Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

Nitrous oxide as a putative novel dual-mechanism treatment for bipolar depression: Proof-of-concept study design and methodology.

INTRODUCTION: Depressive symptoms predominate in the course of bipolar disorder (BD) and there is an urgent need to evaluate novel application of repurposed compounds that act on pre-specified treatment targets. Several lines of reasoning suggest that nitrous oxide (N2O) is an ideal medication to study as a potential treatment and as a strategy to identify the underlying pathophysiology of bipolar depression. N2O is a potent cerebral vasodilator and there is compelling evidence of reduced frontal cerebral blood flow (CBF; i.e. hypoperfusion) in depression. Therefore, N2O may increase CBF and thereby improve symptoms of depression. The goal of this randomized, double-blind trial is to study the effect of a single administration of N2O versus the active comparator midazolam on mood and CBF in adults with treatment-resistant bipolar depression. METHODS: Participants with BD-I/-II currently experiencing a major depressive episode will be randomized to one of two conditions (n = 20/group): 1) inhaled N2O plus intravenous saline, or 2) inhaled room air plus intravenous midazolam. Montgomery-Asberg Depression Rating Scale scores will serve as the primary endpoint. CBF will be measured via arterial spin labelling magnetic resonance imaging. CONCLUSIONS: N2O is a potential novel treatment for bipolar depression, as it causes cerebral vasodilation. This proof-of-concept study will provide valuable information regarding the acute impact of N2O on mood and on CBF. If N2O proves to be efficacious in future larger-scale trials, its ubiquity, safety, low cost, and ease of use suggest that it has great potential to become a game-changing acute treatment for bipolar depression.

Renin-angiotensin blockade is associated with increased mortality after vascular surgery.

PURPOSE: The outcome of patients with preoperative renin-angiotensin system (RAS) blockade, achieved either by angiotensin converting enzyme inhibitors or angiotensin receptor blocking agents, was assessed using 30-day mortality as a primary end point. METHODS: An observational cohort study of 883 consecutive patients undergoing elective open abdominal aortic aneurysm repair (AAA) was undertaken and analyzed using a propensity score matched study. The data collected included medical history, anesthetic techniques, and postoperative outcomes. Logistic regression analysis identified predictors of RAS blockade: hypertension, stroke, congestive heart failure, diabetes, and heart disease. A propensity score for RAS blockade was calculated for each subject using several factors: age, sex, serum creatinine, hypertension, heart disease, congestive heart failure, stroke, diabetes, and exposure to cardiovascular medications. Subjects and controls were matched using the calculated propensity score. RESULTS: The overall 30-day mortality rate was 3.5% (31/883 patients). The crude mortality rate in RAS blocked patients was 5.8% (21/359) vs 1.9% (10/524) in unexposed patients (odds ratio 3.2, with 95% confidence intervals [CI(95)] 1.5-6.7; P < 0.001). Analysis of 261 propensity score matched pairs showed a 30-day mortality rate of 6.1% (16/261) in the RAS blocked group vs 1.5% (4/261) in unblocked patients (P = 0.008). The estimated odds ratio for 30-day mortality associated with RAS blockade was 5.0 (CI(95) 1.4-27). CONCLUSIONS: Examination of 883 cases of AAA repair showed increased mortality associated with preoperative RAS blockade. A better understanding of perioperative pharmacology and physiology of RAS blockade is needed as well as future studies to identify causality.

Variable pre-transfusion patient identification practices exist in the perioperative setting.

PURPOSE: The operating room (OR) has been identified by hemovigilance systems as a hospital area at high risk for transfusion errors. Where it was confirmed that transfusion products were being administered to the intended patient, we sought to determine the frequency that surgical patients' identification (ID) bands were inaccessible, the procedures used to identify patients when ID bands were inaccessible, and the effect on pre-transfusion bedside checks when ID bands were inaccessible. METHODS: We tracked the accuracy, location, and accessibility of patient ID bands in the operative phase over three months at a single Canadian Academic Health Sciences Centre. We also evaluated the surgical team's compliance with transfusion policy, focusing on bedside checks. RESULTS: Forty-four percent of the 426 patients who were tracked had accessible ID bands intraoperatively. The ID bands were removed from 6.3% of surgical patients, primarily for the placement of additional vascular lines. Cardiovascular procedures, which have a high frequency of transfusions, had the highest rate of ID band removals (26.9%) and the third-to-lowest ID band accessibility rate (19.2%). General surgery procedures had the lowest percentage of accessible ID bands (14.8%). Sixty-four of the 77 patients observed receiving transfusions in the OR had inaccessible ID bands due to positioning of the patient's arm, interference from equipment, or the surgeon. No patient ID bands were used at bedside checks, and addressograph cards and anesthetic records were used in place of the ID band in 97.4% and 2.6% of transfusions, respectively. CONCLUSION: Due to intraoperative inacessibility, the system of patient ID banding has inherent limitations as a means for providing consistent pre-transfusion checks in surgical patients. A consistently accessible ID source that is continuously affixed to surgical patients should be introduced in the OR.

Medication safety in the operating room: teaming up to improve patient safety.

A medication safety project for operating rooms (ORs) was initiated under the leadership of the Departments of Anesthesia and Nursing with a representative from the Canadian Anesthesiologists' Society and the Institute for Safe Medication Practices Canada. The aims of the collaborative project were twofold: (1) to identify areas of exposure to risk and make recommendations to enhance medication safety within the hospital and (2) to inform the development of a medication safety checklist specific to the OR setting. The strategies developed and implemented during this project were aimed at reducing the risk of injury induced by medications. Attempts were made to use feasible best practices and managerial support systems for defined areas - in this case, medication-use systems for the ORs and associated patient care areas. The learning from this project will also inform the development of a medication safety checklist for use by other hospitals and OR settings.