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Chronic Lung Disease Associated Pulmonary Hypertension- The Next Epidemic?

Michael A. McCulloch, MD
University of Virginia Children's Hospital
Charlottesville, VA, USA

Advancements in neonatal intensive care unit management have improved average discharge rates to 55% following 24 week gestations and 92% for 28 week gestation [1]. However, as many as 68% of these 'NICU graduates' are diagnosed with bronchopulmonary dysplasia (BPD) and between 18 to 43% of these develop pulmonary hypertension [1,2,3]. This population's vulnerability becomes abundantly clear in mid-term follow up papers demonstrating 2-year mortality rates up to 40% [4,5].

A myriad of reasons exists for this sobering data. Echocardiographic assessments of right ventricular function and pressures are commonly inaccurate, complicating the diagnosis of right ventricular dysfunction and pulmonary hypertension [6]. Aspiration of oral or gastric contents are a frequent source of recurrent lung injury and oftentimes clinically silent [7]. Left ventricular diastolic dysfunction and pulmonary vein stenosis can significantly complicate the care of BPD patients, but are less common and often go unrecognized [8,9]. Most importantly, however, is the incomplete understanding of BPD pathophysiology and a lack of data-driven guidelines on how to care for these patients [10-15].

When pulmonary hypertension complicates BPD, it is tempting to initiate systemic pulmonary vasodilator therapies despite insufficient evidence supporting their use. Mourani, et al. retrospectively evaluated their experience with sildenafil therapy in 25 neonates diagnosed with BPD and pulmonary hypertension [14], and although echocardiographic evaluation suggested improvement in right ventricular systolic pressures, there remained a 20% mortality rate and nearly 10% of patients discontinued therapy due to medication-induced adverse events. Trottier-Boucher, et al. assessed 23 similar neonates receiving sildenafil therapy and also found echocardiographic evidence of decreased right ventricular systolic pressures in nearly 3/4 of patients, but 44% experienced systemic hypotension and only 1/3 appreciated 'clinical improvements' [15]. These are the two largest such studies on this patient population and are clearly inadequate to guide therapy.

The World Symposium of Pulmonary Hypertension Classification System clusters different types of pulmonary hypertension expected to have similar pathophysiology and therapeutic responses. Chronic lung disease/ BPD exists within the 'Developmental Lung Disease' subgrouping of group 3 pulmonary hypertension which also includes its closest adult correlates of chronic obstructive pulmonary disease and emphysema [16,17]. As these diseases are characterized by a 'capillary' level pulmonary hypertension and associated regions of incomplete gas exchange, the most recent guidelines clearly state "there is no specific therapy for (PH) pulmonary hypertension associated with lung diseases" [17] because systemically administered pulmonary vasodilators (i.e. sildenafil and bosentan) have proven to worsen gas exchange in several adult studies [18-20]. Although children and babies are not small adults, it would be shortsighted to extrapolate adult criteria and treatment regimen for all other types of pulmonary hypertension but not consider them for this group.

At our institution, surveillance echocardiograms start with the diagnosis of BPD or earlier in neonates with birth weight less than 1500 g and/or gestational age less than 34 weeks demonstrating hemodynamic compromise or need for mechanical ventilation/ non-invasive positive airway pressure at 4 weeks of life. Management changes are only suggested in patients who have pulmonary hypertension (greater than ½ systemic right ventricular pressures as suggested by interventricular septal position in systole, TR jet or PDA flow) AND evidence of right ventricular failure (two or more echocardiographic measures of abnormal right ventricular function; BNP greater than 2 times the upper limits of normal; hepatomegaly, hemodynamic instability, failure to thrive or feeding intolerance without other etiology). When applicable, initial recommendations are optimization of respiratory support to obtain a goal pH greater than 7.35, paCO2 less than 60 and paO2 greater than 60 or oxygen saturations greater than 92%. 'Dry' lungs are encouraged through the use of diuretics and concentrated formulas are preferably administered through nasoduodenal tubes to minimize micro-aspiration. If right ventricular dysfunction is deemed severe on the initial evaluation or persists after addressing the above issues, a pulmonary vasodilator is typically recommended.

Due to a significant incidence of hepatotoxicity associated with bosentan therapy in a population frequently plagued by hyper-alimentation associated liver disease, sildenafil is our first choice. Goal enteral dosing is the lower of 10 mg q6 or 2 mg/kg/dose q6. Half of the patient's weight based maximum dose is administered for 8 doses and then increased to the full dose with repeat echocardiogram, BNP and physical assessment performed after at least 8 doses of the ultimate regimen. It is not our goal to normalize right heart pressures but to improve right heart failure; bosentan is added at 2 mg/kg/dose q12 if right heart failure persists, or we recommend a gradual return towards a potentially dischargeable respiratory support and feeding regimen if right heart failure has resolved. Repeat assessments are performed with each significant change.

This relatively conservative approach is predicated on a general lack of data, the inherently resilient neonatal right ventricular myocardium, and the fact that newborns are capable of healthy acinar development until approximately their 4th birthday as long as they receive adequate nutrition and are free of ongoing lung injury [21]. Unadulterated lung development is the ultimate goal for these patients, and it has been our experience that this is achievable without pulmonary vasodilatory medications in the vast majority. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


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