Milrinone in congenital diaphragmatic hernia - a randomized pilot trial: study protocol, review of literature and survey of current practices
Satyan Lakshminrusimha, Martin Keszler, Haresh Kirpalani, Krisa Van Meurs, Patricia Chess, Namasivayam Ambalavanan, Bradley Yoder, Maria V Fraga, Holly Hedrick, Kevin P Lally, Leif Nelin, Michael Cotten, Jonathan Klein, Stephanie Guilford, Ashley Williams, Aasma Chaudhary, Marie Gantz, Jenna Gabrio, Dhuly Chowdhury, Kristin Zaterka-Baxter, Abhik Das, Rosemary D Higgins, Satyan Lakshminrusimha, Martin Keszler, Haresh Kirpalani, Krisa Van Meurs, Patricia Chess, Namasivayam Ambalavanan, Bradley Yoder, Maria V Fraga, Holly Hedrick, Kevin P Lally, Leif Nelin, Michael Cotten, Jonathan Klein, Stephanie Guilford, Ashley Williams, Aasma Chaudhary, Marie Gantz, Jenna Gabrio, Dhuly Chowdhury, Kristin Zaterka-Baxter, Abhik Das, Rosemary D Higgins
Abstract
Background: Congenital diaphragmatic hernia (CDH) is commonly associated with pulmonary hypoplasia and pulmonary hypertension (PH). PH associated with CDH (CDH-PH) is frequently resistant to conventional pulmonary vasodilator therapy including inhaled nitric oxide (iNO) possibly due to right and left ventricular dysfunction. Milrinone is an intravenous inotrope and lusitrope with pulmonary vasodilator properties and has been shown anecdotally to improve oxygenation in PH. We developed this pilot study to determine if milrinone infusion would improve oxygenation in neonates ≥36 weeks postmenstrual age (PMA) with CDH.
Methods/design: Data on pulmonary vasodilator management and outcome of CDH patients was collected from 18 university NICUs affiliated with the Neonatal Research Network (NRN) from 2011 to 2012. The proposed pilot will be a masked, placebo-controlled, multicenter, randomized trial of 66 infants with CDH with an oxygenation index (OI) ≥10 or oxygen saturation index (OSI) ≥5. The primary outcome is the oxygenation response, as determined by change in OI at 24 h after initiation of study drug. As secondary outcomes, we will determine oxygenation at 48 h and 72 h post-infusion, right ventricular pressures on echocardiogram and the incidence of systemic hypotension, arrhythmias, intracranial hemorrhage, survival without extracorporeal membrane oxygenation, and chronic lung disease (oxygen need at 28 days postnatal age). Finally, we will evaluate the pulmonary and nutritional status at 4, 8 and 12 months of age using a phone questionnaire.
Results: Three hundred thirty-seven infants with CDH were admitted to NRN NICUs in 2011 and 2012 of which 275 were ≥36 weeks PMA and were exposed to the following pulmonary vasodilators: iNO (39%), sildenafil (17%), milrinone (17%), inhaled epoprostenol (6%), intravenous epoprostenol (3%), and intravenous PGE1 (1%). ECMO was required in 36% of patients. Survival to discharge was 71%.
Discussion: CDH is an orphan disease with high mortality with few randomized trials evaluating postnatal management. Intravenous milrinone is a commonly used medication in neonatal/pediatric intensive care units and is currently used in 17% of patients with CDH within the NRN. This pilot study will provide data and enable further studies evaluating pulmonary vasodilator therapy in CDH.
Trial registration: ClinicalTrials.gov; NCT02951130; registered 14 October 2016.
Keywords: Extracorporeal membrane oxygenation; Oxygen; Persistent pulmonary hypertension; Phosphodiesterase; Pulmonary hypertension.
Conflict of interest statement
Ethics approval and consent to participateNo ethics approval or consent to participate was necessary for this manuscript.
Consent for publicationNot applicable.
Competing interestsThe authors declare that they have no competing interests.
Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
- Yoder BA, Lally PA, Lally KP. Does a highest pre-ductal O(2) saturation <85% predict non-survival for congenital diaphragmatic hernia? J Perinatol. 2012;32(12):947–952. doi: 10.1038/jp.2012.18.
- Schaible T, Kohl T, Reinshagen K, Brade J, Neff KW, Stressig R, Busing KA. Right- versus left-sided congenital diaphragmatic hernia: postnatal outcome at a specialized tertiary care center. Pediatr Crit Care Med. 2012;13(1):66–71. doi: 10.1097/PCC.0b013e3182192aa9.
- Keller RL. Management of the infant with congenital diaphragmatic hernia. In: Bancalari E, Polin RA, editors. The newborn lung. 2. Philadelphia: Elsevier Saunders; 2012. pp. 381–406.
- Aggarwal S, Stockman PT, Klein MD, Natarajan G. The right ventricular systolic to diastolic duration ratio: a simple prognostic marker in congenital diaphragmatic hernia? Acta Paediatr. 2011;100(10):1315–1318. doi: 10.1111/j.1651-2227.2011.02302.x.
- Irish MS, Karamanoukian HL, O'Toole SJ, Glick PL. You gotta have heart. J Pediatr. 1996;129(1):175–176. doi: 10.1016/S0022-3476(96)70218-4.
- Menon SC, Tani LY, Weng HY, Lally PA, Lally KP, Yoder BA. Congenital diaphragmatic hernia study group: clinical characteristics and outcomes of patients with cardiac defects and congenital diaphragmatic hernia. J Pediatr. 2013;162(1):114-19.
- Schwartz SM, Vermilion RP, Hirschl RB. Evaluation of left ventricular mass in children with left-sided congenital diaphragmatic hernia. J Pediatr. 1994;125(3):447–451. doi: 10.1016/S0022-3476(05)83293-7.
- NINOS Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group.[erratum appears in N Engl J Med 1997 Aug 7;337(6):434] N Engl J Med. 1997;336(9):597–604. doi: 10.1056/NEJM199702273360901.
- Snoek KG, Capolupo I, van Rosmalen J, Hout Lde J, Vijfhuize S, Greenough A, Wijnen RM, Tibboel D, Reiss IK, Consortium CE. Conventional mechanical ventilation versus high-frequency oscillatory ventilation for congenital diaphragmatic hernia: a randomized clinical trial (the VICI-trial) Ann Surg. 2016;263(5):867–874. doi: 10.1097/SLA.0000000000001533.
- van den Hout L, Tibboel D, Vijfhuize S, te Beest H, Hop W, Reiss I, Consortium C-E. The VICI-trial: high frequency oscillation versus conventional mechanical ventilation in newborns with congenital diaphragmatic hernia: an international multicentre randomized controlled trial. BMC Pediatr. 2011;11:98. doi: 10.1186/1471-2431-11-98.
- Paden ML, Conrad SA, Rycus PT, Thiagarajan RR, Registry E. Extracorporeal life support organization registry report 2012. ASAIO J. 2013;59(3):202–210. doi: 10.1097/MAT.0b013e3182904a52.
- Peetsold MG, Heij HA, Kneepkens CM, Nagelkerke AF, Huisman J, Gemke RJ. The long-term follow-up of patients with a congenital diaphragmatic hernia: a broad spectrum of morbidity. Pediatr Surg Int. 2009;25(1):1–17. doi: 10.1007/s00383-008-2257-y.
- Muratore CS, Kharasch V, Lund DP, Sheils C, Friedman S, Brown C, Utter S, Jaksic T, Wilson JM. Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic. J Pediatr Surg. 2001;36(1):133–140. doi: 10.1053/jpsu.2001.20031.
- Hollinger LE, Harting MT, Lally KP. Long-term follow-up of congenital diaphragmatic hernia. Semin Pediatr Surg. 2017;26(3):178–184. doi: 10.1053/j.sempedsurg.2017.04.007.
- Opie LH. Inodilators. Lancet. 1986;1(8493):1336.
- Lakshminrusimha S, Steinhorn RH. Inodilators in nitric oxide resistant persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med. 2013;14(1):107–109. doi: 10.1097/PCC.0b013e318250af44.
- Murray F, MacLean MR, Pyne NJ. Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. Br J Pharmacol. 2002;137(8):1187–1194. doi: 10.1038/sj.bjp.0704984.
- Chen B, Lakshminrusimha S, Czech L, Groh BS, Gugino SF, Russell JA, Farrow KN, Steinhorn RH. Regulation of phosphodiesterase 3 in the pulmonary arteries during the perinatal period in sheep. Pediatr Res. 2009;66(6):682–687. doi: 10.1203/PDR.0b013e3181bce574.
- Thelitz S, Oishi P, Sanchez LS, Bekker JM, Ovadia B, Johengen MJ, Black SM, Fineman JR. Phosphodiesterase-3 inhibition prevents the increase in pulmonary vascular resistance following inhaled nitric oxide withdrawal in lambs. Pediatr Crit Care Med. 2004;5(3):234–239. doi: 10.1097/01.PCC.0000124021.25393.2D.
- Lakshminrusimha S, Porta NF, Farrow KN, Chen B, Gugino SF, Kumar VH, Russell JA, Steinhorn RH. Milrinone enhances relaxation to prostacyclin and iloprost in pulmonary arteries isolated from lambs with persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med. 2009;10(1):106–112. doi: 10.1097/PCC.0b013e3181936aee.
- Bailey JM, Miller BE, Lu W, Tosone SR, Kanter KR, Tam VK. The pharmacokinetics of milrinone in pediatric patients after cardiac surgery. Anesthesiology. 1999;90(4):1012–1018. doi: 10.1097/00000542-199904000-00014.
- 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. doi: 10.1097/00003246-199511000-00018.
- Hoffman TM, Wernovsky G, Atz AM, Bailey JM, Akbary A, Kocsis JF, Nelson DP, Chang AC, Kulik TJ, Spray TL, et al. Prophylactic intravenous use of milrinone after cardiac operation in pediatrics (PRIMACORP) study. Prophylactic intravenous use of Milrinone after cardiac operation in pediatrics. Am Heart J. 2002;143(1):15–21. doi: 10.1067/mhj.2002.120305.
- Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC, Bailey JM, Akbary A, Kocsis JF, Kaczmarek R, 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(7):996–1002. doi: 10.1161/01.CIR.0000051365.81920.28.
- 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(2):217–222. doi: 10.1016/j.jcrc.2006.01.001.
- Bassler D, Kreutzer K, McNamara P, Kirpalani H. Milrinone for persistent pulmonary hypertension of the newborn. The Cochrane database of systematic reviews. 2010;10(11):CD007802.
- Bassler D, Choong K, McNamara P, Kirpalani H. Neonatal persistent pulmonary hypertension treated with milrinone: four case reports. Biol Neonate. 2006;89(1):1–5. doi: 10.1159/000088192.
- 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. 2012;
- James AT, Corcoran JD, McNamara PJ, Franklin O, El-Khuffash AF. The effect of milrinone on right and left ventricular function when used as a rescue therapy for term infants with pulmonary hypertension. Cardiol Young. 2016;26(1):90–99. doi: 10.1017/S1047951114002698.
- Paradisis M, Evans N, Kluckow M, Osborn D. Randomized trial of milrinone versus placebo for prevention of low systemic blood flow in very preterm infants. J Pediatr. 2009;154(2):189–195. doi: 10.1016/j.jpeds.2008.07.059.
- Paradisis M, Evans N, Kluckow M, Osborn D, McLachlan AJ. Pilot study of milrinone for low systemic blood flow in very preterm infants. J Pediatr. 2006;148(3):306–313. doi: 10.1016/j.jpeds.2005.11.030.
- 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(3):F204–F209. doi: 10.1136/adc.2005.092817.
- Patel N. 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(2):130–136. doi: 10.1159/000339108.
- Moenkemeyer F, Patel N. Right ventricular diastolic function measured by tissue Doppler imaging predicts early outcome in congenital diaphragmatic hernia. Pediatr Crit Care Med. 2014;15(1):49–55. doi: 10.1097/PCC.0b013e31829b1e7a.
- Siebert JR, Haas JE, Beckwith JB. Left ventricular hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg. 1984;19(5):567–571. doi: 10.1016/S0022-3468(84)80105-0.
- Patel N, Kipfmueller F. Cardiac dysfunction in congenital diaphragmatic hernia: pathophysiology, clinical assessment, and management. Semin Pediatr Surg. 2017;26(3):154–158. doi: 10.1053/j.sempedsurg.2017.04.001.
- Lakshminrusimha S. The pulmonary circulation in neonatal respiratory failure. Clin Perinatol. 2012;39(3):655–683. doi: 10.1016/j.clp.2012.06.006.
- Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, Malcangi V, Petrini F, Volta G, Bobbio Pallavicini FM, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009;301(23):2445–2452. doi: 10.1001/jama.2009.856.
- NINOS Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The neonatal inhaled nitric oxide study group. N Engl J Med. 1997;336(9):597–604. doi: 10.1056/NEJM199702273360901.
- The Neonatal Inhaled Nitric Oxide Study Group N inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The neonatal inhaled nitric oxide study group (NINOS) Pediatrics. 1997;99(6):838–845. doi: 10.1542/peds.99.6.838.
- Park HW, Lee BS, Lim G, Choi YS, Kim EA, Kim KS. A simplified formula using early blood gas analysis can predict survival outcomes and the requirements for extracorporeal membrane oxygenation in congenital diaphragmatic hernia. J Korean Med Sci. 2013;28(6):924–928. doi: 10.3346/jkms.2013.28.6.924.
- Reiss I, Schaible T, van den Hout L, Capolupo I, Allegaert K, van Heijst A, Gorett Silva M, Greenough A, Tibboel D, Consortium CE. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO consortium consensus. Neonatology. 2010;98(4):354–364. doi: 10.1159/000320622.
- Lakshminrusimha S, Mathew B, Leach CL. Pharmacologic strategies in neonatal pulmonary hypertension other than nitric oxide. Semin Perinatol. 2016;40(3):160–173. doi: 10.1053/j.semperi.2015.12.004.
- Young RA, Ward A. Milrinone. A preliminary review of its pharmacological properties and therapeutic use. Drugs. 1988;36(2):158–192. doi: 10.2165/00003495-198836020-00003.
- Bailey JM, Hoffman TM, Wessel DL, Nelson DP, Atz AM, Chang AC, Kulik TJ, Spray TL, Akbary A, Miller RP, et al. A population pharmacokinetic analysis of milrinone in pediatric patients after cardiac surgery. J Pharmacokinet Pharmacodyn. 2004;31(1):43–59. doi: 10.1023/B:JOPA.0000029488.45177.48.
- McNamara PJ, Shivananda SP, Sahni M, Freeman D, Taddio A. Pharmacology of milrinine in neonates with persistent pulmonary hypertension of the newborn (PPHN) and suboptimal response to inhaled nitric oxide. Pediatr Crit Care Med. 2012;
- Giaccone A, Zuppa AF, Sood B, Cohen MS, O'Byrne ML, Moorthy G, Mathur A, Kirpalani H. Milrinone pharmacokinetics and pharmacodynamics in neonates with persistent pulmonary hypertension of the newborn. Am J Perinatol. 2017;
- Chandrasekharan PK, Rawat M, Madappa R, Rothstein DH, Lakshminrusimha S. Congenital diaphragmatic hernia - a review. Maternal health, neonatology and perinatology. 2017;3:6. doi: 10.1186/s40748-017-0045-1.
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