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Home Veterinary Practice Issues The Role of Albumin and Fluids in the Body

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VETERINARY PRACTICE ISSUES

DECEMBER 2005 (VOL 26, NO 12)

The Role of Albumin and Fluids in the Body

BY DANA CALL , RVT , VTS , (ECC)

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JUMP TO: Key Points

What is Albumin? Albumin helps the body maintain intravascular colloid osmotic pressure, neutralize toxins, and transport therapeutic
agents.
How it is Synthe-
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.
Its Physiologic Ac-

Albumin, the main protein produced in the liver, has numerous functions in the body, the most important of which is maintaining
Its Function in the
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.
Indications for Al-
bumin Replacement
What is Albumin?
Fluid and Albumin
Replacement Ther-
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
Conclusion
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 -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.

4
Osmoreceptors within the hepatic interstitial matrix can sense changes
in COP hepatic vascular beds.4 Hepatic
in the
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 non-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.

*A companion article begins here.

REFERENCE:

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 66-69.

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):113-
124, 2002.

3. MARTIN L: HUMAN ALBUMIN SOLUTIONS IN THE CRITICAL PATIENT. IVECCS PROC:274-278, 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 166-188.

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.

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