Issue Date: Veterinary Technician

December 2005
(Vol 26, No 12)

The Role of Albumin and Fluids in the

Body

KEY POINTS

• Albumin helps the body maintain

intravascular colloid osmotic pressure,
neutralize toxins, and transport therapeutic
agents.
• Albumin synthesis occurs exclusively in
the liver and depends on adequate nutrition and nitrogen intake.
• Albumin replacement may be indicated in carefully chosen critical care patients as part of
fluid replacement therapy.

Albumin, the main protein produced in the liver, has numerous functions in the body, the most
important of which is maintaining intravascular colloid osmotic pressure (COP).1 COP helps fluid
stay within the vasculature instead of leaking into tissue. Leakage of albumin or serum albumin
levels less than 1.5 g/dl can worsen edema and effusion and increase oxygen debt.

WHAT IS ALBUMIN?
Albumin is one of the most important proteins in the body because of its role in maintenance of
COP, substrate transport, buffering capacity, free radical scavenging, coagulation, and wound
healing.2 It consists of a single amino acid chain with 17 disulfide bonds in repeating double-loop
domains that are highly flexible.2 Albumin molecules, which are highly soluble in water, carry
many charged amino acid residues, resulting in a net charge of â€"17 at a normal physiologic
pH.3 This creates a strong attraction of sodium ions and other cations around its core structure.
Water is also pulled into the vasculature as a result of the sodium attraction to albumin. Each
gram of albumin is capable of holding 18 ml of water within the intravascular space; this explains
why albumin alone contributes to approximately 80% of plasma COP.2 During times of stress,
acute loss, or decreased synthesis of albumin, there is a rapid equilibration of extravascular and
intravascular albumin to maintain COP.4

HOW IT IS SYNTHESIZED
Endogenous albumin is produced exclusively by liver cells (hepatocytes) at a rate of 9 to 12
g/day.4 Albumin is transported from hepatocytes by transcytosis. Some hepatocytes have direct
access to blood flow in the liver.5 This allows immediate influence on COP.

Osmoreceptors within the hepatic interstitial matrix can sense changes in COP in the hepatic
vascular beds.4 Hepatic vascular capillaries have a bigger pore size than other vascular
structures, rendering them more permeable to large molecules (e.g., albumin).2 The vascular
endothelium of nonhepatic vascular capillaries has a capillary pore size of approximately 6 to 7
nanometers in width. This width is slightly smaller than that of an albumin molecule. Under normal
conditions, this favors albumin retention in the intravascular space. Albumin is responsible for
approximately 80% of the intravascular COP.4 Capillary hydrostatic pressure is influenced by
mean arterial blood pressure and vascular compliance. Hypoalbuminemia decreases hepatic
interstitial oncotic pressure, thereby stimulating albumin synthesis. Hepatocytes can also be
stimulated by cortisol, thyroxine, and sex and growth hormones.2

Although the liver functions at only one-third total capacity to produce albumin, albumin synthesis
represents about 50% of the total energy expenditure of the liver.4 Production is regulated by the
body’s needs. The rate of production is influenced by changes in COP and osmolality of the
extravascular liver space. Synthesis is increased by insulin, thyroxine, and cortisol.4 Potassium
levels, exposure to toxins, or exposing hepatocytes to supranormal COP can hinder albumin
production. As long as 10% to 15% of the liver is functioning normally and no excessive losses
are present, movement of albumin from the interstitial pool keeps albumin synthesis and plasma
albumin concentrations normal.

Adequate supplies of nutrients and nitrogen are essential to fuel albumin synthesis.2 Inadequate
intake of amino acids available for protein synthesis and/or inadequate nutrient absorption by the
intestinal lumen as a result of disease can depress the liver’s ability to synthesize albumin. In
states of metabolic stress, albumin synthesis becomes a low priority. Fasting for as little as 18 to
24 hours can cause a 50% decrease in albumin production.4 Malnutrition decreases synthesis,
increases redistribution of body fluid (ascites), and decreases albumin degradation. During
starvation, albumin is spared as a catabolic protein source and muscle protein is used. Therefore,
the body maintains serum albumin levels at the expense of muscle protein. The caloric needs of
critical patients must be met to avoid secondary decreases in albumin production. This is often
difficult to achieve in the hospital setting. Many patients are anorexic because of their condition,
the unfamiliar environment, and unfamiliar individuals handling them. If the gastrointestinal (GI)
tract is functioning, enteral nutrition may provide an option for nutritional support.5

Intravascular concentrations of albumin are maintained during times of loss by the movement of
interstitial albumin into the lymphatic circulation and then the cranial vena cava, as a means to
maintain the pressure gradient between the intravascular and interstitial spaces.2 When shock
occurs, an influx of interstitial fluid into the capillary beds causes hemodilution and subsequent
dilution of proteins. Interstitial dehydration caused by this shift of fluid must be corrected.

In states of acute hypoalbuminemia, the pressure gradient favors the interstitium.2 It is the COP
gradient rather than the absolute plasma value of albumin concentration that distinguishes
hypoalbuminemia derived from redistribution from that of pure full-body loss. When excess fluid is
pulled into the interstitial space, the lymphatic system becomes overwhelmed, rendering it unable
to effectively clear away excess albumin, which in turn causes edema.4 Hemodilution, such as
that which would occur with large volumes of nonâ€"albumin-containing fluids, causes an overall
dilution of all plasma proteins, hindering their ability to bind and transport toxic substances,
hormones, and medications.4
When therapy is instituted to correct albumin deficits, it is important to remember that the
interstitial stores of albumin are replenished before intravascular concentrations increase.2
Chronic hypoalbuminemia elicited by conditions such as end-state hepatic disease or protein-
losing nephropathy is more difficult to correct by infusion of plasma albumin.2 The intravascular
albumin is quickly lost into sequestered fluid or urine or moved to the interstitium. COP is not
greatly influenced in patients that are normoalbuminemic or have increased vascular permeability
because most of the albumin in the body is found extravascularly. Plasma albumin deficits
represent less than half of the total body deficit.2 Exogenous sources of albumin include fresh-
frozen plasma, whole blood, and albumin replacement solutions.

Hyperadrenocorticism and hyperthyroidism do not result in elevated albumin concentrations

because of an increased rate of albumin degradation and loss. In normal patients, the rate of
albumin degradation is about 4%/day.

ITS PHYSIOLOGIC ACTIVITY

Albumin has many important physiologic roles.4 It supports COP, participates in intermediary drug
metabolism, and is vital for healing. Toxic materials in the body may be detoxified and inactivated
through albumin binding. Albumin also has antioxidant properties. For example, it neutralizes
unused hypochlorite, a byproduct of metabolism that would otherwise be converted to hydroxyl
radicals.

Normal levels of plasma albumin range from 2.7 to 3.9 g/dl.6 The author found that a sample of
fresh-frozen plasma yielded an albumin level of 2.4 g/dl, with a total protein level of 4.5 g/dl
(reference range, 5.2 to 8.2 g/dl) and globulin level of 2.0 g/dl (reference range, 2.5 to 4.5 g/dl).

Approximately 30% to 40% of total body albumin is concentrated in plasma.7 The other 60% to
70% is found in the intracellular and interstitial spaces of the skin, muscle, liver, lung, heart,
kidneys, and spleen. Interstitial albumin is continuously returned to systemic circulation by
lymphatic drainage into the cranial vena cava. Approximately 10% of interstitial albumin remains
tissue bound and unavailable for mobilization.4 Glomerular loss of albumin in nephrotic syndrome
has been thought to cause increased platelet aggregation and thrombosis because of an increase
in circulating levels of arachidonic acid available for metabolism to prostaglandins. Prolonged
hyperglycemia or uncontrolled diabetes mellitus is thought to cause platelet aggregation through
a similar scenario. Albumin has a heparin-like activity by enhancing antithrombin III activity. With
this in mind, it is easy to surmise that states of hypoalbuminemia, nephrotic syndrome, and
uncontrolled diabetes can lead to coagulopathy.

The albumin content in lung interstitial tissue contains about 70% of the albumin in plasma.2
Under normal conditions, the pulmonary lymphatic system clears albumin and fluid rapidly from
the interstitial tissues. When blood becomes hypoosmotic as a result of hypoproteinemia, a
transient increase in lung lymphatic flow decreases the amount of albumin in the lung interstitial
tissue, quickly counterbalancing the change. This shift promotes reequilibration of the osmotic
gradient. Conversely, an increase in serum COP increases the osmotic gradient in the serum so
that cell free fluid drifts from the interstitial tissues into the intravascular space, promoting a drier
lung in patients in shock. If signs of shock are not addressed and fluid dynamics restored,
maldistribution of extracellular fluid accompanied by plasma volume deficiency can predispose
the patient to pulmonary edema and acute respiratory distress syndrome (ARDS).4 ARDS is a
condition that develops as a result of lung inflammation. Leaking capillaries and pulmonary
edema severely injure the lung, leading to respiratory failure. Lymphoid function can become
overwhelmed by increased transcapillary escape or fluid flux from edema and/or ascites. This
volume increase into the lymphatic circulation can cause complications in patients with
congestive heart failure.

Stress response causes marked decreases in synthesis of plasma proteins. Initial decreases in
albumin are associated with increases in acute-phase proteins. Albumin and transferrins
decrease the stress response and are referred to as negative acute phase proteins.4 Once this
has occurred, hepatocytes are stimulated to synthesize proteins.

ITS FUNCTION IN THE BODY

Albumin serves many functions in the body. It is a major component in maintaining COP, platelet
function, and normal coagulation and is a free radical scavenger in inflammation. It is an
important carrier of drugs, fatty acids, divalent cations (e.g., calcium, zinc), hormones, and
bilirubin.4

As a transport vehicle for drugs and metabolites, albumin has binding sites for acidic, basic, and
neutral substances. Albumin binding and transport of bilirubin, drugs, and long-chain fatty acid
anions are clinically important functions in critical care patients.4 In fact, in healthy patients,
almost 100% of bilirubin binds to albumin and is carried to the liver for conjugation and excretion.2
As long as it is bound, bilirubin is not toxic. In states of hypoalbuminemia, more bilirubin is free or
unbound, which can create bilirubin toxicity. Bilirubin actively competes with many drugs for the
same binding site on albumin.4 In states of hyperbilirubinemia, there is the additional threat of
toxicosis from excess unbound drug circulating in the body. Drugs that are known to compete
with bilirubin for binding sites are NSAIDs, such as aspirin and phenylbutazone, and warfarin.
NSAIDs are generally more than 90% protein bound.2 Even slight displacement of the drug can
cause toxic concentrations to accumulate in circulation.
Substances that depend on albumin for binding and transport can be divided into endogenous
and exogenous categories. Endogenous substances include bilirubin, divalent cations, fatty acids,
free radical species, fat-soluble vitamins, and hormones.2 Exogenous substances are drugs that
are introduced. Several classes of drugs are dependent on albumin:

• Antibiotics (e.g., cephalosporins, penicillins, sulfonamides, tetracycline).

• Anticoagulants (e.g., warfarin)
• Antiinflammatory drugs (e.g., ibuprofen, phenylbutazone, salicylic acid)
• Anticonvulsants (e.g., phenobarbital, diazepam, phenytoin)
• Cardiovascular and renal drugs (e.g., digitoxin, furosemide, hydralazine, propranolol,
quinidine)
• Central nervous system drugs (e.g., amitriptyline, chlorpromazine, thiopental)
• Hypoglycemic agents (e.g., glipizide)
• Radiocontrast media

In states of hypoalbuminemia, the pharmacodynamics of substrate transport are altered.2 This

may cause ineffective drug therapy in ICU patients. Drug distribution to the peripheral organs
should be expected to increase as the management of a critical patient progresses and
physiologic responses to shock are medically resolved. Adverse drug reactions can occur in
states of hypoalbuminemia or through displacement of the drug from albumin. In these cases, it is
important to consider decreasing the dose of the drug to be administered to avoid increased
concentrations of the unbound form and subsequent toxicity. Because protein binding is
reversible, the drug with the highest affinity for protein (i.e., albumin) displaces a drug with less
affinity for protein binding.8 Most drug interactions associated with protein binding involve
competition for albumin binding sites because the albumin molecule is the most common binding
protein, particularly for weak acids.

Free fatty acids can bind to several sites on the albumin molecule, which renders them nontoxic
as well. Lipemia and hyperlipidemia are common in patients with decreased albumin
concentration. Increased concentrations of free fatty acids in circulation may injure the pulmonary
endothelium; this has been thought to be a contributing factor in ARDS.

Albumin has the capacity to bind toxic substances generated during inflammation.2 The release of
free radical species and lipid peroxidation during inflammation is thought to be a major cause of
tissue damage. These free radical species are released as a result of oxygen deprivation injury to
tissues. This important function of albumin is carried out at the expense of the albumin molecule
and has been referred to as the sacrificial antioxidant.2 Small quantities are used to scavenge
free radicals as well as bacterial toxins that end up destroying the molecule. Denaturing of
albumin at the site of inflammation can occur through changes in temperature and pH. When
albumin is destroyed, amino acids are released that can be used for tissue repair. The
extravasation of plasma albumin during the inflammatory phase provides carrier transport to and
from the site. This fosters the healing process by delivering amino acids, fatty acids, zinc, and
drugs to the site to promote healing and scavenging of toxic byproducts. Albumin effectively acts
as a pH buffer and mediates coagulation in the healing process.
Albumin is necessary for the proper integrity, function, and healing of the GI tract. It stabilizes
the endothelium and assists in maintaining capillary permeability to macromolecules.
INDICATIONS FOR ALBUMIN REPLACEMENT
Hypoalbuminemia often occurs in patients in intensive care as a result of their injury or illness and
contributes to the development of life-threatening complications, including pulmonary edema,
delayed wound healing, hypercoagulability, and multiorgan dysfunction.2

Any disease that causes systemic inflammatory response syndrome or vasculitis may also cause
protein losses.4 Conditions that compromise the vascular integrity may contribute to the depletion
 of intravascular albumin through leaking
capillaries. In states of vascular
compromise compounded by
hypovolemia, it is thought that an
abnormal elongation of the capillary
pores allows passage of albumin and
globulin, causing abnormal fluid shifts.2

GI compromise, whether from surgical

intervention or a disease process, can
create complications in absorption of
nutrients and cause delayed healing of
the gut postoperatively. Albumin loss
through the mucosal surface of the gut
can be significant.2 This loss can cause
a localized decrease in GI COP, possibly
resulting in decreased absorption of
nutrients, possible GI stasis, bacterial
translocation, and impaired overall GI
function. Pathology associated with the
GI tract has been shown to be reversed
once plasma protein stores are
replenished. Albumin replacement is
thought to improve bowel function and
healing.

When treating veterinary critical care

patients, it is necessary to understand
the role that albumin plays in the body,
the importance of administering the
appropriate fluids, and when albumin
replacement may be beneficial.

FLUID AND ALBUMIN

REPLACEMENT THERAPIES
Fluid therapy is usually initiated in patients that are in acute or chronic critical condition.4
Replacement fluids may or may not contain albumin. Before selecting an appropriate fluid
replacement, several factors should be taken into consideration. Disease states, such as
dehydration, hemorrhage, effusion, sequestration, and alterations in membrane permeability, can
alter COP and fluid distribution throughout the body.6 It should be determined whether fluid is
needed in the intravascular, interstitial, or intracellular space; changes in quantity of fluids or
electrolytes in one of these compartments usually results in changes to the other compartments
through diffusion.4 Diffusion occurs when solutions or substances move from an area of higher
concentration to one of lower concentration to achieve equilibrium.

Crystalloids
Crystalloids are often the primary agents used for fluid replacement therapy.3 Crystalloid solutions
contain electrolyte and nonelectrolyte substances that are capable of passing through cell
membranes and entering body fluid compartments. These isotonic solutions have the same salt
concentrations as those found in normal cells of the body and blood. An overdose of crystalloids
can result in overhydration, restlessness, shivering, serous nasal and/or ocular discharge,
coughing, or pulmonary, cerebral, or peripheral edema. Crystalloids also dilute plasma proteins,
thereby reducing COP, which allows for fluid movement into the interstitial space from the
intravascular space.2 The decrease of intravascular COP contributes to decreased distention of
vessel walls and can result in increased pore size, which can cause increased permeability and
eventual fluid shifts into the interstitium.2 Increased permeability and the altered osmotic gradient
 allow lung tissue to pull water from the hypoproteinemic serum,
causing pulmonary edema. Conversely, inadequate fluid
resuscitation during hemorrhage or intravascular fluid loss can
impair tissue perfusion.2 Cellular dysfunction may occur as a
result of vasoconstriction and oxygen and nutrient deprivation.

It is imperative to repeatedly assess crystalloid administration for

therapeutic advantages and disadvantages. The patient’s
maintenance needs and ongoing losses determine the fluid
volume that should be administered. Interstitial fluid overload
can cause life-threatening complications, such as respiratory
failure and cerebral dysfunction. If crystalloid therapy is not
successful, colloids may be used or added to the regimen.

Colloids
Colloid solutions contain large molecular weight particles (>30,000 daltons) that are unable to
cross pores in biological membranes and, therefore, are confined to the intravascular space.4
These particles are effective in holding fluid in the intravascular space and drawing fluid from the
interstitial space into the intravascular space to expand plasma volume. Albumin in plasma is the
body’s natural colloid.

The osmotic pressure created by colloids creates a “pull� to fluid-deprived areas in the
body. Sodium and glucose provide the greatest pull on water molecules. Increased intravascular
COP is vital to fluid resuscitation and cardiovascular stabilization because it restores intravascular
volume. Smaller volumes of colloidal fluids are required for resuscitation, and they can quickly
correct hypovolemia by creating intravascular pull.

Colloids have an advantage over crystalloids because of their intravascular persistence and
decreased risk of edema formation. Some disadvantages noted with colloid therapy are cost, risk
of anaphylaxis (when natural colloids are used), fluid overload, and coagulopathy caused by
direct interference with platelet interactions (i.e., factor VIII; von Willebrand’s factor). Colloids
can interfere with the strength of fibrin clots and the rate of fibrin degradation. They can also
dilute the effects of clotting factors and platelets. Colloid therapy is not intended for maintenance
or long-term use.

Using colloids can diminish synthesis of albumin in the liver because of the binding of colloids on
hepatocyte osmoreceptors. If the patient is not edematous or volume depleted, the colloid dose
may need to be decreased so the liver is more stimulated to synthesize albumin. When adding a
colloid to ongoing crystalloid therapy, the crystalloid constant-rate infusion should be adjusted to
half of the normal rate.2 The benefits of using colloids along with crystalloids are that they require
a smaller volume of the crystalloid solution to be administered to achieve volume resuscitation.
Colloids should be considered during the initial resuscitation period or when total protein is less
than 3.5 g/dl or albumin is less than 1.5 g/dl. The COP is compromised with decreased total
protein and albumin concentrations in plasma.

Blood and Blood Products

Whole blood, packed red blood cells, and Oxyglobin are the only solutions that can restore
oxygen-carrying ability. Fresh whole blood and fresh-frozen plasma have the benefit of replacing
clotting factors. A liter of plasma (or 2 L of whole blood) contains 30 g of albumin. Approximately
22.5 ml/kg of plasma are required to raise albumin levels 0.5 g/dl.2 Whole blood is a complete
physiologic volume expander that is limited by its poor shelf life, fluctuations in availability, risk of
allergic reactions, and high cost. However, in some patients, this is the most effective choice.
 COP can be affected by the patient’s nutritional
status, which directly influences albumin synthesis.
Albumin negative acute-phase protein synthesis
becomes downregulated during a catabolic state.
Critical care patients should be given enteral or
parenteral nutritional support when possible. Giving
plasma or whole blood as a protein source is not a
very effective way of providing nutritional support
because large volumes are required to raise the
intravascular protein concentration.2 These
therapies are also expensive. The approximate cost
of 1 U of whole blood is $181.00, and 1 U of fresh-
frozen plasma costs approximately $110.00.

Human Serum Albumin

In recent years, there has been much discussion about the use of human serum albumin (HSA)
as an albumin replacement in dogs.2,3 HSA is a concentrated albumin solution derived from
human blood donations. Like other blood products, it is expensive; a 100-ml vial of HSA costs
approximately $105.00. However, HSA may prove to be a new colloid option for canine patients.
In theory, albumin replacement is more advantageous than administration of other colloid fluids
because albumin exerts a greater osmotic pressure than can be explained by its size, weight, or
concentration in plasma.

Conclusion
COP maintains intravascular fluid volumes vital to effective circulation of blood and oxygenation
of tissues. Albumin levels in the body essentially dictate the rate and volume of fluid shift, thereby
ensuring that intravascular volume is adequate and perfusion is optimal. In critical care patients
with decreased intravascular COP and albumin deficits as the result of hypovolemia or fluid
redistribution, albumin replacement may be useful as part of fluid therapy.

References
1. Raffe M: Medical use of colloids, in Bonagura JD (ed): Kirk’s Current Veterinary
Therapy: Small Animal Practice XIII. Philadelphia, WB Saunders, 2000, pp 66â€"69.
2. Mazzaferro EM, Rudloff E, Kirby R: The role of albumin replacement in the critically ill
veterinary patient. J Vet Emerg Crit Care 12(2):113â€"124, 2002.
3. Martin L: Human albumin solutions in the critical patient. IVECCS Proc:274â€"278, 2004.
4. Wingfield WE: Fluid and electrolyte therapy, in Wingfield WE, Raffe MR (eds): The
Veterinary ICU Book. Jackson, WY, Teton New Media, 2002, pp 166â€"188.
5. Caceci T, Virginia Maryland Regional College of Veterinary Medicine: VM8054 Veterinary
Histology Example: Hepatocytes. Accessed October 2005 at:
http://education.vetmed.vt.edu/Curriculum/VM8054/Labs/Lab20/Examples/exhepcyt.htm.
6. Battaglia A: Small Animal Emergency and Critical Care: A Manual for the Veterinary
Technician. Philadelphia, WB Saunders, 2001.
7. Product information: Vet Test 8008 operator manual: Reference ranges for an adult canine.
Westbrook, ME, Idexx Laboratories.
8. Tilley LP, Smith Jr FWK: The 5-Minute Veterinary Consult: Canine and Feline, ed 3.
Philadelphia, Lippincott, Williams & Wilkins, 2003.

*A companion article begins here.