No funding could be obtained for this study

Early stress-dose steroids are of uncertain efficacy in cardiac arrest. The current authors plan to conduct a pertinent mediation analysis using prospectively collected data from 2 prior randomized clinical trials of in-hospital cardiac arrest. These trials reported positive results on the vasopressin-steroids-epinephrine (VSE) combination. The current analysis is aimed at identifying mediators of the benefit associated with VSE, potentially attributable to its stress-dose steroid subcomponent. Tested mediators will include arterial pressure in the early postresuscitation period (primary), and arterial blood lactate in the early postresuscitation period and renal failure free days (secondary).

BACKGROUND AND RATIONALE The usefulness of stress-dose hydrocortisone in cardiac arrest is uncertain, especially when its administration starts at 10 hours after the return of spontaneous circulation (ROSC) (1). Such delay, probably exceeds the therapeutic window for the prevention of detrimental episodes of postresuscitation hypotension (2) through a steroid-induced hemodynamic stabilization (3,4).

In the context of NCT02408939, recent post hoc exploratory analyses in postresuscitation shock (n=191) showed an improved early post-ROSC hemodynamic profile in patients treated with the vasopressin-steroids-epinephrine (VSE) combination. Pooled data originated from our prior VSE 1 and VSE 2 randomized clinical trials (RCTs) (3,4) Recordings of "early post-ROSC systolic arterial pressure (SAP) >90" mmHg [i.e. "absence of early postresuscitation hypotension" (2)], and "≥1 recorded/analyzed, day-1 mean arterial pressure (MAP) value of >80mmHg (2)," were significantly more frequent in VSE patients vs. controls. After considering the short vasopressin half-life of 24 min and that the VSE protocol mandates vasopressin use solely during cardiopulmonary resuscitation (CPR) (3,4), we postulate that the more frequent "day-1 MAP>80 mmHg" can be attributed to the MAP-stabilizing effects of early stress-dose steroids (3,4). Under this assumption, a mediation analysis of VSE outcome benefits through day-1 MAP might further address the knowledge gap of steroids' usefulness in cardiac arrest (5).

METHODS Study Design. Intention-to-treat, retrospective analysis of prospectively collected data from two RCTs (3,4). Study participants were hospitalized in intensive or coronary care units (ICUs or CCUs) of three tertiary care centers: Evaggelismos General Hospital and 401 Greek Army Hospital (both in Athens, Greece), and University Hospital of Larissa, Larissa, Greece.

Ethics and Approval. The present analysis of de-identified, previously collected and electronically stored patient data (see also Detailed Descriptions of NCT00729794 and NCT02408939) is not associated with any clinical intervention, and therefore, the investigators have applied for a waiver of informed consent from either the patient or his/her next of kin.

Analysis Endpoints are presented in the dedicated subsection. Patients. The reference study population consists of 368 patients (Evaggelismos Hospital, n=288/368=78.2%) with in-hospital cardiac arrest, who required epinephrine during CPR according to the 2005 Guidelines for Resuscitation (6). During CPR, VSE group patients (n=178) also received vasopressin and methylprednisolone and controls (n=190) the respective saline placebos. At 4 hours after CPR, there were 211 surviving patients (VSE group, n=115), who were evaluated for postresuscitation shock (3,4). One hundred three VSE group patients were then assigned to stress-dose hydrocortisone and 88 controls to saline placebo. Of the 103 VSE group patients, 102 received stress-dose hydrocortisone, whereas 1 did not because of study pharmacist error; of the 88 control group patients, 73 actually received saline placebo, whereas 15 received open-label stress-dose hydrocortisone by protocol violation and according to the orders of their attending physicians (4).

Multivariable Analysis - Effect Modifiers In addition to variables described in the Outcomes subsection, the multivariable analysis will include the following potential effect modifiers: Data Source (VSE2 vs. VSE1 study), Study Center (4), group (VSE vs, control), cardiac arrest cause (cardiac vs. non-cardiac), area of cardiac arrest occurrence (monitored vs. non-monitored), initial cardiac arrest rhythm (shockable vs. non-shockable) atropine use (yes vs. no), prescribed total dose of sodium bicarbonate, cardiac arrest occurrence on holiday vs. working day; Cardiac arrest occurrence at night (23:00-07:00) vs. morning-to-late evening (07:00-23:00), total dose of epinephrine during CPR, and therapeutic hypothermia (use vs. no use).

All analyses will be conducted with SPSS version 22.0 (IBM, Armonk, NY) and the Process Procedure for SPSS, release 2.15. Statistical methodology reference: Hayes AF. Part II, Mediation Analysis. In: Hayes AF, ed. Introduction to Mediation, Moderation, and Conditional Process Analysis. A Regression-based Approach. The Guilford Press, New York. 2013, 3-419. 85-207.

Inclusion Criteria:

Adult patients with vasopressor-requiring inhospital cardiac arrest according to guidelines for resuscitation 2005, defined as:

• epinephrine requirement for ventricular fibrillation/tachycardia
• or asystole, or
• pulseless electrical activity

Exclusion Criteria:

• Age < 18 years;
• Terminal illness or do-not resuscitate status;
• Cardiac arrest due to exsanguination;
• Cardiac arrest before hospital admission;
• Pre-arrest treatment with intravenous corticosteroids;
• Previous enrollment in or exclusion from the 2 studies included in the analysis.

Adult patients with vasopressor-requiring, inhospital cardiac arrest, i.e., with asystole, pulseless electrical activity, or ventricular fibrillation/pulseless ventricular tachycardia not responsive to two attempts at defibrillation. Patients have already participated in 2 prior RCTs (references 3 and 4). Thus, the below-provided Eligibility Criteria are the Criteria already employed by the prior RCTs.