Reply to “Albumin infusion in cirrhotic patients with non-SBP infections: End of the story?”
Authors: Thierry Thevenot, Elisabeth Monnet, Vincent di Martino
Journal: Journal of Hepatology (2015)

Albumin infusion in cirrhotic patients with infections other than spontaneous bacterial peritonitis: End of the story?Journal of HepatologyVol. 63Issue 3PreviewWe read with interest the recent manuscript by Thevenot et al. [1] which adds data to the debate on the potential beneficial effect of albumin administration during episodes of infections other than spontaneous bacterial peritonitis (SBP) in cirrhotic patients [2–4]. Full-Text PDF Open AccessEffect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trialJournal of HepatologyVol. 62Issue 4PreviewAlbumin infusion improves renal function and survival in cirrhotic patients with spontaneous bacterial peritonitis (SBP) but its efficacy in other types of infections remains unknown. We investigated this issue through a multicenter randomized controlled trial. Full-Text PDF We greatly appreciate the comments by Lucidi et al. [[1]Merli M. Lucidi C. Lattanzi B. Riggio O. Albumin infusion in cirrhotic patients with infections other than spontaneous bacterial peritonitis: end of the story?.J Hepatol. 2015; 63: 767-768Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. Firstly, we acknowledge that, despite well-conducted randomization to reduce the risk of selection bias at trial entry [[2]Thévenot T. Bureau C. Oberti F. Anty R. Louvet A. Plessier A. et al.Effect of albumin in cirrhotic patients with infections other than spontaneous bacterial peritonitis: a randomized trial.J Hepatol. 2015; 62: 822-830Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar], the presence of ascites was more frequently reported in the albumin (ALB) group as compared with the control group (75.8 vs. 59.6; p = 0.017). We have to remember that using an alpha risk of 5%, the probability of there being no imbalance between groups for any one baseline characteristic is 0.95. Assuming the characteristics are independent, there is a non-negligible 1 − (0.95)n probability of observing a significant imbalance between groups when comparing n baseline characteristics. For instance, in Table 1 showing the baseline characteristics of patients [[2]Thévenot T. Bureau C. Oberti F. Anty R. Louvet A. Plessier A. et al.Effect of albumin in cirrhotic patients with infections other than spontaneous bacterial peritonitis: a randomized trial.J Hepatol. 2015; 62: 822-830Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar], there were at least 10 independent variables meaning that the chance of at least one statistically significant imbalance was 0.40. In order to improve the precision of the treatment effect estimate, and to avoid any confounding, the two Cox multivariate analyses performed to determine predictive variables associated with renal failure and death at 3 months were adjusted for ascites, which was no longer significant. Secondly, Lucidi et al. are right in stressing that we omitted to accurately classify infections into healthcare-associated, nosocomial or community-acquired, to analyze the pathogenic organisms identified and the antibiotic resistance pattern, and to prospectively record the occurrence of a second infection [[3]Bajaj J.S. O’Leary J.G. Reddy K.R. Wong F. Olson J.C. Subramanian R.M. et al.Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience.Hepatology. 2012; 56: 2328-2335Crossref PubMed Scopus (298) Google Scholar]. All of these data are of considerable importance for outcome in cirrhotic patients. Our multicenter trial mainly aimed to evaluate the effectiveness of albumin in real-life practice, without any restriction on antibiotic prescriptions. In our study, nosocomial infections were not significantly associated with renal failure (p = 0.53 by univariate Cox model) or death at 3 months (p = 0.13). Finally, Lucidi et al. also underline the protocol violations which may have diluted the treatment effect. These violations are common in interventional research [4Ye C. Giangregorio L. Holbrook A. Pullenayegum E. Goldsmith C.H. Thabane L. Data withdrawal in randomized controlled trials: defining the problem and proposing solutions: a commentary.Contemp Clin Trials. 2011; 32: 318-322Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 5Peduzzi P. Wittes J. Detre K. Holford T. Analysis as-randomized and the problem of non-adherence: an example from the Veterans Affairs Randomized Trial of Coronary Artery Bypass Surgery.Stat Med. 1993; 12: 1185-1195Crossref PubMed Scopus (82) Google Scholar] and to counteract such limitations, we performed sensitivity analyses to assess the robustness of our results regarding our primary endpoint, namely 3 month renal-failure-free survival. We performed; (1) a per-protocol analysis, in which the 15 patients who did not receive albumin infusion in the ALB group were excluded from the analysis; (2) an as-treated analysis, in which patients were analyzed according to the treatment they actually received; and (3) a best-case scenario favouring albumin administration by considering that all seven control patients and none of the four ALB group patients with missing data on serum creatinine developed renal failure [[2]Thévenot T. Bureau C. Oberti F. Anty R. Louvet A. Plessier A. et al.Effect of albumin in cirrhotic patients with infections other than spontaneous bacterial peritonitis: a randomized trial.J Hepatol. 2015; 62: 822-830Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. All these sensitivity analyses showed that the 3 month renal-failure-free survival was not significantly different between the ALB and control groups. Despite these overall negative results, we observed that the proportion of patients with renal failure at one-month was lower among septic patients with ascites and in patients with severe sepsis after albumin infusion, suggesting a beneficial effect of albumin in both these dramatic conditions. Clearly, our message was not to scare practitioners prescribing albumin in the setting of liver cirrhosis, since this drug is largely used all over the world in a wide variety of clinical settings [[6]Bajaj J.S. O’Leary J.G. Wong F. Kamath P.S. Variations in albumin use in patients with cirrhosis: an AASLD members survey.Hepatology. 2015; ([Epub ahead of print])Google Scholar], and recent advances in this field have proved that albumin exerts a protective effect by modulating inflammation, oxidative and cellular stress [[7]Garcia-Martinez R. Andreola F. Mehta G. Poulton K. Oria M. Jover M. et al.Immunomodulatory and antioxidant function of albumin stabilises the endothelium and improves survival in a rodent model of chronic liver failure.J Hepatol. 2015; 62: 799-806Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. However, it is our duty to recommend caution regarding high volumes of albumin administered and rapid infusion rates, which may lead to fluid overload in some patients with unrecognized heart disease. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.