Heart of the Matter? Early Ventricular Dysfunction in Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) represents one of the most challenging causes of respiratory failure managed in neonatal critical care. These challenges arise from the pathophysiological triad of pulmonary hypoplasia, pulmonary vascular disease, and left ventricular (LV) dysfunction associated with herniated abdominal contents, impaired fetal lung growth, and perturbations in umbilical venous return to the developing left ventricle (1). The management of CDH has evolved from a primarily surgical problem to one of integrated prenatal, surgical, respiratory, and cardiac care, principally focusing on lung-protective approaches to support the hypoplastic lungs and reducing the burden of pulmonary hypertension (2–4). Unfortunately, mortality remains persistently high (25–30%) (5), and, in contrast to what has been observed with other causes of severe neonatal respiratory failure, the rates of extracorporeal membrane oxygenation use have not decreased with incremental improvements in ventilatory care (Figure 1). LV hypoplasia has long been recognized as a fetal manifestation of CDH (6), and resultant cardiac dysfunction has been postulated as an important and underappreciated determinant of outcome (1, 7).

Figure 1.

Use of extracorporeal membrane oxygenation for congenital diaphragmatic hernia (gray bars) and meconium aspiration syndrome (solid circles) over the 15-year period after the U.S. Food and Drug Administration approved inhaled nitric oxide for persistent pulmonary hypertension in newborns (16). The marked reduction in the use of extracorporeal membrane oxygenation for meconium aspiration syndrome contrasts with little change in its use for congenital diaphragmatic hernia over this period.

Early cardiac function in CDH is poorly understood, and investigations have been limited to small observational studies (8, 9). The study presented in this issue of the Journal by Patel and colleagues (pp. 1522–1530) is thus timely and provides valuable insight into CDH pathophysiology (10). They report echocardiographic categorizations of LV and right ventricular function performed in the first 48 hours after delivery in 1,173 infants enrolled in the CDH Study Group Registry (59 centers) from 2015 to 2018, a period encompassing current lung-protective ventilatory strategies and a multimodal pharmacological approach to pulmonary hypertension. Some form of ventricular dysfunction was identified on echocardiography in 39% of the infants (15% with isolated right ventricular dysfunction, 5% with LV dysfunction, and 19% with biventricular dysfunction). Both LV and biventricular dysfunction were independently associated with mortality and extracorporeal membrane oxygenation use, with biventricular dysfunction conferring the highest risk of mortality (49%). Importantly, the mortality risks associated with LV/biventricular dysfunction were comparable to established prognosticating factors, specifically the diaphragmatic defect size, presence of liver in the chest, and need for a surgical patch (11). This study provides the first large population signal to support the complex but critical interplay between cardiac function and outcomes for infants born with CDH.

The most important finding of this study is the impact of early LV dysfunction on CDH outcomes. Pulmonary hypertension is established as a hallmark of CDH, and resultant right ventricular systolic and diastolic dysfunction well described (1). The finding that biventricular dysfunction is common in CDH (48% of all infants with any cardiac dysfunction) is thus not surprising. Patel and colleagues show that the left ventricle may also be the primary cause of cardiac dysfunction, whether from hypoplasia and a reduced ability to manage the acute increase in afterload after birth, or by directly elevating pulmonary venous pressure and pulmonary vascular resistance. An understanding of the interplay between right ventricular and LV function will allow the development of targeted therapies. Pulmonary vasodilatation to reduce right-heart afterload is often advocated (3), but in the presence of LV dysfunction this may worsen LV diastolic function and increase systemic hypoxemia and acidosis. In such situations, inotropic and lusitropic support (for example, with the use of milrinone) may be more appropriate; however, there are insufficient data to warrant routine use (12, 13).

The authors provide a strong argument for routine, early assessments of cardiac function. Their study provides the first step toward meaningful translation rather than the definitive answer. In their study, echocardiography was performed in the first 48 hours of life, and only 37.5% of the infants had a second assessment within 14 days, so conclusions regarding balancing LV dysfunction and pulmonary hypertension are limited to the period of immediate preoperative CDH stabilization. Furthermore, echocardiography was not performed on 29% of eligible infants in the registry, highlighting the fact that it is difficult to assess cardiac function. It is also difficult to define “function.” In the study by Patel and colleagues, ventricular function was categorized semiqualitatively by experienced operators. Measures of diastolic and systolic right-sided function were used, but specific parameters for LV dysfunction were not recorded. Although quantitative methods of LV function have been suggested (1, 14), validation of these methods is lacking, and there is a pressing need for international agreement on parameters to define LV function.

In this study, large diaphragmatic defects were common in infants with ventricular dysfunction; however, it is more interesting that early ventricular dysfunction was also present in at least 25% of infants with smaller diaphragmatic defects. Clinicians are often confronted with an infant with relatively favorable prenatal measures of lung growth but a severe postnatal disease course. This highlights the limitation of prognosticating outcomes purely on the basis of antenatal markers (15).

The management of CDH is complicated by structural and functional changes in the heart, pulmonary vasculature, and lung; consequently, it is challenging to determine the optimal management strategies. The study by Patel and colleagues reinforces the need for vigilant management of cardiac function in early life and recognition of the important cardiopulmonary interactions that characterize CDH if outcomes are to improve.