A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression.

Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were -0.75 points on the HDRS-21 at 2 hours (P = 0.73), -1.41 points at 24 hours (P = 0.52), -4.35 points at week 1 (P = 0.05), and -5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were -0.87 points at 2 hours (P = 0.69), -1.93 points at 24 hours (P = 0.37), -2.44 points at week 1 (P = 0.25), and -7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects.

Effect of Nitrous Oxide as a Treatment for Subjective, Idiopathic, Nonpulsatile Bothersome Tinnitus: A Randomized Clinical Trial.

Importance: The tinnitus research literature suggests that N-methyl-d-aspartate (NMDA) receptor antagonists may be useful in reducing tinnitus. Nitrous oxide, a member of the NMDA receptor antagonist class, is a widely used general anesthetic and sedative with a proven safety record. Objective: To investigate whether nitrous oxide can reduce bothersome tinnitus. Design, Setting, and Participants: Randomized, placebo-controlled crossover trial conducted between October 15, 2016, and June 22, 2017. Participants attended 2 interventional sessions separated by at least 14 days and were randomized to receive either placebo first or nitrous oxide first. Participants were followed up through completion of the second arm of the study. The setting was a clinical research unit at an academic medical center. Adults aged 18 to 65 years with subjective, idiopathic, nonpulsatile bothersome tinnitus of 6 months' duration or longer were recruited from 2 clinical research databases. Seventy-one individuals were screened, of whom 40 were enrolled. Of those enrolled, 37 participants completed all components of the study. Interventions: The placebo session consisted of 50% nitrogen and 50% oxygen inhaled for 40 minutes, and the treatment session consisted of 50% nitrous oxide and 50% oxygen inhaled for 40 minutes. Main Outcomes and Measures: Tinnitus was assessed before and after intervention, with the change in the Tinnitus Functional Index (TFI) as the primary outcome measure. Secondary outcome measures included the Patients' Global Impression of Change score and the change in the Global Bothersome Scale score. Results: Among 40 participants in this intent-to-treat randomized clinical trial with 20 participants randomly assigned to each group, the mean (SD) age of participants was 52.9 (11.1) years, with equal numbers of male and female participants. The TFI after intervention was a mean (SD) of 1.8 (8.8) points lower than before intervention in the placebo arm and a mean (SD) of 2.5 (11.0) points lower than before intervention in the nitrous oxide arm. The within-participant mean difference in the change in the TFI of the placebo arm compared with the nitrous oxide arm was -1.1 points (95% CI, -5.6 to 3.4 points). The difference between the placebo and nitrous oxide arms was neither clinically meaningful nor statistically significant. Conclusions and Relevance: Nitrous oxide was no more effective than placebo for the treatment of subjective, idiopathic tinnitus. Trial Registration: ClinicalTrials.gov identifier: NCT03365011.

The effective concentration of tranexamic acid for inhibition of fibrinolysis in neonatal plasma in vitro.

BACKGROUND: Neonates are at high risk for bleeding complications after cardiovascular surgery. Activation of intravascular fibrinolysis is one of the principal effects of cardiopulmonary bypass that causes poor postoperative hemostasis. Antifibrinolytic medications such as tranexamic acid are often used as prophylaxis against fibrinolysis, but concentration/effect data to guide dosing are sparse for adults and have not been published for neonates. Higher concentrations of tranexamic acid than those necessary for inhibition of fibrinolysis may have adverse effects. Therefore, we investigated the concentration of tranexamic acid necessary to inhibit activated fibrinolysis in neonatal plasma. METHODS: We conducted an in vitro study using neonatal plasma derived from the placenta/cord units from 20 term, elective cesarean deliveries. Graded concentrations of tranexamic acid were added to aliquots of the pooled plasma before maximally activating fibrinolysis with high-dose tissue-type plasminogen activator. Thromboelastography was then performed with the primary outcome variable being lysis at 30 minutes. These procedures were repeated on pooled adult normal plasma and dilutions of neonatal plasma. RESULTS: The minimum concentrations of tranexamic acid to completely prevent fibrinolysis were 6.54 µg/mL (95% confidence interval, 5.19-7.91) for neonatal plasma and 17.5 µg/mL (95% confidence interval, 14.59-20.41) for adult plasma. Neonatal plasma requires a significantly lower concentration than adult plasma (P < 0.0001, 2-sided Wald test). CONCLUSIONS: Our data establish the minimal effective concentration of tranexamic acid necessary to completely prevent fibrinolysis in neonatal plasma in vitro. These data may be useful in designing a dosing scheme for tranexamic acid appropriate for neonates.

Second-hand smoking and carboxyhemoglobin levels in children: a prospective observational study.

AIM: To establish baseline noninvasive carboxyhemoglobin (COHb) levels in children and determine the influence of exposure to environmental sources of carbon monoxide (CO), especially environmental tobacco smoke, on such levels. BACKGROUND: Second-hand smoking may be a risk factor for adverse outcomes following anesthesia and surgery in children (1) and may potentially be preventable. PATIENTS AND METHODS: Parents and their children between the ages of 1-12 were enrolled on the day of elective surgery. The preoperative COHb levels of the children were assessed noninvasively using a CO-Oximeter (Radical-7 Rainbow SET Pulse CO-Oximeter; Masimo, Irvine, CA, USA). The parents were asked to complete an environmental air-quality questionnaire. The COHb levels were tabulated and correlated with responses to the survey in aggregate analysis. Statistical analyses were performed using the nonparametric Mann-Whitney and Kruskal-Wallis tests. P < 0.05 was statistically significant. RESULTS: Two hundred children with their parents were enrolled. Children exposed to parental smoking had higher COHb levels than the children of nonsmoking controls. Higher COHb values were seen in the youngest children, ages 1-2, exposed to parental cigarette smoke. However, these trends did not reach statistical significance, and confidence intervals were wide. CONCLUSIONS: This study revealed interesting trends of COHb levels in children presenting for anesthesia and surgery. However, the COHb levels measured in our patients were close to the error margin of the device used in our study. An expected improvement in measurement technology may allow screening children for potential pulmonary perioperative risk factors in the future.