Clinical Pharmacokinetics of Sedatives in Neonates

Abstract

Sedation is currently administered to neonates experiencing pain and stress during intensive care for medical diseases, as well as postoperatively. Drugs commonly used for sedation in neonates include benzodiazepines (midazolam and lorazepam), chloral hydrate and opioids (fentanyl and morphine). Sedation protocols and dosage schedules are, in most cases, adapted from those which have been developed in children and even adults. The effectiveness and safety of the sedative agents remain underevaluated, however, due to the difficulties of quantifying pain and stress in neonates, and because of the limited use of validated scoring methods by practitioners. Among the benzodiazepines, midazolam is probably the drug of choice for continuous sedation. However, its elimination is delayed in the neonatal period and hypotension may occur when given as a bolus injection or when taken with opioids. Lorazepam requires further evaluation to exclude severe neurotoxicity. Chloral hydrate is administered orally, but because of its delayed elimination and risk of accumulation, a single administration for short term sedation is recommended. Among opioids, fentanyl (which was initially administered for postoperative analgesia) is now prescribed for sedation during mechanical ventilation. Tolerance and dependence may develop rapidly, limiting its usefulness for prolonged sedation. Although extensively studied in neonates, the efficacy and safety of morphine are not clearly determined, because of the limited number of patients included in individual studies. In addition, important interindividual differences in metabolism render dosage recommendations difficult. Alfentanil and sufentanil need further investigations to define their pharmacokinetic-pharmacodynamic properties in neonates. Although the choice of drug is important, the way the drug is used and monitored is equally important. All the drugs used for the sedation of neonates have large inter- and intraindividual differences in disposition, justifying specific pharmacological knowledge and individual dosage adjustments based on clinical evaluation of the patient and the monitoring of drug concentrations.

Anaesthesia for the laser treatment of neonates with retinopathy of prematurity

“…9 Analgesics such as fentanyl and morphine when given alone are also not the answer, as even in large doses they do not completely obtund the autonomic response to noxious stimuli, but may result in prolonged respiratory depression. [10][11][12] In the case of fentanyl, rapid large boluses can also result in sudden profound chest wall rigidity, which results in an inability to ventilate.…”

Correction to: Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review

“…Therefore, estimation of halflife may become inaccurate if extrapolation of data is not carefully performed [38]. Postnatal and postmenstrual age both affect pharmacokinetics because preterm infants showed slightly higher CL than neonates born at term (26.2 vs. 21.1 mL/kg/min), but the preterm infants were older regarding postnatal age (36.7 vs. 13.3 days) [29,32].…”

“…During ECMO, neonates rapidly developed tolerance towards the sedating effect of fentanyl, resulting in a progressive escalation of fentanyl infusion rates and rising steady-state plasma concentrations, increasing the risk of neonatal abstinence syndrome [38,73,74]. Clearance may be impaired in seriously ill patients during ECMO, which may be owing to decreased liver blood flow during compromised circulatory function [75].…”

“…Half-life was longest and V d at steady state was largest in newborns compared with the older age groups. Neonates needed additional anesthetic agents at significantly higher plasma concentrations compared with older children to suppress the hemodynamic response to painful stimuli, but younger infants did not receive premedication before surgery [38]. Clearance and V d increased while the half-life decreased slightly in a case series of neonates who were studied twice during the first 4 weeks of life [109].…”

“…Reported chest wall rigidity remains a safety concern in this age group [144]. Therefore, more studies are needed to investigate the relationship of pharmacokinetics and pharmacodynamics [38].…”