Effects of prehospital adrenaline administration on out-of-hospital cardiac arrest outcomes: a systematic review and meta-analysis

Out of hospital cardiac arrest is one of the most urgent Emergency Medical Service (EMS) priorities, in which only 23% of patients survive to hospital admission [1],[2], and only 7.6% survive to hospital discharge [1],[2]. Factors identified as predictors of survival among out of hospital cardiac arrest patients include the cardiac arrest being witnessed by a bystander, arrest witnessed by EMS personnel, initially shockable cardiac rhythms and bystander cardiopulmonary resuscitation (CPR) [2]. Administration of adrenaline has been a part of advanced life support guidelines for decades [3], for both shockable and non-shockable cardiac rhythms [4]-[7], to increase cardiac output and preferentially divert blood circulation to the heart and brain during CPR [3]. Animal models indicate that adrenaline administration significantly increases the probability of return of spontaneous circulation (ROSC) [8]-[11]. However, evidence in humans is limited, with most studies being observational studies with inconsistent results on short term outcomes including ROSC [5],[12]-[18] and hospital admission [5],[13],[14],[16],[18]-[21]. In addition, inconsistent results were also found in long-term outcomes such as one-month survival with good cerebral performance [14],[18] and survival to hospital discharge [5],[14],[16],[18]-[20].

Although three systematic reviews [22]-[24] have been conducted, a more complete review was still required for the following reasons. One previous review studied a mix of in- and out-of hospital cardiac arrest patients without providing any quantitative conclusion [22], and another systematic review pooled adrenaline effect on survival to hospital discharge but not for prehospital ROSC [23]. Finally, Lin et al. conducted a systematic review by including only randomized controlled trials (RCTs), which primarily aimed to compare the standard dosages of adrenaline administration with placebo, vasopressin and high dosage of adrenaline in out of hospital cardiac arrest patients [24]. Although those authors found benefit of adrenaline administration over placebo on ROSC and survival to admission, the results were based on only one RCT. There have been more studies published since these reviews were reported. We, therefore, conducted a systematic review and meta-analysis focused only on out of hospital cardiac arrest patients, which aimed to determine the effects of prehospital adrenaline administration on both short (that is, ROSC, hospital admission) and long term outcomes (that is, survival to discharge and discharged with cerebral performance category (CPC) 1 or 2).

Eight-hundred and eighty-two studies and 804 studies were identified, respectively, from PubMed and Scopus, see Figure 1. Of these, 602 duplicated studies were excluded, leaving 1,084 studies for screening titles and abstracts. Among them, 1,069 studies did not meet our eligibility criteria and the reasons have been clearly described in Figure 1, leaving 54 studies for review of full papers. Of these, 39 studies were later excluded, which finally resulted in 15 studies for inclusion in pooling data [5],[12]-[21],[27],[34]-[36].

The characteristics of the included studies are described in Table 1. Of the 15 eligible studies, 14 were observational studies and only 1 was a RCT [27]. All studies were in adult patients except one which included children [34]. Among 14 adult cohorts, 10 studies [12]-[18],[35]-[37] reported ROSC, 8 studies [5],[13],[14],[16],[18]-[21] reported admission, 7 studies [5],[14],[16],[18]-[20],[35] reported survival to discharge, and only 2 studies reported discharged with CPC 1 or 2 [14],[18]. All studies were EMS based designs, except one study which was hospital-based using a hospital cardiac arrest data registry [18]. Only five studies exclusively included patients with non-trauma [13],[14],[16],[17],[35] whereas the others included cohorts in which trauma patients were combined with non-trauma cases [5],[12],[15],[18]-[21],[36]. Patients with specific initial cardiac rhythms were isolated in five studies, which included three pulseless electrical activity (PEA) [14],[19],[21], one asystole [20] and one ventricular fibrillation [5]. All studies compared administration of a standard dose of adrenaline to no administration. There were four studies [16],[17],[21],[27] which reported the amount of adrenaline administration which ranged from 1 to 5 mg. Since there was only one RCT and one study in children, pooling of the treatment effect versus no administration focused on only thirteen adult cohorts.

We performed a systematic review and meta-analysis to assess the effects of prehospital administration of adrenaline on short-term (that is, ROSC and hospital admission) and long term out of hospital cardiac arrest outcomes (that is, survival to discharge and discharge with CPC 1 or 2) relative to no administration. Pooled treatment effects were performed based on four to eight adult cohorts with total sample sizes of 2,381 to 421,459. Our results indicated that receiving prehospital adrenaline significantly increased prehospital ROSC, but did not increase the overall ROSC, hospital admission, or survival to hospital discharge. However, the treatment effects on prehospital ROSC may be prone to bias from missing studies.

Administration of adrenaline during CPR causes constriction of peripheral vessels, which subsequently increases coronary and cerebral perfusion pressure [3]. Our findings support the effect of adrenaline in increasing prehospital ROSC, which is similar to a previous RCT [27] and systematic reviews by Lin et al. [24]. However, our effect size was more precise than the finding by Lin et al. because the pooling was based on a larger number of included studies than Lin et al., which was based on only one study. In addition, our findings also suggested the adrenaline effect on ROSC in both non-trauma and the mix of trauma and non-trauma cases, although the latter was highly heterogeneous. However, there was no adrenaline effect on overall ROSC, which might be due to variation in the definition and time of ROSC assessment, that is, prehospital, ED, and admission [12],[14],[18],[19],[28],[36]. Assessing ROSC at the ED or on admission could be very different compared to prehospital ROSC because of the quality of CPR, type of facility, and personnel and equipment used.

No other long term effects (that is, hospital admission and survival to discharge) of prehospital adrenaline were identified. This suggests that adrenaline itself may only have efficacy for inducing prehospital ROSC. Ultimately, survival to hospital discharge is determined more by the underlying clinical condition of the patient; for example, a patient with acute myocardial infarction may be more likely to survive than a patient with end stage respiratory disease, and yet most studies [5],[14],[18] did not report the underlying diagnoses which leads to difficulties in interpreting the results. In addition, adrenaline is intrinsically a short acting cardiovascular stimulant, which has a limited half-life, and it may be less likely to have a significant effect on long term outcomes for this reason [3]. Assessing treatment effects without adjusting for these factors, as was the case for the included studies, may bias the results.

Our study has a number of strengths. We pooled treatment effects on most relevant clinical short- and long-term outcomes. We attempted to identify the most relevant studies by two independent reviewers using defined search terms and strategies in order to reduce selection bias. Exhaustive searching of the literature resulted in the number of included studies from four to eight cohorts. Although the number of included studies is still small, but, it is larger than a previous systematic review [22], which included five studies [5],[16],[27],[38],[39] with different study designs. We explored possible sources of heterogeneity by considering whether a bystander witnessed the arrest, types of subjects and initial cardiac rhythms in a meta-regression. In addition, an attempt was made to distinguish the cause of asymmetry of funnel plots to determine if this was due to heterogeneity or missing studies.

However, our study has some weaknesses. Firstly, our results might be subject to some bias because pooled effects were based on only observational studies, which could not adjust for several known and unknown confounders. The most suitable study design is a RCT with a proper sample size, say approximately 4,500 subjects in total to detect a difference of prehospital ROSC rate of 2.5. Secondly, a subgroup analysis could not be flexibly done because of the small number of included studies. Thirdly, insufficient information on study characteristics resulted in limited exploration of sources of heterogeneity. Finally, we did not pool more relevant clinical outcomes (that is, sustained ROSC and discharge with CPR 1 or 2) because data were not available.

In summary, prehospital adrenaline administration might increase prehospital ROSC, but not for survival to discharge in out of hospital cardiac arrest patients. However, our findings might be subject to bias from missing studies.