Etomidate for Rapid Sequence Intubation: Suppressing the Controversy

Elizabeth Oates, Pharm.D. PGY1 Pharmacy Resident Department of Pharmacy, University Health System, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center, University of Texas Health Science Center at San Antonio January 28, 2011

Learning objectives: I. Describe the role of etomidate in rapid sequence intubation II. Evaluate the risks and benefits associated with etomidate use III. Determine significance of etomidate-induced adrenal insufficiency in critically ill patients IV. Critique available literature regarding etomidate and clinical outcomes

Introduction
I.
Critically ill or injured patients frequently require emergent intubation to protect airway and 1,2,3 maintain ventilation and oxygenation A. Intubation often performed under less than ideal circumstances i. Patients may be combative, unfasted, or clinically unstable ii. Options exist regarding method of intubation and type of pharmacologic agent used a. Decisions must be made quickly b. Information about patients medical history may be lacking at time of intubation Rapid sequence intubation (RSI) 1,4 A. Multi-step process that includes intravenous administration of a sedative and a paralytic 1 i. More effective than facilitated intubation using a sedative alone B. Most commonly used method of endotracheal intubation in the emergency department (ED) i. Considered standard of care 1,2,4 ii. Success rates exceed 95% 1 C. Acronym SOAP used to describe steps (Figure 1) Figure 1: Steps in RSI

II.

SUCTION

OXYGEN

AIRWAY EQUIPMENT

PHARMACEUTICAL AGENTS

III.

Induction therapy A. Single doses of sedative agents are given immediately prior to paralytics to render patients 1,2,4 unconscious and create a more favorable intubation environment i. Amnestic properties ii. Relax muscles of oropharynx iii. Decrease patients resistance to endotracheal tube insertion iv. Decrease risk of aspiration B. Doses can be repeated based on patients response C. Multiple sedative agents are used for induction therapy in RSI (Appendix 1) i. Selection of induction agent is based on clinical assessment of the patient and evaluation of risks versus benefits a. Ideal agent would have rapid onset, predictable dose-response relationship, short duration of action, minimal cardiovascular or neurologic side effects ii. Etomidate has been reported as the most commonly used induction agent in RSI 5,6 a. Utilized in approximately 70-80% of emergent intubations

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Etomidate
IV. The Good 1,5-7 A. Pharmacokinetics i. Onset of action is 5-15 seconds a. Highest plasma concentrations occur in the brain within one minute of administration b. Predictable dose-response relationship ii. Duration of action is approximately 5-10 minutes (Figure 2) 8 a. Related to rapid redistribution to inactive tissues, not hepatic or renal clearance iii. Rapidly hydrolyzed by plasma esterases and hepatic enzymes to an inactive metabolite a. Elimination half life is 2.9-5.3 hours b. Midazolam has multiple metabolites that can accumulate in the elderly and patients with renal failure Figure 2: Etomidate Pharmacokinetics

B. Pharmacologic characteristics i. Hemodynamic neutrality a. Decreased risk of hypotension compared with alternative agents 6 1. Hemodynamic stability maintained even in patients with cardiac disease 2. Hypotension prior to intubation is a risk factor for death 2 i. Mortality rate highest when systolic blood pressure (SBP) is < 90 mmHg 3. Midazolam and propofol can decrease mean arterial pressure (MAP) by 106 20% i. More prominent in elderly, patients with coronary artery disease, and hypovolemic patients b. Maintains cardiac blood flow without increasing cardiac oxygen demand 1. May prevent myocardial ischemia ii. Neuroprotective properties 2,6 a. Decreases cerebral metabolic rate 1. May prevent cerebral ischemia b. Blunts spikes in intracranial pressure (ICP) that occur with intubation c. Reduces ICP without compromising cerebral perfusion pressure iii. Other 6 a. Decreases intraocular pressure (IOP) by 30-60% for up to 5 minutes b. Minimal effect on brain stem function and carbon dioxide reactivity c. Lowest risk of hypersensitivity reactions 6 1. Minimal, if any, histamine release upon administration d. Unlikely to cause tissue necrosis or extravasation 1. Necrosis possible if thiopental is inadvertently given intra-arterially e. Not restricted under the Federal Controlled Substances Act

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V.

The Bad A. Historical timeline 6,9 i. 1972-1980 a. Etomidate emerged in Europe as an ideal anesthetic agent for sedation b. Some facilities in England began replacing benzodiazepine-based sedation regimens with etomidate ii. 1981- 1983 a. British physicians, Watt and Ledingham, reported a mortality rate of 47% in their 9 surgical intensive care unit (ICU), a 20% increase from the decade prior 1. Increase in mortality seen specifically in patients who survived at least five days after admission b. Etomidate approved for use as an anesthetic agent in the United States by the FDA iii. 1984 a. Watt and Ledingham subsequently identified lower than expected cortisol levels for 9 patients admitted between 1981-1983 1. Random cortisol levels had been drawn for all patients admitted to the unit after 1981 per protocol 2. Hypothesis that etomidate was the cause i. Chemical structure similar to ketoconazole, a known inhibitor of steroidogenesis b. Watt and Ledingham published retrospective review in Anaesthesia 1. Mortality with benzodiazepine-based regimen was 28% compared to 77% with 9 etomidate-based regimen (p<0.0005) 2. Authors submitted letter to editor of Lancet describing potentially dangerous adrenal suppression with prolonged infusions of etomidate iv. 1985 7 a. Warning about adrenal suppression added to etomidate package insert v. 1985- 2000 a. Etomidate only indicated for induction of anesthesia b. In the early 2000s, concerns arose about the degree and duration of adrenal suppression with single-dose etomidate B. Role of cortisol i. Important mediator of stress response a. Adrenocorticotropic hormone (ACTH) from the pituitary gland stimulates adrenal cortex to produce and release cortisol in a diurnal pattern in healthy individuals 10,11 (Figure 3) 1. Normal levels range from 4-25 mcg/dL in the morning and 2-17 mcg/dL in the 12 evening 2. No storage of cortisol in adrenal medulla 10,12,13 b. Physiologic effects 1. Mediates anti-inflammatory action 2. Increases vascular tone through synergism with endogenous catecholamines 3. Decreases vascular permeability and reduces leak 4. Increases plasma glucose

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Figure 3: Hypothalamic-Pituitary Axis

Stress Hypothalamus CRH Anterior Pituitary

ACTH Adrenal Gland Cortisol Kidney

Metabolic Effects

Production is stimulated in times of stress, illness, or injury 1. Diurnal release is replaced with constant release of cortisol 14 i. Serum cortisol can increase six-fold 14 2. Negative feedback from cortisol to hypothalamus is reduced d. In critically ill patients, initial spikes in serum cortisol can be followed by a subsequent decrease in pituitary function and ACTH release 1. Inability to produce sufficient amounts of cortisol 2. Implicated in vasopressor-resistant shock C. Etomidate-induced adrenal suppression 8,15 i. Decrease in circulating cortisol occurs within 30 minutes of a single dose of etomidate a. Adrenal insufficiency is typically diagnosed by response rate to cortisol stimulation tests (CST) as random cortisol levels alone are often inconclusive 1. Cortisol levels are drawn before and 30 minutes after a 250 mcg dose of synthetic ACTH 14,16,17 2. Serum cortisol should rise by > 9 mcg/dL b. Multiple studies have shown significantly poorer responses to CST in patients who 18-21 received etomidate versus alternative agents 8,6,19,21 c. Duration of adrenal suppression may last anywhere from 6 to 48 hours 15 d. Study of 40 critically ill, non-septic patients requiring intubation 1. Patients assessed for adrenal insufficiency following a single dose of etomidate i. CST given at various times during hospitalization 2. Percentage of patients meeting diagnostic criteria for adrenal insufficiency i. 12 hours post etomidate: 80% ii. 24 hours post etomidate: 46% iii. 48 hours post etomidate: 9% iv. 72 hours post etomidate: 7% ii. Etomidate exposure has since been identified in multiple trials as an independent and 22-25 modifiable risk factor for relative adrenal insufficiency in critically ill patients a. Although not supported by clinical evidence, some clinicians have suggested administration of exogenous steroids for 48 hours following etomidate use to overcome cortisol deficit Oates Page 5

c.

10,13

D. Mechanism of etomidate-induced adrenal suppression 8 i. Inhibition of 11- hydroxylase (Figure 4) a. 11- hydroxylase converts deoxycortisol to cortisol b. Suppression can occur at subanesthetic doses Figure 4: Mechanism of Adrenal Suppression with Etomidate

ii. Enzymatic inhibition was confirmed in an experiment by de Jong, et al in 1984 a. Analyzed healthy patients who received etomidate infusions during elective surgery 1. Mean etomidate dose was 61 mg 2. Mean duration of infusion was 25 minutes b. Patients given etomidate had significantly different changes in serum hormone concentrations when compared with control group 1. Elevated ACTH 2. Elevated deoxycortisol 3. Decreased cortisol c. Hormonal concentration ratios supported the argument that etomidate acted via enzyme inhibition and not centrally on release of ACTH from the pituitary gland d. de Jong concluded that 11- hydroxylase was the primary enzyme inhibited by etomidate VI. The Ugly A. 2002-2010 i. Controversy developed over the impact of etomidate-induced adrenal suppression on 27-31 mortality and other clinical outcomes ii. Focus of controversy was on critically ill patients requiring intubation who may already have altered adrenal function a. High risk for complex syndrome known as critical illness related cortisol insufficiency 10,13,17 (CIRCI) 1. Defined as a lack of adequate response to cortisol at the cellular level, 10 irrespective of circulating cortisol levels 10,13,17 b. Mechanism of CIRCI is multi-factorial 1. Increase in circulating cytokines, including tumor necrosis factor alpha (TNF-) and interleukin-6 (IL-6), decrease release of ACTH and affinity of glucocorticoid 10,11,14,17 receptors i. Inflammatory markers lead to HPA axis suppression as well as glucocorticoid tissue resistance

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2. Oxidative stress and decreased blood flow affect normal functioning of adrenal and pituitary glands and hypothalamus 3. Decreased cholesterol available for cortisol synthesis 11 i. 80% of circulating cortisol is derived from cholesterol 11 4. Decreased affinity for and number of receptors i. Increase production of corticostatins that compete for receptor sites 14,17 c. CIRCI has been shown to correlate with increased mortality 14,16,17 1. Rates of CIRCI highest in septic population i. Up to half of septic patients will have inadequate response to a cortisol 14,17 stimulation test (CST) 2. Unclear whether or not the use of etomidate in patients at risk for CIRCI could further increase mortality 33-36 d. Benefit of supplemental steroids to treat CIRCI has been debated as well B. The con argument for etomidate 35 i. CORTICUS sub-study analysis a. A priori sub-study from a large, multi-center, placebo-controlled trial of 36 hydrocortisone use in septic shock 1. 499 patients i. Total number of patients intubated not provided ii. 96 patients (19.2%) received etomidate within 72 hours of study initiation iii. Etomidate use discouraged by study investigators b. Patients severity of illness unknown at time of intubation c. Mortality rates predicted to be higher in patients who received etomidate 1. Hypothesis based on known adrenal suppressing potential of etomidate d. Endpoints: CST response, all-cause 28-day mortality, and the effect of hydrocortisone administration on mortality in patients who received etomidate 1. Mortality rates 42.7% vs. 30.5% for etomidate and non-etomidate, respectively (univariate analysis p= 0.02, multivariate analyses p= 0.06 and 0.03) 2. Administration of exogenous hydrocortisone had no impact on outcome 3. No difference in time to reversal of shock ii. Post hoc analysis from a clinical trial of prehospital hypertonic saline administration in 20 traumatically injured patients a. Primary outcome was incidence of acute respiratory distress syndrome (ARDS) b. RSI performed in 94 patients 1. Etomidate used in 37% of patients, benzodiazepines used in remaining 63% 2. 24% of patients died within first 24 hours i. Etomidate 15%, non-etomidate 25% (p=0.33) c. Multivariate analysis showed increased incidence of ARDS and multiple organ dysfunction syndrome (MODS) 1. Adjusted odds ratio 3.9 (95% CI, 1.24-12) d. Hospital length of stay (LOS), ICU LOS, and ventilator days were significantly longer with etomidate 1. Hospital LOS: 22 days vs. 19 days (p=0.02) 2. ICU LOS: 16 days vs. 13 days (p=0.02) 3. Ventilator days: 14 days vs. 11 days (p=0.04) C. The pro argument for etomidate i. A retrospective study from Scotland of patients with septic shock evaluated effect of 37 induction agent on mortality as well as use of vasopressors and steroids a. Overall hospital mortality was 65% b. No statistically significant difference for any endpoint 1. Hospital mortality for various agents (p=0.23) i. Etomidate 69% ii. Propofol 56% iii. Thiopental 46% iv. Other 67% v. No agent 81% Oates Page 7

2. Lower doses of etomidate were given: 0.1-0.3 mg/kg 3. Patients who received etomidate had higher predicted mortality based on various disease severity scores ii. Retrospective 18 month cohort study including patients with severe sepsis or septic 38 shock requiring intubation a. 224 patients 1. 113 patients received etomidate b. Endpoints: hospital mortality, intensive care unit (ICU) length of stay, number of ventilator days, and use of corticosteroids or vasopressors c. Multivariate analysis using logistic regression showed no significant increase in mortality with etomidate use (p=0.78) 1. Confounders included age, gender, Acute Physiology and Chronic Health Score (APACHE II), and corticosteroid use 2. Actual mortality rates were not provided d. No significant difference seen in vasopressor use, ICU length of stay, or ventilator days 1. Patients given etomidate received significantly greater doses of corticosteroids

Overview of Clinical Trials

I. Hildreth et al, 2008 A. Prospective, randomized trial i. Traumatically injured patients ii. Etomidate versus midazolam 39 Tekwani et al, 2009 A. Prospective, observational study i. Septic or septic shock patients 40 Tekwani et al, 2010 A. Prospective, randomized, controlled trial i. Septic or septic shock patients ii. Etomidate versus midazolam 41 Jabre et al, 2009 A. Prospective, randomized, controlled trial i. All patients requiring rapid sequence intubation ii. Etomidate versus ketamine
21

II. III.

IV.

Overview of Scoring Systems Used in Clinical Trials

V. Disease or injury severity scoring systems (Appendix 2) A. Simplified acute physiology II (SAPS II) score i. ICU scoring system to quantify disease severity ii. Calculated values correlate with mortality risk B. Sequential organ function assessment (SOFA) score i. Utilized in the ICU to quantify the extent of organ dysfunction and evaluate trends a. Six organ systems are scored individually and summed 42 b. Max score and change in score may correlate with mortality C. Injury severity (ISS) score i. Six different anatomical regions scored from one to six based on severity of injuries ii. Highest three individual scores are squared, then summed, to produce the ISS score a. Any individual score of six denotes an unsurvivable injury, and total score is automatically 75 D. Mortality in emergency department- sepsis (MEDS) score i. Scores nine different clinical markers that have been shown to independently predict s43 mortality in septic patient

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Clinical Trials
Hildreth, A. et al. Adrenal suppression following a single dose of etomidate for rapid sequence induction: a prospective randomized study. J Trauma 2008; 65: 573-579.21 Purpose Design Patient population Intervention Methods Assess effect of a single-dose of etomidate on adrenal function and clinical outcomes in traumatically injured patients Prospective, randomized, controlled, single-center study over 8 month study period Inclusion criteria: o Patients >18 years old, requiring orotracheal intubation during first 48 hours after injury Exclusion criteria: o Incarceration, pregnancy, use of corticosteroids in preceding year, history of adrenal insufficiency or adrenal trauma confirmed by imaging E group: Etomidate 0.3 mg/kg + succinylcholine 1 mg/kg FM group: Fentanyl 100 mcg + midazolam 5 mg + succinylcholine 1 mg/kg Patients randomized to FM or E group - technique not described Serum cortisol levels drawn for all patients meeting study criteria prior to intubation and six hours post intubation CST performed after post intubation cortisol levels were drawn Resuscitation measures at discretion of attending trauma physician Clinical data collected for 24 hours following intubation o Intravenous fluid (IVF), packed red blood cells (pRBCs) fresh frozen plasma (FFP), vasopressor requirements, and urine output Patients removed from study if consent not be obtained within 72 hours Response to CST, hospital LOS, ICU LOS, number of ventilator days Data analyzed using the Kolmogorov-Smirnov test and the Mann-Whitney U test Two-tailed t-test, p value <0.05 61 patients randomized, 30 patients included in results 27 blunt trauma, 3 penetrating trauma o Injury severity scores: E 26.5, FM 19.9 (p=0.11) E group had two patients requiring vasopressor support, and two patients expired Outcome Baseline serum cortisol (mcg/dL) Serum cortisol post intubation (mcg/dL) Change in cortisol after CST (mcg/dL) Hospital LOS (days) ICU LOS (days) Ventilator days Units of pRBCs (units) Units of FFP (units) Total IVF (mL) Authors conclusions Strengths Weaknesses E (n=18) 31.0 18.2 4.2 13.9 8.1 6.3 4.11 2.94 7162 FM (n=12) 26.8 27.9 11.2 6.4 3.0 1.5 0.67 0.33 5115 p value 0.32 0.02 <0.001 0.01 0.01 0.01 0.01 0.05 0.07

Outcomes Statistics Results

Single-dose etomidate causes adrenal suppression in trauma patients Other agents should be utilized first-line for RSI Evaluated effects on cortisol and resource utilization First study to focus on traumatically injured patients alone Appropriate comparator No blinding No hemodynamic parameters provided Did not adjust for confounding variables (injury severity, head injury, age) 31 patients excluded after randomization

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Tekwani K et al. A prospective observational study of the effect of etomidate on septic patient mortality and length of stay. Acad Emerg Med 2009; 16: 11-14.39 Purpose Design Patient population Methods Determine difference in hospital mortality and hospital length of stay in septic patients who received etomidate versus an alternative or no induction agent for rapid sequence intubation Prospective, observational, single center study over 9 month period in a large tertiary community hospital All patients >18 years old meeting SIRS criteria with suspected or confirmed infection and requiring intubation in ED Research coordinators alerted when any septic patient was intubated Weekly records collected from automated medication dispensing machines to determine removal of intubation medications Severity of illness determined by MEDS score Data collection points: demographics, induction agent, time of intubation, supplemental steroid use, laboratory data, hospital length of stay, discharge status Primary outcome: in-hospital mortality Secondary outcomes: hospital length of stay, survival to discharge Multivariate analysis o Confounders: age, vital signs at time of intubation, use of steroids, use of vasopressors, MEDS score

Outcomes Statistics Results

Authors conclusions Strengths

Outcome Etomidate (n=74) Alternative agents (n=27) p value In hospital mortality (%) 38 44 -Hospital LOS (days) 8 6.5 0.18 Hospital LOS for patients surviving to 0.08 10 7.5 discharge (days) Multivariate analysis o Use of vasopressors was a significant predictor of LOS (p=0.008) o Mean arterial pressure at time of intubation was a significant predictor of mortality (p=0.04) Patients receiving etomidate had a potentially clinically significant increase in hospital LOS, but no difference in mortality Previous recommendations to discontinue use of etomidate are not supported by available data Observational study allowed investigators to determine most commonly used induction agents in their facility Performed multivariate analysis with appropriate confounders Separately reported hospital length of stay for patients surviving to discharge to correct for early mortality Observational study - no randomization, no blinding Lack of power to detect significant difference in any outcome No dosage information given Only used MEDS score for disease severity Sensitivity analysis showed lack of robustness - 2 misclassified patients would have resulted in a statistical difference

Weaknesses

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Tekwani K et al. A comparison of the effects of etomidate and midazolam on hospital length of stay in patients with suspected sepsis: a prospective randomized study. Ann Emerg Med 2010; 56:481-489.40 Purpose Design Intervention Patient population Determine if difference in hospital length of stay exists between patients with suspected sepsis who received etomidate versus midazolam for induction therapy in rapid sequence intubation Prospective, double-blind, randomized, single center study conducted over 18 months in a large tertiary suburban hospital Etomidate 0.3 mg/kg vs. Midazolam 0.1 mg/kg Inclusion criteria: o Patients >18 years old intubated in the ED o Suspected infectious cause for illness >2 SIRS criteria markers Exclusion criteria: o Pregnancy, cardiopulmonary arrest prior to arrival in ED, Do Not Resuscitate status Eligible patients identified by the treating physician Patients randomly assigned into computer-generated blocks of 10 Confirmation of sepsis made following randomization o Positive body fluid culture o Diagnostic imaging and physical exam consistent with infection o Strong suspicion of infection leading to antimicrobial use Medication kits with identical vials for study drugs and paralytic agents kept in dispensing machines Data collection points: demographics, supplemental steroids, vasopressors, and blood transfusions in ED, use of early goal-directed therapy in ED, laboratory data, vital signs, time to first antimicrobial use, source of infection, incidence of septic shock Severity of illness defined by SOFA, SAPS II, and MEDS scores Primary outcome: hospital LOS Secondary outcome: in-hospital mortality, ICU LOS, length of time intubated Mann-Whitney U test to compare hospital LOS Chi-square test to compare mortality data Kaplan-Meier survival curves Bonferroni-corrected p value of 0.025 Intention to treat (ITT) analysis Outcome Hospital LOS (days) ICU LOS (days) Ventilator days In-hospital mortality (%) Steroids in first 24 hours (% patients) Change in SBP post induction (mmHg) Authors conclusions Strengths Etomidate (n=63) 7.3 3.1 2.1 43 56 7 Midazolam (n=59) 9.5 4.2 2.8 36 67 16 Difference 2.2 1.1 0.7 7 11 6 p value (95% Confidence Interval) 1.7 (-0.7 to 4.8) (-0.3 to 1.8) (-0.3 to 1.5) (-10% to 24%) (-8% to 29%) (-13 to -16)

Methods

Outcomes Statistics

Results

No significant difference in hospital length of stay for septic patients requiring intubation in the ED Appropriate comparator based off observational study Adjusted hospital length of stay for patients who survived to discharge Evaluated use of early goal directed therapy in sepsis Utilized three severity of illness scoring systems Indirect primary outcome measure No adjustment for co-variants

Weaknesses

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Jabre, P et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomized controlled trial. Lancet 2009; 374: 293-300.41 Purpose Compare effects of etomidate and ketamine on early and 28 day mortality rates in critically ill patients Design Intervention Patient population Methods Randomized, controlled, multi-center, single-blind trial conducted over ten months Etomidate 0.3 mg/kg vs. Ketamine 2 mg/kg Inclusion criteria: o Patients >18 years old requiring sedation for emergency intubation Exclusion criteria: o Cardiac arrest, contraindication to etomidate, ketamine, or succinylcholine, known pregnancy o Patients who expired before reaching the hospital or were discharged from the ICU in <3 days Patients randomly assigned in 1:1 ratio to etomidate or ketamine in computer-generates blocks of four o ED physician not blinded to group assignment All patients received succinylcholine for paralysis SOFA score calculation o GCS on arrival o All remaining components used highest reported scores from preceding 24 hours o Change in SOFA score defined as difference between the maximum reported score and admission score A priori subgroup analysis of trauma and sepsis Primary outcome: SOFA score in first three days after admission to the intensive care unit Secondary outcomes: Ventilator, vasopressor, and ICU-free days, change in SOFA score, 28 day mortality p value <0.05 with Bonferroni adjustment for subgroup analysis (p<0.025) Modified ITT Sensitivity analysis for age, SAPS II score, and gender Students t-test, Wilcoxon rank-sum, Chi square, Fishers exact test where appropriate Kaplan-Meier survival curves utilized to determine time to event Etomidate (n=328) 10.3 1.5 24.7 12 27 4 16 81 Ketamine (n=327) 9.6 1 22 15 28 6 25 42 p value 0.06 0.20 0.36 0.36 0.08 0.57 <0.0001 <0.0001

Outcomes Statistics

Results

Outcome SOFA (max) Change in SOFA 28-day mortality (%) Ventilator-free days Vasopressor-free days ICU-free days Post intubation cortisol (mcg/dL) CST non-responder (%)

Authors conclusion Strengths Weaknesses

Subgroup analysis: o Trauma (22%) Mortality: etomidate 26.3% vs. ketamine 29.8% (p=NS) o Sepsis (16%) Mortality: etomidate 41.4% vs. ketamine 34.3% (p=NS) Ketamine is a safe alternative to etomidate for criticially ill patients, particularly those with sepsis Largest study available to date Performed subgroup analyses in sepsis and trauma populations SOFA score shown to be an appropriate predictor of mortality42 In-hospital mortality may be more appropriate than 28-day mortality Subgroup analyses not powered to show difference in mortality Difficult to interpret results in mixed population

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Summary
VI. VII. VIII. IX. Etomidate is a commonly used agent for induction in RSI A. Many favorable characteristics including rapid onset of action, hemodynamic neutrality, and neuroprotection Single-dose etomidate causes a statistically significant decrease in cortisol function as shown by poor response to cortisol stimulation tests A. Duration of inhibition is likely <48 hours Clinical significance of adrenal suppression with etomidate is debated, but appears to be most pronounced in patients with sepsis or septic shock A. Septic patients already at increased risk for CIRCI Limited data exists regarding clinical outcomes with etomidate in non-critical patients or critically injured trauma patients

Oates E. Research in progress: A retrospective review of etomidate versus non-etomidate for rapid sequence intubation in trauma Purpose Patient population Methods To determine if a difference in mortality exists between multiply-injured trauma patients who receive etomidate versus alternative agents for rapid sequence intubation Inclusion criteria: o Adults >18 years of age intubated in University Hospital Emergency Department Exclusion criteria: o Pregnancy, CPR at scene, allergy to any study drug, duration of mechanical ventilation <2 days Patients identified through query of University Hospital Trauma Registry Data collection points: demographics, mechanism of injury, presence of neurotrauma, injury severity score, laboratory and vital signs at admission, induction agent used, hospital LOS, ICU LOS, ventilator days, resuscitation requirements, serum cortisol levels, and any cosyntropin test performed44 SOFA score and ISS used to quantify disease severity Primary outcome: In-hospital mortality Secondary outcomes: Hospital LOS, ICU LOS, resuscitation requirements Overall mortality: 12% Induction agent o Etomidate 63%, midazolam 22%, no agent 7%, propofol 4%, ketamine 2% Injury Severity Scores: o Etomidate 23 vs. non-etomidate 26 Hypotension at intubation: 24% o Hypotensive mortality 18.8% vs. normotensive mortality 11.7% (p=0.22) Neurotrauma: 54.5% o Neurotrauma mortality 17.3% vs. no neurotrauma mortality 5.4% (p=0.02) Outcomes ICU LOS, median (days) Mortality (%) Preliminary findings Etomidate (n=130) 8 11.5 Non-etomidate (n=72) 7 12.5 p value 0.82

Outcomes Interim results

Etomidate use may not be significant contributor to mortality in trauma patients

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Conclusion
X. Presenters conclusions A. Etomidate use should be avoided in patients with suspected sepsis or septic shock i. Further adrenal suppression may be most detrimental in this patient population a. CIRCI common in sepsis and known to correlate with increased mortality ii. Multiple clinical trials showing increased mortality in septic patients who receive etomidate a. Benefits of exogenous supplemental steroids in septic shock are debatable iii. Ketamine appears to be a safe and effective alternative B. Etomidate should still be considered for RSI in traumatically injured patients i. Etomidate-induced AI not likely a substantial contributor to mortality a. Spikes in cortisol production immediately following injury may decrease significance of etomidate-induced AI ii. Inconclusive evidence on the impact of cortisol inhibition on outcomes C. Routine administration of corticosteroids to all patients who receive etomidate is not supported by available clinical evidence i. Mortality benefit with supplemental steroids is controversial ii. Reserve corticosteroids for patients with poor hemodynamic response to fluid resuscitation and vasopressors D. Additional studies are needed to elucidate the effect of etomidate-induced adrenal suppression on mortality

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Appendix 1: Characteristics of Induction Agents Used in RSI

Agent IV dose (mg/kg) 0.2-0.6 Mechanism of action Imidazole derivative, increases availability of GABA receptors by displacing GABA-antagonists Benefits Hemodynamic stability, rapid onset, short duration of action, predictable dose-response relationship, decreased cerebral metabolic rate Bronchodilation, increased heart rate and blood pressure Anticonvulsant, minimal hypotension in normovolemic patients, decreased ventricular filling pressure, reversal agent available Rapid onset, very short duration of action, antiemetic properties

1,2,4,6,7,45,46

Adverse effects Adrenal suppression, myoclonic movements, nausea and vomiting, decreased threshold for focal seizure activity, no blunting of sympathetic response to intubation Increased intraocular pressure, increased myocardial oxygen demand, reemergence phenomenon, laryngospasm, increase in intracranial pressure in spontaneously breathing patients Hypotension in hypovolemic patients, wide dose-response variation, respiratory depression, apnea, paradoxical agitation Dose-response variation with age, hypotension, hypoxia, bradycardia, apnea Porphyria, negative cardiovascular effects, extravasation, tissue necrosis, bronchospasm, apnea

Etomidate

Ketamine

1- 2

NMDA receptor inhibitor, dissociative anesthetic

Midazolam

0.1- 0.3

GABA receptor agonist

Propofol

1- 2

NMDA receptor inhibitor, GABA receptor agonist

Thiopental

3- 5

Reduces glutamate activity, increases affinity of GABA receptors for agonists

Anticonvulsant, decreased intracranial pressure, decreased cerebral metabolic rate

NMDA=N-methyl-D-aspartic acid; GABA=gamma-aminobutyric acid *All agents are FDA approved for induction of anesthesia

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Appendix 2: Scoring Systems SAPS II Score (Range:0-163) Type of admission Chronic disease Scheduled surgery Medical Unscheduled surgery None Metastatic cancer Hematologic malignancy AIDS <6 6-8 9-10 11-13 14-15 <40 40-59 60-69 70-74 75-79 >80 <70 70-99 100-199 >200 <40 40-69 70-119 120-159 >160 <102.2 >102.2 <100 100-199 >200 Points 0 6 8 0 9 10 17 26 13 7 5 0 0 7 12 15 16 18 13 5 0 2 11 2 0 4 7 0 3 11 9 6 Urine output (L/hr) BUN (mg/dL) <0.5 0.5-0.99 >1 <28 28-83 >84 <1 1-19 >20 <3 3-4.9 >5 >145 122-144 <125 <15 15-19 >20 <4 4-5.9 >6 SAPS score
logit logit

WBC (x 103/mm3) Potassium (mEq/L)

GCS

Sodium (mEq/L) Bicarbonate (mEq/L) Bilirubin (mg/dL)

Age (years)

SBP (mmHg)

11 4 0 0 6 10 12 0 3 3 0 3 1 0 5 6 3 0 0 4 9

HR (beats per minute)

Predicted mortality= e /1+e Logit= -7.7631 + 0.0737(SAPS II) + 0.9971 {ln[SAPS II + 1]}

Temp (F) PaO2/FiO2

SOFA Score (Range: 0-24) 0 PaO2/FiO2 (or >400 SaO2/FiO2) Platelets (x 103/mm3) >150 Bilirubin (mg/dL) <1.2 Hypotension None GCS SCr (mg/dL) or urine output (mL/d) 15 <1.2

1 <400 (221301) <150 1.2-1.9 MAP <70 13-14 1.2-1.9

2 <300 (142-220) <100 2.0-5.9 Dopamine < 5 mcg/kg/min or any dose of dobutamine 10-12 2.0-3.4

3 <200 (67-141) <50 6.0-11.9 Dopamine >5 mcg/kg/min or norepinephrine < 0.1 mcg/kg/min 6-9 3.5-4.9 or <500

4 <100 (<67) <20 >12.0 Dopamine >15 mcg/kg/min or norepinephrine >0.1 mcg/kg/min <6.0 >5.0 or <200 Total SOFA Score

Score (0-4)

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ISS Calculation (Range: 0-75) Abbreviated injury score (AIS) 1 2 3 4 5 6 Description Minor Moderate Serious Severe Critical Unsurvivable Region Head/neck Face Chest Abdomen Extremity External Injury severity score Injury description AIS (1-6) Square 3 highest AIS

MEDS Score Calculation (Range: 0-27) Rapidly terminal co-morbid illness Age >65 years Bands >5% Tachypnea or hypoxemia Shock Platelet count <150,000 mm3 Altered mental status Nursing home resident Lower respiratory tract infection TOTAL Points 6 3 3 3 3 3 2 2 2

MEDS score 0-4 5-7 8-12 13-15 >15 28 day mortality (95% CI) 0.6% (0-3%) 5% (1-13%) 19% (11-29%) 32% (15-54%) 40% (12-74%)

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