Albumin in critically ill patients: controversies and recommendations

Abstracts

O uso de albumina humana como terapêutica nas unidades de terapia intensiva é tradicional há mais de 50 anos. No entanto, estudos no final dos anos 90 apontaram um possível malefício em relação ao seu uso em pacientes graves. O efeito da controvérsia causado por esta publicação perdurou mesmo após a publicação de outras meta-análises e estudos randomizados e controlados, que não encontraram relação de prejuízo para o uso desta solução coloide. No Brasil, vários serviços públicos e privados seguiram recomendações da Agência Nacional de Vigilância Sanitária sobre usos adequados ou não da albumina venosa. Nesta revisão, procuramos abordar as razões da administração de albumina, assim como reunir evidências metabólicas e imunomoduladoras de possíveis efeitos deste coloide no paciente grave. Os estudos de maior impacto desde 1998 até os dias atuais foram pormenorizados, demonstrando que não parece existir aumento de mortalidade com o uso de albumina venosa, em relação às soluções cristaloides. As indicações da Agência Nacional de Vigilância Sanitária foram discutidas diante das evidências atuais sobre o uso de albumina no doente crítico.

Albumina sérica; Edema; Sepse; Hipovolemia; Pressão osmótica; Hipoalbuminemia; Terapêutica; Prognóstico

REVIEW ARTICLE

Albumin in critically ill patients: controversies and recommendations

Haroldo Falcão^I,II; André Miguel Japiassú^I,III

^IHospital Quinta D´Or, Labs D'Or Network - Rio de Janeiro (RJ), Brazil

^IIIntensive Care Unit of Hospital Central da Polícia Militar do Estado do Rio de Janeiro – Rio de Janeiro (RJ), Brazil

^IIIIntensive Care Unit of Instituto de Pesquisa Clínica Evandro Chagas - FIOCRUZ – Rio de Janeiro (RJ), Brazil

Corresponding author

ABSTRACT

Human albumin has been used as a therapeutic agent in intensive care units for more than 50 years. However, clinical studies from the late 1990s described possible harmful effects in critically ill patients. These studies' controversial results followed other randomized controlled studies and metaanalyses that showed no harmful effects of this colloid solution. In Brazil, several public and private hospitals comply with the Agência Nacional de Vigilância Sanitária (the Brazilian Health Surveillance Agency) recommendations for appropriate administration of intravenous albumin. This review discusses indications for albumin administration in critically ill patients and analyzes the evidence for metabolic and immunomodulatory effects of this colloid solution. We also describe the most significant studies from 1998 to the present time; these reveal an absence of incremental mortality from intravenous albumin administration as compared to crystalloid solutions. The National Health Surveillance Agency indications are discussed relative to the current body of evidence for albumin use in critically ill patients.

Keywords: Albumin; Edema; Sepsis; Hypovolemia; Colloid osmotic pressure; Hypoalbuminemia; Therapeutics; Prognosis

INTRODUCTION

Human albumin has been used therapeutically for more than 50 years in several clinical scenarios. This colloid solution is used for volume replacement in critically ill patients, and its use is based on two theoretical arguments. First, it contributes to plasma colloid osmotic pressure recovery by supporting intravascular volume without increasing interstitial edema, a result that is less effectively achieved with crystalloid solutions.⁽¹⁾ Second, serum albumin levels act as a severity indicator for overall clinical status – lower serum albumin levels indicate worse severity.⁽²⁾ However, despite plausible reasons for the use of albumin, trials have failed to show favorable evidence-based data supporting routine use.^(3-6)

This debate is also galvanized by the concomitant discussion of regulation criteria for albumin use and the effect of such guidelines on daily practice. Restrictive prescribing strategies, which are not exclusive to Brazil, appear to be effective for cost reduction.^(7,8) In Brazil, up to 60% of albumin prescriptions may not comply with the Agência Nacional de Vigilância Sanitária (ANVISA, the Brazilian National Health Surveillance Agency,) recommendations.⁽⁹⁾

This paper revisits this topic from the viewpoint of international trials examining the effectiveness of volume replacement using albumin infusions and discusses ANVISA's recommendations.

Study methodology

Two of the investigators independently searched the literature and extracted the data from MEDLINE and SciELo databases using the MeSH terms "albumin," "hypoalbuminemia," "critical care," "intensive care," "prognosis" and "treatment." Randomized and controlled clinical trials were selected and reviewed, as were systematic reviews and meta-analyses of human albumin use in critically ill patients and/or those staying in intensive care units. Large-scale observational studies, if published within the last decade, were also considered.

In vitro effects

Albumin is a relatively small molecule (69,000 Da). It is the most abundant plasma protein, and it represents 50% of this compartment's total protein. ⁽¹⁾ It is synthesized by the liver at a rate of 250 mg/ kg body weight. Its half-life ranges between 18 and 21 days in physiological conditions but can be much shorter in severely ill patients. In normal situations, it is responsible for 80% of colloid osmotic pressure, is part of the acid-base balance, acts as a "buffer" both in metabolic acidosis and alkalosis, and is additionally involved with transport of physiological substances and drugs.⁽¹⁰⁾ After trauma or in sepsis, its serum levels may drop as a result of intravascular space redistribution, reduced synthesis, and increased catabolism despite the molecule's long half-life. This drop may reach levels of 1-1.15 mg/dL within 3 to 7 days.⁽¹¹⁾

Intravenous albumin administration is thought to have multiple effects (Figure 1). It is likely to regulate vascular properties by maintaining osmotic pressure and microvascular integrity; transport hormones (cortisol and thyroxine), fatty acids, biliary salts, bilirubins, and ions (calcium and magnesium); modulate acid-base balance; and exert antioxidant and anti-apoptotic effects.^(1,10-12)

The chemical structure of serum albumin includes a thiol group that contains a sulfhydryl radical (-SH) with antioxidant properties.⁽¹³⁾ It is responsible for 80% of thiol radicals in the circulating blood. Additionally, nitric oxide (NO) may bind to albumin, forming S-nitrous-albumin and regulating its plasma levels.⁽¹⁴⁾

In pathological conditions there is no evidence for this potential NO regulation mechanism, but it acts as a vasodilator in the genesis of septic shock. Albumin's antioxidant effects have previously been demonstrated in the context of acute lung injury.⁽¹³⁾ Albumin may also act as an antioxidant by binding to bilirubin, a molecule that generates a heme radical when metabolized; heme has proinflammatory effects in conditions such as sepsis.⁽¹⁵⁾ Albumin's antioxidant properties are provided by the cisteine-34 radical that binds to NO, its high affinity and low specificity binding sites for bilirubin and heme, and the N-terminal radical that binds copper, chromium and nickel).

After the first meta-analysis showed harm from albumin administration, several experimental trials were developed. Bar-Or et al. tested the effects of six different commercially available human albumin preparations on cytokine release in mononuclear cell cultures.⁽¹⁶⁾ The authors performed dialysis filtration of each commercial solution and tested the effects of the commercially available albumin solutions and dialyzed albumin in cell cultures. The dialysis treatment removed molecules smaller than 15,000 Daltons. The in vitro tumor necrosis factor alpha (TNF-alpha) and interferon production was significantly lower when commercial solutions were used than with dialysis solutions; production of these cytokines dropped about 100% drop from baseline levels. Additionally, lymphocyte T TNF-alpha production stimulated by antigen and autologous antigen presenting cells was reduced with commercial albumin solutions. These data point to possible immunomodulatory effects of exogenous albumin. Albumin oxidation by aspartylalanyl-diketopiperazine (DA-DKP) may be responsible for this immunosuppressive effect. The concern regarding possible immunologic effects of albumin based on amino acid sequence changes in commercial preparations is relatively recent; the authors comment on possible effects for immunologically impaired subjects.⁽¹⁶⁾

Anti-inflammatory effects may alternatively be related to the solute concentration. It is probable that some of these effects are caused by the hyperoncotic presentation. An in vitro study with specimens from healthy subjects has shown variable degrees of neutrophil activation in different types of crystalloid solutions. In the presence of hyperoncotic albumin, neutrophil activation was reduced.⁽¹⁷⁾

Hypoalbuminemia and prognosis

The association between hypoalbuminemia and poor prognosis is well recognized. Herrmann et al. performed a retrospective outcome analysis of 15,511 clinical patients above 40 years old within their first 48 hours of admission.⁽²⁾ For each 2.5 mg/L serum albumin drop, the risk of prolonged hospital stay increased by 16%, and risk of increased death by 39%.⁽¹⁸⁾

In outpatients, morbidity and mortality progressively increased with serum albumin reduction from 4.5 to 2.2 mg/dL. This continuous relationship, which lacks distinct levels or thresholds, blurs pre-established replacement boundaries.⁽¹⁹⁾ In these non-critical patients without significant fluid overload or volume replacement needs, nutrition-based therapy may be appropriate for addressing metabolic waste and hypoalbuminemia. In this scenario, there is no favorable evidence for systematic correction of hypoalbuminemia.

Even in critically ill patients, multivariate analysis has shown that serum albumin levels independently predict in-hospital mortality. However, a post-hoc analysis of the SAFE trial data showed no prognostic difference between critically ill patients receiving intravenous saline or albumin, even when the population was categorized by albumin levels above or below a 2.5 mg/L threshold.⁽²⁰⁾

Albumin's prognostic role is more apparent when a patient with significant comorbidity is admitted to the intensive care unit (ICU) with a critical illness. For example, serum albumin is an independent marker of morbidity and mortality in patients with acute acquired immunodeficiency syndrome (AIDS) admitted to the ICU.⁽²¹⁾ In this population, the serum albumin level is a marker for the nutritional deficiency that may influence prognosis. However, the effect of albumin therapy in certain AIDS-associated conditions, such as acute respiratory failure and sepsis, has not been evaluated.^(22,23)

Main clinical trials and meta-analysis

The four large, landmark trials that have addressed the clinical use of albumin are summarized in Chart 1. In 1998, the Cochrane Collaboration initiated discussions on the use of albumin in critically ill patients. ⁽³⁾ Therapeutic albumin use for volume replacement was reassessed in light of the known association between hypoalbuminemia and unfavorable outcomes. The study systematically reviewed the available evidence with all-causes mortality as its primary endpoint. A total of 1,176 patients, 568 in the intervention group and 608 in the control group, were studied to assess the relationship between albumin use and mortality. The patients were additionally categorized in three groups: first, hypovolemic patients, comprised of surgical or trauma patients independent of possible sepsis (only one trial distinguished septic from non-septic patients); second, burn patients who received albumin as directed by a variety of protocols; third, hypoalbuminemic patients. In addition, at least half of these trials included patients who required parenteral nutrition. In addition to the subjects' enrollment criteria, "use of albumin" was not specified, including interventions with isomolar albumin (4 mg.mL) or hyperosmolar (20 mg.mL^-1. In all three groups, intervention was associated with higher mortality rates relative to the control group: the relative risk of death for hypovolemic patients was 1.46 (95% confidence interval (95%CI) 0.97 to 2.22), burn patients 2.40 (95%CI 1.11 to 5.19) and hypoalbuminemic patients 1.69 (95%CI 1.07 to 2.67). The total accumulated relative risk of death was 1.68 (95%CI 1.26 to 2.23). No significant heterogeneity was identified for the groups, nor was there a distinction between the time of death and albumin use. Notably, however, mortality was not the primary endpoint of all included trials. Although this trial has received a significant amount of criticism, its publication sparked a high volume of discussion. The Cochrane Library study has offered an indisputable contribution to the field by challenging the wide-spread and indiscriminate use of albumin worldwide.^(5,6,24,25) In a recent update of the metaanalysis originally developed in 2002, the Cochrane Group reviewers included one trial with 100 patients but drew no different conclusions from those in the first review.⁽⁴⁾

After the publication of the first Cochrane metaanalysis, Wilkes et al. published another meta-analysis that attempted to include a larger number of clinical trials and considered specific groups such as high risk newborns and liver disease patients that were not included in the population originally studied in 1998.⁽²⁶⁾ The authors controlled the trials based on quality and methodology. They selected studies that were blinded, used mortality as an endpoint, implemented a crossover design and had a large enough study size. In those studies with better methodological quality, subgroup analysis showed a relative risk reduction with albumin treatment, but this was not statistically significant (relative risk 0.73 (95%CI 0.48 to 1.12) in better quality studies and 0.94 (95%CI 0.77 to 1.14) in all trials). Again, albumin modalities were not distinguished in this meta-analysis.⁽²⁶⁾

After these two conflicting meta-analyses, the Saline versus Albumin Fluid Evaluation (SAFE) study was published. This was a randomized, controlled, double-blinded, multicenter trial.⁽²⁷⁾ This large clinical trial was designed to identify non-inferiority of albumin versus crystalloids for volume maintenance or expansion in critically ill patients. There were no significant differences between the control and intervention groups when the authors compared the length of ICU stay, length of hospital stay, length of mechanical ventilation or dialysis. The authors concluded that the small amount of albumin used to replenish volume was as effective as saline replacement. This study reintroduced the possibility of a therapeutic use for albumin, and it had a larger international effect than other trials. Because it evaluated a specific population, the SAFE trial prompted the development of new hypotheses for subgroups of critically ill patients, such as trauma patients and septic patients. The Blood Products Advisory Committee (BPAC) for the U.S. Food And Drug Administration (FDA) stated that "the SAFE trial solved the doubts raised by the Cochrane Injuries Group in 1998, and there is no harm from intravenous albumin in critically ill patients."⁽²⁸⁾

Following these studies, the Sepsis in European Intensive Care Units (SOAP) multicenter trial was conducted in European ICUs to evaluate the clinical characteristics of patients with sepsis.⁽²⁹⁾ Despite the large variability of albumin use across participant countries, an association between intravenous albumin and clinical severity and mortality was found. Because there is a tendency to give albumin to more severely ill patients, and a false association between albumin and increased mortality rates could exist. The authors conducted statistical analysis to mitigate analysis bias, and the association between albumin use and mortality remained significant. Albumin administration was independently associated with survival shorter than 30 days (relative risk 1.57, 95%CI 1.11 – 2.22). This association was maintained even after evaluation of the trauma and severe sepsis subgroups. Additionally, the 30 days mortality rate, ICU mortality and in-hospital mortality were higher among patients who received albumin (RR 1.57; 95%CI 1.19-2.07). The authors raised new questions that highlighted the complexity of this question. The impact of albumin administration may vary (both in terms of clinical effectiveness and safety) depending on timing of delivery within the scope of the patient's illness. Further criticisms of these conclusions are related to the lack of comments regarding drug indications and therapeutic targets. Because the SOAP was an exclusively observational study, it was not possible to determine whether albumin use was harmful.⁽²⁹⁾

More recently, a meta-analysis specifically addressed hyperoncotic albumin formulations (20-25% solution) for small volume resuscitations.⁽³⁰⁾ The overall analysis showed no association between hyperoncotic albumin administration and increased mortality; it was shown to be safe and effective in subgroups such as liver disease patients and newborn patients. No significant mortality increase was shown in adult critically ill patients. Because only two groups conducted these trials, however, the generalization of these conclusions is limited. In addition, it would be useful to analyze patients receiving a variety of colloids and crystalloids.

We hypothesize that, due to the heterogeneity of available studies and clinical scenarios in addition to the different forms of albumin used clinically, it is difficult to draw unequivocal conclusions regarding the use of albumin for volume replacement. These factors may limit detection of definite effects, particularly in subgroups such as those defined by severe sepsis, trauma or burns. It is therefore still necessary to test experimental models and conduct disease-specific population research. There are currently 17 trials registered on the clinicaltrials. gov databank, of which eight address specific albumin replacement effects in sepsis. Some examples include ALBIOS (Volume Replacement With Albumin in Severe Sepsis), CEASE (Comparative Evaluation of Albumin and Starch Effects in Acute Lung Injury) and a study on albumin's antioxidant and hemoglobin-binding effects following extracorporeal circulation in cardiac surgery (Evans TW, personal communication).

Albumin effects in subgroups of severely ill patients

Large cohort studies have failed to detect effects of albumin replacement on mortality; however, a variety of evidence suggests that specific groups studies may reap physiological and biochemical benefits. Additionally, establishing more modest endpoints and focused short-term outcomes, such as hemodynamic stability and improved gas exchange, may provide promising results.

Albumin administration does benefit critically ill patients, most notably by improving respiratory function and gas exchange, cardiovascular stability, neurologic status and fluid balance.^(31,32) Albumin infusion improves organ dysfunction in the first week of stay in ICU in patients with below 3.0 mg/L serum albumin (reduced Sequential Organ Failure Assessment (SOFA) score between the 1^st and 3^rd days of 3.1 ± 1.0 for the albumin group versus 1.4 ± 1.1 for the Ringer lactate group; p=0.03).⁽³¹⁾

Morbidity outcomes in the group of patients with severe hypoalbuminemia are not clear. Product-associated morbidity was much lower in severely hypoalbuminemic subjects than in patients with albumin levels above 3.0 mg/L, suggesting a dose-dependent relationship.^(33,34) Next, we will briefly analyze three patient categories in which albumin infusion may be more strongly indicated:

a) Sepsis

Exogenous albumin administration was evaluated in a prospective non-randomized trial in 28 acute lung injury patients.⁽³²⁾ Albumin, with or without furosemide, leads to improved oxygenation and hemodynamic function. The partial pressure of oxygen improved 5 minutes after albumin plus furosemide, but this oxygenation gain was not maintained. In another randomized, controlled, double-blind trial of 40 acute respiratory distress syndrome (ARDS) and sepsis patients, the authors attempted to achieve negative fluid balance using albumin plus furosemide infusion.⁽³⁵⁾ Oxygenation benefit was achieved without any negative impact on hemodynamic stability. Hyperoncotic albumin use may also be valuable for septic patients with advanced liver disease or nephrotic syndrome. Albumin administration (dose accumulated) is thought to have renoprotective properties.⁽¹⁾

The SAFE trial has shown a trend toward favorable results after albumin resuscitation relative to saline in septic patients.⁽²⁷⁾ In this subpopulation, albumin therapy in septic patients was associated with an absolute mortality reduction of almost 5% with a relative risk of 0.87 (95%CI 0.74 – 1.02). A repeated analysis performed by the same investigators showed that albumin infusion was an independent contributor to increased 28-day survival and was associated with less progression to liver dysfunction.⁽³⁶⁾

b) Severe liver disease

Exogenous albumin infusion in decompensated cirrhosis is justified in three contexts: prevention of circulatory dysfunction following serial or large-volume paracentesis;⁽³⁰⁾ reduction of renal dysfunction and mortality in spontaneous bacterial peritonitis patients, for whom albumin is superior to synthetic colloids;^(37,38) and, finally, for treatment of hepatorenal syndrome.⁽³⁹⁾

Transient liver dysfunction after liver transplantation appears to be a reasonable indication for prescribing albumin, but studies confirming this suspicion are scarce. At this time, there is no apparent prognostic value in maintaining serum albumin levels above or below 3.0 mg/L.⁽⁴⁰⁾ It is also possible that albumin is as effective for volume resuscitation of this type of patient as HES 130/0.4 modified starch.⁽⁴¹⁾

c) Trauma and postoperative

Although 26% of the albumin given in the United States is targeted to acute volume loss therapy in postoperative, traumatic or hemorrhagic contexts,⁽⁶⁾ it is not superior to crystalloids or other colloids in the context of overall postoperative volume replacement.⁽⁴²⁾ Two conflicting trials address albumin use in trauma patients. Hyperoncotic albumin plus furosemide reduced post-contusion brain edema, and this treatment was associated with significant functional outcome improvement in 18 head trauma patients when compared with conventional normal osmolarity colloid.⁽⁴³⁾ On the other hand, a SAFE trial subgroup analysis revealed increased mortality after isotonic albumin replacement.⁽⁴⁴⁾

The Brazilian Health Surveillance Agency (ANVISA) indications

Guidelines for the use of exogenous human albumin were initiated in 1975 when the National Institute of Health (NIH) issued rules for prescribing albumin in the United States, forming the basis for less liberal albumin use criteria.^(7,45) Prescriptions in situations not recommended are generally accompanied by high costs and are found in countries where 90% of prescriptions may depend on inadequate evidence. ^(7,46,47) Development of protocols and compliance with protocols may reduce the use of this drug, leading to cost reductions without influencing outcomes.⁽⁸⁾

In Brazil, albumin prescription is included in the Ministry of Health special procedures. ANVISA issued its guidelines in 2003, analyzing the available evidence to guide use of albumin.⁽⁴⁸⁾ ANVISA's guidelines form the national reference for albumin use, and they provide the guiding parameter for health insurance prescription criteria.

Matos et al. have shown that in a Brazilian public hospital, 60% of human albumin indications were inappropriate, and that one half of the patients had serum levels above 2.0 mg/L.⁽⁹⁾ This may have corresponded to about 8,000 g human albumin theoretically misused, entailing 16 to 20 thousand dollars of inappropriate expenses.

The main ANVISA indications are⁽⁴⁸⁾ extracorporeal circulation, following paracentesis, therapeutic plasmapheresis, prevention of ovarian hyper-stimulation syndrome, refractory edema of cirrhosis or nephrotic syndrome, major burns, and postoperatively after liver transplant (Chart 2). Treatment of ICU patients is disputable and is not based on adequate evidence. ANVISA's position additionally predicts categories where albumin use is considered as an interim measure until more conclusive evidence is available. The unfounded conditions included those not endorsed by the available literature and those described as contra-indications.

Some aspects of ANVISA's rules deserve special consideration. We could not find any specification regarding the critical serum level boundaries for albumin prescription in severe hypoalbuminemia cases (lower than 2.0 mg/L). Also, there is no mention of the timing of use, cumulative dose, or the clinical time for its prescription. While new investigations have not provided better specifications for albumin, there is room to prescribe flexibly within existing approved categories.

CONCLUSIONS AND PERSPECTIVES

The experimental and clinical effects of albumin are not completely understood. The ideal dose definitions, time of use and mode of administration (either iso- or hyperoncotic) remain unclear. Furthermore, industrial formulations may be less effective than the endogenous molecule.

The characteristics of large human albumin therapy clinical trials, which generally include widely heterogeneous populations, require more specific subgroup investigations. The recommendations available in Brazil – those used by both public and private payers – fail to offer guidance beyond defining the diagnosis categories that receive more or less benefit; they do not clarify the dose, cumulative dose, timing or even the underlying disease type (they exclude diagnosis categories not discussed by ANVISA). The large trials currently available illuminate small domains of certainty in a greater context of broad uncertainty.

REFERENCES

• 1. Boldt J. Use of albumin: an update. Br J Anaesth. 2010;104(3):276-84.
• 2. Herrmann FR, Safran C, Levkoff SE, Minaker KL. Serum albumin level on admission as a predictor of death, length of stay and readmission. Arch Intern Med. 1992;152(1):125- 30.
• 3. Human albumin administration in critically ill patients: systematic review of randomized controlled trials. Cochrane Injuries Group Albumin Reviewers. BMJ. 1998;317(7153):235-40.
• 4. Alderson P, Bunn F, Lefebvre C, Li WP, Li L, Roberts I, Schierhout G; Albumin Reviewers. Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev. 2004;(4):CD001208. Review.
• 5. Beale RJ, Wyncoll DL, McLuckie A. Human albumin administration in critically ill patients. Analysis is superficial and conclusions exaggerated. BMJ. 1998;317(7162):884.
• 6. Boldt J. The good, the bad, and the ugly: should we completely banish human albumin from our intensive care units? Anesth Analg. 2000;91(4):887-95, table of contents.
• 7. Vermeulen LC Jr, Ratko TA, Erstad BL, Brecher ME, Matuszewski KA. A paradigm for consensus. The University Hospital Consortium guidelines for the use of albumin, nonprotein colloid, and crystalloid solutions. Arch Intern Med. 1995;155(4):373-9.
• 8. Charles A, Purtill M, Dickinson S, Kraft M, Pleva M, Meldrum C, Napolitano L. Albumin use guidelines and outcome in a surgical intensive care unit. Arch Surg. 2008;143(10):935-9; discussion 939.
• 9. Matos GC, Rozenfeld S. Avaliação do uso de albumina humana em hospital do Rio de Janeiro, Brasil. Cad Saúde Pública = Rep Public Health. 2005;21(4):1224-33.
• 10. Santos NSJ, Draibe SA, Kamimura MA, Cuppari L. Albumina sérica como marcador nutricional de pacientes em hemodiálise. Rev Nutr. 2004;17(3):339-49.
• 11. Margarson MP, Soni N. Serum albumin: touchstone or totem? Anaesthesia. 1998;53(8):789-803. Review.
• 12. Mendez CM, McClain CJ, Marsano LS. Albumin therapy in clinical practice. Nutr Clin Pract. 2005;20(3):314-20.
• 13. Quinlan GJ, Mumby S, Martin GS, Bernard GR, Gutteridge JM, Evans TW. Albumin influences total plasma antioxidant capacity favorably in patients with acute lung injury. Crit Care Med. 2004;32(3):755-9.
• 14. Wang X, Tanus-Santos JE, Reiter CD, Dejam A, Shiva S, Smith RD, et al. Biological activity of nitric oxide in the plasmatic compartment. Proc Natl Acad Sci U S A. 2004;101(31):11477-82.
• 15. Larsen R, Gozzelino R, Jeney V, Tokaji L, Bozza FA, Japiassú AM, et al. A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med. 2010;2(51):51ra71.
• 16. Bar-Or D, Thomas GW, Bar-Or R, Rael LT, Scarborough K, Rao N, Shimonkevitz R. Commercial human albumin preparations for clinical use are immunosuppressive in vitro. Crit Care Med. 2006;34(6):1707-12.
• 17. Chalasani N, Gorski JC, Horlander JC Sr, Craven R, Hoen H, Maya J, Brater DC. Effects of albumin/furosemida mixtures on responses to furosemida in hypoalbuminemic patients. J Am Soc Nephrol. 2001;12(5):1010-6.
• 18. Goldwasser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol. 1997;50(6):693- 703.
• 19. Gibbs J, Cull W, Henderson W, Daley J, Hur K, Khuri SF. Preoperative serum albumin level as a predictor of operative mortality and morbidity: results from the National VA Surgical Risk Study. Arch Surg. 1999;134(1):36-42.
• 20. SAFE Study Investigators, Finfer S, Bellomo R, McEvoy S, Lo SK, Myburgh J, Neal B. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ. 2006;333(7577):1044.
• 21. Croda J, Croda MG, Neves A, De Sousa dos Santos S. Benefit of antiretroviral therapy on survival of human immunodeficiency virus-infected patients admitted to an intensive care unit. Crit Care Med. 2009;37(5):1605-11.
• 22. Davis JL, Morris A, Kallet RH, Powell K, Chi AS, Bensley M, et al. Low tidal volume ventilation is associated with reduced mortality in HIV-infected patients with acute lung injury. Thorax. 2008;63(11):988-93.
• 23. Jacob ST, Moore CC, Banura P, Pinkerton R, Meya D, Opendi P, Reynolds SJ, Kenya-Mugisha N, Mayanja- Kizza H, Scheld WM; Promoting Resource-Limited Interventions for Sepsis Management in Uganda (PRISM-U) Study Group. Severe sepsis in two Ugandan hospitals: a prospective observational study of management and outcomes in a predominantly HIV-1 infected population. PloS One. 2009;4(11):e7782.
• 24. Fogarty BJ, Khan K. More on albumin. Multicentre randomised controlled trail is needed before changing resuscitation formulas for major burns. BMJ. 1999;318(7192):1215.
• 25. Patey R, Wilson G, Hulse T. Albumin controversy continues. Meta-analysis has affected use of albumin. BMJ. 1999;318(7181):464.
• 26. Wilkes MM, Navickis RJ. Patient survival after human albumin administration. A meta-analysis of randomized, controlled trials. Ann Intern Med. 2001;135(3):149-64.
• 27. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-56.
• ²⁸
  Food and Drug Administration. Safety of Albumin Administration in Critically Ill Patients. May 16, 2005. FDA Report. [cited 2010 Sep 19]. Available on: http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/BloodSafety/ucm095539.htm
• 29. Vincent JL, Sakr Y, Reinhart K, Sprung CL, Gerlach H, Ranieri VM; 'Sepsis Occurrence in Acutely Ill Patients' Investigators. Is albumin administration in the acutely ill associated with increased mortality? Results of the SOAP study. Critical Care. 2005;9(6):R745-54.
• 30. Jacob M, Chappell D, Conzen P, Wilkes MM, Becker BF, Rehm M. Small-volume resuscitation with hyperoncotic albumin: a systematic review of randomized clinical trials. Crit Care. 2008;12(2):R34.
• 31. Dubois MJ, Orellana-Jimenez C, Melot C, De Backer D, Berre J, Leeman M, et al. Albumin administration improves organ function in critically ill hypoalbuminemic patients: a prospective, randomized, controlled, pilot study. Crit Care Med. 2006;34(10):2536-40.
• 32. Martin GS, Moss M, Wheeler AP, Mealer M, Morris JA, Bernard GR. A randomized, controlled trial of furosemida with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med. 2005;33(8):1681-7.
• 33. Vincent JL, Dubois MJ, Navickis RJ, Wilkes MM. Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg. 2003;237(3):319-34.
• 34. Rubin H, Carlson S, DeMeo M, Ganger D, Craig RM. Randomized, double-blind study of intravenous human albumin in hypoalbuminemic patients receiving total parenteral nutrition. Crit Care Med. 1997;25(2):249-52.
• 35. Kuper M, Gunning MP, Halder S, Soni N. The shortterm effect of hyperoncotic albumin, given alone or with furosemide, on oxygenation in sepsis-induced acute respiratory distress syndrome. Anaesthesia. 2007;62(3):259-63.
• 36. SAFE Study Investigators, 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(1):86-96.
• 37. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruizdel- 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):403-9.
• 38. Fernández J, Monteagudo J, Bargallo X, Jiménez W, Bosch J, Arroyo V, Navasa M. A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology. 2005;42(3):627-34.
• 39. Umgelter A, Reindl W, Wagner KS, Franzen M, Stock K, Schmid RM, Huber W. Effects of plasma expansion with albumin and paracentesis on haemodynamics and kidney function in critically ill cirrhotic patients with tense ascites and hepatorenal syndrome: a prospective uncontrolled trial. Crit Care. 2008;12(1):R4.
• 40. Mukhtar A, El Masry A, Moniem AA, Metini M, Fayez A, Khater YH. The impact of maintaining normal serum albumin level following living related liver transplantation: does serum albumin level affect the course? A pilot study. Transplant Proc. 2007;39(10):3214-8.
• 41. Mukhtar A, Aboulfetouh F, Obayah G, Salah M, Emam M, Khater Y, et al. The safety of modern hydroxyethyl starch in living donor liver transplantation: a comparison with human albumin. Anesth Analg. 2009;109(3):924- 30. Erratum in: Anesth Analg. 2010;111(1):229.
• 42. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg. 2001;72(2):527-33; discussion 534.
• 43. Tomita H, Ito U, Tone O, Masaoka H, Tominaga B. High colloid oncotic therapy for contusional brain edema. Acta Neurochir Suppl (Wien). 1994;60:547-9.
• 44. SAFE Study Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group; Australian Red Cross Blood Service; George Institute for International Health, Myburgh J, Cooper DJ, Finfer S, Bellomo R, Norton R, Bishop N, et al. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med. 2007;357(9):874-84.
• 45. Tullis JL. Albumin. 2. Guidelines for clinical use. JAMA. 1977;237(5):460-3.
• 46. Tarín Remohí MJ, Sánchez Arcos A, Santos Ramos B, Bautista Paloma J, Guerrero Aznar MD. Costs related to inappropriate use of albumin in Spain. Ann Pharmacother. 2000;34(10):1198-205.
• 47. Yim JM, Vermeulen LC, Erstad BL, Matuszewski KA, Burnett DA, Vlasses PH. Albumin and nonprotein colloid solution use in US academic health centers. Arch Intern Med. 1995;155(22):2450-5.
• ⁴⁸
  Agência Nacional de Vigilância Sanitária (ANVISA). Consulta Pública nº 99, de 11 de novembro de 2003. Proposta de Resolução que aprova as Diretrizes para o uso de Albumina. Diário Oficial da União. Brasília (DF), 12/11/2003.

Publication Dates

• Publication in this collection
  02 May 2011
• Date of issue
  Mar 2011

History

• Received
  22 Nov 2010
• Accepted
  28 Jan 2011