Population pharmacokinetics of intravenous indomethacin in neonates with symptomatic patent ductus arteriosus.

The population pharmacokinetics of intravenous indomethacin were investigated with 665 indomethacin serum concentrations from 83 neonates (mean +/- SD: gestational age, 28.8 +/- 2.5 weeks; postnatal age, 5.7 +/- 4.7 days; birth weight, 1.13 +/- 0.40 kg) receiving indomethacin for symptomatic patent ductus arteriosus. A one-compartment open model was used for pharmacokinetic analysis. Hypotheses were tested to determine which developmental and demographic data influenced clearance (CL) and volume of distribution (V(area)). In the final regression equation CL and V(area) were modeled as a function of body weight and postnatal age (PNA) from 0 to 20 days. Final estimates were as follows: CL (ml/hr) = 2.63.weight (kg) + 0.244.PNA (days) and V(area) (L) = 0.28.weight (kg) + 0.0041.PNA (days). The coefficients of variation for interindividual variability in CL and V(area) were 77% and 28%, respectively. Intraindividual variability was 19%. These mean population parameter estimates should prove useful in designing dosage regimens to achieve desired indomethacin concentrations for neonates from 0 to 20 days of age with symptomatic patent ductus arteriosus.

Rapid sequential phenobarbital treatment of neonatal seizures.

The optimal serum concentration of phenobarbital in newborns and its safety at high doses are not well established. The dose response relationship of rapid sequential phenobarbital loading in the newborn was examined and the efficacy of high-dose monotherapy was compared with the addition of a second anticonvulsant for persistent seizure activity. A single loading dose of phenobarbital 15 to 20 mg/kg was initially administered to 120 newborns. Nonresponders received sequential bolus doses of 5 to 10 mg/kg until seizures ceased or a serum concentration of 40 micrograms/mL was obtained. Infants with refractory seizures received additional phenobarbital to a maximum serum concentration of 100 micrograms/mL. The seizures of 48 babies (40%) were controlled after initial loading and 37 of the remaining 72 subjects (51%) responded at serum concentrations of as great as 40 micrograms/mL. The seizures of only seven subjects were controlled at greater concentrations. A second anticonvulsant controlled seizures in 13 of the 28 subjects (46%) whose seizures were refractory to phenobarbital. A gestational age of less than 32 weeks was associated with a significantly better response to phenobarbital. Serum phenobarbital concentrations greater than 50 micrograms/mL produced only occasional feeding difficulty and sedation. It was concluded that sequentially administered IV phenobarbital controls seizures in both term and preterm newborns (77%). This therapeutic effect is dose dependent but plateaus at a serum concentration of 40 micrograms/mL. At greater serum concentrations, unresponsive patients should receive a second antiepileptic agent.

A multicenter evaluation of gentamicin therapy in the neonatal intensive care unit.

STUDY OBJECTIVE: To evaluate traditional nomogram (TN) versus individualized pharmacokinetic gentamicin dosing practices in neonatal intensive care units, focusing on achieving target therapeutic concentrations (peak > 8 microg/ml, trough < 2 microg/ml), number of dosing changes, number of concentrations obtained, and evidence of nephrotoxicity. DESIGN: Retrospective chart review. SETTING: Three neonatal intensive care units. PATIENTS: Three hundred nine infants prescribed gentamicin. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Sixty-seven percent of patients receiving pharmacokinetic dosing had initial peak concentrations of 8 microg/ml or greater compared with 7% of patients receiving TN dosing (p<0.001). Trough concentrations exceeding 2 microg/ml were reported in 23% of patients receiving TN dosing compared with 2% of pharmacokinetic-dosed patients (p<0.001). Forty-two percent and 6%, respectively, required dosage adjustments (p<0.01). The mean number of concentrations obtained per patient was 2.8 and 2.1, respectively (p<0.01). Neither group had evidence of gentamicin-related nephrotoxicity. CONCLUSION: Compared with TN dosing, administering gentamicin loading doses and performing initial pharmacokinetic analysis resulted in rapid attainment of desired concentrations and fewer dosage adjustments, and allowed for a decrease in the number of gentamicin concentrations.

Indomethacin for patent ductus arteriosus closure. Application of serum concentrations and pharmacodynamics to improve response.

Indomethacin dosing for patent ductus arteriosus closure has been standardized despite wide interpatient variability in indomethacin pharmacokinetics. We compared a novel indomethacin dosing approach using individual pharmacokinetic and pharmacodynamic information (group A) with a control group from our institution (group B) and a level 3 university-based intensive care nursery (group C) who were dosed using current dosing guidelines. Permanent patent ductus arteriosus closure was achieved in 27 of 28 (96.4%) group A patients, 10 of 16 (62.5%) group B patients, and 7 of 13 (52.8%) group C patients. Success rates were significantly higher in group A than Groups B and C (P less than .02). Renal toxicity was the only toxicity reported in any group. The major manifestations of renal toxicity, ie, urine output below 1 mL/kg/h or increased serum creatinine by greater than or equal to 0.5 mg/dL, occurred in none of the group A patients but in seven (43.8%) group B and eight (61.5%) group C patients. Renal toxicity was significantly greater in groups B and C than group A (P less than .02). A pharmacodynamic concentration versus response curve was developed and proved predictive of patent ductus arteriosus closure rates in previous studies where indomethacin concentration versus response data were available. Serum concentration monitoring is a valuable adjunct to indomethacin therapy for patent ductus arteriosus closure, especially when a pharmacodynamic approach is used.

Neonatal thrombosis: treatment with heparin and thrombolytics.

Thrombotic events are a serious and potentially fatal complication during the neonatal period. Despite clinically serious thromboses in up to one percent of neonates and less severe complications (e.g., catheter malfunction secondary to clots) in a much higher percentage, well-designed studies on prevention and treatment of thromboses are lacking. Treatment approaches are largely anecdotal and involve the use of heparin and, occasionally, thrombolytics. Proper monitoring of anticoagulant and thrombolytic effects is difficult because of the limited blood volumes available from neonates and the relatively large sample volumes needed for most coagulation studies. Activated clotting times (ACTs) are preferred because they use low blood volume and are a rapid bedside test. Heparin should be administered with an initial loading dose of 50-100 units/kg followed by a continuous infusion of 20 units/kg/h. Further doses should then be adjusted based on the ACT, targeting a value of 1.5-2.5 times the control. Thrombolytics also have been used in several case reports and are guided by both clinical response and serial D-dimer values. We prefer urokinase 100 units/kg/h for local infusion to the thrombus and urokinase 1000-10,000 units/kg/h for systemic therapy.

Histiocytosis X: abnormal cerebrospinal fluid cytology in extrahypothalamic central nervous system involvement.

The clinical course and long-term survival of a patient with acute disseminated histiocytosis X and extrahypothalamic CNS involement were presented. The clinical significance of histiocytes appearing in the CSF cocomitant with the onset of this neurologic syndrome was discussed. Detailed cytologic examination of the CSF in patients with histiocytosis X and CNS involvement was recommended.

Use of enoxaparin in a preterm infant.

OBJECTIVE: To describe the use of enoxaparin to treat suspected thrombosis in a preterm neonate. CASE DESCRIPTION: A 29-week-gestation white infant with a family history of protein S deficiency lost color and blood flow to the right hand several hours after removal of the umbilical artery catheter. Although normal color returned to all except the distal first, second, and third fingers after warming, Doppler flow showed a radial artery defect, indicating a lack of blood flow. Enoxaparin 1 mg/kg intravenously every eight hours was then started. Heparin concentrations measured via anti-Xa assay drawn four and eight hours after a dose were 0.78 and 0.39 units/mL, respectively. Pharmacokinetic parameters calculated from these concentrations using a one-compartment model were elimination half-life four hours, volume of distribution 0.13 L/kg, and clearance 0.022 L/kg/h. No adverse effects were noted. Blood flow eventually returned, leaving only the third fingertip chronically injured. DISCUSSION: Differences between the neonatal and adult hemostatic systems contribute to an increased risk of thromboembolic events and an altered sensitivity to heparin anticoagulation in the neonate. Although heparin is currently the anticoagulant of choice, it may produce several adverse effects, such as hemorrhage and thrombocytopenia, which may be avoided by use of low-molecular-weight heparins (LMWHs). However, despite the efficacy and improved safety profile of LMWHs in adults, data regarding their use in children and neonates are scarce. This case demonstrates that enoxaparin can be used safely and effectively in a preterm infant through appropriate monitoring of heparin concentrations to adjust dosages. A larger volume of distribution of enoxaparin was noted in this neonate than in adults. CONCLUSIONS: Enoxaparin 1 mg/kg intravenously every eight hours was used safely in this preterm infant with suspected thrombosis, suggesting that more than one dosing regimen may be appropriate in this population.

The role of inhaled steroids in the treatment of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia has been well described in premature infants requiring mechanical ventilation. Systemic steroids are one of many treatment modalities used in the management of these infants, but these agents have been associated with a number of adverse effects. Aerosolized therapy has been proposed as an alternative in order to minimize the systemic complications that occur with the parenteral route. The initial reports of inhaled steroids, although limited, have shown promising results with minimal side effects. This article addresses the mechanism of action, the role in therapy, and potential complications associated with the use of inhaled steroids in the treatment of bronchopulmonary dysplasia.

Gentamicin in neonates: the need for loading doses.

One hundred eighty-four neonates had gentamicin serum concentrations measured twice after an initial loading dose of 5 mg/kg infused over 1 hour. Gentamicin concentrations immediately postinfusion were calculated using a one-compartment pharmacokinetic model. The extrapolated peak gentamicin concentrations achieved with the 5 mg/kg loading dose was optimal (between 5 and 12 micrograms/ml) in 94% of cases. Had an initial dose of 2.5 mg/kg been given as suggested in most references, peak concentrations 5 mg/kg or higher would only have been achieved in 5% of neonates less than 28 weeks' gestation, 10% of neonates 28 to 30 weeks' gestation, 11% of neonates 31 to 34 weeks' gestation, and 36% of neonates more than 34 weeks' gestation. Our data support the need for greater loading doses of gentamicin in newborns. Our recommendation of 5 mg/kg achieves gentamicin concentrations known to be safe and effective.

The effect of total parenteral nutrition-induced cholestasis on theophylline clearance in neonates.

The effect of total parenteral nutrition (TPN) induced cholestasis on theophylline clearance was examined in premature neonates. Thirty-six neonates receiving TPN and theophylline concurrently were reviewed. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose, followed by a maintenance dose of 2.5-5 mg/kg every 12 h. Of the 36 neonates reviewed, 18 developed cholestasis (direct bilirubin greater than or equal to 1 mg/100 ml and direct bilirubin greater than or equal to 60% of total bilirubin). The remaining 18 did not develop cholestasis. The two groups were closely matched for gestational age, 5-min apgar score, and sex. The neonates with cholestasis had a mean maximum direct bilirubin of 5.19 mg/100 ml (range 1-13.8 mg/100 ml) as compared to the patients without cholestasis who had a mean maximum direct bilirubin of 0.54 mg/100 ml (range 0.3-0.8 mg/100 ml). Steady-state theophylline clearance was determined at least once a week for at least 4 separate weeks. The study lasted a minimum of 8 weeks, and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated a significant increase in mean theophylline clearance over time (from 16.09 and 18.60 ml/h/kg to 28.65 and 24.73 ml/h/kg for the cholestatic and noncholestatic groups, respectively). The mean slope, an indicator of the average rate of change of theophylline clearance, was 1.4 for the noncholestatic group and 2.5 for the cholestatic group, indicating that the theophylline clearance for neonates with cholestasis was not significantly different from that for neonates with normal liver function (p = 0.61) over time.

Comparing the delivery of albuterol metered-dose inhaler via an adapter and spacer device in an in vitro infant ventilator lung model.

OBJECTIVE: To compare the delivery of an albuterol metered-dose inhaler (MDI) (Ventolin) via an Aerochamber (Monaghan) with an inline adapter (Medicomp Straight Swivel) in an in vitro infant lung model. METHODS: An in vitro infant lung model was modified to compare the delivery of albuterol MDI 10 inhalations via an Aerochamber with an inline adapter. The adapter and Aerochamber were placed at the endotracheal tube. A 1000 mL intravenous bag filled with 500 mL deionized water was attached to a 3.5 mm endotracheal tube (10 cm length). An Infant Bear Cub ventilator was used at the following settings: positive inspiratory pressure 20 cm H2O, intermittent mandatory ventilation 40 breaths/min, positive end expiratory pressure 4 cm H2O, and inspiratory time 0.5 second. Each device was run at least 10 times and assayed in duplicate by HPLC. An unpaired Student's t-test was used to analyze the statistical significance of the data. RESULTS: There was significantly greater delivery of albuterol with the Aerochamber (19.49 +/- 7.23 microg; 2.17% +/- 0.8%) as compared with an inline adapter (1.0625 +/- 1.36 microg; 0.12% +/- 0.15%) (p = 0.001). CONCLUSIONS: The Aerochamber provides a greater delivery of albuterol metered-dose inhalations to the lung than the inline adapter in an in vitro infant lung model.

Effect of phenobarbital administration on theophylline clearance in premature neonates.

The effect of phenobarbital administration on theophylline clearance was studied in 24 premature neonates. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose followed by a maintenance dose of 2.5-5 mg/kg/12 h. Of the 24 neonates studied, 12 received a mean phenobarbital dose of 26.34 mg/kg/d (ranging from 2 mg every 24 h to 25 mg every 12 h) and the mean phenobarbital concentration was 56.12 micrograms/ml (range 22-112 micrograms/ml). The remaining 12 patients did not require phenobarbital therapy but did receive aminophylline alone. The two groups were closely matched for gestational age, 5-min Apgar scores, and sex (p greater than 0.2). Steady-state theophylline clearance was determined at least once a week for four or more separate weeks. The study lasted a minimum of 8 wk and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated an increase in mean theophylline clearance over time (from 15.75 and 16.67 ml/h/kg to 30.33 and 35.42 ml/h/kg for the aminophylline and aminophylline plus phenobarbital groups, respectively). The mean slope, an indicator of the average change in theophylline clearance, was 2.19 for the aminophylline group and 3.27 for the aminophylline plus phenobarbital group (p greater than 0.2), indicating that the theophylline clearance for neonates receiving phenobarbital was not significantly different from that for neonates receiving aminophylline alone. Based on this information, aminophylline does not need to be adjusted solely based on concomitant phenobarbital administration; however, theophylline concentrations should be monitored since theophylline clearance can change rapidly and unpredictably in neonates.

Indomethacin pharmacokinetics in neonates: the value of volume of distribution as a marker of permanent patent ductus arteriosus closure.

Indomethacin (INDO) pharmacokinetics were examined in 18 neonates on 19 occasions, before and after patent ductus arteriosus (PDA) closure. Patients received INDO as an initial dose of 0.25 mg/kg intravenously, and INDO serum concentrations were measured 2 and 8 h after the dose. Subsequent doses were individualized based on clinical response, toxicity, and INDO pharmacokinetics. PDA status was confirmed echocardiographically at the start and end of therapy. INDO pharmacokinetic parameters varied from dose-to-dose within the same patient, and wide interpatient variability was also observed. Pre- and post-PDA closure, only INDO volume of distribution differed significantly (p less than 0.001) with mean values of 0.36 (+/- 0.06) L/kg and 0.26 (+/- 0.08) L/kg. The reason for this occurrence remains unclear. However, a new application for pharmacokinetics as a probe of physiology is demonstrated.

Gentamicin pharmacokinetics in neonates with patent ductus arteriosus.

OBJECTIVES: To determine the effect of patent ductus arteriosus on the pharmacokinetics of gentamicin in neonates and to examine whether any particular pharmacokinetic parameter is of value as a marker of patent ductus arteriosus. DESIGN: Cohort study of neonates treated with gentamicin, according to a standard dosing protocol. SETTING: A 24-bed, Level III, neonatal intensive care unit. PATIENTS: Neonates treated with gentamicin at the time of admission to the neonatal intensive care unit, using a standard protocol, and who were < 36 wks of gestational age. INTERVENTIONS: All patients received a gentamicin loading dose, and had gentamicin concentrations measured at 2 and 12 hrs after this dose, in order to determine pharmacokinetic parameters and calculate the optimum maintenance dose. Those neonates subsequently diagnosed to have patent ductus arteriosus, based on clinical suspicion and echocardiographic confirmation, were compared with those neonates without clinically suspected patent ductus arteriosus. Gentamicin pharmacokinetic parameters were calculated using a one-compartment model. MEASUREMENTS AND MAIN RESULTS: A total of 322 courses of gentamicin were administered (patent ductus arteriosus, n = 106; control, n = 216). Gentamicin clearance was decreased in the patent ductus arteriosus group vs. the control group (40.02 vs. 44.73 mL/kg/hr; p < .0108). Volume of distribution was greater for patent ductus arteriosus patients (0.61 L/kg) than for controls (0.54 L/kg) (p < .0002). Also, volume of distribution was a useful marker for presence of patent ductus arteriosus, with a 92% specificity for patent ductus arteriosus. CONCLUSIONS: Gentamicin dosing should be altered in neonates with patent ductus arteriosus to reflect the impact of higher volume of distribution and lower clearance. When the gentamicin volume of distribution exceeds 0.7 L/kg, it may be of predictive value for the presence of patent ductus arteriosus.

Retroperitoneal rhabdomyosarcoma in children. Results of multimodality therapy.

The clinical course of 18 consecutive children treated for primary retroperitoneal rhabdomyosarcoma was reviewed. At diagnosis, 8 patients had regional unresected tumor and 10 patients had disseminated tumor, including 3 patients with documented bone marrow infiltration by tumor. Following combined modality therapy, 14 of 18 patients achieved a greater than 50% tumor response (11 complete and 3 partial responses); 4 patients failed to respond and died of progressive disease within eight months of diagnosis. Among the 14 patients responding, 7 patients had subsequent reextension of active tumor three to 16 months (median, 9 months) following the onset of therapy. Three of the 7 remaining patients died of treatment complications, 2 of intestinal obstruction and 1 of disseminated histoplasmosis, within the first year of therapy and at post-mortem examination had no demonstrable tumor. Four patients are alive and free of active tumor for 10+, 10+, 32+ and 33+ months from diagnosis. Treatment complications have included hematopoietic depression, mucositis, enteritis, intestinal obstruction, excessive weight loss, malnutrition, and life-threatening infection. These results illustrate limitations in current combined modality therapy of retroperitoneal rhabdomyosarcoma and the necessity for future treatment modifications to both reduce morbidity and to improve survival.

Hyperpipecolic acidemia associated with hepatomegaly, mental retardation, optic nerve dysplasia and progressive neurological disease.

A male infant with hyperpipecolic acidemia is described. To our knowledge this is only the second report of this disorder. As with the previous case, our patient's course was characterized by persistent hepatomegaly, severe mental retardation, progressive loss of developmental milestones and diminished visual acuity associated with nystagmus, abnormal discs and retinal changes. Death occurred at 2 years of age, following a progressive loss of neurological function. Pipecolic acid was repeatedly present in the serum at a concentrattion of 4-5 mg %. Trace amounts of this compound were also detected in the urine. In addition, an adaption of the method of Piez et al. (1956) for the direct quantitation of pipecolic acid in serum was evaluated and found to be very useful for the biochemical diagnosis of this disorder.