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American Journal of Veterinary Research Sep 2022To evaluate the effects of IM and IV administration of alfaxalone alone and in combination with medetomidine, midazolam, or both on key stress-related neurohormonal and...
A randomized clinical trial on effects of alfaxalone combined with medetomidine and midazolam in preventing stress-related neurohormonal and metabolic responses of isoflurane-anesthetized cats undergoing surgery.
OBJECTIVE
To evaluate the effects of IM and IV administration of alfaxalone alone and in combination with medetomidine, midazolam, or both on key stress-related neurohormonal and metabolic changes in isoflurane-anesthetized cats undergoing ovariohysterectomy or castration.
ANIMALS
72 client-owned mixed-breed cats undergoing ovariohysterectomy or castration between October 4, 2018, and January 10, 2020.
PROCEDURES
For each type of surgery, cats were assigned to 1 of 6 premedication protocols groups, with 6 cats/group: physiologic saline (0.9% NaCl) solution (0.5 mL, IM) and alfaxalone (5 mg/kg, IV); physiologic saline solution (0.5 mL, IM) and alfaxalone (5 mg/kg, IM); medetomidine (50 μg/kg, IM) and alfaxalone (5 mg/kg, IV); medetomidine (50 μg/kg, IM) and alfaxalone (5 mg/kg, IM); midazolam (0.5 mg/kg, IM), medetomidine (50 μg/kg, IM), and alfaxalone (5 mg/kg, IV); or midazolam (0.5 mg/kg, IM), medetomidine (50 μg/kg, IM), and alfaxalone (5 mg/kg, IM). Venous blood was taken before pretreatment, pre- and postoperatively during anesthesia with isoflurane and oxygen, and during early and complete recovery.
RESULTS
Compared with baseline concentrations, plasma adrenaline and noradrenaline concentrations decreased during anesthesia in cats premedicated with alfaxalone alone and in combination with medetomidine. The combination of medetomidine, midazolam, and alfaxalone prevented an excessive increase in catecholamines during anesthesia and surgery in cats. Postoperative plasma cortisol concentration after ovariohysterectomy was lower for cats premedicated with the combination of medetomidine and alfaxalone or the combination of medetomidine, midazolam, and alfaxalone, compared with cats premedicated with alfaxalone alone. Cats treated with combinations that included medetomidine and midazolam had hyperglycemia during anesthesia. Cats treated with medetomidine or medetomidine and midazolam in combination with alfaxalone, compared with alfaxalone alone, had lower concentrations of nonesterified fatty acids during anesthesia. Behavioral recovery scores were lower (better) for cats that received medetomidine in addition to alfaxalone, compared with alfaxalone alone.
CLINICAL RELEVANCE
Results indicated that pretreatments with medetomidine and alfaxalone or with medetomidine, midazolam, and alfaxalone were useful for preventing stress-related hormonal and metabolic responses, other than hyperglycemia, during isoflurane anesthesia and surgery in cats.
Topics: Cats; Animals; Medetomidine; Midazolam; Isoflurane; Pregnanediones; Hyperglycemia; Anesthetics, Combined; Cat Diseases
PubMed: 36103386
DOI: 10.2460/ajvr.22.03.0041 -
Pharmaceutical Research Oct 2021In critically ill mechanically ventilated children, midazolam is used first line for sedation, however its exact sedative effects have been difficult to quantify. In...
AIM
In critically ill mechanically ventilated children, midazolam is used first line for sedation, however its exact sedative effects have been difficult to quantify. In this analysis, we use parametric time-to-event (PTTE) analysis to quantify the effects of midazolam in critically ill children.
METHODS
In the PTTE analysis, data was analyzed from a published study in mechanically ventilated children in which blinded midazolam or placebo infusions were administered during a sedation interruption phase until, based on COMFORT-B and NISS scores, patients became undersedated and unblinded midazolam was restarted. Using NONMEM® v.7.4.3., restart of unblinded midazolam was analysed as event. Patients in the trial were divided into internal and external validation cohorts prior to analysis.
RESULTS
Data contained 138 events from 79 individuals (37 blinded midazolam; 42 blinded placebo). In the PTTE model, the baseline hazard was best described by a constant function. Midazolam reduced the hazard for restart of unblinded midazolam due to undersedation by 51%. In the blinded midazolam group, time to midazolam restart was 26 h versus 58 h in patients with low versus high disease severity upon admission (PRISM II < 10 versus > 21), respectively. For blinded placebo, these times were 14 h and 33 h, respectively. The model performed well in an external validation with 42 individuals.
CONCLUSION
The PTTE analysis effectively quantified the effect of midazolam in prolonging sedation and also the influence of disease severity on sedation in mechanically ventilated critically ill children, and provides a valuable tool to quantify the effect of sedatives. Clinical trial number and registry URL: Netherlands Trial Register, Trial NL1913 (NTR2030), date registered 28 September 2009 https://www.trialregister.nl/trial/1913 .
Topics: Adolescent; Child; Child, Preschool; Critical Illness; Female; Humans; Hypnotics and Sedatives; Infant; Infant, Newborn; Infusions, Intravenous; Male; Midazolam; Models, Statistical; Netherlands; Respiration, Artificial; Severity of Illness Index; Time Factors
PubMed: 34664207
DOI: 10.1007/s11095-021-03113-w -
Anaesthesia Dec 1993A modified patient-controlled analgesia pump provided doses of propofol 3 mg or midazolam 0.1 mg in 0.3 ml, over 5.4 s, with no lockout, during transvaginal oocyte... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
A modified patient-controlled analgesia pump provided doses of propofol 3 mg or midazolam 0.1 mg in 0.3 ml, over 5.4 s, with no lockout, during transvaginal oocyte retrieval. Alfentanil 0.2 mg was administered at three points during the procedure, and on request. Patients were randomly assigned to receive either propofol (25 patients) or midazolam (22 patients). The mean age, weight, duration of procedure and dose of alfentanil were similar in both groups. Onset of sedation with propofol or midazolam took 70.6 (SD 22.4) and 106.3 (50.7) s respectively. Mean doses over the first 5 min were midazolam 2.7 (1.2) mg, and propofol 54 (18) mg. Thereafter requirements decreased: midazolam 0.065 (0.065) mg.min-1, propofol 2.1 (1.3) mg.min-1. All patients successfully completed the procedure; none required additional sedation. P-deletion, reaction time, and critical flicker fusion tests revealed similar depression in both groups immediately postoperatively. After 30 min the p-deletion and critical flicker fusion scores were still impaired in the midazolam, but not in the propofol, group.
Topics: Analgesia, Patient-Controlled; Female; Humans; Hypnotics and Sedatives; Infusion Pumps; Midazolam; Oocytes; Patient Satisfaction; Propofol; Psychomotor Performance; Time Factors
PubMed: 8285322
DOI: 10.1111/j.1365-2044.1993.tb07521.x -
Medical Science Monitor : International... Feb 2021BACKGROUND The aim of this study was to compare the effects of dexmedetomidine versus midazolam on the dreaming of patients undergoing flexible bronchoscopy during...
BACKGROUND The aim of this study was to compare the effects of dexmedetomidine versus midazolam on the dreaming of patients undergoing flexible bronchoscopy during general anesthesia. MATERIAL AND METHODS Patients undergoing flexible bronchoscopy under general anesthesia were randomly divided into a dexmedetomidine group (Group D, n=40) and a midazolam group (Group M, n=40). In group D, patients received 0.5 μg/kg dexmedetomidine and in group M patients received 0.05 mg/kg midazolam intravenously 10 min prior to induction. After bronchoscopy and recovery, a modified Brice questionnaire was used to immediately evaluate the incidence of dreaming of patients. Dreamers were required to complete a 5-point Likert scale survey regarding the contents of their dreams (emotion, voice and movement, memorability) if dreaming was reported. Ramsay Sedation Scale score (Ramsay score) and Visual Analogue Scale (VAS) score were assessed and recorded. RESULTS Patients in group D had higher Ramsay scores and VAS scores (2.9±0.6 and 79.4±4.0, respectively) than group M (2.4±0.7 and 75.0±6.0, respectively), with a statistically significant difference (P<0.05) between groups. The incidence and memorability of dreaming were significantly lower in group D (17.5%) than group M (37.5%, P<0.05), whereas no significant difference was found in emotion, voice, and movement scores of dreaming. CONCLUSIONS Compared to midazolam, pre-injection of dexmedetomidine before induction significantly decreased the incidence of dreaming in patients undergoing flexible bronchoscopy during general anesthesia, without producing undesirable effects on the content of dreams (most of them were pleasant), produces a more efficacious sedation effect during the recovery period and improves the comfort level and satisfaction of patients.
Topics: Adult; Anesthesia Recovery Period; Anesthesia, General; Bronchoscopy; Conscious Sedation; Dexmedetomidine; Dreams; Female; Humans; Hypnotics and Sedatives; Male; Midazolam; Middle Aged
PubMed: 33526763
DOI: 10.12659/MSM.929000 -
British Journal of Clinical Pharmacology Oct 2019Chlorzoxazone is the paradigm marker substrate for CYP2E1 phenotyping in vivo. Because at the commonly used milligram doses (250-750 mg) chlorzoxazone acts as an... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Chlorzoxazone is the paradigm marker substrate for CYP2E1 phenotyping in vivo. Because at the commonly used milligram doses (250-750 mg) chlorzoxazone acts as an inhibitor of the CYP3A4/5 marker substrate midazolam, previous attempts failed to combine both drugs in a common phenotyping cocktail. Microdosing chlorzoxazone could circumvent this problem.
METHOD
We enrolled 12 healthy volunteers in a trial investigating the dose-exposure relationship of single ascending chlorzoxazone oral doses over a 10,000-fold range (0.05-500 mg) and assessed the effect of 0.1 and 500 mg of chlorzoxazone on oral midazolam pharmacokinetics (0.003 mg).
RESULTS
Chlorzoxazone area under the concentration-time curve was dose-linear in the dose range between 0.05 and 5 mg. A nonlinear increase occurred with doses ≥50 mg, probably due to saturated presystemic metabolic elimination. While midazolam area under the concentration-time curve increased 2-fold when coadministered with 500 mg of chlorzoxazone, there was no pharmacokinetic interaction between chlorzoxazone and midazolam microdoses.
CONCLUSION
The chlorzoxazone microdose did not interact with the CYP3A marker substrate midazolam, enabling the simultaneous administration in a phenotyping cocktail. This microdose assay is now ready to be further validated and tested as a phenotyping procedure assessing the impact of induction and inhibition of CYP2E1 on chlorzoxazone microdose pharmacokinetics.
Topics: Administration, Oral; Adult; Area Under Curve; Chlorzoxazone; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Male; Midazolam; Middle Aged; Phenotype; Young Adult
PubMed: 31222796
DOI: 10.1111/bcp.14040 -
Efficacy and Safety of Fentanyl in Combination with Midazolam in Children on Mechanical Ventilation.Journal of Korean Medical Science Jan 2019To evaluate the efficacy and safety of fentanyl for sedation therapy in mechanically ventilated children. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
To evaluate the efficacy and safety of fentanyl for sedation therapy in mechanically ventilated children.
METHODS
This was a double-blind, randomized controlled trial of mechanically ventilated patients between 2 months and 18 years of age. Patients were randomly divided into two groups; the control group with midazolam alone, and the combination group with both fentanyl and midazolam. The sedation level was evaluated using the Comfort Behavior Scale (CBS), and the infusion rates were adjusted according to the difference between the measured and the target CBS score.
RESULTS
Forty-four patients were recruited and randomly allocated, with 22 patients in both groups. The time ratio of cumulative hours with a difference in CBS score (measured CBS-target CBS) of ≥ 4 points (i.e., under-sedation) was lower in the combination group (median, 0.06; interquartile range [IQR], 0-0.2) than in the control group (median, 0.15; IQR, 0.04-0.29) ( < 0.001). The time ratio of cumulative hours with a difference in CBS score of ≥ 8 points (serious under-sedation) was also lower in the combination group ( < 0.001). The cumulative amount of midazolam used in the control group (0.11 mg/kg/hr; 0.07-0.14 mg/kg/hr) was greater than in the combination group (0.07 mg/kg/hr; 0.06-0.11 mg/kg/hr) ( < 0.001). Two cases of hypotension in each group were detected but coma and ileus, the major known adverse reactions to fentanyl, did not occur.
CONCLUSION
Fentanyl combined with midazolam is safe and more effective than midazolam alone for sedation therapy in mechanically ventilated children.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02172014.
Topics: Adjuvants, Anesthesia; Adolescent; Anxiety; Child; Child, Preschool; Double-Blind Method; Drug Therapy, Combination; Female; Fentanyl; Humans; Hypnotics and Sedatives; Hypotension; Infant; Intensive Care Units; Male; Midazolam; Respiration, Artificial; Treatment Outcome
PubMed: 30662387
DOI: 10.3346/jkms.2019.34.e21 -
American Journal of Veterinary Research Dec 2018OBJECTIVE To compare sedation in cockatiels (Nymphicus hollandicus) after intranasal administration of midazolam and midazolam-butorphanol. ANIMALS 9 healthy adult...
OBJECTIVE To compare sedation in cockatiels (Nymphicus hollandicus) after intranasal administration of midazolam and midazolam-butorphanol. ANIMALS 9 healthy adult cockatiels. PROCEDURES A randomized, controlled, blinded, complete crossover study was conducted. Birds were assigned to 3 treatment groups. Midazolam (3 mg/kg), midazolam-butorphanol (3 mg/kg for each drug), or sterile saline (0.9% NaCl) solution (control treatment) was administered intranasally. Sedation quality was assessed at 3 time points by use of eye and body position; response to visual, auditory, and tactile stimulation; and response during manual restraint on the basis of eye position and struggling intensity. To evaluate attenuation of the manual restraint-induced stress response, heart rate, respiratory rate, and cloacal temperature were measured over a 15-minute period. Treatments were repeated after a minimum washout period of 7 days. RESULTS Median onset of first sedation effects was 85 seconds (range, 60 to 120 seconds) for midazolam and 90 seconds (range, 45 to 180 seconds) for midazolam-butorphanol. Midazolam-butorphanol resulted in significantly less vigorous struggling during restraint than did midazolam or the control treatment. Heart rate did not differ significantly among treatments. The stress-induced increase in respiratory rate was significantly attenuated by midazolam and midazolam-butorphanol, whereas the increase in cloacal temperature was not attenuated by midazolam or midazolam-butorphanol. CONCLUSIONS AND CLINICAL RELEVANCE Intranasal administration of midazolam and midazolam-butorphanol resulted in a rapid onset of sedation in cockatiels. Midazolam-butorphanol resulted in deeper sedation in both restrained and unrestrained birds than did midazolam alone. Midazolam and midazolam-butorphanol both provided safe and effective sedation in cockatiels.
Topics: Administration, Intranasal; Anesthesia; Animals; Butorphanol; Cockatoos; Cross-Over Studies; Female; Heart Rate; Hypnotics and Sedatives; Male; Midazolam; Respiratory Rate; Single-Blind Method
PubMed: 30457900
DOI: 10.2460/ajvr.79.12.1246 -
Neonatology 2019Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation,...
BACKGROUND
Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance.
OBJECTIVES
To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines.
METHODS
Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs.
RESULTS
Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam.
CONCLUSIONS
Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.
Topics: Anticonvulsants; Asphyxia Neonatorum; Drug Interactions; Drug Therapy, Combination; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Metabolic Clearance Rate; Midazolam; Phenobarbital; Practice Guidelines as Topic; Prospective Studies
PubMed: 31256150
DOI: 10.1159/000499330 -
Annals of Palliative Medicine Aug 2021Bronchoscopic examination including endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is well established for lung cancer diagnosis and...
BACKGROUND
Bronchoscopic examination including endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is well established for lung cancer diagnosis and staging. Sedation using fentanyl and midazolam is recommended during bronchoscopic examinations. Meanwhile, inadvertent oversedation is a clinical problem. The objective of this research was to estimate the frequency of apnea episodes by end-tidal capnography under fentanyl and midazolam sedation during bronchoscopy.
METHODS
Eighty-five patients were enrolled retrospectively between August 2017 and March 2018 at Okayama Medical Center. Apnea was defined as the cessation of airflow for more than 10 seconds. We reviewed medical records, including capnographic data, by cap-ONE YG-227T (NIHON KOHDEN, Tokyo, Japan) during flexible bronchoscopy under fentanyl and midazolam sedation.
RESULTS
Patients received 49.4±20.6 µg of fentanyl [mean ± standard deviation (SD)] and 4.35±2.0 mg of midazolam (mean ± SD). The patients included 52 males and 33 females; the median age was 71 (range, 31-88) years were enrolled. Apnea episodes were recorded (median duration 18 seconds) in 85 patients (100%). Prolonged apnea episodes with more than 30 seconds occurred in 56 patients (65.8%). Furthermore, the median time was 32 (range, 5-102) seconds whose delay between the onset of an apnea episode and decline in the SpO2 level of ≥4% from baseline.
CONCLUSIONS
End-tidal capnography, cap-ONE YG-227T was effective for detecting the occurrence of apnea in patients undergoing a bronchoscopic examination under fentanyl and midazolam sedation. Monitoring might be useful for preventing inadvertent oversedation.
Topics: Aged; Bronchoscopy; Conscious Sedation; Female; Fentanyl; Humans; Male; Midazolam; Retrospective Studies
PubMed: 34379981
DOI: 10.21037/apm-21-1009 -
Anaesthesia Nov 1997
Topics: Administration, Oral; Child; Humans; Hypnotics and Sedatives; Midazolam; Premedication
PubMed: 9404195
DOI: No ID Found