Controversies in neonatology: The efficacy of inhaled nitric oxide in preterm infants with persistent pulmonary hypertension

Year 2022, Volume: 5 Issue: 5, 1303 - 1311, 25.09.2022

Gonca Vardar , Meliha Aksoy Okan , Sevilay Topçuoğlu , Nilgün Karadağ , Elif Özalkaya , Hande Ozgun Karatepe , Güner Karatekin

https://doi.org/10.32322/jhsm.1104799

Abstract

Introduction: There is limited and conflicting information in literature regarding use of inhaled nitric oxide (iNO) in preterm infants. In this study we examined the characteristics of preterm infants with persistent pulmonary hypertension (PHT) who responded and did not respond to iNO therapy .
Material and Method: We retrospectively reviewed data of infants <34 weeks of gestational age with hypoxic respiratory failure that received iNO for PHT after being diagnosed with severe respiratory distress syndrome after birth. The data of responders and non-responders to iNO therapy were compared.
Results: Twenty-five infants were included in our study. Twelve (48%) had a positive response to iNO administration for PHT. As an antenatal characteristic, oligohydramnios was significantly higher in responders [5 (41.7%) vs 0%, p=0.015] and mortality rate was lower (66% vs. 100%, p=0.039). The SpO2/FiO2 ratio before iNO treatment predicted the response to iNO in preterm neonates with PHT. The ROC analysis yielded an area under curve AUC for SpO2/FiO2 ratio before iNO of AUCSpO2/FiO2before was 0.756; 95% CI, 0.554-0.959; P=0.03. A cut-off value of 79 point by the SpO2/FiO2 ratio before iNO treatment predicted the response to iNO treatment with 83% sensitivity and 70% specificity.
Conclusion: In infants born <34 weeks gestation, response to iNO in PHT has a significant effect on improving survival. The presence of oligohydramnios may be an important factor in prediction of positive response. SpO2/FiO2 ratio can be useful for estimating the effectiveness of iNO.

Keywords

Nitric oxide therapy, premature, pulmonary hypertension

Project Number

yok

References

• Myers TR. Therapeutic gases for neonatal and pediatric respiratory care. Respir Care 2003; 48: 399-422.
• Dani C, Pratesi S. Nitric oxide for the treatment of preterm infants with respiratory distress syndrome. Expert Opinion 2013; 14: 97-103.
• Shiraishi J, Kusuda S, Cho K, et al. Standardization of nitric oxide inhalation in extremely preterm infants in Japan. Pediatr Int 2019; 61: 152-7.
• Sasi A, Sehgal A. Use of inhaled nitric oxide in preterm infants: A regional survey of practices. Heart Lung 2014; 43: 347-50.
• Finer N, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2017; 1: CD000399.
• Nakwan N, Jain S, Kumar K, et al. An Asian multicentre retrospective study on pulmonary hypertension of the newborn: incidence, etiology, diagnosis, treatment and outcome. J Maternal Fetal Neonatal Med 2020; 33: 2032-7.
• Hoyle ES, Slee SL, Subhedar NV. Variation in the definition of pulmonary hypertension and clinical indications for the use of nitric oxide in neonatal clinical trials. Acta Paediatr 2020; 109: 930-4.
• Dani C, Corsini I, Cangemi J, Vangi V, Pratesi S. Nitric oxide for the treatment of preterm infants with severe RDS and pulmonary hypertension. Pediatr Pulmonol 2017; 52: 1461-8.
• Rallis D, Deierl A, Atreja G, Chaban B, Banerjee J. The efficacy of inhaled nitric oxide treatment in premature infants with acute pulmonary hypertension. Early Hum Dev 2018; 127: 1-5.
• Kuba K, Bernstein PS.ACOG Practice Bulletin No. 188: Prelabor Rupture of Membranes. Obstet Gynecol 2018; 131: 1163-4.
• Ehrenkranz RA, Walsh MC, Vohr BR, et al. National Institutes of Child H, Human Development Neonatal Research N, Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116: 1353-60.
• Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92: 529-34.
• International Committee for the Classification of Retinopathy of Prematurity, The international classification of retinopathy of prematurity revisited. Arch Ophthalmol 2005; 123: 991-9.
• Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am1986; 33: 179-201.
• Liu K, Wang H, Yu SJ, Tu GW, Luo Z. Inhaled pulmonary vasodilators: a narrative review. Ann Transl Med 2021; 9: 597.
• Abman SH. Inhaled nitric oxide for the treatment of pulmonary arterial hypertension. Handb Exp Pharmacol 2013; 218: 257-76.
• Davidson D, Barefield ES, Kattwinkel J, et al. 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. The I-NO/PPHN Study Group. Pediatrics1998; 101: 325-34.
• Polin RA, Carlo WA; Committee on Fetus and Newborn; American Academy of Pediatrics. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics 2014; 133: 156-63.
• Evans N. Shunts in patients with respiratory distress syndrome. Pediatrics1993; 92: 737.
• Evans NJ, Archer LN. Doppler assessment of pulmonary artery pressure and extrapulmonary shunting in the acute phase of hyaline membrane disease. Arch Dis Child 1991; 66: 6-11
• Rozé JC, Storme L, Zupan V, Morville P, Dinh-Xuan AT, Mercier JC. Echocardiographic investigation of inhaled nitric oxide in newborn babies with severe hypoxaemia. Lancet 1994; 344: 303-5.
• Clyman RI, Liebowitz M, Kaempf J, et al. PDA-TOLERATE trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at 1 week of age. Pediatr 2019; 205: 41-8.
• Lakshminrusimha S. Neonatal and Postneonatal Pulmonary Hypertension. Children (Basel) 2021; 8: 131.
• Nakwan N. The practical challenges of diagnosis and treatment options in persistent pulmonary hypertension of the newborn: a developing country’s perspective. Am J Perinatol 2018; 35: 1366-75.
• Mat Bah MN, Tan RYH, Razak H, Sapian MH, Abdullah N, Alias EY. Survival and associated risk factors for mortality among infants with persistent pulmonary hypertension of the newborn in Malaysia. J Perinatol 2021; 41: 786-93.
• Nair J, Lakshminrusimha S. Update on PPHN: Mechanisms and treatment. Semin Perinatol 2014; 38: 78–91.
• Kinsella JP, Parker TA, Galan H, Sheridan BC, Halbower AC, Abman SH. Effects of inhaled nitric oxide on pulmonary edema and lung neutrophil accumulation in severe experimental hyaline membrane disease. Pediatr Res 1997; 41: 457-63.
• Roberts JD Jr, Chiche JD, Weimann J, Steudel W, Zapol WM, Bloch KD. Nitric oxide inhalation decreases pulmonary artery remodeling in the injured lungs of rat pups. Circ Res 2000; 87: 140-5.
• Seth SA, Soraisham AS, Harabor A. Risk factors and outcomes of early pulmonary hypertension in preterm infants. J Matern Fetal Neonatal Med 2018; 31: 3147-52.
• Udland CJ, Carey WA, Weaver AL, Mara KC, Clark RH, Ellsworth KR. Birth size and gestational age specific outcomes of inhaled nitric oxide therapy in preterm neonates with clinically diagnosed pulmonary hypertension. Am J Perinatol 2019; 36: 1471-80.
• Peluso AM, Othman HF, Karnati S, Sammour I, Aly HZ. Epidemiologic evaluation of inhaled nitric oxide use among neonates with gestational age less than 35 weeks. Pediatr Pulmonol 2022; 57: 427-34.
• Aikio O, Metsola J, Vuolteenaho R, Perhomaa M, Hallman M. Transient defect in nitric oxide generation after rupture of fetal membranes and responsiveness to inhaled nitric oxide in very preterm infants with hypoxic respiratory failure. J Pediatr 2012; 161: 397–403.e1.
• Chock VY, Van Meurs KP, Hintz SR, et al; NICHD Neonatal Research Network. Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol 2009; 26: 317-22.
• Baczynski M, Ginty S, Weisz DE, et al. Short-term and long-term outcomes of preterm neonates with acute severe pulmonary hypertension following rescue treatment with inhaled nitric oxide. Arch Dis Child Fetal Neonatal Ed 2017; 102: F508-14.
• Tworetzky W, Bristow J, Moore P, et al. Inhaled nitric oxide in neonates with persistent pulmonary hypertension. Lancet 2001; 357: 118-20.
• Fortas F, Di Nardo M, Yousef N, Humbert M, De Luca D. Life-threatening PPHN refractory to nitric oxide: proposal for a rational therapeutic algorithm. Eur J Pediatr 2021; 180: 2379-87.
• Vieira F, Makoni M, Szyld E, Sekar K. The controversy persists: is there a qualification criterion to utilize inhaled nitric oxide in pre-term newborns? Front Pediatr 2021; 9: 631765.
• Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 2002; 106: 913-9.
• Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitric oxide inhalation therapy in very low-birthweight infants with hypoplastic lung due to oligohydramnios. Pediatr Int 2004; 46: 10-4.
• Geary C, Whitsett J. Inhaled nitric oxide for oligohydramnios-induced pulmonary hypoplasia: a report of two cases and review of the literature. J Perinatol 2002;22:82-5.
• Abman SH. New guidelines for managing pulmonary hypertension: what the pediatrician needs to know. Curr Opin Pediatr 2016; 28: 597-606.
• Kwack WG, Lee DS, Min H, et al. Evaluation of the SpO2/FiO2 ratio as a predictor of intensive care unit transfers in respiratory ward patients for whom the rapid response system has been activated. PLoS One 2018; 13: e0201632.