The New England Journal of Medicine

Original Article
Volume 346:549-556

February 21, 2002

Number 8
Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac
Arrest
The Hypothermia after Cardiac Arrest Study Group
ABSTRACT
Background Cardiac arrest with widespread cerebral ischemia frequently leads
to severe neurologic impairment. We studied whether mild systemic
hypothermia increases the rate of neurologic recovery after resuscitation
from cardiac arrest due to ventricular fibrillation.
Methods In this multicenter trial with blinded assessment of the outcome,
patients who had been resuscitated after cardiac arrest due to ventricular
fibrillation were randomly assigned to undergo therapeutic hypothermia
(target temperature, 32°C to 34°C, measured in the bladder) over a period of
24 hours or to receive standard treatment with normothermia. The primary end
point was a favorable neurologic outcome within six months after cardiac
arrest; secondary end points were mortality within six months and the rate
of complications within seven days.
Results Seventy-five of the 136 patients in the hypothermia group for whom
data were available (55 percent) had a favorable neurologic outcome
(cerebral-performance category, 1 [good recovery] or 2 [moderate
disability]), as compared with 54 of 137 (39 percent) in the normothermia
group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81).
Mortality at six months was 41 percent in the hypothermia group (56 of 137
patients died), as compared with 55 percent in the normothermia group (76 of
138 patients; risk ratio, 0.74; 95 percent confidence interval, 0.58 to
0.95). The complication rate did not differ significantly between the two
groups.
Conclusions In patients who have been successfully resuscitated after
cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia
increased the rate of a favorable neurologic outcome and reduced mortality.
  _____

An estimated 375,000 people in Europe undergo sudden cardiac arrest yearly.
1 <http://content.nejm.org/cgi/content/full/346/8/#R1>  Recovery without
residual neurologic damage after cardiac arrest with global cerebral
ischemia is rare. After cardiac arrest with no blood flow for more than five
minutes, the generation of free radicals, together with other mediators,
during reperfusion creates chemical cascades that result in cerebral injury.
2 <http://content.nejm.org/cgi/content/full/346/8/#R2>  Until recently,
there was no therapy with documented efficacy in preventing brain damage
after cardiac arrest.
Several studies have shown that moderate systemic hypothermia (30°C) 3
<http://content.nejm.org/cgi/content/full/346/8/#R3>  or mild hypothermia
(34°C) 4 <http://content.nejm.org/cgi/content/full/346/8/#R4> , 5
<http://content.nejm.org/cgi/content/full/346/8/#R5> , 6
<http://content.nejm.org/cgi/content/full/346/8/#R6> , 7
<http://content.nejm.org/cgi/content/full/346/8/#R7> , 8
<http://content.nejm.org/cgi/content/full/346/8/#R8>  markedly mitigates
brain damage after cardiac arrest in dogs. The exact mechanism for this
cerebral resuscitative effect is not clear. A reduction in cerebral oxygen
consumption 9 <http://content.nejm.org/cgi/content/full/346/8/#R9> , 10
<http://content.nejm.org/cgi/content/full/346/8/#R10>  and other
multifactorial chemical and physical mechanisms during and after ischemia
have been postulated. 11
<http://content.nejm.org/cgi/content/full/346/8/#R11> , 12
<http://content.nejm.org/cgi/content/full/346/8/#R12> , 13
<http://content.nejm.org/cgi/content/full/346/8/#R13> , 14
<http://content.nejm.org/cgi/content/full/346/8/#R14> , 15
<http://content.nejm.org/cgi/content/full/346/8/#R15> , 16
<http://content.nejm.org/cgi/content/full/346/8/#R16>  These include
retardation of destructive enzymatic reactions, suppression of free-radical
reactions, protection of the fluidity of lipoprotein membranes, reduction of
the oxygen demand in low-flow regions, reduction of intracellular acidosis,
and inhibition of the biosynthesis, release, and uptake of excitatory
neurotransmitters.
Preliminary clinical studies have shown that patients treated with mild
hypothermia after cardiac arrest have an improved neurologic outcome,
without important side effects, as compared with the outcome in historical
controls. 17 <http://content.nejm.org/cgi/content/full/346/8/#R17> , 18
<http://content.nejm.org/cgi/content/full/346/8/#R18> , 19
<http://content.nejm.org/cgi/content/full/346/8/#R19> , 20
<http://content.nejm.org/cgi/content/full/346/8/#R20>
We compared mild hypothermia with standard normothermia in patients who had
had cardiac arrest due to ventricular fibrillation. The primary end point
was a favorable neurologic outcome within six months after cardiac arrest.
21 <http://content.nejm.org/cgi/content/full/346/8/#R21> , 22
<http://content.nejm.org/cgi/content/full/346/8/#R22> , 23
<http://content.nejm.org/cgi/content/full/346/8/#R23>  Secondary end points
were mortality at six months and the incidence of complications during the
first seven days. Nine centers in five European countries participated in
the study.
Methods
Patients
Patients seen consecutively in the emergency department in whom spontaneous
circulation had been restored after cardiac arrest were eligible for the
study. The criteria for inclusion were a witnessed cardiac arrest,
ventricular fibrillation or nonperfusing ventricular tachycardia as the
initial cardiac rhythm, a presumed cardiac origin of the arrest, an age of
18 to 75 years, an estimated interval of 5 to 15 minutes from the patient's
collapse to the first attempt at resuscitation by emergency medical
personnel, and an interval of no more than 60 minutes from collapse to
restoration of spontaneous circulation.
Patients were excluded if they met any of the following criteria: a
tympanic-membrane temperature below 30°C on admission, a comatose state
before the cardiac arrest due to the administration of drugs that depress
the central nervous system, pregnancy, response to verbal commands after the
return of spontaneous circulation and before randomization, evidence of
hypotension (mean arterial pressure, less than 60 mm Hg) for more than 30
minutes after the return of spontaneous circulation and before
randomization, evidence of hypoxemia (arterial oxygen saturation, less than
85 percent) for more than 15 minutes after the return of spontaneous
circulation and before randomization, a terminal illness that preceded the
arrest, factors that made participation in follow-up unlikely, enrollment in
another study, the occurrence of cardiac arrest after the arrival of
emergency medical personnel, or a known preexisting coagulopathy.
Study Design
The study was designed as a randomized, controlled trial with blinded
assessment of the outcome. The protocol and consent procedure were approved
by the institutional review board of each participating center. For all
patients, the requirement of informed consent was waived in accordance with
the ethical standards of the local institutional review board and the
guidelines for good clinical practice of the European Agency for the
Evaluation of Medicinal Products. 24
<http://content.nejm.org/cgi/content/full/346/8/#R24>  The patient's family
was informed about the trial, and the protocol specified that if there were
any objections, the patient would be withdrawn from the study. However,
there were no objections.
Treatment assignments were randomly generated by computer in blocks of 10,
with stratification according to center. Sealed envelopes containing the
treatment assignments were provided by the biostatistics center. Immediately
after a patient had been enrolled, an envelope was opened, and the patient
was assigned to the specified group.
Personnel involved in the care of patients during the first 48 hours after
cardiac arrest could not be blinded with respect to treatment assignments.
However, the physicians responsible for assessing the neurologic outcome
within the first six months after the arrest were unaware of the treatment
assignments.
Treatment
All patients received standard intensive care according to a detailed
protocol. Sedation was induced by the intravenous administration of
midazolam (0.125 mg per kilogram of body weight per hour initially) and
fentanyl (0.002 mg per kilogram per hour initially), and the doses were
adjusted as needed for 32 hours for the management of mechanical
ventilation. To prevent shivering, paralysis was induced by the intravenous
administration of pancuronium (0.1 mg per kilogram) every 2 hours for a
total of 32 hours. Intracranial pressure was not monitored.
The temperature on admission was measured with an infrared tympanic
thermometer (Ototemp LighTouch, Exergen, Watertown, Mass.). Further
temperature measurements were made with a bladder-temperature probe (Foley
catheter). Patients randomly assigned to the normothermia group were placed
on a conventional hospital bed, and normothermia was maintained. Those
randomly assigned to the hypothermia group were cooled to a target
temperature of 32°C to 34°C with the use of an external cooling device
(TheraKool, Kinetic Concepts, Wareham, United Kingdom). This device consists
of a mattress with a cover that delivers cold air over the entire body. The
goal was to reach the target bladder temperature within four hours after the
return of spontaneous circulation. If this goal was not achieved, ice packs
were applied. The temperature was maintained at 32°C to 34°C for 24 hours
from the start of cooling, followed by passive rewarming, which we expected
would occur over a period of 8 hours.
Data Collection
Data on cardiac arrest for individual patients were recorded in the Utstein
style. 25 <http://content.nejm.org/cgi/content/full/346/8/#R25>  Laboratory
tests were performed at base line, 12 and 48 hours after cardiac arrest, and
as clinically indicated. Risk factors for an unfavorable outcome
(hypotension or a nonfatal cardiac arrest after resuscitation) were
documented.
Outcome
The primary outcome was a favorable neurologic outcome within six months,
defined as a Pittsburgh cerebral-performance category of 1 (good recovery)
or 2 (moderate disability) on a five-category scale; the other categories
were 3 (severe disability), 4 (a vegetative state), and 5 (death). 21
<http://content.nejm.org/cgi/content/full/346/8/#R21> , 22
<http://content.nejm.org/cgi/content/full/346/8/#R22> , 23
<http://content.nejm.org/cgi/content/full/346/8/#R23>  The neurologic
outcome was determined without knowledge of the patient's treatment
assignment. Patients with good recovery or moderate disability had
sufficient cerebral function to live independently and work at least
part-time.
Secondary end points were overall mortality at six months and the rate of
complications during the first seven days after cardiac arrest. Bleeding of
any severity, pneumonia, sepsis, pancreatitis, renal failure, pulmonary
edema, seizures, arrhythmias, and pressure sores were recorded. Since an
individual patient might have more than one complication at a time, the
occurrence of at least one complication of any kind per patient was also
documented.
Statistical Analysis
Continuous variables, which were not normally distributed, are reported as
medians and interquartile ranges. Categorical variables are reported as
counts and percentages. Primary and secondary outcomes were binary, and the
chi-square test or Fisher's exact test, as appropriate, was used to compare
outcomes in the hypothermia and normothermia groups. Trends across subgroups
were measured with an extension of the Wilcoxon rank-sum test. 26
<http://content.nejm.org/cgi/content/full/346/8/#R26>  The difference in
risk between the two groups, with the corresponding 95 percent confidence
interval, was calculated as a measure of the absolute risk, which was then
used to calculate the number needed to treat. Risk ratios are reported as a
measure of relative risk.
We used a multivariate logistic-regression model to determine whether the
association between the intervention and the primary and secondary outcomes
(neurologic recovery and mortality) was confounded by base-line differences
between the study groups. All the covariables listed in Table 1
<http://content.nejm.org/cgi/content/full/346/8/#T1>  were entered into the
model, except for the dose of epinephrine, which was excluded because of
collinearity with the interval from the patient's collapse to the
restoration of spontaneous circulation. We converted odds ratios to risk
ratios using the following formula:


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Table 1. Base-Line Characteristics of the Patients.

risk ratio = odds ratio ÷ ([1 – incidence in normothermia group] + incidence
in normothermia group x odds ratio). 27
<http://content.nejm.org/cgi/content/full/346/8/#R27>
Confounding can be assumed if the crude risk ratio differs from the adjusted
risk ratio. Goodness of fit was assessed with the Hosmer–Lemeshow chi-square
test. A reasonable fit can be assumed if the result is not significant at
the 5 percent level. Analysis was carried out according to the
intention-to-treat principle. Stata software (version 7, Stata, College
Station, Tex.) was used to analyze the data.
Results
The study was carried out between March 1996 and January 2001. Since the
enrollment rate was lower than expected and funding had ended by July 2000,
enrollment was stopped at this date.
A total of 3551 patients were assessed for eligibility; 3246 of these
patients did not meet the inclusion criteria, and 30 were not included
because of logistic problems. Thus, 275 patients were enrolled, with 137
patients randomly assigned to the hypothermia group and 138 to the
normothermia group (i.e., the group that received standard care after
resuscitation). Hypothermia was discontinued early in 14 patients for the
following reasons: death (6 patients), arrhythmia and hemodynamic
instability (3), technical problems with the cooling device (2), liver
rupture (1), previous random assignment to the hypothermia group (1), and an
error in the duration of cooling (1). All randomized patients were included
in the analysis of mortality. One patient in each group was lost to
follow-up for neurologic status.
At base line, the patients in the two groups were generally similar,
although the patients in the normothermia group were more likely to have a
history of diabetes mellitus or coronary heart disease and to have received
basic life support from a bystander than were those in the hypothermia
group. These differences appear to have been due to random variation ( Table
1 <http://content.nejm.org/cgi/content/full/346/8/#T1> ).
Cooling
In patients randomly assigned to the hypothermia group, the median interval
between the restoration of spontaneous circulation and the initiation of
cooling was 105 minutes (interquartile range, 61 to 192). The median
interval between the restoration of spontaneous circulation and the
attainment of a temperature between 32°C and 34°C was 8 hours (interquartile
range, 4 to 16). In 19 patients, the target temperature could not be
reached. Ice packs were required for 93 of the 132 patients for whom data
were available (70 percent). The median duration of cooling was 24 hours
(interquartile range, 24 to 25), and among patients in whom the target
temperature was reached, it was maintained for a median of 24 hours
(interquartile range, 12 to 29). Passive rewarming to a temperature above
36°C lasted for a median of 8 hours (interquartile range, 8 to 12). The
temperature curves for the normothermia and hypothermia groups are shown in
Figure 1 <http://content.nejm.org/cgi/content/full/346/8/#F1> .


  <http://content.nejm.org/cgi/content/full/346/8/549/F1>
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Figure 1. Bladder Temperature in the Normothermia and Hypothermia Groups.
The T bars indicate the 75th percentile in the normothermia group and the
25th percentile in the hypothermia group. The target temperature in the
hypothermia group was 32°C to 34°C, and the duration of cooling was 24
hours. Only patients with recorded temperatures were included in the
analysis.

Outcome at Six Months
A total of 75 of the 136 patients (55 percent) in the hypothermia group had
a favorable neurologic outcome, as compared with 54 of the 137 (39 percent)
in the normothermia group (risk ratio, 1.40; 95 percent confidence interval,
1.08 to 1.81) ( Table 2
<http://content.nejm.org/cgi/content/full/346/8/#T2> ). To prevent one
unfavorable neurologic outcome, 6 patients would need to be treated with
hypothermia (95 percent confidence interval, 4 to 25 patients). After
adjustment for a history of diabetes mellitus, a history of coronary heart
disease, and receipt of basic life support from a bystander, the risk ratio
changed only marginally (data not shown). After adjustment for all the
base-line variables shown in Table 1
<http://content.nejm.org/cgi/content/full/346/8/#T1> , the risk ratio
increased slightly, to 1.47 (95 percent confidence interval, 1.09 to 1.82).


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Table 2. Neurologic Outcome and Mortality at Six Months.

The rate of death six months after cardiac arrest was 14 percentage points
lower in the hypothermia group than in the normothermia group (risk ratio
for the hypothermia group, 0.74 [95 percent confidence interval, 0.58 to
0.95]) ( Table 2 <http://content.nejm.org/cgi/content/full/346/8/#T2>  and
Figure 2 <http://content.nejm.org/cgi/content/full/346/8/#F2> ). On the
basis of the difference in the risk of death between the two groups, 7
patients would need to be treated with hypothermia (95 percent confidence
interval, 4 to 33 patients) to prevent 1 death. After adjustment for
base-line differences in the proportions of patients with a history of
diabetes mellitus, a history of coronary heart disease, and receipt of basic
life support from a bystander, the risk ratio changed only minimally (data
not shown). After adjustment for all the base-line variables shown in Table
1 <http://content.nejm.org/cgi/content/full/346/8/#T1> , the effect of
hypothermia on mortality was slightly stronger (risk ratio, 0.62; 95 percent
confidence interval, 0.36 to 0.95).


  <http://content.nejm.org/cgi/content/full/346/8/549/F2>
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Figure 2. Cumulative Survival in the Normothermia and Hypothermia Groups.
Censored data are indicated by tick marks.

Most of the patients with unfavorable neurologic outcomes died within six
months after discharge from the hospital. In this subgroup of patients,
mortality after discharge did not differ significantly according to the
assigned treatment ( Table 3
<http://content.nejm.org/cgi/content/full/346/8/#T3> ).


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Table 3. Deaths before Discharge and Deaths after Discharge According to the
Cerebral-Performance Category.

Complications
The proportion of patients with any complication did not differ
significantly between the two groups (93 of 132 patients in the normothermia
group [70 percent] and 98 of 135 in the hypothermia group [73 percent],
P=0.70). Sepsis was more likely to develop in the patients with hypothermia
than in those with normothermia, although this difference was not
statistically significant ( Table 4
<http://content.nejm.org/cgi/content/full/346/8/#T4> ). The total number of
complications was not significantly higher in the hypothermia group than in
the normothermia group (P=0.09).


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Table 4. Complications during the First Seven Days after Cardiac Arrest.

Discussion
Our results show that among patients in whom spontaneous circulation had
been restored after cardiac arrest due to ventricular fibrillation, systemic
cooling to a bladder temperature between 32°C and 34°C for 24 hours
increased the chance of survival and of a favorable neurologic outcome (a
cerebral-performance category of 1 or 2), as compared with standard
normothermic life support.
The use of moderate hypothermia after cardiac arrest was initially reported
in the late 1950s and early 1960s. 28
<http://content.nejm.org/cgi/content/full/346/8/#R28> , 29
<http://content.nejm.org/cgi/content/full/346/8/#R29> , 30
<http://content.nejm.org/cgi/content/full/346/8/#R30>  Although the target
temperature was lower in these studies than in ours and the method and
duration of cooling also differed from those in our study, the results were
similar. However, the findings were inconclusive, and the rate of
complications was higher than that observed with the mild hypothermia used
in our study. There were no further investigations of hypothermia as a
resuscitative measure until the 1990s, when laboratory studies demonstrated
the benefit of mild hypothermia. 4
<http://content.nejm.org/cgi/content/full/346/8/#R4> , 5
<http://content.nejm.org/cgi/content/full/346/8/#R5> , 6
<http://content.nejm.org/cgi/content/full/346/8/#R6> , 7
<http://content.nejm.org/cgi/content/full/346/8/#R7> , 8
<http://content.nejm.org/cgi/content/full/346/8/#R8> , 16
<http://content.nejm.org/cgi/content/full/346/8/#R16>  These studies led to
preliminary clinical studies of mild hypothermia.
In the study by Bernard et al., 17
<http://content.nejm.org/cgi/content/full/346/8/#R17>  cooling was induced
more rapidly (with ice packs) and for a shorter period than in our study.
Nevertheless, the results were similar to ours. The neurologic outcome has
also been consistently favorable in studies of mild hypothermia in animals.
31 <http://content.nejm.org/cgi/content/full/346/8/#R31> , 32
<http://content.nejm.org/cgi/content/full/346/8/#R32> , 33
<http://content.nejm.org/cgi/content/full/346/8/#R33> , 34
<http://content.nejm.org/cgi/content/full/346/8/#R34>  In the pilot studies
by Yanagawa et al. 18 <http://content.nejm.org/cgi/content/full/346/8/#R18>
and Nagao et al., 19 <http://content.nejm.org/cgi/content/full/346/8/#R19>
the frequency of a favorable neurologic outcome was similar to that in our
study, although the method and duration of cooling in these studies differed
from those in our study. In contrast to these encouraging findings, a study
of hypothermia in patients with traumatic brain injury 35
<http://content.nejm.org/cgi/content/full/346/8/#R35>  showed no improvement
in the neurologic outcome. The reasons for this discrepancy are thought to
include the different pathogenesis of direct central nervous system injury,
as well as the late initiation of cooling in some of the patients and
variations in intensive care and life support among participating hospitals.
35 <http://content.nejm.org/cgi/content/full/346/8/#R35> , 36
<http://content.nejm.org/cgi/content/full/346/8/#R36>
Although the proportions of patients with any complication did not differ
significantly between the two treatment groups in our study, a detailed
analysis of the complications and an analysis of the total number of
complications revealed a trend toward a higher rate of infectious problems
in the hypothermia group. Nevertheless, the benefit of hypothermia exceeded
its possible adverse effects.
One limitation of our study was the fact that the attending physicians could
not be blinded to the treatment assignments. The relative risk may be
slightly exaggerated in studies that are not double blind. 37
<http://content.nejm.org/cgi/content/full/346/8/#R37>  Although the outcome
was assessed without knowledge of the treatment assignments, we did not
verify that the blinding was successful. Even if it was not successful in a
few cases, we do not believe that any bias that might have been introduced
would have been strong enough to invalidate our findings.
The study population was restricted to a group of patients with a high risk
of brain damage because of the specified interval between the patient's
collapse and the first attempt at resuscitation by emergency medical
personnel, as well as other factors, so only 8 percent of the patients
assessed for eligibility were included in the trial. Further studies are
warranted to determine whether our findings apply to patients at lower risk
for brain damage and to those with cardiac arrest due to causes other than
ventricular fibrillation.
Treatment with hypothermia may be of value in terms of public health. Each
year, cardiac arrest occurs in approximately 375,000 people in Europe, 1
<http://content.nejm.org/cgi/content/full/346/8/#R1>  about 30,000 of whom
would meet our inclusion criteria. We can be 95 percent confident that
treatment with hypothermia would prevent an unfavorable neurologic outcome
in 1200 to 7500 of these patients.
Supported by grants from the Biomedicine and Health Programme (BIOMED 2)
implemented under the Fourth RTD Framework Programme 1994–1998 of the
European Union (BMH4-CD-96-0667), the Austrian Ministry of Science and
Transport (GZ 5.550/12-Pr/4/95 and GZ 650.0251/2-IV/6/96), and the Austrian
Science Foundation (P11405-MED).
K. Heaton and R. Meier (Kinetic Concepts, Wareham, United Kingdom) provided
technical support and the TheraKool cooling device.
We are indebted to the nurses and staff of the participating centers for
their enthusiastic cooperation, to Elaine Ward for editorial assistance, and
to the patients in the study for their trust and support.
* The investigators who participated in the Hypothermia after Cardiac Arrest
Study Group are listed in the Appendix.
<http://content.nejm.org/cgi/content/full/346/8/#RFN1>

Source Information
Michael Holzer, M.D., Universitätsklinik für Notfallmedizin, Vienna,
Austria, assumes overall responsibility for the integrity of the report.
Address reprint requests to Dr. Fritz Sterz, Universitätsklinik für
Notfallmedizin, Allgemeines Krankenhaus der Stadt Wien, Währinger Gürtel
18–20/6D, 1090 Vienna, Austria or at [log in to unmask]
<mailto:[log in to unmask]> .
References
1.      de Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, et al.
Out-of-hospital cardiac arrest in the 1990's: a population-based study in
the Maastricht area on incidence, characteristics and survival. J Am Coll
Cardiol 1997;30:1500-1505. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9362408&link_type=MED>
2.      Negovsky VA. Postresuscitation disease. Crit Care Med 1988;16:942-946.
[Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3048895&link_type=MED>
3.      Leonov Y, Sterz F, Safar P, Radovsky A. Moderate hypothermia after
cardiac arrest of 17 minutes in dogs: effect on cerebral and cardiac
outcome. Stroke 1990;21:1600-1606. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=21/11/1600>
4.      Leonov Y, Sterz F, Safar P, et al. Mild cerebral hypothermia during and
after cardiac arrest improves neurologic outcome in dogs. J Cereb Blood Flow
Metab 1990;10:57-70. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2298837&link_type=MED>
5.      Sterz F, Safar P, Tisherman S, Radovsky A, Kuboyama K, Oku K. Mild
hypothermic cardiopulmonary resuscitation improves outcome after prolonged
cardiac arrest in dogs. Crit Care Med 1991;19:379-389. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1999100&link_type=MED>
6.      Weinrauch V, Safar P, Tisherman S, Kuboyama K, Radovsky A. Beneficial
effect of mild hypothermia and detrimental effect of deep hypothermia after
cardiac arrest in dogs. Stroke 1992;23:1454-1462. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=23/10/1454>
7.      Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H.
Delay in cooling negates the beneficial effect of mild resuscitative cerebra
l hypothermia after cardiac arrest in dogs: a prospective, randomized study.
Crit Care Med 1993;21:1348-1358. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8370299&link_type=MED>
8.      Safar P, Xiao F, Radovsky A, et al. Improved cerebral resuscitation from
cardiac arrest in dogs with mild hypothermia plus blood flow promotion.
Stroke 1996;27:105-113. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=27/1/105>
9.      Hegnauer AH, D'Amato HE. Oxygen consumption and cardiac output in the
hypothermic dog. Am J Physiol 1954;178:138-142.
10.     Mezrow CK, Sadeghi AM, Gandsas A, et al. Cerebral blood flow and
metabolism in hypothermic circulatory arrest. Ann Thorac Surg
1992;54:609-615. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=annts&resid=54
/4/609>
11.     Chopp M, Knight R, Tidwell CD, Helpern JA, Brown E, Welch KM. The
metabolic effects of mild hypothermia on global cerebral ischemia and
recirculation in the cat: comparison to normothermia and hyperthermia. J
Cereb Blood Flow Metab 1989;9:141-148. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2921288&link_type=MED>
12.     Dempsey RJ, Combs DJ, Maley ME, Cowen DE, Roy MW, Donaldson DL. Moderate
hypothermia reduces postischemic edema development and leukotriene
production. Neurosurgery 1987;21:177-181. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2821445&link_type=MED>
13.     Kramer RS, Sanders AP, Lesage AM, Woodhall B, Sealy WC. The effect of
profound hypothermia on preservation of cerebral ATP content during
circulatory arrest. J Thorac Cardiovasc Surg 1968;56:699-709. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=5697463&link_type=MED>
14.     Natale JA, D'Alecy LG. Protection from cerebral ischemia by brain
cooling without reduced lactate accumulation in dogs. Stroke
1989;20:770-777. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=20/6/770>
15.     Sterz F, Leonov Y, Safar P, et al. Multifocal cerebral blood flow by
Xe-CT and global cerebral metabolism after prolonged cardiac arrest in dogs:
reperfusion with open-chest CPR or cardiopulmonary bypass. Resuscitation
1992;24:27-47. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1332160&link_type=MED>
16.     Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD.
Effect of mild hypothermia on ischemia-induced release of neurotransmitters
and free fatty acids in rat brain. Stroke 1989;20:904-910. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=20/7/904>
17.     Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in
comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med
1997;30:146-153. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9250636&link_type=MED>
18.     Yanagawa Y, Ishihara S, Norio H, et al. Preliminary clinical outcome
study of mild resuscitative hypothermia after out-of-hospital
cardiopulmonary arrest. Resuscitation 1998;39:61-66. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9918449&link_type=MED>
19.     Nagao K, Hayashi N, Kanmatsuse K, et al. Cardiopulmonary cerebral
resuscitation using emergency cardiopulmonary bypass, coronary reperfusion
therapy and mild hypothermia in patients with cardiac arrest outside the
hospital. J Am Coll Cardiol 2000;36:776-783. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10987599&link_type=MED>
20.     Zeiner A, Holzer M, Sterz F, et al. Mild resuscitative hypothermia to
improve neurological outcome after cardiac arrest: a clinical feasibility
trial. Stroke 2000;31:86-94. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=31/1/86>
21.     Jennett B, Bond M. Assessment of outcome after severe brain damage.
Lancet 1975;1:480-484. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=46957&link_type=MED>
22.     Brain Resuscitation Clinical Trial II Study Group. A randomized clinical
study of a calcium-entry blocker (lidoflazine) in the treatment of comatose
survivors of cardiac arrest. N Engl J Med 1991;324:1225-1231. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=324
/18/1225>
23.     Safar P, Bircher NG. Cardiopulmonary cerebral resuscitation: basic and
advanced cardiac and trauma life support: an introduction to resuscitation
medicine. 3rd ed. London: W.B. Saunders, 1988:267.
24.     Human Medicines Evaluation Unit. Note for guidance on good clinical
practice (clinical practice medicinal products [CPMP]/International
Conference of Harmonization [ICH]/135/95). Guidelines for good clinical
practice. ICH topic E6. London: European Agency for the Evaluation of
Medicinal Products, 1995:1-58. (Also available at
http://www.eudra.org/emea.html.)
25.     Cummins RO, Chamberlain DA, Abramson NS, et al. Recommended guidelines
for uniform reporting of data from out-of-hospital cardiac arrest: the
Utstein Style: a statement for health professionals from a task force of the
American Heart Association, the European Resuscitation Council, the Heart
and Stroke Foundation of Canada, and the Australian Resuscitation Council.
Circulation 1991;84:960-975. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1860248&link_type=MED>
26.     Cuzick J. A Wilcoxon-type test for trend. Stat Med 1985;4:87-90.
[Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3992076&link_type=MED>
27.     Zhang J, Yu KF. What's the relative risk? A method of correcting the
odds ratio in cohort studies of common outcomes. JAMA 1998;280:1690-1691.
[Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9832001&link_type=MED>
28.     Benson DW, Williams GR Jr, Spencer FC, Yates AJ. The use of hypothermia
after cardiac arrest. Anesth Analg 1958;38:423-428.
29.     Williams GR Jr, Spencer FC. The clinical use of hypothermia following
cardiac arrest. Ann Surg 1959;148:462-468.
30.     Ravitch MM, Lane R, Safar P, Steichen FM, Knowles P. Lightning stroke:
report of a case with recovery after cardiac massage and prolonged
artificial respiration. N Engl J Med 1961;264:36-38.
31.     Markarian GZ, Lee JH, Stein DJ, Hong SC. Mild hypothermia: therapeutic
window after experimental cerebral ischemia. Neurosurgery 1996;38:542-550.
[Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8837807&link_type=MED>
32.     Coimbra C, Wieloch T. Hypothermia ameliorates neuronal survival when
induced 2 hours after ischaemia in the rat. Acta Physiol Scand
1992;146:543-544. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1492573&link_type=MED>
33.     Colbourne F, Li H, Buchan AM. Indefatigable CA1 sector neuroprotection
with mild hypothermia induced 6 hours after severe forebrain ischemia in
rats. J Cereb Blood Flow Metab 1999;19:742-749. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10413028&link_type=MED>
34.     Hickey RW, Ferimer H, Alexander HL, et al. Delayed, spontaneous
hypothermia reduces neuronal damage after asphyxial cardiac arrest in rats.
Crit Care Med 2000;28:3511-3516. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=11057809&link_type=MED>
35.     Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of
hypothermia after acute brain injury. N Engl J Med 2001;344:556-563.
[Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=344
/8/556>
36.     Safar P, Kochanek PM. Lack of effect of induction of hypothermia after
acute brain injury. N Engl J Med 2001;345:66-66. [Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=nejm&resid=345
/1/66>
37.     Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias:
dimensions of methodological quality associated with estimates of treatment
effects in controlled trials. JAMA 1995;273:408-412. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7823387&link_type=MED>


Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.