REVIEW ARTICLE
Therapeutic Hypothermia in Children After Cardiac Arrest
A Systematic Review and Meta-analysis
Janice F. Bistritz, MS, CPNP, DNP, Lauren M. Horton, MS, CPNP, DNP-C,
and Arlene Smaldone, PhD, CPNP-BC, CDE
Background: Therapeutic hypothermia (TH) has been shown to be ef-
fective in resuscitation of some adults following cardiac arrest and infants
with hypoxic ischemic encephalopathy, but has not been well studied
in children.
Objectives: The purpose of this systematic review/meta-analysis was to
examine mortality, neurologic outcomes, and adverse events in children
following use of TH.
Results: A search of PubMed, the Cumulative Index to Nursing and
Allied Health Literature, and the Institute for Scientific Information’s
Web of Knowledge from 1946 to 2014 yielded 6 studies (3 retrospective
and 3 prospective cohort studies) that met our inclusion criteria. Quantita-
tive synthesis of mortality following TH (136 subjects) was 44% (95%
confidence interval, 32-57) with 28% (95% confidence interval, 11-53)
of survivors (42 subjects) demonstrating poor neurologic outcome. The
most frequently reported adverse events were electrolyte imbalances and
pneumonia.
Conclusions: Evidence is insufficient to support the advantage of TH
compared with normothermia in pediatric resuscitation. The adverse event
profile appears to be different than that reported in adults. Further studies
are needed before TH may be considered a standard protocol for children
after cardiac arrest.
Key Words: therapeutic hypothermia, cardiac arrest, children, systematic
review, meta-analysis
(Pediatr Emer Care 2015;31: 296–303)
P ediatric cardiac arrest (CA) is an unusual yet devastating
event, often associated with decreased survival and in-
creased neurological morbidity. The economic costs of the se-
quelae are substantial, as is the loss of future productive life.1
Approximately 16,000 American children experience an out-of-
hospital CA (OHCA) each year.1–3 Approximately 2% of children
in pediatric intensive care units have an in-hospital CA (IHCA).2–4
The rates of survival to hospital discharge vary greatly between
OHCA and IHCA. Out-of-hospital CA carries a poorer progno-
sis.5,6 Survival in children after OHCA is lower (2%-12%)
compared with IHCA (27%-51%),1,7–9 with infants having the
greatest mortality, whereas children and adolescents exhibit a
higher survival rate compared with adults1,3,10 Poor neurologic
outcomes among survivors of OHCA are very common (76%)
compared with IHCA (24%-53%).4,7,8,11,12
To achieve favorable neurological recovery after successful
resuscitation, it is imperative to stop the ischemia process. The
cessation of cerebral blood flow from CA causes hypoxia, which
leads to ischemic injury to the brain. Even when resuscitation
efforts are successful, additional damage can result from reperfu-
sion injury. This insult to the sensitive neurological structures
From Columbia University School of Nursing, New York, NY.
Disclosure: The authors declare no conflict of interest.
Reprints: Janice F. Bistritz, MS, CPNP, DNP-C, Columbia University School of
Nursing, 630 W 168th St, New York, NY 10032
(e‐mail: jfb29@columbia.edu).
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ISSN: 0749-5161
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leads to permanent damage. Many treatments have been at-
tempted to reduce or reverse the hypoxic and reperfusion injury
to the neurological system; however, none have demonstrated
improved outcomes.13
For 40 years, researchers have studied the use of therapeutic
hypothermia (TH) after CA to determine if its use would improve
neurological outcomes.3 The mechanisms underlying the benefi-
cial effects of hypothermia are complex and include reductions
in the cerebral metabolism of glucose and oxygen consumption,
thereby mitigating the destructive processes that occur after
the insult. These destructive pathways include the accumula-
tion of excitotoxic neurotransmitters, intracellular acidosis, neuro-
inflammation, apoptosis, free radical production, and seizure
activity.14,15 In his systematic review, Bernard5 defined TH as
the controlled lowering of core body temperature to approxi-
mately 34°C, the optimal balance between clinical effect and car-
diovascular toxicity. This temperature provides for easier clinical
management because shivering can occur between 34°C and
35.5°C and may require suppression by additional amounts of
sedation or neuromuscular blockade.5 Lower core temperature
was found to be counterproductive, as temperatures between
28°C and 31°C were associated with atrial fibrillation and ventric-
ular fibrillation, respectively.5
To date, TH is the only treatment demonstrating laboratory
and clinical efficacy in improving neurological outcomes in se-
lected circumstances. Therapeutic hypothermia improves neuro-
logic outcomes in some adults following OHCA,13,16–19 as well
as in newborns who sustained perinatal asphyxia.19–22 Infrequent
use of TH in the pediatric population was noted in an earlier sys-
tematic review5; in addition, in the 3 studies that examined TH in
the treatment of pediatric survivors of submersion accidents,
outcomes were inconsistent.9 At this time, there are no completed
randomized trials utilizing TH in children after CA.23 The
American Heart Association, in 2005, suggested that induced
hypothermia be considered in children who remain comatose after
cardiopulmonary resuscitation,24 and in 2010, the Committee for
the International Consensus on Cardiopulmonary Resuscitation
and Emergency Cardiovascular Care Science further recom-
mended considering TH in the care of pediatric patients following
resuscitation.25 The purpose of this systematic review/meta-
analysis was to examine mortality, neurologic morbidity of survi-
vors, and type and frequency of adverse events in pediatric patients
treated with TH following resuscitation.
METHODS
Search Strategy
We searched the literature using PubMed, Cumulative Index
to Nursing and Allied Health Literature, and Web of Knowledge
to identify studies that examined the intervention of TH in the
treatment of pediatric patients after CA. To reflect all research
on this topic, we searched all studies published from 1946 until
January 2014. Subject headings used in the search included ther-
apeutic hypothermia, cardiac arrest, and child. These headings
Pediatric Emergency Care • Volume 31, Number 4, April 2015
Pediatric Emergency Care • Volume 31, Number 4, April 2015
were then exploded to obtain a more complete listing of all related
resources. All studies reporting mortality and morbidity outcomes
of TH in treatment of pediatric patients, from birth to age 21 years,
who had CA were reviewed. The reference lists of all pertinent
articles were hand searched to identify any additional studies not
previously identified. Studies in which TH was utilized for rea-
sons other than CA (eg, surgery, traumatic brain injury), where
the outcomes of morbidity and mortality were not studied or re-
ported, the subjects were older than 21 years, were published in
a language other than English or Spanish, or were literature re-
views, editorials, individual case studies, or letters to the editor
were excluded.
Assessment of Study Quality
Two reviewers (L.M.H., J.F.B.) independently appraised each
study for quality using the Downs and Black26 criteria, a 27-item
scale developed to assess the quality of nonrandomized interven-
tion studies. The instrument has good test-retest and interrater re-
liability, high internal consistency, and good criterion validity. We
modified the scale by deleting 9 items that were not relevant to ob-
servational studies. Each indicator was scored as 0 (criterion not
met) or 1 (criterion met) with the exception of 1 item (indicator 5),
which was scored as 0 (criterion not met), 1 (criterion partially
met), or 2 (criterion met). After independent review of the studies,
scores were assigned. If there was disagreement regarding the
quality scores, the topic was discussed, and a consensus was
reached. Studies that achieved a score of 15 or greater of the 18
criteria were considered to be of good quality.
Data Extraction and Synthesis
Data extracted from each study included the general charac-
teristics of the sample, location of CA, qualities of hypothermia,
setting of data collection, percent mortality after cardiac event,
neurologic outcome, and type and frequency of reported adverse
events. Neurologic outcome was reported using the Pediatric Ce-
rebral Performance Category (PCPC) or Glasgow Outcome Scale
(GOS). The PCPC scale is a validated scale designed to assess
functional morbidity and cognitive impairment after a critical in-
jury.27 The scale contains 6 categories; each addresses a level of
functional impairment, with lower scores indicating a higher level
of function.28 Researchers frequently utilize this scale to deter-
mine the impact of the CA and compare populations4,7,10,29–35
across studies. A related measurement scale, the GOS,36,37 was
originally devised to describe outcomes of severely head injured
patients. This scale is a variation of the Glasgow Coma Scale,
which is widely used in the Utstein protocol of reporting CA fea-
tures.38 The GOS contains 5 categories, with higher scores indi-
cating higher levels of function.39 Similar to the PCPC, the GOS
has also been used by researchers to quantify the effect of subse-
quent neurologic injury after CA.40 Table 1 compares features of
both scales. We defined poor neurologic outcome as PCPC of 4 or
TABLE 1. Comparison of Scoring Criteria of PCPC and GOS
PCPC GOS Category
1 5 Normal
2 4 Mild disability
3 Moderate disability
4 3 Severe disability
5 2 Coma or vegetative state
6 1 Brain death
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Therapeutic Hypothermia After Cardiac Arrest
greater or GOS of 3 or less (severe disability, coma or vegetative
state, or death).
Data Analysis
Studies reporting mortality and/or neurologic outcome fol-
lowing use of hypothermia during resuscitation were eligible for
inclusion in meta-analysis. Data were extracted as frequency and
sample size and standardized effect sizes computed. Neurologic
outcome was determined for survivors of CA. A pooled effect
was estimated for each outcome using a random-effects meta-
analysis model. Heterogeneity was assessed using Cochran Q
and I2 statistics. Data were analyzed using Comprehensive Meta-
analysis statistical software (Biostat, Inc, Edgewood, NJ). Results
are presented as forest plots.
RESULTS
Figure 1 provides details of the literature search and ultimate
selection of the included studies. Of 562 articles identified, 6 ob-
servational (3 retrospective29,35,40 and 3 prospective cohort30–32)
studies were included in the systematic review. Based on their
study design, these studies provide levels 3 to 4 evidence for prog-
nostic studies,41 with level 1 evidence being of highest quality.
Table 2 reports the results of the evaluation of the methodo-
logical quality of the included studies. The quality scores of the
studies ranged from 13 to 18. The 3 retrospective studies29,35,40
and 2 of 3 of the prospective studies30,31 were found to be of good
quality (≥15). Only the pilot study32 did not meet the standard
for good quality. Of the 6 studies, only 1 adjusted analyses for
confounding variables.
Table 3 summarizes the characteristics of the included stud-
ies. A total of 355 subjects (hypothermia: n = 136, standard care:
n = 219) were included in the studies, with ages ranging from
younger than 1 year to 21 years. Sample sizes of the individual
studies ranged between 6 subjects32 and 181 subjects.40 The ma-
jority of studies were conducted in the United States,30,31,40 with
the remaining studies distributed among Canada, the United
Kingdom, Taiwan, and Chile.29,32,35 One study was multisite29
and involved 5 university-affiliated tertiary care institutions. The
3 retrospective studies30,35,40 included a comparison group of
normothermic resuscitation. Each study identified the location
of CA as either out of or in hospital, with the majority (57.4%
of the 136 subjects treated with TH) having sustained an OHCA.
The methods of induction of TH varied among the studies
and some studies used a combination of methods. The methods in-
cluded use of ice packs,29,31,32 cooling blankets,29–32,35,40 extra-
corporeal membrane oxygenation (ECMO),29 and iced saline
administered either by gastric lavage40 or intravenously.29–32
With the exception of ECMO, methods of inducing hypothermia
are readily available in all tertiary care centers. The time to induc-
tion of TH was reported as being within 8 hours from time of
CA,29,31,32,35 admission to the intensive care unit,40 or return of
spontaneous circulation (ROSC).30
Description
Age-appropriate level of development or functioning
Alert, conscious, possibility of mild neurologic deficit
Conscious, independent activities of daily life, learning deficits
Conscious, dependent for daily support
Coma, cerebral unresponsiveness and some reflexive response
Apnea and/or electroencephalographic silence
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Mortality and neurological performance scores were reported

FIGURE 1. Literature search and selection of studies.
in all studies, although the end points varied from time of dis-
charge30,31,35,40 to 6 months after CA.29,32 The PCPC score27
was used as a measurement of neurological outcome in the major-
ity of studies.29–32,35 The process of instituting TH was the pri-
mary outcome in 2 of the studies: Topjian et al31 evaluated the
feasibility of TH, and Fink et al40 assessed the frequency of ad-
verse events as a result of TH. The addition of electroencephalo-
gram monitoring during the hypothermia procedure and its use
as a predictor of outcomes were other features addressed in the
study of Kessler et al.30
Table 4 provides a synthesis of the findings of the studies
included in this review. Mortality varied among studies. In the
majority of studies,29–31,40 mortality for subjects treated with TH
was 40% or greater, with 2 studies32,35 reporting mortality of less
than 22%. Small sample size may have influenced this finding. In
studies that compared mortality outcomes for subjects treated with
TH with those receiving standard care or normothermia,29,35,40 a
statistically significant advantage for the treatment group was
found in only 1 study.35 In the study conducted by Doherty
and colleagues,29 unadjusted mortality was higher for those who
had received TH; however, when results were adjusted for con-
founders, there were no statistically significant differences be-
tween groups.
Poor neurological performance, reported as a PCPC of 4 or
greater, was greater than 33% in 3 of the studies.29–31 Lin and col-
leagues35 reported poor neurological outcome as a PCPC of 3 to 5,
different than the parameters set by the other studies. Although
poor outcome was found in only 18% of the TH group, it is dif-
ficult to compare the findings to the other studies. Fink and col-
leagues40 assessed poor neurologic outcome using the GOS
scoring system as 3 or less and found no significant differences
between the TH group and the standard care group. Bustos and
colleagues32 reported the most favorable neurologic outcome for
survivors of TH with no subject scoring in the unfavorable range.
Adverse events were reported in each study; 1 study30 re-
stricted its reporting of adverse events to seizures. Table 5 presents
the frequency of occurrence of adverse events in children who

TABLE 2. Quality Appraisals of the Included Studies

Quality of Reporting External Validity

Prospective Cohort Studies
Author Year I II III IV V VI VII VIII IX X XI XII XIII XIV XV XVI XVII XVIII Total
Kessler et al.30 2011 1 1 1 1 1 1 1 0 1 1 1 0 1 1 1 1 1 0 15
Topjian et al31 2011 1 1 1 1 1 1 1 1 1 0 1 0 1 1 1 1 1 0 15
Bustos et al32 2012 1 1 1 1 1 1 1 1 1 0 0 0 0 1 1 1 1 0 13
Retrospective Cohort Studies
Authors Year I II III IV V VI VII VIII IX X XI XII XIII XIV XV XVI XVII XVIII Total
29
Doherty et al 2009 1 1 1 1 2 1 1 1 1 1 1 1 0 1 1 1 1 1 18
Fink et al40 2010 1 1 1 1 2 1 1 1 1 1 1 0 1 1 1 1 1 0 17
Lin et al35 2013 1 1 1 1 2 1 1 1 1 1 1 1 0 1 1 1 1 1 18
I indicates objective described; II, outcomes described; III, sample characteristics described; IV, intervention described; V, confounders described; VI,
findings described; VII, variability of data described; VIII, adverse events described; IX, characteristics of subjects lost to follow-up described; X, proba-
bility values for outcomes described; XI, subjects were representative of the population from which they were recruited; XII, subjects who were prepared
to participate representative of the population from which they were recruited; XIII, were staff, places, and facilities where subjects were treated represen-
tative of the population from which they were recruited; XIV, if any study results were based on “data dredging” and whether this was made clear; XV,
statistical tests were appropriate; XVI, main outcome measures used were valid and reliable; XVII, study subjects were recruited over the same period;
XVIII, results were adjusted for confounders; Each criterion scored as 0, not met; 1, criterion met with exception of criterion V scored as 0, not met; 1,
partially met; 2, criterion met.

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Pediatric Emergency Care • Volume 31, Number 4, April 2015 Therapeutic Hypothermia After Cardiac Arrest

TABLE 3. Characteristics of the Included Studies

Statistical
Sample Characteristics Hypothermia Multisite Outcome Adjustment for
Author, Year Size Age of the Sample Procedure (Yes/No) Measures Confounders
Doherty et al,29 n = 79 Majority IH (95%) Induction: ≤6 h Yes ▪ 0-d mortality Duration of CA
2009 Aged >40 wk to <18 y Study inclusion criteria: Duration: 12-69 h ▪ 6-mo mortality Use of ECMO
CA ≥ 3 min, Survival Type: ▪ PCPC at 6 mo Propensity score
> 12 h after ROSC, ▪ ECMO
PICU admission
after resuscitation ▪ Cooling blanket
▪ Ice packs
▪ Iced IV fluids
Fink et al,40 n = 181 Majority IH (54.9%) Induction: 5-8 h No ▪ Mortality at
2010 discharge
Aged 1 week to 21 y Study inclusion criteria: Duration: 16-48 h ▪ GOS at hospital None
Admitted to PICU with Type: discharge
ROSC after CA ▪ Cooling blanket
▪ Ice lavage with IV
iced saline
Kessler et al,30 n = 35 Majority OH (83%) Induction: 7.3 ± 0.2 h No ▪ Mortality at None
2011 discharge
0.18-16.6 y Study inclusion criteria: Duration 24 h ▪ PCPC at PICU
admitted to PICU with Type: discharge
ROSC after CA ▪ Cooling blanket
Topjian et al,31
n = 12 Majority OH (83%) Induction: <8 h No ▪ Mortality at None
2011 discharge
0.2-15 y Study inclusion criteria: Duration: 24 h ▪ PCPC at hospital
survival >8 h with Type: discharge
ROSC after CA ▪ Cooling blanket
▪ Ice packs
Bustos et al,32 n=6 Majority OH (83%) Induction: <7 h No ▪ 6-mo mortality None
2012 1-14 y Study inclusion criteria: Duration: 42-54 h ▪ PCPC at 6 mo
1 min, ROSC after Type:
CA, GOS ≤8 ▪ Cooling blanket
▪ Ice packs
IV Iced saline
Lin et al,35 2013 n = 43 Majority OH (67.4%) Induction: <6 h No ▪ Mortality at hospital None
discharge
2 mo to 18 y Study inclusion criteria: Duration: 24-72 h ▪ PCPC at hospital
>12 h after ROSC; Type: discharge
PICU admission ▪ Cooling pads
after ROSC
IV indicates intravenous; PICU, pediatric intensive care unit.

received TH following CA. Hypokalemia was reported in more
than half of subjects who received TH. Other frequent adverse
events were pneumonia (27.5%), bradycardia (22.5%), hypomag-
nesemia (23%), and hypophosphatemia (23%). Brain herniation
was reported as an adverse event for 2 of the 122 treated
with TH.29,35
Quantitative Synthesis
Figure 2, the top forest plot, represents mortality data from
136 subjects who received TH as part of resuscitation efforts.
Using a random-effects model, the pooled frequency was 44%
(95% confidence interval, 32%-57%). Heterogeneity between and
within studies was not greater than expected by chance (Q = 9.1;
P = 0.11), with less than half of the variability attributed to differ-
ences between studies (I2 = 44.9). Poor neurologic outcome was re-
ported as a PCPC score of 4 or greater in 4 of the 6 studies.29–32 The
bottom forest plot represents data from 46 survivors of CA who re-
ceived hypothermia as part of resuscitation. Using a random-effects
model, the overall pooled frequency of poor neurologic outcome
was 35% (95% confidence interval, 25%-51%). When stratified
by time point, the pooled frequency was 41% (95% confidence in-
terval, 25%-58%) at hospital discharge and 6% (95% confidence
interval, 1%-34%) at 6 months following discharge with significant
differences noted between time points. Heterogeneity of the over-
all model was not greater than expected by chance (Q = 4.6,
P = 0.20; I2 = 35.2).
DISCUSSION
Therapeutic hypothermia currently has a place in postresus-
citation care in adults.13,14,17–19,42 However, the role of TH in
similar pediatric patients has not been established. Although
recommendations for consideration of this intervention were

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Bistritz et al Pediatric Emergency Care • Volume 31, Number 4, April 2015

TABLE 4. Mortality and Morbidity Outcomes for Children After CA

Outcomes
Doherty et al,29 2009
Fink et al,40 2010
Kessler et al,30 2011
Topjian et al,31 2011
Bustos et al,32 2012
Lin et al,35 2013
NT indicates normothermia.
Timeframe
6 mo
Hospital discharge
Hospital discharge
Hospital discharge
Hospital discharge
Hospital discharge
Morbidity (% survivors)
Mortality (%) PCPC ≥4 or GOS ≤2
38% NT, 69% TH, P = 0.009 42% NT, 67.9% TH
55.3% NT, 55% TH; not GOS = 1: 5% NT, 7.5% TH;
statistically significant not statistically significant
40% TH PCPC: 50% TH
50% TH PCPC: 33.3% TH
17% TH PCPC at 6 mo: 0% TH
53.6% NT, 21.4% TH PCPC score 3–5 25% NT; 14% TH;
not statistically significant

made in 2006,43 few studies have been conducted to examine
its efficacy in children. The study of Bustos et al32 demonstrated
the most promising results with the lowest (17%) mortality and
good neurological outcomes. However, the study was limited by
its small sample of 6 patients. The sample sizes of the other stud-
ies were also relatively small, with the exception of 1 multisite
trial,29 which, despite a larger sample size, may not have had suf-
ficient power to detect differences between groups, as an a priori
power analysis was not reported. Based on findings of the studies
in this systematic review, there is no sufficient evidence to recom-
mend TH as standard protocol after CA in pediatric patients.
Each of the 3 retrospective studies29,35,40 used a matched
control group, which received standard care or normothermia;
however, the populations differed between these 2 studies. The
majority of subjects in the study of Doherty et al29 had preexisting
cardiac conditions and had CA during hospitalization, whereas the
majority of subjects in the other 2 studies35,40 experienced OHCA.
In addition, although the study of Doherty et al29 was a multisite
study including 5 centers, only 3 of the centers used hypothermia
in their treatment. Consequently, the internal validity of this study
may be compromised. Topjian et al31 did not include any subjects
with underlying heart disease, and only 17% had IHCA. The re-
maining 2 prospective studies did not report if their subjects had
prior cardiac conditions, and the majority of their subjects had
OHCA. Out-of-hospital CA is known to be associated with poorer
outcomes; however, the studies did not stratify their outcomes
based on location of CA.
In the prospective studies,30–32 subjects meeting inclusion
criteria were consecutively enrolled on admission to the intensive
care unit. The subjects in the retrospective studies29,35,40 were
chosen from medical record review of patients with the diagnosis
of CA.
All of the studies, whether they were prospective or retro-
spective, utilized various methods of induction of TH. The
methods included ice packs, cooling blankets, gastric lavage
with iced saline, intravenous iced saline, and ECMO. Only 1 study,
Doherty et al29 included ECMO as a method of induction, as 3 of
the 5 participating centers were tertiary care centers equipped with
this technology. The outcomes were not stratified by method
of induction.
The target temperature for TH in all the studies was approx-
imately 34°C with the range of actual temperatures during the

TABLE 5. Reported Adverse Events in Youth Receiving TH After CA

Adverse Event (AE) No. Studies Reporting AE Sample Size n %

Bleeding/hemorrhage 3 102 12 11.8
Pneumonia 4 102 28 27.5
Sepsis 3 102 10 9.8
Bradycardia 3 102 23 22.5
Arrhythmia 4 102 15 14.7
Severe hypotension/shock 1 102 7 6.9
Leukopenia 2 102 8 7.8
Thrombocytopenia 2 102 4 3.9
Hyperglycemia 1 102 9 8.8
Electrolyte abnormalities*
Hypokalemia 3 87 44 50.6
Hypomagnesemia 2 87 20 23.0
Hypophosphatemia 2 87 20 23.0
Hypocalcemia 2 87 11 12.6
Shivering 1 87 3 3.4
Seizures 3 122 22 18.0
Brain herniation 2 102 2 2.0
*One study (Lin et al35) reported electrolyte imbalance (hypokalemia, hypomagnesemia, hypophosphatemia, and hypocalcemia) requiring treatment in
aggregate in 93% of TH sample, not included in the frequencies reported above.

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Pediatric Emergency Care • Volume 31, Number 4, April 2015
FIGURE 2. Forest plots of mortality and poor neurologic outcomes of survivors.
induction period spanning 32°C to 34.8°C. Rewarming periods
varied between 12 and 24 hours in 4 of the studies,29–32 but in 1
study, the range was 5 to 8 hours.40 The 3 prospective studies30–32
each reported a small percentage of patients in whom the core
temperature was not maintained within the target range through-
out the hypothermia period.
One of the more serious complications specific to TH induc-
tion, because of its significant effect on mortality and morbidity,
was overshooting the target temperature. All but 1 study32 re-
ported overshooting the lower limit of hypothermia, 32°C, in
some subjects; however, the frequency of this occurrence was
not greater than 17.2%, illustrating relative safety of the process.
The incidence of mortality increased in those patients whose tem-
peratures dropped less than 32°C.
The process of hypothermia is known to be associated with
adverse effects on cardiac function, coagulation, the immune
system, neurological system, and electrolyte balance.9 Findings
of this systematic review suggest that 4 of the 5 most frequently
occurring adverse events following TH after CA in children were
electrolyte abnormalities. The adverse event profile appears to be
different in children compared with adults. In their multisite pro-
spective observational registry-based study of adults who received
TH following CA at 22 hospitals in Europe and the United States,
Nielsen and colleagues44 examined adverse events and their asso-
ciation with mortality. The most frequent adverse events were
pneumonia (48%), hyperglycemia (37%), and seizures (24%).
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Therapeutic Hypothermia After Cardiac Arrest
Adjusted for confounders, adverse events associated with higher
risk of mortality were hyperglycemia and receipt of anticonvul-
sant therapy. Future research is needed to examine the relationship
between adverse events and mortality in youth treated with TH
following CA.
Findings from the studies of Bustos et al32 and Lin et al35
suggest that improved outcomes are possible for children treated
with TH. Currently, there are 4 ongoing randomized trials,23 the
largest of which is the THAPCA (Therapeutic Hypothermia After
Pediatric Cardiac Arrest) trial, funded by the American Heart,
Lung and Blood Institute, designed to determine if TH improves
survival with good neurologic outcome in children successfully
resuscitated after CA. This trial, the largest study to date, has a
6-year enrollment period and involves 37 clinical sites with a target
enrollment of 900 children.45 Findings of this study may provide
more conclusive evidence to determine if TH can improve out-
comes for children who sustain CA as well as the optimal time of
initial TH induction, treatment, rewarming, method of TH induc-
tion, and the optimal temperature to minimize neurological damage.
Limitations
The findings of this systematic review must be viewed in
light of several limitations. We reviewed only studies published
in English and Spanish and excluded other languages. We may
not have captured all relevant studies as we used only 3 databases
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Bistritz et al
and did not include unpublished research, scientific presentations,
and monographs. Publication bias was unlikely to have influenced
our findings because most of the studies reported no statistically
significant advantage of TH over normothermia in the treatment
of children after CA. The marked variations between the study
populations, location of CA, time to induction, duration and
method of the interventions, and small sample sizes prevent gen-
eralizability to all children who sustain CA.
CONCLUSIONS
The International Liaison Committee on Resuscitation and
the American Heart Association recommend that TH be consid-
ered if a child remains comatose after resuscitation following
CA.43 This recommendation was extrapolated from adult studies
and studies of newborns with birth asphyxia. The results of this
systematic review/meta-analysis do not support the advantage of
TH over normothermia in the treatment of children after CA
in regard to the outcomes of mortality and neurologic damage.
The greatest impact on mortality and morbidity from CA
may come in the form of prevention. Not all CA can be prevented.
Yet some strategies, such as implementation of rapid response
teams within institutions, have been shown to decrease the inci-
dence of preventable CAs46 and improve survival.47 Another area
of practice that may have an impact on improving survival out-
come is the performance of effective cardiopulmonary resuscita-
tion.1 Providing the larger group of first responders with proper
education in the performance of effective cardiopulmonary resus-
citation may increase the numbers of patients who survive in the
prehospital arena and are able to benefit from advanced care in
the hospital.
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