Subscribe to RSS
Milrinone Pharmacokinetics and Pharmacodynamics in Neonates with Persistent Pulmonary Hypertension of the Newborn
09 July 2016
09 December 2016
18 January 2017 (online)
Objective To describe the pharmacokinetics and pharmacodynamics of milrinone in infants with persistent pulmonary hypertension of the newborn (PPHN) and to explore the impact of age on milrinone disposition.
Design Randomized, open label pilot study.
Setting Multicenter; level 3 and level 4 neonatal intensive care units.
Patients Six infants ≥34 weeks' gestational age and <10 days of life with persistent hypoxemia receiving inhaled nitric oxide.
Intervention Intravenous milrinone lactate in one of two dosing regimens: (1) low dose, 20 mcg/kg bolus followed by 0.2 mcg/kg/minute, and (2) standard dose, 50 mcg/kg bolus followed by 0.5 mcg/kg/minute.
Measurements and Main Results The final structural model was a two-compartment disposition model with interindividual variability estimated on clearance (CL). The estimated value of CL is 7.65 mL/minute/3.4 kg (3.05 mL/minute/kg). The addition of age improved the precision of the CL estimate, and CL increased with chronological age in days. The oxygenation index was highly variable within each participant and improved with time. There were no observed safety concerns in either dosing group.
Conclusion The CL of milrinone in newborns with PPHN is reduced and increases with age. In this pilot study, we did not see significant pharmacodynamic or safety effects associated with drug exposure.
- 1 Walsh-Sukys MC, Tyson JE, Wright LL. , et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000; 105 (1 Pt 1): 14-20
- 2 Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997; 336 (09) 597-604
- 3 Clark RH, Kueser TJ, Walker MW. , et al; Clinical Inhaled Nitric Oxide Research Group. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med 2000; 342 (07) 469-474
- 4 Konduri GG, Vohr B, Robertson C. , et al. Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: neurodevelopmental follow-up. J Pediatr 2007; 150: 235-240
- 5 Hintz SR, Van Meurs KP, Perritt R. , et al. Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. J Pediatr 2007; 151: 16-22
- 6 Hoffman TM, Wernovsky G, Atz AM. , et al. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation 2003; 107 (07) 996-1002
- 7 Deb B, Bradford K, Pearl RG. Additive effects of inhaled nitric oxide and intravenous milrinone in experimental pulmonary hypertension. Crit Care Med 2000; 28 (03) 795-799
- 8 Chen EP, Craig DM, Bittner HB, Davis RD, Van Trigt P. Pharmacological strategies for improving diastolic dysfunction in the setting of chronic pulmonary hypertension. Circulation 1998; 97 (16) 1606-1612
- 9 Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics 2006; 117 (06) 1979-1987
- 10 Giaccone A, Kirpalani H. Judgment often impossible without randomized trials. Commentary on N. Patel: use of milrinone to treat cardiac dysfunction in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia: a review of six patients. Neonatology 2012; 102 (02) 137-138
- 11 Bassler D, Choong K, McNamara P, Kirpalani H. Neonatal persistent pulmonary hypertension treated with milrinone: four case reports. Biol Neonate 2006; 89 (01) 1-5
- 12 McNamara PJ, Laique F, Muang-In S, Whyte HE. Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. J Crit Care 2006; 21 (02) 217-222
- 13 Danhaive O, Margossian R, Geva T, Kourembanas S. Pulmonary hypertension and right ventricular dysfunction in growth-restricted, extremely low birth weight neonates. J Perinatol 2005; 25 (07) 495-499
- 14 McNamara PJ, Shivananda SP, Sahni M, Freeman D, Taddio A. Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxide. Pediatr Crit Care Med 2013; 14 (01) 74-84
- 15 Paradisis M, Jiang X, McLachlan AJ, Evans N, Kluckow M, Osborn D. Population pharmacokinetics and dosing regimen design of milrinone in preterm infants. Arch Dis Child Fetal Neonatal Ed 2007; 92 (03) F204-F209
- 16 Bailey JM, Hoffman TM, Wessel DL. , et al. A population pharmacokinetic analysis of milrinone in pediatric patients after cardiac surgery. J Pharmacokinet Pharmacodyn 2004; 31 (01) 43-59
- 17 Zuppa AF, Nicolson SC, Adamson PC. , et al. Population pharmacokinetics of milrinone in neonates with hypoplastic left heart syndrome undergoing stage I reconstruction. Anesth Analg 2006; 102 (04) 1062-1069
- 18 West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science 1999; 284 (5420): 1677-1679
- 19 Roberson DA, Cui W. ; DA. Right ventricular Tei index in children: effect of method, age, body surface area, and heart rate. J Am Soc Echocardiogr 2007; 20 (06) 764-770
- 20 Tei C, Ling LH, Hodge DO. , et al. New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function--a study in normals and dilated cardiomyopathy. J Cardiol 1995; 26 (06) 357-366
- 21 Tei C, Nishimura RA, Seward JB, Tajik AJ. Noninvasive Doppler-derived myocardial performance index: correlation with simultaneous measurements of cardiac catheterization measurements. J Am Soc Echocardiogr 1997; 10 (02) 169-178
- 22 Dyer KL, Pauliks LB, Das B. , et al. Use of myocardial performance index in pediatric patients with idiopathic pulmonary arterial hypertension. J Am Soc Echocardiogr 2006; 19 (01) 21-27
- 23 Barton P, Garcia J, Kouatli A. , et al. Hemodynamic effects of i.v. milrinone lactate in pediatric patients with septic shock. A prospective, double-blinded, randomized, placebo-controlled, interventional study. Chest 1996; 109 (05) 1302-1312
- 24 Chang AC, Atz AM, Wernovsky G, Burke RP, Wessel DL. Milrinone: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery. Crit Care Med 1995; 23 (11) 1907-1914
- 25 Ramamoorthy C, Anderson GD, Williams GD, Lynn AM. Pharmacokinetics and side effects of milrinone in infants and children after open heart surgery. Anesth Analg 1998; 86 (02) 283-289