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Biomedical subjects

R L Weaver

Publications and source records attributed to R L Weaver.

17 recordsLinked to original sources
PubMed1991

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.

Birth Weight↗
PubMed1991

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.

Biomarkers↗
PubMed1990

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.

Dose-Response Relationship, Drug↗
PubMed1990

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.

Critical Care↗
PubMed1990

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.

Algorithms↗
PubMed1989

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.

Dose-Response Relationship, Drug↗
PubMed1988

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.

Bilirubin↗
PubMed1985

In vitro precipitation of calcium phosphate under intracellular conditions: formation of brushite from an amorphous precursor in the absence of ATP.

Release of mitochondrial calcium has been shown to occur concomitant with mineral ion loading of matrix vesicles at the onset of mineralization in epiphyseal growth plate cartilage. Matrix vesicles contain amorphous calcium phosphate (ACP), a mineral form that usually results from rapid precipitation at high initial levels of Ca2+ and/or inorganic P (Pi). Since the cytosol of growth plate chondrocytes has been found to contain high levels of Pi, rapid release of mitochondrial Ca2+ into the cytosol may cause local precipitation of calcium phosphate and thus be coupled with matrix vesicle formation. Studies were carried out to determine the kinetics and nature of mineral formation that occur when small amounts of Ca2+ are added under various conditions to a Pi buffer composed of electrolytes matched in concentrations and pH to that of the cytosol of epiphyseal chondrocytes. Depending on the manner in which Ca2+ was added, ACP, dicalcium phosphate dihydrate (DCPD), or apatite (HA) first formed. In the presence of ATP, ACP was the only solid phase detected, being stable for at least 24 h. However, in its absence, ACP rapidly transformed into DCPD. Increasing the pH of the reaction buffer from 6.9 to 7.5 increased the amount of ACP initially formed, but DCPD was consistently found upon ACP transformation. Yet at pH 8.0, ACP persisted for at least 24 h. The amount of precipitate formed was proportional to the level of added Ca2+; precipitates formed when as little as 1.0 mmole was added per liter of buffer. Our findings support the possibility that rapid release of mitochondrial Ca2+ may cause localized intracellular precipitation of ACP. Since nascent ACP is known to stimulate membrane fusion and blebbing of vesicles, these findings may explain the presence of ACP in matrix vesicles. The rapid conversion of ACP to DCPD in the absence of ATP under these conditions may also explain the reported occurrence of DCPD in samples of early mineralizing tissue.

Adenosine Triphosphate↗
PubMed1983

Gonococcal ventriculitis associated with ventriculoamniotic shunt placement.

Use of a ventriculoamniotic shunt to control fetal hydrocephalus is a new procedure. Early experience suggests possible benefit to the fetus. Complications have been rare. This report describes the first case of Neisseria gonorrhoeae central nervous system infection associated with a ventriculoamniotic shunt and the third case reported in a neonate. On the basis of this clinical experience, we recommend that the mother be monitored closely for cervical pathogens, that delivery be performed prior to amniorrhexis, and that culturing of the shunt and ventricular fluid be carried out at delivery.

Adult↗
PubMed1980

Intrapericardial teratoma in infancy.

Intrapericardial teratoma in the newborn is a rare potentially fatal neoplasm. Pre-operative diagnosis depends upon recognition of specific radiographic and echocardiographic findings in a newborn with a larg cardiothymic image and pericardial effusion. Surgical intervention is usually curative whereas undiagnosed intrapericardial teratoma is often fatal.

Angiocardiography↗
PubMed1979

Infant heart rate response to trigeminal airstream stimulation: determination of normal and deviant values.

In this study, trigeminal airstream stimulation is used on a group of normal, sleeping infants to screen for reflex bradycardia. Infants were tested at 1--3 days and at 4, 8, 12, and 16 weeks of age. The usual heart rate response was acceleration above the prestimulus level. The amount of heart rate change was seen to depend on prestimulus rate and, to a lesser extent, postconceptional age. Multiple regression analysis of the data provided estimates of expected responses, given postconceptional age and prestimulus heart rate. From these, ranges were established for classification of normal or abnormal responses. Six deviant data points over 2 SDs from expected values were identified. Two of these represented heart rate increases and four were heart rate decreases. One deviant heart rate decrease was over 3 SDs from the mean. Although the deviant increases were thought to represent exaggerated startles, the more severe heart rate decreases were believed to be a reflex resembling the diving reflex.

Heart Rate↗