Appendix This appendix was part of the submitted ...

1

SupplementarymaterialLegends:

SupplementaryTable1.PRISMA-Protocol(PreferredReportingItemsforSystematicreviewandMeta-AnalysisProtocols)2015checklist(Pages2-4)

SupplementaryFigure1:Riskofbiassummary:reviewauthors'judgementsabouteachriskofbiasitemforeachincludedstudy.(Page-5)

SupplementaryFigure2:Riskofbiasgraph:reviewauthors'judgementsabouteachriskofbiasitempresentedaspercentagesacrossallincludedstudies.(Page5)

SupplementaryFigure3:ForestPlotofriskratiosofmortalityinthehypothermiatreatmentgroupversusnormothermiagroupforadultstudies(NT=Normothermia,HT=Hypothermia).(Page6)

SupplementaryTable2.SearchtermsbasedonPICOstructure.(Page7)

SupplementaryTable3.Summaryofstudiesthatevaluatedeffectoftherapeutichypothermiaontraumaticbraininjury.(Pages8-11)

SupplementaryTable4.Summaryofstudiesthatevaluatedeffectoftherapeutichypothermiaonpatientswithstroke.(Pages12-13)

SupplementaryTable5.Summaryofstudiesthatevaluatedeffectoftherapeutichypothermiaonpatientswithout-of-hospitalcardiacarrest.(Pages14-15)

SupplementaryTable6.SummaryofstudiesthatevaluatedeffectoftherapeutichypothermiaonpatientswhounderwentCABG.(Pages16-19)

SupplementaryTable7.Summaryofstudiesthatevaluatedeffectoftherapeutichypothermiaonpatientswithotherformsofcriticalcareillnesses.(Pages20-23)

SupplementaryTable8.Summaryofbaselinecharacteristicsofallstudiesincludedinthismeta-analysis.(Pages24-26)

SupplementaryTable9.Riskofbiassummary.(Page27)

SupplementaryFigure4(A-E)Funnelplotstoinvestigateevidenceofpublicationbiasforeachsubgroup:Traumaticbraininjury(A),Stroke(B),Outofhospitalcardiacarrest(C),intra-operativecardiacpulmonarybypass(D)andothers(E).Intheabsenceofpublicationbias,thepatternofpointsshouldresembleaninvertedfunnel (Pages28-30)

PRISMAChecklist(Pages31-32)

AppendixThis appendix was part of the submitted manuscript and has been peer reviewed. It is posted as supplied by the authors.

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Section and topic Item No

Checklist item

ADMINISTRATIVE INFORMATION Title:

Identification 1a Therapeutic Hypothermia and Mortality in the Intensive Care unit: Systematic review and Meta-analysis Update 1b This protocol is not for an update of a previous systematic review.

Registration 2 Not registered Authors:

Contact 3a Shehabaldin Alqalyoobi, MD1 ([email protected]) Noelle Boctor, MD2 ([email protected]) Amir A. Sarkeshik, DO3 ([email protected]) Joshua Hoerger, MD2 ([email protected]) Nicholas Klimberg, MD2 ([email protected]) Brittany G. Bartolome, MD2 ([email protected]) Susan L. Stewart, PhD4 ([email protected]@ucdavis.edu) Timothy E. Albertson, MD, MPH, PhD5,6 ([email protected]) 1 Pulmonary, Critical Care and Sleep Medicine Division, East Carolina University, Greenville, NC, United States 2 Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, United States 3 Division of Cardiothoracic Surgery, University of California Davis Medical Center, Sacramento, CA, United States 4 Division of Biostatistics, University of California Davis School of Medicine, Sacramento, CA, United States 5 Veteran Affairs Northern California Healthcare System, Mather, CA, United States 6 Pulmonary, Critical Care and Sleep Medicine Division, University of California Davis Medical Center, Sacramento, CA, United States

Contributions 3b Clinical data acquisition (Data extraction and bias assessment): SA, AS, NB, JH, NK, BB, TA. Study design: SA, AA, SS, TA. Data analysis: SA, SS, TA. Interpretation of results: SA, AS, NB, JH, NK, BB, SS, TA. Manuscript preparation and review: SA, SS, TA. All authors reviewed, revised, and approved the manuscript for submission.

Amendments 4 This protocol does not represent an amendment of a previously completed or published protocol. Support:

Sources 5a No sources of financial or other support for the review Sponsor 5b No review funder and/or sponsor Role of sponsor or funder 5c Not applicable

INTRODUCTION Rationale 6 Therapeutic Hypothermia (TH) is defined as the designed reduction of the human body's core temperature to 32°C–35°C for the duration of 24-48

hours. TH has been studied extensively in many diseases related to critical care illness in the past decades with controversial results when it comes to mortality as an outcome. In this meta-analysis, the effect of TH on mortality across different indications in medical, neurological and cardiothoracic care is assessed.

Objectives 7 Whether Therapeutic Hypothermia (TH) is superior to conventional Normothermia in patients with different critical care illnesses. Patients population: Patients with acute stroke, out of hospital cardiac arrest, traumatic brain injury, coronary artery bypass surgery and other critical care diseases. Intervention: Therapeutic Hypothermia defined as: the designed reduction of the human body's core temperature to < 37°C duration of 24-72 hours. Comperator: Normothermia convention therapy. Outcome: All-cause mortality

3

METHODS Eligibility criteria 8 Only published randomized controlled trials (Trials) between January, 1940 to October, 2018, in English or foreign language with translation were

included in this study. Studies that had the following PICO question: 1- Patients population: Patients with acute stroke, out of hospital cardiac arrest, traumatic brain injury, coronary artery bypass surgery and other

critical care diseases. 2- Intervention: Therapeutic Hypothermia defined as: the designed reduction of the human body's core temperature to < 37°C duration of 24-72

hours in ICU setting. 3- Comparator: Normothermia convention therapy. 4- Outcome: All-cause mortality.

Information sources 9 Data will be collected from electronic databases Search strategy 10

Study records:

Data management 11a Data will be managed using the following software: Endnote X8, Microsoft Excel and Review Manager 5.3 Selection process 11b Screening process: two independent reviewers.

Eligibility and Inclusion in meta-analysis process: two independent reviewers. Data collection process 11c Data extraction: two independent reviewers.

Data confirmation: performed by a third different independent author, not involved in the data extraction. Data items 12 1- Patients population: Patients with acute stroke, out of hospital cardiac arrest, traumatic brain injury, coronary artery bypass surgery and other

critical care diseases. 2- Intervention: Therapeutic Hypothermia defined as: the designed reduction of the human body's core temperature to < 37°C duration of 24-72

hours in ICU setting. 3- Comparator: Normothermia convention therapy. 4- Outcome: All-cause mortality.

Other items collected: Male percentage, age mean, patient size for each study, method of cooling, methods of cooling, neuroprotection if mentioned in the study, mean temperature achieved in normothermia and conventional hypothermia group.

Outcomes and prioritization 13 All-cause mortality Risk of bias in individual studies 14 Cochrane Collaboration's Risk of Bias tool will be used. Two independent authors assessed the risk of bias for each study and discrepancies will be

resolved by consensus between both authors. Data synthesis 15a If studies are sufficiently homogeneous in terms of design and comparator, we will conduct meta-analyses using a random-effects model

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e-Table1.PRISMA-Protocol(PreferredReportingItemsforSystematicreviewandMeta-AnalysisProtocols)2015checklist

15b Forall-causemortality, we will calculate pooled risk ratios (RRs) were calculated with 95% CIs by the random effect model for analyses Statistical heterogeneity will be tested using the Chi2 test (significance level: 0.1) and I2 statistic (0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity). If high levels of heterogeneity among the trials exist (I2 >=50% or P <0.1) the study design and characteristics in the included studies will be analysed.

15c Meta-regression was performed to adjust for possible confounders. 15d A systematic narrative synthesis will be provided with information presented in tables to summarize and explain the characteristics and findings of

the included studies Meta-bias(es) 16 In order to determine whether publication bias is present, we will use Funnel plot for evaluation Confidence in cumulative evidence

17 We didn’t evaluate the strength of the body of evidence using any tool(such as GRADE)

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SupplementaryFigure1:Riskofbiassummary:reviewauthors'judgementsabouteachriskofbiasitemforeachincludedstudy

SupplementaryFigure2:Riskofbiasgraph:reviewauthors'judgementsabouteachriskofbiasitempresentedaspercentagesacrossallincludedstudies.

6

SupplementaryFigure3:ForestPlotofriskratiosofmortalityinthehypothermiatreatmentgroupversusnormothermiagroupforadultstudies(NT=Normothermia,HT=Hypothermia)

7

Database Population Search term

Intervention search term

Comparator search term

Outcome search term

Embase Adult or aged AND humans

Induced Hypothermia

No specific comparator was

used.

Specific outcomes are not specified in the search strategy

to avoid missing any related outcomes

listed in the articles

Ovid MEDLINE All adult (19 plus years) AMD humans

Induced Hypothermia or

Therapeutic hypothermia

CINAHL humans AND adult

(MH "Hypothermia, Induced")

TRIP

Adult induced

hypothermia

e-Table2.SearchtermsbasedonPICOstructu

8

Study Inclusion Criteria Exclusion Criteria Intervention Outcome: Mortality Outcome: Neuroprotective Outcome: Comments Follow up Normothermia Hypothermia Normothermia Hypothermia

Aibiki 2000 GCS less than or equal to 8, evidence of injury on CT

Patients with abdominal or chest trauma, patients with severe pulmonary infection, admitted in hospital more than 8 hours after injury

hypothermia induced (32-33C)within 3-4 hours of injury with surface cooling after midazolam, vecuronium and buprenorphine

3/11 (27.%) 1/15 (6.7%) 3/11 (27.%) 8/15 (53.3%) Favourable out come was considered as Good Recovery per GOS

6 months

Andrews 2015

Patient that meets the following criteria Age legal for consent, primary/closed TBI, ICP>20mmgHg for at least 5 minutes after stage 1 treatements without obvious reversible cause, initial head injury no more than 10 days prior, availablility of cooling device for more than 48 hours, core temp at least 36C, abnormal CT head

Patients already receiving therapeutic hypothermia or unlikely to survive for next 24 hours, getting barbiturate infusion before randomization, temp of 34C or less on admission, prenancy

hypothermia induced by bolus of IV, refrigerated 0.9% NS (20-30ml/kg), core temp reduced by minimum required to maintain ICP of 20mmHg or less for limits 32-35C, stage 2 treatments (mannitol, hypertonic saline, inotropes) added if hypothermia failed, stage 3 added (barbiturate, compressive craniectomy) if stage 2 failed

51/192 (26.6%) 68/195 (34.9%)

69/192 (36.5%) 49/195 (25.7%)

Favorable outcome is defined Glasgow Outcome Scale – Extended (GOS-E score 5-8)

6 months

Clifton 1993

Patients ages 16 to 60 years with post-resuscitation GCS of 4 to 7 after non-penetrating brain injury

Any of the following: Hypoxia (02 saturation < 94% for > 30 min), Major systemic injuries requiring laparotomy, pulmonary failure, or sustained hypotension (systolic blood pressure =s 90 mmHg for > 2 h)

Surface Cooling: Started within 6 h of injury by use of cooling blankets. Rewarming was at a rate of 1°C per 4 h beginning 48 h after intravascular temperature had reached 33°C. Metocurine and morphine were given hourly during induction and maintenance of hypothermia. Muscle relaxants and sedation were continued until core temperature reached 35°C.

8/22 (36.4%) 8/23 (35%) 8/22 (36.4%) 12/23 (52.2 %)

Favourable out come was considered as Good Recovery/Moderate Disability per GOS

3 months

Clifton 2001

Patient wit age of 16 to 65 years, a nonpenetrating head injury, and a score on the Glasgow Coma Scale of 3 to 8 after resuscitation. A score on the Glasgow Coma Scale of 15 signifies normal mental status, and a score of 8 or less signifies coma. A score of 5 to 8 denotes flexor withdrawal or pur- poseful response to pain, 4 denotes extensor posturing, and 3 denotes no motor response

Excluded if they had a score of 3 with unreactive pupils, a life-threatening injury to an organ other than the brain, a systolic blood pressure of less than 90 mm Hg after resuscitation, oxygen saturation of less than 94 percent after resuscitation, bleeding, pregnancy, or known preexisting medical conditions (e.g., severe heart disease) or if the examiners were unable to initiate cooling within six hours after injury.

Surface cooling with target themperature of 33 within 6 hours for 48 hours

48/178 (27%) 53/190 (28%) 76/178 (43%) 82/190 (43%)


6 months

Clifton 2011

Inclusion criteria were age 16–45 years, non-penetrating brain injury, and not responsive to instructions.

2 sets of exclusion, initially, patients were excluded if they had suspected pregnancy, systolic blood pressure less than 110 mm Hg, diastolic blood pressure less than 60 mm Hg, sustained heart rate greater than 120 beats per minute, or if they could not be reached by study-affiliated personnel within 2·5 h of injury. Second set: patients

Surface cooling with target temperature of 33 for 48 hours. Hypothermia initiated in after 1.6 hrs (Mean).

8/45 (18%) 12/52 (23.1%) 20/45 (44%) had a poor

211/52 (40%)


6 months

9

with Glasgow coma scale score of 3 with nonreactive pupils, Glasgow coma scale score of 7–8 with normal brain CT scan, inability to measure an accurate Glasgow coma scale score, abbreviated injury severity score of 4 or greater for organs other than the brain, systolic blood pressure less than 110 mm Hg, diastolic blood pressure less than 60 mm Hg, persistent hypoxia

Cooper 2018

Patients with head injuries were estimated to be aged 18 to 60 years, had a Glasgow Coma Scale score of less than 9, and had actual or imminent endotracheal intubation

Patients with significant bleeding suggested by systolic hypotension (<90 mm Hg) or sustained tachycardia (>120/min), suspected pregnancy, possible uncontrolled bleeding, Glasgow Coma Scale score of 3 and unreactive pupils, or destination hospital not a study site.

Hypothermi induction with bolus of up to 2000 mL intravenous ice-cold, then maintaining the temperature with Gaymar Meditherm 3 console with surface-cooling wraps for at least 72

44/239 (18.4%) 54/256 (21.1%)

111/226 (49.1%) 117/240 (48.8%)

Favorable outcome is defined Glasgow Outcome Scale – Extended (GOS-E score 5-8)

6 months

Gal 2002

Paients with severe head injuries with Glasgow Coma Scale (GCS) score of 3-8 were enrolled into the study.

Unclear: Everyone who does not meet the inclusion criteria.

Surface cooling with target temperature of 34 within 15 hours for 72 hours.

5/15 (33%) 2/15 (13%) 7/15 (47%) 13/15 (87%)


6 months

Harris 2009

GCS less than or equal to 8, treated for severe TBI, 18 yo, patient ablet o receive hypothermia cooling cap within 48 hours of admission, patient family spoke Enlish, informed consent obtained

patient family unwilling/unable to sign consent, physical placement of cooling cap impeded, patient's core body temp less than or equal to 36C at initial assessment, unable to initial treatment within 48 hours

Cooling cap: compression settin gof 15mmHg, goal intracranial temp 33C for 24 hours

4/13(30.8%) 6/12 (50%) 0/13 (0%) 0/12 (0%)


28 days

Hashiguchi 2003

Patients with Glasgow Coma Scale score for each patient at admission was 8 or less in whom ICP was maintained below 20 mm Hg by conventional therapy

Patients younger than 10 years of age were excluded from the study or in whom ICP was not maintained below 20 mm Hg by conventional therapy

Surface cooling with target temperature of 34 for 48 hours. Unclear the time of cooling initiation.

0/8 (0%) 1/9 (11%) 5/9 (55.6%) 5/9 (55.6%)

Favourable out come was considered as Good Recovery category per GOS

6 months

Jiang 2000 Patients with severe TBI (GCS27 score less than or equal to 8)


Surface cooling for 3-14 days, with target temperature of 33-35. Hypothermia initiation was within 15 hrs (mean)

20/44 (45.45%) 11/43 (25.58%)

12/44 (27.27%) 20 /43 (46.51%)


12 months

Lee 2010

Patients with a history of TBI; Glasgow Coma Scale (GCS) scores of 4–8; and brain damage confirmed by sequential computed tomography (CT) scanning within 6 hours after trauma.

Patients who are pregnant women; patients younger than age 12 years or older than age 70 years; a GCS score of 3; multiply injured patients; and those with any previous disabling neurologic disease.

Surface cooling with target temperature of 33-35. Unclear procedural duration. Unclear time for the initiation.

2/16 (12.5%) 1/15(6.7%) 8/16 (50%) 9/15 (60%)


6 months

Liu 2006

history of TBI, Glasgow Coma Scale score ≤ 8 at admission, and brain injury apparent on sequential computed tomography within 1 – 24 h (mean 8.6 h) of admission.


Surface cooling with target temperature of 33-35 for 72 hours. Hypothermia started after 8.6 hours (mean)

12/23 (52.2%) 6/21 (28.6%) 6/23 (26.1%) 11/21 (52.4%) Favourable out come was considered as Good Recovery per GOS

24 months

10

Maekawa 2015

Age 15–69 years for both sexes, GCS score of 4–8, and ability to initiate cooling within 2 h after the onset of TBI.

Any of the following were excluded: good motor response (GCS motor response = 6), systolic blood pressure < 90 mm Hg after fluid and vasopressor resuscitation, platelet count < 50,000 /mm3, severe pre-existing medical conditions (e.g., liver, kidney, or heart failure, or severe arrhythmia), acute myocardial infarction, pregnancy, severe alcohol intoxication that prevented assessment of consciousness, penetrating brain injury, epidural hematoma without brain parenchymal injury, or core body temperature <30°C.

Surface Cooling and Endovascular cooling: Cooling blankets, rapid cold fluid infusion (up to 1000 mL saline, human plasma products, or dextrose-free plasma expanders), and/or cold gastric lavage were used to achieve a tartget temperature of within 6 hours for ≥72 hours

11/48 (23%) 33/94(35%) 25/48 (52%) 44/94(47%)


6 months

Marion 1993

Patients were included in the study if they were between 16 and 75 years of age and had a closed head injury and a Glasgow Coma Scale (GCS)score of 3 to 7 upon admission to the emergency department.

Patients were excluded if there were normal findings on computerized tomography (CT) of the head, prolonged hypotension with a systolic blood pressure less than 90 mm Hg for over 30 minutes, or prolonged hypoxia with arterial O2 saturation less than 94% for over 30 minutes, if the patient arrived at our hospital more than 6 hours after injury, if a family member refused to consent to the study, or in cases of pregnancy.

Surface cooling: using cooling blankets and cold saline gastric lavage, Cooling was initiated with target temperature of 33 within 6 hours for 24 hours.

2/20 (1%) 0/20 (0%) 8/20 (40%) 12/20 (60%)

Good neurological outcome was defined as moderate, mild, or no disabilities per GOS

3 months

Marion 1997

Patient who had closed head injury and a Glasgow coma score of 3 to 7, an age of 16 to 75 years, admission within six hours after the injury, and an inability to follow commands.

Patients were excluded for the following reasons: clinical brain death (a score of 3 on the Glasgow Coma Scale and no brain-stem reflexes), prolonged hypoxia or hypotension, a gunshot wound, pregnancy, an undetermined time of injury, or normal findings on a computed tomographic (CT) scan of the head.

Surface cooling: using cooling blankets and cold saline nasogastric lavage, Cooling was initiated with target temperature of 33 within 6 hours for 24 hours.

10/42 (24%) 9/39 (23%) 16/42 (38%) 24/39 (62%)


12 months

Qiu 2007

Patient with a history of TBI, Glasgow Coma Scale (GCS) scores of 8 or less, brain injury confirmed by sequential computed tomography (CT) scanning within 6 hours after trauma.

Patients who had one or more of the following criteria were excluded from the study: pregnant women,patients younger than 19 or older than 65 years, multiply injured patients, those with hemorrhagic shock, or without any brain stem reflex on initial examination, those with any previous disabling neurologic disease.

Surface cooling with target temperature of 33-35 for 72 hours.

13/40 (32.5%) 9/40 (22.5%) 19/40 (47.5%) 28/40 (70%) )


12 months

Shiozaki 1993

Patients with Severe TBI, Glasgow Coma Scale scores of 8 or less in whom the ICP remained higher than 20 mm Hg at 5 to 6 hours after induction of high-dose barbiturate therapy were eligible for inclusion in this study.

Patient below younger than 10 years or who didn't meet the inclusion criteria

Surface cooling with target body temperature of 33.5-34.5, unclear time until hypothermia. Duration of cooling was for 24-48 hours.

14/17(82%) 8/16(50%) 1/17 (5.9%) 5/16 (31%)


6 months

11

e-Table3.Summaryofstudiesthatevaluatedeffectoftherapeutichypothermiaontraumaticbraininjury.

Shiozaki 1999

Patients with Severe TBI, Glasgow Coma Scale scores of 8 or less in whom the ICP was below 20 mm Hg.

Patient below younger than 10 years or who didn't meet the inclusion criteria

Surface cooling for 48 hours, unclear initiation time. Target temperature was 34.

0/8 (0%) 0/8 (0%) 7/8 (87.5%) 6/8 (75%)


6 months

Shizoki 2001

patients had a GCS9 score of 8 or less on admission, and none had a severe life-threatening injury to another organ with ICP below 25 with conventional therapies

Patient with ICP > 25 mm Hg despite conventional therapies , ICP was not measured or informed consent was not obtained

Surface cooling for 48 hours, with target temperature of 34.5-35.5. Unclear when was the hypothermia was initiated

6/46 (13%) 8/45(18%) 18/46 14/45


3 months

Tang 2017

ICP >20mmHg after decompressive craniectomy within 24 hours, primary closed TBI, >16 yo, men or non-pregnant women, clear history of head injury, GCS 3-8 on admission or after resuscitation, availablilty of cooling device for >72 hours, brain injury confirmed by CT within 6 hours of trauma

pregnancy, <16 yo, >70yo, multiple injuryeis, hemorrhagic schok, no bilateral pupil fixed on exam, no spontaneous breating, bilaterla hemicraniectom yor bfrontal craniectomy, external ventricular drainage, history o fserious heart, lung , brain and other diseases

Water circulating cooling blanket, goal 32-35C then rewarming considered 48 hours later

(10/30) 33.3% (3/30) 10% 7/30 (36.5%) 12/30 (40%)


6 months

Zhao 2011

Patients older than 16 years; had admission within 6 hours of nonpenetrating brain injury; a score on the Glasgow Coma Scale (GCS) between 3 and 8 after resuscitation and no other chronic illnesses before the injury.

Patients who had life- threatening injuries to other organs or systolic blood pressure less than 70 mm Hg after resuscitation were excluded.

Surface cooling: using cooling blankets, Cooling was initiated with target temperature of 33 within 3-5 hours for 72 hours.

4/41 (9.8%) 1/40(2.5%) 21/41 (51%) 30/40 (75%)


3 months

Zhi 2003

Patients with acute severe head injury [Glasgow Coma Scale Score (GCS) equal to or less than 8] within 24 hours after trauma, uncomplicated with major organ damage or functional failure, and without hypotension (systolic pressure 90 mm Hg).


Surface Cooling: Water circulating cooling blanket with target temperature of 32.0 to 35.0°C within 24 hours for 1-7 days

72/198 (36.4%) 51/198 (26.7%)

75/198 (38%) 122/198 (62%)


6 months

12

Study Inclusion Criteria Exclusion Criteria Intervention Outcome: Mortality Outcome: Neuroprotective Outcome: Comments

Follow up Normothermia Hypothermia Normothermia Hypothermia

De Georgia 2004

Patients were older than 18 years, had anterior circulation territory ischemic stroke, had an NIH Stroke Scale (NIHSS) score of equal to or more than 8 and less than or equal to 25, and presented within 12 hours of symptom onset.

Patients with recent sepsis; contraindication to MRI; platelet count of less than 75,000/mm3; known coagulopathy; significant ventricular cardiac dysrhythmias or QTc interval of more than 450 milli- seconds; pregnancy; intolerance to buspirone or meperidine; treatment with monoamine oxidase inhibitors; life expectancy of less than 6 months; baseline modified Rankin Scale (mRS) score of more than 2; rapidly improving symptoms; intracerebral hemorrhage, mass, or aneurysm by brain CT scan; hypersensitivity to hypothermia; height of less than 1.5 m; inferior vena cava filter in place; and renal insufficiency. Patients returned for a clinical assessment at 30 + 7 days including mRS and NIHSS scores (the NIHSS score was corrected for side of stroke by adding 5 to the NIHSS score in patients with right hemispheric strokes)

Endovascular cooling with target temperature of 33 for 24 hours. The initiation of cooling started within < 12 hours

4/22(18%) 5/18 (28%) Mean NIHSS score: 20.3

Mean NIHSS score: 19.2

Mean NIHSS score was used

1 month

Els 2005 Patients who typical clinical signs for a large supratentorial infarction (National Institute of Health Stroke Scale Score, NIHSSS, more than 15 for right-hemispheric stroke and NIHSSS more than 20 for left-hemispheric stroke), signal changes in early diffusion-weighted and perfusion-weighted MRI involving 12/3 of the hemisphere without mismatch, age is less than 65 years, no preexisting disability (Karnofsky Performance Status 170), no dementia and no tegmental syndrome. The extent of infarction was evaluated on the basis of the initial diffusion- and perfusion-weighted MRI.


Endovascular cooling with target temperature of 35 for 48 hours.

2/13 (15%) in Hemicraniotomy Only

1/12 (8%) in Hemicraniotomy with Hypothermia

NIHSSS after 6 months: 11±3 Hemicraniotomy Only

NIHSSS after 6 months: 10±1 in Hemicraniotomy with Hypothermia

No significant difference in mortality between Hemicraniotomy alone (15%- 2/13) and Hypothermia and hemicraniotomy group (8%-1/12)

3 months

13

Hemmen 2010 Patients who presented with acute ischemic stroke less than six hours from onset, age 18–80, an National Institutes of Health Stroke Scale (NIHSS) ≥ 7, and a score of 0 or 1 on NIHSS Item 1a (arousal) at the time of cooling catheter placement. The institutional review boards of the participating centers approved this protocol.

Unable to extract, any patients who does not meet the inclusion criteria.

Endovascular cooling with target temperature of 33 for 24 hours. Hypothermia initiated in < 6 hours.

5/30 (16.7%) 6/28 (21.4%) 7/30 (24%) 5/28 (18%) modified Rankin Scale (mRS) used as surrogate for neuroprotection (score of 0 to 1) No significant difference in mortality between Hypothermia and Normothermia

3 months

Lyden 2016 Patients presented with ischemic stroke patients treated within 3 hours of symptom onset with intravenous r-tPA, NIHSS >=7 and <=20 for L brain stroke or <=24 for R brain stroke, 22-82yo

Unable to extract, patients who do not meet inclusion criteria

Hypothermia obtained by saline infusions and Intravascular Cooling in the treatmetn of Stroke Protocol

5/57 (8.8%) 10/63 (15.9%) 21/57 (38%) 21/63 (33%) modified Rankin Scale (mRS) used as surrogate for neuroprotection (score of 0 to 1) No significant difference in mortality between Hypothermia and Normothermia

3 months

Piironen 2014 Patients (aged, 18–85 years) with moderate to severe neurological symptoms (National Institutes of Health Stroke Scale [NIHSS], 7–20 or NIHSS <7 with >2 points from motor score of a single limb, or >1 points for aphasia) 1 hour after initiation of intravenous thrombolysis.

Patients with severe congestive cardiac failure, recent history of unstable angina pectoris or sepsis, intracranial hemorrhage or tumor on computed tomographic (CT) scan, pregnancy, hemodynamic instability, severe thrombocytopenia, pre-existing neurological disability with modi ed Ranking Scale (mRS) >2, or violation of the in-house guidelines of thrombolytic therapy

Surface Cooling with target temperature of 35 within 6 hours for 12 hours

2/18 (%) 0/18 (0%) 7/18 (39%) 7/18 (39%) Good outcome was considered as modified Ranking Scale: 0–2

3 Months

Su 2015 age 18-80, acute unilateral ischemic stroke <=48 hours ago, infarction involving at least 2/3 MCA territory on CT or MRI, NIHSS score>=15 if non-dominant hemisphere affected or >=20 if dominant hemisphere, reduced level of consciousness (NIHSS item 1a score>=1), unable to undergo decompressive craniectomy becasue of premorbid use of antiplatelet or anticoagulant

premorbid modified Rankin Scale >=2, secondary hemorrhage involving more than 1/2 of infarction territory with space-occupying effect, GCS without a verbal response item score of <6, rapidly improving symptoms, both puils fixed and dilated, simultaneous other brain lesion, plts <75,000, severe coagulopathy or cardiac/liver/kidney disease, vasospastic disease/hematological disease with increased risk of thormobosis/paramyotonia congenita, sepsis, premorbid treatemtn with a MAOI or allergy to pethidine, IVC fistula or filter or mass near inferior VCA, pregnancy, life expectancy <6 months

Endovascular hypothermia via CVC inserted in teh femoral vein for target bladder temp 33-34C for minimum of 24 hours up to 72 hours

7/17 (41.2%) 8/16 (50%) 4/17 (23.5%) 7/16 (43.8%) Good neurological outcome was modified Rankin Score 1 to 3

6 months

e-Table4.Summaryofstudiesthatevaluatedeffectoftherapeutichypothermiaonpatientswithstroke.

14

Study Inclusion Criteria

Exclusion Criteria

Intervention Outcome: Mortality Outcome: Neuroprotective Outcome: Comments

Follow up

Normothermia Hypothermia Normothermia Hypothermia Bernard 2002

initial cardiac rhythm of Vfib at the time of arrival of ambulance, successful ROSC, persistent coma after ROSC, trasnfer to 1/4 participating EDs

age <18 for men, age<50 for women, cardiogenic shock (SBP <90 despite epinephrine), other possible explanation for coma, no ICU bed available

hypothermia to 33C within 2 hrs of RSOC and maintained temp for 12 hours (basic cooling in ambulance then vigorous cooling with ice packs around head, neck , torso, limbs

23/34 22/43 9/34 (26%) 21/43 (49%) Good outcome considered discharged to home or rehab

24hours?

Bernard 2016

>=18 yo, cardiac arrest on EMS arrival, had IV access estabilshed, still in cardiac arrest after initial resuscitation

in cardiac arrest because of trauma, suspected intracranial bleed, females known or suspected to be pregnant, already hypothermic (<34.5C), inpatients, konwn advanced directives for limited resuscitation

Rapid intravenous infusion of up to 2L cold saline

66/580 (11.4%)

63/618 (10.2%)

63/580 63/618 No note of "good neuro outcome" but considered it patients who were discharge home or rehab

until hospital discharge

Cronberg 2015

unconscious (GCS<8), adults (>=18yo), out-of hospital cardiac arrest from presumed cardiac cause, sustained ROSC

interval from ROSC to screening time >240mins, unwitnessed cardiac arrest with asystole as initial rhythm, suspected or known intracranial hemorrhage or stroke, body temp <30C

Temp goal 33C vs 36C

246/466 245/473 unclear unclear No note of "good neuro outcome" but can use occupational status at time of follow up?

6 months

Hachimi-Idrissi 2001

patients with cardiac arrest due to asystole or PEA who remained unconscious after ROSC, over 18yo, tympanic temp >30C on admission, GCS <7, SBP>100, MAP>60

pregnancy, coagulopathy, hx of CNS depressant drug prior to cardiac arrest

helmet device used to induce hypothermia to 34C

13/14 13/16 unclear unclear not assessed but lower lactate concentration and O2 extraction lower was positive

6 months

Hypothermia after Cardiac Arrest Study Group 2002

witnessed cardiac arrest, ventricular fibrillation or nonperfusing ventricular tachycardia as intial rhythm, age 18-75 yo,

tympanic temp <30C on admission, comatose state before cardiac arrest from drugs that depress CNS, pregnancy,

therapeutic hypothermia to 32-34C

76/138 (55%) 56/137 (41%)

54/137 (39%) 75/135 (55%)

favorable neuro outcome defined as cerebral performance category 1 or 2

6 months

15

presumed cardiac origin of arrest, estimated interval of 5-15 mins from pathient's collapse to first resuscitatino attempt by EMS, interval <60 mins from collapse to ROSC

response to verbal commands after ROSC, hypotension for >60mmHg, evidence of hypoxemia for >15mins after ROSC, terminal illness before arrest, enrolled in another study, occurrence of cardic arrest after arrival of emergency medical personnel

Kamarainen 2009

patients >=18 yo, time to ROSC >9mins, GCS <=5

pregnancy, cardiac arrest due to trauma or intoxication, persistent intital hypotension after ROSC (SBP<100mmHg) not responding to fluid challenge or medication

IV infusion of 4 degrees Celcius of Ringer's solution

10/18 11/19 unclear unclear


Kim 2014 ROSC, tracheal intubation, IV access, succesful placement of esophageal temp prob, unconsciousness

traumatic cardiac arrest, <18yo, awake, following commands, temp <34C

infusion of up to 2L of 4 degree C normal saline as soon as possible folloing ROSC

422/671 429/688 231/671 225/688 favorable neurologic outcome was full recovery or mildly impaired


Laurent 2005 age 18-75, initial Vfib or asystole, estimated interval of <10mins from cardiac arrest to initiation of CPR, interval of <50min from initiation of CPR to ROSC

pregnancy, response to verbal commands after ROSC, terminal illness present before cardiac arrest

cooling of the hemofiltration substitution fluid

15/19 15/22 4/19 7/22 favorable neurologic outcome was Pittsburgh cerebral performac category 1 (good recovery) or 2 (moderate disabtility)

6 months

Nielsen 2013 age 18 or older, GCS<8, out-of-hospital cardiac arrest from presumed cardiac cause, 20 consecutive mins of spontaneous circulation after resuscitation

interval from ROSC to screening time >240mins, unwitnessed cardiac arrest with asystole as initial rhythm, suspected or known intracranial hemorrhage or stroke, body temp <30C

achievement of temp 33C as quickly as possible using ice-cold fluids, ice packs and intravascular/surface temperature-management devices

220/466 226/473 225/464 218/469 favorable neurologic outcome was Cerebral Performance Category 1-2

180 days

e-Table5.Summaryofstudiesthatevaluatedeffectoftherapeutichypothermiaonpatientswithout-of-hospitalcardiacarrest

16

Study Inclusion Criteria Exclusion Criteria Intervention Outcome: Mortality Outcome:

Mortality Outcome: Neuroprotective

Outcome: Neuroprotective

Outcome: Comments Follow up

Arom 1995 patients undergoing elective, urgent, emergent, redo, CABG, valve and CABG/valve operations

Not Discussed blood cardioplegia solution, allowing temperature of intervention patients to drift down to 34C but controls kept at 37C

4% 3% 99/100 100/100 Did not define objective way of measuring CVA (based on clinical, no CT evidence of CVA); Hypothermic group had better UOP; Hypothermic group required less post-op volume (p-0.001)

Hospital discharge

Bert 1993 patients scheduled to undergo elective isolated coronary artery bypass graft operations, patients with triple vessel disease with a significant stenosis (>=70%) of the right coronary artery

Patients without significant stenosis of RCA (>70%); Patietns that were diagnosed with myocardial ischemia before start of CPB (hemodynamic profile changes).

moderate hypothermic perfusion at bladder temperature 25C

0/16 (0%) 0/14 (0%) not mentioned not mentioned not mentioned RV function 24 hours after cardiopulmonary bypass

Birdi 1997 Patients in need of primary isolated coronary revascularization

Previous history of stroke or transient ischemic episodes

CPB Hypothermic Perfusion 28C - 32C

1/100 (1%) 1/200 (0.005%) 99/100 200/200 Both CVA patients recovered at 6-weeks from neurologic defecits; No stroke at 28C; 1 Stroke at 32C; 1 Stroke at 37

6 weeks after surgery

Birdi 1999 Patients with stable angina pectoris undergoing coronary artery bypass surgery

Unstable angina, Recent myocardial infarction (within past 6-months), Diabetes mellitus, Serum creatinine >120umol/litre

CPB Hypothermic Perfusion at 28-32C; Topical cooling with saline 4C

0/22 (0%) 0/44 (0%) 22/22 44/44 Rewarming of the myocardium when using NT perfusion

Hospitalization (7-Days)

Boldt 1994 males, ages 50-70, scheduled for elective aortocoronary bypass grafting

not mentioned (but no patients had peripheral vascular disease, diabetes mellitus, hypertension or renal insufficiency)

cold start of cardiopulmonary bypass consistent of priming room temp to 20C then maintained

0/15 0/15 15/15 15/15 Measured MAP, SVR, LDF (laser doppler flow)

Post-Operative Course

Boldt 1996 30 patients scheduled for first-time elective aortocoronary bypass grafting with expected bypass times of more than 100 minutes

preoperative coagulation disorders, concomitant valvular diseases, medication with heparin, aspirin, COX inhibitors or NSAIDs within last 7 days before operation

via surface cooling and cardiopulmonary bypass system with rectal temperature kept between 27-28C

0/15 0/15 15/15 15/15 measured platelet aggregation by measuring thrombomodulin plasma levels


Boodhwani 2007 Patients aged ≥ 60 elective CABG

known neurologic deficits (previous stroke, history of Parkinson, Canadian Neurological Scale score <11.5, abnormal Modified Mini-Mental State scores), serum creatinine greater than twice normal level

water-circulating thermal control pads maintainted at 34C measured in nasopharynx, no active rewarming used

0/133 1/134 92% 96% deficit defined as 1 standard deviation decrease in individual scores from baseline in 1 or more out of 4 cognitive domains

3 months

Chello 1997 Patients scheduled to undergo non-urgent aorto-coronary bypass grafting

Beta-blocker use preoperatively, ejection fraction <55%, evidence of pulmonary disease on imaging

Cold blood cardioplegia

0/20 0/20 Not mentioned not mentioned density of beta adrenergic receptors and coupling capacity to adenylate cyclase

few hours after cardiopulmonary bypass surgery

Cook 1994 patients undergoing elective, first-time coronary artery bypass grafting

females of childbearing age, patients with clinical or lab evidence of cerebrovascular disease, increased intracranial pressure, insulind-dependent diabetes mellitus, uncontrolled hypertension, contrast

hypothermic cardiopulmonary bypass maintained at 27C

0% 1/26 (3%) 46% 88% oxygen saturation in cerebral venous blood (of 51% or more) was considered neuroprotective

few hours after cardiopulmonary bypass surgery

17

allergy, demonstrated or suspected bacteremia

Dworschak 2004 patients undergoing coronary artery bypass grafting

severe stenosis of the internal carotid artery (>75%), chronic renal failure (Cr>2)

hypothermic cardiopulmonary bypass maintained at 32C

1/24 (4%) 1/24 (4%) 24/24 24/24 higher levels of S-100b was a marker of cerebral injury, measured area under the curve of the marker; no difference between 2 groups

24 hours after cardiopulmonary bypass

Engelman 1999 Patients undergoing elective or urgent coronary revascularization and required 3 or more coronary bypass grafts (equating to at least 60 minute bypass time)

76 years or older, previous history of neurologic dysfunction, poor left ventricular function (<30%), ongoing myocardial ishcemia needing intraaortic ballon, renal dysfunction (Cr>2mg/L), recent (<7 days) postinfarction angina, significant carotid stenosis by duplex of >70%

CPB Perfusion: 20C 1/98 (1%) 3/193 (1.5%) Decrease of 1.3-1.8 points on Mathew scale

decrease of 1.3-1.8 points on Mathew scale

deterioration in neurologic function was measured based on change in Mathew scores in each patient comparing them from before operation to 1 month follow up (at latest point)

1 month

Gaudino 2002 Patients undergoing primary isolated CABG

associated cardiac or non-cardiac surgical procedures, age >80, single vessel disease, emergecy or urgent revascularization, LVEF <30%, carotid artery disease, previous CVA, chronic dialysis, hepatic failure, repiratory or renal insufficiency, hemorrhagic conditions, active infection, chronic anti-inflammatory therapy

CPB Perfusion: 26C 2/55 (3.6%) 0/58 55/55 58/58 neurologic function not measured but events of stroke are included

Hospitalization

Grigore 2001 Patient undergoing CABG

history of cerebrovascular disease with residual deficits, uncontrolled hypertension, alcoholism, pyschiatric illness, renal disease (Cr >2), active liver disease, pregnant women, patients with less than a seventh-grade education

CPB Perfusion: 28-30C 0/136 3/134 136/136 134/134 Hypothermia is not neuroprotective


Grimm 2000 Low-Risk, Elective CABG, Stable Angina, Multivessel CAD

Not Discussed CPB Perfusion: 32C 2/72 3/72 371ms mean P300 evoked potential

378ms mean P300 evoked potential

Normothermic CPB does not adversely affect cognitive brain function as compared to mild hypothermia

4 months after surgery

Jacquet 1999 Scheduled isolated CABG

Emergent surgery CABG+Valve Carotid stenosis > 80%

intermittent antegrade and retrograde cold crystalloid cardioplegia

3/108 (2.7%) 3/92 (3%) 106/108 90/92 not mentioned; used 1-number of patients with stroke

Hospitalization

Kaukoranta 1995 Scheduled isolated CABG

Coronary Reoperation CPB Perfusion: 28-29C 1/51 (1.9%) 0/50 (0%) 50/51 49/50 neurologic complications included TIA and cerebral infarction; used 1-number of patients with neuro complications

Hospitalization

Lajos 1993 Isolated CABG Hemodynamically stable Elective or urgent + unstable angina

not mentioned cold retrograde blood cardioplegia (started antegrade and continued retrograde through coronary

2/54 (3.7%) 0/109 (0%) 51/54 108/109 Warm blood cardioplegia offered no added myocardial protection over cold

Hospitalization

18

sinus). Cardiac temp kept at 10-15C.

Lehot 1992 CABG +/- AVR Respiratory failure Endocrinopathy Cerebral disease Amiodarone or Clonidine Emergency surgery

CPB Perfusion: 29C 0/10 1/10 10/10 10/10 Normothermic: Lower SVR during and after CPB + higher [catecholamine]


Lomivorotov 2014

patients with valvular heart disease with or without coronary artery disease surgically treated under cardiopulmonary bypass between July 2011 and October 2012

urgent surgery, left ventricular ejection fraction <35%, decompensated congestive heart failure, glomerular filtration rate <60ml/min, severe hepatic and pulmonary disease, bleeding diathesis, history of coagulopathy, planned deep hypothermic circulatory arrest, acute myocardial infarction within 3 months prior to surgery

CPB Perfusion: 31C 1/70 1/70 68/70 69/70 Normothermic CPB in patients with VHD is as effective as using hypothermic perfusion in terms of myocardial protection

Hospitalization

Maccherini 1995 Elective CABG Time Period: 1/1/1993 - 9/30/1993

radiological evidence of pleural alterations antecedent to surgical procedures

CPB Perfusion: 28C 1/50 2/50 49/50 47/50 not mentioned, used 1-number of patients with diaphragmatic paralysis

6 Months

Martin 1994 Elective CABG Time Period: 3/1991 - 7/1992

not mentioned cold group received intermittent cold <_8C oxygentated crystalloid cardioplegia with systemic hypothermia (<=28C)

5/493 8/508 471/493 501/508 No difference in normothermic and moderate hypothermia in elective CABG, however significantly more CVA in normothermic group

Hospitalization

Mclean 1994 Urgent or elective isolated CABG

need for concomitant valvular surgery, aneurysmectomy, atrial or ventricular septal defect repair, or other complicating procedure; lack of consent for randomization; factors precluding proper preoperative assessments (ex emergency surgery, unstable cardiac disease, lack of fluency in English; inability to arrange follow up assessment; history of stroke

cold cardiopulmonary bypass temperature was <=28C

1/78 0/77 76/78 73/77 neuro event was a stroke (on Toronto Stroke Scale >=6 stroke score change before and after surgery) and decrease in the neuropyschological test battery (Buschke, Wechsler adult intelligence scale, pegboard test)

3 months

Mora 1996 Scheduled CABG patients scheduled for concomitant procedures (vascular surgery, valvular procedures, aneurysmectomy, repair of atrial or septal defects, placement of internal defibrillators), admitted to operating room directly from cardiac catheterization laboratory

patients cooled to a termperature <28C during cardiopulmonary bypass

1/68 0/70 61/68 70/70 neuro event was measured using 5neuropsychologic tests; used 1-number of patients with neurologic deficit

1 month after surgery

19

Nathan 2001 Age ≥ 60 Scheduled CABG English speaking

neurological deficits, impediment to completing neuropsychological testing

CPB Perfusion: 32C 1/112 3/111 38/100 49/94 neurocognitive deficit is a decrease fo >=0.5 standard deviation in 1 or more domains (domains: memory, attention, psychomotor); used 1-number of patients with neurologic deficit

3 months after surgery

Nathan 2004 Age ≥ 60 Scheduled CABG Consenting patient

neurological deficits, serum creatinine more than twice nromal, those with history of cardiac surgery

nasopharyngeal temperature was maintained at 34C throughout intraoperative period. All patients received tranexamic acid.

0/73 2/71 Unclear Unclear Hospitalization

Parodi 2000 CBP for Cardiac surgery not mentioned CPB Perfusion: 26-30C 2/66 1/66 64/66 (96.9%) 64/66 (96.9%) No significant difference found in mortality and neurologic defecit

Hospitalization

Plourde 1997 Age: 40 - 70 Language: English or French Elective CABG

prior cardiac surgery, history of cerebrovascular disease, severe systemic disease (ex. pulmonary or hepatic disease or bleeding disorders), left ventricular ejection fraction of <0.4

CPB Perfusion: 28C 0/30 0/24 10/30 8/24 neurocognitive deficit is one or more standard deviations deterioration on at least one out of 12 tests; used 1-number of patients with neurocognitive decline

7 days after surgery

Ranucci 1997 patients at risk for postoperative lung dysfunction and undergoing elective coronary revascularization

presence of associated procedures, emergency procedures, existance of preoperative neurologic damage

CPB Perfusion: 28C 0/25 2/25 Unclear Unclear Hospitalization

Rashid 1994 Elective isolated CABG not mentioned CPB Perfusion: 28C 1/137 (0.7%) 3/144 (2.1%) 2/137 (1.4%) 4/144 (2.8%) 1-patients hx of stroke 30 days after surgery

Rashid 1995 Elective isolated CABG Mod-Severe LV Dysfunction

not mentioned CPB Perfusion: 28C 2/58 (3.4%) 0/50 (0%) 2/58 (3.5%) 2/50 (4%) 1-patients hx of stroke 31 days after surgery

Regragui 1996 Elective, primary isolated CABG or Urgent CABG

Previous CVA Psychiatric Illness

CPB Perfusion: 28C 0/29 1/67 9/29 8/67 neurocognitive decline was measured as 1 or more deteriorations in neuropsychologic tests; used 1-number of patients with decline in greater than 1 test


Tonz 1995 Primary elective CABG Scheduled first case of day

patients with ejection fraction <0.35, ager greater than 65, previous cardiac procedures, impaired lung/liver/renal function

CPB Perfusion: 26-28C 0/14 0/16 14/14 16/16 "cerebrovascular insult" was 0 in both groups

Hospitalization

The Warm Heart Investigators 1994

Elective, primary isolated CABG or Urgent CABG

patients enrolled in other studies, scheduled for concomitant cardiac surgical or vascular procedures, cerebrovascular disease (internal carotid artery stenosis >80%), renal insufficiency (Cr>200mmol/L)

CPB Perfusion: 25-30C 12/860 (1.4%) 22/872 (2.5%) 846/860 859/872 1-patients hx of stroke 30 days after surgery

Zey bek 2001 Elective MVR not mentioned CPB Perfusion: 28C 0/15 0/25 15/15 25/25 no "neurological events" 1 hour postoperative

e-Table6.SummaryofstudiesthatevaluatedeffectoftherapeutichypothermiaonpatientswhounderwentCABG.

20

Study Patient Population Inclusion Criteria Exclusion Criteria Intervention

Mortality Neuroprotection Outcome: Comments

Follow up

Normothermia Hypothermia Normothermia Hypothermia

Bernal 2016

Patients with acute liver failure, high-grade encephalopathy and intracranial pressure monitoring in specialist intensive care units in the United Kingdom and Denmark

Patients with acute liver failure (INR >=1.5, absence of previous history and clinical/radiologic findings of liver disease, illenss<=26 weeks, overt encephalopathy of grade >=3, patients 18 years or older, intubated, sedated, mechanically ventilated (considered high risk of intracranial hypertension

Pregnancy, evidence of brain stem death, ongoing or suspected hemorrhage, suspected or microbiologically confirmed severe sepsis, no consent

Targeted temprature management of 34C for 72 hours via surface temperatue managemetn devices and when needed, control of blood temperature through continuous RRT extracorporeal circuits

12/26 (46%) 7/17 (41%) 19/26 (73%) 11/17 (65%)

Negative neurologic effect was measured as sustained elevation in intracranial pressure >25mmHg with onset < 72 hours

72 hours after patients were randomized

Chouhan 2006 Patient who underwent Intracranial Aneurysm Surgery

Any patient posted for intracranial aneurysm clipping, were included in the study

Patients with severe systemic illnesses, sepsis, peripheral vascular diseases and bleeding disorders

HT group: polar Air machine was used along with cold intravenous fluids at room temperature . Goal is core temperature between 34 – 33 in HT and 36.0 - 37.5 NT

1/23 (0.04%) 2/24 (0.08%) 19/23 (82.6%) 20/24 (83.3%)

The overall neurological recovery is considered with patient has returned to independent life style (Glasgow Outcome Scale (GOS) V and IV).

hospital discharge

Dixon 2002 Patients with acute anterior or posterior myocardial infarction (<6 hours from symptom onset)

Any patient presented within 6 hours from symptom onset, chest pain >30 minutes duration with ST-segment elevatation >=1mmin 2 contiguous leads, if inferior acute MI patients were required to have>=1mm reciprocal ST segment depression in 2 precordial leads

Patients with cardiogenic shock, rescue angioplasty, previous acute MI <1 month, Raynaud's disease, hypersensitivity to buspirone or mepiridine, treatment with a monoamine oxidase inhibitor in the previous 14 days, bleeding diathesis or coagulopathy, severe hepatic or renal impairment, pregnancy, patient height <1.5m, presence of an inferior vena cava filter

Endovascular cooling (target core temperature 33C), maintained for 3 hours after reperfusion

2/21 (10%) 0/21 (0%) N/A N/A

Not measured, used number of patients with stroke

hospital discharge

Gotberg 2010 Patients scheduled to undergo primary percutaneous coronary intervention

Patients between ages 18 and 75, presenting with an anterior or inferior STEMI with St-segment elevation of >0.2mV in 2 or more anatomically contiguous leads and duration of symptoms of <6 hours

patients with cardiac arrest, previous acute MI, previous PCI or CABG, known congestive heart failure, end-stage kidney disease or hepatic failure, recent stroke, coagulopathy, pregnancy, Killip class II through IV at presentation

infusion of cold saline and endovascular cooling catheter before reperfusion in acute MI, core body temperature aim of <35C

0/9 (0%) 0/9 (0%) N/A N/A

Not measured, used number of patients with stroke

30 days

Hindman 1999

Patients undergoing cerebral aneurysmal clipping with subarachnoid hemorrhage at 5 academic centers

Patients with intracranial aneurysms were required to have a prehospitalization/pre-SAH Rankin disability score of 0 or 1. Patients with acute SAH were required to have a preoperative World

Patients who were endotracheally intubated when evaluated for the study, cryoglobulinemia, severe Raynaud's disease, sickle cell disease, another

Intraoperative hypothermia with cooling mattress set to 20C, forced air cooling blanket set to deliver unwarmed room

3/28 (11%) 2/24(8%) 16/28 (57%) 17/24 (71%) Glasgow Outcome Scale (GOS) as good

3-6 months

21

Federation of Neurological Surgeons (WFNS) score of I, II, or III

disorder considered to contraindicate hypothermia, entered in a blinded trial of any drug that could affect neurological outcome

air temperature, IVFs and anesthetic gases not warmed, target esophageal temperature 33.5C

Patients undergoing cerebral aneurysmal clipping without subarachnoid hemorrhage at 5 academic centers

Patients with intracranial aneurysms needed prehospitalization/pre-SAH Rankin disability score of 0 or 1

Patients who were endotracheally intubated when evaluated for the study, cryoglobulinemia, severe Raynaud's disease, sickle cell disease, another disorder considered to contraindicate hypothermia, entered in a blinded trial of any drug that could affect neurological outcome

Intraoperative hypothermia with cooling mattress set to 20C, forced air cooling blanket set to deliver unwarmed room air temperature, IVFs and anesthetic gases not warmed, target esophageal temperature 33.5C

0/29 (0%)

2/30(7%) (patients discharged before examination)

22/29 (76%)

23/30 (77%) patients discharged before examination)

Glasgow Outcome Scale (GOS) as good

3-6 months

Itenov 2018 Patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg

Patients with severe sepsis or septic shock were considered for enrolment if they had a mean arterial pressure of less than 70 mm Hg, were on mechanical ventilation in an ICU, were aged at least 50 years, were expected to stay in the ICU for more than 24 h, and could be recruited within 6 h

Patients with uncontrolled bleeding, clinically important bleeding disorder (acute or chronic), recent open surgery, pregnancy or breast-feeding, or involuntary psychiatric admission.

Used to methods for hypothermia, external cooling or endovascular cooling with target temperature of 32–34°C within 2 h.

77/215 (35.8%) 96/217 (44.2%) N/A N/A

Not measured, used different measures other than CPC and GOS

30 days

Legriel 2016 Critically ill patients with convulsive status epilepticus who were receiving mechanical ventilation

Patients older than 18 years old admitted with any seizure activity to the ICU, convulsive status epilepticus (5 minutes or more of continuous clinical seizure activity or more than 2 seizures without return to baseline in the interval), admitted less than 8 hours after onest of seizures, receiving mechanical ventilation

Patients who had full recovery from seizure (return to baseline state of consciousness), needed emergency surgery that would preclude therapeutic hypothermia, postanoxic status epilepticus, imminent death, do-not-resuscitate orders, bacterial meningitis

Target temo was (32 to 24C) for 24 hours .Hypothermia was induced with ice-cold intravenous fluids at 4°C and was maintained with ice packs at the groin and neck and a cold-air tunnel around the patient’s body

20/130 (15%) 18/138 (13%) 56/130 (43%) 67/138 (49%)

Good functional outcome defined as Glasgow Outcome Scale score of 5

90 days after discharge

Mourvillier 2013

Comatose patients (with GCS score <=8 for >12 hours) with community-aquired bacterial meningitis in 49 ICUs in France

Patients who were at least 18 years of age, had suspected or proven bacterial meningitis (by CSF white blood cell count of more than 100/uL and glucose CXF/blood ration of less than 1/3, a CSF protein concentration of >2.2g/L, or microorganisms observed in CSF gram stain, positive soluble antigen test or PCR for Streptococcus penumonia or Neisseria meningitidis, positive CSF cultures, GCS score of 8 or lower for <12 hours

Patient who were pregnant, with positive cryptococcal test, brain abscess, purpura fulminans, complications requiring therapeutic hypothermia (ex cardiac arrest) or if the physician made a decision to limit life support, also, patient had no medical insurance, inclusion in another interventoinal study

Hypothermia was induced by loading dose of 4C cold saline, cooled to 32-24C for 48 hours with passive rewarming

15/49 (31%) 25/49 (51%) 13/49 (27%) 7/49 (14%)

Favorable outcome was Glasgow Outcome Scale score of 5

3 months

Nichol 2015

Patients with ST segment elevation myocardial infarction undergoing primary percutaneous coronary intervention at 7 centers

Patients with ST segment elevation myocardial infarction within 6 hours of symptoms onset, age 18 to 85, clinical symptoms consistent with acute STEMI

Patients who had cardiac arrest, contraindications to periotoneal lavage (prior intraperitoneal surgery, profound obesity, abdominal

Hypothermia induced by an automated peritoneal lavage system before and 3 hours after PCI

0/26 (0%) 1/28 (3.6%) N/A N/A Not measured 30 days

22

lasting >=minutes and starting within 6 hours of hospital presentaion, >=2mm of ST segment elevation in >= 2 contiguous ECG leads, planned coronary angiography with intenteded primary PCI

aortic aneurysm, massive ascites), temperature-sensitive hematologic dyscrasias or vasospastic disorders, oxygen-dependent chronic obstructive pulmonary disease, pulmonary edema or cardiogenic shock, history of previous MI or pathological Q waves on prior ECG, active uncontrolled bleeding, known Hb<9, platelet count <100,000 or >750,000, serum Cr >2, dialysis or maredly abnormal liver function, contraindications for MRI, known allergy/intolerance to meperidine or buspirone or treatmetn with MAOI within 14 days, known hypersensitivity to contrast or antiplatelet meds, prior thrombolytic agent use for index STEMI, chronic oral anticoagulant use, pregnant or nursing, comorbidities with life expectancy <1 year, any conditions leading to noncomplicance with study procedures, currently enrolled in another investigational trial, unable to provide informed consent

Pang 2016 Patients who had cardiac arrest patients with extracorporeal life support who had received CPR

Patients with ventricular fibrillation, asystole or PEA, pulseless ventricular tachycardia, downtime <45 minutes (form onset of cardiac arrest to initiation of ACLS), comatose, not responding appropriately to verbal commands after ROSC, total ACLS time <60 mins, age >=21, intubated with mechanical ventilation

Patients responding appropriately to verbal commands after ROSC, CPR>45mins, severe coagulopathy with evidenc eof bleeding and/or platelets <30,000 and/or INR >=2.5, otehr causes of coma (drug overdose, head trauma, stroke, overt status epilepticus), positive pregnancy test in women <50 yo, premorbid status bedboudn and uncommunicative, temp <30C after cardiac arrest

Hypothermia induced at 34C following ECLS for cardiac arrest by modulating the heat exchanger component of the ECLS circuit.

9/12 (75%) 6/9 (66.7%) 1/12 (8.3%) 2/9 (22.2%)

Considered as good neurological function if cerebral performance category scores 1-2

6 months

Stone 2011

Patients at risk of radiocontrast induced nephropathy (baseline CrCl 20-50ml/min) undergoing cardiac catheterization with iodinated contrast >=50ml

Patients who were at least 18 yo with CKD (CrCl 20-50 ml/min) scheduled to undergo coronary arteriography (with or without PCI) with likely use of iodinated contrast >=50ml

Patients who had acute renal failure or unstable renal function, current or planned dialysis, performance of renal artery angiography, renal drug infusion, known renal artery stenosis, use

Endovascular Temperature Therapy System was used to induce hypothermia with target temperature of 33-34C for 3 hours

1/70 (1.4%) 3/58 (5.2%) N/A N/A Not measured 30 days

23

of mannitol or intravenous diuretics, presence of decompensated heart failure, respiratory failure, hypotension, acute or recent STEMI, allergy to contrast, heparin, mepiridine or buspirone that could not be premedicated, recent MAOI use, addtional contrast administration 10 days before or after the procedure, presence of an inferior vena cava filter, height <1.5m, hypersensitivity to hypothermia (Raynaud), bleeding diathesis, coagulopathy, sickle cell disease, severe hepatic impairment, cryoglobulinemia, untreated hypothyroidism, Addison disease, prostatic hypertrophy or uretheral stricture, refusal of blood transfusions, pregnancy, inability to sign infromed consent, enrollment in another investigational drug or device trial, any condition leading to noncompliance with study procedures

Todd 2005

patients with World Federation of Neurological Surgeons score of I, II, or III who had had a subarachnoid hemorrhage no more than 14 days prior to planned surgical aneurysmal clipping

patients at least 18 years old, had a subarachnoid hemorrhage from a radiologically demonstrated intracranial aneurysm within 14 days before surgery, had a WFNS score of I, II, or III ("good grade") at time of enrollement, Rankin score of 0 or 1 before hemorrhage

Patients who were pregnant. Patient withBMI >35, cold-related disorder, had an endotracheal tube in place

Intraoperative hypothermia (target temperature 33C) with use of surface cooling techniques (foreced-air blanket connected to cooling unit, use of circulating water mattress, intravenous cold saline)

32/501 (6%) 29/499 (6%) 314/501 (63%) 329/499 (66%)

Good outcome was considered Glasgow Outcome Score of 1

90 days after

surgery

e-Table7.Summaryofstudiesthatevaluatedeffectoftherapeutichypothermiaonpatientswithotherformsofcriticalcareillnesses.

24

Study Population type

Total # of Pt

NT Age

HT Age

NT Sex (%M)

HT Sex (%M)

NT deaths

NT # of Pt

HT deaths

HT # of Pt

NT Temp in C

HT Temp in C

Aibiki 2000 TBI 26 38 34 72.7 80 3 11 1 15 36-37 32-33 Andrews 2015

TBI 387 36.7 37.4 N/A N/A 51 192 68 195 37 34

Clifton 1993 TBI 46 30.2 27.5 N/A N/A 8 22 8 24 37 32-33 Clifton 2001 TBI 368 32 31 N/A N/A 48 178 53 190 37.2 33.2 Clifton 2011 TBI 97 31 26 N/A N/A 8 45 12 52 37 33 Cooper 2018 TBI 495 34.1 35 80.8 79.6 44 239 54 256 35 33 Gal 2002 TBI 30 39 35 66.7 60 5 15 2 15 37 34 Harris 2009 TBI 25 33.2 38.1 84.6 91.7 4 13 6 12 37.9 36.9 Hashiguchi 2003

TBI 17 39.1 29 62.5 100 0 8 1 9 36.5-37.5

34

Jiang 2000 TBI 87 40.6 42.2 84 81.4 20 44 11 43 37-38 34 Lee 2010 TBI 31 43.5 44 62.5 60 2 16 1 15 37 34 Lui 2006 TBI 44 42.3 39.6 69.5 57 12 23 6 21 36.5-

37.5 36

Maekawa 2015

TBI 142 39 39 68 70 11 48 33 94 35-36 33-34

Marion 1993 TBI 40 32.1 31.9 85 85 2 20 0 20 37-38 32-33 Marion 1997 TBI 81 35 31 79 90 10 42 9 39 37-

38.5 32-33

Qui 2007 TBI 80 40.2 41.3 67.5 62.5 13 40 9 40 37.5-38

34.5-36

Shiozaki 1993

TBI 33 35.4 35.3 58.8 37.5 14 17 8 16 37 34

Shiozaki 1999

TBI 16 40.3 31.4 62.5 100 0 8 0 8 37 34

Shiozaki 2001

TBI 91 42 35 67 77.7 6 46 8 45 37 34

Tang 2017 TBI 60 39.67 42.47 93.3 76.7 10 30 3 30 36 33.5 Zhao 2011 TBI 81 37.5 36.9 73.2 72.5 4 41 1 40 37 32.7 Zhi 2003 TBI 396 42 43 N/A N/A 72 198 51 198 36.5 -

37.5 32-33

De Georgia 2004

Stroke 40 67.3 60.9 27.2 72.2 4 22 5 18 36.5 33

Els 2005 Stroke 25 49 49 69.2 50 2 13 1 12 37.5 35 Hemmen 2010

Stroke 58 62.3 68.9 53.8 56.7 5 30 6 28 37 33-34

Lyden 2016 Stroke 120 67.5 65.5 61 54 5 57 10 63 36.4 34.1-36

Piironen 2014

Stroke 36 66 70 44 67 2 18 0 18 >36 34.5-35.5

Su 2015 Stroke 33 68.5 59.8 58.8 93.7 7 17 8 16 36.5–37.5

33-34

Bernard 2002

Out of Hospital Cardiac Arrest

77 65 66.8 79 58 23 34 22 43 37.1 32.7

Bernard 2016


1198 64.3 65.3 74.8 73.8 514 580 555 618 35.4 34.7

Cronberg 2015


939 59 61 82.5 85.7 220 466 228 473 36 33

Hachimi-Idrissi 2001


30 74 76.5 64.3 56.3 13 14 13 16 35.7 34

25

Hypothermia after Cardiac Arrest Study Group 2002


275 59 59 76.8 75.9 76 138 56 137 37-38 32-34

Kamarainen 2009


37 63 59 94.7 94.4 10 18 11 19 35.2 34.1

Kim 2014 Out of Hospital Cardiac Arrest

1359 65.2 65.7 62.9 64.4 422 671 429 688 35.8 34.9

Laurent 2005


61 55 56 79.5 81.8 11 39 3 22 37.4 31.7

Nielsen 2013 Out of Hospital Cardiac Arrest

939 64 64 79 83 225 466 235 473 36 33

Arom 1995 Intra-op CABG

200 59.3 60.8 78 70 4 100 3 100 37 34

Bert 1993 Intra-op CABG

30 63.2 62.5 94 93 0 16 0 14 36-38 25

Birdi 1997 Intra-op CABG

300 60.4 60 92 86.5 1 100 2 200 37 28-32

Birdi 1999 Intra-op CABG

66 61 64 86.3 79.5 0 22 0 44 37 28-32

Boldt 1994 Intra-op CABG

30 63.9 64.1 100 100 0 15 0 15 35.8 20

Boldt 1996 Intra-op CABG

30 65 64.1 100 100 0 15 0 15 >35 <28

Boodhwani 2007

Intra-op CABG

267 69.3 68.2 87 88.8 1 134 3 133 37 34

Chello 1997 Intra-op CABG

40 52.7 54.3 75 80 0 20 0 20 37 25-28

Cook 1994 Intra-op CABG

52 66.6 69.2 N/A N/A 0 26 1 26 37 27

Dworschak 2004

Intra-op CABG

48 65 62 N/A N/A 1 24 1 24 37 32

Engelman 1999

Intra-op CABG

291 62.3 63 80.6 85.5 1 98 3 193 37 25-32

Gaudino 2002

Intra-op CABG

113 <80 <80 94.5 91.3 2 55 0 58 37 26

Grigore 2001 Intra-op CABG

270 60 61 79 74 0 136 3 134 36 28-30

Grimm 2000 Intra-op CABG

144 62.4 61 86 90 2 72 3 72 37 32

Jacquet 1999

Intra-op CABG

200 64.5 65.2 75.9 68.4 3 108 3 92 37 30

Kaukoranta 1995

Intra-op CABG

101 58.6 58.6 82 80 1 51 0 50 37 28-29

Lajos 1993 Intra-op CABG

163 64.76 63.31 70 71.5 2 54 1 109 36-37 30

Lehot 1992 Intra-op CABG

20 60 62 80 100 0 10 1 10 37 29

Lomivorotov 2014

Intra-op CABG

140 56.9 57.4 58.6 55.7 1 70 1 70 37 31

Maccherini 1995

Intra-op CABG

100 65 64 76 84 1 50 2 50 37 28

Martin 1994 Intra-op CABG

1001 63.6 62.9 74 77 5 493 8 508 >/=35 </=28

Mclean 1994 Intra-op CABG

155 58.1 59.3 N/A N/A 1 78 0 77 >34 </=28

26

Mora 1996 Intra-op CABG

138 65 61 75 81 1 68 0 70 >/=35 <28

Nathan 2001 Intra-op CABG

223 68 68 85 85 1 112 3 111 37 34

Nathan 2004 Intra-op CABG

144 70 68 84 90 0 73 2 71 37 34

Parodi 2000 Intra-op CABG

132 64.7 64.3 72.7 71.2 2 66 1 66 37 26-30

Plourde 1997

Intra-op CABG

54 58.3 55.9 90 95.8 0 30 0 24 36 29

Ranucci 1997

Intra-op CABG

50 64.5 67 80 84 0 25 2 25 37 28

Rashid 1994 Intra-op CABG

281 60.2 60.2 78.8 87.5 1 137 3 144 37 28

Rashid 1995 Intra-op CABG

108 59 59 86.2 82 2 58 0 50 37 28

Regragui 1996

Intra-op CABG

96 58.7 59 93 85 0 29 1 67 37 30

The Warm Heart Investigators 1994

Intra-op CABG

1732 60 60 83 84 12 860 22 872 37 25-30

Tonz 1995 Intra-op CABG

30 60 63 100 87.5 0 14 0 16 37 26-28

Zeybek 2001 Intra-op CABG

40 37.45 43.64 20 28 0 15 0 25 36 28

Bernal 2016 Others 43 38 39 38 47 12 26 7 17 35.9 33.2 Chouhan 2006

Others 47 49.09 46.32 52 54 1 23 2 24 36.5 33.8

Dixon 2002 Others 42 58 52 76 90 2 21 0 21 35.7 33.2 Gotberg 2010

Others 18 58 62 78 78 0 9 0 9 36.5 34.7

Hindman 1999 (SAH)

Others 52 56 48 46 39 3 28 2 24 36.7 33.7

Hindman 1999 (Without SAH

Others 59 52 54 14 33 0 29 2 30 36.4 33.7

Itenov 2018 Others 432 71 70 60 60 77 215 96 217 36-38 32-34 Legriel 2016 Others 268 57 57 60 69 20 130 18 138 37 32-34 Mourvillier 2013

Others 98 59 59 63 57 15 49 25 49 37 33.3

Nichol 2015 Others 54 57.5 57 80.8 89.3 0 26 1 28 36.2 34.7 Pang 2016 Others 21 57.4 45.9 75 88.9 9 12 6 9 37 34 Stone 2011 Others 128 72 74 68.6 51.7 1 70 3 58 36.1 33.6 Todd 2005 Others 1000 51 52 34 35 32 501 29 499 36.7 33.3

e-Table8.Summaryofbaselinecharacteristicsofallstudiesincludedinthismeta-analysis. Patient population (Traumatic Brain Injury, Stroke,Out of hospital Cardiac arrest, Intra-Operative Coronary Artery Bypass Grafting or others), Total # of Pt (Total number of patients), NT Age (Mean/median age in normothermia group), HT Age (Mean/median age in Hypothermia group), NT Sex (%M) (% males in normothermia group), HT Sex (%M) (% males in hypothermia group), NT deaths (Number of patient deaths in normothermia group), NT # of Pt (Number of patients in normothermia group), HT deaths (Number of patient deaths in Hypothermia group), HT # of Pt (Number of patients in hypothermia group), NT Temp in C (Actual Temp that is reached in the normothermia group (Mean/Median) (in Celcius)), HT Temp in C ( Actual Temp that is reached in the Hypothermia group, (Mean/Median) (in Celcius)), N/A (Not available), TBI (Traumatic Brain Injury), Intra-op CABG (Intra-Operative Coronary Artery Bypass Grafting)

27

e-Table9.Riskofbiassummary.

28

(A)

(B)

29

(C)

(D)

30

(E)

SupplementaryFigure4(A-E)Funnelplotstoinvestigateevidenceofpublicationbiasforeachsubgroup:Traumaticbraininjury(A),Stroke(B),Outofhospitalcardiacarrest(C),intra-operativecardiacpulmonarybypass(D)andothers(E).Intheabsenceofpublicationbias,thepatternofpointsshouldresembleaninvertedfunnel

31

PRISMAChecklist:

Section/topic # Checklist item Reported on page #

TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. 1 ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility

criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

2

INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 3 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions,

comparisons, outcomes, and study design (PICOS). 3&4

METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide

registration information including registration number. 4

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

4

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

4

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

4

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

4

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

4

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

4

Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

4&5

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 5

32

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.

5

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Section/topic # Checklist item Reported on page #

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

5

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

5

RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions

at each stage, ideally with a flow diagram. 6

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

6

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 6 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each

intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. 6

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 6-8 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 6 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 6-8

DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance

to key groups (e.g., healthcare providers, users, and policy makers). 8-9

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

12

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

12

FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for

the systematic review. 1

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

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