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Abstract

Objective

To determine whether patients with return of spontaneous circulation (ROSC) following cardiac arrest who received mild hypothermia have improved mortality and neurological outcomes compared with those who do not receive mild hypothermia.

Methods

Online database searches were performed for English-language randomized controlled trials published before March 2014, comparing mild hypothermia (32–34℃) with normothermia or hypothermia other than mild hypothermia after cardiac arrest, in adults with ROSC. Data were independently extracted using a dedicated form. Mortality rates and neurological outcomes were recorded for the overall population and for in-hospital and prehospital mild hypothermia subgroups.

Results

Seven articles were identified for inclusion in the meta-analysis. Mild hypothermia demonstrated no significant beneficial effects in terms of overall mortality or neurological outcomes. In addition, no significant outcome differences were observed between the pre- and in-hospital subgroups.

Conclusions

On the basis of this limited data set, mild hypothermia does not improve mortality rates or neurological outcomes in patients with ROSC after cardiac arrest, regardless of the timing of the hypothermia. Larger trials need to be carried out to confirm these findings.

Keywords

Therapeutic hypothermia cardiac arrest return of spontaneous circulation neurological outcome mortality

Introduction

The beginning of the modern concept of cardiopulmonary resuscitation (CPR) can be traced to the documentation of 14 patients who survived cardiac arrest with the application of chest compressions, reported by Kouwenhoven et al.¹ in 1960; a few months later, the combination of rescue breaths and chest compressions was introduced,² while defibrillation was first described in 1962.³ Despite improvements in the development of CPR techniques and an increase in the training of health care providers and bystanders, it is still difficult to ensure good neurological outcomes for patients who survive cardiac arrest. Postcardiac arrest care has been highlighted since the publication of the latest American Heart Association guidelines in 2010;⁴ therapeutic hypothermia is one strategy suggested to protect the brain and other organs in patients who remain comatose after the return of spontaneous circulation (ROSC). Since being advocated by a number of international resuscitation guidelines,^4–6 therapeutic hypothermia after ROSC has gained widespread use. In 2012, a meta-analysis reported reduced in-hospital mortality rates after cardiac arrest in adults with ROSC who presented with nonshockable initial rhythms, and who underwent hypothermia.⁷ More recently, two large trials showed that neither the application nor the timing of onset of targeted controlled mild hypothermia (32–34℃) after cardiac arrest improved patient outcomes.^8,9 As new data bring novel results, the benefits and risks of mild hypothermia remain uncertain in patients recovering from cardiac arrest.

The aim of this meta-analysis was to systematically review the literature, to ascertain differences firstly in mortality rates and secondly in neurological outcomes, in patients after ROSC (regardless of the arrest rhythm) who underwent targeted controlled mild hypothermia compared with those who did not. In addition, mortality rates and neurological outcomes were investigated in those receiving mild hypothermia with different onset times (pre- or in-hospital) compared with patients not receiving mild hypothermia.

Materials and methods

Search strategy

Online searches of the PubMed®, Elsevier, Cochrane (Central) and Web of Science databases from inception until March 2014 were performed, using the following search keywords and terms: (“therapeutic hypothermia” OR “induced hypothermia” OR “inducing hypothermia” OR “induce hypothermia” OR “resuscitation hypothermia” OR “mild hypothermia” OR “moderate hypothermia” OR “resuscitative hypothermia” OR “hypothermia treatment”) AND (“cardiac arrest” OR “heart arrest” OR “cardiogenic shock” OR “cardiopulmonary arrest” OR “arrest of the heart” OR “resuscitation of the heart” OR “cardiorespiratory arrest”) AND (“resuscitation” OR “cardiopulmonary resuscitation” OR “resuscitated” OR “cardiac resuscitation”). The search was limited to studies published in English.

Data screening and extraction

Citation titles and abstracts were independently screened by two reviewers (T.Y. and F.L.). All randomized controlled clinical trials of any duration that compared mortality rates and neurological outcomes in human adult patients (aged > 18 years) with ROSC after cardiac arrest, who underwent therapeutic targeted controlled mild hypothermia (32–34℃) compared with those did not (patients with normothermia or hypothermia other than mild hypothermia), irrespective of the presenting rhythm, were identified. All potentially eligible papers were retrieved in full.

The references of all retrieved articles were examined to identify further potentially eligible studies. Trial characteristics and outcomes were independently recorded by the two reviewers using a predesigned data abstraction form. In cases of disagreement, all the authors jointly reviewed the article in question until a consensus was reached. Any duplicate papers were identified and excluded from the meta-analysis.

The Jadad scale¹⁰ was used to assess the quality of the data reporting and randomization, concealed allocation and degree of blinding, and patient flow description. High-quality studies were defined by a score of ≥3.

Endpoints

The primary endpoint was to investigate the potentially beneficial role of targeted controlled mild hypothermia, in terms of mortality rates in patients with ROSC after cardiac arrest; cut-off points for mortality as defined within each study were used in the meta-analysis. The secondary endpoints were to determine whether hypothermia can improve neurological outcomes in patients with ROSC after cardiac arrest and whether differences in either outcome (mortality or neurological) could be found in subgroups of patients receiving pre- or in-hospital mild hypothermia, compared with patients not receiving mild hypothermia.

To evaluate and compare neurological outcomes, the definition of a ‘good’ neurological outcome used within each study was used in the meta-analysis. When the neurological outcome was evaluated using the cerebral performance category scale, values of 1–2 were considered to be a ‘good’ neurological outcome, while values ≥ 3 were considered to be a ‘poor’ outcome.

Statistical analyses

Data related to mortality rates and neurological outcomes in the overall population and in the in-hospital and prehospital subgroups were extracted; a consecutive analysis for subgroups was performed (filtered according to the analysed variable).

For dichotomous outcomes, risk ratios (RRs) with 95% confidence intervals (CIs) were used to represent the effects of mild hypothermia on different outcomes. An RR of < 1 favoured the use of therapeutic mild hypothermia. Data were pooled only when adequate clinical and methodological similarities were present between the studies.

The homogeneity assumption was assessed using the I² value, which describes the percentage of total variation across studies that is due to heterogeneity rather than chance. I² was computed as I²= 100% × (Q − df)/Q, where Q is the Cochran heterogeneity statistic and df is the degrees of freedom. A value of 0% indicates no observed heterogeneity; larger values indicate increasing heterogeneity. Whenever I² was >25% (i.e. heterogeneity was found), random effects model results were presented as the primary analysis.

Publication bias was estimated using a funnel plot. Parametric variables were presented as mean ± SD; nonparametric variables were presented as the median and interquartile range. Statistical analyses were conducted using RevMan® Review Manager software, version 5.0 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). A P-value < 0.05 was considered to indicate statistical significance.

Results

A flowchart of the study selection is given in Figure 1. Seven English-language articles published before March 2014 fulfilled the inclusion criteria.^8,11–16 A total of 1527 patients were included in the meta-analysis. Of these, 773 patients underwent targeted controlled mild hypothermia, while 754 were controls. The characteristics of the studies are shown in Table 1.

Figure 1.

Flow diagram of study selection for meta-analysis to determine whether mild hypothermia (32–34℃) improves mortality and neurological outcomes in patients with return of spontaneous circulation following cardiac arrest. RCT, randomized controlled trial.

Table 1.

Characteristics of the studies included in a meta-analysis to determine whether mild hypothermia (32–34℃) improves mortality and neurological outcomes in patients with return of spontaneous circulation following cardiac arrest.

	Patients, n			Setting	Hypothermia characteristics
Study	Total	Controls	Mild hypothermia		Initiation	Target temperature, ℃	Temperature management in controls	Jadad score
HCAS, 2002¹¹	275	138	137	Multicentre, Europe	In-hospital	32–34	Standard intensive care treatment	5
Bernard et al., 2002¹²	77	34	43	Single centre, Australia	Prehospital	33	Normothermia	4
Laurent et al., 2005¹⁴	41	19	22	Multicentre, France	In-hospital	32–33	Standard care	4
Hachimi-Idrissi et al., 2005¹³	33	17	16	Single centre, Belgium	In-hospital	33	Normothermia	5
Kim et al., 2007¹⁵	125	62	63	Multicentre, USA	Prehospital	32–34	Normothermia	4
Kämäräinen et al., 2009¹⁶	37	18	19	Single centre, Finland	Prehospital	33	Conventional fluid therapy	4
Nielsen et al., 2013⁸	939	466	473	Multicentre	In-hospital	33	36℃	5

HCAS, Hypothermia after Cardiac Arrest Study.

Mild hypothermia and mortality

Dichotomous data on mortality were reported in all the trials included in the meta-analysis.^8,11–16 The overall population in the studies was homogeneous (P = 0.32, I²= 15%). Figure 2 shows the effect of targeted controlled mild hypothermia on mortality; mild hypothermia did not exert a statistically significant protective effect on mortality in patients with ROSC after cardiac arrest.

Figure 2.

Effect of mild hypothermia (32–34℃) on mortality in the overall population and in pre- and in-hospital subgroups using a fixed-effect analysis, with a forest plot showing risk ratio for overall mortality associated with mild hypothermia (experimental) versus controls. Squares and horizontal lines indicate risk ratio and 95% confidence intervals (CIs) for each trial; size of each square is proportional to the statistical weight of the trial in the meta-analysis. Diamonds indicate effect estimate derived from the meta-analysis, with the centre indicating the point estimate and the left and right points indicating 95% CIs.

Similarly, after stratifying for the pre- and in-hospital subgroups, no statistically significant mortality differences were observed between the patients undergoing mild hypothermia and controls. No evidence of publication bias was found using a funnel plot assessment (Figure 3).

Figure 3.

Funnel plot for publication bias for the effect of mild hypothermia (32–34℃) on mortality. Each point represents a separate study included in the meta-analysis. Squares indicate studies assessing the effects of prehospital mild hypothermia compared with normothermia or hypothermia other than mild hypothermia; diamonds indicate studies investigating in-hospital hypothermia compared with normothermia or hypothermia other than mild hypothermia. RR, risk ratio; SE, standard error.

Mild hypothermia and neurological outcome

All studies in the meta-analysis reported data on clinical outcomes, albeit in different forms.^8,11–16 Overall, the studies were shown to be heterogeneous (P = 0.09, I²= 44%). As shown in Figure 4, mild hypothermia was not associated with a statistically significant improvement in neurological outcome in the overall population. After subgroup stratification, no statistically significant differences in outcomes were observed between the pre- or in-hospital subgroups and controls. No publication bias was detected using a funnel plot assessment (Figure 5).

Figure 4.

Effect of mild hypothermia (32–34℃) on neurological outcome (where data available) in the overall population and in pre- and in-hospital subgroups using a fixed-effect analysis, with a forest plot showing risk ratio for overall mortality associated with mild hypothermia (experimental) versus controls. Squares and horizontal lines indicate the risk ratio and 95% confidence intervals (CIs) for each trial; size of each square is proportional to the statistical weight of the trial in the meta-analysis. Diamonds indicate the effect estimate derived from the meta-analysis, with the centre indicating the point estimate and the left and right points indicating 95% CIs.

Figure 5.

Funnel plot for publication bias for the effect of mild hypothermia (32–34℃) on neurological outcomes. Each point represents a separate study included in the meta-analysis. Squares indicate studies assessing the effects of prehospital hypothermia compared with normothermia or hypothermia other than mild hypothermia; diamonds indicate studies investigating in-hospital hypothermia compared with normothermia or hypothermia other than mild hypothermia. RR, risk ratio; SE, standard error.

Discussion

To date, seven randomized clinical trials have analysed the impact of pre- or in-hospital mild hypothermia in patients with ROSC after cardiac arrest, compared with control groups.^8,11–16 After the first encouraging studies,¹¹ later publications showed no benefit of mild hypothermia in terms of neurological outcomes or mortality rate after cardiac arrest.^8,9 The present meta-analysis was performed to clarify the role of targeted controlled mild hypothermia in adults compared with patients not receiving this treatment, based on current published data. The main findings were that mild hypothermia does not benefit patient mortality, regardless of the initiation time (pre- or in-hospital), and does not improve neurological outcomes after ROSC.

Since the advent of CPR, technological development and research have introduced distinct and novel ways of improving the mortality rates and neurological outcomes, in patients with cardiac arrest and ROSC. Although the use of defibrillators and the increased number of individuals trained in CPR have improved survivorship,¹⁷ secondary brain injuries established within minutes after cardiac arrest are the major cause of increased hospital mortality or long-term neurological problems.

The first description of the use of hypothermia was published around 1960.^18,19 The hypothesis that hypothermia could be used to reduce brain oxygen consumption has been considered since the early 1990s; animal studies have shown that hypothermia can improve mortality and neurological outcomes after cardiac arrest.^20–24 Preliminary studies performed in the light of these data demonstrated improved neurological outcomes in patients treated with mild hypothermia after cardiac arrest, compared with historical controls.^25–28

In 2002, the Hypothermia after Cardiac Arrest Study Group¹¹ reported that, among patients with ROSC after cardiac arrest due to ventricular fibrillation, systemic cooling to a bladder temperature between 32 and 34℃ for 24 h increased the survival rate (P = 0.02) and the likelihood of favourable neurological outcomes (P = 0.009) compared with standard normothermic care. Laurent and coworkers¹⁴ then found that the combined use of haemofiltration and hypothermia may decrease patient mortality and improve final outcomes in patients with out-of-hospital cardiac arrest. Similarly, Hachimi-Idrissi et al.¹³ observed improved neurological outcomes in patients treated with mild hypothermia after cardiac arrest; they linked these findings to reduced serum S-100β protein concentrations. However, Kim et al.¹⁵ reported a slight but nonsignificant improvement in mortality and neurological outcomes in patients receiving prehospital hypothermia compared with normal standard care; the authors stated that the study was unlikely to have had sufficient power to demonstrate a significant difference between treatments, having only ∼60 patients per branch. At the end of 2009, another study was published by Kämäräinen et al.,¹⁶ who demonstrated the feasibility of prehospital hypothermia but, similar to Kim et al.,¹⁵ the study was underpowered for mortality or neurological outcome assessments.

Currently, the international guidelines by the American Heart Association⁴ state that comatose adult patients with ROSC after out-of-hospital cardiac arrest with shockable rhythm should be cooled to 32–34℃ for 12–24 h, and that comatose patients with ROSC after out-of-hospital cardiac arrest with a nonshockable rhythm or in-hospital cardiac arrest may also benefit. The guidelines indicate the knowledge gaps regarding the optimal temperature, treatment method, disease onset, treatment duration and rewarming rate; therefore, further investigation is required to determine the benefit of postcardiac arrest therapeutic hypothermia after nonshockable and in-hospital cardiac arrest.

In 2013 and 2014, two large trials investigating the role of hypothermia in patients with ROSC after cardiac arrest were published. Kim and coworkers⁹ investigated whether prehospital intravenous cooling could improve mortality and neurological outcomes in 688 patients after resuscitation from cardiac arrest, with both shockable and nonshockable rhythms, compared with 671 patients with in-hospital cooling only. However, this study was not included in the present meta-analysis as both groups of patients received mild hypothermia. In another study by Nielsen et al.,⁸ 939 unconscious patients were randomized to receive normo- or hypothermia after cardiac arrest resuscitation on hospital admission within 240 min of ROSC. The vast majority of the patients presented with a shockable rhythm. In both studies, the authors found no significant between-group differences in mortality or neurological function. These results were also consistent in all the subgroups analysed.

The results of the present meta-analysis are consistent with the large study by Nielsen et al.,⁸ showing no protective effects on mortality or neurological outcomes associated with mild hypothermia. However, since 939 (61%) of the 1527 patients included in the meta-analysis were from the study of Nielsen et al.,⁸ it had greater statistical weight. Therefore, limitations of this single study should also be considered in the meta-analysis; these included investigator awareness of the treatments assigned to patients, use of unknown sedatives and neuromuscular blocking agents, methods of hypothermia induction and goal threshold temperatures.

It cannot be excluded that possible reasons for the lack of benefits from hypothermia are the large patient heterogeneity and considerable advances in patient care over the last 10 years. The mortality rate was 48% in the Hypothermia after Cardiac Arrest Study in 2002¹¹ (which considered only shockable presenting rhythm); however, in the most recent trial by Kim et al.⁹ in 2014, though not included in the present meta-analysis, the overall mortality in a similar population was 36%. In addition, as Rittenberger and Callaway²⁹ highlighted in their editorial, most studies prior to Nielsen et al.⁸ were influenced by the fact that the most common cause of death was abandonment of life support because of perceived poor neurological prognosis, which is not certain in the long term. A further limitation of the meta-analysis is a possible selection bias in the trials chosen because of the English-language restriction. It should also be noted that the control groups were quite heterogeneous in the treatment they received: the control group in Nielsen et al.⁸ received controlled temperature management targeted to 36℃, whereas other groups received no temperature control (normothermia)¹¹ or a median bladder temperature targeted to 37℃ (though sometimes >37.5℃).¹²

In conclusion, according to data from seven randomized controlled trials reviewed in the present meta-analysis, the induction of mild hypothermia seems to have no role in reducing mortality rates or ameliorating long-term neurological outcomes in patients with ROSC after cardiac arrest, regardless of the timing of the initiation (pre- or in-hospital).

Footnotes

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This study was supported in part by the young and middle-aged scientific research funds of Wannan Medical College, Wuhu, China (no. WK2014F38) and Natural Science Foundation of Anhui Province (no. 1508085MH180).

References

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The role of the induction of mild hypothermia in adult patient outcomes after cardiac arrest: Systematic review and meta-analysis of randomized controlled studies

Abstract

Objective

Methods

Results

Conclusions

Keywords

Introduction

Materials and methods

Search strategy

Data screening and extraction

Endpoints

Statistical analyses

Results

Mild hypothermia and mortality

Mild hypothermia and neurological outcome

Discussion

Footnotes

Declaration of conflicting interest

Funding

References