Effect of albumin on survival in septic cirrhotic patients other than spontaneous bacterial peritonitis. The question remains open
Authors: Thierry Thevenot, Elisabeth Monnet, Vincent Di Martino
Journal: Journal of Hepatology (2012)

Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled studyJournal of HepatologyVol. 57Issue 4PreviewTreatment with albumin in patients with cirrhosis and spontaneous bacterial peritonitis (SBP) prevents renal failure and improves survival. Whether albumin has similar beneficial effects in patients with infections other than SBP is unknown. Full-Text PDF Reply to: "Effect of albumin on survival in septic cirrhotic patients other than spontaneous bacterial peritonitis. The question remains open"Journal of HepatologyVol. 58Issue 3PreviewWe would like to thank Dr. Thevenot et al. for their interest in our study on the effect of albumin administration in patients with cirrhosis and infections other than spontaneous bacterial peritonitis [1]. Our answers to their comments are as follows: (1) the statistical difference between the per-protocol analysis and intention-to-treat analysis is minimal, as indicated by their corresponding hazard ratios (0.29 and 0.35, respectively) and p values (0.042 and 0.06), despite the fact that the latter falls outside the level of significance. Full-Text PDF Open Access We read the manuscript by Guevara et al. with interest [[1]Guevara M. Terra C. Nazar A. Solà E. Fernandez J. Pavesi M. et al.Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study.J Hepatol. 2012; 57: 759-765Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar]. The authors evaluated the effect of albumin administration on the 3-month survival in cirrhotic patients hospitalized for infections other than spontaneous bacterial peritonitis (SBP). After randomization, 54 and 56 patients received respectively antibiotics alone, and both antibiotics plus intravenous albumin (1.5 g/kg the first day and 1 g/kg at day 3). The authors concluded that albumin administration with antibiotics showed a potential survival benefit in per-protocol analysis as compared with the control group, and that such a beneficial effect was probably due to the improvement in effective arterial blood volume reflected by the improvement in renal function. However, we feel that their conclusions may require closer examination. First, this hopeful conclusion contrasts with the absence of a 3-month survival benefit when the analysis was performed on an intention-to-treat basis. The reason for the lack of significance in the intention-to-treat analysis could be related to the patients withdrawn from the per-protocol analysis. Indeed, the overall prognosis of these patients excluded from analysis was worse (these patients had septic shock or unrecognized cardiomyopathy) than those who remained in the analysis, and this may overestimate the albumin efficacy. Thus, the per-protocol analysis represents a "best-case scenario" to demonstrate the treatment effect [[2]Schulz K.F. Altman D.G. MOher D. CONSORT GroupCONSORT 2010: Statement: updated guidelines for reporting parallel group randomised trials.BMJ. 2010; 340: c332Crossref PubMed Scopus (4523) Google Scholar]. The patient selection could also explain this lack of significance since a progressive form of renal failure has been observed only in sub-diaphragmatic infections [[3]Fasolato S. Angeli P. Dallagnese L. Maresio G. Zola E. Mazza E. et al.Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features.Hepatology. 2007; 45: 223-229Crossref PubMed Scopus (238) Google Scholar]. Moreover, the author's assumption that albumin could improve the survival rate by 30% (i.e., 3-month mortality rates of 55% in the control group and 25% in the albumin group) was an over-optimistic projection that is not supported by the literature [4Sort P. Navasa M. Arroyo V. Aldeguer X. Planas R. Ruiz-del-Arbol L. et al.Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.N Engl J Med. 1999; 341: 403-409Crossref PubMed Scopus (1250) Google Scholar, 5Pereira G. Guevara M. Fagundes C. Sola E. Rodriguez E. Fernandez J. et al.Renal failure and hyponatremia in patients with cirrhosis and skin and soft tissue infection. A retrospective study.J Hepatol. 2012; 56: 1040-1046Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. This also explains the absence of any beneficial effect of albumin in their intention-to-treat analysis. Even in the sickest cirrhotic patients with SBP, Sort et al. observed a 3-month mortality rate of 59% in the group treated with antibiotics alone (control group), and the difference in the survival rate between this control group and the group of patients treated with both albumin and antibiotics was only 19% [[4]Sort P. Navasa M. Arroyo V. Aldeguer X. Planas R. Ruiz-del-Arbol L. et al.Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.N Engl J Med. 1999; 341: 403-409Crossref PubMed Scopus (1250) Google Scholar]. Second, the multivariate analysis performed to identify potential predictors of death included more variables than allowed by the low number of events (18 deaths) observed. Consequently, this may fail to provide valid estimates applicable to other sets of patients. To avoid such overfitting, a predefined ratio of candidate prognostic variables to the number of deaths should have been set at 1:10 [[6]Harrell Jr., F.E. Lee K.L. Mark D.B. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors.Stat Med. 1996; 15: 361-387Crossref PubMed Scopus (6938) Google Scholar]. Third, the authors observed a significant decrease in plasma renin activity, aldosterone and norepinephrine concentration, along with the stability of arterial pressure in the albumin group, contrary to that observed in the control group. These data probably support the improvement in renal function during the first week following albumin administration. However, we should interpret this supposed improvement in renal function with caution, because plasma renin activity, aldosterone and norepinephrine concentration were measured in only 48 of the 97 patients enrolled in the analysis, which precludes the extrapolation of measured values to the true mean values for the whole population. From a clinical point of view, the incidence of renal failure (serum creatinine >133 μmol/L) was low and not different between the two groups (27.4% in the control group and 23.9% in the albumin group). As stated honestly by Guevara et al., the low incidence of renal insufficiency suggested that their study population was not so sick. The absolute difference of only 2.2% in the 3-month survival rate between the two groups (80.4% in the control group vs. 82.6% in the albumin group) also precludes any assumptions regarding the putative survival benefit achieved by improving renal function with albumin infusion. Finally, this randomized study allows us to draw some conclusions and assumptions for future trials. As reported previously, albumin administration has demonstrated its beneficial effects on systemic hemodynamic and renal function in cirrhotic patients with SBP, in terms of both an improvement in cardiac function and a decrease in arterial vasodilatation [[7]Fernandez J. Navasa M. Garcia-Pagan J.C. G-Abraldes J. Jiménez W. Bosch J. et al.Effect of intravenous albumin on systemic and hepatic hemodynamics and vasoactive neurohormonal systems in patients with cirrhosis and spontaneous bacterial peritonitis.J Hepatol. 2004; 41: 384-390Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar]. This effect may be unchanged in infections other than SBP. In Guevara's study [[1]Guevara M. Terra C. Nazar A. Solà E. Fernandez J. Pavesi M. et al.Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study.J Hepatol. 2012; 57: 759-765Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar], the beneficial effect of albumin on survival is more controversial, and the high number of patients (approximately 5000 per group) that would have been required to detect a 2.2% difference in survival rate, between those receiving albumin infusion or not, will preclude further trials with such a "hard" end point. Assessment of renal function is surely a valid surrogate, because (1) creatinine level can be measured simply in the post-treatment period, (2) renal insufficiency is strongly associated with death in cirrhotic patients, and (3) renal function improves after albumin treatment. As clearly stated by Guevara et al., the key issue to highlight a beneficial effect of albumin on survival would be to investigate more fragile cirrhotic patients, particularly those with ascites (but without SBP) associated or not with renal failure. Large randomized studies are needed to confirm the results of Guevara's study. We will soon report first results from our ongoing French "ALBCIRINF" study evaluating the effect of albumin on renal function in severe cirrhotic patients, suffering from bacterial infection other than SBP. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.