Possible significance of hemodynamic and immunomodulatory effects of early stress-dose steroids in cardiac arrest

In an interesting randomized clinical trial (RCT), Donnino et al. [1] studied a mixed out-of-hospital cardiac arrest and in-hospital cardiac arrest (IHCA) population and found no hydrocortisone versus placebo hemodynamic or in-hospital outcome benefit. In the hydrocortisone group, the median time to study intervention was 9.9 h after return of spontaneous circulation (ROSC) [1]. This time lag probably exceeds the therapeutic window for the prevention of detrimental episodes of early post-resuscitation hypotension [2] through a mean arterial pressure (MAP)-stabilizing effect of steroids [3, 4].

Analyses of pooled post-resuscitation shock data from our IHCA vasopressin-steroids-epinephrine (VSE) RCTs [3, 4] also showed no between-group differences in the time to, or proportions of, discontinuation of vasopressors, and post-ROSC day 1 hemodynamic support (Table 1). However, VSE patients had higher, early post-ROSC systolic arterial pressure (SAP) and MAP during post-resuscitation follow-up [3, 4]. This reflected an improved hemodynamic response to similar vasopressor support titrated to a “wide” MAP range of 70–100 mmHg [4].

Table 1 Pooled results (from [3] and [4]) on early post-enrollment hemodynamics in survivors for ≥4 h with post-resuscitation shock

Recordings of “early post-ROSC SAP >90 mmHg” (i.e., “absence of early post-resuscitation hypotension” [2]) and “≥1 recorded/analyzed, day 1 MAP value of >80 mmHg [2]” were significantly more frequent in VSE patients than controls. Importantly, such SAP/MAP levels corresponded to more frequent survival to hospital discharge with favorable neurological outcome [4] (Table 1).

Early post-resuscitation hemodynamics of VSE patients could be partly attributable to the steroids-vasopressin combination during cardiopulmonary resuscitation (CPR) [3, 4]. However, a previously postulated major CPR-VSE effect, i.e., shorter advanced life support duration [4], possibly leading to attenuated post-resuscitation cardiovascular dysfunction was not clear in the current subgroup analysis (Table 1). Hence, according to the short (i.e., 24 min) half-life of vasopressin, we propose that the more frequent day 1 MAP >80 mmHg was largely due to a post-ROSC steroid-induced augmentation of vascular responsiveness to vasopressors [3, 4]. A mediation analysis of VSE outcome benefit through day 1 MAP is warranted. Analysis of day 1 MAP data from the study by Donnino et al. might causally link between-RCT differences in corticosteroid timing with differences in survival/neurological outcome results [1, 3, 4].

Post-resuscitation disease is a “sepsis-like” syndrome. In sepsis, acute kidney injury severity is associated with mortality and elevated interleukin (IL)-6. Furthermore, high post-ROSC IL-6 is associated with organ dysfunction and poor long-term outcomes [5]. Notably, post-resuscitation hydrocortisone has been associated with reduced IL-6 levels [1, 3], and VSE patients versus controls had more renal failure-free days [3, 4].

Conclusively, available evidence prompts toward further evaluation of early, stress-dose steroids in cardiac arrest.

Abbreviations

CPR, cardiopulmonary resuscitation; IHCA, in-hospital cardiac arrest; IL, interleukin; MAP, mean arterial pressure; RCT, randomized clinical trial; ROSC, return of spontaneous circulation; SAP, systolic arterial pressure; VSE, vasopressin-steroids-epinephrine