Physiologic effects of stress dose corticosteroids in in-hospital cardiac arrest (CORTICA): A randomized clinical trial

Spyros D Mentzelopoulos, Evanthia Pappa, Sotirios Malachias, Charikleia S Vrettou, Achilleas Giannopoulos, George Karlis, George Adamos, Ioannis Pantazopoulos, Aikaterini Megalou, Zafeiris Louvaris, Vassiliki Karavana, Epameinondas Aggelopoulos, Gerasimos Agaliotis, Marielen Papadaki, Aggeliki Baladima, Ismini Lasithiotaki, Fotini Lagiou, Prodromos Temperikidis, Aggeliki Louka, Andreas Asimakos, Marios Kougias, Demosthenes Makris, Epameinondas Zakynthinos, Maria Xintara, Maria-Eirini Papadonta, Aikaterini Koutsothymiou, Spyros G Zakynthinos, Eleni Ischaki, Spyros D Mentzelopoulos, Evanthia Pappa, Sotirios Malachias, Charikleia S Vrettou, Achilleas Giannopoulos, George Karlis, George Adamos, Ioannis Pantazopoulos, Aikaterini Megalou, Zafeiris Louvaris, Vassiliki Karavana, Epameinondas Aggelopoulos, Gerasimos Agaliotis, Marielen Papadaki, Aggeliki Baladima, Ismini Lasithiotaki, Fotini Lagiou, Prodromos Temperikidis, Aggeliki Louka, Andreas Asimakos, Marios Kougias, Demosthenes Makris, Epameinondas Zakynthinos, Maria Xintara, Maria-Eirini Papadonta, Aikaterini Koutsothymiou, Spyros G Zakynthinos, Eleni Ischaki

Abstract

Aim: Postresuscitation hemodynamics are associated with hospital mortality/functional outcome. We sought to determine whether low-dose steroids started during and continued after cardiopulmonary resuscitation (CPR) affect postresuscitation hemodynamics and other physiological variables in vasopressor-requiring, in-hospital cardiac arrest.

Methods: We conducted a two-center, randomized, double-blind trial of patients with adrenaline (epinephrine)-requiring cardiac arrest. Patients were randomized to receive either methylprednisolone 40 mg (steroids group) or normal saline-placebo (control group) during the first CPR cycle post-enrollment. Postresuscitation shock was treated with hydrocortisone 240 mg daily for 7 days maximum and gradual taper (steroids group), or saline-placebo (control group). Primary outcomes were arterial pressure and central-venous oxygen saturation (ScvO2) within 72 hours post-ROSC.

Results: Eighty nine of 98 controls and 80 of 86 steroids group patients with ROSC were treated as randomized. Primary outcome data were collected from 100 patients with ROSC (control, n = 54; steroids, n = 46). In intention-to-treat mixed-model analyses, there was no significant effect of group on arterial pressure, marginal mean (95% confidence interval) for mean arterial pressure, steroids vs. control: 74 (68-80) vs. 72 (66-79) mmHg] and ScvO2 [71 (68-75)% vs. 69 (65-73)%], cardiac index [2.8 (2.5-3.1) vs. 2.9 (2.5-3.2) L/min/m2], and serum cytokine concentrations [e.g. interleukin-6, 89.1 (42.8-133.9) vs. 75.7 (52.1-152.3) pg/mL] determined within 72 hours post-ROSC (P = 0.12-0.86). There was no between-group difference in body temperature, echocardiographic variables, prefrontal blood flow index/cerebral autoregulation, organ failure-free days, and hazard for poor in-hospital/functional outcome, and adverse events (P = 0.08->0.99).

Conclusions: Our results do not support the use of low-dose corticosteroids in in-hospital cardiac arrest.Trial Registration:ClinicalTrials.gov number: NCT02790788 ( https://www.clinicaltrials.gov ).

Keywords: Heart Arrest; Hemodynamics; Hydrocortisone; Methylprednisolone; Post-cardiac arrest syndrome.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

© 2022 The Authors.

Figures

Fig. 1
Fig. 1
The study flow chart. ROSC, return of spontaneous circulation; ALS, advance life support; ICU, intensive care unit; CPR, cardiopulmonary resuscitation; PRS, postresuscitation shock. *, Pertains to any confirmed deviation from the ALS algorithms presented in references 25 and 26; two patients (control, n = 1) were excluded after randomization. †, Consent was refused within 48 hours of ROSC in all cases; four of these patients were initially randomized to the control group. ‡, Four patients were started on open label, stress-dose hydrocortisone within 24 hours post-ROSC; in 3 of these patients, the prescribed hydrocortisone dose differed from the dose specified by the study protocol; study treatment was withheld in another 3 patients within 24 hours post-ROSC; consequently, a total of 6 patients were not treated as randomized. §, Nine patients were started on open label stress-dose hydrocortisone within 24 hours post-ROSC; consequently, these patients were not treated as randomized.
Fig. 2
Fig. 2
Time course of mean arterial pressure (A), log-transformed vasopressor infusion rate in patients who received vasopressors and no./total no. (%) of patient-days of vasopressor use (B), and log-transformed interleukin (IL)-6 (C) in the Steroids and Control group. Data are presented as mean (95% confidence interval). ITT analysis: intention-to-treat mixed-model analysis corresponding to the first 72 hours postresuscitation; EXPL: exploratory mixed-model analyses corresponding to days 1–10 (A, B) or to days 1–7 (C) postresuscitation. In B, the nos./total nos. (%) of patient days of vasopressor use were compared by Fisher’s exact test. ROSC, return of spontaneous circulation. AIC: Akaike information criterion; %VE: percent variance explained, which reflects the squared Pearson correlation coefficient determined by linear regression with observed variable values as dependent variable and mixed model-estimated variable values as independent variable. A, B, and C: The sequences of numbers just above the horizontal axes represent nos. of patients participating in the analysis at the respective follow-up time points. B: The numbers on the top of the bars reflect numbers of patients not receiving any vasopressor support at the corresponding time-points of follow-up. †, Additional model information: A, ITT and EXPL analysis: effect of center and insulin infusion rate, P = 0.17 to 0.52. ‡, Additional model information: B, ITT and EXPL analysis: effect of center, insulin infusion rate, and blood glucose, P = 0.22 to 0.71. §, Additional model information: C, ITT and EXPL analysis: effect of center P = 0.10 to 0.11. †,‡,§, Log-transformed values were actually used in all analyses, because data exhibited skewed distributions; in A, we present the actually observed/recorded values of mean arterial pressure in mmHg, solely for the purpose of a simplified and clear presentation.
Fig. 3
Fig. 3
Probability of survival with a Cerebral Performance Category (CPC) score of 1 or 2 until day 60 after the return of spontaneous circulation (ROSC), which was identical to survival to hospital discharge with a CPC score of 1 or 2; intention-to-treat (ITT) analysis. “No. Alive:” reflects total number of participants minus (1) those who died before the corresponding time point; and (2) those in whom neurologic failure (i.e. Glasgow Coma Scale score of ≤9) was confirmed (before the corresponding time point) and was followed either by death before hospital discharge (without any intervening neurologic failure free day) or by determination of a CPC score of 3 or 4 at hospital discharge (again, without any intervening neurologic failure free day). Therefore, “No. Alive” reflects patients who could still achieve hospital discharge with a CPC score of 1 or 2.

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