Cardiorespiratory transition in CDH

Abstract

Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly that occurs due to incomplete closure of the diaphragm followed by herniation of abdominal contents into the chest. Fetal hemodynamics are altered in CDH due to pulmonary alveolar and vascular hypoplasia, low pulmonary venous return and in some cases, hypoplasia or dysfunction of the left heart. CDH is associated with high risk of morbidity and mortality due to pulmonary hypoplasia and persistent pulmonary hypertension of the newborn secondary to pulmonary vascular hypoplasia and remodeling. Resuscitation in the delivery room involves optimizing cardiopulmonary transition from fetal to neonatal circulation through gentle ventilation, endotracheal intubation and gastric decompression. Infants with CDH often present with hypoxemic respiratory failure in the immediate postnatal period due to pulmonary hypertension. The understanding of critical cardiopulmonary interactions and the distinguishing features of CDH sub-phenotypes and degree of cardiac involvement may aid in an augmented precision-based approach to invasive ventilation, vasoactive use, and ECMO management. Improved survival is reported after fetal in-utero interventions such as fetoscopic endoluminal tracheal occlusion (FETO) with CDH and severe secondary pulmonary hypoplasia. Clinical outcomes can potentially be improved by optimizing cardiopulmonary transition in the delivery room and cardiopulmonary interactions in the immediate the postnatal period.

1. Introduction

Congenital diaphragmatic hernia (CDH) is a birth defect that affects about 0.2 per 1,000 live births caused by incomplete development of the diaphragm followed by herniation of abdominal contents into the thoracic cavity. Pulmonary hypoplasia, pulmonary vascular abnormalities, and pulmonary hypertension (PH) are characteristic of CDH (Fig. 1). PH in CDH can be a combination of different phenotypes. Precapillary increase in arterial and arteriolar pulmonary vascular resistance (PVR) in CDH results from pulmonary vascular hypoplasia, vasoconstriction and remodeling. Post-capillary PH may occur due to left ventricular hypoplasia and diastolic dysfunction of the left ventricle (LV). In this review, we discuss the fetal developmental abnormalities, cardiorespiratory transition at birth, delivery room resuscitation, pathophysiology of PH, ventricular dysfunction and cardiopulmonary interactions during ventilation and during extracorporeal membrane oxygenation (ECMO) in CDH.

Fig. 1.

Pathophysiology of pulmonary hypoplasia, cardiac dysfunction and pulmonary hypertension in congenital diaphragmatic hernia (CDH). Pulmonary hypoplasia in CDH is a result of a combination of compression and severe hypoplasia of the ipsilateral lung from herniated abdominal contents, and hypoplasia of the contralateral lung due to mediastinal shift. Right ventricular (RV) dysfunction from exposure to high pulmonary vascular resistance and left ventricular (LV) dysfunction can be secondary to RV dysfunction, sharing myocardial fibers with RV, and leftward shift of interventricular septum from change in RV size thus compromising LV end diastolic volume, increasing end diastolic LV pressure and left atrial pressure. Therefore, pulmonary hypertension (PH) in CDH is attributed to a combination of precapillary PH from pulmonary vasoconstriction in the setting of pulmonary vascular hypoplasia and remodeling, and pulmonary venous hypertension from LV dysfunction. Copyright Satyan Lakshminrusimha.

2. Fetal developmental abnormalities in CDH

The diaphragm develops during the 8th week in the fetus from the fusion of the septum transversum, pleuroperitoneal folds, thoracic body mesenchyme and esophageal mesentery. If this fusion remains incomplete, the defect in the diaphragm allows herniation of the abdominal organs into the thoracic cavity resulting in CDH. A constellation of fetal developmental abnormalities with CDH can be classified as follows.

1. Developmental abnormalities in pulmonary parenchyma. The lungs are hypoplastic with arrest in airway branching, decreased alveolar mass and abnormal vasculature. The theory of direct mechanical compression of the lungs by herniated abdominal contents in the thoracic cavity leads to pulmonary hypoplasia is supported by large animal surgical models of CDH and reversal of lung hypoplasia by tracheal occlusion [1]. However, mechanical factors only partially explain the developmental abnormalities in CDH. The contralateral lung is hypoplastic, although to a lesser extent compared to the ipsilateral lung [2]. Moreover, other anomalies that cause mediastinal shift such as space occupying lesions in the thoracic cavity do not consistently result in pulmonary hypoplasia or PH [3]. Rodent models of teratogen-induced CDH suggest that pulmonary hypoplasia is the primary inciting event and precedes the complete development of fetal diaphragm [4]. Therefore, a dual-hit hypothesis explains pulmonary hypoplasia in CDH by 2 insults: one affecting both lungs before the diaphragm develops, and one affecting the lung after defective diaphragm development and compression by herniated abdominal contents [5]. The abnormal lung development may occur independently from the diaphragmatic defect as a result of epithelial-mesenchymal interactions that affect pulmonary parenchymal and vascular smooth muscle development [6]. Furthermore, vascular and airway hyper-reactivity can be attributed to the persistence of smooth muscle dysfunction (Fig. 2).

2. Developmental abnormalities in pulmonary vasculature. Based on the above described dual-hit hypothesis from the Nitrogen animal model of CDH, the mesenchymal progenitors of pulmonary vascular smooth muscle are affected similar to the airway smooth muscle, with resultant arrest in arterial branching, decreased alveolar capillaries, vascular smooth muscle thickening with remodeling and vasoconstriction with altered vascular responsiveness to mediators (Fig. 1).

3. Cardiac developmental abnormalities in CDH. Left ventricular hypoplasia is increasingly recognized in infants with CDH and is multifactorial due to mechanical compression of LV by herniated viscera and from reduced flow, resulting in narrow, elongated LV (Fig. 3) [7]. Congenital heart anomalies have increased incidence in infants with CDH and discussed in a subsequent section.

4. Other major structural anomalies. Renal, central nervous system and limb anomalies have been described in ~5 % of infants with CDH. Bronchopulmonary sequestration, omphalocele, Meckel’s diverticulum and malrotation have also been reported.

Fig. 2.

Lung abnormalities in CDH. The lung abnormalities in CDH include short trachea, compliant upper airway that may contribute to dead space, increased lower airway reactivity, hypoplastic lungs with alveolar and vascular hypoplasia, vascular remodeling, compliant chest wall (contributing to low FRC), mediastinal shift that may affect left ventricular development (LV hypoplasia) that contributes to pulmonary venous hypertension, and right ventricular hypertrophy and dysfunction that contributed to precapillary pulmonary hypertension. Copyright Satyan Lakshminrusimha.

Fig. 3.

Fetal (A) and postnatal (B) circulation in CDH. Fetus with CDH have hypoplastic lungs, pulmonary vascular hypoplasia, rarefaction and remodeling. The umbilical vein brings oxygenated blood from the placenta to the right atrium. Compared to the normal fetal pattern of preferential streaming of this oxygenated blood across the patent foramen ovale to the left atrium to supply the coronary and cerebral circulations, there is abnormal streaming of oxygenated blood across the tricuspid valve into the right ventricle contributing to left ventricular hypoplasia due to less blood flow. This mixes with the deoxygenated blood (brought into right atrium by the superior and inferior vena cavae from upper and lower body) in the right ventricle, enters the pulmonary artery, and most of this blood is shunted right-to-left across ductus arteriosus into the descending aorta resulting in low pulmonary flow. The 2 umbilical arteries bring deoxygenated blood from the fetus to get oxygenated. When the infant is born (B) and the cord is clamped, the systemic vascular resistance increases acutely and may compromise left ventricular function. Due to persistent elevation of pulmonary vascular resistance (pre-capillary), there is tricuspid regurgitation, right to left shunting across both the foramen ovale and ductus arteriosus, and right ventricular dysfunction. Pulmonary hypoplasia, decreased pulmonary blood flow, and intrapulmonary shunt due to ventilation/perfusion (V/Q) mismatch further contribute to hypoxemia in CDH. Copyright Satyan Lakshminrusimha.

3. Cardiopulmonary transition at birth in infants with CDH

In the fetus, the oxygenated blood returning from the placenta through the umbilical vein via the inferior vena cava is preferentially streamed from the right to the left atrium via the foramen ovale to perfuse the coronary and cerebral circulations (Fig. 3A). On the contrary, the deoxygenated blood entering the right atrium via superior vena cava is preferentially streamed to the RV and the pulmonary artery to the aorta (right-to-left shunt across the ductus arteriosus) and finally to the placenta and to perfuse the lower part of the body. The high PVR in the fetus drives the right-to-left shunts across the foramen ovale and ductus arteriosus. In a fetus with CDH, there is increased streaming of umbilical venous blood across the tricuspid valve into the RV instead of across the foramen ovale possibly due to mediastinal shift [8]. Similar increased right-to-left ductal shunt reduces pulmonary blood flow and pulmonary venous return to LV (Fig. 3A).

At the time of birth, physiological neonatal transition in normal fetus is marked by the rapid reduction in PVR (secondary to ventilation and increase in oxygen tension). In neonates with CDH, the decrease in PVR may be blunted due to vascular remodeling and hypoplasia [9]. There is slow increase in pulmonary blood flow and the pulmonary venous return to the left atrium is low. Therefore, the left atrial pressure may not increase and the shunt across the foramen ovale remains right-to-left (Fig. 3B). In a perinatal ovine model of CDH, a decrease in pulmonary blood flow was observed at birth that was proportionate to the degree of pulmonary hypoplasia along with reduced cerebral tissue oxygen saturation [10]. The increase in systemic vascular resistance (SVR) with umbilical cord clamping owing to removal of the low resistance placental circulation may acutely increase the afterload to the LV compromising its function. Due to persistent elevation of PVR despite increase in SVR, the shunts across foramen ovale and ductus arteriosus remain in the fetal pattern of right to left. If the LV is hypoplastic and has diastolic dysfunction, the left atrial pressure may increase allowing bidirectional or left to right shunting across the foramen ovale and pulmonary congestion due to pulmonary venous hypertension (Fig. 3B). The newborn may present at birth with severe respiratory distress/failure, hypoxemia, hypercapnia and metabolic acidosis. As pH and PaO₂ remain low, PVR may remain high in the early neonatal period.

4. Delivery room resuscitation of infants with CDH

Anticipation and preparation are key in resuscitation of newborns with CDH in the delivery room. Maternal health record should be reviewed to help prognostication by assessing antenatal lung volumes (LHR, observed to expected (O/E) LHR), side of the defect, location of liver, presence of other associated anomalies, and amniotic fluid status. Poor prognosis and survival rates of ≤30 % are associated with O/E LHR of ≤25 % with left sided CDH and O/E LHR of ≤50 % with right sided CDH. Additionally, lung volume assessment by fetal MRI with O/E total fetal lung volume (O/E TFLV) < 35 % and intrathoracic liver are associated with low survival rates. The timing of delivery is determined by the obstetric team based on the maternal and fetal status and is typically planned for ~39 weeks to avoid the added complications of prematurity and post-maturity on the fetal lung.

1. Deferred (or delayed) cord clamping (DCC) has been shown to be feasible in newborn infants with CDH in preliminary studies by Foglia et al. and Lefebvre et al. [11,12] Moreover, Lefebvre et al. observed less metabolic acidosis and higher mean blood pressures in infants with CDH who received DCC compared to those who received immediate cord clamping (Fig. 4). In animal models of CDH, prolonged DCC of up to 10 min improved pulmonary blood flow, reduced pulmonary vascular resistance, and improved cerebral tissue oxygenation [13]. Currently randomized trials are ongoing to assess the hemodynamic effects and safety of DCC in CDH [14–17]. DCC allows the placenta to continue as a site of gas exchange until lung aeration is established, thus improving oxygenation in a newborn with CDH. Umbilical venous return to the newborn heart provides preload to the left atrium and sustains the cardiac output and systemic circulation, until the pulmonary veins take over the role bringing in oxygenated blood into the left atrium from the lungs. Moreover, the high fetal hemoglobin content that is delivered to the infant by DCC may improve the oxygen carrying capacity improving tissue oxygenation, reduce alveolar-arterial gradient [18], and reduce metabolic acidosis. If there are no other absolute contraindications to DCC such as maternal abruption, and the infant is not in need of immediate resuscitation, DCC of ≥60 s may be considered in infant with CDH while awaiting further evidence. Although non-vigorous infants ≥35 weeks may benefit from intact cord milking, there are no studies evaluating umbilical cord milking in CDH, and warrants further studies [19].

2. Orogastric suction: Infants antenatally suspected to have CDH who present with respiratory distress at birth require immediate endotracheal intubation and emergent placement of an orogastric tube. The orogastric tube (8–10 Fr Replogle or Anderson tube) is connected to suction to decompress the stomach that is often located within the thoracic cavity. Bag and mask ventilation is absolutely contraindicated due to the risk of gaseous distension of stomach and bowel loops located within the thoracic cavity (Fig. 5).

3. Airway: Infant with CDH often present with respiratory distress at birth and require immediate endotracheal intubation. Bag and mask ventilation is best avoided. However, in infants where CDH was not diagnosed antenatally, the infants may inadvertently receive bag and mask ventilation that may cause gaseous distension of bowel loops within the chest and worsen respiratory distress. An appropriately sized uncuffed endotracheal tube (ETT) may be used for the intubation in the delivery room. Prior to the surgical repair, the anesthesia and pediatric surgery teams may prefer to reintubate with a cuffed ETT (microcuff ETT). If a cuffed ETT is used in the delivery room, the cuff should remain deflated to avoid complications from airway trauma. The initial depth of ETT placement (in cm) is 5.5 cm + birth weight in Kg as the carina may be displaced cephalad in infants with CDH (Fig. 2) [20].

4. Ventilation: Following endotracheal intubation, gentle ventilation strategy with a T-piece resuscitator should be utilized to avoid volutrauma and barotrauma to the lungs that are typically affected by at least some degree of pulmonary hypoplasia in CDH. This includes use of initial peak inspiratory pressures (PIP) of <25 cm H₂O, and low positive end expiratory pressure (PEEP) of 2–4 cm H₂O [21]. However, if chest rise is inadequate and heart rate decreases to < 60/min, then PIP and PEEP can be transiently increased.

5. Oxygen: Ventilation is initiated with 30–50 % inspired oxygen and subsequently titrated up or down to achieve target preductal SpO₂ as recommended by AAP-NRP [22,23]. The goal is to achieve preductal SpO₂ of 80–95 % by 5 min after birth in the delivery room without using very high inspiratory pressures (however, the preductal SpO₂ should improve to 91–95 % by 2–3 h after birth and 91–98 % at ≥ 3 h after birth) [12]. Oxygenation in CDH is a fine balance attempting to optimize systemic oxygen delivery while minimizing pulmonary oxygen toxicity. The post-ductal SpO₂ need not be monitored in the delivery room. At ≥ 3 h after birth, the preductal SpO₂ target is 91–98 % if FiO₂ is < 0.6, but can be more conservative with goals of SpO₂ 88–95 % if FiO₂ > 0.6 (to limit oxygen toxicity to the lungs) [24]. If preductal SpO₂ >95 % or PaO₂ > 100 mm Hg, can gradually wean FiO₂ to 0.25 to 0.30.

6. Sedation and analgesia: A peripheral intravenous (IV) catheter may be placed early in the delivery room or on admission in the NICU to administer sedation. Morphine can be administered IV at 0.1 mg/kg (or intramuscularly if not able to obtain IV access quickly) followed by a continuous morphine infusion at 0.025 mg/kg/hr or as needed doses of 0.025–0.05 mg/kg every 3–4 h. Alternate agents to consider include fentanyl (1–2 mcg/k/hr infusion), and dexmedetomidine (0.3 mcg/kg/hr).

Fig. 4.

Graphic abstract of Lefebvre et al. evaluating delayed cord clamping with intact cord resuscitation in CDH. In 40 term non-syndromic newborn with a prenatal diagnosis of CDH, Lefebvre et al. compared immediate cord clamping (ICC) and intact cord resuscitation (ICR, cord clamping after cardiopulmonary stabilization with heart rate >100 bpm or stable SpO₂) in a prospective observational feasibility study. The authors reported higher hematocrit in the ICR group along with lower PaCO₂ and lactate at 30 min after birth and higher blood pressures for the first 12 h. There was no difference in maternal blood loss and newborn’s FiO₂, SpO₂, packed red blood cell transfusions, use of extracorporeal membrane oxygenation or death. Copyright Satyan Lakshminrusimha.

Fig. 5.

Delivery room management of CDH. Following discussion of umbilical cord management plan with the obstetric team, delayed (deferred) cord clamping can be offered to improve delivery of oxygenated blood from the placenta that also is an important contributor to left ventricular preload before the lungs take over the function of oxygenation. It is reasonable to consider cord milking only in term newborns who require immediate resuscitation at birth. Bag and mask ventilation is contraindicated in CDH. Orogastric tube is placed and connected to suction to evacuate air from the stomach which may be displaced into the thoracic cavity. Following emergent endotracheal intubation in infants with CDH presenting with respiratory distress at birth, ventilation is initiated with 30–50 % oxygen to target preductal SpO₂ 85–95 % in the delivery room. Inspired O₂ may be increased in the setting of bradycardia (heart rate <60 bpm) or hypoxemia with SpO₂ < 80 %. Gentle ventilation to avoid volutrauma and barotrauma is practiced, avoiding peak inspiratory pressure >25 cm H₂O and by using a low-positive end expiratory pressure (low PEEP). Copyright Satyan Lakshminrusimha.

5. Resuscitation of mild CDH

A small subset of infants may have mild CDH with isolated left-sided CDH without other anomalies, O/E LHR >50 % (mild), liver not in the thoracic cavity and born at gestational age ≥37 weeks may not require immediate endotracheal intubation at birth [15]. Delayed cord clamping should be strongly considered in these infants to increase preload to the LV with oxygenated umbilical venous blood that is rich in fetal hemoglobin until the lung is established as the primary site of gas exchange. These infants with mild CDH may tolerate spontaneous respirations with or without the need for non-invasive ventilation after gastric decompression with an emergent placement of an orogastric tube [15]. If the newborn with mild CDH has no respiratory distress and achieves target preductal SpO₂ of 80–95 % by 5 min after birth, the infant can be monitored on room air without additional respiratory support. In the presence of respiratory distress or hypoxemia, non-invasive ventilation ranging from nasal cannula, nasal continuous positive airway pressure (CPAP) and non-invasive positive pressure ventilation (NIPPV) may be considered. However, any clinical deterioration with either an increase in FiO₂ to >0.6 to achieve target preductal SpO₂, worsening of respiratory distress, or gastric distension, intubation should be strongly considered.

6. Pathophysiology OF PH IN CDH

PH occurring in CDH is multifaceted and complex owing to structural and functional alterations in the pulmonary vasculature in the fetus with CDH, LV hypoplasia and dysfunction, disruption of interaction between the RV and pulmonary circulation. These infants present with hypoxemic respiratory failure with the need for increased FiO₂ > 0.6, and large split between the preductal and postductal SpO₂.

Fetal mechanisms:

Infants with CDH are predisposed to PH due to developmental abnormalities in the pulmonary vasculature. Structural changes in fetal pulmonary vasculature in CDH include thickening of the tunica media (containing smooth muscle cells) and tunica adventitia (containing connective tissue, collagen and elastin) lining the pulmonary arterioles and decreased arborization [25]. These in-utero alterations in the structure of the pulmonary arterioles reduce the vessel diameter and increase PVR. In addition to structural alterations, vasculogenesis is disordered due to impeded function of pericytes, vascular growth factors and microRNAs [26,27]. These changes resulting in high PVR are implicated in the pre-capillary PH observed in CDH. That is, the pulmonary vasodilation and decrease in PVR that occur at the time of birth are blunted in the infant with CDH. Therefore, the anticipated increase in pulmonary blood flow and preload to the left atrium via the pulmonary veins at birth are compromised in infants with CDH.

Postnatal mechanisms:

In addition to the preexisting precapillary PH, the ventriculoarterial and interventricular interactions are hampered in CDH contributing to PH. (i) Role of RV dysfunction: The RV in the postnatal newborn is thin-walled and crescent-shaped in cross-section functioning at low pressures connected in series to the low-resistance pulmonary circulation. The optimal functioning of RV relies on adequate systemic venous return. The persistently elevated PVR in CDH creates a high RV afterload that is initially compensated by RV myocardial hypertrophy and remodeling by means of homeometric adaptation. Persistent, severe increase in PVR leads to RV dilation, increased end diastolic RV volume, increase in RV stroke volume and heart rate by way of heterometric adaptation. However, these adaptive mechanisms in the RV fail in the setting of prolonged exposure to high PVR. There is resultant compromise in RV filling during diastole, reduced coronary perfusion and ischemia, and reduction in RV compliance due to RV hypertrophy. Ultimately, there is RV dysfunction with reduction in pulmonary blood flow (“uncoupling from the pulmonary circulation, Fig. 6”) [28]. RV function may improve over time with resolution of the precapillary PH in CDH, or may persist if PVR remains elevated. (ii) LV dysfunction may follow RV maladaptation to precapillary PH in CDH due to ventricular interdependence. LV and RV share myocardial fibrils and RV dysfunction may be accompanied by systolic LV dysfunction. Change in RV size and shape may induce a leftward shift of the interventricular septum compromising the LV end diastolic volume and increasing the end-diastolic LV pressure and left atrial pressure [29]. Furthermore, tachycardia and dys-synchrony of myocardial segments may lower diastolic filling. Interestingly, primary LV dysfunction in CDH has been observed in the absence of RV dysfunction and there is a known association between hypoplastic left-sided structures and CDH. LV diastolic dysfunction (either primary or secondary to RV dysfunction) will increase LA pressure leading to pulmonary venous hypertension or post capillary PH in CDH (Fig. 3). If infants with postcapillary PH, the use of pulmonary vasodilators are contraindicated in use and may lead to clinical deterioration by worsening pulmonary edema from increase in pulmonary blood flow and impaired pulmonary venous return to the left atrium from LV diastolic dysfunction [30].

Fig. 6.

Coupling with homeometric and heterometric adaptation followed by uncoupling of the right ventricle in CDH. The right ventricle (RV) is operating at low pressure coupled to the low resistance pulmonary circulation and pulmonary blood flow is maintained. In infants with CDH with increase in pulmonary vascular resistance, the increase in RV afterload elicits adaptive responses in the right ventricle (RV). With homeometric adaptation, early adaptation to RV afterload results in an increase in RV contractility causing some concentric RV hypertrophy and increased wall thickness (with no change in chamber volume). Cardiac output and RV-PA coupling is preserved (A). With progression of PH, the prolonged exposure to very high RV afterload leads to RV dilation and increased stroke volume (heterometric adaptation). However, persistent, extreme elevation of afterload leads to maladaptive changes in the RV from ischemia, hypoxemia, myocardial stretching, and leftward bowing of the interventricular septum compromising left ventricular (LV) end diastolic volume, LV stroke volume (hypoperfusion and acidosis) and LV function. LV dysfunction is followed by pulmonary venous hypertension. This referred to as uncoupling or maladaptation (B). Copyright Satyan Lakshminrusimha.

7. Risk of congenital heart disease

Cardiac dysfunction is an independent determinant of poor outcomes in CDH patients [31]. Notably, CHD is frequently observed in CDH patients, with an estimated incidence of 15–20 % [32], with higher risk of left-sided obstructive defects, such as hypoplastic left heart syndrome (HLHS), aortic arch hypoplasia, and coarctation of the aorta, compared to the general population [33,34]. The pathophysiological mechanisms that underly the development of LV hypoplasia in utero may be multifactorial [8,33,35]. These include mechanical compression of the left-sided heart structures due to the herniation of abdominal contents into the thoracic cavity, abnormal streaming of flow from the ductus venosus and inferior vena cava to the right side of the heart, and abnormal pulmonary vasculature leading to reduced pulmonary blood flow, compounding the risk of poor LV preload that could impact in-utero development (Fig. 3) [36]. Genetic factors or cellular changes may also predispose the fetus to cardiac dysgenesis, contributing further to the increased prevalence of heart defects in CDH patients [37,38].

8. Postnatal cardiac dysfunction and cardiopulmonary interactions

Following birth, ventricular dysfunction (right, left, biventricular) may develop in the presence or absence of developmental abnormalities that may occur in-utero. Impaired recruitment of the hypoplastic lung, in addition to structural and functional abnormalities of the pulmonary vasculature leads to persistent elevation of PVR and restriction of pulmonary blood flow. The persistently elevated PVR increases RV afterload and may further lead to RV hypertrophy and dilation, resulting in systolic and diastolic RV dysfunction (Fig. 6). The LV can be further compromised due to reduced LV preload from reduced pulmonary blood flow and interventricular dependence from RV dilation and increase in LV afterload following birth after umbilical cord clamping. The presence of LV dysfunction may also compound the risk of worsened postnatal PH, through increases in LV diastolic and left atrial pressures leading to pulmonary venous hypertension (postcapillary PH) and alveolar edema. The compounded effects from the disrupted interplay of critical cardiopulmonary interactions can lead to a dysregulated cycle of physiologic derangements, that are marked by resistant hypoxemia, hypercarbia and lactic acidosis leading to shock, multi-organ failure and death, if not effectively managed.

The pathophysiology of CDH and the severity of the lung disease itself also exacerbates the fine interplay of these critical cardiopulmonary interactions. The severity of lung hypoplasia combined with diaphragmatic dysfunction prevents normal lung aeration and lung recruitment following birth. At birth, the transitioning of an otherwise healthy neonate has relatively lower functional residual capacity (FRC) of the lungs due to a highly compliant chest wall in tandem with relatively lower transpulmonary pressures at end-expiration, increasing the risk of collapse of the small airways [39]. One of the adaptive strategies neonates may exhibit to maintain adequate lung volumes is constant post-inspiratory diaphragmatic activity [40]. Thus, further de-recruitment of diseased/underdeveloped lungs in CDH can be compounded at birth by diaphragmatic dysfunction (Fig. 2), leading to higher PVR and increased risk of PH.

9. Conventional ventilation and cardiopulmonary interactions

Due to lung hypoplasia and abnormalities of pulmonary vasculature, CDH patients may be particularly vulnerable to dynamic changes with increases in intrathoracic pressure during conventional mechanical ventilation (CMV). High intrathoracic pressure during PPV reduces venous return to the heart and decreases RV preload while increasing PVR and RV afterload (Fig. 7). The increase in intrathoracic pressure from CMV also reduces the transmural pressure in the LV and aorta, lowering LV afterload and LV work during systole. The net effect of CMV is determined by the fine balance between its negative effect on preload and RV afterload, and positive effect of decrease in LV afterload. Thus, early recognition and understanding of the various CDH phenotypes (spectrum of severity in lung hypoplasia, presence and severity of PH, presence of CHD/cardiac dysfunction) can best inform CMV management, when transitioning a neonate with CDH from spontaneous negative pressure breathing to CMV [41].

Fig. 7.

Cardiopulmonary interactions due to invasive mechanical Positive Pressure Ventilation (PPV) with CDH pathophysiology. The high intrathoracic pressure during PPV reduces the extrathoracic vein-to-right atrial pressure gradient resulting in decrease in venous return to the heart and decrease in RV preload. The increase in transpulmonary pressure from PPV reduces the transmural pressure in the LV and aorta, lowering LV afterload and LV work during systole. Hypoplastic lungs in CDH results in lowered FRC and the fine balance of PPV to maintain FRC for optimal lung recruitment while avoiding alveolar overdistention and worsening cardiopulmonary interactions must be considered. If PPV brings lung volumes closer to FRC, PVR decreases but if lung volumes are markedly lower or higher than FRC, PVR increases. CDH patients are at higher risk of adverse cardiopulmonary interactions and low cardiac output from PPV. Copyright Satyan Lakshminrusimha.

Optimizing PVR and FRC:

The restoration and maintenance of FRC is essential for optimizing PVR (Fig. 8). FRC is lower in CDH and 6–7 rib expansion on the contralateral lung may be adequate to achieve FRC. High lung volumes secondary to high transpulmonary pressure during CMV can lead to alveolar overdistention and compression of alveolar vessels, exacerbating PVR. In addition, the disruption of the alveolar-capillary interface from high tidal volume ventilation can lead to ventilator-induced lung injury characterized by alveolar epithelial injury, endothelial injury and propagation of biological mediators of inflammation, leading to worsened lung disease and extra-pulmonary organ failure. In contrast, low tidal volume ventilation and a PEEP below the critical opening pressure can lead to atelectotrauma and lung collapse and also increase PVR by increasing the tortuosity of extra-alveolar vessels. With the use of neuromuscular blockade, the chest wall in infants with CDH is prone to collapse, leading to a reduction in FRC and atelectasis. This, combined with the abnormal lung structure in CDH, may increase PVR and worsen ventilation-perfusion mismatch. CMV in CDH must finely balance optimal end-expiratory lung volumes while minimizing excessive tidal volume ventilation that could be injurious. One study showed improved oxygenation with the use of lower PEEP in the postoperative period in patients with CDH suggesting the importance of reducing volutrauma [42]. The inability to effectively maintain optimal FRC can exacerbate ventricular interdependence and result in higher PVR and RV afterload while reducing the LV filling capacity and compliance.

Fig. 8.

Relationship of lung volume and PVR. PVR is minimal at functional residual capacity (FRC) and increased when at lung volumes above FRC and also when at lung volumes below FRC. The effect of lung volumes on resistance in small intra-alveolar and large extra-alveolar vessels accounts for this relationship. At high lung volumes, intra-alveolar resistance increases due to compression of alveolar vessels, increasing total PVR. Extra-alveolar resistance is minimal at high tidal volume due to the tension from alveolar distention pulling extra-alveolar vessels open. At low lung volumes and with lung collapse, extra-alveolar vessel resistance conversely increases, increasing total PVR. The resistance of intra-alveolar vessels at low tidal volume is relatively low. In CDH, FRC is lower than in healthy newborns due to hypoplastic lungs increasing risk of worsened PVR from alveolar overdistention with positive pressure ventilation. PVR is higher at all lung volumes in CDH, compared to healthy newborns, due to abnormal pulmonary vasculature, causing upward shift in this relationship curve. Hyphenated lines represent normal newborn lungs and dark lines represent CDH. Copyright Satyan Lakshminrusimha.

10. High frequency ventilation and cardiopulmonary interactions

High-frequency ventilation (HFV) produces a continuous circuit of airflow within the conducting airways and relies on molecular diffusion for gases in the alveolus. Unlike CMV, HFV does not depend on large volume tidal volume ventilation to overcome anatomic dead space. Rather, HFV employs supra-physiological respiratory rates and low tidal volumes at a high end-expiratory pressure with lung volumes theoretically staying close to FRC and potentially reducing the risk of ventilator induced lung injury (volutrauma, atelectotrauma, and biotrauma). HFV includes high frequency oscillatory ventilation (HFOV), high frequency positive pressure ventilation (HFPPV) and high frequency jet ventilation (HFJV). Although HFV provides gentle ventilation, there may be an increased risk of alveolar overdistention at high mean airway pressures and decreased cardiac preload and compression of pulmonary vasculature leading to increased PVR [43].

In clinical practice, there are contradictory results on the use of CMV vs. HFV and their effect on hemodynamics and early survival in CDH. To date, the only randomized controlled trial investigating CMV vs. HFV in infants with CDH is the VICI trial that showed no difference in the primary outcome of mortality or chronic lung disease [44]. However, the CMV group experienced shorter duration of ventilation and less need for ECMO. The HFV group in the VICI trial was noted to have higher mean airway pressures compared to the CMV that likely increase risk of lung injury and exacerbated cardiopulmonary interactions with higher inotrope and ECLS use. A recent small single center study, using a more conservative protocolized-directed ventilatory strategy in severe CDH patients resulted in improvement in measures early gas exchange and no difference in duration of ventilation, rates of ECMO, and survival between these two ventilatory strategies [45].

Further, the use of HFJV has been argued to be a preferred mode of approach compared to HFOV because it can be utilized at lower mean airway pressure than those requiring CMV. This may lead to improved hemodynamics, especially in those patients who are preload dependent and with RV strain. An observational study comparing HFPPV + HFOV vs. HFOV at a single center showed lower mortality with initial HFPPV use [46]. A clinical trial is being currently conducted comparing the effectiveness of HFJV vs HFOV for initial CDH ventilatory support [clinicaltrials.gov; NCT04774848].

11. Clinical phenotypes of cardiac dysfunction

The presence of LV dysfunction (whether or not in tandem with RV dysfunction) independently predicts those at highest risk of death and needing ECMO support [33]. The variability of cardiac involvement in CDH has shaped CDH management, shifting from a generalized “one-fits all” approach to a precision-based targeted strategy based on type and severity of cardiac involvement. Early echocardiography (within first 12 h of birth) and repeat echocardiographic surveillance are critical to guide treatment strategies based on the phenotype. Distinct cardiac function phenotypes include: 1) intact biventricular function, 2) post-capillary PH/LV dysfunction in isolation, 3) pre-capillary PH/RV dysfunction, and 4) biventricular dysfunction. The use and type of pulmonary vasodilator, systemic vasoconstrictor/inotrope support, use of prostaglandins for ductal patency, ECMO consideration and candidacy, and decision regarding timing of CDH surgical repair, can be guided by the distinction of its clinical phenotypes.

12. Cardiopulmonary interactions in ECLS

The Extracorporeal Life Support Organization (ELSO) registry reports that internationally ~250–300 infants with severe CDH require extracorporeal life support (ECLS) each year for management of respiratory failure and/or management of shock refractory to conservative management, with roughly a 50 % overall survival [47]. Although ECLS for neonates with CDH has been prevalent for over 50 years, there remains a lack of standardization of its use. Practice guidelines may vary across medical institutions in regard to patient selection, timing of repair, and best mode of support (Venovenous (VV) vs Venoarterial (VA)) [48]. VV vs. VA has not been shown to be clinically superior when compared to each other, and the preferred mode of support may vary by individualized indication (anatomic limitations, severe cardiac dysfunction) or by institutional practices. VA is often subjectively the preferred mode of support among centers in the United States. Proponents of VV ECLS highlight potential advantages of delivering oxygenated blood directly to the pulmonary arterial system, leading to direct pulmonary vasodilation and reduction in PVR, and reduced risk of thromboembolic stroke by sparing cannulation of the carotid artery. However, for VV ECLS to be effective, adequate intrinsic cardiac output to support systemic circulation must be maintained. VA ECLS is preferred in the setting of severe cardiac dysfunction, as it provides significant circulatory support. VA ECLS may also further support the failing RV by decreasing preload and offloading the workload of the RV by systemic venous drainage and return of oxygenated blood to the arterial system. However, with VV ECMO, pulmonary vasculature is perfused with more oxygenated blood that may theoretically reduce PVR. Further, the size of the infant’s neck veins is a critical consideration for VV versus VA ECLS support, as VV ECLS would need the support and use of single site cannulation to the internal jugular vein (IJV) with a large 13Fr dual lumen VV cannula. In contrast, the VA approach will allow for smaller size cannulas and a two site-cannulation approach, with an 8 or 10Fr cannula in the carotid artery and an 8, 10, or 12Fr venous cannula in the IJV. There are additional anatomical complexities that arise from CDH that make ECLS cannulation more difficult. Infants with CDH tend to have more hypoplastic neck vascular that may limit the size of the cannulas. The right-sided CDH can cause challenges to venous cannulation due to the intrathoracic liver position, mediastinal shifting to the left, and abnormal vasculature (ectatic SVC-azygous junction, compression of the IVC), leading to higher risk of inadvertent cannulation into the azygous vein [49].

Ventilatory management strategy on ECLS in CDH patients is also critically important to optimize cardiopulmonary function. With the support of ECLS for oxygenation and gas exchange, lung protective measures should be implemented to reduce the risk of ventilator-induced lung injury. Tidal volumes are often reduced to 3–5 ml/kg to reduce mechanical stress and strain to the underdeveloped lung, and the use of lower fractional inspired oxygen may prevent direct oxygen toxicity to the lung. Higher PEEP may limit risk of atelectotrauma and optimize PVR. There is currently no standard evidence-based approach to optimal tidal volume and PEEP or mode of ventilation during ECMO in CDH.

13. Conclusions

CDH is a congenital defect that affects the development of the diaphragm but also the development and maturation of the cardiopulmonary system and is associated with high morbidity and mortality. Although the lesion is congenital, iatrogenic cardiopulmonary interactions can significantly influence outcome. There are a wide variety of presentations in clinical phenotypes and severity of illness depending on the presence and severity of pulmonary hypoplasia and lung disease, pulmonary vascular abnormalities, PH, cardiac dysfunction and congenital heart disease. Understanding critical cardiopulmonary interactions and the distinguishing features of CDH sub-phenotypes may aid in a better precision-based approach to CDH management both during delivery room resuscitation and in the postnatal period.

13.1. Practice points

• Cardiopulmonary transition is disrupted in infants with congenital diaphragmatic hernia due to persistent elevation in PVR and pulmonary parenchymal and vascular abnormalities.

• Pulmonary hypertension (PH) is a hallmark of infants with CDH and is attributed to a combination of precapillary and postcapillary PH.

• The disrupted interplay of critical cardiopulmonary interactions during a pulmonary hypertensive crisis may lead to a dysregulated cycle of physiological derangements, that are marked by resistant hypoxemia, hypercarbia and lactic acidosis.

• The use of invasive mechanical ventilation either with conventional mode vs high frequency ventilation must recognize the critical changes to cardiopulmonary interactions marked by decrease preload, increase RV afterload and decreased LV afterload and possibly exacerbated interventricular dependence that may occur

• Congenital heart disease is associated with CDH, with a trend toward left-sided obstructive defects.

• Ventricular dysfunction involving right and left ventricle can exist in infants with CDH and impact pathophysiology, response to treatment, and survival outcomes. The presence of LV dysfunction is independently associated with highest risk of death and need for ECMO support.

13.2. Research directions

• The effectiveness of HFJV vs. HFOV as an ideal open lung strategy in the management of CDH pathophysiology needs further study

• The early identification of cardiac sub-phenotypes of CDH may further help guide management of precision-based management strategies

Data availability

No data was used for the research described in the article.