**8. Pulmonary hypertension**

Pulmonary hypertension in CDH is persistent, recalcitrant and difficult to treat. The management is compromised by the scarcity of good quality research and evidence. The presence of PPH is the most significant predictor and cause of morbidity and mortality, as well as of the need for ECMO [83]. Pulmonary hypertension in CDH is characterized by the hypoplasia of pulmonary vascular bed, remodeling of pulmonary vasculature, and an altered vasoreactivity of the pulmonary vessels. The pulmonary vasculature remodeling is characterized by the medial and adventitial thickening of the midsized and large vessels' walls and by the neomuscularisation of small capillaries. The vascular remodeling is evidenced to begin at as early as the 19th weeks of gestation in human lungs of CDH patients, and is associated with an earlier maturation of the pulmonary vasculature [167]. The pulmonary hypertension in CDH has both fixed and variable components. Reduced pulmonary vascular cross sectional area and the vascular remodeling contribute to the fixed component

of PPH. The reactive component of PPH is balanced by the circulating vasoconstrictor and vasodilator agents and defines the response to vasodilator treatment. Increased expression of the vasoconstrictive factors (endothelin A and B receptors, endothelin converting enzyme-1) and a decreased expression of the vasodilators (prostaglandin-I2 receptor) have been reported in CDH [168]. The reports about the concentration of endothelial nitric oxide (eNOS) in CDH patients are conflicting [169–172]. An extensive review of the factors and pathways involved in the vascular remodeling in CDH has been published [173].

The utility and selection of pulmonary vasodilator agents for the treatment of PPH often change, as the underlying pathophysiology evolves during the days and weeks following the birth. The management strategies need to be adjusted as the pulmonary vascular abnormalities progress from acute to subacute and finally to the chronic stage. A poor response to the vasodilator therapies during acute phase is attributed to the left ventricular (LV) hypoplasia and dysfunction, in association with pulmonary venous hypertension [174]. In some CDH patients, there may be a "honeymoon" period displaying good oxygenation during the 1st few hours of life. Ratio of the pulmonary arterial to systemic arterial pressure (P/S ratio) is used to evaluate the degree of PPH. A P/S ratio <2/3 of systemic systolic pressures is considered as normal or mild; whereas, that of ≥2/3 of systemic pressure denotes moderate; and if > systemic pressure, severe PPH [175]. Important parameters to check in the neonatal echocardiography are the direction and velocity of flow at ductal and foramen ovale shunts, flattening or left deviation of the interventricular septum, and tricuspid regurgitation jet velocity. Functional evaluation of the right and left ventricles is the key that guides the appropriate pulmonary vasodilator therapy. Lung recruitment with adequate positive end-expiratory (PEEP) or mean airway pressure and/or with surfactant to achieve an expansion up to 8- to 9-ribs during inspiration is the goal. Overriding right-to-left shunt by increasing systemic vascular resistance is not recommended. Severe PPH with right to left shunt at the atrial level necessitates the emptying of right ventricle, which is accomplished by maintaining the patency and reopening of ductus arteriosus with prostaglandin E1 if needed [176, 177]. Such cases may respond favorably to the inhaled nitric oxide therapy (iNO). LV dysfunction is associated with left-to-right atrial shunting and suggests the presence of pulmonary venous hypertension, which is associated with poor response to pulmonary vasodilator therapy [178]. Milrinone is recommended in patients with LV dysfunction due to its lusitropic, inotropic and pulmonary vasodilator properties [174]. A retrospective study reported improved cardiac function and reduced right ventricular pressure with milrinone in PPH associated with CDH [179]. As there is a potential risk of systemic hypotension, the avoidance of loading dose or priming the system with normal saline bolus were suggested by the researchers in some case series studies [180, 181]. Prospective RCTs of milrinone in CDH complicated by PPH are lacking and are warranted [182].

The Neonatal Inhaled Nitric Oxide Study (NINOS), which included 53 infants with CDH showed no difference in the combined primary outcome of death or ECMO utilization between the iNO-treated patients and controls [183]. In fact, ECMO utilization was higher in the iNO-treated group (80% vs 54% control, p = 0.043), indicating an adverse effect of iNO if used early in the course of PPH associated with CDH [183]. The ventilation approach, choice of the ventilator and the OI at enrollment in this study were different from the current practices. Their result further supported the important role of left ventricular dysfunction in PPH in CDH cases [178]. The use of iNO was associated with significantly higher mortality in CDHSG registry cases as well [184]. However, despite a lack of evidence, inhaled nitric oxide is commonly used in the management of PPH in CDH [179, 184].

**133**

**10. Surgery**

*Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists*

reversibility of PPHN is not possible with the current knowledge.

**9. Extracorporeal membrane oxygenation**

ered as a therapeutic option in those centers that offer it.

require a patch (76.9% vs 96.5%) [10].

**11. Follow-up and outcomes**

In the nonresponders to iNO, or in the resource poor settings where iNO is often unavailable, sildenafil is a feasible option. Trials to evaluate the effect of sildenafil in newborns with persistent pulmonary hypertension of the newborn (PPHN) have been conducted. A meta analysis showed that sildenafil reduces mortality and improves oxygenation in PPHN [185]. However, there are limited data on the use of sildenafil in CDH patients. In retrospective studies, both oral and IV formulations of sildenafil were shown to improve oxygenation in CDH patients [186, 187], although IV sildenafil resulted in an increased need for inotropic support [188]. The Congenital Diaphragmatic hernia Nitric Oxide versus Sildenafil (CoDiNOS) trial is the first prospective RCT that has been recently proposed [189]. Other drugs under consideration are epoprostenol, treprostinil, inhaled alprostadil and bosentan. At this time, there is insufficiant evidence in regards to their efficacy or safety for use in PPHN [190–192]. It is reasonable to comment that an accurate prediction of the

Congenital diaphragmatic hernia is the most common non-cardiac indication for extracorporeal membrane oxygenation in the neonates, even though the benefits of the intervention in terms of mortality in CDH are questionable. A retrospective study of the extracorporeal life support organization (ECLS) registry data revealed the overall survival of 48.1% in term neonates representing a 13.8% reduction in survival of neonates with CDH who were treated with ECMO [193]. This result probably represents the fact that more serious CDH cases were subjected to ECMO [194]. CDHSG registry data, on the other hand, have documented an improved survival in the most severely affected CDH patients with ECMO [195]. The recently published VICI trial [136] failed to demonstrate any difference in CDH outcomes between ECLS and non-ECLS centers, further questioning the role of ECMO in CDH. The indication and utility of ECMO in CDH is still evolving, as is the timing of surgery. It should be discussed during prenatal counselling and may be consid-

The reduction of herniated abdominal contents does not improve PPH in CDH

A multidisciplinary approach is needed for the comprehensive long term follow up of the neonates with CDH. A myriad of significant morbidities may affect these neonates, which includes respiratory disorders (chronic lung disease, pulmonary

and thus the outcome remains largely unaffected. A systematic review on the subject has not favored either early or late surgery [154]. The recommended physiologic criteria for preparedness for surgery are not supported by evidence [81, 143]. However, It is possible that early repair on ECMO may improve outcome [154]. In stable patients, CDH repair is usually done between 48–72 h after birth. Recurrence rate is significantly lower in open repair [154]. Polytetrafluoroethylene (PTFE) is the most durable patch repair material. Even though the survival in patients requiring patch repair has significantly improved, it is still lower than those who do not

*DOI: http://dx.doi.org/10.5772/intechopen.94839*

#### *Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists DOI: http://dx.doi.org/10.5772/intechopen.94839*

In the nonresponders to iNO, or in the resource poor settings where iNO is often unavailable, sildenafil is a feasible option. Trials to evaluate the effect of sildenafil in newborns with persistent pulmonary hypertension of the newborn (PPHN) have been conducted. A meta analysis showed that sildenafil reduces mortality and improves oxygenation in PPHN [185]. However, there are limited data on the use of sildenafil in CDH patients. In retrospective studies, both oral and IV formulations of sildenafil were shown to improve oxygenation in CDH patients [186, 187], although IV sildenafil resulted in an increased need for inotropic support [188]. The Congenital Diaphragmatic hernia Nitric Oxide versus Sildenafil (CoDiNOS) trial is the first prospective RCT that has been recently proposed [189]. Other drugs under consideration are epoprostenol, treprostinil, inhaled alprostadil and bosentan. At this time, there is insufficiant evidence in regards to their efficacy or safety for use in PPHN [190–192]. It is reasonable to comment that an accurate prediction of the reversibility of PPHN is not possible with the current knowledge.
