Acute endotoxemia following transjugular intrahepatic stent-shunt insertion is associated with systemic and cerebral vasodilatation with increased whole body nitric oxide production in critically ill cirrhotic patients

Background & Aims

Transjugular intrahepatic stent-shunt (TIPSS) insertion, in patients with uncontrolled gastro-intestinal bleeding, often results in worsening of the systemic hemodynamics which can be associated with intracranial hypertension but the underlying mechanisms are unclear. This study explored the hypothesis that TIPSS insertion results in acute endotoxemia which is associated with increased nitric oxide production resulting in systemic and cerebral vasodilatation.

Methods

Twelve patients with cirrhosis who were undergoing TIPSS for uncontrolled variceal bleeding were studied prior to and 1-h after TIPSS insertion. Changes in cardiac output (CO) and cerebral blood flow (CBF) were measured. NO production was measured using stable isotopes using l-[guanidino-¹⁵N₂] arginine and l-[ureido-¹³C;5,5-²H₂] citrulline infusion. The effect of pre- and post-TIPSS plasma on nitric oxide synthase (NOS) activity on human endothelial cell-line (HUVEC) was measured.

Results

TIPSS insertion resulted in a significant increase in CO and CBF. Endotoxin and induced neutrophil oxidative burst increased significantly without any significant changes in cytokines. Whole body NO production increased significantly and this was associated with increased iNOS activity in the HUVEC lines. The change in NO production correlated with the changes in CO and CBF. Brain flux of ammonia increased without significant changes in arterial ammonia.

Conclusions

In conclusion, the insertion of TIPSS results in acute endotoxemia which is associated with increased nitric oxide production possibly through an iNOS dependent mechanism which may have important pathophysiological and therapeutic relevance to understanding the basis of circulatory failure in the critically ill cirrhotic patient.

Introduction

Acute decompensation of cirrhosis due to a precipitating illness often progresses to acute systemic hypotension which may also be associated with severe hepatic encephalopathy and multi-organ failure, as well as with high mortality rates. Moreover, these symptoms are difficult to distinguish clinically from acute liver failure, a condition often referred to as acute-on-chronic liver failure (ACLF) [1]. A small proportion of patients develops overt intracranial hypertension [2], [3]. Previous studies have shown that TIPSS results in increased cardiac output (CO) and a reduction in systemic vascular resistance (SVR) and mean arterial pressure (MAP) [4], [5]. We have previously reported deaths in four patients due to brain herniation from intracranial hypertension following insertion of a transjugular intrahepatic portosystemic stent-shunt (TIPSS) [2], [3]. These patients had advanced liver disease, uncontrolled variceal bleeding, sepsis, and renal failure. The TIPSS procedure may provide the opportunity to study the hemodynamic effects of acute portacaval shunting in patients with cirrhosis and provide clues to factors important in the pathogenesis of circulatory collapse and the hepatic encephalopathy components of ACLF.

Recent studies also point to an important role of the systemic inflammatory response in the pathogenesis of ACLF and the associated hepatic encephalopathy [6], [7], [8]. Our recent studies have suggested that patients with severe alcoholic hepatitis who progress to ACLF have markedly altered neutrophil function which is possibly mediated through high circulating endotoxin levels. Endotoxin is not only a priming agent but can also fully activate neutrophils [9], [10], [11], probably by up-regulating the NADPH oxidase assembly [11]. The highest levels of endotoxin reported in patients with liver disease are found in portal venous blood [12], [13], highlighting the importance of the bowel and altered gut permeability as the possible source of endotoxin [14]. Hence, it would be reasonable to expect that TIPSS insertion may exacerbate the existing endotoxemia which is known to induce iNOS in endothelial cells.

The aims of the present study were, therefore, to test the hypothesis that TIPSS worsens endotoxemia which increases nitric oxide production resulting in acute systemic and cerebral changes. In endothelial cell culture systems, we also wanted to determine whether incubation of the cells with patient’s plasma would alter the activity of nitric oxide synthase.