Our study showed that etomidate was associated with increased ICU mortality in cirrhotic septic patients. The administration of hydrocortisone improved hemodynamics but did not improve survival irrespective of whether the patient received etomidate or placebo. The lowest mortality was observed in patients who did not receive etomidate but received hydrocortisone.
Etomidate has been a favored agent for rapid sequence intubation due to its presumed hemodynamic profile but it has been shown to be strongly associated with adrenal insufficiency even after single doses. This was shown in several retrospective and prospective studies in the pediatric and adult population particularly in critically ill patients with sustained adrenal insufficiency that can extend up to 72 hours [5
]. Our results showed lower baseline cortisol, lower delta cortisol after ACTH test in the etomidate group compared to placebo but that did not reach statistical significance.
The impact of adrenal suppression by etomidate on mortality in the critically ill septic shock patients is still not clearly understood and highly debated with conflicting results and conclusions mainly from retrospective cohorts with many limitations. Malerba et al., in a retrospective study involving mechanically ventilated patients (33.9% had severe sepsis) demonstrated that etomidate administration leads to higher ICU mortality rates particularly among non-responders to ACTH test (70.4% of non-responders vs.31.4% of responders) [12
]. Furthermore, Annane et al. reported increased mortality rates among patients who received etomidate prior to intubation in a randomized placebo controlled trial looking at the effects of low-dose corticosteroid administration in critically ill septic shock patients [38
]. More recently, Cuthberston et al. in a priori sub-study of the CORTICUS study reported higher mortality rate that was only apparent after 10 days of ICU stay (42.7% vs. 30.5%, p = 0.02) [17
Not all literature supports the theory of increased mortality by etomidate in the critically ill septic shock patients. Mohammad et al. in a retrospective study of 152 septic shock patients, who had received etomidate did not show increased mortality versus control (63 vs. 55%, p = 0.45) in spite of adrenal suppressive effects [11
]. Similarly, Ray et al. in a review of 159 septic shock patients found no difference in mortality among patients that used etomidate versus other induction agents [18
]. A more recent study by Baird et al. also did not support the association of increased mortality by etomidate. His study reviewed the outcomes of 525 consecutive patients of whom only 9% were septic patients. They underwent rapid sequence intubation in the emergency department and were subsequently admitted to the intensive care unit. After correction for age, APACHE II score and presenting diagnosis, etomidate was not an independent predictor of hospital mortality [19
]. Jabre et al. conducted the only prospective randomized controlled trial comparing etomidate to another agent in rapid sequence intubation. Their study enrolling 655 trauma and septic patients showed no increased mortality with the use of etomidate compared to ketamine. Again, etomidate was associated with a significantly higher adrenal insufficiency rate (OR 6.7; 95% CI: 3.5-12.7); however the 28 day mortality for etomidate was 35% versus 31% for ketamine (p = 0.36). Subgroup analysis of the 76 septic patients showed no statistically significant difference in mortality with etomidate vs. ketamine with an odds ratio of 1.4 [95%CI 0.5-0.35] [20
Our study is the first to associate etomidate with increased ICU mortality in cirrhotic septic shock patients and alarm to its use in this vulnerable subset of patients. Our data did not show a statistically significant association between etomidate use and all cause 28-day or hospital mortality. This is possibly related to the high baseline mortality rate in the control group; a finding which is consistent with reported literature [31
]. Our patient population also suffers from high ammonia levels, well correlated with the presence of portosystemic collateral veins and advanced esophageal varices, reflecting further on the acuity of our patient population and possibly making them more vulnerable to vasodilation, worsening hemodynamics and poor prognosis in septic shock [39
]. We observed no significant differences in adrenal responsiveness with etomidate use, possibly because of the high prevalence of relative adrenal insufficiency at baseline. Whether etomidate worsened ICU mortality via its adrenal suppression effects or through other mechanisms still warrants further study. However, etomidate is also well known to cause hypoaldosteronism; to affect levels of interleukin 6 and 10 and may interfere with circulating lymphocytes levels and pro-inflammatory mediators necessary in sepsis. The impact of these factors on patients' outcomes is still not determined [40
Hydrocortisone supplementation in etomidate recipients to counteract its adrenal suppression effects is also a controversial concept. Annane et al. reported in their randomized placebo controlled trial a reduction in mortality among septic shock patients who received low-dose hydrocortisone [38
]. Subgroup analysis of the 68 ACTH test non-responders who had received etomidate showed higher ICU and hospital mortality rates in those who had been randomized to placebo vs. corticosteroids (75.7% vs. 54.8%; P = 0.03). Based on these results, the investigators suggested that hydrocortisone therapy should be administered to all septic patients who receive etomidate [26
]. However, contrary to the Annane study, Cuthberston et al. in the CORTICUS showed no improvement in mortality in patients supplemented with hydrocortisone [17
]. Again, this raises the to question whether the increased mortality by etomidate is due to unknown reasons beyond adrenal suppression.
Looking at our cirrhotic septic patients, hydrocortisone supplementation in the etomidate group lead to more ventilator free days and vasopressor-free days but this did not translate into significant improvement in ICU mortality, hospital mortality or 28 day mortality. In the placebo group, hydrocortisone supplementation also improved hemodynamics through lowering vasopressor requirements but this did not translate into statistically significant improvement in mortality.
We observed 100% mortality in the group that received etomidate but no hydrocortisone. On the other hand, the lowest ICU mortality was observed in the group of patients who did not receive etomidate but received hydrocortisone (Figure ). These results suggest that etomidate may be harmful in cirrhotic septic patients and that hydrocortisone may be beneficial if no etomidate is administered. However, these hypotheses need to be confirmed in future randomized controlled trials. Subsequent hydrocortisone replacement to etomidate seems to be associated with improved hemodynamics irrespective of the mechanism; being by adrenal replacement or by other anti-inflammatory actions and vascular hyporeactivity as suggested by other literature and this warrants further study [44
The results of our study should be interpreted in light of its strengths and limitations. Strengths include being the first study examining this important population, prospective data collection and being nested within a randomized controlled trial. On the other hand, the study is monocenter and the timing of ACTH test was not protocolized to etomidate administration due to the dynamics of the study and the emergent nature of intubations. Although, this might have affected measurements of adrenal function, it mimics real-life situations and would not have affected the main endpoints of the study which were the clinical outcomes.