Seminars in Fetal & Neonatal Medicine 15 (2010) 238e246

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Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Hypothermia: a systematic review and meta-analysis of clinical trials

Prakesh S. Shah a, b, c, *
a
Department of Paediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada
b
Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
c
Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada

s u m m a r y
Keywords: Hypothermia is a potential neuroprotective intervention to treat neonatal post-asphyxial (hypo-
Birth asphyxia xiceischemic) encephalopathy (HIE). In this meta-analysis of 13 clinical trials published to date, thera-
Hypoxiceischemic encephalopathy
peutic hypothermia was associated with a highly reproducible reduction in the risk of the combined
Infant
Newborn
outcome of mortality or moderate-to-severe neurodevelopmental disability in childhood. This
improvement was internally consistent, as shown by significant reductions in the individual risk for
death, moderate-to-severe neurodevelopmental disability, severe cerebral palsy, cognitive delay, and
psychomotor delay. Patients in the hypothermia group had higher incidences of arrhythmia and
thrombocytopenia; however, these were not clinically important. This analysis supports the use of
hypothermia in reducing the risk of the mortality or moderate-to-severe neurodevelopmental disability
in infants with moderate HIE.
Ó 2010 Elsevier Ltd. All rights reserved.

1. Introduction Successful pilot studies7,8 suggested that hypothermia was both

In developed countries, perinatal asphyxia associated with
moderate-to-severe hypoxiceischemic encephalopathy (HIE)
occurs at an approximate rate of 1 to 2 per 1000 live births.1
However, global perspectives on this condition are entirely
different. Worldwide, about a quarter of neonatal deaths every year
are associated with perinatal asphyxia.2 Increasing knowledge of
pathological processes in post-asphyxial neuronal injury, cell death
and secondary apoptosis has led to exploration of avenues for
prevention of secondary neuronal injury.3
Clinical use of hypothermia dates back to the 1960s.4 The
practice became almost extinct with improving survival of preterm
infants and recognition that inadvertent hypothermia in this pop-
ulation can be detrimental.5 Neuronal rescue observed in animal
models of hypoxiaeischemia following induced hypothermia
prompted a series of human investigations of this modality in
infants with encephalopathy.6 As discussed in Chapter 7 of this
issue, suspected mechanisms of action of hypothermia include
reduction in cytotoxins, reduction in metabolic need, and preven-
tion of apoptosis.
* Present address: Department of Paediatrics, Mount Sinai Hospital, 775Ae600
University Avenue, Toronto, Ontario, Canada M5G 1X5. Tel.: þ416 586 4761; fax:
þ416 586 8745.
E-mail address: pshah@mtsinai.on.ca.
feasible and broadly safe, supporting further randomized trials. Data
from the initial randomized controlled trials have been systematically
reviewed.9e11 A workshop organized by the National Institute of Child
Health and Human Development (NICHD) in 2005 indicated that
many questions had not yet been answered and the participants
warned against uncontrolled use.12 Since then, additional studies
have been published, the largest of which reported no effect of ther-
apeutic hypothermia on combined rate of death or severe disability at
18 months of age.13 Further, in reality, many centers have elected to
use hypothermia to treat HIE patients while awaiting follow-up
results from the clinical trials in which they had participated.14 A very
high incidence of adverse outcome (death or moderate-to-severe
disability) after HIE and the lack of any other mode of therapy to avert
these outcomes may be the reason for such practice.
It is important to note that there is still limited information on
whether some of the significant differences in how and in whom
hypothermia is used affect outcome. In particular, two methods of
hypothermia are commonly used (selective head cooling and whole
body hypothermia). Other important issues include variation in the
severity of HIE among patients enrolled in nearly all studies (severe and
moderate encephalopathy), and the different levels of hypothermia
that have been used, which may be classified as two target core body
(rectal or esophageal) temperatures: moderate
34  C vs mild >34  C).
The primary objective of this systematic review was to evaluate
the efficacy and safety of hypothermia used to treat neonates with
post-asphyxial HIE including results from recent trials. The

1744-165X/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2010.02.003
 P.S. Shah / Seminars in Fetal & Neonatal Medicine 15 (2010) 238e246
secondary objective was to assess in subgroup analyses whether
the method of inducing hypothermia, severity of encephalopathy
or degree of hypothermia affect the efficacy of treatment.
2. Methods
2.1. Study selection
For this review, both randomized and quasi-randomized (e.g.
randomization based on day, date, or hospital number) clinical
trials of either systemic hypothermia or selective head cooling were
included. Cohort studies, retrospective studies, preepost compar-
ative studies, case series, case reports, letters to editors that did not
contain primary data, editorials, review articles and commentaries
were not included. These were explored to identify potential new
studies. Multiple reports of primary studies were reviewed to
identify all relevant outcomes for this review.
2.2. Patient population
Definitions used in the included studies regarding asphyxia
severe enough to cause encephalopathy of moderate-to-severe
degree were taken at the face value. There were some apparent
differences between the populations included in various studies;
however, there was a consistent overall theme of use of major
criteria commonly used to define eligible patients. These typically
included various combinations of the following:
 Clinical: low Apgar score, need for resuscitation, neurological
examination demonstrating evidence of encephalopathy,
history of preceding intrapartum event indicative of possi-
bility of asphyxia.
 Biochemical: umbilical arterial or immediate postnatal blood
gas analyses demonstrating severe metabolic acidosis.
Fig. 1. Flow diagram of study selection.
239
 Electrophysiological evidence of HIE: as defined by ampli-
tude-integrated electroencephalogram (aEEG) showing
patterns indicative of moderate or severe encephalopathy.
Types of intervention
Studies of both selective head cooling (with mild systemic
hypothermia in all cases) and whole body hypothermia were
included in the review if the intervention had been given for at
least 48 h.
Literature search
A comprehensive literature search was undertaken, including
MEDLINE (1966eNovember 2009), EMBASE (1980eNovember
2009), Cumulative Index of Nursing and Allied Health Literature
(1982eNovember 2009), The Cochrane Library (Issue 3, 2009)
and abstracts of the annual meetings of the Pediatric Academic
Societies, Hot Topics in Neonatology and the European Society of
Pediatric Research (2003e2009). Bibliographies of relevant and
identified articles were searched to identify additional articles.
Articles in all languages were included. The search strategy is
highlighted in Appendix 1.
2.3. Data extraction
Identified studies were reviewed and data from eligible studies
were abstracted. Each study was assessed for risk of bias using risk
of bias assessment tool from the Cochrane Collaboration except for
the criteria for blinding of intervention, as hypothermia, a physical
therapy, is a challenging intervention to mask. The domains of
assessment included sequence generation, allocation concealment,
method of randomization, and masking of outcome assessment,
completeness of assessment, reporting bias and likelihood of other
biases.15 An overall degree of bias (unlikely, low likelihood,
moderate likelihood and high likelihood) was assigned for each
study considering biases in all domains.
240 P.S. Shah / Seminars in Fetal & Neonatal Medicine 15 (2010) 238e246

Table 1
Clinical characteristics of participants in the included studies.

Author Characteristics Criteria

7
Gunn et al. Inclusion GA 37 weeks, Apgar
6 at 5 min or cord arterial pH
7.09 and clinical signs of encephalopathy
Exclusion Metabolic disease, congenital malformation
Type of hypothermia Head cooling with mild systemic hypothermia
Target temperature 36e36.5  C (N ¼ 6), 35.5e35.9  C (N ¼ 6); rectal
8
Shankaran et al. Inclusion GA 36 weeks, seizures or moderate to severe encephalopathy who had either (a) cord or arterial pH
(within 60 min of birth)
7 or BD 16, or (b) no blood gas or cord or arterial pH 7e7.15 and BD 10e16, history of an acute
perinatal event and Apgar
5 at 10 min or need for mechanical ventilation at 10 min of age
Exclusion Chromosomal anomaly, growth restriction, in extremis, congenital malformation
Type of hypothermia Systemic
Target temperature 34.5  C, esophageal
39
Zhou et al. Inclusion GA 37 weeks, Apgar <5 at 5 min, abnormal electrocardiogram, abnormal neurological examination
Exclusion Congenital abnormality, infection, intracranial hemorrhage, pregnancy complications
Type of hypothermia Selective head cooling with mild systemic hypothermia
Target temperature 34.5  C, nasopharyngeal
31
Akisu et al. Inclusion GA >37 weeks, Apgar
5 at 5 min, pH <7.1 or BD >10, encephalopathy
Exclusion Metabolic disease, congenital infection, congenital malformation, chromosomal anomaly
Type of hypothermia Selective head cooling with mild systemic hypothermia
Target temperature 33e33.5  C, in left ear
38
Shankaran et al. Inclusion GA 36 weeks, seizures or moderate to severe encephalopathy who had either (a) cord or arterial pH (within 60 min
of birth)
7 or BD 16 or (b) no blood gas or cord or arterial pH 7e7.15 and BD 10e16, history of an acute perinatal
event and Apgar
5 at 10 min or need for mechanical ventilation at 10 min of age
Exclusion Chromosomal anomaly, growth restriction, in extremis, congenital malformation
Type of hypothermia Systemic
Target temperature 33.5  C, esophageal
34
Gluckman et al. Inclusion GA 36 weeks, Apgar
5 at 10 min, need for resuscitation including need for ventilation at 10 min or cord or postnatal
pH <7 or BD >16 in umbilical cord sample or cord arterial sample (within 60 min of birth) and aEEG suggestive of
moderate to severe encephalopathy
Exclusion Administration of prophylactic anticonvulsant, BW <1800 g, infants in extremis
Type of hypothermia Selective head
Target temperature 34e35  C, rectal
44
Eicher et al. Inclusion GA 35 weeks, BW 2 kg, and cord pH
7 or cord BD 13 or initial pH <7.1 or continued resuscitation for >5 min or
Apgar
5 at 10 min or fetal bradycardia or postnatal hypoxic ischemic event and two neurological findings of neonatal
encephalopathy
Exclusion Sepsis, chorioamnionitis, growth restriction, chromosomal anomaly
Type of hypothermia Systemic
Target temperature 33  0.5  C, rectal
32
Bhat et al. Inclusion Apgar <5 at 10 min, need for resuscitation at 10 min, cord pH <7 or BD >18
Exclusion Not reported
Type of hypothermia Systemic
Target temperature 33.5  C
36
Lin et al. Inclusion GA 37 weeks, Apgar
5 at 5 min, postnatal arterial pH <7.10 or BD >15, encephalopathy
Exclusion Severe persistent fetal circulation
Type of hypothermia Selective head
Target temperature 34e35  C, rectal
40
Zhou et al. Inclusion GA 36 weeks, BW 2500 g, Apgar
3 at 1 min,
5 at 5 min or cord pH
7 or base deficit
16, abnormal neurological
findings on clinical examination
Exclusion Age >6 h, congenital anomaly, major intracranial hemorrhage, infection, severe anemia
Type of hypothermia Selective head
Target temperature 34  C nasopharyngeal
35
Jacobs et al. Inclusion GA 35 weeks, Apgar
5 at 10 min, need for mechanical ventilation at 10 min, cord or arterial (within 60 min) pH
<7 or BD >12, clinical signs of encephalopathy
Exclusion Congenital anomaly, age >6 h, BW <2 kg, severe respiratory distress, refractory hypotension or acidosis, active cooling
initiated prior to enrolment
Type of hypothermia Systemic
Target temperature 33e34  C, rectal
37
Robertson et al. Inclusion GA 37 weeks, Apgar <6 at 5 min, requirement for resuscitation, abnormal neurological examination in first 3 h
Exclusion Apnea or cyanosis, no response to resuscitation for 10 min, BW <2 kg
Type of hypothermia Systemic
Target temperature 33e34  C, rectal
13
Azzopardi et al. Inclusion GA 36 weeks, Apgar
5 at 10 min or need for resuscitation at 10 min or cord or arterial (within 60 min of birth) pH <7 or
BD 16, moderate to severe encephalopathy and an abnormal aEEG
Exclusion Congenital anomaly, age >6 h, chromosomal anomaly
Type of hypothermia Systemic
Target temperature 33e34  C, rectal

GA, gestational age; BD, base deficit; BW, birth weight; aEEG, amplitude-integrated electroencephalogram.

2.4. Outcomes of interest
Primary and secondary outcomes for this review are listed in
Box 1. The primary outcome was mortality or moderate-to-severe
neurodevelopmental disability in infancy and childhood. Severe
neurodevelopmental disability was considered to have occurred
when the outcomes revealed either cerebral palsy (non-ambula-
tory, severe spasticity or Gross Motor Functional Classification
System class 3),16 or developmental delay as shown by a Mental
Developmental Index (MDI) or Psychomotor Developmental Index
(PDI) of <70 for age, or hearing deficit requiring hearing aids, or
visual acuity below 6/60 in either eye were present. Moderate
 P.S. Shah / Seminars in Fetal & Neonatal Medicine 15 (2010) 238e246 241

Pilot study, subsequent reports included non-randomized patients

Intervention was for 48 h, included mild encephalopathy and two

Box 1. Outcomes

Complete details not available to evaluate bias, study stopped

Control patients were hypothermic for 30 h, marked baseline

Primary outcome

Certain patients in control group developed hyperthermia

Published as abstract only, detailed information awaited

Mortality or moderate-to-severe neuro-
developmental disability
Secondary outcomes
Efficacy
Mortality

Randomization based on day of admission

Moderate to severe neurodevelopmental disability
among survivors

cases of postnatal encephalopathy

Only reported as a letter to editor
Severe cerebral palsy

Pilot study for safety evaluation

Cognitive (MDI <70) delay

before sample size achieved

asymmetry between groups

Psychomotor (PDI <70) delay
Severe visual deficit

Pilot study, low power

Severe hearing deficit
Epilepsy
Withdrawal of life support
Safety

Comments

Pilot study
Arrhythmia
Hypotension
Coagulopathy
Thrombocytopenia (platelet count 109/L)

Moderateehigh
Development of seizures after enrollment

Overall bias
Renal failure

Moderate

Moderate
Moderate

Moderate

Moderate

Moderate
Elevated liver enzymes

Unlikely
Unlikely

Unlikely
Infections

High
Low

Low
Persistent pulmonary hypertension

other bias
MDI, Mental Developmental Index; PDI, Psychomotor

Free of
Developmental Index.

Yes
Yes

Yes
Yes

Yes
Yes
No
No
No
No

No

No

No
Free of selective

neurodevelopmental disability was considered to have occurred

Cannot tell
in cases of moderate motor dysfunction (Gross Motor Functional
reporting

Classification System class 2 or moderate spasticity or ambulatory

cerebral palsy), or developmental delay as identified by MDI or
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Yes
Yes
Yes

Yes

Yes
PDI 70e84 for age, or moderate hearing deficit or visual deficit.
Incomplete data

Data analyses
assessment

Cannot tell
The primary analysis was conducted irrespective of mode of
cooling, severity of encephalopathy or degree of hypothermia.
Yes

Yes
Yes
Yes

Yes
No
No
No

No
No

No

No
Data on efficacy were collected from studies that reported
childhood (age 12 months) outcomes. Data on safety were
outcome assessment

collected from all studies that reported side-effects while

patients were receiving hypothermia. Subgroup analyses were
performed based on (a) methods of hypothermia (whole body
tell
tell

tell

tell

Cannot tell
Blinding of

vs selective hypothermia), (b) degree of encephalopathy e

Cannot
Cannot

Cannot

Cannot

moderate vs severe HIE (Sarnat and Sarnat17 or similar staging

Yes
Yes

Yes

Yes

Yes
No

No

No

system, or aEEG findings suggestive of moderate-to-severe

involvement18) and (c) target temperature range (moderate
concealment

hypothermia
34  C vs mild hypothermia >34  C). A typical

Cannot tell
Cannot tell

Cannot tell

Cannot tell
Allocation

effect size was calculated and reported as pooled relative risk

Assessment of risk of bias among included studies.

(RR), risk difference (RD) and number needed to treat to

Yes
Yes

Yes
Yes
Yes

Yes

Yes

Yes
No

benefit or harm (NNTB/H) as appropriate with 95% confidence

Quasi-randomized

interval (CI). Studies were weighted in all meta-analyses

according to inverse of variance of the outcomes of interest in
individual studies. All analyses (fixed effects model) were
Cannot tell

Cannot tell
generation
Sequence

performed using Revman 5.1 software (Cochrane Collabora-

tion). The c2-test was applied to detect between-study
Yes
Yes

Yes
Yes
Yes
Yes

Yes

Yes

Yes

Yes

heterogeneity and I2 values were calculated to assess statistical

heterogeneity.19 Statistical corrections were not employed to
Shankaran et al. 38

37
Gluckman et al. 34

13
Shankaran et al. 8

Robertson et al.

Azzopardi et al.

adjust for multiple analyses.

Eicher et al. 44

Jacobs et al. 35
Akisu et al. 31
Zhou et al. 39

Zhou et al. 40
32
Gunn et al. 7

Lin et al. 36

3. Results
Bhat et al.
Author
Table 2

Thirty-one reports were evaluated for eligibility (Fig. 1). Three

retrospective studies,20e22 four case series,23e26 and four
242 P.S. Shah / Seminars in Fetal & Neonatal Medicine 15 (2010) 238e246
prospective cohort studies14,27e29 were excluded (Fig. 1). Twenty
reports of 14 clinical trials were identified. One clinical trial that
randomized 129 infants has been presented at a scientific meeting
but presented data were not usable for this review and full publi-
cation is awaited.30 Thus, 19 reports of 13 clinical trials were
included in this review.7,8,13,31e40 Battin and Gunn et al. published
their results of one study in three different reports.7,41,42 To clearly
distinguish between randomized and non-randomized patients,41
only data published in the report that contained distinct compar-
ison of randomized patients was included.7 Shankaran et al.
reported efficacy outcomes and safety outcomes in two reports.38,43
Eicher et al. reported results in two publications.33,44 Jacobs et al.
published an interim report in 200445 and presented safety data at
the Hot Topics in Neonatology conference in 2008.35 Data from the
latest report were included. Azzopardi et al. reported 2-year follow-
up data in one report and magnetic resonance imaging changes at
discharge in another report.13,46 Data from Zhou et al.40 on efficacy
outcomes presented at the Hot Topics in Neonatology conference in
2006 were used, as the full paper is not yet published.
3.1. Clinical heterogeneity assessment among included studies
A total of 1440 patients were randomized in included trials;
a detailed description of the studies included is given in Table 1.
Approximately 56 patients in these studies were reported to have
mild HIE.7,31,33,35,36 One study had two patients with postnatal
asphyxia33; however, data for these patients have not been repor-
ted separately. Seven studies used systemic hypo-
thermia8,13,32,33,35,37,38 and six studies used selective head cooling
with mild systemic hypothermia.7,31,34,36,39,40 In all studies, hypo-
thermia was initiated within the first 6 h after birth. In the study by
Robertson et al.37 patients in the control group were hypothermic
at the start of the study and took 15 h to reach temperature of
>36.5  C. The goal in the intervention group was moderate hypo-
thermia (target temperature
34  C) in eight stud-
ies13,31e33,35,37,38,40 and mild hypothermia (target temperature
>34  C) in five studies.7,8,34,36,39 Systemic hypothermia was ach-
ieved by using a plastic bag containing water and cooling
blanket,33,44 and pre-cooled blankets,8,38 or HotCold gel packs.35
Selective head cooling was achieved by using a cap containing
circulating cold water. One study33,44 used the cooling intervention
for 48 h whereas the remaining studies continued cooling for 72 h.
For rewarming, infants were gradually rewarmed at 0.5  C/h or they
were allowed to warm passively.
Assessment of risk of bias among included studies is reported in
Table 2. One study was quasi-randomized36 (randomization was
based on the day of admission). Publication bias is unlikely, as all
existing studies are known within the community.
Fig. 2. Forest plot of primary outcome of death or moderate-to-severe neurodevelopmental disability in survivors.
3.2. Primary outcome: mortality or neurodevelopmental disability
in childhood
Data on primary outcome were reported in six
studies.7,13,33,34,38,40 Reported numbers of patients lost to follow-up
for primary outcomes were, respectively, 0/22, 2/325, 13/65, 16/234,
5/208, and 30/187. There was a significant reduction in the risk of
mortality or of moderate-to-severe neurodevelopmental disability
(Fig. 2) in infants who received hypothermia compared to control
(six studies, 979 participants, pooled RR: 0.74; 95% CI: 0.65, 0.83;
RD: 0.15, 95% CI: 0.21, 0.09; NNTB: 7; 95% CI: 5, 11; test of
heterogeneity, P ¼ 0.07 and I2 ¼ 51%).
3.3. Effectiveness outcomes
There was significant reduction in the risk of mortality
(RD: 0.07; 95% CI: 0.12, 0.02; NNTB: 15; 95% CI: 8, 50), moderate-
to-severe neurodevelopmental disability (RD: 0.12, 95% CI: 0.19,
0.05; NNTB: 8; 95% CI: 5, 20), cerebral palsy (RD: 0.11; 95% CI:
0.18, 0.03; NNTB 9; 95% CI: 6, 33), severe visual deficit (RD: 0.05,
95% CI: 0.11, 0.01, NNTB 20, 95% CI 9, 100), cognitive delay or MDI
<70 (RD: 0.11; 95% CI: 0.09, 0.03; NNTB: 9; 95% CI: 11, 33), and
psychomotor delay or PDI <70 (RD: 0.11; 95% CI: 0.09, 0.03;
NNTB: 9; 95% CI: 11, 33) in the hypothermia group compared with the
control group (Fig. 3). There was no difference in the risk of epilepsy
or severe hearing deficit. There was no difference in the RR of with-
drawal of life-sustaining medical treatment between hypothermia
and control group. Zhou et al.39 reported neurodevelopmental
outcome at 6 months of age. Normal developmental quotient was
identified in 78% of patients who received hypothermia compared to
70% in the normothermia group.
3.4. Safety outcomes
There was an increased risk of arrhythmia (RD: 0.04, 95% CI:
0.01, 0.06; NNTH: 25, 95% CI: 100, 16) and of thrombocytopenia
(RD: 0.10; 95% CI: 0.03, 0.18; NNTH: 10; 95% CI: 33, 5) in the
hypothermia group (Fig. 4). None of the reports indicated that
either of these side-effects resulted in any clinically significant
impact. No significant between-group differences were observed
for other adverse outcomes, including organ dysfunction.
3.5. Secondary outcomes
3.5.1. Severity of encephalopathy
Five studies reported outcomes based on severity of encepha-
lopathy.7,34,37,38,40 For infants who had moderate encephalopathy,
there was a significant reduction in both the risk of the combined
 P.S. Shah / Seminars in Fetal & Neonatal Medicine 15 (2010) 238e246
Fig. 3. Efficacy outcomes. ND, neurodevelopmental; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index.
outcome of death or moderate-to-severe neurodevelopmental
disability, and of neurodevelopmental disability amongst survivors
in the hypothermia group compared to the control group (Table 3).
There was no difference in any other outcomes for patients based
on severity of encephalopathy.
3.5.2. Mode of hypothermia
Seven studies used systemic hypothermia8,13,32,33,35,37,38 and six
studies used selective head cooling.7,31,34,36,39,40 There was
a reduction in outcomes of mortality or neurodevelopmental
disability, mortality, neurodevelopmental disability, cognitive
delay, psychomotor delay and cerebral palsy among patients who
received systemic hypothermia (Table 4). There was a reduction in
mortality or neurodevelopmental disability and neuro-
developmental disability among survivors but not in other
outcomes among patients who received selective head cooling.
3.5.3. Degree of hypothermia
Five studies used target core temperature >34  C7,8,34,36,39
whereas eight studies13,31,32,35,37,38,40,47 used target core tempera-
ture of
34  C. There were reductions in the risk of mortality or
neurodevelopmental disability, mortality, neurodevelopmental
disability, cognitive delay, psychomotor delay and cerebral palsy
among patients who received hypothermia at target core temper-
ature of
34 C compared with control group (Table 5). There was
no difference in the risk of any outcomes among patients who
received hypothermia with target core temperature of >34  C
compared with control group.
Fig. 4. Safety outcomes.
243
4. Discussion
This updated meta-analysis of 13 eligible trials in infants with
post-asphyxial HIE confirms that therapeutic hypothermia was
associated with a reduced risk of the combined outcome of
mortality or moderate to severe neurodevelopmental disability in
infancy or childhood. Hypothermia was also efficacious in reducing
individual outcomes of mortality, moderate-to-severe neuro-
developmental disability, severe cerebral palsy, cognitive delay, and
psychomotor delay. Patients in the hypothermia group had higher
incidences of arrhythmia and thrombocytopenia; however, these
were not clinically important.
Previously, commentators have recommended caution in the
clinical adoption of the findings of earlier trials of hypothermia in
view of important remaining questions relating to the optimal
degree of hypothermia, type of hypothermia, type of patients, and
effects on childhood outcomes.12,48e50 The present systematic
review updates previous findings with the addition of results from
a further five randomized controlled trials, with a corresponding
increase in the total number of participants to 1440 infants.
Notably, cumulative meta-analysis (data not shown) of these data
revealed that the efficacy of hypothermia (P ¼ 0.003) was evident
after the results of the NICHD study became available (Shankaran
et al.38). The additional data over the last four years has simply
increased the certainty (P < 0.00001) of the point estimate of
primary outcome. Long-term outcome data from one trial35 and
outcome data from another randomized trial30 are still awaited but
involve many fewer patients than reported there; thus it is unlikely
244 P.S. Shah / Seminars in Fetal & Neonatal Medicine 15 (2010) 238e246

Table 3
Results of subgroup analysis according to severity of encephalopathy for hypothermia vs normothermia.

Outcome Results Moderate encephalopathy Severe encephalopathy

Mortality or moderate-to-severe disability No. of studies/participants 4/379 4/188
Relative risk (95% CI) 0.69 (0.55, 0.85)* 0.62 (0.33, 1.18)
Mortality No. of studies/participants 4/267 4
Relative risk (95% CI) 0.76 (0.51, 1.13) 0.87 (0.60, 1.77)
Neurodevelopmental disability among survivors No. of studies/participants 3/179 2/59
Relative risk (95% CI) 0.58 (0.37, 0.89)* 0.97 (0.53, 1.77)
MDI <70 No. of studies/participants 1/110 1/25
Risk difference (95% CI) 0.63 (0.36, 1.09) 1.91 (0.71, 5.13)
PDI <70 No. of studies/participants 1/110 1/25
Relative risk (95% CI) 0.65 (0.36, 1.17) 1.27 (0.59, 2.73)
Epilepsy No. of studies/participants 2/128 1/21
Relative risk (95% CI) 0.93 (0.40, 2.14) 1.17 (0.29, 4.14)

MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index; IC, confidence interval.
*P < 0.05.

that the current conclusions will change materially even when
these additional data become available.
Perhaps more importantly, the additional data have enabled
subgroup analyses in the present review to address at least some
outstanding clinical questions. These analyses indicated reassur-
ingly that both of the commonly used methods of hypothermia
(whole body cooling and selective head cooling with mild systemic
hypothermia) were associated with significant improvement of the
combined outcome of mortality and neurodevelopmental disability
as well as neurodevelopmental disability among survivors. Intui-
tively we might expect that severe HIE, which has an adverse long-
term outcome, would also be less responsive to treatment,51 but
there are very few data. In this analysis, patients with moderate
encephalopathy showed benefit for the composite outcome of
mortality or moderate-to-severe neurodevelopmental disability
and moderate-to-severe neurodevelopmental disability among
survivors. Although patients with severe encephalopathy did not
appear to have a significant improvement in outcome, it is impor-
tant to appreciate that information was available only from a subset
of studies, and from a comparatively small group of infants. Despite
these limitations, the point estimate for the primary outcome of
death or disability in infants with severe HIE was comparable to
that for infants with moderate disability. A further limitation is that
severity was defined using a mixture of clinical and aEEG tech-
niques that may identify subtly different groups.51 These consid-
erations suggest that the efficacy of hypothermia for infants with
severe HIE remains unproven, and that further analysis is essential
to resolve this question.
Hypothermia of
34  C was beneficial for all efficacy outcomes
whereas >34  C was not. Again, possible reasons for the ineffec-
tiveness of mild hypothermia could be that the data come from
small number of infants who received different modes of treat-
ment: either mild whole body cooling or head cooling with mild
systemic hypothermia. At the same time, it must also be noted that
none of the studies had target temperature <33  C.
Prior to the most recent trials being reported, the use of hypo-
thermia as a standard of care has been criticized.49 One important
issue is that potentially, as an unblinded intervention, hypothermia
might lead to a reduced likelihood of withdrawal of life-sustaining
therapy compared with normothermia and thus result in replace-
ment of death by severe disability. This meta-analysis shows that
there was no difference in the risk of withdrawal of life support
between groups, and further, that neurodevelopmental outcomes
were improved in survivors. This concern does not therefore appear
to be valid.
However, do we have all answers? In particular, can we now
recommend use of hypothermia in low resource settings, outside
the developed world? It appears that caution is warranted. As was
evident in the study by Robertson et al.,37 patients in such settings
typically spontaneously become hypothermic after birth and
remain hypothermic for a prolonged period of time. Additionally,
causes of death in these settings may also be a confounder as the
prevalence of sepsis is relatively high.37 Cost of cooling equipment
could also be a prohibitive factor in low-resource settings and other
approaches such as a servo-controlled fan28 or locally made cooling
mattresses or by the use of water bottles37 may need to be explored.
Thus, further careful consideration and planning would be required
for studying hypothermia in low resource settings.37
Given the indications from experimental studies that earlier
initiation of hypothermia may be more beneficial,52 should hypo-
thermia be initiated during or even before neonatal transport from
peripheral centers? Two studies have reported use of hypothermia

Table 4
Subgroup analysis based on type of hypothermia.

Outcome Results Selective head cooling vs normothermia Systemic hypothermia vs normothermia

Mortality or moderate-to-severe disability No. of studies/participants 3/397 3/582
Relative risk (95% CI) 0.69 (0.56, 0.84)* 0.77 (0.66, 0.90)*
Mortality No. of studies/participants 5/481 7/909
Relative risk (95% CI) 0.77 (0.58, 1.03) 0.78 (0.63, 0.96)*
Neurodevelopmental disability No. of studies/participants 3/279 3/408
among survivors Relative risk (95% CI) 0.66 (0.46, 0.95)* 0.68 (0.51, 0.90)*
MDI <70 No. of studies/participants 1/131 3/391
Relative risk (95% CI) 0.76 (0.47, 1.23) 0.67 (0.50, 0.90)*
PDI <70 No. of studies/participants 1/125 3/387
Relative risk (95% CI) 0.74 (0.46, 1.19) 0.68 (0.50, 0.92)*
Cerebral palsy No. of studies/participants 1/140 2/378
Relative risk (95% CI) 0.63 (0.35, 1.14) 0.65 (0.46, 0.93)*

MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index; CI, confidence interval.
*P < 0.05.
 P.S. Shah / Seminars in Fetal & Neonatal Medicine 15 (2010) 238e246 245

Table 5
Subgroup analysis based on degree of hypothermia.

Outcome Results Target temperature >34  C vs normothermia Target temperature
34  C vs normothermia
Mortality or moderate-to- No. of studies/participants 2/240 4/739
severe disability Relative risk (95% CI) 0.84 (0.67, 1.04) 0.70 (0.60, 0.82)*
Mortality No. of studies/participants 3/321 9/1069
Relative risk (95% CI) 0.87 (0.62, 1.21) 0.75 (0.62, 0.91)*
Neurodevelopmental disability No. of studies/participants 2/162 4/525
among survivors Relative risk (95% CI) 0.73 (0.48, 1.11) 0.65 (0.50, 0.85)*
MDI <70 No. of studies/participants 1/131 3/391
Relative risk (95% CI) 0.76 (0.47, 1.23) 0.67 (0.50, 0.90)*
PDI <70 No. of studies/participants 1/125 3/387
Relative risk (95% CI) 0.74 (0.46, 1.19) 0.68 (0.50, 0.92)*
Cerebral palsy No. of studies/participants 1/140 2/378
Relative risk (95% CI) 0.63 (0.35, 1.14) 0.65 (0.43, 0.93)*

MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index; CI, confidence interval.
*P < 0.05.

during transport and have indicated that it is feasible26,53; however,
there appeared to be substantial risk of unintended overcooling.
Further data on the safety of this approach will be available from
the ‘ICE’ trial, in which cooling is initiated during transport.35 For
now, the available data indicate that continuous monitoring of
temperature during transport as well as careful training of staff will
be mandatory.
Can the method of cooling and rewarming be improved?
Azzopardi et al.14 reported that a servo-controlled cooling jacket
was associated with reduced fluctuations in core body temper-
ature compared with a manually controlled cooling blanket.
However, it appears that the rewarming period was very rapid
with the servo-controlled jacket. We need to study this further,
as different methods of rewarming (active or passive) can lead to
variable fluctuations in temperature before it can reach normal
values.27,28 Seizures have been reported during rapid
rewarming.54
The strengths of this updated meta-analysis are the inclusion of
recent trials, increased power based on increased sample size,
detailed assessment of bias in included studies and subgroup
analyses. Several limitations of this systematic review should be
considered. Studies included in this meta-analysis varied from
small single-center studies to large multicenter studies. Other
heterogeneities were explored in subgroup analyses except risk of
bias. An analysis only including studies which had low likelihood of
bias or where bias was unlikely8,13,34,35,38 revealed a pooled RR
of 0.80 (95% CI: 0.70, 0.92) for primary outcome, further suggesting
strong internal validity of results. The subgroup analyses must be
interpreted with caution and the findings should be considered
hypothesis-generating only; however, the power of these analyses
is increasing with additional data and many of these findings
appear to be concordant with experimental data.6
Finally, some important clinical questions still need to be
answered. For example, is therapeutic hypothermia beneficial for
infants with mild encephalopathy? The application of hypothermia
for patients with mild encephalopathy has two major issues. First,
our ability to distinguish mild encephalopathy from other condi-
tions/scenarios leading to transient depression in neurological
status immediately after birth is limited. Second, we may expose
many babies to inadvertent risk of side-effects such as bradycardia
and thrombocytopenia, with much smaller potential benefits than
for infants with moderate-to-severe HIE. We may also deprive them
from bonding with mother for the first 72 h of life, and for these
reasons, practical applicability for such infants is challenging.
Other significant questions include: What should is the optimal
rate of rewarming? How and when should we initiate hypothermia
during or prior to transport? Can we extend the window for initi-
ation of therapeutic hypothermia to 6e12 h after birth? Is the
improvement in neurological disability at 18 months sustained into
late childhood and adulthood?
5. Conclusion
Hypothermia is a safe and effective treatment of neonatal HIE in
term and near-term newborn infants. Continued assessment of
long-term outcomes of patients enrolled in completed trials should
be a key priority to confirm the long-term safety of hypothermia.
Practice points
 Provision of therapeutic hypothermia to patients with
post-asphyxial HIE reduced mortality and neurological
disability at 18e24 months of age.
 Both modalities (whole body hypothermia and head
cooling with systemic hypothermia) were efficacious in
reducing adverse outcomes.
 Subgroup analysis revealed efficacy in patients with
moderate encephalopathy and patients who received
moderate hypothermia (
34  C).
Research directions
 How can we safely facilitate hypothermia at birthing
center and during transport?
 What are the optimal cooling systems to control
temperature with a defined range and to enable cooling
and gradual rewarming, without overshoot?
 Is hypothermia beneficial for patients with mild
encephalopathy?
 Is hypothermia effective if initiated between 6 and 12 h
after birth?
Conflict of interest
None declared.
Funding sources
None.
Appendix 1. Search strategy
Population
Infant-Newborn (MeSH) OR Infant, Newborn, Diseases (MeSH) OR
newborn (text word) OR infant (text word) OR neonate (text word).
246 P.S. Shah / Seminars in Fetal & Neonatal Medicine 15 (2010) 238e246
Intervention
Hypothermia (MeSH); hypothermias (MeSH); Hypothermia,
induced (MeSH); cerebral hypothermia (text word) circulatory
arrest, deep hypothermia induced (MeSH); cooling (text word),
head cooling (text word), whole body cooling (text word).
Comparison
Clinical trials (MeSH) OR Controlled Clinical Trials (MeSH) OR
Randomized Controlled Trials (MeSH) OR Random Allocation
(MeSH) OR Multicenter studies (MeSH) OR Control groups (MeSH)
OR Evaluation studies (MeSH).
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