What might be learned from acute pulmonary vasodilator testing in portopulmonary hypertension?

Abstract

In the current issue of Liver Transplantation, Ricci et al.1 report their results of acute pulmonary vasodilator (VD) testing with inhaled nitric oxide (NO), intravenous prostacyclin (PGI2), and oral isosorbide-5-mononitrate (Is-5-MN) in patients with portopulmonary hypertension (POPH). PGI2 elicited greater reductions in mean pulmonary artery pressure (11.8%) and pulmonary vascular resistance (24%) than NO (5.7% and 11%, respectively). The mechanisms were largely due to a 28% drop in systemic vascular resistance and a 17% increase in cardiac index, although another important difference in hemodynamic response may have been the route of administration. Intravenous administration delivers medication directly to the endothelial cell while diffusion to the vascular smooth muscle cell is required when medication is inhaled. Is-5-MN decreased mean pulmonary artery pressure by 25.6% and pulmonary vascular resistance by 21.5% without systemic changes. Overall, 6 of 19 patients (32%) had decreased mean pulmonary artery pressure <35 mmHg and would have been considered potential liver transplantation candidates. VD, vasodilator; POPH, portopulmonary hypertension; PAH, pulmonary artery hypertension. Traditionally, acute VD testing has been used to determine which patients might have a beneficial response to oral vasodilator therapy (calcium antagonists) as initial treatment for pulmonary artery hypertension (PAH).2, 3 What is a positive VD response? What does it mean? The definition continues to evolve over time and, 2 definitions were used in the current study. In general, a positive VD response identifies patients who have a more favorable hemodynamic profile, such as having vasoconstriction as the predominant mechanism for the increased pulmonary artery pressures.4 Approximately 10% of patients with PAH will have such a positive VD response.5 Several medications are available for acute pulmonary VD testing and which to use depends largely on availability, cost, and convenience. Acute pulmonary VD testing in POPH specifically, has fallen out of favor because these patients do not tolerate calcium channel blockers, which worsen edema and portal hypertension by increasing the hepatic vein portal pressure gradient.6 Unique and varying hemodynamic patterns exist in POPH compared to other forms of PAH and, pressure-flow-volume-resistance relationships may influence therapeutic approaches.7 High-flow states and excess volumes exist in POPH and may be rare in other forms of PAH. What happens to these vascular relationships in response to acute VD testing in POPH and are they prognostic? In the current series, for example, baseline pulmonary artery occlusion pressures were normal; however, we do not know what happened to the individual pulmonary artery occlusion pressures in response to the acute administration of NO compared with PGI2 or Is-5-MN. Given the small sample size, the individual patient data, including the responses of pulmonary artery occlusion pressure and transpulmonary gradient (mean pulmonary artery pressure–pulmonary artery occlusion pressure) rather than the overall median responses of pulmonary vascular resistance and cardiac index would have been helpful. Medications of different classes may influence these vascular relationships in different ways and these interactions may clinically be relevant and are important to understand. It is intuitive that not all patients experience the same response to the same medication, thus the purpose of combining medications with different mechanisms of action.8 One important point that deserves emphasis is that patients who do not respond to acute VD testing may still respond to medications for PAH. In other words, a negative VD challenge should not preclude treatment. This goes beyond acute vasodilatation and involves more complex issues of vascular remodeling. Intimal proliferation and vascular smooth muscle hypertrophy both cause luminal obliteration and obstruction to arterial blood flow. Current therapies for PAH act to prevent or reverse this remodeling while calcium channel blockers and Is-5-MN are pure vasodilators. The authors ask whether acute pulmonary VD testing might have a relevant role in developing a therapeutic strategy for patients with POPH who might ultimately be candidates for liver transplantation. This is a question that must be answered in all severities of pulmonary hypertension to truly understand the pressure-volume-flow-resistance interactions and responses to varying medications in POPH. Indeed, with the development of mechanistically different therapies for PAH, it is time to reevaluate the role of acute pulmonary VD testing and its potential influence on medication selection and outcomes in POPH with or without liver transplantation.