Comparison of Amikacin Pharmacokinetics in Neonates With and Without Congenital Heart Disease.

OBJECTIVES: The primary objective was to compare the volume of distribution (Vd), clearance (CL), elimination rate (Ke), and half-life (t½) of amikacin in neonates with cyanotic defects, acyanotic defects, and controls, adjusted for gestational and postnatal age. Secondary objectives were to compare the incidence of acute kidney injury (AKI) between controls and the congenital heart disease (CHD) group and to identify potential risk factors. METHODS: This retrospective cohort study included neonates receiving amikacin from January 1, 2013 to August 31, 2016. Patients were excluded if concentrations were not appropriately obtained or if AKI or renal anomalies were identified prior to amikacin initiation. Congenital heart disease was classified as acyanotic or cyanotic. Patients with CHD were matched 1:1 with non-CHD controls according to postmenstrual age. Bivariate analyses were performed using Wilcoxon-Mann-Whitney test, Pearson χ2 tests, or Fisher exact as appropriate with a p value <0.05. Regression analyses included logistic and analysis of covariance. RESULTS: Fifty-four patients with CHD were matched with 54 controls. Median (IQR) postnatal age (days) at amikacin initiation significantly differed between CHD and controls, 3.0 (1.0-16.0) versus 1.0 (1.0-3.0), p = 0.016. After adjusting for gestational and postnatal age, there was no difference in the mean (95% CI) Vd (L/kg) and CL (L/kg/hr) between CHD and controls, 0.47 (0.44-0.50) versus 0.46 (0.43-0.49), p = 0.548 and 0.05 (0.05-0.05) versus 0.05 (0.05-0.05), p = 0.481, respectively. There was no difference in Ke or t½ between groups. There was no difference in AKI between the CHD and controls, 18.5% versus 9.3%, p = 0.16. CONCLUSIONS: Clinicians should consider using standard amikacin dosing for neonates with CHD and monitor renal function, since they may have greater AKI risk factors.

Early inhaled nitric oxide therapy in premature newborns with respiratory failure.

BACKGROUND: The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain. METHODS: We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly. RESULTS: Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events. CONCLUSIONS: Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401 [ClinicalTrials.gov].).

Comparison of Amikacin Pharmacokinetics in Neonates Following Implementation of a New Dosage Protocol.

OBJECTIVES: The primary aim was to compare attainment of goal serum amikacin concentrations using two dosage regimens in patients admitted to a neonatal intensive care unit. Secondary objectives included comparison of percentages of supratherapeutic trough concentrations, and subtherapeutic and supratherapeutic peak concentrations. METHODS: This was an Institutional Review Board-approved, retrospective study of neonates receiving amikacin during January-December 2013 (group 1) and January-December 2014 (group 2). Group 1 received amikacin dosage consistent with published recommendations, whereas group 2 was dosed using a modified protocol that was based on postmenstrual and postnatal age. Goal serum amikacin peak concentration was defined as 20 to 35 mg/L; hence, subtherapeutic and supratherapeutic peak concentrations were defined as <20 mg/L and >35 mg/L, respectively. Supratherapeutic trough concentrations were >8 mg/L. Between-group analysis was performed using Wilcoxon-Mann-Whitney test, Student t-test or χ2, or Fisher exact analysis as appropriate with a p value <0.05. RESULTS: A total of 278 neonates were included (group 1: n = 144; group 2: n = 134). Most patients were male (60%) and were admitted for prematurity or respiratory distress (77%). The median gestational age in group 1 was 34.4 weeks (range, 30.0-37.9 weeks) versus group 2 at 36.9 weeks (range, 31.4-38.9 weeks), whereas the postnatal age was similar between both groups at 4 days. There was a significant increase in attaining goal peak amikacin concentrations between groups 1 and 2, 34% versus 84%, p < 0.001, and decrease in supratherapeutic peak concentrations, 65% versus 12%, p < 0.001. There was no significant difference in subtherapeutic peak or supratherapeutic trough concentrations. CONCLUSIONS: A modified neonatal amikacin dosage protocol resulted in increased peak amikacin serum concentration compared with published dosage recommendations. Future research should focus on determination of the optimal dosage regimen in neonates.

Effect of decreasing target oxygen saturation on retinopathy of prematurity.

INTRODUCTION: The authors of previous studies suggest that the oxygenation status of premature infants contributes to the development of retinopathy of prematurity (ROP). In this study we compared the incidence and severity of ROP before and after institution of a new neonatal intensive care unit oxygen protocol. METHODS: A retrospective chart review was performed of all eligible inborn patients screened for ROP during the 2 years immediately before (Group 1) to and the 2 years after (Group 2) the initiation of a new oxygen protocol. In the new protocol, target oxygen saturation was adjusted from 90%-99% to 85%-93%. Treatment criteria adhered to Early Treatment for Retinopathy of Prematurity guidelines for the study's duration. RESULTS: There were 387 infants in Group 1 and 386 infants in Group 2 (descriptive statistics adjusted for correlation due to multiple births). Mean birth weights (BWs) and gestational ages were 1,194 g and 29.2 weeks (ranges, 525-2,085 g; 23 2/7-39 6/7 weeks) for Group 1 and 1,139 g and 28.9 weeks (ranges, 520-2,500 g; 22 6/7-35 3/7 weeks) for Group 2 (p = 0.02/0.10). ROP developed in 32.7% of infants in Group 1 and 27.8% in Group 2 (p = 0.17). The incidence of ROP requiring treatment was 19.9% in Group 1 and 20.5% in Group 2 (p = 0.91). Subanalysis of infants with BW ≤ 1,000g (Group 1, n = 119; Group 2, n = 141) revealed ROP incidence of 75.1% versus 57.1%, respectively (p < 0.01); treatable disease occurred in 37.5% and 21.9% of affected infants (p = 0.19). CONCLUSIONS: Lowering target oxygen saturation for inborn premature infants was associated with decreased incidence of ROP only in infants with BW ≤ 1,000 g. Severity of disease, including need for treatment, was similar in both groups.

Clinical considerations for the pharmacologic management of patent ductus arteriosus with cyclooxygenase inhibitors in premature infants.

When medical management is warranted for closure of a persistent patent ductus arteriosus (PDA) in premature infants, treatment with a cyclooxygenase (COX) inhibitor is indicated. Indomethacin, available since 1976, has been the conventional pharmacologic treatment for PDA, but its use is associated with vasoconstrictive effects that impair renal, mesenteric and cerebral blood flow. Intravenous (IV) ibuprofen lysine, approved in the United States in 2006, has less severe vasoconstrictive effects on these vital organs than IV indomethacin. Clinical trials have shown both of these COX inhibitors to be equally effective in closing the PDA in approximately 70%-80% of treated infants, with less vasoconstrictive and adverse renal effects occurring with IV ibuprofen lysine.1,2 Several clinical considerations are important in the process of medical decision-making when faced with the need for PDA treatment with one of these pharmacologic agents in the premature infant. This paper focuses on these clinical considerations, including cerebral, renal and mesenteric blood flow, renal function, pulmonary effects, protein-binding capacity as it relates to hyperbilirubinemia, and platelet aggregation. No differences in chronic lung disease, pulmonary hypertension, hyperbilirubinemia and coagulopathy were observed in clinical trials when comparing these 2 COX inhibitors; however, significant differences have been observed in arterial blood flow to the cerebral, renal and mesenteric organs, suggesting that IV ibuprofen lysine may be the more favorable agent.