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|Year : 2016
: 19 | Issue : 1 | Page
|Mild therapeutic hypothermia in patients resuscitated from out-of-hospital cardiac arrest: A meta-analysis of randomized controlled trials
Pedro A Villablanca1, Mohammed Makkiya2, Evann Einsenberg1, David F Briceno1, Christia Panagiota3, Mark Menegus1, Mario Garcia1, Daniel Sims1, Harish Ramakrishna4
1 Montefiore Medical Center/Albert Einstein College of Medicine, Division of Cardiovascular Diseases, Bronx, New York, USA
2 Montefiore Medical Center/ Albert Einstein College of Medicine, Department of Medicine, Bronx, New York, USA
3 Jacobi Medical Center/Albert Einstein College of Medicine, Department of Medicine, Bronx, New York, USA
4 Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, Arizona, USA
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|Date of Submission||16-Oct-2015|
|Date of Decision||08-Jan-2016|
|Date of Acceptance||30-Nov-2015|
|Date of Web Publication||31-Dec-2015|
| Abstract|| |
Aims: Guidelines recommend mild therapeutic hypothermia (MTH) for survivors of out-of-hospital cardiac arrest (OHCA). However, there is little literature demonstrating a survival benefit. We performed a meta-analysis of randomized controlled trials (RCTs) assessing the efficacy of MTH in patients successfully resuscitated from OHCA. Materials and Methods: Electronic databases were searched for RCT involving MTH in survivors of OHCA, and the results were put through a meta-analysis. The primary endpoint was all-cause mortality, and the secondary endpoint was favorable neurological function. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using the Mantel-Haenszel method. A fixed-effect model was used and, if heterogeneity (I2 ) was >40, effects were analyzed using a random model. Results: Six RCT (n = 1400 patients) were included. Overall survival was 50.7%, and favorable neurological recovery was 45.5%. Pooled data demonstrated no significant all-cause mortality (OR, 0.81; 95% CI 0.55-1.21) or neurological recovery (OR, 0.77; 95% CI 0.47-1.24). No evidence of publication bias was observed. Conclusion: This meta-analysis demonstrated that MTH did not confer benefit on overall survival rate and neurological recovery in patients resuscitated from OHCA.
Keywords: Cardiac arrest; Meta-analysis; Therapeutic hypothermia
|How to cite this article:|
Villablanca PA, Makkiya M, Einsenberg E, Briceno DF, Panagiota C, Menegus M, Garcia M, Sims D, Ramakrishna H. Mild therapeutic hypothermia in patients resuscitated from out-of-hospital cardiac arrest: A meta-analysis of randomized controlled trials. Ann Card Anaesth 2016;19:4-14
|How to cite this URL:|
Villablanca PA, Makkiya M, Einsenberg E, Briceno DF, Panagiota C, Menegus M, Garcia M, Sims D, Ramakrishna H. Mild therapeutic hypothermia in patients resuscitated from out-of-hospital cardiac arrest: A meta-analysis of randomized controlled trials. Ann Card Anaesth [serial online] 2016 [cited 2019 Nov 18];19:4-14. Available from: http://www.annals.in/text.asp?2016/19/1/4/173013
| Introduction|| |
Out-of-hospital cardiac arrest (OHCA) is a significant problem worldwide, with an estimated rate of 36-128/100,000 patients and a mortality rate of approximately 65-95%.  In the United States alone, approximately, 424,000 people utilize emergency medical service assessment for OHCA each year.  Most of these patients are at high risk for death and poor neurological function. 
In 2002, two landmark randomized controlled trials (RCTs) were published that demonstrated the efficacy of mild therapeutic hypothermia (MTH) in comatose survivors after OHCA by decreasing mortality and improving neurologic outcomes. , Since then, numerous studies, mostly meta-analyses and retrospectives reviews, ,,, supported MTH. The 2015 American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care and the International Liaison Committee on Resuscitation (ILCOR) recommend using MTH. They propose a core temperature goal of 32-34°C for unconscious adult patients with return of spontaneous circulation (ROSC) after witnessed out-of-hospital ventricular fibrillation arrest (strong recommendation, low-quality evidence) and nonventricular fibrillation and in-hospital cardiac arrest (CA) (weak recommendation, very low-quality evidence), for at least 24 h (strong recommendation, moderate-quality evidence).  Despite these recommendations, some investigators argue that the evidence of the early randomized trials has revealed conflicting results, have low power and limited methodology; moreover, a recent publication by Nielsen et al.  challenged the role of MTH in OHCA, demonstrating that normothermia (36°C) results in similar outcomes to MTH. With this new information and the potentially unfavorable side effects reported with hypothermia, ,,, further analyses are warranted assessing the efficacy of MTH therapy on post-CA mortality and neurological outcome. With this in mind, we conducted a systematic review of literature and subsequent meta-analysis investigating the efficacy of MTH.
| Materials and methods|| |
A computerized literature search of all publications in PubMed, CENTRAL, EMBASE, The Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov website, and Google Scholar databases was performed. We also utilized manual searches of the article reference lists and conference proceedings. This was last assessed as up-to-date: June 30, 2015.
Search terms keywords included: Hypothermia, therapeutic hypothermia, mild hypothermia protocol, CA, heart arrest, OHCA, anoxic brain injury, cardiopulmonary resuscitation, RCTs. No language restrictions were enforced. Only human trials were included.
The PRISMA statement for reporting systematic reviews and meta-analyses of RCTs was applied to the methods for this study.  Only human studies were included for analysis.
Included studies met the following specifications: (1) RCT design, (2) evaluation of patients with OHCA defined as any nonperfusing cardiac rhythm, including shockable rhythms (ventricular fibrillation or ventricular tachycardia) and nonshockable rhythms (pulseless electrical activity and asystole) occurring in a patient not already in or admitted to a hospital with age more than 18 years old, (3) patient who successfully had ROSC but comatose after CA, (4) studies which provided data on patients who received MTH on neurological outcome and mortality, (5) MTH at a targeted temperature between 32°C and 34°C either prehospital or hospital initiation (any method of cooling was accepted), and (6) control group intervention treated with standard intensive unit care or maintained patients normothermic  at a target temperature ≥36°C.
Exclusion criteria were patients who are (1) pregnant, (2) did not meet the above-mentioned criteria, (3) age <18 years or patients who were hypotensive and did not achieve ROSC, and (4) control group cooled with MTH at a targeted temperature between 32°C and 34°C.
Two reviewers (PV and DB) independently extracted data from identified RCTs. Disagreements were resolved by consensus or, if necessary, by a third party (MM-EE).
The primary outcome was all all-cause mortality. We considered mortality to hospital discharge or longest follow-up postarrest. The secondary outcome was a favorable neurological function. Neurological function was evaluated according to cerebral performance category (CPC) where CPC 1 and 2 was defined as a good neurological outcome.  We also considered a favorable neurological function to hospital discharge or longest postarrest follow-up. If one of these validated metrics were not reported, reasonably defined favorable neurologic outcome by the individual study authors was accepted. If outcomes were reported at more than one follow-up period, we used data from the longest follow-up for each trial.
Data were summarized
across treatment arms using the Mantel-Haenszel odds ratio (OR) fixed-effects model. We evaluated heterogeneity of effects using the Higgins I2 statistic.  In cases of heterogeneity (defined as I2 > 40%), random effects models were used.  To address publication bias, we used four methods: Funnel plots,  Begg-Mazumdar test,  Egger test,  and the Duval and Tweedie's test.  Sensitivity analyses were performed using the one-study-out method, addressing the influence of each study by testing whether deleting each individual would significantly change the pooled results of the meta-analysis on the final effect and its precision. Finally, chronological cumulative analyses were used to test if the effect size and precision shifts based on the technical advancement of MHT seen over time.  The statistical analysis was performed by the Comprehensive Meta-Analysis version 2.0 software (Biostat, Inc., New Jersey, USA).
Individual study quality appraisal
Two authors (PV, MM) independently assessed the risk of bias of included trials using standard criteria defined in the Cochrane Handbook for Systematic Reviews of Interventions.  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 (DB).
| Results|| |
Study selection and characteristics
The flow diagram of study identification through the review is shown in [Figure 1]. The search strategy identified a total of 2352 potential articles. After removing duplicates and articles not meeting inclusion criteria, we screened 266 titles and abstracts. Of these, 14 were selected for further review of eligibility. Finally, 6 RCTs satisfied inclusion criteria, all of which were published in English. ,,,,,
|Figure 1: Search Strategy and Study Selection. RCT = Randomized Controlled Trial MTH = Mild therapeutic hypothermia|
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Baseline characteristics are presented in [Table 1]. Overall, the 6 RCTs enrolled a total of 1400 patients who were successfully resuscitated from OHCA. Numerous cooling methods were used in these included studies, including surface and invasive cooling. In all the studies, the target temperature of cooling range was between 32°C and 34°C, with a duration time of 12-24 h. Duration of follow-up ranged from hospital discharge up to 6 months.
Quantitative data synthesis
There were a total of 710 deaths reported in all patients that suffered OHCA: 49.7% (352/710) in MTH group and 51.9% (358/690) in the control group. There was no significant difference in all-cause mortality between the two groups (OR, 0.81; 95% confidence interval (CI) 0.55-1.21) [Figure 2].
|Figure 2: All-cause mortality. Comparison of all-cause mortality outcome between patients treated with MTH and the control group using a random model. Heterogeneity ( I2) = 41.4%. CI = Confidence interval; MH = Mantel-Haenszel; MTH = Mild therapeutic hypothermia|
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Among patients with OHCA, 633 had an overall favorable neurological outcome after OHCA. As indicated in [Figure 3], using a random model, no significant difference was observed in favorable neurological outcome in patients who received MTH 46.9% (331/705 patients) versus control 44.1% (302/687 patients) (OR, 0.77; 95% CI 0.47-1.24).
|Figure 3: Favorable neurological outcomes. Comparison of favorable neurological outcome between patients treated with MTH and the control group using a random model. Heterogeneity ( I2) = 56.2%. CI = Confidence interval; MH = Mantel-Haenszel; MTH = Mild therapeutic hypothermia|
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Sensitivity analysis involving the removal of each of the RCT's one at a time did not demonstrate difference or any changes in the overall outcomes, even when the Nielsen et al.  trial was removed; all-cause mortality (OR, 0.68; 95% CI 0.41-1.14) and favorable neurological outcome (OR, 0.64; 95% CI 0.36-1.17) [Figure 1] in the Supplemental Material].
Chronological cumulative analysis for each outcome did not find any significant change in the final effect outcomes; however, when the analysis was performed addressing all-cause mortality and favorable neurological outcomes, we observed transient changes in the final effect favoring the hypothermia group when the Bernard et al.  study was included. Subsequent accumulated analysis did not experience changes in the overall effect when the last two RCTs were added , [Figure 2] in the Supplemental Material].
Funnel plot did not show asymmetry suggesting bias for all-cause mortality outcomes except for favorable neurological outcomes [Figure 4]. However, after quantifying the observed bias with other methods (Begg-Mazumdar, Egger and Duval, and Tweedie's trim and fill test), no evidence of publication bias was observed [Figure 3] in the Supplemental Material]. The individual study quality appraisal and the risk of bias for the 6 included RCTs are summarized in [Table 2].
|Figure 4: Funnel plots for each individual outcome: (a) All-cause mortality; table (b) favorable neurological outcomes. Randomized controlled trials are shown as open circles and the observed summary point estimate in log units is shown as an open diamond. The imputed studies are shown as a filled circle, and the imputed point estimate in log units is shown as a filled diamond, No imputed studies were seen for overall mortality. Two imputed studies were seen for favorable neurological outcomes. Under the random effect model the point estimate and 95% confidence interval for the combined studies is 0.78 (0.73, 0.83). Using trim and fill, the imputed point estimate is 0.77 (0.72, 0.82)|
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| Discussion|| |
This meta-analysis provides a comprehensive update of RCTs assessing the effect of mild MTH on patients successfully resuscitated post-OHCA. To our knowledge, this comprises the largest sample in the literature assessing the role of MTH in patients post-OHCA at the time of submission. This includes two trials not previously cited in meta-analysis, , including the latest trial published by Nielsen et al.  Our meta-analysis did not find a benefit of MTH on mortality or neurological outcome as reported in earlier analyses. ,,,, These results not only correlate with the finding in the strongest powered study to date,  but also correlate with "real world" observational studies , following OHCA showing similar poor outcomes,  and with multicenter trials in children were the evidence of MTH effect was not substantially different from adults,  regardless of the presenting rhythm.
We believe that the outcome differences in our analysis compared to some earlier trials by Holzer  and Bernard et al.  are a reflection not only of tight temperature control but also close monitoring and optimization of other parameters over the past 15 years. This includes, but is not limited to, improved patient monitoring of hemodynamics and metabolic control. In addition, advancements in circulatory support and early coronary interventions may have had an effect on the reported outcome, resulting in improved survival.  Early referral of postarrest patients to tertiary care centers was a vital contributor to improved outcomes, virtually doubling the likelihood that patient will survive to discharge. 
Along with the initial published RCTs and observational data,  current guidelines have influenced many centers to adopt a mandatory protocol utilizing MTH in patients presenting with OHCA. , MTH should be done with the awareness of all the physiological changes in the circulatory and metabolic systems causes by hypothermia.  Potential complications and side effects reported with MTH include but are not limited to coagulopathies, increased rates of infections, cardiovascular complications, hyperglycemia, and electrolyte disorders. ,,,,,, The financial burden of MTH is not to be overlooked. A cost-effectiveness analysis of MTH after OHCA showed that patients treated with MTH had an incremental cost of $31,254 compared to those treated conventionally.  While neurological recovery or survival cannot be predicted among survivors of CA, it is important to consider the additional cost of this intervention.
Many factors are tentative contributors to the potential improvement of CA patients, and the role for MTH should be further investigated. Review of the literature suggests a potential role for simply avoiding hyperthermia and specific means of cooling survivors of OHCA. As described by Zeiner et al.,  patients with hyperpyrexia after CA have worse neurologic outcomes that increase for each degree Celsius higher, with an OR of 2.26. In this same study, patients with favorable neurologic recovery showed a higher lowest temperature and a lower highest temperature during the first 48 h after the restoration of spontaneous circulation. The majority of patients in the control groups included in our analysis were not treated actively for fever to keep them normothermic, allowing natural temperature course. This raises the possibility that the effect seen in early RCTs favoring MTH is due to an increased temperature in the control group. Nielsen et al.  attempted to answer this question comparing MTH with the control group temperature close to normothermia and found no significant differences between the two groups. These findings could be a key point to address future management of OHCA patients. Perhaps avoidance of fever, rather than hypothermia, is actually the most important element of temperature management after CA. Even Bernard et al., the author of one of the early trials that favored MHT,  has changed his own institution guidelines to a target temperature of 36°.  In addition to the limited therapeutic resources to mitigate the postanoxic injury in OHCA, arguments against changes on the target temperature set for MTH (32-34°C) are the lack of differences of adverse events seen with MTH compared to normothermia, and that there might be subgroups of patients, based on the severity of neurologic injury that may require more individualized degrees of hypothermia to achieve the best outcome. Two RCTs are currently recruiting patients to evaluated differences in target temperature; The Centre Hospitalier Departemental Vendee is randomizing patient with OHCA to a targeted temperature between 32.5°C and 33.5°C and the control group between 36.5°C and 37.5°C testing the potential improvement of neurological outcome with these two target temperatures. The other group from the University of Ottawa Heart Institute is being even more aggressive and is determining whether neurologic outcomes at 6 months are improved with moderate (31°C) versus mild (34°C) therapeutic hypothermia following ROSC in patients suffering OHCA. 
Other key point is the duration of MHT; the RCTs included in this meta-analysis utilized different durations of targeted temperature management after OHCA ranging from 12 to 28 h. There are no data that can be used to compare different durations of targeted temperature; however, we know that regardless of the target temperature chosen, temperature in postarrest patients should be tightly controlled and monitored. This important point was recognized in the new guidelines that updated the cooling time duration from 12 to 24 h to at least 24 h.  The TTH48 trial was recently completed and is examined prolonged MTH (32-34°C) in 24 versus 48 h with the primary outcome CPC after 6 months in OHCA patients.  Hopefully, we will have more answer on what is the optimal duration of MHT.
Though the new surface and endovascular (invasive) cooling methods are the most commonly used methods to both induce and maintain hypothermia. Optimal means of cooling have not yet been determined, but both randomized and observational studies suggest that endovascular cooling maintains target temperatures better than conventional surface cooling. Endovascular cooling also has less temperature fluctuation and has fewer complications associated with it than surface cooling. , Current guidelines do not specify which method to use but this may be a valuable consideration.
It has been discussed that a delay of several hours from resuscitation until the target temperature had been reached can impact neurologic outcomes. Some of the trials included in our meta-analysis started prehospital cooling as compared to hospital cooling, postulating earlier cooling results would improve neurologic recovery. This hypothesis was tested in the Hypothermia Network Registry  and some RCTs with adult patients after OHCA. , No differences in outcomes were observed. In fact, the intervention group was more likely to have re-arrest in the field. , The new hypothermia guidelines recommend against prehospital cooling with rapid infusion of large volumes of cold intravenous fluid (strong recommendation, moderate-quality evidence). 
We are not suggesting intensivists abandon temperature management after CA; however, the questions that remain are whether we should cool our postarrest patients to 36°C or continue with the old target temperatures. Regardless of the target temperature chosen, the temperature in postarrest patients should be tightly controlled and monitored. While 36°C may be a sufficient temperature goal, with no temperature control, many postarrest patients may become febrile with detrimental effects on mortality and neurologic function.
The benefit of MTH after in-patient CA has not been tested in RCTs. However, retrospective studies have shown no difference in neurological outcome at discharge among patients treated with MTH compared to control group.  The largest published cohort of patient included 8316 patients with complete data, of whom 214 (2.6%) had hypothermia induced, and 2521 (30%) survived to discharge. Only 40% were documented as achieving a temperature between 32°C and 34°C. Induced hypothermia was not associated with favorable neurological outcomes or improved survival. The lack of benefit in this population may reflect lack of effect, inefficient application of the intervention.  The new ILCOR and AHA, we suggest targeted temperature management as opposed to no targeted temperature management for adults with in-hospital CA (weak recommendation, very low-quality evidence) with any initial rhythm who remain unresponsive after ROSC.
In the perioperative setting, there are no specific guidelines to guide post-CA treatment. CA occurs in 0.7-2.9% of cardiac surgical patients. , The uncommon event of patient requiring MTH needing cardiac surgery can pose significant challenges to the perioperative physician. In terms of anesthetic management, the key goals relate to maintenance of normal hemodynamics (preservation of the myocardial oxygen demand/supply balance, judicious fluid management guided by appropriate intravascular monitoring and transesophageal echocardiographic and satisfactory pain management. Temperature management in the operating room and Intensive Care Unit can be difficult owing to the multiple factors that affect core body temperature in the perioperative period. To date, there is little specific data reporting safety or efficacy of TH in cardiac surgery patients who experience unintentional CA. Only a few published case series experience have been reported with a safe and successful use of MTH after unintentional perioperative CA in 3 cardiac surgery patients. The target temperature range between 32°C and 34°C and was maintained through the use of intermittent fanning for a period of 24 h, followed by passive rewarming.  High-quality controlled studies are required to better characterize the effect of induced hypothermia in this population.
| Limitations|| |
This systematic review and meta-analysis have several important limitations that should be acknowledged. First, this is a meta-analysis performed on study-level data. Second, the studies included in the meta-analysis enrolled heterogeneous populations and were characterized by different study protocols and defined endpoints differently. Third, none of the studies were blinded for the intervention assignments, though some of the latest trials tried to decrease the bias by blinding statisticians. Fourth, there were differences in the target temperature for control groups; the results of our review come from mixed-up analyses that did not separate each hypothermic temperature level between 32°C and 34°C and for most studies included, it stated merely the body temperature level of hypothermia as 32-34°C. Finally, several of the trials we analyzed had premature patient withdrawal that may affect overall neurologic recovery. Most of the trials did not specify whether the decision on withdrawal of intensive care was made and if the assessor of the prognostication was blinded, except for the Nielsen et al.  trial that had a strict protocol for neurologic prognostication and withdrawal of life-sustaining therapies. Short-term follow-up may be troublesome since the neurological status for survivors can evolve over the first 6 months after the arrest.  All these limitations may explain some of the observed heterogeneity of the end points.
Interestingly, considering that none of the included studies were blinded for the intervention assignments, the open nature of the studies might, in theory, slightly favor the MTH intervention group.  This, and the consistency of the magnitude, direction, and the stability of summary effects after the sensitivity and cumulative analyses, further supports the results of this meta-analysis, but results should be interpreted cautiously.
| Conclusions|| |
The results of our meta-analysis did not confer benefit of MTH on overall survival rate or neurological recovery in survivors of OHCA. Overall survival rate and neurological recovery are very limited in these patients. Further studies are needed to determine the optimal temperature level of hypothermia therapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, 5777 East Mayo Blvd., Phoenix, AZ 85054
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]