Journal of Hepatology 48 (2008) 185188 www.elsevier.

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Editorial

Predicting failure to control bleeding and mortality in acute variceal bleeding q

A.K. Burroughs*, C.K. Triantos
The Sheila Sherlock HepaticoPancreaticoBiliary and Liver Transplantation Unit, Royal Free Hospital, Pond Street, London NW3 2QG, UK

See Article, pages 229236

Portal hypertension worsens with increasing severity of cirrhosis, and is responsible for many of its complications, which lead to clinical decompensation. The hepatic venous pressure gradient (HVPG) is a measure of the severity of portal hypertension, with a direct 1:1 correlation between an occluded or wedged hepatic venous pressure and portal pressure in all types of sinusoidal and portal-sinusoidal portal hypertension [1]. HVPG has been shown to be an independent prognostic factor for survival in virtually all studies in which it has been evaluated for this purpose whether in patients with cirrhosis with a history of bleeding or without [2] with isolated exceptions [3]. Measurement of portal pressure is being increasingly used to assess the severity of cirrhosis in specic settings, such as when varices are absent [4], during the course of developing varices [5], to assess progression of recurrent hepatitis C after liver transplantation [68], and response to therapy for prevention of rebleeding from varices [9,10] and lastly as a predictor of complications [5,9,11]. In acute complications of cirrhosis, such as variceal bleeding, there have been fewer studies of portal pressure, but also in this setting, HVPG has been shown to be prognostic for both survival and the course of
Associate Editor: C. Merkel q The authors declare that they do not have anything to disclose regarding funding from industries or conict of interest with respect to this manuscript. * Corresponding author. Tel.: +44 2074726229; fax: +44 2074726226. E-mail address: andrew.burroughs@royalfree.nhs.uk (A.K. Burroughs).

bleeding. In 1986 Vinel et al. [12] documented that short term prognosis in alcoholic cirrhotic patients with variceal bleeding was independently associated with portohepatic gradient measured within 48 h of admission. This was conrmed in a small study of 22 patients, in which the best cut o for continued bleeding or early rebleeding was HVPG >16 mmHg [13]. Villanueva et al. [14] showed that HVPG >20 mmHg and a decrease 610 mmHg under vaso-active therapy were independent predictors of further bleeding. A HVPG >20 mmHg has been shown to correlate with important clinical outcomes such as more diculty in controlling acute variceal bleeding, more early rebleeding, more blood transfusion need, more days in intensive care and increased hospital mortality [15]. Lastly Avgerinos et al. [16] showed that HVPG >16 mmHg was independently associated with death and/or early rebleeding evaluating HVPG measurements before and immediately after endoscopic treatment and every 24 h for a 5-day period. Interestingly there was a sustained rise of portal pressure after sclerotherapy, but not after band ligation. In addition, Vlachogiannakos et al. [17] showed that somatostatin but not octreotide eectively prevents the post-endoscopic increase of HVPG. With the prognostic association of high HVPG with the course of bleeding (using vasoactive drugs and endoscopic therapy) and mortality, a randomized study showed that urgent TIPS in patients with HVPG >20 mmHg protected against continued or repeated bleeding and reduced mortality [15]. This study clearly demonstrated the therapeutic benet of intervention based on HVPG measurement and validated the

0168-8278/$32.00 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2007.11.006

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value of 20 mmHg HVPG as a cut o. The question then arises about the applicability of measuring HVPG in this setting, while although accurate and reproducible with little coecient of variation in measurement and with few complications [18] it is not currently feasible outside of a research setting period. Secondly, what are the clinical factors associated with failure to control bleeding and mortality? There have been several studies which have evaluated this: by consensus, control of variceal bleeding spans within the rst 5 days and mortality as death within 6 weeks of onset of bleeding [19]. Ben Ari et al. [20] showed that in 385 cirrhotics treated initially with vasoactive drugs and then endoscopic therapy, if bleeding continued or recurred (within 5 days), active bleeding at endoscopy (independent of the interval from onset of melaena and/or haematemesis or the interval to admission to hospital), the severity of liver disease (mainly Child-Pugh grade C), as well as encephalopathy, platelet count and history of alcoholism, were all independently associated with failure to control bleeding (internal validation of the model was performed). There were some interactions between variables, in that active bleeding was associated with transfusion need, and transfusion need was associated with Child-Pugh class, and shorter interval to admission. Interestingly, a higher Child-Pugh score and increased mortality were independent of transfusion requirement. Independent factors associated with mortality within 30 days, were failure to control bleeding within 5 days, raised bilirubin, encephalopathy, shorter interval to admission to hospital and plasma urea. Lecleire et al. [21] evaluated prospectively 468 consecutive patients with cirrhosis and upper gastrointestinal bleeding (23.5% died during hospitalization). The independent factors associated with in hospital mortality were: presentation with haematemesis, bleeding starting in hospital, prothrombin time <40% (the strongest association, reecting severity of liver disease), recent use of steroid drugs within 7 days of bleeding, age >60 years and a concomitant hepatocellular cancer. Thomopoulos et al. [22] retrospectively evaluated 141 patients with acute variceal bleeding (18.6% 6 week mortality) treated with somatostatin started before endoscopy and endoscopic ligation. Early rebleeding, Child-Pugh grade C and shock at admission were independent predictors of mortality at 6 weeks, whilst active bleeding and presence of infection (prophylactic antibiotics were not routinely used) were not adverse factors. Lo et al. [23] also found active bleeding to be independently associated with recurrent bleeding but not mortality, although this was higher in the group with active bleeding at endoscopy. In addition, the presence of hepatocellular carcinoma may alter the immediate prognosis [21,24,25], so that early imaging (large tumors will be detected by a bed-side ultrasound) to detect HCC

may alter the therapeutic algorithm for example TIPS rescue therapy may not be indicated and only vasoactive and endoscopic methods applied. A concomitant portal vein thrombosis, whether due to tumor or not, may also worsen prognosis as often bleeding is more dicult to control. The use of prophylactic antibiotics should be standard therapy for patients with cirrhosis who have variceal bleeding [26]. The association with failure to control was shown prospectively [27], following a hypothesis that proposed infection as a trigger for bleeding [28], and the causal association was shown in two randomized trials [29,30]. Antibiotics result in better control of bleeding and less early rebleeding. The prognostic models that assess control of bleeding should now be based in cohorts of patients who have had prophylactic antibiotics. Thus what is needed to rene prognosis in acute variceal bleeding is a study which combines the evaluation of HVPG with clinical variables in which patients have been treated with the current standard of care [19] prophylactic antibiotics, vasoactive drugs from admission prior to endoscopy, and endoscopic therapy at diagnostic endoscopy [31]. This type of study is needed to establish whether HVPG adds signicantly to clinical variables, and if so, how much, so as to gauge the applicability of HVPG measurement in this clinical setting. This study has been completed by Abraldes et al. in this issue of the Journal [32]. In a prospectively evaluated cohort of 117 patients with cirrhosis, HVPG was measured within 48 h. As in a previous study [15] HVPG >20 mmHg was independently predictive of failure to control bleeding at 5 days, together with shock (systolic blood pressure at admission <100 mmHg) and non-alcoholic aetiology of cirrhosis, giving an optimal discrimination with an AUROC curve of 0.79. However removing HVPG, the model contained Child-Pugh class, shock at admission and non-alcoholic cirrhosis as independent associations with a c statistic of 0.8 i.e. the same discriminatory capacity. The authors devised a simple point score which will be useful in clinical practice as it identies a subgroup with 40% or more chance of failure to control variceal bleeding. Thus the papers cited above which uniformly related the severity of liver disease (i.e. Child-grade C class), the severity of bleeding (shock at admission) and active bleeding at endoscopy to the failure to control variceal bleeding within 5 days conrm the ndings of Abraldes et al. [32]. Indeed the authors conrm what is already known clinically about these patients with dicult bleeding [19] with the added data, that this is associated with a higher HVPG. This should intensify clinical research into more eective vasoactive regimens to lower portal pressure [3336] and treatment algorithms which oer more eective therapy to control bleeding ab initio, for example early TIPS after diagnostic endoscopy, or rst line injection with glues at diagnostic endoscopy, or

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indeed the recently described self-expanding covered oesophageal stent [37]. A Spanish collaborative group is due to evaluate a randomized trial of early TIPS, reproposing a management scheme used by Orlo et al. with emergency porto-caval shunt [38]. Although survival following variceal bleeding has progressively improved [39,40], it remains to be proven that complete or better control of bleeding with early TIPS or other measures, over and above what is current practice after failed vasoactive drugs and endoscopy will result in improved survival. In the large study by Ben Ari et al. [20] mortality in Child-Pugh grade C was independent of transfusion need ie of severity of bleeding. Thus there may be an inexorable train of events which is initiated by bleeding in this group of patients, leading to death, independent of good control of bleeding. This concept of going past the point of no return is seen in the development of renal failure despite the prompt resolution of sepsis (not associated with spontaneous bacterial peritonitis) in cirrhosis, where just over 20% of such patients have the complication of renal failure despite optimal treatment and resolution of the precipitating septic event [41]. References
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