Units of Measure

The units of measure commonly utilized in discussion of fluid balance are presented in Table 23.1. Ions or electrolytes combine according to valence (charge) rather than molecular weight. Hence in the case of univalent ions, 1 mM = 1 mEq. One mM of a divalent ion provides 2 mEq. By expressing most electrolyte concentrations in milliequivalents per liter (mEq/l), and comparing the concentration of cations to anions in the body, it becomes clear that electroneutrality exists. Although extracellular cations are often more completely documented in the course of clinical investigations, anions, particularly chloride and bicarbonate, are the electrical counterbalance. Some electrolytes are measured in millimoles per liter (mM/l) because they exist in variable states of protein binding or valence. An example is total calcium, because protein binding confounds any simple assessment of ionized fraction. Phosphorus exists in variable proportions of phosphate and monohydrogen and dihydrogen phosphate, so no valence can be assigned and calculation of milliequivalence is therefore inaccurate. Since mEq/l are the most common and informative unit of comparison for most electrolytes, conversion formulas are also provided in Table 23.1 .

Solutes exert an osmotic effect in solution that is dependent only on the number of particles in solution, not on molecular weight or valence. Hence for nondissociable substances, 1 osmole contains 1 mole of substance. If a substance dissociates in solution, the number of osmoles is increased according to the number of particles generated per mole of dissociated substance. For example, each mmol of a completely dissociated NaCl solution yields 2 mOsm. Osmolarity refers to the number of osmoles per liter, and osmolality indicates the number of osmoles per kilogram of solvent (Rose, 1989). In physiological systems the difference between these two is usually small. The concept of osmolality explains why solutions of diverse chemical and electrical composition (e.g., 5% dextrose, 0.9% NaCl, and 1.3% sodium bicarbonate) can all be considered isotonic. For mammals, isotonic solutions equal approximately 300 mOsm.

Body Fluid Compartments

Total body water (TBW) is approximated at 60% of body weight, but this figure varies from 50 to 75% depending upon age, lean body mass, and individual animal variations. Since fat is lower in water content than lean tissue, obesity is associated with decreased TBW (approximately 50%). To avoid overhydration of obese patients, fluid requirements are best estimated based on lean body mass. Very young animals are about 70–75% water, with TBW declining with advancing age. Table 23.2  provides estimates of selected volumes in dogs. TBW is broadly divided into two types: intracellular (ICF) and extracellular fluid (ECF). The ECF is further divided into four subcompartments: plasma volume, interstitial lymph fluid, transcellular fluid, and fluid present in dense connective tissue and bone. Table 23.3  provides experimentally derived blood volumes as percentages of body weight for various species.

Transcellular fluid is found in diverse locations, including cerebrospinal fluid, pleural cavity, gastrointestinal tract, bladder, synovia, aqueous humor, and peritoneal cavity. Transcellular volumes vary greatly from monogastrics (1–6%) to horses and ruminants (10–15%), dependent largely upon the amount of fluid sequestered in the gastrointestinal tract. Transcellular volumes are not readily mobilized during volume deficits but are of importance in terms of drug disposition and equilibrium. In certain disease processes, transcellular fluids may accumulate, causing ascites, hydropericardium, hydrothorax, synovitis, or other conditions, depending on the location of fluid accumulation.

Fluid and Electrolyte Distribution

Body solutes are not distributed homogeneously throughout TBW. Like drugs, every solute has a defined space or volume of distribution that can be assessed experimentally. As with estimation of body compartment volumes, determination of solute distribution is limited by the features of the labeled solute used. Because normal vascular endothelium is largely impermeable to formed blood elements and plasma protein, these cells and solutes are usually limited to the plasma. Vascular endothelium is freely permeable to ionic solutes, and the concentration of these ions is almost the same in interstitial as in plasma fluid. Table 23.4  provides estimations of ion composition in plasma of normal mammals.

The volume of ICF and ECF compartments is determined by the number of osmotically active particles in each space. ECF osmolality can be estimated from the following formula (Rose, 1989):

Because cell membranes are permeable to urea and K⁺, these substances contribute only ineffective osmoles, as described earlier. At normal blood glucose concentrations, Na⁺ is the primary determinant of effective ECF osmolality. Because Na⁺ is the most abundant and osmotically active ECF cation, maintenance of an extracellular-to-intracellular sodium gradient is critical and is accomplished by the cell membrane Na⁺,K⁺-adenosine triphosphatase (ATPase) pump. This pump is also responsible for maintaining appropriate concentrations of intracellular K⁺. Because K⁺ is the most abundant intracellular cation, the ratio of intracellular-to-extracellular K⁺ concentration is the major determinant of the resting cell membrane potential (−70 to −90 mV). Because all body fluid spaces are isotonic with one another, the effective osmolality of the ICF, and indeed TBW, must be equal to that of the ECF. Acute addition or loss of fluid and/or solutes from the body inevitably results in alterations in compartment volumes and tonicity. Homeostatic shifts of fluid between compartments must then occur to return the system to isotonicity.

The critical distribution of water between the plasma and the interstitium is maintained by the colloidal osmotic pressure of plasma protein (oncotic pressure). This is the force that draws water into the capillaries and balances the hydrostatic pressure driving water out. These so-called “Starling forces” describe the capillary balance between forces that favor filtration of water from plasma and those that retain vascular volume:

where K_f represents permeability of the capillary wall, P represents hydrostatic pressure in the capillaries (P_cap) (blood) or tissues (P_if) (interstitial fluid), and π represents oncotic pressure generated by plasma protein (π_p) or filtered proteins and glycosaminoglycans in the interstitium (π_if). Applying Starling’s relationships yields the prediction that hypoproteinemia (decreased π_p) will increase loss of vascular fluid and that water depletion (with a relative increase in π_p and a decrease in P_cap) will promote reabsorption of interstitial fluid into the vasculature (Kohn and DiBartola, 1992). The volume of intracellular water in a given tissue is maintained by intracellular protein. As plasma water decreases, plasma protein competes with intracellular protein for water, resulting in cellular dehydration. Clinical alterations in plasma osmolality may be assessed by comparing measured osmolality in a patient to calculated serum osmolality as determined using Na⁺, K⁺, glucose, and BUN measurements (see the ECF osmolality equation provided above). Observed changes in the osmolal gap (difference between measured osmolality and the osmolality calculated from normal concentrations) may be useful in determining the presence of unmeasured osmoles associated with toxic substances such as ethylene glycol. The osmolal gap may also be useful in assessing shifts in plasma sodium concentration (Kohn and DiBartola, 1992).

The number of cations in the ECF must equal the number of anions in order to maintain electroneutrality. In practice, only selected cations and anions are routinely measured in a clinical setting. Calculation of the difference between the commonly measured cations and anions in ECF yields the unmeasured anions, or anion gap (Oh and Carrol, 1977; Emmett and Narins, 1977). The anion gap calculation can be useful in assessing the etiology of metabolic acidosis and will be discussed in this context subsequently.

Homeostasis

Normal water intake occurs in response to thirst, which is stimulated by plasma hypertonicity and/or contracted ECF volume. Plasma hypertonicity, the primary stimulus, prompts osmoreceptors in the supraoptic and paraventricular nuclei of the hypothalamus to release vasopressin, also called antidiuretic hormone (ADH), which is released into the circulation at the level of the pituitary neurohypophysis. Binding of vasopressin to receptors in the distal nephron and renal collecting duct cells activates adenylyl cyclase and increases intracellular cyclic AMP. A protein kinase cascade initiated by activation of protein kinase A results in opening of luminal water pores in the tubule cell. Permeability of the collecting duct to water and reabsorption of water increase. Sustained release of vasopressin depends additionally upon calcium cycling across the plasma membrane and activation of protein kinase C–dependent pathways. Prostaglandins inhibit the renal response to vasopressin. Drugs with anticyclooxygenase activity that inhibit prostaglandin synthesis thereby enhance the action of endogenous vasopressin. Figure 23.1 summarizes the effects of selected drugs and electrolytes on vasopressin release and action.

If ECF volume and renal perfusion decrease, volume receptors in the renal juxtaglomerular apparatus respond, causing the secretion (or release) of renin, which converts angiotensinogen to angiotensin I. This is the rate-limiting step in the renin–angiotensin system. Angiotensin I is activated to the potent vasoconstrictor angiotensin II in the lung and in endothelial cells throughout the body by angiotensin-converting enzyme (ACE). Angiotensin II stimulates the zona glomerulosa of the adrenal cortex to secrete aldosterone, which, in turn, causes increased reabsorption of sodium from the distal nephron with excretion of K⁺ and H⁺. Due to the increased concentration of sodium, plasma becomes hypertonic, causing vasopressin release and water retention.

Water intake occurs in response not only to thirst but also to hunger. Water content of food may be as low as 10% (dry food) or as high as 90% (succulent green pasture). Canned pet foods generally contain more than 70% water, and semimoist foods are intermediate (20–40% water) (Lewis and Morris, 1987). Intake of dietary water is governed centrally by appetite control mechanisms rather than by fluid and electrolyte homeostasis. In addition to water intake related to eating and drinking, metabolic water is produced endogenously by catabolism of proteins, fats, and carbohydrates (approximately 5 ml/kg/day) and represents about 10–15% of total water intake in dogs and cats (Anderson, 1983).

Normal water loss occurs via urine, fecal water, and saliva (sensible loss), with insensible losses occurring via evaporation from cutaneous and respiratory epithelia. Insensible losses account for TBW elimination of about 15–30 ml/kg/day in healthy, sedentary animals in a thermoneutral environment (Kohn and DiBartola, 1992).

Metabolic rate, and therefore a portion of daily water turnover, are directly proportional to the ratio of body surface area to total volume. For example, the surface area to volume ratio in a puppy is much larger than in an adult dog and the puppy has a higher basal metabolic rate. Both lead to a much greater evaporative loss of water from the skin per unit volume. Hence, daily water turnover per unit body weight may be nearly twice that of the adult animal. Small, immature animals are therefore at greater risk for insensible water loss than large, mature animals.

The most important and predictable loss of water in healthy, sedentary animals, in a thermoneutral environment, occurs via the urine. Urinary losses can vary from 2 to 20 ml/kg/day. Daily urinary water losses may be divided into obligatory water loss and free water loss (Kohn and DiBartola, 1992). Obligatory water loss represents water eliminated in order to excrete the daily renal solute load. The renal solute load is derived from dietary sources of protein and minerals and consists of urea, Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺, NH₄⁺, and other cations, and PO₄³⁻, Cl⁻, SO₄²⁻, and other anions. Hence, daily renal solute load is a function of the quantity and composition of food ingested. Urea accounts for two-thirds of the urinary solute load in dogs (O’Connor and Potts, 1969).

In normal animals increased urine solute load is eliminated by an increase in urine volume (obligatory water loss) rather than a marked increase in urine osmolality. Hence, urine osmolality is not generally maximized in order to accomplish steady-state elimination of solutes. Obligatory renal water loss is clinically important for removal of renal solutes but also because this type of water loss will continue even in states of relative water deficit. Free water loss represents water excreted unaccompanied by solute. Excretion of free water is controlled by vasopressin and increases during relative water excess or hypotonicity and decreases during water deficit or hypertonicity. Obligatory fecal water loss occurs in order to excrete fecal solutes. Fecal losses ordinarily account for 2–5% of TBW losses and vary with the species. Feces typically contain 50–80% water (Kohn and DiBartola, 1992).

Renal Regulation of Sodium, Chloride, and Water Excretion

As glomerular filtrate flows through the tubules, most of the water (greater than 90%) and varying amounts of solute are reabsorbed into the peritubular capillaries. The composition of the tubular reabsorbate closely approximates that of ECF. Reabsorption is largely achieved by transport of electrolytes and other solutes in two steps: (i) absorption of solutes from tubular fluid into tubular cells and (ii) movement of solutes from tubular cells into the ECF. Several types of transport account for tubular reabsorption of solutes, including passive transport (simple diffusion), facilitated diffusion, active transport, and cotransport. These mechanisms are discussed in more detail in the context of diuretic drugs (Chapter 24) and are summarized in Figure 23.2, which depicts some of the functional processes for regulation of salt and water transport in different segments of the nephron.

As much as 60–65% of filtered solute is reabsorbed in the proximal tubule accompanied by osmotically proportional amounts of water. The tubular fluid at the distal portion of the proximal tubule becomes slightly hypoosmotic. Passive reabsorption of substances, especially sodium and chloride, continues in the thin segment of the loop of Henle. The thick ascending limb of the loop of Henle and the distal convoluted tubule are relatively impermeable to water but actively reabsorb solute. Sodium and chloride enter tubular cells in the thick ascending limb of Henle’s loop by crossing the luminal membrane coupled to potassium in a proportion of 1 Na⁺ : 1 K⁺ : 2 Cl⁻. Sodium is then actively extruded across the basolateral membrane to maintain intracellular sodium at low levels. Potassium and chloride leave the tubular cell passively. Two consequences of this are decreased concentration of sodium and chloride in the tubular lumen and increased concentration of each in interstitial fluid. A concentration gradient across the tubular epithelium is established, and this becomes multiplied in a longitudinal direction by the countercurrent mechanism. The collecting ducts are responsive to vasopressin, and in its presence the ducts become highly permeable to water. Tubular fluid equilibrates with hyperosmotic interstitium, and hypertonic (concentrated) urine results. In the absence of vasopressin, the ducts are relatively impermeable to water. In this case, sodium and chloride have been reabsorbed proximally to the collecting ducts, tubular fluid is hypoosmotic, and voided urine is dilute (Thier, 1987).

Renal reabsorption of sodium in the distal nephron is increased by aldosterone, a mineralocorticoid synthesized in the zona glomerulosa of the adrenal cortex. Aldosterone is produced and released in response to stimulation by angiotensin II, hyperkalemia, and by a decrease in dietary sodium intake. Adrenocorticotropic hormone (ACTH) and hyponatremia play permissive roles in promoting aldosterone secretion. Increased dietary sodium and atrial natriuretic peptide (ANP) decrease aldosterone production. ANP is a polypeptide released from atrial and ventricular myocytes in response to atrial distention associated with volume expansion. ANP causes vascular smooth muscle relaxation, inhibits production of aldosterone in the adrenal glands, and blocks the production of angiotensin II. Study results suggest that parathyroid hormone (PTH) is required for augmented ANP secretion in response to acute volume loading in rats. PTH may play an important role in the regulation of fluid homeostasis via control of ANP (Geiger et al., 1992).

In general, chloride is reabsorbed with sodium throughout the nephron. As previously noted, chloride is exchanged in a ratio of 1 Na⁺ : 1 K⁺ : 2 Cl⁻ in the thick ascending limb of Henle’s loop during sodium reabsorption. Because the cotransporter in this exchange has a very high affinity for both Na⁺ and K⁺, luminal Cl⁻ concentration is normally the rate-limiting step in NaCl entry into the cell (Gregor and Velazquez, 1987). Additional active and passive processes contribute to proximal Cl⁻ reabsorption in the renal tubules. Chloride exchange for formate appears to occur via an anion exchanger in the luminal membrane. Low concentrations of filtered formate combine with H⁺ to form formic acid (HF) in the tubular lumen. Because HF is uncharged, it moves freely into the tubular cell. Two additional mechanisms set the stage for conversion of HF back to formate and H⁺. First, basolateral Na⁺,K⁺-ATPase pumps maintain a low intracellular sodium concentration, and this, in turn, allows for the continued exchange of Na⁺-H⁺ across the luminal membrane. As Na⁺ is reabsorbed and H⁺ is secreted, the interior of the cell is left with a lower [H⁺] than the tubular lumen. Under these conditions HF is converted back to H⁺ and formate, providing for continued chloride–formate exchange. Reabsorbed chloride is returned to the ECF across the basolateral membrane by selective Cl⁻ channels and a K⁺-Cl⁻ cotransporter (Rose, 1994). Additional transport mechanisms in type B intercalated cells in the cortical collecting tubule may exchange bicarbonate for chloride. The favorable inward concentration gradient for chloride (lumen concentration greater than inside the cell) presumably provides the energy for bicarbonate secretion via this mechanism (Bastani et al., 1991).

Understanding the mechanisms for renal regulation of acid–base balance and electrolyte transport is increasingly dependent upon use of transgenic mice in which the function and regulation of key transporter proteins can be assessed (Cantone et al., 2006).

Disorders of Water, Sodium, and Chloride Balance

Hypernatremia

As the most important and abundant ECF cation, sodium is essential for proper maintenance of membrane potentials, initiation of action potentials, and, according to strong ion difference theory, maintenance of acid–base balance. Plasma sodium concentration and plasma osmolality generally vary in parallel since sodium and its associated anions account for greater than 95% of plasma osmolality. Plasma sodium concentration reflects the ratio of body sodium ion concentration to TBW. Total body sodium content, however, is independent of plasma sodium concentration and may be increased, decreased, or unchanged in the presence of hyper- or hyponatremia.

Clinical signs associated with alterations in serum sodium are more related to the rapidity of change rather than to the magnitude of sodium increase or decrease. Hypernatremia (e.g., >155 mEq sodium/l in dogs) and ECF hypertonicity can be caused by a loss of pure water, a loss of hypotonic fluid (extrarenal or renal), or a gain of impermeable sodium-containing solute (Figure 23.3). Clinical signs of hypernatremia are usually observed in dogs and cats as sodium concentration approaches and exceeds 170 mEq/ml. The signs seen are related to the osmotic movement of water out of cells. Negative effects of cellular dehydration are most pronounced in the brain and lead to the characteristic neurological deficits associated with hypernatremia. These deficits include abnormal behavior and mentation, ataxia, seizures, and coma. The more rapidly water shifts out of brain cells, the greater the chance that decreased brain volume will lead to rupture of cerebral vessels and focal hemorrhage (Arieff and Guisado, 1976). If sodium concentration or concentration of sodium-containing impermeable solute increases slowly, the brain attempts to adapt to the hypertonic state by production of intracellular solutes (e.g., sugars, amino acids) known as “idiogenic” osmoles. Production of these osmotically active substances protects the cell by retaining intracellular volume and preventing cellular dehydration. In addition to neurological deficits, other clinical signs of hypernatremia include thirst, anorexia, lethargy, vomiting, and muscle weakness. If hypernatremia is related to hypotonic fluid loss, then clinical signs of dehydration (as previously described) may be present. If a gain of sodium has caused the hypernatremia, volume overload may be a problem, especially in patients with cardiac disease.

Restoration of ECF volume and tonicity is of primary importance in treatment of hypernatremia. Volume replacement must be accomplished slowly to avoid rapid shifts in plasma osmolality. In general, the rate of fluid administration is determined by the rate of onset of the hypernatremia. When treating chronic hypernatremia, the serum sodium concentration should drop at a rate that does not exceed 0.7 mEq/l/h (O’Brien, 1995). If plasma osmolality drops quickly, water may be attracted intracellularly by idiogenic osmoles, resulting in development of cerebral edema.

Patients with clinical hypernatremia are also often dehydrated, and need volume resuscitation. Custom fluid combinations can be designed to gradually bring down sodium while being able to give high rates of fluids to replace volume. In the case of pure-water loss, volume can be replaced with 5% dextrose in water over a 48- to 72-hour period. Since the dextrose ultimately enters cells and is metabolized, 5% dextrose administration is essentially replacement with pure water. Use of a 1 : 1 mixture of normal saline with 5% dextrose solution yields an isotonic solution of 2.5% dextrose, 0.45% saline that has also been utilized. This solution decreases plasma tonicity more slowly and decreases the chance for cerebral edema. Hypotonic fluid losses should generally be replaced with an isotonic crystalloid solution. If hypernatremia has resulted from addition of sodium or sodium-containing impermeable solute, then administration of 5% dextrose and water should be accomplished cautiously to avoid pulmonary edema. Diuretics may be useful in promoting saluresis (sodium excretion) as ECF volume is restored (Marks, 1998).

Evaluation and treatment of hypernatremia in critically ill cats was reviewed with emphasis on the importance of careful monitoring and early recognition of signs for positive therapeutic outcomes (Temol et al., 2004).

Hyponatremia

Causes of hyponatremia (<135–140 mEq sodium/l) are best categorized if two additional variables, osmolality and hydration, are also considered. As indicated in Figure 23.4, the more common causes of hyponatremia are accompanied by decreased plasma osmolality (<290 mOsm/kg) with or without volume depletion. If volume depletion exists with hyponatremia, then loss of body sodium has exceeded water loss. Physiological responses to hypovolemia lead to impaired water excretion and a relative dilution of the sodium remaining in body fluids. Hypovolemia causes decreased renal perfusion and GFR, leading to a decline in water excretion. Slower movement of filtrate through renal tubules enhances isosmotic reabsorption of salt and water in the proximal tubules and decreases presentation of tubular fluid at distal diluting sites. Additionally, hypovolemia prompts vasopressin release, further impairing water elimination. Finally, thirst related to hypovolemia results in consumption of low-sodium fluids that also dilute existing plasma sodium (DiBartola, 1992c).

Hyponatremia accompanied by hypervolemia and low plasma osmolality occurs in clinical disorders where there is a physiological perception of volume depletion by in vivo volume detectors. The physiological response is volume expansion. For example, in congestive heart failure, decreased cardiac output is sensed as volume depletion by baroreceptors. Release of vasopressin impairs water excretion, leading to expanded vascular volume. Decreased effective circulating volume and decreased renal perfusion also lead to activation of the renin–angiotensin–aldosterone system. Enhanced renal retention of sodium contributes to expanded vascular volume. In cirrhosis and the nephrotic syndrome, hypoalbuminemia and decreased oncotic pressure may contribute to decreased effective circulating volume and, ultimately, vasopressin release and volume expansion. Other features of hepatic and renal disease also contribute to decreased circulating volume and/or impaired water excretion (DiBartola, 1992c).

Hyponatremia is relatively less common when associated with increased plasma osmolality. The most frequent cause of sodium decreases in the presence of increased plasma osmolality is the increased circulating glucose levels associated with diabetes mellitus. Each 100 mg/dl increase in glucose results in a measured decrease of serum sodium by 1.6 mEq/l (Katz, 1973). In response to the increased concentration of serum glucose, water shifts from the intracellular to the extracellular compartment, resulting in dilution of measured sodium. Serum osmolality remains high due to elevated glucose concentrations. Hyponatremia associated with normal plasma osmolality is referred to as pseudohyponatremia. The decreased sodium concentrations are spurious and are almost universally related to technical difficulties in sodium measurement when plasma lipid or protein concentrations are high.

As with hypernatremia, clinical signs of hyponatremia are more severe if sodium concentration changes rapidly than if it changes over a more prolonged period of time. If sodium concentrations and plasma osmolality decrease quickly, water shifts out of the ECF and into cells. The central nervous system (CNS) is most affected by a rapid fluid shift, which, in hyponatremia, results in development of cerebral edema. If onset of hyponatremia is slow, the brain can adjust cell volume by decreasing intracellular osmolality and preventing influx of water from the ECF. Patients with chronic hyponatremia will also adjust intracellular osmolality to an extent that clinical signs may not be obvious even though sodium concentrations are quite low.

Treatment of hyponatremia varies with etiology of the disorder. The goals of therapy are to manage the underlying disease and, if necessary, to increase serum sodium and osmolality. Infusion with conventional crystalloid solutions (e.g., normal saline or lactated Ringer’s solution) is reported to accomplish sodium and volume replacement in hyponatremic, hypovolemic patients (DiBartola, 1992c). Use of hypertonic saline solutions is not recommended since overly rapid correction of hyponatremia may do more harm than good. Chronic hyponatremia, in which the brain has adjusted to the decrease in osmolality and sodium, must be handled cautiously to avoid brain dehydration and injury, including osmotic demyelination syndrome. This syndrome, often occurring several days after correction of hyponatremia, results from areas of demyelination caused by treatment-induced increases in serum sodium concentration. Dogs with asymptomatic chronic hyponatremia are best treated by mild water restriction and monitoring of serum sodium. Chronic, symptomatic dogs should be treated such that the rate of increase of serum sodium does not exceed 10–12 mEq/l/day (0.5 mEq/l/h) (DiBartola, 1998). Again, the most important therapeutic goal in management of hyponatremia should be treatment of the underlying disease.

Homeostasis

Renal Regulation of Potassium Excretion

Disorders of Potassium Balance

Hypokalemia

Since 97% of total body potassium is intracellular, depletion can occur with no change in plasma potassium concentration or even with an increase if acidosis is present. Clinical signs of hypokalemia (<2.5–3.0 mEq/l) can include weakness of skeletal and respiratory muscles and loss of intestinal smooth muscle tone. As in hyperkalemia, cardiac changes occur as potassium concentration changes. Supraventricular and ventricular arrhythmias are most commonly observed in animals. ECG hallmarks of hypokalemia in humans are flattened or inverted T waves, depressed S-T segment, and the appearance of U waves. Prolongation of the QT interval and U waves have been reported in dogs but are not as consistently seen as they are in humans. Hypokalemia is increasingly recognized as an important clinical problem in cats, especially in association with chronic renal failure and geriatric animals (Phillips and Polzin, 1998). Feline hypokalemic polymyopathy syndrome, characterized by generalized muscle weakness associated with hypokalemia, is often manifest in cats as ventroflexion of the head and a stiff, stilted gait.

Increased loss associated with the gastrointestinal or the urinary system is a common cause of hypokalemia, as indicated in Table 23.8. Differentiating gastrointestinal from urinary causes of hypokalemia is largely accomplished by clinical signs and physical exam, but fractional potassium excretion rates (FE_K) may also be useful. Fractional potassium excretion can be calculated using the following formula:

Increased loss

Gastrointestinal (FEK <4–6%)

Persistent vomiting of stomach contents

Diarrhea

Urinary (FEK >4–6%)

Chronic renal failure in cats

Diet-induced hypokalemic nephropathy in cats

Renal tubular acidosis

Postobstructive diuresis

Excess circulating mineralocorticoid

Hyperadrenocorticism

Primary hyperaldosteronism (hyperplastic or neoplastic)

Diuretics (loop acting, thiazides and osmotic)

Antibiotics (penicillins, amphotericin B, aminoglycosides)

Translocation from extracellular fluid to intracellular

Alkalemia

Overadministration of insulin and glucose-containing fluids

Hyperthyroidism

Hypokalemic periodic paralysis

Possible complication of hypothermia

Decreased intake

Unlikely as sole cause

where U indicates the urine concentration of potassium (K⁺) or creatinine (CR), and S indicates the serum concentration.

Treatment of hypokalemia is indicated if significant potassium loss is expected based on history and clinical signs (e.g., vomiting, diarrhea, overzealous use of diuretics) or if clinical signs of hypokalemia are present. Appropriate potassium administration is often required with prolonged fluid therapy. If feasible, oral potassium supplementation is most desirable since this is the safest route of administration. If intravenous potassium supplementation is warranted, the amount administered should be based on clinical status of the animal and measured serum potassium values. Table 23.9  provides approximate potassium dosages for treatment of hypokalemia in small animals. Alternatively, a rule of thumb may be applied in which 20 mEq/l of potassium is supplemented with careful monitoring of changes in serum potassium. An important caution regarding the administration of intravenous potassium is not to exceed a rate of 0.5 mEq/kg/h. Parenteral potassium administration should always be monitored to ensure that rate of potassium addition does not exceed rate of potassium movement into cells.

Serum potassium concentration (mEq/l)	Supplement fluids (mEq/l)a
3.5 to 4.5	20
3.0 to 3.5	30
2.5 to 3.0	40
2.0 to 2.5	60
<2.0	80

^aQuantity of potassium to add per liter of fluid. Do not exceed administration rate of 0.5 mEq K⁺/kg/h.

Homeostasis  

Blood pH is highly regulated and is normally maintained between 7.38 and 7.42. Pulmonary and renal functions are necessary for precise regulation of pH of all body fluids, blood, and extravascular tissues. An acid is defined by Bronsted and Lowry as a substance that can supply H⁺ (protons), and a base is defined as a substance that can accept H⁺. In aqueous solutions, H⁺ are hydrated; therefore, H₃O⁺ is considered an acid and is implied by the symbol H⁺. Blood pH is the negative logarithm of the hydrogen ion concentration. Although hydrogen ion concentration cannot be measured directly, hydrogen ion activity is measured chemically using a pH electrode. In body fluids, the difference between activity of hydrogen ions and concentration of hydrogen ions is negligible; hence hydrogen ion concentration and pH are commonly referred to in acid–base discussions. The hydrogen ion concentration of blood at pH 7.4 is 40 nmol/l (nanoequivalents per liter) and is therefore approximately a millionfold lower than the blood concentration of electrolytes such as sodium and potassium. Appropriate hydrogen ion concentration is critical in order to maintain body proteins in configurations required for enzymatic and structural function. An increase in hydrogen ion concentration with a decrease in blood pH is termed acidemia and can be caused by pathophysiological processes that cause accumulation of acids in the body. As the concentration of hydrogen ions decreases, and blood pH increases, alkalemia occurs and can be associated with pathophysiological processes that cause accumulation of alkali in the body. The disordered processes leading to acidemia and alkalemia are termed acidosis and alkalosis, respectively.

On a daily basis, an excess of acid (70–100 mEq) is generated in the body as a result of dietary intake and intermediary metabolism. Catabolism of carbohydrate, fat, and protein account for most of this as a result of: oxidation of sulfur-containing amino acids to sulfuric acid; oxidation of phosphoproteins to phosphoric acid; incomplete oxidation of fats and carbohydrates to organic acid; production of lactate/lactic acid during anaerobic glycolysis; and conversion of carbon dioxide and water produced in the tricarboxylic acid cycle to carbonic acid. Buffers throughout the body minimize changes in blood pH associated with alterations of acid–base balance. The most effective physiological buffers have pK_a values between 6.1 and 8.4, with buffering capacity being maximal within one pH unit of the pK_a. Important extracellular buffers include bicarbonate, inorganic phosphates, and plasma proteins.

Most extracellular buffering occurs as a result of the bicarbonate–carbonic acid buffer pair (pKa = 6.1). Equilibrium of this buffer pair is indicated with the following:

The hydration of CO₂ is a rapid reaction in the presence of the enzyme carbonic anhydrase, which is found primarily in red blood cells and renal tubular cells. The dissociation of any acid, in this case carbonic acid, can be described utilizing the concept that the velocity of a reaction is proportional to the product of the concentration of the reactants. In the case of the bicarbonate buffer system, the carbonic anhydrase–catalyzed hydration of CO₂ to form H₂CO₃ reaches equilibrium almost instantaneously, with the number of dissolved CO₂ molecules far exceeding the number of carbonic acid molecules. By defining dissociation constants and rearranging, the useful Henderson–Hasselbalch form of the dissociation equilibrium equation can be derived:

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