The main findings of this study are that the rates of ROSC on arrival at hospital, survival and favourable neurological outcome all decreased as the interval from cardiac arrest to the administration of drug or placebo increased. The best outcomes are seen early after the onset of cardiac arrest. Models of time to drug administration showed a pattern which suggests that the relative effects of adrenaline to placebo on ROSC increased over time, although the absolute difference remained fairly consistent over time. By contrast, the effects of adrenaline relative to placebo on survival and favourable neurological outcomes did not change over time.

The observation that ROSC, survival and neurological outcomes deteriorate the longer a patient is in cardiac arrest is consistent with previous studies [15,16,17,18]. This underlies the phenomenon known as resuscitation time bias, whereby interventions given early after the onset of cardiac arrest appear to be beneficial relative to late interventions, but the better outcomes are in fact related to earlier treatment [11, 19]. The randomised design of the PARAMEDIC2 study removes the influence of resuscitation time bias, allowing an unbiased assessment of changes in treatment effect over time. The study reaffirms that during cardiac arrest, any traditional time-to intervention analyses are likely to be severely biased. It highlights the importance of more sophisticated statistical analyses of observational data which can partly deal with this problem [11, 20].

The novel finding that the effects of adrenaline on ROSC compared with placebo increase over time are consistent with experimental studies. In a rat model of cardiac arrest Angelos et al. found no difference between placebo and adrenaline in the rate of ROSC in cardiac arrests of very short duration (less than 2 min) [21]. As the duration of cardiac arrest increased, adrenaline played an increasingly important role in restoring ROSC. These findings are consistent with the 3-phase cardiac arrest model described by Weisfeldt and Becker which reflects the time sensitive changes in metabolic and physiological profiles the longer the duration of a cardiac arrest. In this model, vasopressors are recommended during the later circulatory and metabolic phases (> 4 min) [22]. At a cellular level this can be explained as within minutes of the onset of cardiac arrest, myocardial adenosine triphosphate levels decrease, leading to the disruption of normal myocardial cellular homeostasis [6]. Unlike the heart, the brain is more sensitive to tissue ischaemia as it has no myoglobin oxygen stores [23, 24]. Furthermore, CPR and vasopressors may be less effective at restoring mitochondrial function in the brain than it is at restoring cardiac mitochondrial performance [25].

A key unanswered question in PARAMEDIC2 was the influence of time to drug administration. The time from collapse to drug treatment was on average 22 min. This is longer than the interval during in-hospital cardiac arrest (average 3 min) [9, 10] and during the majority of animal cardiac arrest models (average 9.5 min) [26]. The timing is similar to a systematic review of time to drug administration across 17 studies [19.4 min (95% CI 12.8–25.9)] [27] and with more recent studies (range 13–24 min) [28,29,30,31]. This analysis of time to treatment shows that the shorter the time to treatment, whether treatment was adrenaline or placebo, is associated with the best outcomes. Current treatment algorithms recommend that CPR is started (and if indicated defibrillation) before adrenaline is administered. This finding is, therefore, probably related to a shorter duration of low or no flow time after the onset of cardiac arrest. The later administration of adrenaline increases the chances of ROSC relative to placebo but without incremental improvement in longer term outcomes. This discordance may in part explain improved ROSC, but smaller effects on long-term survival and minimal influence on favourable neurological outcome.

The present study explored if the treatment effects differed according to whether the initial rhythm was shockable or non-shockable. In an analysis of in-hospital cardiac arrests with an initial shockable rhythm, Andersen et al. found that very early (within 2 min of first defibrillation) compared with no or late adrenaline (> 2 min) was associated with lower rates of ROSC (OR 0.71, 95% CI 0.60–0.83), survival (OR 0.70, 95% CI 0.59–0.82) and survival with a favourable neurological outcome (OR 0.69, 95% CI 0.58–0.83) [9]. In OHCA (time to drug administration 13 min), Ewy et al. found that delayed adrenaline reduced survival (aOR 0.94, 95% CI 0.91–0.97) in patients with shockable rhythms but did not affect neurological outcomes. Hayashi noted both improved survival and better neurological outcomes in those who received adrenaline within 10 min of cardiac arrest [32]. The present study suggests that very early adrenaline does not increase the rates of ROSC in patients with an initially shockable rhythm.

Overall outcomes are worse where the initial rhythm is non-shockable. During in-hospital cardiac arrest, Donnino et al. noted a stepwise reduction in survival and favourable neurological outcome with delays in adrenaline administration exceeding 1–3 min [10]. In OHCA, Hansen et al. found that every minute delay to the administration of adrenaline decreased survival (OR 0.96, 95% CI 0.95–0.98) and favourable neurological outcomes (OR 0.94, 95% CI 0.89–0.98) [33]. By contrast, the present study was consistent with Ewy et al. in finding no difference in longer term outcomes according to the time of adrenaline administration for patients with non-shockable rhythms [29].

Compared with observational studies, the randomised double-blind design of this trial reduced the influence of confounding (due to patient characteristics and resuscitation time bias), performance and ascertainment bias. The pragmatic nature of the trial, embedded within National Health Service Ambulance Services, increased generalisability to similar settings. Although defined a priori, analysis of time to drug administration was not the primary intent of the PARAMEDIC2 study. As such, the results should be considered exploratory and interpreted with caution. The study pooled EMS-witnessed and bystander witnessed cardiac arrests as there were insufficient numbers to analyse separately. For the sub-group analysis according to rhythm, patients were analysed in groups according to their initial presenting rhythm. This does not account for any subsequent rhythm transitions. The relatively few patients with an initial shockable mean the findings need to be interpreted cautiously. Post-resuscitation care treatments (targeted temperature management, haemodynamic and ventilator management, percutaneous coronary intervention, prognostication) were recommended but were not strictly protocolised or monitored. It is possible that different approaches to post-resuscitation care may have influenced longer term outcomes. Alternative dosing regimens such as higher or lower doses, use of a continuous infusion, may have produced different results. Finally, the findings of worse outcomes overall with later interventions should be considered when designing and estimating sample sizes in future trials.

In conclusion, rate of ROSC, survival and favourable neurological outcomes reduce the longer the duration of cardiac arrest. This confirms that early treatment of cardiac arrest rather than specifically the administration of adrenaline, provides the best outcomes. As time progresses, the effects of adrenaline on the rate of ROSC increase relative to placebo. By contrast, the rate of survival and favourable neurological outcomes was not substantively different over time between the adrenaline and placebo groups.