HUMAN ALBUMIN AS A TOKEN OF MEDICAL PRACTICE PARADIGMLuíza O Rodrigues, Silvana M B Kelles, Augusto C S Santos Júnior, Daniela C Azevedo, Lélia M A Carvalho, Maria da Glória C Horta, Mariana R Fernandes, Sandra O

S Avelar

UNIMED BH

INTRODUCTION AND OBJECTIVESHuman albumin solutions have been prescribed in diverse situations, in spite of considerable controversy about its benefits. The unnecessary costs related to this practice are not negligible and it denotes a paradigm of medical practice that is still not evidence-based. As a matter of fact, many of the established indications for albumin use are based on very low level evidence. Therefore, we assessed the available evidence regarding common albumin use in Brazil, comprising nine situations: ascites management, diuretic refractory edema, hepatorenal syndrome, cirrhosis and spontaneous bacterial peritonitis, critical patients, major burns, hepatic transplant, pump priming in cardiopulmonary bypass and plasmapheresis.

METHODSWe broadly searched Cochrane, MEDLINE, LILACS and reference lists of relevant articles for evidence on albumin use in those nine situations. Since many clinical situations were not evaluated in properly designed randomized clinical trials, our search included non-randomized trials and observational studies as well. Each clinical situation was queried using MeSH terms (when available) and alternative keywords, as shown in table 1.

Table 1: Clinical situations for albumin use and the terms used for literature search

Clinical situation for albumin use Search terms*

After therapeutic paracentesis MeSH: Ascites, Paracentesis, Paracentesis/therapyAlternative keywords: large volume paracentesis.

Adjunctive treatment of spontaneous bacterial peritonitis

MeSH: Peritonitis, Peritonitis/therapyAlternative keywords: Spontaneous bacterial peritonitis

Pump priming in cardiac surgeryMeSH: Cardiopulmonary Bypass, Colloids/therapeutic use, Crystalloid solutions [Supplementary Concept]Alternative keywords: Pump priming, Priming solutions

Supplementation for hypoalbuminemia after liver transplantation MeSH: Hypoalbuminemia, Liver Transplantation

Management of major burn injuries MeSH: BurnsAlternative keywords: Major burn injury, burn injury resuscitation

Fluid resuscitation in critically ill patients MeSH: Critical illness, Intensive careAlternative keywords: Critically ill, Fluid resuscitation

Plasmapheresis Mesh: PlasmapheresisAlternative keywords: Replacement fluids

Refractory ascites or edema Mesh: Edema, AscitesAlternative keywords: Nephrotic edema, refractory ascites

Hepatorenal syndrome type 1 and 2 Mesh: Hepatorenal syndromeAlternative keywords: Hepatorenal syndrome type 1 and 2

*All queries also had the MeSH terms “Albumins, Albumins/therapeutic use, Albumins/therapy” and the alternative keywords “Human albumin, Human albumin solution”.

RESULTS1. After therapeutic paracentesis: the widespread recommendation of albumin infusion (6 to 8 g/L of removed ascites)after large volume (≥5 L) therapeutic paracentesis is based on a pivotal case series with 12 patients1. 2. Adjunctive treatment of spontaneous bacterial peritonitis (SBP): the pivotal study2 that suggested a survival benefit of albumin infusion in septic cirrhotic patients with SBP had a major limitation concerning the comparator arm, that received no systematic hydration, a known beneficial measure in the treatment of sepsis. Therefore, the alleged survival benefit may have been due to more robust volume expansion in the albumin arm, and not to albumin itself.3. Pump priming in cardiac surgery: Two systematic reviews with metanalysis3, 4 failed to demonstrate any clinically relevant benefit of albumin as the priming fluid of cardiopulmonary bypass pump, when compared to other colloids or crystalloids. The quality of the studies included in these metanalysis was generally low.4. Supplementation for hypoalbuminemia after liver transplantation: Hypoalbuminemia is a known predictor of post-operatory mortality. Nevertheless, there is no evidence that albumin supplementation alters any clinically relevant outcome.5 The evidence concerning hepatic transplant patients is even scarcer than that for the general surgical patient.5. Management of major burn injuries: The use of colloids might reduce the amount of fluid necessary for resuscitation after major burn injuries, specially in the presence of fluid creep.

HUMAN ALBUMIN AS A TOKEN OF MEDICAL PRACTICE PARADIGMLuíza O Rodrigues, Silvana M B Kelles, Augusto C S Santos Júnior, Daniela C Azevedo, Lélia M A Carvalho, Maria da Glória C Horta, Mariana R Fernandes, Sandra O

S Avelar

UNIMED BH

RESULTS CONTINUEDHowever, this reduction does not translate into clinically relevant benefits. Also, a subgroup analysis of the Cochrane’s Systematic Review on albumin for volume expansion in critically ill patients suggested that burn patients may be at a higher mortality risk when exposed to albumin.6

6. Fluid resuscitation in critically ill patients: There is evidence from a large RCT8 and from two metanalysis6, 7 that albumin does not improve any outcome of critically ill patients. It has been suggested that, due to increased capillary permeability (which also occurs in major burn injuries), the albumin shift from the intravascular to the interstitial space might actually aggravate edema (including pulmonary congestion).7. Plasmapheresis: The use of albumin as a replacement fluid is based solely on biological rationale and expert opinion.8. Refractory ascites or edema: No good quality RCT has demonstrated any clinically relevant benefit of the association of albumin and diuretics in the treatment of refractory edema or ascites.9 Some lower quality studies suggested that volume expansion itself can have some impact on urinary volume, but without a natriuretic effect, probably due to better renal perfusion.10

9. Hepatorenal syndrome (HRS) type 1 and 2: Prevention: The study that suggested the use of albumin for the prevention of HRS has already been commented in the item 2 (SBP).2

RESULTS CONTINUED

REFERENCES

Diagnosis: The failure of recovery of renal function after the use of 1g/kg for two days of albumin infusion is a diagnostic criterion for HRS. However, this is a guideline recommendation based on expert opinion, funded on extrapolations of findings from low quality studies, with albumin use in other clinical situations.11

Treatment: The use of vasoconstrictors and albumin has not been compared to the use of vasoconstrictors and other plasma expanders. Therefore, albumin effect in the treatment of HRS may be due to efficient volume expansion.12

1. Peltekian KM, Wong F, Liu PP, Logan AG, Sherman M, Blendis LM. Cardiovascular, renal, and neurohumoral responses to single large-volume paracentesis in patients with cirrhosis and diuretic-resistant ascites. Am J Gastroenterol. 1997; 92(3):394–9.

2. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999; 341(6):403–93. Russell JA, Navickis RJ, Wilkes MM. Albumin versus crystalloid for pump priming in cardiac surgery: meta-analysis of controlled trials. J Cardiothorac Vasc Anesth. 2004; 18(4):429-37.4. Himpe D. Colloids versus crystalloids as priming solutions for cardiopulmonary bypass: a meta-analysis of prospective, randomised clinical trials. Acta Anaesthesiol Belg. 2003; 54(3):207-15.5. Golub R, Sorrento JJ, Cantu R, Nierman DM, Moideen A, Stein HD. Efficacy of albumin supplementation in the surgical intensive care unit: a prospective, randomized study. Crit Care Med. 1994; 22(4):613-9.6. 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; (11):CD001208.7. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane database Syst Rev. 2013; 2:CD000567.8. 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(22):2247-56.9. Gentilini P, Casini-Raggi V, Di Fiore G, Romanelli RG, Buzzelli G, Pinzani M, et al. Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial. J Hepatol.; 30(4):639-45.10. Chalasani N, Gorski JC, Horlander JC, Craven R, Hoen H, Maya J, et al. Effects of albumin/furosemide mixtures on responses to furosemide in hypoalbuminemic patients. J Am Soc Nephrol. 2001; 12(5):1010-6.11. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007; 56(9):1310-8.12. Gluud LL, Christensen K, Christensen E, Krag A. Terlipressin for hepatorenal syndrome. Cochrane database Syst Rev. 2012; 9:CD005162.

CONCLUSIONSThere are no RCTs of adequate methodological quality that demonstrates a clear benefit of albumin infusion (when compared to other plasma expanders) in hard endpoints, such as mortality, in the clinical situations we analyzed. Most of the benefits attributed to albumin are probably due to adequate volume expansion, which can be achieved by other fluids. The use of alternative fluids for most situations in which human albumin has been used is a scientifically adequate choice, which could result in better cost-effectiveness of healthcare, without offering additional risks or reducing efficacy to patients. This practice paradigm change, from pragmatic to evidence-based, is especially relevant and needed in public healthcare systems, since the rational allocation of restricted resource is a critical step for the overall improvement of clinical outcomes.