Clinical Data with Glucocorticoids During Cardiac Arrest
The high mortality rate that has been observed in patients with CA-related adrenal dysfunction and the positive correlation of cortisol levels with survival in CPR raised the question of glucocorticoid supplementation during CPR [
6]. The use of glucocorticoids in CPR was first investigated in 1976 with the use of dexamethasone in pulseless electrical activity (PEA). White et al. reported the use of a single intravenous bolus of 100 mg dexamethasone in five patients with PEA. They showed a success in rhythm correction and increase in cardiac output after dexamethasone administration in resuscitation [
42]. Moreover, in 1979, White reported that supplementation of corticosteroids in PEA increased ROSC rate and long term survival. However, this study exhibited several limitations as it was a retrospective study with no assessment of CPR quality. Moreover, patients with pseudo-pulseless electrical activity were also likely included in the study [
43]. Furthermore, in a small (
n = 29) prospective, randomized study of patients with pre-hospital bradyasystolic CA, a larger proportion of patients treated with dexamethasone (
n = 17) were successfully resuscitated and discharged, compared to patients treated with saline (
n = 12). However, this difference was not statistically significant [
44]. Paris et al. conducted a prospective, randomized study with administration of 100 mg dexamethasone in patients with PEA in the pre-hospital setting. They failed to demonstrate any benefit from the administration of dexamethasone in PEA [
45]. However, the aforementioned studies demonstrated the effects of glucocorticoids in small sample size studies and did not provide information on the effect of glucocorticoid treatment on CA rhythms other than PEA.
This prospective and non-randomized trial evaluated the effect of hydrocortisone in ROSC rates. In this study hydrocortisone or placebo were given upon patient arrival to the emergency department. The results showed statistically significant increases in ROSC rates with 100 mg hydrocortisone (90 % vs 50 %,
p = 0. 045). Additionally, serum cortisol levels were not correlated with ROSC rates. Nevertheless, there was no significant difference between the two groups in terms of short-term survival and hospital discharge [
10]. These findings are in agreement with previous studies which showed that administration of glucocorticoids improved ROSC rates through supplying adequate serum cortisol levels [
24,
29]. Moreover, the authors reported that the incidence of electrolyte disturbances, infection, and GI tract bleeding in the early phase after ROSC did not increase with hydrocortisone use. However this study had several limitations as it was non-randomized and open-labeled and could potentially suffer from selection bias. Moreover, this pilot study had a small sample size and did not assess glucocorticoids efficacy with respect to neurologically favorable survival to hospital discharge [
10].
Vasopressin augments the release of cortisol and improves the rate of ROSC compared to epinephrine during CPR in an animal study [
16]. Therefore studies investigated the administration of stress hormone “cocktails” in order to improve the outcome of patients in cardiac arrest. In a double-blinded randomized single center study, 100 patients with CA were treated with either the combination of epinephrine and vasopressin during CPR and glucocorticoid supplementation during and after CPR or epinephrine alone during CPR and no steroids. Patients who received the drug combination had more frequent ROSC (81 vs 52 %,
p = 0. 003) and improved survival to hospital discharge (19 % vs 4 %,
p = 0. 02) vs patients who received only epinephrine. Furthermore, patients who received hydrocortisone in the post-resuscitation period had improved survival to hospital discharge (30 % vs 0 %,
p = 0. 02), improved hemodynamics and central venous oxygen saturation compared to patients who received placebo. Moreover, the authors pointed out that glucocorticoid administration increased the efficacy of vasopressors in maintaining adequate perfusion pressures. Glucocorticoids enhanced the inotropic actions of catecholamines and maintained vascular tone [
46]. However, this study only refers to in-hospital CA. Out-of-hospital trials must be conducted, given the different natures of these two populations. It must also be taken into account that the issue of chest compression quality was not addressed in this study. Moreover, patients were given a combination of vasopressors with glucocorticoids, which made difficult to isolate the effect of glucocorticoids on the outcome. Thus, it is unclear if these findings were related to corticosteroid supplementation or the combination of the medications used [
46].
In a randomized, double-blind, placebo-controlled study conducted by Mentzelopoulos, 268 patients with CA were randomly assigned to receive either epinephrine and vasopressin during the first five CPR cycles (
n = 130), or epinephrine plus saline placebo (
n = 138). During the first CPR cycle after randomization patients in the epinephrine, vasopressin, methylprednisolone group received methylprednisolone (40 mg) compared to saline placebo in the control group. Shock after resuscitation was treated with stress-dose hydrocortisone in the epinephrine, vasopressin, methylprednisolone group, (
n = 76) or with saline placebo (
n = 73). The combination of vasopressin and epinephrine along with methylprednisolone during CPR and hydrocortisone in post-resuscitation shock, resulted in improved survival to hospital discharge with favorable neurological status, compared with epinephrine and saline placebo (
p = 0. 02). The authors suggested that methylprednisolone during CPR conferred benefits with respect to hemodynamics by potentiating the vasoconstrictive effects of vasopressors [
9].
However, other studies show conflicting results regarding neurological outcome. In a retrospective comparison of low, medium and high steroid dose treatment to placebo in 191 patients with 8 h of ROSC after CA, the outcomes were similar with respect to one year mortality or neurological recovery (
p = NS). The authors concluded that glucocorticoid treatment was not likely to be beneficial after CA. However, this study had limitations. There were differences between the steroid-treated and the non-steroid treated groups with respect to baseline characteristics and CA etiology potentially favoring the no steroid-group. Moreover, this study evaluated a variable steroid treatment with low, medium, and high doses and not a stress-dose steroid supplementation [
12]. Furthermore another non-randomized retrospective study examined the effect of steroid treatment on the outcome of 458 consecutive patients admitted after out-of-hospital CA. In that study patients were assigned to either receive glucocorticoids or saline. No significant differences in survival or neurological recovery were identified [
47]. However, the aforementioned studies both exhibit limitations, as they were retrospective and non-randomized. Moreover, there was a variation in the dose of steroids as well as in the duration of steroid treatment. In addition to that, the protocol of the first study [
12] included post-resuscitation hyperventilation, which could compromise cerebral perfusion and adversely affect the neurological outcome. Finally, in the second study there was no pre-specified determination of hemodynamic targets [
47]. Thus, the above methodological and clinical practice differences could possibly explain the discrepancy in the results regarding the neurological outcome with recent studies [
9,
46]. Large, multicenter, randomized, placebo-controlled studies must be conducted in order to further evaluate the effect of glucocorticoid administration in global cerebral ischemia.
Several studies have addressed the relationship between timing of glucocorticoid administration and outcome of CPR. Glucocorticoid administration within 22 min after CA showed a higher ROSC rate in patients with witnessed CA (9). Moreover, in another study glucocorticoid treatment within 8 h after ROSC did not improve neurological recovery. The authors suggest that the negative outcome of CPR was related to late administration of glucocorticoids (12). Furthermore, Paris et al. failed to demonstrate any benefit from the administration of dexamethasone in PEA in the pre-hospital setting. They suggested that further studies with earlier and higher doses of glucocorticoids must be conducted [
45]. Mentzelopoulos et al. showed that a combination of vasopressors with glucocorticoid administration during CPR resulted in improved hemodynamics and survival. Although these results cannot be attributed solely to methylprednisolone [
46], early CPR drug administration might improve resuscitation outcome, especially in out-of-hospital CA [
48,
49]. Further studies must be undertaken in order to clarify whether early administration of glucocorticoids could improve the outcome of patients resuscitated after CA (Τable
1).
Table 1
Summary of studies regarding the use of glucocorticoids in the setting of cardiac arrest
Mentzelopoulos et al. [ 8] | 2013 | Prospective randomized clinical study | Combined vasopressin- epinephrine and methylprednisolone during CPR and hydrocortisone administration in post-resuscitation period, hydrocortisone in post-resuscitation shock, resulted in improved survival to hospital discharge with favorable neurological status |
| 2007 | Prospective non randomized clinical study | Hydrocortisone administration during CPR improved ROSC rate |
| 1989 | Prospective non-randomized clinical study | Glucocorticoid treatment after ROSC failed to demonstrate a beneficial effect on survival rate and neurological function |
| 1993 | Rat model of VF-induced CA | Hydrocortisone administered during CPR significantly increased ROSC rate |
| 1989 | Rat model of asphyxia- induced CA | Methylprednisolone given post CA facilitate ROSC and return of EEG activity |
| 1976 | 5 patients with pulseless idioventricular rhythms | Dexamethasone administered during CPR corrected rhythm and increased cardiac output |
| 1979 | 24 patients with pulseless idioventricular rhythms | Dexamethasone administered during CPR increased ROSC rate and long term survival |
| 1983 | Prospective randomized clinical study | Dexamethasone administered during CPR improved initial resuscitation (ROSC) and hospital discharge |
| 1984 | Prospective randomized clinical study | Dexamethasone administration failed to demonstrate a beneficial effect on long term survival |
Mentzelopoulos et al. [ 43] | 2009 | Prospective randomized clinical study | Combined vasopressin- epinephrine and methylprednisolone during CPR and hydrocortisone administration in post-resuscitation period improved ROSC and survival to hospital discharge |
| 1988 | Retrospective non-randomized clinical study | Glucocorticoid administration failed to demonstrate a beneficial effect on survival or neurological recovery |