The results of our study show that, first, intubation in septic shock patients was associated with a 36% rate of short-term life-threatening complications and that this rate was independent of the hypnotic used to facilitate the procedure. Second, to our surprise, in unmatched cohorts and after matching using a propensity score analysis, the administration of a single dose of etomidate in septic shock patients treated with hydrocortisone was associated with a lower risk of day-28 mortality (Table ).
Potential confounding factors of the study must be addressed. First, this study was a single-center observational study in which the hypnotic used for induction of anesthesia was not randomized. Second, this was a small study subject to unmeasured or residual confounding (for example, patient heterogeneity, heterogeneity for intubation indication, protocol deviation), which is a limitation. The propensity score, however, is a tool to increase the accuracy of results in cohort studies [37
]. Moreover, external validity of observational studies may be higher than for randomized controlled trials. Third, because of the study design, we cannot provide detailed explanations about the protective mechanisms of etomidate on long-term outcomes.
In the present study, the hypnotic used to facilitate intubation in critically ill patients was mainly etomidate to limit the risk of cardiovascular collapse that may occur after intubation [5
]. Propofol or pentobarbital represented 20% of the administered hypnotics (Table ), mainly in the operating room for urgent surgery. The difficult intubation rate was high (near 10%), which is above the usual rate in the operating room but is similar to the rate reported in the few studies existing in this field [2
]. To facilitate intubation, almost all of the patients received a myorelaxant agent (Table ), mostly succinylcholine, as recommended by our local protocol. Interestingly, the short-term life-threatening complications that occurred within 1 hour after intubation concerned 36% of the patients. This rate is similar to that in the literature [2
] and above the rate we reported after the implementation of a care bundle in nonselected critically ill patients [5
]. The discrepancy between the present study and our previous results [5
] may be explained by the severity of the patients in the present study, all of them intubated with cardiovascular instability related to sepsis. In the multivariate analysis, the sole factor associated with short-term outcome was the administration, prior to intubation, of norepinephrine (Table ). Norepinephrine administration before intubation may be protective by both limiting the risk of severe cardiovascular collapse following sympatholysis induced by the hypnotic and the detrimental effect of thoracic positive pressure on venous return. In our unit, norepinephrine prior to induction is suggested for diastolic blood pressure < 45 to 50 mmHg [5
In the present study, we assessed the short-term life-threatening complication rate, but also the long-term effect of hypnotics on outcome. Patients intubated with etomidate were more likely to present CIRCI (Table ) and needed a longer hydrocortisone treatment and a higher total amount of hydrocortisone. One bolus of etomidate impairs cortisol secretion [8
] by the inhibition, for at least 24 to 48 hours, of 11β-hydroxylase, the enzyme that converts 11β-deoxycortisol to cortisol in critically ill patients [8
]. The higher rate of CIRCI when patients received etomidate may explain the higher cumulative dose of hydrocortisone because, in the present study, hydrocortisone was tapered and stopped according to the reversal of shock. CIRCI is associated with increased morbidity and mortality in septic shock patients [8
]. However, despite a higher rate of CIRCI, we showed that etomidate was a protective factor for mortality in both unmatched and matched cohorts (Figure ).
Our study provides new data on the effect of etomidate in septic shock. In a post-hoc
analysis of a multiple-center trial designed to evaluate the impact of hydrocortisone treatment in septic shock patients, the authors reported an increased death rate in patients that had been intubated with etomidate compared with other hypnotics [28
]. In contradiction, this increase was not statistically significant after adjustment in a multivariate analysis [21
]. Furthermore, Cuthbertson and colleagues showed that administration of etomidate was associated with increased mortality, but in only one of two multiple regression models [20
]. Despite higher severity of illness scores in patients intubated with etomidate compared with patients intubated with another hypnotic (Table ), our study demonstrated a protective effect of etomidate on day-28 mortality using Cox regression. This effect was confirmed after matching (Figure ).
The consequences of etomidate on long-term outcomes in the present study must be discussed in light of the co-administration of hydrocortisone. In the present study, hydrocortisone treatment was started within the first 12 hours after etomidate administration, earlier than in other studies [28
]. To date, studies have failed to demonstrate an improved outcome when supplementing etomidate treatment with corticosteroids [10
] and hydrocortisone is not recommended in every patient presenting septic shock but is suggested in those refractory to fluid challenge and dependent on high-dose vasopressors [12
]. However, because the inhibition of cortisol synthesis due to etomidate is immediate, hydrocortisone must be administered immediately after an etomidate bolus to counter its effects on steroid synthesis [20
]. Evaluating the role of hydrocortisone in patients who received etomidate may thus be interesting. To explain the impact of etomidate, it has also been reported that ketamine - which was the main drug used in the non-etomidate cohort - may have an anti-inflammatory effect in experimental sepsis models [41
]. Whether this anti-inflammatory effect may exacerbate late sepsis-induced immunosuppression, however, is unknown.