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Reassessing the role of milrinone in the treatment of heart failure and pulmonary hypertension in neonates and children: a systematic review and meta-analysis

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A CORRESPONDENCE to this article was published on 26 December 2023

Abstract

To evaluate milrinone’s impact on pediatric cardiac function, focusing on its specific role as an inotrope and lusitrope, while considering its systemic and pulmonary vasodilatory effects. Search of PubMed, EMBASE, and the Cochrane Library up to August 2023. We included all studies that evaluated milrinone in children under 18 years old in neonatal, pediatric, or cardiac intensive care units. We excluded case reports, studies that did not provide tabular information on milrinone’s outcomes, and studies focused on non-intensive care populations. We extracted data on the research design, objectives, study sample, and results of each study, including the impact of milrinone and any associated factors. We screened a total of 9423 abstracts and 41 studies were ultimately included. Milrinone significantly improved left ventricular ejection fraction (WMD 3.41 [95% CI 0.61 – 6.21]), left ventricle shortening fraction (WMD 4.25 [95% CI 3.43 – 5.08]), cardiac index (WMD 0.50 [95% CI 0.32 to 0.68]), left ventricle output (WMD 55.81 [95% CI 4.91 to 106.72]), serum lactate (WMD -0.59 [95% CI -1.15 to -0.02]), and stroke volume index (WMD 2.95 [95% CI 0.09 – 5.82]). However, milrinone was not associated with improvements in ventricular myocardial performance index (WMD -0.01 [95% CI -0.06 to 0.04]) and ventricular longitudinal strain (WMD -2.14 [95% CI -4.56 to 0.28]). Furthermore, milrinone was not associated with isovolumetric relaxation time reduction (WMD -8.87 [95% CI -21.40 to 3.66]).

Conclusion: Our meta-analysis suggests potential clinical benefits of milrinone by improving cardiac function, likely driven by its systemic vasodilatory effects. However, questions arise about its inotropic influence and the presence of a lusitropic effect. Moreover, milrinone’s pulmonary vasodilatory effect appears relatively weaker compared to its systemic actions. Further research is needed to elucidate milrinone’s precise mechanisms and refine its clinical applications in pediatric practice.

What is Known:

• Milrinone is a phosphodiesterase III inhibitor that has been used to treat a variety of pediatric and neonatal conditions.

• Milrinone is believed to exert its therapeutic effects by enhancing cardiac contractility and promoting vascular relaxation.

What is New:

• Milrinone may not have a significant inotropic effect.

• Milrinone's pulmonary vasodilatory effect is less robust than its systemic vasodilatory effect.

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Data availability

The datasets and analysis are available from the corresponding author on reasonable request.

References

  1. Meyer S, Gortner L, Brown K, Abdul-Khaliq H (2011) The role of milrinone in children with cardiovascular compromise: review of the literature. Wien Med Wochenschr 161(7–8):184–191. https://doi.org/10.1007/s10354-011-0869-7

    Article  PubMed  Google Scholar 

  2. Shipley JB, Tolman D, Hastillo A, Hess ML (1996) Milrinone: basic and clinical pharmacology and acute and chronic management. Am J Med Sci 311(6):286–291. https://doi.org/10.1016/S0002-9629(15)41723-9

    Article  CAS  PubMed  Google Scholar 

  3. Rahiman S, Kowalski R, Kwok SY et al (2020) Milrinone acts as a vasodilator but not an inotrope in children after cardiac surgery-insights from wave intensity analysis. Crit Care Med 48(11):e1071–e1078. https://doi.org/10.1097/CCM.0000000000004622

    Article  PubMed  Google Scholar 

  4. Chen EP, Craig DM, Bittner HB, Davis RD, Van Trigt P (1998) Pharmacological strategies for improving diastolic dysfunction in the setting of chronic pulmonary hypertension. Circulation 97(16):1606–1612. https://doi.org/10.1161/01.cir.97.16.1606

    Article  CAS  PubMed  Google Scholar 

  5. Shamseer L, Moher D, Clarke M et al (2015) Preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: Elaboration and explanation. BMJ 349(7647):1–25. https://doi.org/10.1136/bmj.g7647

    Article  Google Scholar 

  6. Higgins J, Thomas J, Chandler J et al (2021) Cochrane handbook for systematic reviews of interventions. version 6. Cochrane

  7. McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C (2016) PRESS peer review of electronic search strategies: 2015 guideline statement. J Clin Epidemiol 75(7):40–46. https://doi.org/10.1016/j.jclinepi.2016.01.021

    Article  PubMed  Google Scholar 

  8. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A (2016) Rayyan-a web and mobile app for systematic reviews. Syst Rev 5(1):1–10. https://doi.org/10.1186/s13643-016-0384-4

    Article  Google Scholar 

  9. Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14(1):1–13. https://doi.org/10.1186/1471-2288-14-135

    Article  Google Scholar 

  10. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188. https://doi.org/10.1016/0197-2456(86)90046-2

    Article  CAS  PubMed  Google Scholar 

  11. Barnwal NK, Umbarkar SR, Sarkar MS, Dias RJ (2017) Randomized comparative study of intravenous infusion of three different fixed doses of milrinone in pediatric patients with pulmonary hypertension undergoing open heart surgery. Ann Card Anaesth 20(3):318–322. https://doi.org/10.4103/aca.ACA_231_16

    Article  PubMed  PubMed Central  Google Scholar 

  12. Imam SS, El-Farrash RA, Taha AS, Saleh GA (2022) Milrinone versus sildenafil in treatment of neonatal persistent pulmonary hypertension: a randomized control trial. J Cardiovasc Pharmacol 80(5):746–752. https://doi.org/10.1097/FJC.0000000000001332

    Article  CAS  PubMed  Google Scholar 

  13. El-Ghandour M, Hammad B, Ghanem M, Antonios MAM (2020) Efficacy of milrinone plus sildenafil in the treatment of neonates with persistent pulmonary hypertension in resource-limited settings: results of a randomized. Double-Blind Trial Pediatr Drugs 22(6):685–693. https://doi.org/10.1007/s40272-020-00412-4

    Article  Google Scholar 

  14. Cavigelli-Brunner A, Hug MI, Dave H et al (2018) Prevention of low cardiac output syndrome after pediatric cardiac surgery: a double-blind randomized clinical pilot study comparing dobutamine and milrinone. Pediatr Crit Care Med 19(7):619–625. https://doi.org/10.1097/PCC.0000000000001533

    Article  PubMed  Google Scholar 

  15. Nag P, Chowdhury SR, Behera SK, Das M, Narayan P (2023) Levosimendan or milrinone for ventricular septal defect repair with pulmonary arterial hypertension. J Cardiothorac Vasc Anesth 37(6):972–979. https://doi.org/10.1053/j.jvca.2023.01.032

    Article  CAS  PubMed  Google Scholar 

  16. Khazin V, Kaufman Y, Zabeeda D et al (2004) Milrinone and nitric oxide: combined effect on pulmonary artery pressures after cardiopulmonary bypass in children. J Cardiothorac Vasc Anesth 18(2):156–159. https://doi.org/10.1053/j.jvca.2004.01.020

    Article  CAS  PubMed  Google Scholar 

  17. Korkmaz L, Ozdemir A, Pamukçu O, Güneś T, Ozturk MA (2022) Which inotropic drug, dobutamine or milrinone, is clinically more effective in the treatment of postligation cardiac syndrome in preterm infants? Am J Perinatol 39(2):204–215. https://doi.org/10.1055/s-0040-1715118

    Article  PubMed  Google Scholar 

  18. Chi C-Y, Khanh TH, Thoa LPK et al (2013) Milrinone therapy for enterovirus 71-induced pulmonary edema and/or neurogenic shock in children: a randomized controlled trial. Crit Care Med 41(7):1754–1760. https://doi.org/10.1097/CCM.0b013e31828a2a85

    Article  CAS  PubMed  Google Scholar 

  19. Mears M, Yang M, Yoder BA (2020) Is milrinone effective for infants with mild-to-moderate congenital diaphragmatic Hernia? Am J Perinatol 37(3):258–263. https://doi.org/10.1055/s-0039-1678558

    Article  PubMed  Google Scholar 

  20. Halliday M, Kavarana M, Ebeling M, Kiger J (2017) Milrinone use for hemodynamic instability in patent ductus arteriosus ligation. J Matern Neonatal Med 30(5):529–533. https://doi.org/10.1080/14767058.2016.1177720

    Article  CAS  Google Scholar 

  21. McNamara PJ, Shivananda SP, Sahni M, Freeman D, Taddio A (2013) Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxide. Pediatr Crit Care Med 14(1):74–84. https://doi.org/10.1097/PCC.0b013e31824ea2cd

    Article  PubMed  Google Scholar 

  22. Lee J, Kim GB, Kwon HW et al (2014) Safety and efficacy of the off-label use of milrinone in pediatric patients with heart diseases. Korean Circ J 44(5):320–327. https://doi.org/10.4070/kcj.2014.44.5.320

    Article  PubMed  PubMed Central  Google Scholar 

  23. Beshish AG, Aljiffry A, Aronoff E et al (2022) Milrinone for treatment of elevated lactate in the pre-operative newborn with hypoplastic left heart syndrome. Cardiol Young. https://doi.org/10.1017/S1047951122003171

    Article  PubMed  Google Scholar 

  24. Hoffman TM, Wernovsky G, Atz AM et al (2003) Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation 107(7):996–1002

    Article  CAS  PubMed  Google Scholar 

  25. Lechner E, Hofer A, Leitner-Peneder G et al (2012) Levosimendan versus milrinone in neonates and infants after corrective open-heart surgery: a pilot study. Pediatr Crit Care Med 13(5):542–548. https://doi.org/10.1097/PCC.0b013e3182455571

    Article  PubMed  Google Scholar 

  26. James AT, Corcoran JD, McNamara PJ, Franklin O, El-Khuffash AF (2016) The effect of milrinone on right and left ventricular function when used as a rescue therapy for term infants with pulmonary hypertension. Cardiol Young 26(1):90–99

    Article  PubMed  Google Scholar 

  27. Thorlacius EM, Wåhlander H, Ojala T et al (2020) Levosimendan versus milrinone for inotropic support in pediatric cardiac surgery: results from a randomized trial. J Cardiothorac Vasc Anesth 34(8):2072–2080. https://doi.org/10.1053/j.jvca.2020.02.027

    Article  CAS  PubMed  Google Scholar 

  28. Li W, Peng Y, Li Z, Huang J (2023) Ventriculo-arterial coupling for predicting cardiac index increase in infants after heart surgery. Interdiscip Cardiovasc Thorac Surg. https://doi.org/10.1093/icvts/ivad064

    Article  PubMed  PubMed Central  Google Scholar 

  29. Costello JM, Dunbar-Masterson C, Allan CK et al (2014) Impact of empiric nesiritide or milrinone infusion on early postoperative recovery after Fontan surgery: a randomized, double-blind, placebo-controlled trial. Circ Heart Fail 7(4):596–604. https://doi.org/10.1161/CIRCHEARTFAILURE.113.001312

    Article  CAS  PubMed  Google Scholar 

  30. Bianchi MO, Cheung P-Y, Phillipos E, Aranha-Netto A, Joynt C (2015) The effect of milrinone on splanchnic and cerebral perfusion in infants with congenital heart disease prior to surgery: an observational study. Shock 44(2):115–120. https://doi.org/10.1097/SHK.0000000000000388

    Article  CAS  PubMed  Google Scholar 

  31. James AT, Bee C, Corcoran JD, McNamara PJ, Franklin O, El-Khuffash AF (2015) Treatment of premature infants with pulmonary hypertension and right ventricular dysfunction with milrinone: a case series. J Perinatol 35(4):268–273. https://doi.org/10.1038/jp.2014.208

    Article  CAS  PubMed  Google Scholar 

  32. Jothinath K, Balakrishnan S, Raju V, Menon S, Osborn J (2021) Clinical efficacy of levosimendan vs milrinone in preventing low cardiac output syndrome following pediatric cardiac surgery. Ann Card Anaesth 24(2):217–223. https://doi.org/10.4103/aca.ACA_160_19

    Article  PubMed  PubMed Central  Google Scholar 

  33. Chang AC, Atz AM, Wernovsky G, Burke RP, Wessel DL (1995) Milrinone: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery. Crit Care Med 23(11):1907–1914. https://doi.org/10.1097/00003246-199511000-00018

    Article  CAS  PubMed  Google Scholar 

  34. Paradisis M, Evans N, Kluckow M, Osborn D, McLachlan AJ (2006) Pilot study of milrinone for low systemic blood flow in very preterm infants. J Pediatr 148(3):306–313. https://doi.org/10.1016/j.jpeds.2005.11.030

    Article  CAS  PubMed  Google Scholar 

  35. El-Khuffash AF, Jain A, Weisz D, Mertens L, McNamara PJ (2014) Assessment and treatment of post patent ductus arteriosus ligation syndrome. J Pediatr 165(1):46-52.e1. https://doi.org/10.1016/j.jpeds.2014.03.048

    Article  CAS  PubMed  Google Scholar 

  36. Momeni M, Rubay J, Matta A et al (2011) Levosimendan in congenital cardiac surgery: a randomized, double-blind clinical trial. J Cardiothorac Vasc Anesth 25(3):419–424. https://doi.org/10.1053/j.jvca.2010.07.004

    Article  CAS  PubMed  Google Scholar 

  37. Cai J, Su Z, Shi Z et al (2008) Nitric oxide and milrinone: combined effect on pulmonary circulation after Fontan-type procedure: a prospective, randomized study. Ann Thorac Surg 86(3):882–888. https://doi.org/10.1016/j.athoracsur.2008.05.014

    Article  PubMed  Google Scholar 

  38. Duggal B, Pratap U, Slavik Z, Kaplanova J, Macrae D (2005) Milrinone and low cardiac output following cardiac surgery in infants: is there a direct myocardial effect? Pediatr Cardiol 26(5):642–645. https://doi.org/10.1007/s00246-005-0881-z

    Article  CAS  PubMed  Google Scholar 

  39. Barton P, Garcia J, Kouatli A et al (1996) Hemodynamic effects of i.v. milrinone lactate in pediatric patients with septic shock. A prospective, double-blinded, randomized, placebo-controlled, interventional study. Chest 109(5):1302–1312. https://doi.org/10.1378/chest.109.5.1302

    Article  CAS  PubMed  Google Scholar 

  40. Patel N (2012) Effects of milrinone on ventricular function and pulmonary artery pressure and infants with congenital diaphragmatic hernia. J Paediatr Child Heal 48:128

    Google Scholar 

  41. Thorlacius EM, Suominen PK, Wåhlander H et al (2019) The effect of levosimendan versus milrinone on the occurrence rate of acute kidney injury following congenital heart surgery in infants: a randomized clinical trial. Pediatr Crit Care Med 20(10):947–956. https://doi.org/10.1097/PCC.0000000000002017

    Article  PubMed  Google Scholar 

  42. Pellicer A, Riera J, Lopez-Ortego P et al (2013) Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery. Pediatr Res 73(1):95–103. https://doi.org/10.1038/pr.2012.154

    Article  CAS  PubMed  Google Scholar 

  43. Wang S-M, Lei H-Y, Huang M-C et al (2005) Therapeutic efficacy of milrinone in the management of enterovirus 71-induced pulmonary edema. Pediatr Pulmonol 39(3):219–223. https://doi.org/10.1002/ppul.20157

    Article  PubMed  Google Scholar 

  44. Paradisis M, Evans N, Kluckow M, Osborn D (2009) Randomized trial of milrinone versus placebo for prevention of low systemic blood flow in very preterm infants. J Pediatr 154(2):189–195. https://doi.org/10.1016/j.jpeds.2008.07.059

    Article  CAS  PubMed  Google Scholar 

  45. Farah P, Ahmad-Ali A, Hanane G, Abbas E (2013) Additive effect of phosphodiesterase inhibitors in control of pulmonary hypertension after congenital cardiac surgery in children. Iran J Pediatr 23(1):19–26

    PubMed  Google Scholar 

  46. Fan Y, Zhang A-M, Weng Y-G et al (2013) Factors associated with the need of biventricular mechanical circulatory support in children with advanced heart failure. Eur J Cardio-Thoracic Surg 43(5):1028–1035. https://doi.org/10.1093/ejcts/ezs481

    Article  Google Scholar 

  47. Kanazawa T, Shimizu K, Iwasaki T et al (2021) Perioperative milrinone infusion improves one-year survival after the norwood-sano procedure. J Cardiothorac Vasc Anesth 35(7):2073–2078. https://doi.org/10.1053/j.jvca.2021.02.017

    Article  CAS  PubMed  Google Scholar 

  48. Bailey JM, Miller BE, Lu W, Tosone SR, Kanter KR, Tam VK (1999) The pharmacokinetics of milrinone in pediatric patients after cardiac surgery. Anesthesiology 90(4):1012–1018. https://doi.org/10.1097/00000542-199904000-00014

    Article  CAS  PubMed  Google Scholar 

  49. McNamara PJ, Laique F, Muang-In S, Whyte HE (2006) Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. J Crit Care 21(2):217–222. https://doi.org/10.1016/j.jcrc.2006.01.001

    Article  CAS  PubMed  Google Scholar 

  50. Dillard J, Pavlek LR, Korada S, Chen B (2022) Worsened short-term clinical outcomes in a cohort of patients with iNO-unresponsive PPHN: a case for improving iNO responsiveness. J Perinatol 42(1):37–44. https://doi.org/10.1038/s41372-021-01228-x

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all the colleagues at the NICU staff and CICU staff at the Faculty of Medicine of the University of São Paulo

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Authors and Affiliations

  1. Department of Pediatrics, Neonatology Division, Faculty of Medicine of the University of São Paulo, Instituto da Criança, Av. Dr. Enéas de Carvalho Aguiar, 647, São Paulo, 05403-000, Brazil

    Felipe Yu Matsushita, Vera Lúcia Jornada Krebs & Werther Brunow de Carvalho

  2. Department of Pediatric Cardiology, Faculty of Medicine of the University of São Paulo, Instituto do Coração, São Paulo, Brazil

    Felipe Yu Matsushita, Carolina Vieira de Campos & Paula Vieira de Vincenzi Gaiolla

  3. Department of Pediatrics and Neonatology, Hospital Samaritano, São Paulo, São Paulo, Brazil

    Felipe Yu Matsushita

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Contributions

F.Y.M., V.L.J.K, C.V.C, W.B.C conceptualized and designed the study, reviewed and revised the manuscript. F.Y.M. and V.L.J.K collected data, carried out statistical analysis, interpreted the data, drafted the initial manuscript. C.V.C and P.V.V.G interpreted the data and reviewed the results. All authors approved the final manuscript.

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Correspondence to Felipe Yu Matsushita.

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Because this is a meta-analysis, patient consent was not required.

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Communicated by Peter de Winter

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Research in context

• Milrinone is a phosphodiesterase III inhibitor that is used to improve cardiac function and vascular tone in children and newborns with a variety of diseases. However, its mechanism of action is not fully understood.

• Recent studies suggest that milrinone may not have a significant inotropic effect, and its dual role as a systemic and pulmonary vasodilator can be challenging to manage.

• This meta-analysis aims to elucidate the precise mechanism of milrinone and to guide its optimal use in pediatric practice.

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Matsushita, F.Y., Krebs, V.L.J., de Campos, C.V. et al. Reassessing the role of milrinone in the treatment of heart failure and pulmonary hypertension in neonates and children: a systematic review and meta-analysis. Eur J Pediatr 183, 543–555 (2024). https://doi.org/10.1007/s00431-023-05342-0

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