Hypothermia for neuroprotection in adults after
cardiopulmonary resuscitation (Review)
Arrich J, Holzer M, Havel C, Müllner M, Herkner H
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2012, Issue 9
http://www.thecochranelibrary.com
Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
5BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
13DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Neurological outcome: cooling versus no cooling, Outcome 1 Good neurological outcome. 30
Analysis 2.1. Comparison 2 Survival: cooling versus no cooling, Outcome 1 Survival. . . . . . . . . . . . 31
31ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
40INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iHypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Hypothermia for neuroprotection in adults aftercardiopulmonary resuscitation
Jasmin Arrich1, Michael Holzer1, Christof Havel1, Marcus Müllner2, Harald Herkner1
1Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria. 2AGES PharmMed, Austrian Medicines and
Medical Devices Agency, Vienna, Austria
Contact address: Jasmin Arrich, Department of Emergency Medicine, Medical University of Vienna, Währinger Gürtel 18-20 / 6D,
Vienna, 1090, Austria. [email protected].
Editorial group: Cochrane Anaesthesia Group.
Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 9, 2012.
Review content assessed as up-to-date: 25 July 2011.
Citation: Arrich J, Holzer M, Havel C, Müllner M, Herkner H. Hypothermia for neuroprotection in adults after cardiopulmonary
resuscitation. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD004128. DOI: 10.1002/14651858.CD004128.pub3.
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Good neurologic outcome after cardiac arrest is hard to achieve. Interventions during the resuscitation phase and treatment within
the first hours after the event are critical. Experimental evidence suggests that therapeutic hypothermia is beneficial, and a number of
clinical studies on this subject have been published. This review was originally published in 2009.
Objectives
We performed a systematic review and meta-analysis to assess the effectiveness of therapeutic hypothermia in patients after cardiac
arrest. Neurologic outcome, survival and adverse events were our main outcomes. We aimed to perform individual patient data analysis,
if data were available, and to form subgroups according to the cardiac arrest situation.
Search methods
We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2001,
Issue 7); MEDLINE (1971 to July 2011); EMBASE (1987 to July 2011); CINAHL (1988 to July 2011); PASCAL (2000 to July
2011); and BIOSIS (1989 to July 2011). The original search was performed in January 2007.
Selection criteria
We included all randomized controlled trials assessing the effectiveness of therapeutic hypothermia in patients after cardiac arrest,
without language restrictions. Studies were restricted to adult populations cooled with any cooling method, applied within six hours
of cardiac arrest.
Data collection and analysis
Validity measures, the intervention, outcomes and additional baseline variables were entered into a database. Meta-analysis was only
done for a subset of comparable studies with negligible heterogeneity. For these studies, individual patient data were available.
1Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
We included four trials and one abstract reporting on 481 patients in the systematic review. The updated search resulted in no new studies
to include. Quality of the included studies was good in three out of five studies. For the three comparable studies on conventional cooling
methods all authors provided individual patient data. With conventional cooling methods, patients in the hypothermia group were
more likely to reach a best cerebral performance categories (CPC) score of one or two (five point scale: 1 = good cerebral performance,
to 5 = brain death) during the hospital stay (individual patient data; RR 1.55; 95% CI 1.22 to 1.96) and were more likely to survive
to hospital discharge (individual patient data; RR 1.35; 95% CI 1.10 to 1.65) compared to standard post-resuscitation care. Across all
studies, there was no significant difference in reported adverse events between hypothermia and control.
Authors’ conclusions
Conventional cooling methods to induce mild therapeutic hypothermia seem to improve survival and neurologic outcome after cardiac
arrest. Our review supports the current best medical practice as recommended by the International Resuscitation Guidelines.
P L A I N L A N G U A G E S U M M A R Y
Cooling the body after cardiac arrest
Sudden cardiac death means that the heart and subsequently the circulation stops. Patients with a structural heart disease like coronary
heart disease have a higher risk for sudden cardiac death. Around 30% to 50% of all patients with coronary heart disease suffer sudden
cardiac death at some stage of their illness. In cardiac arrest the brain lacks blood and oxygen and the patient loses consciousness. After
a few minutes of lack of oxygen brain cells begin to be irreversibly damaged. Although potentially lethal, if a patient in cardiac arrest
is found and resuscitated early, they may be saved and brain damage prevented. To date about one tenth to a third of successfully
resuscitated patients leave hospital to live an independent life again.
One form of therapy that may help to improve these neurologic deficits is called ’therapeutic hypothermia’ or ’resuscitative hypothermia’.
It is a form of therapy where patients that have been resuscitated after cardiac arrest and are still unconscious after resuscitation are
cooled to 33 °C for several hours. Clinical trials have shown that with therapeutic hypothermia the neurologic damage caused by the
cardiac arrest may be attenuated. Pathophysiologic studies discovered that therapeutic hypothermia works in many different ways. One
way is that it lowers cell metabolism and prevents the production of harmful substances that form during resuscitation and continuously
damage the brain cells. Hypothermia may be initiated by different methods like cold drips, cooling pads or cooling catheters.
We have summarized three randomized trials with conventional cooling methods on a total of 383 patients that evaluated the effects of
therapeutic hypothermia in patients resuscitated after cardiac arrest in comparison to resuscitated patients treated without therapeutic
hypothermia. With conventional cooling methods like cooling blankets or cooling helmets, patients were 55% more likely to leave
the hospital without major brain damage. When the results of two additional studies (one study only published as an abstract and
another comparing cooling through haemofiltration) were added, this effect remained unchanged. No cooling specific adverse events
were reported. One of the limitations of our review is that the majority of patients had a specific form of cardiac arrest, with ventricular
fibrillation and ventricular tachycardia as the underlying cardiac rhythm. In summary, there is current evidence supporting the use of
conventional cooling to induce mild hypothermia in cardiac arrest survivors within the first hours of resuscitation.
2Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
SU
MM
AR
YO
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IN
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OR
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EM
AI
NC
OM
PA
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N[E
xpla
nati
on]
NeurologicalOutcomeandSurvival:conventionalcoolingcomparedtonocoolingforneuroprotectionandsurvivalinadultsaftercardiopulmonaryresuscitation
Patientorpopulation:comatosepatientsaftercardiopulmonaryresuscitation
Settings:
Intervention:conventionalcooling
Comparison:no
cooling
Outcomes
Illustrative
comparativerisks*
(95%CI)
Relativeeffect
(95%CI)
NoofParticipants
(studies)
Qualityoftheevidence
(GRADE)
Com
ments
Assumed
risk
Correspondingrisk
nocooling
conventionalcooling
Goodneurologicalout-
come
-Conventional
cooling
withoutextra-
corporalmethods(IPD,
besteverreachedCPC
of1or2during
hospital
stay)
CPC
1
Studypopulation
RR1.55
(1.22to1.96)
383
(3studies)
⊕⊕
⊕©
moderate
2,3
35per100
54per100
(42to68)
Mediumriskpopulation
27per100
42per100
(33to53)
Survival-Conventional
cooling
withoutextra-
corporalmethods(IPD,
survivalto
discharge)
(Copy)
discharge
information
andtelephonefollowup
Studypopulation
RR1.35
(1.1to1.65)
383
(3studies)
⊕⊕
⊕©
moderate
42per100
57per100
(46to69)
Mediumriskpopulation
32per100
44per100
(36to53)
3Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
*The
basisfortheassumedrisk
(e.g.themediancontrolgroupriskacross
studies)isprovided
infootnotes.Thecorrespondingrisk(and
its95%confidence
interval)isbasedon
the
assumedriskinthecomparison
groupandtherelativeeffectoftheintervention(andits95%CI).
CI:Confidenceinterval;RR:Riskratio;
GRADEWorkingGroupgradesofevidence
Highquality:Furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect.
Moderatequality:Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychangetheestimate.
Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate.
Verylowquality:Weareveryuncertainabouttheestimate.
1CerebralPerformanceCategory(I-V)
2Onequasi-random
isedtrialbutnotcontributingthemajorityofdata
3Totalnum
berofevents<300
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4Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
B A C K G R O U N D
Description of the condition
The incidence of out-of-hospital sudden cardiac arrest in industrial
countries varies greatly over different study groups. It is reported
to range between 0.05% and 0.19% per year (Chugh 2004; Rea
2004). Of all patients where resuscitation was attempted, 14% to
40% achieved return of spontaneous circulation and were admit-
ted to hospital (Finn 2001; Fischer 1997; Giraud 1996; Herlitz
2003b; Kuisma 1996; Leung 2001; Rewers 2000). Of those pa-
tients admitted to hospital, only between 7% and 30% were dis-
charged from hospital with good neurologic outcome (Absalom
1999; Böttiger 1999; Fischer 1997; Herlitz 1999; Jennings 2001;
Westfal 1996; Weston 1997). Many new concepts in post-resus-
citation care have been developed in the past few years that aim
at improving neurological outcome and survival of patients af-
ter cardiac arrest. These comprise optimising haemodynamics and
ventilation, electrolytes, seizure control, temperature and glucose
control and are summarized in the main resuscitation guidelines
(Deakin 2010; Peberdy 2010)
Description of the intervention
Therapeutic hypothermia is still a relatively new concept for the
preservation of cerebral function in patients who are resuscitated
after cardiac arrest. After patients have been stabilized their body
temperature is lowered to 32 °C to 34 °C for a duration of 24
hours.
How the intervention might work
It is believed that therapeutic hypothermia works in multiple ways.
Cerebral reperfusion after successful resuscitation, although essen-
tial and effective in restoring energy stores, can also trigger harm-
ful chemical cascades. The generation of free radicals and other
mediators, which leads to multifocal damage of the brain, was first
described by Negovsky as “postresuscitation syndrome” (Negovsky
1988). In contrast to accidental hypothermia, therapeutic mild hy-
pothermia (32 °C to 34 °C) is administered in a controlled way. In-
tra-ischaemic hypothermia for brain protection has been used for
several years with certain surgical procedures and circulatory arrest
states. Clinical and experimental results show a protective effect of
hypothermia during and also after ischaemic situations (Rosomoff
1954). Therapeutic hypothermia can inhibit the biosynthesis, re-
lease and uptake of several catecholamines and neurotransmit-
ters (Okuda 1986; Sun 2010; Szelenyi 2012), especially glutamate
and dopamine, which could lead to tissue damage (D’Cruz 2002;
Hachimi-Idrissi 2004). Other beneficial effects of hypothermia in-
clude the preservation of the blood brain barrier (Baumann 2009;
Karibe 1994); the protection of adenosine triphosphate (ATP)
stores (McCullough 1999; Mizuhara 1996), which are necessary
for energy provision; the restitution of post-ischaemic cerebral mi-
crocirculation (Takasu 1996); and possibly also decreased intracra-
nial pressure (Lee 2010; Schreckinger 2009). Subsequently, hy-
pothermia seems to act in a multifactorial way by influencing sev-
eral damaging pathways simultaneously (Holzer 2010) to reduce
the amount of cell death in the brain.
Why it is important to do this review
Two randomized controlled trials (RCTs) showed that induced
hypothermia has a neuroprotective effect in patients who are pri-
marily resuscitated from cardiac arrest (Bernard 2002; HACA
2002). A meta-analysis pooled the data of these two RCTs plus
the data of one additional feasibility study and showed a clear ben-
efit in terms of neurologic outcome and survival with hypother-
mia treatment for patients successfully resuscitated after cardiac
arrest (Holzer 2005). Although recommended in the guidelines of
the International Liaison Committee on Resuscitation (ILCOR)
(Nolan 2003) and the recent resuscitation guidelines (Deakin
2010; Peberdy 2010), therapeutic hypothermia still is a relatively
new concept. At the moment many different cooling methods ex-
ist. Conventional cooling comprises extracorporeal methods with
cooling pads, ice packs, water immersion or intravascular cooling
with cooling catheters or simply cold fluids. Cooling can also be
combined with haemofiltration or any extracorporeal cardiopul-
monary support. Studies with different treatment modalities are
emerging and therefore systematic and regular updates of the lit-
erature are important to monitor new and effective developments.
We present an update of a Cochrane review (Arrich 2009) with a
view to assembling the data from the published randomized con-
trolled trials.
O B J E C T I V E S
We aimed to perform a systematic review and meta-analysis to
assess the effectiveness of therapeutic hypothermia in patients after
cardiac arrest. Neurologic outcome, survival and adverse events
were our main outcomes. We aimed to perform individual patient
data analysis if data were available. We intended to form subgroups
according to the cardiac arrest situation.
M E T H O D S
Criteria for considering studies for this review
Types of studies
5Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
We included randomized and ’quasi-randomized’ controlled tri-
als. Quasi-randomized refers to allocation procedures such as al-
ternating days, odd and even days, and the like.
Types of participants
We included studies in adult patients who suffered from cardiac
arrest (regardless of if in-hospital or out-of-hospital cardiac arrest)
and were successfully resuscitated.
We excluded studies on children and adolescents (aged less than
18 years) as the presumed cause of cardiac arrest is different to the
causes in adults.
Although patients with a prior neurologic history may not greatly
benefit from the intervention, we did not exclude them for the
following reasons:
1. the number of such patients is most likely negligible; and
2. in a real life situation information on neurological
performance before the arrest is often not available when starting
post-resuscitation therapy.
Types of interventions
The intervention of interest was therapeutic hypothermia, regard-
less of how body temperature was reduced, applied within six hours
of arrival at hospital. We defined therapeutic as any body target
temperature below 35 °C. We defined the control intervention as
treatment according to the standard treatment after cardiac arrest
at the time of the trial.
Types of outcome measures
Primary outcomes
The primary outcome measure was neurological recovery. Ideally,
we expected the outcome to be reported as best neurologic out-
come during hospital stay and in cerebral performance categories
(CPC) (Stiell 2009). The CPC categories are defined as follows.
1. Good cerebral performance: conscious, alert, capable of
normal life. Normal cerebral function. May have minor
psychological or neurological deficits, which do not significantly
compromise cerebral or physical function.
2. Moderate cerebral disability: conscious, alert, sufficient
cerebral function for activities of daily life (e.g. dress, travel by
public transportation, food preparation). May have hemiplegia,
seizures, ataxia, dysarthria, dysphasia, or permanent memory or
mental changes.
3. Severe cerebral disability: conscious, has at least limited
cognition. Dependant on others for daily life support (i.e.,
institutionalised or at home with exceptional family effort)
because of impaired brain function. Includes wide range of
cerebral abnormalities, from ambulatory patients who have
severe memory disturbance or dementia precluding independent
existence to paralysed patients who can only communicate with
their eyes (e.g. the locked-in syndrome).
4. Coma or vegetative state: not conscious, unaware of
surroundings, no cognition. No verbal or psychological
interaction with environment. May appear awake because of
spontaneous eye opening or sleep-wake cycle. Includes all degrees
of unresponsiveness, which are neither CPC three (conscious)
nor CPC five (coma, which satisfies brain death criteria).
5. Certified brain death.
If authors grouped this outcome into one or two (good recov-
ery) and three to five (unfavourable recovery) we adapted it for
our meta-analysis. If not reported in CPC categories, we accepted
when authors reported ’good’ neurologic outcome and we assumed
it to be comparable with a CPC score of one or two.
Secondary outcomes
Survival to hospital discharge, survival at six months and long-
term, quality of life at six months and long-term, dependency, and
cost-effectiveness. We defined long-term as a minimum of one
year.
Adverse events
We aimed at reporting adverse events as given by the authors.
Search methods for identification of studies
Electronic searches
We searched the following databases: the Cochrane Central Regis-
ter of Controlled Trials (CENTRAL) (The Cochrane Library 2011,
Issue 7); MEDLINE (1971 to July 2011); EMBASE (1987 to July
2011); CINAHL (1988 to July 2011); PASCAL (2000 to July
2011); and BIOSIS (1989 to July 2011). The original search was
performed in January 2007 (Arrich 2009).
We performed the searches by entering search terms as multi-
ple postings (.mp, term appears in the title, abstract or MeSH)
and some as medical subject headings (MeSH) for MEDLINE
and exploded terms for EMBASE and CINAHL (search terms
for CENTRAL, Appendix 1; MEDLINE, Appendix 2; EM-
BASE, Appendix 3; CINAHL, Appendix 4; BIOSIS and PAS-
CAL, Appendix 5).
A search strategy for identifying RCTs was used with MEDLINE (
Dickersin 1994) and EMBASE (Lefebvre 1996). We did not apply
any language restrictions.
Searching other resources
In an attempt to identify further studies we asked experts in the
field whether they were aware of any ongoing, unpublished or
published trials on this subject.
6Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data collection and analysis
Selection of studies
We imported all retrieved results into EndNote (version 7.0,
Thomson Corporation) and eliminated duplicates. Two authors
(JA, MH or CH; HH as arbiter in case of discrepancies) indepen-
dently scanned each reference for inclusion in the review.
Data extraction and management
We independently extracted data using a data extraction form (see
Appendix 6). As we intended to use the original individual pa-
tient data of the identified trials we contacted the respective cor-
responding authors and asked for collaboration. Two review au-
thors independently entered all relevant data into the Cochrane
Collaboration’s software program Review Manager (RevMan 5.1).
We compared the two versions and resolved disagreements by dis-
cussion.
The following variables were entered into RevMan 5.1:
1. allocated intervention;
2. event (best neurological recovery during hospital stay,
survival to hospital discharge);
3. additional baseline variables: cause of cardiac arrest
(presumed cardiac versus non-cardiac); location of arrest (in-
hospital versus out-of-hospital); witnessed versus non-witnessed
arrest; primary electrocardiogram (ECG) rhythm (ventricular
fibrillation versus other).
Assessment of risk of bias in included studies
To assess the internal validity of the identified trials, we assessed
allocation sequence generation, allocation concealment, blinding
of outcome assessment, exclusion of randomized patients from the
analysis, comparability of groups, and loss to follow up.
Measures of treatment effect
We calculated risk ratios (RR) and their 95% confidence intervals.
Unit of analysis issues
Cluster randomized trials were not included in the analysis; in
the case of multiple treatment groups we planned to combine the
groups to create a single pair-wise comparison; cross-over trials,
by nature of the outcome, did not appear.
Dealing with missing data
All analyses were according to the intention-to-treat principle. If
data were missing we attempted to receive information by con-
tacting the study authors. An assessment of loss to follow up
was included in our quality assessment and reported in the table
’Characteristics of included studies’. If a considerable amount of
data was missing we would investigate the possible mechanism
of the missing data (randomly or not). We planned to assess the
influence of this possible selection bias on our estimates in a sen-
sitivity analysis.
Assessment of heterogeneity
We assessed data for clinical and statistical heterogeneity. We only
performed quantitative synthesis of the data if clinical heterogene-
ity was negligible. Clinical heterogeneity may be caused by dif-
ferences in study populations, interventions or definitions of the
endpoint (Thompson 2001). In the case of severe heterogeneity it
may not be suitable to pool the data because the trials measure a
different effect altogether.
Assessment of reporting biases
We assessed the presence of possible publication bias and hetero-
geneity using funnel plots (plotting the effect against precision)
(Egger 1997).
Data synthesis
Analysis at the individual level
Quantitative analysis of individual patient data was intended when
studies had negligible heterogeneity and individual patient data
were available at least for a clinically comparable subset. In the
case that individual patient data were unavailable for at least one
study, we planned to do an analysis at the study level. This applies
in particular to further updates. We performed quantitative anal-
ysis of individual patient data using standard statistical procedures
provided in RevMan 5.1. The principal measure of effect was the
relative risk of achieving good neurological recovery defined as a
best CPC category of one or two or the definition which was given
by the author for ’good neurologic outcome’.
Analysis at the study level
Here also the principal measure of effect was the relative risk of
achieving good neurological recovery at hospital discharge in pa-
tients allocated to hypothermia when compared to those not re-
ceiving hypothermia. In the case of negligible statistical hetero-
geneity we used fixed-effect models to calculate summary effects,
otherwise we used random-effects models. Statistical heterogene-
ity was assessed using the I2 statistic (Higgins 2003). Statistical
heterogeneity was considered relevant with I2 > 50%.
Subgroup analysis and investigation of heterogeneity
For the primary endpoint we formed subgroups using the indi-
vidual patient data and according to the following variables:
7Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
• cause of cardiac arrest (presumed cardiac versus non-
cardiac);
• location of arrest (in-hospital versus out-of-hospital);
• witnessed versus non-witnessed arrest;
• primary ECG rhythm (ventricular fibrillation versus other).
Sensitivity analysis
We performed sensitivity analyses for the impact of study quality
issues, as measured by allocation concealment, on the overall effect
estimate and the effect size of all identified trials when neglecting
heterogeneity and publication status.
R E S U L T S
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of ongoing studies.
Results of the search
Our original systematic search of databases (inception to 2007)
(Arrich 2009) and our updated search (searching from 2007 to
July 2011) of the medical literature resulted in 1851 hits (dupli-
cates excluded). From these, we excluded 1819 according to our
eligibility criteria (randomized studies on adult cardiac arrest pa-
tients treated with therapeutic hypothermia) by judging the ab-
stract or the title. Thirty-two papers remained for closer inspec-
tion. From those we excluded 11 non-original papers (comments,
editorials, reviews, correspondences), 10 non-randomized papers,
and six papers where the intervention or control groups did not
meet the inclusion criteria. In addition, we identified one ongoing
study (see Characteristics of excluded studies and Figure 1).
8Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 1. Study flow diagram.
Looking through the references of a recently published systematic
review on therapeutic hypothermia (Cheung 2006) we found one
additional reference, published only as an abstract (Mori 2000).
Hence five randomized and quasi-randomized controlled trials
with a total of 481 patients remained for analysis (Bernard 2002;
HACA 2002; Hachimi-Idrissi 2001; Laurent 2005; Mori 2000),
see Characteristics of included studies.
One previously unclassified study (Tiainen 2007) and two addi-
tional studies (Tiainen 2003; Tiainen 2005) were found to be re-
ports of the HACA 2002 study. The updated search resulted in
no new studies for inclusion.
Included studies
See table Characteristics of included studies.
Clinical heterogeneity
We identified clinical heterogeneity due to cooling methods. In
contrast to the other studies, Laurent 2005 used haemofiltration as
the mode of cooling, which is substantially different to the standard
cooling methods used in the other RCTs. As the cooling method
of Mori 2000 was unclear, we presented this study separately and
did not pool the effect with those of the remaining studies. For
the three comparable studies on conventional cooling methods
all three authors provided individual patient data (Bernard 2002;
HACA 2002; Hachimi-Idrissi 2001). We tried to contact Kazuhisa
Mori (Mori 2000) for more information on his study but were
unsuccessful.
Excluded studies
9Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
See table Characteristics of excluded studies.
Risk of bias in included studies
We assessed each included trial by the following criteria: mode of
randomization, allocation concealment, level of blinding, loss to
follow up, comparability of groups and use of measures to account
for differences between groups (see Characteristics of included
studies; Figure 2; Figure 3). Quality of the included studies was
good in three out of five studies.
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
10Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
11Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Allocation
Three trials (HACA 2002; Hachimi-Idrissi 2001; Laurent 2005)
reported adequate randomization methods and the use of opaque
envelopes to conceal treatment allocation.
Blinding
Three trials reported blinded outcome assessment (Bernard 2002;
HACA 2002; Hachimi-Idrissi 2001).
Incomplete outcome data
One study lost information for two patients for the primary end-
point (HACA 2002). All other studies had a complete follow up.
Selective reporting
There was no indication of selective outcome reporting.
Other potential sources of bias
In two studies the treatment and control groups did not differ
significantly in reported baseline characteristics (Hachimi-Idrissi
2001; Laurent 2005) while one of these had rather small groups
(Hachimi-Idrissi 2001). In HACA 2002 there were some baseline
differences between groups. Patients in the normothermia group
were more likely to have a history of diabetes mellitus or coro-
nary heart disease and to have received basic life support from
a bystander than were those in the hypothermia group. The au-
thors adjusted for all baseline variables and the risk ratio increased
slightly, from 1.40 (95% confidence interval (CI) 1.08 to 1.81) to
1.47 (95% CI 1.09 to 1.82). Bernard 2002 reported differences in
sex and rate of bystander cardiopulmonary resuscitation between
groups but did not further adjust for this possible bias. Mori 2000
did not provide information on the baseline characteristics of the
patient groups.
Effects of interventions
See: Summary of findings for the main comparison
Neurological outcome and survival: conventional cooling
compared to no cooling for neuroprotection and survival in adults
after cardiopulmonary resuscitation
Primary outcome
Good neurologic outcome
With only three studies reporting on conventional cooling meth-
ods (involving 195 cases and 188 controls), the pooled result
showed a better neurologic outcome for the hypothermia group
(individual patient data; RR 1.55; 95% CI 1.22 to 1.96; I2 = 32%;
see Analysis 1.1.1).
As there was only one study for patients undergoing haemofil-
tration after cardiac arrest (Laurent 2005) it was not possible to
employ meta-analysis. Using the data in the study, however, and
carrying out a Chi2 test we found no statistical difference (Pearson
Chi2 statistic = 0.16, P = 0.69; RR 0.71; 95% CI 0.32 to 1.54;
see Analysis 1.1.2).
The one study reporting on an unknown cooling method (Mori
2000) showed better survival for the hypothermia group (Pearson
Chi2 = 7.78, P = 0.005; RR 4.50; 95% CI 1.17 to 17.30; see
Analysis 1.1.3).
Secondary outcomes
Survival to hospital discharge
With only three studies reporting on conventional cooling meth-
ods (involving 195 cases and 188 controls) the pooled result
showed better survival for the hypothermia group (individual pa-
tient data; RR 1.35; 95% CI 1.10 to 1.65; I2 = 0%; see Analysis
2.1.1).
As there was only one study for patients undergoing haemofiltra-
tion after cardiac arrest (Laurent 2005) the Chi2 test found that
there was no statistical difference (Pearson Chi2 = 0.77, P = 0.38;
RR 0.71; 95% CI 0.32 to 1.54; see Analysis 2.1.2).
Survival at six months and long-term
We found no data on this outcome.
Quality of life at six months and long-term
dependency
We found no data on this outcome.
Cost-effectiveness
We found no data on this outcome.
Subgroup analyses
According to the number of patients and information provided by
the authors we formed subgroups of the meta-analysis by the fol-
lowing variables: cause of cardiac arrest (presumed cardiac versus
12Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
non-cardiac); location of arrest (in-hospital versus out-of-hospi-
tal); witnessed versus non-witnessed arrest; primary ECG rhythm
(ventricular fibrillation (VF) or ventricular tachycardia (VT) ver-
sus other). The endpoint was ’best ever reached CPC during hos-
pital stay’ (see Additional Table 1).
• The effect size for patients with a cardiac cause (three
studies) and VF or VT was nearly the same (two studies).
• Groups of patients with non-VF or VT rhythm as the first
cardiac rhythm (n = 52), patients with a non-cardiac cause (n =
11), and in-hospital arrests (n = 17) were small and did not show
a statistically significant effect (non-VF or VT: RR 2.17; 95% CI
0.68 to 6.93; I2 = 50%; two studies) (non-cardiac cause: RR
3.80; 95% CI 0.55 to 26.29; I2 = 0%; two studies) (in-hospital:
RR 1.67; 95% CI 0.47 to 5.73).
• Also a small number of patients had non-witnessed arrest (n
= 22). Among these patients the effect size was substantially
bigger than the summary effect for the whole study population
(RR 5.31; 95% CI 1.40 to 20.21; I2 = 0%; three studies).
• For patients with witnessed cardiac arrest the effect size was
slightly smaller than the effect size for the whole study population
(RR 1.43; 95% CI 1.13 to 1.81; I2 = 0%; three studies).
Long-term outcome, cost-effectiveness and quality of
life
None of the retrieved studies provided data on long-term survival
and dependency, quality of life or cost-effectiveness.
Adverse events
We included all trials that reported on adverse events in the analy-
sis, regardless of heterogeneity. The following adverse events were
reported in the four studies: bleeding of any severity, need for
platelet transfusions, pneumonia, sepsis, pancreatitis, renal fail-
ure or oliguria, haemodialysis, pulmonary oedema, seizures, lethal
or long-lasting arrhythmias, cardiac complications, hypocalcaemia
and hypophosphataemia. There were no significant differences be-
tween the groups (see Additional Table 2).
Sensitivity analysis
Does allocation concealment influence the effect?
For studies using conventional cooling methods, cooling had a
favourable effect on good neurological outcome in studies with
adequate allocation concealment. This effect, however, was sig-
nificant in a fixed-effect model (RR 1.50; 95% CI 1.16 to 1.93)
(see Additional Table 3) but not significant in a random-effects
model (RR 1.97; 95% CI 0.71 to 5.45). This result comes from
two studies which showed both a significant and positive effect
but there was statistical heterogeneity (I2 = 59%) and the total
sample size comprised only 306 patients.
As we were concerned that the model choice might influence our
results, we also examined whether the model choice might cause
changes in our main effect as a post hoc sensitivity analysis. The
effect for conventional cooling as presented in Analysis 1.1.1 did
not change by model choice (fixed-effect RR 1.55; 95% CI 1.22
to 1.96) (random-effects RR 1.64; 95% CI 1.10 to 2.45; data not
shown). This indicates that the effect is robust according to model
choice.
Does allowing for clinical heterogeneity and publication status
affect the results?
When we ignored clinical heterogeneity and publication status the
pooled effect of all studies did not change substantially, whether
fixed-effect models (RR 1.55; 95% CI 1.24 to 1.94; Table 3),
or random-effects models (RR 1.68; 95% CI 1.00 to 2.68; data
not shown) were used. There was some indication of a subgroup
difference (test for subgroup difference Chi² = 6.20 (df = 2), P =
0.05).
Publication bias
At the moment there are too few studies to draw inferences from
funnel plots, we have therefore not presented them in the current
version of this review.
D I S C U S S I O N
Summary of main results
Our review shows that therapeutic hypothermia with conventional
cooling methods improves neurologic outcome and survival of pa-
tients successfully resuscitated after cardiac arrest. Currently avail-
able evidence suggests that patients with out-of-hospital cardiac
arrest, a presumed cardiac cause of cardiac arrest, and for patients
with a VF or VT rhythm as the first recorded cardiac rhythm ben-
efit from therapeutic hypothermia. For patients with in-hospital
cardiac arrest, asystole and non-cardiac causes of arrest the group
sizes are too small to make firm inferences. There were no statis-
tically significant differences in any of the reported adverse events
between hypothermia and non-hypothermia patients.
Overall completeness and applicability ofevidence
After our literature search we were able to include the data of all
eligible studies we retrieved. It was not possible to obtain indi-
vidual patient data for Laurent 2005 or Mori 2000, but even if
they had been available we would not have included either study
in the meta-analysis. In the case of Laurent 2005 the two treat-
ment modalities (mild therapeutic hypothermia with or without
haemodialysis) are clinically too heterogeneous to be combined
with the other studies. As mentioned in the background section,
13Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
one of the theories of the beneficial effects of cooling deals with
attenuation of the effect of free radicals and other mediators.
Haemofiltration may act in a similar way, by reducing the number
of free radicals. It may add to or even supersede the effect of ther-
apeutic hypothermia. In the case of Mori 2000 we do not know
anything about the treatment.
The major limitation of this review is the small number of ran-
domized controlled trials and hence small numbers of included pa-
tients. Therefore, the precision of our effects is generally low and,
particularly in subgroup and sensitivity analyses, this is a matter for
concern. The confidence intervals of the intervention come near
the null difference and looking in our sensitivity analysis at studies
with adequate allocation concealment resulted in an effect which
was not robust to model choice. On the other hand, only two stud-
ies have been included in the sensitivity analysis, which is probably
too small a number to make firm conclusions. Nonetheless, given
these limitations the effect of conventional cooling methods con-
sistently points towards a favourable neurological outcome. An-
other consequence of the small number of available studies is the
many single study comparisons.
One might argue that therapeutic hypothermia is only available
to countries with sufficient financial resources. But there are many
cooling methods, ranging from expensive device controlled meth-
ods to very cheap cold fluids and ice packs which are available in
all facilities where post-resuscitation care is performed. Proof of
superiority of any cooling method above others is still lacking, and
there are currently no formal cost-benefit analyses.
After the publication of the two RCTs on therapeutic hypother-
mia (Bernard 2002; HACA 2002), guidelines were published by
the International Liaison Committee on Resuscitation (ILCOR)
on the application of therapeutic hypothermia after cardiac arrest
(Nolan 2003). Despite a small number of included trials and pa-
tients the results of our review support those recommendations.
Quality of the evidence
We found five studies on the application of mild hypother-
mia, with a total of 481 patients (Bernard 2002; HACA 2002;
Hachimi-Idrissi 2001; Laurent 2005; Mori 2000). All studies were
academia initiated. Quality of the studies was generally good. Ex-
cept for the abstract (Mori 2000), all studies reported on almost
all essential quality criteria and loss to follow up was within an
acceptable range. One study could have done better on the ran-
domization process and the adjustment for inequalities in base-
line characteristics between the treatment and the control groups
(Bernard 2002).
All studies planned to include consecutive patients (no informa-
tion available on Mori 2000). In HACA 2002 10% and in Bernard
2002 8% of all eligible patients were not randomized because of
logistic problems or because the next of kin did not give consent.
In Laurent 2005 and Hachimi-Idrissi 2001 inclusion of all eligible
patients was reported. We do not have any information on the
patients that were not randomized.
In HACA 2002 hypothermia was discontinued in 14 patients be-
cause of death, arrhythmia, haemodynamic instability, technical
problems with the cooling device, one liver rupture, one random-
ized patient that had already been included in the study before,
and one error in the duration of cooling. These patients were in-
cluded in the intention-to-treat analysis of primary and secondary
outcomes. One patient in each group was lost to follow up for the
primary outcome. All other studies had a complete follow up.
The control groups differed with regard to fever control. Mean
body temperature 12 hours after start of cooling in the ’normoth-
ermia group’ was around 37.6 °C in HACA 2002 and 37.4 °C in
Bernard 2002. Hachimi-Idrissi 2001 did not report on the body
temperature of the control group. It is known that for each degree
rise in temperature over 37 °C the risk of an unfavourable neuro-
logic outcome increases, with an odds ratio of 2.26 (Zeiner 2001).
If this is true even for smaller temperature differences, the ben-
eficial effect of therapeutic hypothermia might at least partly be
due to an antipyretic rather than a hypothermic effect. It is ques-
tionable whether a strict temperature control would have the same
effect as mild hypothermia, as shown in a study of fever control
in patients in a neurologic intensive care unit, where no difference
in outcome was found with fever control (Diringer 2001).
Potential biases in the review process
For the primary data analysis, individual patient analysis gave the
same results as the study-based results. We still made the effort to
obtain individual patient data as it was useful for investigating the
subgroups.
All studies with individual patient data reported on the same
outcome and all outcome assessors were blind to the treatment
(Bernard 2002; HACA 2002; Hachimi-Idrissi 2001; Laurent
2005). The cerebral performance category (CPC) is easy to mea-
sure and gives a crude approximation of the patient’s ability to per-
form tasks of daily life. One of its limitations is the lack of accuracy
when it comes to estimating cognitive functions and personal and
social impacts of cardiac arrest.
For the subgroup of patients with non-witnessed arrests we ob-
served an effect size substantially bigger than the pooled summary
effect (RR 5.31; 95% CI 1.40 to 20.21) (Table 1). However, the
group of non-witnessed arrests was small (22 patients only) and
yielded large confidence intervals. Although it seems that patients
benefit from the treatment, the result should be interpreted with
caution.
One of the problems with merging the data for this review was the
difference in the inclusion criteria. Generally, among all patients
that are resuscitated and brought to hospital between 18% and
42% have non-witnessed arrests, only 30% to 58% have a con-
firmed VF rhythm as first rhythm (Haukoos 2004; Herlitz 2003a;
Kim 2001) and 40% of all resuscitations happen in hospital. In
14Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
this review the two bigger studies included only patients with a
cardiac cause of cardiac arrest, and with VF or VT rhythm as the
first cardiac rhythm (Bernard 2002; HACA 2002). Most of these
patients had an out-of-hospital cardiac arrest. From the pathogen-
esis of global cerebral ischaemia and the theories as to why thera-
peutic hypothermia is effective, there is no reason why therapeutic
hypothermia should not be as effective in patients with asystole as
the first cardiac rhythm or non-cardiac causes for cardiac arrest. In
a meta-analysis (Holzer 2005) the effect of therapeutic hypother-
mia was only sightly changed by baseline variables. A retrospective
cohort study showed that the effect of therapeutic hypothermia
was independent of various confounders including cardiac arrest
conditions (Arrich 2006).
Agreements and disagreements with otherstudies or reviews
We are aware of three other meta-analyses with similar objectives.
The meta-analysis by Holzer et al is very similar to our review
method-wise and was in many ways a predecessor to our current
Cochrane review. We were able to include two additional studies
(Laurent 2005; Mori 2000) but the main result is comparable.
Another meta-analysis was published recently (Nielsen 2011). The
authors judged the overall quality of the included studies at a lower
level than we did in our review. From the available five studies they
combined four and five based on a different judgement on clinical
heterogeneity, and they provided a trial sequential analysis. The
main findings were comparable between the two reviews, whereas
their interpretation was much more conservative than ours. Their
main conclusion was proposing a new large scale clinical trial.
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
Conventional cooling methods to induce mild therapeutic hy-
pothermia seem to improve survival and neurologic outcome after
cardiac arrest. Our review supports the current best medical prac-
tice as recommended by the International Resuscitation Guide-
lines.
Implications for research
Future research should be done with standardized temperature
monitoring (either oesophagus or bladder temperature measure-
ments) in order to be able to compare between groups and be-
tween studies at a later stage. Effective measures need to be ad-
vanced to cool the patient to the target temperature within a short
time period, which should decrease heterogeneity within the study
population. For studies with a focus on out-of-hospital cooling,
practical methods need to be evaluated. To further investigate the
effect of cooling on subgroups, like patients with non-VF or VT as
primary cardiac rhythm, or patients with in-hospital cardiac arrest,
methodologically sound studies are needed. There is a knowledge
gap concerning an optimal cooling protocol. For this purpose, in-
clusion criteria should be widened and comparisons of earlier cool-
ing (pre-hospital) versus late cooling (in-hospital), different levels
of hypothermia (for example 32 °C versus 34 °C) and different
durations of cooling (for example 12 hours versus 24 hours versus
48 hours) should be included. Reporting on safety should not only
comprise the known but also any unexpected adverse events. It
would be useful to include cost-benefit analyses in future studies.
A C K N O W L E D G E M E N T S
We would like to thank Dr Mathew Zacharias (content editor), Dr
Marialena Trivella (statistical editor) and Dr Malcolm G Booth,
Dr George Djaiani and Shafi Mussa (peer reviewers) for their help
and editorial advice during the preparation of the published review
(Arrich 2009).
We would also like to thank Dr Mathew Zacharias, Dr Marialena
Trivella, Dr Malcolm Booth, Dr Karen Rees, Prof Ian Jacobs and
Jane Cracknell for their help and editorial advice during the prepa-
ration of the protocol for the systematic review.
R E F E R E N C E S
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References to other published versions of this review
Arrich 2009
Arrich J, Holzer M, Herkner H, Müllner M. Hypothermia
for neuroprotection in adults after cardiopulmonary
resuscitation. Cochrane Database of Systematic Reviews 2009,
Issue 4. [DOI: 10.1002/14651858.CD004128.pub2]∗ Indicates the major publication for the study
20Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Bernard 2002
Methods Randomization: pre-hospital
Participants Total number of patients 77, mean age of 66 years, 33% female
Out-of-hospital cardiac arrest of cardiac cause, ventricular fibrillation as first cardiac
rhythm, comatose after resuscitation
Participating sites: Australian university and community hospitals
Multicentre: yes
Language: English
Allocation concealment: not applicable (odd and even days)
Outcome assessor blind: yes
Intention-to-treat: yes
Groups comparable: more females and more bystander CPR in hypothermia group
Follow up > 80% of randomized patients: yes
Interventions Therapeutic hypothermia versus standard pre-hospital treatment protocols and intensive
care treatment
Means of cooling: packs placed around the head, neck, torso, and limbs
Cooling rate: time from ROSC to target temperature: two hours
Target temperature: 33°C
Duration of cooling: 12 hours after target temperature was reached
Rewarming: passive after 12 hours, active after 18 hours
Outcomes Survival with good neurologic function to be sent home or to a rehabilitation facility at
discharge
In-hospital death
Haemodynamic, biochemical, and haematologic effects of hypothermia
For IPD analysis best ever reached CPC during hospital stay and CPC discharge were
provided
Notes Randomization: odd and even days
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
High risk Odd and even days
Allocation concealment (selection bias) High risk Odd and even days
Blinding (performance bias and detection
bias)
All outcomes
Low risk Outcome assessment blinded
21Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Bernard 2002 (Continued)
Incomplete outcome data (attrition bias)
All outcomes
Low risk Complete follow up
Other bias Low risk No other major biases seen
HACA 2002
Methods Randomization: in hospital
Participants Total number of patients 275, mean age 59 years, 24% female
In and out-of-hospital bystander-witnessed cardiac arrest of presumed cardiac cause,
ventricular fibrillation or non-perfusing ventricular tachycardia as first cardiac rhythm,
comatose after resuscitation
Participating sites: European university and community hospitals
Multicenter: yes
Language: English
Allocation concealment: opaque envelopes
Outcome assessor blind: yes
Intention-to-treat: yes
Groups comparable: significantly more diabetes and coronary heart disease and bystander
CPR in control group
Follow up > 80% of randomized patients: yes
Interventions Therapeutic hypothermia versus standard intensive care treatment
Means of cooling: cooling blanket that covered the whole body and released cooled air
Cooling rate: time from ROSC to target temperature: median of 8 hours
Target temperature: 32 to 34°C
Duration of cooling: median of 24 hours
Rewarming: passive over eight hours
Outcomes Best CPC of 1, 2 versus CPC of 3, 4, 5 during six months
Mortality at six months, rate of complication during first seven days after cardiac arrest
(bleeding of any severity
Pneumonia, sepsis, pancreatitis, renal failure, pulmonary edema, seizures, arrhythmias,
and pressure sores)
For IPD analysis best ever reached CPC during hospital stay and CPC discharge were
provided
Notes Randomization: computer generated random sequence
Centre-specific subsets of this study are also published as Tiainen 2003 (n=70), Tiainen
2005 (n=60), and Tiainen 2007 (n=70) with more detailed investigations of neuropsy-
chological and laboratory outcomes
Risk of bias
Bias Authors’ judgement Support for judgement
22Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
HACA 2002 (Continued)
Random sequence generation (selection
bias)
Low risk
Allocation concealment (selection bias) Low risk
Blinding (performance bias and detection
bias)
All outcomes
Low risk
Incomplete outcome data (attrition bias)
All outcomes
Low risk Two patients lost to follow up, properly addressed
Other bias Low risk
Hachimi-Idrissi 2001
Methods Randomization: in hospital
Participants Total number of patients 33, mean age 72 years, 39% female
Out-of-hospital cardiac arrest of cardiac cause, asystole as first cardiac rhythm, comatose
after resuscitation
Participating site: Belgian university hospital.
Multicenter: no
Language: English
Outcome assessor blind: yes
Intention-to-treat: yes
Groups comparable: yes, although groups were small, no significant difference
Follow up > 80% of randomized patients: yes
Interventions Therapeutic hypothermia versus standard post-resuscitation care protocol
Means of cooling: helmet device placed around the head and neck and containing a
solution of aqueous glycerol
Cooling rate: starting point until target temperature not clearly stated
Target temperature: 34°C
Duration of cooling: start of cooling to start of rewarming, mean three hours
Rewarming: passive over eight hours
Outcomes Haemodynamic data, arterial pH, electrolytes, haematological data
Complications such as pneumonia, sepsis, cardiac arrhythmia, coagulopathy
Survival to hospital discharge and overall performance categories (OPC)
For IPD analysis best ever reached CPC during hospital stay and CPC discharge were
provided
Notes Randomization: random number tables
IPD included 33 patients, the article only reported on 30 as the follow up was not
completed at the time of submission
Risk of bias
23Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hachimi-Idrissi 2001 (Continued)
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk
Allocation concealment (selection bias) Low risk
Blinding (performance bias and detection
bias)
All outcomes
Low risk
Incomplete outcome data (attrition bias)
All outcomes
Low risk Difference between published report and IPD properly
reported
Other bias Low risk
Laurent 2005
Methods Randomization: pre-hospital
Participants Total number of patients 42, mean age 52 years in the HF group, 56 years in the HF+HT
group, 19% female
Out-of-hospital cardiac arrest of presumed cardiac cause, ventricular fibrillation or asys-
tole as first cardiac rhythm, comatose after resuscitation
Participating sites: French university and community hospital
Multicentre: yes
Language: English
Allocation concealment: opaque envelopes
Outcome assessor blind: not stated
Intention-to-treat: yes
Groups comparable: yes
Follow up > 80% of randomized patients: yes
Interventions High-flow haemofiltration versus high-flow haemofiltration plus therapeutic hypother-
mia versus standard supportive care
Means of cooling: direct external cooling of the blood
Cooling rate: four hours after ICU admission the median temperature was 31.7°C
Target temperature: 32 to 33°C
Duration of cooling: 24 hours
Rewarming: passive
Outcomes Survival at six months
Rate of death by intractable shock in patients who had a favourable Glasgow coma scale
(M5 or M6) or required sedation
Survival at CPC 1, 2 versus all else at six months
24Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Laurent 2005 (Continued)
Notes Randomization pre-hospital to save time for haemofiltration
We did not pool data from this study with data from the three other studies, since
the treatment schemes with haemofiltration are not comparable to non-haemofiltration
treatment (clinical heterogeneity)
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk
Allocation concealment (selection bias) Low risk
Blinding (performance bias and detection
bias)
All outcomes
Unclear risk Not reported
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Other bias Low risk
Mori 2000
Methods Randomization: unknown
Participants Total number of patients 54, mean age unknown, gender distribution unknown
Out-of-hospital cardiac arrest of unknown cause with a Glasgow Coma Scale of less than
eight
Participating site: Japanese university hospital
Multicentre: unknown
Language of abstract: English
Allocation concealment: unknown
Outcome assessor blind: not stated
Intention-to-treat: unknown
Groups comparable: unknown
Follow up > 80% of randomized patients: yes
Interventions “Brain-hypothermic treatment” versus “brain normothermic treatment”
Means of cooling: unknown
Cooling rate: unknown
Target temperature: 32 to 34°C
Duration of cooling: three days
Rewarming: unknown
Outcomes Glasgow outcome scale at one month (5 point scale). The categories “moderate, mild,
or no disabilities” were defined as “good neurologic outcome”
25Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mori 2000 (Continued)
Notes Only abstract published
Study was not included in the pooled analysis as we did not have any information on
the cooling method, whether cooling was applied locally or systemically, and whether
cooling was successful
Attempts to contact the authors were unsuccessful.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk No information available from abstract
Allocation concealment (selection bias) Unclear risk No information available from abstract
Blinding (performance bias and detection
bias)
All outcomes
Unclear risk No information available from abstract
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk No information available from abstract
Other bias Unclear risk No information available from abstract
CPR=cardiopulmonary resuscitation
ROSC=restoration of spontaneous circulation
CPC=cerebral performance categories
HF=haemofiltration
ICU=intensive care unit
M5=localizes painful stimuli
M6=obeys commands
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Ballew 2002 Comment
Batista 2010 Non-randomized
Bernard 1997 Non-randomized, controlled study, historical controls
Bernard 2004 Review
26Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Bernard 2010 Intervention or control groups did not meet the inclusion criteria
Callaway 1997 Review
Callaway 2002 Non-randomized
Castrejon 2009 Non-randomized
Castrén 2010 Intervention or control groups did not meet the inclusion criteria
Chanin 2002 Editorial
Ebell 2002 Comment
Gwinnutt 2003 Editorial
Heard 2007 Intervention or control groups did not meet the inclusion criteria
Huang 2008 Non-randomized
Kamarainen 2009 Intervention or control groups did not meet the inclusion criteria
Kim 2007 Intervention or control groups did not meet the inclusion criteria
Kim 2011 Non-randomized
Kitamura 1989 Non-randomized
Mayer 2002 Summary and comment of HACA 2002
Nagao 2008 Non-randomized
Nielsen 2010a Ongoing study
Nielsen 2011a Correspondance
Smith 2002 Review
Takeda 2009 Intervention or control groups did not meet the inclusion criteria
Ungerleider 1998 Review
Ungerleider 2004 Comment
Yanagawa 1998 Non-randomized controlled study, historical controls
Zeiner 2000 Non-randomized controlled study, historical controls
27Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of ongoing studies [ordered by study ID]
Nielsen 2010
Trial name or title Target temperature management after out-of-hospital cardiac arrest, an international, multicentre, random-
ized, parallel groups, assessor blinded clinical trial-rationale and design of the ttm-trial
Methods European multicentre trial
Randomization: in-hospital
Participants Patients over 17 years of age resuscitated from out-of hospital cardiac arrest of presumed cardiac cause,
unconscious (Glasgow Coma Score < 8) (patients not able to obey verbal commands) after resuscitation
Interventions Therapeutic hypothermia at 33°C versus normothermia at 36°C.
Means of cooling: 30 ml/kg of crystalloid infusion (4°C or room temperature according to treatment arm)
initially. Further temperature control will be at the discretion of the trial sites
Cooling rate: not specified
Target temperature: 33°C
Target temperature of control: 36°C
Duration of cooling: 24 hours
Rewarming: not specified
Outcomes Primary Outcome Measures: All-cause mortality [Time Frame: Maximum follow-up with a minimum of 180
days] [Designated as safety issue: No]
Secondary Outcome Measures: Composite outcome of all-cause mortality and poor neurological function
(CPC 3 and 4) [Time Frame: 180 days]
Bleeding [Time Frame: During day 1-7 of intensive care treatment]
Neurological status and quality of life (Cerebral Performance Category, Modified Rankin Scale, Mini-mental
test, IQCODE, SF-3)6 [Time Frame: 180 days]
Pneumonia [Time Frame: During day 1-7 of intensive care treatment]
Electrolyte disorders [Time Frame: During day 1-7 of intensive care treatment]
Hyperglycaemia > 10 mmol/l [Time Frame: During day 1-7 of intensive care treatment]
Hypoglycaemia < 3mmol/l [Time Frame: During day 1-7 of intensive care treatment]
Cardiac arrhythmia [Time Frame: During day 1-7 of intensive care treatment]
The need for renal replacement therapy [Time Frame: During day 1-7 of intensive care treatment]
Starting date November 2010
Contact information Niklas Nielsen, Helsingborgs Hospital, [email protected]
Notes NCT01020916
28Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
D A T A A N D A N A L Y S E S
Comparison 1. Neurological outcome: cooling versus no cooling
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Good neurological outcome 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Conventional cooling
without extracorporal methods
(IPD, best ever reached CPC of
1 or 2 during hospital stay)
3 383 Risk Ratio (M-H, Fixed, 95% CI) 1.55 [1.22, 1.96]
1.2 Cooling with
haemofiltration (no IPD, CPC
of 1 or 2 at six months)
1 42 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.32, 1.54]
1.3 Unknown method (no
IPD, Glasgow Outcome scale
of 1-3 at one month)
1 54 Risk Ratio (M-H, Fixed, 95% CI) 4.5 [1.17, 17.30]
Comparison 2. Survival: cooling versus no cooling
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Survival 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Conventional cooling
without extracorporal methods
(IPD, survival to discharge)
3 383 Risk Ratio (M-H, Fixed, 95% CI) 1.35 [1.10, 1.65]
1.2 Cooling with
haemofiltration (no IPD,
six-months survival))
1 42 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.32, 1.54]
29Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.1. Comparison 1 Neurological outcome: cooling versus no cooling, Outcome 1 Good
neurological outcome.
Review: Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation
Comparison: 1 Neurological outcome: cooling versus no cooling
Outcome: 1 Good neurological outcome
Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Conventional cooling without extracorporal methods (IPD, best ever reached CPC of 1 or 2 during hospital stay)
Bernard 2002 21/43 9/34 15.3 % 1.84 [ 0.97, 3.49 ]
HACA 2002 75/136 54/137 81.8 % 1.40 [ 1.08, 1.81 ]
Hachimi-Idrissi 2001 8/16 2/17 2.9 % 4.25 [ 1.06, 17.08 ]
Subtotal (95% CI) 195 188 100.0 % 1.55 [ 1.22, 1.96 ]
Total events: 104 (Experimental), 65 (Control)
Heterogeneity: Chi2 = 2.92, df = 2 (P = 0.23); I2 =32%
Test for overall effect: Z = 3.64 (P = 0.00027)
2 Cooling with haemofiltration (no IPD, CPC of 1 or 2 at six months)
Laurent 2005 7/22 9/20 100.0 % 0.71 [ 0.32, 1.54 ]
Subtotal (95% CI) 22 20 100.0 % 0.71 [ 0.32, 1.54 ]
Total events: 7 (Experimental), 9 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.87 (P = 0.38)
3 Unknown method (no IPD, Glasgow Outcome scale of 1-3 at one month)
Mori 2000 18/36 2/18 100.0 % 4.50 [ 1.17, 17.30 ]
Subtotal (95% CI) 36 18 100.0 % 4.50 [ 1.17, 17.30 ]
Total events: 18 (Experimental), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.19 (P = 0.029)
Test for subgroup differences: Chi2 = 6.20, df = 2 (P = 0.05), I2 =68%
0.2 0.5 1 2 5
Favours no cooling Favours cooling
30Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.1. Comparison 2 Survival: cooling versus no cooling, Outcome 1 Survival.
Review: Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation
Comparison: 2 Survival: cooling versus no cooling
Outcome: 1 Survival
Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Conventional cooling without extracorporal methods (IPD, survival to discharge)
Bernard 2002 21/43 11/34 15.4 % 1.51 [ 0.85, 2.68 ]
HACA 2002 85/136 67/137 83.4 % 1.28 [ 1.03, 1.58 ]
Hachimi-Idrissi 2001 4/16 1/17 1.2 % 4.25 [ 0.53, 34.10 ]
Subtotal (95% CI) 195 188 100.0 % 1.35 [ 1.10, 1.65 ]
Total events: 110 (Experimental), 79 (Control)
Heterogeneity: Chi2 = 1.56, df = 2 (P = 0.46); I2 =0.0%
Test for overall effect: Z = 2.90 (P = 0.0038)
2 Cooling with haemofiltration (no IPD, six-months survival))
Laurent 2005 7/22 9/20 100.0 % 0.71 [ 0.32, 1.54 ]
Subtotal (95% CI) 22 20 100.0 % 0.71 [ 0.32, 1.54 ]
Total events: 7 (Experimental), 9 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.87 (P = 0.38)
0.01 0.1 1 10 100
Favours no cooling Favours cooling
A D D I T I O N A L T A B L E S
Table 1. Subgroup analyses
Outcome or Subgroup Studies Participants Risk Ratio (M-H, Fixed, 95% CI)
Good neurological outcome by
cardiac cause versus non-car-
diac cause
3 383 1.54 [1.22, 1.95]
Cardiac cause 3 372 1.51 [1.19, 1.91]
Non-cardiac cause 2 11 3.80 [0.55, 26.29]
Good neurological outcome by
location of cardiac arrest
3 382 1.56 [1.23, 1.98]
31Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Subgroup analyses (Continued)
In-hospital 1 17 1.64 [0.47, 5.73]
Out-of-hospital 3 365 1.56 [1.23, 1.99]
Good neurological outcome by
witnessed cardiac arrest
3 382 1.49 [1.18, 1.88]
Witnessed cardiac arrest 3 360 1.43 [1.13, 1.81]
Non-witnessed cardiac arrest 3 22 5.31 [1.40, 20.21]
Good neurological outcome by
primary ECG rhythm
3 382 1.51 [1.19, 1.91]
VF/VT rhythm 2 330 1.47 [1.15, 1.88]
Non- VF/VT rhythm 2 52 2.17 [0.68, 6.93]
Table 2. Adverse events
Outcome or Subgroup Studies Participants Risk Ratio
(M-H, Fixed, 95%CI)
Bleeding of any severity 1 273 1.38 [0.88, 2.16]
Need for platelet transfusion 1 273 5.11 [0.25, 105.47]
Pneumonia 1 273 1.27 [0.90, 1.78]
Sepsis 1 273 1.93 [0.89, 1.78]
Pancreatitis 1 273 0.51 [0.05, 5.57]
Renal failure or oliguria 2 303 0.88 [0.48, 1.61]
Haemodialysis 2 350 1.11 [0.41, 3.01]
Pulmonary edema 1 273 1.76 [0.61, 5.12]
Seizures 1 273 0.89 [0.39, 2.02]
Lethal or long lasting arrhyth-
mia
2 315 1.21 [0.88, 1.67]
Pressure sores 1 273 Not estimable
32Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Adverse events (Continued)
Significant haemorrhagic com-
plications
1 77 Not estimable
Cardiac complications 1 77 0.16 [0.01, 3.21]
Hypokalaemia 1 42 0.91 [0.31, 2.68]
Hypophosphataemia 1 42 1.12 [0.65, 2.25]
Table 3. Sensitivity analysis
Outcome or Subgroup Studies Participants Risk Ratio
(M-H, Fixed, 95%CI)
Good neurological outcome all
studies
5 479 1.55 [1.24, 1.94]
Studies with conventional cool-
ing and adequate allocation
concealment
2 306 1.50 [1.16, 1.93]
Studies with conventional cool-
ing and inadequate or unknown
allocation concealment
1 77 1.84 [0.97, 3.49]
Studies with other cooling
methods and adequate alloca-
tion concealment
1 42 0.71 [0.32, 1.54]
Studies with other cooling
method and inadequate or un-
known allocation concealment
1 54 4.50 [1.17, 17.30]
33Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A P P E N D I C E S
Appendix 1. Search strategy: CENTRAL, The Cochrane Library
#1 MeSH descriptor Resuscitation explode all trees
#2 MeSH descriptor Cardiopulmonary Resuscitation explode all trees
#3 MeSH descriptor Resuscitation Orders explode all trees
#4 MeSH descriptor Heart Arrest explode all trees
#5 MeSH descriptor Heart Massage explode all trees
#6 ((cardio?pulmonary or order*) near2 resuscitation):ti,ab
#7 reanimation:ti,ab
#8 ((circulatory or circulation or cardiac) near arrest):ti,ab or heart standstill:ti,ab
#9 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8)
#10 MeSH descriptor Cryotherapy explode all trees
#11 MeSH descriptor Hypothermia explode all trees
#12 MeSH descriptor Hypothermia, Induced explode all trees
#13 ((resuscitative or therapeutic or artificial or induced or extracorporeal) near hypothermia)
#14 artificial hibernation or body cooling or refrigeration anesthesia or body temperature:ti,ab or refrigeration:ti,ab
#15 (#10 OR #11 OR #12 OR #13 OR #14)
#16 (#9 AND #15)
Appendix 2. Search strategy: MEDLINE (Ovid SP)
1. Resuscitation/ or Cardiopulmonary Resuscitation/ or Resuscitation Orders/ or Heart Arrest/ or Heart Massage/ or advanced cardiac
life support.mp. or ((cardio?pulmonary or order*) adj2 resuscitation).ti,ab. or reanimation.ti,ab. or ((circulatory or circulation or
cardiac) adj3 arrest).ti,ab. or heart standstill.ti,ab.
2. Cryotherapy/ or Hypothermia/ or Circulatory Arrest, Deep Hypothermia Induced/ or Hypothermia, Induced/ or ((resuscitative
or therapeutic or artificial or induced or extracorporeal) adj3 hypothermia).mp. or artificial hibernation.mp. or body cooling.mp. or
chilling.mp. or refrigeration anesthesia.mp. or body temperature.ti,ab. or refrigeration.ti,ab.
3. 1 and 2
4. ((randomised controlled trial or controlled clinical trial).pt. or randomised.ab. or placebo.ab. or clinical trials as topic.sh. or ran-
domly.ab. or trial.ti.) not (animals not (humans and animals)).sh.
5. 3 and 4
Appendix 3. Search strategy: EMBASE (Ovid SP)
1. resuscitation/ or heart arrest/ or heart massage/ or advanced cardiac life support.mp. or ((cardio?pulmonary or order*) adj2 resusci-
tation).ti,ab. or reanimation.ti,ab. or ((circulatory or circulation or cardiac) adj3 arrest).ti,ab. or heart standstill.ti,ab.
2. cryotherapy/ or hypothermia/ or ((resuscitative or therapeutic or artificial or induced or extracorporeal) adj3 hypothermia).mp. or
artificial hibernation.mp. or body cooling.mp. or chilling.mp. or refrigeration anesthesia.mp. or body temperature.ti,ab. or refrigera-
tion.ti,ab.
3. 1 and 2
4. (placebo.sh. or controlled study.ab. or random*.ti,ab. or trial*.ti,ab. or ((singl* or doubl* or trebl* or tripl*) adj3 (blind* or
mask*)).ti,ab.) not (animals not (humans and animals)).sh.
5. 3 and 4
34Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 4. Search strategy: CINAHL (EBSCO host)
S1 ( (MH “Resuscitation”) OR (MH “Resuscitation Orders”) OR (MH “Resuscitation, Cardiopulmonary”) OR (MH “Heart Arrest”)
OR (MH “Heart Massage”) ) OR AB ( ((cardio?pulmonary or order*) and resuscitation) ) OR AB reanimation OR ( (circulatory or
circulation or cardiac) and arrest ) OR heart standstill
S2 ( (MH “Cryotherapy”) OR (MH “Hypothermia”) OR (MH “Hypothermia, Induced”) ) OR ( ((resuscitative or therapeutic or
artificial or induced or extracorporeal) and hypothermia) ) OR artificial hibernation OR body cooling OR refrigeration anesthesia
S3 ( (MH “randomised Controlled Trials”) OR (MH “Random Assignment”) OR (MH “Prospective Studies”) OR (MH “Multicenter
Studies”) OR (MH “Clinical Trials”) OR (MH “Clinical Trial Registry”) OR (MH “Double-Blind Studies”) OR (MH “Single-Blind
Studies”) OR (MH “Triple-Blind Studies”) OR (MH “Placebos”) ) OR ( random* or controlled clinical trial or placebo )
S4 S1 and S2 and S3
Appendix 5. Search Strategy: BIOSIS (Ovid SP)and PASCAL
1. advanced cardiac life support.mp. or ((cardio?pulmonary or order*) adj2 resuscitation).ti,ab. or reanimation.ti,ab. or ((circulatory or
circulation or cardiac) adj3 arrest).ti,ab. or heart standstill.ti,ab.
2. (((resuscitative or therapeutic or artificial or induced or extracorporeal) adj3 hypothermia) or artificial hibernation or body cooling
or chilling or refrigeration anesthesia).mp. or body temperature.ti,ab. or refrigeration.ti,ab.
3. 1 and 2
35Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 6. Data extraction sheet
Data extraction sheet
Hypothermia for neuroprotection after
cardiopulmonary resuscitation
Reviewer:
Date:
Decision:
• Inclusion
• Exclusion
Reasons for exclusion:
Study characteristics
Publication type:
Language:
Setting
Multicenter:
• yes
• no
Participating sites:
• university hospital
• community hospital
• other, please specify
Participants, inclusion/exclusion criteria
Total number of patients:
Mean age:
Percent female:
Cardiac arrest:
• out-of-hospital
• in-hospital
Cause of cardiac arrest:
• cardiac
• non cardiac
Primary cardiac rhythm:
• ventricular fibrillation
• ventricular tachycardia
• asystole
• pulseless electrical activity
Quality
Allocation conceal-
ment
A. adequate
B. unclear
C. inadequate
Outcome assessor
blind
• yes
• no
• if unclear,
please explain
Outcome assessor
blind
• yes
• no
• if unclear,
please explain
Intention-to-treat:
• yes
• no
• if unclear,
please explain
Groups
comparable:
• yes
• if not, please
specify
Follow-up > 80%
of randomized pa-
tients:
• yes
• if not, please
specify
Intervention Type of interven-
tion:
Controls: Time from restora-
tion of spontaneous
circulation to target
temperature:
36Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Cooling rate: Duration of cool-
ing:
Rewarming:
Outcomes Types of outcome
measures:
• ..
• ..
• ..
• ..
• ..
• ..
Time point
of assessment of out-
come measures:
• ..
• ..
• ..
• ..
• ..
• ..
Funding
Notes
Results primary:
Type of outcome:
Cooling No cooling
Events (n) Total (N) Events (n) Total (N)
Results secondary:
Type of outcome:
Cooling No cooling
Events (n) Total (N) Events (n) Total (N)
37Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
W H A T ’ S N E W
Last assessed as up-to-date: 25 July 2011.
Date Event Description
31 July 2012 New search has been performed This review is an update of the previous Cochrane sys-
tematic review (Arrich 2009) that included four trials and
one abstract reporting on 481 patients
In the previous version (Arrich 2009) we searched the
databases until January 2009. In this updated version we
reran the searches to July 2011
We updated the methods, allocated all chapters, updated
references, added a risk of bias table and summary of find-
ings table
A typing error (survival instead of neurologic outcome) in
the results section was spotted by a reader and corrected
accordingly
31 July 2012 New citation required but conclusions have not changed Christof Havel was added as an author.
H I S T O R Y
Protocol first published: Issue 2, 2003
Review first published: Issue 4, 2009
Date Event Description
28 June 2010 Amended Contact details updated
29 October 2009 Amended Typo corrected in co-author’s address (Müllner)
C O N T R I B U T I O N S O F A U T H O R S
Conceiving the review and update: Harald Herkner (HH), Michael Holzer (MH), Marcus Müllner (MM), and Christof Havel (CH)
Co-ordinating the review: HH, MM
Undertaking manual searches: MH, Jasmin Arrich (JA)
Screening search results: MH, JA, CH
Organizing retrieval of papers: JA
Screening retrieved papers against inclusion criteria: MH, JA, MM, CH
Appraising quality of papers: MH, HH, JA, MM, CH
Abstracting data from papers: MH, JA, CH
38Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Writing to authors of papers for additional information: MH
Providing additional data about papers: MH
Obtaining and screening data on unpublished studies: MH, JA
Data management for the review: HH, JA, MM
Entering data into Review Manager (RevMan 5.1): MH, JA
RevMan statistical data: HH, MM, JA
Other statistical analyses not using RevMan: HH, MM
Double entry of data: MH, JA
Interpretation of data: MH, HH, JA, MM, CH
Statistical inferences: HH, MM, JA
Writing the review: JA, MM, HH
Securing funding for the review: not applicable
Performing previous work that was the foundation of the present study: MM, MH, CH
Guarantor for the review (one author): JA
Person responsible for reading and checking review before submission: HH
D E C L A R A T I O N S O F I N T E R E S T
The Medical University of Vienna received an unrestricted scientific grant from Alsius Corporation for an independent scientific project,
which was used for financing the post of Jasmin Arrich.
Michael Holzer received travel grants for scientific conferences from Alsius Corporation and Kinetic Concepts, Inc (KCI) and honoraria
for lectures from Medivance and KCI. He is a member of the scientific advisory board of KCI.
Marcus Müllner, Michael Holzer and Christof Havel were involved in the design, conduct and publication of the HACA 2002 trial.
Harald Herkner has no conflicts of interest.
S O U R C E S O F S U P P O R T
Internal sources
• Medical University of Vienna, Austria.
39Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
External sources
• No sources of support supplied
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
In our protocol we aimed to include additional endpoints like the six month and final CPC score, long-term mortality, quality of
life at six months, long-term dependency, and cost-effectiveness. The retrieved studies did not provide any information on long-term
mortality and dependency, quality of life, or cost-effectiveness.
All studies that were included in the individual patient analysis provided data on both best and final neurologic outcome (Bernard
2002; HACA 2002; Hachimi-Idrissi 2001). In our opinion the ’best neurological score during hospital stay’ is superior to the final
score as the final score may be influenced by other factors like worsening of body functions or re-arrests.
Bernard 2002 and Hachimi-Idrissi 2001 gave information on survival to hospital discharge, HACA 2002 additionally on six-month
survival, Laurent 2005 only gave information on the six-month survival. As the study by Laurent was not included in the individual
patients analysis we chose survival to hospital discharge as a secondary endpoint for the individual patient analysis.
The documentation of adverse effects was overlooked in the original protocol. As they form a vital part of every review we included
them in the data extraction sheet before we performed the literature search.
In accordance with our reviewers, to better explain the reasons for dual analysis and the way it was carried out, we have changed the
wording of the objectives from:
“The aim of this study is to present a systematic review of the literature and, if applicable, a meta-analysis, concerning the neuroprotective
effect of induced hypothermia in primary cardiac arrest survivors. We plan to use data at the aggregate (study) level and the individual
(patient) level.”
to:
“We aimed to perform a systematic review and meta-analysis to assess the effectiveness of therapeutic hypothermia in patients after
cardiac arrest. Neurologic outcome, survival and adverse events were our main outcomes. We aimed to perform individual patient data
analysis if data were available. We intended to form subgroups according to the cardiac arrest situation.”
The title has been changed from “Hypothermia for neuroprotection after cardiopulmonary resuscitation” to “Hypothermia for neuro-
protection in adults after cardiopulmonary resuscitation”.
I N D E X T E R M S
Medical Subject Headings (MeSH)
Brain Diseases [∗prevention & control]; Cardiopulmonary Resuscitation [∗adverse effects]; Heart Arrest [∗complications; therapy];
Hypothermia, Induced [∗methods]; Randomized Controlled Trials as Topic; Recovery of Function
MeSH check words
Adult; Humans
40Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.