Therapeutic Hypothermia (Di

fferent Depths, Durations, andRewarming Speeds) for Acute Ischemic Stroke: AMeta-analysis

Yue-Hong Wan, MM,* Chen Nie, MM,† Hui-Ling Wang, MM,*

and Chao-Yun Huang, MM*

From the *Department

logy, Zhongnan Hospital

Received May 29, 2014

Grant support: The au

Address corresponde

Donghu Road, Wuchan

znhuangchaoyun@gmail

1052-3057/$ - see front

� 2014 by National Str

http://dx.doi.org/10.1

2736

Objectives: Whether therapeutic hypothermia benefits patients with acute ischemic

stroke (AIS) remains controversial. The aim of this studywas to evaluate the efficacy

and safety of the different depths, durations, and rewarming speeds of therapeutic

hypothermia for AIS. Methods: The MEDLINE (OVID), EMBASE, and Cochrane

Central Register of Controlled Trials were systematically searched for randomized

controlled trials (RCTs) of therapeutic hypothermia for AIS from the inception of

the databases to October 2013. After data extraction and quality assessment, a

meta-analysis was performed using RevMan 5.1. Results: A total of 6 RCTs involving

252 AIS patients were eligible for the meta-analysis. Subanalyses stratified by depth,

duration, and rewarming speed of therapeutic hypothermia were also performed.

Our results showed that therapeutic hypothermia was associated with an increased

risk of pneumonia (risk ratio 5 3.30, 95% CI 1.48-7.34; P 5 .003, P for heterogeneity

5 .91, I2 5 0%). No significant difference was observed between the 2 groups in terms

of neurologic outcomes, mortality, and other complications including symptomatic or

fatal intracranial hemorrhage, deepvein thrombosis, andatrial fibrillation.Conclusions:These limited data suggest that therapeutic hypothermia does not significantly

improve stroke outcomes and may lead to higher rates of pneumonia. Multicenter

RCTs with larger samples are needed to confirm the current findings. Key Words:

Acute ischemic stroke—therapeutic hypothermia—meta-analysis—systematic review.

� 2014 by National Stroke Association

Introduction

Stroke is one of the leading causes of death and

disability around the world. From 1970 to 2008, the yearly

percentage change in pooled age-standardized stroke

incidence rates increased by 5.3% in developing coun-

tries, and the overall incidence rates in developing coun-

tries is 20% higher than that in developed countries.1

Currently, the major strategies for the treatment of acute

ischemic stroke (AIS) are thrombolysis and antiplatelet

of Neurology; and †Department of Cardio-

of Wuhan University, Wuhan, China.

; accepted June 20, 2014.

thors have no grant support to report.

nce to Chao-Yun Huang, MM, No. 169

g District, Wuhan 430071, China. E-mail:

.com.

matter

oke Association

016/j.jstrokecerebrovasdis.2014.06.017

Journal of Stroke and Cerebrovascular Diseases

treatment. Unfortunately, because of the small treatment

window (3-4.5 hours) and the higher risk of symptomatic

intracranial hemorrhage,2 less than 10% of AIS patients

can benefit from thrombolysis.3 Therefore, effective treat-

ments that are safer and easier to administer are urgently

needed.

Therapeutic hypothermia is a treatment for preserving

neurologic function by an intentional and controlled

reduction of a patients’ core temperature to 32�C-35�C.4

Therapeutic hypothermia has become one of the most

potent neuroprotective strategies because it simulta-

neously activates multiple pathways by almost all mech-

anisms involved in ischemia/reperfusion to elicit a

neuroprotective effect. The protective mechanisms of

therapeutic hypothermia include decreasing cerebral

metabolism, interrupting apoptotic pathways, inhibiting

harmful excitatory processes and free radical production,

and suppressing ischemia-induced inflammatory reac-

tions and the release of pro-inflammatory cytokines.5

, Vol. 23, No. 10 (November-December), 2014: pp 2736-2747

THERAPEUTIC HYPOTHERMIA FOR ACUTE ISCHEMIC STROKE 2737

In addition, hypothermia reduces the permeability of

the blood–brain barrier and decreases cerebral edema

formation.5

Numerous AIS studies have shown the neuroprotective

effect of therapeutic hypothermia. Through a meta-

analysis of animal studies including 101 publications

reporting the effect of hypothermia on infarct size or func-

tional outcome, the researchers found that hypothermia

reduced infarct size by 44% (95% confidence interval

[CI], 40%-47%).6 In humans, an early observational study

indicated that higher the body temperature on admission,

the worse the clinical outcome in stroke patients; for each

1�C increase in body temperature, the relative risk of poor

outcome increased more than 2-fold.7 Furthermore, self-

controlled clinical trials showed that moderate hypother-

mia may improve clinical outcomes in AIS patients.8

As the gold standard for clinical trials, randomized

controlled trials (RCTs) also concluded that induced

hypothermia was feasible and safe in AIS patients.9,10

The following factors have a key impact on the success

or failure of therapeutic hypothermia: speed of induction,

duration of cooling, rewarming speed, and prevention of

side effects.5 In addition, the depth of therapeutic hypo-

thermia may have an effect on the clinical outcome.11

However, currently, there is no unified standard on the

depth, duration, and rewarming speed of therapeutic hy-

pothermia. How the effect of different depths, durations,

and rewarming speeds affect mortality and neurologic

outcomes in AIS patients is still unknown. To answer

this question, we performed this meta-analysis based on

current RCTs or quasi-RCTs.

Methods

This meta-analysis complied with the guidelines estab-

lished by PRISMA (Preferred Reporting Items for System-

atic Reviews and Meta-Analysis).12 We used the PICOS

(Participants, Intervention, Comparison, Outcome, and

Study Design) approach to develop the research question.

The participants included patients older than 18 years

with AIS, and cerebral hemorrhage had been excluded

as the cause of the symptoms based on computed tomog-

raphy (CT) or magnetic resonance imaging. The interven-

tion of interest was therapeutic hypothermia including

thrombolytic therapy if indicated; moreover, information

about the depth, duration, and rewarming speed of ther-

apeutic hypothermia had to be available for the study to

be included. Therapeutic hypothermia was compared

with standard treatment. The outcomes were neurologic

at the end of more than 1 month of follow-up, all-cause

mortality, and complications including symptomatic or

fatal intracranial hemorrhage (confirmed by CT or mag-

netic resonance or autopsy), pneumonia, and other com-

plications that have a major impact on the treatment

decision. A favorable neurologic outcome was defined

as a score of 0-1 on the modified Rankin Scale (mRS),13

and poor neurologic outcome was defined as a score of

3-6.14 The study design was RCTs or quasi-RCTs.

Literature Search

We performed a systematic search of the MEDLINE

(OVID), EMBASE, and Cochrane Central Register of

Controlled Trials for literature on therapeutic hypother-

mia for AIS from the inception of the databases to October

2013. The following medical subject headings (MeSH)

were searched: ‘‘stroke,’’ ‘‘intracranial embolism and

thrombosis,’’ ‘‘hypothermia,’’ ‘‘hypothermia, induced,’’

and ‘‘randomized controlled trial.’’ The detailed search

strategy of the MEDLINE (OVID) database is shown in

supplemental Text 1.We also included trials that were

completed and published by February 2014. Furthermore,

we checked the reference lists of the obtained articles and

of relevant systematic reviews to identify relevant reports.

No language restrictions were applied. Animal studies

were excluded.

Data Extraction

Two of the researchers (Y.H.W. and C.N.) indepen-

dently screened each article for inclusion in the meta-

analysis. The following data from the included studies

were extracted independently by 2 reviewers (C.N. and

H.L.W.): baseline characteristics of the study population,

interventions (the depth, duration, and rewarming speed

of therapeutic hypothermia), comparison groups, and

outcomes. We resolved any disagreements by discussion

and consensus. If necessary, we contacted the authors of

the articles by e-mail to obtain additional information.

Assessment of the Risk of Bias

The Cochrane risk of bias tool was used to assess the

risk of bias of the included studies independently by 2 re-

viewers (Y.H.W. and C.N.).15 Disagreements were

resolved by discussion or by correspondence with the

trial authors. The following aspects were assessed: (1)

random sequence generation (selection bias), (2) alloca-

tion concealment (selection bias), (3) blinding of partici-

pants and personnel (performance bias), (4) blinding of

outcome assessments (detection bias), (5) incomplete

outcome data (attrition bias), (6) selective reporting (re-

porting bias), and (7) other biases.

Evidence Grading

We used the Grading of Recommendations, Assess-

ment, Development, and Evaluation (GRADE) system16

to grade the quality of evidence for our outcomes. The ev-

idence strength was classified as follows: (1) high—

further research is very unlikely to change our confidence

in the estimate of the effect; (2) moderate—further

research is likely to have an important impact on our con-

fidence in the estimate of the effect and may change the

Y.-H. WAN ET AL.2738

estimate; (3) low—further research is very likely to have

an important impact on our confidence in the estimate

of the effect and is likely to change the estimate; and (4)

very low—any estimate of the effect is very uncertain.

Although evidence based on RCTs is classified as high

quality at the beginning, our confidence in the estimate of

the effect may be reduced by the following 5 factors: (1)

limitations in the study design or execution, (2) inconsis-

tency of the results, (3) indirectness of the evidence, (4)

imprecision, and (5) publication bias.

Finally, we analyzed the data using GRADE profiler

software (version 3.6).

Statistical Analysis

Statistical analyses were conducted by Review Man-

ager Software (RevMan 5.1). The chi-square test for het-

erogeneity was performed. I2 values of 50% or less and

P values greater than .1 were considered to indicate no

statistical heterogeneity, and we used a fixed-effects

model for the calculations; otherwise, a random-effects

model was applied. We reported the risk ratio (RR) and

95% CIs for dichotomous data and weighted mean differ-

ences and 95% CI for continuous data. Subanalyses were

conducted based on the depth (32�C-33.9�C versus 34�C-35.9�C), duration (#24 versus.24 hours), and rewarming

speed (#12 versus .12 hours) of therapeutic hypother-

mia. P values of .05 or less were considered statistically

significant.

Results

Characteristics of the Included Studies

A total of 3628 studies were identified in the electronic

databases, and an additional study was identified

through other sources. Finally, 6 studies that met our in-

clusion criteria were included in the quantitative synthe-

sis. The details of the selection process are shown in

Figure 1. The included studies were published between

2004 and 2014, and they all were published in English.

The sample size of each study ranged from 25 to 62 (total

252). The characteristics of the 6 studies are summarized

in Table 1.

Risk of Bias

According to the approach for assessing the risk of bias

recommended by the Cochrane Collaboration, adequate

methods of random sequence generation including the

numbered envelope9,17 and the computer-generated

sequence10,18 were used in 4 trials; 1 trial19 did not report

the methods of random sequence generation, and an inad-

equate method of sequence generation based on the order

of enrollment was used in 1 trial.20 Four trials used alloca-

tion concealment,9,10,17,18 whereas 2 trials included unclear

descriptions. Participants and personnel were blinded in

only 1 trial,20 and participants and personnel were not

blinded in the other 5 trials. The assessors of outcomes

were blinded in 2 trials9,20; however, the other 4 trials did

Figure 1. Search results and selection of arti-

cles. Abbreviation: RCT, randomized controlled

trial.

Table 1. Characteristics of included trials of hypothermia for acute ischemic stroke

References Participants

Interventions Outcomes

Hypothermia group Control group

De Georgia et al9 Patients with acute anterior circulation ischemic stroke #12 h

of symptom onset, 40 participants (hypothermia 18 and

control 22). Mean age (SD): hypothermia 60.9 y (12.1 y),

control 67.3 y (12.5 y). Hypothermia, 13 male (72%);

control, 6 male (27%). Stroke severity (NIHSS) mean

(SD): hypothermia, 15.2 (4.4); control, 14.6 (5.6). In

the hypothermia group, esophageal temperatures were

monitored. Bladder or rectal temperatures were monitored

in the control group.

Endovascular cooling: time from stroke

onset to cooling start (mean 6 SD):

9.0 h 6 2.9 h; depth: 33�C; duration:24 h; rewarming speed: .2�C/h.

Standard medical

treatment,

including

thrombolytic

therapy

if indicated

Neurologic outcome

at 1 month mortality

at 1 month

complications:

intracranial

hemorrhage,

infections, and other

side effects

Els et al19 Patients with severe supratentorial ischemic stroke, 25

participants (hypothermia 12 and control 13). Mean

age (SD): hypothermia, 49.0 y (12.0 y); control,

49.0 y (6.0 y). Hypothermia, 6 male (50%); control, 9

male (69%). Stroke severity (NIHSS) mean (SD):

hypothermia, 18 (2); control 19 (2). Continuous esophageal

temperatures were monitored in all patients.

Intravenous cooling: 10 external cooling:

2 times from stroke onset to cooling

start: NR; depth: 35�C; duration:48 h; rewarming speed: .04�C/h.

Hemicraniectomy Neurologic outcome at

6 months mortality

at 6 months

complications:

intracranial

hemorrhage,

pulmonary

embolism,

and other side

effects

Hemmen et al10 Patients with acute ischemic stroke #6 h of symptom onset,

58 participants (hypothermia 28, control 30). Mean age (SD):

hypothermia, 68.9 y (7.9 y); control, 62.3 y (14.5 y).

Hypothermia, 16 male (56.7%); control, 16 male (53.8%).

Stroke severity (NIHSS): mean (SD) hypothermia, 14.3 (5.0);

control, 13.7 (5.1). The method of measuring body

temperature: NR.

Intravenous cooling: time from stroke

onset to cooling start (median): 5.9 h;

depth: 33�C; duration: 24 h;

rewarming speed: .3�C/h.

Standard treatment,

including

thrombolytic

therapy

Neurologic outcome at

3 months mortality

at 3 months

complications:

intracranial

hemorrhage,

infections, and other

side effects

Krieger 201317 Patients with acute ischemic stroke #24 h of symptom

onset, 31 participants (hypothermia 17, control 14). Mean age

(SD): hypothermia, 62.3 y (12.2 y); control, 65.9 y (12.3 y).

Hypothermia, 9 male (53%); control, 8 male (57%). Stroke

severity (NIHSS): median (range) hypothermia 8 (4-17),

control 9 (4-17). In the hypothermia group, temperatures were

measured via bladder thermister probe. Tympanic temperatures

were monitored in the control group.

Endovascular cooling: 7 surface-based

cooling: 10 times from stroke onset

to cooling start (mean 6 SD):

12.2 h 6 4.9 h; depth: 33�C;duration: 24 h; rewarming speed:

.25�C/h-.5�C/h.

Standard treatment,

including

thrombolytic

therapy if

indicated

Neurologic outcome at

3 months mortality

at 3 months

complications:

intracranial

hemorrhage,

infections, and other

side effects

(Continued )

THERAPEUTIC

HYPOTHERMIA

FOR

ACUTE

ISCHEMIC

STROKE

2739

Table

1.(Con

tinu

ed)

References

Participants

Interventions

Outcomes

Hypothermiagroup

Controlgroup

Piironen

etal18

Patientswithacuteischem

icstrokeafterintravenousthrombolysis,

36participants(hypothermia18,control18).Medianage

(interquartilerange):hypothermia,70y(62-74y);control,

66y(55-71y).Hypothermia,12male(67%);control,8

male(44%).Strokeseverity(N

IHSS)median(interquartile

range):hypothermia,11(8-17);control,14(6-18).

Continuousbladder

temperaturesweremonitoredin

allpatients.

Surface-based

coolingandcold

saline

infusions:timefrom

strokeonset

tocoolingstart(m

edian):6.0

h;

depth:34.5

� C-35.5

� C;duration:

10.5

h;rewarmingspeed:

.2� C

/h-.5� C

/h.

Betreatedaccording

tothein-house

guidelines

Neurologicoutcomeat

3monthsmortality

at3months

complications:

intracranial

hem

orrhage,

infections,andother

sideeffects

Tong,201120

Patientswithacuteischem

icstroke#6hofsymptom

onset,62

participants(hypothermia31,control31).Meanage(SD):

hypothermia,68.5y(6.9y);control,68.6y(6.3y).Hypothermia,

10male(32.3%);control,13male(41.9%).Strokeseverity

(NIH

SS)mean(SD):hypothermia,11.4(2.8);control,11.0(2.7).

Continuousrectaltemperaturesweremonitoredin

allpatients.

Surface-based

cooling:timefrom

strokeonsetto

coolingstart

(mean6

SD):3.9

h6

1.0

h;

depth:32� C

-34� C

;duration:

24h;rewarmingspeed:NR.

Thrombolytic

therapy

Neurologicoutcomeat

3monthsmortality

at3months

complications:

intracranial

hem

orrhage,

infections,andother

sideeffects

Abbreviations:NIH

SS,NationalInstitutesofHealthStrokeScale;NR,notreported.

Y.-H. WAN ET AL.2740

not provide information on the blinding of outcome

assessment. Complete outcome data were reported in

4 trials,9,10,17,18 and whether there were incomplete

outcome data in the other 2 trials was unclear because

we did not have enough information. A comparison

between the protocols and trial reports revealed no

selective reporting in 4 trials.9,10,17,18 Selective reporting

was unclear in the other 2 trials. We could not

determine other potential biases because of insufficient

information. The detailed risk of bias in the included

studies is elaborated and summarized in Figures 2

and 3, respectively.

Meta-Analysis Results

Favorable neurologic outcome

Five studies reported data on favorable neurologic

outcome. No statistical heterogeneity (P 5 .66, I2 5 0%)

was found, and the pooled analysis showed no significant

difference between the hypothermia group and the con-

trol group for favorable neurologic outcome (RR 5 .85,

95% CI .56-1.29; P 5 .46) (Fig 4). Subanalyses were con-

ducted according to different depths (32�C-33.9�C versus

34�C-35.9�C), durations (#24 hours), and rewarming

speeds (#12 versus .12 hours) of therapeutic hypother-

mia. None of the subanalyses was statistically significant.

Because of a lack of studies, we could not estimate the ef-

fect of duration that was longer than 24 hours. The results

are presented in Figure 5.

Poor neurologic outcome

Three studies reported data on poor neurologic

outcome. The degree of heterogeneity (I2) was 0% in the

analysis (Fig 6), suggesting no heterogeneity among

studies. The data were combined using a fixed-effects

model. The pooled data indicated no tendency toward a

decrease in poor neurologic outcome when treated with

hypothermia (RR 5 1.20, 95% CI .88-1.64; P 5 .24). In

the meta-analysis limited to studies of the effect of

different depths, durations, or rewarming speeds, no dif-

ferences were found between both groups. Because there

was a lack of studies on duration that was longer than 24

hours, we could not estimate the effect. The results are

presented in Figure 7.

Mortality

All 6 included studies reported mortality from all

causes. Considering no heterogeneity (P 5 .82, I2 5 0%),

the data were pooled using a fixed-effects model, and

no significant difference was detected in total mortality

(RR 5 1.12, 95% CI .62-2.05; P 5 .70) (Fig 8). Additionally,

there was no significant difference between the 2 groups

in terms of mortality based on the different depths, dura-

tions, and rewarming speeds of therapeutic hypothermia

(Fig 9).

Figure 2. Risk of bias summary. Review authors’ judgments about each

risk of bias item for each included study.

THERAPEUTIC HYPOTHERMIA FOR ACUTE ISCHEMIC STROKE 2741

Complications

The analyses of complications are shown in Figure 10.

Our analyses revealed that 5 studies mentioned pneu-

monia, and the pooled data suggested a greater inci-

dence of pneumonia in the hypothermia group (RR 5

3.30, 95% CI 1.48-7.34; P 5 .003, P for heterogeneity 5

.91, I2 5 0%). However, there was no significant differ-

ence between the 2 groups in the incidence of symptom-

atic intracranial hemorrhage (RR5 1.07, 95% CI .37-3.04;

Figure 3. Risk of bias graph. Review authors’

judgments about each risk of bias item presented

as percentages across all included studies.

P5 .90, P for heterogeneity5 .40, I2 5 0%), fatal intracra-

nial hemorrhage (RR 5 1.40, 95% CI .33-5.99; P 5 .65,

P for heterogeneity5 .54, I2 5 0%), deep vein thrombosis

(RR 5 2.25, 95% CI .68-7.44; P 5 .18, P for heterogeneity

5 .32, I2 5 12%), and atrial fibrillation (RR5 1.14, 95% CI

.40-3.25; P 5 .80, P for heterogeneity 5 .71, I2 5 0%).

Sensitivity Analysis and Publication Bias

We performed sensitivity analysis by sequentially

removing each study. Significant pooled RR and 95% CI

were not influenced by omitting any single study, which

indicates that the results of this meta-analysis were stable.

Because the number of studies included in the meta-

analysis is still relatively small, we did not conduct funnel

plots to assess the publication bias.

GRADE system assessment

A summary of our outcomes and the strength of evi-

dence evaluated through the GRADE system are shown

in supplemental Text 2. The evidence quality for each

outcome was low or very low, for several reasons

including the blinding of outcome assessment not being

used in most studies in this meta-analysis and low total

number of events. This low evidence quality may reduce

the confidence in any recommendation.

Discussion

Stroke seriously influences people’s lives and health

with high morbidity, mortality, and disability and causes

huge economic losses for individuals, families, and soci-

ety. With the trend of an aging population, there is

no time to delay the search for more efficient and safer

treatments for stroke. Many studies7,21,22 have shown

that there is an association between increased body

temperature and poor outcomes in stroke patients and

have suggested that controlling body temperature may

improve the functional outcome after stroke. Further

studies have revealed that therapeutic hypothermia

improved neurologic outcomes and reduced mortality

in patients resuscitated after cardiac arrest23 and in

newborns with hypoxic–ischemic encephalopathy.24

Figure 4. Forest plots of favorable neurologic

outcome (modified Rankin Scale score 0-1).

Abbreviation: CI, confidence interval.

Y.-H. WAN ET AL.2742

Additionally, hypothermia is feasible and could improve

outcomes compared with historical controls in stroke pa-

tients.25 However, based on various studies, the depth of

hypothermia varied from 32�C to 35�C and the duration

Figure 5. Forest plots of favorable neurologic outcome (modified Rankin Scale sc

confidence interval.

varied from 12 hours to more than 5 days. The induction

time and rewarming speed also differed in every study.

Although 2 previous reviews14,26 on hypothermia for

stroke have been published, non-RCTs were included in

ore 0-1) according to different hypothermia interventions. Abbreviation: CI,

Figure 6. Forest plots of poor neurologic

outcome (modified Rankin Scale score 3-6).

Abbreviation: CI, confidence interval.

THERAPEUTIC HYPOTHERMIA FOR ACUTE ISCHEMIC STROKE 2743

those reports, and neither report systematically investi-

gated the effects of different depths, induction times, du-

rations, and rewarming speeds on mortality and

neurologic outcome in AIS patients. We, therefore, per-

formed this meta-analysis with current RCTs to explore

this issue.

Neurologic outcomewas themost important outcome as

the aim of stroke therapy should be to prevent not only

Figure 7. Forest plots of poor neurologic outcome (modified Rankin Scale score 3

fidence interval.

death but also disability and dependency in survivors.

We evaluated the neurologic outcomes using the mRS,

which is the most common outcome measure in large ran-

domized controlled stroke trials. In this meta-analysis, all

included studies reported the mRS at the end of follow-

up. We found that patients in the hypothermia group did

not obtain better neurologic outcomes than patients in

the control group. The results were the same in the

-6) according to different hypothermia interventions. Abbreviation: CI, con-

Figure 8. Forest plots of mortality. Abbrevia-

tion: CI, confidence interval.

Y.-H. WAN ET AL.2744

subanalyses stratified by depth, duration, and rewarming

speed of therapeutic hypothermia. Although European

Resuscitation Council Guidelines for Resuscitation recom-

mend the use of hypothermia after cardiac arrest27 and hy-

Figure 9. Forest plots of mortality according to different hypoth

pothermia is strongly recommended for infants with

moderate-to-severe hypoxic–ischemic encephalopathy,28

currently, there is insufficient evidence from RCTs to

support the routine use of hypothermia for AIS patients.

ermia interventions. Abbreviation: CI, confidence interval.

Figure 10. Forest plots of complications. Abbreviation: CI, confidence interval.

THERAPEUTIC HYPOTHERMIA FOR ACUTE ISCHEMIC STROKE 2745

Regarding the mortality from all causes, all included

studies reported related results and the pooled results

showed that no significant difference was found between

the hypothermia group and the control group. Our results

were consistent with previous studies.14,26 We also found

no significant difference between the 2 groups in terms of

mortality at different depths, durations, and rewarming

speeds. The mortality rates of the hypothermia group in

the trials were 27.8%,9 21.4%,10 11.8%,17 0%,18 8.3%,19

and 12.9%,20 and the pretreatment mean National Insti-

tutes of Health Stroke Scale score was 15.2, 14.3, 8.0

(median), 12.0, 18.0, and 11.4, respectively. The lower

mortality rate of more serious stroke patients in the study

by Els et al may be because of improved surgical expertise

or the short follow-up period. The cause of death in pa-

tients included the following: hemorrhagic transforma-

tion, massive cerebral infarction, myocardial infarctions,

cardiac arrest, pulmonary embolism, multiple organ fail-

ure, and pulmonary infection. None of the deaths were

considered to be related to hypothermia.

Complications, which had a major impact on the

treatment decision, were also analyzed in our study. The

pooled results with no heterogeneity showed an increased

incidence rate of pneumonia in the hypothermia group

Y.-H. WAN ET AL.2746

compared with the control group. However, there were no

significant differences in mortality associated with pneu-

monia between the 2 groups. This finding may be related

to antishivering treatment29 andhypothermic immune sup-

pression.30 Further study is needed. Furthermore, no signif-

icant differences were found between the 2 groups for

symptomatic or fatal intracranial hemorrhage, deep vein

thrombosis, and atrial fibrillation. The sensitivity analysis

indicated that the pooled results were not influenced by

omitting any single study.

In this study, we used the GRADE system recommended

by the Cochrane Collaboration to evaluate the quality of

evidence of each outcome. There was no serious inconsis-

tency and indirectness among the studies included in our

analyses; however, the quality of the evidence of outcomes

was low or very lower for the following reasons: (1) most

studies lacked blinding, which resulted in a serious risk

of bias; (2) the total number of events was small, and the

95% confidence interval was too wide, and (3) some sub-

groups only had 1 or 2 associated studies.

Compared with previous systematic reviews, several

advantages in our meta-analysis should be discussed.

First, because all studies included in this analysis were

RCTs, we could perform a high-quality meta-analysis

and acquire dependable results. Moreover, therapeutic

hypothermia was further stratified based on the different

depths, durations, and rewarming speeds, reducing the

potential bias risk and providing valuable information

for the design of future clinical trials. Next, the 6 RCTs

included in this meta-analysis were performed in not

only Western countries but also Asian countries. Finally,

to better guide clinical practice, the GRADE system was

adopted to assess the quality of the evidence.

In addition to these advantages, some limitations in this

study should be noted. First, our meta-analysis was based

on 6 RCTs; therefore, assessing the publication bias by con-

ducting funnel plots was difficult. The small sample size in

most studies made it difficult to achieve enough power to

detect a difference between the 2 groups. Second, the

blinding of outcome assessment was unclear in most

studies, which resulted in detection bias. Third, related

bias may be caused by various types of cooling methods

and devices such as surface cooling devices and core cool-

ing devices. Fourth, because some of our subanalyses were

based on only 2 or 3 trials, some conclusions should be in-

terpreted with caution. Lastly, because we did not have

enough information, time from stroke onset to cooling start

could not be explored, which may lead to bias.

In summary, our study was the first meta-analysis

composed only of RCTs to explore the effect of therapeu-

tic hypothermia on AIS. Our results are the first to sug-

gest that therapeutic hypothermia is related to a higher

incidence of pneumonia compared with the standard

treatment. In addition, there was no significant difference

in neurologic outcome, mortality, or other complications

including symptomatic or fatal intracranial hemorrhage,

deep vein thrombosis, and atrial fibrillation. Future

trials should try to find ways of reducing the incidence of

pneumonia. It is hoped that the ongoing large

hypothermia-for-stroke clinical trial (the European Multi-

centre, Randomised, Phase III Clinical Trial of Therapeutic

HypothermiaPlusBestMedicalTreatmentVersusBestMed-

ical Treatment Alone for Acute Ischemic Stroke and The

Intravascular Cooling in the Treatment of Stroke 2/3 Trial)

will confirm and update the findings of this analysis, and

future studies could establish the optimumdepth, duration,

and rewarming speed of therapeutic hypothermia.

Supplementary Data

Supplementary data associated with this article can be

found, in the online version, at http://dx.doi.org/10.

1016/j.jstrokecerebrovasdis.2014.06.017.

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