) and improve analgesia quality (13).
There are no existing studies directly comparing continuous infusion to bolus dosing.
Bolus dosing is the use of these medications when needed rather than constantly. By targeting
times when they will be helpful, we will be able to control pain without giving unnecessary
medication. This will be beneficial as it will limit the negative side effects experienced with
morphine and midazolam. An example of this benefit is from a study involving children
(n=50), rectal diclofenac was as effective as morphine, but caused significantly less nausea and
vomiting following squint surgery (12).
Our current approach to pain control in the PSHU is mixed. Some children after early
extubation are managed with continuous drips and bolus dosing and some are managed with
bolus dosing only. Based on our experience, pain control as evaluated with the Face, Legs,
Activity, Cry, Consolability (FLACC) scores (17), has been very good with either strategy.
Currently, most are now treated with ketorolac on the first post-operative night, but the start
time is physician dependent. Bolus dosing has required 2-4 doses which is approximately a
quarter of the total dose given over 24 hours for the continuous infusions. We used some of
our early experience and a previous study of pain control in children with Down syndrome
(DS) to derive our power estimates and to help with study design (5). Part of our design is to
randomize by Down syndrome as our experience has been that they are harder to sedate. This
was shown to be true in a retrospective review of morphine usage in children with and without
Down syndrome after cardiac surgery (16).
This study will advance current research by demonstrating that good pain control can
be achieved in a more targeted approach. Our bolus only strategy will use significantly less
morphine and midazolam which also may lead to shorter length of stay, vomiting etc.. This
will help other institutions design their pain control strategies and may lead to fewer children
on continuous infusions when not needed. Our overall goal in conducting this study is to
examine whether we can reduce opiate use in children after cardiothoracic surgery while
maintaining adequate pain control.
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 3 of 16 Use most current version on IRB website and complete all sections
5) Inclusion and Exclusion Criteria*
Patients scheduled for pediatric cardiothoracic surgery at Advocate Children’s Hospital – Oak
Lawn (ACH_OL) will be screened for eligibility.
Inclusion criteria:
Age 3 months – 4 years (48 months)
Anticipated cardiothoracic surgery with midline sternotomy incision
Planned early extubation (e.g. within 3 hours post surgery)
Planned admission to the PSHU
Exclusion Criteria: (limits on ketorolac set per prospective study of ketorolac safety (6))
Presence of renal insufficiency defined as a creatinine greater than 0.8mg/dL on the
standard basic metabolic profile sent after surgery or history of chronic renal failure.
Significant development delay that the bedside nurse or treating physician judges would
make pain scoring difficult (Down syndrome is not excluded)
History of bleeding disorder or gastrointestinal bleed within the past 2 months.
Presence of chronic hepatic disease or elevation of AST or ALT greater than 250 U/L
before or after surgery.
More than 3 previous surgeries with a sternotomy incision (this may alter pain
perception).
Children on immunosuppressents
Children whose parents have provided permission prior to surgery, will be evaluated for
randomization after surgery. Children who have any of the following exclusion criteria will not
be randomized or undergo any study procedures, and after surgery will receive conventional
care.
Platelet count less than 80,000 due to limitation on ketorolac use (6)
Admission to the PICU (due to use of different nursing staff)
Creatinine of more than 0.8mg/dL
Not extubated within three hours of arriving in the PSHU
6) Study-Wide Number of Subjects*
We will enroll 60 subjects, 30 in each pain strategy group. All patients will be enrolled from a
single site. We anticipate 15 parents may refuse and another 10 may be excluded post surgery.
Furthermore, we anticipate 20 patients will be excluded pre-surgery due to renal/hepatic
disease, thoracotomies rather than midline sternotomies or other factors based on our data from
2012. We anticipate needing to screen 105 patients to reach our goal of 60 for the study.
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 4 of 16 Use most current version on IRB website and complete all sections
7) Study-Wide Recruitment Methods*
Potential subjects will be recruited from patients scheduled for cardiothoracic surgery at
Advocate Children's Hospital-Oak Lawn. The scheduling coordinator currently sends a
letter (Attachment A) to each family and with it will be included a description of our
study (see Attachment B). The coordinator has clinical experience and sits in on our
pre-surgery planning. She will perform the initial screening based on our inclusion
criteria and will include the study description in communication with parents of
potential subjects. The family will be offered the opportunity to speak with the PI to
learn more about the study and answer any questions prior to their pre-surgery visit.
Parents will also have time to ask questions and give consent at the pre-surgery visit
where the consent/parent permission process will take place.
8) Study Timelines*
Based on the surgical volume from 2013 a total of 133 cardiovascular surgeries were
performed on children in our defined age group. Approximately 90 would have met our
inclusion criteria, therefore we anticipate subject enrollment to be accomplished 8-12
months after approval.
See below for a timeline of overall study activities:
Calendar
Year
2014 2015
Month Feb Mar Apr May Jun Aug Sept Oct Nov Dec Jan Feb Mar Apr May Jun
Advocate IRB
Review
PSHU
Training
Subject
Enrollment
Data Analysis
Dissemination
9) Study Endpoints*
The primary endpoints in this study are the total dosage of morphine and midazolam
given to patients in the PSHU after surgery over the first 24 hours.
Secondary endpoints include total and median pain scores in the first 24 hours, number
of bolus doses given of morphine and midazolam, length of stay in ICU and total
hospital length of stay, mortality and re-intubation rates.
10) Procedures Involved*
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 5 of 16 Use most current version on IRB website and complete all sections
This study will compare two different specific, comprehensive pain management strategies
using medications that have been approved for use and are currently in use for this population
of patients in the PSHU. No procedures that are outside our standard of care will be performed
as part of this study.
The specific procedures we will use during this study are as follows:
Prior to surgery, eligible patients scheduled for surgery will be sent our standard surgery letter
(Attachment A) along with our study informational sheet (Attachment B) describing our study.
The study informational sheet will have a telephone number to call to set up a phone
appointment to discuss the study with the PI should parents have questions not answered on the
sheet. During the pre-operative visit, the study will again be discussed with the parents. Our
nurse practitioners will be trained on this study and will obtain written consent at this time. If
the parents would like to further discuss the study directly with the PI, this will be arranged
prior to surgery.
The PI will be notified by the NPs of all parents who give permission for their child to
participate in the study, and he will notify the on service medical team. On the day of surgery,
a computerized order for the study will be entered to notify the pharmacy to randomize the
subject to the control or treatment group. Randomization will be stratified based on whether
the child has DS, as children with DS are known to have a heightened pain response and
require large doses of medication to treat pain. Only the pharmacist will know the random
assignment, health care providers and subjects/families will be blinded as to treatment arm.
Treatment Group:
Intravenous (IV) drip of 0.03 mg/kg/hour morphine and 0.03 mg/kg/hour midazolam
Control Group:
IV drip of normal saline (NS) at same volume as what the morphine/midazolam drip would be
Both Groups
Subjects in both the control and treatment group will receive the following post-operative pain
control orders that are currently in use in the PSHU:
1. Morphine 0.05 mg/kg/dose IV q 2 hours prn pain score 4 or greater
2. Midazolam 0.05 mg/kg/dose IV q1 hours prn agitation
3. Additional prn doses of morphine and midazolam may be given as determined by the
treating team (these doses will be recorded in the EMR)
4. Acetaminophen 30 mg/kg PR x 1 to be given on admission to PSHU post surgery
5. Acetaminophen 15 mg/kg PR q4 hours to be started 4 hours after first dose
6. Acetaminophen 15 mg/kg PO q4 hours to be started after subject starts drinking by
mouth and PR doses stopped
7. Ketorolac 0.5 mg/kg/dose IV q 6 hours to start 6-12 hours after surgery when chest tube
drainage criteria are met. Will start when chest tube drainage is no longer frankly
bloody and if chest tube drainage is less than 3 cc/kg/hour for two hours in a row
If the subject is extubated, or is extubated in the first three hours, the IV drip sent from the
pharmacy with either NS or morphine/midazolam (according to treatment arm) will be started.
Additional pain control will be provided to all subjects with scheduled acetaminophen every
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 6 of 16 Use most current version on IRB website and complete all sections
four hours (rectally or orally as tolerated). Ketorolac will be started as well in both groups no
earlier than six hours after surgery. Consistent with routine PSHU practice for this patient
population, pain scores as measured by the FLACC will be recorded by the bedside nurse
every hour and charted in the medical record. As needed, unblinded, single dose morphine will
be given for pain score of 4 or greater and unblinded, single dose midazolam, may be given for
agitation as needed. This pain regimen will continue for the first 24 hours after arrival in the
PSHU. Every medication given (acetaminophen, ketorolac, morphine and midazolam) will be
recorded in the electronic medical record as is our current practice. After 24 hours, the infusion
(morphine/midazolam or saline) will be discontinued and further pain control treatments will
be at the discretion of the attending physician. After discharge, a chart abstraction will be
performed.
Data to be recorded:
Demographics(age, gender, presence of Down syndrome, history of liver/renal
dysfunction, history of bleeding disorders or recent gastrointestinal bleeds, type of
surgery)
Laboratory values(AST/ALT, creatinine, hemoglobin level, platelet count)
Hourly FLACC pain scores
Total amount of morphine and midazolam used in 24 hours
Total amount of Phenobarbital received in 24 hours
Number of times a patient vomits
Number of 'as needed' (prn) morphine and midazolam doses in 24 hours
Length of stay in both the PSHU and the hospital
Episodes of re-intubation
Episodes of gastrointestinal bleeding (stool, from nasogastric tube or emesis, graded as
clinically significant or not using practical judgment (6)
Episodes of excessive bleeding from chest tube defined as 5cc/kg in one hour of bright
red blood
Time to first oral intake
11) Data and Specimen Banking*
NA
12) Data Management*
Sample Size Estimation
Sample size estimation was calculated using PASS 12 (9) based on the number of
subjects needed to compare the difference in total amount of morphine dosed in the 24
hour study period between treatment groups. Power analysis was run based on
published up to a 60% narcotic dose difference when acetaminophen and ketorolac are
used proactively(4) A sample size of 28 achieves 80% power to detect a dose difference
of 30% with an estimated standard deviation of 0.9 and with a significance level (alpha)
of 0.05 using a two sample t-test. We will enroll 30 subjects in each group to
accommodate for any subjects that may be withdrawn due to medical condition.
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 7 of 16 Use most current version on IRB website and complete all sections
Data Management
Dosing of medication, lab values and pain scores will be recorded in the electronic
medical record (EMR) per routine procedure in the PSHU. Investigators will extract
study data from the EMR and enter it into a REDCap password protected web-based
database. A REDCap data collection form (see Attachment C) is attached.
Analysis
Data analysis will include measures of central tendency for all demographic and
outcome variables. Number of adverse events (as determined by lab values out of
range) that occurred within each group will also be described. The primary endpoint of
total morphine dose in the first 24 hours will be compared between groups using a
Student’s t-test and a p-value less than, or equal to, 0.05 will be regarded statistically
significant.
Secondary outcomes to be compared between groups include the median and maximum
pain score recorded in the first 24 hours, PSHU length of stay, hospital length of stay
and episodes of re-intubation. Analysis will be done using ANOVA, Student’s t-test or
chi-square according to appropriate level of measurement and a p-value less than, or
equal to, 0.05 will be regarded statistically significant.
Data Storage
All information gathered during this study will be kept confidential. Subjects will be
assigned case numbers and data collection forms that including the patient name will
only be seen by the research team. These forms will be placed in a confidential folder
within the principal investigator’s locked office. Tabulation of data will be stored in a
into a REDCap password protected web-based database.. The results of this study may
be published in scientific journals or be presented at professional meetings, but no
individuals will be identified. The collection and handling of data will be in complete
accordance with the HIPPA regulations. The research-related records for this study may
be inspected by a federal regulatory agency and the Institutional Review Board.
13) Provisions to Monitor the Data to Ensure the Safety of Subjects*
MONITORING PLAN
The individuals responsible for data safety and monitoring will be Dr. Penk (PI) and
Kim Wittmayer (Pediatric Pain APN). Quality control will include regular data
verification and protocol compliance checks by Dr. Penk.
COLLECTION AND REPORTING OF SAEs AND AEs
Throughout the study, Dr. Penk will monitor study participants for adverse events. Dr.
Penk will review all adverse events (AEs) and serious adverse events (SAEs)
individually and in aggregate on a biweekly basis. Dr. Penk will report all AEs and
SAEs to the Advocate Health Care IRB according to the AE reporting guidelines.
Events determined by the PI to involve injury or to be unanticipated problems involving
risks will be reported by the PI to the IRB within 24 hours per policy. Adverse events
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 8 of 16 Use most current version on IRB website and complete all sections
that are determined by the PI not to involve injury or not to be unanticipated problems
involving risks will be reported per IRB policy at the time of continuing review.
For this study, the following standard AE definitions will be used:
Adverse event: Any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom or disease, that did not exist at the time of the subject’s
entry into the study and that is temporally associated with the use of the study
medication, regardless of whether it is considered related to the study medication.
Serious Adverse Event: A significant hazard or side effect, regardless of the
Investigator’s opinion on the relationship to treatment group. A serious adverse event
is any untoward medical occurrence that at any dose:
• Results in death
• Is life-threatening (defined in this case as an event in which the subject
was at risk of death at the time of the event/reaction; it does not refer to an
event/reaction which hypothetically might have caused death if it were
more severe)
• Requiring prolongation of existing hospitalization
• Results in persistent or significant disability/incapacity
• Is a medically important event or reaction
AEs will be graded by the investigator according to the following scale:
Mild: An event that is easily tolerated by the subject, causing minimal
discomfort and not interfering with everyday activities. This includes transient
laboratory test alterations.
Moderate: An event that is sufficiently discomforting to interfere with normal
everyday activities. This includes laboratory test alterations indicating injury,
but without long-term risk.
Severe: An event that prevents normal everyday activities. If prolongation of
hospitalization is required for treatment it becomes an SAE. (An AE that is
severe should not be confused with a SAE. Severity is a category utilized for
rating the intensity of an event; and both AEs and SAEs can be assessed as
mild, moderate or severe.)
However, relating the intensity of clinical AEs to functional daily life and everyday
activities may not be assessable in children in the PSHU. Therefore, if not possible to
assess, the intensity of clinical AEs will be assessed by the investigator as per his/her
best judgment.
The study will use the following AE attribution scale:
Unrelated: The AE is clearly related to other factors such as the subject’s
clinical state, therapeutic interventions, or concomitant drugs administered to
the subject (i.e., another cause of the event is most plausible and/or a clinically
plausible temporal sequence is inconsistent with the onset of the event).
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 9 of 16 Use most current version on IRB website and complete all sections
Not likely related: The event was most likely produced by other factors such
as the subject’s clinical state, therapeutic interventions or concomitant drugs
administered to the subject, and does not follow a known response pattern to the
study drug.
Possibly related: The event follows a reasonable temporal sequence from the
time of drug administration and/or follows a known response pattern to the
study drug; but it could have been produced by other factors such as the
subject’s clinical state, therapeutic interventions, or concomitant drugs
administered to the subject.
Probably related: The event follows a reasonable temporal sequence from the
time of drug administration and follows a known response pattern to the study
drug; and it cannot be reasonably explained by other factors such as the
subject’s clinical state, therapeutic interventions, or concomitant drugs
administered to the subject.
AEs will be monitored throughout the time that a subject is in the trial (24 hours). AEs
and SAEs still ongoing after study drug discontinuation will be followed until 30 days
after study drug discontinuation or until resolution or stabilization or until the event is
otherwise explained. AEs will be assessed through a review of the hospital chart on a
weekly basis and with a physical examination of the subject, if indicated. SAEs will be
reported to the AHC IRB within 24 hours of the investigator’s awareness of the SAE.
DATA ANALYSIS PLANS AND INTERRIM REPORTS
An independent Data Safety Monitoring Board (DSMB) will perform a statistical
review of the study data and will have access to fully unblinded* patient data if
necessary, to ensure patient safety. The DSMB will be empowered to recommend,
based on safety considerations, modifications to the protocol or early termination of the
study. The board will function independently of the investigators. AEs and SAEs (i.e.
presence of gastrointestinal bleed, excessive chest tube bleeding, renal injury, liver
function as measured by AST/ALT) will be monitored by the DSMB in an unblinded*
manner during the study at the following time points:
• after half of the subjects (N=30, 15 in each group) are enrolled
*The randomization code will be kept strictly confidential. It will be provided to the
DSMB by the research pharmacist (Chris Steffensen, PharmD) to ensure patient safety.
Interim analyses will be performed to evaluate differences in AE and SAE rates
between the two treatment groups, and to evaluate the primary endpoint (total dose of
morphine and midazolam). The DSMB will prepare a report after each review which
will be given to the PI, and, in turn, this report will be submitted by Dr. Penk to the
IRB.
The DSMB will be comprised of the following individuals:
Denise Angst, PhD, RN – Chair of DSMB, Director, Advocate Center for
Pediatric Research
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 10 of 16 Use most current version on IRB website and complete all sections
Jackie Kessler, MS, FASHP – Clinical Pharmacist, Investigational Drug
Services, Advocate Lutheran General Hospital
Luis E. Torero, MD – Pediatric Pulmonologist, Torero Pulmonary Specialists,
S.C.
14) Withdrawal of Subjects*
At any time, the attending physician can withdraw a patient from this study if they feel
pain control is not adequate. If, for any other reason, including suspected complication,
the attending would like to withdraw the patient so as to ascertain which medications
are being given or to change medication class, they may do so. Parents will be notified
by the attending physician. The new plan for pain management will be discussed at
that time.
AFTER the decision is made to withdraw, the attending may ask the pharmacy to
disclose which study arm the patient is in and may then switch medications as
necessary. The attending physician is responsible for notifying the PI why the patient
was withdrawn. Data collection will continue to discharge.
Subjects will be withdrawn from the study if lab values or bleeding lead to
discontinuation of ketorolac. Subjects to be withdrawn for doubling of creatinine value
compared to immediate post-operative AND it is over 1 mg/dL. Frankly bloody chest
tube drainage or drainage not less than 3 cc/kg/hour for two consecutive hours 12 hours
post surgery. This bleeding criteria means that if we cannot start the ketorolac 12 hours
post operatively, the patient will be withdrawn as they are not receiving the same pain
control as other subjects. Additionally, if a patient has 5cc/kg over an hour of bright
red blood from the chest tube after initiation of ketorolac, this is considered significant
bleeding and the subject will be withdrawn. Platelet count less than 80,000 on post-
operative day one would lead to discontinuation of ketorolac so those subjects will be
withdrawn. Finally, a significant GI bleed will also lead to withdrawal from the study.
Due to use of around the clock acetaminophen, we will also withdraw subjects with
doubling of AST or ALT between post-operative values and post-operative day one
values if the absolute value is over 300 U/L.
15) Risks to Subjects*
There are minimal risks to the study subjects related to pain management because subjects will
receive adequate pain management in both study groups. Both strategies outlined in this study
have been used in clinical practice and study participants are not at increased risk compared to
other patients undergoing the clinical procedure and not in this study.
A safety and monitoring plan is being proposed as described in section 13 of this protocol.
Ketorolac and acetaminophen have been previously studied and shown to be safe. We would
like to add to that literature again documenting the safety of these medications. Adverse events
related to the use of ketorolac may include risk of bleeding, thus we will monitor the presence of
gastrointestinal bleeds and for excessive chest tube bleeding. We will also evaluate for renal
injury defined as creatinine twice the immediate post-operative value (7). Previous studies done
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 11 of 16 Use most current version on IRB website and complete all sections
on our specific population as young as 3 months have shown no increase in bleeding, chest tube
drainage or incidence of renal injury with the use of these medications (6,7). Finally, as we are
using acetaminophen around the clock we will evaluate for a two fold increase in AST/ALT on
post-operative day 2 over post-operative day 1. A previous study of acetaminophen dose of 30
mg/kg did not find any increase in adverse events (8).
16) Potential Benefits to Subjects*
There are no guaranteed benefits to subjects given that all medications proposed in this study
are currently in use. The results of this study will be used to guide clinical management of pain
and provide support for a single pain management strategy for this population. Future benefits
are possible as many of our patients require multiple surgeries and data from this study may
improve our pain control regimen.
17) Vulnerable Populations*
This research involves children as a vulnerable population (see Attachment D, Checklist HRP-
416). Informed consent/parental permission will be assured by offering parents multiple
opportunities to ask and have their questions answered about the study before enrollment and
throughout the study time period. Informed consent/parental permission documentation will be
completed as discussed in protocol section 29. Subjects will be too young to provide assent as
they will all be under 4 years of age. Our study does not exceed minimal risk as the treatment in
both arms of our study have been used for clinical management. There is no guarantee that
individual subjects will benefit from participating in this study but this research will enhance our
understanding of the effectiveness of these two pain control strategies and may benefit future
patients. This research presents a reasonable opportunity to determine a method of providing
good pain control while limiting the untoward effects of opioid and sedative medications.
18) Multi-Site Research*
NA
19) Community-Based Participatory Research*
NA
20) Sharing of Results with Subjects*
The results of some study outcomes including pain medication boluses, pain scores and lab
values may be shared with the family by the physician involved in the care. No further sharing of
group assignment or data will be provided.
21) Setting
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 12 of 16 Use most current version on IRB website and complete all sections
This study will be conducted at Advocate Children's Hospital-Oak Lawn will be the
only site. Recruitment performed in the Heart Institute for Children. Study performed
in the Pediatric Surgical Heart Unit.
22) Resources Available
Dr. Penk, the PI has extensive experience in pain control related and unrelated to
cardiothoracic surgery. Significant experience includes 1.5 years as a pediatric
hospitalist covering the emergency room, PICU and NICU. Sedation service was also
covered for one week per month with a wide variety of sedation techniques employed.
Pain control post cardiothoracic surgery specifically was observed and performed as a
cardiology fellow at Lurie Children's Hospital. He also provided continued sedation,
pain management and airway management in general ICU patients and in the
cardiothoracic ICU at Children's National Medical Center as a critical care fellow.
Finally, the PI has worked with International Children's Heart Foundation with a total
of 3 months spent on volunteer missions using pain control strategies described above.
PI also has experience in carrying out and designing scientific studies. Publications
include reference 2 and 3 with a third study regarding unplanned admissions to the
cardiothoracic ICU submitted for publication.
Kim Wittmayer, is an advance practice nurse (APN), board certified as a pediatric
clinical nurse specialist, who is also certified in pain management. She started the
pediatric pain service program 5 years ago at Advocate Children’s Hospital-Oak Lawn
and works primarily with patients experiencing acute pain. Prior to working with the
pain service, she was a staff nurse within the pediatric intensive care unit (PICU) for
four years and participated in several research studies. She served as the site nurse co-
investigator for the NIH-funded RESTORE study, which examined the effects of a
nurse driven pain and sedation protocol in the mechanically ventilated child, as well as
the site PI for BALI (an ancillary study to RESTORE looking at genetic variation and
Biomarkers in Children with Acute Lung Injury) (10). In 2012, The American Society
for Pain Management Nursing presented her with the Nurse Exemplar Award for the
Pediatric Patient. Publications include the topics related to nonmedical use and abuse of
prescription opioids in older children, as well as pediatric pain quality improvement
(11).
Pharmacy staff will be available to the study team for randomization. They will also
prepare the normal saline or morphine/midazolam drips and deliver them to the PSHU
so as to keep the PSHU staff blinded to the contents.
Additionally, Cheryl Lefaiver, PhD, RN, CCRP, Manager, Pediatric Research Support
& Analytics as part of the Advocate Center for Pediatric Research will be a collaborator
on this project and will assist with data management and statistical analysis.
Feasibility of patient recruitment has been derived from previous years surgical
volume. In 2012, 115 patients were eligible for enrollment in this study. Some of those
may have been excluded according to post-surgery exclusion criteria (late extubation,
low platelet count, bleeding etc..) but that is rare. We anticipate if only 60% of the
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 13 of 16 Use most current version on IRB website and complete all sections
remaining patients consent, our target numbers can be met in one year. We anticipate a
much higher consent rate and that the study can be completed much earlier.
All investigators, pediatric cardiovascular surgeons and clinicians in the Pediatric
Surgical Heart Unit (PSHU) in the study have been informed about the purpose and
specifics of the study. Nurses in the PSHU will be trained on the specific medication
administration for the study protocol. In addition, re-training will be provided to nurses
on the use of the FLACC (pain scoring instrument) to ensure internal consistency of the
pain scores.
23) Prior Approvals
NA
Recruitment Methods
See protocol section 7 above.
24) Local Number of Subjects
See protocol section 6 above.
25) Confidentiality
All information gathered during this study will be kept confidential. Data collection forms and
the database that include the patient name and other PHI will be seen only by the principal
investigator and research team. All information and data gathered in this study will be placed in a
password protected computer with restricted access by only the investigative team. The results of
this study may be published in scientific journals or be presented at professional meetings, but no
individuals will be identified. The research-related records for this study may be inspected by a
federal regulatory agency and the Institutional Review Board.
Data will be stored on Advocate’s secure computer network which will only be accessible by the
study investigators.
26) Provisions to Protect the Privacy Interests of Subjects
Study participants data will be collected via the electronic medical record. This data will be
stored it into a REDCap password protected web-based database.. Only the PI and co-
investigators will have access to the data.
27) Compensation for Research-Related InjuryThe procedures used in the two study arms are currently in use for clinical care. Appropriate
medical care will be provided for any adverse event. Adverse events are not anticipated and there
is no compensation available for research-related injury.
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 14 of 16 Use most current version on IRB website and complete all sections
28) Economic Burden to Subjects
None. Participants will not be billed for either NS or morphine/midazolam drips. The pharmacy
will absorb the cost of the drips being used in this study.
29) Consent Process
Consent from parents will be obtained prior to enrollment.
Where will the consent process take place
-The consent/parental permission process will take place at the pre-screening
visit at the Heart Institute for Children. Our nurse practitioners, Carrie Miller or
Jane Flanagan, will obtain consent/parental permission for this study. The PI may
also obtain consent.
Any waiting period available between informing the prospective subject and
obtaining the consent.
-After scheduling the surgery, a packet of information that includes a
description of the study will be sent to parents. A phone conversation will be
scheduled prior to the pre-operative visit. Final questions will be answered at the
pre-operative visit itself and there is again opportunity for questions on the day of
surgery.
We will follow HRP-090 to obtain informed consent/parental permission.
Non-English Speaking Subjects
During the pre-operative visit a translator or translating service will be provided
per our usual practice.
Waiver or Alteration of Consent Process (consent will not be obtained, required
information will not be disclosed, or the research involves deception)
NA
Subjects who are not yet adults (infants, children, teenagers)
All of our patients will be under four years of age, thus are considered children and
due to age will be too young to give assent.
Consent/parental permission will be obtained from one parent before any study
procedures are performed.
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 15 of 16 Use most current version on IRB website and complete all sections
30) Process to Document Consent in Writing
We will be following HRP-091. See Attachment E – informed consent/parental
permission form. See Attachment F for HIPPA form.
31) Drugs or Devices
All of the drugs being used in this study are approved for use in this study population
by the pharmacy. All except ketorolac are approved by the FDA. However, ketorolac is
widely used in this population with safety data included in the background above. An
IND for ketorolac has been submitted to the FDA for this study. Medications will be
stored and distributed by the Children’s Hospital pharmacy.
References:
1.Tirotta CF, Munro HM, Salvaggio J, et al. Continuous incisional infusion of local anesthetic
in pediatric patients following open heart surgery. Paediatr Anaesth, 2009 Jun;19(6):571-6
2. Penk J, Webb C, Shulman S, Anderson E. Echocardiography in Infective Endocarditis. Pediatric
Infectious Disease Journal 2012 January
3. Jamie Penk, Angira Patel, Amy Lay, Catherine Webb. Longitudinal Strain and Strain Rate in
Patients With Hemodynamically Significant Ventricular Septal Defects.
World Journal for Pediatric and Congenital Heart Surgery. Accepted, pending publication.
4. Hong JY. Fentanyl sparing effects of combined ketorolac and acetaminophen for outpatient inguinal
hernia repair in children. J Urol. 2010 Apr;183(4):1551-5
5. Van Driest SL. Opioid use after cardiac surgery in children with Down syndrome. Pediatr Crit
Care Med. 2013 Nov;14(9):862-8
6. Gupta A. Prospective Randomized Trial of Ketorolac After Congenital Heart Surgery. Journal of
Cariothoracic and Vascular Anesthesia. 2004 August;18 (4):454-457
7. Dawkins T. Saftey of intravenous use of ketorolac in infants following cardiothoracic surgery.
Cardiol Young. 2009;19:105-108
8. Treluyer J. Antipyretic Efficacy of an Initial 30 mg/kg Loading Dose of Acetaminophen Versus a
15 mg/kg maintenance dose. Pediatrics. 2001;108:73
9. Hintze, J. (2013). PASS 12. NCSS, LLC. Kaysville, Utah, USA. www.ncss.com.
Example
PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric
cardiothoracic surgery Ver1_9.16.14
HRP-503 Template Protocol
Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR Page 16 of 16 Use most current version on IRB website and complete all sections
10. Frese, W. A., & Eiden, K. (2011). Prescription opioids: Nonmedical use and abuse in older
children. Pediatrics in Review, 32(4), e44-52.
11. Kimberly Eiden, MS, APRN, PCNS-BC. Improving pain assessment and management on pediatric
medical-surgical units. (p. 93-97). In Duncan, J., Montalvo, I., & Dunton, N., NDNQI Case Studies in
Nursing Quality Improvement. (2011). Nursesbooks.org
12. Wernnstrom, B and Reinsfelt, B. (2002). Rectally administered diclofenac (voltaren) reduces
vomiting compared with opioid (morphine) after strabismus surgery in children, Acta
Anaesthesiologica Scandanavica, 46 (4): 430-434.
13. Morton, N.S. and O'Brien, K. (1999). Analgesic efficacy of paracetamol and diclofenac in children
receiving PCA morphine, British Journal of Anaesthesia, 82: 715-717
14. Pickering, A.E., Bridge, H.S., Nolan, J. and Stoddart, P.A. (2002). Double-blinded placebo-controlled analgesic study of ibuprofen or rofecoxib in combination with paracetamol fortonsillectomy in children, British Journal of Anaesthesia. 88(1): 72-77
15. Vittanen, H., Tuominen, N., Vaaraniemi, H., Nikanne, E. and Annila, P. (2003). Analgesic effacy
of rectal acetaminophen and ibuprofen alone or in combination for paediatric day-case adenoidectomy,
British Journal of Anaesthesia, 91: 363-367.
16. Gakhal B1, Scott CS, MacNab AJ. Comparison of morphine requirements for sedation in Down's
syndrome and non-Down's patients following paediatric cardiac surgery. Paediatr
Anaesth.1998;8(3):229-33.
17. Merkel SI1, Voepel-Lewis T, Shayevitz JR, Malviya S.. The FLACC: a behavioral scale for
scoring postoperative pain in young children. Pediatr Nurs 1997 May-Jun;23(3):293-7.
ATTACHMENTS
Attachment A = Standard surgery letter
Attachment B = Study information sheet
Attachment C = Data collection form
Attachment D = Checklist HRP-416
Attachment E = Informed consent/Parental Permission document
Attachment F = HIPPA document
Example