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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 -
Ugeskrift For Laeger Mar 2023The spasmolytic agent baclofen is regarded as having a low dependence potential. This is a case report of a 46-year-old woman with an escalating use of baclofen to four...
The spasmolytic agent baclofen is regarded as having a low dependence potential. This is a case report of a 46-year-old woman with an escalating use of baclofen to four times the highest recommended dose. She was initially admitted to hospital due to decreased consciousness. Later, during tapering, she was readmitted unresponsive with myoclonus. Baclofen was discontinued abruptly during sedation with propofol and remifentanil infusion as well as midazolam in refract doses. Eight days later she was discharged without sequelae.
Topics: Female; Humans; Middle Aged; Hypnotics and Sedatives; Baclofen; Muscle Cramp; Propofol; Midazolam
PubMed: 36999288
DOI: No ID Found -
Indian Pediatrics Aug 2023Benzodiazepines are the first-line anti-seizure medication (ASM) for generalized convulsive status epilepticus (GCSE), but they fail to end seizures in a third of cases.... (Randomized Controlled Trial)
Randomized Controlled Trial
Levetiracetam and Midazolam vs Midazolam Alone for First-Line Treatment of Children With Generalized Convulsive Status Epilepticus (Lev-Mid Study): A Randomized Controlled Trial.
BACKGROUND
Benzodiazepines are the first-line anti-seizure medication (ASM) for generalized convulsive status epilepticus (GCSE), but they fail to end seizures in a third of cases. Combining benzodiazepines with another ASM that acts by a different pathway could be a potential strategy for rapid control of GCSE.
OBJECTIVES
To evaluate the efficacy of adding levetiracetam to midazolam in the initial treatment of pediatric GCSE.
DESIGN
Double-blind randomized controlled trial.
SETTING
Pediatric emergency room at Sohag University Hospital between June, 2021 and August, 2022.
PARTICIPANTS
Children aged between 1 month and 16 years with GCSE lasting more than 5 min.
INTERVENTIONS
Intravenous levetiracetam (60 mg/kg over 5 min) and midazolam (Lev-Mid group) or placebo and midazolam (Pla-Mid group) as first-line anticonvulsive therapy.
OUTCOME MEASURES
Primary: cessation of clinical seizures at 20-min study time point. Secondary: cessation of clinical seizures at 40-min study time point, need for a second midazolam dose, seizure control at 24-hr, need for intubation, and adverse effects.
RESULTS
Cessation of clinical seizures at 20-min occurred in 55 children (76%) in Lev-Mid group compared with 50 (69%) in the Pla-Mid group [RR (95% CI) 1.1 (0.9-1.34); P=0.35]. No significant difference was found between the two groups regarding the need for a second midazolam dose [44.4% vs 55.6%; RR (95% CI) 0.8 (0.58-1.11); P=0.18] as well as cessation of clinical seizures at 40-min [96% vs 92%; RR (95% CI)1.05 (0.96-1.14); P=0.49] and seizure control at 24-hr [85% vs 76%; RR (95% CI) 1.12 (0.94-1.3); P=0.21]. Intubation was required for three patients in the Lev-Mid group and six patients in the Pla-Mid group [RR (95%CI) 0.5 (0.13- 1.92); P=0.49]. No other adverse effects or mortality were observed during the 24-hour study timeframe.
CONCLUSION
Combined levetiracetam and midazolam for initial management of pediatric GCSE presents no significant advantage over midazolam alone in cessation of clinical seizures at 20-min.
Topics: Humans; Child; Infant; Levetiracetam; Midazolam; Anticonvulsants; Treatment Outcome; Status Epilepticus
PubMed: 37211889
DOI: No ID Found -
Clinical Pharmacology in Drug... Jan 2022Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection and disease in allogeneic hematopoietic stem-cell transplant...
Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection and disease in allogeneic hematopoietic stem-cell transplant recipients. In vitro studies have identified letermovir as a potential cytochrome P450 (CYP) 3A inhibitor. Thus, the effect of letermovir on the CYP3A isoenzyme-specific probe drug midazolam was investigated in a phase 1 trial. Healthy female subjects received single-dose intravenous (IV; 1 mg) and oral (2 mg) midazolam on days -4 and -2, respectively. Letermovir 240 mg once daily was administered on days 1 to 6, and further single doses of midazolam 1 mg IV and oral midazolam 2 mg were administered on days 4 and 6, respectively. Pharmacokinetics, tolerability, and safety were monitored throughout the trial. Following coadministration with letermovir, the least square means ratio for maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last measurable concentration was 172.4% and 225.3%, respectively, for oral midazolam, and 105.2% and 146.6%, respectively, for midazolam IV. The area under the plasma concentration-time curve from time 0 to the last measurable concentration ratio of midazolam to 1-hydroxymidazolam increased slightly in the presence of letermovir following IV (8.8-13.1; 49% increase) and oral (3.3-5.3; 59% increase) midazolam. Letermovir reached steady state, on average, by days 5 to 6. All treatments were generally well tolerated. Letermovir demonstrated moderate CYP3A inhibition.
Topics: Acetates; Area Under Curve; Drug Interactions; Female; Healthy Volunteers; Humans; Midazolam; Quinazolines
PubMed: 34714967
DOI: 10.1002/cpdd.1027 -
British Dental Journal Jan 2023
Topics: Benzodiazepines; Midazolam; Hypnotics and Sedatives
PubMed: 36707554
DOI: 10.1038/s41415-023-5475-8 -
Epilepsia Open Jun 2023The aim of this study was to provide seizure etiology, semiology, underlying conditions, and out-of- and in-hospital diagnostics, treatment, and outcome data on children...
OBJECTIVE
The aim of this study was to provide seizure etiology, semiology, underlying conditions, and out-of- and in-hospital diagnostics, treatment, and outcome data on children with out-of- or in-hospital-onset status epilepticus (SE) according to the International League Against Epilepsy definition that required admission to the pediatric intensive care unit (PICU) for ≥4 hours.
METHODS
This prospective national surveillance study on SE in childhood and adolescence was conducted over 2 years (07/2019-06/2021).
RESULTS
This study examined 481 SE episodes in 481 children with a median age of 43 months (1 month to 17 years 11 months), of which 46.2% were female and 50.7% had a previous seizure history. The most frequent acute SE cause was a prolonged, complicated febrile seizure (20.6%). The most common initial seizure types were generalized seizures (49.9%), focal seizures (18.0%), and unknown types (12.1%); 40.5% of patients suffered from refractory SE and 5.0% from super-refractory SE. The three most common medications administered by nonmedically trained individuals were diazepam, midazolam, and antipyretics. The three most frequent anti-seizure medications (ASMs) administered by the emergency physician were midazolam, diazepam, and propofol. The three most common ASMs used in the clinical setting were midazolam, levetiracetam, and phenobarbital. New ASMs administered included lacosamide, brivaracetam, perampanel, stiripentol, and eslicarbazepine. Status epilepticus terminated in 16.0% in the preclinical setting, 19.1% in the emergency department, and 58.0% in the PICU; the outcome was unknown for 6.9%. The median PICU stay length was 2 (1-121) days. The median modified Rankin scale was 1 (0-5) on admission and 2 (0-6) at discharge. New neurological deficits after SE were observed in 6.2%. The mortality rate was 3.5%.
SIGNIFICANCE
This study provides current real-world out-of- and in-hospital data on pediatric SE requiring PICU admission. New ASMs are more frequently used in this population. This knowledge may help generate a more standardized approach.
Topics: Adolescent; Child; Humans; Female; Male; Midazolam; Anticonvulsants; Prospective Studies; Status Epilepticus; Epilepsy; Diazepam; Critical Care
PubMed: 36764666
DOI: 10.1002/epi4.12707 -
Current Pain and Headache Reports Sep 2023There is increasing interest in the use of cannabis and cannabinoid therapies (CCT) by the general population and among people with headache disorders, which results in... (Review)
Review
PURPOSE OF REVIEW
There is increasing interest in the use of cannabis and cannabinoid therapies (CCT) by the general population and among people with headache disorders, which results in a need for healthcare professionals to be well versed with the efficacy and safety data. In this manuscript, we review cannabis and cannabinoid terminology, the endocannabinoid system and its role in the central nervous system (CNS), the data on efficacy, safety, tolerability, and potential pitfalls associated with use in people with migraine and headache disorders. We also propose possible mechanisms of action in headache disorders and debunk commonly held myths about its use.
RECENT FINDINGS
Preliminary studies show that CCT have evidence for the management of migraine. While this evidence exists, further randomized, controlled studies are needed to better support its clinical use. CCT can be considered an integrative treatment added to mainstream medicine for people with migraine who are refractory to treatment and/or exhibit disability and/or interest in trying these therapies. Further studies are warranted to specify appropriate formulation, dosage, and indication(s). Although not included in guidelines or the AHS 2021 Consensus Statement on migraine therapies, with the legalization of CCT for medical or unrestricted use across the USA, recent systematic reviews highlighting the preliminary evidence for its use in migraine, it is vital for clinicians to be well versed in the efficacy, safety, and clinical considerations for their use. This review provides information which can help people with migraine and clinicians who care for them make mutual, well-informed decisions on the use of cannabis and cannabinoid therapies for migraine based on the existing data.
Topics: Humans; Cannabinoids; Cannabis; Midazolam; Medical Marijuana; Migraine Disorders; Cannabinoid Receptor Agonists
PubMed: 37515745
DOI: 10.1007/s11916-023-01144-z -
Journal of Clinical Oncology : Official... Oct 2021
Topics: Cancer Pain; Deep Sedation; Humans; Hypnotics and Sedatives; Male; Midazolam; Palliative Care; Terminal Care
PubMed: 34357800
DOI: 10.1200/JCO.21.01621 -
PloS One 2023Midazolam and α2-adrenoceptor agonists have been widely used off-label as intranasal sedatives for children. The present meta-analysis aimed to evaluate the effects of... (Meta-Analysis)
Meta-Analysis
A comparative evaluation of intranasal α2-adrenoceptor agonists and intranasal midazolam as premedication in pediatric sedation: A meta-analysis of randomized controlled trials.
BACKGROUND
Midazolam and α2-adrenoceptor agonists have been widely used off-label as intranasal sedatives for children. The present meta-analysis aimed to evaluate the effects of two interventions in pediatric sedation.
METHODS
PubMed, Embase, and Cochrane Library were searched from inception to April 2022. All randomized controlled trials used intranasal α2-adrenoceptor agonists and midazolam as sedatives in children were enrolled. Parental separation, anesthesia induction or facemask acceptance, sedation level, different hemodynamic parameters and adverse events were considered as outcomes.
RESULTS
Totally 21 studies with 1,495 patients were included. Only one study reported comparison between midazolam and clonidine met the inclusion criteria, and patients in clonidine group had significantly better mask acceptance compared to midazolam group. Compared with midazolam, using of dexmedetomidine was associated with higher rate of satisfactory parental separation (52.88% vs 75.18%, RR = 0.70, with 95%CI [0.55, 0.90]), anesthesia induction or facemask acceptance (60.92% vs 81.47%, RR = 0.76, 95% CI [0.68, 0.84]) and less incidence of postoperative pain and nasal irritation.
CONCLUSION
Compared with midazolam, dexmedetomidine should be considered as the preferred intranasal sedative option for pediatric patients, since it provides more satisfactory sedative level with less incidence of several side effects. But insufficient evidences about effects of intranasal clonidine and overall low and moderate quality evidences evaluated by GRADE system indicate that superiority of intranasal α2-adrenoceptor agonists in pediatric sedation needs to be validated by more studies with high quality and large sample size in future.
Topics: Child; Humans; Midazolam; Dexmedetomidine; Clonidine; Randomized Controlled Trials as Topic; Hypnotics and Sedatives; Premedication; Anesthesia, General; Receptors, Adrenergic; Administration, Intranasal
PubMed: 36787332
DOI: 10.1371/journal.pone.0281751 -
Veterinary Anaesthesia and Analgesia Mar 2020To estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats.
OBJECTIVE
To estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats.
STUDY DESIGN
Prospective pharmacokinetic study.
ANIMALS
A group of six healthy adult, female domestic cats.
METHODS
Anesthesia was induced and maintained with sevoflurane. After 30 minutes of anesthetic equilibration, cats were administered midazolam (0.3 mg kg) over 15 seconds. Venous blood was collected at 0, 1, 2, 4, 8, 15, 30, 45, 90, 180 and 360 minutes after administration. Plasma concentrations for midazolam and 1-hydroxymidazolam were measured using high-pressure liquid chromatography. The heart rate (HR), respiratory rate (f), rectal temperature, noninvasive mean arterial pressure (MAP) and end-tidal carbon dioxide (Pe'CO) were recorded at 5 minute intervals. Population compartment models were fitted to the time-plasma midazolam and 1-hydroxymidazolam concentrations using nonlinear mixed effect modeling.
RESULTS
The pharmacokinetic model was fitted to the data from five cats, as 1-hydroxymidazolam was not detected in one cat. A five-compartment model best fitted the data. Typical values (% interindividual variability where estimated) for the volumes of distribution for midazolam (three compartments) and hydroxymidazolam (two compartments) were 117 (14), 286 (10), 705 (14), 53 (36) and 334 mL kg, respectively. Midazolam clearance to 1-hydroxymidazolam, midazolam fast and slow intercompartmental clearances, 1-hydroxymidazolam clearance and 1-hydroxymidazolam intercompartment clearance were 18.3, 63.5 (15), 22.1 (8), 1.7 (67) and 3.8 mL minute kg, respectively. No significant changes in HR, MAP, f or Pe'CO were observed following midazolam administration.
CONCLUSION AND CLINICAL RELEVANCE
In sevoflurane-anesthetized cats, a five-compartment model best fitted the midazolam pharamacokinetic profile. There was a high interindividual variability in the plasma 1-hydroxymidazolam concentrations, and this metabolite had a low clearance and persisted in the plasma for longer than the parent drug. Midazolam administration did not result in clinically significant changes in physiologic variables.
Topics: Adjuvants, Anesthesia; Anesthetics, Inhalation; Animals; Cats; Drug Interactions; Female; Half-Life; Injections, Intravenous; Midazolam; Sevoflurane
PubMed: 31983556
DOI: 10.1016/j.vaa.2019.11.005