A Window of Opportunity for Treating Patients with Cirrhosis

Despite the ability of nonselective β blockers (NSBBs) to reduce portal pressure and lower the risk of variceal hemorrhage in patients with cirrhosis, these drugs have detrimental effects on those who have developed spontaneous bacterial peritonitis, researchers show in the June issue of Gastroenterology.

Variceal hemorrhage, the most common lethal complication of cirrhosis, results from portal hypertension. NSBBs inhibit binding of catecholamines to β1 and β2 adrenergic receptors, reducing cardiac output and the hepatic venous portal pressure gradient.

Guidelines recommend administration of NSBBs to prevent variceal hemorrhage and rebleeding in patients with cirrhosis.

However, some studies have reported detrimental effects of NSBBs in patients with cirrhosis and refractory ascites, initiating debates over the therapeutic window during which these drugs are effective for these patients.

Patients with advanced cirrhosis can develop bacterial infections that cause large changes in systemic hemodynamics, such as peripheral vasodilation, reducing responsiveness to vasoconstrictors and increasing cardiac output.

Development of spontaneous bacterial peritonitis, an acute bacterial infection of ascitic fluid, might therefore preclude treatment of patients with advanced cirrhosis with NSBBs.

Mattias Mandorfer et al. analyzed data from 607 consecutive patients with cirrhosis and ascites, with and without spontaneous bacterial peritonitis.

They found that NSBBs increase transplant-free survival and reduce hospitalization of patients without spontaneous bacterial peritonitis.

However, among patients with spontaneous bacterial peritonitis, the drugs were associated with hemodynamic compromise and decreased blood pressure. These reduced transplant-free survival, increased rates of hospitalization, and increased incidences of the hepatorenal syndrome and acute kidney injury.

Effects of NSBBs on transplant-free survival of patients with and without spontaneous bacterial peritonitis.

Mandorfer et al. conclude that development of spontaneous bacterial peritonitis closes the window of opportunity for NSBB treatment, as maintaining the circulatory reserve is crucial in critically ill patients with cirrhosis.

They explain that the main adaptive mechanism to circulatory stress is increased heart rate, mediated by β1 adrenoreceptors, which are down-regulated and desensitized in patients with advanced cirrhosis. Additional blockade, such as with a drug, induces chronotropic incompetence, decreases cardiac output and blood pressure, and can increase the rate at which hepatorenal syndrome develops in patients with spontaneous bacterial peritonitis, leading to death.

In an editorial that accompanies the article, Phillip S. Ge and Bruce A. Runyon summarize the therapeutic window for NSBBs in patients with cirrhosis:

During early stages cirrhosis, NSBBs have no effect on survival or increase adverse events and do not prevent the formation of varices. As cirrhosis progresses, portal pressures increase and the sympathetic nervous system becomes increasingly activated. Ascites and esophageal varices develop, and there is increased risk of variceal bleeding and bacterial translocation. However, systemic hemodynamics are preserved, and blood pressure and cardiac output deliver adequate end-organ perfusion. In this middle stage of cirrhosis, the window for NSBBs to prevent gastrointestinal bleeding opens. In patients with advanced cirrhosis with refractory ascites, the inability of the circulatory system to increase cardiac output via the β-adrenergic system reduces mean arterial pressures, perfusion to vital organs, increasing risk for the hepatorenal syndrome and end-organ damage.

Mandorfer et al. add that it is not clear whether the therapeutic window for NSBBs reopens after spontaneous bacterial peritonitis resolves. Prospective studies are needed establish the appropriate, stage-dependent use of this treatment of portal hypertension.

Ge and Runyon state that the next iteration of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver practice guidelines on the prevention and management of variceal hemorrhage will need to incorporate these recent studies and their clinical implications.

This article has a continuing medical education activity.