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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 -
Clinical Pharmacokinetics Jul 2022Many patients treated for COVID-19 related acute respiratory distress syndrome in the intensive care unit are sedated with the benzodiazepine midazolam. Midazolam...
BACKGROUND AND OBJECTIVE
Many patients treated for COVID-19 related acute respiratory distress syndrome in the intensive care unit are sedated with the benzodiazepine midazolam. Midazolam undergoes extensive metabolism by CYP3A enzymes, which may be inhibited by hyperinflammation. Therefore, an exaggerated proinflammatory response, as often observed in COVID-19, may decrease midazolam clearance. To develop a population pharmacokinetic model for midazolam in adult intensive care unit patients infected with COVID-19 and to assess the effect of inflammation, reflected by IL-6, on the pharmacokinetics of midazolam.
METHODS
Midazolam blood samples were collected once a week between March 31 and April 30 2020. Patients were excluded if they concomitantly received CYP3A4 inhibitors, CYP3A4 inducers and/or continuous renal replacement therapy. Midazolam and metabolites were analyzed with an ultra-performance liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was developed, using nonlinear mixed effects modelling. IL-6 and CRP, markers of inflammation, were analyzed as covariates.
RESULTS
The data were described by a one-compartment model for midazolam and the metabolites 1-OH-midazolam and 1-OH-midazolam-glucuronide. The population mean estimate for midazolam clearance was 6.7 L/h (4.8-8.5 L/h). Midazolam clearance was reduced by increased IL-6 and IL-6 explained more of the variability within our patients than CRP. The midazolam clearance was reduced by 24% (6.7-5.1 L/h) when IL-6 increases from population median 116 to 300 pg/mL.
CONCLUSIONS
Inflammation, reflected by high IL-6, reduces midazolam clearance in critically ill patients with COVID-19. This knowledge may help avoid oversedation, but further research is warranted.
Topics: Adult; Critical Illness; Cytochrome P-450 CYP3A; Humans; Hypnotics and Sedatives; Inflammation; Interleukin-6; Midazolam; COVID-19 Drug Treatment
PubMed: 35397768
DOI: 10.1007/s40262-022-01122-5 -
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 -
British Journal of Anaesthesia Apr 2022Anaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the...
BACKGROUND
Anaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the antitumour, anti-inflammatory, and analgesic effects of midazolam on LSL-Kras;Trp53;Pdx-1 transgenic mice with pancreatic ductal adenocarcinoma.
METHODS
Six-week-old transgenic mice were administered midazolam 30 mg kg day p.o. (n=13); midazolam 30 mg kg day with 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) 3 mg kg day i.p., a peripheral benzodiazepine receptor antagonist (n=10); or vehicle (water; n=14) until the humane endpoint. Cancer-associated pain was evaluated using hunching score and mouse grimace scale. Tumour stage and immuno-inflammatory status were determined histopathologically. Anti-proliferative and apoptotic potentials of midazolam were investigated using mouse pancreatic ductal adenocarcinoma cell lines.
RESULTS
Midazolam significantly inhibited tumour size and proliferative index of Ki-67 and cyclins in pancreatic ductal adenocarcinoma, which was blocked by administration of PK11195. Local myeloperoxidase tumour-associated neutrophils, arginase-1 M2-like tumour-associated macrophages, and CD11bLy-6G polymorphonuclear myeloid-derived suppressor cells were reduced by midazolam, which was antagonised by administration of PK11195. Hunching and mouse grimace scale were improved by midazolam, whereas the scores increased with midazolam+PK11195 treatment. Plasma pro-inflammatory cytokines, such as interleukin-6 and CC chemokine ligand (CCL)2, CCL3, and CCL5, were reduced by midazolam, whereas these cytokines increased with PK11195. Midazolam inhibited pancreatic ductal adenocarcinoma proliferation through downregulation of cyclins and cyclin-dependent kinases and induced apoptosis in vitro.
CONCLUSIONS
These results suggest that midazolam inhibits pancreatic ductal adenocarcinoma proliferation and local infiltration of tumour-associated neutrophils, tumour-associated macrophages, and polymorphonuclear myeloid-derived suppressor cells, thereby inhibiting pancreatic ductal adenocarcinoma progression.
Topics: Animals; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Midazolam; Pancreatic Neoplasms
PubMed: 35120712
DOI: 10.1016/j.bja.2021.12.042 -
British Journal of Clinical Pharmacology Nov 2015In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its... (Observational Study)
Observational Study
AIM
In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents.
METHODS
Overweight (BMI for age ≥ 85(th) percentile) and obese (BMI for age ≥ 95(th) percentile) adolescents undergoing surgery received 2 or 3 mg intravenous midazolam as a sedative drug pre-operatively. Blood samples were collected until 6 or 8 h post-dose. Population pharmacokinetic modelling and systematic covariate analysis were performed using nonmem 7.2.
RESULTS
Nineteen overweight and obese patients with a mean body weight of 102.7 kg (62-149.8 kg), a mean BMI of 36.1 kg m(-2) (24.8-55 kg m(-2)), and a mean age of 15.9 years (range 12.5-18.9 years) were included. In the model for midazolam and metabolites, total body weight was not of influence on clearance (0.66 l min(-1) (RSE 8.3%)), while peripheral volume of distribution of midazolam (154 l (11.2%)), increased substantially with total body weight (P < 0.001). The increase in peripheral volume could be explained by excess body weight (WTexcess ) instead of body weight related to growth (WTfor age and length ).
CONCLUSIONS
The pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents show a marked increase in peripheral volume of distribution and a lack of influence on clearance. The findings may imply a need for a higher initial infusion rate upon initiation of a continuous infusion in obese adolescents.
Topics: Adolescent; Body Weight; Child; Female; Humans; Hypnotics and Sedatives; Male; Midazolam; Models, Biological; Obesity; Overweight; Prospective Studies
PubMed: 26044579
DOI: 10.1111/bcp.12693 -
Epilepsia Open Dec 2021Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate...
OBJECTIVE
Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABA R to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate-induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman-induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist.
METHODS
We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABA R modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA-dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI-6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset.
RESULTS
The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman-induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic-induced toxicity.
SIGNIFICANCE
Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine-refractory cholinergic-induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.
Topics: Animals; Anticonvulsants; Brain; Drug Therapy, Combination; Ketamine; Midazolam; Phenobarbital; Rats; Soman
PubMed: 34657398
DOI: 10.1002/epi4.12552 -
American Journal of Veterinary Research Feb 2013To determine pharmacokinetic and pharmacodynamic properties of midazolam after IV and IM administration in alpacas. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To determine pharmacokinetic and pharmacodynamic properties of midazolam after IV and IM administration in alpacas.
ANIMALS
6 healthy alpacas.
PROCEDURES
Midazolam (0.5 mg/kg) was administered IV or IM in a randomized crossover design. Twelve hours prior to administration, catheters were placed in 1 (IM trial) or both (IV trial) jugular veins for drug administration and blood sample collection for determination of serum midazolam concentrations. Blood samples were obtained at intervals up to 24 hours after IM and IV administration. Midazolam concentrations were determined by use of tandem liquid chromatography-mass spectrometry.
RESULTS
Maximum concentrations after IV administration (median, 1,394 ng/mL [range, 1,150 to 1,503 ng/mL]) and IM administration (411 ng/mL [217 to 675 ng/mL]) were measured at 3 minutes and at 5 to 30 minutes, respectively. Distribution half-life was 18.7 minutes (13 to 47 minutes) after IV administration and 41 minutes (30 to 80 minutes) after IM administration. Elimination half-life was 98 minutes (67 to 373 minutes) and 234 minutes (103 to 320 minutes) after IV and IM administration, respectively. Total clearance after IV administration was 11.3 mL/min/kg (6.7 to 13.9 mL/min/kg), and steady-state volume of distribution was 525 mL/kg (446 to 798 mL/kg). Bioavailability of midazolam after IM administration was 92%. Peak onset of sedation occurred at 0.4 minutes (IV) and 15 minutes (IM). Sedation was significantly greater after IV administration.
CONCLUSIONS AND CLINICAL RELEVANCE
Midazolam was well absorbed after IM administration, had a short duration of action, and induced moderate levels of sedation in alpacas.
Topics: Administration, Intravenous; Animals; Area Under Curve; Biological Availability; Camelids, New World; Chromatography, Liquid; Cross-Over Studies; Female; Half-Life; Heart Rate; Hypnotics and Sedatives; Injections, Intramuscular; Male; Mass Spectrometry; Midazolam; Respiratory Rate
PubMed: 23363357
DOI: 10.2460/ajvr.74.2.294 -
The pharmacokinetics and pharmacodynamics of midazolam after intravenous administration to donkeys .Canadian Journal of Veterinary Research... Apr 2022The pharmacokinetics and pharmacodynamics of midazolam were studied in eight 1-to-3-year-old healthy gelded donkeys. Blood samples were obtained. Heart rate, respiratory...
The pharmacokinetics and pharmacodynamics of midazolam were studied in eight 1-to-3-year-old healthy gelded donkeys. Blood samples were obtained. Heart rate, respiratory rate, rectal temperature, sedation/excitement, ataxia, and response to tactile and auditory stimuli were recorded at baseline until 48 hours after intravenous (IV) midazolam (0.1 mg/kg) administration. Plasma midazolam and 1-hydroxymidazolam were measured using reversed-phase high-performance liquid chromatography. Pharmacokinetic variables were calculated using non-compartmental analysis. Physiologic data were analyzed using a mixed-effects model followed by Dunnett's test and behavioral data were analyzed using a Friedman test then a Dunn's test; < 0.05 was considered significant. Midazolam was detectable for up to 60 minutes post-treatment in 7 donkeys. The median total body clearance, volume of distribution at steady state, elimination half-life, and area under concentration-time profile were 1210 mL/kg/h, 359 mL/kg, 0.27 hours, and 82.7 h × ng/mL, respectively. 1-hydroxymidazolam was detected (29 to 105 ng/mL) between 5 to 15 minutes post-treatment in 4 donkeys. Compared to baseline, rectal temperature and ataxia increased from 90 to 720 minutes ( ≤ 0.038) and 3 to 15 minutes ( ≤ 0.024) post-treatment, respectively. No other parameters showed statistically significant differences. Healthy donkeys cleared midazolam rapidly from plasma after IV administration. Transient ataxia and recumbency without sedation were observed.
Topics: Administration, Intravenous; Animals; Ataxia; Equidae; Half-Life; Midazolam
PubMed: 35388227
DOI: No ID Found -
CJEM Mar 2022
Topics: Anesthetics, Dissociative; Haloperidol; Humans; Hypnotics and Sedatives; Ketamine; Midazolam
PubMed: 34971446
DOI: 10.1007/s43678-021-00249-x -
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