Factors influencing theophylline disposition in 179 newborns.

The pharmacokinetics of intravenous theophylline were prospectively studied in 179 premature babies. Interrelated variables were analyzed for their influence on theophylline serum clearance. Gestational age, gender, duration of treatment, body weight, and Apgar scores were not found to correlate significantly with theophylline clearance. Weak but statistically significant correlations were found between serum clearance and postnatal (p less than 0.005) and postconceptional age (p less than 0.01). No significant difference in mean serum clearance (Cls) values was found between small-for-gestational-age (SGA) patients (Cls = 17.9 +/- 5.3 ml/kg/h) and appropriate-for-gestational-age (AGA) patients (Cls = 18.8 +/- 5.8 ml/kg/h). Conversely, asphyxiated patients had significantly lower mean clearance values than nonasphyxiated patients (16.4 +/- 5.3 ml/kg/h vs. 20.2 +/- 5.4 ml/kg/h, respectively, p less than 0.001). Volume of distribution for theophylline (n = 147) was 0.77 +/- 0.17 L/kg; there was no significant difference in distribution volumes between asphyxiated and nonasphyxiated patients or between SGA and AGA patients. Step-wise multiple regression analysis revealed postnatal age as the most important determinant of theophylline clearance among the variables analyzed (p less than 0.01). Postconceptional age had a statistically significant association with theophylline clearance in the entire group (n = 179, p less than 0.05). Duration of treatment had a small and statistically borderline effect (p less than 0.10) on theophylline clearance among nonasphyxiated infants when age factors were considered. Analysis of covariance confirmed the statistical effects of both postnatal age and asphyxia on theophylline serum clearance.

The influence of asphyxia on phenobarbital dosing requirements in neonates.

phenobarbital dosing requirements and plasma clearance were examined for asphyxiated and nonasphyxiated neonates. The gestational age, postnatal age, duration of phenobarbital therapy and plasma phenobarbital concentrations were similar for the two groups. The plasma phenobarbital clearance was 4.1 +/- 1.0 (SD) and 8.7 +/- 3.9 (SD) ml/kg/h for asphyxiated and nonasphyxiated neonates, respectively. Asphyxiated neonates only require about half the maintenance dose of nonasphyxiated neonates to achieve similar plasma concentrations.

Usefulness of theophylline saliva levels in neonates.

In order to establish an alternative means for monitoring serum theophylline concentrations in neonates, the reliability of salivary theophylline concentrations was investigated. Eight premature neonates with apnea of prematurity were studied. Neonates received between 1.25 and 2.5 mg/kg of intravenous aminophylline every 12 h. Simultaneous samples of blood (0.25 ml) and unstimulated saliva (0.25-0.50 ml) were obtained 4 and 8 h after drug administration. Serum and salivary theophylline concentrations statistically correlated (r = 0.98, p less than 0.01). The mean serum/saliva ratio was 1.02 +/- 0.09, with an 8.9% interpatient variation. Serum theophylline concentrations can be predicted from the equation: serum concentration = 1.069 x saliva concentration - 0.193. The data suggest that theophylline serum and saliva concentrations in the apneic neonate are approximately equal. Salivary theophylline concentrations may be clinically useful when serum is not readily available.

Individualizing phenobarbital dosing in neonates.

A method was developed for estimating elimination rate constants for phenobarbital in neonates on the basis of two serum samples drawn at any interval. Phenobarbital serum concentrations were obtained for 16 neonates being treated for fetal asphyxia, intraventricular hemorrhage, narcotic withdrawal, or seizure activity. The mean birth weight was 2.18 kg, mean gestational age was 34.8 weeks, and mean postnatal age was 12.1 days. The first blood sample was drawn two hours after an i.v. loading dose of phenobarbital sodium 7-15 mg/kg; maintenance doses ranging from 1.3 to 7.5 mg/kg/day were given by single i.v. injection. On the third day of therapy, trough concentration was determined; elimination rate constants were calculated using the two concentrations and the total dosage administered. Maintenance doses were adjusted to achieve desired serum concentrations, and predicted concentrations were compared with actual concentrations on the seventh day of therapy. Measured and predicted serum concentrations on day 7 were not significantly different. Only one patient exhibited phenobarbital toxicity. Phenobarbital serum half-life did not show a correlation with either gestational age or postnatal age. This method is clinically useful for individualizing phenobarbital dosing in neonates because it allows for integration of therapeutic drug monitoring with maintenance dosing based on the patient's metabolic capacity for the drug.

Efficacy of phenobarbital monotherapy in treatment of neonatal seizures -- relationship to blood levels.

Seventy-one neonates were observed for the relationship between phenobarbital plasma concentrations and elimination of seizures. Sixty neonates (85%) had seizures controlled by phenobarbital alone. Effective plasma concentrations were 10.1 to 46.4 mg per liter. Although 36 neonates had seizures controlled by phenobarbital concentrations below 20 mg per liter, 7 neonates required levels above 30 mg per liter. We recommend that plasma phenobarbital concentrations should equal or surpass 40 mg per liter before additional anticonvulsants are used for neonates with seizures.

Effect of asphyxia on theophylline clearance in newborns.

The effect of asphyxia on theophylline clearance was studied in 30 newborns who were matched for gestational age, postnatal age, and the presence or absence of asphyxia. Asphyxiated newborns cleared theophylline at approximately half the rate of nonasphyxiated newborns. We found that, in order to achieve a steady-state plasma concentration of 8 mg/L of theophylline, asphyxiated neonates should receive 2.1 mg/kg/day, while nonasphyxiated neonates should receive 3.9 mg/kg/day.

Theophylline-induced seizures in accidentally overdosed neonates.

Theophylline-induced seizures are reported in two neonates. The serum theophylline concentration during seizures were 51.0 mg/liter and 54.0 mg/liter. Toxic symptoms prior to seizures may be absent or undetected, suporting the necessity of blood level monitoring during theophylline therapy.