therapeutic hypothermia for neuroprotection post cpr

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)


[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.


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)


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.



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Patientorpopulation:comatosepatientsaftercardiopulmonaryresuscitation

Settings:

Intervention:conventionalcooling

Comparison:no

cooling

Outcomes

Illustrative

comparativerisks*

(95%CI)

Relativeeffect

(95%CI)

NoofParticipants

(studies)

Qualityoftheevidence

(GRADE)

Com

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Assumed

risk

Correspondingrisk

nocooling

conventionalcooling

Goodneurologicalout-

come

-Conventional

cooling

withoutextra-

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CPC

1

Studypopulation

RR1.55

(1.22to1.96)

383

(3studies)

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moderate

2,3

35per100

54per100

(42to68)

Mediumriskpopulation

27per100

42per100

(33to53)

Survival-Conventional

cooling

withoutextra-

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survivalto

discharge)

(Copy)

discharge

information

andtelephonefollowup

Studypopulation

RR1.35

(1.1to1.65)

383

(3studies)

⊕⊕

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moderate

42per100

57per100

(46to69)

Mediumriskpopulation

32per100

44per100

(36to53)



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Moderatequality:Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychangetheestimate.

Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate.

Verylowquality:Weareveryuncertainabouttheestimate.

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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



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.



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:



• 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).



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



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.



Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



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


Cost-effectiveness


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



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,



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



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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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



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



Groups comparable: significantly more diabetes and coronary heart disease and bystander

CPR in control group


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)


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




HACA 2002 (Continued)


bias)

Low risk

Allocation concealment (selection bias) Low risk


bias)

All outcomes

Low risk


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



Groups comparable: yes, although groups were small, no significant difference


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


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)


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



Hachimi-Idrissi 2001 (Continued)



bias)

Low risk



bias)

All outcomes

Low risk


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


Groups comparable: 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


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



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)

Low risk



bias)

All outcomes

Unclear risk Not reported


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


Interventions “Brain-hypothermic treatment” versus “brain normothermic treatment”

Means of cooling: unknown

Cooling rate: unknown


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”



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)

Unclear risk No information available from abstract

Allocation concealment (selection bias) Unclear risk No information available from abstract


bias)

All outcomes



All outcomes


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



(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



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 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



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)


1.3 Unknown method (no

IPD, Glasgow Outcome scale

of 1-3 at one month)


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)


1.2 Cooling with

haemofiltration (no IPD,

six-months survival))




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 ]


Heterogeneity: not applicable


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 ]




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



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 ]


Heterogeneity: Chi2 = 1.56, df = 2 (P = 0.46); I2 =0.0%


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 ]




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]


location of cardiac arrest

3 382 1.56 [1.23, 1.98]



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]


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]


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



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]



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



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



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:



(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)



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



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.



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



therapeutic hypothermia for neuroprotection post cpr

Documents

cochrane review

cochrane collaboration

cochrane library2012

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cochrane anaesthesia

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havel c

medical university of