Klaus T. Olkkola

Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole

Interaction between ketoconazole, itraconazole, and midazolam was investigated in a double‐blind, randomized crossover study of three phases at intervals of 4 weeks. Nine volunteers were given either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo orally once daily for 4 days. On day 4, the subjects ingested 7.5 mg midazolam. Plasma samples were collected and psychomotor performance was measured. Both ketoconazole and itraconazole increased the area under the midazolam concentration‐time curve from 10 to 15 times (p < 0.001) and mean peak concentrations three to four times (p < 0.001) compared with the placebo phase. In psychomotor tests (e.g., the Digit Symbol Substitution Test), the interaction was statistically significant (p < 0.05) until at least 6 hours after drug administration. Inhibition of the cytochrome P450IIIA by ketoconazole and itraconazole may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving ketoconazole and itraconazole should be avoided.

A potentially hazardous interaction between erythromycin and midazolam

Interaction between erythromycin and midazolam was investigated in two double‐blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pre‐treatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration–time curve after oral intake more than four times (p <0.001) and reduced clearance of intravenously administered midazolam by 54% (p <0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p <0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole

Triazolam is metabolized by CYP3A4 isozyme. Ketoconazole and itraconazole may seriously interact with some of the substrates of CYP3A4 (e.g., terfenadine); hence their possible interaction with triazolam in humans is important to uncover.

The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin

AbstractObjective: To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics of oral midazolam during and 4 days after the end of the treatment. Methods: Nine healthy volunteers received itraconazole (200 mg daily) for 4 days and, 2 weeks later, rifampicin (600 mg daily) for 5 days. In addition, they ingested 15 mg midazolam before the first treatment, 7.5 mg on␣the␣last day of itraconazole administration, and 4 days␣later,␣and 15 mg 1 day and 4 days after the last dose␣of␣rifampicin.␣The disposition of midazolam and its α-hydroxy metabolite was determined and its pharmacodynamic effects were measured. Results: During itraconazole treatment, or 4 days after, α-hydroxymetabolite the dose-corrected area under the plasma midazolam concentration–time curve (AUC0–∞) was 8- or 2.6-fold larger than that before itraconazole (i.e. 1707 or 695 versus 277 ng · h · ml−1), respectively. One day after rifampicin treatment, the AUC0–∞ of midazolam was 2.3% (i.e. 4.4 ng · h · ml−1) of the before-treatment value and only 0.26% of its value during itraconazole treatment; 4 days after rifampicin, the AUC0–∞ was still only 13% (i.e. 27.1 ng · h · ml−1) of the before-treatment value. The peak concentration and elimination half-life of midazolam were also increased by itraconazole and decreased by rifampicin. The ratio of plasma α-hydroxymidazolam to midazolam was greatly decreased by itraconazole and increased by rifampicin. In addition, the effects of midazolam were greater during itraconazole and smaller 1 day after rifampicin than without treatment. Conclusion: Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great (400-fold) change in the AUC of oral midazolam. During oral administration of CYP3A substrates that undergo extensive first-pass metabolism, similar changes in pharmacokinetics are expected to occur when potent inhibitors or inducers of CYP3A are added to the treatment. After cessation of treatment with itraconazole or rifampicin, the risk of significant interaction continues up to at least 4 days, probably even longer.

Rifampin drastically reduces plasma concentrations and effects of oral midazolam

Midazolam is a short‐acting benzodiazepine that is metabolized by CYP3A enzymes. Rifampin is a potent enzyme inducer that may seriously interact with some substrates of CYP3A4.

The effect of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam

We studied the interaction of azole antimycotics with intravenous (IV) and oral midazolam using a cross-over design in 12 volunteers, who ingested placebo, itraconazole, or fluconazole for 6 days. A 7.5-mg dose of midazolam was ingested on the first day, 0.05 mg/kg was administered IV on the fourth day, and 7.5 mg orally on the sixth day. Itraconazole reduced the clearance of IV midazolam by 69% and fluconazole reduced the clearance of IV midazolam by 51% (P < 0.001). A single dose of itraconazole and fluconazole increased the area under the oral midazolam concentration-time curve [AUC(0-infinity)] 3.5-fold (P < 0.001) and the peak concentration two-fold (P < 0.05) compared to placebo. On the sixth day the AUC(0- infinity) of oral midazolam was almost seven times greater with itraconazole (P < 0.001) and 3.6 times greater with fluconazole (P < 0.001) than without the antimycotics. The psychomotor effects of midazolam were also profoundly increased (P < 0.001). The psychomotor tests demonstrated only a weak interaction between the antimycotics and IV midazolam. When bolus doses of midazolam are given for shorttime sedation, the effect of midazolam is not increased to a clinically significant degree by itraconazole and fluconazole, and it can be used in normal doses. However, the use of large doses of IV midazolam increases the risk of clinically significant interactions also after IV midazolam. Use of oral midazolam with itraconazole and fluconazole should be avoided. (Anesth Analg 1996;82:511-6)

Measurement of pain in children with self‐reporting and behavioral assessment

There are several studies on the correlation of various pain‐rating scales in adults but few such studies have been done on children. To gain information on the correlation of self‐reporting pain scales (one verbal and two visual analog scales) with each other and with a scale based on behavioral assessment, we analyzed retrospectively the pain evaluations of 141 pediatric patients participating in our analgesic studies. Eighty‐two patients were male and 59 were female. The ages ranged from 1.6 to 17.6 years. The patients were divided into three age groups. All pain‐rating scales were correlated (P < 0.001) with each other and they showed a good internal consistency. There were no differences in correlation coefficients between the age groups and the two sexes. Accordingly, any of the now‐employed scales can be used in clinical analgesic studies in children on the condition that the child has comprehended the use of the scale during the preoperative visit.

Utstein style reporting of in-hospital paediatric cardiopulmonary resuscitation.

STUDY OBJECTIVE To report paediatric in-hospital cardiac arrest data according to Utstein style and to determine the effectiveness of cardiopulmonary resuscitation (CPR) in hospitalized children. DESIGN Retrospective 5-year case series. SETTING Urban, tertiary-care childrens hospital. PARTICIPANTS All patients who sustained cardiopulmonary arrest. RESULTS Altogether 227 patients experienced a cardiopulmonary arrest during the study period, 109 (48.0%) were declared dead without attempted resuscitation, and CPR was initiated in 118 (52.0%). The incidence of cardiac arrest was 0. 7% of all hospital admissions and 5.5% of PICU admissions; the incidence of CPR attempts was 0.4 and 2.5%, respectively. Most of the CPR attempts (64.4%) took place in the PICU and the most frequent aetiology was cardiovascular (71.2%). The 1-year survival rate was 17.8%. Short duration of external CPR was the best prognostic factor associated with survival. With few exceptions, the Paediatric Utstein Style was found to be applicable for reporting retrospective data from in-hospital cardiac arrests in children. CONCLUSIONS In-hospital cardiopulmonary resuscitation was shown to be an uncommon event in children; the survival rate was similar to earlier studies.

Oral Activated Charcoal in the Treatment of Intoxications

SummaryActivated charcoal has an ability to adsorb a wide variety of substances. This property can be applied to prevent the gastrointestinal absorption of various drugs and toxins and to increase their elimination, even after systemic absorption.Single doses of oral activated charcoal effectively prevent the gastrointestinal absorption of most drugs and toxins present in the stomach at the time of charcoal administration. Known exceptions are alcohols, cyanide, and metals such as iron and lithium. In general, activated charcoal is more effective than gastric emptying. However, if the amount of drug or poison ingested is very large or if its affinity to charcoal is poor, the adsorption capacity of activated charcoal can be saturated. In such cases properly performed gastric emptying is likely to be more effective than charcoal alone.Repeated dosing with oral activated charcoal enhances the elimination of many toxicologically significant agents, e.g. aspirin, carbamazepine, dapsone, dextropropoxyphene, cardiac glycosides, meprobamate, phenobarbitone, phenytoin and theophylline. It also accelerates the elimination of many industrial and environmental intoxicants.In acute intoxications 50 to 100g activated charcoal should be administered to adult patients (to children, about 1 g/kg) as soon as possible. The exceptions are patients poisoned with caustic alkalis or acids which will immediately cause local tissue damages. To avoid delays in charcoal administration, activated charcoal should be a part of firstaid kits both at home and at work. The ‘blind’ administration of charcoal neither prevents later gastric emptying nor does it cause serious adverse effects provided that pulmonary aspiration in obtunded patients is prevented.In severe acute poisonings oral activated charcoal should be administered repeatedly, e.g. 20 to 50g at intervals of 4 to 6 hours, until recovery or until plasma drug concentrations have fallen to non-toxic levels. In addition to increasing the elimination of many drugs and toxins even after their systemic absorption, repeated doses of charcoal also reduce the risk of desorbing from the charcoal-toxin complex as the complex passes through the gastrointestinal tract. Charcoal will not increase the elimination of all substances taken. However, as the drug history in acute intoxications is often unreliable, repeated doses of oral activated charcoal in severe intoxications seem to be justified unless the toxicological laboratory has identified the causative agent as not being prone to adsorption by charcoal.The role of repeated doses of oral activated charcoal in chronic intoxications has not been clearly defined. Charcoal seems able to accelerate the elimination of many industrial and environmental toxicants like dioxins, polychlorinated biphenyls and possibly also some heavy metals, including their radioactive isotopes. Further studies will be needed to define the value of repeated doses of oral activated charcoal in chronic intoxications.

Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice

Grapefruit juice increases the bioavailability of several drugs known to be metabolized by CYP3A enzymes. Ketoconazole and itraconazole can increase the area under the concentration‐time curve [AUC(0‐∞)] of triazolam, a substrate of CYP3A, by more than twenty times.