Etomidate Exposure Research Articles

Steroid administration after anaesthetic induction with etomidate does not reduce in-hospital mortality or cardiovascular morbidity after non-cardiac surgery

BackgroundWe tested the primary hypothesis that corticosteroid administration after etomidate exposure reduces a composite of in-hospital mortality and cardiovascular morbidity after non-cardiac surgery. MethodsWe evaluated ASA physical status III and IV patients who had non-cardiac surgery with general anaesthesia at the Cleveland Clinic. Amongst 4275 patients in whom anaesthesia was induced with etomidate, 804 were also given steroid intraoperatively, mostly dexamethasone at a median dose of 6 mg. We successfully matched 582 steroid patients with 1023 non-steroid patients. The matched groups were compared on composite of in-hospital mortality and cardiovascular morbidity using a generalized-estimating-equation model. Secondly, the matched groups were compared on length of hospital stay using a Cox proportional hazard model, and were descriptively compared on intraoperative blood pressures using a standardized difference. ResultsThere was no significant association between intraoperative steroid administration after anaesthetic induction with etomidate and the composite of in-hospital mortality or cardiovascular morbidity; the estimated common odds ratio across the two components of the composite was 0.86 [95% confidence interval (CI): 0.64, 1.16] for steroid vs non-steroid, P=0.33. The duration of postoperative hospitalisation was significantly shorter amongst steroid patients [median (Q1, Q3): 6 (3, 10) days] than non-steroid patients [7 (4, 11) days], with an estimated hazard ratio of 0.89 (0.80, 0.98) for steroid vs non-steroid, P=0.01. Intraoperative blood pressures were similar in steroid and non-steroid patients. ConclusionsSteroid administration after induction of anaesthesia with etomidate did not reduce mortality or cardiovascular morbidity.

Role of environmental stressors in determining the developmental outcome of neonatal anesthesia

BackgroundThe majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure. MethodsPostnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na+-K+-2Cl− (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2h. To simulate stress after anesthesia, the animals were exposed to a single maternal separation for 3h at P10. 3–7days after exposure to etomidate the rats had increased hypothalamic NKCC1 mRNA and corticotropin releasing hormone (CRH) mRNA and decreased K+-2Cl− (KCC2) mRNA levels with greater changes in males. In rats neonatally exposed to both etomidate and maternal separation, these abnormalities persisted into adulthood. These animals also exhibited extended corticosterone responses to restraint stress with increases in total plasma corticosterone more robust in males, as well as behavioral abnormalities. Pretreatment with the NKCC1 inhibitor ameliorated most of these effects. ConclusionsPost-anesthesia stressors may exacerbate/unmask neurodevelopmental abnormalities even after a relatively short anesthetic with etomidate, leading to dysregulated stress response systems and neurobehavioral deficiencies in adulthood. Amelioration by bumetanide suggests a mechanistic role for etomidate-enhanced gamma-aminobutyric acid type A receptor-mediated depolarization in initiating long-lasting alterations in gene expression that are further potentiated by subsequent maternal separation.

Neonatal Propofol and Etomidate Exposure Enhance Inhibitory Synaptic Transmission in Hippocampal Cornus Ammonis 1 Pyramidal Neurons.

Background:Propofol and etomidate are the most important intravenous general anesthetics in the current clinical use and that mediate gamma-aminobutyric acid's (GABAergic) synaptic transmission. However, their long-term effects on GABAergic synaptic transmission induced by neonatal propofol or etomidate exposure remain unclear. We investigated the long-term GABAergic neurotransmission alterations, following neonatal propofol and etomidate administration.Methods:Sprague-Dawley rat pups at postnatal days 4–6 were underwent 6-h-long propofol-induced or 5-h-long etomidate-induced anesthesia. We performed whole-cell patch-clamp recording from pyramidal cells in the cornus ammonis 1 area of acute hippocampal slices of postnatal 80–90 days. Spontaneous and miniature inhibitory GABAergic currents (spontaneous inhibitory postsynaptic currents [sIPSCs] and miniature inhibitory postsynaptic currents [mIPSCs]) and their kinetic characters were measured. The glutamatergic tonic effect on inhibitory transmission and the effect of bumetanide on neonatal propofol exposure were also examined.Results:Neonatal propofol exposure significantly increased the frequency of mIPSCs (from 1.87 ± 0.35 Hz to 3.43 ± 0.51 Hz, P < 0.05) and did not affect the amplitude of mIPSCs and sIPSCs. Both propofol and etomidate slowed the decay time of mIPSCs kinetics (168.39 ± 27.91 ms and 267.02 ± 100.08 ms vs. 68.18 ± 12.43 ms; P < 0.05). Bumetanide significantly blocked the frequency increase and reversed the kinetic alteration of mIPSCs induced by neonatal propofol exposure (3.01 ± 0.45 Hz and 94.30 ± 32.56 ms).Conclusions:Neonatal propofol and etomidate exposure has long-term effects on inhibitory GABAergic transmission. Propofol might act at pre- and post-synaptic GABA receptor A (GABAA) receptors within GABAergic synapses and impairs the glutamatergic tonic input to GABAergic synapses; etomidate might act at the postsynaptic site.

Etomidate exposure in early infant mice (P10) does not induce apoptosis or affect behaviour.

Numerous animal studies have shown that all commonly used intravenous anaesthetic drugs and volatile agents may cause neuronal apoptosis following exposure in early life. Most studies have focussed on detecting increased apoptosis but their methods are not always readily transferrable to humans. The lipid formulation of etomidate represents an alternative to the currently established intravenous anaesthetic agents but there is no animal or human data on apoptosis or long-term behavioural changes. The aim of our study was to investigate the effects of etomidate on cerebral neuronal apoptosis and long-term behavioural effects using an established mouse model that represents the clinically relevant period of anaesthesia during early infancy in humans. Six groups of 10 day old mice (P10) were injected with either etomidate 0.3, 3 or 10 mg/kg, propofol 60 mg/kg, ketamine 50 mg/kg or placebo only. Apoptosis in the cerebral cortex and hippocampus was assessed 24 h after treatment (activated caspase-3). Late behavioural effects were tested at 2 months of age (spontaneous activity in a new environment). No evidence was found of differences in activated caspase 3-concentrations among the study groups. Significant late behavioural changes were only observed in the ketamine group. A single dose of etomidate in early infant mice at P10 did not produce evidence of cerebral apoptosis or impaired adult motor behaviour.

Etomidate Use and Postoperative Outcomes among Cardiac Surgery Patients

Although a single dose of etomidate can cause relative adrenal insufficiency, the impact of etomidate exposure on postoperative outcomes is unknown. The objective of this study was to examine the association between a single induction dose of etomidate and clinically important postoperative outcomes after cardiac surgery. The authors retrospectively examined the association between etomidate exposure during induction of anesthesia and postoperative outcomes in patients undergoing cardiac surgery from January 2007 to December 2009 by using multivariate logistic regression analyses and Cox proportional hazards regression analyses. Postoperative outcomes of interest were severe hypotension, mechanical ventilation hours, hospital length of stay, and in-hospital mortality. Sixty-two percent of 3,127 patients received etomidate. Etomidate recipients had a higher incidence of preoperative congestive heart failure (23.0 vs. 18.3%; P = 0.002) and a lower incidence of preoperative cardiogenic shock (1.3 vs. 4.0%; P < 0.001). The adjusted odds ratio for severe hypotension and in-hospital mortality associated with receiving etomidate was 0.80 (95% CI, 0.58-1.09) and 0.75 (95% CI, 0.45-1.24), respectively, and the adjusted hazard ratio for time to mechanical ventilation removal and time to hospital discharge was 1.10 (95% CI, 1.00-1.21) and 1.07 (95% CI, 0.97-1.18), respectively. Propensity score analysis did not change the association between etomidate use and postoperative outcomes. In this study, there was no evidence to suggest that etomidate exposure was associated with severe hypotension, longer mechanical ventilation hours, longer length of hospital stay, or in-hospital mortality. Etomidate should remain an option for induction of anesthesia in cardiac surgery patients.

Controversies Surrounding the Use of Etomidate for Rapid Sequence Intubation in Patients with Suspected Sepsis

To evaluate the risk of adrenal insufficiency following a single dose of etomidate in patients with suspected sepsis requiring rapid sequence intubation. A literature search was conducted using PubMed, MEDLINE, EMBASE, and International Pharmaceutical Abstracts from the dates of database inception until April 2010, utilizing the terms adrenal insufficiency, etomidate, and sepsis. Data were synthesized in a qualitative manner, as variable study designs were identified. All studies that evaluated the clinical association between etomidate-induced adrenal insufficiency and sepsis in adults were reviewed and included. A search of the literature revealed 7 studies that specifically evaluated clinical endpoints in septic adults receiving etomidate for induction prior to intubation. Three of the studies evaluated risk factors associated with adrenal insufficiency in critically ill patients. Each of these studies determined that etomidate exposure was independently associated with an inappropriate response to cosyntropin stimulation testing (CST). Two studies found no significant difference in hospital mortality rates when evaluating patients receiving induction with etomidate compared with alternative regimens. Three studies found an increased risk of adrenal insufficiency in patients exposed to etomidate. The majority of studies that evaluated the use of etomidate in sepsis were underpowered, leading to difficulty in establishing a causal relationship between drug-related adrenal insufficiency, morbidity, and mortality. Until further studies are available, etomidate should be reserved for hemodynamically unstable patients who cannot tolerate an alternative induction agent despite the administration of fluids or vasoactive agents.

Appropriateness of Adrenocorticotropic Hormone Stimulation Test for Critically Ill Patients

In earlier work, it was shown that patients with septic shock who also have adrenal insufficiency experience a benefit in terms of lower mortality rates with hydrocortisone supplementation. As such, the adrenocorticotropic hormone (ACTH) stimulation test has been used frequently to identify these patients. However, recent evidence has suggested that the identification and treatment of adrenal insufficiency in patients with septic shock does not reduce mortality. These results call into question the utility of the ACTH stimulation test in this patient population. To determine the indications for ordering the ACTH stimulation test for critically ill patients at a tertiary care hospital and to classify the indications as either appropriate (e.g., primary adrenal insufficiency or medication-induced suppression of the hypothalamus-pituitary-adrenal axis) or inappropriate (e.g., patients with septic shock, prior etomidate exposure, or absence of steroid use). A retrospective analysis of health care records was conducted for all patients who had been admitted to the intensive care unit and who had undergone an ACTH stimulation test during 2007. For each patient, the indication for the test was identified and classified as appropriate or inappropriate. A total of 35 ACTH stimulation tests were performed during the study period, of which 8 (23%) were classified as having an appropriate indication and 27 (77%) as having an inappropriate indication. Of the tests with an inappropriate indication, 15 (56%) were ordered for patients with septic shock. However, the number of ACTH tests ordered for this indication declined as the year progressed. The ACTH stimulation test was often used inappropriately for patients with septic shock. Over time, there appeared to be a trend away from use of this test in this patient population, perhaps reflecting increasing awareness of the lack of benefit.

Increased Risk of Adrenal Insufficiency Following Etomidate Exposure in Critically Injured Patients: Cotton BA, Guillamondegui OD, Fleming SB, et al. Arch Surg 2008;143:62–7

Increased Risk of Adrenal Insufficiency Following Etomidate Exposure in Critically Injured Patients: Cotton BA, Guillamondegui OD, Fleming SB, et al. Arch Surg 2008;143:62–7

Increased Risk of Adrenal Insufficiency Following Etomidate Exposure in Critically Injured Patients

Timely diagnosis and treatment of adrenal insufficiency (AI) dramatically reduces mortality in trauma patients. We sought to identify risk factors and populations with a high risk of developing AI. Retrospective registry study. Academic level I trauma center. All trauma patients in the intensive care unit who underwent cosyntropin stimulation testing (CST) for presumed AI from January 1, 2002, through December 31, 2004. Cosyntropin stimulation testing, in which response was defined as an increase of 9 mug/dL (248 nmol/L) or more in cortisol level. Risk factors for developing AI in critically ill trauma patients. In 137 patients, CST was performed; 83 (60.6%) were nonresponders and 54 (39.4%) were responders. Age, sex, race, trauma mechanism, Injury Severity Score, and Revised Trauma Score were not statistically different between the groups. Rates of sepsis/septic shock, mechanical ventilation, and mortality were also similar between the 2 groups. However, rates of hemorrhagic shock on admission (45 [54%] vs 16 [30%]), requirement of vasopressor support (65 [78%] vs 28 [52%]), and etomidate exposure (59 [71%] vs 28 [52%]) were all significantly higher in the nonresponder group (P < .01). The increased risk of AI remained after controlling for potential confounding covariates (age, mechanism, Injury Severity Score, and Revised Trauma Score). Exposure to etomidate is a modifiable risk factor for the development of AI in this sample of critically injured patients. The use of etomidate for procedural sedation and rapid-sequence intubation in this patient population should be reevaluated.

Increased Risk of Adrenal Insufficiency Following Etomidate Exposure in Critically Injured Patients—Invited Critique

Increased Risk of Adrenal Insufficiency Following Etomidate Exposure in Critically Injured Patients—Invited Critique

The effect of injection rate on etomidate-induced myoclonus

Background: Etomidate frequently causes myoclonus. Since the myoclonus is caused by a transient disequilibrium due to etomidate exposure in the CNS, we hypothesized that a slow rate of injection of the drug may decrease the incidence of myoclonus. We conducted a prospective randomized study to compare the effect of two different types of the etomidate injection rate on the incidence and severity of myoclonus. Methods: Fifty patients were randomly assigned to the fast-injection group (group F) or slow-injection group (group S): Group F patients received etomidate (0.3 mg/kg) over ten seconds. The same dose was administered over two minutes for group S patients. The response to the injection of etomidate was grade d on a four-point scale in a blinded manner. The time to loss of consciousness (LOC) was also recorded. Results: The incidence of myoclonus was significantly lower (P ＜ 0.001) in group S patients; 84% and 28% in group F and group S patients, respectively. The myoclonus was also significantly less severe in group S patients (P ＜ 0.001). The time to LOC was significantly longer in group S patients (106 ± 22 sec) than that of group F patients (49 ± 18 sec, P ＜ 0.001). Conclusions: With same dose, a slower rate of injection resulted in a lower incidence of myoclonus and can effectively reduce myoclonus without the use of a pretreatment agent. (Korean J Anesthesiol 2008; 55: 305～7)