Population pharmacokinetics and pharmacodynamics of dobutamine in neonates on the first days of life.

AIMS: To describe the pharmacokinetics (PK) and concentration-related effects of dobutamine in critically ill neonates in the first days of life, using nonlinear mixed effects modelling. METHODS: Dosing, plasma concentration and haemodynamic monitoring data from a dose-escalation study were analysed with a simultaneous population PK and pharmacodynamic model. Neonates receiving continuous infusion of dobutamine 5-20 µg kg-1 min-1 were included. Left ventricular ejection fraction (LVEF) and cardiac output of right and left ventricle (RVO, LVO) were measured on echocardiography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxygen saturation and cerebral regional oxygen saturation were recorded from patient monitors. RESULTS: Twenty-eight neonates with median (range) gestational age of 30.4 (22.7-41.0) weeks and birth weight (BW) of 1618 (465-4380) g were included. PK data were adequately described by 1-compartmental linear structural model. Dobutamine clearance (CL) was described by allometric scaling on BW with sigmoidal maturation function of postmenstrual age (PMA). The final population PK model parameter mean typical value (standard error) estimates, standardised to median BW of 1618 g, were 41.2 (44.5) L h-1 for CL and 5.29 (0.821) L for volume of distribution, which shared a common between subject variability of 29% (17.2%). The relationship between dobutamine concentration and RVO/LVEF was described by linear model, between concentration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by sigmoidal Emax model. CONCLUSION: In the postnatal transitional period, PK of dobutamine was described by a 1-compartmental linear model, CL related to BW and PMA. A concentration-response relationship with haemodynamic variables has been established.

Population Pharmacokinetics and Dosing of Milrinone After Patent Ductus Arteriosus Ligation in Preterm Infants.

OBJECTIVES: The postoperative course of patent ductus arteriosus ligation is often complicated by postligation cardiac syndrome, occurring in 10-45% of operated infants. Milrinone might prevent profound hemodynamic instability and improve the recovery of cardiac function in this setting. The present study aimed to describe the population pharmacokinetics of milrinone in premature neonates at risk of postligation cardiac syndrome and give dosing recommendations. DESIGN: A prospective single group open-label pharmacokinetics study. SETTINGS: Two tertiary care neonatal ICUs: Tallinn Children's Hospital and Tartu University Hospital, Estonia. PATIENTS: Ten neonates with postmenstrual age of 24.6-30.1 weeks and postnatal age of 5-27 days undergoing patent ductus arteriosus ligation and at risk of postligation cardiac syndrome, based on echocardiographic assessment of left ventricular output of less than 200 mL/kg/min 1 hour after the surgery. INTERVENTIONS: Milrinone at a dose of 0.73 µg/kg/min for 3 hours followed by 0.16 µg/kg/min for 21 hours. Four blood samples from each patient for milrinone plasma concentration measurements were collected. MEASUREMENTS AND MAIN RESULTS: Concentration-time data of milrinone were analyzed with nonlinear mixed-effects modeling software (NONMEM Version 7.3 [ICON Development Solutions, Ellicott City, MD]). Probability of target attainment simulations gave a dosing schedule that maximally attains concentration targets of 150-250 µg/L. Milrinone pharmacokinetics was described by a one-compartmental linear model with allometric scaling to bodyweight and an age maturation function of glomerular filtration rate. Parameter estimates for a patient with the median weight were 0.350 (L/hr) for clearance and 0.329 (L) for volume of distribution. The best probability of target attainment was achieved with a loading dose of 0.50 µg/kg/min for 3 hours followed by 0.15 µg/kg/min (postmenstrual age < 27 wk) or 0.20 µg/kg/min (postmenstrual age ≥ 27 wk). CONCLUSIONS: Population pharmacokinetic modeling and simulations suggest a slow loading dose followed by maintenance infusion to reach therapeutic milrinone plasma concentrations within the timeframe of the postligation cardiac syndrome.

Low Serum IGF-1 in Boys with Recent Onset of Juvenile Idiopathic Arthritis.

BACKGROUND: Liver-derived insulin-like growth factor-1 (IGF-1) contributes bone formation. Decreased IGF-1 levels are common in juvenile idiopathic arthritis (JIA), but whether IGF-1 is related to sex and differ during the pathogenic progress of JIA is unknown. OBJECTIVE: The aim of this study was to examine IGF-1 levels in boys and girls with newly diagnosed JIA, with established JIA and in controls. METHODS: The study group included 131 patients from the Estonian population-based prevalence JIA study. Blood samples were obtained from 27 boys and 38 girls with early JIA (≤1 month from the diagnosis), 29 boys and 36 girls with established JIA (mean disease duration 18 months), and from 47 age- and sex-matched controls. RESULTS: IGF-1 levels in boys were significantly decreased in early JIA compared to male controls, while IGF-1 levels in girls were comparable between JIA and controls. In early JIA, IGF-1 levels were 12-fold lower in boys relative to girls. In controls, IGF-1 levels correlated with both age and height, while these correlations were lost in boys with early JIA. CONCLUSION: We report a sex-dependent deficiency in serum IGF-1 in boys with early JIA, which argues for sex-related differences in biological mechanisms involved in the disease pathogenesis.

High mobility group box protein 1-A prognostic marker for structural joint damage in 10-year follow-up of patients with juvenile idiopathic arthritis.

OBJECTIVE: High mobility group box protein 1 (HMGB1) is an important pro-inflammatory mediator in adult rheumatoid arthritis. The diagnostic utility of HMGB1 in Juvenile Idiopathic Arthritis (JIA) is still unclear. The aim was to examine whether serum HMGB1 levels are associated with inflammation, radiological disease progression, and long-term prognosis in JIA. METHODS: We included 131 children with JIA from a population-based prevalence study; 38 of them were prospectively followed up for 10 years. Clinical and laboratory disease characteristics at study entry and after 10 years as well as radiological progression over 10 years were recorded. HMGB1 levels were analyzed by an ELISA. RESULTS: The HMGB1 levels were similar in children with different JIA subgroups and in children with established (53%) or newly diagnosed (47%) disease. HMGB1 levels did not differ between groups at entry into the study or at 10 years, by sex, or by the presence or absence of RF or ANA antibodies. HMGB1 levels at the study entry correlated with HMGB1 levels at 10 years and with blood neutrophil count. Most importantly, children with destructive arthritis at 10 years had a tendency toward higher HMGB1 levels at study entry (median 1.2 vs 0.6ng/ml, ns) and displayed 4-fold higher circulating HMGB1 levels (median 3.4 vs 0.8ng/ml, p = 0.0014) than children without radiological destructions. CONCLUSIONS: Our results suggest that HMGB1 is a marker of inflammatory activity in children with JIA. Higher serum HMGB1 levels are related to more destructive JIA and could be used as a negative prognostic marker at the disease start. TRIAL REGISTRATION: Clinicaltrials.gov NCT01905319. Registered July 16, 2013.