Dexmedetomidine-ketamine combination versus fentanyl-midazolam for patient sedation during flexible bronchoscopy: a prospective, single-blind, randomized controlled trial.

BACKGROUND: Sedation during flexible bronchoscopy (FB) should maintain an adequate respiratory drive, ensure maximum comfort for the patient, and warrant that the objectives of the procedure are achieved. Nevertheless, the optimal sedation method for FB has yet to be established. This study aimed to compare the standard recommended combination of midazolam-fentanyl (MF) with that of dexmedetomidine-ketamine (DK) for patient sedation during FB. METHODS: Patients subjected to FB were randomly assigned to a DK (n = 25) and an MF group (n = 25). The primary outcome was the rate of critical desaturation events (arterial oxygen saturation < 80% with nasal oxygen supply 2 L/min). Secondary outcomes included sedation depth, hemodynamic complications, adverse events, and patient and bronchoscopist satisfaction. RESULTS: The incidence rates of critical desaturation events were similar between the two groups (DK: 12% vs. MF: 28%, p = 0.289). DK achieved deeper maximum sedation levels (higher Ramsay - lower Riker scale; p < 0.001) and was associated with longer recovery times (p < 0.001). Both groups had comparable rates of hemodynamic and other complications. Patient satisfaction was similar between the two groups, but bronchoscopist satisfaction was higher with the DK combination (p = 0.033). CONCLUSION: DK demonstrated a good safety profile in patients subjected to FB and achieved more profound sedation and better bronchoscopist satisfaction than the standard MF combination without increasing the rate of adverse events.

No harmful effect of propranolol administered prior to fear memory extinction in rats and humans.

Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure therapy efficacy. Clinical and laboratory evidence indeed suggests that benzodiazepines may have detrimental effects. Large clinical trials with propranolol, a common beta-blocker, are currently lacking, but several preclinical studies do indicate impaired establishment of safety memories. Here, we investigated the effects of propranolol given prior to extinction training in 9 rat studies (N = 215) and one human study (N = 72). A Bayesian meta-analysis of our rat studies provided strong evidence against propranolol-induced extinction memory impairment during a drug-free test, and the human study found no significant difference with placebo. Two of the rat studies actually suggested a small beneficial effect of propranolol. Lastly, two rat studies with a benzodiazepine (midazolam) group provided some evidence for a harmful effect on extinction memory, i.e., impaired extinction retention. In conclusion, our midazolam findings are in line with prior literature (i.e., an extinction retention impairment), but this is not the case for the 10 studies with propranolol. Our data thus support caution regarding the use of benzodiazepines during exposure therapy, but argue against a harmful effect of propranolol on extinction learning.

Study on Risk Factors and Receiver Operator Characteristic Curve of Iatrogenic Withdrawal Syndrome in Pediatric Intensive Care Units: A Retrospective Study.

INTRODUCTION: The aims of this study were to investigate the independent risk factors associated with iatrogenic withdrawal syndrome in pediatric intensive care units (PICUs) and to establish receiver operator characteristic (ROC) curve to facilitate the diagnosis of iatrogenic withdrawal syndrome in clinical settings. METHODS: Pediatric patients who received analgesic and sedative medication at a tertiary hospital in the southern Zhejiang region of China between January 2016 and December 2022 were selected for the study. Clinical case data were retrospectively analyzed to gather information including age, gender, weight, total dose of analgesic and sedative medication, total treatment duration, average maintenance dose, and other relevant parameters. Medically induced withdrawal symptom scores were assessed using the Sophia Observation Scale for Withdrawal Symptoms (SOS). Univariate and multivariate logistic regression analyses were conducted on the above indicators to identify the risk factors for iatrogenic withdrawal, and an ROC curve was constructed. RESULTS: The study encompassed a total of 104 pediatric patients, comprising 47 patients in the SOS score ≥4 group and 57 patients in the SOS score ≤3 group. The incidence of iatrogenic withdrawal was 45.19%. Univariate analysis identified cumulative total dose of fentanyl, average daily dose of fentanyl, average daily dose of midazolam, and patient weight (p < 0.05) as factors associated with iatrogenic withdrawal syndrome. The logistic multiple regression analysis revealed that the average daily dose of fentanyl was an independent risk factor for the occurrence of iatrogenic withdrawal syndrome in critically ill children (p < 0.05). ROC curve analysis indicated an area under the curve of 0.711 (95% CI: 0.610-0.811) with sensitivity and specificity of 73.7% and 61.7%, respectively. CONCLUSION: The average daily maintenance dose of fentanyl holds significant clinical value in diagnosing and evaluating the prognosis of iatrogenic withdrawal syndrome and can provide a scientific foundation for enhancing sedative and analgesic management in clinical practice.

Safety and efficacy of a low-dose combination of midazolam, alfentanil, and propofol for deep sedation of elderly patients undergoing ERCP.

BACKGROUND: Proper sedation of patients, particularly elderly individuals, who are more susceptible to sedation-related complications, is of significant importance in endoscopic retrograde cholangiopancreatography (ERCP). This study aims to assess the safety and efficacy of a low-dose combination of midazolam, alfentanil, and propofol for deep sedation in elderly patients undergoing ERCP, compared to a group of middle-aged patients. METHODS: The medical records of 610 patients with common bile duct stones who underwent elective ERCP under deep sedation with a three-drug regimen, including midazolam, alfentanil, and propofol at Shandong Provincial Third Hospital from January 2023 to September 2023 were retrospectively reviewed in this study. Patients were categorized into three groups: middle-aged (50-64 years, n = 202), elderly (65-79 years, n = 216), and very elderly (≥ 80 years, n = 192). Intraoperative vital signs and complications were compared among these groups. RESULTS: The three groups showed no significant difference in terms of intraoperative variation of systolic blood pressure (P = 0.291), diastolic blood pressure (P = 0.737), heart rate (P = 0.107), peripheral oxygen saturation (P = 0.188), bispectral index (P = 0.158), and the occurrence of sedation-related adverse events including hypotension (P = 0.170) and hypoxemia (P = 0.423). CONCLUSION: The results suggest that a low-dose three-drug regimen consisting of midazolam, alfentanil, and propofol seems safe and effective for deep sedation of elderly and very elderly patients undergoing ERCP procedures. However, further studies are required to verify these findings and clarify the benefits and risks of this method.

Integration of Certified Child Life Specialists to Decrease in Periprocedural Benzodiazepine Use: A Pilot Study.

INTRODUCTION: Periprocedural anxiety is common in pediatric patients and is characterized by tension, anxiety, irritability, and autonomic activation. Periprocedural anxiety increases during certain events including admission to the preoperative area, separation from caregivers, induction of anesthesia, and IV placement. A study of children aged 2-12 showed that perioperative anxiety in children may be influenced by high parental anxiety and low sociability of the child. While these are nonmodifiable variables in the perioperative setting, there are numerous ways to ameliorate both parental and patient anxiety including the use of certified child life specialists (CCLSs) to aid in child comfort. In this study, our objective was to evaluate the integration of CCLS in our perioperative setting on the rate of benzodiazepine use. METHODS: We used a prospectively maintained database to identify patients undergoing outpatient elective surgical and radiologic procedures from July 2022 to September 2023 and January 2023 to September 2023 respectively. CCLSs were used to work with appropriately aged children in order to decrease the use of benzodiazepines and reduce possible adverse events associated with their use. RESULTS: A total of 2175 pediatric patients were seen by CCLS in same day surgery from July 2022 to September 2023. During this period, midazolam use decreased by an average of 11.4% (range 6.2%-19.3%). An even greater effect was seen in the radiologic group with 73% reduction. No adverse events were reported during this period. CONCLUSIONS: CCLSs working with age-appropriate patients in the periprocedural setting is a useful adjunct in easing anxiety in pediatric patients, reducing the need for periprocedural benzodiazepine administration and the risk of exposure to unintended side effects.

Safety and efficacy of dexmedetomidine vs. midazolam in complex gastrointestinal endoscopy: A systematic review and meta-analysis.

OBJECTIVE: This study aims to perform a meta-analysis to evaluate the safety and efficacy of dexmedetomidine versus midazolam for complex digestive endoscopy procedures, with the goal of offering comprehensive clinical evidence. METHODS: Following predefined inclusion criteria, five databases were systematically searched, with a focus on identifying randomized controlled trials (RCTs) that compared the administration of dexmedetomidine and midazolam during complex digestive endoscopy procedures. The statistical software Stata 15.1 was employed for meticulous data analysis. RESULTS: Sixteen RCTs were encompassed, involving a total of 1218 patients. In comparison to the midazolam group, dexmedetomidine administration was associated with a reduced risk of respiratory depression (RR=0.25, 95 %CI: 0.11-0.56) and hypoxemia (RR=0.22, 95 %CI: 0.12-0.39). Additionally, the dexmedetomidine group exhibited lower incidence rates of choking (RR=0.27, 95 %CI: 0.16-0.47), physical movement (RR=0.16, 95 %CI: 0.09-0.27), and postoperative nausea and vomiting (RR=0.56,95 %CI: 0.34-0.92). Patients and endoscopists in the dexmedetomidine group reported higher levels of satisfaction (patient satisfaction: SMD=0.73, 95 %CI: 0.26-1.21; endoscopist satisfaction: SMD=0.84, 95 %CI: 0.24-1.44). The incidence of hypotension and anesthesia recovery time did not significantly differ between the two groups (hypotension: RR=1.73,95 %CI:0.94-3.20; anesthesia recovery time: SMD=0.02, 95 %Cl: 0.44-0.49). It is noteworthy that the administration of dexmedetomidine was associated with a significant increase in the incidence of bradycardia in patients. CONCLUSION: Compared to midazolam, dexmedetomidine exhibits a favorable safety profile for use in complex gastrointestinal endoscopy by significantly reducing the risk of respiratory depression and hypoxemia. Despite this, dexmedetomidine is associated with a higher incidence of bradycardia. These findings underscore the need for further research through larger, multi-center studies to thoroughly investigate dexmedetomidine's safety and efficacy.

The risk of delirium after sedation with propofol or midazolam in intensive care unit patients.

AIM: Knowledge of risk factors may provide strategies to reduce the high burden of delirium in intensive care unit (ICU) patients. We aimed to compare the risk of delirium after deep sedation with propofol versus midazolam in ICU patients. METHODS: In this prospective cohort study, ICU patients who were in an unarousable state for ≥24 h due to continuous sedation with propofol and/or midazolam were included. Patients admitted ≤24 h, those with an acute neurological disorder and those receiving palliative sedation were excluded. ICU patients were assessed daily for delirium during the 7 days following an unarousable state due to continuous sedation. RESULTS: Among 950 included patients, 605 (64%) subjects were delirious during the 7 days after awaking. The proportion of subsequent delirium was higher after midazolam sedation (152/207 [73%] patients) and after both propofol and midazolam sedation (257/377 [68%] patients), compared to propofol sedation only (196/366 [54%] patients). Midazolam sedation (adjusted cause-specific hazard ratio [adj. cause-specific HR] 1.32, 95% confidence interval [CI] 1.05-1.66) and propofol and midazolam sedation (adj. cause-specific HR 1.29, 95% CI 1.06-1.56) were associated with a higher risk of subsequent delirium compared to propofol sedation only. CONCLUSION: This study among sedated ICU patients suggests that, compared to propofol sedation, midazolam sedation is associated with a higher risk of subsequent delirium. This risk seems more apparent in patients with high cumulative midazolam intravenous doses. Our findings underpin the recommendations of the Society of Critical Care Medicine Pain, Agitation/sedation, Delirium, Immobility (rehabilitation/mobilization), and Sleep (disruption) guidelines to use propofol over benzodiazepines for sedation in ICU patients.

Seizures in 3 juvenile dogs after intravenous anesthetic drug withdrawal during weaning from mechanical ventilation suspected to be a sign of iatrogenic withdrawal syndrome.

OBJECTIVE: To describe seizure activity in juvenile dogs successfully weaned from long-term mechanical ventilation. CASE SERIES SUMMARY: Three juvenile dogs (all approximately 3 months old) underwent long-term mechanical ventilation with IV anesthesia for suspected noncardiogenic pulmonary edema. Within 24 hours of extubation and within 10 hours of discontinuing midazolam continuous infusions, all dogs experienced seizures, which is 1 sign of iatrogenic withdrawal syndrome. Each dog was treated with an anticonvulsant protocol, and none experienced seizures after being discharged. NEW OR UNIQUE INFORMATION PROVIDED: Each dog received IV anesthesia, including fentanyl, dexmedetomidine, midazolam, and propofol, during mechanical ventilation and subsequently experienced seizures after successful weaning from mechanical ventilation. Juvenile dogs may be at risk for seizures after weaning from mechanical ventilation and IV anesthesia. Neurological monitoring and further research into an appropriate weaning protocol may prove beneficial in juvenile dogs requiring prolonged anesthesia.

Cognitive outcomes from the randomised, active-controlled Ketamine for Adult Depression Study (KADS).

BACKGROUND: Due to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS). METHODS: In this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5-0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment. RESULTS: Results showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes. LIMITATIONS: The study included two Cohorts with different dosing regimes. CONCLUSIONS: The findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD.

Pharmacological agents for procedural sedation and analgesia in the emergency department and intensive care unit: a systematic review and network meta-analysis of randomised trials.

BACKGROUND: We aimed to evaluate the comparative effectiveness and safety of various i.v. pharmacologic agents used for procedural sedation and analgesia (PSA) in the emergency department (ED) and ICU. We performed a systematic review and network meta-analysis to enable direct and indirect comparisons between available medications. METHODS: We searched Medline, EMBASE, Cochrane, and PubMed from inception to 2 March 2023 for RCTs comparing two or more procedural sedation and analgesia medications in all patients (adults and children >30 days of age) requiring emergent procedures in the ED or ICU. We focused on the outcomes of sedation recovery time, patient satisfaction, and adverse events (AEs). We performed frequentist random-effects model network meta-analysis and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty in estimates. RESULTS: We included 82 RCTs (8105 patients, 78 conducted in the ED and four in the ICU) of which 52 studies included adults, 23 included children, and seven included both. Compared with midazolam-opioids, recovery time was shorter with propofol (mean difference 16.3 min, 95% confidence interval [CI] 8.4-24.3 fewer minutes; high certainty), and patient satisfaction was better with ketamine-propofol (mean difference 1.5 points, 95% CI 0.3-2.6 points, high certainty). Regarding AEs, compared with midazolam-opioids, respiratory AEs were less frequent with ketamine (relative risk [RR] 0.55, 95% CI 0.32-0.96; high certainty), gastrointestinal AEs were more common with ketamine-midazolam (RR 3.08, 95% CI 1.15-8.27; high certainty), and neurological AEs were more common with ketamine-propofol (RR 3.68, 95% CI 1.08-12.53; high certainty). CONCLUSION: When considering procedural sedation and analgesia in the ED and ICU, compared with midazolam-opioids, sedation recovery time is shorter with propofol, patient satisfaction is better with ketamine-propofol, and respiratory adverse events are less common with ketamine.

Comparison of remimazolam and dexmedetomidine for intraoperative sedation in patients undergoing lower extremity surgery under spinal anesthesia: a randomized clinical trial.

BACKGROUND: Dexmedetomidine sedation has advantages, such as low incidence of respiratory depression and prolonged block duration, but also significant disadvantages, such as slow onset, high rate of sedation failure, and a long context-sensitive half-life. Remimazolam provides rapid sedation and recovery, high sedation efficacy and has minimal hemodynamic effects. We hypothesized that patients who received remimazolam would require less rescue midazolam than dexmedetomidine. METHODS: Patients (n=103) scheduled for surgery under spinal anesthesia were randomized to receive dexmedetomidine (DEX group) or remimazolam (RMZ group) targeting a Modified Observer's Assessment of Alertness/Sedation score of 3 or 4. Rescue midazolam was administered if the patient failed to be sedated after the initial loading dose or despite infusion rate adjustment. RESULTS: Rescue midazolam administration was significantly higher in the DEX group (0% vs 39.2%; p<0.001). Patients in the RMZ group reached the target sedation level more rapidly. The incidences of bradycardia (0% vs 25.5%; p<0.001) and hypertension (0% vs 21.6%; p<0.001) were higher in the DEX group. Respiratory depression occurred at a higher rate in the RMZ group (21.2% vs 2.0%; p=0.002), but no patients required manual ventilation. Patients in the RMZ group recovered faster, had a shorter PACU stay and higher satisfaction scores. Hypotensive episodes in the PACU were more frequent in the DEX group (1.9% vs 29.4%; p<0.001). CONCLUSIONS: Remimazolam showed excellent sedation efficacy, minimal hemodynamic effects, and fewer adverse events in the PACU than dexmedetomidine. However, it is important to note that respiratory depression was more frequent with the use of remimazolam. TRIAL REGISTRATION NUMBER: NCT05447507.

Pulsed-field versus cryoballoon ablation for atrial fibrillation-Impact of energy source on sedation and analgesia requirement.

INTRODUCTION: Pulsed field ablation (PFA) represents a novel, nonthermal energy modality that can be applied for single-shot pulmonary vein isolation (PVI) in atrial fibrillation (AF). Comparative data with regard to deep sedation to established single-shot modalities such as cryoballoon (CB) ablation are scarce. The aim of this study was to compare a deep sedation protocol in patients receiving PVI with either PFA or CB. METHODS: Prospective, consecutive AF patients undergoing PVI with a pentaspline PFA catheter were compared to a retrospective CB-PVI cohort of the same timeframe. Study endpoints were the requirements of analgesics, cardiorespiratory stability, and sedation-associated complications. RESULTS: A total of 100 PVI patients were included (PFA n = 50, CB n = 50, mean age 66 ± 10.6, 61% male patients, 65% paroxysmal AF). Requirement of propofol, midazolam, and sufentanyl was significantly higher in the PFA group compared to CB [propofol 0.14 ± 0.04 mg/kg/min in PFA vs. 0.11 ± 0.04 mg/kg/min in CB (p = .001); midazolam 0.00086 ± 0.0004 mg/kg/min in PFA vs. 0.0006295 ± 0.0003 mg/kg/min in CB (p = .002) and sufentanyl 0.0013 ± 0.0007 µg/kg/min in PFA vs. 0.0008 ± 0.0004 µg/kg/min in CB (p < .0001)]. Sedation-associated complications did not differ between both groups (PFA n = 1/50 mild aspiration pneumonia, CB n = 0/50, p > .99). Nonsedation-associated complications (PFA: n = 2/50, 4%, CB: n = 1/50, 2%, p > .99) and procedure times (PFA 75 ± 31, CB 84 ± 32 min, p = .18) did not differ between groups. CONCLUSIONS: PFA is associated with higher sedation and especially analgesia requirements. However, the safety of deep sedation does not differ to CB ablation.

The association between midazolam premedication and postoperative delirium - a retrospective cohort study.

STUDY OBJECTIVE: To evaluate the association between midazolam premedication and postoperative delirium in a large retrospective cohort of patients ≥70 years. DESIGN: Retrospective cohort study. SETTING: A single tertiary academic medical center. PATIENTS: Patients ≥70 years having elective non-cardiac surgery under general anesthesia from 2020 to 2021. INTERVENTIONS: Midazolam premedication, defined as intravenous midazolam administration prior to induction of general anesthesia. MEASUREMENTS: The primary outcome, postoperative delirium, was a collapsed composite outcome including at least one of the following: a positive 4A's test during post-anesthesia care unit stay and/or the initial 2 postoperative days; physician or nursing records reporting new-onset confusion as captured by the CHART-DEL instrument; or a positive 3D-CAM test. The association between midazolam premedication and postoperative delirium was assessed using multivariable logistic regression, adjusting for potential confounding variables. As secondary analysis, we investigated the association between midazolam premedication and a composite of other postoperative complications. Several sensitivity analyses were performed using similar regression models. MAIN RESULTS: In total, 1973 patients were analyzed (median age 75 years, 47% women, 50% ASA score ≥ 3, 32% high risk surgery). The overall incidence of postoperative delirium was 15.3% (302/1973). Midazolam premedication was administered to 782 (40%) patients (median [IQR] dose 2 [1,2] mg). After adjustment for potential confounding variables, midazolam premedication was not associated with increased odds of postoperative delirium, with adjusted odds ratio of 1.09 (95% confidence interval 0.82-1.45; P = 0.538). Midazolam premedication was also not associated with the composite of other postoperative complications. Furthermore, no association was found between midazolam premedication and postoperative delirium in any of the sensitivity analyses preformed. CONCLUSIONS: Our results suggest that low doses of midazolam can be safely used to pre-medicate elective surgical patients 70 years or older before non-cardiac surgery, without significant effect on the risk of developing postoperative delirium.

Preoperative Midazolam and Patient-Centered Outcomes of Older Patients: The I-PROMOTE Randomized Clinical Trial.

Importance: The effect of oral midazolam premedication on patient satisfaction in older patients undergoing surgery is unclear, despite its widespread use. Objective: To determine the differences in global perioperative satisfaction in patients with preoperative administration of oral midazolam compared with placebo. Design, Setting, and Participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial was conducted in 9 German hospitals between October 2017 and May 2019 (last follow-up, June 24, 2019). Eligible patients aged 65 to 80 years who were scheduled for elective inpatient surgery for at least 30 minutes under general anesthesia and with planned extubation were enrolled. Data were analyzed from November 2019 to December 2020. Interventions: Patients were randomized to receive oral midazolam, 3.75 mg (n = 309), or placebo (n = 307) 30 to 45 minutes prior to anesthesia induction. Main Outcomes and Measures: The primary outcome was global patient satisfaction evaluated using the self-reported Evaluation du Vécu de l'Anesthésie Generale (EVAN-G) questionnaire on the first postoperative day. Key secondary outcomes included sensitivity and subgroup analyses of the primary outcome, perioperative patient vital data, adverse events, serious complications, and cognitive and functional recovery up to 30 days postoperatively. Results: Among 616 randomized patients, 607 were included in the primary analysis. Of these, 377 (62.1%) were male, and the mean (SD) age was 71.9 (4.4) years. The mean (SD) global index of patient satisfaction did not differ between the midazolam and placebo groups (69.5 [10.7] vs 69.6 [10.8], respectively; mean difference, -0.2; 95% CI, -1.9 to 1.6; P = .85). Sensitivity (per-protocol population, multiple imputation) and subgroup analyses (anxiety, frailty, sex, and previous surgical experience) did not alter the primary results. Secondary outcomes did not differ, except for a higher proportion of patients with hypertension (systolic blood pressure ≥160 mm Hg) at anesthesia induction in the placebo group. Conclusion and Relevance: A single low dose of oral midazolam premedication did not alter the global perioperative patient satisfaction of older patients undergoing surgery or that of patients with anxiety. These results may be affected by the low dose of oral midazolam. Further trials-including a wider population with commonplace low-dose intravenous midazolam and plasma level measurements-are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03052660.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

Success and safety of deep sedation as a primary anaesthetic approach for transvenous lead extraction: a retrospective analysis.

There is a rising number in complications associated with more cardiac electrical devices implanted (CIED). Infection and lead dysfunction are reasons to perform transvenous lead extraction. An ideal anaesthetic approach has not been described yet. Most centres use general anaesthesia, but there is a lack in studies looking into deep sedation (DS) as an anaesthetic approach. We report our retrospective experience for a large number of procedures performed with deep sedation as a primary approach. Extraction procedures performed between 2011 and 2018 in our electrophysiology laboratory have been included retrospectively. We began by applying a bolus injection of piritramide followed by midazolam as primary medication and would add etomidate if necessary. For extraction of leads a stepwise approach with careful traction, locking stylets, dilator sheaths, mechanical rotating sheaths and if needed snares and baskets has been used. A total of 780 leads in 463 patients (age 69.9 ± 12.3, 31.3% female) were extracted. Deep sedation was successful in 97.8% of patients. Piritramide was used as the main analgesic medication (98.5%) and midazolam as the main sedative (94.2%). Additional etomidate was administered in 15.1% of cases. In 2.2% of patients a conversion to general anaesthesia was required as adequate level of DS was not achieved before starting the procedure. Sedation related complications occurred in 1.1% (n = 5) of patients without sequalae. Deep sedation with piritramide, midazolam and if needed additional etomidate is a safe and feasible strategy for transvenous lead extraction.

Retrospective Evaluation of Moderate Sedation Visits That Used Oral Meperidine and Hydroxyzine With Oral or Intranasal Midazolam.

Purpose: To examine the influence of substituting intranasal (IN) midazolam (MID) for oral (PO) MID, within the three-drug combination of meperidine (MEP), hydroxyzine (H) and MID, on sedation treatment outcomes. Methods: A retrospective, cross-sectional analysis examined patient variables and sedation outcomes in 508 pediatric dental patients sedated by single- and multi-drug sedation regimens (MEP-H; MEP-H-(PO)-MID; MEP-H-(IN)-MID; single-agent MID). The outcome assessment examined sedation visit effectiveness, sedation treatment completion, treatment time and medication administration to discharge time. Multivariable logistic regression analyses assessed predictive variables associated with sedation visit effectiveness. Results: Both three-drug combinations (MEP-H-(PO)-MID; MEP-H-(IN)-MID) were used for behavior guidance in children of a similar age (median age=7.1 and 6.5 years, respectively, for the two drug combinations) and weight (median weight = 23.7 and 23.5 kg, respectively, for the two drug combinations). These three-drug combinations had a higher likelihood of sedation effectiveness over the reference sedation regimen of single-agent midazolam (MEP-H-(PO)-MID adjusted odds ratio [OR] = 2.65; 95 percent confidence interval [95% CI]=1.09 to 6.45; P=0.032; and MEP-H-(IN)-MID OR=2.08; 95% CI=1.03 to 4.18; P=0.039). MEP-H-(IN)MID was associated with a shorter medication administration to discharge time for patients by 23 minutes (interquartile range [IQR]=9.5 to 34 minutes) compared to MEP-H-(PO) MID (P<0.05) while providing a comparable number of teeth treated (median=five). All sedation drug regimens, including MEP-H-(IN)MID, had high levels of oxygen saturation during all sedation appointments. Conclusion: Substituting IN for PO MID in MEP-H-MID was associated with a shorter total time to discharge while demonstrating comparable efficacy during sedation.

Safety and efficacy of remimazolam compared with midazolam during bronchoscopy: a single-center, randomized controlled study.

Although remimazolam is an ultra-short-acting benzodiazepine with a shorter elimination half-life and faster recovery time than midazolam, studies evaluating its safety and efficacy during bronchoscopy are limited. This study aimed to compare the safety and efficacy of remimazolam with those of midazolam for bronchoscopy. This prospective randomized parallel-group study was conducted at a single institution. The primary outcome was the time from the end of the procedure to full alertness. Other procedural time parameters, satisfaction profiles, and adverse effects were thoroughly evaluated. The time taken to reach peak sedation and the time from the end of the procedure to full alertness was significantly shorter in the remimazolam group than in the midazolam group (median [interquartile range], 2 min [1-4] vs. 3 min [2-5], P = 0.006; and median, 2 min [1-5] vs. 5 min [1-12], P = 0.035, respectively). In patients with non-biopsy procedures (n = 79), participant satisfaction was significantly higher in the remimazolam group than in the midazolam group (median rated scale, 10 vs. 7, P = 0.042). Physician satisfaction and willingness to repeat the procedure were similar between groups. Although the incidence of adverse effects was similar between the groups and there was no significant difference, the midazolam group had a higher antidote administration rate than the remimazolam group (15.7% vs. 4.1%, P = 0.092). Remimazolam is effective and safe for achieving adequate sedation, with a shorter onset time and faster neuropsychiatric recovery than midazolam. It may be a new option for sedation during bronchoscopy.Trial registration: The trial registration number is NCT05994547, and the date of first registration is 16/08/2023.

Comparison of S-ketamine and midazolam for intravenous preoperative sedative and anxiolytic effects in preschool children: study protocol for a randomized controlled clinical trial.

BACKGROUND: Preoperative anxiety management is gaining particular attention in paediatric anaesthesia. Pharmacological and non-pharmacological resorts can be implemented to address this special issue. Despite the various approaches currently used for preoperative sedation in children, the different sedative and anti-anxiety effects between the newly marketed anaesthetic, S-ketamine, and the traditional sedative, midazolam, are still unclear. METHODS: This is a patient- and assessor-blinded randomized controlled clinical trial. Participants (n = 110) will receive S-ketamine (0.5 mg/kg) or midazolam (0.08 mg/kg) intravenously administrated at a ratio of 1:1 in the anaesthesia holding area. The primary outcome of this study is the sedative effect evaluated via the change in the modified Yale preoperative anxiety scale. It will be performed at two timepoints: in the pre-anaesthetic holding area before premedication (baseline, marked as T0) and about 5 min after premedication in the operating room without the existence of their guardians (marked as T1). Our secondary objectives include the parent separation anxiety score, postoperative agitation, caregivers' and anaesthesia care providers' satisfaction, and mask compliance. DISCUSSION: This randomized controlled trial is the first study to compare the anti-anxiety effect of intravenous S-ketamine and midazolam. We will provide a new approach for the clinical management of preoperative anxiety in preschool children posted for elective surgery. TRIAL REGISTRATION: ChiCTR2300069998. Registered on 30 March 2023.

A comparation of dexmedetomidine and midazolam for sedation in patients with mechanical ventilation in ICU: A systematic review and meta-analysis.

BACKGROUND: The use of dexmedetomidine rather than midazolam may improve ICU outcomes. We summarized the available recent evidence to further verify this conclusion. METHODS: An electronic search of PubMed, Medline, Embase, Cochrane Library, and Web of Science was conducted. Risk ratios (RR) were used for binary categorical variables, and for continuous variables, weighted mean differences (WMD) were calculated, the effect sizes are expressed as 95% confidence intervals (CI), and trial sequential analysis was performed. RESULTS: 16 randomized controlled trials were enrolled 2035 patients in the study. Dexmedetomidine as opposed to midazolam achieved a shorter length of stay in ICU (MD = -2.25, 95%CI = -2.94, -1.57, p<0.0001), lower risk of delirium (RR = 0.63, 95%CI = 0.50, 0.81, p = 0.0002), and shorter duration of mechanical ventilation (MD = -0.83, 95%CI = -1.24, -0.43, p<0.0001). The association between dexmedetomidine and bradycardia was also found to be significant (RR 2.21, 95%CI 1.31, 3.73, p = 0.003). We found no difference in hypotension (RR = 1.44, 95%CI = 0.87, 2.38, P = 0.16), mortality (RR = 1.02, 95%CI = 0.83, 1.25, P = 0.87), neither in terms of adverse effects requiring intervention, hospital length of stay, or sedation effects. CONCLUSIONS: Combined with recent evidence, compared with midazolam, dexmedetomidine decreased the risk of delirium, mechanical ventilation, length of stay in the ICU, as well as reduced patient costs. But dexmedetomidine could not reduce mortality and increased the risk of bradycardia.