Albumin

Chapter 21

Albumin Elizabeth E. Culler

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Lennart E. Lögdberg

INTRODUCTION

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Over the past 70 years, significant progress has been made in the isolation and purification of human plasma proteins for use as therapeutic products. This chapter focuses on albumin, the first such protein to be made commercially available through large-scale purification. The majority of this chapter will focus on the product Albumin (Human), a sterile solution of purified human plasma albumin, now dominating the therapeutic albumin market.1 Less commonly used is Plasma Protein Fraction (Human), which is a sterile solution of albumin and globulin derived from human plasma.1 The development of a method to purify albumin was begun in 1940. By the end of 1941, human serum albumin (HSA) was put into clinical use on the battlefield.2 The administration of human serum albumin proved so effective in the treatment of shock that the demand by the military resulted in the production of over 500,000 units in the United States by the end of World War II in 1945.3 In the decades following the war, albumin continued to be used in the treatment of shock but was also used experimentally in the treatment of various other conditions, such as malnutrition or hypoalbuminemia. Owing to the use of albumin for an expanding number of conditions and because of its significant cost, guidelines for albumin usage were established by the Division of Blood Diseases and Resources, National Heart and Lung Institute, National Institutes of Health, in 1975.4 Since that time, further studies have prompted even more conservative albumin usage guidelines, such as those established by the University HealthSystem Consortium (UHC) in 2000.5 Auditing of albumin transfusion practices, based on current guidelines, indicates substantial inappropriate use of this product.6,7 This chapter provides an overview of albumin products and begins by discussing plasma donation, the plasma industry, infectious disease testing, manufacturing methods, and regulatory aspects of albumin product production. This is followed by a review of the current guidelines for the therapeutic use of Albumin (Human), which is hereafter referred to as albumin. Finally, the adverse effect profile for the product will be summarized, including the risk of infectious disease transmission.

ALBUMIN, THE PROTEIN Albumin is the quantitatively dominant plasma protein. A 66-kDa, water-soluble protein, it is synthesized in the liver at a rate of about 15 g/day and has a half-life of around

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25 days.8 In a healthy person with normal nutrition, albumin synthesis and catabolism are regulated by the colloid osmotic pressure.9 An average 70-kg man contains about 320 g of albumin,8 of which 35% to 40% is localized to the intravascular space, where it contributes about 80% of the colloidal osmotic pressure of plasma. Accordingly, albumin is important for physiologic maintenance and regulation of plasma volume. In addition, albumin has a high negative charge10 and a thiol group on the surface of the molecule that enables albumin to function effectively as a ligand binder, a radical scavenger, and a versatile transport protein.11 Thus, albumin also serves as a major carrier for hormones, medications, enzymes, fatty acids, cholesterol, and many other substances.9

PLASMA DONATION AND COLLECTION Albumin is derived from plasma collected either by whole blood donation (Recovered Plasma) or by apheresis (Source Plasma).1 The following subsections discuss plasma collection and its regulation, plasma pooling, donor suitability, and prefractionation infectious disease testing. Refer to Chapter 12 for further information on these subjects and on the preparation and storage of Recovered Plasma and Source Plasma.

Regulation of Plasma Collection The World Health Organization (WHO) has established guidelines for the collection and production of human plasma for fractionation.12 In addition, regional or national regulatory authorities such as the U.S. Food and Drug Administration (FDA) and the Council of Europe are responsible for the establishment and enforcement of regulations pertaining to the safety and quality of the products in their respective areas.13 The FDA inspects facilities that it licenses for plasma fractionation every 2 years. There are 26 facilities worldwide that are licensed by the FDA to produce plasma fractions for use in the United States.14 In addition, almost all of the approximately 450 source plasma collection facilities in the world belong to the Plasma Protein Therapeutics Association (PPTA). The PPTA offers an International Quality Plasma Program (IQPP) certification requiring that facilities meet voluntary standards established by the PPTA. Approximately 90% of source plasma collection facilities around the world have qualified for IQPP certification. Source plasma facilities currently account for approximately 12 million liters of plasma production annually.13

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MANUFACTURE OF ALBUMIN PRODUCTS

A donation of plasma by apheresis contains approximately 450 to 880 mL of plasma, while a donation of Recovered Plasma contains only around 100 to 260 mL of plasma.12 Thus, albumin derived from pools of Source Plasma requires contributions from fewer donors than albumin derived from pools of Recovered Plasma. Because about 1 liter of plasma must be processed to produce 20 to 25 grams of albumin,15 plasma from tens of thousands of donors must be pooled to make the production process efficient.

Development of a Technique for Plasma Fractionation

Donor Suitability Pooling of the large number of plasma donations required to manufacture albumin allows a single infected donor unit the potential to transmit disease to a large number of final product recipients. Therefore, steps are added throughout the manufacturing process to limit infectious disease transmission. The initial step is to select appropriate donors by reviewing the donor’s medical history and by conducting a medical examination. Although the WHO guidelines encourage the use of plasma from voluntary, nonremunerated donors,12 many plasma collection facilities provide $15 to $25 per donation. To decrease the risk of infectious disease transmission, donors of Source Plasma must present themselves twice within a 6-month period to be considered acceptable by voluntary PPTA standards.13 An “applicant donor” is an individual who comes in to donate and who has not qualified as a donor in the previous 6 months. Until the applicant donor screens negative for viral markers and passes the medical history screen on two separate occasions within a 6-month period, the initial donation is quarantined. When the donor successfully passes all tests twice within the 6-month period, the donor is considered “qualified” and the donations are used in manufacturing pools. When more than 6 months pass between donations, individuals are reclassified as “applicant donors” and must become qualified again. After donation, Source Plasma must be held for at least 60 days prior to pooling to allow time for investigation of any postdonation information that might become available.13

Infectious Disease Testing After donors at low risk for infectious disease transmission have been selected, the plasma donations are screened using approved tests for hepatitis B surface antigen (HBsAg), anti–human immunodeficiency virus (HIV), and anti–hepatitis C virus (HCV).12 The PPTA voluntary standards also require that nucleic acid testing (NAT) be performed for HIV, hepatitis B virus (HBV), HCV, and parvovirus B19. Manufacturing pools of plasma must contain less than 105 IU of parvovirus B19 DNA per milliliter according to PPTA standards.13 Testing for HTLV-1 and HTLV-2 is not required because these are cell-associated viruses.12 The risk of infectious disease transmission is further reduced by the cold ethanol processing method and by filtration steps that eliminate microbes with diameters larger than 0.2 μm.12 This is discussed below in the section on Commercial Albumin Preparations, Quality Specifications, and Formulations and the section on Infectious Potential.

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ALBUMIN

Plasma Pooling

The development of a process for the isolation and purification of plasma components was driven by the need to provide blood products for casualties of World War II. In 1940, a meeting was held in Washington, D.C., to discuss the large number of blood products requested by the U.S. armed forces. Because of the limited supply, Dr. Edwin J. Cohn at the Harvard Medical School was asked to determine whether animal plasma could be used for human treatment.16 Cohn developed a plasma fractionation technique (cold ethanol fractionation; see below) that he used to separate and characterize plasma components.17 Albumin, responsible for 80% of the colloid osmotic pressure of plasma, was the most suitable component for volume replacement.18 Because bovine albumin was found to cause serum sickness in human recipients, the focus instead became the development of a human albumin preparation. Thus, treatment with a 25% human albumin solution was found to restore blood volume in volunteers made hypovolemic by removal of a measured volume of blood by venesection.16 Further studies were cut short when the total albumin supply was needed at Pearl Harbor to treat burn victims.16 The military experience with the product’s clinical efficacy, ease of transport, and stability at a wide temperature range prompted initiation of mass production of albumin.2 The 25% albumin solution used by the military contained sodium at a concentration of 300 mEq/L to maintain product stability. After the introduction of new stabilizers, the sodium content of albumin was reduced and the new product became known as “salt-poor albumin,” a term still occasionally used within the medical community.15 Currently the FDA requires that all albumin preparations contain 130 to 160 mEq/L of sodium.1 Producing plasma products during World War II was challenging. Of more than 12.5 million blood donations delivered to plasma processing facilities during this period, more than 204,800, or 1.6%, were ultimately rejected.19 The biggest losses were due to bacterial contamination (>125,700 or 0.99% of the donations) or to breakage of the glass bottles used for plasma storage (>18,700 or 0.14% of the donations).19 An investigation revealed that the main causes of bacterial contamination were the use of multiple technicians in the preparation process, break-in technique, nonsterile processing conditions, and, in some cases, collection facilities exceeding their capacity at the expense of quality. After these issues had been addressed, the rate of bacterial contamination was reduced.

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Commercial Albumin Preparations, Quality Specifications, and Formulations Because the implementation of new technology in albumin manufacturing requires a substantial capital investment and because the cold ethanol fractionation technique (see below) has a proven safety record, U.S. suppliers continue to use methods based on Cohn fractionation for albumin concentration and purification. In Europe, by comparison, some manufacturers have either incorporated chromatography into their production methods or switched to processes based exclusively on chromatographic purification methods.20 The

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addition of chromatography to plasma processing has significantly increased the yield (80% to 85% vs 60% to 70%) and purity (>98% vs 95%) of albumin products when compared to cold ethanol fractionation.10 In addition, chromatography has allowed significant reductions in the concentration of unwanted elements such as endotoxin, aluminum, and trace proteins.10 It is uncertain whether these alternative purification schemes will be incorporated into commercial albumin production in the United States. Cold Ethanol Fractionation Albumin purification using Cohn fractionation begins with frozen plasma, which is thawed at a low temperature, permitting the removal of cryoprecipitate. The product then undergoes cold ethanol plasma fractionation, which relies on the manipulation of pH, ionic strength, temperature, protein concentration, and ethanol concentration to precipitate plasma fractions. The ethanol content is increased and the pH and temperature are decreased in a stepwise fashion with separation of fractions by centrifugation and filtration. Fibrinogen is precipitated in fraction I, immunoglobulins in fraction II + III, α1-proteinase inhibitor, antithrombin III, and factor IX complex in fraction IV-1, and plasma protein fraction in fraction IV-4. Albumin, which has the highest solubility of the major proteins in plasma, precipitates in the

final fraction (fraction V). The ethanol is then removed by ultracentrifugation or freeze-drying.21 After the albumin has been purified and within 24 hours of being placed in the final container, the product is heated to 60 ± 0.5°C for 10 to 11 hours.1 This inactivates a variety of viruses, including HBV and HIV. Albumin does not denature under these conditions owing to the presence of 17 stabilizing disulphide bonds in its structure18 and to the addition of stabilizing compounds (sodium caprylate or a combination of sodium acetyltryptophanate and sodium caprylate). All final containers of albumin are incubated at 20–35 °C for at least 14 days after heat treatment. After the incubation period, each final container is examined for turbidity before it is released.1 The label on the final product must state the sodium (range in mEq/L) and the protein concentration (4%, 5%, 20%, or 25%).1 Table 21–1 summarizes the FDA regulations pertaining to the production of Albumin (Human) and Plasma Protein Fraction (Human) and also lists FDA-required testing on the final albumin products. Toward Commercialization of Recombinant Albumin Over the past couple of decades, efforts have been directed toward producing recombinant human albumin.22,23 A recent phase I trial compared the safety, tolerability, and

Table 21–1 FDA Requirements for Manufacturing of Therapeutic-Grade Albumin (Human) and Plasma Protein Fraction (Human) Characteristic

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Albumin (Human)

Required Production Characteristics Source material Pasteurization

Plasma Protein Fraction (Human)

Recovered Plasma or Source Plasma

Heated within 24 hours of the filling of the final containers at 60 ± 0.5°C for 10–11 hours

Incubation

Incubated in final containers at 20–35°C for at least 14 days

Processing

The processing method should not affect the integrity of the product and should consistently produce a safe product Components with an electrophoretic mobility similar to that of α globulin should account for ≤5% of the total protein when tested after the pasteurization step The product should contain <5% protein with a sedimentation coefficient greater than 7.0 S

Stabilizer

Either 0.08 ± 0.016 mmol sodium caprylate or 0.08 ± 0.016 mmol sodium acetyltryptophanate and 0.08 ± 0.016 mmol sodium caprylate per gram of protein

Preservative

None

Required Tests on Final Products Protein concentration

The protein concentration of the final solution may be 4.0 ± 0.25%, 5.0 ± 0.30%, 20.0 ± 1.2%, or 25.0 ± 1.5%

5.0 ± 0.30%

Protein composition

≥96% of the total protein in the final product must consist of albumin, as determined by a Center for Biologics Evaluation and Research (CBER)–approved method

The protein composition of the final product must consist of ≥83% albumin and ≤17% globulins; ≤1% of the total protein should be gammaglobulin, as determined by a CBERapproved method

pH

When the final product is diluted to a concentration of 1% protein with sodium chloride 0.15 mol/L, the pH must be 6.9 ± 0.5 7.0 ± 0.3

Sodium concentration

130 to 160 mEq/L

Potassium concentration

≤2 mEq/L

Heat stability

The final product is inspected visually after it is heated to 57°C for 50 hours It must be not be visually different from an unheated control sample taken from the same lot

From Code of Federal Regulations. Title 21 CFR 640. Washington, D.C., U.S. Government Printing Office, 2005 (revised annually).

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DOSING AND ADMINISTRATION Choosing a Product Albumin solutions with protein concentrations of 5%, 20%, and 25% are currently available on the U.S. market. Because PPF solutions contain a greater proportion of proteins other than albumin, they are not often used. Thus, the focus of this section is on albumin solutions. The infusion of 5% albumin solutions, which are isooncotic with human plasma, increases the plasma volume by the volume of albumin solution infused,8 while the infusion of the hyperoncotic 25% albumin solutions causes the plasma volume to expand by 3.5 times the volume of albumin solution infused.25 For treating pediatric patients or volume- or sodium-sensitive patients, the more concentrated 20% or 25% albumin solutions are more commonly used, whereas the 5% albumin solutions are especially useful for hypovolemic patients.26 Dehydrated patients usually require additional fluids along with the 20% or 25% albumin solutions.1 If necessary, a 5% albumin solution can be prepared by diluting a 20% or 25% albumin solution with either normal saline or 5% dextrose. Sterile water should not be used to dilute albumin because the resulting hypotonic solution can cause hemolysis when infused. This has occurred in at least 10 patients with one reported death.27 When large volumes of diluted albumin are required, normal saline is the diluent of choice, since the infusion of large volumes of albumin diluted with dextrose 5% can cause hyponatremia leading to cerebral edema.28 When choosing a product, clinicians must also consider the aluminum concentration. As mentioned in the section on Potential Adverse Effects, albumin products contain small amounts of aluminum, which can accumulate in premature infants or in patients with chronic renal failure.10 Talecris Biotherapeutics produces low-aluminum formulations of 5%, 20%, and 25% human albumin, each of which has an aluminum content of less than 200 μg/L.29–31

situations. When evaluating the appropriate dose of albumin to administer, study investigators have relied on parameters such as serum albumin level, urine output, pulse, blood pressure, hematocrit, and degree of venous and pulmonary congestion.26

ALBUMIN

hemodynamic responses in volunteers receiving either recombinant human albumin or human serum albumin.24 Thirty participants in the double-blind, randomized trial received intravenous doses of 10 g on day 1, 20 g on day 22, and 50 g on day 43 of either recombinant human albumin or human serum albumin. There were no significant differences in safety or tolerability between the two products. The serum albumin, colloid osmotic pressure, and hematocrit pre- and postinfusion were measured and were not significantly different between the groups receiving either recombinant human albumin or human serum albumin. Since recombinant human albumin is virus- and prion-free, there is incentive for manufacturers to continue the clinical development of this product.

Rate There are no guidelines addressing the optimal infusion rate for albumin solutions. The infusion rate should be based on the patient’s condition and is limited only by the capacity of the administration set when an albumin infusion is needed emergently. Because high rates of albumin infusion can cause circulatory overload and pulmonary edema, 5% albumin solutions are commonly started at a rate of 1 to 2 mL/min and are not usually infused at a faster rate than 4 mL/min, and 25% albumin solutions are not infused at rates faster than 1 mL/min.26

Administration Albumin should be inspected for turbidity prior to administration. Although albumin does not have to be infused through a filter, some manufacturers either recommend or include a filter in administration sets to be used during albumin administration. Hospital policy also may require the use of a filter.15 Administration must begin within 4 hours of entry into the container.1 Because blood group isohemagglutinins are removed from albumin products during preparation, albumin is given without regard to ABO type. The Code of Federal Regulations (CFR) does not address the measurement of isohemagglutinin titers in albumin products; however, the European Pharmacopoeia states that plasma products intended for intravenous use should have an isohemagglutinin titer of less than 1:64.12

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CLINICAL CONSIDERATIONS Hypoalbuminemia may result from the decreased production, altered distribution, increased metabolism, or excessive loss of albumin. Some causes of decreased albumin production are liver dysfunction, malnutrition, and malabsorption. Approximately 40 cases of congenital analbuminemia (defined as HSA < 1 g/L) have been reported in the literature; however, this disorder is usually associated with only mild signs and symptoms.32 Hypoalbuminemia also may result from a redistribution of albumin to the extravascular space as a result of increased vascular permeability, as seen in inflammatory states. Thyrotoxicosis and pancreatitis are two conditions associated with increased albumin catabolism. Increased albumin loss occurs in patients with protein-losing gastroenteropathy and nephrotic syndrome.

Dose According to the American Hospital Formulary Service (AHFS) Drug Information guide, a typical initial adult dose of albumin is 25 g, which can be repeated in 15 to 30 minutes depending on the patient’s response. Up to 250 g of albumin may be infused in a 48-hour period.26 However, because studies have used different end points to assess clinical improvement after the administration of albumin, no standard dose of albumin can be recommended to fit all clinical

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Indication Guidelines for Albumin Usage Although decreased albumin levels are present in many conditions, albumin infusion is not usually required to treat hypoalbuminemia. Rather, albumin infusions are used therapeutically for plasma expansion. Historically, this led to broad indications and widespread use of the product. Later studies showed albumin to be ineffective in many of these uses, leading to a still-ongoing evolution toward more

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Table 21–2

UHC Guidelines on Albumin Usage

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From Technology assessment: albumin, nonprotein colloid, and crystalloid solutions. Oak Brook, JH, University HealthSystem Consortium, 2000. Aboulghar M, Evers JH, Al-Inany H. Intravenous albumin for preventing severe ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2002:CD001302.

conservative indication guidelines such as the most recent UHC guidelines for the use of albumin (summarized and updated in Table 21–2), nonprotein colloid, and crystalloid solutions.5 Reflecting the liberal guidelines of the past, a 2003 report that examined albumin prescribing patterns in 53 member institutions of the University HealthSystem Consortium found that albumin was inappropriately used in 57.8% of adult patients and 52.2% of pediatric patients. In the report, which collected data on 1649 adult and 23 pediatric patients receiving albumin, two of the most common inappropriate uses of albumin were for intradialytic blood pressure support (159 patients) and for serum albumin values of <2 g/dL (142 patients).6 The consensus of the panelists involved in creating the 2000 UHC guidelines for albumin use was that the available evidence did not support the use of albumin in these situations. Table 21–3 provides a list of common misuses of therapeutic albumin infusions. In the following sections, we discuss alternatives to the use of albumin for plasma expansion and then summarize some of the well-recognized clinical indications for albumin infusions, noting that such infusions are often a secondary treatment option.

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Alternatives to Albumin for Plasma Expansion The two major categories of products that may be used for plasma expansion are crystalloids (e.g., 0.9% sodium chloride, Ringer’s lactate) and colloids, including protein (e.g., albumin) and nonprotein substances (e.g., dextrans, gelatins, and starches). Crystalloids have not demonstrated a definite clinical advantage over albumin, but are considerably cheaper and are therefore widely used as first-line treatment.33 Although nonprotein colloids have been associated with side effects such as alterations in hemostatic laboratory results, pruritus, and, rarely, with severe head and back pain, they also are less expensive than albumin and are preferred by some.34–39 In those clinical conditions in which plasma expansion through albumin or nonprotein colloids has demonstrated equivalent patient outcomes, the 2000 UHC guidelines recommend the use of the latter due to their lower cost. Neither crystalloids nor colloids can be substituted for red blood cells when oxygen-carrying capacity is needed or for platelets or plasma when coagulopathy exists.5

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Common Misuses of Albumin

From Technology assessment: albumin, nonprotein colloid, and crystalloid solutions. Oak Brook, Ill: University HealthSystem Consortium, 2000. Tanzi M, Gardner M, Megellas M, et al. Evaluation of the appropriate use of albumin in adult and pediatric patients. Am J Health Syst Pharm 2003;60:1330–1335. Tarin Remohi MJ, Sanchez Arcos A, Santos Ramos B, et al. Costs related to inappropriate use of albumin in Spain. Ann Pharmacother 2000;34:1198–1205.

Clinical Usage of Albumin Infusions Therapeutic Plasma Exchange Albumin is commonly used as the replacement fluid in therapeutic plasma exchange (TPE) unless a condition exists that specifically requires factors present in fresh frozen plasma (FFP).40 Albumin solutions have a lower probability of viral transmission and a decreased risk of citrate-induced hypocalcemia than FFP.41 According to the Circular of Information, FFP should not be used when other volume expanders can safely and adequately replace blood volume.42 Although albumin is a frequently used replacement fluid in TPE, cryopoor plasma or FFP are the preferred replacement fluids in thrombotic thrombocytopenic purpura (TTP) and related disorders.43 In TTP, a metalloprotease (ADAMTS-13) that usually cleaves von Willebrand factor (vWF) into multimers is rendered ineffective by antibody inhibitors or by mutations in the ADAMTS-13 gene.44–48 This results in the accumulation of ultralarge von Willebrand factor multimers, which interact with platelets, causing aggregation.45,47 Plasma exchange treats the disease by removing the metalloprotease inhibitor and the ultralarge von Willebrand factor multimers and by replacing functional ADAMTS-13 metalloprotease through FFP or cryopoor plasma. Cryopoor plasma contains fewer ultralarge von Willebrand factor multimers than FFP does and is, therefore, preferred by some.43 The use of FFP as the TPE replacement fluid may also be considered in patients undergoing treatment with angiotensin-converting enzyme (ACE) inhibitors. In such patients, plasma exchange with albumin is associated with atypical reactions such as flushing, hypotension, dyspnea, and bradycardia.49 Paracentesis Ascites associated with cirrhosis follows elevated portal pressure that results from increased intrahepatic vascular resistance, leading to increased nitric oxide levels and systemic arterial vasodilatation.50 In patients with ascites, the vasoconstrictor systems become activated in response and the kidney retains sodium, causing ascites and edema.50 Approximately 10% of patients with ascites are

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refractory to first-line treatment, which consists of a sodiumrestricted diet and high-dose diuretics.51 These patients’ treatment options include serial therapeutic paracenteses, transjugular intrahepatic portosystemic stent shunt (TIPS), peritoneovenous shunts, and liver transplantation.51 For cirrhotic patients with refractory ascites who require serial therapeutic paracenteses, controversy exists concerning whether volume expansion is useful and, if so, which expander is most effective. A study by Gines and colleagues found that paracentesis in cirrhotic patients with tense ascites without albumin infusion resulted in significant increases in blood urea nitrogen, plasma renin activity, and plasma aldosterone concentration, whereas patients who received postparacentesis albumin did not experience those changes.52 There were no significant differences in mortality between the groups. On the other hand, it has been shown that a single paracentesis of 4 to 6 L may be performed as a short-term option without albumin infusion in patients with tense, diuretic-resistant ascites.51,53 Thus, given the safety of paracentesis of smaller volumes, the guidelines released by the American Association for the Study of Liver Diseases (AASLD) in 1998 suggest that postparacentesis albumin infusion is unnecessary for removed volumes of less than 4 to 5 L but that an albumin infusion can be considered for larger volume paracenteses.51 Alternatives to serial paracentesis with albumin infusion have been studied, and none has clearly demonstrated a better patient outcome. Albumin infusion more effectively prevents hemodynamic deterioration than the infusion of other plasma expanders such as dextran 70 and polygeline after large-volume paracentesis.54 Results are conflicting when comparing treatment of cirrhotic patients with ascites refractory to diuretic treatment, with either TIPS or large-volume paracenteses followed by albumin, using survival without transplantation as outcome.55–57 Because no other treatment has demonstrated a superior patient outcome, the 1998 AASLD guideline advising that albumin infusion be considered for large-volume paracentesis still seems applicable.51

ALBUMIN

Table 21–3 Infusions

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Cirrhosis and Spontaneous Bacterial Peritonitis Albumin infusion may be beneficial for patients with cirrhosis and spontaneous bacterial peritonitis, as demonstrated in a study in which such patients received either antibiotics or antibiotics plus albumin infusion.58 The latter group had less renal impairment and a lower mortality rate. This clinical benefit may due to the thiol-related antioxidant effect of albumin.59 Nephrotic Syndrome The nephrotic syndrome is caused by increased permeability of the glomerular capillary basement membranes, resulting in a urine protein excretion rate of greater than 3.5 g/24 hr.60 Nephrotic syndrome is associated with hypoalbuminemia, edema, renal dysfunction, and hyperlipidemia. The standard treatment consists of corticosteroid and cytotoxic therapies to treat the underlying disease and diuretic therapy with a sodium-restricted diet to reduce peripheral edema and improve quality of life. A few patients may become refractory to these treatments. In such patients, investigators have attempted to increase diuresis by administering albumin in combination with furosemide with some success.61 In one

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study in which patients with hypoalbuminemia received either furosemide alone, albumin alone, or a mixture of the two, the latter regimen led to modest increases in sodium and volume excretion.62 In contrast, more recent studies in nephrotic patients with hypoalbuminemia found no benefit in combining albumin with furosemide.63,64 In fact, several detrimental effects have been linked to combined furosemide-albumin treatment, including response delays, frequent relapse to primary immunosuppressive therapy,65 hypertension, respiratory distress, and electrolyte abnormalities.66 Given the above limitations, combining 25% albumin with diuretic drugs is primarily indicated for patients with nephrotic syndrome refractory to standard diuretic therapy with a sodium-restricted diet. Accordingly, the University Hospital Consortium Guidelines for the Use of Albumin, No-Protein Colloid, and Crystalloid Solutions recommend the short-term use of albumin with diuretics only for such refractory patients with acute, severe peripheral, or pulmonary edema.67 Ovarian Hyperstimulation Syndrome

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Ovarian hyperstimulation syndrome (OHSS) is a complication of ovulation induction that occurs after the additional administration of human menopausal gonadotrophin (hMG) but rarely after the use of clomiphene citrate alone.68 The incidence of severe OHSS is estimated to occur in 0.5% to 5% of in vitro fertilization cycles.69 OHSS is graded as mild, moderate, or severe; in the last case, it can be fatal.70,71 The pathophysiology of the syndrome is not yet clearly defined, but it is thought that the ovaries secrete vasoactive substances when final follicular maturation occurs, causing increased capillary permeability.72 This results in the movement of protein-rich fluid out of the intravascular space, and patients can have vomiting, diarrhea, large ovarian cysts, thromboembolism, ascites, hydrothorax, hemoconcentration, oliguria, and anasarca. Although the panelists involved in making the 2000 UHC guidelines concluded that there was not enough information on the pathophysiology of OHSS to recommend the use of albumin to prevent it, a recent meta-analysis demonstrated that albumin administration was effective in the prevention of severe OHSS.73 The meta-analysis of five randomized controlled trials compared the use of human albumin with placebo or no treatment on patient outcome. The albumin dose ranged from 10 to 50 g and was given at 2 hours before, 1 hour before, or just after oocyte retrieval. Albumin infusion was estimated to prevent one case of severe OHSS for every 18 women at risk. As an alternative treatment to albumin infusion, some clinicians have attempted to prevent OHSS by withholding gonadotropins (so-called coasting). A retrospective study comparing intravenous albumin and coasting found that the latter was as effective as albumin in preventing OHSS in high-risk patients but that pregnancy rates were lower.74 Although prophylactic albumin infusion has been shown to prevent severe OHSS, it is unknown whether therapeutic albumin infusion for women with an established diagnosis of severe OHSS is effective. Resuscitation and Volume Expansion in Critically Ill Patients In the past, albumin was given for volume expansion in critically ill patients because it was assumed to be more effective than crystalloids at increasing plasma volume while minimizing interstitial volume expansion. However, Fleck

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and colleagues demonstrated that the rate of albumin loss from the vasculature to the tissue spaces was markedly increased in critically ill patients, such as those with cachectic cancer or septic shock and those who had undergone cardiac surgery,75 suggesting that albumin administration may not be beneficial in these patient populations. Albumin infusion may also have detrimental effects and can cause renal dysfunction, decreased sodium clearance, and increased free water clearance in patients with hypovolemic shock.76 It has been suggested that albumin inhibits platelet aggregation and enhances antithrombin III activity.77,78 In the late 1990s, a meta-analysis of 30 randomized controlled trials compared the use of albumin versus crystalloids or no albumin and found that when albumin was used to treat patients with hypovolemia, burns, or hypoalbuminemia the risk of death was 6% higher than in patients not treated with albumin.33 The results prompted the FDA to issue a letter to health care providers on August 19, 1998, urging discretion in the use of albumin in the critically ill population.79 Subsequently, a review of 17 studies found no difference in the incidence of pulmonary edema, length of hospital stay, and mortality in adult patients receiving crystalloids compared to those receiving albumin.80 A metaanalysis of 55 trials conducted by Wilkes and Navickis81 also did not show a significant difference in the mortality rate when albumin was administered versus crystalloids, no albumin, or lower doses of albumin. The patient populations studied included high-risk neonates, burn patients, patients with ascites, patients with hypoalbuminemia, and trauma patients, among others. The more recent Saline versus Albumin Fluid Evaluation (SAFE) trial82 supported the conclusion of the Choi review and the Wilkes and Navickis meta-analysis.80,81 The SAFE-trial randomly assigned 6997 ICU patients to receive either 4% albumin or saline for fluid resuscitation and found no significant differences in outcome in the number of days of mechanical ventilation, number of days in the ICU, length of the hospital stay, or in mortality rate at 28 days. The study included subgroups of patients with trauma, severe sepsis, and acute respiratory distress syndrome (ARDS); however, the study had insufficient power to draw conclusions regarding albumin use in these populations.82 These studies prompted the FDA’s Blood Products Advisory Committee (BPAC) to release an information sheet on May 16, 2005, indicating that the SAFE study resolved previous safety concerns and urging further studies on the use of albumin in burn patients and in patients with traumatic brain injury and septic shock.83 An updated meta-analysis from the Cochrane Injuries Group concludes that that there is no evidence that albumin reduces mortality to a greater extent than much less expensive and equally safe options such as crystalloids in the overall critically ill patient population.84 Table 21–2 lists subsets of critically ill patients (e.g., burn patients, patients in hemorrhagic or nonhemorrhagic shock, patients in particular postoperative situations, etc.) who may benefit from albumin administration according to UHC guidelines. In these situations, albumin is typically used when other treatments are ineffective.

POTENTIAL ADVERSE REACTIONS The incidence of adverse reactions to albumin infusions is approximately 1 in 6600 infusions, with only 1 in 30,000

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INFECTIOUS POTENTIAL Because plasma derivatives are made from pooled plasma from thousands of donors, reduction of infectious disease transmission is an important issue in plasma processing. The process of cold ethanol fractionation significantly reduces the concentration of viruses in plasma fractions. The pasteurization process also limits the transmission of infectious agents by denaturing viral proteins and nucleic acids, inactivating the viruses.87–90 When plasma is deliberately spiked with viruses, the manufacturing process for the production of 25% albumin results in a global viral reduction (log10) of ≥17.8 for HIV; ≥16.3 for bovine viral diarrhea virus (BVDV), which is a model virus for HCV; and ≥16.4 for pseudorabies virus (PRV), which is a model virus for HBV.91 The process results in a global viral reduction (log10) of 14.9 for reovirus, which is a small, nonenveloped virus; 7.8 for hepatitis A virus (HAV); and 6.8 for porcine parvovirus (PPV), which is a model virus for parvovirus B19.91 There has never been a report of HIV or hepatitis C transmission through albumin infusion. One hepatitis B outbreak was reported in relation to PPF infusion in 1976,92 but it probably resulted from a lack of uniform heating of the bulk product during the pasteurization process. Since 1977, the FDA has required that the heating step take place after the product is placed in individual containers.1 Since that time, there have been no other reports of hepatitis B transmission through albumin products. Since albumin is acellular, cell-associated viruses such as CMV and Epstein-Barr virus are eliminated from the final product. Cold ethanol fractionation and pasteurization reduces but does not eliminate the risk of bacterial contamination of albumin products. An outbreak of Pseudomonas bacteremia occurred in seven patients who had received albumin from the same lot in 1973. When 190 albumin vials from the suspected lot were cultured, one vial grew Pseudomonas cepacia. A subsequent experiment showed that, in addition

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to P. cepacia, Escherichia coli, Bacillus subtilis, Candida albicans, and Staphylococcus epidermidis also are able to grow in 25% albumin. In the experiment, P. cepacia remained viable in sealed vials of albumin kept at room temperature for 17 months after inoculation.93 Although albumin solutions can support the growth of many types of bacteria, bacterial contamination of albumin products is rarely reported in the literature.

ALBUMIN

infusions being life threatening.39 Most adverse reactions to albumin are mild and are either allergic in nature or are related to albumin’s function as a volume expander. Some of the mild reactions that can occur include nausea, vomiting, increased salivation, chills, and febrile reactions.85 Owing to albumin’s role in increasing colloidal osmotic pressure and intravascular volume, rapid infusion can result in circulatory overload, pulmonary edema, and decreases in hematocrit and hemoglobin. Albumin, with its high negative charge, binds calcium and can also cause complications related to hypocalcemia.86 In addition, because albumin contains aluminum in trace amounts, large doses can cause aluminum to accumulate in patients with chronic renal failure and lead to hypercalcemia, vitamin D–refractory osteodystrophy, anemia, and severe progressive encephalopathy.8 PPF preparations can cause allergic reactions and reactions related to intravascular volume expansion as well. PPF differs from other albumin-containing solutions because it includes a larger percentage of proteins other than albumin. PPF has been associated with hypocoagulability, which could be due to the platelet factor-4 and β-thromboglobulin present in the preparations. Owing to a higher concentration of contaminating proteins such as PKA, PPF causes more hypotensive episodes than albumin does and has been associated with metabolic acidosis in patients with renal dysfunction.21

CONCLUSION The development of therapeutic albumin formulations was critical for soldiers in need of volume support during World War II. Over the decades following that war, albumin was used in a wide variety of settings despite the relative lack of published evidence supporting its use in those situations. This led to the establishment of guidelines in 1975 that recommended more conservative use of albumin.4 Since that time, studies have compared albumin with alternative fluids for volume expansion. When crystalloid administration was compared with albumin use in several clinical situations, no significant difference was demonstrated in terms of patient outcome.80–82 Thus, usage guidelines for albumin have become even more conservative. Since albumin is more expensive than crystalloids and is a plasma derivative with related risks, crystalloids currently serve as first-line therapy for plasma expansion in most cases. The exceptions are those clinical scenarios in which albumin has demonstrated a significant clinical benefit over crystalloids, including large-scale therapeutic plasma exchange. At present, albumin is a valuable second-line treatment in many patients with conditions refractory to other plasma expanders. 21

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