Plasma concentrations and sedation scores after nebulized and intranasal midazolam in healthy volunteers

Background: An efficacious, reliable, and non-invasive route of administrationfor midazolam, a drug used for sedation and pre-anaestheticmedication, would have obvious advantages. This study comparestwo potential methods of administering midazolam by the nasaland nebulized routes. Methods: Midazolam (0.2 mg kg^–1) was given by both nebulizer andnasally by liquid instillation to 10 healthy volunteers in arandomized, double-blind crossover study. Plasma concentrationsof midazolam, Ramsay sedation scores, visual analogue scores,critical flicker fusion frequency, and parameters of cardiovascularand respiratory function were measured over 60 min and summarizedusing ‘area under the curve’. Results: Nasal instillation caused more sedation than nebulized administration.This was demonstrated by higher Ramsay sedation scores (P=0.005),lower visual analogue scores (P<0.001), and lower criticalflicker fusion frequency (P<0.02). Nasal instillation wasassociated with higher plasma concentrations of midazolam (P<0.001).Unpleasant symptoms were recorded by six volunteers in the intranasaland one in the nebulized group (P=0.06). Conclusions: There was some evidence that midazolam caused less discomfortwhen given by nebulizer compared with intranasally. Comparativebioavailability of midazolam, estimated by the ratio (nebulized:nasal)of area under the 60 min plasma concentration curve, was 1:2.9.A higher dose may need to be administered for adequate pre-anaestheticmedication when midazolam is given by nebulizer.     

Plasma level changes of fentanyl and midazolam after release of a prolonged thigh tourniquet

In 14 elderly orthopedic patients undergoing total knee joint replacement, the influence of complete arterial occlusion of the limb on the course of plasma levels of fentanyl and midazolam was examined. The patients were premedicated with midazolam intramuscularly (0.05 mg/kg) and were then given neurolept anesthesia in dosages of 0.1 mg/kg midazolam and 0.01 mg/kg fentanyl intravenously prior to the placement of the tourniquet. Up to 4 h after the tourniquet was released, plasma levels of fentanyl and midazolam as well as pH value, PaCO2 and plasma lactate levels were measured. In 12 patients there was an increase in fentanyl and in 10 patients an increase in midazolam plasma levels after tourniquet release. The maximum increase varied between 1 min and 2 h after release. The plasma levels of midazolam after removal of the tourniquet varied greatly between individuals. Especially patients older than 70 years showed excessively high concentrations of midazolam. These results would indicate that there can be a clinically significant increase of fentanyl and midazolam levels due to initial reperfusion of the lower extremity following prolonged ischemia. Therefore a correspondingly extended period of postoperative surveillance is advisable.     

Comparison between three transmucosal routes of administration of midazolam in children

Midazolam was applied transmucosally in 47 children randomly assigned to three different groups. Group N received 0.2 mg·kg⁻¹ nasally, group R 0.5 mg·kg⁻¹ rectally, and group S 0.2 mg·kg⁻¹ sublingually. All groups were treated 60 min prior to a planned i.v. puncture with EMLA^®. Reliable and valid psychological parameters (such as emotional situation, shivering, awareness, respiratory rate and facial colour) were scored after premedication and before and after i.v. puncture, 20 min after premedication and until induction. A blood sample was drawn 10, 30 and 60 min after premedication and the levels of midazolam, alpha-hydroxy-midazolam, ACTH, glucose and cortisol were measured. In all three groups the plasma levels of midazolam 10 min after premedication were higher than 70 ng·ml⁻¹ (accepted as a sedative level). 30 min after premedication the midazolam level in the sublingual group was statistically significantly higher than in the nasal group and the psychological parameters in all three groups were significantly changed (10 min after premedication). The psychological parameters were not significantly different between the three groups over the whole study. Sublingual premedication has some advantages (most readily accepted, highest plasma levels and lowest deviations) and could be the first choice in premedication of children. All three transmucosal applications are safe and well accepted, although nasal application was rejected by two of the children.     

Optimal administration time of intramuscular midazolam premedication

The optimal administration time for intramuscular injection of midazolam as premedication was studied. Sixty patients ranging in age from 40 to 65 were included. A combination of atropine 0.3–0.5 mg and midazolam 0.08 mg·kg⁻¹ was given to four groups of 15 subjects each in intramuscular injections 45, 30, 15 min, and immediately before entering the operating room. Blood pressure, heart rate, respiratory rate, depression of the root of the tongue, eyelash reflex, degree of sedation, and amnestic effect at the time of arriving the operating room were compared among the groups. There was no difference among the groups in blood pressure, heart rate, and respiratory rate. The depression of the root of the tongue, disappearance of verbal response, and eyelash reflex were found in the 30- and 45-min groups. The degree of sedation and amnestic effect were good except for the group who received midazolam immediately before entering the operating room. From the above results, intramuscular injection of midazolam 0.08 mg·kg⁻¹ with atropine 0.3–0.5 mg is considered best when administered 15 min before entering the operating room. This paper was presented at the 40th meeting of the Japan Society of Anesthesiology held in Morioka in 1993     

Resedation after bolus administration of midazolam to an infant and its reversal by flumazenil

A 4-month-old infant was sedated with bolus doses of midazolam, and after initial apparent complete arousal, became unresponsive and hypotonic. Administration of flumazenil enabled differentiation of a residual drug effect from an intracerebral event.     

Premedication with midazolam in young children: a comparison of four routes of administration

BACKGROUND: We undertook a study to determine the effects of four routes of administation on the efficacy of midazolam for premedication. METHODS: In a randomized double-blind study, 119 unmedicated children, ASA I-II, aged 1.5-5 years, who were scheduled for minor elective surgery and who had been planned to received midazolam as a premedicant drug, were randomly assigned to one of four groups. Group I received intranasal midazolam 0.3 mg.kg-1; group II, oral midazolam 0.5 mg x kg(-1); group III, rectal midazolam 0.5 mg x kg(-1); and group IV, sublingual midazolam 0.3 mg x kg(-1). A blinded observer assessed the children for sedation and anxiolysis every 5 min prior to surgery. Quality of mask acceptance for induction, postanaesthesia care unit behaviour and parents' satisfaction were evaluated. Thirty patients were enrolled in each of groups I, III and IV. Twenty-nine patients were enrolled in group II. RESULTS: There were no significant differences in sedation and anxiety levels among the four groups. Average sedation and anxiolysis increased with time, achieving a maximum at 20 min in group I and at 30 min in groups II-IV. Patient mask acceptance was good for more than 75% of the children. Although the intranasal route provides a faster effect, it causes significant nasal irritation. Seventy-seven percent of the children from this group cried after drug administration. Most parents in all groups (67-73%) were satisfied with the premedication. CONCLUSIONS: Intranasal, oral, rectal and sublingual midazolam produces good levels of sedation and anxiolysis. Mask acceptance for inhalation induction was easy in the majority of children, irrespective of the route of drug administration.     

Pharmacokinetics of midazolam and alfentanil in outpatient general anesthesia: A study with concomitant thiopentone, flumazenil or placebo administration

The pharmacokinetics of alfentanil, midazolam and thiopentone used for induction of short general anaesthesia were studied in 55 gynaecological outpatients. All the patients received midazolam as premedication. The patients received intravenous anaesthesia with alfentanil and either thiopentone or midazolam, supplemented with either nitrous oxide or air in oxygen ventilation, reversed by the end of anaesthesia with either placebo or flumazenil. Blood sampling for serum concentration measurements of midazolam, alfentanil and thiopentone was performed regularly for 7 h. The following mean pharmacokinetic parameters (mean ± –s.e.mean) were calculated for midazolam and alfentanil, respectively: elimination half–life 3.9 ± 0.3 h and 1.2 ± 0.05 h, apparent volume of distribution 107 ± 6 1 and 31 ± 1.5 1, total body clearance 20 ± 0.7 1/h and 18 ± 0.8 1/h. No influence of flumazenil on the kinetics of midazolam and no influence of thiopentone, midazolam, flumazenil or nitrous oxide on the kinetics of alfentanil was found. The serum levels of thiopentone were below the detection limit of the assay after 60 min, which made an evaluation of pharmacokinetic parameters impossible. Significant positive correlations were found in the individual patient between midazolam and alfentanil for all pharmacokinetic variables evaluated. For midazolam, an increase in the elimination half–life and the apparent volume of distribution was positively correlated to an increase of body–weight. For alfentanil, a decrease in the total body clearance and an increase in the elimination half–life were positively correlated to an increase of age. A prolonged elimination half–life of alfentanil was positively correlated to use of alcohol. High serum levels of thiopentone were positively correlated to increasing age of the patients.     

Continuous epidural administration of midazolam and bupivacaine for postoperative analgesia

BACKGROUND: Midazolam has been reported to have a spinally mediated analgesic effect. Clinically, single-shot epidural or spinal administration of midazolam has been shown to have an analgesic effect on perioperative pain. In this study, we investigated the analgesic effect of continuous epidural administration of midazolam with bupivacaine on postoperative pain. METHODS: Four groups of 20 patients who underwent gastrectomy or cholecystectomy were studied. Continuous epidural infusion of bupivacaine 100 mg (Group C), bupivacaine 100 mg + midazolam 10 mg (Group M10), or bupivacaine 100 mg + midazolam 20 mg (Group M20) in 40 ml per 12 h was started after surgery using the balloon infuser. Group I received intermittent epidural bupivacaine (2.5 mg.ml-1) 6 ml every 2 h. When necessary, an indomethacin suppository and then a single epidural shot of bupivacaine (2.5 mg.ml-1) 6 ml was administered. Blood pressure, heart rate, respiratory rate, analgesic area, analgesia score, and sedation score were monitored for 12 h postoperatively. Memory and frequencies of supplemental analgesia (indomethacin suppositories and epidural bupivacaine) were also checked. RESULTS: Group M20 showed a significantly wider area of pinprick analgesia and better analgesia scores than other groups. The need for rescue analgesics were significantly less in Group M20. Sedation and amnesia were more pronounced in Group M20 than the other groups. CONCLUSION: Adding midazolam (10 to 20 mg per 12 h) to continuous epidural infusion of bupivacaine for postoperative pain can provide a better analgesia, amnesia and sedation than bupivacaine alone.     

The effect of pre-operative administration of midazolam on the development of intra-operative hypothermia

(Midazolam is often used for premedication; it is known to promote vasodilation and may therefore affect redistribution of heat during surgery. We examined the effect of pre-operative administration of midazolam on the development of intra-operative hypothermia. Forty-five patients were randomly allocated to one of three groups to receive no premedication (Group C), IM midazolam 0.04 mg.kg(-1) (Group M1) or 0.08 mg.kg(-1) (Group M2) 30 min prior to anaesthesia. Sedation levels were assessed, and then general anaesthesia was induced and maintained using propofol and fentanyl. During surgery, core temperature, which was similar for the three groups prior to induction of anaesthesia, decreased significantly less in the midazolam groups M1 and M2 compared to the control group C. Patients who were more heavily sedated prior to induction of anaesthesia, had significantly lower core temperatures peri-operatively than those who were less sedated, and core temperatures in unpremedicated patients fell to significantly lower levels during surgery than those who were drowsy. We conclude that pre-operative administration of midazolam produces an effect on the development of peri-operative hypothermia. We found that moderate pre-operative sedation reduces the peri-operative heat loss, possibly by affecting core-to-peripheral heat distribution.     

Continuous infusion of midazolam during anaesthesia and postoperative sedation after maxillofacial surgery

The clinical effects and pharmacokinetics of 24 h infusion of midazolam (MDZ) during major maxillofacial surgery and postoperative observation in an Intensive Care Unit (ICU) were studied in 20 patients. During anaesthesia, infusion of MDZ at 5 mg/h combined with 67% nitrous oxide, 1.8 (s.d. = 0.8) mg of fentanyl, and 26.5 (s.d. = 11.4) mg of vecuronium, adequately suppressed clinical responses to surgical nociceptive stimuli. Postoperatively, infusion of MDZ was continued in the ICU at 5 mg/h until 9 a.m. of the first postoperative day for sedation of the intubated but spontaneously breathing patients. The depth of sedation in the ICU was scored from 1-5 (1 = "awake and tense", 5 = "unable to communicate"). During infusion the sedation score decreased from 3.8 after ICU arrival to 2.2 at 8 a.m. of the first postoperative day. Neither ventilatory nor circulatory depression were observed. After cessation of MDZ, recovery from sedation was fast. The degree of amnesia was low. During constant rate infusion no increase in plasma concentration of either MDZ or metabolites occurred. T1/2 beta of MDZ after cessation was 125 min (range 90-320) and its total body clearance was 10.5 ml/kg/min (s.d. = 3.1). The volume of distribution, clearance and T1/2 beta were significantly longer in women than in men. It was concluded that 24 h of MDZ infusion at 5 mg/h caused satisfactory ICU sedation with fast recovery, but that individual tailoring of the infusion rate may still improve the quality of sedation.     

Sedation for local anaesthesia. Comparison of intravenous midazolam and diazepam

Intravenous midazolam and diazepam have been compared as sedatives during surgery performed under local anaesthesia. Satisfactory conditions were produced by both drugs. No difference was detected in the rate of recovery, but a highly significant greater degree of amnesia followed the use of midazolam.     

Temazepam or midazolam for night sedation. A double-blind study

The effects of oral temazepam (20 mg), oral midazolam (15 mg) and a placebo were compared for night sedation on the evening prior to surgery in a double-blind study. Patients in the placebo group had significantly worse sleep than those in the temazepam (p = 0.004) or midazolam groups (p = 0.04). There was no significant difference between the two drug groups, nor between the residual effects of the three treatments. Temazepam appears to be somewhat more effective than the ultrashort-acting midazolam in pre-operative transient insomnia.     

A comparison of two different doses of ketamine with midazolam and midazolam alone as oral preanaesthetic medication on recovery after sevoflurane anaesthesia in children

BACKGROUND: This investigation prospectively evaluated the effect of oral premedication of two different doses of ketamine with midazolam and midazolam alone on the recovery of children after sevoflurane anaesthesia. METHODS: In a randomized, double-blind study, 79 children (aged 1-8 years, ASA physical status I or II) were assigned to receive one of three premedications in a volume of 0.5 ml x kg(-1): group 1 received midazolam 0.5 mg x kg(-1) (MD); group 2 received midazolam 0.5 mg x kg(-1) with ketamine 1.8 mg x kg(-1) (MK-1); and group 3 received midazolam 0.5 mg x kg(-1) with ketamine 3 mg x kg(-1) (MK-2). The reactions of the children during administration were noted. Anaesthesia was induced by facemask with incremental sevoflurane administration. All children received alfentanil (15 micro g x kg(-1)). Tracheal intubation was facilitated by mivacurium (0.2 mg x kg(-1)). Anaesthesia was maintained with sevoflurane and an additional dose of alfentanil, if necessary. During recovery, the time interval between discontinuation of anaesthesia and arousal (spontaneous ventilation, extubation) were recorded. RESULTS: Emergence (spontaneous ventilation, extubation) and recovery times (discharge, Aldrete score=9) did not differ significantly between groups (P=0.24, P=0.59 and P=0.145, respectively). CONCLUSIONS: The combination of midazolam and ketamine as oral preanaesthetic medication did not significantly affect the recovery time of children after sevoflurane anaesthesia.     

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.     

Response to carbon dioxide after oral midazolam and pentobarbitone

Midazolam (15 mg), pentobarbitone (100 mg) and a placebo were administered orally to nine male volunteers in double-blind crossover studies and the effect on the ventilatory response to carbon dioxide was observed for periods of 6 hours. It was concluded that neither drug caused any significant degree of respiratory depression.