Explore the vast range of titles available.

In this trial, subjects in status epilepticus were given either intramuscular midazolam or intravenous lorazepam by paramedics before arrival in the ER. Seizures were controlled in more subjects with midazolam, and midazolam was at least as safe and effective as lorazepam. Early termination of prolonged epileptic seizures in response to intravenous administration of benzodiazepines by paramedics in the prehospital setting is associated with better patient outcomes. The randomized, controlled Prehospital Treatment of Status Epilepticus (PHTSE) trial (ClinicalTrials.gov number, NCT00004297) compared diazepam, lorazepam, and placebo given intravenously by paramedics to treat subjects with prolonged convulsive seizures. 1 The trial showed that both these benzodiazepines were an effective prehospital treatment for seizures, as compared with placebo. The proportion of subjects whose seizures were terminated at the time of arrival in the emergency department was 59.1% in the group receiving intravenous lorazepam, 42.6% in the . . .

In a randomized trial involving 700 mechanically ventilated ICU patients, 90-day mortality did not differ significantly between those assigned to a plan of no sedation and those assigned to a plan of light sedation with daily interruption. There was a low number of thromboembolic events, but they were more numerous in the sedation group.

In this trial, high-frequency oscillatory ventilation was compared with conventional ventilation with a lung-protective protocol. When the study was stopped early, hospital mortality was 47% with HFOV versus 35% with the control ventilation strategy. The acute respiratory distress syndrome (ARDS) is a common complication of critical illness. 1 , 2 Mortality is high, and survivors often have long-term complications. 3 , 4 Although mechanical ventilation is life-sustaining for patients with ARDS, it can perpetuate lung injury. Basic research suggests that repetitive overstretching or collapse of lung units with each respiratory cycle can generate local and systemic inflammation, contributing to multiorgan failure and death. 5 Consistent with these findings are data from clinical trials that support the use of smaller tidal volumes (6 vs. 12 ml per kilogram of predicted body weight) 6 and higher levels of positive end-expiratory pressure (PEEP). . . .

Sevoflurane improves gas exchange, and reduces alveolar edema and inflammation in preclinical studies of lung injury, but its therapeutic effects have never been investigated in acute respiratory distress syndrome (ARDS). To assess whether sevoflurane would improve gas exchange and inflammation in ARDS. We did a parallel, open-label single-center randomized controlled trial at three intensive care units from a French university hospital between April 2014 and February 2016. Adult patients were randomized within 24 hours of moderate-to-severe ARDS onset to receive either intravenous midazolam or inhaled sevoflurane for 48 hours. The primary outcome was the Pa /Fi ratio on Day 2. Secondary endpoints included alveolar and plasma levels of cytokines and soluble form of the receptor for advanced glycation end-products, and safety. Investigators who did the analyses were masked to group allocation. Analysis was by intention to treat. Twenty-five patients were assigned to the sevoflurane group and 25 to the midazolam group. On Day 2, Pa /Fi ratio was higher in the sevoflurane group than in the midazolam group (mean ± SD, 205 ± 56 vs. 166 ± 59, respectively; P = 0.04). There was a significant reduction over time in cytokines and soluble form of the receptor for advanced glycation end-products levels in the sevoflurane group, compared with the midazolam group, and no serious adverse event was observed with sevoflurane. In patients with ARDS, use of inhaled sevoflurane improved oxygenation and decreased levels of a marker of epithelial injury and of some inflammatory markers, compared with midazolam. Clinical trial registered with www.clinicaltrials.gov (NCT 02166853).

Abstract Objective We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. Methods Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment–emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion. Results Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P  = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012). Conclusion We did not find evidence that ketamine’s acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.

Background Preliminary evidence suggests intravenous ketamine has rapid effects on suicidal cognition, making it an attractive candidate for depressed patients at imminent risk of suicide. In the first randomized controlled trial of ketamine using an anesthetic control condition, we tested ketamine's acute effects on explicit suicidal cognition and a performance‐based index of implicit suicidal cognition (Implicit Association Test; IAT) previously linked to suicidal behavior. Method Symptomatic patients with treatment‐resistant unipolar major depression (inadequate response to ≥3 antidepressants) were assessed using a composite index of explicit suicidal ideation (Beck Scale for Suicidal Ideation, Montgomery‐Asberg Rating Scale suicide item, Quick Inventory of Depressive Symptoms suicide item) and the IAT to assess suicidality implicitly. Measures were taken at baseline and 24 hr following a single subanesthetic dose of ketamine (n = 36) or midazolam (n = 21), a psychoactive placebo agent selected for its similar, rapid anesthetic effects. Twenty four hours postinfusion, explicit suicidal cognition was significantly reduced in the ketamine but not the midazolam group. Results Fifty three percent of ketamine‐treated patients scored zero on all three explicit suicide measures at 24 hr, compared with 24% of the midazolam group (χ2 = 4.6; P = .03). Implicit associations between self‐ and escape‐related words were reduced following ketamine (P = .01; d = .58) but not midazolam (P = .68; d = .09). Ketamine‐specific decreases in explicit suicidal cognition were largest in patients with elevated suicidal cognition at baseline, and were mediated by decreases in nonsuicide‐related depressive symptoms. Conclusions Intravenous ketamine produces rapid reductions in suicidal cognition over and above active placebo. Further study is warranted to test ketamine's antisuicidal effects in higher‐risk samples.

Purpose To evaluate efficacy and adverse events related to inhaled sevoflurane for long-term sedation compared with standard intravenous (IV) sedation with propofol or midazolam. Methods Randomized controlled trial. Sixty intensive care unit (ICU) patients expected to require more than 24 h sedation were randomly assigned to one of three groups: group S, inhaled sevoflurane; group P, IV propofol; group M, IV midazolam. All patients also received IV remifentanil for goal-directed sedation (Ramsay scale and pain score) until extubation or for a maximum of 96 h. Primary end points were wake-up times and extubation delay from termination of sedative administration. Proportion of time within Ramsay score 3–4, IV morphine consumption at 24 h post extubation, hallucination episodes after end of sedation, adverse events, inorganic fluoride plasma levels, and ambient sevoflurane concentrations were recorded. Results Forty-seven patients were analyzed. Wake-up time and extubation delay were significantly ( P  < 0.01) shorter in group S (18.6 ± 11.8 and 33.6 ± 13.1 min) than in group P (91.3 ± 35.2 and 326.11 ± 360.2 min) or M (260.2 ± 150.2 and 599.6 ± 586.6 min). Proportion of time within desired interval of sedation score was comparable between groups. Morphine consumption during the 24 h following extubation was lower in group S than in groups P and M. Four hallucination episodes were reported in group P, five in group M, and none in group S ( P  = 0.04). No hepatic or renal adverse events were reported. Mean plasma fluoride value was 82 μmol l −1 (range 12–220 μmol l −1 ), and mean ambient sevoflurane concentration was 0.3 ± 0.1 ppm. Conclusions Long-term inhaled sevoflurane sedation seems to be a safe and effective alternative to IV propofol or midazolam. It decreases wake-up and extubation times, and post extubation morphine consumption, and increases awakening quality.

S-ketamine and midazolam are frequently used to provide sedation while maintaining spontaneous respiration. However, the effects of these agents on respiratory variability, which reflects the adaptability of the respiratory system, have not been thoroughly explored. We evaluated these effects in a randomized controlled pilot trial. This study was conducted as part of a randomized controlled trial originally designed to assess the effects of s-ketamine conditioning on pain sensitivity in patients with fibromyalgia syndrome. Participants were randomly assigned to receive an infusion of either s-ketamine (0.3 mg kg -1 h -1 ), midazolam (0.05 mg kg -1 h -1 ), or saline in a blinded fashion. Mean respiratory rate, variability of respiratory rate (VRR), and variability of tidal volume (VTV) were measured continuously and non-invasively with a bio-impedance method. Changes during drug infusion were compared in a linear mixed model to assess the effects of s-ketamine and midazolam compared to saline. Data were analyzed for 57 experiments in 28 participants. Their median baseline variabilities of respiratory rate and tidal volume were 0.19 (IQR: 0.16–0.25) and 0.23 (0.19–0.34), respectively. While mean respiratory rate was not affected, midazolam resulted in a significant decrease in both VRR (ß = −0.071, 95% CI: −0.120 to −0.021) and VTV (ß = −0.117, 95% CI: −0.170 to −0.062). In contrast, s-ketamine appeared to produce a smaller decrease in VTV (ß = −0.062, 95% CI: −0.118 to −0.003) with VRR remaining unaffected (ß = −0.036, 95% CI: −0.092 to 0.019). In conclusion, our study demonstrates that midazolam reduces respiratory variability, potentially impairing the adaptability of the respiratory system. In contrast, s-ketamine largely preserved respiratory variability, suggesting it may be a safer alternative for sedation in patients with impaired spontaneous breathing. Further studies are needed to assess the clinical implications of these observations in patients undergoing sedation.

Standard treatment of critically ill patients undergoing mechanical ventilation is continuous sedation. Daily interruption of sedation has a beneficial effect, and in the general intesive care unit of Odense University Hospital, Denmark, standard practice is a protocol of no sedation. We aimed to establish whether duration of mechanical ventilation could be reduced with a protocol of no sedation versus daily interruption of sedation. Of 428 patients assessed for eligibility, we enrolled 140 critically ill adult patients who were undergoing mechanical ventilation and were expected to need ventilation for more than 24 h. Patients were randomly assigned in a 1:1 ratio (unblinded) to receive: no sedation (n=70 patients); or sedation (20 mg/mL propofol for 48 h, 1 mg/mL midazolam thereafter) with daily interruption until awake (n=70, control group). Both groups were treated with bolus doses of morphine (2·5 or 5 mg). The primary outcome was the number of days without mechanical ventilation in a 28-day period, and we also recorded the length of stay in the intensive care unit (from admission to 28 days) and in hospital (from admission to 90 days). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00466492. 27 patients died or were successfully extubated within 48 h, and, as per our study design, were excluded from the study and statistical analysis. Patients receiving no sedation had significantly more days without ventilation (n=55; mean 13·8 days, SD 11·0) than did those receiving interrupted sedation (n=58; mean 9·6 days, SD 10·0; mean difference 4·2 days, 95% CI 0·3–8·1; p=0·0191). No sedation was also associated with a shorter stay in the intensive care unit (HR 1·86, 95% CI 1·05–3·23; p=0·0316), and, for the first 30 days studied, in hospital (3·57, 1·52–9·09; p=0·0039), than was interrupted sedation. No difference was recorded in the occurrences of accidental extubations, the need for CT or MRI brain scans, or ventilator-associated pneumonia. Agitated delirium was more frequent in the intervention group than in the control group (n=11, 20% vs n=4, 7%; p=0·0400). No sedation of critically ill patients receiving mechanical ventilation is associated with an increase in days without ventilation. A multicentre study is needed to establish whether this effect can be reproduced in other facilities. Danish Society of Anesthesiology and Intensive Care Medicine, the Fund of Danielsen, the Fund of Kirsten Jensa la Cour, and the Fund of Holger og Ruth Hess.

Background While in vitro and animal studies have shown reduced cytochrome P450 (CYP) 3A activity due to obesity, clinical studies in (morbidly) obese patients are scarce. As CYP3A activity may influence both clearance and oral bioavailability in a distinct manner, in this study the pharmacokinetics of the CYP3A substrate midazolam were evaluated after semi-simultaneous oral and intravenous administration in morbidly obese patients, and compared with healthy volunteers. Methods Twenty morbidly obese patients [mean body weight 144 kg (range 112–186 kg) and mean body mass index 47 kg/m 2 (range 40–68 kg/m 2 )] participated in the study. All patients received a midazolam 7.5 mg oral and 5 mg intravenous dose (separated by 159 ± 67 min) and per patient 22 samples over 11 h were collected. Data from 12 healthy volunteers were available for a population pharmacokinetic analysis using NONMEM ® . Results In the three-compartment model in which oral absorption was characterized by a transit absorption model, population mean clearance (relative standard error %) was similar [0.36 (4 %) L/min], while oral bioavailability was 60 % (13 %) in morbidly obese patients versus 28 % (7 %) in healthy volunteers ( P  < 0.001). Central and peripheral volumes of distribution increased substantially with body weight (both P  < 0.001) and absorption rate (transit rate constant) was lower in morbidly obese patients [0.057 (5 %) vs. 0.130 (14 %) min –1 , P  < 0.001]. Conclusions In morbidly obese patients, systemic clearance of midazolam is unchanged, while oral bioavailability is increased. Given the large increase in volumes of distribution, dose adaptations for intravenous midazolam should be considered. Further research should elucidate the exact physiological changes at intestinal and hepatic level contributing to these findings.