Steady-State Plasma Concentrations of Midazolam in Critically Ill Infants and Children

Hughes, Joseph P.; Gill, Andrea; Mulhearn, Helen; Powell, Edward; Choonara, Imti

doi:10.1177/106002809603000104

Cited by 56 publications

(37 citation statements)

References 27 publications

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“…The authors noted a large inter-individual variability in drug disposition in their study population. 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: 93%

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: 93%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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“…20–22 The CV ranged from 31% to 130%. The CV was lowest in the study where the infants were not ventilated 21.…”

Section: Resultsmentioning

confidence: 99%

“…15 17–19 21 Six other papers provided individual data allowing calculation of CV 1216 20 22 29 31 In nine papers, only the SD was reported and therefore CV was estimated assuming normal distribution 1120 25–28 30 33 34 The CV for all paediatric age groups ranged between 13% and 170% (figure 2).…”

Section: Resultsmentioning

confidence: 99%

Inter-individual variation in midazolam clearance in children

2014

Self Cite

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ObjectivesTo determine the extent of inter-individual variation in clearance of midazolam in children and establish which factors are responsible for this variation.MethodsA systematic literature review was performed to identify papers describing the clearance of midazolam in children. The following databases were searched: Medline, Embase, International Pharmaceutical Abstracts, CINAHL and Cochrane Library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined.Results25 articles were identified. Only 13 studies gave the full range of clearance values for individual patients. The CV was greater in critically ill patients (18%–170%) than non-critically ill patients (13%–54%). Inter-individual variation was a major problem in all age groups of critically ill patients. The CV was 72%–106% in preterm neonates, 18%–73% in term neonates, 31%–130% in infants, 21%–170% in children and 47%–150% in adolescents. The mean clearance was higher in children (1.1–16.7 mL/min/kg) than in neonates (0.78–2.5 mL/min/kg).ConclusionsLarge inter-individual variation was seen in midazolam clearance values in critically ill neonates, infants, children and adolescents.

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“…The plasma clearance of midazolam is impaired in infants and children younger than three years of age, who therefore have increased susceptibility to its toxicity (41). It should also be administered cautiously in very low-birth-weight (VLBW) babies because it can cause hypotension and adverse neurological events such as grade III-IV intraventricular haemorrhage (42,43).…”

Section: Benzodiazepinesmentioning

confidence: 99%

Untitled

2016

IJPSR

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Steady-State Plasma Concentrations of Midazolam in Critically Ill Infants and Children

Abstract: The plasma clearance in children 3 years and older was higher than in infants and children up to 2 years old. There was considerable interindividual variation in the steady-state plasma concentrations of midazolam in critically ill infants and children.

Cited by 56 publications

References 27 publications

Neonatal Hepatic Drug Elimination

Neonatal Hepatic Drug Elimination

Inter-individual variation in midazolam clearance in children

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