The efficacy and safety of pre-hospital cooling after out-of-hospital cardiac arrest: a systematic review and meta-analysis

The online search strategy used both the MEDLINE and Cochrane Library databases from inception until October 2017. The following terms were used: “out-of-hospital cardiac arrest” or “heart arrest” or “cardiac arrest” or “death, sudden” or “ventricular fibrillation” or “pulseless electrical activity” or “PEA” or “asystole” or “tachycardia” and “cryotherapy” or “hypothermia, induced” or “hypothermia” or “cooling” or “targeted temperature management or TTM” and “emergency medical services” or “emergency responders” or “emergency medical technicians” or “paramedic” or “prehospital” or “advanced life support” or “out of hospital.” Additionally, we checked reference lists of relevant studies and review articles.

Retrieved abstracts were assessed by two reviewers (PJL and DB) to evaluate whether they met the following inclusion criteria for full-text review: (1) RCT evaluating pre-hospital TH vs no pre-hospital TH after cardiac arrest; (2) patients > 14 years of age; (3) patients with documented cardiac arrest from rhythms, including ventricular fibrillation (VF), ventricular tachycardia, pulseless electrical activity and asystole; and (4) outcome data that included survival to hospital discharge and temperature at hospital arrival. The same two reviewers completed full-text reviews to identify included studies. A third reviewer resolved any disagreements.

Two authors (DB and PJL) extracted the following data independently using a standard data extraction form: publication year, study design, study population characteristics, initial cardiac rhythm, timing of cooling, cooling procedures, primary and secondary outcome measures, and study quality.

Study quality was appraised using the Cochrane Risk of Bias Tool for RCTs [13]. The assessment includes evaluation of random sequence generation, allocation concealment, blinding, incomplete outcome data and selective outcome reporting.

The primary outcome of this systematic review was survival to hospital discharge with a favourable neurological outcome. Favourable neurological outcome was defined as a the patient discharged to home or to rehabilitation, Cerebral Performance Categories Scale (CPC) score of 1 or 2 or a modified Rankin Scale score of 0, 1 or 2 [14, 15]. Secondary outcomes were survival to hospital discharge and temperature upon hospital admission. The safety outcomes included pulmonary oedema and recurrent arrest during transport to the hospital.

We conducted a meta-analysis of results of the included studies using Review Manager software version 5.3. We summarized categorical data using the risk ratio (RR) according to the Mantel-Haenszel method and a random effects model [16]. For continuous data, we estimated the mean difference (MD) using the inverse variance method and fixed effects. Heterogeneity was detected with a chi-square test with n − 1 degrees of freedom, which was expressed as I². When the I² statistic was > 50, statistical heterogeneity was considered to be relevant. Sensitivity analysis were performed to further explore heterogeneity by excluding one study at a time, deleting studies with excessively high weights in pooled studies, and excluding studies that used discharge destination as a surrogate for neurological outcome.

Our search strategy yielded 798 citations in MEDLINE and 84 citations in the Cochrane database, from which 121 duplicates were removed, leaving 761 studies to be screened. Of these, 21 full texts were reviewed, with 10 meeting the study inclusion criteria. All ten were included in the systematic review (Fig. 1).

Table 1 demonstrates the characteristics of the ten included studies, all of which were RCTs published between 2007 and 2017. Nine were single-country trials, and one was a multi-country trial. Of the single-country trials, four were conducted in Australia [6, 11, 17, 18], two in the United States [19, 20], one in Canada [12], one in Finland [21] and one in France [22]. The multi-country trial included five European countries [23]. Seven of the ten studies included patients with any initial cardiac rhythm. The remaining three studies included only patients with VF [6, 17] and non-shockable rhythms [18], respectively, as the initial cardiac rhythm. TH was initiated after return of spontaneous circulation (ROSC) in seven studies [6, 12, 17‐21] and intra-arrest in three [11, 22, 23]. The majority of studies reported cooling the patients in the pre-hospital TH arm using surface cooling measures [12, 17‐19, 22], an infusion of a cold solution, normal saline or Ringer’s lactate [11, 12, 17‐22], and one used trans-nasal evaporative cooling [23]. One study used only ice packs applied to the patient’s head and torso [6]. All studies reported survival at hospital discharge and neurological status at discharge, and all studies reported temperature at time of admission to hospital. A summary of the results of the studies is provided in Table 2.

Overall, the risk of bias for the included studies was low (Additional file 1: Figures S1 and S2). A potential for selection bias was noted in one study owing to randomization according to day of the month and possible unmasking of allocation concealment [6]. Across the studies, the nature of the intervention made true blinding of the providers impossible. Additionally, in one study, leaving the receiving practitioner unblinded was an intended intervention, because the authors postulated that this would reduce the time to in-hospital cooling [12]. Outcome assessors for the primary endpoints were blinded in eight of the ten studies. In all of the studies except two, researchers performed an intention-to-treat analysis [6, 21]. All studies had concerns for other sources of bias: Four studies were terminated before the target sample size was recruited [11, 12, 17, 18]; one study was funded by a company with an invested interest [23]; and two studies had concerns for possible selection bias, with 7, 497 and 23 patients simply missed and not included in the study [6, 19, 20].