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Hemodynamic response to milrinone for refractory hypoxemia during therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy

Journal of Perinatology volume 41, pages 2345–2354 (2021)Cite this article

Subjects

Abstract

Objective

Characterize the impact of milrinone on arterial pressure of neonates with persistent hypoxemic respiratory failure (HRF) and hypoxic ischemic encephalopathy (HIE) treated with inhaled nitric oxide and therapeutic hypothermia (TH).

Study design

Retrospective cohort study. Arterial pressure was assessed hourly for 24 h. The primary outcome was change in diastolic arterial pressure (DAP).

Results

56 patients were included [(i) cases: HIE/TH who received milrinone (n = 9), (ii) Milrinone controls (n = 17), (iii) HIE controls (n = 30)]. Baseline demographics, severity of HRF and arterial pressure were comparable between groups. Only milrinone treated patients with HIE/TH had a marked drop in DAP in the first hour, which persisted for more than 12 h despite escalation in inotropes (p = 0.008).

Conclusion

Milrinone treated patients with HRF and HIE/TH develop profound reduction in DAP and require escalation of cardiovascular support. The risk benefit profile of milrinone should be considered and pharmacological studies are warranted to evaluate drug metabolism and clearance in this population.

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Fig. 1: Description of the population.
Fig. 2: Hemodynamic parameters over time.

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References

  1. Rubini A. Effect of perfusate temperature on pulmonary vascular resistance and compliance by arterial and venous occlusion in the rat. Eur J Appl Physiol. 2005;93:435–9.

    Article  PubMed  Google Scholar 

  2. Giesinger RE, Bailey LJ, Deshpande P, McNamara PJ. Hypoxic-ischemic encephalopathy and therapeutic hypothermia: the hemodynamic perspective. J Pediatr. 2017;180:22–30.e22.

    Article  PubMed  Google Scholar 

  3. Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy. Pediatrics. 2000;106:92–9.

    Article  CAS  PubMed  Google Scholar 

  4. More KS, Sakhuja P, Giesinger RE, Ting JY, Keyzers M, Sheth JN, et al. Cardiovascular associations with abnormal brain magnetic resonance imaging in neonates with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia and rewarming. Am J Perinatol. 2018;35:979–89.

    Article  PubMed  Google Scholar 

  5. Giesinger RE, El Shahed AI, Castaldo MP, Breatnach CR, Chau V, Whyte HE, et al. Impaired right ventricular performance is associated with adverse outcome following hypoxic ischemic encephalopathy. Am J Respir Crit Care Med. 2019.

  6. LeJemtel TH, Scortichini D, Levitt B, Sonnenblick EH. Effects of phosphodiesterase inhibition on skeletal muscle vasculature. Am J Cardiol. 1989;63:27A–30A.

    Article  CAS  PubMed  Google Scholar 

  7. Silver PJ, Harris AL, Canniff PC, Lepore RE, Bentley RG, Hamel LT, et al. Phosphodiesterase isozyme inhibition, activation of the cAMP system, and positive inotropy mediated by milrinone in isolated guinea pig cardiac muscle. J Cardiovasc Pharm. 1989;13:530–40.

    Article  CAS  Google Scholar 

  8. Akita T, Joyner RW, Lu C, Kumar R, Hartzell HC. Developmental changes in modulation of calcium currents of rabbit ventricular cells by phosphodiesterase inhibitors. Circulation. 1994;90:469–78.

    Article  CAS  PubMed  Google Scholar 

  9. 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;26:90–99.

    Article  PubMed  Google Scholar 

  10. 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;21:217–22.

    Article  CAS  PubMed  Google Scholar 

  11. Bassler D, Choong K, McNamara P, Kirpalani H. Neonatal persistent pulmonary hypertension treated with milrinone: four case reports. Biol Neonate. 2006;89:1–5.

    Article  PubMed  Google Scholar 

  12. Joynt C, Cheung PY. Cardiovascular supportive therapies for neonates with asphyxia - a literature review of pre-clinical and clinical studies. Front Pediatr. 2018;6:363.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Samiee-Zafarghandy S, Raman SR, van den Anker JN, McHutchison K, Hornik CP, Clark RH, et al. Safety of milrinone use in neonatal intensive care units. Early Hum Dev. 2015;91:31–5.

    Article  CAS  PubMed  Google Scholar 

  14. Gien J, Kinsella JP. Differences in preductal and postductal arterial blood gas measurements in infants with severe congenital diaphragmatic hernia. Arch Dis Child Fetal Neonatal Ed. 2016;101:F314–8.

    Article  PubMed  Google Scholar 

  15. Lakshminrusimha S, Russell JA, Wedgwood S, Gugino SF, Kazzaz JA, Davis JM, et al. Superoxide dismutase improves oxygenation and reduces oxidation in neonatal pulmonary hypertension. Am J Respir Crit Care Med. 2006;174:1370–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lemyre B, Chau V. Hypothermia for newborns with hypoxic-ischemic encephalopathy. Paediatr Child Health. 2018;23:285–91.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33:696–705.

    Article  CAS  PubMed  Google Scholar 

  18. Davidson J, Tong S, Hancock H, Hauck A, da Cruz E, Kaufman J. Prospective validation of the vasoactive-inotropic score and correlation to short-term outcomes in neonates and infants after cardiothoracic surgery. Intensive Care Med. 2012;38:1184–90.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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;14:74–84.

    Article  PubMed  Google Scholar 

  20. Giaccone A, Zuppa AF, Sood B, Cohen MS, O’Byrne ML, Moorthy G, et al. Milrinone pharmacokinetics and pharmacodynamics in neonates with persistent pulmonary hypertension of the newborn. Am J Perinatol. 2017;34:749–58.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bassler D, Kreutzer K, McNamara P, Kirpalani H. Milrinone for persistent pulmonary hypertension of the newborn. Cochrane Datab Syst Rev. 2010: Cd007802.

  22. Lakshminrusimha S, Konduri GG, Steinhorn RH. Considerations in the management of hypoxemic respiratory failure and persistent pulmonary hypertension in term and late preterm neonates. J Perinatol. 2016;36:S12–9.

    Article  PubMed  Google Scholar 

  23. McNamara PJ, Weisz DE, Giesinger RE, Jain A. Hemodynamics. In: MG MacDonald MMKS (ed). Avery’s neonatology: pathophysiology and management of the newborn. Wolters Kluwer, Philadelphia, 2016, pp 457–86.

  24. Jain A, Mcnamara PJ. Persistent pulmonary hypertension of the newborn: physiology, hemodynamic assessment and novel therapies. Curr Pediatr Rev. 2013;9:55–66.

    Article  Google Scholar 

  25. Roka A, Melinda KT, Vasarhelyi B, Machay T, Azzopardi D, Szabo M. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics. 2008;121:e844–9.

    Article  PubMed  Google Scholar 

  26. Bijleveld YA, de Haan TR, van der Lee HJ, Groenendaal F, Dijk PH, van Heijst A, et al. Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia. Br J Clin Pharm. 2016;81:1067–77.

    Article  CAS  Google Scholar 

  27. Favie LMA, Groenendaal F, van den Broek MPH, Rademaker CMA, de Haan TR, van Straaten HLM, et al. Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia. PLoS One. 2019;14:e0211910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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:F204–9.

    Article  PubMed  Google Scholar 

  29. Zuppa AF, Nicolson SC, Adamson PC, Wernovsky G, Mondick JT, Burnham N, et al. Population pharmacokinetics of milrinone in neonates with hypoplastic left heart syndrome undergoing stage I reconstruction. Anesth Analg. 2006;102:1062–9.

    Article  CAS  PubMed  Google Scholar 

  30. Bailey JM, Hoffman TM, Wessel DL, Nelson DP, Atz AM, Chang AC, et al. A population pharmacokinetic analysis of milrinone in pediatric patients after cardiac surgery. J Pharmacokinet Pharmacodyn. 2004;31:43–59.

    Article  CAS  PubMed  Google Scholar 

  31. Lakshminrusimha S, Steinhorn RH. Inodilators in nitric oxide resistant persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med. 2013;14:107–9.

    Article  PubMed  Google Scholar 

  32. Lindsay CA, Barton P, Lawless S, Kitchen L, Zorka A, Garcia J, et al. Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock. J Pediatr. 1998;132:329–34.

    Article  CAS  PubMed  Google Scholar 

  33. Stroshane RM, Koss RF, Biddlecome CE, Luczkowec C, Edelson J. Oral and intravenous pharmacokinetics of milrinone in human volunteers. J Pharm Sci. 1984;73:1438–41.

    Article  CAS  PubMed  Google Scholar 

  34. Gist KM, Goldstein SL, Joy MS, Vinks AA. Milrinone dosing issues in critically ill children with kidney injury: a review. J Cardiovasc Pharm. 2016;67:175–81.

    Article  CAS  Google Scholar 

  35. Aggarwal A, Kumar P, Chowdhary G, Majumdar S, Narang A. Evaluation of renal functions in asphyxiated newborns. J Trop Pediatr. 2005;51:295–9.

    Article  PubMed  Google Scholar 

  36. Sarkar S, Barks JD, Bhagat I, Donn SM. Effects of therapeutic hypothermia on multiorgan dysfunction in asphyxiated newborns: whole-body cooling versus selective head cooling. J Perinatol. 2009;29:558–63.

    Article  CAS  PubMed  Google Scholar 

  37. LaRosa DA, Ellery SJ, Walker DW, Dickinson H. Understanding the full spectrum of organ injury following intrapartum asphyxia. Front Pediatr. 2017;5:16.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gist KM, Mizuno T, Goldstein SL, Vinks A. Retrospective evaluation of milrinone pharmacokinetics in children with kidney injury. Ther Drug Monit. 2015;37:792–6.

    Article  CAS  PubMed  Google Scholar 

  39. 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;86:283–9.

    Article  CAS  PubMed  Google Scholar 

  40. Gist KM, Cooper DS, Wrona J, Faubel S, Altmann C, Gao Z, et al. Acute kidney injury biomarkers predict an increase in serum milrinone concentration earlier than serum creatinine-defined acute kidney injury in infants after cardiac surgery. Therapeutic drug Monit. 2018;40:186–94.

    Article  CAS  Google Scholar 

  41. Smolich JJ. Ultrastructural and functional features of the developing mammalian heart: a brief overview. Reprod Fertil Dev. 1995;7:451–61.

    Article  CAS  PubMed  Google Scholar 

  42. Mahony L. Maturation of calcium transport in cardiac sarcoplasmic reticulum. Pediatr Res. 1988;24:639–43.

    Article  CAS  PubMed  Google Scholar 

  43. Jain A, McNamara PJ. Persistent pulmonary hypertension of the newborn: advances in diagnosis and treatment. Semin Fetal Neonatal Med. 2015;20:262–71.

    Article  PubMed  Google Scholar 

  44. Tanaka M, Ishikawa T, Nishikawa T, Goto K, Sato S. Influence of acidosis on cardiotonic effects of milrinone. Anesthesiology. 1998;88:725–34.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Adrianne R. Bischoff & Sharifa Habib

  2. Department of Pediatrics, University of Iowa, Iowa city, IA, USA

    Patrick J. McNamara & Regan E. Giesinger

  3. Department of Internal Medicine, University of Iowa, Iowa city, IA, USA

    Patrick J. McNamara

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  1. Adrianne R. Bischoff
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  2. Sharifa Habib
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  4. Regan E. Giesinger
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Correspondence to Regan E. Giesinger.

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Bischoff, A.R., Habib, S., McNamara, P.J. et al. Hemodynamic response to milrinone for refractory hypoxemia during therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy. J Perinatol 41, 2345–2354 (2021). https://doi.org/10.1038/s41372-021-01049-y

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