The goal of resuscitation of a patient with a cardiac arrest (CA) is to re-establish blood flow and oxygen delivery to all tissues as quickly as possible and minimize detrimental physiological changes that may impact the long-term outcome of the patient, which is usually recorded as return of spontaneous circulation (ROSC), survival, or favorable neurologic outcome. Outcomes of cardiopulmonary resuscitation (CPR) vary dramatically depending on the availability of resources and health service delivery but even in a single city or country, the results of resuscitation in patients having a CA (and a nonshockable rhythm) will vary depending on three main factors. The first is the location of the CA with out-of-hospital CA patients doing worse than ward CA patients and ward CA patients doing worse than intensive care CA patients. The second is the pathophysiological diagnosis of the condition leading to the CA (septic shock, myocarditis with biventricular failure, cardiogenic shock following surgery, acute pulmonary hypertension, etc) and any underlying patient comorbidities. The third main factor is the type of cardiac rhythm at the time of initiation of CPR, in that, patients with bradycardia do better than those with pulseless electrical activity while asystolic patients have the worst outcome (1). Irrespective of location, diagnosis, and rhythm, epinephrine is usually the first drug requested and administered. When ROSC does not occur with the first dose of epinephrine, there are well-established international guidelines for the management of resuscitation, with repeated doses of epinephrine as one of the key parts of the CPR resuscitation protocols.

However, there has been much controversy over epinephrine dosing, with numerous studies evaluating the dose and frequency of administration of epinephrine during CPR. A randomized control trial of standard and high-dose epinephrine established that high-dose epinephrine was not better than a standard dose and possibly worse, with increased morbidity and lower survival (2). There have been conflicting studies evaluating the frequency of epinephrine dosing during prolonged resuscitation with studies showing better outcomes with frequent dosing (every 2 min [3]) or longer intervals between dosing (longer than 5 min and 8–10 min [4]) or intervals of 3–5 minutes (5). Current recommendations find a middle ground of approximately every 3–5 minutes, but it is unknown as to how frequently, in fact, these recommendations are followed during an actual CA given that, during simulation, deviations from protocol occurred in 7 of 15 scenarios, with incorrect or delayed adrenaline doses being ~89% of these (6).

The assessment of response to resuscitation is paramount to decision-making about further treatment. Simple assessment of heart rate, blood pressure, and central capillary refill time is useful, but hemodynamic goals of resuscitation linked to blood pressure and cerebral blood flow have been re-evaluated and importantly, linked to survival and even more importantly, linked to neurologic outcome. In one study, an increase in diastolic blood pressure of greater than or equal to 5 resulted in an increased adjusted likelihood ROSC; an increase in diastolic blood pressure of greater than or equal to 10 and greater than or equal to 15 was also associated with an increased likelihood of survival to hospital discharge and survival with favorable neurologic outcome (7). In an interesting pilot study, Kirschen et al (8) evaluated cerebral autoregulation after CA by using near-infrared spectroscopy (NIRS) and measured mean blood pressure (MAP); a cerebral oximetry index (COx) was calculated and used in determining optimal MAP and both Cox and MAP were related to outcome. Patients with unfavorable outcomes had a very low median COx 0.06 (0–0.2). A mean optimal blood pressure (MAPopt) was also developed and importantly, related to patient survival and neurologic outcome. A greater difference between MAP and MAPopt, as well as more time with MAP less than MAPopt were associated with unfavorable outcomes. If and when these studies are confirmed, all of these parameters provide useful objective targets for resuscitation and ongoing patient management.

There is no doubt that when standard CPR is failing, the use of extracorporeal membrane oxygenation (ECMO) improves survival. In a recent study, hospitals that had ECMO capability had a 50% survival of both in-house and out-of-hospital CA, as compared to 32% in non-ECMO-capable hospitals (9). Previous to this, a meta-analysis of 28 studies with 1,348 patients showed 46% survival and 30% favorable neurologic outcomes in pediatric extracorporeal CPR (eCPR) (10). However, in a systematic review evaluating adult and pediatric eCPR studies, it was unclear as to which adult patients were most likely to benefit (11) but children with congenital heart disease clearly had increased survival. A systematic review published in 2020, in Pediatric Critical Care Medicine (12), revealed marked variation in all aspects of peri-ECMO and post-ECMO management; results had survival outcomes of 8–80%. Many aspects of care were different, and this included the site of cannulation (central vs peripheral) which had studies with conflicting results, with some showing increased survival and improved neurologic outcome with central cannulation (13) but an Extracorporeal Life Support Organization Registry study showed improved survival with peripheral cannulation. Those who choose to do central cannulation (especially in children after cardiac surgery) argue that patient survival improves due to three factors—the chest opening itself decreasing pressure on a dilated heart, the improved performance of direct manual cardiac compressions, and the central ECMO cannulation itself having improved blood flow; the increase in mediastinitis that occurs with chest opening is justified by the improved neurologic outcome and overall survival. There is insufficient data to determine which cannulation strategy is best.

In this issue of Pediatric Critical Care Medicine, the study by Kucher et al (14) evaluates the impact of epinephrine doses on blood pressure and ECMO flow following cannulation after CA. The fundamental finding was minimal or no change in ECMO performance (ECMO flow rate, clearance of blood lactate) over the first few hours. This article gives a range of valuable data in this clinical scenario and also emphasizes a very important and sometimes neglected issue, namely, that the medication or treatments given immediately before or during eCPR cannulation need to be carefully evaluated for efficacy and safety, like all treatments in PICU. Epinephrine-induced hypertension may or may not be related to epinephrine dosing or epinephrine effects, it may or may not be sustained and it may or may not be related to other concurrent events associated with the CA, such as inadequate sedation or analgesia, hypothermia, encephalopathy or seizures, rapid decrease of hypercarbia (which had induced vasodilation and now vasoconstriction), other vasoconstrictor drugs being given before the CA or indeed the causes of the CA. The potential impact of hypertension and systemic vasoconstriction on ECMO flow (particularly with afterload sensitive centrifugal or impeller pumps) has been recognized and as shown in the study by Kucher et al (14), the target ECMO flow can usually be achieved (with or without the use of systemic vasodilation or extra volume expansion). Another very interesting point in this study is the very large variation in the number of doses of epinephrine administered (median 7, interquartile range [IQR] 4–10), the total amount of resuscitation dose of epinephrine (median 69, IQR 40–110 μg/kg) and the variation in time between the last dose of epinephrine and the time to ECMO cannulation (median 6, IQR 2–16 min). This is despite attempts to follow standard guidelines and reflects the complexity and variability of prolonged resuscitation and ECMO use after CPR and is also consistent with other publications.

Part of the impetus to evaluate epinephrine and eCPR was to provide data “in response to the findings of clinical practice change based on theoretical concerns about epinephrine during CPR leading to ECMO. For example, in a small 2018 cross-sectional survey of 150 cardiac ICU members of a U.S.-based professional society (15), 64% reported providing epinephrine doses in accordance with the Pediatric Advanced Life Support algorithm before ECMO cannulation, whereas 17% of the remainder limited resuscitation to 4–10 doses, and 19% to 1–3 only doses before cannulation. The data provided in the study by Kucher et al (14) confirm the safety of the guidelines and the practice of using epinephrine, 3–5 minutes, during CPR in preparation for ECMO cannulation; the data also document effective ECMO performance in clearing lactate and maintaining appropriate blood pressure. It is most appropriate that some vasoactive medication is used in the postresuscitation ECMO stabilization phase (whether vasoconstrictors, vasodilators, or inotropes) to provide optimal hemodynamics/organ perfusion (according to the goals of therapy).

The study by Kucher et al (14) has shown us that judicious use of epinephrine is safe and not associated with substantial negative effects on the achievement of adequate organ flow but that more research is needed to determine the optimal use of epinephrine and ECMO in patients with refractory CA. After the prevention of CA, optimization of organ perfusion and minimization of ischemia/reperfusion injury should remain the key issues in resuscitation after CA.

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