Hyponatremia and Hypernatremia

An In-Depth Look: CE NORMAL AND ABNORMAL WATER BALANCE Article #1 s e e R

a r a

m Normal and Abnormal Water a T

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n o i t a

r Balance: Hyponatremia and t s u l l I Hypernatremia*

Katherine M. James, DVM, PhD, DACVIM Veterinary Information Network

Katharine F. Lunn, BVMS, MS, PhD, MRCVS, DACVIMa Colorado State University

ABSTRACT: This article discusses normal and abnormal water balance in small animals.The terms and concepts central to understanding the maintenance of normal salt and water balance and the manifestations of dysregulation are presented, the physiology of body fluid balance is reviewed, and the concepts of sodium content and sodium concentration are explored.The emphasis of this review is that abnormalities of serum sodium concentration are, in fact, abnormalities of water balance.Thus, hyponatremia reflects too much water relative to sodium in the extracellular fluid, whereas hypernatremia reflects a relative deficit of water.

everal important terms relating to water water. The extracellular fluid (ECF) compart- balance are defined in the box on page ment is further divided into interstitial water and S590. plasma water. The relative distribution of body water for a typical dog is shown in Figure 1; how- TERMS AND CONCEPTS ever, the percentage of total body water in an Body Fluid Balance individual animal is affected by body fat content.1 Balance refers to the ratio of the amount of a Body fluid balance depends on the interrelation- substance assimilated into the body to the ship between two key components that must be amount that is lost from the body. When this simultaneously kept in balance: salt and water. ratio approximates 1:1 (unity), the body is in bal- Salt balance refers to the maintenance of ance for that substance. Under normal steady- optimal body fluid volume, as shown in Figure state conditions, on a day-to-day basis, the 2. It depends primarily on the sodium ion (Na+) volume of total body fluid stays the same; this content of the ECF because Na+ is the principal body fluid balance is achieved when fluid intake extracellular cation. Although the total solute and losses are equivalent. Total concentrations in the extracellular and intracel- body water comprises two lular compartments are equivalent, their com- main compartments: intracel- positions differ; within cells, potassium and •Take CE tests lular water and extracellular magnesium ions are the principal cations, • See full-text articles *A companion article on polyuria and polydipsia begins on page 612. aDr. Lunn discloses that she has received financial support from ContinuEd Continuing CompendiumVet.com Education Company and Fort Dodge Animal Health.

October 2007 589 COMPENDIUM 590 CE Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia

Glossary of Important Terms Total Body Water (TBW) Content—The total amount of a substance in a given space. The content of a substance such as Na+ only Intracellular water Extracellular water changes when molecules of that substance are gained Interstitial Plasma or lost from a body space, such as the extracellular 60% water water fluid space. This term is used in contrast to TBW TBW 67% 25% 8% concentration, which reflects the content of a TBW TBW TBW substance contained within a certain volume of water, typically plasma or urine. Concentrations of electrolytes (e.g., Na+) are measured by laboratory

investigations. The content of a substance is s e e

calculated by multiplying the concentration of the R

25% of a r

substance by the volume of the fluid space. 75% of ECF a

ECF volume volume m a T

Osmolality—The concentration of an osmotic solution, y b

Water moves Water moves due to due to n

especially when measured in osmoles or milliosmoles o i

osmotic forces Starling’s forces t a

per 1,000 g of solvent (usually water). Osmolarity is a r t s u l l

similar term and is often used interchangeably with I osmolality when the solvent is water. However, Figure 1. The distribution of body fluids by osmolarity refers to the measurement in osmoles compartment. Starling’s forces are hydrostatic and oncotic or milliosmoles of solute per liter of water—a forces that determine fluid movement across capillary measurement of osmoles per volume rather than per membranes as a result of filtration. weight of solvent. Osmosis—The movement of water through a semipermeable membrane (such as a cell membrane) into a solution of higher solute concentration that tends to equalize the concentrations of solute on the two sides of the membrane. Solutions that cause water to move by osmosis are termed osmotic solutions. Tonicity—The osmotic pressure of a solution. The tonicity of a solution (e.g., an intravenous fluid solution, plasma, urine) is only relevant in reference to another physiologic system. For example,

intravenous fluids are hypertonic, isotonic, or s e e

hypotonic relative to plasma. A patient’s plasma R

a r

is hypertonic, isotonic, or hypotonic relative to a m a T

normal plasma. A patient’s urine is hypertonic y b

(hypersthenuria), isotonic (isosthenuria), or hypotonic n o i t

(hyposthenuria) relative to the patient’s plasma. a r t s u l l I Figure 2. Normal salt balance exists when the intake of replacing Na+. These differences in solute composition Na+ in food is equivalent to losses, principally in feces and between intracellular and extracellular space are main- urine. A dog in normal salt balance has an appropriate number of + tained by active ion transport.2 Na in its total body fluid, including the interstitial space (tan) and + the intravascular space (blue and red vessel representing a Because Na is the principal extracellular cation, and composite of arterial, venous, and capillary blood volumes). because the osmolality of body fluids is regulated within Anions (not shown) are present in equal numbers to maintain a very narrow range,2 the Na+ content of the body deter- electroneutrality.Water molecules are present in appropriate mines the volume of ECF and total body fluid volume. proportion (depicted as equal numbers) to maintain a normal If sodium ions (always with accompanying anions) are ECF osmolality.The cells (depicted by a single representative brown cell) contain sufficient intracellular osmoles to maintain an added to the ECF space, the same proportion of water equal concentration of water in intracellular fluid and ECF, molecules must be added to the ECF space or the resulting in an optimal cell volume.(O = osmole) osmolality will increase beyond the limits compatible

COMPENDIUM October 2007 Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia CE 591

2 Renal Na+ retention

3 Diarrhea s s e e 1 Renal loss e e R R

a a r r a a m m a a T T

y y

+ b b 1 Na n n

ingestion o o Salt i i t 2 Vomiting t a a r r t t s s u u l l l l I I Figure 3. A dog in positive salt balance has too many Figure 4. A dog in negative salt balance has too few sodium ions in its total body fluid. Both the interstitial space sodium ions in its total body fluid. Both the interstitial space and vascular volume are expanded.The dog can drink water, and and vascular volume are reduced.The number of water molecules the number of water molecules has increased proportionally to has decreased proportionally through isotonic fluid loss, and maintain a normal ECF osmolality.Thus the equilibrium between normal ECF osmolality is maintained.With mild negative salt the intracellular and extracellular fluid spaces is unchanged (red balance, the equilibrium between the intracellular and arrows of equal size). Positive salt balance can result from (1) an extracellular fluid spaces is unchanged (red arrows of equal size). increase in salt intake through ingestion or intravenous fluid Negative salt balance commonly results from (1) renal or (2 and administration or (2) renal Na+ retention (blue arrows), such as in 3) gastrointestinal or urinary fluid loss.Very little Na+ is present in patients with heart failure or cirrhosis. vomit; however, without oral replacement of Na+, there will be ongoing obligate renal Na+ loss in a vomiting patient. with a healthy state. Thus, increasing the number of sodium ions in the ECF (the Na+ content) increases the ECF volume. Similarly, if sodium ions are removed from the ECF space, water molecules must leave in proportion, thereby reducing the ECF volume; otherwise, the osmolality of the ECF would decrease below the level allowed in a healthy individual. The dog shown in Figure 3 has increased total body fluid and ECF volumes due to increased Na+ content. s

+ e e

Increased Na content can be the result of increased R

+ r dietary salt intake or increased renal Na retention. Con- a m a T versely, the dog shown in Figure 4 has decreased total y b + body fluid and ECF volumes due to decreased Na con- n o i t a r

tent. This solute deficit can result from gastrointestinal t s u l l or urinary losses. I Water balance (Figure 5) defines the maintenance of Figure 5. Normal water balance exists when water optimal body fluid tonicity. Tonicity refers to the osmotic intake is equal to insensible (nonmeasurable; primarily pressure of a solution—its ability to cause water to move through the respiratory tract) and sensible (measurable in urine and feces) losses. Intracellular fluid and ECF are across a membrane. Body fluid tonicity is tightly regu- isotonic (have an equal water concentration); therefore, water lated because it determines the volume of the body’s movement is in equilibrium (red arrows of equal size).The volume cells, which in turn affects cell function.2 Although ECF of body cells and the plasma osmolality are appropriate. and intracellular fluid have very different compositions, they must maintain the same solute concentrations (the same tonicity) so that water can move freely across most fluid must remain the same. Inequalities of water con- cell membranes. Looking at this concept “in reverse,” the centration between body fluid compartments exist only water concentrations of the ECF and the intracellular transiently because water immediately and rapidly moves

October 2007 COMPENDIUM 592 CE Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia

osmolality of body fluids. Glucose and urea make minor contributions, as reflected in the following equationa: Plasma osmolality = 2(Na+ concentration [mEq/L]) + (glucose concentration [mg/dl] ÷ 18) + (BUN concentration [mg/dl] ÷ 2.8) Osmolality is usually measured by freezing point depression, and the measured value is often higher than s

e the calculated value because equations such as the one e R

a presented above do not include all osmotically active r a 3 m particles present in the plasma. The difference between a T

y b

the measured and the calculated values is termed the n o i

t osmolal gap. In the clinical setting, the term osmolar gap a r t s

u is often used (see the box on page 590 for an explana- l l I tion of the difference between osmolarity and osmolal- Figure 6. The hypertonic hyponatremia that occurs in unregulated diabetes mellitus is an example of ity). This value should be no higher than 10 mOsm/kg 4 translocation hyponatremia. The baseline influence of in normal dogs. Two situations are associated with a intracellular and extracellular osmoles on water movement significantly elevated osmolal gap: (1) the presence of remains (thick red arrows), but the presence of an additional exogenous solutes (e.g., metabolites of ethylene glycol) impermeant solute (▲) in the ECF drives water translocation in the plasma and (2) a reduced fraction of plasma water from the intracellular to extracellular space (thin red arrows) resulting from high plasma triglycerides or proteins to maintain an equal concentration of water across the cell (e.g., myeloma proteins). membrane.Thus the proportion of water molecules relative to Plasma Na+ concentration accurately reflects plasma Na+ in the ECF is increased, resulting in hyponatremia (illustrated by a 2:1 ratio of water to Na+).The dog has a decreased tonicity in normal patients. As stated previously, tonicity intracellular fluid volume (shrunken cell and brain) and a is the ability of a solution to move water across a mem- correspondingly increased ECF volume. Because fluid has moved brane. This movement affects cellular volume. Hyper- between compartments, the dog’s body weight is unchanged. tonicity results when impermeant solutes are added to the ECF; this promotes cellular dehydration. Hypo- tonicity results from a decrease in the concentration of to correct these inequalities when the two compartments impermeant solutes in the ECF and promotes water have different tonicities. movement into cells and cell swelling. Hypertonic solutions are always hyperosmolar. The reverse is not always Osmolality Versus Tonicity true: hyperosmolar solutions are not necessarily hyper- The concentration of solutes in a solvent defines a tonic because ineffective osmoles contribute to osmolal- solution’s osmolality. Because cell membranes are per- ity but not tonicity. As a clinical example, the addition meable to water, and because water will move across a of glucose to a saline solution with the same Na+ con- membrane until the solutions on either side of the centration as plasma results in a hyperosmolar solution. membrane are isosmolar, the osmolality of plasma However, the solution is not hypertonic when infused reflects the osmolality of total body fluid. When consid- into a nondiabetic patient because glucose moves freely ering how osmolality affects tonicity, it is important to into cells in the presence of insulin. In a diabetic patient, distinguish between permeant and impermeant solutes. due to the lack of insulin, glucose is not rapidly taken up Permeant solutes (e.g., urea) move freely across cell by the cells. In this case, the glucose molecules are effec- membranes and thus do not induce net water movement tive osmoles, rendering the solution hypertonic: water when they are introduced into a solution; they are aThis equation is a simplification because it does not account termed ineffective osmoles. Impermeant solutes (e.g., Na+) for the fact that plasma is only 93% water; that sodium salts do not freely move across cell membranes. Thus, they do are incompletely dissociated in solution; that some anions are induce water movement when introduced into a solu- polyvalent; or that calcium, magnesium, and potassium salts also contribute. However, these factors cancel out numerically, tion and are termed effective osmoles. allowing 2 × Na+ concentration to be used as an estimate of Plasma Na+ concentration is the key determinant of the the osmotic effect of the plasma ions.1,2

COMPENDIUM October 2007 Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia CE 593

Table 1. Mechanisms That Sense and Regulate Na+ Content and Na+ Concentrationa Type of Mechanism Regulation Regulation Signal Sensors Effectors Effected Characteristics Na+ concentration; Plasma Hypothalamic • Vasopressin • Urine • Rapid osmoregulation osmolality osmoreceptor • Thirst osmolality (urine • Precise (water balance) concentration) • Water intake

Na+ content; Effective • Carotid sinus • Renin–angiotensin– Urine Na+ • Slow volume regulation plasma • Juxtaglomerular aldosterone system excretion • Dominant (salt balance) volumeb cell • Sympathetic in deficiency • Atrial pressure nervous system receptors • Peritubular capillary • Hepatic volume hemodynamics receptors • Atrial natriuretic • Cerebrospinal fluid peptide volume receptors aAdapted from Rose BD: Clinical Physiology of Acid-Base and Electrolyte Disorders, ed 3. New York, Raven, 1992, pp 2837–2872. bEffective plasma volume is a phrase used to describe salt-retaining states. It is not a measurable quantity, and the concept lacks a precise definition. It refers to the fullness of the vascular volume and is the portion of the vascular volume that is being sensed by the mechanisms that regulate body fluid volume. An inadequate effective circulating volume is inferred when salt-retaining mechanisms are activated. moves out of the cells into the ECF, the ECF Na+ con- animals have evolved a salt appetite to increase Na+ centration declines, and so-called hypertonic hypona- intake in salt-deficient states. tremia is observed (Figure 6). When hyperglycemia Regulation of Na+ content is generally a slow process develops slowly, idiogenic osmoles are generated within compared with regulation of Na+ concentration. While the cells; this helps to increase intracellular water con- excess water intake stimulates the osmoregulatory mecha- tent and mitigate the decrease in cell volume.5 nisms and is dealt with very rapidly, many hours pass before excessive sodium intake (e.g., infusion of isotonic Osmoregulation saline) is corrected by increased renal Na+ excretion. The term osmoregulation refers to the control of body When dietary Na+ intake is increased, it takes several days fluid tonicity. Because cell membranes are permeable to to reach a new steady state of neutral Na+ balance.2 Na+ water, cells are in osmotic equilibrium with the fluid excretion is influenced by several regulatory factors, and that surrounds them. Therefore, by stabilizing body mechanisms for Na+ retention are generally better devel- fluid tonicity, osmoregulation controls cell volume. oped than are those for Na+ excretion. It can be extremely Hypothalamic cells called osmoreceptors sense changes in difficult to sort out the roles of the many sensors and their own volume in response to an osmotic gradient mediators involved (Table 1) and understand the relative between themselves and plasma.2 importance of the various regulatory systems.7 In contrast, plasma Na+ concentration is regulated by Content Versus Concentration osmoregulatory control mechanisms.2 Changes in Separate mechanisms regulate Na+ content and Na+ plasma osmolality (pOsm) sensed by the hypothalamic concentration (Table 1). The Na+ content of the body is osmoregulatory cells alter the secretion of vasopressin regulated by mechanisms that control the renal excre- (antidiuretic hormone [ADH]). ADH is the primary tion of Na+,6 which can vary more than 500-fold, regulator of renal water excretion. Its primary function depending on Na+ intake and physiologic need. These is to increase the water permeability of the luminal mechanisms operate in response to body fluid volume, membrane of the renal collecting duct through the not plasma Na+ concentration. The kidneys have evolved insertion of water channels called aquaporins. Water is mechanisms to conserve salt; however, the homeostatic reabsorbed through these channels in the collecting mechanisms that control Na+ content are poorly under- ducts along the concentration gradient established in stood. Although species differences may exist, many the renal medullary interstitium.8 Changes in pOsm also

October 2007 COMPENDIUM 594 CE Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia

Proximal tubule Loop of Henle Distal tubule Collecting duct plasma. In this segment of the tubule, the bulk of the urinary solutes (e.g., Na+ and other electrolytes, amino acids, glucose) and water is reabsorbed isosmotically. As the filtrate traverses the descending limb of the loop of Henle, water diffuses from the tubule lumen to the hypertonic medullary interstitium. The tubular fluid then becomes

H2O NaCl progressively more dilute as it travels through the ascend- NaCl ing limb of the loop of Henle. This diluting process occurs + H2O ADH because active Na reabsorption is unaccompanied by H2O NaCl water in this segment. The fluid is hypoosmotic to plasma V2 on its arrival in the distal tubule. ADH stimulates reabsorption of sodium chloride in the ascending limb and H2O

NaCl H2O V2 ADH thus facilitates generation of the renal medullary solute gradient necessary for urinary concentration.11 Urea Hormonal action on the collecting ducts determines the final concentration of urine produced. In a state of

H2O

NaCl s antidiuresis, ADH increases water permeability and aug- e

e + R

ments aldosterone-stimulated Na reabsorption, thereby a r a promoting water movement from the tubule lumen to m a T

y the interstitium for reclamation. In a state of water b

n o

i diuresis, when ADH is not present, the collecting duct t a r t

s remains impermeable to water, and dilute urine is pro- u l l I duced. Also, in the distal collecting duct, urea permeabil- Figure 7. Differences in solute transport and water ity is relatively high and is increased in the presence of permeability in specific nephron segments are essential to renal concentrating and diluting ability. In the presence ADH; thus, urea moves back into the renal medullary 2 of ADH, water channels (V2) allow water to move from the interstitium for maintenance of the medullary gradient. collecting duct to the hypertonic renal medullary interstitium. The ability of the kidneys to maintain a normal water balance through creation of hypertonic or hypotonic urine can be disrupted in many ways (Table 2). Disor- strongly affect the thirst mechanism. This is why ders that affect renal concentrating ability are discussed patients that are deficient in ADH (those with central in more detail in the companion article on p. 612. diabetes insipidus) cannot conserve water through renal mechanisms but can maintain a normal pOsm if they CONCEPTS OF WATER BALANCE have access to water.2 In contrast to salt balance and IN CLINICAL SITUATIONS control of body fluid volume, when pOsm changes, the Dehydration changes in thirst and ADH secretion and the resultant Dehydration can have several different meanings, renal response are brisk, occurring within minutes.9,10 which may lead to confusion and therapeutic error. One Hypotension and hypovolemia also stimulate ADH definition is based on clinical findings when hydration release. ADH release is not as sensitive to hemodynamic tests such as skin turgor, mucous membrane moisture, stimuli as it is to changes in pOsm; however, when the pulse rate, and capillary refill time are conducted. Typi- hemodynamic stimulus is sufficiently strong, the ADH cally, when a clinician considers the issue of whether a response will be of greater magnitude, and volume will patient is clinically dehydrated, he or she is referring to be preserved at the expense of decreased osmolality.4 physical examination findings that assess interstitial and The kidneys have a primary role in water balance plasma fluid volume status.12 These findings reflect the through their concentrating and diluting functions. The patient’s low ECF volume and negative sodium balance. details of these complex hormonally regulated processes However, another definition of dehydration is a decrease are beyond the scope of this article but are summarized in intracellular water (i.e., dehydrated cells). This here and in Figure 7. The osmolality of the glomerular fil- reflects a high plasma tonicity and a problem of negative trate as it enters the proximal tubule is identical to that of water balance. Yet another definition is a decrease in

COMPENDIUM October 2007 Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia CE 595

Table 2. Clinical Situations That Disrupt the Renal Mediation of Normal Water Balance Clinical Situation That Clinical Situation That Prerequisites for Disrupts This Portion Prerequisites for Creation Disrupts This Portion of Creation of Dilute Urine of the Mechanism of Concentrated Urine the Mechanism A sufficient number of Decreased functional A sufficient number of Decreased functional renal nephrons to provide the renal mass, as in nephrons to provide the GFR mass, as in chronic renal glomerular filtration rate chronic renal failure necessary for delivery of failure (GFR) necessary for the ultrafiltrate to the thick delivery of ultrafiltrate to the ascending loop of Henle, thick ascending loop of Henle, distal convoluted tubule, and distal convoluted tubule, and collecting duct collecting duct

Sufficient delivery of sodium • Hypovolemia Sufficient delivery of sodium Low blood urea nitrogen to the diluting segments of • Very low solute to the ascending loop of concentration such as with the nephron (thick ascending diets Henle and distal convoluted an ultralow protein diet or loop of Henle, distal tubule and of urea to the hepatic failure convoluted tubule) distal collecting duct for countercurrent multiplication

Optimal active transport of • Osmotic diuresis Generation and preservation • Osmotic diuresis Na+ out of the ascending loop • Loop and thiazide of a maximal renal • Water diuresis of Henle coupled with diuretics corticomedullary gradient • Loop diuretics impermeability to water for generation of a maximal hypotonic fluid in the diluting segments of the nephron

Maintenance of water • Syndrome of A collecting duct permeable • Lack of ADH (central impermeability in the inappropriate to water through the action of diabetes insipidus) collecting ducts determined ADH secretion ADH (or other antidiuretic • Primary nephrogenic diabetes by the absence of ADH (or (SIADH) substances) and functional insipidus, including heritable other antidiuretic substances) • Desmopressin vasopressin (V2) receptors, abnormalities in V2 receptors therapy their second messengers and or aquaporins aquaporins • Diuretics that interfere with second messengers of the V2 receptors, such as caffeine • Hypercalcemia • Obstructive and postobstructive diuresis total body water, which also reflects a negative sodium deficits. Some patients may have both. These distinc- balance, provided the pOsm is normal. tions determine therapeutic decisions: is the patient Therefore, rather than using the imprecise term dehy- lacking Na+, water, or both? dration, clinicians are better served by thinking about body fluid status in terms of the body’s compartments Plasma Sodium Ion Concentration and the overall sodium balance and water balance. Thus, Clinicians should become familiar not only with the patients with decreased skin turgor and membrane published laboratory reference ranges for plasma Na+ moisture or acute loss of body weight reflecting fluid concentration but also with the mean and variance in loss are best described as having ECF volume depletion. their own population of patients. The amount of devia- Patients with a high pOsm (hypertonicity) and intracel- tion in the pOsm that ordinarily alters ADH and thirst lular fluid losses are best described as having free water b in an individual animal is smaller than normal labora- bFree water is used as a contraction of the terms solute-free tory ranges (e.g., a 1% to 2% increase in osmolality is water or electrolyte-free water. sufficient to induce thirst).2 In other words, laboratory

October 2007 COMPENDIUM 598 CE

Clinical Questions and Answers Question: My patient’s plasma Na+ concentration is only mildly outside the laboratory’s reference range. I don’t include such minor abnormalities in serum enzymes on the problem list. Why is this analyte different? Answer: Any abnormalities in plasma Na+ concentration warrant clinical attention, even if the Na+ concentration is only 1 or 2 mEq/L outside the normal reference range. The body tightly regulates plasma Na+ concentration (as well as the plasma concentration of the other electrolytes), so any deviations in plasma Na+ concentration suggest a water balance disorder.

Question: Can I begin therapy for hyponatremia pending diagnostics? Answer: Empirical treatment for hyponatremia depends primarily on the mechanism. Thus the patient’s volume status must be assessed to determine appropriate fluid therapy.

Question: Why don’t animals with central diabetes insipidus have hypernatremia? Answer: ADH is not necessary to maintain a normal pOsm. Even patients with complete central diabetes insipidus can have a normal pOsm, provided they are able to drink.17 However, it is important to realize that their obligate urinary water losses are exceptionally high. Life-threatening hypernatremia can ensue in a matter of a few hours in these patients, which can lead to the clinical description of “water hunger” (extreme water- seeking behavior, even after short periods of deprivation) in these patients.

reference ranges are often wider than differences that are important for clinical decision making. For example, a patient may normally have a plasma Na+ concentration of 145 mEq/L. If water losses are ongoing and the plasma Na+ concentration begins to increase, ADH and thirst will be fully stimulated before the plasma Na+ concentration reaches 150 mEq/L, which may still be well within the laboratory’s reported reference range. Such a change in plasma Na+ concentration for a patient that is receiving intravenous fluid therapy and unable to drink would warrant a change in the free water prescription. By the time the plasma Na+ concentration increases beyond the reference range, even by 1 mEq/L, it may be clinically significant and abnormal for that animal. Similarly, trends in plasma Na+ concentration can be very significant in patients being monitored over

COMPENDIUM October 2007 Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia CE 599

Hyponatremia

Hypoosmolar hyponatremia Pseudohyponatremia

1 Defect in renal water excretion 1 Hyperlipidemia • Volume depletion • Advanced renal failure 2 Hyperproteinemia • Diuretics • SIADH • Decreased solute intake Translocational hyponatremia

2 Water intake exceeding a normal 1 Hyperglycemia renal excretory capacity (normal osmolar gap)

2 Exogenous solutes • Mannitol • Glycine

Figure 8. Low Na+ concentration can be hypoosmolar or hyperosmolar (translocational) or can reflect pseudohyponatremia.

a prolonged period, such as cats receiving subcutaneous in plasma Na+ concentration should not be dismissed fluids for chronic renal failure. If such a cat were to have and omitted from the problem list because the osmoreg- a plasma Na+ concentration of 150 to 152 mEq/L con- ulatory system controls the pOsm within such a narrow sistently for several months, followed by an upward range in healthy animals.2 trend of 153, 155, and 156 mEq/L over the next few months, the increase may be very significant for that cat, HYPONATREMIA despite the value consistently remaining within the lab- Diagnostic Approach oratory’s reported reference range for cats.c The plasma Na+ concentration does not measure the When clinicians are dealing with laboratory values in total Na+ content in the ECF and, therefore, does not which minor changes can be clinically meaningful, the reflect the volume of ECF or total body fluid. The plasma “noise” of day-to-day measuring variance can cloud Na+ concentration merely reflects the amount of water interpretation. This makes it even more important for relative to the Na+ content, which is determined by the each clinician to become familiar with the assay from osmoregulatory system. Thus hyponatremia is a disorder his or her specific laboratory. Generally speaking, any of water balance because the amount of water is increased deviation of plasma Na+ concentration should be noted. relative to the amount of Na+ in the ECF. The Na+ con- When it is unexpected, the first course of action may be tent of the ECF (and, therefore, the body), and thus the verification of repeatability. However, small deviations total body fluid volume, can be normal, increased, or decreased in hyponatremia. Further localization of c Although uncommon, cats with chronic renal failure that receive hyponatremia by mechanism is shown in Figure 8. subcutaneous fluids can receive a sufficient chronic Na+ load such that the kidneys cannot excrete it and hypernatremia ensues. The Hyponatremia is usually associated with hypoosmo- fact that this often occurs before clinical volume overload may lality. Exceptions are so-called pseudohyponatremia and reflect an inadequate thirst response in this species. translocational hyponatremia secondary to exogenous

October 2007 COMPENDIUM 600 CE Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia

glycine) will lead to water translocation from inside to outside cells and cause hyponatremia (Figure 6). In diagnosing true hypoosmolar hyponatremia, two principal pathophysiologic mechanisms must be consid- ered.13 The first is impaired renal excretion of free water, or impaired diluting ability. In this situation, the animal can- s e

e not excrete maximally dilute urine (urine osmolality R

r [uOsm] <100 mOsm/L). Several disease states and condi- a m a

T tions can be associated with impaired renal diluting capac-

y b

n ity and free water excretion. Most common is o i t a

r hypovolemia, which can reflect either absolute volume t s u l

l depletion caused by gastrointestinal, transepidermal, or I Figure 9. A patient with Addison’s disease typifies renal losses or high-volume edematous states associated hypovolemic hyponatremia. Renal Na+ wasting results in a with reduced effective plasma volume. When absolute or sufficient decrease in ECF to stimulate ADH.Thirst is stimulated effective plasma volume is decreased, the ensuing reduced + despite a decreasing plasma Na concentration, which falls further renal perfusion limits the quantity of glomerular filtrate as the ECF volume declines.The hyponatremia is illustrated by the 2:1 ratio of water molecules to Na+. Water moves reaching the diluting segment of the kidneys. In volume + intracellularly to maintain an equivalent water concentration depletion, Na conservation in the proximal nephron is inside and outside cells (red arrows of unequal size). enhanced and less Na+ reaches the thick ascending limb of the loop of Henle. ADH may also be released in response to volume depletion, overriding the effect of the hypo- tonicity and compounding the defect in water excretion. osmoles, in which a large concentration of alternative Impaired diluting ability is also a feature of advanced osmoles is present (Figure 6). renal failure13 in which the ability to excrete water is Pseudohyponatremia results from an in vitro artifact approximately 20% of that of a normal, healthy kidney.14 observed when measuring serum Na+ concentration by It is a common misconception that renal azotemia is flame photometry in the presence of elevated plasma ruled out by the finding of hyposthenuria. In early and lipids or proteins. In these situations, the measured Na+ moderate renal failure, the kidneys retain some tubular concentration is lower than the true Na+ concentration.4 function and, therefore, meaningful diluting capacity.2,14 Although newer ion-selective electrodes have largely Urinary water excretion is also impaired when ADH eliminated this problem in undiluted samples, the term remains elevated in the presence of plasma hypoosmo- persists as a way to distinguish this in vitro phenomenon lality, as in hypovolemia. Figure 9 shows hypovolemic

The serum sodium concentration does not reflect the total amount of sodium in the extracellular fluid. from clinically significant hyponatremia. hyponatremia in a patient with Addison’s disease. Simi- Translocational hyponatremia may be divided into larly, gastrointestinal Na+ losses in a patient that is still two categories: (1) conditions in which the measured drinking water will result in hypovolemic hyponatremia. and calculated serum osmolalities are the same (hyper- In contrast to hypovolemia, in which ADH elevation glycemia); and (2) conditions in which there is an osmo- is appropriate (i.e., in response to hypovolemic shock), lar gap: some osmoles are clearly present and are the syndrome of inappropriate ADH secretion (SIADH) measured but have not been identified. Unidentified refers to conditions in which the ADH elevation lead- osmoles may include mannitol, glycine, and alcohols ing to hyponatremia is not a consequence of volume such as ethanol and ethylene glycol.2 Only impermeant depletion. The urine Na+ concentration in these patients solutes (e.g., glucose in the absence of insulin, mannitol, is greater than 20 mEq/L, indicating no volume deple-

COMPENDIUM October 2007 Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia CE 601

tion. SIADH, although well described in humans, is Because the kidneys are ordinarily highly efficient in rarely reported in dogs or cats.4 In humans, SIADH excreting water, patients with primary polydipsia are may be associated with the following conditions: more likely to have overt hyponatremia when impaired (1) ectopic production of ADH by certain neoplasms; renal water excretion is concurrently present.9 Thus it is (2) administration of exogenous ADH or oxytocin; clinically important to assess patients with primary (3) enhanced hypothalamic ADH secretion due to neu- polydipsia and hyponatremia for concurrent renal dilut- ropsychiatric disorders, drugs, or pulmonary disease; or ing defects such as SIADH or abnormally regulated (4) drug-related potentiation of ADH effects.2 ADH secretion.18 Certain diuretics, such as loop diuretics and thiazides, impair renal water excretion because they decrease Na+ Clinical Approach transport in the diluting segment of the nephron.2 For the clinician, distinguishing between the physical Decreased renal diluting ability is also reported with causes of hyponatremia relies heavily on a complete his- highly reduced dietary solute intake.15 This is unlike tory and an analysis of the patient’s other problems. The other causes of decreased free water excretory capacity first question that should come to mind when assessing because the uOsm is less than 100 mOsm/L. In humans, any patient with hyponatremia is, “Why is there too this occurs with the practice of beer potomania—a syn- much water?” Evaluation of a blood sample for lipemia drome in which individuals consume large quantities of and assessment of the plasma protein concentration can beer (which is hypoosmolar) but an inadequate amount rapidly rule out pseudohyponatremia. Translocational

Any abnormality in serum sodium concentration warrants clinical attention; this includes minor changes beyond laboratory reference ranges and changes within the reference range that deviate from typical values for an individual patient. of food, leading to insufficient dietary solute and hyponatremia is easily ruled out by assessment of the impaired ability to excrete free water.13,16 This would be a serum glucose concentration and the absence of a his- highly unexpected mechanism in dogs or cats. tory of administration of an exogenous solute, such as The second principal mechanism for the development mannitol. The clinician is then left to distinguish pri- of hypoosmolar hyponatremia is when water intake mary polydipsia exceeding renal excretory capacity from exceeds maximal renal excretory capacity. This is a far impaired diluting capacity (impaired water excretion), less common cause of hyponatremia than is impaired although the two may exist simultaneously. The history renal water excretion. Normally, renal diluting capacity is often illuminating in cases of true psychogenic poly- is adequate to keep pace even with ardent drinkers. dipsia, such as a “high-strung,” bored dog. Other pri- Thus most primary polydipsias do not result in overt mary polydipsias rarely cause overt hyponatremia in the hyponatremia. In humans, hyponatremia may occur presence of normal renal diluting capacity. with polydipsia accompanying psychosis.13 Perhaps anal- The patient should be carefully assessed for ECF vol- ogous in dogs is so-called psychogenic polydipsia, in which ume depletion. Some animals can sustain a loss of 5% nervous or hyperactive dogs respond to the stress of body weight from ECF volume depletion without confinement or boredom by drinking obsessively.17 Such detectable clinical signs.19 Because clinical estimates of dogs usually have hyposthenuria and mild hypona- body fluid deficits can be inaccurate,20 the patient his- tremia, although they may remain within a laboratory’s tory should be carefully scrutinized for clues to suggest published range. Often, removing these patients from gastrointestinal or urinary fluid loss. their routine, such as through overnight hospitalization For more difficult cases, key laboratory evaluations with free access to water, will disrupt the unwanted include pOsm, uOsm, and urine Na+ concentration. uOsm behavior and demonstrate the polydipsia as primary by can be used to help distinguish impaired water excretion revealing a concentrated urine specific gravity when the from polydipsia. Hyponatremic animals with a uOsm abnormal drinking routine is interrupted. greater than 100 mOsm/L have impaired water excretion.

October 2007 COMPENDIUM 604 CE

A decreased pOsm with a uOsm less than 100 mOsm/L suggests primary polydipsia (when polyuria is present) or low solute intake (in which case, a recognizable increase in urine volume may be notably absent). Decreased solute intake is rare in the veterinary setting; therefore, a low uOsm typically suggests primary polydipsia. A low urinary Na+ concentration (<20 mEq/L in human patients) suggests hypovolemia as the cause of hyponatremia. Veterinary patients with SIADH, diuretic-induced hyponatremia, mineralocorticoid deficiency, or renal failure should have a urine Na+ concentration greater than 20 mEq/L.11 The clinical signs of hyponatremia arise from the effects on the central nervous system. Reduction of the plasma Na+ concentration drives water from the ECF into cells. Clinical signs—lethargy, confusion, nausea, vomiting, seizures, and coma—result from cerebral edema. The development of signs depends on the magnitude of hyponatremia and the rate at which it developed; the signs of chronic hyponatremia are generally more subtle and nonspecific than those of acute hyponatremia.13 Although severe hyponatremia can lead to neurologic signs, too rapid a rate of correction of this disorder can also lead to brain disease, termed myelinolysis. Clinical signs may include weakness, obtundation, ataxia, paresis, and coma, and death may result. Myelinolysis has been well documented in humans, dogs, rats, and rabbits as a result of rapid correction of chronic (>48 hr duration) hyponatremia.21–23 Some canine patients have survived the development of myelinolysis with supportive care.22–24 The pathogenesis of myelinolysis is complex and incompletely understood, but it appears that the lower the rate of correction of chronic hyponatremia, the lower the risk of myelinolysis. It has, therefore, been recommended that chronic hyponatremia should be corrected as slowly as possible, with an upper rate limit of no more than 10 mEq/L during any 24-hour period.21

Treatment Regardless of the cause of hyponatremia, moderation in therapy is key. The serum Na+ concentration should be measured frequently and therapy adjusted to ensure that chronic hyponatremia is not corrected by more than 10 mEq/L/day.4 Although there are no rules for how frequently to monitor (and frequency may decrease as severely affected patients improve), we recommend using a central venous catheter to allow monitoring as often as every 3 to 4 hours initially.

COMPENDIUM October 2007 Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia CE 605

Patients with hypovolemia (negative sodium balance) intoxication are rare in veterinary medicine; however, require restoration of the ECF Na+ content; this will these patients may have clinical signs related to hypo- return control of ADH secretion and thirst to osmotic tonicity. Treatment generally consists of water restriction factors, and the kidneys will excrete the excess free water and careful monitoring. once the diluting defect resulting from the hypovolemia is corrected. Thus patients with hypovolemia can initially be HYPERNATREMIA treated safely with isotonic (or very mildly hypertonic for Hypernatremia is also a disorder of water balance. It that patient) fluid replacement. In a hyponatremic patient, reflects a state of too little water relative to Na+ content in a fluid that is truly isotonic would, in fact, be of lower the ECF. The Na+ content of the body can be normal, osmolality than a fluid that is isotonic for a normal increased, or decreased. Similar to hyponatremia, in patient. Thus typical balanced electrolyte solutions used in patients with hypernatremia, the plasma Na+ concentration hyponatremic patients are actually mildly hypertonic for does not provide a measurement of an animal’s volume sta- those individuals. Fluids that are hypotonic to the patient tus. The first question a clinician should ask after detecting should always be avoided, as should hypertonic saline, hypernatremia is, “Why is there too little water?” unless death from hypovolemic shock is imminent. How- Many cases of hypernatremia develop while patients are ever, even if isotonic fluids are used, as indicated above, hospitalized, and the diagnosis involves analysis of the solute-free water will be excreted once hypovolemia is cor- patient’s fluid intake and losses. The presence or absence rected, and this alone could lead to rapid correction of of hypovolemia helps to distinguish pure water losses from hyponatremia; thus, serial monitoring of serum Na+ con- hypotonic fluid losses. uOsm can help to distinguish the centration is essential in these patients. It is also important cause of hypernatremia. In patients with extrarenal hypo- to remember that hypovolemia is a result of fluid losses tonic losses, such as those with severe diarrhea, the renal exceeding intake, so a provision must be made in the fluid salt-conserving mechanisms should be maximally stimu-

Chronic hyponatremia must be corrected slowly to avoid the development of myelinolysis. therapy prescription to meet these ongoing losses, in addi- lated to preserve ECF volume. The urine of these patients tion to restoring deficits, until the underlying disease (e.g., has a low Na+ concentration and a low water content due Addison’s disease, primary gastrointestinal disease) can be to high ADH, but the uOsm is high because other solutes resolved with appropriate specific therapy. are present. Patients with a very low uOsm (<150 Patients with translocational hyponatremia may mmol/L)25 in a setting of hypertonicity and polyuria have have different fluid needs, depending on the osmole diabetes insipidus, which may be central or nephrogenic.2 involved. The most common clinical scenario is unregulated diabetes mellitus, in which hypovolemia is often Diagnostic Approach present and needs to be corrected. Subsequent initiation Impaired water intake leading to a water deficit, as of insulin therapy lowers plasma glucose levels and shown in Figure 10, is one cause of hypernatremia. In returns the excess ECF water to its intracellular location. dogs, pOsm increases of as little as 1% stimulate thirst.26 Patients with edema or ascites have excess ECF Na+ These deviations are normally rapidly corrected by and an even greater excess of ECF water. Therapy is water ingestion; thus, sustained hypertonicity implies a more challenging because these patients have a defect in thirst sensation, restricted access to water, or a decreased effective plasma volume and renal mecha- physical inability to drink. nisms for retention of Na+ are stimulated. Correction of Primary hypodipsia is a condition of diminished or hyponatremia generally requires restriction of water absent thirst that results in hypernatremia. Thirst is the intake to below the level of urine output. This can be ultimate defense against hypernatremia. If an animal very difficult because thirst is stimulated. Therapy for does not drink, hypernatremia will develop due to nor- the primary underlying disorder is required; therefore, mal insensible water losses. Hypodipsia is usually associ- therapy before diagnostics is generally not indicated. ated with identifiable hypothalamic disease.2,4,17 If ADH Patients with hyponatremia secondary to water production is intact, renal water conservation will miti-

October 2007 COMPENDIUM 606 CE Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia

2 Panting s s e e e e R R

a a r r a a m m a a T T

y y b b

n n o o

i i t t

a 1 ADH deficiency or a r r t t

s lack of efficacy s u u l l l l I I Figure 10. When water is available, thirst is the primary Figure 11. Excess water loss, such as from (1) urinary or defense against hypernatremia. When water is not available, (2) respiratory losses, predisposes a patient with obligate respiratory and urinary losses are not offset.The ECF inadequate water intake to hypernatremia. Excessive Na+ concentration increases (hypernatremia), illustrated by the urinary water loss may result from central or nephrogenic 2:1 ratio of Na+ to water molecules. ADH is stimulated, and the diabetes insipidus and can lead to hypernatremia if the patient is kidneys retain water (blue arrow), producing a small volume of unable to drink enough water to compensate for this loss. In this concentrated urine. Net water movement is from intracellular to situation, the ECF Na+ concentration increases (illustrated by the extracellular space until the water concentration is again 2:1 ratio of Na+ to water molecules) and net water movement is equivalent (red arrows of unequal size). In this situation, the patient from the intracellular to extracellular space (red arrows of unequal has a decreased intracellular fluid volume (shown as shrunken size).The patient has a decreased intracellular fluid volume (shown cell and brain), and ECF Na+ content is unchanged. as shrunken cell and brain), and ECF Na+ content is unchanged.

gate the hypernatremia, provided the defect in the thirst ity, weakness, behavior changes, hyperreflexia, disorien- mechanism is not severe. tation, ataxia, seizures, and coma. These signs result Essential hypernatremia2 is a similar condition in from water translocation to the hypertonic ECF and the which the osmostat in the hypothalamus is reset and a associated rupture of cerebral vessels4 and may be suffi- greater degree of hypertonicity is required to trigger the ciently severe and rapid in onset to impair the thirst thirst and ADH responses. A number of case reports response that would ordinarily protect the animal. have proposed this syndrome in a cat27 and several Inadequate free water intake in the presence of excess dogs28–32; miniature schnauzers appear to be overrepre- water loss (Figures 11 and 12) accounts for most cases of sented in some case series.4 hypernatremia. In humans, geriatric patients are particu- Salt toxicity resulting from ingestion of salt or admin- larly at risk due to decreased thirst.9 The same risk may istration of hypertonic fluids is rare in veterinary medi- apply to geriatric animals and would be increased in the cine. Nonetheless, it is an issue of too little water presence of declining renal concentrating ability. Water relative to salt, as opposed to a problem of too much intake is often impaired in very sick, hospitalized patients salt. These patients typically do not have significant due to debility, sedation, or other problems that impair clinical signs related to extracellular volume overload the ability to drink. Long-term use of intravenous or sub- unless cardiac disease is present, leading to intolerance cutaneous fluids that are isotonic and do not provide suf- of an acutely expanded ECF volume. Hypernatremia ficient free water will also lead to hypernatremia in associated with salt ingestion should be mild and tran- patients that do not drink. This is particularly true if renal sient, provided water intake is not impaired. In cases of water-conserving mechanisms are impaired. salt poisoning, or when hypertonic saline is given without free water, neurologic signs consequent to rapid Therapy decreases in brain cell volume include lethargy, irritabil- For all patients, ECF volume deficits must be replaced.

COMPENDIUM October 2007 Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia CE 607

Free Water Losses

Pure Water Losses Hypotonic Fluid Losses • Fever • Gastrointestinal fluid loss • Hyperventilation • Diuretic therapy • Panting • Osmotic diuresis • Central or nephrogenic • Movement of fluid to the diabetes insipidus third space • Burns

Fluid is lost from both the ECF loss exceeds intracellular intracellular and extracellular fluid loss. Signs of ECF volume compartments. Signs of ECF depletion are often present. volume depletion are rarely present.

Figure 12. Increased free water losses may result from pure water loss or hypotonic fluid loss.

The fluid therapy plan for hypernatremic patients must 5% dextrose in water. include a provision for maintenance and replacement of Hypernatremia that is known to have developed ongoing losses in addition to restoration of the free water acutely (over no more than 24 to 36 hr34) can be corrected deficit. Patients with mild hypernatremia that have been relatively rapidly. This may be observed in patients with restricted from water and are normal neurologically will acute water deprivation, especially in hot environments correct their own deficits when water is provided, and where respiratory water losses for thermoregulation are they do not require fluid therapy support. Therapeutic very high. Therapy requires rapid correction of both the correction of more severe hypernatremia when the patient free water and the ECF Na+ content deficits. This acute is sick requires replacement of the calculated water deficit time course is also likely in rare cases when hyperna- with fluid therapy. Data from the patient history about tremia results from solute administration (e.g., hypertonic the time course over which the hypernatremia likely fluid administration). These patients require both water developed are particularly important. administration and solute removal (with loop diuretics). The volume of the deficit can be estimated using the In contrast, patients with more chronic hypernatremia following equation33,d: adapt by increasing intracellular solutes in the brain to protect against the adverse effects of intracellular dehy- Free water deficit = 0.6 × body weight (kg) × dration. The initial response of the brain to hyperna- + [(plasma Na ÷ 148) – 1] tremia is to accumulate intracellular electrolytes, but this Water can be replaced either enterally (orally or by can impair brain function. So, with time, the brain accu- gastric tube) or intravenously with hypotonic saline or mulates organic solutes (idiogenic osmoles) such as 4,5,35 dThe value of 148 in this formula is modified from the stan- amino acids, trimethylamines, and myoinositol. dard 140 mEq/L used in humans to better estimate a desired Although these adaptations diminish the effects of the target plasma Na+ concentration for dogs and cats. ECF hypertonicity, they put the patient at risk for cere-

October 2007 COMPENDIUM 608 CE Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia

bral edema if the hypernatremia is corrected too quickly. 13. Sterns RH, Ocdol H, Schrier RW, Narins RG: Hyponatremia: Pathophysiol- ogy, diagnosis, and therapy, in Narins RG (ed): Maxwell and Kleeman’s Clini- When these brain adaptations have taken place, hyper- cal Disorders of Fluid and Electrolyte Metabolism. New York, McGraw-Hill, natremia must be corrected more slowly. No ideal, uni- 1994, pp 583–615. versally safe rate of correction has been established for 14. Black RM: Diagnosis and management of hyponatremia. J Intensive Care dogs and cats in which neurologic signs of hyperna- Med 4:205–220, 1989. tremia are present; however, based on recommendations 15. Thaler SM, Teitelbaum I, Berl T: “Beer potomania” in non-beer drinkers: in human medicine, a rate of no more than 0.5 to 1 Effect of low dietary solute intake. Am J Kidney Dis 31(6):1028–1031, 1998. mEq/L/hr can serve as a guideline until the signs 16. Fenves AZ, Thomas S, Knochel JP: Beer potomania: Two cases and review of the literature. Clin Nephrol 45(1):61–64, 1996. resolve. In human medicine, a rate of correction of no 9 17. Feldman EC, Nelson RW: Canine and Feline Endocrinology and Reproduction. more than 0.5 mEq/L/hr has been recommended. St. Louis, Saunders, 2004. Once neurologic signs have resolved, the rate can be 18. van Vonderen IK, Kooistra HS, Elpetra PM, Rijnberk A: Disturbed vaso- adjusted to provide the remainder of the correction over pressin release in 4 dogs with so-called primary polydipsia. J Vet Intern Med the next 48 hours. Deterioration of the neurologic status 13(5):419–425, 1999. with correction of hypernatremia suggests cerebral 19. Hardy RM, Osborne CA: Water deprivation test in the dog: Maximal normal values. JAVMA 174(5):479–483, 1979. edema and too rapid a rate of correction. When the 20. Hansen B, DeFrancesco T: Relationship between hydration estimate and time course over which hypernatremia developed is body weight change after fluid therapy in critically ill dogs and cats. J Vet unknown, clinicians should err on the side of slow, Emerg Crit Care 12(4):235–243, 2002. steady correction. 21. Laureno R, Karp BI: Myelinolysis after correction of hyponatremia. Ann Int Med 126(1):57–62, 1997. REFERENCES 22. Churcher RK, Watson ADJ, Eaton A: Suspected myelinolysis following rapid correction of hyponatremia in a dog. JAAHA 35:493–497, 1999. 1. Oh GS, Carroll HJ: Regulation of intracellular and extracellular volume, in Arieff AI, DeFronzo RA (eds): Fluid, Electrolyte, and Acid-Base Disorders. 23. O’Brien DP, Kroll RA, Johnson GC, et al: Myelinolysis after correction of New York, Churchill Livingstone, 1995, pp 1–22. hyponatremia in two dogs. J Vet Intern Med 8(1):40–48, 1994. 2. Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte Disorders. 24. O’Brien DP: CNS effects of sodium imbalances. Proc 24th ACVIM New York, McGraw-Hill, 2001. Forum:323–324, 2006. 3. Wellman ML, DiBartola SP, Kohn CW: Applied physiology of body fluids 25. Halperin ML, Goldstein MB: Fluid, Electrolyte, and Acid-Base Physiology: A in dogs and cats, in DiBartola SP (ed): Fluid, Electrolyte, and Acid-Base Disor- Problem-Based Approach. Philadelphia, WB Saunders, 1999. ders in Small Animal Practice. St. Louis, Saunders, 2006, pp 3–26. 26. O’Connor WJ, Potts DJ: Kidneys and drinking in dogs, in Michell AR (ed): 4. DiBartola SP: Disorders of sodium and water: Hypernatremia and hypona- Renal Disease in Dogs and Cats: Comparative and Clinical Aspects. Oxford, tremia, in DiBartola SP (ed): Fluid, Electrolyte, and Acid-Base Disorders in Blackwell Scientific Publications, 1988, pp 30–47. Small Animal Practice. St. Louis, Saunders, 2006, pp 47–79. 27. Dow SW, Fettman MJ, LeCouteur RA, Allen TA: Hypodipsic hyperna- 5. Morrison G, Singer I: Hyperosmolar states, in Narins RG (ed): Maxwell and tremia and associated myopathy in a hydrocephalic cat with transient hypopi- Kleeman’s Clinical Disorders of Fluid and Electrolyte Metabolism. New York, tuitarism. JAVMA 191(2):217–221, 1987. McGraw-Hill, 1994, pp 617–658. 28. Crawford MA, Kittleson MD, Fingk GD: Hypernatremia and adipsia in a 6. Kirchner KA, Stein JH: Sodium metabolism, in Narins RG (ed): Maxwell dog. JAVMA 184(7):818–821, 1984. and Kleeman’s Clinical Disorders of Fluid and Electrolyte Metabolism. New York, McGraw-Hill, 1994, pp 45–80. 29. Hawks D, Giger U, Miselis R, Bovee KC: Essential hypernatremia in a young dog. J Small Anim Pract 32:420–424, 1991. 7. Briggs JP, Singh I, Sawaya BE, Schnermann J: Disorders of salt balance, in Kokko JP, Tannen RL (eds): Fluids and Electrolytes. Philadelphia, WB Saun- 30. Bagley RS, de Lahunta A, Randolph JF, Center SA: Hypernatremia, adipsia, ders, 1996, pp 3–62. and diabetes insipidus in a dog with hypothalamic dysplasia. JAAHA 29:267–271, 1993. 8. Cohen M, Post GS: Water transport in the kidney and nephrogenic diabetes insipidus. J Vet Intern Med 16(5):510–517, 2002. 31. DiBartola SP, Johnson SE, Johnson GC, Robertson GL: Hypodipsic hypernatremia in a dog with defective osmoregulation of antidiuretic hormone. 9. Sterns RH, Spital A, Clark AC: Disorders of water balance, in Kokko JP, JAVMA 204(6):922–925, 1994. Tannen RL (eds): Fluids and Electrolytes. Philadelphia, WB Saunders, 1996, pp 63–109. 32. Sullivan SA, Harmon BG, Purinton PT, et al: Lobar holoprosencephaly in a miniature schnauzer with hypodipsic hyponatremia. JAVMA 223(12):1783– 10. Zerbe RL, Robertson GL: Osmotic and nonosmotic regulation of thirst and 1787, 2003. vasopressin secretion, in Narins RG (ed): Maxwell and Kleeman’s Clinical Dis- orders of Fluid and Electrolyte Metabolism. New York, McGraw-Hill, 1994, pp 33. Fried LF, Palevsky PM: Hyponatremia and hypernatremia. Med Clin North 81–100. Am 81(3):585–609, 1997. 11. Blumenfeld JD, Vaughan ED: Renal physiology and pathophysiology, in 34. Sterns RH, Heilig CW, Narins RG: Water and sodium metabolism: Walsh PC, Retik AB, Vaughan ED, Wein AJ (eds): Campbell’s Urology. Hyponatremia and hypernatremia, in Massry SG, Glassock RJ (eds): Massry Philadelphia, WB Saunders, 2002, pp 169–227. and Glassock’s Textbook of Nephrology. Baltimore, Williams & Wilkins, 1995, pp 276–292. 12. DiBartola SP, Bateman S: Introduction to fluid therapy, in DiBartola S (ed): Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice. St. Louis, 35. Lien Y-HH, Shapiro JI, Chan L: Effects of hypernatremia on organic brain Saunders, 2006, pp 325–344. osmoles. J Clin Invest 85:1427–1435, 1990.

COMPENDIUM October 2007 Normal and Abnormal Water Balance: Hyponatremia and Hypernatremia CE 609

ARTICLE #1 CE TEST This article qualifies for 2 contact hours of continuing education credit from the Auburn University College of Veterinary CE Medicine. Subscribers may purchase individual CE tests or sign up for our annual CE program. Those who wish to apply this credit to fulfill state relicensure requirements should consult their respective state authorities regarding the applicability of this program. CE subscribers can take CE tests online and get real-time scores at CompendiumVet.com.

1. Effective osmoles c. used for provision of free water. a. move freely across cellular membranes and thus do d. used to expand the ECF volume. not induce net water movement across cell membranes. b. affect a solution’s tonicity. 7. A patient presenting with hypernatremia within 2 hours of ingesting a rock salt driveway deicer c. include urea and ethanol. should have its hypernatremia corrected d. are subtracted from ineffective osmoles to determine the osmolar gap. a. as rapidly as possible by provision of intravenous and/or enteral free water. b. over 24 to 48 hours by provision of enteral free 2. A patient with increased plasma Na+ content has water. a. hypervolemic hypernatremia. c. over 24 to 48 hours by provision of intravenous free b. hypovolemic hypernatremia. water. c. hypovolemia. d. as rapidly as possible for the first 35% of the calcu- d. hypervolemia. lated free water deficit and then over 24 to 48 hours.

3. A patient with hypernatremia has a. a salt balance disorder. 8. The osmolality of the ultrafiltrate as it enters the renal proximal tubule is b. a water balance disorder. c. too high a plasma Na+ content. a. the same as that of plasma. d. expanded intracellular volume. b. much higher than that of plasma. c. much lower than that of plasma. 4. Patients with congestive heart failure, edema, d. unpredictable. and hyponatremia have a. impaired renal diluting capacity due to hypovolemia. 9. Which of the following does not impair renal b. impaired renal diluting capacity due to decreased diluting ability? effective plasma volume. a. thiazide diuretics c. renal salt wasting. b. central diabetes insipidus d. primary polydipsia. c. markedly reduced dietary solute intake d. Addison’s disease 5. Which of the following values indicates only primary polydipsia? a. uOsm = 50 mOsm/L c. pOsm = 330 mOsm/L 10. Myelinolysis b. uOsm = 310 mOsm/L d. pOsm = 360 mOsm/L a. is caused by translocational hyponatremia. b. is the delayed effect of incomplete correction of 6. A 5% dextrose solution given intravenously to a chronic hypernatremia. nondiabetic patient with a normal plasma Na+ c. can result from rapid correction of chronic hypona- concentration is tremia. a. hypoosmolar but hypertonic. d. is rare, provided glucocorticoids are given before any b. hypertonic and hyperosmolar. correction of the plasma Na+ concentration.

October 2007 COMPENDIUM