To the Editor:
We greatly appreciate the comments by Lucidi et al. [
[1]
]. Firstly, we acknowledge that, despite well-conducted randomization to reduce the risk of selection bias at trial entry [[2]
], 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]
], 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]
]. 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 [
4
, 5
] 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]
]. 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]
], and recent advances in this field have proved that albumin exerts a protective effect by modulating inflammation, oxidative and cellular stress [[7]
]. 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.Conflict of interest
The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
References
- Albumin infusion in cirrhotic patients with infections other than spontaneous bacterial peritonitis: end of the story?.J Hepatol. 2015; 63: 767-768
- Effect of albumin in cirrhotic patients with infections other than spontaneous bacterial peritonitis: a randomized trial.J Hepatol. 2015; 62: 822-830
- 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: 2328-2335
- Data withdrawal in randomized controlled trials: defining the problem and proposing solutions: a commentary.Contemp Clin Trials. 2011; 32: 318-322
- 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: 1185-1195
- Variations in albumin use in patients with cirrhosis: an AASLD members survey.Hepatology. 2015; ([Epub ahead of print])
- Immunomodulatory and antioxidant function of albumin stabilises the endothelium and improves survival in a rodent model of chronic liver failure.J Hepatol. 2015; 62: 799-806
Article info
Publication history
Published online: May 18, 2015
Accepted:
May 11,
2015
Received:
May 10,
2015
Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier B.V.
User license
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) | How you can reuse 
Elsevier's open access license policy
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)
Permitted
For non-commercial purposes:
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article (private use only, not for distribution)
- Reuse portions or extracts from the article in other works
Not Permitted
- Sell or re-use for commercial purposes
- Distribute translations or adaptations of the article
Elsevier's open access license policy
