In the era when other colloids have been shown to be unsafe, albumin has come into its own as a safe, effective therapy with demonstrable cost effectiveness
The development of albumin’s role as a blood substitute and plasma-expanding agent has been reviewed.1 This role appeared unquestioned until the publication of a rapidly discredited Cochrane review in 1998,2 which threw doubts on the safety of albumin. It is probable that this contributed to the consideration of other fluids and to the rapid ascendancy of hydroxyethyl starch solutions (HES) as the predominant colloid fluid therapy in the 2000s, despite the already established adverse events associated with these compounds. The obviation of much of the evidence base for HES through the Boldt scandal,3 coupled with the increasing body of evidence that all types of HES were associated with serious adverse effects,4 has led the regulatory agencies of the US and Europe to severely restrict or disallow totally the use of these products in critical illness. It seems unlikely that HES will regain a significant position in fluid replacement therapy and the position of albumin as the colloid least associated with adverse events5 has undergone a remarkable evolution since the questions raised by the Cochrane review. The body of evidence demonstrating the efficacy of albumin in areas of critical care and hepatology is impressive, and a recently published meta-analysis6 demonstrates its superiority relative to other treatments in conferring a survival benefit to patients with sepsis (Figure 1).
Pharmacoeconomic perspectives on fluid therapy
Despite these developments, it is likely that the controversy around the choice of fluid therapy in clinical care will continue, as it is essentially reflective of economic concerns, which, if anything, are increasingly acute in the current healthcare landscape worldwide. It is intriguing that even supposedly objective and clinical evidence-based processes such as the Cochrane Collaboration cannot help including comments on costs in their reports, irrespective of the relevance of such comments to the issue of best evidence care. Pharmacoeconomic analysis is one area of health technology assessment (HTA) which is increasingly used by healthcare agencies and payers to assist decision making. This kind of decision making is being rapidly devolved to individual hospital departments, particularly pharmacies in the case of drug purchasing.
The pressure on these individual areas, each fighting to retain their budgets and provide services, makes them particularly vulnerable to commercial claims regarding the relative costs of treatments. Such claims have included material from the manufacturers of HES, drawing attention to the higher cost of albumin versus HES, and are reflective of earlier analyses comparing the costs of different fluids in areas such as cardiac surgery, where simple ‘bottle to bottle’ costs were compared as a basis for suggested choices.7 A rigorous cost-effectiveness analysis is needed in making such comparisons, in which all costs and outcomes such as morbidity, mortality and length of intensive care stay, for example, can be factored into the final outcome. Some areas of fluid treatment have been subjected to such an exercise, for example, in the area of goal-directed therapy.8 The role of albumin in cirrhosis has also been examined for its cost–benefit9 in a study demonstrating the usefulness of using such analyses in identifying sub-groups of patients where clinical and cost benefits may be targeted. Given the evolving perspective of albumin as a drug with specific pharmacological effects in different diseases,10 the use of these approaches will assist the assessment of albumin in the therapeutic armamentarium.
Albumin in sepsis
Severe sepsis is a clinical syndrome, originating in the systemic inflammatory response following infection, which is a major cause of hospital mortality and a considerable economic burden.11 Resuscitation in sepsis is initially based on fluid therapy, through guidelines that now specify albumin as the treatment of choice following first line resuscitation.12 Despite the clinical evidence and the relative harms of alternative therapies, it is important to subject albumin’s role in this condition to pharmacoeconomic assessment. A previous study addressed the scenario utilising the data from the SAFE study for a population of French ICU patients, and found that, in this hypothetical case, albumin usage in sepsis led to favourable cost-effectiveness outcomes relative to other funded interventions13 but did not examine the important issue of alternative therapies. The availability of commercial decision analysis software for conducting such work has facilitated the conduct of cost-effectiveness analysis of competing treatments.
A cost-effectiveness analysis comparing the three alternative fluids – albumin, crystalloid and HES – was therefore performed using data from the literature and other public information for costs. A preliminary report has been published.14 The relevant decision tree outlining the choices available and the path through which the patient population was taken is shown in Figure 2. The model predicted that albumin treatment leads to an increased life gain of 0.22 life years relative to crystalloid fluid treatment for sepsis, while treatment with HES leads to a loss of 1.00 life years. The calculated cost of $9149 per life year gained with albumin is well within the range of measures considered cost effective by reimbursement agencies. Added attractions to this approach include the ability to analyse the effect of variables such as age on the outcomes.
Further research on sepsis including the effect of quality of life on cost-effectiveness outcomes may also be informed by models such as these. The key issue is that these analyses are more sophisticated than ‘bottle to bottle’ comparisons and give payers the opportunity to assess the effect of therapeutic choice on total medical costs. The risk of developing budgets to small areas within hospitals includes the temptation to ignore global, long-term benefits to healthcare for patients and focus on the immediate need to cut costs regardless of ultimate outcomes.15 The introduction of approaches such as the one described is therefore highly desirable.
Albumin in cardiac surgery
Cardiac surgery frequently requires fluid replacement intra- and perioperatively.16 Albumin is used widely for this purpose and in coronary artery by grafting (CABG), its administration resulted in a 25% reduction in postoperative mortality, compared to synthetic colloids.17 Acute kidney injury is a major problem in hospital interventions.18 Notably, a randomised, controlled trial of albumin administration for a serum albumin level of less than 4.0g/dl prior to off-pump coronary artery bypass surgery resulted in a significant decrease in stage 1 acute kidney injury in patients given albumin.19 The cost-effectiveness of this intervention is not yet fully established, as the study did not detect differences in expensive parameters such as hospital length of stay, despite the firm establishment of the effect of acute kidney injury on these parameters in other patient populations.
Albumin in liver cirrhosis
The use of albumin in hepatology currently represents the best evidence of its use in clinical medicine.20 Besides clear benefits in enhancing survival and decreasing morbidity, the use of albumin in this area is also cost effective. Patients with cirrhosis treated with 20% human albumin showed significantly lower liver-related complications compared to those treated with 3.5% polygeline and, in addition, the median hospital cost for a 30-day period was significantly lower in the albumin group (1915 Euros vs. 4612 Euros).21
In the recently completed Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study, the unequivocal efficacy of long-term human albumin administration in patients with decompensated cirrhosis was accompanied by demonstrable cost-effectiveness in a conventional cost–utility analysis (Table 1).22
Conclusions – albumin as the last colloid standing?
Albumin stands centre-stage in the debate over fluid therapies and management costs. This natural colloid would clearly be the therapy of choice if the decision was not obscured by cost issues. Approaching such a decision has to be done in the context of assessing total medical costs, which, in the case of the diseases treated by albumin (for example, sepsis and cirrhosis) are high, irrespective of the costs of fluids and the pharmacoeconomic outcomes show that the additional cost of fluid, irrespective of its nature, has no effect on outcome.14 Hence, this level of decision making has to be taken from the purview of areas where the focus is immediate, short-term, competitive resource management. In the era when other colloids have been shown to be unsafe, albumin has come into its own as a safe, effective therapy with demonstrable cost effectiveness.
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- Reviewers CIGA. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ 1998;317(7153):235–40.
- Wise J. Boldt: the great pretender. BMJ 2013;346:f1738.
- Myburgh J, McIntyre L. New insights into fluid resuscitation. Intens Care Med 2013;39(6):998–1001.
- Farrugia A. Safety of plasma volume expanders. J Clin Pharmacol 2011;51(3):292–300.
- Bansal M et al. Relative survival benefit and morbidity with fluids in severe sepsis – A network meta-analysis of alternative therapies. Curr Drug Saf 2013;8(4):236–45.
- Palanzo DA et al. Hetastarch as a prime for cardiopulmonary bypass. Ann Thorac Surg 1982;34(6):680–3.
- Huang DT et al. Implementation of early goal-directed therapy for evere sepsis and septic shock: A decision analysis. Crit Care Med 2007;35(9):2090–100.
- Gentilini P et al. Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial. J Hepatol 1999;30(4):639–45.
- Evans TW. Review article: albumin as a drug-biological effects of albumin unrelated to oncotic pressure. Aliment Pharmacol Ther 2002;16 Suppl 5:6–11.
- Burchardi H, Schneider H. Economic aspects of severe sepsis: a review of intensive care unit costs, cost of illness and cost effectiveness of therapy. Pharmacoeconomics 2004;22(12):793–813.
- Dellinger RP et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41(1):580–637.
- Guidet B et al. The COASST study: cost-effectiveness of albumin in severe sepsis and septic shock. J Crit Care 2007;22(3):197–203.
- Farrugia A, Martin G, Bult M. Colloids for sepsis: Effectiveness and cost issues. Ann Update Crit Care Emer Med 2013;515–26.
- Bernard K et al. Should hospital pharmacy drug budgets be the responsibility of each individual department in an institution, or should such budgets be controlled centrally by the pharmacy department? Can J Hosp Pharm 2010;63(4):330–2.
- Lange M et al. Intravascular volume therapy with colloids in cardiac surgery. J Cardiothorac Vasc Anesth 2011;25(5):847–55.
- Sedrakyan A et al. Volume expansion with albumin decreases mortality after coronary artery bypass graft surgery. Chest 2003;123(6):1853–7.
- Chertow GM et al. Acute kidney injury. Mortality, length of stay, and costs in hospitalized patients. JASN 2005;16(11):3365–70.
- Lee EH et al. Effect of exogenous albumin on the incidence of postoperative acute kidney injury in patients undergoing off-pump coronary artery bypass surgery with a preoperative albumin level of less than 4.0 g/dl. Anesthesiology 2016;124(5):1001–11.
- Caraceni P et al; Italian Association for the Study of the Liver (AISF). AISF-SIMTI position paper: the appropriate use of albumin in patients with liver cirrhosis. Blood Transfus 2016;14(1):8–22.
- Moreau R et al. Comparison of outcome in patients with cirrhosis and ascites following treatment with albumin or a synthetic colloid: a randomised controlled pilot trial. Liver Int 2006;26(1):46–54.
- Caraceni P et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet 2018;391(10138):2417–29.