Cardiac arrest remains a leading cause of morbidity and mortality worldwide [1]. Refractory cardiac arrest is defined by requiring >10 min of conventional cardiopulmonary resuscitaiton (CCPR) or >3 defibrillation attempts, and carries an even more dismal outcome [2]. In such cases, advanced cardiac life support and standard pharmacologic therapy have proven to be ineffective [2]. To address the poor survival and neurologic outcomes associated with refractory cardiac arrest, extracoporeal cardiopulmonary resuscitation (ECPR) is a modality that is being increasingly applied in this context with an exponential increase over the last 10 years, with >1500 cases performed annually worldwide [3]. ECPR is an extension of CCPR when standard therapy has proven ineffective by utilizing extracorporeal membrane oxygenation (ECMO) to provide approprate perfusion and gas exchange thereby facilitating the necessary time for etiologies of arrest to be addressed [[3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]].

Epinephrine is recommended during CCPR to increase systemic blood pressure, coronary artery perfusion, and improve rates of return of spontaneous circulation [1,[16], [17], [18], [19]]. Based on national and international guidelines, epinephrine is adminsitered every 3 to 5 min with seemingly no maximum dosage [20,21]. Currently, however, there are no specific guidelines directing epinephrine administration during the special case of ECPR. Unlimited administration of epinephrine during refractory cardiac arrest, however, can have a direct impact on ECPR given that escalating doses of epinpehrine can aggravate its adverse effects, especially with regards to neurologic function. Indeed, repeated doses of epinephrine beyond the third dose, can impair cerebral microvasular flow and increase cerebral ischemia despite providing no additional circulatory benefit as demonstrated by experiments in animals [22,23].

The concept of ECPR.

During refractory cardiac arrest, the primary goal in resuscitation is to deliver adequate perfusion of oxygenated and decarboxylated bood to vital end organs. The concept of ECPR necessitates alterations to the mechanisms employed to achieve this endpoint by relying on the rapid institution of extracorporeal circulation as opposed to exogenously applied external compression of the myocardial chambers in conjunction with pharmacotherapy to augment systemic diastolic perfusion pressure. Consequently, in the context of ECPR, all measures and interventions taken during the interim period preceeding institution of ECMO support should aim to optimize cerebral blood flow and perfusion to preserve neurologic function. In such instances, the benefit of increasing return of spontaneous circulation rates may no longer outweigh the potential harm of cumulative epinephrine doses. Therefore, the appropriateness of continual administration of epinephrine in this subgroup of refractory cardiac arrest patients receiving ECPR remains uncertain.

We therefore aimed to evaluate the impact of cumulative epinephrine dose during cardiac arrest on neurologic outcome after ECPR. Our secondary aim was to report the incidence of adverse events.