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
Time to discontinuation of vasopressors (days), median (IQR)b
| 4 (2–8) | 3 (2–6) | 0.86 |
Discontinuation of vasopressors during follow-up, n (%) | 43 (41.7) | 34 (38.6) | 0.77 |
Estimated cumulative vasopressor dose (μg/kg) over the first 24 h post-ROSC, median (IQR)c,d,e
| 552 (216–1225) | 629 (321–1236) (n = 87) | 0.15 |
Cumulative 24-h post-ROSC fluid balance (mL), mean ± SD | 2168 ± 2398 (n = 78) | 2034 ± 2198 (n = 60) | 0.74 |
SAP >90 mmHg within 15–20 min post-ROSC, n (%) | 76 (80.9) (n = 94) | 40 (55.6) (n = 72) | 0.001 |
At least 1 recorded/analyzed MAP value >80 mmHg over day 1, n (%) | 82 (80.4) (n = 102) | 35 (42.2) (n = 83) | <0.001 |
ALS duration (min), median (IQR) | 10 (6–16) | 12 (6–20) | 0.11 |
| SAP >90 mmHg (n = 116) | SAP ≤90 mmHg (n = 50) |
P value |
Survival to hospital discharge with CPC score of 1 or 2, n (%) | 23 (19.8) | 3 (6.0) | 0.02 |
| MAP >80 mmHg (n = 117) | MAP ≤80 mmHg (n = 68) |
P value |
Survival to hospital discharge with CPC score of 1 or 2, n (%) | 25 (21.4) | 4 (5.9) | 0.006 |
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
Availability of data and materials
For the purpose of the above-mentioned re-analysis protocol (Clinicaltrials.gov identifier, NCT02408939), we extracted individual peri-arrest and follow-up data from survivors for ≥4 h with post-resuscitation shock (
n = 191) from an electronic masterfile containing de-identified data from references [
3] and [
4]. Extracted, de-identified data was saved in a Microsoft Excel datafile. Data will not be shared because we plan to use it in a future mediation analysis mentioned in the fourth paragraph of the current main text.
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