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BMC Pharmacology & Toxicology Jan 2023Regulations have broadened to allow moderate sedation administration for gastrointestinal endoscopy by non-anesthesia personnel. The line between moderate and deep...
PURPOSE
Regulations have broadened to allow moderate sedation administration for gastrointestinal endoscopy by non-anesthesia personnel. The line between moderate and deep sedation is ambiguous. Deep sedation offers patient comfort as well as greater safety concerns. Unintended deep sedation can occur if drug interactions are overlooked. We present a pharmacodynamic model for moderate sedation using midazolam, alfentanil and propofol. The model is suitable for training and devising rationales for appropriate dosing.
METHODS
The study consists of two parts: modeling and validation. In modeling, patients scheduled for esophagogastroduodenoscopy (EGD) or colonoscopy sedation are enrolled. The modified observer's assessment of alertness/sedation (MOAA/S) score < 4 is defined as loss of response to represent moderate sedation. Two patient groups receiving bronchoscopy or endoscopic retrograde cholangiopancreatography (ERCP) are used for validation. Model performance is assessed by receiver operating characteristic (ROC) curves and area under the curve (AUC). Simulations are performed to demonstrate how the model is used to rationally determine drug regimen for moderate sedation.
RESULTS
Interaction between propofol and alfentanil is stronger than the other pairwise combinations. Additional synergy is observed with three drugs. ROC AUC is 0.83 for the modeling group, and 0.96 and 0.93 for ERCP and bronchoscopy groups respectively. Model simulation suggests that 1 mg midazolam, 250 µg alfentanil and propofol maximally benefits from drug interactions and suitable for moderate sedation.
CONCLUSION
We demonstrate the accurate prediction of a three-drug response surface model for moderate sedation and simulation suggests a rational dosing strategy for moderate sedation with midazolam, alfentanil and propofol.
Topics: Humans; Midazolam; Alfentanil; Propofol; Conscious Sedation; Endoscopy, Gastrointestinal
PubMed: 36647160
DOI: 10.1186/s40360-023-00642-5 -
Anesthesia and Analgesia Mar 2016Previous randomized controlled trials regarding the effectiveness of perioperative midazolam in preventing postoperative nausea and vomiting (PONV) have produced... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Previous randomized controlled trials regarding the effectiveness of perioperative midazolam in preventing postoperative nausea and vomiting (PONV) have produced conflicting results. Consequently, the present systematic review was performed to assess the effect of perioperative administration of midazolam on PONV.
METHODS
The MEDLINE®, Embase, and Cochrane Central Register of Controlled Trials databases were searched to identify all randomized controlled trials that investigated the effectiveness of midazolam under general anesthesia. The primary end points were defined as postoperative nausea (PON), postoperative vomiting (POV), and PONV.
RESULTS
From 16 studies, 1433 patients were included in the final analysis. Compared with the control group, patients who received midazolam showed a lower overall incidence of PON (risk ratio [RR], 0.51; 95% confidence interval [CI], 0.40-0.65; I = 35%; number needed to treat [NNT] = 6; number of included studies [n] = 11), POV (RR, 0.46; 95% CI, 0.33-0.65; I = 0%; NNT = 8; n = 10), and PONV (RR, 0.45; 95% CI, 0.36-0.57; I = 31%; NNT = 3; n = 7).
CONCLUSIONS
Perioperative administration of midazolam was effective in preventing PON, POV, and PONV.
Topics: Antiemetics; Humans; Injections, Intravenous; Midazolam; Postoperative Nausea and Vomiting; Randomized Controlled Trials as Topic
PubMed: 26516802
DOI: 10.1213/ANE.0000000000001062 -
Journal of Anesthesia Jun 2023
Topics: Benzodiazepines; Midazolam; Hypnotics and Sedatives
PubMed: 37079100
DOI: 10.1007/s00540-023-03186-4 -
Biomedicine & Pharmacotherapy =... May 2021Midazolam is one of top three drugs used in palliative care. Its use increases in the last days of hospice patients' lives while safe dosage can be challenging....
RATIONALE & OBJECTIVE
Midazolam is one of top three drugs used in palliative care. Its use increases in the last days of hospice patients' lives while safe dosage can be challenging. Equations currently used to estimate glomerular filtration rate, e.g: the Cockroft-Gault (eGFR) and the Modification of Diet in Renal Disease (eGFR) ones, do not generate precise calculations, especially in palliative patients exhibiting variations in body parameters. Our aim was to seek new relationships between mean midazolam (M) and alfahydroxymidazolam (OH-M) concentrations in plasma, and selected biochemical and physiological parameters of palliative patients, to enable optimal midazolam pharmacotherapy.
STUDY DESIGN, PARTICIPANTS AND INTERVENTIONS
The pilot study included 11 Caucasians, aged 42-95, with advanced cancer disease, receiving midazolam in a hospice in-patient unit. We tested correlations among M, BMI, eGFR, midazolam clearance (CL), OH-M, bilirubin (Bil) and blood creatinine concentration (Cr). F test and leave-one out (LOO) validation was applied to verify the correlations' significance and predictive ability.
RESULTS
We found ten statistically significant (p < 0.05) correlations related to midazolam pharmacokinetics and physiological factors. We formulated two equations with high degree of predictive ability, based on the eGFR→CL and the (Bil + BMI × Ln(Cr))→M-(OH-M) correlations. The limitations of the study mainly revolve around its pilot nature and the need to continue testing the results on a bigger population. No funding to disclose.
CONCLUSIONS
The significance of correlations corresponding to the arithmetic expressions confirms that Bil, BMI, Ln(Cr) analyzed simultaneously report a series of processes on which midazolam metabolism depends. Two of ten correlations proposed came close to meet all LOO validation criteria. Current findings can help optimize midazolam treatment in palliative therapy.
Topics: Adult; Aged; Aged, 80 and over; Bilirubin; Biomarkers; Body Mass Index; Creatinine; Drug Dosage Calculations; Drug Monitoring; Female; Glomerular Filtration Rate; Humans; Hypnotics and Sedatives; Male; Midazolam; Middle Aged; Models, Biological; Palliative Care; Pilot Projects; Reproducibility of Results
PubMed: 33550045
DOI: 10.1016/j.biopha.2021.111304 -
JAMA Surgery Feb 2024The effect of oral midazolam premedication on patient satisfaction in older patients undergoing surgery is unclear, despite its widespread use.
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.
Topics: Aged; Humans; Male; Female; Midazolam; Double-Blind Method; Patient Satisfaction; Anesthesia, General; Personal Satisfaction; Patient-Centered Care
PubMed: 38117527
DOI: 10.1001/jamasurg.2023.6479 -
Annali Italiani Di Chirurgia 2021Intraoperative awareness is a serious adverse event under general anesthesia. Midazolam has a good anterograde amnesia-inducing effect, can prevent and reduce the...
BACKGROUND
Intraoperative awareness is a serious adverse event under general anesthesia. Midazolam has a good anterograde amnesia-inducing effect, can prevent and reduce the occurrence of intraoperative awareness. However, if the dosage of midazolam is improperly controlled, it may not produce forgetting effect, or bring obvious adverse side effects, such as respiratory depression, and delay of recovery. However, the half maximal effective dose (ED50 ) of midazolam for amnesia, the duration of amnesia and the factors affecting the duration of amnesia are still inconclusive. Therefore, it is of great clinical significance to observe and determine the dose, duration and influencing factors of amnesia induced by midazolam METHODS: A total of 106 patients who underwent ASA grades I-II elective operation under spinal-epidural anesthesia were intravenously injected with different doses of midazolam at 10 minutes after spinal-epidural anesthesia, every 5 minutes, the patient was presented with pictures or sounds as memory content, and heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), blood oxygen saturation (SpO2), bispectral index (BIS), OAA/S and adverse events were recorded. The patient's forgetfulness was followed up in the early morning after operation.
RESULTS
ED50 (the dose for amnesia in half of the subjects) was 0.031 mg/kg (95% CI: 0.027-0.036 mg/kg); ED95 (the dose for amnesia in 95% of the subjects) was 0.044 mg/kg (95% CI: 0.038-0.071 mg/kg). After the patients were injected intravenously with 0.04 mg/kg of midazolam, the respiratory and circulatory systems were basically stable, no serious adverse events occurred, and the forgetting rate was 88.5%. ET50 (the time for half of the subjects in a state of forgetfulness) was 23.77 minutes (95% CI: 20.18-27.07 min), and the corresponding BIS was 83.22; ET05 (the time for 5% of the subjects in a state of forgetfulness) was 53.90 minutes (95% CI: 48.54-61.47 min) and the corresponding BIS was 91.38. The amnesia-inducing effect of midazolam was correlated to sedation grade, BIS and age, and was not correlated to visual memory or auditory memory.
CONCLUSION
In this study, the ED50 , ED95 and maintenance time of the forgetting effect of intravenous midazolam were preliminarily determined.
KEY WORDS
Amnesia, Duration of amnesia, ED50, Midazolam.
Topics: Amnesia; Anesthesia, Spinal; Humans; Midazolam
PubMed: 34524117
DOI: No ID Found -
Veterinary Medicine and Science Nov 2022Sometimes it is necessary to use sedatives or even general anaesthetics to examine animals with spinal cord injuries. These drugs may affect spinal reflexes, alter the...
BACKGROUND
Sometimes it is necessary to use sedatives or even general anaesthetics to examine animals with spinal cord injuries. These drugs may affect spinal reflexes, alter the outcome of neurological examinations, and make it difficult to diagnose location of the lesion.
OBJECTIVES
The aim of this study was to evaluate the effects of five pre-anaesthetic and anaesthetic agents commonly used in clinics on spinal reflexes in dogs.
METHODS
Ten native adult dogs were participated in three groups. In all groups, the dogs were premedicated with medetomidine and midazolam; then, in the first group, ketamine, in the second group, propofol and in the third group, isoflurane were used for induction of anaesthesia. The spinal reflexes were evaluated before injection, 15 min after medetomidine, 20 min after midazolam, and at 15, 30, 45 and 60 min after induction of anaesthesia.
RESULTS
Medetomidine did not reduce monosynaptic reflexes (patellar and cranial tibial reflexes) but increased them while it had no effect on the polysynaptic limb withdrawal reflexes. Midazolam had no effect on the spinal reflexes; Ketamine did not affect the patellar, cranial tibial and extensor carpi radialis reflexes, but reduced polysynaptic pain-related reflexes; and propofol and isoflurane abolished the all spinal reflexes.
CONCLUSIONS
Medetomidine, midazolam and ketamine have no effect on reducing monosynaptic reflexes (patellar and cranial tibial reflexes) and may be used for neurological examination of restless animals in the clinic. Propofol and isoflurane eliminated all spinal reflex responses and are not suitable for neurological examinations.
Topics: Dogs; Animals; Medetomidine; Midazolam; Propofol; Ketamine; Isoflurane; Reflex
PubMed: 36084272
DOI: 10.1002/vms3.938 -
Xenobiotica; the Fate of Foreign... Mar 2023To characterise the dose-dependent pharmacokinetics of midazolam and evaluate the intestinal and hepatic first-pass effects on midazolam in Sprague-Dawley rats, the...
To characterise the dose-dependent pharmacokinetics of midazolam and evaluate the intestinal and hepatic first-pass effects on midazolam in Sprague-Dawley rats, the concentrations and area under the concentration-time curve (AUC) of midazolam in the portal and systemic plasma were simultaneously determined with a double cannulation method.It was found that about 75% of the dose was left in the portal blood with different oral administration doses, while the bioavailability in the liver was 37.86% at 20 mg/kg, significantly higher than 9.16% at 2 mg/kg.The disproportional increase in AUC of midazolam and significant decrease in exposure of metabolites were observed in systemic plasma after hepatic portal vein administration. And in the study, the formation rate of the metabolites of midazolam significantly decreased when midazolam was at 300 μM compared with 100 μM.These results indicated that not only the saturation of first-pass metabolism but also the inhibition of hepatic metabolism is responsible for the nonlinear PK of midazolam. Thus, a rational dose should be chosen when midazolam is used as a probe in the drug-drug interaction study, particularly for orally administered drugs that undergo hepatic first-pass metabolism.
Topics: Rats; Animals; Midazolam; Rats, Sprague-Dawley; Liver; Intestines; Biological Availability; Administration, Oral; Area Under Curve
PubMed: 37042732
DOI: 10.1080/00498254.2023.2200524 -
Annals of Emergency Medicine Oct 2022Guidelines recommend 10-mg intramuscular midazolam as the first-line treatment option for status epilepticus. However, in real-world practice, it is frequently...
STUDY OBJECTIVE
Guidelines recommend 10-mg intramuscular midazolam as the first-line treatment option for status epilepticus. However, in real-world practice, it is frequently administered intranasally or intravenously and is dosed lower. Therefore, we used conventional and instrumental variable approaches to examine the effectiveness of midazolam in a national out-of-hospital cohort.
METHODS
This retrospective cohort study of adults with status epilepticus used the ESO Data Collaborative research dataset (January 1, 2019, to December 31, 2019). The exposures were the route and dose of midazolam. We performed hierarchical logistic regression and 2-stage least squares regression using agency treatment patterns as an instrument to examine our outcomes, rescue therapy, and ventilatory support.
RESULTS
There were 7,634 out-of-hospital encounters from 657 EMS agencies. Midazolam was administered intranasally in 20%, intravenously in 46%, and intramuscularly in 35% of the encounters. Compared with intramuscular administration, intranasal midazolam increased (risk difference [RD], 6.5%; 95% confidence interval [CI], 2.4% to 10.5%) and intravenous midazolam decreased (RD, -11.1%; 95% CI, -14.7% to -7.5%) the risk of rescue therapy. The differences in ventilatory support were not statistically significant (intranasal RD, -1.5%; 95% CI, -3.2% to 0.3%; intravenous RD, -0.3%; 95% CI, -1.9% to 1.2%). Higher doses were associated with a lower risk of rescue therapy (RD, -2.6%; 95% CI, -3.3% to -1.9%) and increased ventilatory support (RD, 0.4%; 95% CI, 0.1% to 0.7%). The instrumental variable analysis yielded similar results, except that dose was not associated with ventilatory support.
CONCLUSION
The route and dose of midazolam affect clinical outcomes. Compared with intramuscular administration, intranasal administration may be less effective and intravenous administration more effective in terminating status epilepticus, although the differences between these and previous results may reflect the nature of real-world data as opposed to randomized data.
Topics: Administration, Intranasal; Adult; Anticonvulsants; Hospitals; Humans; Midazolam; Retrospective Studies; Status Epilepticus; United States
PubMed: 35931608
DOI: 10.1016/j.annemergmed.2022.05.024 -
Brain Topography Nov 2021Reliable measures of cognitive brain activity from functional neuroimaging techniques may provide early indications of efficacy in clinical trials. Functional magnetic... (Randomized Controlled Trial)
Randomized Controlled Trial
Reliable measures of cognitive brain activity from functional neuroimaging techniques may provide early indications of efficacy in clinical trials. Functional magnetic resonance imaging and electroencephalography provide complementary spatiotemporal information and simultaneous recording of these two modalities can remove inter-session drug response and environment variability. We sought to assess the effects of ketamine and midazolam on simultaneous electrophysiological and hemodynamic recordings during working memory (WM) processes. Thirty participants were included in a placebo-controlled, three-way crossover design with ketamine and midazolam. Compared to placebo, ketamine administration attenuated theta power increases and alpha power decreases and midazolam attenuated low beta band decreases to increasing WM load. Additionally, ketamine caused larger blood-oxygen-dependent (BOLD) signal increases in the supplementary motor area and angular gyrus, and weaker deactivations of the default mode network (DMN), whereas no difference was found between midazolam and placebo. Ketamine administration caused positive temporal correlations between frontal-midline theta (fm-theta) power and the BOLD signal to disappear and attenuated negative correlations. However, the relationship between fm-theta and the BOLD signal from DMN areas was maintained in some participants during ketamine administration, as increasing theta strength was associated with stronger BOLD signal reductions in these areas. The presence of, and ability to manipulate, both positive and negative associations between the BOLD signal and fm-theta suggest the presence of multiple fm-theta components involved in WM processes, with ketamine administration disrupting one or more of these theta-linked WM strategies.
Topics: Brain; Brain Mapping; Cross-Over Studies; Electroencephalography; Humans; Ketamine; Magnetic Resonance Imaging; Memory, Short-Term; Midazolam
PubMed: 34642836
DOI: 10.1007/s10548-021-00876-8