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Am J Perinatol 2023; 40(14): 1495-1508
DOI: 10.1055/a-1711-0778
Review Article

Evidence-Based Guidelines for Acute Stabilization and Management of Neonates with Persistent Pulmonary Hypertension of the Newborn

Molly K. Ball 
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
2   Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio
,
Ruth B. Seabrook
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
2   Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio
,
Elizabeth M. Bonachea
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
2   Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio
,
Bernadette Chen
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
2   Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio
3   Department of Pediatrics Pulmonary Hypertension Group, Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio
,
Omid Fathi
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
2   Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio
,
Craig A. Nankervis
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
2   Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio
,
Ahmed Osman
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
2   Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio
,
Amy B. Schlegel
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
2   Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio
,
Jacqueline Magers
4   Department of Pharmacy, Nationwide Children's Hospital, Columbus, Ohio
,
Taylor Kulpa
5   Division of Neonatology Nationwide Children's Hospital Neonatal Intensive Care Unit, Neonatal Service Line, Columbus, Ohio
,
Paula Sharpin
5   Division of Neonatology Nationwide Children's Hospital Neonatal Intensive Care Unit, Neonatal Service Line, Columbus, Ohio
,
Mary Lindsay Snyder
5   Division of Neonatology Nationwide Children's Hospital Neonatal Intensive Care Unit, Neonatal Service Line, Columbus, Ohio
,
Robert J. Gajarski
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
6   Division of Cardiology, Nationwide Children's Hospital, Columbus, Ohio
,
Deipanjan Nandi
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
6   Division of Cardiology, Nationwide Children's Hospital, Columbus, Ohio
,
Carl H. Backes Jr.
1   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
2   Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio
6   Division of Cardiology, Nationwide Children's Hospital, Columbus, Ohio
7   Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Columbus, Ohio
› Author Affiliations Funding The study was funded by the Ohio Perinatal Research Network (C.H.B.) with funding number 5 R01 HL136963 (B.C.).
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Abstract

Persistent pulmonary hypertension of the newborn, or PPHN, represents a challenging condition associated with high morbidity and mortality. Management is complicated by complex pathophysiology and limited neonatal specific evidence-based literature, leading to a lack of universal contemporary clinical guidelines for the care of these patients. To address this need and to provide consistent high-quality clinical care for this challenging population in our neonatal intensive care unit, we sought to develop a comprehensive clinical guideline for the acute stabilization and management of neonates with PPHN. Utilizing cross-disciplinary expertise and incorporating an extensive literature search to guide best practice, we present an approachable, pragmatic, and clinically relevant guide for the bedside management of acute PPHN.

Key Points

  • PPHN is associated with several unique diagnoses; the associated pathophysiology is different for each unique diagnosis.

  • PPHN is a challenging, dynamic, and labile process for which optimal care requires frequent reassessment.

  • Key management goals are adequate tissue oxygen delivery, avoiding harm.

Keywords

PPHN - pulmonary vasodilators - neonatal intensive care unit - clinical management


Publication History

Received: 05 June 2021

Accepted: 30 November 2021

Accepted Manuscript online:
01 December 2021

Article published online:
11 January 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Hendricks-Muñoz KD, Walton JP. Hearing loss in infants with persistent fetal circulation. Pediatrics 1988; 81 (05) 650-656
    CrossrefPubMedGoogle Scholar
  • 2 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
    CrossrefPubMedGoogle Scholar
  • 3 Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT. Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. J Pediatr 2002; 140 (03) 306-310
    CrossrefPubMedGoogle Scholar
  • 4 Konduri GG, Sokol GM, Van Meurs KP. et al. Impact of early surfactant and inhaled nitric oxide therapies on outcomes in term/late preterm neonates with moderate hypoxic respiratory failure. J Perinatol 2013; 33 (12) 944-949
    CrossrefPubMedGoogle Scholar
  • 5 Aleem S, Robbins C, Murphy B. et al. The use of supplemental hydrocortisone in the management of persistent pulmonary hypertension of the newborn. J Perinatol 2021; 41 (04) 794-800
    CrossrefPubMedGoogle Scholar
  • 6 Robertson CM, Tyebkhan JM, Hagler ME, Cheung PY, Peliowski A, Etches PC. Late-onset, progressive sensorineural hearing loss after severe neonatal respiratory failure. Otol Neurotol 2002; 23 (03) 353-356
    CrossrefPubMedGoogle Scholar
  • 7 Nair J, Lakshminrusimha S. Update on PPHN: mechanisms and treatment. Semin Perinatol 2014; 38 (02) 78-91
    CrossrefPubMedGoogle Scholar
  • 8 Steinhorn RH. Diagnosis and treatment of pulmonary hypertension in infancy. Early Hum Dev 2013; 89 (11) 865-874
    CrossrefPubMedGoogle Scholar
  • 9 Jain A, McNamara PJ. Persistent pulmonary hypertension of the newborn: advances in diagnosis and treatment. Semin Fetal Neonatal Med 2015; 20 (04) 262-271
    CrossrefPubMedGoogle Scholar
  • 10 Berenz A, Vergales JE, Swanson JR, Sinkin RA. Evidence of early pulmonary hypertension is associated with increased mortality in very low birth weight infants. Am J Perinatol 2017; 34 (08) 801-807
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Steurer MA, Jelliffe-Pawlowski LL, Baer RJ, Partridge JC, Rogers EE, Keller RL. Persistent pulmonary hypertension of the newborn in late preterm and term infants in California. pediatrics 2017; 139 (01) e20161165
    CrossrefPubMedGoogle Scholar
  • 12 Sharma V, Berkelhamer S, Lakshminrusimha S. Persistent pulmonary hypertension of the newborn. Matern Health Neonatol Perinatol 2015; 1: 14
    CrossrefPubMedGoogle Scholar
  • 13 Lakshminrusimha S, Keszler M. Persistent pulmonary hypertension of the newborn. Neoreviews 2015; 16 (12) e680-e692
    CrossrefPubMedGoogle Scholar
  • 14 Siefkes HM, Lakshminrusimha S. Management of systemic hypotension in term infants with persistent pulmonary hypertension of the newborn: an illustrated review. Arch Dis Child Fetal Neonatal Ed 2021; 106 (04) 446-455
    CrossrefPubMedGoogle Scholar
  • 15 Kinsella JP, McCurnin DC, Clark RH, Lally KP, Null Jr DM. Cardiac performance in ECMO candidates: echocardiographic predictors for ECMO. J Pediatr Surg 1992; 27 (01) 44-47
    CrossrefPubMedGoogle Scholar
  • 16 Mandell E, Kinsella JP, Abman SH. Persistent pulmonary hypertension of the newborn. Pediatr Pulmonol 2021; 56 (03) 661-669
    CrossrefPubMedGoogle Scholar
  • 17 Abman SH, Hansmann G, Archer SL. et al; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation 2015; 132 (21) 2037-2099
    CrossrefPubMedGoogle Scholar
  • 18 Bendapudi P, Rao GG, Greenough A. Diagnosis and management of persistent pulmonary hypertension of the newborn. Paediatr Respir Rev 2015; 16 (03) 157-161
    PubMedGoogle Scholar
  • 19 Fletcher K, Chapman R, Keene S. An overview of medical ECMO for neonates. Semin Perinatol 2018; 42 (02) 68-79
    CrossrefPubMedGoogle Scholar
  • 20 Totaro RJ, Raper RF. Epinephrine-induced lactic acidosis following cardiopulmonary bypass. Crit Care Med 1997; 25 (10) 1693-1699
    CrossrefPubMedGoogle Scholar
  • 21 Hansmann G, Apitz C, Abdul-Khaliq H. et al. Executive summary. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart 2016; 102 (Suppl. 02) ii86-ii100
    CrossrefPubMedGoogle Scholar
  • 22 Kinsella JP, Abman SH. Inhaled nitric oxide and high frequency oscillatory ventilation in persistent pulmonary hypertension of the newborn. Eur J Pediatr 1998; 157 (Suppl. 01) S28-S30
    CrossrefPubMedGoogle Scholar
  • 23 Kinsella JP, Truog WE, Walsh WF. et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr 1997; 131 (1 Pt 1): 55-62
    CrossrefPubMedGoogle Scholar
  • 24 Hintz SR, Suttner DM, Sheehan AM, Rhine WD, Van Meurs KP. Decreased use of neonatal extracorporeal membrane oxygenation (ECMO): how new treatment modalities have affected ECMO utilization. Pediatrics 2000; 106 (06) 1339-1343
    CrossrefPubMedGoogle Scholar
  • 25 Kinsella JP, Abman SH. Clinical approaches to the use of high-frequency oscillatory ventilation in neonatal respiratory failure. J Perinatol 1996; 16 (2 Pt 2 Su): S52-S55
    PubMedGoogle Scholar
  • 26 Clark RH. High-frequency ventilation. J Pediatr 1994; 124 (5 Pt 1): 661-670
    CrossrefPubMedGoogle Scholar
  • 27 Clark RH, Yoder BA, Sell MS. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in candidates for extracorporeal membrane oxygenation. J Pediatr 1994; 124 (03) 447-454
    CrossrefPubMedGoogle Scholar
  • 28 Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Survanta in Term Infants Study Group. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. J Pediatr 1998; 132 (01) 40-47
    CrossrefPubMedGoogle Scholar
  • 29 Lakshminrusimha S, Swartz DD, Gugino SF. et al. Oxygen concentration and pulmonary hemodynamics in newborn lambs with pulmonary hypertension. Pediatr Res 2009; 66 (05) 539-544
    CrossrefPubMedGoogle Scholar
  • 30 Rudolph AM, Yuan S. Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes. J Clin Invest 1966; 45 (03) 399-411
    CrossrefPubMedGoogle Scholar
  • 31 Heidersbach RS, Johengen MJ, Bekker JM, Fineman JR. Inhaled nitric oxide, oxygen, and alkalosis: dose-response interactions in a lamb model of pulmonary hypertension. Pediatr Pulmonol 1999; 28 (01) 3-11
    CrossrefPubMedGoogle Scholar
  • 32 Lakshminrusimha S, Russell JA, Steinhorn RH. et al. Pulmonary arterial contractility in neonatal lambs increases with 100% oxygen resuscitation. Pediatr Res 2006; 59 (01) 137-141
    CrossrefPubMedGoogle Scholar
  • 33 Lakshminrusimha S, Russell JA, Steinhorn RH. et al. Pulmonary hemodynamics in neonatal lambs resuscitated with 21%, 50%, and 100% oxygen. Pediatr Res 2007; 62 (03) 313-318
    CrossrefPubMedGoogle Scholar
  • 34 Dias-Freitas F, Metelo-Coimbra C, Roncon-Albuquerque Jr R. Molecular mechanisms underlying hyperoxia acute lung injury. Respir Med 2016; 119: 23-28
    CrossrefPubMedGoogle Scholar
  • 35 Farrow KN, Groh BS, Schumacker PT. et al. Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. Circ Res 2008; 102 (02) 226-233
    CrossrefPubMedGoogle Scholar
  • 36 Lakshminrusimha S, Porta NF, Farrow KN. et al. 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 (01) 106-112
    CrossrefPubMedGoogle Scholar
  • 37 Jankov RP, Lewis P, Kantores C. et al. Peroxynitrite mediates right-ventricular dysfunction in nitric oxide-exposed juvenile rats. Free Radic Biol Med 2010; 49 (09) 1453-1467
    CrossrefPubMedGoogle Scholar
  • 38 Dworetz AR, Moya FR, Sabo B, Gladstone I, Gross I. Survival of infants with persistent pulmonary hypertension without extracorporeal membrane oxygenation. Pediatrics 1989; 84 (01) 1-6
    CrossrefPubMedGoogle Scholar
  • 39 Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 1985; 76 (04) 488-494
    CrossrefPubMedGoogle Scholar
  • 40 Bifano EM, Pfannenstiel A. Duration of hyperventilation and outcome in infants with persistent pulmonary hypertension. Pediatrics 1988; 81 (05) 657-661
    PubMedGoogle Scholar
  • 41 Ostrea EM, Villanueva-Uy ET, Natarajan G, Uy HG. Persistent pulmonary hypertension of the newborn: pathogenesis, etiology, and management. Paediatr Drugs 2006; 8 (03) 179-188
    CrossrefPubMedGoogle Scholar
  • 42 Auten RL, Vozzelli M, Clark RH. Volutrauma. What is it, and how do we avoid it?. Clin Perinatol 2001; 28 (03) 505-515
    PubMedGoogle Scholar
  • 43 Tripathi S, Saili A. The effect of steroids on the clinical course and outcome of neonates with meconium aspiration syndrome. J Trop Pediatr 2007; 53 (01) 8-12
    CrossrefPubMedGoogle Scholar
  • 44 Alsaleem M, Malik A, Lakshminrusimha S, Kumar VH. Hydrocortisone improves oxygenation index and systolic blood pressure in term infants with persistent pulmonary hypertension. Clin Med Insights Pediatr 2019; 13: 1179556519888918
    CrossrefPubMedGoogle Scholar
  • 45 Perez M, Lakshminrusimha S, Wedgwood S. et al. Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 2012; 302 (06) L595-L603
    CrossrefPubMedGoogle Scholar
  • 46 Perez M, Wedgwood S, Lakshminrusimha S, Farrow KN, Steinhorn RH. Hydrocortisone normalizes phosphodiesterase-5 activity in pulmonary artery smooth muscle cells from lambs with persistent pulmonary hypertension of the newborn. Pulm Circ 2014; 4 (01) 71-81
    CrossrefPubMedGoogle Scholar
  • 47 Giesinger RE, McNamara PJ. Hemodynamic instability in the critically ill neonate: an approach to cardiovascular support based on disease pathophysiology. Semin Perinatol 2016; 40 (03) 174-188
    CrossrefPubMedGoogle Scholar
  • 48 Byers HM, Dagle JM, Klein JM. et al. Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn. Pediatr Res 2012; 71 (02) 162-167
    CrossrefPubMedGoogle Scholar
  • 49 Watterberg KL. Hydrocortisone dosing for hypotension in newborn infants: less is more. J Pediatr 2016; 174: 23-26.e1
    CrossrefPubMedGoogle Scholar
  • 50 Dempsey E, Rabe H. The use of cardiotonic drugs in neonates. Clin Perinatol 2019; 46 (02) 273-290
    CrossrefPubMedGoogle Scholar
  • 51 Subhedar NV. Treatment of hypotension in newborns. Semin Neonatol 2003; 8 (06) 413-423
    CrossrefPubMedGoogle Scholar
  • 52 Scheurer MA, Bradley SM, Atz AM. Vasopressin to attenuate pulmonary hypertension and improve systemic blood pressure after correction of obstructed total anomalous pulmonary venous return. J Thorac Cardiovasc Surg 2005; 129 (02) 464-466
    CrossrefPubMedGoogle Scholar
  • 53 Mohamed A, Nasef N, Shah V, McNamara PJ. Vasopressin as a rescue therapy for refractory pulmonary hypertension in neonates: case series. Pediatr Crit Care Med 2014; 15 (02) 148-154
    CrossrefPubMedGoogle Scholar
  • 54 Acker SN, Kinsella JP, Abman SH, Gien J. Vasopressin improves hemodynamic status in infants with congenital diaphragmatic hernia. J Pediatr 2014; 165: 53-58
    CrossrefPubMedGoogle Scholar
  • 55 Rios DR, Moffett BS, Kaiser JR. Trends in pharmacotherapy for neonatal hypotension. J Pediatr 2014; 165 (04) 697-701.e1
    CrossrefPubMedGoogle Scholar
  • 56 Osborn D, Evans N, Kluckow M. Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow. J Pediatr 2002; 140 (02) 183-191
    CrossrefPubMedGoogle Scholar
  • 57 Barrington KJ, Finer NN, Chan WK. A blind, randomized comparison of the circulatory effects of dopamine and epinephrine infusions in the newborn piglet during normoxia and hypoxia. Crit Care Med 1995; 23 (04) 740-748
    CrossrefPubMedGoogle Scholar
  • 58 Cheung PY, Barrington KJ, Pearson RJ, Bigam DL, Finer NN, Van Aerde JE. Systemic, pulmonary and mesenteric perfusion and oxygenation effects of dopamine and epinephrine. Am J Respir Crit Care Med 1997; 155 (01) 32-37
    CrossrefPubMedGoogle Scholar
  • 59 Joynt C, Bigam DL, Charrois G, Jewell LD, Korbutt G, Cheung PY. Milrinone, dobutamine or epinephrine use in asphyxiated newborn pigs resuscitated with 100% oxygen. Intensive Care Med 2010; 36 (06) 1058-1066
    CrossrefPubMedGoogle Scholar
  • 60 McGovern JJ, Cheifetz IM, Craig DM. et al. Right ventricular injury in young swine: effects of catecholamines on right ventricular function and pulmonary vascular mechanics. Pediatr Res 2000; 48 (06) 763-769
    CrossrefPubMedGoogle Scholar
  • 61 Barton AM, Abubakar MK, Berg J, Keszler M. The effect of arterial pH on oxygenation persists even in infants treated with inhaled nitric oxide. Pulm Med 2011; 2011: 189205
    CrossrefPubMedGoogle Scholar
  • 62 S. Lakshminrusimha, GC Konduri, RH Steinhorn. Considerations in the Management of hypoxemic respiratory failure and persistent pulmonary hypertension in term and late preterm neonates. J Perinatology 2016; 36: S12-S19
    CrossrefPubMedGoogle Scholar
  • 63 Fuloria M, Aschner JL. Persistent pulmonary hypertension of the newborn. Semin Fetal Neonatal Med 2017; 22 (04) 220-226
    CrossrefPubMedGoogle Scholar
  • 64 Runkle B, Bancalari E. Acute cardiopulmonary effects of pancuronium bromide in mechanically ventilated newborn infants. J Pediatr 1984; 104 (04) 614-617
    CrossrefPubMedGoogle Scholar
  • 65 Cholette JM, Willems A, Valentine SL. et al. Recommendations on RBC transfusion in infants and children with acquired and congenital heart disease from the pediatric critical care transfusion and anemia expertise initiative. Pediatr Crit Care Med 2018; 19 (9S suppl 1): S137-S148
    CrossrefPubMedGoogle Scholar
  • 66 Girelli G, Antoncecchi S, Casadei AM. et al. Recommendations for transfusion therapy in neonatology. Blood Transfus 2015; 13 (03) 484-497
    PubMedGoogle Scholar
  • 67 Alverson DC, Isken VH, Cohen RS. Effect of booster blood transfusions on oxygen utilization in infants with bronchopulmonary dysplasia. J Pediatr 1988; 113 (04) 722-726
    CrossrefPubMedGoogle Scholar
  • 68 Plaisant F. [Evolution of neonatal transfusion practices: current recommendations]. Transfus Clin Biol 2011; 18 (02) 262-268
    PubMedGoogle Scholar
  • 69 Venkatesh V, Khan R, Curley A, Hopewell S, Doree C, Stanworth S. The safety and efficacy of red cell transfusions in neonates: a systematic review of randomized controlled trials. Br J Haematol 2012; 158 (03) 370-385
    CrossrefPubMedGoogle Scholar
  • 70 Red blood cell transfusions in newborn infants: revised guidelines. Paediatr Child Health 2002; 7 (08) 553-566
    CrossrefPubMedGoogle Scholar
  • 71 Ozek E, Soll R, Schimmel MS. Partial exchange transfusion to prevent neurodevelopmental disability in infants with polycythemia. Cochrane Database Syst Rev 2010; (01) CD005089
    PubMedGoogle Scholar
  • 72 Murphy Jr DJ, Reller MD, Meyer RA, Kaplan S. Effects of neonatal polycythemia and partial exchange transfusion on cardiac function: an echocardiographic study. Pediatrics 1985; 76 (06) 909-913
    CrossrefPubMedGoogle Scholar
  • 73 Gao Y, Raj JU. Regulation of the pulmonary circulation in the fetus and newborn. Physiol Rev 2010; 90 (04) 1291-1335
    CrossrefPubMedGoogle Scholar
  • 74 Naghavi M, Marczak LB, Kutz M. et al; Global Burden of Disease 2016 Injury Collaborators. Global mortality from firearms, 1990-2016. JAMA 2018; 320 (08) 792-814
    CrossrefPubMedGoogle Scholar
  • 75 Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2017; 1: CD000399
    PubMedGoogle Scholar
  • 76 Roberts Jr JD, Fineman JR, Morin III FC. et al; The Inhaled Nitric Oxide Study Group. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997; 336 (09) 605-610
    CrossrefPubMedGoogle Scholar
  • 77 Davidson D, Barefield ES, Kattwinkel J. et al; The I-NO/PPHN Study Group. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. Pediatrics 1998; 101 (3 Pt 1): 325-334
    CrossrefPubMedGoogle Scholar
  • 78 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
    CrossrefPubMedGoogle Scholar
  • 79 Barst RJ, Ivy DD, Gaitan G. et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation 2012; 125 (02) 324-334
    CrossrefPubMedGoogle Scholar
  • 80 Barst RJ, Beghetti M, Pulido T. et al; STARTS-2 Investigators. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation 2014; 129 (19) 1914-1923
    CrossrefPubMedGoogle Scholar
  • 81 Vargas-Origel A, Gómez-Rodríguez G, Aldana-Valenzuela C, Vela-Huerta MM, Alarcón-Santos SB, Amador-Licona N. The use of sildenafil in persistent pulmonary hypertension of the newborn. Am J Perinatol 2010; 27 (03) 225-230
    Article in Thieme ConnectPubMedGoogle Scholar
  • 82 El-Ghandour M, Hammad B, Ghanem M, Antonios MAM. 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. Paediatr Drugs 2020; 22 (06) 685-693
    CrossrefPubMedGoogle Scholar
  • 83 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
    CrossrefPubMedGoogle Scholar
  • 84 Kumar VH, Swartz DD, Rashid N. et al. Prostacyclin and milrinone by aerosolization improve pulmonary hemodynamics in newborn lambs with experimental pulmonary hypertension. J Appl Physiol (1985) 2010; 109 (03) 677-684
    CrossrefPubMedGoogle Scholar
  • 85 Thelitz S, Oishi P, Sanchez LS. et al. Phosphodiesterase-3 inhibition prevents the increase in pulmonary vascular resistance following inhaled nitric oxide withdrawal in lambs. Pediatr Crit Care Med 2004; 5 (03) 234-239
    CrossrefPubMedGoogle Scholar
  • 86 Kinsella JP, Steinhorn RH, Krishnan US. et al. Recommendations for the use of inhaled nitric oxide therapy in premature newborns with severe pulmonary hypertension. J Pediatr 2016; 170: 312-314
    CrossrefPubMedGoogle Scholar
  • 87 Arnold WP, Mittal CK, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A 1977; 74 (08) 3203-3207
    CrossrefPubMedGoogle Scholar
  • 88 Tworetzky W, Bristow J, Moore P. et al. Inhaled nitric oxide in neonates with persistent pulmonary hypertension. Lancet 2001; 357 (9250): 118-120
    CrossrefPubMedGoogle Scholar
  • 89 Finer NN, Barrington KJ. Nitric oxide therapy for the newborn infant. Semin Perinatol 2000; 24 (01) 59-65
    CrossrefPubMedGoogle Scholar
  • 90 Heilman RP, Lagoski MB, Lee KJ. et al. Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice. Am J Physiol Heart Circ Physiol 2015; 308 (12) H1575-H1582
    CrossrefPubMedGoogle Scholar
  • 91 Steinhorn RH, Kinsella JP, Pierce C. et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 2009; 155 (06) 841-847.e1
    CrossrefPubMedGoogle Scholar
  • 92 Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006; 117 (04) 1077-1083
    CrossrefPubMedGoogle Scholar
  • 93 Khorana M, Yookaseam T, Layangool T, Kanjanapattanakul W, Paradeevisut H. Outcome of oral sildenafil therapy on persistent pulmonary hypertension of the newborn at Queen Sirikit National Institute of Child Health. J Med Assoc Thai 2011; 94 (Suppl. 03) S64-S73
    PubMedGoogle Scholar
  • 94 Kelly LE, Ohlsson A, Shah PS. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev 2017; 8: CD005494
    PubMedGoogle Scholar
  • 95 Ruan CH, Dixon RA, Willerson JT, Ruan KH. Prostacyclin therapy for pulmonary arterial hypertension. Tex Heart Inst J 2010; 37 (04) 391-399
    PubMedGoogle Scholar
  • 96 Yilmaz O, Kahveci H, Zeybek C, Ciftel M, Kilic O. Inhaled iloprost in preterm infants with severe respiratory distress syndrome and pulmonary hypertension. Am J Perinatol 2014; 31 (04) 321-326
    Article in Thieme ConnectPubMedGoogle Scholar
  • 97 Kahveci H, Yilmaz O, Avsar UZ. et al. Oral sildenafil and inhaled iloprost in the treatment of pulmonary hypertension of the newborn. Pediatr Pulmonol 2014; 49 (12) 1205-1213
    CrossrefPubMedGoogle Scholar
  • 98 Levy M, Celermajer DS, Bourges-Petit E, Del Cerro MJ, Bajolle F, Bonnet D. Add-on therapy with subcutaneous treprostinil for refractory pediatric pulmonary hypertension. J Pediatr 2011; 158 (04) 584-588
    CrossrefPubMedGoogle Scholar
  • 99 Eronen M, Pohjavuori M, Andersson S, Pesonen E, Raivio KO. Prostacyclin treatment for persistent pulmonary hypertension of the newborn. Pediatr Cardiol 1997; 18 (01) 3-7
    CrossrefPubMedGoogle Scholar
  • 100 Janjindamai W, Thatrimontrichai A, Maneenil G, Chanvitan P, Dissaneevate S. Effectiveness and safety of intravenous iloprost for severe persistent pulmonary hypertension of the newborn. Indian Pediatr 2013; 50 (10) 934-938
    CrossrefPubMedGoogle Scholar
  • 101 Levy M, Del Cerro MJ, Nadaud S. et al. Safety, efficacy and management of subcutaneous treprostinil infusions in the treatment of severe pediatric pulmonary hypertension. Int J Cardiol 2018; 264: 153-157
    CrossrefPubMedGoogle Scholar
  • 102 Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr 2002; 141 (06) 830-832
    CrossrefPubMedGoogle Scholar
  • 103 Chotigeat U, Champrasert M, Khorana M, Sangtaweesin V, Kanjanapattanakul W. Iloprost inhalation for the treatment of severe persistent pulmonary hypertension of the newborn, experience at QSNICH. J Med Assoc Thai 2014; 97 (Suppl. 06) S89-S94
    PubMedGoogle Scholar
  • 104 Lakshminrusimha S, Steinhorn RH. Inodilators in nitric oxide resistant persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med 2013; 14 (01) 107-109
    CrossrefPubMedGoogle Scholar
  • 105 Degerman E, Belfrage P, Manganiello VC. Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3). J Biol Chem 1997; 272 (11) 6823-6826
    CrossrefPubMedGoogle Scholar
  • 106 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
    CrossrefPubMedGoogle Scholar
  • 107 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
    CrossrefPubMedGoogle Scholar
  • 108 Giaccone A, Zuppa AF, Sood B. et al. Milrinone pharmacokinetics and pharmacodynamics in neonates with persistent pulmonary hypertension of the newborn. Am J Perinatol 2017; 34 (08) 749-758
    Article in Thieme ConnectPubMedGoogle Scholar
  • 109 El-Khuffash A, McNamara PJ, Breatnach C. et al. The use of milrinone in neonates with persistent pulmonary hypertension of the newborn—a randomised controlled trial pilot study (MINT 1): study protocol and review of literature. Matern Health Neonatol Perinatol 2018; 4: 24
    CrossrefPubMedGoogle Scholar
  • 110 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
    CrossrefPubMedGoogle Scholar
  • 111 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 (01) 90-99
    CrossrefPubMedGoogle Scholar
  • 112 James AT, Bee C, Corcoran JD, McNamara PJ, Franklin O, El-Khuffash AF. Treatment of premature infants with pulmonary hypertension and right ventricular dysfunction with milrinone: a case series. J Perinatol 2015; 35 (04) 268-273
    CrossrefPubMedGoogle Scholar
  • 113 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
    CrossrefPubMedGoogle Scholar
  • 114 Martinho S, Adão R, Leite-Moreira AF, Brás-Silva C. Persistent pulmonary hypertension of the newborn: pathophysiological mechanisms and novel therapeutic approaches. Front Pediatr 2020; 8: 342
    CrossrefPubMedGoogle Scholar
  • 115 Filan PM, McDougall PN, Shekerdemian LS. Combination pharmacotherapy for severe neonatal pulmonary hypertension. J Paediatr Child Health 2006; 42 (04) 219-220
    CrossrefPubMedGoogle Scholar
  • 116 Gupta N, Kamlin CO, Cheung M, Stewart M, Patel N. Prostaglandin E1 use during neonatal transfer: potential beneficial role in persistent pulmonary hypertension of the newborn. Arch Dis Child Fetal Neonatal Ed 2013; 98 (02) F186-F188
    CrossrefPubMedGoogle Scholar