A Pharmacokinetic Study of Midazolam in Paediatric Patients Undergoing Cardiac Surgery

Mathews, Hannah Morris; Carson, Ian; Lyons, Seán; Orr, I. A.; Collier, P. S.; Howard, P. J.; Dundee, J. W.

doi:10.1093/bja/61.3.302

Cited by 52 publications

(18 citation statements)

References 8 publications

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“…These clearance values are in agreement with smaller studies in neonates conducted by the same group (2.1 ml/min./kg, Jacqz- Aigrain et al 1990Aigrain et al & 1992 and others (3.1 ml/min./ kg, Hughes et al 1996). The clearance values in neonates are generally considerably lower than those in infants older than 3 months (9.1 ml/min./kg, Mathews et al 1988), children (9.1 ml/min./kg, Payne et al 1989) and young adults (6-9 ml/min./kg, Dundee et al 1984).…”

Section: Midazolamsupporting

confidence: 91%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

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Section: Midazolamsupporting

confidence: 91%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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“…Half of the patients had an age less than 6 months [34]. Mean Cl rate is lower than that reported in patients with age greater than 2 years (mean ± SD = 9.6 ± 3.5 mL/kg per min [61, 62]).…”

Section: Resultsmentioning

confidence: 99%

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

Pacifici

2014

International Journal of Pediatrics

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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.

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“…In neonates there is a decreased volume of distribution of lipophilic drugs resulting in higher peak drug concentrations. With increasing age, the volume of distribution of midazolam increases from approximately 1 l/kg in neonates to 1.3 l/kg in children of 5 years of age and 2 l/kg in teenagers, with large differences between different study populations [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. This indicates that changes in body composition have a moderate influence on the pharmacokinetic disposition of midazolam [12].…”

Section: Distributionmentioning

confidence: 99%

Growing up with Midazolam in the Neonatal and Pediatric Intensive Care

Swart

Slort²,

Plötz³

2012

CDM

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A variety of developmental changes is of influence on the pharmacokinetics and pharmacodynamics of midazolam in neonatal and pediatric intensive care patients. However, dosing regimens in children are based upon rather empirical extrapolations from the dosing regimens in adults. Based on current available studies it appears that with the rising of age, the pharmacokinetics of intravenously administered midazolam alter, resulting in a shorter half-life due to a higher hepatic clearance in older children as compared to newborn. Also, with the rising of age, the pharmacodynamics of intravenously administered midazolam may alter due to a decrease in density of receptors, possibly leading to a decreased clinical response. These findings implicate opposite effects and it is uncertain which of these effects are predominant. In conclusion, there is a large interindividual variability in the response to midazolam in children, which may be caused by differences in pharmacokinetics and pharmacodynamics. Both are subject to considerable developmental changes. It remains remarkable that high-quality evidence to support the use of midazolam for continuous sedation in the neonatal and pediatric intensive care setting is lacking.

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A Pharmacokinetic Study of Midazolam in Paediatric Patients Undergoing Cardiac Surgery

Cited by 52 publications

References 8 publications

Neonatal Hepatic Drug Elimination

Neonatal Hepatic Drug Elimination

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

Growing up with Midazolam in the Neonatal and Pediatric Intensive Care

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