Effect of Stress-dose Steroids on Post-resuscitation Infectious (Septic) Complications After In-hospital Cardiac Arrest. Individual Patient Data-based Re-analysis of Synthesized Prior Randomized Clinical Trial Data

BACKGROUND AND RATIONALE Patients successfully resuscitated after cardiac arrest experience a "sepsis-like" syndrome characterized by cytokine storm, endotoxemia, coagulopathy, and various degrees of adrenal insufficiency. These pathophysiological mechanisms contribute to the development of circulatory failure, i.e. post-resuscitation shock. Post-resuscitation shock patients resuscitated from vasopressor-requiring cardiac arrest are frequently poorly responsive to high-rate vasopressor infusions (e.g. norepinephrine ≥0.5 μg/kg/min) and intravenous fluids.

The postresuscitation systemic inflammatory response syndrome (SIRS) may be partly caused and subsequently amplified by ischemia/reperfusion (I/R)-associated disruption of the intestinal mucosal barrier. Steroids may suppress key events of I/R injury propagation. Furthermore, in shock states, stress-dose steroids improve vascular responsiveness to vasopressors and preserve monocyte and neutrophil phagocytosis, and dendritic cell function. Low-dose steroids may reduce the mortality of severely ill patients with septic shock.

Nosocomial infections constitute an important cause of postresuscitation mortality. We hypothesized that exposure to stress-dose steroids during and/or after CPR may be associated with reduced risk of death due to postresuscitation infectious complications. To test this hypothesis, we combined data from two prior, prospective studies of in-hospital cardiac arrest. These studies compared the combination of vasopressin, steroids, and epinephrine (VSE) to epinephrine alone, with respect to survival to hospital discharge and good functional outcome. Patients with post-resuscitation shock of the VSE groups received stress dose hydrocortisone (300 mg/day for 7 days maximum, followed by gradual taper at a rate of 100 mg / day and discontinuation on day 10). Patients with post-resuscitation shock of the control groups received saline placebo. Follow-up rates were high in both studies and the reported incidence of post-resuscitation infectious complications was similar in the VSE and control groups.

METHODS Study Design Retrospective analysis of prospectively collected data from two randomized, clinical studies. 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 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. Moreover, the investigators have requested the permission to confirm previously recorded microbiological data through the hospitals' electronic databases The institutional review boards (IRBs) of the aforementioned hospitals have granted their approval for the current study. Evaggelismos Hospital approval No. 14/9/1/2015; 401 Greek Army Hospital approval No. 3/2015/5/2/2015; Larissa University Hospital approval No. 58905/2014/14/1/2015. Modifications of statistical terminology [from individual patient data (IPD) meta-analysis to IPD re-analysis] and of infections' classification in the definition of the primary outcome were also approved by the Evaggelismos IRB (respective Approval Nos. 30/25/2/2016 and 29/25/2/2016) and communicated to the other 2, aforementioned IRBs. These approvals were ratified by the IRBs of the other 2 participating centers (401 Greek Army Hospital, IRB Decision No.: 4-2016/6/4/2016; Larissa University Hospital, IRB Decision No.: 5/19-5-2016/Θ.18). Additional, significant amendments of the analysis protocol aimed at primarily evaluating the effect of stress-dose steroids on lethal septic shock were approved by the Evaggelismos IRB (Approval No. 9/26/1/2017) and appropriately communicated to the other 2, aforementioned IRBs.