CardioExchange Archive

Graham Nichol takes a close look at a recent randomized trial that examined whether combined vasopressin-epinephrine plus corticosteroids during CPR could improve survival and neurologic status in patients with in-hospital cardiac arrest. The trials results appear in JAMA.

Out-of-hospital and in-hospital cardiac arrest continue to be major public health problems in the U.S., with a combined burden of more than 500,000 fatalities annually.^1,2 Many communities have not reported improved outcomes after out-of-hospital cardiac arrest (OHCA) for more than 30 years.³ Despite the apparent lack of progress, there is a more than fivefold variation in survival after treatment of OHCA across communities.⁴ This large variation suggests that cardiac arrest is a treatable condition that warrants further investigation.

Cardiac arrest involves sudden, global ischemia. Reperfusion occurs during cardiopulmonary resuscitation (CPR) and restoration of circulation, and is associated with a marked release of circulating inflammatory molecules including cytokines, activated complement and polymorphonuclear leukocytes, and endothelial cell adhesion molecules.^5-8 After cardiac arrest, non-survivors demonstrate plasma interleukin-6 concentrations 20-fold greater than survivors,⁵ which is approximately 50-fold greater than normal human baseline values.⁹ In addition, patients with cardiac arrest have lower serum cortisol levels than those observed in other stress states.¹⁰ There is an association between serum cortisol and short-term outcomes in this population. Impaired response to corticotropin stimulation is not modified by application of induced hypothermia.¹¹ These inflammatory and coagulation changes contribute to poor capillary perfusion, tissue ischemia, multi-organ dysfunction, and death.^12-15 But many patients with early hemodynamic dysfunction that is reduced or treated do survive to have good neurologic outcomes.^5,16 Therefore, treatments that decrease early mortality related to inflammation and intractable shock could increase the number of survivors with good outcomes.

Differences in how manual chest compressions are applied to patients with OHCA by EMS providers are associated with differences in outcomes. Greater chest compression fraction,¹⁷ greater depth of chest compression,¹⁸ greater chest compression rate,¹⁹ and briefer perishock pauses are associated with better outcomes.²⁰ Thus, potential improvements in advanced cardiac life support should not be implemented at the expense of good basic care.

Previous studies provide conflicting estimates of the effect of intravenous epinephrine and vasopressors in patients with cardiac arrest. A randomized trial reported that use of intravenous drugs – including, but not limited to, epinephrine – improved survival to admission but not discharge compared with no intravenous drugs in patients with OHCA.²¹ Large effectiveness trials reported no survival benefit with vasopressin compared with epinephrine in patients with cardiac arrest.^22-24 A recent large observational study derived from a Japanese OHCA registry suggested that use of epinephrine was not associated with improved outcomes compared with no epinephrine.²⁵ However, concurrent analyses of overlapping datasets from the same registry suggested that early use of epinephrine was associated with improved outcomes compared with late or no epinephrine.^26,27 Importantly, the only trial of epinephrine versus placebo in patients with OHCA did not achieve its intended sample size because of lack of EMS provider equipoise. Nonetheless, this trial reported that epinephrine significantly improved restoration of circulation and admission to hospital and tended to improve survival to discharge.²⁸ Opinions of experts differ as to whether the consistent effect estimate and inconsistent significance observed in this trial reflects lack of power or lack of effect. In the absence of a randomized trial with adequate power to detect a significant difference in a clinically important outcome such as survival to discharge, I believe that the current standard of care during attempted resuscitation is to provide epinephrine as early as possible without disrupting provision of high-quality CPR.

Previously, a single-center, randomized, double-blind, placebo-controlled trial in Greece evaluated whether early immune modulation with or without vasopressors could improve outcomes in patients with in-hospital cardiac arrest with a first recorded rhythm of ventricular fibrillation.²⁹ Eligible patients allocated to the intervention group received intravenously vasopressin 20 IU during the first five CPR cycles and methylprednisonlone 40 mg during the first CPR cycle (n=48), followed by treatment of post-resuscitation shock with hydrocortisone 300 mg daily for 7 days (n=27). Patients allocated to the control group received intravenous saline placebo during each time period (n=52 in resuscitation phase; n=15 in post-resuscitation phase). Concurrent interventions in both groups included intravenous epinephrine 1 mg during each CPR cycle. Intervention group patients, compared with controls, had greater restoration of circulation (81% vs. 52%, p=0.003) and survival to discharge (19% vs. 4%, p=0.02). Among patients with post-resuscitation shock (apparently defined as inability to maintain mean arterial pressure greater than 70 mm Hg without vasopressors after volume loading), those who received corticosteroids had improved survival to discharge compared with controls (30% vs. 0%, p=0.02). The significant and important benefits of vasopressin and corticosteroids during attempted resuscitation and corticosteroids after resuscitation were considered sufficiently promising as to warrant replication in a larger trial.

Now, results from that larger trial have been published in JAMA. The multicenter, randomized, double-blind, placebo-controlled trial, also in Greece, used similar methods to the pilot study to evaluate similar interventions, with the notable exception that the current study enrolled patients with in-hospital cardiac arrest who required vasopressors as opposed to patients with a first-recorded rhythm of ventricular fibrillation. The intervention patients (n=130), who were allocated to vasopressin and corticosteroids during attempted resuscitation, had greater restoration of circulation than the control patients (n=138), who received saline alone (84% vs. 66%, p=0.005). The intervention group also had greater functional neurologic status at discharge (14% vs. 5%, p=0.02). Among patients with post-resuscitation shock (n=149), intervention patients who received corticosteroids had greater functional neurologic status at discharge than did controls (21% vs. 8%, p=0.02).

The study investigators should be congratulated on demonstrating significant and important benefits associated with the use of vasopressors and corticosteroids during attempted resuscitation as well as corticosteroids after resuscitation. The present trial used multiple methods to confirm its internal validity, including deploying chromatography to confirm drug stability, monitoring concurrent care, and achieving a high rate of follow-up. A notable strength of this trial was the use of masked allocation, as unblinding can increase estimates of treatment benefit by about 50%.³⁰ Use or non-use of blinding may explain discordant estimates of the effect of interventions in patients with OHCA.^31,32

The study has a few limitations that may affect whether these results apply to patients with OHCA or in-hospital arrest in other settings. First, patients who were randomized but had circulation restored before study drug administration were excluded from the analysis, so the aggregate benefit of the intervention may be overestimated. Second, the intervention group received both vasopressin and corticosteroids during attempted resuscitation, so it is difficult to determine their relative contributions to improved outcome. Of note, patients in the control group frequently received open-label corticosteroids. But given the prior lack of incremental benefit of vasopressin in addition to epinephrine, it seems plausible that the primary benefit is attributable to immune modulation with corticosteroids. Third, patients with post-resuscitation shock were not re-randomized to corticosteroids versus placebo. Instead, patients who were allocated to vasopressin and corticosteroids during resuscitation and then subsequently developed shock received additional doses of corticosteroids. Thus, the relative importance of early versus later corticosteroids warrants further study.

There is large regional variation in the processes of care for patients with cardiac arrest.^33,34 Importantly, interventions may have differential effects in patients with OHCA versus in-hospital cardiac arrest.^35,36 Interventions that improve outcomes in one geographic region may not improve it in another due at least in part to differences in patient characteristics and processes of care.^37,38 In addition, corticosteroids can impair myocardial healing in patients with acute myocardial infarction, which is commonly observed in patients with OHCA. The promising results of this trial warrant replication in a multicenter trial in centers that provide high-quality care to a high volume of patients with OHCA before adoption into clinical practice.

References

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