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Editorial September 29, 2021

Vasopressin and Steroids as Adjunctive Treatment for In-Hospital Cardiac Arrest

Jason Haukoos, Ivor S. Douglas, Comilla Sasson

JAMA. Published online September 29, 2021. doi:10.1001/jama.2021.15460

Cardiopulmonary arrest occurs in approximately 290 000 hospitalized patients annually in the United States, representing nearly 1% of all admissions and with survival estimated at 20%.1 To date, most research on cardiopulmonary arrest has focused on patients who experience cardiac arrest in the out-of-hospital setting with results extrapolated to those with cardiac arrest in hospitals. However, there are distinct differences in the treatment of patients who experience cardiac arrest in the hospital setting where disease processes, etiologies, and illness severity differ and medical response time is often shorter.

Cardiac arrest survival is affected by immediate recognition of the arrest, performance of high-quality chest compression with minimal interruptions, rapid defibrillation for shockable rhythms (ie, ventricular fibrillation or pulseless ventricular tachycardia), and prompt use of medications such as epinephrine.2,3 Epinephrine, a potent α- and β-adrenergic agonist augments coronary perfusion pressure by increasing aortic pressure and thus coronary perfusion pressure. Increased coronary perfusion pressure has been shown to be associated with increased rates of return of spontaneous circulation, the first critical target necessary for survival.4

Over the past several decades, investigators have explored numerous other medications for the treatment of cardiac arrest with the objective of increasing the probability of return of spontaneous circulation and enhancing functional survival. Vasopressors (eg, vasopressin), antidysrhythmic medications (eg, amiodarone), and other adjunctive therapies (eg, magnesium, sodium bicarbonate, calcium, and steroids) have all been evaluated with limited efficacy.

Two randomized clinical trials by Mentzelopoulos et al5,6 published in 2009 and 2013 reported improved functional survival among patients who experienced in-hospital cardiac arrest when vasopressin and methylprednisolone were bundled with epinephrine during resuscitation with the addition of hydrocortisone for up to 7 days for those with postresuscitation shock. A recent meta-analysis that pooled the results of these studies further confirmed significant associations between the use of these therapeutic adjuncts and return of spontaneous circulation, survival to hospital discharge, and survival with good neurological function.7

In this issue of JAMA, Andersen and colleagues8 report findings of the VAM-IHCA randomized clinical trial, a multicenter study to evaluate the efficacy of vasopressin and methylprednisolone administered in combination with standard advanced life support, including use of epinephrine, during resuscitation among patients who experienced in-hospital cardiac arrest. This study included 501 adult patients from 10 hospitals in Denmark who were randomized to receive either a combination of vasopressin (20 IU) and methylprednisolone (40 mg) or placebo after the first dose of epinephrine with additional doses of vasopressin or placebo administered after each additional dose of epinephrine for a maximum of 4 doses (up to 80 IU). Subsequent care was otherwise not standardized, including administration of glucocorticoids during the postresuscitation phase, which was left to the clinicians’ discretion.

The authors report a significant improvement in return of spontaneous circulation among patients who received vasopressin and methylprednisolone (100/237 [42%]) compared with those who received placebo (86/264 [33%]) (P = .03), but no difference in 30-day survival (23/237 [10%] vs 31/264 [12%], P = .48) or survival with good neurologic function (18/237 [7.6%] vs 20/264 [7.6%], P > .99). The authors subsequently concluded that use of vasopressin and methylprednisolone, when combined with usual advanced life support, improved return of spontaneous circulation but had uncertain subsequent survival benefit.

The VAM-IHCA trial was well executed, although several important considerations from this study should be understood and contextualized. This clinical trial represents the largest and most generalizable study to evaluate the combination of vasopressin and steroids when added to usual care advanced life support for in-hospital cardiac arrest, and was ostensibly performed to validate results of the prior trials by Mentzelopoulos et al. Those trials were conducted over a decade ago in Greece and included a total of 368 patients (in one study, 100 patients from a single center5 and in the other study, 268 patients from 3 tertiary care centers6). Combined data from the trials demonstrated similar, statistically significant, and clinically meaningful improvements in return of spontaneous circulation (difference of 21% in favor of vasopressin and methylprednisolone) and survival with good neurologic function (defined by a Cerebral Performance Category score of 1 or 2) (difference, 11% [95% CI, 4%-17%] in favor of vasopressin and methylprednisolone). Moreover, among the subgroup of 191 patients with postresuscitation shock included in both trials, use of vasopressin and steroids was associated with a larger increase in survival with good neurologic function (difference, 17% [95% CI, 7%-26%] in favor of vasopressin and steroids). These results provided a foundation for subsequent study and generated interest in use of these additional therapies, with adoption by some clinicians in clinical practice, for patients who experience in-hospital cardiac arrest with subsequent shock.

However, a notable difference between the current study by Andersen et al8 and the previously published studies5,6 was the use of glucocorticoids during the postresuscitation period. The VAM-IHCA trial did not stipulate glucocorticoid use following return of spontaneous circulation, suggesting that the study protocol may have mechanistically targeted return of spontaneous circulation as an outcome. During resuscitation, epinephrine and vasopressin, both strong vasoconstrictors, improve the likelihood of return of spontaneous circulation, whereas glucocorticoids upregulate expression of α receptors on vascular endothelium, thus potentiating the effects of adrenergic agents.9 Subsequent postresuscitation effects of glucocorticoids in the setting of shock likely also include support of adrenal insufficiency and modulation of the systemic inflammatory response syndrome that results after ischemia reperfusion. Thus, the combination of both immediate and sustained use of glucocorticoids, especially among patients identified with adrenal insufficiency,10 has the potential to improve outcomes.

In the VAM-IHCA trial, all patients received targeted temperature management, although several differences existed between study groups during the postresuscitation period. Among the 124 patients who survived at least 24 hours, 46% (28/61) from the placebo group received some form of glucocorticoid administration vs 24% (15/63) from the vasopressin and methylprednisolone group (P = .01), and 30% (18/61) from the placebo group underwent venoarterial extracorporeal membrane oxygenation vs 14% (9/63) from the vasopressin and methylprednisolone group (P = .04). Whether extracorporeal life support was implemented as a cardiopulmonary resuscitation modality or in the context of postarrest vasopressor-resistant shock was not fully characterized. Most guidelines consider extracorporeal membrane oxygenation as contraindicated among patients who are deemed to have a severe neurologic injury and lower probability of functional neurocognitive recovery,11 suggesting a potential unmeasured imbalance in early neurocognitive assessments between the study groups. Ultimately, although the study was not powered to independently evaluate these subgroups, these differences in postresuscitation care may have attenuated a true survival difference.

In addition, although nonshockable cardiac rhythms (asystole and pulseless electrical activity) were the most common initial postarrest rhythms across all 3 trials, ranging from approximately 83% to 90%, the prevalence of pulseless electrical activity as an initial arrest rhythm was substantially higher in the VAM-IHCA trial (54%) than in the 2 earlier trials (19%).5,6 In these earlier smaller trials, vasopressin and steroids were significantly associated with a survival benefit despite most patients in the study cohorts presenting with initial rhythms of asystole, which is commonly associated with the poorest prognosis.12 The postulated mechanisms of improved systemic vascular resistance by vasopressin and steroid therapy during resuscitation is highly effective in primary cardiac and circulatory arrest, often associated with ventricular fibrillation, pulseless ventricular tachycardia, and asystole. However, it is unclear whether the same amplitude of effect would be anticipated in primary respiratory arrest that degenerates into pulseless electrical activity arrest, raising the question as to whether vasopressin and steroids during resuscitation may be more or less effective in certain subpopulations.

The study by Andersen et al8 in this issue of JAMA provides important new data from a contemporary multicenter clinical trial that adds to the evidence base regarding the use of vasopressin and steroids for in-hospital cardiac arrest. As with all resuscitation research, there are challenges with conducting studies involving patients with cardiac arrest in both out-of-hospital and in-hospital environments, highlighting the need for enhanced global efforts to standardize the design, implementation, and analysis of resuscitation studies to improve external validity and reproducibility. Additional research is needed to further define the effect of vasopressin and steroids, and other interventions, on outcomes for patients with in-hospital cardiac arrest (including continued use of steroids during the highly vulnerable postresuscitation phase and standardized postresuscitation modalities), evaluated in clinical trials specifically powered to test a difference in survival with good neurologic function. Until then, the use of vasopressin and steroids for patients with in-hospital cardiac arrest is not ready for usual care but may be considered when patients remain unresponsive to more conventional treatments.

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