0
Editorials: Point and Counterpoint |

COUNTERPOINT: Should Intravenous Albumin Be Used for Volume Resuscitation in Severe Sepsis/Septic Shock? No FREE TO VIEW

Angel O. Coz Yataco, MD, FCCP; Alexander H. Flannery, PharmD, BCPS; Steven Q. Simpson, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

aDivision of Pulmonary, Critical Care and Sleep Medicine, University of Kentucky, Lexington, Kentucky

bCollege of Pharmacy, University of Kentucky HealthCare, Lexington, Kentucky

cDivision of Pulmonary and Critical Care, University of Kansas, Kansas City, KS

CORRESPONDENCE TO: Angel O. Coz Yataco, MD, FCCP, University of Kentucky, KY Clinic, 740 S Limestone L-543, Lexington, KY 40536


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


Chest. 2016;149(6):1368-1370. doi:10.1016/j.chest.2016.03.050
Text Size: A A A
Published online

Hypoalbuminemia is common in patients with severe sepsis and septic shock and is associated with poor outcomes. The use of albumin for resuscitation in this population remains controversial. Despite theoretical benefits to the use of albumin, multiple clinical trials and systematic reviews have failed to demonstrate an outcome benefit. We believe that the use of albumin in the resuscitation of patients with severe sepsis and septic shock is not warranted, given the lack of evidence of outcome benefits and its high cost. We present a few important questions.

On the basis of a meta-analysis indicating that critically ill patients receiving albumin had a higher mortality than patients who received plasma protein fraction or crystalloids, the US Food and Drug Administration released a letter urging clinicians to exercise discretion in the use of albumin., The Saline vs Albumin Fluid Evaluation (SAFE) trial compared albumin 4% and normal saline as volume expanders and found that there was no mortality difference in the overall population and the subgroup with severe sepsis. Although multivariate analysis after adjustment for baseline characteristics showed a decreased odds ratio for death at 28 days favoring albumin, these results represent the post hoc analysis of a trial not designed to assess the benefits of albumin in patients with sepsis. The Therapy in the Colloids vs Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial showed no benefit in 28- or 90-day mortality in septic patients treated with albumin (4% and 20% solutions) vs those treated with normal saline.

The Albumin Italian Outcome Sepsis (ALBIOS) trial assessed whether albumin replacement with a 20% solution in septic patients for 28 days to a target of 3 g/dL was beneficial., Despite achieving higher serum albumin levels in the treatment group, there was no difference in 28-day or 90-day mortality. Post hoc analysis of the septic shock subgroup showed no difference in 28-day mortality but suggested a 90-day mortality benefit favoring albumin, an effect that lost significance when adjusted for clinically relevant variables. ALBIOS did not show that albumin provides a benefit in the occurrence of new organ failure or duration of mechanical ventilation. Although lower heart rates and higher mean arterial pressures were reported in the albumin-treated group, such differences do not represent patient-centered outcomes.

Multiple meta-analyses have shown that albumin does not provide a benefit in mortality or the need for renal replacement therapy in critically ill patients, including those with hypoalbuminemia and sepsis.,,, A meta-analysis, using data dominated by the ALBIOS trial, found no mortality benefit in patients with severe sepsis. In the septic shock group, a 90-day mortality benefit was reported, but 28-day mortality was not analyzed.

In summary, albumin used either as a resuscitation agent or to normalize albumin levels in septic patients has not been shown to provide a benefit in mortality, new organ failure, or duration of mechanical ventilation. Furthermore, the hemodynamic benefits should be interpreted with caution because they are not associated with beneficial outcomes.

Albumin is typically considered a drug product, but it is in reality a blood product. Albumin is obtained from pooled human plasma, using a fractionation process and pasteurization to reduce the transmission of microorganisms. It seems prudent to limit albumin administration with the same vigilance used with other blood products.

Although the purity and sterility of albumin solutions are standard quality control measures in manufacturing, the screening for posttranscriptional modifications (possibly manufacturing-induced) is not. These modifications may result from nonenzymatic glycation reactions, leading to irreversible formation of advanced glycation end products (AGEs). Whether these pro-inflammatory modifications result in clinically relevant consequences in humans remains unknown. Animal models show that high-AGE containing albumin is associated with higher mortality than the low-AGE solution, a difference that could be due to the increased activation of nuclear factor-κβ in the former. Commercially available albumin solutions have posttranscriptional modifications that differ markedly from albumin from healthy volunteers and have up to a 10-fold difference in AGE content between batches and manufacturers., It remains unknown if these modifications affect the effectiveness, increase the safety risks, or have deleterious consequences. However, clinicians should realize that they are not likely prescribing human albumin as it exists in vivo.

Although not detected with the typical primary outcomes of large randomized controlled trials, albumin use has been associated with clinical consequences of unknown certainty. Analysis of the SAFE trial suggested that albumin was associated with a larger reduction in pH and increase in serum chloride compared with normal saline when a large amount of resuscitation fluids were administered in the first 24 h. Moreover, albumin was associated with a more prolonged activated partial thromboplastin time and higher hepatic sequential organ failure assessment scores (driven by bilirubin levels) compared with normal saline., The latter finding has been attributed to the presence of bilirubin in the albumin solution from the chromatographic fractionation manufacturing process in the product studied; the clinical significance is unclear. Albumin has also been associated with histamine release following infusion. Finally, albumin, used indiscriminately, has the potential to accumulate in the pulmonary extravascular space with greater likelihood than crystalloids alone. This outcome is well documented in animal models with increased capillary permeability, as small changes in the oncotic pressure of the pulmonary interstitial space act as an important driver of fluid movement from plasma.

Pharmacovigilance studies have shown that adverse events reported with albumin are rare, but these conclusions are tempered by two important points. First, these numbers are inclined to be artificially low due to underreporting. In addition, it is likely that clinicians are unaware of some of albumin’s potentially deleterious biological effects and their clinical consequences and may not attribute certain clinical conditions to albumin use.

If, as we have discussed, albumin is no more effective than crystalloids in the treatment of septic shock, then a cost analysis becomes trivial. The US acquisition cost of normal saline or lactated Ringer’s solution is $1 to $2, whereas the acquisition cost of 100 mL of 25% albumin is approximately $82 from large-scale purchasing organizations (Cardinal Health pricing). At these costs, one bottle of albumin would need to replace at least 40 L of crystalloids, which even our opponent will admit is not the case. Given that there is no documented survival benefit associated with albumin administration, the product represents a waste of precious health care dollars.

One could assume the possibility of increased 90-day survival for patients with septic shock, as suggested by the ALBIOS post hoc analysis. The ALBIOS data do not indicate how much albumin was received by patients with septic shock; the data indicate the amount taken by all patients with sepsis and only for the first 7 days of treatment. The median volume of albumin was 1,100 mL. Using our cost of $82 for 100 mL of 25% albumin as a guide, this approach in the United States would add a median cost of $902 per case of septic shock (in the first 7 days). The median volume of crystalloid in the albumin group was reduced by 2 L, reducing the bill by approximately $3. The post hoc analysis suggested an absolute reduction in 90-day mortality of 6.6% in the albumin group, indicating a number-needed-to-treat of 16 patients per additional life saved. The additional critical care cost per life saved would then be $14,384, a reasonable cost, on the order of an annual mammography, bone marrow transplant vs chemotherapy for acute myeloid leukemia, or beta-blocker for postmyocardial infarction risk reduction. However—and this is a huge however—the calculation depends on the reliability of the data, and it cannot be overemphasized that the data are from an unplanned, post hoc analysis, which the trial was not designed to address. The ALBIOS trial was itself based on such an analysis of the SAFE trial, and one readily sees where that has brought us.

Herrmann F.R. .Safran C. .Levkoff S.E. .Minaker K.L. . Serum albumin level on admission as a predictor of death, length of stay, and readmission. Arch Intern Med. 1992;152:125-130 [PubMed]journal. [CrossRef] [PubMed]
 
Fan E. .Stewart T.E. . Albumin in critical care: SAFE, but worth its salt? Crit Care. 2004;8:297-299 [PubMed]journal. [CrossRef] [PubMed]
 
Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ. 1998;317:235-240 [PubMed]journal. [CrossRef] [PubMed]
 
Dear Doctor Letter—Albumin Use in Seriously Ill Patients. US Food and Drug Administration website.http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm105919.htm. Accessed August 11, 2015.
 
Finfer S. .Bellomo R. .Boyce N. .French J. .Myburgh J. .Norton R. . 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]
 
Finfer S. .McEvoy S. .Bellomo R. .McArthur C. .Myburgh J. .Norton R. . 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]
 
Annane D. .Siami S. .Jaber S. .et al Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013;310:1809-1817 [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]
 
Gattinoni L. ALBIOS trial: Albumin in sepsis.http://www.criticalcarecanada.com/presentations/2013/albios_trial_%E2%80%93_albumin_in_sepsis.pdf. Accessed August 13, 2015.
 
Roberts I. .Blackhall K. .Alderson P. .Bunn F. .Schierhout G. . Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev. 2011;:CD001208- [PubMed]journal
 
Rochwerg B. .Alhazzani W. .Gibson A. .et al Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med. 2015;41:1561-1571 [PubMed]journal. [CrossRef] [PubMed]
 
Xu J.Y. .Chen Q.H. .Xie J.F. .et al Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials. Crit Care. 2014;18:702- [PubMed]journal. [CrossRef] [PubMed]
 
Patel A. .Laffan M.A. .Waheed U. .Brett S.J. . Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ. 2014;349:g4561- [PubMed]journal. [CrossRef] [PubMed]
 
Humpert P.M. .Lukic I.K. .Thorpe S.R. .et al AGE-modified albumin containing infusion solutions boosts septicaemia and inflammation in experimental peritonitis. J Leukoc Biol. 2009;86:589-597 [PubMed]journal. [CrossRef] [PubMed]
 
Bar-Or D. .Bar-Or R. .Rael L.T. .Gardner D.K. .Slone D.S. .Craun M.L. . Heterogeneity and oxidation status of commercial human albumin preparations in clinical use. Crit Care Med. 2005;33:1638-1641 [PubMed]journal. [CrossRef] [PubMed]
 
Bellomo R. .Morimatsu H. .French C. .et al The effects of saline or albumin resuscitation on acid-base status and serum electrolytes. Crit Care Med. 2006;34:2891-2897 [PubMed]journal. [CrossRef] [PubMed]
 
Bellomo R. .Morimatsu H. .Presneill J. .et al Effects of saline or albumin resuscitation on standard coagulation tests. Crit Care Resusc. 2009;11:250-256 [PubMed]journal. [PubMed]
 
Celik I. .Duda D. .Stinner B. .Kimura K. .Gajek H. .Lorenz W. . Early and late histamine release induced by albumin, hetastarch and polygeline: some unexpected findings. Inflamm Res. 2003;52:408-416 [PubMed]journal. [CrossRef] [PubMed]
 
Geer R.T. .Soma L.R. .Barnes C. .Leatherman J.L. .Marshall B.E. . Effects of albumin and/or furosemide therapy on pulmonary edema induced by hydrochloric acid aspiration in rabbits. J Trauma. 1976;16:788-791 [PubMed]journal. [PubMed]
 
Vincent J.L. .Wilkes M.M. .Navickis R.J. . Safety of human albumin—serious adverse events reported worldwide in 1998-2000. Br J Anaesth. 2003;91:625-630 [PubMed]journal. [PubMed]
 

Figures

Tables

References

Herrmann F.R. .Safran C. .Levkoff S.E. .Minaker K.L. . Serum albumin level on admission as a predictor of death, length of stay, and readmission. Arch Intern Med. 1992;152:125-130 [PubMed]journal. [CrossRef] [PubMed]
 
Fan E. .Stewart T.E. . Albumin in critical care: SAFE, but worth its salt? Crit Care. 2004;8:297-299 [PubMed]journal. [CrossRef] [PubMed]
 
Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ. 1998;317:235-240 [PubMed]journal. [CrossRef] [PubMed]
 
Dear Doctor Letter—Albumin Use in Seriously Ill Patients. US Food and Drug Administration website.http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm105919.htm. Accessed August 11, 2015.
 
Finfer S. .Bellomo R. .Boyce N. .French J. .Myburgh J. .Norton R. . 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]
 
Finfer S. .McEvoy S. .Bellomo R. .McArthur C. .Myburgh J. .Norton R. . 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]
 
Annane D. .Siami S. .Jaber S. .et al Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013;310:1809-1817 [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]
 
Gattinoni L. ALBIOS trial: Albumin in sepsis.http://www.criticalcarecanada.com/presentations/2013/albios_trial_%E2%80%93_albumin_in_sepsis.pdf. Accessed August 13, 2015.
 
Roberts I. .Blackhall K. .Alderson P. .Bunn F. .Schierhout G. . Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev. 2011;:CD001208- [PubMed]journal
 
Rochwerg B. .Alhazzani W. .Gibson A. .et al Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med. 2015;41:1561-1571 [PubMed]journal. [CrossRef] [PubMed]
 
Xu J.Y. .Chen Q.H. .Xie J.F. .et al Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials. Crit Care. 2014;18:702- [PubMed]journal. [CrossRef] [PubMed]
 
Patel A. .Laffan M.A. .Waheed U. .Brett S.J. . Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ. 2014;349:g4561- [PubMed]journal. [CrossRef] [PubMed]
 
Humpert P.M. .Lukic I.K. .Thorpe S.R. .et al AGE-modified albumin containing infusion solutions boosts septicaemia and inflammation in experimental peritonitis. J Leukoc Biol. 2009;86:589-597 [PubMed]journal. [CrossRef] [PubMed]
 
Bar-Or D. .Bar-Or R. .Rael L.T. .Gardner D.K. .Slone D.S. .Craun M.L. . Heterogeneity and oxidation status of commercial human albumin preparations in clinical use. Crit Care Med. 2005;33:1638-1641 [PubMed]journal. [CrossRef] [PubMed]
 
Bellomo R. .Morimatsu H. .French C. .et al The effects of saline or albumin resuscitation on acid-base status and serum electrolytes. Crit Care Med. 2006;34:2891-2897 [PubMed]journal. [CrossRef] [PubMed]
 
Bellomo R. .Morimatsu H. .Presneill J. .et al Effects of saline or albumin resuscitation on standard coagulation tests. Crit Care Resusc. 2009;11:250-256 [PubMed]journal. [PubMed]
 
Celik I. .Duda D. .Stinner B. .Kimura K. .Gajek H. .Lorenz W. . Early and late histamine release induced by albumin, hetastarch and polygeline: some unexpected findings. Inflamm Res. 2003;52:408-416 [PubMed]journal. [CrossRef] [PubMed]
 
Geer R.T. .Soma L.R. .Barnes C. .Leatherman J.L. .Marshall B.E. . Effects of albumin and/or furosemide therapy on pulmonary edema induced by hydrochloric acid aspiration in rabbits. J Trauma. 1976;16:788-791 [PubMed]journal. [PubMed]
 
Vincent J.L. .Wilkes M.M. .Navickis R.J. . Safety of human albumin—serious adverse events reported worldwide in 1998-2000. Br J Anaesth. 2003;91:625-630 [PubMed]journal. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
Guidelines
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543