Fluid, Electrolyte, and Acid-Base Balance

Gary P. Carlson

Department of Medicine and Epidemiology
School of Veterinary Medicine
University of California, Davis
Davis, California

Michael Bruss

Department of Anatomy, Physiology, and Cell Biology
School of Veterinary Medicine
University of California, Davis
Davis, California

II. PHYSIOLOGY OF FLUID AND ELECTROLYTE BALANCE

A variety of units have been used in the quantitative evaluation of biological specimens. To avoid confusion, this chapter describes the units of measure that apply directly to the body fluids and electrolytes. An international standard for clinical chemistry units, the “Systeme Internationale d’Unites” (SI units), was developed to provide consistent terminology and usage. Although SI units are the international standard, they may not be familiar to all students or clinicians. All solute concentrations are expressed in moles or millimoles per l, blood gas partial pressure in kilopascals, and osmolality in millikelvins of freezing point depression.

Electrolytes are substances that exist as positive or negative charged particles in aqueous solution. The positively charged particles are “cations,” and the negatively charged particles are “anions.” For univalent ions such as sodium, potassium, chloride, and bicarbonate, 1 mole equals 1 equivalent. For multivalent ions, 1 equivalent is equal to the molecular weight in grams (i.e., 1 mole) divided by the charge on the particle. To maintain electrical neutrality in biological fluids, there must be an equal number of equivalents or milliequivalents of anions and cations in solution. Electrolytes in solution combine equivalent for equivalent, not on a gram for gram or mole for mole basis.

The osmotic properties of a solute in solution are related to the number of particles in solution and not to its weight or its charge. One osmole of a nondissociable substance is equal to its molecular weight in grams. One osmole of any substance that dissociates in solution into two or more particles is equal to the molecular weight in grams divided by the number of particles into which each molecule dissociates. Osmolarity is defined as the number of osmoles per l of final solution, whereas osmolality is the number of osmoles per kilogram of water. Although the expressions are similar, osmolality more correctly describes the osmotic properties as measured in the clinical laboratory.

FIGURE 17-1 Body fluid compartments in a normal 450-kg horse. Serum sodium concentration is 140 mEq/l (140 mmol/l). Extracellular fluid (ECF) volume is 1001 and intracellular fluid (ICF) volume is 2001.

Because most cell membranes are very permeable to water, there are no major osmotic gradients between the ECF and the ICF, and serum sodium concentration and osmolality reflect the osmolality of the ICF compartment as well as that of the ECF compartment (Edelman et al., 1958; Saxton and Seldin, 1986; Scribner, 1969).

B. Extracellular Fluid Volume

C. Intracellular Fluid Volume

The ICF volume represents the fluid content within the body’s cells. This volume cannot be measured directly but is calculated as the difference between the measured TBW and the measured ECF volume. Potassium provides the osmotic skeleton for the ICF in much the same way that sodium provides the osmotic skeleton for the ECF. Because water is freely diffusible into and out of the cell, changes in the tonicity of the ECF are rapidly reflected by similar changes in ICF tonicity (Saxton and Seldin, 1986). This is largely the result of the movement of water across the cell membrane with resultant changes of ICF volume. Thus, whereas plasma sodium concentration decreases in response to water retention, ICF volume increases (Humes, 1986). On the other hand, with water depletion resulting in hypernatremia, ICF volume decreases (Humes, 1986). Relatively little is known about the organization of intracellular water into the various subcellular compartments and organelles.

IV. REGULATION OF BODY FLUIDS AND ELECTROLYTES

A. Effective Circulating Volume

The effective circulating volume refers to that part of the ECF that is within the vascular space and is effectively perfusing the tissues (Rose, 1984). Effective circulating volume tends to vary with ECF volume, and both parameters vary with the total body sodium stores (Rose, 1984). Sodium loading produces volume expansion, whereas sodium depletion leads to volume depletion.

Effective circulating volume is not a quantitatively measurable entity but refers to the rate of perfusion of the capillary circulation. Effective circulating volume is maintained by varying vascular resistance, cardiac output, as well as renal sodium and water excretion (Rose, 1984). Decreases in effective circulating volume result in decreased venous return, decreased cardiac output, and decreased blood pressure. Decreased volume and pressure are recognized by special volume receptors in the cardiopulmonary circulation and kidney, which trigger increased sympathetic tone resulting in increased arterial and venous constriction as well as increased cardiac contractility and heart rate. These responses tend to correct for the volume deficit by increasing cardiac output and systemic blood pressure. Volume and pressure changes associated with decreases in effective circulating volume also result in activation of the renin-angiotensin system with subsequent enhancement of aldosterone secretion by the adrenal cortex (Brobst, 1984). Aldosterone acts to enhance renal sodium resorption, which is a critical factor for maintaining and eventually restoring effective circulating volume. Additional factors that influence sodium resorption in response to changes in fluid volume include alterations in glomerular filtration rate, renal hemodynamics, atrial natriuretic factor, and plasma sodium concentration.

B. Antidiuretic Hormone

C. Renin-Angiotensin

The renin-angiotensin system plays an important role in the maintenance of effective circulating fluid volume. Renin is a proteolytic enzyme produced by special juxtaglomerular cells of the glomerular afferent arteriole. Renin is released in response to reduced renal perfusion produced by hypotension, volume depletion, or increased sympathetic activity. Renin converts the circulating globulin angiotensinogen to angiotensin I, which is subsequently converted by an enzyme in the lung and vascular endothelial cells to the biologically active form, angiotensin II. Angiotensin II exerts a variety of systemic effects that tend to correct hypovolemia and hypotension. Angiotensin II increases renal retention of sodium and water by enhancing secretion of aldosterone from the adrenal cortex as well as having direct effects on the renal tubule. Angiotensin II exerts hemodynamic effects, which tend to increase blood pressure by inducing arteriolar vasoconstriction.

D. Aldosterone

Aldosterone plays a central role in the maintenance of effective circulating fluid volume and potassium balance largely through its effects on renal resorption of sodium in exchange for potassium and hydrogen ion. Aldosterone is produced in the adrenal cortex and exerts its effects on sensitive cells, such as the renal collecting tubules, by interacting with specific cytoplasmic receptors. The aldosterone receptor complexes subsequently enhance RNA-mediated production of specific proteins, which actually mediate the physiological effects of the hormone. There is evidence for aldosterone-mediated effects on gastrointestinal sodium and potassium absorption as well as effects on sweat glands to alter the electrolyte composition of sweat in response to sodium depletion (Michell, 1974). Aldosterone secretion is enhanced by the renin-angiotensin system in response to changes in effective circulating fluid volume.

E. Atrial Natriuretic Factor

Atrial natriuretic factor (ANF), also known as atrial natriuretic peptide (ANP), exists as a group of diverse peptide hormones produced in the heart and released into the circulation in response to processes that increase central venous pressure and thereby stretch the atrial wall (Inagami, 1994). The actions of ANF that tend to reduce cardiac output and systemic blood pressure are mediated by transmembrane receptors, which result in the production of cyclic guanidine monophosphate generated by guanylyl cyclase (Inagami, 1994). ANF results in natriuresis and diuresis by the kidneys. ANF also causes vasodilatation and reduces fluid volume by acting directly on vascular smooth muscle and inhibiting the release of aldosterone from the adrenal cortex and norepinephrine from peripheral adrenergic neurons. Additionally, ANF has been found in the brain, and centrally medicated effects on fluid volume regulation may be important. Elevated plasma ANF has been noted in humans with a variety of diseases ranging from congestive heart failure to obstructive lung disease to chronic renal failure. However, the physiological importance of ANF in these disease processes is not completely resolved. In humans, Bartter’s syndrome and Gordon’s syndrome are thought to be due to an excess or deficiency of ANF, respectively (Christensen, 1993). In horses, the elevation of plasma ANF has been associated with treadmill exercise (McKeever et al., 1991).

V. PHYSIOLOGY OF ACID-BASE BALANCE

The hydrogen ion concentration of the ECF is maintained within remarkably narrow limits and is normally approximately 40 nmol/l. This concentration is roughly one-millionth the concentration of other common electrolytes. Even at these extremely low concentrations, hydrogen ions have profound effects on metabolic events largely through interaction with cellular proteins. These interactions alter protein configuration and thus alter protein function. Most enzymatic reactions have a narrowly defined range of pH optimum, and changes in hydrogen ion concentration have direct effects on the rates of reaction and, thus, many basic biological processes.

A. Definition of pH

Although the hydrogen ion concentration can be expressed in nmol/l a more useful expression is that of pH. The pH of a solution is equal to the negative logarithm of the hydrogen ion concentration.

It is important to remember that the pH varies inversely with hydrogen ion concentration. When hydrogen concentration in the blood increases, pH decreases, and the animal develops an acidosis. When the hydrogen ion concentration in the blood decreases, the pH rises, and the animal develops an alkalosis. The traditional view of acid-base balance involves the following:

1. Extracellular and intracellular buffering

2. Regulation of the rate of alveolar ventilation to control carbon dioxide concentration

3. Regulation of renal hydrogen excretion

B. Buffers

where K_a is the dissociation constant for the reaction. The equation can be rewritten

Taking the negative logarithm of both sides of the equation yields

Substituting pH for –log [H⁺], log [A^–]/[HA] for –log [HA]/[A^–] and defining pK_a as –log K_a, the formula now reads

This formula is the familiar Henderson-Hasselbalch equation for the dissociation of a weak acid. The buffering capacity of the body includes the extracellular buffers, intracellular buffers, and bone. The extracellular buffers include the bicarbonate (HCO₃/H₂CO₃) and phosphate (HPO₄/) buffer pairs as well as the plasma proteins. The intracellular buffers include protein; organic and inorganic phosphates; and in the red cell, hemoglobin. Cation exchange involving the intracellular movement of hydrogen ion in exchange for potassium and (to a much lesser extent) sodium is an additional and important means whereby cellular mechanisms buffer an acid load. The carbonate in bone provides a large and often overlooked buffer store. Although difficult to accurately measure, it has been estimated that bone carbonate may contribute up to 40% of the buffering capacity of an acute acid load. It is important to remember that a change in hydrogen ion concentration will affect all the body’s buffer pairs. Thus, evaluation of any one buffer pair reflects the changes that occur in all of the buffer pairs.

1. Bicarbonate/Carbonic Acid Buffer System

Large amounts of carbon dioxide are produced by oxidative metabolism each day. Although carbon dioxide is not an acid, it combines with water as it is added to the bloodstream resulting in the formation of carbonic acid. The enzyme carbonic anhydrase in red blood cells and other cells facilitates this reaction:

The ensuing elevation in the hydrogen concentration is minimized because most of the excess H⁺ ions combine with the intracellular buffers, particularly hemoglobin (Hb):

The bicarbonate generated by this reaction then leaves the erythrocyte and enters the extracellular fluid in exchange for extracellular chloride ion. The net effect is that CO₂ is primarily carried in the venous circulation as with little change in the extracellular pH. These processes are reversed in the alveoli. As HHb is oxygenated, H⁺ is released and combines with to form H₂CO₃, which dissociates to CO₂ and H₂O. Carbon dioxide then is excreted by alveolar ventilation.

From a clinical and physiological standpoint, the bicarbonate-carbonic acid buffer pair is clearly the most important. Bicarbonate is present in relatively high concentrations, it is relatively easy to measure, and it is the buffer system over which the body has the greatest control. The Henderson-Hasselbalch equation applied to this buffer pair becomes

where 6.1 = pK_a for the /H₂CO₃ buffer pair.

Plasma pH is determined by the concentration of bicarbonate and carbonic acid or, more importantly, the ratio between bicarbonate and carbonic acid. An equilibrium exists between the partial pressure of CO₂ in the alveolar air, the partial pressure of gaseous CO₂ dissolved in the blood, and the carbonic acid concentration of the blood. The conventional method of evaluating carbonic acid is the determination of the partial pressure of carbon dioxide (pCO₂) in the blood. The carbonic acid concentration can be calculated by multiplying pCO₂ by 0.03 (0.03 is the solubility constant for carbon dioxide in plasma). The Henderson-Hasselbalch equation for this buffer pair then becomes

Blood samples drawn for acid-base evaluation must be drawn anaerobically and sealed so as to avoid alteration in the blood gas tension. Heparin is the anticoagulant of choice. The rectal temperature of the patient should be taken so that appropriate temperature corrections can be made. For evaluation of blood gases during intense exercise, central blood temperature should be used for this correction because rectal temperature may not accurately reflect blood temperature under these non-steady-state conditions. The temperature correction usually has a greater impact on the pO₂ and pCO₂ than bicarbonate or base balance. Arterial blood samples are generally preferred and are essential for the evaluation of primary respiratory disorders or the patient’s status under general anesthesia. Venous blood samples provide reliable data on metabolic acid-base abnormalities, and because they are easier to obtain, they are routinely used. Acid-base parameters of venous blood are significantly influenced by the acid-base status of the tissues from which the blood is draining. Central veins (e.g., vena cava) provide blood that better reflects the acid-base status of the body as a whole. As a general rule, blood gas determination should be made as soon after collection as possible. However, appropriately collected blood samples can be held in ice water for as long as 4 h and still yield reliable results.

The effects of various sampling sites (arterial, venous, and capillary blood) on blood gas determination have been evaluated in dogs (Ilkiw et al., 1991; van Sluijs et al., 1983), horses (Littlejohn and Mitchell, 1969; Speirs, 1980), and swine (Hannon et al., 1990). Consistent differences were demonstrated between arterial and venous blood. Arterial blood samples yield higher values for pH and lower values for pCO₂ and bicarbonate than venous blood, but calculated base balances tend to be similar for both arterial and venous blood samples. In horses, venous-arterial differences in bicarbonate can exceed 10 mEq/l during intense exercise. The higher venous bicarbonate reflects the important role of bicarbonate as a means of CO₂ transport in the venous circulation (Carlson, 1995). At rest and during exercise, more than 70% of the CO₂ produced in the tissues is transported in the venous circulation to the lungs as bicarbonate. This process is greatly facilitated by erythrocyte carbonic anhydrase and the mechanism of the “chloride shift.” The effects of temperature on oxygen content of dog blood have been studied (Hedley-Whyte and Laver, 1964), as has the oxygen affinity and Bohr coefficient of dog blood (Reeves et al., 1982). Recumbency in neonatal patients and body position during general anesthesia may have a significant impact on both arterial and mixed venous blood gas data (Madigan et al., 1992; Mason et al., 1987; Steffey et al., 1977). Nomograms have been developed relating the effects of temperature, CO₂ content, and hemoglobin saturation for dog blood (Rossing and Cain, 1966). The use of blood gas data for the evaluation of acid-base imbalances for clinical problems has been reviewed (DiBartola, 1992a, 1992b, 1992c; George, 1994; de Morais, 1992a, 1992b).

C. Acidosis

1. Metabolic

Metabolic acidosis is characterized by a decrease in pH and bicarbonate. Metabolic acidosis, as traditionally viewed, can be produced by the addition of hydrogen ions or a loss of bicarbonate ions. The initial buffering of an acid load is by the ECF buffers, primarily the bicarbonate-carbonic acid buffer pair (Rose, 1984). Intracellular buffers, particularly protein and phosphate, assist in the buffering process. The intracellular movement of hydrogen in exchange for potassium helps to prevent an excessive increase of the ECF hydrogen ion concentration in the face of an acid load. This exchange is called the “cation shift” and can result in hyperkalemia even though the total body potassium stores have been depleted due to renal or gastrointestinal losses.

a Causes of Metabolic Acidosis

b. Compensation

A metabolic acidosis is recognized quickly, and the compensating respiratory response of increased ventilation will begin reduction of the pCO₂ within minutes. In dogs, the anticipated respiratory response is a reduction of pCO₂ by 0.7 mmHg for each mEq/l decrease in bicarbonate (de Morais, 1992a, 1992b). This minimizes the fall in pH, but the protective effects of the respiratory response are relatively short lived, lasting only a few days. Long-term correction of a metabolic acidosis requires renal bicarbonate retention and enhanced renal acid excretion, primarily as ammonium ion because there is little ability to increase the titratable acidity, which consists primarily of phosphate buffers (Rose, 1984). Complete correction of a metabolic acidosis may be difficult in patients with intrinsic renal disease or diseases that would impair the kidney’s ability to excrete acid or retain bicarbonate such as renal tubular acidosis.

2. Respiratory

A respiratory acidosis is characterized by a decrease in pH and an increase in pCO₂. Respiratory acidosis develops because of decreased effective alveolar ventilation or breathing an atmosphere with elevated CO₂. The initial buffering of the acid load produced by a respiratory acidosis is almost exclusively by the intracellular buffers. The principal ECF buffer, the bicarbonate-carbonic acid buffer pair, cannot buffer a respiratory acidosis. Carbon dioxide diffuses through the lung much more readily than O₂; thus, diseases that compromise ventilation normally result in decreases in pO₂ before significant increases in pCO₂ develop. The respiratory center is extremely sensitive to minor changes in pCO₂, and increased pCO₂ normally provides the major stimulus to ventilation (Rose, 1984). In contrast, hypoxemia does not begin to promote enhanced ventilation until the arterial pO₂ is substantially decreased. If, however, the arterial pCO₂ is held at normal values or is elevated because of intrinsic lung disease, then ventilation begins to be enhanced as the arterial pO₂ falls below 70 to 80 mmHg (Rose, 1984).

a. Causes of Respiratory Acidosis

Any disorder that interferes with normal effective ventilation may produce a respiratory acidosis. The most common causes are primary pulmonary diseases ranging from acute upper respiratory obstruction, to pneumonia, to pneumothorax, and chronic obstructive lung disease. Diseases or drugs that affect the central nervous system may inhibit the medullary respiratory center and can produce a profound respiratory acidosis. An additional cause of special importance in veterinary medicine is general anesthesia with volatile agents using a closed system. Under these conditions, ventilation may be seriously reduced without producing hypoxia. The high oxygen content of the gas mixture maintains high pO₂ in the blood, but depression of the respiratory center may result in insufficient alveolar ventilation so that CO₂ accumulates. This problem can be overcome through the use of a positive pressure ventilatory apparatus and careful monitoring of arterial blood gases during general anesthesia.

b. Compensation

The compensating response for a respiratory acidosis is renal retention of bicarbonate and increased excretion of hydrogen ion. This response requires several days, and thus the response is seen only in a chronic respiratory acidosis. In dogs with chronic respiratory acidosis, a compensating increase of 0.35 mEq/l of bicarbonate is anticipated for each mmHg increase in pCO₂ (de Morais, 1992a, 1992b). The extent of the rise in the plasma bicarbonate concentration in chronic respiratory acidosis is determined by increased renal hydrogen secretion (Rose, 1984). Exogenous bicarbonate is unnecessary, and should bicarbonate be administered to patients with a respiratory acidosis, it would be excreted without affecting the final plasma bicarbonate concentration.

D. Alkalosis

1. Metabolic Alkalosis

a. Causes of Metabolic Alkalosis

The most common causes of increased hydrogen loss are gastrointestinal losses of chloride-rich fluids associated with vomiting in small animals (Strombeck, 1979) or sequestration of chloride-rich fluid in the abomasum and forestomach of ruminants (Gingerich and Murdick, 1975b; McGuirk and Butler, 1980). Excessive renal hydrogen loss associated with mineralocorticoid excess, diuretic usage (particularly the loop diuretics such as furosemide), and low chloride intake may cause or contribute to the generation of a metabolic alkalosis (Rose, 1984). Most of these disorders are also associated with the development of significant sodium and chloride deficits and resultant decreases in effective circulating volume. These deficits and the responses that decreased effective circulating volume induce are central features of the processes that maintain and perpetuate a metabolic alkalosis. Hydrogen loss from the ECF can also occur with hydrogen movement into the cells in response to potassium depletion (Irvine and Dow, 1968). Excessive bicarbonate administration is an additional potential cause of metabolic alkalosis. Most normal animals can tolerate large doses of bicarbonate, and excesses are rapidly eliminated by renal excretion (Rumbaugh et al., 1981). However, patients with decreases in effective circulating blood volume or with potassium or chloride deficits may not tolerate a bicarbonate load because renal clearance of excess bicarbonate is likely to be impaired.

The factors that are responsible for the maintenance of a metabolic alkalosis all impair renal bicarbonate excretion. These factors may include decreased glomerular filtration of bicarbonate seen in some types of renal failure. However, the most common factor is increased renal tubular bicarbonate resorption, which is associated with the renal response to decreases in the effective circulating fluid volume, potassium depletion, or chloride depletion (Rose, 1984). Sodium resorption is enhanced in response to hypovolemia to help restore normal effective circulating fluid volume. The maintenance of electroneutrality requires that sodium resorption in the proximal tubule must be accompanied by a resorbable anion such as chloride, whereas in the distal tubule, sodium resorption is associated with the secretion of a cation, usually hydrogen or, to a lesser extent, potassium. The only resorbable anion normally present in appreciable quantities in the proximal tubular fluid is chloride. In a metabolic alkalosis, plasma bicarbonate is increased and chloride concentration is generally decreased as the result of disproportionately high chloride losses that result from vomiting, sequestration of gastric fluid (Whitlock et al., 1975b), diuretic usage, or heavy sweat losses in exercising horses (Carlson, 1975, 1979b). The relative lack of the resorbable anion, chloride, in the proximal tubule thus allows a larger amount of sodium to reach the distal tubule where the action of aldosterone enhances hydrogen loss into the tubular lumen in exchange for sodium. The maintenance of effective circulating volume is so critical that the body chooses to maintain circulating volume by enhanced sodium resorption by whatever means necessary, even at the expense of extracellular pH. Renal hydrogen excretion is directly linked with bicarbonate resorption. Thus, it is not possible to eliminate the excess bicarbonate, and the metabolic alkalosis is maintained (Rose, 1984). This mechanism is the reason for the paradoxic acid urine seen in some patients with metabolic alkalosis (Gingerich and Murdick, 1975a, 1975b; McGuirk and Butler, 1980). Hypokalemia is another factor that contributes to the maintenance of a metabolic alkalosis. Hypokalemia is associated with an increase in intracellular hydrogen ion concentration. Increased renal tubular cell hydrogen ion concentration may enhance hydrogen secretion and thus bicarbonate reabsorption by the tubular cells.

b. Compensation

Chemoreceptors in the respiratory center sense the alkalosis, and the respiratory response to a metabolic alkalosis is hypoventilation resulting in an increase in pCO₂. In dogs, the expected compensating response is an increase of pCO₂ of 0.7 mmHg for each mEq/l increase in bicarbonate.

2. Respiratory Alkalosis

Respiratory alkalosis is associated with an increase in pH and a decrease in pCO₂.

a. Causes of Respiratory Alkalosis

Respiratory alkalosis is due to hyperventilation, which may be stimulated by hypoxemia associated with pulmonary disease, congestive heart failure, or severe anemia. Hyperventilation may also be associated with psychogenic disturbances or neurological disorders that stimulate the medullary respiratory center such as salicylate intoxication or Gram-negative sepsis. Respiratory alkalosis may be seen in animals in pain or under psychological stress. Hyperventilation may occur in dogs and other nonsweating animals as they employ respiratory evaporative processes for heat loss to prevent overheating (Tasker, 1980).

b. Compensation

E. Mixed Acid-Base Imbalances

Mixed acid-base disorders occur when several primary acid-base imbalances coexist (de Morais, 1992a). Metabolic acidosis and alkalosis can coexist and either or sometimes both of these metabolic abnormalities may occur with either respiratory acidosis or alkalosis (Nairns and Emmett, 1980; Wilson and Green, 1985). Evaluation of mixed acid-base abnormalities requires an understanding of the anion gap, the relationship between the change in serum sodium and chloride concentration, and the limits of compensation for the primary acid-base imbalances (Saxton and Seldin, 1986; Wilson and Green, 1985). Clinical findings and history are also necessary to define the factors that may contribute to the development of mixed acid-base disorders. The following are important considerations in evaluating possible mixed acid-base disorders:

1. Compensating responses to primary acid-base disturbances do not result in overcompensation.

2. With the possible exception of chronic respiratory acidosis, compensating responses for primary acid-base disturbances rarely correct pH to normal. In patients with acid-base imbalances, a normal pH indicates a mixed acid-base disturbance.

3. A change in pH in the opposite direction to that predicted for a known primary disorder indicates a mixed disturbance.

4. With primary acid-base disturbances, bicarbonate and pCO₂ always deviate in the same direction. If these parameters deviate in opposite directions, a mixed abnormality exists.

Although mixed acid-base abnormalities undoubtedly occur in animals and have been documented in the veterinary literature, they are often overlooked (Wilson and Green, 1985). An appreciation of the potential for the development of mixed abnormalities is essential for the correct interpretation of clinical and clinicopathological data, which would otherwise be quite confusing. Care should be taken when evaluating suspected mixed acid-base abnormalities that sufficient time has elapsed so that anticipated compensating responses could have occurred (de Morais, 1992a).

F. Anion Gap

The anion gap can be calculated as the difference between the major cation (sodium) and the measured anions (chloride + bicarbonate) (Emmett and Narins, 1977). Some investigators prefer to use the following formula:

This calculation provides only a crude guide to bicarbonate requirements, but it can be a useful step in the quantitative approach for correcting a serious primary metabolic acidosis.

I. Nontraditional or Strong Ion Approach to Acid-Base Balance

Peter Stewart (Stewart 1981, 1983) was the first to describe a quantitative physiochemical approach to acid-base balance. In this approach, the acid-base status of the aqueous solutions of the body is determined not only by the Henderson-Hasselbalch equation but also by a series of seven other relationships, all of which could be represented by equations which must be satisfied simultaneously. Acid-base balance is determined by three independent variables: (1) strong ion difference [SID], (2) the partial pressure of CO₂, and (3) the total concentration of nonvolatile weak acids [Atot], the principal component of which is the plasma proteins but also includes inorganic phosphate. Bicarbonate and hydrogen ion concentration, and thus pH, are dependent variables determined by the independent variables listed here. The appeal of Stewart’s approach is the focus on factors that are causally related to acid-base balance, the independent variables. The interested reader is referred to Stewart’s original work. A number of authors have attempted to adapt Stewart’s approach for practical application in human and veterinary medicine (de Morais, 1992b; Fencl and Leith, 1993; Fencl and Rossing, 1989; Frischmeyer and Moon 1994; Gilfix et al., 1993; Jones, 1990; Kowalchuk and Scheuermann, 1994; Whitehair et al., 1995). Many of these early papers directed to animal species used the human values for Atot and Ka, which may not be appropriate. Species-specific data are now available.

In a landmark paper, Peter Constable (1997) refined Stewart’s model and developed an approach that he called the simplified strong ion model of acid-base equilibrium. The simplified strong ion model was developed from the assumption that plasma ions act as strong ions, volatile buffer ions (), or nonvolatile buffer ions. Plasma pH is determined by five independent variables: pCO₂, strong ion difference, concentration of individual nonvolatile plasma buffers (albumin, globulin, and phosphate), ionic strength, and temperature. The simplified strong ion model conveys, on a fundamental level, the mechanism for change in acid-base status, explains many of the anomalies when the Henderson-Hasselbalch equation is applied to plasma, and is conceptually and algebraically simpler than Stewart’s strong ion model. The model has provided an in vitro method for determination of species-specific values for [Atot] and Ka, which has been applied to the plasma of horses, dogs, cattle, pigeons, and humans (Constable, 1997; Constable and [192]Stampfli, 2005; Stampfli et al., 1999, 2006; Stampfli and Constable, 2003).

Strong electrolytes are completely dissociated in aqueous solution and chemically nonreactive. The [SID] is simply the difference between the total concentration of strong cations (sodium, potassium, and magnesium) and the total concentration of strong anions (chloride, sulfate, lactate, acetoacetate, and 3-OH-hydroxybutyrate). Because they are present in higher concentrations in the body fluids, sodium, potassium, and chloride are normally the principal determinants of [SID]. The [SID] is synonymous with buffer base as described by Singer and Hastings (1948) and, as such, can be considered as roughly equivalent to the metabolic component of the traditional approach to acid-base balance. In fluids such as the CSF, which are normally devoid of protein, bicarbonate concentration is the same as the [SID]. Abnormalities in pCO₂ are viewed in essentially the same manner in both the traditional and nontraditional approach to acid-base balance as described earlier. The contribution of plasma proteins to acid-base balance is not considered in the traditional approach to acid-base balance. The plasma proteins, or, perhaps more correctly, plasma albumin, make up the majority of [Atot], whereas inorganic phosphate normally accounts for less than 5% of [Atot]. The [Atot] in body fluids exists in both dissociated [A^–] and undissociated [HA] forms. A decrease in [Atot] because of hypoalbuminemia causes an alkalosis with an increase in bicarbonate, whereas hyperalbuminemia has the opposite effect. Hypoalbuminemia is one of the most common causes of alkalosis in older human patients (McAuliffe et al., 1986). Changes in A^– associated with changes in albumin concentration also have a direct and frequently overlooked effect on anion gap. Increases in A^– result in an increase in anion gap, whereas decreases in A^– cause a decrease in anion gap (McAuliffe et al., 1986). Change in protein concentration may potentiate or ameliorate the effects of alterations in SID on acid-base balance. As an example, in a vomiting dog, the elevated plasma protein associated with dehydration may reduce the bicarbonate increase anticipated for a given change in chloride concentration and SID.

Protein and inorganic phosphate remain within the normal range in many clinical situations, and acid-base balance is then largely controlled by changes in pCO₂ mediated by the respiratory system, whereas changes in [SID] are largely under the control of the kidneys. Renal compensation for primary respiratory disorders and respiratory compensation for primary metabolic acid-base disturbances are thought to be similar in both the traditional and nontraditional approach. Precise quantification of the anticipated compensating responses to primary acid-base disturbances based on change in SID has not yet been determined.

Calculation of SID is simple and provides useful insight in patients with metabolic acid-base disturbances. Factors that influence SID range from changes in free water, to sodium-chloride imbalances that result from excessive losses or disproportionate retention of sodium or chloride, to the accumulation of strong organic anions. Organic acidosis can be produced by the accumulation of exogenous as well as endogenous organic anions. Examples of exogenous anions include salicylate, glycolate and formate associated with the ingestion of aspirin, ethylene glycol, and methanol, respectively. Many of these endogenous and exogenous organic anions are not routinely monitored in the diagnostic laboratory. This situation can create problems when calculating the SID because the presence of these unmeasured strong anions may not be appreciated. Although the anion gap can be helpful, it does not always accurately predict the presence of these compounds. More sophisticated mathematical methods have been suggested as a means for the detection of unmeasured anions the strong ion gap (Constable et al., 1998; Stewart, 1981) and, more recently, the simplified strong ion gap (Constable and [192]Stampfli, 2005). In animals with major changes in protein or albumin concentration, the primary concern must be a thorough investigation of the cause of the increase or decrease in protein. The acid-base consequences of change in protein and albumin concentration tend to be modest but are a potential source of confusion when evaluating acid-base data.

The traditional approach and the nontraditional or strong ion approach to acid-base balance each has its supporters, and discussion over the benefits and limitations of either approach has at times been strident. However, this need not be an either-or situation. Both approaches have proven useful to address practical problems in both research and medical settings. The traditional approach based on the Henderson-Hasselbalch equation is simpler, more user friendly, and more widely accepted. Bicarbonate concentration estimates the severity of the acid-base disorder, but the strong ion approach may provide a better understanding as to why the bicarbonate is changing because it integrates acid-base and electrolyte disorders (de Morais, 2005). The strong ion approach has been gaining acceptance from the critical care community, which finds it useful in the analysis of the complex fluid, electrolyte, and acid-base problems presented to intensive care units. A number of computer programs adaptable to hand-held electronic devices have been developed and take some of the mathematical fear out of using the strong ion approach.

J. Dietary Factors in Acid-Base Balance

Dietary factors, particularly the dietary cation-anion balance (DCAB), have been extensively studied in cattle, swine, poultry, and horses. The calculation of DCAB of a dry feed ration is remarkably similar to the calculation SID of body fluids. The DCAB in mEq is generally represented as (sodium + potassium) – (chloride + sulfate) per kg of dry matter of the diet. Diets with a high DCAB, such as alfalfa hay, have an alkalinizing effect and are an important factor in the alkaline urine of most herbivores. High grain rations tend to have a lower DCAB. Manipulation of the DCAB has been employed to enhance milk yield in dairy cattle, to reduce the incidence and severity of gastric ulceration in swine, to decrease the incidence of milk fever in cattle, and to alter the urine pH and calcium balance in horses. The addition of sodium bicarbonate to the ration of lactating dairy cattle to raise the DCAB from –100 to + 200 mEq/kg diet DM resulted in an increase of milk production of over 8%, which was due, in part, to more effective ruminal digestion (Block, 1984). On the other hand, supplementation of the diet of late-term cattle with calcium chloride or ammonium chloride so as to lower the DCAB and have an acidifying effect has been shown to reduce the incidence of milk fever by enhancing the mobilization of calcium from the bone (Block, 1984). As the application of these dietary practices becomes more widespread, it is essential that we appreciate the implications of dietary factors and electrolyte supplementation on mineral metabolism and acid-base balance (Fredeen et al., 1988).

VI. EVALUATION OF IMBALANCES

It is important to understand the difference between volume regulation and osmoregulation. Osmoregulation is governed by osmoreceptors influencing ADH and thirst, whereas volume disturbances are sensed by multiple volume receptors that activate effectors such as aldosterone. Antidiuretic hormone increases water resorption (and therefore urine osmolality), but it does not affect sodium transport directly. Aldosterone enhances sodium reabsorption but not directly that of water. Thus, osmoregulation is achieved by changes in water balance and volume regulation mostly by changes in sodium balance.

Water balance is achieved when water intake from all sources is equal to water output by all routes. Water is available as drinking water, as water content of feedstuffs, and as metabolic water derived by oxidative metabolism. Oxidation of 1g of fat, carbohydrate, or protein results in the production of 1.07, 0.06, or 0.41g of water, respectively. Water is normally lost from the body by four basic routes: urine, feces, insensible loss (respiratory and cutaneous evaporation), and sensible perspiration (sweat) in some animal species. Water intake and output may vary considerably from day to day, but normal animals are able to maintain water balance within remarkably narrow limits and, at the same time, maintain the critical interrelationship between water balance and electrolyte balance.

For human subjects, there are well-established normal values for water intake and output via various routes. Although there is a substantial amount of data on water balance for many domestic animals (English, 1966a; Fonnesbeck, 1968; Hinton, 1978; Kamal et al., 1972; Leitch and Thomson, 1944; Sufit et al., 1985; Tasker, 1967a; Yoshida et al., 1967), these data vary markedly from species to species and are valid only for the specific experimental conditions under which they were collected. Animals eat to meet their caloric requirements. The nursing or grazing animal may have a feed intake that is greater than 90% water as compared to animals on dry hay or dried prepared pet food, which may contain less than 10% water. Some desert rodents are so well adapted that they are able to maintain water balance without water intake and rely on the water content of feedstuffs and metabolic water derived from oxidative metabolism. The koala in its native state in Australia obtains virtually all its water from the leaves of specific species of eucalyptus trees, which constitute its entire diet. Dehydration because of water restriction with and without heat stress has been studied widely in a variety of animal species (Bianca et al., 1965; Brobst and Bayly, 1982; Carlson et al., 1979a; Elkinton and Taffel, 1942; Genetzky et al., 1987; Hix et al., 1953; Kamal et al., 1972; Rumbaugh et al., 1982; Rumsey and Bond, 1976; Schultze et al., 1972; Tasker, 1967b).

Quantitative assessment of the compartmental distribution of TBW between the ECF and the ICF has largely been based on the volume dilution of certain compounds or isotopic tracers. These studies require steady-state conditions and take a substantial period of time; as such, they are not well suited to the dynamic and often rapidly changing fluid balance characteristic of many clinical situations. Bioelectrical impedance analysis (BIA) may prove a useful tool in this regard. Bioelectrical impedance has been used for the assessment of body fat and fluid balance in humans and many animal species. Multifrequency bioelectrical impedance analysis has been successfully employed to monitor the rapid fluid changes in small animal patients undergoing dialysis. Algorithms for multifrequency BIA have been developed for use in the horse (Fielding et al., 2004).

A. Water

1. Depletion-Dehydration

FIGURE 17-2 Body fluid compartments in a 450-kg horse with a pure water loss of 301. Hypertonic fluid volume contraction is indicated by the increase in serum sodium concentration from 140 mEq/l (140 mmol/l) to 155 mEq/l (155 mmol/l). Fluid losses are shared by the extracellular fluid (ECF) volume and the intracellular fluid (ICF) volume.

FIGURE 17-3 Body fluid compartments in a 450-kg horse with an isotonic fluid loss of 301 of water, 3800 mEq (3800 mmol) sodium, and 400 mEq (400 mmol) potassium. Serum sodium remains unchanged at 140 mEq/l (140 mmol/l) despite the development of the substantial sodium deficit. Fluid losses are borne primarily by the extracellular fluid (ECF) volume.

FIGURE 17-4 Body fluid compartments in a 450-kg horse after administration and retention of 301 of water. Although no sodium or potassium losses have occurred, serum sodium concentration has declined from 140 mEq/l (140 mmol/l) to 127 mEq/l (127 mmol/l) reflecting a relative water excess. Water retention results in proportionate expansion of extracellular fluid (ECF) volume and intracellular fluid (ICF) volume.

2. Water Excess-Overhydration

1. Sodium Depletion

Sodium depletion is rarely the result of dietary sodium deficiency (Aitken, 1976). This is true even for herbivores whose feedstuffs are normally very low in sodium. Chronic sodium depletion has been reported in lactating dairy cows on a low salt diet (Whitlock et al., 1975a), but the sodium deficit was most probably the result of sodium losses in milk (Michell, 1985). Mastitis markedly enhances sodium loss in milk and could play a role in sodium depletion in lactating cows maintained on a low-salt diet (Michell, 1985). Sodium depletion almost invariably is associated with excessive losses of sodium-containing fluid (McKeown, 1986; Rose, 1984), most often occurring as the result of gastrointestinal losses through vomiting or diarrhea (Fisher and Martinez, 1976; Lakritz et al., 1992). Excessive renal sodium losses can occur with intrinsic renal disease or as the result of diuretic therapy (Rose, 1984; Rose and Carter, 1979; Rose et al., 1986). Cutaneous losses via sweating are important in the exercising horse and may occur in any animal with extensive exfoliative dermatitis or burns. Salivary losses as the result of esophagostomy have been reported as a cause of sodium depletion in horses (Stick et al., 1981). A history suggestive of excessive loss of sodium-containing fluid is thus an extremely important criterion for the diagnosis of sodium depletion in domestic animals. The foregoing discussion applies indirectly to the so-called third space problems associated with a sequestration or compartmentalization of a portion of the ECF volume (Rose, 1984). This situation can occur with obstructive bowel disease or with the sudden accumulation of fluid within the abdomen or thorax resulting from peritonitis, ruptured bladder, ascites, or pleural effusion. These fluids have an electrolyte composition similar to the ECF and initially are drawn from the plasma volume and interstitial fluids. The resultant change in plasma volume and effective circulating fluid volume produce the same clinical and clinicopathological changes as those observed with excessive external losses of sodium containing fluid (Billig and Jordan, 1969). In these cases, fluids have not been lost from the body, but there has been an internal sequestration of fluid which can be mobilized if treatment is effective.

2. Sodium Excess

Sodium excess occurs most often in association with an increase in body water leading to an isotonic expansion of ECF volume and the development of hypertension or generalized edema (Saxton and Seldin, 1986). Congestive heart failure, hypoalbuminemia, and hepatic fibrosis may lead to a failure to maintain effective circulating volume, which then, in turn, results in compensating renal sodium retention (Rose, 1984). In these cases, expanded ECF volume represents an attempt to restore effective circulating fluid volume, and, at least initially, plasma volume may decrease whereas ECF volume expands. An expansion of ECF volume of 20% to 30% may be necessary before edema is first evident (Scribner, 1969). Sodium excess and edema can develop iatrogenically as the result of the excessive administration of sodium-containing fluid to patients with severely compromised renal function.

Most domestic animals can tolerate a large sodium intake provided they have adequate drinking water (Aitken, 1976; Buck et al., 1976; Pierce, 1957). Excessive salt intake may occur when animals that had been on salt-restricted diets are first allowed free access to salt (Michell, 1985). Salt intoxication can occur in cattle that are feeding in reclaimed salt water marshes or on pastures contaminated by oil field wastes when they are deprived of fresh water (Aitken, 1976; McCoy and Edwards, 1979; Michell, 1985; Pierce, 1957; Sandals, 1978). Salt poisoning in swine also occurs in association with water restriction followed by access to water (Aitken, 1976; Buck et al., 1976). Salt intoxication is generally associated with increases in plasma or cerebrospinal fluid sodium concentrations. Neurological signs associated with excessive salt consumption coupled with water restriction are related to development of cortical edema and, in swine, a characteristic eosinophilic meningoencephalitis (Aitken, 1976).

C. Potassium

1. Potassium Depletion

Potassium depletion is the result of altered external balance in which potassium losses by all routes exceed intake. Potassium is present in relatively high concentrations in most animal feeds. Therefore, dietary deficiency alone is not a common cause for potassium depletion (Tasker, 1980). However, dietary factors were associated with hypokalemia in hospitalized cats, particularly when associated with diseases linked to increased potassium loss (Dow et al., 1987a). Herbivores, such as the horse, fed an all-hay diet may have a daily potassium intake of 3000 to 4000 mEq (3000 to 4000 mmol) per day (Hintz and Schryver, 1976; Tasker, 1967a). Most of this potassium is absorbed in the small intestine and colon with subsequent renal excretion of more than 90% of the daily potassium intake (Hintz and Schryver, 1976). These animals are thus highly adept at excretion of a large daily potassium intake. However, renal compensation for deficient potassium intake is not efficient, and renal conservation of potassium may be delayed for several days when animals normally fed a high-potassium diet are suddenly taken off feed or develop anorexia (Tasker, 1967b).

Potassium depletion most commonly develops as the result of gastrointestinal losses from vomiting or diarrhea. Excessive renal losses can occur as the result of diuretic usage, mineralocorticoid excess, renal tubular acidosis, and in the diuresis state that follows relief of urinary obstruction (Saxton and Seldin, 1986). Potassium depletion may result in decreased ICF volume, altered membrane potential, altered intracellular pH, and alterations of potassium-dependent enzymatically mediated reactions (Elkinton and Winkler, 1944). Clinical features include muscle weakness, ileus, cardiac arrhythmias, rhabdomyolysis, and renal dysfunction (Dow et al., 1987a, 1987b; Earley and Daugharty, 1969; Tannen, 1986).

2. Potassium Excess

Potassium excess occurs relatively rarely and is generally a consequence of some alteration of renal excretion of potassium. Potassium excess may be associated with Addison’s disease, some forms of renal disease, and clinical situations associated with hypovolemia and renal shutdown (Rose, 1984; Weldon et al., 1992). Care should be taken to avoid the rapid administration of large amounts of potassium salts orally or intravenously to patients with severely compromised renal function. Even normal animals can develop significant electrocardiographic abnormalities with potassium (Dhein and Wardrop, 1995; Epstein, 1984; Glazier et al., 1982) or calcium infusions (Glazier et al., 1979).

D. Chloride

Modest changes in hydration tend to produce roughly proportional changes in plasma sodium and chloride relative to sodium concentration. Acid-base alterations are associated with disproportionate changes in plasma chloride concentration (Saxton and Seldin, 1986). A disproportionate hyperchloremia is seen in association with a low to normal anion gap metabolic acidosis. Chloride concentration increases in this type of acidosis as the result of proportionately smaller losses of chloride than bicarbonate and enhanced renal chloride resorption in response to decreased bicarbonate (Saxton and Seldin, 1986). Disproportionate hypochloremia is a consistent feature of metabolic alkalosis (Rose, 1984). Chloride depletion develops in these animals as a result of excessive loss or sequestration of fluids with high chloride content. Changes in water balance can result in modest alterations in the relative concentrations of plasma sodium and chloride. A pure water deficit produces increased sodium concentration, which exceeds the increases in chloride. This contributes to the development of a contraction alkalosis with an increase in bicarbonate. A pure water excess has the opposite effect and can result in an expansion acidosis.

VII. CLINICAL FEATURES OF FLUID AND ELECTROLYTE BALANCE

Rational fluid therapy depends on accurate evaluation of the fluid and electrolyte deficits, the associated acid-base alterations, and the primary disease processes that underlie these imbalances. Evaluation must include an accurate history, a complete physical examination, and, of course, laboratory evaluation of appropriate parameters.

A. History

An accurate history is absolutely essential for the evaluation and management of the patient with fluid and electrolyte imbalances. Basic signalment factors of age, sex, breed, pregnancy, and stage of lactation are important because these factors influence the incidence and severity of many disorders. The presence of a preexisting or coexisting disease process and an accurate drug history can be exceedingly important not only in the evaluation of fluid and electrolyte disorders but also in fluid selection and patient management. Of particular importance is the history of prior renal disease, diuretic usage, or exposure to potentially nephrotoxic drugs. Status of feed and water intake is exceedingly useful. Most animals that continue to eat and drink normally are able to maintain fluid balance even in the face of excessive fluid losses. However, reduced or restricted fluid intake in the face of normal to enhanced fluid losses can quickly result in dehydration. Inadequate fluid intake may result from neurological disorders or traumatic injuries to the head or neck, whereas painful or obstructive lesions in the mouth, pharynx, or gastrointestinal tract may restrict feed and water intake. Inadequate water intake is often the result of management errors, broken or frozen water lines, and other factors. A history of polydipsia suggests that excessive fluid losses have occurred. Vomiting and diarrhea are obvious causes of fluid and electrolyte loss, but these findings also reflect gastrointestinal disorders, which may contribute to inadequate fluid and electrolyte intake or absorption.

Excessive fluid losses may be associated with vomiting, diarrhea, polyuria, excessive salivation, copious drainage from cutaneous wounds or burns, and as the result of heavy sweat losses in exercising horses. The water losses that occur in these situations are generally associated with significant sodium depletion and subsequent decreases in the effective circulating fluid volume. Vomiting in small animals (Clark, 1980), gastrointestinal stasis in ruminants (Gingerich and Murdick, 1975b), and excessive sweat losses in endurance horses (Carlson, 1983b) are associated with large losses or compartmentalization of chloride-rich fluids, which contribute to the metabolic alkalosis that frequently accompanies these disorders.

B. Clinical Signs

Dehydration is defined as a loss of body water. Clinical signs of dehydration are said to be first apparent with fluid losses equivalent to 4% to 6% of body weight. Moderate dehydration is said to be present with fluid losses of 8% to 10%, and severe dehydration is present when fluid losses exceed 12% of body weight. It is important to realize that although these guidelines have been clinically useful, there is relatively little documentation of this precise quantitative relationship in most animal species. Accurate measurement of fluid intake from all sources and output by all routes is not possible in most clinical situations. In acute situations, changes in body weight provide the most accurate guide to change in net water balance. Repeated measurement of body weight is a key component of the monitoring of patients on fluid therapy. The clinical signs of dehydration include weight loss, altered skin turgor, sunken eyes, and dry mucous membranes. If control of renal function is normal, urine volume is generally markedly reduced. The clinical consequences of dehydration depend much more on the pattern of electrolyte loss than the absolute water deficit.

Clinical signs associated with acute sodium deficits are largely related to hypovolemia and decreases in the effective circulating volume. These signs include increased pulse rate, decreased pulse pressure, delayed jugular distensibility, increased capillary refill time, and decreased blood pressure. Urine output is generally decreased and urine sodium and chloride concentrations are normally reduced. Decreases in ECF volume are always reflected by decreases in plasma volume, but the reverse is not always true. In the absence of blood or protein loss, the PCV and TPP concentrations increase, reflecting the decrease in plasma and ECF volume as will be discussed more fully in Section VIII.A.

VIII. CLINICOPATHOLOGICAL INDICATORS OF FLUID AND ELECTROLYTE IMBALANCE

A. Packed Cell Volume and Total Plasma Protein

If it is assumed that the quantity of plasma proteins within the plasma volume remains constant (this assumption is not always correct), it is possible to calculate the percentage change in plasma volume based on protein concentration (Boyd, 1981):

where PV indicates plasma volume, PP₁ indicates initial plasma protein concentration, and PP₂ indicates final plasma protein concentration. It is also possible to calculate the change in plasma volume based on the change in PCV provided it is assumed that the number of erythrocytes within the circulating blood volume and the mean corpuscular volume remain constant (Boyd, 1981):

FIGURE 17-5 Effects of decreasing plasma volume on PCV and plasma protein concentration as calculated using Eqs. 17–13 and 17–14.

In most clinical situations, the initial PCV and plasma protein concentration are not known, and to make these estimates, it must be assumed that these values were within the normal range before dehydration. A large disparity in the change in PCV and TPP concentrations in the face of a history of loss of sodium-containing fluid and clinical evidence of reduced effective circulating volume suggests either erythrocytes or protein has been lost from the circulation. Marked increases in PCV with normal to low plasma proteins are frequently encountered in animals with acute toxic enteritis because of losses of protein into the gastrointestinal tract (Merritt et al., 1977). This finding suggests erosive bowel disease but also could be seen in animals with low protein as a result of preexisting renal or hepatic disease. Increases in plasma protein with little or no change in PCV are seldom seen in dehydrated animals but could occur with a preexisting anemia or hyperproteinemia. Blood loss generally results in a decrease in both PCV and TPP concentration.

Sodium deficits result in decreases in ECF volume, which are usually reflected by changes in plasma volume (Hopper et al., 1944; Saxton and Seldin, 1986). As plasma volume decreases, the PCV and TPP concentrations increase. Changes in PCV and TPP are thus particularly useful in evaluating the need for and the response to sodium-containing replacement fluid (Carlson, 1983a). When sodium-containing fluids are administered to dehydrated volume-depleted subjects, plasma volume reexpansion is reflected by the return of PCV and TPP toward the normal range (Hayter et al., 1962). Declining PCV and TPP in response to fluid therapy are the two most useful laboratory indicators of return of effective circulating fluid volume and should be correlated with clinical evidence such as return of normal pulse pressure, capillary refill time, and jugular distensibility.