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PubMed2006

Limited sampling models for oral midazolam: midazolam plasma concentrations, not the ratio of 1-hydroxymidazolam to midazolam plasma concentrations, accurately predicts AUC as a biomarker of CYP3A activity.

Oral midazolam is used as a phenotyping probe for cytochrome P450 (CYP) 3A activity and requires multiple plasma samples to measure drug exposure. Limited sampling is a useful strategy for optimizing sampling and reducing costs and labor. We studied limited sampling models using multiple linear regressions to predict the area under the concentration versus time curve (AUC) of midazolam using either midazolam plasma concentrations or the ratio of 1-hydroxymidazolam (1-OH MDZ) to midazolam plasma concentrations. CYP3A baseline activity data for oral midazolam from previous studies were used (45 healthy adults for models using midazolam plasma concentrations and 41 healthy adults for models using the ratios of 1-OH MDZ to midazolam plasma concentrations). Limited sampling models were derived, validated, and evaluated for precision and bias. Two equations using the time points at 0.5 and 6 hours and 0.5, 2, and 6 hours were acceptable and predictive of midazolam AUC using midazolam plasma concentrations. No 1-OH MDZ to midazolam plasma concentration ratios accurately predicted midazolam AUC.

Adult↗
PubMed2000

Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit.

BACKGROUND: The need for sedation for neonates undergoing uncomfortable procedures in the neonatal intensive care unit (NICU) has often been overlooked. Proper sedation may reduce stress and avoid complications during procedures such as mechanical ventilation. Midazolam is a short acting benzodiazepine that has been increasingly used in the NICU. However, the effectiveness of intravenous midazolam as a sedative in neonates has not been systematically evaluated. OBJECTIVES: To determine whether intravenous midazolam infusion is an effective sedative, as evaluated by behavioural and/or physiologic measurements, for critically ill neonates undergoing intensive care, and to assess clinically significant short and long term adverse effects associated with its use. SEARCH STRATEGY: Literature search according to the Cochrane Neonatal Collaborative Review Group search strategy. Randomized and quasi-randomized controlled trials of intravenous midazolam use in neonates were identified by searching MEDLINE, EMBASE, the Cochrane Controlled Trials Register, reference lists of published studies, personal files, and abstracts published in Pediatric Research from 1990-1999. SELECTION CRITERIA: Randomized controlled trials of intravenous midazolam infusion in infants </= 28 days of age for sedation during mechanical ventilation or radiologic investigations were selected for review. Studies on midazolam use as an anesthetic or an anticonvulsant were excluded. Studies involving neonates and older infants and children were excluded if data for neonates could not be extracted. DATA COLLECTION AND ANALYSIS: Data regarding the primary outcome of level of sedation (as evaluated by behavioural scales or physiologic parameters) were abstracted. Secondary outcomes including intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), death within 28 days of age, adverse effects associated with midazolam (hemodynamic and neurologic), days of ventilation, days of supplemental oxygen use, pneumothorax, length of NICU stay, and long term neurodevelopmental outcome were assessed. When appropriate, meta-analyses were performed using relative risk (RR), risk difference (RD), along with their 95% confidence intervals (95% CI) for categorical variables and weighted mean difference (WMD) for continuous variables. MAIN RESULTS: Two trials were eligible for inclusion in the review. Data on level of sedation from the two trials could not be combined because of differences in tools used to measure sedation levels. One study (Jacqz-Aigrain 1994) showed statistically a significant higher level of sedation in the midazolam group compared to the placebo group. The other study (Anand 1999) comparing midazolam to morphine and placebo found no statistically significant difference in sedation level among the three groups, but statistically significantly higher level of sedation was found in the midazolam group compared with the placebo group during the treatment infusion. However, since the sedation scales used in both studies have not been validated in preterm infants, the effectiveness of midazolam as a sedative in this population could not be ascertained based on the findings of these two studies. In the study by Jacqz-Aigrain (1994), blood pressures were statistically significantly lower in the midazolam group than in the placebo group on days 1 and 2, although there was no statistically significant difference in the incidence of hypotension requiring albumin or vasoactive drugs between groups. The study by Anand (1999) showed a statistically significant higher incidence of adverse neurologic events (death, grade III-IV IVH, PVL) in the midazolam group compared with the other groups. In addition, the midazolam group had a statistically significantly longer duration of NICU stay compared to the placebo group (WMD 5.4 days, 95%CI 0.4, 10.5). (ABSTRACT TRUNCATED)

Humans↗
PubMed1999

Characterization of the pharmacodynamic interaction between parent drug and active metabolite in vivo: midazolam and alpha-OH-midazolam.

The pharmacodynamic interaction between midazolam and its active metabolite alpha-OH-midazolam was investigated to evaluate whether estimates of relevant pharmacodynamic parameters are possible after administration of a mixture of the two. Rats were administered 10 mg/kg of midazolam, 15 mg/kg of alpha-OH-midazolam, or a combination of 3.6 mg/kg of midazolam and 35 mg/kg of alpha-OH-midazolam. Increase in the 11.5- to 30-Hz frequency band of the electroencephalogram was used as the pharmacodynamic endpoint. The pharmacodynamics of midazolam and alpha-OH-midazolam after combined administration were first analyzed according to an empirical and a competitive interaction model to evaluate each model's capability in retrieving the pharmacodynamic estimates of both compounds. Both models failed to accurately estimate the true pharmacodynamic estimates of midazolam and alpha-OH-midazolam. The pharmacodynamic interaction was subsequently analyzed according to a new mechanism-based model. This approach is based on classical receptor theory and allows estimation of the in vivo estimated receptor affinity and intrinsic in vivo drug efficacy. The relationship between stimulus and effect is characterized by a monotonically increasing function f, which is assumed to be identical for midazolam and alpha-OH-midazolam. The pharmacodynamic interaction is characterized by the classical equation for the competition between two substrates for a common receptor site. This mechanism-based interaction model was able to estimate the pharmacodynamic parameters of both midazolam and alpha-OH-midazolam with high accuracy. It is concluded that pharmacodynamic parameters of single drugs can be estimated after a combined administration when a mechanistically valid interaction model is applied.

Algorithms↗
PubMed2006

A comparison of midazolam and midazolam with remifentanil for patient-controlled sedation during operations on third molars.

Our aim was to compare patients' satisfaction and cooperation, and clinical efficacy, of midazolam alone, and midazolam and remifentanil for patient-controlled sedation during removal of third molars. Forty patients, American Society of Anesthesiologists grades I and II, admitted for extraction of impacted mandibular third molars were included in this randomised, prospective study. They were given an intravenous bolus of midazolam 0.03 mg/kg and then allowed to use patient-controlled sedation. In the midazolam group, 2 ml of 0.5 mg/ml midazolam was given automatically. In the midazolam-remifentanil group, 2 ml of 0.5 mg/ml midazolam and 12.5 microg/ml remifentanil were given in the same manner. The lockout period was 5 min. Vital signs and oxygen saturation were recorded. Patients' and surgeons' satisfaction, and the patients' degree of amnesia about the local anaesthetic, drilling, removal of the tooth, and pain during extraction were also assessed. There were no significant differences between systolic and diastolic blood pressures during sedation, but heart rate after 30 min in the combined group was significantly lower than in the midazolam group (p<0.05). Surgeons described the midazolam group as excellent in 9 and good in 11. In the combined group, satisfaction was excellent in 11, good in 7, and satisfactory or unacceptable in 1 of each. Immediately postoperatively, 19 patients in each group ranked their satisfaction as excellent and 1 as good. Twenty-four hours later it was unchanged in the midazolam group, while 15 patients in the other group thought it was excellent, 3 good, and 2 poor. Patient-controlled analgesia with midazolam or midazolam and remifentanil is safe and reliable during extraction of third molars.

Adolescent↗
PubMed2002

Single plasma concentrations of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam do not predict midazolam clearance in healthy subjects.

The 30-minute ratio of 1'-hydroxymidazolam:midazolam plasma concentrations has been used as a measure of midazolam clearance in liver transplant patients. This study determined if a single concentration of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam could be used to predict midazolam clearance in healthy subjects. Plasma midazolam and 1'-hydroxymidazolam concentrations from three previous studies were used for analyses. Data obtained predose and at 5, 30, 60, 120, 240, 300, and 360 minutes following intravenous doses of midazolam in 61 adults were divided and used to derive and validate equations to predict midazolam clearance. Equations were derived using linear regression and then validated by comparing predicted to observed clearance. Only one equation was related to midazolam clearance as afunction of 1'-hydroxymidazolam, but it did not predict midazolam clearance (r = 0.29, p = 0.31). Single sampling of 1'-hydroxymidazolam or 1'-hydroxymidazolam:midazolam plasma concentrations cannot be used to predict midazolam clearance in healthy adults.

Adult↗
PubMed2000

Oral preanaesthetic medication for children: double-blind randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone.

Anxiolysis and sedation with oral midazolam are common practice in paediatric anaesthesia. However, good or excellent results are seen in only 50-80% of cases. For this reason, we investigated if addition of a low dose of oral ketamine (MIKE: ketamine 3 mg kg-1, midazolam 0.5 mg kg-1) resulted in better premedication compared with oral midazolam 0.5 mg kg-1 or ketamine 6 mg kg-1 alone, in a prospective, randomized, double-blind study. We studied 120 children (mean age 5.7 (range 2-10) yr) undergoing surgery of more than 30 min duration. After oral premedication in the ward and transfer, the child's condition in the induction room was evaluated by assigning 1-4 points to the quality of anxiolysis, sedation, behaviour at separation from parent and during venepuncture (transfer score). On days 1 and 7 after operation, parents were interviewed for changes in behaviour (eating, sleep, dreams, toilet training), recollection and satisfaction, using a standardized questionnaire. The groups were similar in age, sex, weight, intervention and duration of anaesthesia. The transfer score was significantly better in the MIKE group (12.5 (95% confidence interval (CI) 11.9-13.1)) than in the ketamine or midazolam groups (10.6 (9.8-11.4) and 11.5 (10.7-12.3), respectively). Success rates for anxiolysis and behaviour at separation were greater than 90% with the combination, approximately 70% with midazolam and only 51% with ketamine alone. The incidence of salivation, excitation and psychotic symptoms was low in all groups. Vertigo and emesis before induction were significantly more frequent after ketamine premedication. During recovery, there were no differences in sedation or time of possible discharge. After 1 week, parents reported nightmares (ketamine five, midazolam three, MIKE one), restless sleep (five/four/four) or negative memories (three/four/one). There were no major or continuing disturbances in behaviour or development. In summary, significantly better anxiolysis and separation were observed with a combination of ketamine and midazolam, even in awake children (sedation was not successful according to the preset criteria), than with midazolam or ketamine alone. Duration of action and side effects of the combination were similar to those of midazolam. The combination of both drugs in strawberry flavoured glucose syrup (pH 4.5 approximately) is chemically stable for 8 weeks.

Anesthesia Recovery Period↗
PubMed2006

Oral sedation with midazolam and diphenhydramine compared with midazolam alone in children undergoing magnetic resonance imaging.

BACKGROUND: The purpose of this study was to compare the safety and efficacy of oral midazolam and midazolam-diphenhydramine combination to sedate children undergoing magnetic resonance imaging (MRI). METHODS: We performed a prospective randomized double-blind study in 96 children who were randomly allocated into two groups. Group D received oral diphenhydramine (1.25 mg x kg(-1)) with midazolam (0.5 mg x kg(-1)), and Group P received oral placebo with midazolam (0.5 mg x kg(-1)) alone. Sedation scores, onset and duration of sleep were evaluated. Adverse effects, including hypoxemia, failed sedation, and the return of baseline activity, were documented. RESULTS: Diphenhydramine facilitated an earlier onset of midazolam sedation (P < 0.01), and higher sedation scores (P < 0.01). In children who received midazolam alone, 20 (41%) were inadequately sedated, compared with 9 (18%) children who received midazolam and diphenhydramine combination (P < 0.01). Time to complete recovery was not significantly different between the two groups. CONCLUSIONS: Our study indicates that the combination of oral diphenhydramine with oral midazolam resulted in safe and effective sedation for children undergoing MRI. The use of this combination might be more advantageous compared with midazolam alone, resulting in less sedation failure during MRI.

Administration, Oral↗
PubMed1992

Locomotor activity after recovery from hypnosis: midazolam-morphine versus midazolam.

This study was performed to test the hypothesis that sedation after recovery from pharmacologic hypnosis is less pronounced if hypnosis is induced with a midazolam-morphine combination compared with midazolam administered alone. Loss of the righting reflex was used as an index for the hypnotic effect and reduction of locomotor activity as an index for the sedative effect. One group of rats received midazolam (20 mg/kg i.v) and another group an equipotent (in relation to the hypnotic ef.fect) combination of midazolam (4 mg/kg i.v.) and morphine (1.3 mg/kg i.v.). The duration of loss of the righting reflex in the midazolam and midazolam-morphine groups was 30 +/- 3 and 28 +/- 2 min, respectively (mean +/- SE). The difference between the groups in locomotor activity after recovery from hypnosis was very pronounced. The locomotor activity in the midazolam-morphine group at 1 and 2 h was seven and five times greater, respectively, than in the midazolam group (P < 0.005). The profound difference in locomotor activity for the two treatment groups was explained on the basis of the difference in the outcomes of midazolam-morphine interactions with regard to hypnosis (synergism) and sedation (summation). When the animals recovered from hypnosis, the synergism of the drug interaction ceased to be a contributing factor.

Animals↗
PubMedDate not supplied

[Does propofol have advantages over midazolam and isoflurane? Comparative study of 2 total intravenous anesthesia techniques using midazolam and propofol, versus balanced anesthesia with isoflurane].

OBJECTIVES: To compare two techniques for total intravenous anesthesia (TIVA): midazolam-alfentanil-flumazenil and propofol-alfentanil, contrasting them with combined anesthesia (thiopental-isoflurane-alfentanil) and assessing the efficacy of flumazenil in continuous perfusion for preventing resedation in TIVA with midazolam. PATIENTS AND METHODS: The efficacy and clinical tolerance of the 3 anesthetic techniques with propofol, midazolam or isoflurane were studied in 63 patients undergoing elective breast, lumbar or gynecological surgery. Anesthetic induction was achieved with midazolam 0.3 mg/kg-1 (group M), propofol 2.5 mg/kg-1 (group P) or thiopental 3 mg/kg-1 (group I); all patients also received 50 micrograms/kg-1 alfentanil and vecuronium bromide 0.12 mg/kg-1/h-1. Maintenance was achieved with midazolam in perfusion at 0.12 mg/kg-1/h-1 (group M); propofol in perfusion at 7 mg/kg-1/h-1 and a pre-incision dose of 1.5 mg/kg-1 (group P); and isoflurane at 1.15% (group I). The 3 groups also received one pre-incision dose of alfentanil 25 micrograms/kg-1 and post-incision perfusion at 60 micrograms/kg-1/h-1. The infusion of alfentanil was changed by amounts of 20 micrograms/kg-1/h-1 in accordance with the patient's response to surgery. After surgery patients in group M received flumazenil 0.5 mg i.v. over 30 sec and a perfusion of flumazenil 0.5 mg over 60 min. Parameters indicating efficacy were: 1) total dose and timing of alfentanil; 2) number of instances of inadequate anesthesia; 3) peri-operative amnesia; 4) times of awakening and extubation after surgery, and 5) the number of patients in each group who required naloxone. Parameters indicating tolerance were: 1) hemodynamic variables; 2) the number of postoperative desaturations; 3) level of sedation, comprehension and motor coordination and orientation; 4) the "G/g detection" test and the memory recall test; 5) adverse side effects; 6) need for postoperative analgesia, and 7) evaluation of the anesthetic technique. RESULTS: The 3 techniques afforded effective control of hemodynamic response to intubation and surgical incision. Anesthetic maintenance was easy and safe with isoflurane and propofol. Higher doses of alfentanil, however, were needed with midazolam and we found a higher incidence of signs of superficial anesthesia. Reversion of midazolam with flumazenil 0.5 mg i.v. produced earlier awakening, although this was followed later by relapse into hypno-sedation that could not be prevented with a perfusion of flumazenil. Although recovery from anesthesia was slower with propofol than with isoflurane, we observed no differences in level of sedation, motor coordination and postoperative comprehension. Maintenance with isoflurane produced a higher incidence of adverse side effects such as tremors and nausea after surgery. CONCLUSIONS: None of the TIVA techniques proved superior in all the parameters studied during anesthetic maintenance when compared with balanced isoflurane-alfentanil, although the propofol-alfentanil combination was found to be superior to that of midazolam-alfentanil. After anesthesia, however, recovery was better with the association of propofol-alfentanil and adverse side effects were fewer. Flumazenil at the doses used was ineffective for preventing resedation due to midazolam.

Adolescent↗
PubMed1984

Premedication with intramuscular midazolam: effect on induction time with intravenous midazolam compared to intravenous thiopentone or ketamine.

Our study sought to determine whether premedication with intramuscular midazolam would decrease the time to induction of anaesthesia with intravenous midazolam, and if so whether induction of anaesthesia would be as rapid as with thiopentone or ketamine, intravenously. Eight-nine patients, ASA physical status I or II, received midazolam 0.2 mg X kg-1, thiopentone 3.0 mg X kg-1, or ketamine 2.0 mg X kg-1 intravenously 60-90 min after intramuscular injection of either midazolam 0.07 mg X kg-1 or matching placebo. Time to induction of anaesthesia or the dose required to induce anaesthesia with intravenous midazolam was not decreased by midazolam premedication. Both with or without premedication, midazolam induction time was longer than with thiopentone or ketamine. Midazolam induction was associated with a lower incidence of blood pressure increase than with ketamine induction, and a lower incidence of apnea than that with either thiopentone or ketamine.

Adolescent↗
PubMed2004

Dose-finding study of intravenous midazolam for sedation and amnesia during spinal anesthesia in patients premedicated with intramuscular midazolam.

PURPOSE: We investigated the effective and safe dose of intravenous midazolam for sedation and amnesia during spinal anesthesia in patients premedicated with intramuscular midazolam. METHODS: One hundred and eighty patients aged 20-50 years scheduled for spinal anesthesia received midazolam 0.06 mg.kg(-1) and atropine 0.01 mg.kg(-1) intramuscularly 15 min before entering the operating room. Spinal anesthesia was performed with 0.5% hyperbaric tetracaine. Five minutes after starting surgery, midazolam 0 (control group), 0.01, 0.02, 0.03, 0.04, or 0.05 mg.kg(-1) was intravenously administered (30 patients each). Blood pressure, heart rate, respiratory rate, percutaneous oxygen saturation (S(p)(O)(2)), verbal response, eyelash reflex, and involuntary body movement were measured every 5 min for 30 min. Memory during surgery was also investigated. RESULTS: The number of the patients with loss of verbal response, with loss of eyelash reflex, and with no memory during surgery were significantly larger in the groups receiving midazolam >or=0.03 mg.kg(-1), >or=0.04 mg.kg(-1), and >or=0.02 mg.kg(-1), respectively. The decrease in blood pressure or increase in respiratory rate with decrease in S(p)(O)(2) was significantly larger in the groups receiving midazolam >or=0.03 mg.kg(-1) or 0.05 mg.kg(-1), respectively. CONCLUSION: For sedation and amnesia of the patients aged 20-50 years in spinal anesthesia with about 1 h duration receiving intramuscular midazolam 0.06 mg.kg(-1) as a premedication, intravenous midazolam 0.02 mg.kg(-1) might be effective and safe.

Adult↗
PubMed2002

BIS monitoring during midazolam and midazolam-ketamine conscious intravenous sedation for oral surgery.

OBJECTIVE: The purpose of this study was to determine whether the bispectral index scale (BIS) would provide added benefit to established methods of monitoring conscious sedation with midazolam (M group) or midazolam supplemented with ketamine (MK group). STUDY DESIGN: BIS was prospectively and blindly examined in 22 patients receiving outpatient oral surgery with conscious sedation supplemented with local anesthesia. RESULTS: The average midazolam dose in the midazolam group over the treatment period was 0.01 mg/kg/h, and the average midazolam plus ketamine dose was 0.01 and 0.05 mg/kg/h, respectively. Mean BIS values throughout the sedation study period were 90 for the midazolam group and 94 for the midazolam plus ketamine group. The addition of ketamine did not lower BIS. BIS values did not alter significantly over time except for an expected transient drop after the midazolam bolus induction. CONCLUSION: BIS levels remained close to baseline levels, suggesting that BIS would not provided any additional benefit to currently established methods of monitoring patient consciousness during conscious sedation for oral surgery.

Adult↗
PubMed2002

Synergistic sedation with midazolam and propofol versus midazolam and pethidine in colonoscopies: a prospective, randomized study.

OBJECTIVE: The aim of our study was to compare the safety and efficacy of the synergistic sedation with a low dose of midazolam combined with propofol versus the standard regimen of midazolam and pethidine for conscious sedation in colonoscopy in a group of patients that included a sufficient number of elderly patients with several comorbidities. METHODS: A total of 120 consecutive patients undergoing colonoscopy in a prospective study were randomly assigned to one of two medication regimens (55 patients were over 65 yr). Patients in group A (n = 64) received i.v. 2 mg (<70 kg b.w.) or 3 mg (>70 kg b.w.) of midazolam and a median dose of 80 mg of propofol (range 40-150). Patients in group B (n = 56) received i.v. a median dose of 5 mg of midazolam (range 3-7) and 75 mg of pethidine (range 50-125). The patient's comfort level was assessed by a 4-point scale 24 h after the procedure. The time to recover from sedation was assessed at 5, 10, and 30 min after the procedure by using the Aldrete score. RESULTS: Multivariate stepwise logistic regression analysis revealed that among sex, age, duration of the test, American Society of Anesthesiologists' Physical Status Classification grade, and the sort of sedation, the synergistic sedation with midazolam and propofol was the only factor associated with a higher level of patient comfort (chi2 = 5.5, p < 0.05). Additional multivariate stepwise logistic regression analysis revealed that among sex, age, duration of the test, American Society of Anesthesiologists' Physical Status Classification grade, and the sort of sedation, the synergistic sedation with midazolam and propofol was the only factor associated with a quicker patient recovery time (chi2 = 24.5, p < 0.01; chi2 = 51.7, p < 0.01; chi2 = 148.4, p < 0.01 for Aldrete in 10 min, 20 min, and 30 min, respectively). The endoscopist's evaluation of patient sedation and cardiorespiratory parameters were similar in both groups and in all age groups. CONCLUSIONS: Our data suggest that the synergistic sedation with a low dose of midazolam combined with propofol was superior to a standard combination of midazolam and the opioid pethidine for colonoscopies as far as the patient comfort and recovery times are concerned.

Adjuvants, Anesthesia↗
PubMed1991

[Comparison of midazolam and hydroxyzine as premedicants for combination of spinal and epidural anesthesia with midazolam sedation].

Midazolam 4 mg i.m. (Group M, n = 15) was compared with hydroxyzine 50 mg i.m. (Group H, n = 13) in a randomized double-blind study, as premedicants for patients undergoing simple total hysterectomy under combination of spinal and epidural anesthesia with midazolam sedation. Reduction of anxiety and amnesic effects about procedure under regional anesthesia with sufficient patient co-operation were greater following midazolam. The doses for intraoperative sedation of midazolam and pentazocine were the same in both groups. Mean doses of midazolam 2 mg and pentazocine 6 mg were required to induce sleep. Maintenance doses of midazolam and pentazocine were 3.7 and 11.4 mg.hr-1, respectively. No patient had recall of surgical procedure. Midazolam did not delay the postoperative resedation which lasted about 2 hours. The decrease in O2 saturation by pulse oxymetry is significant in Group M (4.5%) than Group H (2.7%). Nevertheless two patients in each group required oxygen 2 liter.min-1 via a nasal catheter. These results indicate that premedication by midazolam is more effective for procedures under regional anesthesia.

Adult↗
PubMed1996

A double-blind randomized comparison of midazolam alone and midazolam combined with ketamine for sedation of pediatric dental patients.

PURPOSE: The safety and efficacy of a new sedation technique for children having dental procedures under local anesthesia were evaluated. MATERIALS AND METHODS: One hundred children between the ages of 2 and 7 years who required sedation for dental procedures were administered either a combination of midazolam (0.35 mg/kg) and ketamine (5 mg/kg) or midazolam alone (1 mg/kg) rectally 30 minutes before removal to the dental chair. Pulse rate, respiratory rate, arterial pressure, oxygen saturation, adverse reactions, postoperative recovery, and behavior were recorded. RESULTS: Satisfactory sedation and anxiolysis were achieved with both drugs used in the study. When evaluating postoperative recovery, statistically significantly more children receiving midazolam alone were fully awake on admission to the recovery room and 30 minutes later. Results of physiologic monitoring, behavioral ratings, and adverse effects are reported. Excessive salivation occurred in 26% of children receiving the combination of drugs, compared with 14% receiving midazolam alone. Seven (14%) of the children receiving the combination of drugs hallucinated, compared with 21 (42%) receiving midazolam alone. Both drug groups had reliably good anxiolysis and sedation without loss of respiratory drive or protective airway reflexes. CONCLUSION: The use of a combination of midazolam and ketamine or midazolam alone is a safe, effective, and practical approach to managing children for minor dental procedures under local anesthesia. With this technique, advanced airway management proficiency is recommended.

Administration, Rectal↗
PubMed1999

Population pharmacokinetic modeling in very premature infants receiving midazolam during mechanical ventilation: midazolam neonatal pharmacokinetics.

BACKGROUND: Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants. METHODS: Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program. RESULTS: Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL. CONCLUSIONS: Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.

Anesthetics, Intravenous↗
PubMed2005

Comparative evaluation of midazolam and ketamine with midazolam alone as oral premedication.

BACKGROUND: Oral premedication with midazolam and ketamine is widely used in pediatric anesthesia to reduce emotional trauma and ensure smooth induction. However, various dosing regimens when used alone or in combination have variable efficacy and side effect profile. The aim of our study was to investigate and compare the efficacy of oral midazolam alone with a low-dose combination of oral midazolam and ketamine. METHODS: We performed a prospective randomized double-blind study in 100 children who were randomly allocated into two groups. Group M received 0.5 mg.kg(-1) oral midazolam and group MK received 0.25 mg.kg(-1) oral midazolam with 2.5 mg.kg(-1) oral ketamine. The preoperative sedation score, ease of parental separation and ease of mask acceptance were evaluated on a 4-point scale. The time to recovery from anesthesia and to achieve satisfactory Aldrete score was also noted. RESULTS: Uniform and acceptable sedation scores were seen in both the groups (group M 95.9%; group MK 97.96%), without any serious side effects. However, the combination offered significantly more children in an awake, calm and quiet state, who were easily separated from their parents (73.46% in MK vs 41% in group M). The induction scores were comparable between the groups. The recovery room characteristics and time to achieve satisfactory Aldrete score were also comparable between the two groups. CONCLUSIONS: Oral midazolam alone and a combination of midazolam with ketamine provide equally effective anxiolysis and separation characteristics. However, the combination provided more children in an awake, calm and quiet state who could be separated easily from parents.

Adjuvants, Anesthesia↗