Sepsis is the systemic inflammatory response syndrome that occurs during infection. Its incidence is approximately 750,000 per year in the US with a mortality of 30 to 50% and an annual cost of $17 billion. When severe, sepsis is often associated with profound hypotension, massive vasodilatation, shock, and multiple organ failure. Patients with sepsis commonly need general anesthesia for important therapeutic interventions such as intubation and surgery. Unfortunately, nearly all general anesthetics produce cardiovascular depression, which can be life threatening particularly in the setting of sepsis. Etomidate is an imidazole-based general anesthetic that is distinguished from other general anesthetics by its lesser effects on cardiovascular function. This would seem to make it an ideal anesthetic for use in critically ill patients with sepsis. However because etomidate binds with high affinity to 112-hydroxylase, it potently suppresses synthesis of adrenocortical steroids that are critical for the stress response during sepsis that serves to restore homeostasis and enhance survival. Such """"""""chemical adrenalectomy"""""""" by etomidate precludes its administration by continuous infusion to maintain anesthesia or sedation and has raised concerns regarding the administration of even a single IV bolus dose for anesthetic induction in septic patients. We hypothesize that this side effect can be """"""""designed out"""""""" of etomidate by removing a single atom in the drug that is thought to mediate high affinity binding to 112-hydroxylase, while maintaining etomidate's favorable anesthetic and cardiovascular-sparing properties. To test this, we have developed carbo-etomidate as the lead compound in a new class of highly potent pyrrole-based anesthetics. Preliminary data show that like etomidate, carbo- etomidate is a highly potent general anesthetic that enhances GABAA receptor function and maintains hemodynamic stability. However, its potency for inhibiting in vitro steroid synthesis by adrenocortical cells is three orders of magnitude lower than that of etomidate and it does not suppress in vivo Cortrosyn-stimulated steroid synthesis following IV bolus administration. These observations suggest that carbo-etomidate or similar analogues could be exceptionally safe anesthetic agents for use in septic critically ill patients who are already at high risk for adrenocortical insufficiency and death. As the first step toward testing this hypothesis and establishing the basis for future preclinical and clinical studies of promising novel pyrrole-based anesthetics, we propose pilot studies to define in a septic rat model the impact of carbo-etomidate infusions on the adrenocortical and cytokine response to sepsis (Aim 1) and hemodynamic stability (Aim 2). These results will be compared to those obtained using the two most commonly used IV anesthetics, propofol and etomidate. The successful development of novel etomidate analogues that spare cardiovascular function without suppressing adrenocortical steroid synthesis will significantly improve human health by permitting anesthesia to be induced and maintained more safely in critically ill patients, and particularly those with sepsis.

Public Health Relevance

Critically ill patients with sepsis commonly need general anesthesia for important therapeutic interventions such as intubation and surgery. Unfortunately, all general anesthetics have deleterious side effects that can be life threatening to such patients. We have developed a novel general anesthetic for use in septic critically ill patients that our preliminary data suggest could be safer than all currently available agents. The proposed studies will test this by defining its physiological actions in an experimental model of sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA029253-01
Application #
7872292
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Singh, Hari
Project Start
2010-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$263,190
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Shanmugasundararaj, Sivananthaperumal; Zhou, Xiaojuan; Neunzig, Jens et al. (2013) Carboetomidate: an analog of etomidate that interacts weakly with 11?-hydroxylase. Anesth Analg 116:1249-56
Desai, Rooma; Miller, Keith W; Raines, Douglas E (2013) The pyrrole etomidate analog carboetomidate potently inhibits human 5-HT3A receptor function: comparisons with etomidate and potential implications for emetogenesis. Anesth Analg 116:573-9
Husain, S Shaukat; Pejo, Ervin; Ge, Rile et al. (2012) Modifying methoxycarbonyl etomidate inter-ester spacer optimizes in vitro metabolic stability and in vivo hypnotic potency and duration of action. Anesthesiology 117:1027-36
Pejo, Ervin; Feng, Yan; Chao, Wei et al. (2012) Differential effects of etomidate and its pyrrole analogue carboetomidate on the adrenocortical and cytokine responses to endotoxemia. Crit Care Med 40:187-92
Ge, Rile; Pejo, Ervin; Husain, S Shaukat et al. (2012) Electroencephalographic and hypnotic recoveries after brief and prolonged infusions of etomidate and optimized soft etomidate analogs. Anesthesiology 117:1037-43
Pejo, Ervin; Ge, Rile; Banacos, Natalie et al. (2012) Electroencephalographic recovery, hypnotic emergence, and the effects of metabolite after continuous infusions of a rapidly metabolized etomidate analog in rats. Anesthesiology 116:1057-65
Pejo, Ervin; Cotten, Joseph F; Kelly, Elizabeth W et al. (2012) In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate. Anesth Analg 115:297-304
Ge, Ri Le; Pejo, Ervin; Haburcak, Marian et al. (2012) Pharmacological studies of methoxycarbonyl etomidate's carboxylic acid metabolite. Anesth Analg 115:305-8
Cotten, Joseph F; Le Ge, Ri; Banacos, Natalie et al. (2011) Closed-loop continuous infusions of etomidate and etomidate analogs in rats: a comparative study of dosing and the impact on adrenocortical function. Anesthesiology 115:764-73