Effect of prehospital high-dose glucocorticoid on hemodynamics in patients resuscitated from out-of-hospital cardiac arrest: a sub-study of the STEROHCA trial

This was a sub-study of the STEROHCA trial, an investigator-initiated randomized placebo-controlled multicenter study investigating the anti-inflammatory and neuroprotective effects of early high-dose glucocorticoid treatment following resuscitated OHCA. The study protocol and the primary results have previously been published [12]. Prior to initiation, approvals for the study were obtained from the Regional Ethics Committee (ID: H-20022320) and the Danish Medicines Agency (ID: 2020033425). Further, the trial was registered at clinicaltrials.gov (NCT04624776), and monitored for Good Clinical Practice. According to the Declaration of Helsinki and national requirements, informed consent was provided from an independent physician prior to inclusion, from relatives after hospital admission, and from patients surviving and deemed cognitive habile to understand information regarding the study.

The study was performed at two cardiac arrest centers, Rigshospitalet and Gentofte Hospital, and the Emergency Medical Services, Capital Region, Denmark. From October 2020 to July 2022, 158 patients were enrolled. Of these, 137 patients encompassed the modified intention-to-treat population. Patients resuscitated from OHCA were prehospitally enrolled according to the following inclusion criteria: Age ≥ 18 years, unconsciousness (Glasgow Coma Scale ≤ 8), OHCA due to a presumed cardiac cause, and minimum five minutes of ROSC. In brief, the main exclusion criteria were asystole as primary rhythm and known therapy limitation. All inclusion and exclusion criteria are provided in the Additional file 1: Appendix. In the present sub-study, only patients who arrived at the hospital in a comatose state and were subsequently admitted to an ICU were studied.

A random number generator was used to create the allocation sequence, randomizing patients in a 1:1 ratio in permuted blocks of four. Study medication and placebo were placed in indistinguishable opaque boxes, assigned with random numbering according to allocation. Subsequently from inclusion of a patient, the prehospital staff were unblinded upon opening of a study box and administering study medication. In-hospital personnel, in addition to patients, relatives and outcome assessors, remained blinded for allocation.

Patients were assigned to receive either a bolus injection of 250 mg methylprednisolone (Solu-Medrol, Pfizer©) or placebo in the prehospital setting. Study medication was administered intravenously or intraosseous at the discretion of the treating physician. The intervention was completed as soon as possible following resuscitation with obtained ROSC for a minimum of 5 min and always before hospital arrival.

All patients underwent conventional treatment according to international post-resuscitation guidelines [6]. This included maintenance of a targeted temperature of 36° C in comatose patients, sedation primarily with propofol and fentanyl, and using vasopressors and inotropes at the discretion of the treating physician. Neurologic prognostication followed contemporary guidelines and remained blinded to the treatment. Balloon-tipped pulmonary artery catheters (PAC, Edwards Lifesciences, Irvine, CA) were routinely inserted at one of the sites (Rigshospitalet), but not at the other. PACs were inserted through the internal jugular or subclavian vein and subsequently removed either at the time of discharge from the ICU or after 72 h unless it was required for further clinical hemodynamic monitoring.

The aim of this sub-study was primarily to assess how high-dose glucocorticoid affected vasopressor use in the acute hospitalization phase following resuscitated cardiac arrest. Norepinephrine was the first-line vasopressor used at the two sites, and we defined the acute phase as the initial 48 h of ICU admission. The primary outcome was the average dose of norepinephrine used from ICU admission to 48 h in each patient. Secondarily, to further characterize hemodynamics and pharmacological supportive treatment, we examined MAP, heart rate and the vasoactive-inotropic score (VIS) which is calculated by all vasoactive and inotropic medications administered, reflecting support of the cardiovascular system [14]. A VIS/MAP-ratio was calculated at all time points to quantify the relationship between vasopressor and inotropic support provided and MAP, with a lower ratio indicating less reliance on pharmacological support to reach a certain MAP target, and a higher ratio suggesting the need for more aggressive treatment. We assessed central venous pressure (CVP), mean pulmonary arterial pressure (PAPm), cardiac output (CO), pulmonary capillary wedge pressure (PCWP), systemic vascular resistance (SVR), and mixed venous saturation (SvO2). Thermodilution-based CO, central venous blood for SvO2 drawn from the PAC, PCWP, and SVR measurements were only available in patients from one of the sites (Rigshospitalet), where PACs were routinely implanted. As secondary outcomes, we also aimed to assess clinical status and myocardial injury. Overall sequential organ failure assessment (SOFA) score and cardiovascular SOFA alone were assessed on calendar days 1–3 to describe clinical status. Further, survival status at hospital discharge and a minimum of 180 days from the cardiac arrest were obtained. Myocardial injury was characterized by the trajectory of Troponin T (TnT) or Troponin I (TnI) depending on the site, Creatine Kinase MB (CKMB), and N-terminal pro B-type natriuretic peptide (NT-proBNP). Biomarker measurements were performed using a COBAS 8000 and analyzed as part of routine biochemistry using a DS/EN ISO 15189 standardized laboratory.

All analyses in this sub-study were conducted in comatose patients within the modified intention-to-treat population from the STEROHCA trial. Dichotomous outcomes were presented with counts (n) and percentages (%) and compared between treatment groups using the Chi-squared test or Fisher exact test. Continuous outcomes were presented with medians and quartiles and compared with a Mann–Whitney U test. The primary outcome was compared between treatment groups using a two-sample t-test. Moreover, a sensitivity analysis was performed using a linear regression model to examine potential interactions between the treatment group and temperature target (specifically, 36 degrees Celsius vs. fever avoidance). Temporal differences between groups were compared using a linear mixed model including time, treatment, and the treatment-by-time interactions as fixed effects and with an unstructured covariance pattern to account for repeated measurements on each study participant. Skewed outcomes were log-transformed prior to analysis to approximate normal distribution (TnT, TnI, CKMB, and NT-proBNP) or square root function if values of “0” were present (norepinephrine, VIS, and VIS/MAP-ratio). Comparisons were made at all times of measurement predefined in the study protocol and reported as mean difference with 95% confidence interval (CI). The results are further visualized as group-specific medians with CI after back-transformation if necessary. Missing data were handled implicitly via maximum likelihood estimation in the linear mixed models.

All analyses were conducted with R version 4.2.2 [15]. The LMMstar-package [16] was used for linear mixed model analyses. Statistical significance was defined as a p value below 0.05 for all analyses.

The glucocorticoid group showed a lower cumulative dose of norepinephrine from ICU admission to 48 h after (mean difference − 0.04 mcg/kg/min, 95% CI − 0.07 to − 0.01, p = 0.02). There was no interaction of treatment group and temperature target on norepinephrine use (Treatment group x temperature target, p = 0.55). Although the norepinephrine dose was similar at ICU admission between the groups [0.03 mcg/kg/min (95% CI 0.01–0.04) vs. 0.02 mcg/kg/min (95% CI 0.01–0.03), p = 0.64], the glucocorticoid group exhibited lower norepinephrine use at various time points, with the most significant difference observed after 24 h (0.05 mcg/kg/min (95% CI 0.03–0.07) vs. 0.09 mcg/kg/min (95% CI 0.07–0.12), p = 0.01). No difference in MAP was found between the two groups at ICU admission (76 mmHg (95% CI 72–80) vs. 76 mmHg (95% CI 71–80), p = 0.95). However, from 6 to 48 h, the glucocorticoid group consistently exhibited higher MAP values, with the most significant difference noted after 18 h (78 mmHg (95% CI 74–81) vs. 70 mmHg (95% CI 67–74), p < 0.001). Consequently, from ICU admission to 48 h, the glucocorticoid group demonstrated lower values of the VIS at various time points. No differences in heart rate were observed between the two groups. The treatment effect for the hemodynamic parameters is depicted in Fig. 2A–D.

Evaluation of the VIS/MAP ratio revealed lower ratios in the glucocorticoid group at several time points, as illustrated in Fig. 3.

Hemodynamic values, along with their corresponding confidence intervals at each time point, are summarized in Additional file 2: Table S2.

At Rigshospitalet, a PAC was inserted in 54 (68%) patients as soon as possible after admission, and all patients had at least one measurement performed during ICU stay or until dying. Baseline characteristics of patients with- and without a PAC inserted are summarized in Additional file 2: Table S3. No differences in CVP, PAPm, SvO2, SVR, PCWP or CO were found between the two treatment arms, Fig. 4A–F.

No distinctions between groups were observed in ICU length of stay, ventilator days, or SOFA total score during the initial three days of admission. Nevertheless, on the second and third day, the glucocorticoid group exhibited a reduction in SOFA cardiovascular score. There was no difference in mortality rates at hospital discharge or 180 days after the cardiac arrest. All clinical outcomes are summarized in Table 1.

There was no difference between groups in biomarkers of myocardial injury or NT-proBNP during the initial 48 h of admission, Additional file 2: Fig. S2.