ABSTRACT
Postpartum hemorrhage (PPH) persists as a leading cause of maternal death worldwide, and in the United States, most maternal deaths due to hemorrhage are deemed preventable. While essential preparations for hemorrhage include protocols and checklists, implementation science has revealed that it is not enough to merely introduce these tools into units. Simulation affords safe opportunities for practice and produces reliable behavior change, and it does not always need to be highly expensive and resource consuming. We review how simulation can be applied to address a unit's vulnerabilities in identifying, managing, and resolving PPH, as well as considerations for crafting a comprehensive simulation program for your unit.
Subject(s)
Postpartum Hemorrhage , Pregnancy , Female , United States , Humans , Postpartum Hemorrhage/diagnosis , Postpartum Hemorrhage/prevention & control , Maternal MortalityABSTRACT
BACKGROUND: R-etomidate possesses unique desirable properties but potently suppresses adrenocortical function. Consequently, efforts are being made to define structure-activity relationships with the goal of designing analogues with reduced adrenocortical toxicity. The authors explored the pharmacological impact of modifying etomidate's chiral center using R-etomidate, S-etomidate, and two achiral etomidate analogues (cyclopropyl etomidate and dihydrogen etomidate). METHODS: The γ-aminobutyric acid type A receptor modulatory potencies of drugs were assessed in oocyte-expressed α1(L264T)ß3γ2L and α1(L264T)ß1γ2L γ-aminobutyric acid type A receptors (for each drug, n = 6 oocytes per subtype). In rats, hypnotic potencies and durations of action were measured using a righting reflex assay (n = 26 to 30 doses per drug), and adrenocortical potencies were quantified by using an adrenocorticotropic hormone stimulation test (n = 20 experiments per drug). RESULTS: All four drugs activated both γ-aminobutyric acid type A receptor subtypes in vitro and produced hypnosis and suppressed adrenocortical function in rats. However, drug potencies in each model ranged by 1 to 2 orders of magnitude. R-etomidate had the highest γ-aminobutyric acid type A receptor modulatory, hypnotic, and adrenocortical inhibitory potencies. Respectively, R-etomidate, S-etomidate, and cyclopropyl etomidate were 27.4-, 18.9-, and 23.5-fold more potent activators of receptors containing ß3 subunits than ß1 subunits; however, dihydrogen etomidate's subunit selectivity was only 2.48-fold and similar to that of propofol (2.08-fold). S-etomidate was 1/23rd as potent an adrenocortical inhibitor as R-etomidate. CONCLUSION: The linkage between the structure of etomidate's chiral center and its pharmacology suggests that altering etomidate's chiral center may be used as part of a strategy to design analogues with more desirable adrenocortical activities and/or subunit selectivities.
Subject(s)
Anesthetics, Intravenous/chemistry , Anesthetics, Intravenous/pharmacology , Carbon/chemistry , Etomidate/analogs & derivatives , Etomidate/pharmacology , Adrenal Cortex/drug effects , Adrenal Cortex Diseases/chemically induced , Adrenal Cortex Diseases/pathology , Anesthetics, Intravenous/toxicity , Animals , Etomidate/chemistry , Female , GABA Agonists/chemical synthesis , GABA Agonists/chemistry , GABA Agonists/pharmacology , Hypnotics and Sedatives/chemical synthesis , Hypnotics and Sedatives/chemistry , Hypnotics and Sedatives/pharmacology , Indicators and Reagents , Lethal Dose 50 , Male , Molecular Conformation , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/drug effects , Solubility , Stereoisomerism , Structure-Activity Relationship , Xenopus laevisABSTRACT
BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate (CPMM) is a "soft" etomidate analogue currently being developed as a propofol alternative for anesthetic induction and maintenance. METHODS: We compared the potencies of CPMM and propofol by assessing their abilities to directly activate α1(L264T)ß3γ2 gamma-aminobutyric acid type A (GABAA) receptors and induce loss of righting reflexes in tadpoles. We also measured the rates of encephalographic recovery in rats after CPMM and propofol infusions ranging in duration from 5 to 120 minutes. RESULTS: CPMM and propofol activate GABAA receptors and induce loss of righting reflexes in tadpoles with respective 50% effective concentrations (EC50s) of 3.8 ± 0.4 and 3.9 ± 0.2 µM (GABAA receptor) and 2.6 ± 0.19 and 1.3 ± 0.04 µM (tadpole). Encephalographic recovery after prolonged infusion was faster with CPMM and lacked propofol's context sensitivity. CONCLUSION: CPMM and propofol have similar potencies in GABAA receptors and tadpoles; however, CPMM provides more rapid and predictable recovery than propofol, particularly after prolonged infusion.
