Congenital Diaphragmatic Hernia: Not Quite There Yet

Abstract

See related article, p 114Congenital diaphragmatic hernia (CDH) remains one of the most challenging and frustrating conditions that neonatologists and pediatric surgeons encounter in their daily practice. Although not rare, the condition is uncommon enough that it has proven to be quite difficult to study systematically, with no single center having a large-enough population to conduct a good randomized trial. Multicenter trials are the obvious solution for uncommon conditions, but the realities of shared management and the strong practice style preferences as determined by personal experience and training have conspired against effective collaborative research. In the absence of prospective intervention trials, database analyses and observational studies such as the article by Wynn et al1Wynn J. Krishnan U. Aspelund G. Zhang Y. Duong J. Stolar C.J.H. et al.Outcomes of congenital diaphragmatic hernia (CDH) in the modern era of management: impact of right sided lesions, birth weight and associated anomalies with pulmonary hypertension and mortality.J Pediatr. 2013; 163: 114-119Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar in this issue of The Journal have been the most useful, if limited, source of knowledge. Despite some progress during the past 20 years, even the basic question of whether survival has really improved is in some doubt. Although individual center reports have highlighted excellent survival rates for defined time periods, population-based studies paint a less-optimistic picture, suggesting that the rate of pregnancy termination and death before reaching a tertiary center introduce a major case selection bias and lead to overestimation of true survival rates.2Stege G. Fenton A. Jaffray B. Nihilism in the 1990s: the true mortality of congenital diaphragmatic hernia.Pediatrics. 2003; 112: 532-535Crossref PubMed Scopus (398) Google Scholar, 3Ontario Congenital Anomalies Study GroupApparent truth about congenital diaphragmatic hernia: a population-based database is needed to establish benchmarking for clinical outcomes for CDH.J Pediatr Surg. 2004; 39: 661-665Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 4Colvin J. Bower C. Dickinson J.E. Sokol J. Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia.Pediatrics. 2005; 116: e356-e363Crossref PubMed Scopus (337) Google Scholar, 5Mah V.K. Chiu P. Kim P.C. Are we making a real difference? Update on ‘hidden mortality’ in the management of congenital diaphragmatic hernia.Fetal Diagn Ther. 2011; 29: 40-45Crossref PubMed Scopus (19) Google ScholarIn the present study, the authors focus on pulmonary hypertension (PH), perhaps the most important aspect of the complex CDH pathophysiology and a key factor affecting survival. They report that persistently increased pulmonary artery pressure was associated with all the factors known to correlate with worse outcomes: need for patch repair, need for extracorporeal membrane oxygenation, and presence of associated major congenital anomalies. Unsurprisingly, the persistence of PH at 1 and 3 months was a poor prognostic sign for survival. Although these findings are not especially novel, this association has not previously been so systematically documented. The study has important strengths, including the relatively large cohort of patients with this uncommon diagnosis, the expertise of the collaborating centers, and the central reading of echocardiograms by 2 cardiologists with final classification by consensus.As is the case with most observational studies, the present work suffers from some limitations. Although the parent Diaphragmatic Hernia Research & Exploration, Advancing Medical Science study has a prospective design, it appears that the observations reported here are derived from echocardiograms obtained for clinical indications, suggested by the very wide window defining the “1-month” echocardiogram (any study done between 14 and 45 days) and the “3-month” echocardiogram (anywhere between 2 and 6 months). Despite these generous windows, many infants did not have a study echocardiogram available. In addition, there would inevitably be substantial variation in practice that may affect the outcomes.6Baird R. Eeson G. Safavi A. Puligandla P. Laberge J.M. Skarsgard ED for the Canadian Pediatric Surgery NetworkInstitutional practice and outcome variation in the management of congenital diaphragmatic hernia and gastroschisis in Canada: a report from the Canadian Pediatric Surgery Network.J Pediatr Surg. 2011; 46: 801-807Abstract Full Text Full Text PDF PubMed Scopus (62) Google ScholarThe authors attempted to address this by comparing certain outcomes among the participating centers, but a more robust approach would probably be to include “center” as a variable in the multiple regression model. At first blush, it appears that PH improves over time, because fewer infants have PH at 3 months. However, the infants with the worst PH may have died (there were 23 deaths in the interval), and the results of many echocardiograms were unavailable. Although informative, the study does not help us understand the specific mechanisms responsible for the persistence of PH nor to elucidate what therapies, if any, among the many that have been tried may be effective. Clearly, there is a complex interaction between pulmonary hypoplasia and the associated volutrauma, the dysregulated pulmonary vasculature, and the small size of the pulmonary vascular tree, resulting in a relative increase in blood flow through each vessel, which may lead to endothelial damage.In a recent study, Keller et al7Keller R.L. Tacy T.A. Hendricks-Munoz K. Congenital diaphragmatic hernia endothelin-1, pulmonary hypertension, and disease severity.Am J Respir Crit Care Med. 2010; 182: 555-561Crossref PubMed Scopus (117) Google Scholar explored the role of endothelin in the progression of PH in a cohort of 40 patients with CDH. They reported an association of elevated endothelin levels, persistence of PH, and poor outcome. They postulated that dysregulation of the endothelin pathway may contribute to persistence of PH. However, it could not be determined from the study whether endothelin elevation was a marker or a cause of persistent PH because ventilator associated lung injury also causes elevated endothelin levels.8Shinkai T. Shima H. Solari V. Puri P. Expression of vasoactive mediators during mechanical ventilation in nitrofen-induced diaphragmatic hernia in rats.Pediatr Surg Int. 2005; 21: 143-147Crossref PubMed Scopus (19) Google Scholar The endothelin pathway is 1 of the 3 pathways known to be involved in the regulation of vascular tone and thus, if in fact endothelin dysregulation is an important contributing factor to the persistence of PH, it would provide the justification to study the use of bosentan as a long-term therapy for PH. Such research is greatly needed because the off-label use of bosentan, sildenafil, and various prostanoids is widespread, with essentially no published data on safety and efficacy in the neonatal population.Patients with CDH often do not respond to therapies shown to be effective in patients with persistent PH of the newborn resulting from other etiologies. This is likely the result of the complex pathophysiology found in infants with CDH that includes deficient pulmonary parenchymal mass, hypoplastic pulmonary vasculature with dysregulated vascular development, and various degrees of underdevelopment of the left ventricle. This constellation of abnormalities makes these infants uniquely susceptible to volutrauma and refractory PH. Pulmonary hypoplasia leads to extreme susceptibility to overexpansion, especially after the abdominal contents are removed from the thoracic cavity and the lung is potentially able to fill the void. Although re-expansion of a previously normal-sized lung that was acutely compressed by air or liquid is clearly beneficial, rapid expansion of a hypoplastic lung results in volutrauma and in compression of intrapulmonary capillaries that can acutely worsen PH. This element of the pathophysiology of CDH explains the commonly observed “paradoxical” response to ventilator adjustments; oxygenation often improves when mean airway pressure is reduced.The lack of response to inhaled nitric oxide in infants with CDH has long perplexed neonatologists.9The Neonatal Inhaled Nitric Oxide Study Group (NINOS)Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia.Pediatrics. 1997; 99: 838-845Crossref PubMed Scopus (381) Google Scholar A possible explanation for this phenomenon relates to relative left ventricular (LV) hypoplasia and dysfunction in infants with CDH.10Karamanoukian H.L. Glick P.L. Wilcox D.T. O'Toole S.J. Rossman J.E. Azizkhan R.G. Pathophysiology of congenital diaphragmatic hernia. XI: anatomic and biochemical characterization of the heart in the fetal lamb CDH model.J Pediatr Surg. 1995; 30 (discussion 929): 925-928Abstract Full Text PDF PubMed Scopus (58) Google Scholar LV hypoplasia, as assessed by echocardiographic estimation of LV mass, has been suggested as a predictor of poor outcome.11Schwartz S.M. Vermilion R.P. Hirschl R.B. Evaluation of left ventricular mass in children with left-sided congenital diaphragmatic hernia.J Pediatr. 1994; 125: 447-451Abstract Full Text PDF PubMed Scopus (94) Google Scholar, 12Siebert J.R. Haas J.E. Beckwith J.B. Left ventricular hypoplasia in congenital diaphragmatic hernia.J Pediatr Surg. 1984; 19: 567-571Abstract Full Text PDF PubMed Scopus (135) Google Scholar, 13Baumgart S. Paul J.J. Hubta J.C. Katz A.L. Paul K.E. Spettell C. et al.Cardiac malposition, redistribution of fetal cardiac output, and left heart hypoplasia reduce survival in neonates with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation.J Pediatr. 1998; 133: 57-62Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 14Springer S.C. Fleming D. Hulsey T.C. A statistical model to predict nonsurvival in congenital diaphragmatic Hernia.J Perinatol. 2002; 23: 263-267Crossref Google Scholar In the face of downstream functional obstruction caused by LV dysfunction, dilation of the pulmonary vasculature with inhaled nitric oxide may be akin to pouring more water into a clogged sink. The increased pulmonary blood flow increases oxygenation transiently but may eventually lead to pulmonary edema with subsequent deterioration of respiratory status. This pathophysiology appears to be uniquely suitable for treatment with milrinone, a phosphodiesterase-3 inhibitor that is a pulmonary vasodilator that also has inotropic and lusitropic effects that improve both systolic and diastolic function. With only a single case series in the literature suggesting benefit of this therapy,15Patel 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: 130-136Crossref PubMed Scopus (53) Google Scholar this promising intervention is also in need of further investigation.In the era of aggressive respiratory support, the clinical course of infants with CDH used to be characterized by relative stability early in their course, followed by sometimes-dramatic deterioration resulting from rapidly progressing lung injury and worsening PH. It is well known that both static and cyclic overexpansion of alveoli leads to volutrauma. Excessive tidal volume is now widely recognized as more important than pressure as the cause of ventilator-associated lung injury. Even tidal volumes that are at the low end of the physiologic range of 4-6 mL/kg are likely to lead to volutrauma, given the dramatic reduction in the number of alveoli present in infants with severe CDH, which translates into a larger tidal volume per alveolus, a fact that provides a clear rationale for the use of high-frequency, low-tidal-volume ventilation and permissive hypercapnia. Favorable anecdotal experiences with gentle ventilation and the use of high-frequency ventilation have been at the root of the modern “gentle” approach to mechanical ventilation of infants with CDH, which appears to be the single most important factor in the apparent improvement in survival. Despite the sound rationale for its use, the widespread use of high-frequency ventilation in infants with CDH has not been based on randomized controlled trials. That may soon change with the Ventilation in Infants with Congenital Diaphragmatic Hernia: An International Randomized clinical trial currently on-going in Europe.16van den Hout L. Tibboel D. Vijfhuize S. te Beest H. Hop W. Reiss I. The VICI-trial: high frequency oscillation versus conventional mechanical ventilation in newborns with congenital diaphragmatic hernia: an international multicenter randomized controlled trial.BMC Pediatr. 2011; 11: 98Crossref PubMed Scopus (38) Google Scholar Successful conclusion of this trial would not only provide greatly needed evidence of safety and efficacy for one of the more widely used therapies in this population but finally demonstrate that it is possible to carry out multicenter randomized trials in this challenging population. See related article, p 114Congenital diaphragmatic hernia (CDH) remains one of the most challenging and frustrating conditions that neonatologists and pediatric surgeons encounter in their daily practice. Although not rare, the condition is uncommon enough that it has proven to be quite difficult to study systematically, with no single center having a large-enough population to conduct a good randomized trial. Multicenter trials are the obvious solution for uncommon conditions, but the realities of shared management and the strong practice style preferences as determined by personal experience and training have conspired against effective collaborative research. In the absence of prospective intervention trials, database analyses and observational studies such as the article by Wynn et al1Wynn J. Krishnan U. Aspelund G. Zhang Y. Duong J. Stolar C.J.H. et al.Outcomes of congenital diaphragmatic hernia (CDH) in the modern era of management: impact of right sided lesions, birth weight and associated anomalies with pulmonary hypertension and mortality.J Pediatr. 2013; 163: 114-119Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar in this issue of The Journal have been the most useful, if limited, source of knowledge. Despite some progress during the past 20 years, even the basic question of whether survival has really improved is in some doubt. Although individual center reports have highlighted excellent survival rates for defined time periods, population-based studies paint a less-optimistic picture, suggesting that the rate of pregnancy termination and death before reaching a tertiary center introduce a major case selection bias and lead to overestimation of true survival rates.2Stege G. Fenton A. Jaffray B. Nihilism in the 1990s: the true mortality of congenital diaphragmatic hernia.Pediatrics. 2003; 112: 532-535Crossref PubMed Scopus (398) Google Scholar, 3Ontario Congenital Anomalies Study GroupApparent truth about congenital diaphragmatic hernia: a population-based database is needed to establish benchmarking for clinical outcomes for CDH.J Pediatr Surg. 2004; 39: 661-665Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 4Colvin J. Bower C. Dickinson J.E. Sokol J. Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia.Pediatrics. 2005; 116: e356-e363Crossref PubMed Scopus (337) Google Scholar, 5Mah V.K. Chiu P. Kim P.C. Are we making a real difference? Update on ‘hidden mortality’ in the management of congenital diaphragmatic hernia.Fetal Diagn Ther. 2011; 29: 40-45Crossref PubMed Scopus (19) Google Scholar See related article, p 114 See related article, p 114 In the present study, the authors focus on pulmonary hypertension (PH), perhaps the most important aspect of the complex CDH pathophysiology and a key factor affecting survival. They report that persistently increased pulmonary artery pressure was associated with all the factors known to correlate with worse outcomes: need for patch repair, need for extracorporeal membrane oxygenation, and presence of associated major congenital anomalies. Unsurprisingly, the persistence of PH at 1 and 3 months was a poor prognostic sign for survival. Although these findings are not especially novel, this association has not previously been so systematically documented. The study has important strengths, including the relatively large cohort of patients with this uncommon diagnosis, the expertise of the collaborating centers, and the central reading of echocardiograms by 2 cardiologists with final classification by consensus. As is the case with most observational studies, the present work suffers from some limitations. Although the parent Diaphragmatic Hernia Research & Exploration, Advancing Medical Science study has a prospective design, it appears that the observations reported here are derived from echocardiograms obtained for clinical indications, suggested by the very wide window defining the “1-month” echocardiogram (any study done between 14 and 45 days) and the “3-month” echocardiogram (anywhere between 2 and 6 months). Despite these generous windows, many infants did not have a study echocardiogram available. In addition, there would inevitably be substantial variation in practice that may affect the outcomes.6Baird R. Eeson G. Safavi A. Puligandla P. Laberge J.M. Skarsgard ED for the Canadian Pediatric Surgery NetworkInstitutional practice and outcome variation in the management of congenital diaphragmatic hernia and gastroschisis in Canada: a report from the Canadian Pediatric Surgery Network.J Pediatr Surg. 2011; 46: 801-807Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar The authors attempted to address this by comparing certain outcomes among the participating centers, but a more robust approach would probably be to include “center” as a variable in the multiple regression model. At first blush, it appears that PH improves over time, because fewer infants have PH at 3 months. However, the infants with the worst PH may have died (there were 23 deaths in the interval), and the results of many echocardiograms were unavailable. Although informative, the study does not help us understand the specific mechanisms responsible for the persistence of PH nor to elucidate what therapies, if any, among the many that have been tried may be effective. Clearly, there is a complex interaction between pulmonary hypoplasia and the associated volutrauma, the dysregulated pulmonary vasculature, and the small size of the pulmonary vascular tree, resulting in a relative increase in blood flow through each vessel, which may lead to endothelial damage. In a recent study, Keller et al7Keller R.L. Tacy T.A. Hendricks-Munoz K. Congenital diaphragmatic hernia endothelin-1, pulmonary hypertension, and disease severity.Am J Respir Crit Care Med. 2010; 182: 555-561Crossref PubMed Scopus (117) Google Scholar explored the role of endothelin in the progression of PH in a cohort of 40 patients with CDH. They reported an association of elevated endothelin levels, persistence of PH, and poor outcome. They postulated that dysregulation of the endothelin pathway may contribute to persistence of PH. However, it could not be determined from the study whether endothelin elevation was a marker or a cause of persistent PH because ventilator associated lung injury also causes elevated endothelin levels.8Shinkai T. Shima H. Solari V. Puri P. Expression of vasoactive mediators during mechanical ventilation in nitrofen-induced diaphragmatic hernia in rats.Pediatr Surg Int. 2005; 21: 143-147Crossref PubMed Scopus (19) Google Scholar The endothelin pathway is 1 of the 3 pathways known to be involved in the regulation of vascular tone and thus, if in fact endothelin dysregulation is an important contributing factor to the persistence of PH, it would provide the justification to study the use of bosentan as a long-term therapy for PH. Such research is greatly needed because the off-label use of bosentan, sildenafil, and various prostanoids is widespread, with essentially no published data on safety and efficacy in the neonatal population. Patients with CDH often do not respond to therapies shown to be effective in patients with persistent PH of the newborn resulting from other etiologies. This is likely the result of the complex pathophysiology found in infants with CDH that includes deficient pulmonary parenchymal mass, hypoplastic pulmonary vasculature with dysregulated vascular development, and various degrees of underdevelopment of the left ventricle. This constellation of abnormalities makes these infants uniquely susceptible to volutrauma and refractory PH. Pulmonary hypoplasia leads to extreme susceptibility to overexpansion, especially after the abdominal contents are removed from the thoracic cavity and the lung is potentially able to fill the void. Although re-expansion of a previously normal-sized lung that was acutely compressed by air or liquid is clearly beneficial, rapid expansion of a hypoplastic lung results in volutrauma and in compression of intrapulmonary capillaries that can acutely worsen PH. This element of the pathophysiology of CDH explains the commonly observed “paradoxical” response to ventilator adjustments; oxygenation often improves when mean airway pressure is reduced. The lack of response to inhaled nitric oxide in infants with CDH has long perplexed neonatologists.9The Neonatal Inhaled Nitric Oxide Study Group (NINOS)Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia.Pediatrics. 1997; 99: 838-845Crossref PubMed Scopus (381) Google Scholar A possible explanation for this phenomenon relates to relative left ventricular (LV) hypoplasia and dysfunction in infants with CDH.10Karamanoukian H.L. Glick P.L. Wilcox D.T. O'Toole S.J. Rossman J.E. Azizkhan R.G. Pathophysiology of congenital diaphragmatic hernia. XI: anatomic and biochemical characterization of the heart in the fetal lamb CDH model.J Pediatr Surg. 1995; 30 (discussion 929): 925-928Abstract Full Text PDF PubMed Scopus (58) Google Scholar LV hypoplasia, as assessed by echocardiographic estimation of LV mass, has been suggested as a predictor of poor outcome.11Schwartz S.M. Vermilion R.P. Hirschl R.B. Evaluation of left ventricular mass in children with left-sided congenital diaphragmatic hernia.J Pediatr. 1994; 125: 447-451Abstract Full Text PDF PubMed Scopus (94) Google Scholar, 12Siebert J.R. Haas J.E. Beckwith J.B. Left ventricular hypoplasia in congenital diaphragmatic hernia.J Pediatr Surg. 1984; 19: 567-571Abstract Full Text PDF PubMed Scopus (135) Google Scholar, 13Baumgart S. Paul J.J. Hubta J.C. Katz A.L. Paul K.E. Spettell C. et al.Cardiac malposition, redistribution of fetal cardiac output, and left heart hypoplasia reduce survival in neonates with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation.J Pediatr. 1998; 133: 57-62Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 14Springer S.C. Fleming D. Hulsey T.C. A statistical model to predict nonsurvival in congenital diaphragmatic Hernia.J Perinatol. 2002; 23: 263-267Crossref Google Scholar In the face of downstream functional obstruction caused by LV dysfunction, dilation of the pulmonary vasculature with inhaled nitric oxide may be akin to pouring more water into a clogged sink. The increased pulmonary blood flow increases oxygenation transiently but may eventually lead to pulmonary edema with subsequent deterioration of respiratory status. This pathophysiology appears to be uniquely suitable for treatment with milrinone, a phosphodiesterase-3 inhibitor that is a pulmonary vasodilator that also has inotropic and lusitropic effects that improve both systolic and diastolic function. With only a single case series in the literature suggesting benefit of this therapy,15Patel 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: 130-136Crossref PubMed Scopus (53) Google Scholar this promising intervention is also in need of further investigation. In the era of aggressive respiratory support, the clinical course of infants with CDH used to be characterized by relative stability early in their course, followed by sometimes-dramatic deterioration resulting from rapidly progressing lung injury and worsening PH. It is well known that both static and cyclic overexpansion of alveoli leads to volutrauma. Excessive tidal volume is now widely recognized as more important than pressure as the cause of ventilator-associated lung injury. Even tidal volumes that are at the low end of the physiologic range of 4-6 mL/kg are likely to lead to volutrauma, given the dramatic reduction in the number of alveoli present in infants with severe CDH, which translates into a larger tidal volume per alveolus, a fact that provides a clear rationale for the use of high-frequency, low-tidal-volume ventilation and permissive hypercapnia. Favorable anecdotal experiences with gentle ventilation and the use of high-frequency ventilation have been at the root of the modern “gentle” approach to mechanical ventilation of infants with CDH, which appears to be the single most important factor in the apparent improvement in survival. Despite the sound rationale for its use, the widespread use of high-frequency ventilation in infants with CDH has not been based on randomized controlled trials. That may soon change with the Ventilation in Infants with Congenital Diaphragmatic Hernia: An International Randomized clinical trial currently on-going in Europe.16van den Hout L. Tibboel D. Vijfhuize S. te Beest H. Hop W. Reiss I. The VICI-trial: high frequency oscillation versus conventional mechanical ventilation in newborns with congenital diaphragmatic hernia: an international multicenter randomized controlled trial.BMC Pediatr. 2011; 11: 98Crossref PubMed Scopus (38) Google Scholar Successful conclusion of this trial would not only provide greatly needed evidence of safety and efficacy for one of the more widely used therapies in this population but finally demonstrate that it is possible to carry out multicenter randomized trials in this challenging population. Outcomes of Congenital Diaphragmatic Hernia in the Modern Era of ManagementThe Journal of PediatricsVol. 163Issue 1PreviewTo identify clinical factors associated with pulmonary hypertension (PH) and mortality in patients with congenital diaphragmatic hernia (CDH). Full-Text PDF