Etomidate is an imidazole derivative that is widely

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1 Should We Use Etomidate as an Induction Agent for Endotracheal Intubation in Patients With Septic Shock?* A Critical Appraisal William L. Jackson, Jr, MD, FCCP Etomidate is commonly used for the facilitation of endotracheal intubation. While etomidate possesses multiple qualities that are beneficial in hemodynamically unstable patients who require a sedative or amnestic, its potential to negatively impact corticosteroid production is welldocumented. Given the frequency of relative adrenal insufficiency observed in the critically ill and the increasing use of corticosteroids in patients with septic shock, an appraisal of the status of etomidate as an induction agent in patients with evolving or established septic shock is indicated. A review of the relevant literature suggests that its use in this setting may be harmful. It is proposed that, pending the performance of a randomized, controlled clinical trial, considerable caution should accompany its administration in patients with evolving or established septic shock. The potential role for concomitant empiric steroid replacement and the comparability of alternative induction regimens are also discussed. (CHEST 2005; 127: ) Key words: adrenal insufficiency; endotracheal intubation; etomidate; sepsis; septic shock Abbreviations: APACHE acute physiology and chronic health evaluation; CST cosyntropin stimulation testing; ED emergency department Etomidate is an imidazole derivative that is widely used as an IV induction agent to facilitate endotracheal intubation. It possesses several characteristics that are particularly advantageous in the critical care setting, including rapid, predictable onset of action and recovery, relative cardiovascular stability, limited suppression of ventilation, lack of histamine release, and favorable safety profile. 1 However, etomidate is known to inhibit adrenal mitochondrial hydroxylase activity, 2 with a resultant observable decrease in steroidogenesis after administration by both single-bolus 3 and maintenance infusion. 4 Importantly, the normal response to stress states such as trauma, *From the Critical Care Medicine Service, Department of Surgery, Walter Reed Army Medical Center, Washington, DC. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Manuscript received May 11, 2004; revision accepted August 3, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( permissions@chestnet.org). Correspondence to: William L. Jackson, Jr, MD, FCCP, Walter Reed Army Medical Center, Department of Surgery, Critical Care Medicine Service, Building 2, Room 3M12, 6900 Georgia Ave NW, Washington, DC ; William.Jackson1@ NA.AMEDD.ARMY.MIL burns, surgery, and infection is characterized by a proportional increase in cortisol production and release. 5 Given the renewed interest and debate concerning the For editorial comment see page 707 evaluation of relative adrenal insufficiency in critically ill patients 5 7 and the value of corticosteroid administration in septic shock patients, 8,9 as well as the increasing prevalence 10 and established lethality 11 of septic shock, conditions that affect the hypothalamic-pituitaryadrenal response to stress and may deleteriously impact patient survival are being increasingly scrutinized. Consequently, the use of etomidate for the induction of intubation in patients who require critical care in general 12 and manifest septic shock in particular 13 has come into question. The purpose of this article is to explore the basis for such concern and to propose management options as the evidence dictates. Etomidate for Long-term Anesthesia and Sedation Shortly after its introduction, etomidate was promoted as a safe agent for continuous sedation in CHEST / 127 / 3/ MARCH,

2 mechanically ventilated patients. 14 However, in 1983, Ledingham and Watt 15,16 preliminarily reported an increase in fatalities related to etomidate infusion in multitrauma patients who had been admitted to their ICU. Despite similar injury severity scores and a lower mean age for patients in the latter time period, mortality increased significantly from to (25% vs 44%, respectively; p 0.05). This increase was observed exclusively in patients receiving mechanical ventilation who survived 5 days from the time of injury and appeared to be primarily related to higher rates of infection. A further examination of the practice at their institution revealed that the predominant means of sedation had been changed from benzodiazepine agents in to etomidate in , and retrospectively assigning patients by means of sedation accounted for the difference in case fatality rates. Notably, these reports coincided with observations from other researchers at the same institution correlating adrenal insufficiency with mortality in the ICU population. 17,18 A series of preliminary related correspondences and an editorial 37 followed the initial reports by Ledingham and Watt, 15,16 with sentiment including both cautious agreement 25,32,35,37 and critical skepticism. 22,24,27,30,33 Nonetheless, the detrimental effects of etomidate as a long-term anesthetic and sedative were convincingly established by the subsequent publication of the definitive data from the study by Ledingham and Watt 38 and of two additional studies 4,39 illustrating adrenal insufficiency as a direct consequence of etomidate therapy. The first article 38 looked retrospectively at 428 patients with multiple trauma from 1969 to 1982, evenly matching patients by age, sex, and injury severity score from the comparison periods and , and confirmed the previously reported increase in mortality (28% vs 47%, respectively; p 0.05). This increase was more pronounced when patients were further classified according to the duration of mechanical ventilation ( , 23%; , 61%; p 0.005) and the means of sedation (benzodiazepine agents, 28%; etomidate, 77%; p ). Vasopressors were utilized more frequently in the group receiving etomidate (p ), and all 17 patients receiving etomidate who had serum cortisol measurements performed manifested at least one subnormal level. Additional prospective data acquired in 12 patients after the discontinuation of therapy with etomidate and the resumption of therapy with benzodiazepine agents as primary sedatives in their ICU showed a decrease in mortality rate that was similar to previously observed levels (25%; p 0.01). 38 Wagner et al 4 reported persistent adrenal suppression in one patient 4 days after a 20-h etomidate infusion for sedation and in four patients 4 h after etomidate infusion for anesthesia (dose range, 0.2 to 0.7 mg/kg) when examined by cosyntropin stimulation testing (CST); in vitro study of rat mitochondria steroidogenesis revealed the mechanism to be the dose-dependent inhibition of cytochrome P-450-dependent enzymes by etomidate. Fellows and colleagues 39 described reversible and reproducible adrenal suppression in six critically ill trauma patients who received etomidate infusions for sedation, four of whom exhibited clinical sequelae of frank adrenal insufficiency. Based on these reports, the long-term use of etomidate fell into disfavor, and the current package insert for etomidate 40 (Amidate; Abbott Laboratories; Abbott Park, IL) states, this formulation is not intended for administration by prolonged infusion. Evidence for Adrenal Insufficiency With Etomidate for Induction in Adults A number of small randomized studies 3,30,31,41 57 have examined adrenal hormone concentrations after single subanesthetic or induction doses of etomidate (ie, 0.04 to 0.5 mg/kg) for elective surgery in healthy adults, and most 3,31,41 43,45 57 have described significant but transient (ie, 12 to 24 h) adrenocortical suppression postadministration. Neither persistent functional suppression nor evidence of overt clinical adrenocortical insufficiency (eg, electrolyte abnormalities, hypotension, or prostration) has been consistently demonstrated under these conditions. However, these investigations and their relevance to the use of etomidate for induction in critically ill patients who are at risk for adrenal insufficiency are limited for the following reasons: all have been of brief duration; all have examined healthy patients undergoing elective surgery, most of which were minor procedures at extremely low risk for significant morbidity or mortality; the means of assessing adrenocortical function (including random measurement of cortisol levels and cosyntropin stimulation testing [CST]) have not been uniform or standardized, with resultant unclear significance; most have failed to address the possible influence of diurnal adrenocorticotropic hormone variations, which may potentiate morning cortisol levels coincident with induction for elective surgery but may be lost in critically ill patients; none have included patients with preexisting endocrinopathy; and 200 patients have been studied in aggregate. While these studies have confirmed the existence of adrenal dysfunction after induction with etomidate, they do not establish it as innocuous. Moreover, the literature addressing the influence 1032 Opinions/Hypotheses

3 of induction doses of etomidate on measurable adrenocortical suppression and relevant clinical measures in uncontrolled settings remains inadequate for establishing safety. McGrady and Wright 58 described a patient with pulmonary alveolar proteinosis who received a total of 0.88 mg/kg etomidate to facilitate two intubations over an 18-h period. The patient subsequently developed hyperkalemia, hyponatremia, and hypotension with low serum cortisol levels, necessitating hydrocortisone therapy and volume and inotropic support. Braams et al 59 administered 10 to 20 mg of etomidate for induction and assessed adrenocortical function by high-dose CST in 32 patients undergoing surgery for a ruptured abdominal aortic aneurysm (mean acute physiology and chronic health evaluation [APACHE] II score, 19). Postoperative baseline cortisol levels (measured a mean of 15 h post-hospital admission) and post-cst cortisol levels were significantly lower than in the 22 matched control subjects who did not receive etomidate (p 0.01), although there was no difference in mortality rate. Hilbert and colleagues 60 utilized etomidate, 0.3 mg/kg, to facilitate laryngeal mask airway placement prior to bronchoscopy in 46 immunosuppressed patients with hypoxemia and pulmonary infiltrates. Although the mean ( SD) simplified acute physiology score was 48 10, shock was an exclusion criterion. In the discussion, the authors reported the decision to administer etomidate at the beginning of the procedure was based on our habitual use of this drug when performing preoxygenation before intubation in our ICU. While the procedure was well-tolerated, all 20 patients who subsequently required endotracheal intubation (and presumably received additional doses of etomidate) died. Without additional information on these patients (who are at exceedingly high risk for mortality after intubation regardless of cofactors), it is difficult to assess the impact of etomidate on their ensuing clinical course. The few randomized studies examining etomidate for the induction of intubation also have failed to prove that the resultant adrenal dysfunction was either insignificant or transient. In a randomized trial, Absalom and colleagues 61 examined cortisol levels preinduction and 24 h after high-dose CST (ie, 250 g cosyntropin) in 35 critically ill adults (American Society of Anesthesiologists grade III or worse, with two or more organ system failures) requiring intubation. The 17 patients who received etomidate had a median APACHE II score of 18.5, and the indications for intubation included respiratory failure and laparotomy for acute abdomen. The incidence of sepsis and subsequent steroid therapy requirements were not reported. Despite higher baseline serum cortisol levels, patients receiving etomidate had a lower median increment in cortisol levels after CST compared to control subjects who received thiopental (p 0.004), with lower post-cst cortisol levels (p 0.052). In another prospective, randomized study, Schenarts et al 62 administered etomidate (0.3 mg/kg) to 16 patients requiring emergent or urgent endotracheal intubation in the emergency department (ED) and assessed adrenocortical function by high-dose CST at 4, 12, and 24 h postadministration. In patients who received etomidate, a significant difference in normal CST results was observed at 4 h, but not at 12 h or 24 h, when compared to control subjects receiving midazolam. However, specific indications for intubation, details regarding steroid administration, and severity of illness were not described, pre-cst and post-cst cortisol levels were lower in the etomidate group at all times, and one patient (who received twice the normal dose of etomidate) exhibited an abnormal CST response at 24 h. Stuttmann and coworkers 63 randomized 20 patients undergoing elective colorectal surgery to hydrocortisone supplementation (100 mg in 5% glucose over 10 h) or placebo (5% glucose) after induction with etomidate (0.2 to 0.3 mg/kg) and predefined therapeutic interventions based on heart rate, central venous pressure, BP, and serum sodium concentrations. While hemodynamic parameters and catecholamine requirements were not significantly different between groups, serum cortisol levels were considerably lower and the amount of crystalloid administered intraoperatively was considerably higher in the group that received placebo. The authors surmised that the transient cortisol deficiency caused by induction doses of etomidate could potentiate vascular leakage under physiologic stress, with an attendant requirement for increased volume resuscitation. Given the well-described increase in capillary permeability observed early in patients with sepsis, 64,65 the potential role of corticosteroids in minimizing this vascular leak, 65 and the emerging evidence correlating aggressive early resuscitation in septic shock patients with survival, 66 the data suggest that etomidate therapy for the induction of intubation may impair the ability to maintain vascular homeostasis in patients with evolving sepsis and may negatively impact mortality. Most recently, Annane et al 67 reported a reduction in the risk of mortality following low-dose corticosteroid administration in patients with septic shock who exhibited relative adrenal insufficiency as assessed by high-dose CST. Notably, 21 months after initiating enrollment into the study, the investigators amended the eligibility criteria in this trial to exclude patients who had received etomidate for induction. 67,68 Of the 72 patients who had received etomidate (mean dose, mg/kg) prior to the amendment, 68 CHEST / 127 / 3/ MARCH,

4 subsequently did not respond to high-dose CST. 13 A subgroup analysis of these 68 CST nonresponders revealed significantly higher ICU and hospital mortality rates in patients who had been randomized to receive placebo vs corticosteroids (75.7% vs 54.8%, respectively; p ) [D. Annane, MD, PhD; personal communication; April 24, 2004]. Additional Potential Effects In addition to directly inhibiting cortisol levels, etomidate may interfere with other steroid-mediated cellular responses that are thought to be protective in sepsis. Endogenous cytokines such as interleukin and interleukin-10, 70 among others, modulate the hypothalamic-pituitary-adrenal axis in critical illness. Etomidate has been shown to affect levels of interleukin-6 53,56,57 and interleukin-10, 71 may impact circulating lymphocyte levels, 53 and may upset the counterbalance of proinflammatory mediators such as macrophage migration inhibitory factor. Furthermore, some of the patterns of immunomodulation that appear to correlate with favorable hemodynamics during corticosteroid administration in patients with septic shock in particular, 72,73 including selective attenuation of both proinflammatory and antiinflammatory responses, 73 may be detrimentally altered by single-dose etomidate. While the determinants and mechanisms of the immunologic response in sepsis patients and the impact of corticosteroids on this response remain to be fully elucidated, 74 the potential consequences of altering this milieu should be considered. Assessing Use of Etomidate in the Context of Relative Adrenal Insufficiency in Septic Shock Both the incidence and definition of adrenal insufficiency 7,75 77 and the value of corticosteroid administration 8,9 in septic shock patients remain topics of considerable debate and sources of clinical uncertainty. 78 Moreover, adrenal insufficiency after etomidate administration has been described both as absolute 4,79 and relative, 6 creating additional confusion. Though a recent investigation 80 suggesting a determination of free cortisol levels in critically ill patients holds promise in eventually clarifying this issue, only 18 of the patients in this study were septic, and none had received etomidate (B. Arafah, MD; personal communication; April 19, 2004). While patients with absolute adrenal insufficiency (as assessed by history or testing in a nonstressed state) clearly require physiologic doses of corticosteroids when stressed, 6,81 and while the administration of corticosteroids in refractory septic shock appears to offer a benefit, 67,82 84 general agreement on these distinct scenarios still does not address the question of whether absolute adrenal insufficiency caused by etomidate is sustained and profound enough to affect outcomes in patients with septic shock that would not otherwise require therapy with corticosteroids. Management Alternatives Patients with evolving or established septic shock frequently require endotracheal intubation for treatment of hypoxemia, work of breathing, progressive metabolic acidosis, or airway protection, 85 and almost uniformly need vasopressor support. The ideal choice of medications for facilitating intubation in this setting is often a difficult one. Clearly, the potential harm from etomidate must be weighed against its acknowledged benefits 1,86 in facilitating intubation in this population, and the limitations of other agents, particularly relating to cardiovascular stability, onset, and duration of activity, and the effects on spontaneous ventilation, should not be underestimated. Alternative regimens usually include a combination of opioids, benzodiazepines, barbiturates, propofol, ketamine, and/or neuromuscular blockers, and their use has been reviewed. 87,88 Admittedly, the patient with evolving septic shock is most likely to require intubation (often emergently) in the ED or ICU, where respective providers may be less experienced in airway management, and such circumstances may understandably favor means of intubation that will simplify the immediate correction of an unstable situation at the expense of a risk that is delayed and may be perceived as hypothetical. Acknowledging this context, different approaches to management may be proposed while awaiting a definitive study. One option is to eliminate the use of etomidate altogether in patients with septic shock. Notably, the literature on the ease of etomidate use in uncontrolled settings is neither extensive nor unequivocal. The majority of published data, from the prehospital arena, are composed of both favorable results and unfavorable results, and its applicability to patients with septic shock is restricted by patient population (predominantly trauma patients), sample size, variety of induction regimens, variable outcome measures, and use of historical control subjects. The value of studies from the ED is limited as well. Using records from a multicenter registry, Sivilotti et al 97 examined the use of sedative adjuncts for 2,380 rapid-sequence intubations. Of 1,468 patients who received etomidate (mean dose, mg/kg), 1034 Opinions/Hypotheses

5 155 were assigned a diagnosis of shock (62% of all patients with this diagnosis), 235 patients (16.0%) required multiple attempts at intubation, and 25 patients (1.7%) could not be intubated (ie, they required other agents or modalities). First-attempt success for intubation using etomidate carried an odds ratio of 0.35 (95% confidence interval, 0.17 to 0.72; p 0.005) when compared to barbiturates. Plewa and coworkers 98 studied the use of etomidate (0.3 mg/kg) for intubation induction in 20 trauma patients and noted minimal hemodynamic effects, but 6 patients each required neuromuscular blockade or additional etomidate, and 12 patients required multiple intubation attempts. Smith et al 99 combined the use of etomidate (0.3 mg/kg) with neuromuscular blockers in 34 heterogeneous ED patients and achieved good conditions for intubation with hemodynamic stability in all patients. Given the occasional difficulty in establishing an airway in the critically ill patient, multiple doses of etomidate may be required to attain adequate sedation, 96 98,100 with a resultant potential increase in magnitude and duration of steroidogenesis inhibition. In sum, the available evidence suggests that in uncontrolled situations other agents may be at least equally safe and efficacious, and should be used preferentially. Another option is the continued use of etomidate in patients with septic shock with the automatic concomitant administration of corticosteroids. This strategy is suboptimal for several reasons. First, and most importantly, administering etomidate instead of using an alternative agent (and assuming an appropriate response to high-dose CST) might actively worsen a patient s prognostic classification, with an attendant increase in the 28-day mortality rate (from 26 to 67% or 67 to 82%). 101 As noted previously, the incidence of adrenal insufficiency (when assessed by high-dose CST) in patients manifesting septic shock who receive etomidate for the induction of intubation may be as high as 94.4%. 13 While the 28-day mortality rate reported by Annane et al 67 for CST nonresponders who received steroids was equivalent to CST responders who received placebo (53% in each group), there were only 34 patients in the latter category. Second, while there may be a role for low-dose corticosteroid administration in septic shock patients independent of the demonstrated adrenal dysfunction, this role remains unproved. The indiscriminate use of steroids in septic shock patients may not be without risk, 102 with the effect on glucose control 103 being of particular importance. Third, the dose, timing, and duration of corticosteroid therapy for such an indication would be speculative and might differ considerably from that warranted for a particular patient with vasopressor-dependent septic shock. Acknowledging these limitations, the empiric administration of corticosteroids after etomidate administration while awaiting an assessment of adrenal function or establishing hemodynamic stability (similar to that proposed for adrenal insufficiency in critically ill patients in general 5,7 ) may be a reasonable, if imperfect, approach if etomidate is administered for induction. A third option is the use of subanesthetic dosing of etomidate as an adjunct to allow for lower doses of other agents that may cause hemodynamic instability. While intuitively appealing, CST responses have been blunted with doses of etomidate as low as 0.04 mg/kg, 51 and the efficacy of this approach to induction is not known. Instead, if an alternative induction agent may potentiate hemodynamic instability, the transient proactive escalation of vasopressor therapy can allow for intubation with the maintenance of normotension and tissue perfusion (unpublished observations). In sum, until the risks of using etomidate for intubation in septic shock patients are clearly defined, the availability and training of experienced providers who are comfortable with airway management and the use of alternative medications should be emphasized. How To Resolve Clinical Equipoise Previously expressed concerns 12,13 and the emerging literature on etomidate administration in septic shock patients have indicated a state of clinical equipoise. 104 As it is increasingly recognized that early management decisions for evolving septic shock 66,105,106 may markedly impact subsequent mortality, the consequences of the continued use of etomidate require clarification, and a trial that specifically examines this intervention is warranted. While any comprehensive analysis must take into consideration the potential morbidity of alternative induction regimens (including the incidence and duration of postprocedural hypotension, the rate and ease of successful intubations, the need for neuromuscular blockade, and the type and number of airway complications), this need not be a requisite in establishing harm with etomidate in septic shock patients if mortality is a powered outcome measure. Alternatively, the performance of a subgroup analysis of a large prospective study of corticosteroids in patients with septic shock that possesses adequate sample size (eg, the ongoing CORTICUS trial), irrespective of the definitions used for adrenal insufficiency and steroid responsiveness, may be helpful. However, as the hypoadrenalism observed postetomidate administration approaches uniformity 13 and might best be considered absolute, 4,79 the use of CHEST / 127 / 3/ MARCH,

6 etomidate admittedly may confound trials that attempt to assess the incidence and significance of relative adrenal insufficiency in septic shock patients. 107 Summary In conclusion, there is ample evidence to suggest that etomidate when used for the induction of intubation may deleteriously impact steroidogenesis, and consequently morbidity and mortality, in patients with evolving septic shock who require intubation. With the growing appreciation that corticosteroids may have beneficial immunomodulatory and hemodynamic effects in sepsis patients, the cautionary note (and personal moratorium) on etomidate use expressed by Longnecker decades ago appears even more persuasive today. Consensus agreement on a standardized definition for relative adrenal insufficiency in septic shock patients, and its optimal diagnosis and management should be accompanied by a randomized, controlled study examining the use of etomidate in this population. ACKNOWLEDGMENT: The author thanks Andrew F. 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