Hepatopulmonary syndrome (HPS) results when chronic
liver disease or
portal hypertension causes intrapulmonary microvascular dilatation with
hypoxemia. In experimental HPS,
tumor necrosis factor alpha (
TNF-alpha) overproduction contributes to vasodilatation, which is improved by
pentoxifylline, a
TNF-alpha inhibitor. The effectiveness of
pentoxifylline in humans is unknown. The aim of this open-label, single-arm clinical trial was to assess the efficacy and tolerability of
pentoxifylline in patients with
cirrhosis and advanced HPS undergoing
liver transplantation evaluation. Nine adults with
cirrhosis and moderate to severe HPS were enrolled. All patients had an initial 2-week titration to a target dose of
pentoxifylline of 400 mg by mouth every 8 hours, which was continued for 6 weeks. Baseline and follow-up arterial blood
gases and
TNF-alpha levels were evaluated. Adverse effects and tolerability were assessed. The 9 patients had a mean age of 55 +/- 10 years, and 67% were female. The most common causes of
cirrhosis were hepatitis C virus and alcohol (55%). The mean Model for
End-Stage Liver Disease score was 11 (range, 6-19), and patients had advanced
hypoxemia [mean partial pressure of arterial
oxygen (PaO(2)) = 54 +/- 12 mm Hg, mean alveolar-arterial
oxygen gradient (A-a PaO(2)) = 57 +/- 15 mm Hg]. Of the 9 patients enrolled, follow-up blood
gases were done in 7. There was no significant change in PaO(2) (P = 0.3) or A-a PaO(2) (P = 0.3) with treatment.
Pentoxifylline was poorly tolerated.
Nausea (100%) and
vomiting (56%) were the predominant side effects, and only a single patient was able to complete full-dose
therapy. Treatment with
pentoxifylline did not improve arterial oxygenation in advanced HPS, and tolerance was limited by gastrointestinal toxicity.