Clinical Pharmacology of Midazolam in Neonates and Children: Effect of Disease—A Review

Abstract

Midazolam is a benzodiazepine with rapid onset of action and short duration of effect. In healthy neonates the half-life (t 1/2) and the clearance (Cl) are 3.3-fold longer and 3.7-fold smaller, respectively, than in adults. The volume of distribution (Vd) is 1.1 L/kg both in neonates and adults. Midazolam is hydroxylated by CYP3A4 and CYP3A5; the activities of these enzymes surge in the liver in the first weeks of life and thus the metabolic rate of midazolam is lower in neonates than in adults. Midazolam acts as a sedative, as an antiepileptic, for those infants who are refractory to standard antiepileptic therapy, and as an anaesthetic. Information of midazolam as an anaesthetic in infants are very little. Midazolam is usually administered intravenously; when minimal sedation is required, intranasal administration of midazolam is employed. Disease affects the pharmacokinetics of midazolam in neonates; multiple organ failure reduces the Cl of midazolam and mechanical ventilation prolongs the t 1/2 of this drug. ECMO therapy increases t 1/2, Cl, and Vd of midazolam several times. The adverse effects of midazolam in neonates are scarce: pain, tenderness, and thrombophlebitis may occur. Respiratory depression and hypotension appear in a limited percentage of infants following intravenous infusion of midazolam. In conclusion, midazolam is a safe and effective drug which is employed as a sedative, as antiepileptic agent, for infants who are refractory to standard antiepileptic therapy, and as an anaesthetic.

Comparison of sedation scores after nebulized and intravenous Midazolam in children

“…The safety and tolerability profile of midazolam in pediatric patients is comparable/superior to that observed in adults. 6 Despite its common use, the preferred route of administration remains in dispute. The most popular routes being oral and rectal.…”

Intranasal therapies for acute seizures

“…The greater that a drug's lipid solubility (lipophilicity) at physiological pH is, the faster its absorption across membranes including nasal tissues as well as the blood-brain barrier. Nasally administered midazolam reaches peak concentrations (T max ) within 10 min, and its bioavailability ranges from 50% to 72% [11,12] ( Table 1). The elimination half-life is short (3 h), but diseases like multiorgan failure may decrease the clearance [12].…”

“…Use of intranasal midazolam (0.1-0.3 mg/kg) has been reported especially in children undergoing dental procedures, anesthesia induction, suture laceration, and pediatric imaging studies [12,15]. Sedation occurs rapidly, generally within 5-10 min, and lasts for 30-60 min.…”

“…The most common adverse effects reported following intranasal midazolam are burning or irritation in the nose lasting for 30-45 s and a bitter taste in the mouth [12,15]. Other adverse effects are similar to those of benzodiazepines administered via other routes and primarily include cardiorespiratory depression.…”

Challenges Associated with Route of Administration in Neonatal Drug Delivery

“…Several studies in adults have demonstrated that CYP3A metabolism in the small intestine plays a large role in the metabolism of several drugs, including cyclosporine and midazolam [32][33][34]. Taking this into consideration with the limited expression of CYP3A4 and 3A5 in neonates, it follows that presystemic clearance of these drugs will be decreased, and therefore bioavailability may be increased in neonates [35,36].…”