Online Appendix to CCMED-D-10-00817



Online Appendix to CCMED-D-10-00817

This appendix contains the tabular and graphical data supporting the deliberations of the jury. While they are integral to the consensus document, conservative use of printed space prompted collection in an appendix available online in perpetuity.

The figures and table collected herein define the GRADE process of systematic analysis used in the deliberations.

• The “included studies” tables compare the trials included in each analysis. Funnel plots accompany those tables where the number of included studies is sufficient to make a visual estimate of the degree of symmetry.

• Summary of findings tables collect the GRADE evidence assessment and illuminate the rationale for each GRADE ranking. Each of these summary tables is referenced in the text.

Legend to Figures and Tables

Table 1: Organizers, speakers and jurors

Table 2: Studies defining levels of temperature management, degrees centigrade

Table 3: Different temperature ranges for target terms, degrees centigrade

Table 4: Physiological variables for consideration in planning and reporting targeted temperature management

Table 5: Randomized controlled trials evaluated comparing targeted temperature management to unstructured management in cardiac arrest. VF: ventricular fibrillation, VT: ventricular tachycardia, PEA: pulseless electrical activity, d/c: discharge, PAC: pulmonary artery catheter, SD: standard deviation.

Table 6: GRADE summary of findings table for jury analysis of targeted temperature management in ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest.

Table 7: GRADE summary of findings table for jury analysis of targeted temperature management in asystole/pulseless electrical activity out-of-hospital cardiac arrest.

Table 8. Controlled trials comparing targeted temperature management to unstructured management in perinatal asphyxia. D/C: discharge, SD: standard deviation. Numbers assessed for mortality are listed separately when follow-up was different for this outcome or the neurologic outcome was not assessed.

Table 9: GRADE summary of findings table for jury analysis of targeted temperature management in perinatal asphyxia.

Table 10: Randomized controlled trials evaluated comparing targeted temperature management to unstructured management in traumatic brain injury. NS: not stated, SD: standard deviation.

Table 11: GRADE summary of findings table for jury analysis of targeted temperature management in traumatic brain injury.

Figure 1. Schematic profile of targeted temperature management

Figure 2: Forest plot: targeted temperature management versus control for ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest, outcome of survival, follow-up range discharge to 6 months. M-H: Mantel-Haenszel test, CI: confidence interval.

Figure 3: Forest plot: targeted temperature management versus control for ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest, outcome of favorable neurologic outcome (cerebral-performance category of 1 (good recovery) or 2 (moderate disability), follow-up range discharge to 6 months. M-H: Mantel-Haenszel test, CI: confidence interval.

Figure 4: Forest plot: targeted temperature management versus control for asystole/pulseless electrical activity out-of-hospital cardiac arrest, outcome of survival, in-hospital follow-up. M-H: Mantel-Haenszel test, CI: confidence interval.

Figure 5: Forest plot: targeted temperature management versus control for asystole/pulseless electrical activity out-of-hospital cardiac arrest, favorable neurologic outcome, defined as no, mild or moderate disability by outcome score, in-hospital follow-up. M-H: Mantel Haenszel test, CI: confidence interval.

Figure 6: Forest plot of Holzer M et al.’s meta-analysis of targeted temperature management for cardiac arrest. Outcome: survival to hospital discharge with a favorable neurologic outcome. The risk ratio and 95% confidence interval (CI) are slightly different (1.52 [1.19, 1.95] versus 1.68 [1.29, 2.07]), likely the result of a slightly different statistical method. M-H: Mantel-Haenszel test.

Figure 7: Forest plot, target temperature management versus control for mortality in perinatal asphyxia, follow-up range: discharge to 18 months. M-H: Mantel-Haenszel test, CI: confidence interval.

Figure 8: Forest plot, targeted temperature management versus control for death or major disability, defined as severe disability in cognitive or outcomes index, in perinatal asphyxia, follow-up range: 6 to 22 months. M-H: Mantel-Haenszel test, CI: confidence interval.

Figure 9: Forest plot, targeted temperature management versus control for major disability in survivors, defined as severe disability in cognitive or outcomes index, in perinatal asphyxia, follow-up range: 6 to 22 months. M-H: Mantel-Haenszel test, CI: confidence interval.

Figure 10: Funnel plot: targeted temperature management for perinatal asphyxia, outcome of mortality. SE: standard error, OR: odds ratio.

Figure 11: Funnel plot: targeted temperature management for perinatal asphyxia, outcome of death or major disability, follow-up 6-22 months. SE: standard error, OR: odds ratio.

Figure 12: Funnel plot: targeted temperature management for perinatal asphyxia, outcome of major disability in survivors, follow-up range: 6 to 22 months. SE: standard error, OR: odds ratio.

Figure 13: Cochrane meta-analysis: Targeted temperature management for newborn hypoxic ischemic encephalopathy, outcome of mortality stratified by follow-up interval (Jacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis RG, 2009, The Cochrane Library). M-H: Mantel-Haenszel test, CI: confidence interval.

Figure 14: Cochrane meta-analysis: targeted temperature management for newborn hypoxic ischemic encephalopathy, outcome of death or major disability stratified by follow-up interval (Jacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis RG, 2009, The Cochrane Library). M-H: Mantel-Haenszel test, CI: confidence interval.

Figure 15: Forest plot, targeted temperature management versus control for mortality in traumatic brain injury, follow-up 3 to 24 months. M-H: Mantel Haenszel test, CI: confidence interval.

Figure 16: Forest plot, targeted temperature management versus control for favorable neurologic outcome in traumatic brain injury, defined as no, mild or moderate disability in cognitive or outcomes index, follow-up 3-24 months. M-H: Mantel-Haenszel test, CI: confidence interval.

Figure 17: Funnel plot: targeted temperature management for traumatic brain injury, outcome of mortality. SE: standard error, OR: odds ratio.

Figure 18: Funnel plot: targeted temperature management for traumatic brain injury, outcome of favorable neurologic outcome. SE: standard error, OR: odds ratio.

Figure 19: Cochrane meta-analysis: targeted temperature management for traumatic head injury, outcome: death at final follow-up (Sydenham E, Roberts I, Alderson P, 2009 The Cochrane Library). M-H: Mantel-Haenszel test, CI: confidence interval.

Figure 20: Cochrane meta-analysis: targeted temperature management for traumatic head injury, outcome: unfavorable neurological outcome at final follow-up (Sydenham E, Roberts I, Alderson P, 2009 The Cochrane Library) M-H: Mantel-Haenszel test, CI: confidence interval.

|Chairs |Scientific Advisors |

|Clifford S. Deutschman, MD, MC, FCCM |Patrick M. Kochanek, MD, FCCM |

|University of Pennsylvania School of Medicine |University of Pittsburgh Medical Center |

|Philadelphia, Pennsylvania, USA |Pittsburgh, Pennsylvania, USA |

| | |

|Antoinette Spevetz, MD, FCCM |Fritz Sterz, MD |

|Cooper University Hospital |Medical University of Vienna |

|Camden, New Jersey, USA |Wien, Austria |

|FACULTY |

|Peter Andrews, MD |Patrick M. Kochanek, MD, FCCM |

|Western General Hospital |University of Pittsburgh Medical Center |

|Edinburgh, Scotland, United Kingdom |Pittsburgh, Pennsylvania, USA |

| | |

|Wilhem Behringer, MD |Donald W. Marion, MD |

|Medizinische Universität Wien |Boston Medical Center |

|Vienna, Austria |Boston, Massachusetts, USA |

| | |

|Nicolas Deye, MD |Ken Nagao, MD |

|Lariboisière Hospital |Nihon University School of Medicine |

|Paris, France |Tokyo, Japan |

| | |

|W. Dalton Dietrich, PhD |Samuel M. Poloyac, PharmD, PhD |

|University of Miami School of Medicine |University of Pittsburgh School of Pharmacy |

|Miami, Florida, USA |Pittsburgh, Pennsylvania, USA |

| | |

|Michael N. Diringer, MD, FCCM |John T. Povlishock, PhD |

|Washington University School of Medicine |Virginia Commonwealth University |

|St. Louis, Missouri, USA |Richmond, Virginia, USA |

| | |

|Simon R. Dixon, MD |Stefan Schwab, MD |

|William Beaumont Hospital |University of Heidelberg |

|Royal Oak, Michigan, USA |Heidelberg, Germany |

| | |

|Larry M. Gentilello, MD |Seetha Shankaran, MD |

|University of Texas Southwestern Medical Center |Wayne State University School of Medicine |

|Dallas, Texas, USA |Detroit, Michigan, USA |

| | |

|Michael Holzer, MD |Fritz Sterz, MD |

|Medical University of Vienna |Medical University of Vienna |

|Wien, Austria |Wien, Austria |

| | |

|Jamie S. Hutchison, MD |Kjetil Sunde, MD, PhD |

|The Hospital for Sick Children |Ulleval University Hospital |

|Toronto, Ontario, Canada |Oslo, Norway |

| | |

|Francis Kim, MD |Samuel A. Tisherman, MD, FCCM |

|Harborview Medical Center |University of Pittsburgh Medical Center |

|Seattle, Washington, USA |Pittsburgh, Pennsylvania, USA |

| | |

|David S. Warner, MD | |

|Duke University Medical Center | |

|Durham, North Carolina, USA | |

|JURORS |

|Jury Chairman | |

|Timothy Buchman, MD, PhD, FCCM |Gloria M. Rodriguez-Vega, MD, FCCM |

|Washington University School of Medicine |University District Hospital |

|St. Louis, Missouri, USA |San Juan, Puerto Rico |

| | |

|Geoffrey J. Bellingan, MD |Sten Rubertsson, MD, PhD, FCCM |

|University College London Hospitals |Uppsala University Hospital |

|London, England, United Kingdom |Uppsala, Sweden |

| | |

|Roman Jaeschke, MD |Theodoros Vassilakopoulos, MD |

|McMaster University |Evangelismos Hospital |

|Hamilton, Ontario, Canada |Athens, Greece |

| | |

|Jacques Lacroix, MD |Craig Weinert, MD |

|University of Montreal |University of Minnesota |

|Montreal, Quebec, Canada |Minneapolis, Minnesota, USA |

| | |

|Bruno Mourvillier, MD |Sergio Zanotti-Cavazzoni, MD |

|Bichat Claude Bernard Hospital |Cooper University Hospital |

|Paris, France |Camden, New Jersey, USA |

| | |

|Mark E. Nunnally, MD | |

|University of Chicago | |

|Chicago, Illinois, USA | |

| | |

Table 1: Organizers, speakers and jurors

|Author | Mild | Moderate | Deep |

| Wong et al. (1) | 32-35 | 26-31 | 20-25 |

| Varnathan (2) | 32-35 | 26-31 | 20-25 |

| Zeiner et al. (3) | 34-36 | 28-33 | 17-27 |

| Reuler et al.(4) | 34-36 | 28-33 | 17-27 |

| Hammer et al. (5) | >32 | 28-32 | 20-28 |

| Safar and Behringer (6) | 33-36 | 28-32 | 11-27 |

| Werner (7) | 34-36 | 29-33 | 17-28 |

Table 2: Studies defining levels of temperature management, degrees centigrade

|Author | Pathology | Target Temperature | Term |

| Clifton et al. (8) | TBI | 33.0 | Moderate |

| Bernard (9) | Cardiac arrest | 33.0 | Moderate |

| THACAS Group (10) | Cardiac arrest | 32-34 | Mild |

| Todd et al. (11) | Cerebral Aneurysm | 32.5-33.5 | Mild |

| Shankaran (12) | Neonatal Asphyxia | 33.5 | Not Defined |

| Gluckman et al.(13) | Neonatal Asphyxia | 34-35 | Mild |

Table 3: Different temperature ranges for target terms, degrees centigrade

|Neurologic |Electroencephalogram (EEG) slowing, seizures, myoclonus |

| | |

|Cardiovascular |Heart rate, Arrhythmias, EKG abnormalities |

|  |Primary and Derived Hemodynamic measures (Cardiac Output (CO), Systemic |

| |Vascular Resistance (SVR)) |

|  |Fluid balance and use of vasoactive and inotropic agents |

|  |  |

|Respiratory |Increased use of mechanical ventilation (MV), MV days due to need for muscle |

| |relaxant and/or additional sedation or analgesia to prevent shivering |

|  |Oxygenation, saturation |

|  |Use of alpha-stat or pH stat management strategy (14) |

|  |  |

|Metabolic |Hyperglycemia; insulin requirements for glycemic control |

|  | |

|  |Acidosis assessments, including lactate levels |

|  |  |

|GI |Tolerance of enteral feeding; gastroparesis |

|  |Intestinal function; requirement for parenteral nutrition |

|  |Stress ulceration |

|  |  |

|Renal |Urine rates and volumes |

|  |Electrolyte abnormalities (e.g. K, Mg, PO4) |

|  |  |

|Hematologic |Increased blood viscosity (hemoconcentration) |

|  |Platelet dysfunction |

| |Bleeding |

|  |  |

|Shivering |Requirements of sedation, analgesia and/or muscle relaxant |

|  |CK (Creatine kinase) levels |

|Skin integrity |Pressure sore assessments |

| | |

|Infectious |Increased risk of infection |

| | |

|Pharmacokinetic |Reduced drug clearance |

Table 4: Physiological variables for consideration in planning and reporting targeted temperature management

|Study |

|Patient or population: patients with ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest |

|Settings: out-of hospital |

|Intervention: targeted temperature management (32-34 degrees C) |

|Comparison: control (less managed) |

|Outcomes |Illustrative comparative risks (95% CI) |Relative |No of |Quality of the |

| | |effect(95%|participants(|evidence(GRADE) |

| | |CI) |studies) | |

| |Assumed risk |Corresponding risk | | | |

| |Control (less |Targeted Temperature Management | | | |

| |managed) |(32-34 degrees C) | | | |

|Survival: Follow-up interval discharge|428 per 1000 |583 per 1000 (483 to 675) |OR 1.87 |403 (3 |moderatea |

|to 6 mo | | |(1.25 to |studies) | |

| | | |2.78) | | |

|Good outcome: CPC 1-2 @ 6mos (HACA) or|368 per 1000 |540 per 1000(435 to 644) |OR 2.02 |350(2 |moderatea |

|D/C home or rehab (Bernard) | | |(1.32 to |studies) | |

| | | |3.11) | | |

|The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and |

|its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95%|

|CI). CI: confidence interval; OR: odds ratio; CPC: Cerebral Performance Category; D/C: discharge |

|GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect.|

|Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the |

|estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is |

|likely to change the estimate. Very low quality: We are very uncertain about the estimate. |

|a Temperature > 37.5 degrees C in estimated 15% or more of controls in 2 studies. |

Table 6: GRADE summary of findings table for jury analysis of targeted temperature management in ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest.

|Targeted temperature management (32-34 degrees C) compared to control (less managed)) for asystole/pulseless ventricular activity cardiac |

|arrest |

|Patient or population: patients with non ventricular fibrillation cardiac arrestSettings: out-of hospitalIntervention: targeted |

|temperature management (32-34 degrees C)Comparison: control (less managed) |

|Outcomes |Illustrative comparative risks (95% CI) |Relative |No of |Quality of the |

| | |effect(95% |participants(s|evidence(GRADE) |

| | |CI) |tudies) | |

| |Assumed risk |Corresponding risk | | | |

| |Control (less |Targeted Temperature Management | | | |

| |managed) |(32-34 degrees C) | | | |

|Survival to discharge |167 per 1000 |101 per 1000(33 to 264) |OR 0.56 |104(2 studies)|very lowa,b,c |

| | | |(0.17 to | | |

| | | |1.79) | | |

|Outcome Performance Category 1-2 |Medium risk populationd |OR 5 (0.22 |30(1 study) |lowe |

|@ discharge | |to 113.5) | | |

| |10 per 1000 |48 per 1000(2 to 534) | | | |

|The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and |

|its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95%|

|CI). CI: confidence interval; OR: odds ratio |

|GRADE Working Group grades of evidence: High quality: Further research is very unlikely to change our confidence in the estimate of |

|effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may |

|change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect |

|and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |

|a Kim et al: patients received variable amounts of cooling before admission, after admission at the discretion of receiving physician. b |

|Nonsignificant tests for heterogeneity (p=0.09), but an I squared of 65% with poorly-overlapping confidence intervals. Only 14 events in |

|total. c Results using the fixed model were not significant (p=0.33). d The probability of a good outcome in this small study was zero for|

|the control group; for the purposes of calculation we have assumed this probability to be 1%.e Results using the fixed effects model were |

|not significant (p=0.31). Only 2 events in total. |

Table 7: GRADE summary of findings table for jury analysis of targeted temperature management in asystole/pulseless electrical activity out-of-hospital cardiac arrest.

|Study |

|Patient or population: patients with perinatal asphyxia |

|Settings: in-hospital |

|Intervention: targeted temperature management (32.5-36.5 degrees C) |

|Comparison: control (less managed) |

|Outcomes |Illustrative comparative risks (95% CI) |Relative |No of |Quality of the |

| | |effect(95% CI) |participants(st|evidence(GRADE) |

| | | |udies) | |

| |Assumed risk |Corresponding risk | | | |

| |Control (less |Targeted Temperature | | | |

| |managed) |Management (32.5-36.5 | | | |

| | |degrees C) | | | |

|Death: Follow-up interval |302 per 1000 |243 per 1000(184 to 312) |OR 0.74 (0.52 to |677(8 studies) |lowa,b |

|discharge to 18 months | | |1.05) | | |

|Death or severe disability: |601 per 1000 |444 per 1000(364 to 534) |OR 0.53 (0.38 to |548(5 studies) |moderatec |

|Follow-up interval 6-22 months | | |0.76) | | |

|Severe disability in survivors: |389 per 1000 |259 per 1000(182 to 351) |OR 0.55 (0.35 to |380(5 studies) |moderatec |

|Follow-up interval 6-22 months | | |0.85) | | |

|The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and |

|its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% |

|CI). CI: confidence interval; OR: odds ratio |

|GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. |

|Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the |

|estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is |

|likely to change the estimate. Very low quality: We are very uncertain about the estimate. |

|a Temperature > 37.5 degrees C in estimated 15% or more controls in 7 studies, no data in 1 study. |

|b Results nonsignificant: OR 0.74 [0.52, 1.05]. |

|c Temperature > 37.5 degrees C in estimated 15% or more of controls in 4 studies, no data in 1 study. |

Table 9: GRADE summary of findings table for jury analysis of targeted temperature management in perinatal asphyxia.

|Study |

|Patient or population: patients with traumatic brain injury |

|Settings: in-hospital |

|Intervention: targeted temperature management (32-35 degrees C) |

|Comparison: control (less managed) |

|Outcomes |Illustrative comparative risks (95% CI) |Relative |No of |Quality of the |

| | |effect (95% |participants(s|evidence(GRADE) |

| | |CI) |tudies) | |

| |Assumed risk |Corresponding risk | | | |

| |Control (less |Targeted Temperature Management| | | |

| |managed) |(32-35 degrees C) | | | |

|Death: Follow-up interval |291 per 1000 |223 per 1000(165 to 293) |OR 0.7 (0.48 |1702(15 |lowa,b |

|discharge-24mo | | |to 1.01) |studies) | |

|Favorable neurologic outcome |460 per 1000 |594 per 1000(497 to 686) |OR 1.72 (1.16 |1715(16 |lowc,d |

|(GOS 4-5, CPC 1-3 @ 3-12mo) | | |to 2.56) |studies) | |

|The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding |

|risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the |

|intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio; GOS: Glasgow Outcome Score; CPC: Cerebral Performance |

|Category |

|GRADE Working Group grades of evidence: High quality: Further research is very unlikely to change our confidence in the estimate|

|of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect |

|and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the |

|estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |

|a I squared = 50%, Significant test for heterogeneity. |

|b Temperature > 37.5 degrees in estimated 15% or more of controls in 8 studies, no data in 4 studies. |

|c I squared = 66%, significant test for heterogeneity. |

|d Temperature > 37.5 degrees in estimated 15% or more of controls in 8 studies, no data in 5 studies. |

Table 11: GRADE summary of findings table for jury analysis of targeted temperature management in traumatic brain injury.

[pic]

Figure 1. Schematic Profile of Targeted Temperature Management

[pic]

Figure 2: Forest plot: targeted temperature management versus control for ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest, outcome of survival, follow-up range discharge to 6 months. M-H: Mantel-Haenszel test, CI: Confidence interval.

[pic]

Figure 3: Forest plot: targeted temperature management versus control for ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest, outcome of favorable neurologic outcome (cerebral-performance category of 1 (good recovery) or 2 (moderate disability), follow-up range discharge to 6 months. M-H: Mantel-Haenszel test, CI: Confidence interval.

[pic]

Figure 4: Forest plot: targeted temperature management versus control for asystole/pulseless electrical activity out-of-hospital cardiac arrest, outcome of survival, in-hospital follow-up. M-H: Mantel-Haenszel test, CI: Confidence interval.

[pic]

Figure 5: Forest plot: targeted temperature management versus control for asystole/pulseless electrical activity out-of-hospital cardiac arrest, favorable neurologic outcome, defined as no, mild or moderate disability by outcome score, in-hospital follow-

[pic]

Figure 6: Forest plot of Holzer M et al.’s meta-analysis of targeted temperature management for cardiac arrest. Outcome: survival to hospital discharge with a favorable neurologic outcome. The Risk Ratio and 95% Confidence Interval (CI) are slightly different (1.52 [1.19, 1.95] versus 1.68 [1.29, 2.07]), likely the result of a slightly different statistical method. M-H: Mantel-Haenszel test.

[pic]

Figure 7: Forest plot, target temperature management versus control for mortality in perinatal asphyxia, follow-up range: discharge to 18 months. M-H: Mantel-Haenszel test, CI: confidence interval.

[pic]

Figure 8: Forest plot, targeted temperature management versus control for death or major disability, defined as severe disability in cognitive or outcomes index, in perinatal asphyxia, follow-up range: 6 to 22 months. M-H: Mantel-Haenszel test, CI: confidence interval.

[pic]

Figure 9: Forest plot, targeted temperature management versus control for major disability in survivors, defined as severe disability in cognitive or outcomes index, in perinatal asphyxia, follow-up range: 6 to 22 months. M-H: Mantel-Haenszel test, CI: confidence interval.

[pic]

Figure 10: Funnel plot: targeted temperature management for perinatal asphyxia, outcome of mortality. SE: Standard error, OR: Odds ratio.

[pic]

Figure 11: Funnel plot: targeted temperature management for perinatal asphyxia, outcome of death or major disability, follow-up 6-22 months. SE: Standard error, OR: Odds ratio.

[pic]

Figure 12: Funnel plot: targeted temperature management for perinatal asphyxia, outcome of major disability in survivors, follow-up range: 6 to 22 months. SE: Standard error, OR: Odds ratio.

[pic]

Figure 13: Cochrane Meta-Analysis: Targeted temperature management for newborn hypoxic ischemic encephalopathy, outcome of mortality stratified by follow-up interval (Jacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis RG, 2009, The Cochrane Library). M-H: Mantel-Haenszel test, CI: confidence interval.

[pic]

Figure 14: Cochrane Meta-Analysis: targeted temperature management for newborn hypoxic ischemic encephalopathy, outcome of death or major disability stratified by follow-up interval (Jacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis RG, 2009, The Cochrane Library). M-H: Mantel-Haenszel test, CI: confidence interval.

[pic]

Figure 15: Forest Plot, targeted temperature management (TTM) versus control for mortality in traumatic brain injury, follow-up 3 to 24 months. M-H: Mantel Haenszel test, CI: Confidence interval.

[pic]

Figure 16: Forest plot, targeted temperature management (TTM) versus control for favorable neurologic outcome in traumatic brain injury, defined as no, mild or moderate disability in cognitive or outcomes index, follow-up 3-24 months. M-H: Mantel-Haenszel test, CI: Confidence interval.

[pic]

Figure 17: Funnel plot: targeted temperature management for traumatic brain injury, outcome of mortality. SE: Standard error, OR: Odds ratio.

[pic]

Figure 18: Funnel plot: targeted temperature management for traumatic brain injury, outcome of favorable neurologic outcome. SE: Standard error, OR: Odds ratio.

[pic]

Figure 19: Cochrane Meta-Analysis: targeted temperature management for traumatic head injury, outcome: death at final follow-up (Sydenham E, Roberts I, Alderson P, 2009 The Cochrane Library). M-H: Mantel-Haenszel test, CI: confidence interval.

[pic]

Figure 20: Cochrane Meta-Analysis: targeted temperature management for traumatic head injury, outcome: unfavorable neurological outcome at final follow-up (Sydenham E, Roberts I, Alderson P, 2009 The Cochrane Library) M-H: Mantel-Haenszel test, CI: confidence interval.

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