Vasoconstrictor therapy for patients with cirrhosis with ascites but without hepatorenal syndrome† (2008)

Preliminary work from our group1, 2 and other investigators3, 4 showed that the a1 adrenergic agonist midodrine improves systemic hemodynamics and renal function, and suppresses the activity of antinatriuretic factors, such as renin-aldosterone axis and sympathetic nervous system, in patients with cirrhosis with ascites but without hepatorenal syndrome (HRS). A preferential effect of midodrine on splanchnic vasculature has been suggested experimentally,5 and by the fact that the peripheral arterial resistance is not modified under midodrine treatment in non-HRS patients with cirrhosis with ascites,3 despite the systemic hemodynamic improvement. The above observations support the pathophysiologic basis of cirrhotic ascites6 and indicate a role of vasoconstrictor therapy in the management of non-HRS patients with cirrhosis. In a previous issue of HEPATOLOGY, Krag et al. reported on the beneficial systemic hemodynamic and renal effects of the acute administration of the vasopressin analog terlipressin in non-HRS patients with cirrhosis with nonrefractory and refractory ascites,7 reminiscent of the observations in patients treated with midodrine. In particular, a significant increase in natriuresis was noted, suggesting possible therapeutic implications, particularly for patients with refractory ascites. However, three previous single-dose terlipressin studies failed to show a significant effect on natriuresis in non-HRS patients with cirrhosis with ascites, either refractory8 or not.9, 10 Urine production was not increased in any of the above studies, even when adequate hydration was provided.9 Likewise, natriuresis was not modified by the administration of terlipressin for several days in patients with cirrhosis with HRS, though renal function and the activity of antinatriuretic hormonal systems were significantly ameliorated.11, 12 Therefore, more evidence is clearly required, particularly from multiple-dose terlipressin studies, to establish the natriuretic effects of terlipressin in non-HRS patients with cirrhosis with ascites, regardless of other beneficial renal or hormonal effects. By contrast, single-dose3 and multiple-dose1, 4 midodrine studies on non-HRS patients with cirrhosis without1, 3 or with4 refractory ascites consistently show a significant increase in renal sodium excretion. The intravenous route of administration and the need for hospitalization are major disadvantages of terlipressin treatment, excluding a role of terlipressin in the management of nonrefractory ascites and precluding prolonged therapy in patients with refractory ascites. The administration of terlipressin also harbors the risk of dangerous side effects,13 which should be taken seriously into account in treating clinically stable non-HRS patients with cirrhosis. On the other hand, the oral route of midodrine administration along with the lack of significant adverse effects related to midodrine treatment favor a possible therapeutic use in patients with or without refractory ascites. Another drawback is the cost of terlipressin treatment. Specifically, the mean cost of a 10-day course of terlipressin, on a basis of 3 mg/day, is close to 1000 euros, a figure 60-fold higher than the expected cost of a 10-day midodrine course, that on a 30 mg/day basis would be approximately 15 euros. All in all, the potential benefits of vasoconstrictor therapy in non-HRS patients with cirrhosis with ascites are attracting increasing interest. The therapeutic use and the clinical applicability of terlipressin in these patients are questionable, although the effects of midodrine warrant further attention. Georgios N. Kalambokis*, Epameinondas V. Tsianos* , * First Division of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece, Hepato-gastroenterology Unit, Medical School, University of Ioannina, Ioannina, Greece.