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: MantelHaenszel 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 followup (Sydenham E, Roberts I, Alderson P, 2009 The Cochrane Library) M-H:
Mantel-Haenszel test, CI: confidence interval.
Chairs
Clifford S. Deutschman, MD, MC, FCCM
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania, USA
Scientific Advisors
Patrick M. Kochanek, MD, FCCM
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, USA
Antoinette Spevetz, MD, FCCM
Cooper University Hospital
Camden, New Jersey, USA
Fritz Sterz, MD
Medical University of Vienna
Wien, Austria
FACULTY
Peter Andrews, MD
Western General Hospital
Edinburgh, Scotland, United Kingdom
Patrick M. Kochanek, MD, FCCM
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, USA
Wilhem Behringer, MD
Medizinische Universität Wien
Vienna, Austria
Donald W. Marion, MD
Boston Medical Center
Boston, Massachusetts, USA
Nicolas Deye, MD
Lariboisière Hospital
Paris, France
Ken Nagao, MD
Nihon University School of Medicine
Tokyo, Japan
W. Dalton Dietrich, PhD
University of Miami School of Medicine
Miami, Florida, USA
Samuel M. Poloyac, PharmD, PhD
University of Pittsburgh School of Pharmacy
Pittsburgh, Pennsylvania, USA
Michael N. Diringer, MD, FCCM
Washington University School of Medicine
St. Louis, Missouri, USA
John T. Povlishock, PhD
Virginia Commonwealth University
Richmond, Virginia, USA
Simon R. Dixon, MD
William Beaumont Hospital
Royal Oak, Michigan, USA
Stefan Schwab, MD
University of Heidelberg
Heidelberg, Germany
Larry M. Gentilello, MD
University of Texas Southwestern Medical
Center
Dallas, Texas, USA
Seetha Shankaran, MD
Wayne State University School of Medicine
Detroit, Michigan, USA
Michael Holzer, MD
Medical University of Vienna
Wien, Austria
Jamie S. Hutchison, MD
The Hospital for Sick Children
Toronto, Ontario, Canada
Francis Kim, MD
Harborview Medical Center
Seattle, Washington, USA
Fritz Sterz, MD
Medical University of Vienna
Wien, Austria
Kjetil Sunde, MD, PhD
Ulleval University Hospital
Oslo, Norway
Samuel A. Tisherman, MD, FCCM
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, USA
David S. Warner, MD
Duke University Medical Center
Durham, North Carolina, USA
JURORS
Jury Chairman
Timothy Buchman, MD, PhD, FCCM
Washington University School of Medicine
St. Louis, Missouri, USA
Gloria M. Rodriguez-Vega, MD, FCCM
University District Hospital
San Juan, Puerto Rico
Geoffrey J. Bellingan, MD
University College London Hospitals
London, England, United Kingdom
Sten Rubertsson, MD, PhD, FCCM
Uppsala University Hospital
Uppsala, Sweden
Roman Jaeschke, MD
McMaster University
Hamilton, Ontario, Canada
Theodoros Vassilakopoulos, MD
Evangelismos Hospital
Athens, Greece
Jacques Lacroix, MD
University of Montreal
Montreal, Quebec, Canada
Craig Weinert, MD
University of Minnesota
Minneapolis, Minnesota, USA
Bruno Mourvillier, MD
Bichat Claude Bernard Hospital
Paris, France
Sergio Zanotti-Cavazzoni, MD
Cooper University Hospital
Camden, New Jersey, USA
Mark E. Nunnally, MD
University of Chicago
Chicago, Illinois, USA
Table 1: Organizers, speakers and jurors
Author
Wong et al. (1)
Varnathan (2)
Zeiner et al. (3)
Reuler et al.(4)
Hammer et al. (5)
Safar and Behringer (6)
Werner (7)
Mild
32-35
32-35
34-36
34-36
>32
33-36
34-36
Moderate
26-31
26-31
28-33
28-33
28-32
28-32
29-33
Deep
20-25
20-25
17-27
17-27
20-28
11-27
17-28
Table 2: Studies defining levels of temperature management, degrees
centigrade
Author
Clifton et al. (8)
Bernard (9)
THACAS Group (10)
Todd et al. (11)
Shankaran (12)
Gluckman et al.(13)
Pathology
TBI
Cardiac arrest
Cardiac arrest
Cerebral Aneurysm
Neonatal Asphyxia
Neonatal Asphyxia
Target Temperature
33.0
33.0
32-34
32.5-33.5
33.5
34-35
Term
Moderate
Moderate
Mild
Mild
Not Defined
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
Skin integrity
Requirements of sedation, analgesia and/or
muscle relaxant
CK (Creatine kinase) levels
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
Numbers of Patients
Assessed for Outcome
Arrest
Rhythm
Study
Studied
1. Bernard SA VF
2002 (9)
Randomize
d
Participants
77
VF/
VT
77
Mortality
(reported
separate from Neurologic
Neuro
Outcome:
outcome)
(follow-up)
77
(hospital d/c)
Age (mean
or
median),
years
66a
Intentio
Allocation
n to
Blinding Concealment? Treat?
Unblinded No
Yes
2. HachimiAsystole/PE 30
0
30
75
Unblinded
Idrissi S 2001 A
(unspecified)
(median)
(15)
3. Holzer M
VF, Pulseless 275
265
275
273
59
Unblinded
(HACA) 2002 VT, asystole
(6mo)
(median)
(10)
4. Kim F 2007 VF & PEA 125
51
125
66
Unblinded
(16)
(no VT seen)
(hospital d/c)
Intention to Treat presumed if follow-up numbers reported and no mention of crossover.
Portion of patients with T>37.5 degrees C based on SD data or error bars and assumption of a normal distribution.
a
average of group medians.
Durati
Target
on of
Tempera
Targe
ture
ting
Indirectness
33C
12h
>15% of controls
tympanic or
estimated T>37.5C
bladder,
until PAC
inserted
34C bladder 4h
Unclear data on control
temp
Yes
Yes
Yes
Yes
32-34C
24h
Yes
Yes
Not
Specified
Not
Fever in <15% of
specified controls
>15% of controls
estimated T>37.5C
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.
Targeted temperature management (32-34 degrees C) compared to control (less managed) for ventricular
fibrillation/pulseless ventricular tachycardia cardiac arrest
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
managed)
Targeted Temperature
Management (32-34 degrees
C)
428 per 1000
583 per 1000 (483 to 675)
OR 1.87 403 (3
(1.25 to studies)
2.78)
moderatea
Good outcome: CPC 1-2 @ 6mos 368 per 1000
(HACA) or D/C home or rehab
(Bernard)
540 per 1000(435 to 644)
OR 2.02 350(2
(1.32 to studies)
3.11)
moderatea
Survival: Follow-up interval
discharge to 6 mo
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)
Assumed risk
Corresponding risk
Relative No of
Quality of the
effect(95% participants( evidence(GRADE)
CI)
studies)
Control (less Targeted Temperature
managed)
Management (32-34 degrees
C)
Survival to discharge
167 per 1000
Outcome Performance
Category 1-2 @ discharge
Medium risk populationd
10 per 1000
101 per 1000(33 to 264)
OR 0.56
(0.17 to
1.79)
104(2
studies)
OR 5 (0.22 30(1 study)
to 113.5)
very lowa,b,c
lowe
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.
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.
b
Number of Patients
Assessed for Outcome
Randomized
Study
Participants
1. Eicher DJ 2005 (18) 65
Mortality
65
(12mo)
2. Gluckman PD 2005 234
(13)
3. Gunn AJ 1998 (19) 22
22
4. Lin ZL 2006 (20)
62
62
5. Robertson NJ 2008 36
(21)
6. Shankaran S 2002 19
(22)
7. Shankaran S 2005 208
(12), 2008 (23)
8. Zhou WH 2002 (24) 50
36
Neurologic
Outcome,
Including Death:
(Follow-Up)
53
(12mo)
218
(18mo)
22
(12mo)
58
(5-7d)a
17
(17d)
19
(D/C)
205
(18mo)
50
(6mo)
Blinding
Unblinded
Allocation
Concealment?
Yes
Intention to treat?
Yes
Unblinded
Yes
Yes
Unblinded
Yes
Yes
Unblinded
No
(odd or even day)
Yes
Yes
Unblinded
Unblinded
Yes
Yes
Unblinded
Yes
Yes
Unblinded
No
Yes
Yes
Duration
of
Targetin
g
Indirectness
48h
>15% of controls
estimated T>37.5C
72h
No data on control
temp
35.5-36.5C
72h
>15% of controls
rectal (2 groups)
estimated T>37.5C
34-35C rectal 72h
>15% of controls
estimated T>37.5C
33-34C rectal 72h
>15% of controls
estimated T>37.5C
34.5C
72h
>15% of controls
esophageal
estimated T>37.5C
33.5C
72h
>15% of controls
esophageal
estimated T>37.5C
34.5 (SD 0.3) C 72h
>15% of controls
rectal, 34.0 (SD
estimated T>37.5C
0.2) C
nasopharyngeal
(2 groups)
Target
Temperature
32.5-33.5C
rectal
34-35C rectal
Intention to Treat presumed if follow-up numbers reported and no mention of crossover.
Proportion of patients with T>37.5 degrees C based on SD data or error bars and assumption of a normal distribution.
a
: Head CT findings. Not included in disability assessment.
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.
Targeted temperature management (32.5-36.5 degrees C) compared to control (less managed ) for perinatal asphyxia
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)
Assumed risk
Corresponding risk
Relative
effect(95% CI)
No of
Quality of the
participants(s evidence(GRADE)
tudies)
Control (less Targeted Temperature
managed)
Management (32.5-36.5
degrees C)
Death: Follow-up interval
discharge to 18 months
302 per 1000
243 per 1000(184 to 312) OR 0.74 (0.52 to 677(8 studies) lowa,b
1.05)
Death or severe disability:
Follow-up interval 6-22
months
601 per 1000
444 per 1000(364 to 534) OR 0.53 (0.38 to 548(5 studies) moderatec
0.76)
389 per 1000
Severe disability in
survivors: Follow-up interval
6-22 months
259 per 1000(182 to 351) OR 0.55 (0.35 to 380(5 studies) moderatec
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.
Number of patients assessed
Age
(mean or
median),
years
Blinding
6.91
Unblinded
Duration
of
Targetin
g
48h
45
NS (Adult) Unblinded
Intentio
Target
Allocation
n to
Tempera
Concealment? treat?
ture
Yes
2 TTM pts 32-33C
to control rectal
Unclear
Yes
32-34C
rectal
Yes
Yes
33C PAC
4. Clifton GL 2001(8) 392
368
31.5
Unblinded
Yes
Yes
33C bladder 48h
5. Hutchison JS 2008
(28)
225
205
10.0
Unblinded
Yes
Yes
6. Jiang J 2000 (29)
87
87 (12mo)
41.4
Unblinded
Unclear
Yes
7. Liu WG 2006 (30)
66
66 (24mo)
40.6
Unblinded
Unclear
Yes
8. Marion DW 1993
(31)
9. Marion DW 1997
(32)
10. Qiu W 2005 (33)
40
40
32.0
Unblinded
Yes
Yes
32.5 (SD
0.5) C
esophageal
33-35C
rectal
33-35C
rectal, 3335C brain
group
33C brain
82
82
81 (12mo)
33
Unblinded
Yes
Yes
86 (24mo)
41.2
Unblinded
No
Yes
11. Shiozaki T 1993
(34)
12. Shiozaki T 1999
(35)
13. Shiozaki T 2001
(36)
14. Smrcka M 2005
(37)
15. Wang W 2005 (38)
33
33
35.4
Unblinded
Unclear
Yes
16
16
35.8
Unblinded
Unclear
Yes
Unblinded
Unclear
Yes
72
72
NS
(1pt<9yr)
41
Unblinded
Unclear
Yes
40
40a
NS
Unblinded
Unclear
Yes
16. Zhi D 2003 (39)
396
396
42.5
Unblinded
Unclear
Yes
Random
Study
ized
1. Adelson PD 2005
75
(25)
2. Biswas AK 2002
21
(26)
3. Clifton GL 1993 (27) 46
Hospital
death
75
Neurologic Outcome
3mo
6mo
69
67
21
18
45
82
86
91
91
other
14 (12mo)
6.21
Unblinded
48h
48h
24h
Indirectness
>15% of controls
estimated T>37.5C
>15% of controls
estimated T>37.5C
>15% of controls
estimated T>37.5C
>15% of controls
estimated T>37.5C
Fever in <15% of
controls
3-14d, based >15% of controls
on ICP
estimated T>37.5C
72h
No data on control
temp
24h
>15% of controls
estimated T>37.5C
32-33C
24h
>15% of controls
rectal
estimated T>37.5C
33-35C
3-5d (mean >15% of controls
nasopharyng 4.3d)
estimated T>37.5C
eal or brain
33.5-34.5C 48h
No data on control
bladder
temp
33.5-34.5C 48h
Fever in <15% of
intracranial
controls
33.5-34.5C 48h
Fever in <15% of
core or brain
controls
34C bladder 72h
No data on control
temp
33.5-34.5C 48h
No data on control
intracranial
temp
32-35C
1-7d (mean No data on control
rectal
(SD)
temp
62(28)h)
Intention to Treat presumed if follow-up numbers reported and no mention of crossover.
Proportion of patients with T>37.5 degrees C based on SD data or error bars and assumption of a normal distribution.
a
: Favorable outcome did not include moderate disability.
Table 10: Randomized controlled trials evaluated comparing targeted temperature
management to unstructured management in traumatic brain injury. NS: not stated, SD:
standard deviation.
Targeted temperature management (32-35 degrees C) compared to control (less managed) for traumatic brain
injury
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)
Assumed risk Corresponding risk
Relative
No of
Quality of the
effect (95% participants( evidence(GRAD
CI)
studies)
E)
Control (less Targeted Temperature
managed)
Management (32-35
degrees C)
291 per 1000 223 per 1000(165 to 293)
OR 0.7 (0.48 1702(15
to 1.01)
studies)
lowa,b
460 per 1000 594 per 1000(497 to 686)
Favorable neurologic
outcome (GOS 4-5, CPC 1-3
@ 3-12mo)
OR 1.72
1715(16
(1.16 to 2.56) studies)
lowc,d
Death: Follow-up interval
discharge-24mo
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.
Targeted Temperature Management
Core Temperature (Degrees C)
37
Induction phase.
Typically, cooling as
fast as possible, at
least 3⁰C/hr
36
35
Maintenance phase.
Control to within 0.5 ⁰C
34
Reversion phase.
Managed recovery to
target level, typically
normal or just below
normal, warming rates
typically 0.3 ⁰C/hr
33
32
31
0
500
1000
1500
2000
2500
3000
Profile Time (minutes)
Figure 1. Schematic Profile of Targeted Temperature Management
Study or Subgroup
Bernard S 2002
Holzer HACA 2002
Kim F 2007
Experimental
Control
Events Total Events Total Weight
21
43
11
34 17.7%
81
137
62 138 71.2%
19
29
10
22 11.1%
Total (95% CI)
209
194 100.0%
Total events
121
83
Heterogeneity: Chi² = 0.18, df = 2 (P = 0.91); I² = 0%
Test for overall effect: Z = 3.08 (P = 0.002)
Odds Ratio
M-H, Fixed, 95% CI
2.00 [0.78, 5.08]
1.77 [1.10, 2.86]
2.28 [0.73, 7.10]
Odds Ratio
M-H, Fixed, 95% CI
1.87 [1.25, 2.78]
0.01
0.1
1
10
100
Favours control Favours experimental
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: MantelHaenszel test, CI: Confidence interval.
Study or Subgroup
Bernard S 2002
Holzer HACA 2002
Experimental
Control
Events Total Events Total Weight
21
43
9
34 17.3%
74
136
54
137 82.7%
Total (95% CI)
179
171 100.0%
Total events
95
63
Heterogeneity: Chi² = 0.45, df = 1 (P = 0.50); I² = 0%
Test for overall effect: Z = 3.11 (P = 0.002)
Odds Ratio
M-H, Fixed, 95% CI
2.65 [1.01, 6.98]
1.83 [1.13, 2.97]
Odds Ratio
M-H, Fixed, 95% CI
1.98 [1.29, 3.04]
0.01
0.1
1
10
100
Favours control Favours experimental
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.
Study or Subgroup
Hachimi-Idrissi 2001
Kim F 2007
Experimental
Control
Events Total Events Total Weight
3
16
1
14 11.1%
2
34
8
40 88.9%
Total (95% CI)
50
54 100.0%
Total events
5
9
Heterogeneity: Chi² = 2.84, df = 1 (P = 0.09); I² = 65%
Test for overall effect: Z = 0.98 (P = 0.33)
Odds Ratio
M-H, Fixed, 95% CI
3.00 [0.27, 32.75]
0.25 [0.05, 1.27]
Odds Ratio
M-H, Fixed, 95% CI
0.56 [0.17, 1.79]
0.01
0.1
1
10
100
Favours control Favours experimental
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.
Study or Subgroup
Hachimi-Idrissi 2001
Experimental
Control
Events Total Events Total Weight
2
16
0
14 100.0%
Total (95% CI)
16
Total events
2
Heterogeneity: Not applicable
Test for overall effect: Z = 1.01 (P = 0.31)
14 100.0%
Odds Ratio
M-H, Fixed, 95% CI
5.00 [0.22, 113.50]
Odds Ratio
M-H, Fixed, 95% CI
5.00 [0.22, 113.50]
0
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-
0.01
0.1
1
10
100
Favours control Favours experimental
Study or Subgroup
Bernard SA 2002
HACA 2002
Hachimi-Idrissi S 2001
Experimental
Control
Events Total Events Total Weight
21
43
9
34 15.2%
72
136
50 137 84.0%
3
16
0
17
0.7%
Total (95% CI)
195
188 100.0%
Total events
96
59
Heterogeneity: Tau² = 0.00; Chi² = 1.67, df = 2 (P = 0.43); I² = 0%
Test for overall effect: Z = 3.31 (P = 0.0009)
Risk Ratio
M-H, Random, 95% CI
1.84 [0.97, 3.49]
1.45 [1.11, 1.90]
7.41 [0.41, 133.11]
Risk Ratio
M-H, Random, 95% CI
1.52 [1.19, 1.95]
0.01
0.1
1
10
100
Favours control Favours experimental
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.
Study or Subgroup
Battin MR 2001
Eicher DJ 2005
Gluckman PD 2005
Gunn AJ 1998
Lin ZL 2006
Robertson N 2008
Shankaran S 2002
Shankaran S 2005
Zhou WH 2002
Experimental
Control
Events Total Events Total Weight
3
25
3
15
4.3%
10
32
14
33 12.4%
36
108
42 110 36.4%
2
12
2
10
2.4%
2
32
2
30
2.5%
7
21
1
15
1.0%
2
9
3
10
2.9%
24
102
38 103 38.0%
0
23
0
27
Total (95% CI)
364
353 100.0%
Total events
86
105
Heterogeneity: Chi² = 5.50, df = 7 (P = 0.60); I² = 0%
Test for overall effect: Z = 1.81 (P = 0.07)
Odds Ratio
M-H, Fixed, 95% CI
0.55 [0.09, 3.13]
0.62 [0.22, 1.71]
0.81 [0.46, 1.41]
0.80 [0.09, 7.00]
0.93 [0.12, 7.08]
7.00 [0.76, 64.61]
0.67 [0.08, 5.30]
0.53 [0.29, 0.97]
Not estimable
Odds Ratio
M-H, Fixed, 95% CI
0.73 [0.52, 1.03]
0.01
0.1
1
10
100
Favours experimental Favours control
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.
Study or Subgroup
Battin MR 2001
Eicher DJ 2005
Gluckman PD 2005
Gunn AJ 1998
Shankaran S 2005
Zhou WH 2002
Experimental
Control
Events Total Events Total Weight
7
25
4
13
4.2%
14
27
19
26 10.3%
59
108
73 110 36.3%
3
12
3
10
2.7%
43
102
63 103 40.1%
5
23
8
27
6.4%
Total (95% CI)
297
289 100.0%
Total events
131
170
Heterogeneity: Chi² = 1.41, df = 5 (P = 0.92); I² = 0%
Test for overall effect: Z = 3.48 (P = 0.0005)
Odds Ratio
M-H, Fixed, 95% CI
0.88 [0.20, 3.79]
0.40 [0.13, 1.25]
0.61 [0.35, 1.06]
0.78 [0.12, 5.10]
0.46 [0.26, 0.81]
0.66 [0.18, 2.40]
Odds Ratio
M-H, Fixed, 95% CI
0.55 [0.39, 0.77]
0.01
0.1
1
10
100
Favours experimental Favours control
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.
Study or Subgroup
Battin MR 2001
Eicher DJ 2005
Gluckman PD 2005
Gunn AJ 1998
Shankaran S 2005
Zhou WH 2002
Experimental
Control
Events Total Events Total Weight
4
22
1
10
2.1%
4
17
5
12
8.2%
23
72
31
68 39.7%
1
10
1
8
1.8%
19
78
25
65 37.7%
5
23
8
27 10.5%
Total (95% CI)
222
190 100.0%
Total events
56
71
Heterogeneity: Chi² = 1.40, df = 5 (P = 0.92); I² = 0%
Test for overall effect: Z = 2.51 (P = 0.01)
Odds Ratio
M-H, Fixed, 95% CI
2.00 [0.19, 20.61]
0.43 [0.09, 2.14]
0.56 [0.28, 1.11]
0.78 [0.04, 14.75]
0.52 [0.25, 1.06]
0.66 [0.18, 2.40]
Odds Ratio
M-H, Fixed, 95% CI
0.58 [0.38, 0.89]
0.01
0.1
1
10
100
Favours experimental Favours control
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.
Experimental
Control
Study or Subgroup
Events Total Events Total Weight
1.2.2 Long term Follow-up 18-22 months
Gluckman 2005
36
108
42 110 39.0%
Gunn 1998
3
18
3
13
3.3%
Shankaran 2005
24
102
38 103 35.4%
Subtotal (95% CI)
228
226 77.7%
Total events
63
83
Heterogeneity: Chi² = 1.22, df = 2 (P = 0.54); I² = 0%
Test for overall effect: Z = 2.00 (P = 0.05)
1.2.3 Short-term Folow-up 12 months or less
Akisu 2003
0
11
2
Eicher 2005
10
32
14
ICE 2002
1
7
3
Lin 2006
2
32
2
Shankaran 2002
2
9
3
Subtotal (95% CI)
91
Total events
15
24
Heterogeneity: Chi² = 1.09, df = 4 (P = 0.90); I² = 0%
Test for overall effect: Z = 1.47 (P = 0.14)
10
33
10
30
10
93
Risk Ratio
M-H, Fixed, 95% CI
Risk Ratio
M-H, Fixed, 95% CI
0.87 [0.61, 1.25]
0.72 [0.17, 3.03]
0.64 [0.41, 0.98]
0.76 [0.58, 0.99]
2.4%
12.9%
2.3%
1.9%
2.7%
22.3%
0.18 [0.01, 3.41]
0.74 [0.38, 1.41]
0.48 [0.06, 3.69]
0.94 [0.14, 6.24]
0.74 [0.16, 3.48]
0.67 [0.39, 1.15]
Total (95% CI)
319
319 100.0%
Total events
78
107
Heterogeneity: Chi² = 2.40, df = 7 (P = 0.93); I² = 0%
Test for overall effect: Z = 2.45 (P = 0.01)
Test for subgroup differences: Not applicable
0.74 [0.58, 0.94]
0.01
0.1
1
10
100
Favours experimental Favours control
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.
Experimental
Control
Study or Subgroup
Events Total Events Total Weight
1.1.1 High quality follow-up at 18-22 months
Gluckman 2005
59
108
73 110 44.5%
Gunn 1998
7
18
4
13
2.9%
Shankaran 2005
45
102
64 103 39.2%
Subtotal (95% CI)
228
226 86.6%
Total events
111
141
Heterogeneity: Chi² = 1.60, df = 2 (P = 0.45); I² = 0%
Test for overall effect: Z = 2.82 (P = 0.005)
1.1.2 Lower quality follow-up at 12 months
Eicher 2005
14
27
21
Subtotal (95% CI)
27
Total events
14
21
Heterogeneity: Not applicable
Test for overall effect: Z = 2.35 (P = 0.02)
25
25
Risk Ratio
M-H, Fixed, 95% CI
Risk Ratio
M-H, Fixed, 95% CI
0.82 [0.66, 1.02]
1.26 [0.46, 3.44]
0.71 [0.54, 0.93]
0.79 [0.67, 0.93]
13.4%
13.4%
0.62 [0.41, 0.92]
0.62 [0.41, 0.92]
Total (95% CI)
255
251 100.0%
Total events
125
162
Heterogeneity: Chi² = 2.80, df = 3 (P = 0.42); I² = 0%
Test for overall effect: Z = 3.42 (P = 0.0006)
Test for subgroup differences: Not applicable
0.76 [0.65, 0.89]
0.01
0.1
1
10
100
Favours experimental Favours control
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.
Study or Subgroup
Adelson PD 2005
Biswas AK 2002
Clifton GL 1993
Clifton GL 2001
Hutchinson JS 2008
Jiang J 2000
Liu WG 2006
Marion DW 1993
Marion DW 1997
Qiu W 2005
Shiozaki T 1993
Shiozaki T 1999
Shiozaki T2001
Smrcka M 2005
Zhi D 2002
TTM (32-35)
Control (36.5-38.5)
Events Total
Events
Total Weight
7
37
7
38
6.3%
3
10
0
11
1.3%
8
23
8
22
5.9%
53
190
48
178 13.4%
23
108
14
117 10.2%
11
43
20
44
8.4%
11
43
12
23
7.0%
0
20
2
20
1.3%
9
39
10
42
7.3%
11
43
22
43
8.3%
8
16
14
17
4.1%
0
8
0
8
8
45
6
46
6.4%
5
35
11
37
6.2%
51
198
72
198 13.8%
Total (95% CI)
858
844 100.0%
Total events
208
246
Heterogeneity: Tau² = 0.21; Chi² = 26.40, df = 13 (P = 0.02); I² = 51%
Test for overall effect: Z = 1.77 (P = 0.08)
Odds Ratio
M-H, Random, 95% CI
1.03 [0.32, 3.30]
10.73 [0.48, 238.90]
0.93 [0.28, 3.16]
1.05 [0.66, 1.66]
1.99 [0.97, 4.11]
0.41 [0.17, 1.02]
0.32 [0.11, 0.92]
0.18 [0.01, 4.01]
0.96 [0.34, 2.69]
0.33 [0.13, 0.81]
0.21 [0.04, 1.05]
Not estimable
1.44 [0.46, 4.55]
0.39 [0.12, 1.28]
0.61 [0.39, 0.93]
Odds Ratio
M-H, Random, 95% CI
0.72 [0.50, 1.04]
0.005
0.1
1
10
200
Favours experimental Favours control
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.
Study or Subgroup
Adelson PD 2005
Biswas AK 2002
Clifton GL 1993
Clifton GL 2001
Hutchinson JS 2008
Jiang J 2000
Liu WG 2006
Marion DW 1993
Marion DW 1997
Qiu W 2005
Shiozaki T 1993
Shiozaki T 1999
Shiozaki T2001
Smrcka M 2005
Wang W 2005
Zhi D 2002
TTM (32-35)
Control (36.5-38.5)
Events Total
Events
Total Weight
14
32
14
36
6.9%
7
10
11
11
1.4%
12
23
8
22
5.6%
82
190
76
178 10.4%
70
102
80
103
9.0%
20
43
12
44
7.3%
28
43
8
23
6.3%
12
20
8
20
5.3%
24
39
16
42
7.3%
28
43
16
43
7.4%
6
16
1
17
2.4%
6
8
7
8
1.9%
21
45
27
46
7.7%
30
35
18
37
5.9%
15
20
13
20
4.9%
122
198
75
198 10.4%
Total (95% CI)
867
848 100.0%
Total events
497
390
Heterogeneity: Tau² = 0.34; Chi² = 43.00, df = 15 (P = 0.0002); I² = 65%
Test for overall effect: Z = 2.73 (P = 0.006)
Odds Ratio
M-H, Random, 95% CI
1.22 [0.46, 3.22]
0.09 [0.00, 2.07]
1.91 [0.58, 6.30]
1.02 [0.67, 1.54]
0.63 [0.34, 1.17]
2.32 [0.95, 5.67]
3.50 [1.21, 10.13]
2.25 [0.63, 7.97]
2.60 [1.06, 6.37]
3.15 [1.31, 7.60]
9.60 [1.00, 91.96]
0.43 [0.03, 5.98]
0.62 [0.27, 1.41]
6.33 [2.01, 19.91]
1.62 [0.41, 6.34]
2.63 [1.75, 3.95]
Odds Ratio
M-H, Random, 95% CI
1.73 [1.17, 2.56]
0.005
0.1
1
10
200
Favours control Favours experimental
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.
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.
Hypothermia
Control
Study or Subgroup
Events Total Events Total Weight
1.1.2 Concealled allocation
Adelson 2005 HYPO I
4
25
4
25
2.0%
Adelson 2005 HYPO II
3
14
3
13
1.5%
Clifton 1992
1
5
1
5
0.5%
Clifton 1993
8
23
8
22
3.2%
Clifton 2001
53
190
48
178 21.6%
Hutchinson 2008
23
102
14 103
6.5%
Marion 1997
9
39
10
42
4.5%
Meissner 1998
3
12
3
13
1.3%
Qiu 2007
9
40
13
40
6.1%
Subtotal (95% CI)
450
441 47.3%
Total events
113
104
Heterogeneity: Chi² = 3.58, df = 8 (P = 0.89); I² = 0%
Test for overall effect: Z = 0.49 (P = 0.62)
1.1.3 Non-concealed allocation
Aibiki 2000
1
15
3
11
Biswas 2002
3
8
0
6
Hashiguchi 2003
1
9
0
8
Hirayama 2004
4
12
5
10
Jiang 2000
11
43
20
44
Meissner 2003b
3
15
3
13
Shiozaki 1993
8
16
14
17
Shiozaki 1999
0
8
0
8
Shiozaki 2001
8
45
6
46
Smrcka 2005
5
35
11
37
Yan 2001
13
24
16
20
Zhang 2000
41
123
50 123
Subtotal (95% CI)
353
343
Total events
98
128
Heterogeneity: Chi² = 11.14, df = 10 (P = 0.35); I² = 10%
Test for overall effect: Z = 2.83 (P = 0.005)
2.0%
0.2%
0.3%
2.2%
8.9%
1.6%
4.1%
3.0%
5.5%
4.8%
20.2%
52.7%
Total (95% CI)
803
784 100.0%
Total events
211
232
Heterogeneity: Chi² = 20.61, df = 19 (P = 0.36); I² = 8%
Test for overall effect: Z = 1.57 (P = 0.12)
Odds Ratio
M-H, Fixed, 95% CI
Odds Ratio
M-H, Fixed, 95% CI
1.00 [0.22, 4.54]
0.91 [0.15, 5.58]
1.00 [0.05, 22.18]
0.93 [0.28, 3.16]
1.05 [0.66, 1.66]
1.85 [0.89, 3.84]
0.96 [0.34, 2.69]
1.11 [0.18, 6.97]
0.60 [0.22, 1.63]
1.08 [0.79, 1.47]
0.19 [0.02, 2.15]
8.27 [0.35, 197.61]
3.00 [0.11, 84.56]
0.50 [0.09, 2.81]
0.41 [0.17, 1.02]
0.83 [0.14, 5.08]
0.21 [0.04, 1.05]
Not estimable
1.44 [0.46, 4.55]
0.39 [0.12, 1.28]
0.30 [0.08, 1.15]
0.73 [0.43, 1.23]
0.62 [0.44, 0.86]
0.84 [0.67, 1.05]
0.01
0.1
1
10
100
Favours experimental Favours control
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.
Immediate Hypothermia
Normothermia
Study or Subgroup
Events
Total Events
Total Weight
1.2.2 Concealed allocation
Adelson 2005 HYPO I
4
25
4
25
1.6%
Adelson 2005 HYPO II
3
14
3
13
1.2%
Clifton 1992
1
5
2
5
0.8%
Clifton 1993
11
23
14
22
3.6%
Clifton 2001
108
190
102
178 22.1%
Hutchinson 2008
32
102
23
103
7.6%
Marion 1997
15
39
26
42
7.5%
Meissner 1998
3
12
3
13
1.0%
Qiu 2007
9
40
13
40
4.9%
Subtotal (95% CI)
450
441 50.3%
Total events
186
190
Heterogeneity: Chi² = 8.66, df = 8 (P = 0.37); I² = 8%
Test for overall effect: Z = 0.68 (P = 0.49)
1.2.3 Non-concealed allocation
Aibiki 2000
3
15
Biswas 2002
3
8
Hashiguchi 2003
3
9
Hirayama 2004
4
12
Jiang 2000
23
43
Meissner 2003b
3
15
Shiozaki 1993
10
16
Shiozaki 1999
2
8
Shiozaki 2001
24
45
Smrcka 2005
5
35
Yan 2001
13
24
Zhang 2000
41
123
Subtotal (95% CI)
353
Total events
134
Heterogeneity: Chi² = 24.64, df = 11 (P = 0.01); I² = 55%
Test for overall effect: Z = 3.19 (P = 0.001)
Total (95% CI)
803
Total events
320
Heterogeneity: Chi² = 36.70, df = 20 (P = 0.01); I² = 45%
Test for overall effect: Z = 2.65 (P = 0.008)
Test for subgroup differences: Not applicable
7
0
1
7
32
3
16
1
19
19
16
50
11
6
8
10
44
13
17
8
46
37
20
123
343
Odds Ratio
M-H, Fixed, 95% CI
Odds Ratio
M-H, Fixed, 95% CI
1.00 [0.22, 4.54]
0.91 [0.15, 5.58]
0.38 [0.02, 6.35]
0.52 [0.16, 1.73]
0.98 [0.65, 1.48]
1.59 [0.85, 2.97]
0.38 [0.16, 0.94]
1.11 [0.18, 6.97]
0.60 [0.22, 1.63]
0.91 [0.69, 1.20]
3.1%
0.2%
0.3%
2.5%
7.1%
1.2%
2.8%
0.4%
4.3%
7.7%
3.9%
16.2%
49.7%
0.14 [0.02, 0.83]
8.27 [0.35, 197.61]
3.50 [0.28, 43.16]
0.21 [0.04, 1.31]
0.43 [0.18, 1.05]
0.83 [0.14, 5.08]
0.10 [0.01, 1.00]
2.33 [0.17, 32.58]
1.62 [0.71, 3.72]
0.16 [0.05, 0.50]
0.30 [0.08, 1.15]
0.73 [0.43, 1.23]
0.60 [0.44, 0.82]
784 100.0%
0.76 [0.61, 0.93]
171
361
0.01
0.1
1
10
100
Favours experimental Favours control
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.
1.
Wong KC. Physiology and pharmacology of hypothermia. West J Med. 1983
Feb;138(2):227-32.
2.
Varathan S, Shibuta S, Shimizu T, Mashimo T. Neuroprotective effect of
hypothermia at defined intraischemic time courses in cortical cultures. J Neurosci Res.
2001 Sep 15;65(6):583-90.
3.
Zeiner A, Holzer M, Sterz F, Behringer W, Schorkhuber W, Mullner M, et al. Mild
resuscitative hypothermia to improve neurological outcome after cardiac arrest. A
clinical feasibility trial. Hypothermia After Cardiac Arrest (HACA) Study Group. Stroke.
2000 Jan;31(1):86-94.
4.
Reuler JB. Hypothermia: pathophysiology, clinical settings, and management.
Ann Intern Med. 1978 Oct;89(4):519-27.
5.
Hammer MD, Krieger DW. Acute ischemic stroke: is there a role for
hypothermia? Cleve Clin J Med. 2002 Oct;69(10):770, 3-4, 6-7 passim.
6.
Safar P, Behringer W. Brain resuscitation after cardiac arrest. . In: Layon AJ,
Gabrielli A, Friedman W, editors. Textbook of neurointensive care. ed. Philadelphia:
Saunders; 2003. p. 457-98.
7.
Werner C. [Mild and moderate hypothermia as a new therapy concept in
treatment of cerebral ischemia and craniocerebral trauma. Pathophysiologic principles].
Anasthesiol Intensivmed Notfallmed Schmerzther. 1997 Apr;32(4):210-8.
8.
Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, Smith KR, Jr., et al. Lack
of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001 Feb
22;344(8):556-63.
9.
Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al.
Treatment of comatose survivors of out-of-hospital cardiac arrest with induced
hypothermia. N Engl J Med. 2002 Feb 21;346(8):557-63.
10.
Mild therapeutic hypothermia to improve the neurologic outcome after cardiac
arrest. N Engl J Med. 2002 Feb 21;346(8):549-56.
11.
Todd MM, Hindman BJ, Clarke WR, Torner JC. Mild intraoperative hypothermia
during surgery for intracranial aneurysm. N Engl J Med. 2005 Jan 13;352(2):135-45.
12.
Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan
EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.
N Engl J Med. 2005 Oct 13;353(15):1574-84.
13.
Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et
al. Selective head cooling with mild systemic hypothermia after neonatal
encephalopathy: multicentre randomised trial. Lancet. 2005 Feb 19-25;365(9460):66370.
14.
Kollmar R, Georgiadis D, Schwab S. Alpha-stat versus pH-stat guided ventilation
in patients with large ischemic stroke treated by hypothermia. Neurocrit Care.
2009;10(2):173-80.
15.
Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild
hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation. 2001
Dec;51(3):275-81.
16.
Kim F, Olsufka M, Longstreth WT, Jr., Maynard C, Carlbom D, Deem S, et al.
Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-ofhospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline.
Circulation. 2007 Jun 19;115(24):3064-70.
17.
Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. Neurodevelopmental
outcome of infants treated with head cooling and mild hypothermia after perinatal
asphyxia. Pediatrics. 2001 Mar;107(3):480-4.
18.
Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, et al.
Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol.
2005 Jan;32(1):11-7.
19.
Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants
after perinatal asphyxia: a safety study. Pediatrics. 1998 Oct;102(4 Pt 1):885-92.
20.
Lin ZL, Yu HM, Lin J, Chen SQ, Liang ZQ, Zhang ZY. Mild hypothermia via
selective head cooling as neuroprotective therapy in term neonates with perinatal
asphyxia: an experience from a single neonatal intensive care unit. J Perinatol. 2006
Mar;26(3):180-4.
21.
Robertson NJ, Nakakeeto M, Hagmann C, Cowan FM, Acolet D, Iwata O, et al.
Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised
controlled trial. Lancet. 2008 Sep 6;372(9641):801-3.
22.
Shankaran S, Laptook A, Wright LL, Ehrenkranz RA, Donovan EF, Fanaroff AA,
et al. Whole-body hypothermia for neonatal encephalopathy: animal observations as a
basis for a randomized, controlled pilot study in term infants. Pediatrics. 2002 Aug;110(2
Pt 1):377-85.
23.
Shankaran S, Pappas A, Laptook AR, McDonald SA, Ehrenkranz RA, Tyson JE,
et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial
of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics.
2008 Oct;122(4):e791-8.
24.
Zhou WH, Shao XM, Cao Y, al. E. Safety study of hypothermia for treatment of
hypoxic-ischemic brain damage in term neonates. Acta Pharmacologica Sinica. 2002;23
(Supplement):64-8.
25.
Adelson PD, Ragheb J, Kanev P, Brockmeyer D, Beers SR, Brown SD, et al.
Phase II clinical trial of moderate hypothermia after severe traumatic brain injury in
children. Neurosurgery. 2005 Apr;56(4):740-54; discussion -54.
26.
Biswas AK, Bruce DA, Sklar FH, Bokovoy JL, Sommerauer JF. Treatment of
acute traumatic brain injury in children with moderate hypothermia improves intracranial
hypertension. Crit Care Med. 2002 Dec;30(12):2742-51.
27.
Clifton GL, Allen S, Barrodale P, Plenger P, Berry J, Koch S, et al. A phase II
study of moderate hypothermia in severe brain injury. J Neurotrauma. 1993
Fall;10(3):263-71; discussion 73.
28.
Hutchison JS, Ward RE, Lacroix J, Hebert PC, Barnes MA, Bohn DJ, et al.
Hypothermia therapy after traumatic brain injury in children. N Engl J Med. 2008 Jun
5;358(23):2447-56.
29.
Jiang J, Yu M, Zhu C. Effect of long-term mild hypothermia therapy in patients
with severe traumatic brain injury: 1-year follow-up review of 87 cases. J Neurosurg.
2000 Oct;93(4):546-9.
30.
Liu WG, Qiu WS, Zhang Y, Wang WM, Lu F, Yang XF. Effects of selective brain
cooling in patients with severe traumatic brain injury: a preliminary study. J Int Med Res.
2006 Jan-Feb;34(1):58-64.
31.
Marion DW, Obrist WD, Carlier PM, Penrod LE, Darby JM. The use of moderate
therapeutic hypothermia for patients with severe head injuries: a preliminary report. J
Neurosurg. 1993 Sep;79(3):354-62.
32.
Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, et al.
Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997 Feb
20;336(8):540-6.
33.
Qiu WS, Liu WG, Shen H, Wang WM, Hang ZL, Zhang Y, et al. Therapeutic
effect of mild hypothermia on severe traumatic head injury. Chin J Traumatol. 2005
Feb;8(1):27-32.
34.
Shiozaki T, Sugimoto H, Taneda M, Yoshida H, Iwai A, Yoshioka T, et al. Effect
of mild hypothermia on uncontrollable intracranial hypertension after severe head injury.
J Neurosurg. 1993 Sep;79(3):363-8.
35.
Shiozaki T, Kato A, Taneda M, Hayakata T, Hashiguchi N, Tanaka H, et al. Little
benefit from mild hypothermia therapy for severely head injured patients with low
intracranial pressure. J Neurosurg. 1999 Aug;91(2):185-91.
36.
Shiozaki T, Hayakata T, Taneda M, Nakajima Y, Hashiguchi N, Fujimi S, et al. A
multicenter prospective randomized controlled trial of the efficacy of mild hypothermia
for severely head injured patients with low intracranial pressure. Mild Hypothermia
Study Group in Japan. J Neurosurg. 2001 Jan;94(1):50-4.
37.
Smrcka M, Vidlak M, Maca K, Smrcka V, Gal R. The influence of mild
hypothermia on ICP, CPP and outcome in patients with primary and secondary brain
injury. Acta Neurochir Suppl. 2005;95:273-5.
38.
Wang WP, Ren HJ, Chi JY, Xu FL, Quan Y. Effects of mild hypothermia on
patients with lower intracranial pressure following severe brain injury. Chin J Traumatol.
2005 Feb;8(1):54-6.
39.
Zhi D, Zhang S, Lin X. Study on therapeutic mechanism and clinical effect of mild
hypothermia in patients with severe head injury. Surg Neurol. 2003 May;59(5):381-5.