To determine the tolerance, safety, and potential efficacy of sildenafil in the treatment of PH in young infants with CLD, we evaluated the clinical course and outcomes of 25 patients with CLD who began treatment with sildenafil for late PH during a hospitalization prior to the age of 2 years. We found that, as part of an aggressive program to treat PH in infants with CLD, sildenafil therapy was associated with improvement in PH by echocardiogram in most (88%) patients without significant rates of adverse events. Although the time to improvement was variable, many patients were able to wean off mechanical ventilator support and other PH therapies, especially iNO, during the course of sildenafil treatment without worsening of PH. However, several (28%) were treated with additional or alternate PH medications. Five (20%) patients died during the course of sildenafil treatment, although none specifically from refractory PH. No severe adverse effects with sildenafil treatment were observed, with only one patient discontinuing sildenafil use after 950 days secondary to frequent erections.
Previous studies have shown that patients with CLD and late PH represent a very high-risk population with increased morbidities and mortality.3-5
However, the natural course of disease in these patients is poorly understood. A recent study of patients with BPD and PH reported survival rates of 64% at 6 months, 61% at one year and 52% at two years after the diagnosis of PH.5
Although it is difficult to directly compare study populations, patients with BPD in our study group had a survival rate of 83% and the entire study group experienced 80% survival during a median follow-up period of 8 months after sildenafil initiation. These results suggest that sildenafil therapy as part of an overall program to aggressively treat lung disease and PH in infants with CLD may improve outcomes.
Sildenafil has been shown to improve hemodynamics and other outcome measures in adults with PH.31
Furthermore, in a small study of older children with idiopathic PH and PH secondary to congenital heart disease, long-term sildenafil use showed improved and sustained hemodynamics and exercise tolerance.35
Current reports of sildenafil in infants have been limited to its use for the acute treatment of PPHN36
acute PH treatment after cardiac surgery,38, 39
and to assist in weaning off iNO.40
This study represents the largest evaluation of prolonged sildenafil use in infants with CLD to date, and reinforces the findings of previous studies.
At the time of sildenafil initiation, most study patients underwent successful cardiac catheterization without adverse events. In addition to documentation of PH severity and reactivity to iNO, catheterization identified other previously unrecognized abnormalities that altered patient management including hemodynamically significant shunt lesions, pulmonary vein stenosis, and left ventricular diastolic dysfunction. In patients who underwent iNO reactivity testing, we found a statistically significant increase in PCWP measurements on iNO. Because iNO may increase pulmonary blood flow to the left heart, iNO treatment may unmask subtle left ventricular dysfunction that may contribute to pulmonary hypertension in these patients.41
Based on these findings, we recommend patients with CLD and PH undergo cardiac catheterization prior to the initiation of chronic PH medications for prolonged therapy. Interestingly, of the 3 infants who did not show acute pulmonary vasoreactivity to iNO, 2 demonstrated improvement in PH during long-term sildenafil therapy. Thus, the role of reactivity testing in determining PH therapy in this population remains unclear.
The pharmacokinetics and optimal dosing for sildenafil in young infants remains somewhat uncertain. Patients treated in this study were started at a dose of 1.5 mg/kg/day in 3 divided doses that was steadily increased over 1-2 weeks until the desired clinical response was achieved or to a maximum dose of 8 mg/kg/day in 4 divided doses. Avoidance of systemic hypotension was achieved with this dosing regimen. Most patients were treated with the maximum dose which was adjusted as patients gained weight during the follow-up period. Optimal criteria and timing to wean from sildenafil therapy also remain unclear. The general practice in this study was to begin weaning after at least two echocardiograms showing resolution of PH, and weaning occurred over weeks to months. Whether this strategy is too conservative and leads to unnecessarily prolonged therapy is currently unknown.
There are several potential limitations to this study. Although we and many clinicians rely on echocardiogram findings to assess hemodynamic improvement and response to therapy in this population, there are inherent limitations to this methodology because there is no data-derived definition of PH. Thus, defining the levels of pulmonary artery pressure to identify the presence and severity of PH and to guide therapy remains uncertain. However, severity of late PH in the BPD population does appear to correlate with survival.5
Because there was no control group, clinical improvement cannot be directly attributed to sildenafil therapy. Other factors, such as aggressive management of respiratory disease or time, may have affected outcomes. Due to the retrospective design of this study, all possible side-effects were not necessarily documented resulting in an underestimation of adverse events. For example, the potential adverse contribution of sildenafil treatment to retinopathy of prematurity remains a concern. However, prematurely born patients in our study were not started on sildenafil therapy until at least 40 weeks post-conceptual age, generally after patients may have developed or received therapy for retinopathy of prematurity. Furthermore, although neurological and ophthalmologic evaluations were not routinely performed in all subjects, the data available did not suggest worsening after sildenafil therapy However, any prospective study of sildenafil therapy in this population should include neurological and ophthalmologic follow-up to evaluate potential adverse outcomes.
In summary, we report the outcomes of infants with PH and CLD who were treated with long-term sildenafil therapy. We found that chronic sildenafil therapy, as part of an aggressive treatment program to treat underlying lung disease and PH, was well-tolerated, had few adverse events, and was related to progressive improvement in PH in most patients. This study provides the basis for large scale clinical trials to evaluate the efficacy and safety of long-term sildenafil use in infants with PH and CLD.