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POINT: Should Intravenous Albumin Be Used for Volume Resuscitation in Severe Sepsis/Septic Shock? Yes FREE TO VIEW

Pietro Caironi, MD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST the following: P. C. has received lecture honoraria from Grifols, B. Braun, and Baxter.

Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy

Dipartimento di Anestesia, Rianimazione ed Emergenza Urgenza, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Milan, Italy

CORRESPONDENCE TO: Pietro Caironi, MD, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Via F. Sforza 35, 20122, Milan, Italy


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(6):1365-1367. doi:10.1016/j.chest.2016.03.048
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Published online

The controversial debate on the IV use of albumin-containing solutions in patients with severe sepsis or septic shock and, more generally, in critically ill patients, dates back to 1998, when the first high-quality meta-analysis investigating this issue reported a potential increased risk of death associated with the administration of human albumin. After several years of lively debate and suboptimal clinical evidence, the first large, randomized controlled trial (RCT) conducted in critically ill patients showed no effect on 28-day survival as associated with IV administration of 4% albumin, compared with 0.9% sodium chloride, for volume resuscitation. Despite the overall equipoise of the two strategies in the entire study population, the trial suggested, for the first time, a potential benefit of human albumin in the predefined subgroup of patients with severe sepsis. To test such a hypothesis, in 2014, we concluded the first large RCT (ie, the Albumin Italian Outcome Sepsis [ALBIOS] study) comparing an albumin replacement strategy (including albumin and crystalloid administration) vs the use of crystalloids alone, for the first 28 days of treatment in patients with severe sepsis or septic shock. The trial reported no advantages of albumin administration on 28- or 90-day survival. Nonetheless, in a post hoc and not predefined subgroup analysis, patients with septic shock randomized to the albumin group reported a significant 6.3% absolute reduction in 90-day mortality compared with the crystalloid group.

When investigators accept an invitation to a “pro/con” debate on a topic related to the publication of a large RCT, they usually have two choices. Either they confront each other on that specific publication, looking for specific and detailed flaws or hidden slips within the manuscript, or they focus the discussion on the merit of the topic proposed, based first on the rationale and the overall biological plausibility of the hypothesis tested, and second on the solidity of the available evidence. Here, I chose to follow the latter approach, doubting that for the rebuttal to my opponents I will have to join the former one also.

Why should the administration of human albumin in severe sepsis or septic shock be beneficial? Physiologically, human albumin is the most abundant plasma protein. Because of its macromolecular structure, human serum albumin is the main determinant of plasma oncotic pressure, playing a key role in regulating microvascular fluid dynamics. Moreover, human serum albumin displays pivotal secondary functions, including ligand-binding capacity for several endogenous and exogenous molecules, antioxidant and anti-inflammatory properties, and buffering capacities within the extracellular acid–base equilibrium. All these properties may be potentially relevant during severe sepsis or septic shock (Table 1)., Sepsis syndromes present a complex pathophysiology involving the interaction between: the infecting microorganisms; the host immune response; and inflammatory, immune, and coagulation processes. Activation of these systems is often disproportionate, leading to organ failure. Human albumin, based on its primary and secondary functions, is potentially at the intersection of the main biological pathways involved in sepsis. Moreover, recent preclinical studies have added further evidence on the potential importance of human albumin during severe sepsis.

Table Graphic Jump Location
Table 1 Possible Beneficial Effects of Human Serum Albumin and Albumin-Containing Solutions in Patients With Severe Sepsis/Septic Shock, From Selected References

Experimental data have suggested a potential role for albumin as a positive inotropic agent in an animal model of cirrhosis-induced myocardial depression. In a multi-model investigation, albumin-containing solutions seemed to counteract the immune paralysis associated with the release of prostaglandin E2 that characterizes patients with acutely decompensated cirrhosis. In vitro studies have hypothesized a key role for human albumin in preserving endothelial glycocalyx integrity and vascular permeability via sphingosine-1-phosphate-dependent pathways. Finally, studies on patients with cirrhosis have highlighted the association between conformational modifications of the N-terminal residue of serum albumin, with a reduced antioxidant activity, and the development of bacterial infection. Although all of these results were obtained in in vitro/experimental studies or in patients with cirrhosis, these findings—if translated to sepsis syndromes—provide a further rationale for a key role of human albumin in attenuating the pathophysiology of severe sepsis/septic shock.

In this context, it is worth mentioning that severe sepsis or septic shock, at the time of development, is often associated with hypoalbuminemia. At the same time, hypoalbuminemia is an independent risk factor for increased morbidity and mortality. In the ALBIOS trial, most of the patients enrolled had a serum albumin concentration < 30 g/L at the time of randomization. Similarly, the higher the degree of hypoalbuminemia, the higher the 90-day mortality rate (Fig 1). Based on these considerations, two issues need to be addressed: first, whether the treatment that is available to correct hypoalbuminemia is adequate and beneficial, or whether we have different options; and second, whether the treatment that is available is safe with no detrimental effects. An additional issue is whether the correction of hypoalbuminemia is a cost-effective treatment. The treatment currently available to acutely correct hypoalbuminemia is IV administration of human albumin. There are few data on the similarity of the molecular structure and properties between exogenous and endogenous albumin. It may be sufficient, as an example, to consider albumin antioxidant activity. Bar-Or et al reported a high rate of oxidation (likely reversible) of the free thiol group in the cysteine-34 position in most of the commercially available preparations of albumin, suggesting a reduced antioxidant capacity of albumin in albumin-containing solutions. Nonetheless, IV administration of human albumin during severe sepsis has been associated with an increased total plasma thiol concentration. This finding therefore indicates that IV administration of albumin, although not retaining all its physiological properties, may be the only available treatment to correct hypoalbuminemia. Indeed, although estimated, cost-effective analyses have suggested a potential advantage of using albumin-containing solutions in patients with sepsis, when including all the medical costs indicted for their treatment. A final controversial argument might concern whether hypoalbuminemia is just an epiphenomenon, without any pathogenic meaning. I believe that simplicity and biological plausibility may be sufficient to fully address this issue.

Figure Jump LinkFigure 1 Association between serum albumin concentration at the time of randomization and 90-day mortality in patients with severe sepsis or septic shock enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) study. Data are expressed as percentages and were available for 1,609 patients (from the first to the last group: 443, 492, 448, and 226 patients). As shown, the higher the degree of hypoalbuminemia, the higher the probability of death.Grahic Jump Location

In the end, what clinical evidence supports IV albumin administration during severe sepsis or septic shock? The ALBIOS trial was specifically designed to verify whether the correction of hypoalbuminemia (ie, albumin replacement) could be beneficial during severe sepsis or septic shock. In the overall population, we observed no effect on survival. Nonetheless, we did observe improvements in hemodynamics during the early phase of treatment, with possible clinical relevance; these improvements included a slightly higher mean arterial pressure, a lower need for vasoactive drugs, and a lower daily net fluid balance as associated with albumin administration. Moreover, in a post hoc analysis of the subgroup of patients with septic shock, a significant 6.3% absolute reduction in 90-day mortality was observed in the albumin group, compared with the crystalloid group, suggesting a specific beneficial effect of albumin in this category of patients. Certainly, such an analysis is limited because it was not predefined. Methodologically, such statements hold true; clinically, however, the presence of shock within the general context of severe sepsis defines a well-characterized subset of patients, with a specific pathophysiology, clinical manifestation, and severity of the septic syndrome. Being a subgroup analysis, even if predefined, the study would have been underpowered to test such a hypothesis. Therefore, from a purely statistical point of view, a non-predefined analysis would not differ from a predefined analysis. The real concern should be whether such findings pertain to a data-dredging analysis; or, from a different perspective, whether there is a plausible biological and pathophysiologic rationale for accepting this hypothesis. Based on what I have discussed earlier, I think that the answer may be simple.

While waiting for confirmatory evidence on the mechanisms and clinical relevance regarding albumin administration in patients with sepsis, based on the absence of detrimental effects, the potential beneficial effect, and the strong biological plausibility, I believe that IV albumin administration should be included in the treatment of patients with septic shock.

Cochrane Injuries Group Albumin Reviewers Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ. 1998;317:235-240 [PubMed]journal. [CrossRef] [PubMed]
 
Finfer S. .Bellomo R. .Boyce N. .et al A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247-2256 [PubMed]journal. [CrossRef] [PubMed]
 
Caironi P. .Tognoni G. .Masson S. .et al Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370:1412-1421 [PubMed]journal. [CrossRef] [PubMed]
 
Peters T. . Historical perspective. All About Albumin.  :1-8 [PubMed]journal
 
Erstad B.L. .Gales B.J. .Rappaport W.D. . The use of albumin in clinical practice. Arch Intern Med. 1991;151:901-911 [PubMed]journal. [CrossRef] [PubMed]
 
Quinlan G.J. .Martin G.S. .Evans T.W. . Albumin: biochemical properties and therapeutic potential. Hepatology. 2005;41:1211-1219 [PubMed]journal. [CrossRef] [PubMed]
 
Caironi P. .Gattinoni L. . The clinical use of albumin: the point of view of a specialist in intensive care. Blood Transfus. 2009;7:259-267 [PubMed]journal. [PubMed]
 
Brink A.J. .Richards G.A. .Lautenbach E.E. .et al Albumin concentration significantly impacts on free teicoplanin plasma concentrations in non-critically ill patients with chronic bone sepsis. Int J Antimicrob Agents. 2015;45:647-651 [PubMed]journal. [CrossRef] [PubMed]
 
Oettl K. .Birner-Gruenberger R. .Spindelboeck W. .et al Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival. J Hepatol. 2013;59:978-983 [PubMed]journal. [CrossRef] [PubMed]
 
Angus D.C. .van der Poll T. . Severe sepsis and septic shock. N Engl J Med. 2013;369:840-851 [PubMed]journal. [CrossRef] [PubMed]
 
Hotchkiss R.S. .Karl I.E. . The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138-150 [PubMed]journal. [CrossRef] [PubMed]
 
Bortoluzzi A. .Ceolotto G. .Gola E. .et al Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms. Hepatology. 2013;57:266-276 [PubMed]journal. [CrossRef] [PubMed]
 
O'Brien A.J. .Fullerton J.N. .Massey K.A. .et al Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat Med. 2014;20:518-523 [PubMed]journal. [CrossRef] [PubMed]
 
Zeng Y. .Adamson R.H. .Curry F.R. .et al Sphingosine-1-phosphate protects endothelial glycocalyx by inhibiting syndecan-1 shedding. Am J Physiol Heart Circ Physiol. 2014;306:H363-H372 [PubMed]journal. [CrossRef] [PubMed]
 
Giannone F.A. .Domenicali M. .Baldassarre M. .et al Ischaemia-modified albumin: a marker of bacterial infection in hospitalized patients with cirrhosis. Liver Int. 2015;35:2425-2432 [PubMed]journal. [CrossRef] [PubMed]
 
Finfer S. .McEvoy S. .Bellomo R. .et al Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. 2011;37:86-96 [PubMed]journal. [CrossRef] [PubMed]
 
Vincent J.L. .Dubois M.J. .Navickis R.J. .et al Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg. 2003;237:319-334 [PubMed]journal. [PubMed]
 
Bar-Or D. .Bar-Or R. .Rael L.T. .et al Heterogeneity and oxidation status of commercial human albumin preparations in clinical use. Crit Care Med. 2005;33:1638-1641 [PubMed]journal. [CrossRef] [PubMed]
 
Quinlan G.J. .Margarson M.P. .Mumby S. .et al Administration of albumin to patients with sepsis syndrome: a possible beneficial role in plasma thiol repletion. Clin Sci (Lond). 1998;95:459-465 [PubMed]journal. [CrossRef] [PubMed]
 
Farrugia A. .Bansal M. .Balboni S. .Kimber M.C. .Martin G.S. .Cassar J. . Choice of fluids in severe septic patients—a cost-effectiveness analysis informed by recent clinical trials. Rev Recent Clin Trials. 2014;9:21-30 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 Association between serum albumin concentration at the time of randomization and 90-day mortality in patients with severe sepsis or septic shock enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) study. Data are expressed as percentages and were available for 1,609 patients (from the first to the last group: 443, 492, 448, and 226 patients). As shown, the higher the degree of hypoalbuminemia, the higher the probability of death.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Possible Beneficial Effects of Human Serum Albumin and Albumin-Containing Solutions in Patients With Severe Sepsis/Septic Shock, From Selected References

References

Cochrane Injuries Group Albumin Reviewers Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ. 1998;317:235-240 [PubMed]journal. [CrossRef] [PubMed]
 
Finfer S. .Bellomo R. .Boyce N. .et al A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247-2256 [PubMed]journal. [CrossRef] [PubMed]
 
Caironi P. .Tognoni G. .Masson S. .et al Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370:1412-1421 [PubMed]journal. [CrossRef] [PubMed]
 
Peters T. . Historical perspective. All About Albumin.  :1-8 [PubMed]journal
 
Erstad B.L. .Gales B.J. .Rappaport W.D. . The use of albumin in clinical practice. Arch Intern Med. 1991;151:901-911 [PubMed]journal. [CrossRef] [PubMed]
 
Quinlan G.J. .Martin G.S. .Evans T.W. . Albumin: biochemical properties and therapeutic potential. Hepatology. 2005;41:1211-1219 [PubMed]journal. [CrossRef] [PubMed]
 
Caironi P. .Gattinoni L. . The clinical use of albumin: the point of view of a specialist in intensive care. Blood Transfus. 2009;7:259-267 [PubMed]journal. [PubMed]
 
Brink A.J. .Richards G.A. .Lautenbach E.E. .et al Albumin concentration significantly impacts on free teicoplanin plasma concentrations in non-critically ill patients with chronic bone sepsis. Int J Antimicrob Agents. 2015;45:647-651 [PubMed]journal. [CrossRef] [PubMed]
 
Oettl K. .Birner-Gruenberger R. .Spindelboeck W. .et al Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival. J Hepatol. 2013;59:978-983 [PubMed]journal. [CrossRef] [PubMed]
 
Angus D.C. .van der Poll T. . Severe sepsis and septic shock. N Engl J Med. 2013;369:840-851 [PubMed]journal. [CrossRef] [PubMed]
 
Hotchkiss R.S. .Karl I.E. . The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138-150 [PubMed]journal. [CrossRef] [PubMed]
 
Bortoluzzi A. .Ceolotto G. .Gola E. .et al Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms. Hepatology. 2013;57:266-276 [PubMed]journal. [CrossRef] [PubMed]
 
O'Brien A.J. .Fullerton J.N. .Massey K.A. .et al Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat Med. 2014;20:518-523 [PubMed]journal. [CrossRef] [PubMed]
 
Zeng Y. .Adamson R.H. .Curry F.R. .et al Sphingosine-1-phosphate protects endothelial glycocalyx by inhibiting syndecan-1 shedding. Am J Physiol Heart Circ Physiol. 2014;306:H363-H372 [PubMed]journal. [CrossRef] [PubMed]
 
Giannone F.A. .Domenicali M. .Baldassarre M. .et al Ischaemia-modified albumin: a marker of bacterial infection in hospitalized patients with cirrhosis. Liver Int. 2015;35:2425-2432 [PubMed]journal. [CrossRef] [PubMed]
 
Finfer S. .McEvoy S. .Bellomo R. .et al Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. 2011;37:86-96 [PubMed]journal. [CrossRef] [PubMed]
 
Vincent J.L. .Dubois M.J. .Navickis R.J. .et al Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg. 2003;237:319-334 [PubMed]journal. [PubMed]
 
Bar-Or D. .Bar-Or R. .Rael L.T. .et al Heterogeneity and oxidation status of commercial human albumin preparations in clinical use. Crit Care Med. 2005;33:1638-1641 [PubMed]journal. [CrossRef] [PubMed]
 
Quinlan G.J. .Margarson M.P. .Mumby S. .et al Administration of albumin to patients with sepsis syndrome: a possible beneficial role in plasma thiol repletion. Clin Sci (Lond). 1998;95:459-465 [PubMed]journal. [CrossRef] [PubMed]
 
Farrugia A. .Bansal M. .Balboni S. .Kimber M.C. .Martin G.S. .Cassar J. . Choice of fluids in severe septic patients—a cost-effectiveness analysis informed by recent clinical trials. Rev Recent Clin Trials. 2014;9:21-30 [PubMed]journal. [CrossRef] [PubMed]
 
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