One single dose of etomidate negatively influences adrenocortical performance for at least 24 h in children with meningococcal sepsis
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- den Brinker, M., Hokken-Koelega, A.C.S., Hazelzet, J.A. et al. Intensive Care Med (2008) 34: 163. doi:10.1007/s00134-007-0836-3
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To investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis.
Retrospective study conducted between 1997 and 2004.
University-affiliated paediatric intensive care unit (PICU).
Patients and participants
Sixty children admitted to the PICU with meningococcal sepsis, not treated with steroids.
Adrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12 h and 24 h. To assess disease severity, PRISM score and selected laboratory parameters were determined.
Measurements and main results
On admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11-deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24 h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with still significantly lowered cortisol/11-deoxycortisol ratios 24 h after admission.
Our data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24 h. It might therefore increase risk of death.
KeywordsAdrenal insufficiency Etomidate Critical illness Meningococcal disease Child
Materials and methods
The group consisted of 69 previously healthy children (42 boys and 27 girls) consecutively admitted to the PICU of the Erasmus MC–Sophia Children's Hospital, with a clinical picture of meningococcal sepsis, defined as sepsis with petechiae and/or purpura as described previously [8, 9, 10]. Blood cultures revealed Neisseria meningitidis in 58 children. Nine children who received corticosteroid therapy for suspected adrenal insufficiency before admission were excluded. Children who received corticosteroid therapy after admission were included until they received corticosteroids. The lack of research staff to ensure an adequate 24-h stand-by service necessitated two study periods: from October 1997 to October 1999 and from October 2001 to January 2004. The study was approved by the local medical ethics committee and adhered to the tenets of the Declaration of Helsinki.
Concomitant therapy on admission included antibiotics (cefotaxime) and administration of fluids in all 60 children and inotropics in 51 children. On admission 31 children were mechanically ventilated, whereas 29 children were not. Mechanically ventilated children were intubated at a median of 2 h and 40 min (range 5 min to 7 h) before study enrolment with etomidate (n = 23) or with combinations of opiate agonists, propofol, ketamine or midazolam (n = 8). The median dose of the etomidate bolus was 0.29 mg/kg (range 0.20–0.67 mg/kg) and was significantly higher in children who died than in those who survived (0.46 vs 0.29, p = 0.038). The sedatives and doses used for rapid-sequence intubation depended on the physicians' choice. After admission four more children were intubated with etomidate. Mechanically ventilated children were all intubated for their clinical status only and were sedated with benzodiazepines and/or morphine. On admission, patients received intravenous glucose at a rate of 4–6 mg/kg/min.
Collection of blood samples and analysis
Results are expressed as medians unless specified otherwise. We used Mann–Whitney U, chi-square or Fisher's exact test, Spearman's correlation coefficient (r) and analysis of covariance (ANCOVA). The graph of the course of cortisol/ACTH ratios was constructed using mixed-model analysis of variance. Two-tailed p-values of < 0.05 were considered statistically significant.
Clinical parameters on admission
Patients' characteristics and adrenal function on admission according to intubation and etomidate use
Intubated with etomidate (n = 23)
Intubated without etomidate (n = 8)
Not intubated (n = 29)
Septic shock (%)
5 (0–18)a, c
IL-6 x 103 (pg/ml)
620 (502–782)a, b
146.1 (79.3–222.0)a, b
4.7 (2.3–8.4)a, b
181 (137–248)a, b
3.2 (2.1–4.3)a, b
Adrenal function on admission
On admission, cortisol levels were significantly lower and ACTH levels significantly higher with concomitantly lower cortisol/ACTH ratios in children who were intubated with etomidate than in those who did not receive etomidate, independently of intubation (Table 1). Furthermore, children who were intubated with etomidate had significantly higher 11-deoxycortisol levels with concomitantly lower cortisol/11-deoxycortisol ratios than children who did not receive etomidate, independently of intubation. Compared to non-stressed values, 11-deoxycortisol levels were elevated in 95% of the children who received etomidate and in 65% of the children who did not receive etomidate ( p = 0.019), independently of intubation. Neither time from intubation to admission nor etomidate dose per kilogram body weight correlated significantly with serum levels of cortisol, ACTH, 11-deoxycortisol or their ratios on admission (data not shown).
Adrenal function time course
This retrospective study shows major differences in ACTH, cortisol and 11-deoxycortisol levels between children intubated with one single bolus of etomidate and those who did not receive etomidate, independently of intubation.
Although our study was not designed to investigate the direct relation between etomidate administration and adrenal function, we found significantly more signs of impaired adrenal function, as shown by the combination of significantly lower cortisol with increased ACTH levels, in children who received etomidate than in those who did not, even after correction for disease severity (Fig. 2). On admission cortisol levels were 3.2 times lower and ACTH levels were 4.1 times higher in children who received etomidate than in those who did not. Serum 11-deoxycortisol (the precursor of cortisol that exerts no endocrine actions) was significantly higher, and cortisol/11-deoxycortisol lower, in children who received etomidate than in those who did not, indicating impaired 11β-hydroxylase activity (CYP11B1, Fig. 1). This is in accordance with in vitro and in vivo studies that show etomidate to interfere mainly with 11β-hydroxylase, and at higher concentrations also with 11β- and 18-hydroxylase (CYP11B2) and the cholesterol side-chain cleavage enzyme system (CYP11A) [2, 14, 15, 16, 17]. Despite the fact that etomidate is known to suppress adrenal function in a dose-dependent manner in vitro , we did not find such a relation, probably due to lack of study power. However, the dose of etomidate was higher in children who died than in those who survived. Because we studied the effect of etomidate retrospectively in an uncontrolled setting, it is difficult to report on relevant clinical deterioration, such as persistent hypotension or the course of glucose levels. We found, nevertheless, significantly lower glucose levels on admission in children receiving etomidate than in those who did not. Furthermore, in this study seven of the eight children who died during admission received etomidate. Significant but transient adrenocortical suppression 24 h after a single bolus of etomidate has been described [18, 19]. Although we found cortisol concentrations and cortisol/ACTH ratios to reach comparable levels between the studied groups more than 24 h after intubation, cortisol/11-deoxycortisol ratios were still significantly decreased in children who received etomidate compared to those who did not, indicating adrenocortical suppression at the level of 11β-hydroxylase. Future investigations using corticotropin test should be performed to study the duration of this adrenocortical suppression.
In summary, our data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24 h and therefore might increase risk of death. As recently stated , considerable caution should accompany the administration of etomidate in patients with septic shock.