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Acs0824 Disorders Of Water And Sodium Balance


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  • 1. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 1 24 DISORDERS OF WATER AND SODIUM BALANCE Richard H. Sterns, M.D. Overview of Body Fluid Homeostasis mated with reasonable accuracy from the concentrations of the ma- Life takes place in an aqueous solution. Cells, the blood bringing jor extracellular solutes, as follows: nutrients and oxygen to them, and the interstitial fluid bathing them are all mostly water. Each day, water and salt are lost and replaced. [Glucose] BUN Posm ≅ 2 × plasma [Na+ ] + 18 + 2.8 To maintain stability of the internal milieu, body fluids are processed by the kidney, guided by intricate physiologic control systems that The multiple of 2 reflects the anions accompanying sodium ions, regulate fluid volume and composition. and 18 and 2.8 are the corrections required to convert glucose and urea nitrogen concentration from mg/dl (the units used by most lab- DISTRIBUTION AND COMPOSITION OF BODY WATER oratories in the United States) to mmol/L. Exogenous solutes (e.g., Water accounts for approximately half of an adult human’s body ethanol, methanol, ethylene glycol, glycine, mannitol) are measured weight. Because fat contains little water, individuals with more body by osmometers but are not included in the formula shown above. A fat have less body water. On average, total body water constitutes discrepancy between the measured and the calculated plasma osmo- 60% of lean body weight in young men, 50% in young women and lality values (an osmolar gap) is useful clinically as a way to recognize older men, and 45% in older women. Two thirds of body water is the presence of an exogenous solute.2 intracellular and the remainder is contained in the extracellular flu- id compartment, which includes intravascular (plasma) and intersti- Fluid Movement between Body Fluid Compartments tial fluid. Small amounts of water are also contained in bone, dense The intravascular and interstitial subdivisions of the extracellu- connective tissue, digestive secretions, and cerebrospinal fluid.1 lar fluid compartment are separated by capillary walls that are Extracellular solutes are predominantly sodium salts (primarily a freely permeable to small extracellular solutes but relatively imper- mixture of NaCl and NaHCO3). Thus, extracellular fluid can be meable to plasma proteins. Protein-free saltwater continuously thought of as saltwater. Except for protein (present at a higher con- moves across the capillary endothelial barrier by filtration, driven centration in plasma [approximately 1 mmol/L] than in interstitial by a hydrostatic pressure gradient (generated by contractions of fluid), the compositions of the intravascular and interstitial subdivi- the heart), which forces fluid from the capillary into the intersti- sions of the extracellular fluid compartment are similar. tium, and an oncotic pressure gradient (the consequence of the os- The sodium-potassium adenosine triphosphatase (Na+,K+- motic force created by intravascular protein), which draws intersti- ATPase) pump on cell membranes keeps intracellular sodium at tial fluid into capillaries [see Figure 1]. These so-called Starling low levels. Potassium, the dominant intracellular cation, is electri- forces, which regulate the disposition of fluid within the extracellu- cally balanced, in large part, by anionic charges on impermeant lar compartment, determine how much extracellular saltwater is macromolecules. Stability in the number of intracellular anionic contained in intravascular plasma and how much is in interstitial charges makes the total solute content of cells much less variable fluid [see Disorder of Saltwater Excess: Edematous States, below]. than that of the extracellular fluid. Sodium salts, urea, glucose, and other small extracellular solutes freely cross the capillary wall, achieving similar concentrations in Osmolality the interstitial fluid and plasma.Thus, changes in plasma osmolal- Extracellular and intracellular fluids contain different types of ity do not influence water movement between the intravascular solutes, but the concentrations of solutes inside and outside of cells and interstitial fluid compartments. are equal. Concentration differences exist only transiently because Fluid movement between the extracellular and the intracellu- they create an extremely strong force for water movement across cell lar fluid compartments is unaffected by Starling forces. Rather, membranes. Osmotic pressure moves water rapidly to the fluid com- transcellular water movement is driven by osmotic forces, a func- partment with the higher solute concentration until concentrations tion of the concentration of solutes in the extracellular fluid. A de- once again become equal.The osmotic pressure responsible for wa- crease in extracellular solute concentration (hypotonicity) drives ter movement across cell membranes depends on the total number water into cells, causing cell swelling; an increase in the concentra- of solute particles (osmoles) dissolved in solution, a property known tion of exclusively extracellular solutes (hypertonicity) draws fluid as osmolality.2 Osmolality is usually expressed as milliosmoles of out of cells, dehydrating them. solute per kilogram of solvent (mOsm/kg), but it can be thought of Not all solutes contribute to the tonicity of extracellular fluid.2 more simply as the number of millimoles of solute particles per liter Permeant solutes such as urea and ethanol readily cross cell mem- of solution. A solute particle’s contribution to osmolality is indepen- branes, achieving equal concentrations in the extracellular and intra- dent of its charge and molecular size. Ionic substances such as sodi- cellular fluid compartments without driving transcellular water um chloride that dissociate in solution contribute more than one os- movement and without affecting cell volume. Such solutes, which in- motically active particle. Sodium salts, glucose, and urea, commonly crease plasma osmolality without altering plasma tonicity, are some- measured as blood urea nitrogen (BUN), are responsible for most of times called ineffective osmoles. Impermeant solutes are excluded the solute particles normally present in extracellular fluid. Plasma os- from cell water either by active transport (e.g., sodium ions) or be- molality can be measured directly with an osmometer or can be esti- cause the cell membrane is impermeable to them (e.g., mannitol).
  • 2. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 2 um is bound to bone and is therefore osmotically inactive.) Luminal Membrane Thus, the plasma sodium concentration is, in effect, a measure of the concentration of tonicity of all body fluids.3 In the absence of an osmolar gap, the plasma sodium concentration is a more valid measure of body fluid tonicity than plasma osmolality (which in- Na+ cludes the ineffective osmole, urea). With a few exceptions, most Tubular Tubular Peritubular notably hyperglycemia, a low plasma sodium concentration indi- Lumen Cell Capillary cates hypotonicity and cell swelling, whereas a high plasma sodium X concentration indicates hypertonicity and cellular dehydration. 3Na+ RENAL PROCESSING OF BODY FLUIDS Na+, K+ - ATPase Glomerular Filtration Approximately 170 L of extracellular saltwater containing over 2K+ 25,000 mmol of sodium are filtered by the glomerulus each day. Although glomerular hydrostatic pressure is considerably higher K+ than the pressure of other capillary beds, the Starling forces that – + control fluid movement between intravascular and interstitial fluid also drive glomerular filtration.The glomerular filtrate contains the Basolateral same concentrations of sodium and other solutes as interstitial flu- Membrane id and is nearly protein free. Figure 1 Sodium reabsorption by the renal tubules is driven Tubular Reabsorption by the Na+, K+-ATPase pump in the basolateral (blood side) On a conventional diet, all but 2 L of filtered fluid and all but membrane, which maintains a low sodium concentration within 175 mmol of filtered sodium is reabsorbed by the renal tubules. the tubular cell. Filtered sodium in the tubular lumen enters the Regulation of tubular reabsorption of salt and water is the key to re- cell down its concentration gradient via a transmembrane carri- nal regulation of body fluid balance.4 er (which may also transport another solute, X) or via a channel At the end of the proximal tubule, the remaining filtrate has the in the luminal membrane [see Figure 2]. same sodium concentration as plasma has; as the filtrate passes through downstream tubular segments, it undergoes major changes Such solutes, which cause both hyperosmolality and hypertonicity, in composition. In these more distal segments, sodium and water re- are sometimes called effective osmoles. absorption are uncoupled; salt can be reabsorbed without water, and water can be reabsorbed without salt.Thus, depending on con- Body Fluid Tonicity and the Plasma Sodium Concentration ditions, the sodium concentration of the final urine can vary from Normally, sodium salts are the major effective osmoles in extra- less than 1 mEq/L to nearly 300 mEq/L, and urine osmolality can cellular fluid, and potassium salts are the major effective osmoles vary from one sixth (50 mOsm/kg) to four times (1,200 mOsm/kg) in cells. Given that effective osmolality is equal in all fluid com- that of plasma. partments, body fluid tonicity can be described by the following The process of sodium reabsorption is mediated by carriers or equation: channels embedded in the tubular cell’s luminal and basolateral Tonicity ≅ (blood side) membranes. In each nephron segment, sodium reab- 2 (Exchangeable Na+ + Exchangeable K+ ) sorption is powered by the so-called sodium pump, Na+,K+- 2 × Plasma [Na+] ≅ ATPase, which is located on the blood side of the tubular cell [see Total body water therefore, Figure 1].This sodium pump exports sodium from the cell, lower- Exchangeable Na+ + Exchangeable K+ ing the intracellular sodium concentration.The lowered concentra- Plasma [Na+] ≅ tion of cellular sodium creates an electrochemical gradient driving Total body water sodium from the tubular lumen into the cell.Tubular segments at (Only the exchangeable fractions of sodium and potassium are various regions of the nephron utilize different luminal mechanisms included in the equation, because one third of overall body sodi- for sodium reabsorption [see Table 1 and Figure 2]. Luminal ex- Table 1—Sodium Transport in Different Nephron Segments Glomerular Mechanism of Luminal Nephron Segment Physiologic Regulation Diuretic Site of Action Filtrate Reabsorbed Sodium Entry + + Na -H exchange; cotrans- Angiotensin II; renal nerves; Carbonic anhydrase inhibitors (e.g., Proximal tubule 60%–70% port with glucose and other peritubular Starling forces acetazolamide) organic solutes Flow dependent; peritubular Loop diuretics (e.g., furosemide, Na -K -2Cl - cotransport + + Loop of Henle 20%–25% Starling forces bumetanide, ethacrynic acid) Na -Cl - cotransport + Distal tubule 5% Flow dependent Thiazide diuretics Collecting tubule 4% + Na channels Aldosterone; atrial natriuretic factor Potassium-sparing diuretics (e.g., amiloride, triamterene, spironolactone)
  • 3. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 3 changers, cotransporters, and ion channels along the nephron are nels—called aquaporins—are inserted in the luminal membrane of subject to physiologic control, and they can be inhibited pharmaco- the distal tubule and collecting duct.7,8 When plasma levels of ADH logically by specific diuretic agents.5 Mutations in these transport are high, water is attracted osmotically from the tubular lumen to proteins are responsible for well-defined clinical disorders.6 the hypertonic medullary interstitium, permitting excretion of a The luminal membrane of the collecting duct is impermeable to small volume (as little as 0.5 L daily) of concentrated urine. water in the absence of arginine vasopressin, an antidiuretic hor- REGULATION OF BODY FLUID VOLUMES mone (ADH).Thus, when plasma ADH levels are low, this segment progressively reduces the osmolality and sodium concentration of Saltwater (isotonic saline) is confined to the extracellular space. the final urine and permits the excretion of large volumes (as much Accumulation of saltwater expands extracellular volume; loss of salt- as 20 L daily) of dilute urine. In the presence of ADH, water chan- water causes volume depletion. In either case, changes in saltwater balance do not alter the plasma sodium concentration or cell vol- ume. By contrast, so-called electrolyte-free water, or pure water, is distributed throughout body fluids, affecting both extracellular and intracellular fluid compartments. Because only one third of body water is extracellular, electrolyte-free water has only one third the impact on extracellular volume that saltwater has; however, unlike saltwater balance, electrolyte-free water balance has a major impact on the plasma sodium concentration, body fluid tonicity, and cell volume. Extracellular and intracellular fluid volumes are maintained by separate but interacting control systems [see Table 2]; the extracellu- Proximal lar system primarily regulates urinary sodium excretion, whereas Tubule the intracellular system regulates the intake and excretion of water. Distal Tubule Extracellular fluid volume maintains a proper degree of vascular Na+ fullness, a variable that is sensed by atrial stretch receptors and arte- rial baroreceptors. Intracellular volume is regulated by hypothalam- H+ Na+ ic osmoreceptor cells that swell or shrink in response to changes in Na+ Cl– plasma tonicity. Glucose Control of Extracellular Fluid Volume Phosphate Amino Acids In a healthy person, the amount of sodium in the extracellular Citrate space can vary considerably, depending on dietary salt intake. On the other hand, under normal conditions, the extracellular sodium concentration remains almost constant because of physiologic con- Collecting trol systems that tightly regulate water intake and excretion. In Tubule healthy persons, more salt in the extracellular space means an ex- Na+ panded extracellular fluid volume; less salt means a smaller extra- K+ cellular volume. In either case, the extracellular sodium concentra- 2Cl– Na+ tion does not change. + Sodium balance and intravascular volume are affected by numer- K+ ous hormonal and nonhormonal mediators; in addition to aldos- K K+ + - terone and angiotensin—the best known mediators of sodium excre- - tion—the sympathetic nervous system, natriuretic peptides, and changes in the renal circulation all play important regulatory roles [see Table 2].9 Because of redundancy and overlap in the control sys- tem, failure of a single factor does not cause major, sustained abnor- malities in intravascular volume.The relative importance of the vari- ous mediators that affect urinary sodium excretion are incompletely understood, and it is likely that some sodium regulatory factors re- Loop of Henle main undiscovered. Control of Intracellular Fluid Volume Water balance and cell volume are controlled by a single hor- monal mediator, arginine vasopressin [see Tubular Reabsorption, Figure 2 In each tubular segment, sodium enters the tubular above], which is released into the systemic circulation by the neuro- cell passively, down the favorable electrochemical gradient creat- hypophysis [see Table 2 and Figure 3].The hormone activates V2 re- ed by the Na+, K+-ATPase pump. Luminal sodium enters by a dif- ceptors on the basolateral membrane of principal cells in the renal ferent mechanism in each of the nephron segments. The proximal collecting duct, initiating a cyclic adenosine monophosphate−de- tubule reabsorbs filtered bicarbonate and other solutes, such as glucose, phosphate, amino acids, and citrate. An Na+, K+, 2Cl- pendent (cAMP-dependent) process that culminates in the inser- transporter mediates Na+ entry into the ascending limb of the tion of water channels (aquaporins) into the cells’ luminal mem- loop of Henle. The distal tubule has an Na+, Cl- cotransporter. branes.7,8 Modulation of the number of water channels controls Na+ enters the principal cells of the cortical collecting tubules urine osmolality and the rate of water excretion by the kidney.Vaso- through Na+ channels in the luminal membrane. pressin’s short half-life in the circulation and continuous shuttling of
  • 4. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 4 Table 2—Control of Body Fluid Volumes Electrolyte-Free Water Balance Saltwater Balance Day to Day Emergency Backup Extracellular volume Regulated variable Cell volume Arterial filling Vascular fullness Blood pressure Blood pressure Clinical indicator Plasma sodium concentration Edema Edema Sensors Baroreceptors, atrial volume receptors Hypothalamic osmoreceptors Baroreceptors, atrial volume receptors Renin-angiotensin-aldosterone system Antidiuretic hormone (arginine Antidiuretic hormone (arginine Sympathetic nervous system Mediators vasopressin) vasopressin) Atrial natriuretic peptide Thirst Thirst Starling forces in peritubular capillaries Urine osmolality Urine osmolality Affected variable Urinary sodium excretion Water intake Water intake aquaporins between the collecting duct’s cell membrane and cy- Normally, water intake and excretion are modulated to maintain tosol ensure that urinary water excretion responds rapidly to body fluid tonicity within a narrow physiologic range. However, un- changes in body fluid tonicity. der pathologic conditions, body cells can be exposed to a hypotonic Vasopressin levels are normally unmeasurable when the plasma or hypertonic milieu.10 The first response to osmotic stress is a com- sodium concentration falls to 135 mEq/L or lower [see Figure 3]. pensatory adjustment to intracellular electrolytes: loss of potassium Low levels of the hormone result in the excretion of large volumes in hypotonicity and accumulation of sodium and potassium in hy- of a maximally dilute urine (50 mOsm/kg). Above a sodium level of pertonicity. With time, changes in organic solutes dominate the 135 mEq/L, plasma vasopressin levels are linearly related to the response. plasma sodium concentration and increase measurably in response Most cells maintain relatively high concentrations of small, os- to changes in the plasma sodium concentration of as little as 1 motically active organic molecules known as organic osmolytes. Or- mEq/L. Once the plasma sodium concentration reaches approxi- mately 142 mEq/L, plasma vasopressin levels are high enough to promote the excretion of maximally concentrated urine (1,200 mOsm/kg). A rising plasma sodium concentration also causes hypo- thalamic cell volume receptors to relay signals to nearby thirst cen- ters. Mediated by thirst and changes in vasopressin secretion, the Plasma Vasopressin (pg/ml) Urine Osmolality (mOsm/kg) 5 1,200 plasma sodium concentration is normally prevented from rising above 142 mEq/L or falling below 135 mEq/L. Under day-to-day conditions, water intake, vasopressin secretion, and urinary free water excretion primarily respond to changes in the plasma sodium concentration created by variations in electrolyte- Thirst free water balance. Unlike sodium excretion, which is affected only by changes in intravascular volume, free water excretion can be af- fected by two types of stimuli—intravascular volume and tonicity. Under pathologic conditions, osmotic control of vasopressin secre- 0 50 tion and thirst can be overridden by hemodynamic stimuli.The hy- pothalamic neurons that secrete vasopressin receive neural input from baroreceptors in the great vessels and volume receptors in the 135 142 atria.When these receptors are stimulated by hypotension or by a Serum Sodium (mEq/L) major reduction in plasma volume, impulses are carried via cranial nerves IX and X.8 Vasopressin and thirst responses to hypovolemia Figure 3 Graph depicts the normal relation between plasma vaso- and hypotension can be regarded as back-up systems that serve to pressin levels and urine osmolality (black line) and the plasma maintain arterial blood volume under emergency conditions, sacri- sodium concentration (red line). Plasma vasopressin levels ficing tonicity to tissue perfusion. change within minutes in response to changes in plasma sodium, and urine osmolality changes within minutes in response to changes CELL VOLUME REGULATION IN HYPOTONICITY AND in vasopressin levels. When hydration reduces the plasma sodium HYPERTONICITY level below 135 mEq/L, plasma vasopressin becomes undetectable Cell volume is determined by the amount and concentration of and the urine becomes maximally dilute (osmolality, 50 mOsm/kg). Between sodium concentrations of 135 and 142 intracellular solute. Because intracellular and extracellular solute mEq/L, vasopressin levels are linearly related to the plasma sodi- concentrations must be equal, the relation between cell water and um, causing nearly a 100 mOsm/kg increase in urine osmolality for extracellular osmolality can be described by the following equation: every 0.5 mEq/L increase in sodium concentration. Above a plasma sodium concentration of 142 mEq/L, the urine is maximally con- Cell water centrated; increased water intake, mediated by thirst, then Cell volume = Extracellular osmolality becomes the major defense against progressive hypernatremia.
  • 5. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 5 ganic osmolytes are nonperturbing solutes; unlike sodium and whose normal kidneys are unable to excrete maximally dilute urine. potassium, their intracellular concentrations may vary widely with- A pathologically low plasma sodium concentration occurs when out affecting tertiary protein structure. Cells accumulate organic os- water is taken in at a time when renal diluting mechanisms are not molytes under hypertonic conditions and lose them when confront- functioning maximally because either (1) diuretics or tubular trans- ed with hypotonicity. port defects are blocking sodium reabsorption in the renal diluting The need for cell volume regulation is most imperative in the segments or (2) antidiuretic hormone levels are elevated. brain, where the rigid calvaria places sharp limits on the degree of tis- sue expansion or contraction that can be tolerated.10-13 An increase Nonosmotic Release of Vasopressin in brain water content of more than about 5% to 10% is incompati- Vasopressin is a water-retaining hormone that is released when ble with life.Variations in the intracellular concentration of organic water is needed. Because hypotonic hyponatremia normally inhibits osmolytes provide the brain with an astonishing ability to adapt to vasopressin secretion, detectable vasopressin in a patient who is hy- chronic osmotic disturbances. However, because changes in the os- ponatremic indicates that a nonosmotic stimulus for vasopressin re- molyte content of brain cells require a few days to develop fully, the lease must be present.Vasopressin action increases the urine osmo- brain is imperiled by rapid osmotic changes. Thus, acute hypona- lality, which can be thought of as a bioassay for the hormone. tremia or hypernatremia may be fatal at plasma sodium concentra- tions that are well tolerated chronically. Hemodynamic stimuli for vasopressin Hypovolemia, heart With sustained osmotic disturbances, adaptations that protect failure, and cirrhosis are the most common nonosmotic stimuli for against brain swelling and shrinkage also predispose to injury when antidiuretic hormone secretion.16-18 The hemodynamic abnormali- the osmotic disturbance is suddenly corrected. In chronic hypona- ties that stimulate vasopressin release also promote sodium reab- tremia, cellular solutes lost in the adaptive phase must be recovered sorption by the renal tubules; thus, these conditions result in both when the plasma sodium concentration returns to normal—a process sodium and water retention. that may require several days. Unless solute recovery keeps pace with the rising extracellular osmolality, brain cells will become dehy- Inappropriate antidiuretic hormone secretion Nonos- drated.11,12 This phenomenon may cause clinical complications [see motic release of vasopressin without a hemodynamic stimulus to Disorder of Water Excess: Hyponatremia, Chronic Hyponatremia, account for it is considered “inappropriate.” Patients with the syn- Complications of Therapy: Myelinolysis and Osmotic Demyelina- drome of inappropriate antidiuretic hormone secretion (SIADH) tion Syndrome, below]. Similarly, in chronic hypernatremia, accu- retain water because of nonosmotic release of vasopressin but have mulated solutes must be shed during correction of the electrolyte no abnormality in sodium balance, evidence of volume depletion, disturbance.10,13 Cells that have become acclimated to a hypertonic or tendency to form edema; in the steady state, sodium excretion environment lose organic osmolytes slowly because of slow turnover matches intake.8,12,19 Because of water retention, SIADH causes of the efflux mechanism, slow downregulation of hypertonically mild, subclinical volume expansion. Any additional volume expan- stimulated uptake pathways, or both.Thus, when chronic hyperna- sion is met by a brisk increase in urinary sodium excretion. tremia is corrected rapidly, brain cells swell to a greater than normal volume. Reset osmostat Reset osmostat is a variant of SIADH, com- monly seen in patients with chronic, debilitating illness; it is also a characteristic of normal pregnancy. Patients with this condition are Disorder of Water Excess: Hyponatremia able to dilute their urine normally but at a lower set-point than in Hyponatremia simply means a low plasma sodium concentra- normal individuals. Such patients are thus mildly hyponatremic, but tion. In most cases, hyponatremia is associated with a low plasma unlike other patients with SIADH, they are not predisposed to pro- osmolality level and body fluids that are too dilute (hypotonic hy- gressive water retention and do not require dietary water restriction ponatremia). However, there are exceptions to this rule [see Differ- or other measures used to treat chronic hyponatremia.11 Reset os- ential Diagnosis for Hyponatremia, below]. mostat can, however, be seen in malignancies, and like other causes of SIADH, it requires a diagnostic evaluation to determine its cause. PATHOGENESIS OF HYPONATREMIA Hypotonic hyponatremia results from two basic mechanisms in- Urinary Electrolyte Losses: Desalination and Hyponatremia dividually or together: (1) massive water intake, exceeding the ca- If the urine is concentrated, urinary sodium and potassium loss- pacity to excrete electrolyte-free water, or (2) impaired water excre- es can contribute to the pathogenesis of hyponatremia.The plasma tion. Normally, the capacity for water excretion is rather large. In sodium concentration can be reduced either by loss of sodium or the absence of vasopressin, urine osmolality falls to approximately potassium or by water gain. However, to lower the plasma sodium 50 mOsm/kg. A typical American diet provides 600 to 900 mOsm concentration, electrolytes must be lost in urine that has a higher of electrolytes and urea that must be excreted each day. At this rate electrolyte concentration than plasma. The combination of high of solute excretion, the volume of maximally dilute urine equals 12 vasopressin levels (which concentrate the urine) and a high rate of to 18 L.Water intake can occasionally exceed the normal excretory sodium and potassium excretion can yield hypertonic urine capable capacity, primarily in psychotic patients who frantically ingest gal- of generating free water, which in essence desalinates the plasma.20 lons of water over a few hours14 and in very heavy beer drinkers who DIFFERENTIAL DIAGNOSIS FOR HYPONATREMIA ingest large volumes of fluid but take in small amounts of salt and protein.15 More commonly, hyponatremia occurs in patients with a Several conditions can lower the plasma sodium concentration diminished ability to excrete free water.8,12 without causing hypotonicity and are referred to as nonhypotonic hyponatremia [see Table 3].The diagnostic and therapeutic approach Impaired Water Excretion to these conditions differs fundamentally from the approach to hy- Water excretion is obviously compromised in severe renal failure; potonic hyponatremia.Thus, it is important that nonhypotonic hy- oliguric patients become hyponatremic if they are given too much ponatremia be excluded whenever a low plasma sodium concentra- water. However, most cases of hyponatremia occur in patients tion is encountered.
  • 6. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 6 Table 3—Causes of Nonhypotonic Hyponatremia Condition Plasma Osmolality Pathogenesis Therapeutic Implications During treatment of hyperglycemia, anticipate Hyperglycemia High Extracellular glucose osmotically draws water 3 mEq/L increase in serum sodium for every into the ECF, diluting extracellular sodium 200 mg/dl reduction in blood sugar Intravenous hypertonic Water shift from ICF to ECF as with Mannitol is rapidly excreted when renal func- mannitol therapy High hyperglycemia tion is normal Intravenous γ-globulin therapy High Maltose present in solution acts like Measure plasma osmolality when hyponatrem- mannitol ia is suspected Mannitol is rapidly excreted; sorbitol is metab- Normal or low Absorbed solute—mannitol, sorbitol, olized, causing late-onset hypotonic Irrigant absorption (prostatectomy (when hypoosmo- or glycine (most common)—initially con- hyponatremia; glycine is neurotoxic and or intrauterine surgery) lar irrigants are fined to ECF, causing severe hyponatremia causes transient blindness and is metabo- used) but little change in plasma osmolality lized to ammonia, causing encephalopathy; consider hemodialysis Pseudohyponatremia (severe Laboratory artifact; plasma water constitutes Suspect when serum is lactescent; compare hyperlipidemia, multiple a smaller fraction of the plasma sample, measured plasma osmolality with calculated Normal myeloma, macroglobulinemia) causing a more serious underestimate of osmolality or measure plasma sodium with the true sodium concentration direct-reading sodium electrode ECF—extracellular fluid—–ICF—intracellular fluid Hyperglycemic Hyponatremia eventually to urea and glucose. Hyperammonemia may be responsi- Hyperglycemia lowers the plasma sodium concentration; in the ble for most of the symptomatology, and glycine itself has direct neu- absence of insulin, glucose is an effective osmole that attracts wa- roinhibitory effects and may cause hypotension, bradycardia, and vi- ter from cells and thereby dilutes extracellular sodium.Therefore, sual disturbances. the blood glucose level should always be examined when a low Pseudohyponatremia plasma sodium concentration is being evaluated. The plasma sodium concentration falls by approximately 3 mEq for every 200 High plasma concentrations of lipid or protein cause mild non- mg/dl (10 mmol) increase in blood glucose and will increase by hypotonic hyponatremia because of an artifact of laboratory mea- this amount when hyperglycemia is corrected with insulin. To surement [see Table 3].2,11 With extremely high concentrations of evaluate hyponatremia in the presence of hyperglycemia, the lipid (enough to cause lactescent serum) or protein (from multiple serum sodium concentration must be “corrected” for the osmotic myeloma or Waldenstrom macroglobulinemia), plasma water may effect of glucose. In effect, the clinician must ask the question, constitute a smaller fraction of the plasma sample than normal, What would the serum sodium concentration be if the excess glu- which can result in an underestimate of the “true” sodium concen- cose were no longer present? The correction factor most com- tration. The plasma osmolality and the sodium concentration in monly used today is a 1.6 mEq/L decrease in serum sodium con- plasma water (as measured by a sodium-sensitive electrode) are un- centration for every 100 mg/dl increase in blood glucose. A small affected.There are no symptoms, and no therapy is required. study has suggested that the true correction factor is approximate- ACUTE HYPONATREMIA (WATER INTOXICATION) ly 2.4 mEq/L for every 100 mg/dl increase in blood glucose.21 A precise correction factor is probably unobtainable because in The term water intoxication was coined in the early 1920s to de- practice, hyperglycemia develops, in part, from the ingestion of scribe a neurologic syndrome that develops when large volumes of glucose with water and resolves, in part, from the urinary excre- water are retained within a relatively short period of time (< 48 tion of glucose with water.22 hours).The syndrome is often called acute hyponatremia.12,24 Exogenous solutes such as mannitol and maltose (a sugar con- tained in intravenous immunoglobulin preparations) are confined Etiology to the extracellular space and have an effect on the plasma sodium Acute hyponatremia develops when water intake is large and concentration similar to that of hyperglycemia. When the clinical electrolyte-free water excretion is impaired. Potentially, hypona- setting suggests that these solutes might be responsible for hypona- tremia can develop rapidly in any patient predisposed to water re- tremia, their presence can be confirmed by measuring the plasma tention who takes in a large volume of water in a short period of osmolality and comparing it with the calculated value to identify time. However, this is likely to occur in a limited number of settings an osmolar gap [see Overview of Body Fluid Homeostasis, Distrib- [see Table 4], and such instances account for most cases of severe ution and Composition of Body Water, Osmolality, above].2,11 symptomatic hyponatremia and for most of the recorded fatalities. Postprostatectomy Syndrome and Hysteroscopic Hyponatremia Postoperative hyponatremia Vasopressin is released imme- Irrigants containing mannitol, sorbitol, or glycine are used for en- diately after surgical procedures in what appears to be a stress re- doscopic transurethral and intrauterine procedures [see Table 3].2,23 sponse [see Table 4].20,25 Particularly during the first 24 hours, the Occasionally, several liters of irrigant may be absorbed systemically, concentration of urinary cations (sodium plus potassium) may reducing the plasma sodium in a matter of minutes. Immediately af- greatly exceed the plasma sodium concentration. As a result, even ter surgery, the serum sodium concentration is much lower than isotonic fluids may be “desalinated” and can lower the plasma sodi- would be anticipated, because the electrolyte-free solution is initially um concentration.20 Thus, all hypotonic fluids and excessive confined to the extracellular space. Glycine, the most commonly amounts of isotonic fluids should be avoided after surgery. As dis- used irrigant in the United States, is metabolized to ammonia and cussed earlier, endoscopic prostatectomy and intrauterine proce-
  • 7. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 7 Table 4—Causes and Treatment of Acute Hyponatremia Causes Pathogenesis Effect of Treatment Recommendations Vasopressin is secreted in response Avoid hypotonic fluid (e.g., D5W, to surgical stress for 2 or more Normal saline ineffective for correc- 0.45% saline) and excessive vol- days; free water from hypotonic I.V. tion—administered sodium excret- umes of isotonic fluid (lactated Postoperative stress* fluids is retained and sodium and ed in concentrated urine, “desali- Ringer solution or 0.9% saline) after potassium are excreted in urine at nating” isotonic fluid and causing surgery; treat symptomatic hypona- high concentrations water retention tremia with 3% saline and furosemide Used in obstetrics to induce labor; Avoid administration of oxytocin in or direct antidiuretic effect of drug Urine becomes dilute when oxytocin Oxytocin with hypotonic fluids; treat hypona- mimics SIADH; free water from I.V. is discontinued tremia by discontinuing drug fluids retained Drug has antidiuretic effect that per- sists for as long as 12 hours; Normal saline ineffective for correc- Treat symptomatic hyponatremia with Cyclophosphamide patients are encouraged to drink tion as in other causes of persis- 3% saline and furosemide large volumes of water to prevent tent SIADH chemically induced cystitis Normal ability to dilute urine in most Monitor diurnal weight in institutional- Extreme polydipsia (> 1 L/hr) com- patients so hyponatremia self-cor- ized patients for early detection; mon among patients with severe rects when water intake stops; avoid antidiuretic medications; treat Psychotic self-induced water psychosis; retained water causes some patients have vasopressin hyponatremia with water restriction; intoxication hyponatremia by late afternoon or release (often transient) from use hypertonic saline and evening, and water diuresis re- stress, smoking, or medications furosemide for occasional patient stores normonatremia by morning (e.g., carbamazepine) with SIADH Extracellular volume depletion caused by saltwater losses from 3% saline without furosemide for sweating and possibly stress are Isotonic saline restores ability to seizures; isotonic saline and water Marathon running nonosmotic stimuli for vasopressin dilute urine restriction for more moderate secretion; large volumes of sugar symptoms water consumed during race are retained Excessive fluid intake and inappropri- Isotonic saline ineffective; self- Ecstasy (MDMA) use ate antidiuretic hormone secretion, correction typical but may be Hypertonic saline for severe symptoms induced by MDMA, is implicated delayed *Excluding irrigant absorption syndromes [see Table 3]. D5W—5% dextrose in water MDMA—methylenedioxymethamphetamine SIADH—syndrome of inappropriate antidiuretic hormone dures can cause hyponatremia if irrigant used in the procedures is evening; however, water diuresis typically restores normonatremia absorbed systemically.The management of irrigant absorption syn- by the following morning. Occasionally, individuals drink enough dromes differs from that of other causes of postoperative hypona- water to produce seizures. By monitoring diurnal changes in body tremia [see Postprostatectomy Syndrome and Hysteroscopic Hy- weight, water intoxication can be recognized before the onset of se- ponatremia, above].25 vere neurologic symptoms. Transient release of vasopressin (most commonly provoked by nausea and vomiting) may contribute to Oxytocin infusions Oxytocin, which is used in obstetrics to in- water retention.There is little evidence that any of the major tran- duce labor, has a direct antidiuretic effect. If the drug is adminis- quilizers has a significant antidiuretic effect; however, carbamaze- tered in 5% dextrose in water (formerly a common practice), symp- pine, an anticonvulsant, enhances sensitivity to vasopressin. tomatic hyponatremia may emerge after the infusion of less than 3 L of fluid [see Table 4].11 Termination of the infusion permits a water Water intoxication during exercise During a race, runners diuresis and correction of hyponatremia; however, the syndrome is sweat profusely, losing large volumes of saltwater. Extracellular vol- best avoided by using isotonic saline as a vehicle for the drug. ume contraction and possibly the stress of exertion cause the release of vasopressin.When saltwater losses are replaced by the intake of Cyclophosphamide infusion Intravenous cyclophosphamide sugar water, water retention and symptomatic hyponatremia may impairs water excretion by an unknown mechanism.26 The anti- occur.27,28 Most severe cases have been reported after marathons or diuretic effect of the drug begins 4 to 12 hours after injection and ultramarathons. However, symptomatic hyponatremia may occur persists for as long as 12 hours. Patients receiving cyclophosphamide after recreational running and military fitness training. are particularly susceptible to hyponatremia, because they are en- couraged to drink large volumes of water to prevent chemically in- Water intoxication from “ecstasy” During the 1990s, 3,4- duced cystitis [see Table 4]. methylenedioxymethamphetamine (MDMA, or ecstasy) gained widespread popularity as a recreational drug taken at dances.29 Psychotic self-induced water intoxication Extreme poly- When malignant hyperthermia was recognized as a complication as- dipsia is relatively common in patients with psychiatric illnesses, sociated with this drug, MDMA users were advised in underground particularly schizophrenia, and it may lead to symptomatic hypona- magazines and the lay press to drink plenty of fluids. Subsequently, tremia [see Table 4].14 Daily intake of 10 to 15 L has been docu- acute water intoxication emerged as a potentially lethal complication mented, and much of the intake may take place over a few hours. of the drug [see Table 4]. Excessive fluid intake and inappropriate Many patients become hyponatremic in the late afternoon and ADH secretion, induced by MDMA, have been implicated.
  • 8. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 8 Diagnosis Table 5—Causes of the Syndrome of Symptoms of water intoxication include headaches, weakness, Inappropriate Antidiuretic Hormone nervousness, and vomiting, progressing to disorientation, delirium, Bronchogenic (small cell) tremulousness, and ultimately convulsions and coma.12,24 The Pancreatic pupils are often dilated, and bilateral Babinski signs may be present. Duodenal On occasion, patients may present with hemiparesis, mimicking a Urethral cerebrovascular accident. The syndrome reflects cerebral edema, Tumors Nasopharyngeal which can lead to herniation of the brain and death. Clinical find- Leukemia ings may emerge explosively. Complaints of headache and mild Hodgkin disease confusion may be followed within hours by respiratory arrest and, Thymoma in some cases, neurogenic pulmonary edema. For reasons that re- Psychosis main obscure, almost all reported fatalities from acute postoperative Trauma hyponatremia have been in women (usually of childbearing age) Neoplasms (primary and metastatic) Neurologic and young children. Fatal cases of acute hyponatremia from other disorders Vascular (hemorrhage, infarction, and vasculitis) etiologies have been recorded in men and women. Infection (meningitis, brain abscess, and encephalitis) Acute hyponatremia should be suspected in any patient who Miscellaneous (Guillain-Barré syndrome, multiple sclero- sis, hydrocephalus, Shy-Drager syndrome) has unexplained neurologic symptoms, especially in psychiatric patients, marathon runners, users of ecstasy, and patients receiv- Infectious (bacterial, viral, and fungal pneumonia and Pulmonary tuberculosis) ing hypotonic fluids intravenously (e.g., after surgery). Serum disorders Functional (asthma, acute respiratory failure, and electrolytes should be obtained immediately. In the proper set- mechanical ventilation) ting, a tentative diagnosis of water intoxication is advisable when Endocrine Glucocorticoid deficiency (hypopituitarism) symptoms develop in a patient whose serum sodium concentra- diseases Hypothyroidism tion is lower than 130 mEq/L (provided that causes of nonhypo- tonic hyponatremia have been excluded). Although severe neuro- Antidiuretic hormones (vasopressin, DDAVP, and oxytocin) logic symptoms do not usually appear until the sodium level has Psychotropic agents (tricyclic antidepressants, serotonin reuptake inhibitors, monoamine oxidase inhibitors, and fallen below 120 mEq/L, some patients may be unusually suscep- carbamazepine) tible to brain edema when they become acutely hyponatremic; Ecstasy (MDMA) rare fatalities have been reported at plasma sodium concentrations Drugs Antineoplastic agents (cyclophosphamide, vincristine, between 120 and 128 mEq/L.20,25 and vinblastine) Nonsteroidal anti-inflammatory drugs Computed axial tomography demonstrates cerebral edema in se- Diabetic agents (chlorpropamide and tolbutamide) vere cases of water intoxication, and it rules out other potential ex- Miscellaneous (bromocriptine and nicotine) planations for neurologic findings. However, when symptoms are severe, therapy should not be delayed while imaging studies are be- Postoperative stress ing obtained. Alcohol withdrawal Other causes AIDS Treatment Nausea Free-water intake should be stopped immediately whenever wa- DDAVP—1-desamino-8-d-arginine vasopressin MDMA—methylenedioxymethamphetamine ter intoxication is suspected. Hypertonic saline is the treatment of choice for water-intoxicated patients who cannot autocorrect their electrolyte disturbance.24,25 Each 1 ml of 3% saline contains 0.5 to gradually return the plasma sodium concentration to normal.To mEq of sodium. Because there are approximately 0.5 L of body avoid complications from excessive correction of hyponatremia, the water for every 1 kg of body weight, 1 ml of 3% saline per 1 kg of plasma sodium concentration should not be intentionally increased body weight can be expected to increase the plasma sodium con- by more than 12 mEq/L during the first day of therapy or by more centration by 1 mEq/L. For patients with severe neurologic symp- than 6 mEq/L/day thereafter. toms, an infusion of 3% saline at 1 to 2 ml/kg/hr will increase the CHRONIC HYPONATREMIA plasma sodium concentration by approximately 1 to 2 mEq/L/hr, a rate that is considered appropriate for initial therapy. Hypertonic The distinction between acute and chronic hyponatremia is some- saline is best infused in 100 ml containers to avoid inadvertently what arbitrary.We consider hyponatremia to be chronic when it has giving an excessive dose. Except when volume depletion is suspect- evolved over the course of 48 hours or more.11,12,24 Although the pre- ed (as in marathon runners), concurrent administration of a loop cise duration of an electrolyte disturbance cannot be known when it diuretic (furosemide, bumetanide, or torsemide) is advisable.The develops outside the hospital (except for psychotic water drinkers, diuretic prevents volume overload and, by blocking sodium reab- marathon runners, and users of ecstasy) outpatients can be assumed sorption in the loop of Henle, impedes the formation of concen- to have chronic hyponatremia.30 Prolonged hyponatremia cannot trated urine. occur unless there is a sustained defect in water excretion. Except for The goal of therapy in acute hyponatremia is to decrease the patients with renal failure, virtually all chronically hyponatremic pa- severity of cerebral edema and to stop seizures. A 4 to 6 mEq/L in- tients have some abnormality in vasopressin secretion. crease in plasma sodium concentration is usually sufficient to ac- complish these goals. Thus, the plasma sodium concentration Etiology should be monitored frequently during therapy and emergency Advanced renal failure A low glomerular filtration rate lim- treatment with hypertonic saline should be stopped after 2 to 3 its the ability to excrete electrolyte-free water. Many patients with hours. Once initial therapy with high-dose hypertonic saline has advanced renal failure excrete urine that has the same osmolality as been completed, more conservative measures should be substituted plasma regardless of physiologic conditions (fixed isosthenuria). In
  • 9. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 9 acute oliguric renal failure, the ability to excrete free water is virtual- a common complication of chest infection. Antidiuretic activity has ly nil; administration of hypotonic fluids must be scrupulously been demonstrated by bioassay in patients with tuberculous lung avoided to avoid hyponatremia. tissue, and tuberculosis causes SIADH.11 In pneumonia, vaso- pressin levels are increased during the acute phase of the disease Diuretics Thiazide diuretics are commonly the sole cause or a and return to baseline within a few days. Isolated glucocorticoid de- major contributing factor of hyponatremia requiring hospital admis- ficiency caused by anterior pituitary dysfunction also causes hy- sion.30,31 For unknown reasons, severe hyponatremia caused by thi- ponatremia; patients with hypopituitarism develop inappropriate azides affects elderly women much more often than other groups. ADH secretion, but unlike patients with Addison disease, they have By blocking the reabsorption of sodium and chloride in the distal normal levels of mineralocorticoid and do not become hypovolemic tubule, thiazides and metolazone prevent the generation of maxi- or hyperkalemic. Hyponatremia caused by glucocorticoid deficien- mally dilute urine.32 Because sodium reabsorption in the ascending cy promptly resolves when cortisol is replaced. Hypothyroidism also limb of the loop of Henle is left unaffected by these agents, they per- causes inappropriate ADH secretion; hyponatremia gradually re- mit excretion of maximally concentrated, hypertonic urine and can solves when thyroid hormone is replaced.36 A number of therapeu- lead to simultaneous retention of water and depletion of sodium tic agents can induce SIADH.12,37 Nonsteroidal anti-inflammatory and potassium. Extraordinarily severe hyponatremia can result from drugs (NSAIDs) decrease water excretion because they inhibit for- thiazides, with plasma sodium levels as low as 100 mEq/L. Vaso- mation of prostaglandin E2, which modulates vasopressin action.8 pressin levels are usually elevated in patients who present with thi- Rare cases of hyponatremia solely attributable to NSAIDs have azide-induced hyponatremia, sometimes because of diuretic- been reported, but these commonly used agents may exacerbate induced volume depletion but more often because of the stress of other causes of hyponatremia. minor intercurrent illnesses. Patients with thiazide-induced hypona- tremia do not usually appear clinically volume depleted, presumably Hyponatremia in AIDS Hyponatremia is an extremely com- because retained water partially sustains extracellular fluid volume. mon finding in AIDS.38 Many AIDS patients have features of Patients who have become hyponatremic on thiazides should not be SIADH associated with opportunistic infections that cause pneu- given these agents again; recurrent episodes of severe hyponatremia monia and meningitis. Others have clinical signs of volume deple- are common. tion without low urine sodium values, a finding that may indicate coexistent renal disease or adrenal insufficiency.39 Hyponatremia of- Hypovolemia Hypovolemic hyponatremia is most often associ- ten occurs when antibiotics are administered in hypotonic intra- ated with gastrointestinal fluid losses caused by vomiting, diarrhea, venous solutions. or laxative abuse. Surprisingly, particularly in alcoholics, patients who continue to drink while vomiting repeatedly can still absorb Diagnosis enough ingested water to become hyponatremic. Electrolyte losses Hyponatremia should be approached in a systematic fashion. in the vomitus, combined with urinary sodium and potassium loss- First, the various disorders that can lower the plasma sodium con- es that result from metabolic alkalosis, lower the plasma sodium centration without causing hypotonicity should be excluded [see concentration. Differential Diagnosis for Hyponatremia, above]. Once it has been established that hypotonic hyponatremia is present, the mechanism Beer potomania Patients who subsist on beer (a practice for impaired water excretion is identified (hypovolemia versus an known as beer potomonia) are susceptible to hyponatremia because edematous condition versus SIADH), and the differential diagnosis of their low rates of solute excretion (beer contains little protein or that applies to that mechanism is considered.The most challenging electrolyte). Nonosmotic stimuli to vasopressin secretion caused by goals of the diagnostic process are to determine whether chronic nausea or gastrointestinal fluid losses or by treatment with thiazide SIADH is present and, if it is, to define the specific disease responsi- diuretics are often contributing factors.15 ble for the syndrome. Edematous conditions Any disease that can cause edema Clinical manifestations Because cerebral edema is usually also predisposes to water retention and hyponatremia.The same he- not severe, the symptoms of chronic hyponatremia are much more modynamic factors that promote sodium retention are nonosmotic subtle, vague, and nonspecific than those of acute water intoxica- stimuli for vasopressin release.8,16-18 Elevated vasopressin levels have tion.12,24 The electrolyte disturbance is often asymptomatic at sodi- been reported in hyponatremic patients with congestive heart fail- um levels that may be lethal to a patient with acute water intoxica- ure, cirrhosis, and nephrotic syndrome. In heart failure, hypona- tion. As the plasma sodium concentration falls below 115 to 120 tremia is associated with a low cardiac output and a poor prognosis. mEq/L, patients often experience anorexia, nausea, vomiting, mus- cle weakness, and muscle cramps.They may be irritable and show SIADH Nonosmotic release of vasopressin that has no hemo- personality changes, becoming uncooperative, confused, hostile, or dynamic explanation is termed inappropriate [see Table 5].12,19 A simply slow to respond. At plasma sodium concentrations below number of tumors (most commonly small cell carcinoma of the 110 mEq/L, gait disturbances, falling, stupor, tremulousness, and, lung) ectopically synthesize and secrete vasopressin.33 Unexplained, more rarely, seizures may occur. persistent hyponatremia should be considered a marker for an un- Chronic hyponatremia itself is rarely, if ever, fatal. However, be- derlying malignancy. cause hyponatremia can be a marker for severe underlying illness, SIADH may also complicate the course of a wide variety of con- hospitalized patients with hyponatremia often have a high mortality ditions in which there is damage to or inflammation of the central rate, dying with but not of chronic hyponatremia.There is little evi- nervous system.8,12 In patients with subarachnoid hemorrhage, na- dence that chronic hyponatremia itself leads to permanent sequelae, triuretic peptides released by the brain may directly promote uri- even when the plasma sodium concentration falls below 105 nary sodium loss, regardless of extracellular volume (cerebral salt mEq/L.30,40 However, patients with prolonged severe hyponatremia wasting).34,35 Urinary salt losses combined with vasopressin-in- are susceptible to iatrogenic injury if their electrolyte disturbance is duced water retention are responsible for hyponatremia. SIADH is corrected too rapidly [seeTreatment, below].
  • 10. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 10 History and physical examination The history of patients um, developing clinically obvious edema.Volume-depleted patients with chronic hyponatremia should include information about diet, initially retain the administered sodium, but as soon as hypo- fluid intake, gastrointestinal fluid losses, and use of diuretics, antide- volemia is corrected, the urine becomes dilute, the rate of urinary pressants, or other antidiuretic drugs. During the physical examina- sodium excretion increases to match intake, and hyponatremia im- tion, physicians should look for clinical signs of volume depletion or proves as water is excreted in the urine. Urinary sodium excretion an edematous condition. Evidence of volume depletion may not al- promptly increases in patients with SIADH, but the urine remains ways be definitive, however. For example, vomiting may be a symp- concentrated and hyponatremia persists. Isotonic saline should be tom rather than the cause of hyponatremia; extreme hyponatremia given with extreme caution to patients with very low plasma sodi- may occasionally impair baroreceptor reflexes causing postural hy- um concentrations; in SIADH, saline can exacerbate hyponatrem- potension and a false impression of volume depletion; and retained ia, whereas in volume depletion, hyponatremia may correct too water may mask underlying volume depletion.When the distinction rapidly. between hyponatremia caused by hypovolemia and hyponatremia caused by inappropriate antidiuretic hormone secretion is not obvi- Identifying a specific cause for SIADH SIADH is a mech- ous, laboratory clues may helpful. anism for developing hyponatremia, not a diagnosis. In all patients with SIADH, a specific etiology for inappropriate vasopressin secre- Laboratory tests Measurement of the urinary sodium, tion should be sought.When hyponatremia develops in the hospital, chloride concentration, or both is often the most helpful test.41 the cause is sometimes obvious (e.g., pneumonia, meningitis, acute Water retention caused by hypovolemia or by an edematous con- respiratory failure) and no further testing is indicated. In a patient dition is usually associated with a urinary sodium concentration with clinical features of SIADH but no obvious cause for it, a more lower than 20 mEq/L. Hypovolemia caused by upper gastroin- extensive evaluation is indicated.The workup should include a care- testinal fluid losses is an important exception. Loss of gastric fluid ful search for malignancy and central nervous system pathology and causes a metabolic alkalosis that may increase urinary sodium ex- an endocrine evaluation to exclude hypothyroidism and hypocorti- cretion despite volume depletion; the diagnosis can be made by solism. Sometimes, no cause for SIADH is found, especially in el- measuring the urine chloride concentration, which is reduced in derly patients and patients with psychiatric disorders, mental retar- this condition. In SIADH, urinary sodium matches intake; as the dation, or alcoholism.42 Careful follow-up is important, because urine is usually concentrated, the urinary sodium concentration malignancies may become clinically apparent after several years in exceeds 40 mEq/L unless dietary sodium intake is very low. Mea- so-called idiopathic SIADH. surements of the BUN and serum uric acid complement these measurements.When a hemodynamic abnormality is responsible Treatment for hyponatremia, the kidney is underperfused, urea and uric acid Patients with very low plasma sodium concentrations usually clearances are diminished, and the BUN and serum uric acid lev- have some neurologic symptoms, and they are at risk of injuries els are usually elevated. Conversely, SIADH is a volume-expand- from falls. However, unlike acute water intoxication, there is little ed state, and BUN and uric acid levels are usually low. Uric acid is risk of an explosive onset of seizures or a fatal outcome in chronic a more reliable indicator of volume status than the BUN, because hyponatremia. On the other hand, patients with chronic hypona- the latter value is affected by dietary protein intake as well as renal tremia are at considerable risk of neurologic injury caused by over- clearance. Assessment of acid-base and potassium balance may aggressive correction.Thus, there are four major goals in managing provide helpful clues to the diagnosis.The serum potassium and chronic hyponatremia: (1) prevention of a progressive decrease in bicarbonate levels are normal in SIADH. Hypokalemia and meta- plasma sodium concentration; (2) amelioration of symptoms bolic alkalosis suggest diuretic therapy or vomiting, which can be caused by hyponatremia; (3) avoidance of excessive correction; and surreptitious. Hyperkalemia and metabolic acidosis suggest the (4) gradual restoration and maintenance of a normal plasma sodi- possibility of adrenal insufficiency. Hypokalemia and acidosis are um concentration. found in diarrhea and raise the possibility of surreptitious laxative Free-water restriction should be instituted in all patients until the abuse. plasma sodium concentration has begun to increase. Intravenous fluids should be at least isotonic, and oral fluid intake should be lim- Withdrawal of hyponatremic drugs When a patient is tak- ited to 500 to 1,000 ml/day, depending on the severity of the elec- ing a drug that can cause hyponatremia, it is important to exclude trolyte disturbance. In patients with reversible defects in water ex- another underlying cause for hyponatremia before attributing the cretion, limitations on free-water intake should be lifted once the electrolyte disturbance to the medication. For example, thiazide di- plasma sodium concentration has begun to increase. uretics can exacerbate hyponatremia caused by SIADH. The best Attempts to calculate the dose of sodium chloride needed to cor- way to make a diagnosis of drug-induced hyponatremia is to elimi- rect hyponatremia are doomed to failure. The increase in plasma nate the offending agent and be sure that water excretion returns to sodium concentration depends on the amounts of administered normal when the patient is off the drug. Full resolution of hypona- sodium and potassium that have been retained without being ex- tremia and full recovery of diluting function may be delayed for a creted, as well as on the amount of electrolyte-free water that is week or two in patients with thiazide-induced hyponatremia. Dur- eliminated in the urine. Indeed, in some cases, the plasma sodium ing repair of sodium and potassium deficits, transient resetting of concentration will return to normal solely because of a water diure- the osmostat is common and should not necessarily prompt an ex- sis, with no sodium given. The measures required to increase the tensive search for an underlying cause. plasma sodium concentration, along with the likelihood of inadver- tent rapid correction, vary depending on the cause of hyponatrem- Response to therapy On occasion, evidence regarding the ia. For therapeutic purposes, the causes can be divided into re- cause of hyponatremia can be equivocal. In such cases, the pa- versible and persistent defects in water excretion. tient’s response to isotonic saline (or a generous oral salt intake and the passage of time) is the best clue to the diagnosis. Patients with Reversible defects in water excretion Hyponatremia cor- subclinical edematous conditions will retain the administered sodi- rects easily when the cause for defective water excretion can be
  • 11. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 11 eliminated by volume expansion, by withdrawal of a therapeutic are the mainstay of treatment of hyponatremia for patients with agent, or by treatment of an underlying illness [see Table 4]. In pa- edematous conditions because they increase free-water excretion tients with reversible defects in water excretion, prevention of ex- and improve hyponatremia, particularly when dietary salt intake is cessive correction may become a major challenge. increased.There is a natural inclination to discontinue loop diuret- Hypovolemic hyponatremia responds readily to 0.9% sodium ics when severely edematous patients develop hyponatremia. The chloride because the sodium concentration of isotonic saline is usual problem, however, is oliguria and diuretic resistance rather higher than the cation concentration of the excreted urine. Once than overdiuresis; the proper response is to increase the dose of the volume deficit is repaired and the hemodynamic stimulus to loop diuretics and restrict water intake.The combination of a loop vasopressin secretion is removed, the urine becomes dilute and a diuretic and an angiotensin converting enzyme (ACE) inhibitor is water diuresis may rapidly return the plasma sodium concentration particularly effective in patients with congestive heart failure.The to normal. Similarly, patients with diuretic-induced hyponatremia beneficial effect of an ACE inhibitor can be explained by reduced are extremely susceptible to rapid correction; restoration of the re- thirst and vasopressin secretion attributable to angiotensin II and nal diluting mechanism when the diuretic is discontinued and re- by a direct effect on the hydro-osmotic effect of vasopressin, medi- placement of sodium and potassium deficits contribute to the in- ated by prostaglandins.11 crease in plasma sodium concentration. Hyponatremia in edematous conditions is mediated by vaso- Intravenous saline should be discontinued once clinically appar- pressin. Clinical trials have shown that vasopressin receptor antago- ent hypovolemia has been corrected and the plasma sodium con- nists can be effective in managing patients with hyponatremia and centration has begun to increase. Saline should be given cautiously, edema.43,44 if at all, to hypokalemic patients who require potassium replace- ment. During repair of a potassium deficit, potassium enters cells, Treatment of hyponatremic seizures A small percentage displacing sodium, which then returns to the extracellular fluid; ad- of chronically hyponatremic patients with very low plasma sodium ministered potassium is therefore as effective as sodium in raising concentrations present with seizures. Regardless of the suspected the plasma sodium concentration. Diuretic-induced hyponatremia duration or cause of the electrolyte disturbance, active seizures does not usually necessitate use of intravenous saline; for most pa- may be resistant to anticonvulsants alone and should be treated tients, an adequate diet, replacement of potassium deficits, and dis- with hypertonic saline.The therapeutic approach is similar to that continuance of thiazide diuretics are sufficient. In severely hypona- used for patients with acute water intoxication, except that even tremic patients, the plasma sodium concentration should be more vigilance is required to prevent an excessive increase in plas- monitored every 6 to 8 hours for the first 2 to 3 days of therapy. If it ma sodium concentration once emergency measures have been appears that a water diuresis is going to increase the plasma sodium discontinued.12,24 by more than the desired amount, replacement of fluid losses with oral water or 5% dextrose in water may become necessary. Complications of Therapy: Myelinolysis and Osmotic Demyelination Syndrome Persistent defects in water excretion: SIADH Patients Excessive correction of chronic hyponatremia may be compli- with SIADH tend to be resistant to rapid changes in plasma sodi- cated by neurologic injury.40,45 Typically, the patient’s hypona- um concentration (unless the cause of SIADH is short-lived).Wa- tremic symptoms improve as the plasma sodium concentration ter restriction is the cornerstone of therapy, but if used alone, water increases, but after a delay of one to several days, new findings restriction often leads to an extremely slow resolution of hypona- emerge.The patient may become confused and may exhibit psy- tremia. Isotonic saline is ineffective and may even be counterpro- chotic or catatonic behavior, pathologic crying, or a movement ductive. Furosemide and loop diuretics are often useful therapeu- disorder. Swallowing dysfunction, progressive unresponsiveness, tic adjuncts because by blocking sodium reabsorption in the and a spastic quadriparesis may develop. In severe cases, locked- ascending limb of the loop of Henle, they interfere with the renal- in syndrome occurs—that is, the patient is awake but unable to concentrating mechanism, partially blocking the effect of vaso- move or respond.The stereotypical pattern of delayed neurologic pressin. Loop diuretics can be combined with oral salt or a slow deterioration after rapid correction of hyponatremia has been infusion (approximately 15 ml/hr) of 3% saline. Oral and intra- named the osmotic demyelination syndrome,45 because these venous urea have been used extensively to treat SIADH in some clinical features are associated with brain lesions (myelinolysis) parts of Europe, but experience with this agent in the United characterized by disruption of myelin and sparing of neurons and States is very limited. Demeclocycline, a tetracycline that blocks axons.46,47 Lesions, which are best identified by magnetic reso- the effect of vasopressin on the collecting duct, is another thera- nance imaging, are typically found in the center of the basal pons peutic option in chronic SIADH; however, its expense and long (central pontine myelinolysis [CPM]), but histologically similar duration of action limit its effectiveness. Several orally active vaso- lesions may also occur in a symmetrical distribution in extrapon- pressin receptor blockers have been developed and are currently in tine areas of the brain where there is a close admixture of gray clinical trials.43,44 and white matter.The osmotic demyelination syndrome has been reproduced in animal studies46; these experiments have shown Persistent defects in water excretion: edematous condi- that the disorder is a complication of rapid correction of hypona- tions and renal failure Saline should rarely, if ever, be given to tremia rather than the electrolyte disturbance itself. Observation- correct hyponatremia in edematous patients or patients with renal al studies in severely hyponatremic patients suggest that this ther- failure (except for those with prerenal azotemia). Because it has no apeutic complication can be avoided if rates of correction are effect on water excretion, 1 L of 0.9% saline will increase the plasma maintained below 10 to 12 mEq/L/day and 18 mEq/L/48 hr. Be- sodium concentration by only 1 mEq/L.12 In addition, saline exac- cause large increases in the serum sodium concentration are sel- erbates edema and ascites in patients with cirrhosis and may cause dom required to relieve hyponatremic symptoms and because un- pulmonary edema in patients with congestive heart failure or renal intentional excessive correction is common, the goal of therapy failure. should be to increase serum sodium concentration by 8 Although thiazide diuretics are contraindicated, loop diuretics mEq/L/day or less.12
  • 12. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 12 Disorder of Water Deficiency: Hypernatremia Table 6—Causes of Hypernatremia PATHOGENESIS Extrarenal Persistent hypernatremia results from one of two basic mecha- Insensible loss (skin and lungs) nisms: water is lost and not adequately replaced or, less commonly, Renal too much salt is taken in without enough water [see Table 6].13,48-50 In Neurogenic (central) diabetes insipidus either case, electrolyte-free water is needed to return the plasma Nephrogenic diabetes insipidus sodium concentration to normal. Because thirst is the primary de- Congenital X-linked (V2 vasopressin receptor defect) fense against hypertonicity, persistent hypernatre-mia means there Electrolyte-free water losses Recessive (aquaporin defects) is a defect in water intake. A maximally concentrated urine mini- Acquired mizes but does not prevent water losses. Insensible water losses Electrolyte abnormalities: hypokalemia, from the skin and lungs are unavoidable and urea excretion oblig- hypercalcemia ates some urinary losses. Maintenance of a normal serum sodium Drugs: lithium, demeclocycline, concentration (135 to 142 mEq/L) requires that daily water losses methoxyflurane Pregnancy (vasopressinase) be replaced. Excess urea excretion Most hypernatremic patients are too sick, too young, or too old to obtain water themselves or ask for it.13,48 Sometimes, the thirst Extrarenal sensation itself is impaired, so that the patient has no desire to drink Sweat when the plasma sodium concentration increases above the normal Upper GI tract Hypotonic losses Osmotic cathartics range. Inadequate water intake by itself will lead to hypernatremia. Renal When impaired intake is coupled with excessive water losses, severe Glycosuria, mannitol, glycerol, diuretics hypernatremia results. Oral ETIOLOGY Parenteral Salt poisoning NaHCO 3 , 3% or 5% I.V. saline, therapeutic Electrolyte-free water can be lost as pure water, with no accom- abortion (inadvertent 29% I.V. saline) panying electrolyte, or it can be lost in hypotonic fluids, which Hemodialysis with hypertonic dialysate have lower electrolyte concentrations than plasma. Hypotonic losses can be thought of as mixtures of isotonic fluid and free wa- ter. Pure-water and hypotonic fluid losses, the most common Diabetes insipidus Because sodium excretion is unaffected causes of hypernatremia, are typically associated with a contracted in diabetes insipidus (see below), the excess fluid lost in the urine is extracellular fluid volume.13 However, this is not always the case. pure water. As long as water is available and the patient is able to When hypernatremia is caused by a rapid intake of salt (acute salt drink, hypernatremia does not occur.Without water replacement, poisoning), the extracellular volume expands because of water however, hypernatremia develops within a few hours drawn from the intracellular space.48 In critically ill patients, extra- cellular volume expansion with edema often coexists with hyper- Hypotonic Losses natremia49,51; the finding reflects free-water losses in patients who Hypernatremia caused by hypotonic fluid loss is associated with become edematous after fluid resuscitation for shock or underly- extracellular volume depletion. ing conditions such as congestive heart failure, renal disease, and hepatic cirrhosis. Sweat Sweat is a hypotonic solution containing water, sodium, potassium, and chloride. Sweat glands respond to aldosterone by Pure-Water Losses lowering the sodium concentration and increasing the potassium If pure-water losses are responsible for hypernatremia, each concentration of their secretions. body-fluid compartment loses an equal percentage of its vol- ume.13,48 Plasma constitutes only one twelfth of total body water Gastric fluid losses Fluid lost by vomiting or nasogastric suc- (one quarter of extracellular fluid volume), and plasma volume is tion is hypotonic to plasma.Without adequate water replacement, defended by oncotic pressure, which increases with water loss. large gastric fluid losses can cause hypernatremia. Thus, plasma volume contracts by less than 83 ml for each 1 L of water lost; clinical signs of hypovolemia are unusual unless the water Osmotic cathartics Fecal losses of water contain electrolytes deficit is extremely large. at a concentration comparable to that of plasma, except when os- motic cathartics such as sorbitol or lactulose are given. These Insensible water losses Water is constantly lost by evapora- cathartic agents osmotically attract electrolyte-free water to the in- tion from the skin and lungs and must be replaced to avoid dehy- testinal lumen, leading to hypotonic fluid losses. Oral sorbitol is a dration. Daily insensible water losses, normally about 0.5 L, can be nonabsorbable solute, given with sodium polystyrene sulfonate increased severalfold by high environmental temperature, fever, or (Kayexalate) to treat hyperkalemia or with charcoal to treat poison- hypermetabolic states such as thyrotoxicosis. ing; the sugar osmotically attracts electrolyte-free water into the in- testinal lumen, where it is eliminated in the stool. Similarly, lactu- Increased urea excretion Although urea is an ineffective os- lose, which is used to treat hepatic encephalopathy, can promote mole that freely crosses most cell membranes, urinary urea excre- large electrolyte-free water losses, causing a high incidence of hyper- tion can play an important role in water balance. High rates of urea natremia unless the lost water is replaced. excretion caused by protein-rich diets, catabolism, or recovery from renal failure obligate increased rates of water loss.When the urine Osmotic diuretics and glycosuria Glucose in the extracel- solute is composed almost exclusively of urea, the urine becomes an lular fluid acts as an effective osmole that attracts water to the extra- electrolyte-free water solution, regardless of its osmolality. cellular fluid, dehydrating cells and lowering the plasma sodium
  • 13. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 13 concentration.22,48 Excretion of glucose in the urine acts as an os- pernatremia can be given diuretics along with electrolyte-free water motic diuretic that can provoke the loss of several liters of hypoton- to replace urinary electrolyte-free water losses; the net effect is re- ic fluid. Electrolyte-free water losses induced by glycosuria raise the duction of the extracellular volume surfeit and restoration of normo- plasma sodium concentration, offsetting the hyponatremic effect of tonicity and cell volume. the high blood glucose levels. Intravenous hyertonic mannitol has a Electrolyte-free water can be given intravenously in a 5% dex- similar effect on body fluids. trose solution (D5W) to patients who are unable to drink. Dextrose solutions cannot be infused more rapidly than approximately 500 Acute Salt Poisoning ml/hr. More-rapid infusions provide more glucose than can be me- Water losses increase the serum sodium concentration over tabolized and therefore cause hyperglycemia, glycosuria, and uri- hours or days.The oral ingestion of large amounts of salt without nary water losses, which are counterproductive to the correction of water—1 tbsp of salt contains nearly 350 mEq of NaCl, enough to hypertonicity.Water replacement should not be based on formulas increase the plasma sodium concentration by 8 mEq/L—or the in- alone; the serum sodium concentration and urine output should be travenous infusion of hypertonic salt solutions can increase the monitored frequently so that the fluid prescription can be adjusted plasma sodium concentration much more rapidly (i.e., cause acute appropriately. salt poisoning).13,48 Rate of Correction DIAGNOSIS In the vast majority of cases, the onset of hypertonicity is slow enough for brain adaptations to minimize cerebral dehydration. Or- Clinical Manifestations ganic osmolytes that accumulate in the adaptation to hypernatrem- An acute onset of hypernatremia (seen virtually exclusively in ia are slow to leave the cell during rehydration. If hypernatremia is acute salt poisoning) causes the brain to shrink, leading to vascular corrected too rapidly, cerebral edema results.13,48 To be safe, the injury and intracranial bleeding. Patients present with seizures, serum sodium concentration should be reduced by no more than coma, hyperventilation, hyperreflexia, hypertonia, and high fever. 10 to 12 mEq/L/day.To achieve the desired rate of correction, elec- Acutely hypernatremic patients with plasma sodium levels above trolyte-free water intake should exceed free-water losses by no more 170 mEq/L often die.13,48 than 2 L daily. Given time to adapt, brain cells protect their volume by accumu- Acute salt poisoning causes devastating brain injury that is lating organic osmolytes, preventing the hemorrhages caused by largely irreversible. In rare cases when acute salt poisoning can acute hypernatremia. Thus, the clinical manifestations of chronic be rapidly diagnosed (e.g., in a case of inadvertent intravenous hypernatremia are less dramatic than those seen in acute salt poi- infusion of hypertonic saline during therapeutic abortion), an soning, ranging from lethargy to coma, depending on the severity of effort to prevent a neurologic catastrophe can be made with the electrolyte disturbance.13,48,50 rapid infusions of electrolyte-free water along with a loop diu- The clinical signs of pure-water loss and acute salt poisoning are retic before the results of the serum electrolyte measurements are primarily neurologic. Hypotonic fluid losses may be associated with known. signs and symptoms of extracellular fluid volume depletion in addi- tion to symptoms related to hypernatremia. Diabetic Dehydration Hypertonicity associated with diabetes mellitus is a complex Recognition of Water Deficit disorder.22 The osmotic diuresis induced by glycosuria results in The plasma or serum sodium concentration can be used to de- both saltwater and electrolyte-free water losses; the accumulation termine how much water is needed to restore normotonicity; it seri- of glucose in the extracellular fluid adds impermeant solute, which ously underestimates the magnitude of the water deficit in diabetic contributes to hypertonicity and neurologic symptoms. Severely patients with hyperglycemic dehydration [see Treatment, Diabetic dehydrated hyperglycemic patients may not appear hypovolemic at Dehydration, below]. In patients without severe hyperglycemia, the first, because the high glucose concentration in the extracellular percentage increase in the serum sodium concentration approxi- fluid osmotically attracts water from cells, masking the loss of salt- mates the percentage decrease in total body water, as stated more water.With correction of hyperglycemia, marked hypovolemia may precisely in the following: emerge. Initial treatment should include 1 to 2 L of isotonic saline in anticipation of this complication, even in patients who are ini- Water deficit = Normal body water (1 − serum [Na+]/140) tially normotensive.With volume expansion, excess glucose will be The value for body water is based on the patient’s usual body excreted in the urine, creating an ongoing requirement for both weight (often an estimate), age, and sex. saline and electrolyte-free water. An infusion of 0.45% saline at a The calculated water deficit is the amount of water that will rate that exceeds urine output by approximately 250 ml/hr will return the serum sodium concentration to normal. It reveals serve to replace the electrolyte-free water deficit and remaining nothing about the volume status of the extracellular fluid. Extra- saltwater deficits.The serum sodium concentration, blood glucose cellular fluid volume deficits (or surfeits) must be estimated from level, and urine output should be monitored carefully so that fluid the history and physical examination, not from the serum sodium replacement can be tailored to the patient’s needs. Rapid correc- concentration. tion of hypertonicity should be avoided because of the risk of cere- bral edema. TREATMENT Patients with oliguric renal failure do not become dehydrated Correction of severe extracellular volume depletion takes prece- when they become severely hyperglycemic. Such patients often ex- dence over correction of hypernatremia. When the patient is hy- perience hypertension or congestive heart failure because of fluid potensive, initial therapy should include a rapid infusion of isotonic shifts from cells to the extracellular fluid. Even after adjusting for saline to quickly achieve hemodynamic stability. In hemodynamical- the effect of hyperglycemia, the serum sodium concentration is of- ly stable patients, pure-water losses should be replaced with pure wa- ten low. Insulin is the only required treatment; neither isotonic ter, and isotonic saline is not required. Edematous patients with hy- saline nor 0.45% saline is indicated.
  • 14. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 14 Disorder of Water Conservation: Diabetes Insipidus genic DI is best treated with a synthetic antidiuretic hormone, 1-des- amino-8-D-arginine vasopressin (DDAVP), which can be given par- PATHOGENESIS enterally or intranasally.8,53 Chlorpropamide or carbamazepine, Neurogenic diabetes insipidus (DI) is caused by deficient secre- both of which enhance vasopressin action, or thiazide diuretics, tion of vasopressin8,52,53; nephrogenic DI results from the kidney’s which limit the ability to maximally dilute the urine, can be used in unresponsiveness to normally secreted hormone.54 Both disorders patients with mild disease. Limiting dietary salt and protein intake is present with polyuria (loosely defined as the passage of excessive also helpful. Nephrogenic diabetes can also be treated with dietary volumes of urine—generally more than 3 to 4 L daily) and polydip- measures or with thiazides and indomethacin (which helps concen- sia (excessive thirst). Most patients with polyuria do not become hy- trate the urine by inhibiting prostaglandin synthesis). Lithium-in- pernatremic, because thirst maintains electrolyte-free water balance. duced nephrogenic DI may be improved by amiloride, which Defective responsiveness to vasopressin (nephrogenic DI) may blocks lithium entry into the collecting duct cell. be inherited as an X-linked trait, caused by a mutation in the gene encoding for the V2 vasopressin receptor or as an autosomal reces- sive trait caused by a mutation in the gene encoding for the vaso- Disorder of Saltwater Excess: Edematous States pressin-responsive water channel (aquaporin 2). Acquired nephro- Edema, a swelling of the soft tissues that can be indented or pitted genic DI may be caused by lithium or demeclocycline therapy, by the examiner’s fingers, is the clinical manifestation of an expand- hypokalemia, or hypercalcemia; or it may complicate a number of ed interstitial fluid volume.To be detected clinically, interstitial vol- renal diseases [see Table 6]. Vasopressin-resistant DI may emerge ume must increase by at least 2.5 to 3 L, nearly equaling the total during the late stage of pregnancy as a result of vasopressinase re- amount of fluid in the intravascular space.Thus, generalized edema leased by the placenta; many affected patients have underlying, sub- requires an increase in the total amount of saltwater in the extracel- clinical partial neurogenic or nephrogenic DI that has been exacer- lular space, and it implies retention of dietary or infused sodium, bated by increased catabolism of circulating vasopressin. with an impaired ability to excrete saltwater. DIAGNOSIS PATHOGENESIS Excess fluid collects in the interstitial space in response to Star- Clinical Manifestations ling forces, which govern the movement of extracellular fluid into Patients with DI complain of polyuria, nocturia (the need to uri- and out of the vasculature. Edema occurs when there is increased nate during the night), and polydipsia.The only significant physical capillary blood pressure, decreased plasma oncotic pressure, in- findings or laboratory abnormalities are those of the underlying creased capillary permeability to protein, or obstruction to lymph cause. flow. When fluid overflows from an overfilled vascular space into the Laboratory Tests interstitium, impaired sodium excretion is clearly implicated. How- A diagnosis of DI can be made if the urine osmolality is less than ever, even when edema formation results from decreased oncot- 250 mOsm/kg despite hypernatremia.8 When the disease is suspect- ic pressure or increased capillary permeablity, renal sodium reten- ed in a polyuric patient whose serum sodium concentration is nor- tion is required to replace the saltwater that has been lost from the mal or borderline, the urine osmolality level can be monitored while vasculature. the patient is deprived of water, allowing the serum sodium level to increase to higher than 143 mEq/L. Exogenous vasopressin increas- ETIOLOGY es urine osmolality by more than 150 mOsm/kg in patients with neurogenic, but not nephrogenic, DI. It is possible to misdiagnose Primary Renal Sodium Retention: Edema Caused by DI in patients who actually have a primary thirst disorder. Excessive Renal Disease water intake suppresses vasopressin secretion and causes polyuria Nephrotic syndrome The nephrotic syndrome is character- with dilute urine. Because patients with primary polydipsia secrete ized by heavy urinary protein losses (in excess of 3 g/day), hypoal- vasopressin normally, they do not become hypernatremic during di- buminemia, and edema.55 The syndrome, which can be seen in a agnostic water deprivation. Correlation with plasma vasopressin lev- variety of glomerular diseases, is caused by increased permeability els is often necessary in borderline cases. Polyuric patients whose of the glomerular capillary to protein.Traditionally, edema in the urine osmolality equals or exceeds plasma osmolality should be dis- nephrotic syndrome has been ascribed to decreased plasma oncot- tinguished from patients with DI; polyuria in such cases is usually ic pressure.This no longer appears to be the sole explanation. Cor- caused by excessive excretion of salt, urea, or glucose or by an os- rection of hypoalbuminemia by infusing albumin does not consis- motic diuretic (solute diuresis). tently improve the edema, and resolution of edema in steroid- Magnetic resonance imaging of the brain can be helpful in the responsive cases may precede improvement of hypoalbuminemia. evaluation of patients with suspected DI.8,53 In 85% to 90% of Thus, in most patients, primary sodium retention by the kidney, healthy adults and children, the posterior pituitary emits a hyperin- independent of an underfilled vasculature, plays a major contribut- tense signal, or so-called bright spot, on T1-weighted magnetic reso- ing role. nance images, apparently related to the vasopressin release of the gland. This bright spot is also normal in 85% to 90% of patients Nephritic edema Glomerular diseases characterized by pro- with primary polydipsia, but it is almost always absent or greatly di- liferation of mesangial cells (e.g., diffuse proliferative glomeru- minished in patients with pituitary DI. lonephritis and membranoproliferative glomerulonephritis) often cause primary sodium retention that is not associated with heavy TREATMENT proteinuria or hypoalbuminemia (the nephritic syndrome). Patients When access to water is limited, patients with DI are more sus- with nephritic edema are typically hypertensive and may present ceptible to dehydration than normal persons. Thus, water losses with congestive heart failure because of an overexpanded vascular must be carefully replaced during superimposed illnesses. Neuro- volume.
  • 15. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 15 Secondary Renal Sodium Retention: Edema Caused by Extrarenal Disease The diagnosis of edema should be approached systematically, looking for evidence of heart, renal, or liver disease. A diagnosis can In congestive heart failure and hepatic cirrhosis, the body re- usually be made from the history and physical examination, urinaly- sponds as if it were volume depleted. Despite an expanded intersti- sis, liver function tests, and chest x-ray. More puzzling cases may re- tial fluid volume, as well as increased total body sodium content, the quire echocardiography or, rarely, right heart catheterization. Plasma kidney avidly retains salt and water.The normal renal response to a levels of B-type natriuretic peptide (BNP) are increased in patients high salt intake is lost, and progressive salt retention occurs. In these with heart failure. Used in conjunction with other clinical informa- conditions, volume regulatory mechanisms are responding to re- tion, rapid-measurement BNP is useful in establishing or excluding duced fullness of the arterial portion of the vascular system, which the diagnosis of congestive heart failure in patients who present with normally contains about 15% of the total blood volume. acute dyspnea.58 TREATMENT Congestive heart failure Advanced stages of the many disor- ders that affect the pericardium, myocardium, or heart valves can Dietary salt restriction is important for patients with edema, but produce congestive heart failure, a disorder characterized by renal this measure alone is impractical or insufficient when urinary sodium sodium retention and interstitial edema in systemic or pulmonary excretion is reduced to very low levels.Thus, most edematous patients capillary beds.16,17 Arterial receptors are activated when cardiac out- whose underlying condition cannot be reversed require treatment put falls (low-output congestive failure) or when cardiac output is with diuretics.5,59 Salt restriction and diuretics are adjunctive treat- not high enough to compensate for decreased peripheral resistance ments for heart failure.Therapy is also directed at improving cardiac (high-output failure). performance by using digoxin and vasodilators to reduce afterload. Recombinant human BNP (nesiritide) has become available for the Cirrhosis Patients with severe liver disease may exhibit pro- treatment of acute decompensated heart failure. The agent reduces found salt retention, often excreting less than 10 mEq of sodium in pulmonary capillary wedge pressure and systemic vascular resistance, the urine each day. Scarring of the hepatic parenchyma increases re- improves cardiac performance, and has a diuretic effect, in part be- sistance to blood flow in the postsinusoidal venules, resulting in high cause of its effect on sodium reabsorption in the distal nephron.60 sinusoidal pressures and venous hypertension throughout the portal Ascitic fluid is a separate compartment of the extracellular fluid system. Portal hypertension and hypoalbuminemia promote the for- compartment that is much more difficult to mobilize than peripher- mation of ascites. In addition, the cirrhotic patient is vasodilated be- al edema.Thus, cirrhotic patients who have ascites but no peripher- cause of endotoxins, vasodilatory prostaglandins, nitric oxide, various al edema are susceptible to intravascular volume depletion when gut hormones, and other mediators.The combined effects of blood they are treated with diuretics; weight loss should thus be limited to pooling in the splanchnic circulation (caused by portal hypertension) 0.5 kg daily. Repeated large-volume paracenteses combined with in- and systemic vasodilatation lead to underfilling of the arterial circu- travenous albumin is a safe and effective alternative to diuretics that lation and subsequent activation of sodium-retaining factors.56 avoids intravascular volume depletion.61 The subsequent adminis- tration of diuretics prevents reaccumulation of ascitic fluid. Idiopathic edema Idiopathic edema is a benign disorder of Use of Diuretics young, menstruating women who have no cardiac, hepatic, or renal disease.57 Fluid retention often begins premenstrually and then be- Diuretics increase saltwater excretion by impairing tubular reab- comes persistent. Depression and neurotic symptoms are commonly sorption of the sodium filtered by the glomerulus.The diuretic effect present, and affected patients are often weight conscious and is dose-dependent; the maximum response is determined by the di- markedly concerned about even minor degrees of edema. Some pa- uretic’s site of action within the nephron, the filtered load of sodium, tients episodically fast for days at a time and then accumulate edema and the amount of sodium reabsorbed by nephron segments unaf- on refeeding. In many others, diuretics play an important role in the fected by the diuretic. pathogenesis of idiopathic edema. Long-term diuretic or cathartic use leads to persistent hypovolemia and chronic activation of sodium- Mechanism of action All diuretics except spironolactone are retaining mechanisms, which include hypertrophy of the nephron specific inhibitors of luminal transporters and must gain access to segments distal to the site of action of the diuretic.When the diuretic the tubular fluid to block sodium reabsorption.5,59 Because diuretic is stopped, marked sodium retention occurs because the sodium-re- agents are highly protein bound, they are not readily filtered at the taining forces cannot be shut off rapidly.The patient thus becomes glomerulus; instead, they are actively transported into the urine by convinced of the need for diuretics, and the cycle continues. the organic acid (e.g., acetazolamide, thiazide, and loop diuretic) or organic base (e.g., amiloride and triamterene) secretory pumps in DIAGNOSIS the proximal tubule. A dose-response curve links the amount of The symptoms and laboratory findings associated with edematous drug reaching the urine to the amount of sodium excretion that is conditions depend on the underlying cause. Dyspnea on exertion elicited [see Figure 4]. Spironolactone binds to the cytosolic receptor and orthopnea provoked by pulmonary interstitial edema are for aldosterone, and its diuretic action, unlike that of other diuretics, prominent features in patients with left ventricular failure or nephrit- does not depend on secretion into the tubular lumen. ic edema, but these symptoms are usually absent when edema is The most potent agents are those that block sodium transport in caused by right heart failure, nephrotic syndrome, or cirrhosis. Mild the loop of Henle. At high doses, loop diuretics almost totally block peripheral edema collects in the dependent portions of the anatomy sodium reabsorption in this nephron segment, causing about 20% and is usually asymptomatic. Although more severe edema, which of the filtered load of sodium to be excreted in the urine; at low can extend to the thighs and buttocks, may be uncomfortable, it is glomerular filtration rates, the same percentage of filtered sodium is usually harmless. A large volume of ascites not only causes discom- excreted, but the total amount is reduced. Conditions such as vol- fort but also may elevate the diaphragm, causing shortness of breath; ume depletion, heart failure, and cirrhosis, which cause avid sodium promote reflux of gastric fluid, causing bleeding from esophageal reabsorption in the proximal and distal tubules, blunt the maximum varices; or become infected spontaneously. response to the diuretic.
  • 16. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 16 a b c d Amount of Na+ Excreted Amount of Na+ Excreted % Filtered Na+ Excreted % Filtered Na+ Excreted Urine Diuretic Levels Diuretic Dose Urine Diuretic Levels Diuretic Dose Figure 4 Dose-response curves for a loop diuretic in patients with normal (black line) and reduced (red line) renal function. Urinary sodium excretion responds to diuretic levels in the tubular lumen (as reflected by urinary drug levels). The diuretic effect reaches a maximum at approximately 20% of the filtered load of sodium regardless of renal function (a). Secretion of the diuretic into the tubular lumen is reduced in renal failure; thus, higher doses are required in azotemic patients to achieve the same urinary drug levels found in patients with normal renal function (b). Because the filtered load of sodium is reduced in patients with renal failure, absolute sodium excretion is also reduced, even at high doses (c and d). Because gastrointestinal absorption of diuretics is often delayed uretic response than does bolus administration and is associated with in edematous conditions (presumably because of bowel edema), a shorter hospital stay in patients with advanced heart failure.62 higher oral doses must be used to achieve adequate blood levels. In renal disease and cirrhosis, organic anions such as hippurate and Diuretic resistance Resistance to high doses of loop diuretics bile acids compete with the diuretic for secretion into the proximal may be overcome by administering loop diuretics in combination tubule; thus, higher plasma levels may be required to achieve ade- with thiazide or metolazone. Acetazolamide may be used along with quate drug levels in the urine. Similarly, severe hypoalbuminemia or in place of a thiazide or metolazone.This strategy blocks sodium can diminish drug secretion into the tubular lumen, because albu- reabsorption at several sites along the nephron, avoiding resistance min binding of most diuretics maximizes the rate of diuretic deliv- caused by increased sodium reabsoption proximal or distal to the ery to the organic anion secretory pump in the proximal tubule. Re- loop of Henle. Careful monitoring is extremely important, because duced renal blood flow also limits delivery of drug to the tubular these combinations can be extremely potent, causing large potassi- lumen. Some patients with advanced cirrhosis who are resistant to um and sodium losses. furosemide respond to spironolactone, a generally weak diuretic whose effectiveness does not depend on tubular secretion. Diuretic complications All diuretic agents may cause volume Agents that act in the proximal tubule, loop of Henle, or distal depletion and azotemia, but these complications are most likely to tubule cause potassium wasting and hypokalemia because they in- occur with loop diuretics.4 Hypokalemic alkalosis, hyperglycemia, crease delivery of tubular fluid to the cortical collecting tubule, where and hyperuricemia (sometimes with clinical gout) are common dose- potassium secretion is flow dependent. Potassium-sparing diuretics, dependent complications of both thiazides and loop diuretics.Thi- which act in the cortical collecting tubule, cause hyperkalemia be- azides decrease calcium excretion and may cause hypercalcemia in cause sodium reabsorption at this site favors potassium secretion. patients with underlying conditions that increase gastrointestinal cal- The carbonic anhydrase inhibitor, acetazolamide, causes metabolic cium absorption (e.g., sarcoidosis) or bone reabsorption (e.g., hyper- acidosis, as do the potassium-sparing diuretics.Thiazides and loop parathyroidism). Thiazides are also much more likely to cause hy- diuretics cause metabolic alkalosis because of increased distal deliv- ponatremia than other agents and should be avoided in patients who ery of sodium to sites where sodium reabsorption stimulates hydro- habitually drink large amounts of fluid. Potassium-sparing agents gen ion secretion. (e.g., triamterene, amiloride, and spironolactone) may cause hyper- kalemia; these agents should generally not be given with potassium Clinical use Diuretic doses should be adjusted to achieve ex- supplements, and they should be used with caution in patients with plicit therapeutic goals. Outpatient therapy is usually designed to pro- renal insufficiency (particularly diabetic nephropathy) and patients duce a gradual loss of fluid, increasing the dose until a desired target receiving ACE inhibitors or angiotensin II blocking agents. Loop di- weight is reached.The patient should be instructed to keep a daily log uretics can predispose to hearing loss, particularly when high doses that records weight and diuretic dose. Patients are instructed to stop are administered by bolus injection to patients receiving other oto- the diuretic if their weight falls too low, resuming at a lower dose toxic drugs.32 Hearing loss from ethacrynic acid is more likely to be when enough saltwater has been retained to restore the target weight. permanent. Inpatient diuretic management should also employ the target- weight concept, but dose adjustments can be made more often and more aggressively, particularly at the start of therapy. It is important Disorder of Saltwater Deficiency: Volume Depletion to rapidly define the dose that can deliver enough drug to the tubular PATHOGENESIS OF VOLUME DEPLETION lumen to reach the steep portion of the dose-response curve. Once an effective dose is defined, larger doses of diuretic provide little ben- Volume depletion occurs when saltwater is lost from the extracel- efit. If a greater response is needed, the effective dose should be re- lular fluid at a rate that exceeds intake. Saltwater can be lost from peated several times during the day, or alternatively, a continuous in- the gastrointestinal tract, kidney, or skin, or it can result from ex- fusion can be given to maintain effective urinary drug levels. travascular sequestration (third-space losses) in the abdominal cav- Continuous infusion of loop diuretics induces a slightly larger natri- ity or in traumatized tissues.
  • 17. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 24 DISORDERS OF WATER AND SODIUM BALANCE — 17 Underfilling of the arterial circulation triggers a cascade of physi- condition is allowed to continue. ologic responses that preserve blood flow to vital organs.Volume re- Loss of weight within a short period is the most reliable sign of ceptors and baroreceptors activate the sympathetic nervous system volume depletion. Physical findings include a low jugular venous and the renin-angiotensin-aldosterone system. Except when renal pulse rate and orthostatic changes in blood pressure and heart salt wasting is the cause, these responses reduce urinary sodium ex- rate.63,64 However, because postural hypotension can occur in up to cretion so that nearly all ingested salt is retained.Volume-depleted 30% of normovolemic persons older than 65 years, these changes persons also become thirsty; ingested water is retained because va- must be interpreted with caution. Decreased skin turgor and dry sopressin, released in response to volume depletion, concentrates mucous membranes are generally unreliable findings in volume-de- the urine, decreasing water excretion.The plasma sodium concen- pleted adults; these signs can be absent in severe hypovolemia, and tration can be high, normal, or low in volume-depleted persons, de- they can be present (particularly in mouth breathers and the elderly) pending on electrolyte-free water intake and excretion. Vasocon- when the patient is actually volume overloaded.The presence of ede- striction maintains the systemic blood pressure and also reduces ma makes true volume depletion unlikely. renal blood flow. Initially, efferent arteriolar resistance, mediated by angiotensin II, predominates, sustaining intraglomerular pressure Laboratory Tests and the glomerular filtration rate; in more severe hypovolemia, renal Laboratory findings are related to the decreased volume of in- blood flow is further reduced and glomerular filtration falls. travascular saltwater and to decreased renal perfusion. Hematocrit increases in proportion to the contraction of plasma volume, and ETIOLOGY the serum albumin may be increased as well. Urinary sodium is Because renal sodium conservation can reduce urinary sodium usually less than 20 mEq/L except in metabolic alkalosis (in which losses to less than 10 mmol/day, volume depletion is unlikely to oc- the urine chloride is low) or when renal sodium wasting is the cur from decreased intake alone.The small bowel and colon are the cause of the condition.41,65 Renal blood flow is reduced, but unless most common sources of isotonic fluid loss. Spectacular amounts of the patient is frankly hypotensive, the glomerular filtration rate is isotonic saltwater can be lost in diarrhea. For example, rice-water maintained by vasoconstriction of the efferent glomerular arteri- stool losses in cholera can reach 20 L/day, causing death within a ole.Thus, except in severe volume depletion, the serum creatinine few hours without fluid replacement. Small bowel obstruction caus- changes very little. Unlike creatinine, urea is reabsorbed from the es pooling of several liters of saltwater within the bowel lumen. Flu- glomerular filtrate.Thus, in volume depletion (prerenal azotemia), id may also be sequestrated in the abdominal cavity in patients with the BUN is increased disproportionately to the increase in creati- pancreatitis or peritonititis. Sequestration of fluid in the soft tissues nine.65 Azotemia may be blunted in patients with a poor dietary- may also complicate crush injuries with rhabdomyolysis or burns. protein intake and may be exacerbated in patients who are catabol- Renal salt wasting can cause volume depletion, but only a few dis- ic, bleeding, or receiving steroid therapy. orders can cause enough renal salt loss to be clinically apparent. Di- TREATMENT uretics and osmotic diuresis caused by glycosuria are the most fre- quent causes of renal salt wasting.Transient renal salt wasting may Patients with mild volume depletion can be treated by increasing occur in the recovery phases of acute tubular necrosis or obstructive their dietary intake of salt, relying on normal thirst mechanisms to uropathy, and it can also occur in toxic nephropathies. Renal salt provide the appropriate amount of water. For most patients, the fa- wasting also occurs in adrenal insufficiency. miliar (but misguided) order to drink fluids should be replaced with an order to salt one’s food. Even severe volume depletion can be DIAGNOSIS treated with oral solutions containing electrolytes, sugar, and amino acids.66 Glucose and amino acids promote intestinal absorption of Clinical Manifestations sodium through cotransport mechanisms similar to those found in Minor degrees of volume depletion (less than 10% of plasma vol- the proximal tubule of the kidney. Rice-based oral replacement so- ume, equivalent to the loss of one unit of blood) cause an increase in lutions have been a major advance in the treatment of diarrhea in heart rate and may also be associated with complaints of fatigue, developing countries. thirst, or muscle cramps.With modest hypovolemia, arteriolar vaso- Intravenous fluids are necessary when fluids cannot be taken constriction is sufficient to maintain the blood pressure when the pa- orally. If the patient is hypotensive, isotonic saline should be given as tient is recumbent. 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