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The Role of Hypothermia in the Management of Severe Brain Injury
A Meta-analysis
Odette A. Harris, MD, MPH;
John M. Colford, Jr, MD, PhD;
Matthew C. Good;
Paul G. Matz, MD
Arch Neurol. 2002;59:1077-1083.
ABSTRACT
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Context Hypothermia is utilized in the management of severe traumatic brain
injury despite the lack of unequivocal evidence supporting its use. Because
of its widespread use, the effects of hypothermia are a concern.
Objective To determine the effectiveness of hypothermia in the management of severe
brain injury.
Data Sources Two investigators working independently abstracted data in a blinded
fashion from studies identified using multiple literature databases, including
MEDLINE, Ovid, PubMed, the Cochrane Database of Systematic Reviews, EMBASE,
and the abstract center for the American Association of Neurological Surgery
and the Congress of Neurological Surgery, as well as the bibliographies of
these articles. Additionally, experts in the field of hypothermia and neurotrauma
provided additional references.
Study Selection Seven studies met predetermined inclusion criteria: (1) the study was
a randomized clinical trial comparing the efficacy of hypothermia vs normothermia
in patients with posttraumatic head injury, (2) only subjects aged 10 years
or older were included in the study, and (3) relative risks (odds ratios [ORs],
cumulative incidence, or incidence density measures) and 95% confidence intervals
(CIs) or weighted mean differences and 95% CIs could be calculated from the
data presented in the article. These criteria were applied in a blinded fashion
by 2 independent investigators.
Data Extraction No single outcome variable was evaluated in all studies. The following
outcome variables were assessed: intracranial pressure, Glasgow Outcome Scale
score, pneumonia, cardiac arrhythmia, prothrombin time, and partial thromboplastin
time. Either ORs or weighted mean differences (when the data provided did
not permit calculation of an OR) comparing the effects of hypothermia vs normothermia
were calculated from the data provided.
Data Synthesis The weighted mean difference (hypothermia - normothermia) for
intracranial pressure was -2.98 mm Hg (95% CI, –7.58 to 1.61; P = .2). The OR (hypothermia vs normothermia) for Glasgow
Outcome Scale score was 0.61 (95% CI, 0.26-1.46; P
= .3). The OR for pneumonia was 2.05 (95% CI, 0.79-5.32; P = .14). The OR for cardiac arrhythmia was 1.27 (95% CI, 0.38-4.25; P = .7). The weighted mean difference for prothrombin time
was 0.02 seconds (95% CI, –0.07 to 0.10; P
= .7). The weighted mean difference for partial thromboplastin time was 2.22
seconds (95% CI, 1.73-2.71; P<.001).
Conclusions This meta-analysis of randomized controlled trials suggests that hypothermia
is not beneficial in the management of severe head injury. However, because
hypothermia continues to be used to treat these injuries, additional studies
are justified and urgently needed.
INTRODUCTION
TRAUMA AFFECTS an estimated 1.9 million persons annually in the United
States and accounts for approximately 1% of all injuries and annual visits
to emergency departments.1 In addition, traumatic
brain injury accounts for 40% of all deaths from acute injuries. Of those
surviving, 200 000 patients require hospitalization each year and often
are permanently disabled. An additional 1.74 million persons suffer mild traumatic
brain injury.1 The direct costs of traumatic
brain injury in the United States are estimated at $4 billion annually, with
indirect costs estimated at 10 times that amount.2
Although prevention has been the main focus of efforts to address the incidence
of primary traumatic brain injury, efforts to address secondary injury have
been quite varied. One of the oldest such modalities used is hypothermia.
Defined simply as body temperature significantly below 37°C, hypothermia
has long been used for cerebral protection in the management of traumatic
brain injury.3 Although the beneficial effects
of hypothermia in head injury were reportedly observed by Hippocrates,4 the first reported clinical application of hypothermia
was performed by Fay in 1938.3, 5
The procedure was limited to the terminally ill, who were subjected to temperatures
of approximately 80°F (27°C). His results are noteworthy for tumor
shrinkage and their palliative effect, specifically pain relief associated
with metastatic cancer.3, 6 His
work led to widespread application of the procedure in neurosurgery and cardiothoracic
surgery, where deep hypothermia (15°C-22°C) demonstrated an effective
method of neuroprotection.7
Deep hypothermia, however, led to significant secondary complications,
including cardiac arrhythmia; inhibition of coagulation cascade enzymes, predisposing
patients to hemorrhage; and systemic complications, such as infection.7-14
In addition, it demanded significant use of hospital resources.7, 9, 15-17
Milder degrees of hypothermia were later studied in an attempt to address
the complications posed by cooling to deeper temperatures. At 30°C to
35°C, hypothermia was found to "offer significant neuroprotection in both
global and focal models."7(p36), 15, 18-24
In addition, the milder temperatures were safer and less expensive to induce
and maintain.7-8,22, 24
These results led to the implementation of mild to moderate hypothermia in
various clinical settings. The principal purpose of this meta-analysis is
to investigate the hypothesis that induced hypothermia improves outcomes in
patients with severe brain injuries when compared with normothermia.
In the field of traumatic brain injury, several clinical studies have
sought to establish hypothermia as a treatment modality. The results of early
studies suggesting the benefits of hypothermia were met with significant scrutiny
because of their lack of randomization and the heterogeneous subject populations.
The generalizability of the data was thus limited, and the efficacy of the
procedure remained in question. More recent studies have responded to these
criticisms. These studies include several single-center trials and 1 multicenter
trial, with various outcomes of interest. As a result, it has been difficult
to fully assess the efficacy of induced hypothermia and, thus, endorse the
procedure as beneficial in the management of traumatic brain injuries.
METHODS
The medical literature published since 1966 was searched in all languages
using electronic databases. The initial search included the MEDLINE, Ovid,
and PubMed databases. The commands used in these searches were "hypothermia
and head injury," "hypothermia and brain injury," "hypothermia and trauma,"
and "hypothermia and neurosurgery." The Cochrane Database of Systematic Reviews,
EMBASE, and the abstract center for the American Association of Neurological
Surgery and the Congress of Neurological Surgeons were searched using the
same keywords. Additional references from any year of publication were retrieved
from the bibliographies of the relevant articles reviewed and from experts
in the field of hypothermia and/or neurotrauma: Gary K. Steinberg, MD, PhD;
Donald Marison, MD; Alois Zauner, MD; and one of us (P.G.M.).
Studies with titles or abstracts discussing hypothermia or the management
of head injuries or trauma were retrieved. Any original randomized controlled
trial investigating hypothermia as an exposure was submitted for further review
with all references to author names, journal titles, and funding sources removed.
All pertinent articles were reviewed, and the resulting studies were analyzed
independently by 2 of us (O.A.H. and M.C.G.). The following inclusion criteria
were applied: (1) the study was a randomized clinical trial comparing the
efficacy of hypothermia vs normothermia in patients with posttraumatic head
injury; (2) only subjects 10 years or older were included (established to
exclude very young pediatric patients in whom the pathophysiologic effects
of trauma are believed to be different5); and
(3) relative risks (odds ratios [ORs], cumulative incidence, or incidence
density measures) and 95% confidence intervals (CIs) or weighted mean differences
and 95% CIs could be calculated from the data presented in the article. When
multiple publications reported information from the same study subjects, only
the publication with the most recent analysis of data was included.
The following data were abstracted from the eligible studies in a blinded
fashion, using a standard data form (with the abstractors blinded to journal
and author names): classification of head injury (Glasgow Coma Scale score),
category of hypothermia (mild or moderate), ages of subjects, initiation and
duration of hypothermia, extent of blinding, and the various outcomes studied.
Several variables were assessed in the studies included in the meta-analysis.
Because no single variable was available for evaluation in every study, the
decision was made to evaluate the more frequently used and clinically relevant
variables25: Glasgow Outcome Scale score, intracranial
pressure, pneumonia, cardiac arrhythmia, prothrombin time, and partial thromboplastin
time.
Relative risk estimates were not provided in any of the included studies.
Thus, all estimates were calculated from the data provided. In the majority
of the studies, 2 x 2 tables were reconstructed, and the appropriate
estimates were calculated. When the means and SDs of outcome variables were
given, this information was used directly to calculate weighted mean differences.
Whenever possible, an OR was calculated and used in the summary calculations.
Summary relative risk estimates were then calculated as a weighted average
of individual study results. Weightings and the summary estimate for each
outcome were determined based on the random effects model (DerSimonian and
Laird26). This model explicitly incorporates
any heterogeneity of treatment effects across studies and provides a conservative
compensation for heterogeneity by inflating the estimated variance (thus enlarging
the estimated CIs). Summary estimates were compared using a z statistic. All summary measures of effect and associated CIs were
calculated using the software package RevMan,27
developed by the Cochrane Collaboration for meta-analysis and systematic reviews.
Heterogeneity was evaluated using the Mantel-Haenszel method, and the results
were considered heterogeneous (ie, differences unlikely to be due to chance
alone) if the P value was less than .2.28
Study quality was assessed and scored using 3 criteria highlighted by
the scale by Jadad et al.29 The following items
were used to measure the internal validity of each clinical trial: (1) concealment
of treatment allocation, (2) randomization, (3) blinding of outcome assessment,
and (4) handling of withdrawals and dropouts. All 7 trials scored points for
randomization. None of the studies addressed blinding or gave a description
of withdrawals and dropouts. However, given the critical nature of injury
in both treatment and control groups, the loss of time introduced by blinding
would have been clinically inappropriate. Furthermore, it may be inferred
that no patient withdrew because of the clinical severity of injury. The likelihood
of publication bias was addressed using funnel plots to compare relative outcome
measure and sample size.
RESULTS
A total of 528 references (445 when duplicates were deleted) were retrieved
from PubMed (n = 327), Ovid (n = 83), pre-MEDLINE (n = 4) and MEDLINE (n =
79), the abstract center for the American Association of Neurological Surgery
and the Congress of Neurological Surgeons (n = 1), contacting experts (n =
5), and bibliographic review (n = 29). Fifty-four publications were submitted
for blinded review. The blinded review excluded all but 9 studies because
the studies did not contain original data or because they lacked information
regarding hypothermia specific to the management of severe head injury. Another
study was excluded because of redundancy in data reporting8
and another because it was a nonrandomized trial in which there was no control
group.30 The final 7 studies are summarized
in Table 1. Each study focused
on several variables as outcomes of interest. Because no single variable was
evaluated in every study, the more frequently reported and clinically relevant
variables were chosen as the focus of this analysis.
GLASGOW OUTCOME SCALE SCORE
Four of the 7 studies included in the meta-analysis assessed Glasgow
Outcome Scale score as a variable of interest.11, 31-33
The summary estimate (OR, 0.61; 95% CI, 0.26-1.46; P
= .3) demonstrated no statistically significant effect for hypothermia (Figure 1A). There was evidence of heterogeneity
among these studies (P = .08).
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The odds ratios (ORs) or the weighted mean differences (WMDs) and
95% confidence intervals (CIs) comparing the effects of hypothermia vs normothermia
with the outcome variables Glasgow Outcome Scale score (A), intracranial pressure
(B), pneumonia (C), cardiac arrhythmia (D), prothrombin time (E), and partial
thromboplastin time (F). With regard to sample size, n indicates the number
of subjects who were positive for the outcome; N, the total number of subjects
in the group.
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INTRACRANIAL PRESSURE
Five studies assessed intracranial pressure as an outcome variable.11, 32-35
However, only 2 studies provided sufficient data to allow statistical analysis
of this outcome. Using the random effects model, the weighted mean difference
was –2.98 (95% CI, –7.58 to 1.61; P =
.2; Figure 1B), suggesting that
hypothermia had no benefit. There was evidence of heterogeneity among these
studies (P<.001).
PNEUMONIA AND CARDIAC ARRHYTHMIA
Three studies included pneumonia and cardiac arrhythmia as outcome variables.11, 31, 34 The summary estimate
for the effect of hypothermia on pneumonia was OR, 2.05 (95% CI, 0.79-5.32; P = .14), suggesting that hypothermia had no benefit (Figure 1C). There was no evidence of heterogeneity
among these studies ( 2 = 2.83; P
= .24). The summary estimate data for the effect of hypothermia on cardiac
arrhythmia (OR, 1.27; 95% CI, 0.38-4.25; P = .7)
suggested that hypothermia had no benefit (Figure 1D). There was no evidence of heterogeneity among these studies
(P = .23).
PROTHROMBIN TIME AND PARTIAL THROMBOPLASTIN TIME
Three studies assessed prothrombin time and partial thromboplastin time.32, 35-36 Only 2 of these studies
provided sufficient data to allow statistical analysis. Using the random effects
model, the weighted mean difference for prothrombin time was 0.02 (95% CI,
–0.07 to 0.10; P = .7; Figure 1E). There was no evidence of heterogeneity among these studies
(2 = 1.0; P = .32). For partial thromboplastin
time, the weighted mean difference was 2.22 (95% CI, 1.73-2.71) with an overall
effect (P<.001; Figure 1F). These results favored normothermia over hypothermia.
There was no evidence of heterogeneity among these studies (2
= 0.62; P = .43).
PUBLICATION BIAS
The possibility of publication bias in the literature on hypothermia
was assessed using a funnel plot.28 The studies
that evaluated Glasgow Outcome Scale score and cardiac arrhythmia were chosen
as representative because they included the largest subcategory of studies.
Each of the funnel plots examines effect size vs sample size. These plots
do not support the existence of publication bias in these studies.
COMMENT
Meta-analyses are relatively uncommon in the field of neurosurgery;
fewer than 20 studies have been published in the last 10 years. Because this
method of analysis is useful in the synthesis and evaluation of available
data, we believe increased use will add greatly to the field. This meta-analysis
is the first study evaluating the use of hypothermia in the management of
severe brain injury.
We examined 5 clinically relevant outcome variables in the evaluation
of the value of hypothermia in the management of patients with severe head
injury: Glasgow Outcome Scale score, intracranial pressure, cardiac arrhythmia,
pneumonia, prothrombin time, and partial thromboplastin time.25
Glasgow Outcome Scale score is widely recognized as a functional rating scale
in neurosurgical trauma.37 The meta-analysis
of Glasgow Outcome Scale score indicated a statistically significant risk
associated with hypothermia (Figure 1B).
Intracranial pressure was included in this meta-analysis because it is an
integrated marker of cerebral edema, secondary injury, and deteriorating neurologic
status.38 The meta-analysis of the effects
of hypothermia on intracranial pressure did not suggest that hypothermia was
beneficial for patients with severe head injury (Figure 1A).
The added morbidity of the systemic effects observed during the use
of hypothermia is one criticism of its early use. We chose to examine cardiac
arrhythmia and pneumonia as representatives of systemic effect because several
studies included them as outcome variables. Neither of these meta-analyses
suggested that hypothermia had any benefit (Figure 1D and Figure 1C).
Early studies involving deep hypothermia were plagued by concerns regarding
coagulopathy and the resulting hemorrhage.39-42
Subsequent research demonstrated a disruption in the extrinsic and intrinsic
clotting pathways, fibrinolytic cascade, and platelet number and function.5, 43-44 The results of current
studies were reported to be without any clinically deleterious effect. We
chose to look more closely at this issue and selected prothrombin time and
partial thromboplastin time as markers for coagulation. There was no evidence
that hypothermia affected prothrombin time, although our meta-analyses suggested
that hypothermia is associated with a statistically significant risk of elevated
partial thromboplastin time (Figure 1F).
There are several limitations inherent to the design of the individual
studies included in the meta-analysis. Potential confounding factors, such
as sex, age, mechanism of injury, time to initiation of hypothermia, duration
of treatment, rate of rewarming, and ideal target temperature range, could
introduce bias into the results.
There is a consensus that initiation of hypothermia in the treatment
of traumatic brain injury should be done as soon as possible. Although the
majority of the clinical trials (5 of 7) included in this meta-analysis initiated
treatment in patients randomized to hypothermia within 6 hours postinjury
(Table 1), there was no uniform
protocol established to determine the ideal interval for humans. Further complicating
the issue was the time to target temperature level, which varied considerably
among trials. Of those reporting this parameter, the range was 8 to 15 hours
postinjury. This differs significantly from the animal studies in which delay
in treatment initiation demonstrated a decrease in potential benefit.42-43
The duration of hypothermia and the ideal rate of rewarming are controversial.
The duration of treatment employed by the clinical trials included in the
meta-analysis ranged from 24 hours to 14 days. Two of the 7 studies maintained
hypothermia for 24 hours, 4 for 48 hours, and 1 for 3 to 14 days (Table 1). The rewarming schedule used in
recent trials varied as well, ranging from 12 hours to 5 days. From these
studies, the optimal length of therapy and rate of reversal remain uncertain.
The definition of the specific target temperature for hypothermia is
another important potential source of bias. Although hypothermia is defined
as temperature significantly below 37°C, there are many subcategories
of hypothermia to be considered, and each is associated with its own benefits
and complications.3 There are several classification
schemes for hypothermia, ranging from mild to ultra-profound.5, 44
Regardless of the classification scheme, among studies included in the meta-analysis,
little distinction exists between mild (34°C-35°C) and moderate (32°C-33°C)
hypothermia. Recent studies have been too few to determine whether any benefit
exists between the subcategories of mild and moderate hypothermia.
Temperature determination was another source of potential bias. Available
methods for assessing temperature included ventricular, bladder, rectal, and
intravascular sites. Although there is evidence to suggest that the route
of measurement was irrelevant,15, 45
it must be noted that several methods were used to assess temperature in the
studies included in the meta-analysis. The majority used a thermistor placed
in the ventricle.
Patient age is an important factor in traumatic brain injury. Two of
the studies included the specific age range of the patients, approximately
15 to 75 years. Two additional studies excluded only the very young, with
an age inclusion criterion of 10 years or older. One study did not report
specific ages but provided a mean age of 42.2 years for the hypothermia group
and 40.6 years for the normothermia group. Average age provided little useful
information because it did not exclude the possibility of either the very
young or very old, 2 groups with different posttraumatic pathophysiological
characteristics, being included. With regard to sex and mechanisms of injury,
in all studies, the majority of patients were men, and the primary mechanism
of injury was motor vehicle accident. This is consistent with previous studies
outlining the demographics of trauma.1-2
The severity of neurologic impairment may act as a confounder and as
such would be important to control. Thus, subcategorizing severe traumatic
brain injury beyond a Glasgow Coma Scale score of 3 to 8 would be important
because lower scores indicate a greater degree of neurologic impairment. Of
the studies included in this meta-analysis, only 3 took this into account
by using a block randomization scheme to balance the injury severity between
hypothermia and normothermia groups. There was insufficient data to explore
this issue further, specifically to determine if there was an excess of patients
with lower Glasgow Coma Scale scores in either the hypothermia or normothermia
groups, which could have influenced the summary estimates of effect.
There are several limitations inherent in all meta-analyses.28, 45 Any biases present in the individual
studies are not removed when a quantitative synthesis is performed. Thus,
any summary estimate generated from a synthesis of studies represents an estimate
of the association of interest (hypothermia and outcome variable) available
from the literature. Both the availability of the literature and the studies
presented may be biased. Many potential confounding variables of interest
(time to target temperature, choice of specific target temperature, and duration
of hypothermia) could not be thoroughly explored because of inconsistencies
in reporting or lack of relevant information for subgroup analyses. Although
every attempt was made to secure all published and unpublished studies in
all languages, publication bias may never be totally excluded.
CONCLUSIONS
The meta-analysis of the existing literature does not support the use
of hypothermia in the management of posttraumatic brain injury. We do not
believe that the results of this meta-analysis should define the clinical
use of hypothermia because of the limitations imposed by the low number of
studies and the lack of consistent outcome measurement. However, because hypothermia
is widely used and the results of this meta-analysis suggest that there may
be no benefit to this treatment, a definitive and rigorously conducted randomized
controlled trial is urgently needed.
AUTHOR INFORMATION
Accepted for publication March 19, 2002.
Author contributions: Study concept and design (Drs Harris and Colford); acquisition of data (Drs Harris and Matz and Mr Good); analysis and interpretation of data (Drs Harris, Colford, and Matz and Mr Good); drafting of
the manuscript (Drs Harris and Colford); critical
revision of the manuscript for important intellectual content (Drs Harris, Colford, and Matz and Mr Good); statistical expertise (Drs Harris and Colford); administrative, technical, and
material support (Drs Harris, Colford, and Matz and Mr Good); study supervision (Drs Harris, Colford, and Matz).
Corresponding author and reprints: Odette A. Harris, MD, MPH, Department
of Neurosurgery, Stanford University Medical Center, 300 Pasteur Dr, Edwards
Bldg, Second Floor, Stanford, CA 94305 (e-mail: odette{at}leland.stanford.edu).
From the Department of Neurosurgery, Stanford University Medical Center,
Stanford, Calif (Drs Harris and Matz); and the Division of Public Health Biology
and Epidemiology, School of Public Health, University of California, Berkeley
(Dr Colford and Mr Good).
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SECTION EDITOR: DAVID E. PLEASURE, MD
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