We thank Drs. Groneberg and Fischer for their interest and Dr. Fallon (1) for his excellent editorial. In our study, no significant change was seen in hepatic or renal function before and after methylene blue infusion, respectively (total bilirubin level, 183 ± 202 µmol/L [10.7 ± 11.8 mg/dL] vs. 180 ± 188 µmol/L [10.5 ± 11 mg/dL] [P > 0.2]; serum albumin level, 289 ± 43 g/L vs. 299 ± 38 g/L [P = 0.17]; prothrombin time, 37.7 ± 10 seconds vs. 38 ± 9 seconds [P > 0.2]; serum creatinine concentration, 115 ± 71 µmol/L [1.3 ± 0.8 mg/dL] vs. 115 ± 62 µ mol/L [1.3 ± 0.7 mg/dL] [P > 0.2]). Six patients died. Median survival time was 69 days (range, 6 to 322 days); patient 6 is still alive 34 months after the study. The prognosis of patients with the hepatopulmonary syndrome seems poor (2), but prospective studies are needed.

To answer the questions posed by Dr. Fallon (1), there is some correlation between the improvement in oxygenation (alveolar-arterial difference for PaO ₂ [PAO ₂-PaO ₂]) and the increase in mean pulmonary artery pressure and pulmonary vascular resistance after methylene blue infusion. The correlation coefficient for the difference at 0.5 hour minus baseline was –0.59 for PAO ₂-PaO ₂ compared with mean pulmonary artery pressure (P = 0.16) and 0.67 for PAO ₂-PaO ₂ compared with pulmonary vascular resistance (P = 0.1). The correlation between changes of systemic vascular resistance and pulmonary vascular resistance was 0.79 (P = 0.03). However, these correlations must be interpreted with caution because of the small sample size. Regarding septic shock, one study reported a decrease in arterial oxygenation after methylene blue administration (3); however, other studies did not report this result (4, 5). Septic shock and the hepatopulmonary syndrome are different diseases with different causes, and direct comparisons are of limited value.

Although methylene blue is relatively safe, its long-term use is limited because it is a strong dye. If used regularly, it would discolor not only urine but also lacrimal fluid, saliva, and probably mucous membranes and the skin. Treatment, especially long-term treatment, is still problematic (1), and further clinical studies using substances that inhibit the production or action of nitric oxide are needed.