Cannabis use is associated with a small increase in the risk of postoperative nausea and vomiting: a retrospective machine-learning causal analysis.

BACKGROUND: Cannabis legalization may contribute to an increased frequency of chronic use among patients presenting for surgery. At present, it is unknown whether chronic cannabis use modifies the risk of postoperative nausea and vomiting (PONV). METHODS: This study was a retrospective cohort study conducted at 2 academic medical centers. Twenty-seven thousand three hundred eighty-eight adult ASA 1-3 patients having general anesthesia for non-obstetric, non-cardiac procedures and receiving postoperative care in the Post Anesthesia Care Unit (PACU) were analyzed in the main dataset, and 16,245 patients in the external validation dataset. The main predictor was patient reported use of cannabis in any form collected during pre-anesthesia evaluation and recorded in the chart. The primary outcome was documented PONV of any severity prior to PACU discharge, including administration of rescue medications in PACU. Relevant clinical covariates (risk factors for PONV, surgical characteristics, administered prophylactic antiemetic drugs) were also recorded. RESULTS: 10.0% of patients in the analytic dataset endorsed chronic cannabis use. Using Bayesian Additive Regression Trees (BART), we estimated that the relative risk for PONV associated with daily cannabis use was 1.19 (95 CI% 1.00-1.45). The absolute marginal increase in risk of PONV associated with daily cannabis use was 3.3% (95% CI 0.4-6.4%). We observed a lesser association between current, non-daily use of cannabis (RR 1.07, 95% CI 0.94-1.21). An internal validation analysis conducted using propensity score adjustment and Bayesian logistic modeling indicated a similar size and magnitude of the association between cannabis use and PONV (OR 1.15, 90% CI 0.98-1.33). As an external validation, we used data from another hospital in our care system to create an independent model that demonstrated essentially identical associations between cannabis use and PONV. CONCLUSIONS: Cannabis use is associated with an increased relative risk and a small increase in the marginal probability of PONV.

Ethical Issues in Organ Transplantation at End of Life: Defining Death.

End-of-life vital organ transplantation involves singular ethical issues, because survival of the donor is impossible, and organ retrieval is ideally as close to the death of the donor as possible to minimize organ ischemic time. Historical efforts to define death have been met with confusion and discord. Fifty years on, the Harvard criteria for brain death continue to be problematic and now face significant legislative efforts to limit their authority.

Partnership with Interventional Pulmonologist: An Anesthesiologist's Perspective.

Via the emergence of new bronchoscopic technologies and techniques, there is enormous growth in the number of procedures being performed in nonoperating room settings. This, coupled with a greater focus from the Centers for Medicare and Medicaid Services for mandated anesthesiology oversight of procedural sedation for bronchoscopy by the pulmonologists has led to a more frequent working partnership between interventional pulmonologists and anesthesiologists. This article offers the interventional pulmonologist insight into how the anesthesiologist thinks and approaches anesthetic care delivery.

Memory and hippocampal architecture following short-term midazolam in western diet-treated rats.

The impact of short-term benzodiazepine exposure on cognition in middle-aged or older patients is a highly debated topic among anesthesiologists, critical care physicians and public media. "Western diet" (WD) consumption is linked to impaired cognition as well. The combination of benzodiazepines with substantial exposure to WD might set the stage for increased hippocampal vulnerability for benzodiazepines leading to exaggerated cognitive impairment in the postoperative period. In this study, Fischer 344 rats were fed either WD or standard rodent diet from 5 to 10.5 months of age. Rats were exposed to midazolam or placebo two days prior to an MRI scan using Diffusional Kurtosis Imaging (DKI) to assess brain microstructural integrity, followed by behavioral testing using a water radial arm maze. Hippocampal tissue was collected to assess alterations in protein biochemistry in brain regions associated with learning and memory. Our results showed that rats exposed to the combination of midazolam and WD had significantly delayed time of learning and exhibited spatial memory impairment. Further, we observed an overall increase of kurtosis metrics in the hippocampus and increased expression of the mitochondrial protein VDAC2 in midazolam-treated rats. Our data suggest that both the short-acting benzodiazepine midazolam and WD contribute to negatively affect the brain in middle-aged rats. This study is the first application of DKI on the effects of midazolam and WD exposure, and the findings demonstrate that diffusion metrics are sensitive indicators of changes in the complexity of neurite architecture.

Sex differences in the mRNA, protein, and functional expression of organic anion transporter (Oat) 1, Oat3, and organic cation transporter (Oct) 2 in rabbit renal proximal tubules.

Sex differences in transport of the organic anion (OA) substrate p-aminohippurate (PAH) and the organic cation (OC) substrate tetraethylammonium (TEA) have been recognized for some time. In the rat kidney, androgens up-regulate and estrogens down-regulate PAH and TEA transport, which correlate with similar changes in mRNA and protein expression for the renal basolateral membrane transporters organic anion transporter (Oat) 1 and organic cation transporter (Oct) 2. However, these sex differences are not readily demonstrated in other species. The present study characterizes the kinetics of basolateral membrane PAH, estrone sulfate (ES), and TEA uptake in renal proximal tubule (RPT) suspensions isolated from female and male rabbits to compare functional expression of transport with mRNA and protein expression for rbOat1, rbOat3, and rbOct2. Although rbOat1-rbOat3 mRNA expression exhibited developmental differences, no sex differences in mRNA levels were observed. Oat1 and Oat3 protein expression in RPT suspensions also was similar between adult female and male rabbits. In contrast, rbOct1 and rbOct2 mRNA levels did not show developmental differences, but rbOct2 mRNA expression was greater in adult male than female rabbits. However, the sex difference in rbOct2 mRNA level did not translate to rbOct2 protein expression. Importantly, functional expression of Oat1, Oat3, and Oct2 transport as measured by kinetics (J(max) and K(t)) of PAH, ES, and TEA uptake was similar between adult male and female rabbits, and correlated with rbOat1, rbOat3, and rbOct2 protein expression. Thus, unlike rodents, rabbit renal OA and OC transport does not exhibit sex differences, pointing to the need for caution in extrapolating transport-related sex differences between species.

Functional influence of N-glycosylation in OCT2-mediated tetraethylammonium transport.

OCT2, an organic cation transporter critical for removal of many drugs and toxins from the body, contains consensus sites for N-glycosylation at amino acid position 71, 96, and 112. However, the extent to which these sites are glycosylated by the cell, and the influence glycosylation has on OCT2 function, remains unknown. To address these issues, the acquisition of N-glycosylation was disrupted by mutating the amino acid asparagine (N) to glutamine (Q) at these sites in the rabbit ortholog of OCT2, which was expressed in Chinese hamster ovary cells. Disruption of N-glycosylation followed by Western blotting indicated that each site is indeed glycosylated and that OCT2 contains no other sites of N-glycosylation. Plasma membrane expression (determined by surface biotinylation) of the N112Q mutant, but not N71Q or N96Q mutants, was fourfold lower than that of wild-type OCT2, and unglycosylated OCT2 (N71Q/N96Q/N112Q) was sequestered in an unidentified intracellular compartment. The N71Q, N96Q, and N112Q mutants had a higher affinity ( approximately 2-fold) for tetraethylammonium (TEA). Maximum transport rate was reduced in the N96Q (3-fold) and N112Q (5-fold) mutants, but not the N71Q mutant, and unglycosylated OCT2 failed to transport TEA (associated with its absence in the plasma membrane). Whereas the reduction in maximum transport rate of the N112Q mutant is consistent with its reduced plasma membrane expression, the lower rate of the N96Q mutant, which appeared to traffic properly, suggests that glycosylation at N96 increases the transporter turnover number.

Molecular determinants of substrate/inhibitor binding to the human and rabbit renal organic cation transporters hOCT2 and rbOCT2.

Organic cation transporters are important for the elimination of many drugs and toxins from the body. In the present study, substrate-transporter interactions were investigated in Chinese hamster ovary cells stably transfected with either the human or rabbit orthologs of the principal organic cation transporter in the kidney, OCT2. IC(50) values, ranging from 0.04 muM to >3 mM, for inhibition of [(14)C]tetraethylammonium transport were determined for more than 30 structurally diverse compounds. Although the two OCT orthologs displayed similar IC(50) values for some of these compounds, the majority varied by as much as 20-fold. Marked differences in substrate affinity were also noted when comparing hOCT2 to the closely related homolog hOCT1. These data suggest the molecular determinants of substrate binding differ markedly among both homologous and orthologous OCT transporters. The software package Cerius(2) (Accelrys, San Diego, CA) was used to generate a descriptor-based, two-dimensional, quantitative structure-activity relationship (QSAR) to produce a model relating the affinity of hOCT2 to particular physicochemical features of substrate/inhibitor molecules (r(2) = 0.81). Comparative molecular field analysis (Tripos, St. Louis, MO) was used to generate three-dimensional QSARs describing the structural basis of substrate binding to hOCT2 and rbOCT2 (q(2) = 0.60 and 0.53, respectively, and each with r(2) = 0.97). The quality of the models was assessed by their ability to successfully predict the inhibition of a set of test compounds. The current models enabled prediction of OCT2 affinity and may prove useful in the prediction of unwanted drug interactions at the level of the renal secretory process.