Population pharmacokinetics of vancomycin in neonates.

OBJECTIVE: To determine population pharmacokinetic parameters of vancomycin in neonates. METHODS: This was a retrospective design, with prospective validation. Two hundred ten sequential neonates were evaluated at the neonatal intensive care units of Minneapolis Children's Medical Center and Children's Hospital of St. Paul. Five hundred twenty serum concentrations from 192 patients were included. A mean +/- SD gestational age of 29.5 +/- 5.1 weeks, postnatal age of 16.5 +/- 19.6 days, and dosing weight of 1492 +/- 1053 gm described the population. Thirty additional patients were studied for validation. Dosing, serum concentrations, and 28 covariates were collected. Data were evaluated with NONMEM. Forward selection and backward elimination regression identified significant covariates. One- and two-compartment population pharmacokinetic parameters and predictive performance of the models were measured. RESULTS: Two-compartment final regression equations were as follows: Clearance (CL) = 0.0590 L/kg/hr (multiplied by 0.460 if exposed to dopamine and 0.643 if gestational age was < or = 32 weeks), central volume (VC) = 0.440 L/kg, intercompartmental clearance (Q) = 0.0313 L/hr/kg, and steady-state volume of distribution (Vss) = 0.764 L/kg. Interindividual variability was 40.6% for CL, 54.1% for Vss, and 16.8% for VC. Residual variability was 3.3 micrograms/ml. One-compartment final regression equations were: CL = 0.0626 L/kg/hr (multiplied by 0.455 if exposed to dopamine and 0.656 if gestational age was < or = 32 weeks), and Vd = 0.496 L/kg. Differences in relative performance were insignificant by use of one- or two-compartment parameters. CONCLUSIONS: Gestational age < or = 32 weeks and concurrent use of dopamine were significant factors in prediction of vancomycin clearance. alpha Half-lives of 2.8 to 3.7 hours and beta half-lives of 13.4 to 33.7 hours suggest that some individuals in this neonatal population have considerably longer half-lives than those previously reported.

Pharmacokinetics of fluconazole in immune-compromised children with leukemia or other hematologic diseases.

STUDY OBJECTIVE: To describe the pharmacokinetics of fluconazole in immune-compromised children with leukemia or other hematologic disease. DESIGN: Prospective. SETTING: Children's Health Care-Minneapolis hematology/oncology inpatient ward and outpatient clinic. PATIENTS: Ten immune-compromised children (mean +/- SD age 7.4 +/- 4.0 yrs, weight 31.6 +/- 25.9 kg) with leukemia or other hematologic disease. INTERVENTIONS: Serum was sampled before and after a single 6-mg/kg intravenous dose and after seven oral 3-mg/kg doses of fluconazole. MEASUREMENTS AND MAIN RESULTS: Mean (SD) pharmacokinetics were distribution half-life 1.67 (1.25) hours, elimination half-life 15.62 (3.21) hours, total body clearance 0.63 (0.19) ml/min/kg, volume of distribution for the central compartment 0.56 (0.10) L/kg, volume of distribution at steady state 0.77 (0.12) L/kg, absorption half-life 0.41 (0.26) hour, and oral bioavailability 0.92 (0.09). Volume of distribution for the central compartment was highly correlated with body surface area (r2 = 0.891) and weight (r2 = 0.949). Volume of distribution at steady state correlated with body surface area (r2 = 0.986), and total body clearance correlated with body surface area (r2 = 0.867). CONCLUSIONS: Fluconazole elimination was well described using a two-compartment model. Oral absorption was rapid and nearly complete. Children have a larger volume of distribution for the central compartment and faster elimination rate than adults. Body surface area and weight are important factors in determining pharmacokinetics in these patients.

Predictive performance of three methods of activated clotting time measurement in neonatal ECMO patients.

Previously reported activated clotting time (ACT) data in adults demonstrated higher values with the HemoTec LRACT (HT) and TriMed ACTivator (TM) techniques than with the Hemochron System P214/215 (HC) technique throughout a range of heparin concentrations. This study sought to determine if a difference exists in ACT values of neonatal patients receiving ECMO. ACTs were performed in nine neonatal ECMO patients using the HC, HT, and TM techniques. Techniques were compared for positive or negative direction of any prediction difference (bias), and the typical value of a difference (precision). Simultaneous, duplicate, morning, and afternoon ACT comparisons were obtained using all three techniques. Forty-six comparisons of HC values in the 180-240 sec range were analyzed. All techniques produced results different from the same sample. The HT and TM techniques were upwardly biased by 51 and 148 sec, respectively, when evaluated against HC. HT was negatively biased by 123 sec when evaluated against TM. Because ACT values vary among techniques, ACT target ranges should be technique specific. Future references to ACT data should identify the equipment and procedures employed.

Prospective, randomized, double-blind, placebo-controlled comparison of metoclopramide and ondansetron for prevention of posttonsillectomy or adenotonsillectomy emesis.

STUDY OBJECTIVE: To compare the antimetic efficacy of prophylactic ondansetron, metoclopramide, and placebo for prevention of postoperative vomiting in pediatric tonsillectomy or adenotonsillectomy patients. DESIGN: Prospective, randomized, double-blind, placebo controlled study. SETTING: Children's hospital. PATIENTS: 132 ASA status I and II children, ages 2 to 12 years, undergoing tonsillectomy or adenotonsillectomy. INTERVENTIONS: Patients received intravenous (IV) melodopramide 0.25 mg/kg, IV on dansetron 0.15 mg/kg, or IV saline placebo after induction of standardized halothane, nitrous oxide, and oxygen anesthesia. Muscle relaxants and their antagonists were allowed. Patients received postoperative analgesics as needed. MEASUREMENTS AND MAIN RESULTS: Incidence of postoperative vomiting, time of vomitting onset, and hospital length of stay (LOS) were measured. Patients who were admitted were excluded from LOS analysis. The postoperative incidence of vomiting was 54% for patients receiving metoclopramide, 26% for patients receiving ondansetron, and 69% for the placebo group. These differences were significant for ondansetron versus metoclopramide (p = 0.008) and placebo (p = 0.001). The mean (SD) LOS was significantly shorter for patients not vomiting 488 (88) minutes for vomiters versus 435 (65) minutes for non-vomiters. CONCLUSIONS: Prophylactic ondansetron is more effective than metoclopramide or placebo for the prevention of vomiting after tonsillectomy or adenotonsillectomy. Patients who do not vomit postoperatively have shorter LOS.

The effect of heparin on three whole blood activated clotting tests and thrombin time.

Whole blood activated clotting time (ACT) can be determined by many different methods that use a variety of clotting cascade activators and end-points. This study compared the results of three whole blood ACT instruments at equivalent concentrations of heparin. Whole blood (9.8 ml) from 10 healthy adult volunteers without coagulation abnormalities was added to 0.2 ml of heparin solution producing heparin concentrations of 0, 0.1, 0.2, 0.4, 0.6, 0.8, and 1.0 U/ml. Coagulation status was determined in duplicate with the Hemochron 400 System (HC), the HemoTec Automated Coagulation Timer (HT), and the TriMed ACTivator (TM). Thrombin times or dilutions (TT) were also determined for each sample. Baseline values did not differ (p greater than 0.05); however, the HT and TM ACT values were significantly longer (p less than 0.05) than the HC ACT values at predicted heparin concentrations greater than 0.2 U/ml. Results from the HT and TM instruments were not significantly different. The HT and TM instruments both provided a greater ACT range over the heparin concentrations tested. Of the tests studied to monitor heparin therapy, mean scaled TTs showed the best correlation with predicted heparin concentrations.