This systematic review and meta-analysis aimed to explore the relationship between circulating cortisol level and adrenal reservation with eventual outcome of cardiopulmonary arrest. As far as our knowledge, no systematic reviews and meta-analysis has been conducted on the link between cortisol levels and adrenal reserve in cardiac arrest. The results of this meta-analysis indicated that although the baseline serum cortisol levels were higher in the survivors of CPA compared to the non-survivors, the differences between groups did not reach the significance level in CPA patients.
The self-defense responses of the body to stressful events include releasing stress hormones, such as cortisol, ACTH, and vasopressin [
22]. Since CPA is the most stressful crisis, it is presumed that the proper and timely secretion of these hormones contributes to the outcome and survival of these patients [
23]. Various studies have examined the effects of exogenous administration of these hormones, as therapeutic interventions on the clinical outcome of patients resuscitated after CA [
24‐
27]. As described in prior studies, the hypothalamic-pituitary-adrenal axis is moderately suppressed in this condition. This leads to a diminished release of cortisol from the adrenal cortex. This relative adrenal insufficiency is presented as an inadequate response of the adrenal cortex to the ACTH in victims of CPA [
1,
11,
14,
15]. Presumably, the underlying mechanism of this partial insufficiency is ischemia and anoxia of the adrenal glands. Vasopressors compensate for this defect, and cortisol, in turn, improves the vasoconstrictive responses to the effects of vasopressors [
28,
29]. Previous studies showed a direct relationship between high ACTH serum levels and relative adrenal insufficiency with poor clinical outcome and mortality rate [
1,
15].
Steroids have key roles in suppressing the over-activated systemic inflammation, scavenging the free radicals, and apoptosis. Furthermore, they improve the immune responses, boost cardiac performance, and reinforce the adrenergic responses [
30‐
32]. Moreover, the corticosteroids strengthen and maintain the vascular glycocalyx barrier integrity, which breaks down during cardiac arrest [
33]. Therefore, due to mentioned relative adrenal insufficiency and consequent endogenous deficiency of these compounds, it appears that supplemental doses of glucocorticoids may improve the clinical condition of patients and their eventual outcome. The results of our recent systematic review on the efficacy of steroids in patients with cardiac arrest suggested that supplementation with corticosteroids may improve the rate of survival and ROSC, especially in patients with hemodynamic instability and past medical history for cardiovascular disorders [
34].
The results obtained from this meta-analysis are crucial, yet they need to be interpreted carefully. Although we tried to explore all the studies in this field, only five studies met the inclusion criteria for meta-analysis. In three of these studies, non-survivors of CPA not only did have low baseline cortisol levels, but the patients’ cortisol levels were even higher than normal [
1,
11,
19]. Simultaneously, two clinical studies aligned to the results of this meta-analysis suggested a lower baseline cortisol level in non-survivors of CPA [
17,
18]. In the study by Hékimian et al., 32 resuscitated patients after out-of-hospital cardiac arrest were prospectively evaluated for baseline cortisol and adrenal reserve after ROSC. The authors of this high-quality cohort concluded that early death following CPA may be associated with adrenal insufficiency and inadequate response of the adrenal cortex to this stressful event [
11]. In another cohort study by Tavakoli et al., the serum levels of cortisol were assessed in 50 resuscitated OHCA patients after ROSC. In this prospective study, cortisol levels were significantly higher in those who neurologically survived than non-survivors [
18]. Mosaddegh et al. investigated the clinical outcome of 52 IHCA patients over 3 months. Regarding the design of the study, although the authors used the term “clinical trial,” no intervention was made and patients were only evaluated for the relationship between serum cortisol levels following ACTH stimulation test and in-hospital mortality and discharge from the hospital. No significant difference was observed in baseline levels of cortisol between survivor and non-survivors of IHCA [
19]. In the study by Ito, the possible link between the serum levels of stress hormones, including cortisol and the eventual outcomes of resuscitated patients after OHCA was investigated. In this study, with high quality and low risk of bias, the serum levels of cortisol were significantly higher in those who survived after CPA [
17]. Finally, in the fifth study included in this meta-analysis by Kim et al., the prevalence of relative adrenal insufficiency following ROCS after cardiac arrest was evaluated. In this study, basal cortisol levels were measured in 30 patients as a secondary endpoint. Contrary to expectations, the basal levels of cortisol were normal or even high in patients experiencing CPA [
1].
Unfortunately, the diversity of eligible studies for meta-analysis was high, and they did not have similar endpoints. These studies excluded the patients with unsuccessful CPR. Basal cortisol levels were not measured at all in the patients who did not effectively resuscitate. This may vigorously affect the taken results. The second major limitation of the present systematic review was the variation of the eligible studies for meta-analysis. As the significance between-study heterogeneity indicates, the included studies were inconsistent and heterogeneous. Moreover, the number of enrolled patients in these studies was limited so that the results of this meta-analysis were obtained from only 201 participants in total. This could justify the fact that the observed differences among the study groups did not reach a significant level, but still favored the lower basal cortisol in the non-survivors of CPA. Moreover, using therapeutic hypothermia is an effective intervention in CPA patients. Thus, this modality can act as a confounding factor on serum cortisol levels [
35,
36]. This intervention was initiated in two studies of Hékimian et al. and Kim et al. in all admitted patients as early as possible by using wet and cold wraps, ice packs, and with neuromuscular blocking and continued for 24 h [
1,
11]. Due to the small sample size in these studies, it was not possible to eliminate the effect of this confounder. High mortality in CPA patients can also affect the interpretation of mortality data.