Continuing Education Activity

Albumin colloid plays a pivotal role in the intricate balance of blood plasma proteins, with albumin constituting approximately 50% of the total. Originating from the liver, albumin undergoes immediate secretion, devoid of storage, and its metabolism is intricately linked to synthesis, distribution across interstitial and intravascular compartments, and subsequent excretion. This activity discusses the physiological regulation of albumin, emphasizing the colloid osmotic pressure and nutritional status as primary determinants.

Participants explore the normal blood plasma concentration range of 3.5 to 5 g/dL, with 60% of total albumin in the interstitial space. Beyond its fundamental physiological roles, this activity sheds light on albumin colloid's significance as a pharmaceutical therapeutic intervention and as a biomarker for diagnosing a spectrum of medical conditions. Learners gain insights into the multifaceted applications of albumin colloid, extending beyond its primary role as a predominant blood protein.

Objectives:

• Identify the appropriate clinical indications for albumin colloid therapy based on patient assessment and medical history.

• Differentiate between albumin colloid and other intravenous fluid options, considering their composition, indications, and potential adverse effects.

• Screen patients for contraindications or conditions requiring special consideration before implementing albumin colloid therapy.

• Implement the monitoring and management of patients receiving albumin colloid therapy, ensuring appropriate follow-up and timely adjustments.

Indications

Albumin is the most abundant protein in the blood and accounts for about 50% of all plasma proteins; it is synthesized by the liver and secreted immediately without storage. The physiological regulators of albumin are the colloid osmotic pressure and nutritional status. The metabolism of albumin depends on the synthesis, distribution over the interstitium and intravascular compartment, and excretion. Normal blood plasma concentration is between 3.5 to 5 g/dL, and 60% of the total albumin is in the interstitial space.[1][2] The mean half-life is about 28 to 36 days.[3]

The chief medical uses are pharmacological therapy, as a serum marker to monitor diseases, biomaterials, and vaccines.

FDA-Approved Indications

Hypovolemia with or without shock: During fluid resuscitation in patients with hypovolemia, intravenous albumin is suggested as a second-line therapy if there is an inadequate response to crystalloids. In critically ill patients, the survival rate at 90 days showed no significant difference when treated with albumin or crystalloids as first-line therapy (RR 0.98; 95% CI, 0.92 to 1.04).[4] The albumin group had more free days of ventilation and vasopressor therapy than the crystalloid group (mean difference 1.10 and 1.04, respectively).[5] The recommended dosage is 500 mL of albumin 5% and repeats every 30 minutes if necessary.

Prevention of central volume depletion after paracentesis due to cirrhotic ascites: In a study by Runyon et al, albumin infusion has been shown to improve cardiovascular function after large-volume paracentesis (over 5 L) in patients with cirrhosis and tense ascites.[6] A meta-analysis by Bernardi et al reported an overall decrease in mortality (OR 0.64; 95% CI, 0.41 to 0.98).[7] Albumin also prevents hyponatremia and increases BUN, aldosterone, and renin.[8] The recommended dosage is 1 dose of albumin 25%, 5 to 10 g/L of ascites, for more than 5 L of fluid drained.[7] Albumin infusion lacks benefit when ascites drainage volume is less than 5 L. However, based on consensus, the International Ascites Club recommends using plasma expanders for less than 5 L fluid drained.[9][10]

Hypoalbuminemia: The mainstay of therapy is to treat the underlying cause. Data are insufficient to recommend albumin in hypoalbuminemia patients. In a few cases, albumin 25% can relieve symptoms due to hypoalbuminemia, but there is a high risk of fluid overload. One meta-analysis evaluated mortality as an outcome in hypoalbuminemia patients receiving albumin infusions. They concluded that there was no significant effect on mortality if hypoalbuminemia was corrected, with a relative risk of 1.59 (0.91 to 2.78).[11]

A clinical trial by Dubois et al evaluated the effect of albumin infusion on organ function in critically ill patients with hypoalbuminemia. They reported improved organ function and a higher caloric intake in those who received albumin versus placebo.[12] Supplementation of albumin to malnourished patients with hypoalbuminemia is not a recommended therapy.[13]

Ovarian hyperstimulation syndrome: This is a severe complication of assisted reproduction technologies, leading to increased vascular permeability and a shift of intravascular volume into the third space, which can cause thromboembolic events or ischemia. Albumin 25% is indicated as a plasma volume expansion in addition to crystalloids (Grade C recommendation). Studies have not shown strong evidence of its efficacy.[14] The dosage recommended is 15 to 20 mL/hr for 4 hours.[15] Albumin administration is not indicated to prevent ovarian hyperstimulation syndrome.[16]

Acute respiratory distress syndrome (ARDS): Albumin colloid is used with loop diuretics in ARDS treatment when pulmonary overload and hypoalbuminemia are present. A small clinical trial demonstrated improved oxygenation, total fluid balance, and hemodynamic function in patients who received albumin plus furosemide versus those with furosemide, resulting in reduced organ failure.[17] The recommended dosage is albumin 25 g plus furosemide over 30 minutes, repeated every 8 hours for up to 3 days. There is no improvement in the long-term outcome measurements of critically ill patients, such as mortality or ventilator-free days.[18]

Acute nephrosis: This recommendation is based on a review article from 1977. Albumin colloid is indicated to treat edema in patients with nephrotic syndrome refractory to cyclophosphamide and corticosteroids. Such cases may respond with loop diuretics and 100 mL of albumin 25% solution daily for 7 to 10 days.[19] More recent small clinical trials have shown a good resolution of edema with loop diuretics and albumin infusion vs diuretics alone in children with nephrotic syndrome. Despite low samples, there was a statistical difference.[20][21]

Hemolytic disease of the newborn: Albumin is indicated as an adjunct therapy to treat neonatal hyperbilirubinemia during exchange transfusions. The efficacy is believed to be due to its ability to bind unconjugated bilirubin. The recommended dose is 1 g/kg per dose of albumin 25% during the exchange transfusion.[22] A significant difference in the reduction of total bilirubin levels at 6 and 12 hours was seen in patients treated with albumin 1 hour before exchange transfusion versus those with only exchange transfusion (p <0.001).[23] The combined use of albumin with phototherapy is not indicated because it may cause detrimental effects.[24]

Burn hypovolemia: Historically, albumin infusion was recommended in conjunction with crystalloids 24 hours after thermal injury if burns had covered more than 50% of the body surface or crystalloid therapy had failed.[22] The current recommendation suggests it may be helpful in terms of decreasing fluid volume requirements. A recent meta-analysis showed that albumin solutions for acute resuscitation in burn-injured patients have no benefit on mortality (RR 1.6; 95% CI, 0.63 to 4.08), but the total volume used during resuscitation was less (RR -1; 95% CI, -1.42 to 0.48) compared to non-albumin solutions.[25]

Extensive hemodialysis: About 20% to 55% of patients on hemodialysis develop hypotension during their hemodialysis session. High rates or excessive volume ultrafiltration are the leading causes. Albumin 5% is used as second-line therapy when hypotension does not respond to crystalloids.[26] One study compared the use of albumin versus crystalloids in hypotension during hemodialysis. The results showed no significant differences in the primary and secondary outcomes, the achievement of the ultrafiltration volume target, and time to restore blood pressure or treatment failure, respectively.[27]

Cardiopulmonary bypass: Albumin is useful as a colloid for priming extracorporeal circuits and volume expansion in cardiopulmonary bypass. These recommendations have their basis in a study by Wilkes that showed a reduction of acute postoperative mediastinal hemorrhage after cardiopulmonary bypass in patients exposed to albumin solutions compared to another colloid.[28] Moreover, another study reported a favorable result in preserving platelet counts and maintaining the colloid osmotic pressure during cardiopulmonary bypass compared to crystalloids.[29]

Off-Label Uses

Spontaneous bacterial peritonitis (SBP): This is a significant cause of mortality in patients with cirrhosis. Administration of albumin 1.5 g/kg within 6 hours and 1 g/kg on day 3 and antibiotics have a better effect on preventing renal impairment and reducing mortality from 29% to 10% in cirrhotic patients with SBP compared to those receiving antibiotics only.[30] Another clinical trial confirmed the benefit of this therapy with laboratory, cardiac, and Doppler parameters. Improvement in portal vein flow volume (p = 0.01) and reduction of inflammatory marker TNF-α in ascites (p = 0.04) were reported.[31]

Preoperative nutrition status: Albumin as a marker of preoperative nutrition status and postoperative outcome in older general surgery patients. Serum albumin is the most used preoperative nutrition parameter. Low serum albumin was a significant preoperative predictor of postoperative complications and mortality. Low serum albumin predicted the prolonged length of stay in the hospital. Serum albumin can be a reliable predictor of postoperative outcomes in older general surgery patients. Whether serum albumin represents a good marker of nutrition status is questionable.

The consensus generally advocates against serum albumin being seen as a nutrition parameter but views it as a "marker of inflammatory metabolism." Serum albumin might be used to identify the sickest patients, who, as a consequence, are also at risk for nutrition deterioration. Weight loss in the previous 6 months might indicate postoperative outcomes, but the current evidence is not strong. Serum prealbumin is also utilized as a nutritional marker.[32][33]

Albumin dialysis (molecular adsorbent recirculating system, also called MARS): This has been used as an extracorporeal liver replacement device to treat acute liver failure secondary to toxin ingestion or trauma or as a bridge to transplantation for massive hepatic necrosis.[34]

The regular price of intravenous albumin solution is around $0.50 to $6 per mL. Compared to saline solutions ($0.01 to $0.10 per mL), albumin solutions are 60 times more expensive. Price takes priority when saline solutions and albumin infusions are equally effective in treating a disease.

Mechanism of Action

Albumin has the following 2 essential physiologic functions: 

• Contribute to colloid osmotic pressure
• Aid in the transportation, distribution, and metabolism of endogenous and exogenous molecules (fatty acids, thyroid hormones, metals, oxide nitric, peptides, and drugs)[2] 

The principal mechanism of action of albumin infusion is to increase the colloid osmotic pressure. Albumin drives the interstitial fluid into the intravascular compartment and increases the effective volume of the circulatory system.[3] For patients undergoing large-volume paracentesis, albumin helps prevent a further decrease in effective arterial blood volume.[35]

Administration

The only mode of albumin administration is by intravenous (IV) infusion. There are 2 formulations available that differ in albumin concentration: albumin 5% and 25%. In general terms, albumin 25% is the therapeutic choice when either sodium or fluid is restricted or in cases of oncotic deficiencies. Albumin 5% is more commonly used in situations of volume loss, such as dehydration. However, concentration, the rate of infusion, and dosage depend on the patient's clinical condition, as stated above. 

To prevent hemolysis, avoid diluting albumin (5%) with sterile water; use D5W or 0.9% NaCl for dilution. Albumin 25% can be administered either undiluted or diluted in 0.9% NaCl. According to the AASLD, large-volume paracentesis (LVP) is the first-line treatment for refractory ascites.

To reduce the risk of post-paracentesis circulatory dysfunction (PPCD), the recommendation is to administer albumin infusion when removing more than 5 L of fluid during LVP. The risk of PPCD may increase when removing more than 8 L in a single session. Guidelines suggest administering 6 to 8 grams of albumin/L of ascites removed for effective replacement.[35] The administration of albumin colloid should be guided by the patient's fluid status rather than achieving target albumin levels.[36]

Specific Patient Population

Hepatic impairment: In individuals with hepatic impairment, the recommended starting dose of albumin is 25%, 12 to 25 grams. The infusion rate should be adjusted to a flow of 1 to 2 mL/min.

Renal impairment: The maximum recommended initial dose of 25% albumin is 25 grams for patients undergoing dialysis. Monitor for signs of fluid overload.

Pregnancy considerations: The use of albumin colloid during pregnancy should be carefully considered, as there is limited available data. Consider risk-benefit evaluation.

Breastfeeding considerations: Insufficient clinical data exists regarding albumin colloid in breast milk and its effects on breastfeeding infants or milk production.

Pediatric patients: The use of albumin 5% in children, including premature infants, is based on limited data. Albumin should only be administered when necessary. According to the American Academy of Pediatrics, the clinical significance of albumin infusions in neonatal intensive care units (NICUs) for hypoalbuminemia is uncertain and requires further research.[37]

Older patients: There is insufficient data from clinical studies to determine whether individuals 65 and older respond differently to albumin 5% compared to younger subjects. The use of albumin 25% in this age group should be limited based on need.

Adverse Effects

Since albumin solution is a human-derived blood product, adverse effects are rare. According to the manufacturer's prescribing information, in less than 0.1% of those receiving the drug, anaphylactoid reactions, flushing, urticaria, fever, chills, nausea, vomiting, tachycardia, and hypotension can occur. These reactions typically disappear when the infusion rate is slowed or stopped. Edema and fluid overload are common adverse effects, depending on the volume, speed of the infusion, and the clinical scenario. In sporadic cases, anaphylactic shock may occur (from the pharmaceutical prescribing information).

Interactions and incompatibilities: Y site: Vancomycin, midazolam, fat emulsions [38][39]

Contraindications

The following contraindications have been reported for albumin colloid use:

• Hypersensitivity to any component in albumin preparations or excipients is a contraindication. Anaphylaxis to human albumin has been reported.[40][41]
• Contraindications include clinical situations with volume overloads, such as severe anemia, congestive heart failure, or renal insufficiency, at high risk of hemodynamic instability when treated with albumin solutions.
• Do not dilute any albumin solution with sterile water because it may cause hemolysis and acute kidney injury (AKI) in the recipient.[42] (Pregnancy Category C)

Warning and Precautions

Hypervolemia: Adjust the albumin dosage and infusion rate based on the patient's fluid status to prevent excessive fluid overload. Albumin use requires caution if there is a risk of hypervolemia and hemodilution.

Hypovolemia: The concentrated albumin (25%) has a colloid-osmotic effect about 5 times stronger than blood plasma. Therefore, when administrating 25% albumin, it is vital to ensure the patient is hydrated. If patients are severely dehydrated, additional fluids may be required. Exercise caution when using albumin in specific conditions that pose a risk of low blood volumes, such as decompensated heart failure, hypertension, esophageal varices, pulmonary edema, bleeding disorders, severe anemia, and impaired kidney function leading to reduced urine production.

Laboratory parameters: Twenty percent to 25% of human albumin solutions have lower electrolyte levels compared to 5% of solutions. When replacing large volumes of albumin, ensure proper substitution of other vital blood components, including coagulation factors, electrolytes, platelets, and red blood cells.

Albumin is generally considered a safe blood derivative in terms of infection transmission. There are theoretical concerns regarding the transmission of prions associated with diseases such as Creutzfeldt-Jakob disease.[43]

Monitoring

It is recommended to assess fluid overload, hemodilution, and electrolyte disturbances. This is preventable by monitoring blood pressure, heart rate, central venous pressure, pulmonary artery occlusion pressure, electrolytes, hemoglobin, and hematocrit.

Toxicity

Albumin solution is derived from a large pool of human plasma; it goes through a sterilization process, pasteurization, and heating but is not entirely sterile. However, the risk of infectious disease transmission through viruses is remote. The solution contains no preservatives. Once opened, it must be used immediately, and the unused portion must be discarded. Albumin formulations contain sodium to achieve isotonicity, which can lead to hypernatremia when administered for prolonged periods.[36]

Enhancing Healthcare Team Outcomes

Healthcare workers, including emergency department and ICU nurses, must understand the indications and contraindications of albumin and how to administer the drug. While the colloid is safe, it may rarely induce an anaphylactoid reaction. With larger doses, albumin infusions can cause fluid overload and electrolyte disturbances. Thus, the clinical team must understand how to manage this adverse reaction.

The clinician will decide to use albumin colloid, and the nursing staff will administer it in most cases. They can verify administration and dose with the pharmacy and understand the adverse reactions mentioned above to alert the managing clinician promptly. The pharmacist should also check the patient's administration record so the team can make dose adjustments for protein-bound drugs, if necessary. Pharmacists work with the ordering clinician to help select the appropriate concentration, typically 25% albumin, for patients with cirrhosis.[36] 

The collaborative approach of the interprofessional healthcare team, including physicians, mid-level practitioners, specialists, pharmacists, and nurses, is the most effective way to optimize patient outcomes when using albumin therapeutically.