Am J Perinatol 2020; 37(09): 939-946
DOI: 10.1055/s-0039-1692182
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Neonates Effects and Tolerability of Treprostinil in Hypertension with Persistent Pulmonary

Mariela Jozefkowicz
1   Neonatal Intensive Care Unit, Children's Hospital SAMIC Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
,
Dora Fabiana Haag
2   Cardiology Department, Children's Hospital SAMIC Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
,
María Teresa Mazzucchelli
1   Neonatal Intensive Care Unit, Children's Hospital SAMIC Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
,
Gladys Salgado
2   Cardiology Department, Children's Hospital SAMIC Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
,
Diana Fariña
1   Neonatal Intensive Care Unit, Children's Hospital SAMIC Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
› Author Affiliations
Further Information

Publication History

28 December 2018

23 April 2019

Publication Date:
05 June 2019 (online)

Abstract

Objective The aim of this study was to establish the effects of treprostinil in congenital diaphragmatic hernia (CDH) patients with persistent pulmonary hypertension (PHT) after 1 week of treatment. Drug effects were assessed by oxygenation index (OI), clinical end points, serial biochemical markers, and pre- and posttreatment echocardiogram. Treatment complications were also described.

Study Design This is a quasi-experimental study of neonates with PHT admitted to the NICU within 48 hours showing persistent clinical instability, receiving mechanical ventilation with FiO2 > 60%, milrinone therapy, and inhaled nitric oxide. Clinical data were compared before and after treprostinil treatment.

Results Seventeen neonates met the inclusion criteria. Median age was 17 days. Before treatment, median OI was 20 (IQR: 12–27). Suprasystemic PHT was estimated by echocardiogram in 8/17 patients; the rest were systemic. After 1 week of treatment, 15/17 patients were alive and median OI was 8 (IQR: 5–12, p = 0.0089). There were no statistically significant changes in laboratory data. Echocardiogram still showed suprasystemic PHT in 20% of patients. Adverse effects included hypotension, hematoma at the infusion site, and surgical persistent ductus arteriosus (PDA) closure in 4/17 patients. Fourteen patients were discharged. The median treatment time was 61 days.

Conclusion Treprostinil was well tolerated with satisfactory clinical response. Further studies are required to identify early responder subgroups.

 
  • References

  • 1 Nair J, Lakshminrusimha S. Update on PPHN: mechanisms and treatment. Semin Perinatol 2014; 38 (02) 78-91
  • 2 Cabral JE, Belik J. Persistent pulmonary hypertension of the newborn: recent advances in pathophysiology and treatment. J Pediatr (Rio J) 2013; 89 (03) 226-242
  • 3 Konduri GG, Solimano A, Sokol GM. , et al; Neonatal Inhaled Nitric Oxide Study Group. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics 2004; 113 (3 Pt 1): 559-564
  • 4 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
  • 5 Kinsella JP, Ivy DD, Abman SH. Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol 2005; 29 (02) 123-128
  • 6 Hagadorn JI, Brownell EA, Herbst KW, Trzaski JM, Neff S, Campbell BT. Trends in treatment and in-hospital mortality for neonates with congenital difragmatic hernia. Semin Perinatol 2015; 35 (09) 748-754
  • 7 McLaughlin VV, Palevsky HI. Parenteral and inhaled prostanoid therapy in the treatment of pulmonary arterial hypertension. Clin Chest Med 2013; 34 (04) 825-840
  • 8 Tissot C, Ivy DD, Beghetti M. Medical therapy for pediatric pulmonary arterial hypertension. J Pediatr 2010; 157 (04) 528-532
  • 9 McIntyre CM, Hanna BD, Rintoul N, Ramsey EZ. Safety of epoprostenol and treprostinil in children less than 12 months of age. Pulm Circ 2013; 3 (04) 862-869
  • 10 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 (07) 1184-1190
  • 11 Carpentier E, Mur S, Aubry E. , et al. Safety and tolerability of subcutaneous treprostinil in newborns with congenital diaphragmatic hernia and life-threatening pulmonary hypertension. J Pediatr Surg 2017; 52 (09) 1480-1483
  • 12 Vijlbrief DC, Benders MJ, Kemperman H, van Bel F, de Vries WB. B-type natriuretic peptide and rebound during treatment for persistent pulmonary hypertension. J Pediatr 2012; 160 (01) 111-115
  • 13 Ali FY, Egan K, FitzGerald GA. , et al. Role of prostacyclin versus peroxisome proliferator-activated receptor β receptors in prostacyclin sensing by lung fibroblasts. Am J Respir Cell Mol Biol 2006; 34 (02) 242-246
  • 14 Lusk LA, Wai KC, Moon-Grady AJ, Steurer MA, Keller RL. Persistence of pulmonary hypertension by echocardiography predicts short-term outcomes in congenital diaphragmatic hernia. J Pediatr 2015; 166 (02) 251-256
  • 15 Olson E, Lusk LA, Fineman JR, Robertson L, Keller RL. Short-term treprostinil use in infants with congenital diaphragmatic hernia following repair. J Pediatr 2015; 167 (03) 762-764
  • 16 Zharikov SI, Swenson ER, Lanaspa M, Block ER, Patel JM, Johnson RJ. Could uric acid be a modifiable risk factor in subjects with pulmonary hypertension?. Med Hypotheses 2010; 74 (06) 1069-1074
  • 17 Nagaya N, Uematsu M, Satoh T. , et al. Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 1999; 160 (02) 487-492
  • 18 Reynolds EW, Ellington JG, Vranicar M, Bada HS. Brain-type natriuretic peptide in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatrics 2004; 114 (05) 1297-1304
  • 19 Salas GL, Jozefkowicz M, Goldsmit GS. , et al. B-type natriuretic peptide: Usefulness in the management of critically-ill neonates. Arch Argent Pediatr 2017; 115 (05) 483-489
  • 20 Steurer MA, Moon-Grady AJ, Fineman JR. , et al. B-type natriuretic peptide: prognostic marker in congenital diaphragmatic hernia. Pediatr Res 2014; 76 (06) 549-554
  • 21 El-Kersh K, Ruf KM, Smith JS. Rapid inpatient titration of intravenous treprostinil for pulmonary arterial hypertension: safe and tolerable. Am J Ther 2018; 25 (02) e213-e217
  • 22 Park BY, Chung SH. Treprostinil for persistent pulmonary hypertension of the newborn, with early onset sepsis in preterm infant: 2 case reports. Medicine (Baltimore) 2017; 96 (26) e7303
  • 23 Barst RJ, Galie N, Naeije R. , et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J 2006; 28 (06) 1195-1203
  • 24 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
  • 25 Tapson VF, Gomberg-Maitland M, McLaughlin VV. , et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest 2006; 129 (03) 683-688
  • 26 Harting MT, Lally KP. The congenital diaphragmatic hernia study group registry update. Semin Fetal Neonatal Med 2014; 19 (06) 370-375