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Drug Design, Development and Therapy 2022Remimazolam (CNS7056) is a novel benzodiazepine for intravenous sedation; it has an ultra-short duration of action and was recently approved for use in procedural... (Review)
Review
Remimazolam (CNS7056) is a novel benzodiazepine for intravenous sedation; it has an ultra-short duration of action and was recently approved for use in procedural sedation and general anaesthesia. It acts on γ-aminobutyric acid type A receptors and is rapidly converted into an inactive metabolite by tissue esterase enzymes. Remimazolam has been successfully used in endoscopic inspection or surgery and general anaesthesia induction and maintenance with fast and predictable onset and recovery times, high procedure success rates, and minor respiratory and hemodynamic fluctuations and without serious drug-related adverse reactions. If needed, the effects of remimazolam can be reversed by flumazenil, which allows prompt termination of sedation. Although remimazolam has great potential for sedation in patients admitted to intensive care units, future studies are needed to evaluate its efficacy and safety in patients requiring sedation for a long period, and numerous studies are warranted to explore the optimal dose in different application scenarios. The review aimed to provide an introduction to the process of remimazolam synthesis and its current clinical uses and future clinical developments.
Topics: Humans; Hypnotics and Sedatives; Midazolam; Double-Blind Method; Benzodiazepines; Anesthetics; Anesthesia, General
PubMed: 36411859
DOI: 10.2147/DDDT.S384155 -
Korean Journal of Anesthesiology Aug 2022Intravenous anesthetic agents such as midazolam, propofol, and ketamine are routinely used to provide anesthesia and sedation. They have been shown to effectively induce... (Review)
Review
Intravenous anesthetic agents such as midazolam, propofol, and ketamine are routinely used to provide anesthesia and sedation. They have been shown to effectively induce and maintain amnesia, sedation, and hypnosis in various patient groups and clinical settings. However, all anesthetic agents have the potential to cause unwanted side effects such as hemodynamic instability, respiratory depression, or slow recovery due to prolonged post-procedural sedation. Remimazolam, a recently approved benzodiazepine for general anesthesia and procedural sedation in Korea, has been successfully used for these purposes. To date, inconclusive knowledge has been obtained regarding the use of remimazolam in different patient populations and under various surgical conditions. With respect to the specific pharmacokinetic and pharmacodynamic characteristics of remimazolam, the use of remimazolam is expected to increase providing safe general anesthesia and sedation. This review aims to provide an overview of the basic and clinical pharmacology of remimazolam and to compare it with midazolam and propofol.
Topics: Anesthesia, General; Anesthetics, Intravenous; Benzodiazepines; Double-Blind Method; Humans; Hypnotics and Sedatives; Midazolam; Propofol
PubMed: 35585830
DOI: 10.4097/kja.22297 -
Journal of Oral Science Jun 2021Remimazolam is a new ultrashort-acting benzodiazepine with fast onset, quick recovery, and few side effects, such as hypotension and respiratory depression. It is... (Review)
Review
Remimazolam is a new ultrashort-acting benzodiazepine with fast onset, quick recovery, and few side effects, such as hypotension and respiratory depression. It is expected to be safe and effective for a wide range of patients undergoing intravenous sedation for dental procedures. The aim of this literature review was to evaluate clinical and sedation outcomes for remimazolam, including method of administration, level of sedation at the dose required, and clinical adverse events. An electronic literature search of databases was conducted, and eight articles were selected for inclusion in this review. Onset time from drug administration to optimal sedation level was faster for remimazolam (around 1.5-6.4 min) than for midazolam. Recovery time was significantly shorter for remimazolam than for midazolam and propofol. A study comparing various doses of remimazolam with midazolam found no significant difference in safety. Comparison of a remimazolam group with a propofol group showed that incidences of hypotension (13.0% vs 42.9%, respectively) and respiratory depression (1.1% vs 6.9%, respectively) were significantly lower for remimazolam. Remimazolam appears to be an ideal sedative.
Topics: Benzodiazepines; Humans; Hypnotics and Sedatives; Midazolam
PubMed: 34092775
DOI: 10.2334/josnusd.21-0051 -
Dexmedetomidine versus Midazolam in Procedural Sedation. A Systematic Review of Efficacy and Safety.PloS One 2017To systematically review the literature comparing the efficacy and safety of dexmedetomidine and midazolam when used for procedural sedation. (Review)
Review
OBJECTIVES
To systematically review the literature comparing the efficacy and safety of dexmedetomidine and midazolam when used for procedural sedation.
MATERIALS AND METHODS
We searched MEDLINE, EMBASE and COCHRANE for clinical trials comparing dexmedetomidine and midazolam for procedural sedation up to June 20, 2016. Inclusion criteria: clinical trial, human subjects, adult subjects (≥18 years), article written in English, German, French or Dutch, use of study medication for conscious sedation and at least one group receiving dexmedetomidine and one group receiving midazolam. Exclusion criteria: patients in intensive care, pediatric subjects and per protocol use of additional sedative medication other than rescue medication. Outcome measures for efficacy comparison were patient and clinician satisfaction scores and pain scores; outcome measures for safety comparison were hypotension, hypoxia, and circulatory and respiratory complications.
RESULTS
We identified 89 papers, of which 12 satisfied the inclusion and exclusion criteria; 883 patients were included in these studies. Dexmedetomidine was associated with higher patient and operator satisfaction than midazolam. Patients receiving dexmedetomidine experienced less pain and had lower analgesic requirements. Respiratory and hemodynamic safety were similar.
CONCLUSIONS
Dexmedetomidine is a promising alternative to midazolam for use in procedural sedation. Dexmedetomidine provides more comfort during the procedure for the patient and clinician. If carefully titrated, the safety profiles are similar.
Topics: Dexmedetomidine; Hemodynamics; Humans; Hypnotics and Sedatives; Midazolam; Respiration
PubMed: 28107373
DOI: 10.1371/journal.pone.0169525 -
Critical Care (London, England) May 2016Daily interruption of sedative therapy and limitation of deep sedation have been shown in several randomized trials to reduce the duration of mechanical ventilation and... (Review)
Review
Daily interruption of sedative therapy and limitation of deep sedation have been shown in several randomized trials to reduce the duration of mechanical ventilation and hospital length of stay, and to improve the outcome of critically ill patients. However, patients with severe acute brain injury (ABI; including subjects with coma after traumatic brain injury, ischaemic/haemorrhagic stroke, cardiac arrest, status epilepticus) were excluded from these studies. Therefore, whether the new paradigm of minimal sedation can be translated to the neuro-ICU (NICU) is unclear. In patients with ABI, sedation has 'general' indications (control of anxiety, pain, discomfort, agitation, facilitation of mechanical ventilation) and 'neuro-specific' indications (reduction of cerebral metabolic demand, improved brain tolerance to ischaemia). Sedation also is an essential therapeutic component of intracranial pressure therapy, targeted temperature management and seizure control. Given the lack of large trials which have evaluated clinically relevant endpoints, sedative selection depends on the effect of each agent on cerebral and systemic haemodynamics. Titration and withdrawal of sedation in the NICU setting has to be balanced between the risk that interrupting sedation might exacerbate brain injury (e.g. intracranial pressure elevation) and the potential benefits of enhanced neurological function and reduced complications. In this review, we provide a concise summary of cerebral physiologic effects of sedatives and analgesics, the advantages/disadvantages of each agent, the comparative effects of standard sedatives (propofol and midazolam) and the emerging role of alternative drugs (ketamine). We suggest a pragmatic approach for the use of sedation-analgesia in the NICU, focusing on some practical aspects, including optimal titration and management of sedation withdrawal according to ABI severity.
Topics: Analgesia; Brain Injuries; Critical Care; Critical Illness; Deep Sedation; Humans; Hypnotics and Sedatives; Intensive Care Units; Ketamine; Midazolam; Propofol; Respiration, Artificial
PubMed: 27145814
DOI: 10.1186/s13054-016-1294-5 -
Physiological Research Sep 2020Midazolam is a short acting sedative with small number of adverse effects. Administered orally, it is currently the most common form of conscious sedation in children....
Midazolam is a short acting sedative with small number of adverse effects. Administered orally, it is currently the most common form of conscious sedation in children. The objective of this paper is to describe effect of midazolam administered to children during dental treatment on their vital signs, and to monitor changes in children's behavior. We described values of vital signs and behavior in 418 sedations conducted in 272 children between 1-12 years of age. To achieve the following results, we used data from 272 all first-time sedations. After administration of midazolam arterial blood pressure and blood oxygen saturation decreased by values which were not clinically significant. The heart rate increased, with values staying within the limits of physiological range. The speed of onset of midazolam's clinical effects depends on age and dose. The lower age and dose correlated with the higher behavior score. The effectiveness of midazolam treatment is 97.8 %. Unwillingness of child to receive midazolam is predictor for disruptive behavior during sedation. 1.8 % of all sedation cases showed paradoxical reactions. The administration of midazolam in dose of 0.5 mg per 1 kg of child's body weight is safe and could be recommended for dental treatment in pediatric dentistry.
Topics: Administration, Oral; Child; Child Behavior; Child, Preschool; Conscious Sedation; Dentistry; Female; Humans; Hypnotics and Sedatives; Infant; Male; Midazolam; Vital Signs
PubMed: 33094628
DOI: 10.33549/physiolres.934511 -
European Journal of Heart Failure Oct 2022Benzodiazepines have been used as safe anxiolytic drugs for decades and some authors have suggested they could be an alternative for morphine for treating acute... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Benzodiazepines have been used as safe anxiolytic drugs for decades and some authors have suggested they could be an alternative for morphine for treating acute cardiogenic pulmonary oedema (ACPE). We compared the efficacy and safety of midazolam and morphine in patients with ACPE.
METHODS AND RESULTS
A randomized, multicentre, open-label, blinded endpoint clinical trial was performed in seven Spanish emergency departments (EDs). Patients >18 years old clinically diagnosed with ACPE and with dyspnoea and anxiety were randomized (1:1) at ED arrival to receive either intravenous midazolam or morphine. Efficacy was assessed by in-hospital all-cause mortality (primary endpoint). Safety was assessed through serious adverse event (SAE) reporting, and the composite endpoint included 30-day mortality and SAE. Analyses were made on an intention-to-treat basis. The trial was stopped early after a planned interim analysis by the safety monitoring committee. At that time, 111 patients had been randomized: 55 to midazolam and 56 to morphine. There were no significant differences in the primary endpoint (in-hospital mortality for midazolam vs. morphine 12.7% vs. 17.9%; risk ratio[RR] 0.71, 95% confidence interval [CI] 0.29-1.74; p = 0.60). SAE were less common with midazolam versus morphine (18.2% vs. 42.9%; RR 0.42, 95% CI 0.22-0.80; p = 0.007), as were the composite endpoint (23.6% vs. 44.6%; RR 0.53, 95% CI 0.30-0.92; p = 0.03).
CONCLUSION
Although the number of patients was too small to draw final conclusions and there were no significant differences in mortality between midazolam and morphine, a significantly higher rate of SAEs was found in the morphine group.
Topics: Humans; Adolescent; Midazolam; Morphine; Pulmonary Edema; Heart Failure; Hospital Mortality
PubMed: 35780488
DOI: 10.1002/ejhf.2602 -
Annals of Emergency Medicine Dec 2021We hypothesized that the use of intramuscular ketamine would result in a clinically relevant shorter time to target sedation. (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVE
We hypothesized that the use of intramuscular ketamine would result in a clinically relevant shorter time to target sedation.
METHODS
We conducted a randomized clinical trial comparing the rapidity of onset, level of sedation, and adverse effect profile of ketamine compared to a combination of midazolam and haloperidol for behavioral control of emergency department patients with severe psychomotor agitation. We included patients with severe psychomotor agitation measured by a Richmond Agitation Score (RASS) ≥+3. Patients in the ketamine group were treated with a 5 mg/kg intramuscular injection. Patients in the midazolam and haloperidol group were treated with a single intramuscular injection of 5 mg midazolam and 5 mg haloperidol. The primary outcome was the time, in minutes, from study medication administration to adequate sedation, defined as RASS ≤-1. Secondary outcomes included the need for rescue medications and serious adverse events.
RESULTS
Between June 30, 2018, and March 13, 2020, we screened 308 patients and enrolled 80. The median time to sedation was 14.7 minutes for midazolam and haloperidol versus 5.8 minutes for ketamine (difference 8.8 minutes [95% confidence interval (CI) 3.0 to 14.5]). Adjusted Cox proportional model analysis favored the ketamine arm (hazard ratio 2.43, 95% CI 1.43 to 4.12). Five (12.5%) patients in the ketamine arm and 2 (5.0%) patients in the midazolam and haloperidol arm experienced serious adverse events (difference 7.5% [95% CI -4.8% to 19.8%]).
CONCLUSION
In ED patients with severe agitation, intramuscular ketamine provided significantly shorter time to adequate sedation than a combination of intramuscular midazolam and haloperidol.
Topics: Adult; Anesthetics, Dissociative; Canada; Female; Haloperidol; Humans; Hypnotics and Sedatives; Injections, Intramuscular; Ketamine; Male; Midazolam; Middle Aged; Psychomotor Agitation
PubMed: 34353650
DOI: 10.1016/j.annemergmed.2021.05.023 -
JAMA Network Open Aug 2022Perioperative respiratory adverse events (PRAEs) are the most common complication during pediatric anesthesia, and they may be affected by the administration of... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of Intranasal Dexmedetomidine or Midazolam for Premedication on the Occurrence of Respiratory Adverse Events in Children Undergoing Tonsillectomy and Adenoidectomy: A Randomized Clinical Trial.
IMPORTANCE
Perioperative respiratory adverse events (PRAEs) are the most common complication during pediatric anesthesia, and they may be affected by the administration of preoperative sedatives.
OBJECTIVE
To investigate the effect of intranasal dexmedetomidine or midazolam used for premedication on the occurrence of PRAEs.
DESIGN, SETTING, AND PARTICIPANTS
This single-center, double-blind, randomized clinical trial was conducted among children aged 0 to 12 years undergoing elective tonsillectomy and adenoidectomy from October 2020 to June 2021 at Children's Hospital of Xuzhou Medical University, Xuzhou, China. Data analysis was performed from June to October 2021.
INTERVENTIONS
Children were randomly assigned to 3 groups: the midazolam group received intranasal midazolam (0.1 mg/kg), and the dexmedetomidine group received intranasal dexmedetomidine (2.0 μg/kg) for premedication. The normal saline group received intranasal 0.9% saline for control.
MAIN OUTCOMES AND MEASURES
The primary outcome was the difference in the incidence of PRAEs among the 3 groups. The secondary outcomes were the frequency of the individual PRAEs, including the incidence of such events during the induction and recovery periods, postoperative emergence delirium, postoperative pain score, sedation success rate, and heart rate values.
RESULTS
A total of 384 children (median [IQR] age, 7 [5-10] years; 227 boys [59.1%]) were enrolled and randomized; 373 data sets were available for intention-to-treat analysis (124 children in the midazolam group, 124 children in the dexmedetomidine group, and 125 children in the normal saline group). After the data were adjusted for age, sex, American Society of Anesthesiologists physical status, body mass index, obstructive sleep apnea, upper respiratory tract infection, and passive smoking, children in the midazolam group were more likely to experience PRAEs than those in the normal saline group (70 of 124 children [56.5%] vs 51 of 125 children [40.8%]; adjusted odds ratio [aOR], 1.99; 95% CI, 1.18-3.35), whereas the dexmedetomidine group had a significantly lower PRAEs incidence than the normal saline group (30 of 124 children [24.2%] vs 51 of 125 children [40.8%]; aOR, 0.45; 95% CI, 0.26-0.78). Compared with the dexmedetomidine group, the midazolam group had a higher risk of PRAEs (aOR, 4.44; 95% CI, 2.54-7.76), but no other serious clinical adverse events were observed.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, intranasal midazolam used for premedication was associated with increased incidence of PRAEs, whereas premedication with intranasal dexmedetomidine was associated with reduced incidence of PRAEs. Where clinically appropriate, anesthesiologists should consider using intranasal dexmedetomidine for sedation in children undergoing tonsillectomy and adenoidectomy.
TRIAL REGISTRATION
Chinese Clinical Trial Register Identifier: ChiCTR2000038359.
Topics: Adenoidectomy; Child; Child, Preschool; Dexmedetomidine; Humans; Male; Midazolam; Premedication; Prospective Studies; Saline Solution; Tonsillectomy
PubMed: 35943745
DOI: 10.1001/jamanetworkopen.2022.25473 -
Gastrointestinal Endoscopy Sep 2018Remimazolam is an ultrashort-acting benzodiazepine. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND AND AIMS
Remimazolam is an ultrashort-acting benzodiazepine.
METHODS
We performed a randomized double-blind comparison of remimazolam to placebo for outpatient colonoscopy. This study design was a requirement of the U.S. Food and Drug Administration. An additional group was randomized to open-label midazolam administered according to its package insert instructions (the randomization ratio for remimazolam:placebo:midazolam was 30:6:10). Study medications were administered under the supervision of the endoscopist, without any involvement of an anesthesia specialist. Patients were given 50 to 75 μg of fentanyl before receiving study medications. Patients who failed to achieve adequate sedation in any arm were rescued with midazolam dosed at the investigator's discretion. The primary endpoint was a composite that required 3 criteria be met: completion of the colonoscopy, no need for rescue medication, and ≤5 doses of remimazolam or placebo in any 15-minute interval (≤3 doses of midazolam in any 12-minute interval in the open-label midazolam arm).
RESULTS
There were 461 randomized patients in 12 U.S. sites. The primary endpoint was met for remimazolam, placebo, and midazolam in 91.3%, 1.7%, and 25.2% of patients, respectively (P < .0001 for remimazolam vs placebo). Patients administered remimazolam received less fentanyl, had faster recovery of neuropsychiatric function, were ready for discharge earlier, and felt back to normal sooner than patients with both placebo and midazolam. Hypotension was less frequent with remimazolam, and hypoxia occurred in 1% of patients with remimazolam or midazolam. There were no treatment-emergent serious adverse events.
CONCLUSION
Remimazolam can be administered safely under the supervision of endoscopists for outpatient colonoscopy, and it allows faster recovery of neuropsychiatric function compared with placebo (midazolam rescue) and midazolam. (Clinical trial registration number: NCT02290873.).
Topics: Adult; Aged; Aged, 80 and over; Ambulatory Surgical Procedures; Benzodiazepines; Colonoscopy; Double-Blind Method; Female; Fentanyl; Humans; Hypnotics and Sedatives; Male; Midazolam; Middle Aged; Young Adult
PubMed: 29723512
DOI: 10.1016/j.gie.2018.04.2351