Remimazolam besylate for sedation of postoperative patients in intensive care units: a phase I, open label, dose-finding study.
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SUBMITTER: Tang Y
PROVIDER: S-EPMC9746757 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Remimazolam besylate for sedation of postoperative patients in intensive care units: a phase I, open label, dose-finding study.
Tang Yun Y Yang Xiaobo X Shu Huaqing H Yu Yuan Y Xu Jiqian J Pan Shangwen S Zou Xiaojing X Yuan Shiying S Shang You Y
Chinese medical journal 20220905 17
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Project description:Introduction: The most common physiological and psychological disorders associated with critical care patients are pain and anxiety. Sedatives and analgesics are commonly used to relieve these symptoms. However, the adverse effects of sedatives and analgesics are common and inevitable. As a new type of sedative drug, limited number of trials are available to evaluate Remimazolam Besylate's availability and safety compared with propofol. Methods: This study is a single center, randomized, open-label, controlled trial. A total of 84 patients who meet ERAS criteria and receive mechanical ventilation in ICU, aged ≥18 years old will be included. Patients will be randomized (1:1) into two groups: Remimazolam Besylate group and Propofol group. The Primary outcomes includes satisfaction rate of sedation and incidence rate of major clinical events. Secondary outcomes including incidence of delirium, time to weaning and extubation, Difficulty of nursing RASS, BIS and PI, 28-days survival, side-effect and vital signs during medications, total dose and dose per kilogram body weight of analgesic and sedatives and incidence of rescue therapy in experimental group. Ethics and Dissemination: This trial has been approved by the ethics boards of Peking Union Medical College Hospital. Recruitment began in January 2022 and will continue until June 2022. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04947345.
| S-EPMC8603912 | biostudies-literature
Project description:ObjectiveTo compare the efficacy and safety of remimazolam besylate and propofol for deep sedation in critically ill patients.MethodsIn this single-center, prospective, randomized, controlled pilot study, patients in the intensive care unit (ICU) requiring deep sedation were randomized to receive remimazolam besylate or propofol intravenously. Deep sedation was defined as a Richmond Agitation and Sedation Scale (RASS) score of - 4 or - 5. Sedation depth was monitored using RASS and Narcotrend Index (NI). The primary outcome was the percentage of time within the target sedation range without rescue sedation. The secondary outcomes included ventilator-free hours within 7 days, successful extubation, length of ICU stay, and 28-day mortality. Adverse events during the interventional period were also recorded.ResultsThirty patients were assigned to each group. The median (IQR) RASS score was - 5.0 (- 5.0, - 4.0), and the median (IQR) NI value was 29.0 (21.0, 37.0) during the intervention period. Target RASS was reached a median of 100% of the sedation time in the two groups. No significant differences were observed in ventilator-free hours within 7 days, successful extubation, length of ICU stay, or 28-day mortality among groups. Hypotension occurred in 16 (53.3%) patients of remimazolam group and 18 (60.0%) patients of propofol group (p > 0.05). No patient experienced bradycardia.ConclusionsRemimazolam besylate appears to be an effective and safe agent for short-term deep sedation in critically ill patients. Our findings warrant large sample-sized randomized clinical trials.
| S-EPMC10694930 | biostudies-literature
Project description:ObjectiveThe aim of this study was to evaluate the efficacy and safety of remimazolam besylate compared with propofol in maintaining mild-to-moderate sedation in patients receiving long-term mechanical ventilation.MethodsIn this single-centered randomized pilot study, adult patients mechanically ventilated longer than 24 h were randomized to receive remimazolam besylate or propofol. The target sedation range was - 3 to 0 on the Richmond Agitation and Sedation Scale (RASS). The primary outcome was the percentage of time in the target sedation range without rescue sedation. The secondary outcomes were ventilator-free days at day 7, the length of ICU stay and 28-day mortality.ResultsThirty patients were assigned to each group. No difference was identified between the remimazolam group and propofol group in median age [60.0 (IQR, 51.5-66.3) years vs. 64.0 (IQR, 55.0-69.3) years, respectively, p = 0.437] or the median duration of study drug infusion [55.0 (IQR, 28.3-102.0) hours vs. 41.0 (IQR, 24.8-74.3) hours, respectively, p = 0.255]. The median percentage of time in the target RASS range without rescue sedation was similar in remimazolam and propofol groups [73.2% (IQR, 41.5-97.3%) vs. 82.8% (IQR, 65.6-100%), p = 0.269]. No differences were identified between the two groups in terms of ventilator-free days at day 7, length of ICU stay, 28-day mortality or adverse events.ConclusionsThis pilot study suggested that remimazolam besylate was effective and safe for long-term sedation in mechanically ventilated patients compared with propofol.
| S-EPMC9482181 | biostudies-literature
Project description: Not available
| S-EPMC5141349 | biostudies-literature
Project description:BackgroundHigh on-treatment platelet reactivity (HTPR) remains a major problem in the acute management of ST-elevation myocardial infarction (STEMI), leading to higher rates of stent thrombosis and mortality. We aimed to investigate a novel, prehospital treatment strategy using cangrelor and tested its pharmacodynamic effects in a model using healthy volunteers.MethodsWe conducted a dose-finding, open-label, pilot trial including 12 healthy volunteers and tested three ascending bolus infusions of cangrelor (5 mg, 10 mg and 20 mg) and a bolus infusion followed by a continuous infusion via an intravenous (IV) flow regulator. Platelet function was assessed using multiple electrode aggregometry (MEA), vasodilator-stimulated phosphoprotein phosphorylation assay (VASP-P) and the platelet function analyzer. In an ex vivo experiment, epinephrine was used to counteract the antiplatelet effect of cangrelor.ResultsAll cangrelor bolus infusions resulted in immediate and pronounced platelet inhibition. Bolus infusions of cangrelor 20 mg resulted in sufficient platelet inhibition assessed by MEA for 20 min in 90% of subjects. Infusion of cangrelor via the IV flow regulator resulted in sufficient platelet inhibition throughout the course of administration. Ex vivo epinephrine, in concentrations of 200 and 500 ng/mL was able to partially reverse the antiplatelet effect of cangrelor in a dose-dependent manner.ConclusionsWeight-adapted bolus infusions followed by a continuous infusion of cangrelor via IV flow regulator result in immediate and pronounced platelet inhibition in healthy subjects. Cangrelor given as weight-adapted bolus infusion followed by a continuous infusion using an IV flow regulator may be a viable treatment approach for effective and well controllable prehospital platelet inhibition.Trial registrationEC (Medical University of Vienna) 1835/2019 and EudraCT 2019-002792-34 .
| S-EPMC9008922 | biostudies-literature
Project description:BackgroundSedation is used frequently for patients in intensive care units who require mechanical ventilation, but oversedation is one of the main side effects. Different strategies have been proposed to prevent oversedation. The extent to which these strategies have been adopted by intensivists is unknown.MethodsWe developed a six-section questionnaire that covered the drugs used, modalities of drug administration, use of sedation scales and procedural pain scales, use of written local procedures, and targeted objectives of consciousness. In November 2011, the questionnaire was sent to 1,078 intensivists identified from the French ICU Society (SRLF) database.ResultsThe questionnaire was returned by 195 intensivists (response rate 18.1%), representing 135 of the 282 ICUs (47.8%) listed in the French ICU society (SRLF) database. The analysis showed that midazolam and sufentanil are the most frequently used hypnotics and opioids, respectively, administered in continuous intravenous (IV) infusions. IV boluses of hypnotics without subsequent continuous IV infusion are used occasionally (in <25% of patients) by 65% of intensivists. Anxiolytic benzodiazepines (e.g., clorazepam, alprazolam), hydroxyzine, and typical neuroleptics, via either an enteral or IV route, are used occasionally by two thirds of respondents. The existence of a written, local sedation management procedure in the ICU is reported by 55% of respondents, 54% of whom declare that they use it routinely. Written local sedation procedures mainly rely on titration of continuous IV hypnotics (90% of the sedation procedures); less frequently, sedation procedures describe alternative approaches to prevent oversedation, including daily interruption of continuous IV hypnotic infusion, hypnotic boluses with no subsequent continuous IV infusion, or the use of nonhypnotic drugs. Among the responding intensivists, 98% consider eye opening, either spontaneously or after light physical stimulation, a reasonable target consciousness level in patients with no severe respiratory failure or intracranial hypertension.ConclusionsDespite a low individual response rate, the respondents to our survey represent almost half of the ICUs in the French SRLF database. The presence of a written local sedation procedure, a cornerstone of preventing oversedation, is reported by only half of respondents; when present, it is used in for a limited number of patients. Sedation procedures mainly rely on titration of continuous IV hypnotics, but other strategies to limit oversedation also are included in sedation procedures. French intensivists no longer consider severely altered consciousness a sedation objective for most patients.
| S-EPMC3751696 | biostudies-literature
Project description:BackgroundCurrent rheumatoid arthritis therapies target immune inflammation and are subject to ceiling effects. Seliciclib is an orally available cyclin-dependent kinase inhibitor that suppresses proliferation of synovial fibroblasts-cells not yet targeted in rheumatoid arthritis. Part 1 of this phase 1b/2a trial aimed to establish the maximum tolerated dose of seliciclib in patients with active rheumatoid arthritis despite ongoing treatment with TNF inhibitors, and to evaluate safety and pharmacokinetics.MethodsPhase 1b of the TRAFIC study was a non-randomised, open-label, dose-finding trial done in rheumatology departments in five UK National Health Service hospitals. Eligible patients (aged ≥18 years) fulfilled the 1987 American College of Rheumatology (ACR) or the 2010 ACR-European League Against Rheumatism classification criteria for rheumatoid arthritis and had moderate to severe disease activity (a Disease Activity Score for 28 joints [DAS28] of ≥3·2) despite stable treatment with anti-TNF therapy for at least 3 months before enrolment. Participants were recruited sequentially to a maximum of seven cohorts of three participants each, designated to receive seliciclib 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg administered in 200 mg oral capsules. Sequential cohorts received doses determined by a restricted, one-stage Bayesian continual reassessment model, which determined the maximum tolerated dose (the primary outcome) based on a target dose-limiting toxicity rate of 35%. Seliciclib maximum concentration (Cmax) and area under the plasma concentration time curve 0-6 h (AUC0-6) were measured. This study is registered with ISRCTN, ISRCTN36667085.FindingsBetween Oct 8, 2015, and Aug 15, 2017, 37 patients were screened and 15 were enrolled to five cohorts and received seliciclib, after which the trial steering committee and the data monitoring committee determined that the maximum tolerated dose could be defined. In addition to a TNF inhibitor, ten (67%) enrolled patients were taking conventional synthetic disease modifying antirheumatic drugs. The maximum tolerated dose of seliciclib was 400 mg, with an estimated dose-limiting toxicity probability of 0·35 (90% posterior probability interval 0·18-0·52). Two serious adverse events occurred (one acute kidney injury in a patient receiving the 600 mg dose and one drug-induced liver injury in a patient receiving the 400 mg dose), both considered to be related to seliciclib and consistent with its known safety profile. 65 non-serious adverse events occurred during the trial, 50 of which were considered to be treatment related. Most treatment-related adverse events were mild; 20 of the treatment-related non-serious adverse events contributed to dose-limiting toxicities. There were no deaths. Average Cmax and AUC0-6 were two-times higher in participants developing dose-limiting toxicities.InterpretationThe maximum tolerated dose of seliciclib has been defined for rheumatoid arthritis refractory to TNF blockade. No unexpected safety concerns were identified to preclude ongoing clinical evaluation in a formal efficacy trial.FundingUK Medical Research Council, Cyclacel, Research into Inflammatory Arthritis Centre (Versus Arthritis), and the National Institute of Health Research Newcastle and Birmingham Biomedical Research Centres and Clinical Research Facilities.
| S-EPMC8062952 | biostudies-literature
Project description:A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days.This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg.42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n?=?3 and n?=?6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively).Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.
| S-EPMC2964291 | biostudies-literature
Project description:ObjectiveRemimazolam besylate and Ciprofol are newer sedatives used in minor surgeries. Propofol is a classic drug mainly used for short surgeries. This trial was conducted to compare the efficacy and safety of remimazolam besylate, ciprofol, and propofol during hysteroscopic surgeries.MethodsPatients undergoing hysteroscopy were randomly assigned to receive remimazolam besylate (Group R), ciprofol (Group C), or propofol (Group P). A total of 194 patients were assessed for eligibility. One patient in Group P was excluded because the operation had timed out of 60 min. Patients all in Group R、Group C and Group P received an induction dose of 0.2 mg/kg remimazolam besylate、0.4 mg/kg ciprofol、2.0 mg/kg propofol seperately over 30 s. A corresponding dosage of 1 mg/kg/h、0.6-1.2 mg/kg/h and 3.0-6.0 mg/kg/h was given by continuous intravenous infusion to maintain a BIS of 40-60 till the end of the surgery. The incidence rates of body movement, respiratory depression, and adverse effects were compared among the groups.ResultsThe incidence of injection pain was much higher in Group P (64.1%) than that in Group R (3.4%) and Group C (3.2%, both P < 0.001). The onset time was significantly shorter in Group P than that in Group R and Group C (both P < 0.01). The awakening time (MOAA/S score = 3) was longest in Group R, followed by Groups C and Group P (P < 0.01). The time to complete recovery (MOAA/S score = 5) has no significantly difference between Group C and Group P, whereas the onset time was significantly shorter in Group R (P < 0.01). The number of body movements was significantly higher in Group R than that in Group C and Group P (P < 0.01). The incidence of hypotension was significantly lower in Group R than that in Group C and Group P (both P < 0.01). The rate of respiratory inhibition was significantly lower in Group R and Group C than that in Group P (both P < 0.05).ConclusionConsidering jointly the safety and efficacy, ciprofol seems to be the best choice for sedation.
| S-EPMC11750796 | biostudies-literature
Project description:BackgroundDelirium is a primary adverse event in ventilated patients who receive long-term monosedative treatment. Sequential sedation may reduce these adverse effects. This study evaluated risk factors for delirium in sequential sedation patients.MethodsA total of 141 patients who underwent sequential sedation were enrolled. Delirium was diagnosed using Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scale. Univariate and multivariate Cox proportional hazards regressions were used to predict risk factors.ResultsOlder age (≥51) (RR = 2.432, 95% CL 1.316-4.494, p = 0.005), higher SOFA score (≥14) (RR = 2.022, 95% CL 1.076-3.798, p = 0.029), regular smoking (RR = 2.366, 95% CL 1.277-4.382, p = 0.006), and higher maintenance dose of midazolam (RR = 1.052, 95% CL 1.000-1.107, p = 0.049) and fentanyl (RR = 1.045, 95% CL 1.019-1.072, p = 0.001) when patients met sequential criteria, were independent risk factors of delirium. Sequential sedation with dexmedetomidine (RR = 0.448, 95% CL 0.209-0.963, p = 0.040) was associated with a lower risk of delirium.ConclusionsOlder age, higher SOFA score, regular smoking, and higher maintenance dose of midazolam and fentanyl when patients met sequential criteria were independent risk factors of delirium in sequential sedation patients. Sequential sedation with dexmedetomidine reduced risk of delirium.
| S-EPMC5684530 | biostudies-literature