Recurrent spontaneous globe subluxation: a case report and review of manual reduction techniques.

BACKGROUND: Spontaneous globe subluxation is an uncommon problem that develops acutely and can present with significant patient distress from ocular pain and vision loss. OBJECTIVES: To present an unusual case of recurrent spontaneous globe subluxation and describe several methods emergency physicians can use to reduce a subluxation. CASE REPORT: We describe a patient with recurrent spontaneous globe subluxation who presented to the Emergency Department with acute ocular pain and vision loss. The subluxation was emergently reduced, resolving the pain and restoring normal vision. Various manual reduction techniques are discussed. CONCLUSION: There are a number of manual reduction techniques used for treating spontaneous globe subluxation.

In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate.

BACKGROUND: We previously developed 2 etomidate analogs that retain etomidate's favorable hemodynamic properties but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl (MOC)-etomidate is rapidly metabolized and ultrashort acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11ß-hydroxylase. We hypothesized that MOC-etomidate's labile ester could be incorporated into carboetomidate to produce a new agent that possesses favorable properties individually found in each agent. We describe the synthesis and pharmacology of MOC-(R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (MOC-carboetomidate), a "soft" analog of carboetomidate. METHODS: MOC-carboetomidate's octanol:water partition coefficient was determined chromatographically and compared with those of etomidate, carboetomidate, and MOC-etomidate. MOC-carboetomidate's 50% effective concentration (EC(50)) and 50% effective dose for loss of righting reflexes (LORR) were measured in tadpoles and rats, respectively. Its effect on γ-aminobutyric acid A (GABA(A)) receptor function was assessed using 2-microelectrode voltage clamp electrophysiological techniques and its metabolic stability was determined in pooled rat blood using high performance liquid chromatography. Its duration of action and effects on arterial blood pressure and adrenocortical function were assessed in rats. RESULTS: MOC-carboetomidate's octanol:water partition coefficient was 3300 ± 280, whereas those for etomidate, carboetomidate, and MOC-etomidate were 800 ± 180, 15,000 ± 3700, and 190 ± 25, respectively. MOC-carboetomidate's EC(50) for LORR in tadpoles was 9 ± 1 µM and its EC(50) for LORR in rats was 13 ± 5 mg/kg. At 13 µM, MOC-carboetomidate enhanced GABA(A) receptor currents by 400% ± 100%. Its metabolic half-life in pooled rat blood was 1.3 min. The slope of a plot of the duration of LORR in rats versus the logarithm of the hypnotic dose was significantly shallower for MOC-carboetomidate than for carboetomidate (4 ± 1 vs 15 ± 3, respectively; P = 0.0004123). At hypnotic doses, the effects of MOC-carboetomidate on arterial blood pressure and adrenocortical function were not significantly different from those of vehicle alone. CONCLUSIONS: MOC-carboetomidate is a GABA(A) receptor modulator with potent hypnotic activity that is more rapidly metabolized and cleared from the brain than carboetomidate, maintains hemodynamic stability similar to carboetomidate, and does not suppress adrenocortical function.

Residency Support During a Natural Disaster: Hurricane Ida.

Description Natural disasters can have extraordinary impacts on a community and its infrastructure. Disasters can weaken systems that provide crucial resources, such as shelter, food security, water and health care. Recently, southeast Louisiana sustained devastating damage from Hurricane Ida on the 16th anniversary of Hurricane Katrina. Our medical workforce faced challenges caring for patients in a facility without potable water and powered by a generator. With the support of corporate entities and our academic institution, however, these barriers were quickly overcome and thus highlights the importance of collective resilience in the face of a natural disaster.

Carboetomidate: a pyrrole analog of etomidate designed not to suppress adrenocortical function.

BACKGROUND: Etomidate is a sedative hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However, it also binds with high affinity to 11beta-hydroxylase, potently suppressing the synthesis of steroids by the adrenal gland that are necessary for survival. The authors report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analog of etomidate specifically designed not to bind with high affinity to 11beta-hydroxylase. METHODS: The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type alpha1beta2gamma2l and etomidate-insensitive mutant alpha1beta2M286Wgamma2l human gamma-aminobutyric acid type A receptor activities was assessed using electrophysiologic techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats. RESULTS: Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type but not etomidate-insensitive mutant gamma-aminobutyric acid type A receptors. Carboetomidate was a three orders of magnitude less-potent inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses. CONCLUSIONS: Carboetomidate is an etomidate analog that retains many beneficial properties of etomidate, but it is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable.

Inhibition of human alpha4beta2 neuronal nicotinic acetylcholine receptors by volatile aromatic anesthetics depends on drug hydrophobicity.

BACKGROUND: Volatile aromatic compounds such as benzene are general anesthetics that cause amnesia, hypnosis, and immobility in response to noxious stimuli when inhaled. Although these compounds are not used clinically, they are frequently found in commercial items such as solvents and household cleaning products and are abused as inhalant drugs. Volatile aromatic anesthetics are useful pharmacological tools for probing the relationship between chemical structure and drug activity at putative general anesthetic targets. Neuronal nicotinic acetylcholine (nACh) receptors are ligand-gated ion channels widely expressed in the brain, which are thought to play important roles in learning and memory. In this study, we tested the hypothesis that aromatic anesthetics reversibly inhibit alpha(4)beta(2) neuronal nACh receptor function and sought to determine the structural correlates of receptor inhibition. METHODS: Electrophysiological techniques were used to quantify the effects of 8 volatile aromatic anesthetics on currents elicited by 1 mM ACh and mediated by human alpha(4)beta(2) nACh receptors expressed in Xenopus oocytes. RESULTS: All of the volatile aromatic anesthetics used in this study reversibly inhibited alpha(4)beta(2) nACh receptors with IC(50) values ranging from 0.00091 atm for 1,2-difluorobenzene to 0.045 atm for hexafluorobenzene. With the exception of hexafluorobenzene, all of the compounds had IC(50) values less than minimum alveolar concentration. Inhibitory potency correlated poorly with the cation-pi binding energies of the compounds (r(2) = 0.48, P = 0.059). However, there was a good correlation between inhibitory potency and the octanol/gas partition coefficient (r(2) = 0.87, P = 0.0008). CONCLUSIONS: Volatile aromatic anesthetics potently and reversibly inhibit human alpha(4)beta(2) neuronal nACh receptors. This inhibition may play a role in producing amnesia. In contrast to N-methyl-d-aspartate receptors, the inhibitory potencies of aromatic anesthetics for alpha(4)beta(2) neuronal nACh receptors seem to be dependent on drug hydrophobicity rather than electrostatic properties. This implies that the volatile aromatic anesthetic binding site in the alpha(4)beta(2) neuronal nACh receptor is hydrophobic in character and differs from the nature of the binding site in N-methyl-D-aspartate receptors.

Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression.

BACKGROUND: Etomidate is a rapidly acting sedative-hypnotic that provides hemodynamic stability. It causes prolonged suppression of adrenocortical steroid synthesis; therefore, its clinical utility and safety are limited. The authors describe the results of studies to define the pharmacology of (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), the first etomidate analogue designed to be susceptible to ultra-rapid metabolism. METHODS: The gamma-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared by using electrophysiological techniques in human alpha1beta2gamma2l receptors. MOC-etomidate's hypnotic concentration was determined in tadpoles by using a loss of righting reflex assay. Its in vitro metabolic half-life was measured in human liver S9 fraction, and the resulting metabolite was provisionally identified by using high-performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats. RESULTS: MOC-etomidate potently enhanced gamma-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order, with an in vitro half-life of 4.4 min versus more than 40 min for etomidate. MOC-etomidate's only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 min after administration. CONCLUSIONS: MOC-etomidate is an etomidate analogue that retains etomidate's important favorable pharmacological properties. However, it is rapidly metabolized, ultra-short-acting, and does not produce prolonged adrenocortical suppression after bolus administration.

A Survey of Women and Their Providers Regarding Gestational Weight Gain.

Background: Inappropriate gestational weight gain (GWG) is prevalent in the United States. About 20% of women gain below Institute of Medicine (IOM) recommendations; more than 50% gain above. GWG outside of recommendations is linked to poor birth outcomes and health issues for mother and baby. Counseling by health care providers is important to encourage appropriate GWG. Methods: Assess patient recall of counseling regarding GWG, provider knowledge, and opinions about IOM GWG guidance, and GWG outcomes in a subset of women. Cross-sectional, with questionnaires distributed by 8 medical centers across the United States to patients. Questionnaires were distributed to providers and data on maternal body mass index (BMI) and GWG collected at seven sites. Results: A total of 1,157 women returned questionnaires (1,820 maximum possible). A majority at all sites reported a provider discussed their expected GWG with them. Close to half reported that a provider had discussed potential harms from inappropriate GWG. Most of the women (71.2%) considered their obstetrician to be a helpful resource for GWG advice. Most providers (87.5%) reported they were aware of IOM guidelines. As many providers disagreed (18.8%) as agreed (20.8%) that they were successful helping their patients attain appropriate GWG (58.3% were neutral). Physician self-reported confidence was associated with whether they believed they could help their patients avoid excessive GWG. The most common outcome was GWG above recommendations (51.4%). Overweight and obese women were more likely to gain above recommendations. Providers underestimated the proportion of their patients that gained below IOM recommendations (8.5% vs. 18.6%). Conclusions: Providers are aware of the dangers of excessive GWG and a majority of patients report receiving counseling. Providers appear more cognizant of excessive GWG and underestimate inadequate GWG. Most women are not achieving an appropriate GWG, with overweight and obese women especially likely to gain above recommendations.

Menthol shares general anesthetic activity and sites of action on the GABA(A) receptor with the intravenous agent, propofol.

Menthol and related compounds were investigated for modulation of recombinant human gamma-aminobutyric acid type A (GABA(A), alpha(1)beta(2)gamma(2s)) receptor currents expressed in Xenopus oocytes. Sub-maximal (EC(20)) GABA currents were typically enhanced by co-applications of 3-300 microM (+)-menthol (e.g. by approximately 2-fold at 50 microM) > isopulegol > isomenthol> alpha-terpineol >> cyclohexanol. We studied menthol's actions on GABA(A) receptors compared to sedatives (benzodiazepines) and intravenous anesthetics (barbiturates, steroids, etomidate and propofol). Flumazenil (a benzodiazepine antagonist) did not inhibit menthol enhancements while currents directly activated by 50 microM propofol were significantly inhibited (by 26+/-3%) by 50 microM (+)-menthol. GABA(A) receptors containing beta(2) subunits with either a point mutation in a methionine residue to a tryptophan at the 286 position (in transmembrane domain 3, TM-3) or a tyrosine to a tryptophan at the 444 position (TM-4) are insensitive to modulation by propofol. Enhancements of GABA EC(20) currents by menthol were equally abolished in GABA(A) alpha(1)beta(2)(M286W)gamma(2s) and alpha(1)beta(2)(Y444W)gamma(2s) receptors while positive modulations by benzodiazepines, barbiturates and steroids were unaffected. Menthol may therefore exert its actions on GABA(A) receptors via sites distinct from benzodiazepines, steroids and barbiturates, and via sites important for modulation by propofol. Finally, using an in vivo tadpole assay, addition of (+)-menthol resulted in a loss of righting reflex with an EC(50) of 23.5+/-4.7 microM (approximately10-fold less potent anesthesia than propofol). Thus, menthol and analogs share general anesthetic action with propofol, possibly via action at similar sites on the GABA(A) receptor.

Volatile aromatic anesthetics variably impact human gamma-aminobutyric acid type A receptor function.

BACKGROUND: The gamma-aminobutyric acid type A (GABA(A)) and N-methyl-d-aspartate (NMDA) receptors are important inhibitory and excitatory neurotransmitter receptors, respectively, in the central nervous system. At the concentrations required to produce immobility in the face of a noxious stimulus, volatile aromatic anesthetics inhibit NMDA receptors to varying degrees, strongly suggesting that they also act at other targets to produce immobilization. In this study, we sought to assess the potential role that GABA(A) receptors play in mediating the behavioral actions of volatile aromatic anesthetics. METHODS: Electrophysiological techniques were used to quantify the effects of eight volatile aromatic anesthetics and three clinical anesthetics on currents mediated by alpha1beta2gamma2L GABA(A) receptors expressed in Xenopus oocytes. RESULTS: At equivalent minimal alveolar anesthetic concentration multiples, volatile aromatic anesthetics vary widely in the degrees to which they enhance GABA(A) receptor-mediated currents elicited by low concentrations of GABA. In general, anesthetics that inhibit NMDA receptors most, enhanced GABA(A) receptors least. This reciprocal relationship between anesthetic potency on GABA(A) versus NMDA receptors was also observed for the clinical anesthetics isoflurane, halothane, and cyclopropane. Studies using a range of GABA concentrations indicated that volatile aromatic anesthetics enhance GABA(A) receptor activity by shifting the open-close (gating) equilibrium towards the open channel state. CONCLUSIONS: These findings suggest that GABA(A) receptors contribute variably to the behavioral actions of volatile anesthetics and imply that the molecular determinants of anesthetic action on NMDA and GABA(A) receptors are distinctly different.

Six Sigma process utilization in reducing door-to-balloon time at a single academic tertiary care center.

BACKGROUND: Rapid reperfusion in patients with ST-elevation myocardial infarction (STEMI) is associated with lower mortality. Reduction in door-to-balloon (D2B) time for percutaneous coronary intervention requires multidisciplinary cooperation, process analysis, and quality improvement methodology. METHODS: Six Sigma methodology was used to reduce D2B times in STEMI patients presenting to a tertiary care center. Specific steps in STEMI care were determined, time goals were established, and processes were changed to reduce each step's duration. Outcomes were tracked, and timely feedback was given to providers. RESULTS: After process analysis and implementation of improvements, mean D2B times decreased from 128 to 90 minutes. Improvement has been sustained; as of June 2010, the mean D2B was 56 minutes, with 100% of patients meeting the 90-minute window for the year. CONCLUSION: Six Sigma methodology and immediate provider feedback result in significant reductions in D2B times. The lessons learned may be extrapolated to other primary percutaneous coronary intervention centers.