Pulmonary Hypertension in Patients with Congenital Diaphragmatic Hernia: Does Lung Size Matter?

Abstract

Purpose The relationship between pulmonary hypoplasia and pulmonary arterial hypertension (PHTN) in patients with congenital diaphragmatic hernia (CDH) remains ill-defined. We hypothesized that prenatal estimates of lung size would directly correlate with PHTN severity.

Methods Infants with isolated CDH (born 2004–2015) at a single institution were included. Estimates of lung size included observed-to-expected LHR (o:eLHR) and %-predicted lung volumes (PPLV = observed/predicted volumes). The primary outcome was severity of PHTN (grade 0–3) on echocardiography performed between day of life 3 and 30.

Results Among 62 patients included, there was 32% mortality and 65% ECMO utilization. PPLV (odds ratio [OR] = 0.94 per 1 grade in PHTN severity, 95% confidence interval [CI] = 0.89–0.98, p < 0.01) and o:eLHR (OR = 0.97, 95% CI = 0.94–0.99, p < 0.01) were significantly associated with PHTN grade. Among patients on ECMO, PPLV (OR = 0.92, 95% CI = 0.84–0.99, p = 0.03) and o:eLHR (OR = 0.95, 95% CI = 0.92–0.99, p = 0.01) were more strongly associated with PHTN grade. PPLV and o:eLHR were significantly associated with the use of inhaled nitric oxide (iNO) (OR = 0.90, 95% CI = 0.83–0.98, p = 0.01 and OR = 0.94, 95% CI = 0.91–0.98, p < 0.01, respectively) and epoprostenol (OR = 0.91, 95% CI = 0.84–0.99, p = 0.02 and OR = 0.93, 95% CI = 0.89–0.98, p < 0.01, respectively).

Conclusion Among infants with isolated CDH, PPLV, and o:eLHR were significantly associated with PHTN severity, especially among patients requiring ECMO. Prenatal lung size may help predict postnatal PHTN and associated therapies.

Keywords

congenital diaphragmatic hernia - pulmonary hypertension - pulmonary hypoplasia - prenatal ultrasonography - magnetic resonance imaging

^* Both the authors contributed equally to the article.

• References

• 1 Lally KP, Lally PA, Lasky RE. , et al; Congenital Diaphragmatic Hernia Study Group. Defect size determines survival in infants with congenital diaphragmatic hernia. Pediatrics 2007; 120 (03) e651-e657
• 2 Boloker J, Bateman DA, Wung J-T, Stolar CJ. Congenital diaphragmatic hernia in 120 infants treated consecutively with permissive hypercapnea/spontaneous respiration/elective repair. J Pediatr Surg 2002; 37 (03) 357-366
• 3 Downard CD, Jaksic T, Garza JJ. , et al. Analysis of an improved survival rate for congenital diaphragmatic hernia. J Pediatr Surg 2003; 38 (05) 729-732
• 4 Javid PJ, Jaksic T, Skarsgard ED, Lee S. ; Canadian Neonatal Network. Survival rate in congenital diaphragmatic hernia: the experience of the Canadian Neonatal Network. J Pediatr Surg 2004; 39 (05) 657-660
• 5 Cortes RA, Keller RL, Townsend T. , et al. Survival of severe congenital diaphragmatic hernia has morbid consequences. J Pediatr Surg 2005; 40 (01) 36-45
• 6 Peetsold MG, Heij HA, Kneepkens CM, Nagelkerke AF, Huisman J, Gemke RJ. The long-term follow-up of patients with a congenital diaphragmatic hernia: a broad spectrum of morbidity. Pediatr Surg Int 2009; 25 (01) 1-17
• 7 Chiu P, Hedrick HL. Postnatal management and long-term outcome for survivors with congenital diaphragmatic hernia. Prenat Diagn 2008; 28 (07) 592-603
• 8 Pober BR. Overview of epidemiology, genetics, birth defects, and chromosome abnormalities associated with CDH. Am J Med Genet C Semin Med Genet 2007; 145C [phone]
• 9 Pober BR, Lin A, Russell M. , et al. Infants with Bochdalek diaphragmatic hernia: sibling precurrence and monozygotic twin discordance in a hospital-based malformation surveillance program. Am J Med Genet A 2005; 138A (02) 81-88
• 10 Bleyl SB, Moshrefi A, Shaw GM. , et al. Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFRalpha reveals rare variants in diaphragmatic hernia patients. Eur J Hum Genet 2007; 15 (09) 950-958
• 11 Ackerman KG, Pober BR. Congenital diaphragmatic hernia and pulmonary hypoplasia: new insights from developmental biology and genetics. Am J Med Genet C Semin Med Genet 2007; 145C [phone]
• 12 Robinson PD, Fitzgerald DA. Congenital diaphragmatic hernia. Paediatr Respir Rev 2007; 8 (04) 323-334
• 13 Kinane TB. Lung development and implications for hypoplasia found in congenital diaphragmatic hernia. Am J Med Genet C Semin Med Genet 2007; 145C [phone]
• 14 Ruano R, Aubry MC, Barthe B, Mitanchez D, Dumez Y, Benachi A. Quantitative analysis of fetal pulmonary vasculature by 3-dimensional power Doppler ultrasonography in isolated congenital diaphragmatic hernia. Am J Obstet Gynecol 2006; 195 (06) 1720-1728
• 15 Keller RL. Antenatal and postnatal lung and vascular anatomic and functional studies in congenital diaphragmatic hernia: implications for clinical management. Am J Med Genet C Semin Med Genet 2007; 145C [phone]
• 16 Lin AE, Pober BR, Adatia I. Congenital diaphragmatic hernia and associated cardiovascular malformations: type, frequency, and impact on management. Am J Med Genet C Semin Med Genet 2007; 145C [phone]
• 17 Jesudason EC. Airway smooth muscle: an architect of the lung?. Thorax 2009; 64 (06) 541-545
• 18 Jesudason EC. Small lungs and suspect smooth muscle: congenital diaphragmatic hernia and the smooth muscle hypothesis. J Pediatr Surg 2006; 41 (02) 431-435
• 19 Keller RL, Moore P, Teitel D, Hawgood S, McQuitty J, Fineman JR. Abnormal vascular tone in infants and children with lung hypoplasia: findings from cardiac catheterization and the response to chronic therapy. Pediatr Crit Care Med 2006; 7 (06) 589-594
• 20 Bagolan P, Morini F. Long-term follow up of infants with congenital diaphragmatic hernia. Semin Pediatr Surg 2007; 16 (02) 134-144
• 21 Pederiva F, Aras Lopez R, Martinez L, Tovar JA. Abnormal development of tracheal innervation in rats with experimental diaphragmatic hernia. Pediatr Surg Int 2008; 24 (12) 1341-1346
• 22 Hedrick HL, Danzer E, Merchant A. , et al. Liver position and lung-to-head ratio for prediction of extracorporeal membrane oxygenation and survival in isolated left congenital diaphragmatic hernia. Am J Obstet Gynecol 2007; 197 (04) 422.e1-422.e4
• 23 Metkus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996; 31 (01) 148-151
• 24 Lipshutz GS, Albanese CT, Feldstein VA. , et al. Prospective analysis of lung-to-head ratio predicts survival for patients with prenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 1997; 32 (11) 1634-1636
• 25 Jani J, Peralta CF, Van Schoubroeck D, Deprest J, Nicolaides KH. Relationship between lung-to-head ratio and lung volume in normal fetuses and fetuses with diaphragmatic hernia. Ultrasound Obstet Gynecol 2006; 27 (05) 545-550
• 26 Walsh DS, Hubbard AM, Olutoye OO. , et al. Assessment of fetal lung volumes and liver herniation with magnetic resonance imaging in congenital diaphragmatic hernia. Am J Obstet Gynecol 2000; 183 (05) 1067-1069
• 27 Jani J, Cannie M, Sonigo P. , et al. Value of prenatal magnetic resonance imaging in the prediction of postnatal outcome in fetuses with diaphragmatic hernia. Ultrasound Obstet Gynecol 2008; 32 (06) 793-799
• 28 Sharma S, Abubakar KM, Keszler M. Tidal volume in infants with congenital diaphragmatic hernia supported with conventional mechanical ventilation. Am J Perinatol 2015; 32 (06) 577-582
• 29 Congenital Diaphragmatic Hernia Study Group. Estimating disease severity of congenital diaphragmatic hernia in the first 5 minutes of life. J Pediatr Surg 2001; 36 (01) 141-145
• 30 Peralta CF, Cavoretto P, Csapo B, Vandecruys H, Nicolaides KH. Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol 2005; 26 (07) 718-724
• 31 Rypens F, Metens T, Rocourt N. , et al. Fetal lung volume: estimation at MR imaging-initial results. Radiology 2001; 219 (01) 236-241
• 32 Kang C, Zhao E, Zhou Y. , et al. Dynamic changes of pulmonary arterial pressure and ductus arteriosus in human newborns from birth to 72 hours of age. Medicine (Baltimore) 2016; 95 (03) e2599
• 33 Lai WW, Geva T, Shirali GS. , et al; Task Force of the Pediatric Council of the American Society of Echocardiography; Pediatric Council of the American Society of Echocardiography. Guidelines and standards for performance of a pediatric echocardiogram: a report from the Task Force of the Pediatric Council of the American Society of Echocardiography. J Am Soc Echocardiogr 2006; 19 (12) 1413-1430
• 34 Ruano R, Aubry MC, Barthe B, Dumez Y, Benachi A. Three-dimensional ultrasonographic measurements of the fetal lungs for prediction of perinatal outcome in isolated congenital diaphragmatic hernia. J Obstet Gynaecol Res 2009; 35 (06) 1031-1041
• 35 Russo FM, Eastwood MP, Keijzer R. , et al. Lung size and liver herniation predict the need for extra corporeal membrane oxygenation but not pulmonary hypertension in isolated congenital diaphragmatic hernia: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2017; 49 (06) 704-713
• 36 Ruano R, Aubry MC, Barthe B, Mitanchez D, Dumez Y, Benachi A. Predicting perinatal outcome in isolated congenital diaphragmatic hernia using fetal pulmonary artery diameters. J Pediatr Surg 2008; 43 (04) 606-611
• 37 Sokol J, Shimizu N, Bohn D, Doherty D, Ryan G, Hornberger LK. Fetal pulmonary artery diameter measurements as a predictor of morbidity in antenatally diagnosed congenital diaphragmatic hernia: a prospective study. Am J Obstet Gynecol 2006; 195 (02) 470-477
• 38 Vuletin JF, Lim FY, Cnota J. , et al. Prenatal pulmonary hypertension index: novel prenatal predictor of severe postnatal pulmonary artery hypertension in antenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 2010; 45 (04) 703-708
• 39 Spaggiari E, Stirnemann JJ, Sonigo P, Khen-Dunlop N, De Saint Blanquat L, Ville Y. Prenatal prediction of pulmonary arterial hypertension in congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2015; 45 (05) 572-577
• 40 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
• 41 Lally KP. The role of ECMO in neonates with CDH. AAP Grand Rounds 1999; 2: 28
• 42 Rothenbach P, Lange P, Powell D. The use of extracorporeal membrane oxygenation in infants with congenital diaphragmatic hernia. Semin Perinatol 2005; 29 (01) 40-44
• 43 Kim ES, Stolar CJ. ECMO in the newborn. Am J Perinatol 2000; 17 (07) 345-356
• 44 Dillon PW, Cilley RE, Mauger D, Zachary C, Meier A. The relationship of pulmonary artery pressure and survival in congenital diaphragmatic hernia. J Pediatr Surg 2004; 39 (03) 307-312
• 45 The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997; 99 (06) 838-845
• 46 Campbell BT, Herbst KW, Briden KE, Neff S, Ruscher KA, Hagadorn JI. Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia. Pediatrics 2014; 134 (02) e420-e426
• 47 Hayward MJ, Kharasch V, Sheils C. , et al. Predicting inadequate long-term lung development in children with congenital diaphragmatic hernia: an analysis of longitudinal changes in ventilation and perfusion. J Pediatr Surg 2007; 42 (01) 112-116
• 48 Coughlin MA, Werner NL, Gajarski R. , et al. Prenatally diagnosed severe CDH: mortality and morbidity remain high. J Pediatr Surg 2016; 51 (07) 1091-1095
• 49 Madenci AL, Sjogren AR, Treadwell MC. , et al. Another dimension to survival: predicting outcomes with fetal MRI versus prenatal ultrasound in patients with congenital diaphragmatic hernia. J Pediatr Surg 2013; 48 (06) 1190-1197