Therapeutic Hypothermia For Neuroprotection Post CPR

Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)
Arrich J, Holzer M, Havel C, Mllner M, Herkner H
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, 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.
TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Neurological outcome: cooling versus no cooling, Outcome 1 Good neurological outcome. Analysis 2.1. Comparison 2 Survival: cooling versus no cooling, Outcome 1 Survival. . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 5 5 5 8 9 10 11 13 15 15 15 20 29 30 31 31 33 37 38 38 39 39 40 40
[Intervention Review]
Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation

Jasmin Arrich1 , Michael Holzer1 , Christof Havel1 , Marcus Mllner2 , Harald Herkner1
1 Department
of Emergency Medicine, Medical University of Vienna, Vienna, Austria. 2 AGES PharmMed, Austrian Medicines and Medical Devices Agency, Vienna, Austria Contact address: Jasmin Arrich, Department of Emergency Medicine, Medical University of Vienna, Whringer Grtel 18-20 / 6D, Vienna, 1090, Austria. jasmin.arrich@meduniwien.ac.at.
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, Mllner 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.
ABSTRACT Background Good neurologic outcome after cardiac arrest is hard to achieve. Interventions during the resuscitation phase and treatment within the rst hours after the event are critical. Experimental evidence suggests that therapeutic hypothermia is benecial, 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.
Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1
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 ve 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 (ve 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 signicant 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.
PLAIN LANGUAGE SUMMARY 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 decits 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 haemoltration) were added, this effect remained unchanged. No cooling specic adverse events were reported. One of the limitations of our review is that the majority of patients had a specic form of cardiac arrest, with ventricular brillation 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 rst hours of resuscitation.
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Neurological Outcome and Survival: conventional cooling compared to no cooling for neuroprotection and survival in adults after cardiopulmonary resuscitation
Patient or population: comatose patients after cardiopulmonary resuscitation Settings: Intervention: conventional cooling Comparison: no cooling Illustrative comparative risks* (95% CI) Relative effect (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments
Outcomes
Assumed risk no cooling Study population 35 per 100 54 per 100 (42 to 68) RR 1.55 (1.22 to 1.96) 383 (3 studies) conventional cooling
Corresponding risk
moderate2,3
Good neurological outcome - Conventional cooling without extracorporal methods (IPD, best ever reached CPC of 1 or 2 during hospital stay) CPC1 Medium risk population 27 per 100 42 per 100 (33 to 53) RR 1.35 (1.1 to 1.65) 57 per 100 (46 to 69)
Survival - Conventional Study population cooling without extracorporal methods (IPD, 42 per 100 survival to discharge) (Copy) discharge information Medium risk population and telephone follow up 32 per 100 44 per 100 (36 to 53)
383 (3 studies)
moderate
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Cerebral Performance Category (I-V) One quasi-randomised trial but not contributing the majority of data Total number of events < 300
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BACKGROUND
stores (McCullough 1999; Mizuhara 1996), which are necessary for energy provision; the restitution of post-ischaemic cerebral microcirculation (Takasu 1996); and possibly also decreased intracranial pressure (Lee 2010; Schreckinger 2009). Subsequently, hypothermia seems to act in a multifactorial way by inuencing several damaging pathways simultaneously (Holzer 2010) to reduce the amount of cell death in the brain.
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 admitted to hospital (Finn 2001; Fischer 1997; Giraud 1996; Herlitz 2003b; Kuisma 1996; Leung 2001; Rewers 2000). Of those patients admitted to hospital, only between 7% and 30% were discharged from hospital with good neurologic outcome (Absalom 1999; Bttiger 1999; Fischer 1997; Herlitz 1999; Jennings 2001; Westfal 1996; Weston 1997). Many new concepts in post-resuscitation care have been developed in the past few years that aim at improving neurological outcome and survival of patients after 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)
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 primarily 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 benet in terms of neurologic outcome and survival with hypothermia 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 exist. Conventional cooling comprises extracorporeal methods with cooling pads, ice packs, water immersion or intravascular cooling with cooling catheters or simply cold uids. Cooling can also be combined with haemoltration or any extracorporeal cardiopulmonary support. Studies with different treatment modalities are emerging and therefore systematic and regular updates of the literature 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 controlled trials.
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 essential and effective in restoring energy stores, can also trigger harmful chemical cascades. The generation of free radicals and other mediators, which leads to multifocal damage of the brain, was rst described by Negovsky as postresuscitation syndrome (Negovsky 1988). In contrast to accidental hypothermia, therapeutic mild hypothermia (32 C to 34 C) is administered in a controlled way. Intra-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, release and uptake of several catecholamines and neurotransmitters (Okuda 1986; Sun 2010; Szelenyi 2012), especially glutamate and dopamine, which could lead to tissue damage (DCruz 2002; Hachimi-Idrissi 2004). Other benecial effects of hypothermia include the preservation of the blood brain barrier (Baumann 2009; Karibe 1994); the protection of adenosine triphosphate (ATP)
OBJECTIVES
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.
METHODS
Criteria for considering studies for this review

Types of studies
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We included randomized and quasi-randomized controlled trials. Quasi-randomized refers to allocation procedures such as alternating 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 benet 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, regardless of how body temperature was reduced, applied within six hours of arrival at hospital. We dened therapeutic as any body target temperature below 35 C. We dened the control intervention as treatment according to the standard treatment after cardiac arrest at the time of the trial. Types of outcome measures
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 ve (coma, which satises brain death criteria). 5. Certied brain death. If authors grouped this outcome into one or two (good recovery) and three to ve (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 longterm, quality of life at six months and long-term, dependency, and cost-effectiveness. We dened long-term as a minimum of one year. Adverse events We aimed at reporting adverse events as given by the authors.
Search methods for identication of studies

Electronic searches We searched the following databases: the Cochrane Central Register 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 multiple 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; EMBASE, Appendix 3; CINAHL, Appendix 4; BIOSIS and PASCAL, 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 eld whether they were aware of any ongoing, unpublished or published trials on this subject.
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Primary outcomes
The primary outcome measure was neurological recovery. Ideally, we expected the outcome to be reported as best neurologic outcome during hospital stay and in cerebral performance categories (CPC) (Stiell 2009). The CPC categories are dened as follows. 1. Good cerebral performance: conscious, alert, capable of normal life. Normal cerebral function. May have minor psychological or neurological decits, which do not signicantly compromise cerebral or physical function. 2. Moderate cerebral disability: conscious, alert, sufcient 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
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) independently 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 patient data of the identied trials we contacted the respective corresponding authors and asked for collaboration. Two review authors independently entered all relevant data into the Cochrane Collaborations software program Review Manager (RevMan 5.1). We compared the two versions and resolved disagreements by discussion. 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 (inhospital versus out-of-hospital); witnessed versus non-witnessed arrest; primary electrocardiogram (ECG) rhythm (ventricular brillation versus other). Assessment of risk of bias in included studies To assess the internal validity of the identied 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% condence 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 contacting 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 inuence of this possible selection bias on our estimates in a sensitivity analysis. Assessment of heterogeneity We assessed data for clinical and statistical heterogeneity. We only performed quantitative synthesis of the data if clinical heterogeneity was negligible. Clinical heterogeneity may be caused by differences in study populations, interventions or denitions 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 heterogeneity 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 analysis 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 dened as a best CPC category of one or two or the denition 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 patients allocated to hypothermia when compared to those not receiving hypothermia. In the case of negligible statistical heterogeneity we used xed-effect models to calculate summary effects, otherwise we used random-effects models. Statistical heterogeneity 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 individual patient data and according to the following variables:
cause of cardiac arrest (presumed cardiac versus noncardiac); location of arrest (in-hospital versus out-of-hospital); witnessed versus non-witnessed arrest; primary ECG rhythm (ventricular brillation versus other).
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies. Results of the search
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 identied trials when neglecting heterogeneity and publication status.
RESULTS
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 (duplicates excluded). From these, we excluded 1819 according to our eligibility criteria (randomized studies on adult cardiac arrest patients treated with therapeutic hypothermia) by judging the abstract or the title. Thirty-two papers remained for closer inspection. 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 identied one ongoing study (see Characteristics of excluded studies and Figure 1).
Figure 1. Study ow 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 ve 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 unclassied study (Tiainen 2007) and two additional studies (Tiainen 2003; Tiainen 2005) were found to be reports of the HACA 2002 study. The updated search resulted in no new studies for inclusion. Included studies
Clinical heterogeneity
We identied clinical heterogeneity due to cooling methods. In contrast to the other studies, Laurent 2005 used haemoltration 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.
See table Characteristics of included studies.
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 ve studies. Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as percentages across all included studies.
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Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included study.
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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 endpoint (HACA 2002). All other studies had a complete follow up.
With only three studies reporting on conventional cooling methods (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 haemoltration 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).
Selective reporting There was no indication of selective outcome reporting.

Secondary outcomes
Other potential sources of bias In two studies the treatment and control groups did not differ signicantly 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 coronary heart disease and to have received basic life support from a bystander than were those in the hypothermia group. The authors adjusted for all baseline variables and the risk ratio increased slightly, from 1.40 (95% condence 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.
Survival to hospital discharge With only three studies reporting on conventional cooling methods (involving 195 cases and 188 controls) the pooled result showed better survival for the hypothermia group (individual patient 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 haemoltration 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.
Effects of interventions
See: Summary of ndings for the main comparison Neurological outcome and survival: conventional cooling compared to no cooling for neuroprotection and survival in adults after cardiopulmonary resuscitation
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.
Primary outcome
Subgroup analyses According to the number of patients and information provided by the authors we formed subgroups of the meta-analysis by the following variables: cause of cardiac arrest (presumed cardiac versus
Good neurologic outcome
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non-cardiac); location of arrest (in-hospital versus out-of-hospital); witnessed versus non-witnessed arrest; primary ECG rhythm (ventricular brillation (VF) or ventricular tachycardia (VT) versus other). The endpoint was best ever reached CPC during hospital 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 rst 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 signicant 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 analysis, 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 failure or oliguria, haemodialysis, pulmonary oedema, seizures, lethal or long-lasting arrhythmias, cardiac complications, hypocalcaemia and hypophosphataemia. There were no signicant differences between the groups (see Additional Table 2). Sensitivity analysis Does allocation concealment inuence 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 signicant in a xed-effect model (RR 1.50; 95% CI 1.16 to 1.93) (see Additional Table 3) but not signicant 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 signicant 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 inuence 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 (xed-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 xed-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 Chi = 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.
DISCUSSION
Summary of main results

Our review shows that therapeutic hypothermia with conventional cooling methods improves neurologic outcome and survival of patients successfully resuscitated after cardiac arrest. Currently available 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 rst recorded cardiac rhythm benet 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 rm inferences. There were no statistically signicant differences in any of the reported adverse events between hypothermia and non-hypothermia patients.
Overall completeness and applicability of evidence

After our literature search we were able to include the data of all eligible studies we retrieved. It was not possible to obtain individual 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 treatment 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,
13
one of the theories of the benecial effects of cooling deals with attenuation of the effect of free radicals and other mediators. Haemoltration may act in a similar way, by reducing the number of free radicals. It may add to or even supersede the effect of therapeutic 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 randomized controlled trials and hence small numbers of included patients. Therefore, the precision of our effects is generally low and, particularly in subgroup and sensitivity analyses, this is a matter for concern. The condence 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 studies have been included in the sensitivity analysis, which is probably too small a number to make rm conclusions. Nonetheless, given these limitations the effect of conventional cooling methods consistently points towards a favourable neurological outcome. Another 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 sufcient nancial resources. But there are many cooling methods, ranging from expensive device controlled methods to very cheap cold uids 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-benet analyses. After the publication of the two RCTs on therapeutic hypothermia (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 patients the results of our review support those recommendations.
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 because of death, arrhythmia, haemodynamic instability, technical problems with the cooling device, one liver rupture, one randomized patient that had already been included in the study before, and one error in the duration of cooling. These patients were included 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 normothermia 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 neurologic outcome increases, with an odds ratio of 2.26 (Zeiner 2001). If this is true even for smaller temperature differences, the benecial effect of therapeutic hypothermia might at least partly be due to an antipyretic rather than a hypothermic effect. It is questionable 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 measure and gives a crude approximation of the patients ability to perform 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 observed 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 condence intervals. Although it seems that patients benet 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 conrmed VF rhythm as rst rhythm (Haukoos 2004; Herlitz 2003a; Kim 2001) and 40% of all resuscitations happen in hospital. In
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Quality of the evidence

We found ve studies on the application of mild hypothermia, 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. Except 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 randomization process and the adjustment for inequalities in baseline characteristics between the treatment and the control groups (Bernard 2002). All studies planned to include consecutive patients (no information 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
this review the two bigger studies included only patients with a cardiac cause of cardiac arrest, and with VF or VT rhythm as the rst cardiac rhythm (Bernard 2002; HACA 2002). Most of these patients had an out-of-hospital cardiac arrest. From the pathogenesis of global cerebral ischaemia and the theories as to why therapeutic hypothermia is effective, there is no reason why therapeutic hypothermia should not be as effective in patients with asystole as the rst cardiac rhythm or non-cardiac causes for cardiac arrest. In a meta-analysis (Holzer 2005) the effect of therapeutic hypothermia 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).
cardiac arrest. Our review supports the current best medical practice as recommended by the International Resuscitation Guidelines.
Implications for research

Future research should be done with standardized temperature monitoring (either oesophagus or bladder temperature measurements) in order to be able to compare between groups and between studies at a later stage. Effective measures need to be advanced 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, inclusion criteria should be widened and comparisons of earlier cooling (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-benet analyses in future studies.
Agreements and disagreements with other studies 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 ve studies they combined four and ve based on a different judgement on clinical heterogeneity, and they provided a trial sequential analysis. The main ndings 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.
ACKNOWLEDGEMENTS
We would like to thank Dr Mathew Zacharias (content editor), Dr Marialena Trivella (statistical editor) and Dr Malcolm G Booth, Dr George Djaiani and Sha 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 preparation of the protocol for the systematic review.
AUTHORS CONCLUSIONS Implications for practice

Conventional cooling methods to induce mild therapeutic hypothermia seem to improve survival and neurologic outcome after
REFERENCES
References to studies included in this review

Bernard 2002 {published data only} Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al.Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. New England Journal of Medicine 2002;346(8):55763. [MEDLINE: 11856794] HACA 2002 {published data only} Hypothermia after Cardiac Arrest Study Group. Mild
therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. New England Journal of Medicine 2002;346(8):54956. [MEDLINE: 11856793] Tiainen M, Kovala TT, Takkunen OS, Roine RO. Somatosensory and brainstem auditory evoked potentials in cardiac arrest patients treated with hypothermia. Critical Care Medicine 2005;33(8):173640. [PUBMED: 16096450] Tiainen M, Poutiainen E, Kovala T, Takkunen O, Happola O, Roine RO. Cognitive and neurophysiological
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outcome of cardiac arrest survivors treated with therapeutic hypothermia. Stroke 2007;38(8):23038. [PUBMED: 17585081] Tiainen M, Roine RO, Pettila V, Takkunen O. Serum neuron-specic enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke 2003;34(12): 28816. [PUBMED: 14631087] Hachimi-Idrissi 2001 {published and unpublished data} Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation 2001;51(3):27581. [MEDLINE: 11738778] Laurent 2005 {published data only} Laurent I, Adrie C, Vinsonneau C, Cariou A, Chiche JD, Ohanessian A, et al.High-volume hemoltration after out-of-hospital cardiac arrest: A randomized study. Journal of the American College of Cardiology 2005;46(3):4327. [MEDLINE: 16053954] Mori 2000 {published data only} Mori K, Takeyama Y, Itoh Y, Nara S, Yoshida M, Ura H, et al.A multivariate analysis of prognostic factors in survivors of out-of-hospital cardiac arrest with brain hypothermia. Critical Care Medicine. 2000; Vol. 28:A168.
Callaway 1997 {published data only} Callaway CW. Improving neurologic outcomes after out-ofhospital cardiac arrest. Prehospital Emergency Care 1997;1 (1):4557. [MEDLINE: 9709320] Callaway 2002 {published data only} Callaway CW, Tadler SC, Katz LM, Lipinski CL, Brader E. Feasibility of external cranial cooling during out-ofhospital cardiac arrest. Resuscitation 2002;52(2):15965. [MEDLINE: 11841883] Castrejon 2009 {published data only} Castrejon S, Cortes M, Salto ML, Benittez LC, Rubio R, Juarez M, et al.Improved prognosis after using mild hypothermia to treat cardiorespiratory arrest due to a cardiac cause: comparison with a control group. Revista Espanola de Cardiologia 2009;62(7):73341. [PUBMED: 19709508] Castrn 2010 {published data only} Castrn M, Nordberg P, Svensson L, Taccone F, Vincent JL, Desruelles D, et al.Intra-Arrest Transnasal Evaporative Cooling: A Randomized, Prehospital, Multicenter Study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness). Circulation 2010;122(7):72936. [MEDLINE: 20679548] Chanin 2002 {published data only} Chanin K, Fong E, Marik P, Fromm RE, Varon J. Neurologic outcome after cardiac arrest with the use of mild therapeutic hypothermia. Critical Care and Shock 2002;5 (3):1902. [: 2002330015] Ebell 2002 {published data only} Ebell M. Does induced hypothermia improve outcomes after cardiac arrest?. Evidence Based Practice 2002;5(5):56. [: 2003067281] Gwinnutt 2003 {published data only} Gwinnutt CL, Nolan JP. Resuscitative hypothermia after cardiac arrest in adults. European Journal of Anaesthesiology 2003;20(7):5114. [: 2003284871] Heard 2007 {published data only} Heard K, Peberdy MA, Sayre MR, Sanders A, Geocadian RG, ONeil BJ, Group RS. A randomized, controlled trial comparing the arctic sun to standard cooling for hypothermia after cardiac arrest. Circulation 2007;116 Suppl(16):529. Huang 2008 {published data only} Huang S, Chen Y, Ko W, Wang S-S. Hypothermia therapy in patients rescued with extracorporal membrane oxygenation for in-hospital cardiac arrest with initial coma. Circulation 2008;118 Suppl 2(18):1479. [: PREV200900200522] Kamarainen 2009 {published data only} Kamarainen A, Virkkunen I, Tenhunen J, Yli-Hankala A, Silfvast T. Prehospital therapeutic hypothermia for comatose survivors of cardiac arrest: a randomized controlled trial. Acta Anaesthesiologica Scandinavica 2009;53(7):9007. [PUBMED: 19496762] Kim 2007 {published data only} Kim F, Olsufka M, Longstreth WT Jr, Maynard C, Carlbom D, Deem S, et al.Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of16
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Ballew 2002 {published data only} Ballew KA. Mild hypothermia improved neurologic outcome and reduced mortality after cardiac arrest because of ventricular arrhythmia. ACP Journal Club 2002;137(2): 46. [MEDLINE: 12207424] Batista 2010 {published data only} Batista LM, Lima FO, Januzzi JL Jr, Donahue V, Snydeman C, Greer DM. Feasibility and safety of combined percutaneous coronary intervention and therapeutic hypothermia following cardiac arrest. Resuscitation 2010;81 (4):398403. [MEDLINE: 20083333] Bernard 1997 {published data only} Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Annals of Emergency Medicine 1997;30:14653. [MEDLINE: 9250636] Bernard 2004 {published data only} Bernard SA. Therapeutic hypothermia after cardiac arrest. Hypothermia is now standard care for some types of cardiac arrest. Medical Journal of Australia 2004;181(9):4689. [MEDLINE: 15516186] Bernard 2010 {published data only} Bernard SA, Smith K, Cameron P, Masci K, Taylor DM, Cooper DJ, et al.Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular brillation cardiac arrest: A randomized controlled trial. Circulation 2010;122(7):73742. [MEDLINE: 20679551]
hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 2007;115(24): 306470. [PUBMED: 17548731] Kim 2011 {published data only} Kim JJ, Yang HJ, Lim YS, Kim JK, Hyun SY, Hwang SY, et al.Effectiveness of each target body temperature during therapeutic hypothermia after cardiac arrest. American Journal of Emergency Medicine 2011;29(2):14854. [PUBMED: 20825779] Kitamura 1989 {published data only} Kitamura S, Okutsu Y. A new device of cold air topical cooling and its clinical application. Kokyu to Junkan Respiration & Circulation 1989;37(1):5760. [MEDLINE: 2734492] Mayer 2002 {published data only} Mayer SA. Hypothermia for neuroprotection after cardiac arrest. Current Neurology and Neuroscience Reports 2002;2 (6):5256. [: CN00410324] Nagao 2008 {published data only} Nagao K, Kikushima K, Watanabe K, Tachibana E, Mukouyama T, Tominaga Y, et al.Extracorporeal cardiopulmonary resuscitation for induction of hypothermia in patients with out-of-hospital cardiac arrest. Circulation 2008;118 Suppl 2(18):585. [MEDLINE: 19942784] Nielsen 2010a {published data only} Nielsen N. Target temperature management after outof-hospital cardiac arrest, an international, multi-centre, randomised, parallel groups, assessor blinded clinical trial-rationale and design of the ttm-trial. Intensive Care Medicine 2010;Conference: 23rd Annual Congress of the European Society of Intensive Care Medicine, ESICM Barcelona Spain. Conference Start: 2010-10-09, Conference End: 2010-10-13. Conference Publication: (var.pagings). 36:S178. [: 70290590] Nielsen 2011a {published data only} Nielsen N, Wise MP, Finfer S, Target Temperature Management Trial Investigators. Therapeutic hypothermia after cardiac arrest. New England Journal of Medicine 2011; 364(2):186; author reply 187-8. [MEDLINE: 21226600] Smith 2002 {published data only} Smith TL, Bleck TP. Hypothermia and neurologic outcome in patients following cardiac arrest: Should we be hot to cool off our patients?. Critical Care 2002;6(5):37780. [MEDLINE: 12398769] Takeda 2009 {published data only} Takeda Y, Shiraishi K, Naito H, Hagioka S, Morimoto N, Morita K. A randomized controlled trial of pharyngeal cooling system during cardiopulmonary resuscitation. Journal of Neurosurgical Anesthesiology 2009;21(4):4078. [DOI: http://dx.doi.org/10.1097/ 01.ana.0000358102.35410.08; EMBASE: 70034508] Ungerleider 1998 {published data only} Ungerleider RM, Pouard P, Dietrich W, Hill A, Williams GD. Effects of cardiopulmonary bypass and use of modied ultraltration. Annals of Thoracic Surgery 1998;65 Suppl (6):359. [: 1998224828]
Ungerleider 2004 {published data only} Ungerleider RM, Gaynor JW. The Boston Circulatory Arrest Study: An analysis. Journal of Thoracic and Cardiovascular Surgery 2004;127(5):125661. [: 2004193222] Yanagawa 1998 {published data only} Yanagawa Y, Ishihara S, Norio H, Takino M, Kawakami M, Takasu A, et al.Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest. Resuscitation 1998;39:616. [MEDLINE: 9918449] Zeiner 2000 {published data only} Zeiner A, Holzer M, Sterz F, Behringer W, Schorkhuber W, Mullner M, et al.Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest. A clinical feasibility trial. Hypothermia After Cardiac Arrest (HACA) Study Group. Stroke 2000;31:8694. [MEDLINE: 10625721]
References to ongoing studies

Nielsen 2010 {published data only} Nielsen N. Target temperature management after outof-hospital cardiac arrest, an international, multi-centre, randomised, parallel groups, assessor blinded clinical trial-rationale and design of the ttm-trial. Intensive Care Medicine 2010;Conference: 23rd Annual Congress of the European Society of Intensive Care Medicine, ESICM Barcelona Spain. Conference Start: 2010-10-09, Conference End: 2010-10-13. Conference Publication: (var.pagings). 36:S178. [: 70290590]
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Okuda 1986 Okuda C, Saito A, Miyazaki M, Kuriyama K. Alteration of the turnover of dopamine and 5-hydroxytryptamine in rat brain associated with hypothermia. Pharmacology, Biochemistry and Behaviour 1986;24:7983. [MEDLINE: 2418447] Peberdy 2010 Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al.Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122 Suppl 3(18): 76886. [PUBMED: 20956225] Rea 2004 Rea TD, Pearce RM, Raghunathan TE, Lemaitre RN, Sotoodehnia N, Jouven X, et al.Incidence of out-of-hospital cardiac arrest. The American Journal of Cardiology 2004;93 (12):145560. [MEDLINE: 15194012] RevMan 5.1 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1.4. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011. Rewers 2000 Rewers M, Tilgreen RE, Crawford ME, Hjortso N. One-year survival after out-of-hospital cardiac arrest in Copenhagen according to the Utstein style. Resuscitation 2000;47:13746. [MEDLINE: 11008151] Rosomoff 1954 Rosomoff H, Holaday D. Cerebral blood ow and cerebral oxygen consumption during hypothermia. American Journal of Physiology 1954;179:858. [MEDLINE: 13207391] Schreckinger 2009 Schreckinger M, Marion DW. Contemporary management of traumatic intracranial hypertension: is there a role for therapeutic hypothermia?. Neurocritical Care 2009;11(3): 42736. [PUBMED: 19644773] Stiell 2009 Stiell IG, Nesbitt LP, Nichol G, Maloney J, Dreyer J, Beaudoin T, et al.Comparison of the Cerebral Performance Category score and the Health Utilities Index for survivors of cardiac arrest. Annals of Emergency Medicine 2009;53(2): 2418. [PUBMED: 18450329] Sun 2010 Sun S, Tang W, Song F, Yu T, Ristagno G, Shan Y, et al.The effects of epinephrine on outcomes of normothermic and therapeutic hypothermic cardiopulmonary resuscitation. Critical Care Medicine 2010;38(11):217580. [PUBMED: 20693888] Szelenyi 2012 Szelenyi M, Laszlo Z, Szabo Z, Kromplak Z, Tischler E, Lakatos M, et al.Hypothermia down-regulates the LPSinduced norepinephrine (NE) release in ischaemic human heart cells. Brain Research Bulletin 2012;87(1):6773. [PUBMED: 21963948]
19
Takasu 1996 Takasu A, Yagi K, Okada Y. Effect of mild hypothermia on ischemia-induced release of endothelin-1 in dog brain. Resuscitation 1996;31:5964. [MEDLINE: 8701110] Thompson 2001 Thompson SG. Why sources of heterogeneity in metaanalysis should be investigated. In: Chalmers I, Altman DG editor(s). Systematic reviews. 1st Edition. London: BMJ Publishing Group, 1995:4863. Tiainen 2003 Tiainen M, Roine RO, Pettila V, Takkunen O. Serum neuron-specic enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke 2003;34(12): 28816. [PUBMED: 14631087] Tiainen 2005 Tiainen M, Kovala TT, Takkunen OS, Roine RO. Somatosensory and brainstem auditory evoked potentials in cardiac arrest patients treated with hypothermia. Critical Care Medicine 2005;33(8):173640. [PUBMED: 16096450] Tiainen 2007 Tiainen M, Poutiainen E, Kovala T, Takkunen O, Happola O, Roine RO. Cognitive and neurophysiological outcome of cardiac arrest survivors treated with therapeutic
hypothermia. Stroke 2007;38(8):23038. [PUBMED: 17585081] Westfal 1996 Westfal RE, Reissman S, Doering G. Out-of-hospital cardiac arrests: an 8-year New York City experience. The American Journal of Emergency Medicine 1996;14:3648. [MEDLINE: 8768156] Weston 1997 Weston CF, Jones SD, Wilson RJ. Outcome of out-ofhospital cardiorespiratory arrest in south Glamorgan. Resuscitation 1997;34:22733. [MEDLINE: 9178383] Zeiner 2001 Zeiner A, Holzer M, Sterz F, Schorkhuber W, Eisenburger P, Havel C, et al.Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Archives of Internal Medicine 2001;161(16):200712. [MEDLINE: 11525703]
References to other published versions of this review

Arrich 2009 Arrich J, Holzer M, Herkner H, Mllner 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
20
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Bernard 2002 Methods Participants Randomization: pre-hospital Total number of patients 77, mean age of 66 years, 33% female Out-of-hospital cardiac arrest of cardiac cause, ventricular brillation as rst 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 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: 33C Duration of cooling: 12 hours after target temperature was reached Rewarming: passive after 12 hours, active after 18 hours 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 Randomization: odd and even days
Interventions
Outcomes
Notes Risk of bias Bias
Authors judgement
Support for judgement Odd and even days
Random sequence generation (selection High risk bias) Allocation concealment (selection bias) High risk
Odd and even days Outcome assessment blinded
Blinding (performance bias and detection Low risk bias) All outcomes
21
Bernard 2002
(Continued)
Incomplete outcome data (attrition bias) All outcomes Other bias
Low risk
Complete follow up
Low risk
No other major biases seen
HACA 2002 Methods Participants Randomization: in hospital 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 brillation or non-perfusing ventricular tachycardia as rst 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: signicantly more diabetes and coronary heart disease and bystander CPR in control group Follow up > 80% of randomized patients: yes 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 34C Duration of cooling: median of 24 hours Rewarming: passive over eight hours Best CPC of 1, 2 versus CPC of 3, 4, 5 during six months Mortality at six months, rate of complication during rst 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 Randomization: computer generated random sequence Centre-specic 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 neuropsychological and laboratory outcomes
Interventions
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement
22
HACA 2002
(Continued)
Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Low risk
Blinding (performance bias and detection Low risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Other bias Hachimi-Idrissi 2001 Methods Participants Randomization: in hospital Total number of patients 33, mean age 72 years, 39% female Out-of-hospital cardiac arrest of cardiac cause, asystole as rst 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 signicant difference Follow up > 80% of randomized patients: yes 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: 34C Duration of cooling: start of cooling to start of rewarming, mean three hours Rewarming: passive over eight hours 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 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 Low risk Two patients lost to follow up, properly addressed
Low risk
Interventions
Outcomes
Notes
Risk of bias
Hachimi-Idrissi 2001
(Continued)
Bias
Authors judgement
Support for judgement
Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Low risk
Blinding (performance bias and detection Low risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Other bias Laurent 2005 Methods Participants Randomization: pre-hospital 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 brillation or asystole as rst 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 High-ow haemoltration versus high-ow haemoltration plus therapeutic hypothermia versus standard supportive care Means of cooling: direct external cooling of the blood Cooling rate: four hours after ICU admission the median temperature was 31.7C Target temperature: 32 to 33C Duration of cooling: 24 hours Rewarming: passive 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 Low risk Difference between published report and IPD properly reported
Low risk
Interventions
Outcomes
24
Laurent 2005
(Continued)
Notes
Randomization pre-hospital to save time for haemoltration We did not pool data from this study with data from the three other studies, since the treatment schemes with haemoltration are not comparable to non-haemoltration treatment (clinical heterogeneity)
Risk of bias Bias Authors judgement Support for judgement
Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Low risk Not reported
Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Other bias Mori 2000 Methods Participants Randomization: unknown Low risk
Low risk
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 Brain-hypothermic treatment versus brain normothermic treatment Means of cooling: unknown Cooling rate: unknown Target temperature: 32 to 34C Duration of cooling: three days Rewarming: unknown Glasgow outcome scale at one month (5 point scale). The categories moderate, mild, or no disabilities were dened as good neurologic outcome
25
Interventions
Outcomes
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 No information available from abstract
Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk
No information available from abstract No information available from abstract
Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Other bias Unclear risk
No information available from abstract
Unclear risk
No information available from abstract
CPR=cardiopulmonary resuscitation ROSC=restoration of spontaneous circulation CPC=cerebral performance categories HF=haemoltration ICU=intensive care unit M5=localizes painful stimuli M6=obeys commands
Characteristics of excluded studies [ordered by study ID]
Study Ballew 2002 Batista 2010 Bernard 1997 Bernard 2004
Reason for exclusion Comment Non-randomized Non-randomized, controlled study, historical controls Review
26
(Continued)
Bernard 2010 Callaway 1997 Callaway 2002 Castrejon 2009 Castrn 2010 Chanin 2002 Ebell 2002 Gwinnutt 2003 Heard 2007 Huang 2008 Kamarainen 2009 Kim 2007 Kim 2011 Kitamura 1989 Mayer 2002 Nagao 2008 Nielsen 2010a Nielsen 2011a Smith 2002 Takeda 2009 Ungerleider 1998 Ungerleider 2004 Yanagawa 1998 Zeiner 2000
Intervention or control groups did not meet the inclusion criteria Review Non-randomized Non-randomized Intervention or control groups did not meet the inclusion criteria Editorial Comment Editorial Intervention or control groups did not meet the inclusion criteria Non-randomized Intervention or control groups did not meet the inclusion criteria Intervention or control groups did not meet the inclusion criteria Non-randomized Non-randomized Summary and comment of HACA 2002 Non-randomized Ongoing study Correspondance Review Intervention or control groups did not meet the inclusion criteria Review Comment Non-randomized controlled study, historical controls Non-randomized controlled study, historical controls
27
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, randomized, parallel groups, assessor blinded clinical trial-rationale and design of the ttm-trial European multicentre trial Randomization: in-hospital 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 Therapeutic hypothermia at 33C versus normothermia at 36C. Means of cooling: 30 ml/kg of crystalloid infusion (4C or room temperature according to treatment arm) initially. Further temperature control will be at the discretion of the trial sites Cooling rate: not specied Target temperature: 33C Target temperature of control: 36C Duration of cooling: 24 hours Rewarming: not specied 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, Modied 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] November 2010 Niklas Nielsen, Helsingborgs Hospital, info@ttm-trial.org NCT01020916
Methods
Participants
Interventions
Outcomes
Starting date Contact information Notes
28
DATA AND ANALYSES
Comparison 1. Neurological outcome: cooling versus no cooling
Outcome or subgroup title 1 Good neurological outcome 1.1 Conventional cooling without extracorporal methods (IPD, best ever reached CPC of 1 or 2 during hospital stay) 1.2 Cooling with haemoltration (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)
No. of studies 5 3
No. of participants
Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size Subtotals only 1.55 [1.22, 1.96]
383
42
Risk Ratio (M-H, Fixed, 95% CI)
0.71 [0.32, 1.54]
54
4.5 [1.17, 17.30]
Comparison 2. Survival: cooling versus no cooling
Outcome or subgroup title 1 Survival 1.1 Conventional cooling without extracorporal methods (IPD, survival to discharge) 1.2 Cooling with haemoltration (no IPD, six-months survival))
No. of studies 4 3
No. of participants
Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size Subtotals only 1.35 [1.10, 1.65]
383
42
0.71 [0.32, 1.54]
29
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 n/N
Control n/N
Risk Ratio M-H,Fixed,95% CI
Weight
1 Conventional cooling without extracorporal methods (IPD, best ever reached CPC of 1 or 2 during hospital stay) Bernard 2002 HACA 2002 Hachimi-Idrissi 2001 21/43 75/136 8/16 9/34 54/137 2/17 15.3 % 81.8 % 2.9 % 1.84 [ 0.97, 3.49 ] 1.40 [ 1.08, 1.81 ] 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 haemoltration (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)

Total events: 7 (Experimental), 9 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.87 (P = 0.38)
22
20
100.0 %
0.71 [ 0.32, 1.54 ]
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
Favours no cooling
Favours cooling
30
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 n/N
Control n/N
Weight
1 Conventional cooling without extracorporal methods (IPD, survival to discharge) Bernard 2002 HACA 2002 Hachimi-Idrissi 2001 21/43 85/136 4/16 11/34 67/137 1/17 15.4 % 83.4 % 1.2 % 1.51 [ 0.85, 2.68 ] 1.28 [ 1.03, 1.58 ] 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 haemoltration (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
10
100
Favours no cooling
Favours cooling
ADDITIONAL TABLES
Table 1. Subgroup analyses
Outcome or Subgroup
Studies
Participants 383
Risk Ratio (M-H, Fixed, 95% CI) 1.54 [1.22, 1.95]
Good neurological outcome by 3 cardiac cause versus non-cardiac cause Cardiac cause Non-cardiac cause 3 2
372 11 382
1.51 [1.19, 1.91] 3.80 [0.55, 26.29] 1.56 [1.23, 1.98]
Good neurological outcome by 3 location of cardiac arrest
31
Table 1. Subgroup analyses
(Continued)
In-hospital Out-of-hospital
1 3
17 365 382
1.64 [0.47, 5.73] 1.56 [1.23, 1.99] 1.49 [1.18, 1.88]
Good neurological outcome by 3 witnessed cardiac arrest Witnessed cardiac arrest Non-witnessed cardiac arrest 3 3
360 22 382
1.43 [1.13, 1.81] 5.31 [1.40, 20.21] 1.51 [1.19, 1.91]
Good neurological outcome by 3 primary ECG rhythm VF/VT rhythm Non- VF/VT rhythm Table 2. Adverse events Outcome or Subgroup Studies 2 2
330 52
1.47 [1.15, 1.88] 2.17 [0.68, 6.93]
Participants
Risk Ratio (M-H, Fixed, 95%CI) 1.38 [0.88, 2.16] 5.11 [0.25, 105.47] 1.27 [0.90, 1.78] 1.93 [0.89, 1.78] 0.51 [0.05, 5.57] 0.88 [0.48, 1.61] 1.11 [0.41, 3.01] 1.76 [0.61, 5.12] 0.89 [0.39, 2.02] 1.21 [0.88, 1.67]
Bleeding of any severity Need for platelet transfusion Pneumonia Sepsis Pancreatitis Renal failure or oliguria Haemodialysis Pulmonary edema Seizures
1 1 1 1 1 2 2 1 1
273 273 273 273 273 303 350 273 273 315
Lethal or long lasting arrhyth- 2 mia Pressure sores 1
273
Not estimable
32
Table 2. Adverse events
(Continued)
Signicant haemorrhagic com- 1 plications Cardiac complications Hypokalaemia Hypophosphataemia Table 3. Sensitivity analysis 1 1 1
77
Not estimable
77 42 42
0.16 [0.01, 3.21] 0.91 [0.31, 2.68] 1.12 [0.65, 2.25]
Outcome or Subgroup
Studies
Participants
Risk Ratio (M-H, Fixed, 95%CI) 1.55 [1.24, 1.94]
Good neurological outcome all 5 studies Studies with conventional cool- 2 ing and adequate allocation concealment Studies with conventional cool- 1 ing and inadequate or unknown allocation concealment Studies with other cooling 1 methods and adequate allocation concealment Studies with other cooling 1 method and inadequate or unknown allocation concealment
479
306
1.50 [1.16, 1.93]
77
1.84 [0.97, 3.49]
42
0.71 [0.32, 1.54]
54
4.50 [1.17, 17.30]
33
APPENDICES 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 articial or induced or extracorporeal) near hypothermia) #14 articial 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 articial or induced or extracorporeal) adj3 hypothermia).mp. or articial 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 randomly.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 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 ((resuscitative or therapeutic or articial or induced or extracorporeal) adj3 hypothermia).mp. or articial 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. (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
34
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 articial or induced or extracorporeal) and hypothermia) ) OR articial 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 articial or induced or extracorporeal) adj3 hypothermia) or articial hibernation or body cooling or chilling or refrigeration anesthesia).mp. or body temperature.ti,ab. or refrigeration.ti,ab. 3. 1 and 2
35
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 brillation ventricular tachycardia asystole pulseless electrical activity Quality Intention-to-treat: yes no if unclear, please explain
Allocation concealment A. adequate B. unclear C. inadequate
Outcome assessor Outcome assessor blind blind yes yes no no if unclear, if unclear, please explain please explain
Groups comparable: yes if not, please specify
Follow-up > 80% of randomized patients: yes if not, please specify Time from restoration of spontaneous circulation to target temperature:
36
Intervention
Type of intervention:
Controls:
(Continued)
Cooling rate:
Duration of cooling: Time point Funding of assessment of outcome measures: .. .. .. .. .. ..
Rewarming:
Outcomes
Types of outcome measures: .. .. .. .. .. ..
Notes
Results primary:
Type of outcome: Cooling Events (n) Total (N) No cooling Events (n) Total (N)
Results secondary:
Type of outcome: Cooling Events (n) Total (N) No cooling Events (n) Total (N)
37
WHATS NEW
Last assessed as up-to-date: 25 July 2011.
Date 31 July 2012
Event New search has been performed
Description This review is an update of the previous Cochrane systematic 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 ndings 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.
HISTORY
Protocol rst published: Issue 2, 2003 Review rst published: Issue 4, 2009
Date 28 June 2010 29 October 2009
Event Amended Amended
Description Contact details updated Typo corrected in co-authors address (Mllner)
CONTRIBUTIONS OF AUTHORS
Conceiving the review and update: Harald Herkner (HH), Michael Holzer (MH), Marcus Mllner (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
DECLARATIONS OF INTEREST
The Medical University of Vienna received an unrestricted scientic grant from Alsius Corporation for an independent scientic project, which was used for nancing the post of Jasmin Arrich. Michael Holzer received travel grants for scientic conferences from Alsius Corporation and Kinetic Concepts, Inc (KCI) and honoraria for lectures from Medivance and KCI. He is a member of the scientic advisory board of KCI. Marcus Mllner, Michael Holzer and Christof Havel were involved in the design, conduct and publication of the HACA 2002 trial. Harald Herkner has no conicts of interest.
SOURCES OF SUPPORT Internal sources

Medical University of Vienna, Austria.
39
External sources
No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

In our protocol we aimed to include additional endpoints like the six month and nal 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 nal neurologic outcome (Bernard 2002; HACA 2002; Hachimi-Idrissi 2001). In our opinion the best neurological score during hospital stay is superior to the nal score as the nal score may be inuenced 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 neuroprotection in adults after cardiopulmonary resuscitation.
INDEX TERMS 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
40

Therapeutic Hypothermia For Neuroprotection Post CPR

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Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review)

Arrich J, Holzer M, Havel C, Mllner M, Herkner H

Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation

Description of the condition

Why it is important to do this review

Description of the intervention

How the intervention might work

Criteria for considering studies for this review

Search methods for identication of studies

Data collection and analysis

Figure 1. Study ow diagram.

See table Characteristics of included studies.

See table Characteristics of excluded studies.

Risk of bias in included studies

Selective reporting There was no indication of selective outcome reporting.

Survival at six months and long-term We found no data on this outcome.

Cost-effectiveness We found no data on this outcome.

Good neurologic outcome

Summary of main results

Overall completeness and applicability of evidence

Potential biases in the review process

Quality of the evidence

Implications for research

Agreements and disagreements with other studies or reviews

AUTHORS CONCLUSIONS Implications for practice

References to studies included in this review

References to studies excluded from this review

References to ongoing studies

References to other published versions of this review

Characteristics of included studies [ordered by study ID]

Notes Risk of bias Bias

Support for judgement Odd and even days

Odd and even days Outcome assessment blinded

Incomplete outcome data (attrition bias) All outcomes Other bias

No other major biases seen

Risk of bias Bias Authors judgement Support for judgement

Support for judgement

Risk of bias Bias Authors judgement Support for judgement

No information available from abstract No information available from abstract

No information available from abstract

No information available from abstract

Characteristics of excluded studies [ordered by study ID]

Study Ballew 2002 Batista 2010 Bernard 1997 Bernard 2004

Characteristics of ongoing studies [ordered by study ID]

Starting date Contact information Notes

DATA AND ANALYSES

Comparison 1. Neurological outcome: cooling versus no cooling

Effect size Subtotals only 1.55 [1.22, 1.96]

Risk Ratio (M-H, Fixed, 95% CI)

0.71 [0.32, 1.54]

Risk Ratio (M-H, Fixed, 95% CI)

4.5 [1.17, 17.30]

Comparison 2. Survival: cooling versus no cooling

Effect size Subtotals only 1.35 [1.10, 1.65]

Risk Ratio (M-H, Fixed, 95% CI)

0.71 [0.32, 1.54]

Risk Ratio M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

Subtotal (95% CI)

1.55 [ 1.22, 1.96 ]

Subtotal (95% CI)

0.71 [ 0.32, 1.54 ]

Subtotal (95% CI)