Etomidate and Adrenocortical Suppression: Should We Take the Concerns to Heart?

IN THE current issue of the Journal Cardiothoracic and Vascular Anesthesia, Yao et al. presented a meta-analysis to assess effect etomidate on morbidity mortality in patients undergoing cardiac surgery.1Yao YT He LX Fang NX al.Anesthetic induction with surgical patients: A PRISMA-compliant systematic review meta-analysis.J Cardiothorac Vasc Anesth. 2021; (Accessed 1/4/2021. [e-pub ahead print])https://doi.org/10.1053/j.jvca.2020.11.068Abstract Full Text PDF PubMed Scopus (2) Google Scholar Despite use surgery across centers worldwide for decades, comprehensive its hemodynamic effects side when used as an agent is lacking. The authors 18 previously published randomized clinical trials totaling 1,241 evaluate consequences using single bolus induce anesthesia. found that even though who received had plasma cortisol concentrations after were significantly lower (beginning 30 minutes but lasting <24 hours) than those other agents; they also outcomes no worse sometimes better. Those included higher systolic, diastolic, mean arterial blood pressures; heart rates; requirements vasopressors; more nitroglycerin; equivalent incidences new-onset myocardial ischemia arrythmias; similar endogenous catecholamine mortality. Etomidate has remarkable history can be traced 1960s Janssen Pharmaceuticals first sought develop imidazole carboxylate esters novel antifungal agents.2Godefroi EF PA Vandereycken CA al.Dl-1-(1-arylalkyl)imidazole-5-carboxylate esters. type hypnotic agents.J Med Chem. 1965; 8: 220-223Crossref (64) Similar classes imidazole-containing antifungals, these intended inhibit 14α-demethylase, enzyme structurally homologous adrenocortical 11β-hydroxylase necessary synthesis fungal cell membrane steroid ergosterol. These compounds have high affinities this superfamily cytochrome P450 steroidogenic enzymes because their nitrogen forms coordination bond heme iron at enzymatic active site.3Roumen L Sanders MP Pieterse K al.Construction 3D models CYP11B family tool predict ligand binding characteristics.J Comput Aided Mol Des. 2007; 21: 455-471Crossref (47) When tested rodents, unexpectedly produced sedation hypnosis. subsequently was synthesized second-generation compound therapeutic index much any anesthetic available time. This highly desirable feature explained by relatively benign respiratory cardiovascular function.4Schuermans V Dom J Dony al.Multinational evaluation anesthesia induction. Conclusions consequences.Anaesthesist. 1978; 27: 52-59PubMed After introduction into practice 1972, widely adopted maintenance agent. By early 1980s, it recommended continuous infusion sedate critically ill mechanical ventilation.5Edbrooke DL Newby DM Mather SJ al.Safer ventilated patients. new application etomidate.Anaesthesia. 1982; 37: 765-771Crossref (32) However, enthusiasm such abruptly ended Ledingham Watt seminal work describing approximately three-fold increase trauma prolonged infusions.6Ledingham IM I. Influence multiple patients.Lancet. 1983; 1: 1270Abstract (344) attributed etomidate's ability potently suppress synthesis.7Allolio B Stuttmann R Leonhard U al.Adrenocortical suppression dose etomidate.Klin Wochenschr. 1984; 62: 1014-1017Crossref (54) Scholar,8de Jong FH Mallios C Jansen al.Etomidate suppresses function inhibition 11 beta-hydroxylation.J Clin Endocrinol Metab. 59: 1143-1147Crossref (118) So, ironically, drug from class designed kill fungi inhibiting synthesize ergosterol, wound up killing cortisol. Although dangers are now well-established, debate continued regarding single-bolus-dose Even studies shown boluses many hours or days ill, there broad consensus patient outcome. How does compare ones similarly define induction? In contrast analysis performed al., previous analyses focused exclusively whom outcome seemed most likely closely linked. consistent finding among all (and present one) suppressed function, reflected significant reduction varied. For example, Albert increased risk ratio versus alternative agents (risk 1.19 [95% confidence interval, 1.10-1.30]).9Albert SG Ariyan S Rather A. adrenal critical illness: review.Intensive Care Med. 2011; 901-910Crossref (108) another sepsis, Chan concluded rapid-sequence intubation associated 1.20 1.02-1.42]).10Chan CM Mitchell AL Shorr AF. insufficiency sepsis: meta-analysis.Crit 2012; 40: 2945-2953Crossref (128) contrast, recent sepsis Gu either controlled 0.84-1.72]) observational 1.05 0.97-1.13]).11Gu WJ Wang F Tang al.Single-dose not studies.Chest. 2015; 147: 335-346Abstract (75) Such varied results presumably reflect inclusion different each statistical approaches. challenge trying account heterogeneity influence results. includes differences sample sizes, study designs, populations, definitions, control groups. narrowly patients, potentially important characteristics (adult v pediatric); procedures (coronary artery bypass grafting [CABG] structural repairs); exigency (elective urgent); comparator groups (eg, propofol, ketamine, thiopental). may obscured between certain subgroups. Similarly, conclusions derived focuses one population patients) cannot necessarily extrapolated populations sepsis). especially difficult extrapolate era which incidence isolated CABG aortic valve replacement waning transcatheter percutaneous Patients presenting arriving comorbidities requiring complex multivalve redo procedures. 2016, Komatsu propensity-score-matching retrospective cohort analyzing induced compared agent.12Komatsu Makarova N You complications surgery: analysis.J 2016; 30: 1516-1522Abstract (5) combined valve/CABG surgery, cardiopulmonary bypass. They, too, postoperative atrial arrythmias (odds 1.07 [98.3% 0.92-1.23]) intensive care unit hospital length stay 1.00 0.94-1.06]). It emphasize did conclude harmful Rather, despite produce suppression, agents. subtle distinction maintain stability reduce vasopressor offset deleterious Thus, might been function. concept recently emphasized Pisano last year same Journal13Pisano Torella M Yavorovskiy al.The impact regimen adult narrative review.J print])https://doi.org/10.1053/j.jvca.2020.03.054Abstract (1) Scholar; date, investigation exists demonstrates improvement use. within context efforts being made analogs retain superior lack profound long-lasting suppression. Two general approaches taken achieve goal. One approach pharmacodynamic nature, whereas pharmacokinetic. attempts leverage distinct molecular targets responsible sedative-hypnotic inhibitory activities (the GABAA receptor 11β-hydroxylase, respectively) modifying structure substantially without greatly affecting receptor. way replacing form methylene group. Studies lone modification reduces potency ∼1,000-fold while largely maintaining potency.14Cotten JF Forman SA Laha JK al.Carboetomidate: pyrrole analog function.Anesthesiology. 2010; 112: 637-644Crossref pharmacokinetic seeks so rapidly metabolized incapable producing prolonged, clinically periods ABP-700 thoroughly studied example reached trials.15Struys Valk BI Eleveld DJ al.A phase 1, single-center, double-blind, placebo-controlled healthy subjects safety, tolerability, effects, pharmacokinetics-pharmacodynamics intravenous cyclopropyl-methoxycarbonylmetomidate (ABP-700) ascending dose.Anesthesiology. 2017; 127: 20-35Crossref (13) contains metabolically labile ester group that, remifentanil esmolol, renders susceptible nonspecific esterase hydrolysis. carboxylic acid metabolite formed negligible suppressive (or sedative-hypnotic) activity. Consequently, resulting cease administration rather persisting days. An additional binds affinity etomidate.16Pejo E Zhou X Husain SS al.Sedative-hypnotic 11beta-hydroxylase.Anesthesiology. 125: 943-951Crossref (10) findings encouraging indicated administered Whether true specific subgroups remains unclear. development do someday make issues moot. meantime, provide support Massachusetts General Hospital holds patents related D.E. Raines lead inventor technology could receive compensation sale. A.A. Dalia consults Edwards Lifesciences, Irvine, CA. Anesthetic Induction With Cardiac Surgical Patients: PRISMA-Compliant Systematic Review Meta-AnalysisJournal AnesthesiaVol. 35Issue 4PreviewThis aimed systematically (ETM) during surgery. Full-Text