Continuing Medical Education Activity in Academic Emergency Medicine CME Editor: Hal Thomas, MD Authors: Benton R. Hunter, MD, Daniel P. O’Donnell, MD, Kacy L. Allgood, MLS, and Rawle A. Seupaul, MD Article Title: No Benefit to Prehospital Initiation of Therapeutic Hypothermia in Out-of-hospital Cardiac Arrest: A Systematic Review and Meta-analysis If you wish to receive free CME credit for this activity, please refer to the website:

Accreditation and Designation Statement: Blackwell Futura Media Services designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Educational Objectives After completing this exercise the participant will be better able to identify the role of therapeutic hypothermia (TH) in patients with out-of-hospital cardiac arrest (OHCA). Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. Faculty Disclosures: CME editor – Hal Thomas, MD: No relevant financial relationships to disclose. Authors: Benton R. Hunter, MD, Daniel P. O’Donnell, MD, Kacy L. Allgood, MLS, and Rawle A. Seupaul, MD: No relevant financial relationships to disclose. This manuscript underwent peer review in line with the standards of editorial integrity and publication ethics maintained by Academic Emergency Medicine. The peer reviewers have no relevant financial relationships. The peer review process for Academic Emergency Medicine is double-blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review.

Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’s Policy on Activity Disclosure and Conflict of Interest. No relevant financial relationships exist for any individual in control of the content and therefore there were no conflicts to resolve. Instructions on Receiving Free CME Credit For information on applicability and acceptance of CME credit for this activity, please consult your professional licensing board. This activity is designed to be completed within an hour; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial publication. Follow these steps to earn credit: • Log on to • Read the target audience, educational objectives, and activity disclosures. • Read the article in print or online format. • Reflect on the article. • Access the CME Exam, and choose the best answer to each question. • Complete the required evaluation component of the activity. This activity will be available for CME credit for twelve months following its publication date. At that time, it will be reviewed and potentially updated and extended for an additional twelve months.


No Benefit to Prehospital Initiation of Therapeutic Hypothermia in Out-of-hospital Cardiac Arrest: A Systematic Review and Meta-analysis Benton R. Hunter, MD, Daniel P. O’Donnell, MD, Kacy L. Allgood, MLS, and Rawle A. Seupaul, MD

Abstract Objectives: The aim of this review was to define the effect of prehospital therapeutic hypothermia (TH) on survival and neurologic recovery in patients who have suffered out-of-hospital cardiac arrest (OHCA). Methods: Included in this review are randomized trials assessing the effect of prehospital TH in adult patients suffering nontraumatic OHCA. Trials assessing the effect of in-hospital TH were excluded. Only studies with a low risk of bias were eligible for meta-analysis. A medical librarian searched PubMed, Ovid, EMBASE, Ovid Global Health, the Cochrane Library,, EM Association Websites, CenterWatch, IFPMA Clinical Trial Results Portal, CINAHL, ProQuest, and the Emergency Medical Abstracts Database without language restrictions. was searched for unpublished studies. Bibliographies were hand searched and experts in the field were queried about other published or unpublished trials. Using standardized forms, two authors independently extracted data from all included trials. Results from high-quality trials were pooled using a random-effects model. Two authors, using the Cochrane risk of bias tool, assessed risk of bias independently. Results: Of 740 citations, six trials met inclusion criteria. Four trials were at a low risk of bias and were included in the meta-analysis (N = 715 patients). Pooled analysis of these trials revealed no difference in overall survival (relative risk [RR] = 0.98, 95% CI = 0.79 to 1.21) or good neurologic outcome (RR = 0.96, 95% CI = 0.76 to 1.22) between patients randomized to prehospital TH versus standard therapy. Heterogeneity was low for both survival and neurologic outcome (I2 = 0). Conclusions: Randomized trial data demonstrate no important patient benefit from prehospital initiation of TH. Pending the results of ongoing larger trials, resources dedicated to this intervention may be better spent elsewhere. ACADEMIC EMERGENCY MEDICINE 2014;21:356–364 © 2014 by the Society for Academic Emergency Medicine


ut-of-hospital cardiac arrest (OHCA) is a major public health issue. The American Heart Association (AHA) estimates that approximately 360,000 episodes of OHCA occur each year in the United States,1 with 60% treated by emergency medical

services (EMS).1,2 Similarly, the estimated incidence of EMS-treated OHCA in Europe is 275,000 annually.3 The overall survival of EMS-treated OHCA in adults is estimated to be 9.5%.1 Of those who survive to hospital discharge, the proportion of patients who survive with

From the Department of Emergency Medicine, Indiana University School of Medicine (BRH, DPO), Indianapolis, IN; the Division of Out of Hospital Care, Department of Emergency Services, Indiana University (KLA), Indianapolis, IN; and the Department of Emergency Medicine, University of Arkansas for Medical Sciences (RAS), Little Rock, AR. Received September 17, 2013; revision received November 4, 2013; accepted November 10, 2013. Presented at the Society for Academic Emergency Medicine Annual Meeting, Atlanta, GA, May 2013. There was no financial support from any source related to this manuscript. The authors have no potential conflicts of interest to report. Supervising Editor: Alan Jones, MD. Address for correspondence and reprints: Benton R. Hunter, MD; e-mail: [email protected].


ISSN 1069-6563 PII ISSN 1069-6563583

© 2014 by the Society for Academic Emergency Medicine doi: 10.1111/acem.12342

ACADEMIC EMERGENCY MEDICINE • April 2014, Vol. 21, No. 4 •

good neurologic function (Cerebral Performance Category [CPC] ≤ 2) ranges from 70% to 90%.4 With such dismal outcomes, resuscitation science continues to focus on finding interventions to improve survival and neurologic function after OHCA. Therapeutic hypothermia (TH) has been shown, in randomized trials, to increase both survival and favorable neurologic outcomes in patients suffering from OHCA.5–7 These trials have led the International Liaison Committee on Resuscitation to recommend adoption of TH for patients resuscitated after OHCA.8 While in-hospital TH provides proven benefit, it is unclear if initiating this intervention earlier would further improve outcomes. Animal studies suggest that the benefits of TH diminish over time if cooling is delayed.9–12 This has led to interest in achieving TH earlier after OHCA, specifically in the prehospital setting. Several small nonrandomized trials have demonstrated that initiating TH in the prehospital setting is feasible and safe.13–18 However, randomized trials have been underpowered to detect differences in clinically relevant outcomes.19,20 Despite this uncertainty, many EMS systems have implemented TH strategies.21 The goal of this systematic review and meta-analysis is to define the effect of prehospital TH on both survival and neurologic recovery in patients who have suffered OHCA. METHODS Study Design This was a systematic review and meta-analysis. It conforms to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Search Strategy A medical librarian (KA) searched the medical literature from 1946 through December 2012 using the search terms outlined in Appendix A. PubMed, Ovid, EMBASE, Ovid Global Health, the Cochrane Library,, EM Association Web sites, CenterWatch, IFPMA Clinical Trial Results Portal, CINAHL, ProQuest, and the Emergency Medical Abstracts database were searched without language restriction. was searched for unpublished studies. Experts in the field were queried and bibliographies of relevant trials and reviews were hand searched to identify additional published or unpublished trial data. All titles and abstracts identified by the search were independently screened by two authors (RS, BH) for relevance. The full text of all potentially relevant trials was reviewed for inclusion. Disagreements were settled by consensus or adjudication by a third author (DO). Inclusion and Exclusion Criteria All randomized, cluster-randomized, or quasi-randomized trials comparing prehospital TH to standard prehospital care without TH in adult humans were included in this systematic review. “Prehospital TH” was defined as any active intervention aimed at lowering the body temperature of patients prior to hospital arrival. Any method of cooling was accepted. OHCA was defined as any nonperfusing cardiac rhythm occurring in a patient


not already in or admitted to a hospital. To be included, trials had to report survival to hospital discharge, 28 days, or any period longer than 28 days after cardiac arrest. Nonrandomized trials, studies of traumatic cardiac arrest, pediatric arrest, and in-hospital arrest were excluded. Studies that randomized patients to in-hospital TH versus no in-hospital TH were also excluded. While all trials meeting the inclusion criteria and no exclusion criteria are included in the review, only trials with a low risk of bias were eligible to be included in the statistical meta-analysis. Individual Study Quality Appraisal Two authors (RS, BH) independently assessed the risk of bias of included trials using standard criteria defined in the Cochrane Handbook for Systematic Reviews of Interventions.22 This validated instrument for appraising randomized trials measures risk of bias in seven categories: 1) adequate random sequence generation, 2) allocation concealment, 3) blinding of participants and personnel, 4) blinding of outcome assessment, 5) incomplete outcome data, 6) selective reporting, and 7) other bias. Each trial is described as having a high, low, or unclear risk of bias in each of the seven domains. Discrepancies were resolved by discussion or adjudication by a third author (DO). Data Abstraction Two authors (RS, BH) independently abstracted data using standardized forms. Data abstraction included study design, method of cooling, inclusion and exclusion criteria, number of patients randomized to each arm of the study, number of patients who survived in each arm of the study, and any patients randomized who were not accounted for in the results. Neurologic outcome data, how it was assessed, and number of patients in each group with a “good neurologic outcome” were also abstracted. Additionally, we recorded information regarding known predictors of outcome in cardiac arrest patients: presenting rhythm (ventricular fibrillation [VF] vs. pulseless electrical activity [PEA]/ asystole), witnessed arrest, bystander cardiopulmonary resuscitation (CPR), and whether or not patients were cooled in hospital. Outcomes The primary outcome was survival to hospital discharge or any point at least 28 days postarrest. If survival at discharge and at 28+ days was reported, then whichever endpoint came first was used. The secondary outcome was good neurologic outcome, defined as a score of ≤2 for any of the following metrics: CPC score, overall performance category, or the modified Rankin score. If one of these validated metrics was not reported, reasonably defined good neurologic outcome by the individual study authors was accepted (e.g., discharged to home/acute rehabilitation vs. discharged to long term care facility or death). We defined, a priori, two subgroups for analysis: patients with a presenting rhythm of VF and those with PEA/asystole. Data Analysis Only trials with a low risk of bias were eligible for meta-analysis (StatsDirect Version 2.7.9, StatsDirect Ltd,



Cheshire, UK). Heterogeneity was assessed using the I2 statistic23 and the chi-square test. Data were pooled if statistical heterogeneity was low (I2 < 50%). Dichotomous variables were reported as relative risks (RRs) with 95% confidence intervals (CIs). Data were pooled using a random-effects model with sensitivity analyses performed if significant clinical heterogeneity was suspected. RESULTS Search Results The search identified 740 unique publications. After screening titles and abstracts, 29 full-text articles were reviewed, of which six24–29 met inclusion criteria (see Figure 1). Hand searching reference lists and contacting experts in the field did not reveal additional data. No unpublished trials fitting our inclusion criteria were identified. Risk of Bias of Included Studies Risk of bias for the six included trials is summarized in Table 1.24–29 Study quality was variable and is described below. Regarding sequence generation and allocation concealment, four studies24,25,27,29 were low risk of bias, while two trials26,28 gave no description and were scored as having an unclear risk of bias. Because it was not possible to blind medical personnel to treatment assignment (and no attempts were made to do so), this domain was scored as a high risk of bias for all trials. Blinding for the assessment of survival was deemed unnecessary; hence all of the included studies were graded as low risk of bias for this outcome. With respect to neurologic outcome, Callaway et al.26 was

1,118 articles identiied by search

378 duplicate articles removed

740 original articles identiied by search

711 articles excluded after review of titles and abstracts

29 full text articles reviewed for inclusion

23 articles removed (did not meet inclusion criteria)

6 randomized trials included in review

2 trials excluded from analysis (high risk of bias)

4 randomized trials included in primary

Figure 1. Study selection process.

similarly scored as low risk, since no patients survived, providing an objectively poor neurologic outcome for all patients. Both studies by Bernard et al.24,25 were considered to be at low risk of bias for blinding of outcome assessment, while Castren et al.27 was graded as high risk based on the admission by the authors that the “assessment may not always have been performed by an individual blinded to the treatment group.”27 The remaining trials were unclear risk28 or did not report neurologic outcomes.29 Risk of bias for incomplete outcome data was low for four studies24,25,27,29 and high for two.26,28 All studies except Kim et al.,29 which did not report neurologic outcomes, were at low risk of bias for selective outcome reporting. We assessed all studies for “other risk of bias.” Both studies by Bernard et al.24,25 were graded as high risk because they were stopped early due to futility of their 2010 study.24 The study by Castren et al.27 was at unclear risk of bias in that there was participation in the study design, data analysis, and writing of the manuscript by the corporate sponsor. Callaway et al. had a high risk for other bias because their protocol called for cessation of cooling if return of spontaneous circulation (ROSC) was achieved, body temperature of intervention patients was not effectively lowered, and the intervention and control groups appeared prognostically dissimilar at the start of the trial.26 The remaining trials28,29 were at low risk for other bias. Results of Individual Studies and Meta-analysis Methods and results of the included trials are summarized in Table 2. Inclusion and exclusion criteria were generally consistent across studies, with the exception of initial cardiac rhythm (VF vs. non-VF). The most common method of cooling was cold saline infusion.24,25,28,29 Four of the six trials began cooling after ROSC,24,25,28,29 while two trials initiated TH intraarrest.26,27 None of the six trials found a statistically significant difference in survival or neurologic outcomes between patients randomized to prehospital TH versus controls. There were no significant differences between the intervention and control groups in terms of presenting rhythm, bystander CPR, or witnessed arrest, although these were not reported consistently across studies. After quality assessment, four trials24,25,27,29 were deemed to have a low risk of bias and were included in the meta-analysis. The two excluded studies26,28 had poorly defined methods of randomization and allocation concealment, as well as an excessive number of patients lost to follow-up. Each of the four trials included in the pooled analysis24,25,27,29 demonstrated a statistically significant difference in average temperature between intervention patients and controls (–0.8 to –1.3°C). The average temperature at hospital arrival of intervention patients in the four trials was 34.2 to 34.7°C. Pooled analysis of the four trials revealed no significant difference in overall survival (RR = 0.98, 95% CI = 0.79 to 1.21) or good neurologic outcome (RR = 0.96, 95% CI = 0.76 to 1.22) between patients randomized to prehospital TH versus standard therapy (Figure 2). Heterogeneity was low for both survival and good neurologic outcome (I2 = 0).

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Table 1 Risk of Bias of Included Studies


Sequence Generation

Allocation Concealment

Blinding of Participants

Blinding of Outcome Assessors (Mortality)

Bernard24 Bernard25 Castren26 Callaway27 € ma € ra €inen28 Ka Kim29

Low Low Low Unclear Unclear Low

Low Low Low Unclear Unclear Low

High High High High High High

Low Low Low Low Low Low

Blinding of Outcome Assessors (Neurologic)

Incomplete Outcome Data

Selective Outcome Reporting

Other Bias

Low Low High Low Unclear NR

Low Low Low High High Low

Low Low Low Low Low High

High High Unclear High Low Low

NR = study did not report neurologic outcomes

Prespecified subgroup analyses also revealed no differences between groups (Figure 3). Survival data were available from three trials24,27,29 (n = 344) for patients suffering VF arrests (RR = 1.05, 95% CI = 0.77 to 1.44, I2 = 30.8%). Two trials24,27 (n = 293) reported neurologic outcomes for patients with VF arrests (RR = 1.00, 95% CI = 0.65 to 1.52). Three trials25,27,29 (n = 372) addressed survival in patients suffering non-VF arrests (RR = 0.95, 95% CI = 0.35 to 2.57, I2 = 46.8%). Neurologic outcomes were reported for non-VF patients in two trials25,27 (n = 298; RR = 1.30, 95% CI = 0.59 to 2.88). DISCUSSION There is a growing body of literature examining prehospital TH. We identified six randomized trials,24–29 including four high-quality studies24,25,27,29 (total patients N = 715), assessing the impact of prehospital TH on survival in patients suffering from OHCA. Consistent with the pooled analysis, none of the identified trials demonstrated a statistically significant survival or neurologic outcome benefit. The prehospital treatment of OHCA continues to evolve. While animal studies9–12 suggest that the benefit of TH diminishes over time with delays in cooling, human observational studies have not demonstrated any consistent effect of delays in achieving TH.30–35 This uncertainty has led to an interest in studying early initiation of TH in the prehospital setting, in the hopes that it might provide added benefit. In the past 10 years, several nonrandomized studies have demonstrated the feasibility and safety of TH in the prehospital setting.13–18 The first randomized trial, performed by Callaway et al.,26 demonstrated no difference in temperature or survival when applying ice bags around the heads of OHCA victims. In 2007, Kim et al.29 were able to effectively decrease the body temperature of patients after OHCA for the first time in a prehospital randomized trial, but did not find differences in mortality between groups. Despite showing statistical differences in temperature at hospital arrival between intervention and control patients, subsequent randomized trials24,25,27,28 have been unable to demonstrate any statistically significant benefit in survival or neurologic outcomes. It is unclear why prehospital TH has not been shown to augment the strong evidence supporting in-hospital

TH for OHCA patients after ROSC.6,7 It is possible that current randomized trials have failed to find benefit due to inability to achieve meaningful decreases in core temperature in the short time period prior to hospital arrival. Variability in application of in-hospital TH after prehospital initiation is another possible explanation. Absent these potential shortcomings in existing trials, it is also possible that prehospital TH has not proven beneficial because short decreases in the time to initiation or achievement of TH do not provide clinically meaningful benefit. If TH is not continued in hospital after prehospital initiation, no benefit would be expected. Three of the four trials24,25,27 included in this meta-analysis followed protocols for in-hospital TH for all enrolled patients, and exclusion of the trial that did not29 had no appreciable effect on the pooled results. This makes variability between in-hospital therapies an unlikely explanation for the lack of benefit demonstrated in the meta-analysis. In the studies included in our meta-analysis,24,25,27,29 the difference in average temperature upon ED arrival between patients cooled in the field and controls was modest, ranging from –0.8 to –1.3°C. None of these trials achieved an average temperature of 32 to 34°C in intervention patients prior to ED arrival. More rapid and effective means of cooling in the field, and the subsequent effect on patient outcomes, is an area for further research. What this review and meta-analysis does demonstrate, however, is that using currently available methods for inducing TH in the prehospital setting modestly decreases average temperature at ED arrival, without any evidence of improvement in patient-important outcomes. The intuitive benefit of prehospital TH is based on the assumption that earlier initiation of TH, with earlier time to target temperature, improves outcomes. Unfortunately, this assumption has not been proven in human trials. There are conflicting results from comparative studies in humans undergoing TH, all of which are observational.30–35 A small trial (n = 49) in 2009 by Wolff et al.35 found an independent association between shorter time to coldest temperature and CPC score of ≤2, although there was no association with either time to TH initiation or time to target temperature. That same year, Nielsen et al.32 reported on a much larger cohort (n = 986) and found no association between time

Adults, witnessed arrest, < 20 min collapse to EMS arrival

Castren27 2010

Adults with ROSC, intubated, unresponsive

Trauma, hypothermic

Trauma, pregnancy, overdose, GCS > 5

Trauma, CVA, overdose, electrocution, asphyxia, hypothermic, nasal obstruction

Trauma, drug-induced arrest, hypothermic

Trauma, pregnancy, dependent before arrest, hypothermic, not intubated Trauma, pregnancy, dependent before arrest, hypothermic, not intubated









Infusion of ice cold normal saline

Infusion of ice cold Ringer’s acetate

Intranasal coolant delivered via catheter

Infusion of ice cold lactated Ringer’s solution Infusion of ice cold lactated Ringer’s solution Ice bags applied to head/neck†

Method of Cooling

After ROSC

After ROSC



After ROSC

After ROSC

Timing of Cooling

Not reported

1.15 (0.68–1.94)

0.86 (0.40–1.82)

1.15 (0.59–2.35)

CPC ≤ 2

CPC ≤ 2

No survivors in either group

1.55 (0.65- 3.72)

0.89 (0.69–1.15)

RR* Survival (95% CI)

Not reported (all patients died)

Released to home or acute rehab (vs. long-term care/death) Released to home or acute rehab (vs. longterm care/death)

Definition of Good “Neurologic Good Outcome”

Not reported

0.86 (0.40–1.82)

1.32 (0.59–2.99)

No survivors in either group

1.41 (0.58–3.44)

0.90 (0.70–1.17)

RR* Good Neurologic Outcome (95% CI)

Patients were rewarmed if ROSC was achieved, no in-hospital cooling mentioned “Patients in both groups were cooled in the hospital according to institutional standards.” At discretion of treating physicians. All involved hospitals had policy of cooling VF patients. No universal protocol. At least one participating hospital had a 24 hour cooling protocol, others did not.

All patients in both groups cooled in hospital for 24 hours. All patients in both groups cooled in hospital for 24 hours.

Cooling at Hospital Arrival

CPC = Cerebral Performance Category; CVA = cerebrovascular accident; GCS = Glasgow Coma Scale score; ROSC = return of spontaneous circulation; RR = relative risk; GCS = Glasgow Coma Scale score; VF = ventricular fibrillation. *RR for survival or good neurologic outcome in intervention group compared to controls †Hypothermia not achieved.

Kim29 2007

€ ma € ra €inen28 Ka 2009

Adults, arrest > 9 min, ROSC, sBP > 100 mm Hg

Arrest with CPR in progress

Callaway26 2002

Bernard25 2012

Adults with ROSC after VF arrest > 10 min, sBP > 90 mm Hg Adults with ROSC after non-VF arrest > 10 min, sBP > 90 mm Hg


Bernard24 2010


Table 2 Methods and Results of Included Studies


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Figure 2. Primary and secondary outcomes. (A) Overall survival. (B) Overall good neurologic outcome.





Figure 3. Subgroup analyses according to initial rhythm. (A) Non-VF good neurologic outcome. (B) Non-VF survival. (C) VF survival. (D) VF good neurologic outcome. VF = ventricular fibrillation.

to initiation or time to target temperature and patient outcomes. Mooney et al.,34 in 2011, reported a 20% increase in mortality for every hour delay in TH initiation among 140 patients. The ICE study group, however, found a significant independent association between early initiation of TH and increased mortality

in their cohort of 121 Italian patients.33 Similarly, Haugk et al.31 found improved survival (adjusted odds ratio of 1.86) among 588 patients to be independently associated with longer time to target temperature. While the results of the above studies show only associations, and not causality, there is no convincing evidence that very



early TH offers additive benefit over slightly delayed TH. It is also noteworthy that the median time to target temperature for patients randomized to TH in the Hypothermia After Cardiac Arrest trial7 was relatively long, at 8 hours. Even if earlier initiation of TH does prove to be beneficial, there remains the possibility that with short transport times, the time lapse associated with delaying TH until hospital arrival is not long enough to measurably affect patient outcomes. Despite disappointing results from existing randomized trials, prehospital TH has been instituted in many settings around the world.21 These programs may require significant resources in the form of purchasing and maintaining equipment, training personnel, and quality assurance. Proponents of prehospital TH suggest that the initiation of TH in the prehospital setting ensures that cooling will be continued after hospital arrival. Unfortunately, there is no evidence from randomized trials to either support or refute that assumption. It should be noted that the CIs around our point estimate of effect are not narrow enough to exclude a clinically meaningful benefit or harm. The results of this meta-analysis were largely driven by a single study,24 in which prehospital TH trended toward harm. While it seems unlikely that prehospital TH would be truly harmful, the potential exists. Prehospital providers focused on achieving TH may pay less attention to other details (e.g., arrhythmia management or continuous pulse checks) that are more important for patient survival. Kim et al.36 recently published a high-quality trial in which 1359 OHCA patients were randomized to prehospital TH versus standard prehospital care. All patients were cooled in hospital. Unfortunately, the study was published after our meta-analysis was completed, but the results of this much larger study (RR for hospital survival = 1.01, 95% CI = 0.88–1.16) are nearly identical to the results found by our meta-analysis. Future studies37,38 will investigate whether or not intraarrest initiation of TH offers some benefit not found when TH is started after ROSC. These studies will be conducted in environments with standardized in-hospital TH and will be powered to find even small differences in outcomes between intervention and control patients. There are two large randomized trials of prehospital intraarrest TH currently under way.37,38 Most of the data in the current meta-analysis were obtained from trials evaluating prehospital initiation of TH after ROSC (n = 522).24,25,29 The recent trial by Kim36 similarly enrolled patients after ROSC had been obtained. Currently there are little available data on the effect of intraarrest TH, with Castren et al.27 being the only randomized controlled trial that has achieved intraarrest TH in the prehospital setting. While the results of Castren et al. are similar to those of the trials that began TH after ROSC,24,25,29 there remains the possibility that intraarrest TH may result in clinical benefits not realized with post-ROSC cooling. Svensson et al.37 are currently planning to enroll 900 patients in a randomized trial in which intervention patients will be cooled intraarrest using similar methods to those employed in the study by Castren et al.27 Additionally, the multicenter RINSE study38 is aiming to enroll 2,500 OHCA victims who will

be randomized to intraarrest cooling with chilled saline versus standard prehospital care. These large trials should provide valuable information regarding the clinical utility of prehospital intraarrest cooling. LIMITATIONS This systematic review and meta-analysis may have several important limitations. None of the included studies blinded health care workers to treatment assignment. While this may not have been possible, it could have introduced bias in the form of discrepant cointerventions. Aside from the lack of blinding, the four studies included in our primary analysis24,25,27,29 were at a low risk of bias. While results across trials were consistent (I2 = 0), there were important methodologic differences between studies. The primary differences were initial cardiac rhythm and method and timing of cooling. While two trials27,29 included patients with any rhythm after OHCA, a single study included only patients with VF arrest,24 and another included only patients with nonVF arrest.25 Because patients suffering VF arrests have higher survival rates,27,29,39 the trial by Bernard et al.24 disproportionately influenced the pooled results. After a sensitivity analysis excluding this trial was performed, however, there remained no statistically significant differences in outcomes. Of the four studies included in the primary analysis, three used chilled saline infusion24,25,29 to cool patients after ROSC. Castren et al. however, relied on coolant infused via an intranasal catheter to cool patients. Castren et al.27 was also the only one of the four trials to begin the cooling process intraarrest, as opposed to after ROSC. Despite these differences, the findings of Castren et al. were consistent with the other included trials. It is unclear what effect, if any, these differences would have on patient outcomes. Perhaps even more important than between-study differences in methods of prehospital cooling are the differences between studies in terms of cooling after hospital arrival. Prehospital TH would not be expected to provide any clinically important benefit if cooling is not appropriately continued in hospital. In both studies by Bernard et al.,24,25 all patients in both groups were cooled in-hospital for 24 hours, and the trial by Castren et al.27 states that all patients in both groups were “cooled in the hospital according to institutional standards.” However, Kim et al.29 reported that some receiving hospitals had policies calling for in-hospital TH, while others did not. There was no universal protocol for in-hospital cooling applied to study participants, and the authors were not able to provide information on in-hospital utilization of TH. A sensitivity analysis excluding the trial of Kim et al. did not significantly change the results of the meta-analysis. Callaway et al.26 called for rewarming after ROSC had been achieved, and Kamarainen et al.28 left in-hospital cooling up to the treating physicians. These latter two studies26,28 were not included in the meta-analysis. Lastly, all of the included studies were performed at large urban centers with short transport times and may not be generalizable to prehospital settings with longer transport times.

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CONCLUSIONS Analysis of available randomized trial data demonstrates no benefit from prehospital therapeutic hypothermia on either mortality or neurologic outcome in patients suffering from out-of-hospital cardiac arrest. Additionally, no benefit has been demonstrated in any subgroup of patients. Ongoing trials will help determine whether initiation of therapeutic hypothermia during the intraarrest period offers beneficial effects not provided by therapeutic hypothermia begun after return of spontaneous circulation.




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No benefit to prehospital initiation of therapeutic hypothermia in out-of-hospital cardiac arrest: a systematic review and meta-analysis.

The aim of this review was to define the effect of prehospital therapeutic hypothermia (TH) on survival and neurologic recovery in patients who have s...
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