Management Practice and Mortality for Infants with Congenital Diaphragmatic Hernia

Abstract

Objective Congenital diaphragmatic hernia (CDH) is fatal in 20 to 40% of cases, largely due to pulmonary dysmaturity, lung hypoplasia, and persistent pulmonary hypertension. Evidence for survival benefit of inhaled nitric oxide (iNO), extracorporeal membrane oxygenation (ECMO), and other medical interventions targeting pulmonary hypertension is lacking. We assessed medical interventions and mortality over time in a large multicenter cohort of infants with CDH.

Study Design We identified all infants ≥ 34 weeks' gestation with CDH discharged from 29 neonatal intensive care units between 1999 and 2012 with an average of ≥ 2 CDH admissions per year. We examined mortality and the proportion of infants exposed to medical interventions, comparing four periods of time: 1999–2001, 2002–2004, 2005–2007, and 2008–2012.

Results We identified 760 infants with CDH. From 1999–2001 to 2008–2012, use of iNO increased from 20% of infants to 50%, sildenafil use increased from 0 to 14%, and milrinone use increased from 0 to 22% (p < 0.001). Overall mortality (28%) did not significantly change over time compared with the earliest time period.

Conclusion Despite changing use of iNO, sildenafil, and milrinone, CDH mortality has not significantly decreased in this population of infants.

Keywords

infants - congenital diaphragmatic hernia - lung dysmaturity - lung hypoplasia - pulmonary hypertension - respiratory management

• References

• 1 Colvin J, Bower C, Dickinson JE, Sokol J. Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia. Pediatrics 2005; 116 (3) e356-e363
• 2 Langham Jr MR, Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic hernia. Epidemiology and outcome. Clin Perinatol 1996; 23 (4) 671-688
• 3 Philip N, Gambarelli D, Guys JM, Camboulives J, Ayme S. Epidemiological study of congenital diaphragmatic defects with special reference to aetiology. Eur J Pediatr 1991; 150 (10) 726-729
• 4 Logan JW, Rice HE, Goldberg RN, Cotten CM. Congenital diaphragmatic hernia: a systematic review and summary of best-evidence practice strategies. J Perinatol 2007; 27 (9) 535-549
• 5 Seetharamaiah R, Younger JG, Bartlett RH, Hirschl RB ; Congenital Diaphragmatic Hernia Study Group. Factors associated with survival in infants with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation: a report from the Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg 2009; 44 (7) 1315-1321
• 6 van den Hout L, Schaible T, Cohen-Overbeek TE , et al. Actual outcome in infants with congenital diaphragmatic hernia: the role of a standardized postnatal treatment protocol. Fetal Diagn Ther 2011; 29 (1) 55-63
• 7 Abdullah F, Zhang Y, Sciortino C , et al. Congenital diaphragmatic hernia: outcome review of 2,173 surgical repairs in US infants. Pediatr Surg Int 2009; 25 (12) 1059-1064
• 8 George DK, Cooney TP, Chiu BK, Thurlbeck WM. Hypoplasia and immaturity of the terminal lung unit (acinus) in congenital diaphragmatic hernia. Am Rev Respir Dis 1987; 136 (4) 947-950
• 9 Congenital Diaphragmatic Hernia Study Group. Estimating disease severity of congenital diaphragmatic hernia in the first 5 minutes of life. J Pediatr Surg 2001; 36 (1) 141-145
• 10 Tsao K, Allison ND, Harting MT, Lally PA, Lally KP. Congenital diaphragmatic hernia in the preterm infant. Surgery 2010; 148 (2) 404-410
• 11 Rocha G, Azevedo I, Pinto JC, Guimarães H. Follow-up of the survivors of congenital diaphragmatic hernia. Early Hum Dev 2012; 88 (4) 255-258
• 12 Lally KP, Engle W ; American Academy of Pediatrics Section on Surgery; American Academy of Pediatrics Committee on Fetus and Newborn. Postdischarge follow-up of infants with congenital diaphragmatic hernia. Pediatrics 2008; 121 (3) 627-632
• 13 Friedman S, Chen C, Chapman JS , et al. Neurodevelopmental outcomes of congenital diaphragmatic hernia survivors followed in a multidisciplinary clinic at ages 1 and 3. J Pediatr Surg 2008; 43 (6) 1035-1043
• 14 Muratore CS, Kharasch V, Lund DP , et al. Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic. J Pediatr Surg 2001; 36 (1) 133-140
• 15 Ng GY, Derry C, Marston L, Choudhury M, Holmes K, Calvert SA. Reduction in ventilator-induced lung injury improves outcome in congenital diaphragmatic hernia?. Pediatr Surg Int 2008; 24 (2) 145-150
• 16 van den Hout L, Reiss I, Felix JF , et al; Congenital Diaphragmatic Hernia Study Group. Risk factors for chronic lung disease and mortality in newborns with congenital diaphragmatic hernia. Neonatology 2010; 98 (4) 370-380
• 17 Maier S, Zahn K, Wessel LM, Schaible T, Brade J, Reinshagen K. Preventive antireflux surgery in neonates with congenital diaphragmatic hernia: a single-blinded prospective study. J Pediatr Surg 2011; 46 (8) 1510-1515
• 18 Morini F, Capolupo I, Masi R , et al. Hearing impairment in congenital diaphragmatic hernia: the inaudible and noiseless foot of time. J Pediatr Surg 2008; 43 (2) 380-384
• 19 Muratore CS, Utter S, Jaksic T, Lund DP, Wilson JM. Nutritional morbidity in survivors of congenital diaphragmatic hernia. J Pediatr Surg 2001; 36 (8) 1171-1176
• 20 Azarow K, Messineo A, Pearl R, Filler R, Barker G, Bohn D. Congenital diaphragmatic hernia—a tale of two cities: the Toronto experience. J Pediatr Surg 1997; 32 (3) 395-400
• 21 Bagolan P, Casaccia G, Crescenzi F, Nahom A, Trucchi A, Giorlandino C. Impact of a current treatment protocol on outcome of high-risk congenital diaphragmatic hernia. J Pediatr Surg 2004; 39 (3) 313-318 , discussion 313–318
• 22 Bohn D. Congenital diaphragmatic hernia. Am J Respir Crit Care Med 2002; 166 (7) 911-915
• 23 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 (4) 488-494
• 24 Rocha GM, Bianchi RF, Severo M , et al. Congenital diaphragmatic hernia - the neonatal period (part I). Eur J Pediatr Surg 2008; 18 (4) 219-223
• 25 Rozmiarek AJ, Qureshi FG, Cassidy L, Ford HR, Hackam DJ. Factors influencing survival in newborns with congenital diaphragmatic hernia: the relative role of timing of surgery. J Pediatr Surg 2004; 39 (6) 821-824 , discussion 821–824
• 26 Tracy ET, Mears SE, Smith PB , et al. Protocolized approach to the management of congenital diaphragmatic hernia: benefits of reducing variability in care. J Pediatr Surg 2010; 45 (6) 1343-1348
• 27 Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006; (4) CD000399
• 28 The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997; 99 (6) 838-845
• 29 Van Meurs K ; Congenital Diaphragmatic Hernia Study Group. Is surfactant therapy beneficial in the treatment of the term newborn infant with congenital diaphragmatic hernia?. J Pediatr 2004; 145 (3) 312-316
• 30 Noori S, Friedlich P, Wong P, Garingo A, Seri I. Cardiovascular effects of sildenafil in neonates and infants with congenital diaphragmatic hernia and pulmonary hypertension. Neonatology 2007; 91 (2) 92-100
• 31 Downey LC, Benjamin Jr DK, Clark RH , et al. Urinary tract infection concordance with positive blood and cerebrospinal fluid cultures in the neonatal intensive care unit. J Perinatol 2013; 33 (4) 302-306
• 32 Frenckner B, Ehrén H, Granholm T, Lindén V, Palmér K. Improved results in patients who have congenital diaphragmatic hernia using preoperative stabilization, extracorporeal membrane oxygenation, and delayed surgery. J Pediatr Surg 1997; 32 (8) 1185-1189
• 33 Wung JT, Sahni R, Moffitt ST, Lipsitz E, Stolar CJ. Congenital diaphragmatic hernia: survival treated with very delayed surgery, spontaneous respiration, and no chest tube. J Pediatr Surg 1995; 30 (3) 406-409
• 34 Jacobs P, Finer NN, Robertson CM, Etches P, Hall EM, Saunders LD. A cost-effectiveness analysis of the application of nitric oxide versus oxygen gas for near-term newborns with respiratory failure: results from a Canadian randomized clinical trial. Crit Care Med 2000; 28 (3) 872-878
• 35 Downard CD, Jaksic T, Garza JJ , et al. Analysis of an improved survival rate for congenital diaphragmatic hernia. J Pediatr Surg 2003; 38 (5) 729-732
• 36 Kim H, Park JD, Kim HS , et al. Survival rate changes in neonates with congenital diaphragmatic hernia and its contributing factors. J Korean Med Sci 2007; 22 (4) 687-692
• 37 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 (4) 1077-1083
• 38 Carroll WD, Dhillon R. Sildenafil as a treatment for pulmonary hypertension. Arch Dis Child 2003; 88 (9) 827-828
• 39 FDA Drug Safety Communication. FDA recommends against use of Revatio in children with pulmonary hypertension. 2012; Available at: http://www.fda.gov/Drugs/DrugSafety/ucm317123.htm
• 40 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 (2) 324-334
• 41 Hunter L, Richens T, Davis C, Walker G, Simpson JH. Sildenafil use in congenital diaphragmatic hernia. Arch Dis Child Fetal Neonatal Ed 2009; 94 (6) F467
• 42 Patel N. Use of milrinone to treat cardiac dysfunction in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia: a review of six patients. Neonatology 2012; 102 (2) 130-136
• 43 Bassler D, Kreutzer K, McNamara P, Kirpalani H. Milrinone for persistent pulmonary hypertension of the newborn. Cochrane Database Syst Rev 2010; (11) CD007802
• 44 Khazin V, Kaufman Y, Zabeeda D , et al. Milrinone and nitric oxide: combined effect on pulmonary artery pressures after cardiopulmonary bypass in children. J Cardiothorac Vasc Anesth 2004; 18 (2) 156-159
• 45 Frenckner B, Broomé M, Lindström M, Radell P. Platelet-derived growth factor inhibition—a new treatment of pulmonary hypertension in congenital diaphragmatic hernia?. J Pediatr Surg 2008; 43 (10) 1928-1931
• 46 Inamura N, Kubota A, Nakajima T , et al. A proposal of new therapeutic strategy for antenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 2005; 40 (8) 1315-1319
• 47 Hofmann SR, Stadler K, Heilmann A , et al. Stabilisation of cardiopulmonary function in newborns with congenital diaphragmatic hernia using lung function parameters and hemodynamic management. Klin Padiatr 2012; 224 (4) e1-e10
• 48 Shiyanagi S, Okazaki T, Shoji H , et al. Management of pulmonary hypertension in congenital diaphragmatic hernia: nitric oxide with prostaglandin-E1 versus nitric oxide alone. Pediatr Surg Int 2008; 24 (10) 1101-1104
• 49 Lally KP, Lally PA, Langham MR , et al; Congenital Diaphragmatic Hernia Study Group. Surfactant does not improve survival rate in preterm infants with congenital diaphragmatic hernia. J Pediatr Surg 2004; 39 (6) 829-833
• 50 Bucher BT, Guth RM, Saito JM, Najaf T, Warner BW. Impact of hospital volume on in-hospital mortality of infants undergoing repair of congenital diaphragmatic hernia. Ann Surg 2010; 252 (4) 635-642
• 51 Clark RH, Hardin Jr WD, Hirschl RB , et al. Current surgical management of congenital diaphragmatic hernia: a report from the Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg 1998; 33 (7) 1004-1009
• 52 Evans MJ, McKeever PA, Pearson GA, Field D, Firmin RK. Pathological complications of non-survivors of newborn extracorporeal membrane oxygenation. Arch Dis Child 1994; 71 (2) F88-F92
• 53 Hanekamp MN, Mazer P, van der Cammen-van Zijp MH , et al. Follow-up of newborns treated with extracorporeal membrane oxygenation: a nationwide evaluation at 5 years of age. Crit Care 2006; 10 (5) R127
• 54 McNally H, Bennett CC, Elbourne D, Field DJ ; UK Collaborative ECMO Trial Group. United Kingdom collaborative randomized trial of neonatal extracorporeal membrane oxygenation: follow-up to age 7 years. Pediatrics 2006; 117 (5) e845-e854
• 55 Grushka JR, Laberge JM, Puligandla P, Skarsgard ED ; Canadian Pediatric Surgery Network. Effect of hospital case volume on outcome in congenital diaphragmatic hernia: the experience of the Canadian Pediatric Surgery Network. J Pediatr Surg 2009; 44 (5) 873-876
• 56 Su W, Berry M, Puligandla PS, Aspirot A, Flageole H, Laberge JM. Predictors of gastroesophageal reflux in neonates with congenital diaphragmatic hernia. J Pediatr Surg 2007; 42 (10) 1639-1643