[size=20px]A three-kg term infant with prenatally identified congenital diaphragmatic hernia (CDH) is on high frequency oscillation ventilation. Persistent pulmonary hypertension and evidence of left ventricular dysfunction is noted on echocardiogram. Addition of which of the following pharmacologic agents is the best next step in management for this child?

 

a Treprostinil

 

b Sodium Nitroprusside

 

c Milrinone

 

d Sildenafil

 

e Inhaled Nitric Oxide[/size]

C

C

C

C

C

Correct answer

C Milrinone

 

Pulmonary hypertension associated with congenital diaphragmatic hernia (CDH-PH) has been recognized for decades. Even in the absence of overt right to left shunting, the range of severity is wide in CDH-PH. Recent emphasis has shifted to the identification of pulmonary hypertension as a marker of severity (e.g. need for extracorporeal life support, mortality) and the use of multi-modal pharmacotherapeutic interventions to reduce CDH-PH. Echocardiogram is a useful non-invasive method for evaluating cardiac anatomy, function and can be used to assess disease progression or response to therapy.

Initial management strategies include oxygenation, appropriate fluid management to avoid overload, optimization of blood pressure and avoidance of barotrauma. Various vasodilators have been recommended and trialed as evidenced by the current literature. In 2011 and 2012, over three hundred infants with CDH were admitted to a neonatal research network NICU. They were exposed to the following pulmonary vasodilators: iNO (39%), sildenafil (17%), milrinone (17%), inhaled epoprostenol (6%), intravenous epoprostenol (3%), and intravenous PGE1 (1%).

Although a large randomized study demonstrated no improvement in survival, many centers use inhaled nitric oxide for CDH-PH (greater than two-thirds systemic pressures in the right ventricle) and significant right to left shunting in CDH infants. This remains controversial and there are continued investigations into whether inhaled nitric oxide provides benefit. A 2017 Cochrane review showed that infants with CDH do not share similar benefits from iNO when compared to controls – in fact it has been suggested that outcomes could be worse in children with CDH who receive iNO. However, in the setting of severe left ventricular dysfunction, the use of inhaled nitric oxide causes a decrease in PVR and an increase in LV pressure, which may exacerbate left heart failure. Therefore, iNO should not be initiated at this time.

Recent studies have shown that addition of milrinone (a phosphodiesterase 3 inhibitor) may be associated with improved oxygenation and survival. A retrospective review of infants with CDH at two centers showed that milrinone lowered the right ventricular pressure and improved ejection fraction. In the clinical setting provided, milrinone would be the best next agent for management of pulmonary hypertension.

Sildenafil (a phosphodiesterase 5 inhibitor) and Treprostinil (a synthetic prostacyclin smooth muscle relaxant) have shown some benefit in the management of pulmonary hypertension in CDH. Sildenafil leads to pulmonary vasodilation by potentiating the effects of nitric oxide. It has been shown to decrease pulmonary artery pressure and pulmonary vascular resistance while improving the cardiac index. Treprostinil has been shown to reduce pulmonary hypertension through direct vasodilation. Retrospective data has shown improvement in children with CDH who have refractory pulmonary hypertension. There are no randomized controlled studies of these various agents or combinations thereof, but some have shown promise in limited trials.

Sodium nitroprusside results in too much systemic hypotension to be useful.