Electrolytes - Na, K, Cl PDF

CHAPTER 16 n ELECTROLYTES 349 supercooled to -7°C and seeded to initiate the freez- to ADP. Because water follows electrolytes across cell ing process. When temperature equilibrium has been membranes, the continual removal of N...

CHAPTER 16 n ELECTROLYTES 349 supercooled to -7°C and seeded to initiate the freez- to ADP. Because water follows electrolytes across cell ing process. When temperature equilibrium has been membranes, the continual removal of Na+ from the cell reached, the freezing point is measured, with results for prevents osmotic rupture of the cell by also drawing serum and urine osmolality reported as milliosmoles per water from the cell. kilogram. Calculation of osmolality has some usefulness either Regulation The plasma Na+ concentration depends greatly on the as an estimate of the true osmolality or to determine intake and excretion of water and, to a somewhat lesser the osmolal gap, which is the difference between the degree, on the renal regulation of Na+. Three processes measured osmolality and the calculated osmolality. The are of primary importance: (1) the intake of water in osmolal gap indirectly indicates the presence of osmoti- response to thirst, as stimulated or suppressed by plasma cally active substances other than Na+, urea, or glucose, osmolality; (2) the excretion of water, largely affected such as ethanol, methanol, ethylene glycol, lactate, or by AVP release in response to changes in either blood β-hydroxybutyrate. volume or osmolality; and (3) the blood volume sta- Two formulas are presented, each having theoretic tus, which affects Na+ excretion through aldosterone, advantages and disadvantages. Both are adequate for the angiotensin II, and ANP. The kidneys have the ability purpose previously described. For more discussion, the to conserve or excrete large amounts of Na+, depending reader may consult other references.2 on the Na+ content of the ECF and the blood volume. BUN (mg/dL) glucose (mg/dL) ____________ Normally, 60% to 75% of filtered Na+ is reabsorbed in 2 Na + ​ ______________  ​    + ​   ​    20 3 the proximal tubule; electroneutrality is maintained by glucose _____ BUN either Cl− reabsorption or hydrogen ion (H+) secretion. 1.86 Na + _______ ​   ​  + ​   ​ + 9 (Eq. 16-1) 18 2.8 Some Na+ is also reabsorbed in the loop and distal tubule and (controlled by aldosterone) exchanged for K+ in the Reference Ranges connecting segment and cortical collecting tubule. The See Table 16-1.3 regulation of osmolality and volume has been summa- rized in Figure 16-1. The Electrolytes Sodium Na+ is the most abundant cation in the ECF, representing 90% of all extracellular cations, and largely determines CASE STUDY 16-1 the osmolality of the plasma. A normal plasma osmolal- A 32-year-old woman was admitted to the hospital ity is approximately 295 mmol/L, with 270 mmol/L being following 2½ days of severe vomiting. Before this the result of Na+ and associated anions. episode, she was reportedly well. Physical findings Na+ concentration in the ECF is much larger than revealed decreased skin turgor and dry mucous inside the cells. Because a small amount of Na+ can dif- membranes. Admission study results were as follows: fuse through the cell membrane, the two sides would eventually reach equilibrium. To prevent equilibrium Serum from occurring, active transport systems, such as ATPase Na+: 129 mmol/L ion pumps, are present in all cells. K+ (see section “Potassium”) is the major intracellular cation. Like Na+, K+: 5.0 mmol/L K+ would eventually diffuse across the cell membrane Cl−: 77 mmol/L until equilibrium is reached. The Na+, K+-ATPase ion HCO3−: 9 mmol/L pump moves three Na+ ions out of the cell in exchange Osmolality: 265 mOsm/kg for two K+ ions moving into the cell as ATP is converted Urine Na+: 8 mmol/d Ketones: trace Reference Ranges For TABLE 16-1 Osmolality Questions Serum 275–295 mOsm/kg 1. What is the cause for each abnormal plasma elec- Urine (24 h) 300–900 mOsm/kg trolyte result? Urine/serum ratio 1.0–3.0 2. What is the significance of the urine sodium and Random urine 50–1200 mOsm/kg serum osmolality results? Osmolal gap 5–10 mOsm/kg 18698_ch16_p346-374.indd 349 28/11/12 12:00 PM  350 PART 2 n CLINICAL CORRELATIONS AND ANALYTIC PROCEDURES Thirst Brain Hyperosmolality ADH Hypernatremia Heart Hypovolemia ANP Renal Na and H2O excretion Hypervolemia Vasodilation Lungs Artery Angiotensin II ACE Angiotensinogen Angiotensin I Adrenal Vasoconstriction Aldosterone Renin Na+ retention K+ excretion Renal perfusion Kidneys H2O retention pressure FIGURE 16-1 Responses to changes in blood osmolality and blood volume. ANP, atrial natriuretic peptide; ADH, antidi- uretic hormone; ACE, angiotensin-converting enzyme. The primary stimuli are shown in boxes (e.g., hypovolemia). Clinical Applications seen with congestive heart failure (CHF) as a result of increased venous pressure. Urine Na+ levels can be used Hyponatremia to differentiate the cause for increased water retention. Hyponatremia is defined as a serum/plasma level less When urine Na+ is ≥20 mmol/d, acute or chronic renal than 135 mmol/L.4 Hyponatremia is one of the most failure is the likely cause. When urine levels are less than common electrolyte disorders in hospitalized and non- hospitalized patients.5,6 Levels below 130 mmol/L are clinically significant. Hyponatremia can be assessed by the cause for the decrease or with the osmolality level. Table 16-2 Causes Of Hyponatremia Decreased levels may be caused by increased Na+ loss, increased water retention, or water imbalance Increased Sodium Loss (Table 16-2). Increased Na+ loss in the urine can occur Hypoadrenalism with decreased aldosterone production, certain diuretics Potassium deficiency (thiazides), ketonuria (Na+ lost with ketones), or a salt- Diuretic use losing nephropathy (with some renal tubular disorders). K+ deficiency also causes Na+ loss because of the inverse Ketonuria relationship of the two ions in the renal tubules. When Salt-losing nephropathy serum K+ levels are low, the tubules will conserve K+ and Prolonged vomiting or diarrhea excrete Na+ in exchange for the loss of the monovalent Severe burns cation. Each disorder results in an increased urine Na+ level (≥20 mmol/d), which exceeds the amount of water Increased Water Retention loss.7 Renal failure Prolonged vomiting or diarrhea or severe burns can Nephrotic syndrome result in Na+ loss. Urine Na+ levels are usually less than Hepatic cirrhosis 20 mmol/d in these disorders, which can be used to dif- ferentiate among causes for urinary loss. Congestive heart failure Increased water retention causes dilution of serum/ Water Imbalance plasma Na+ as with acute or chronic renal failure. In Excess water intake nephrotic syndrome and hepatic cirrhosis, plasma pro- teins are decreased, resulting in a decreased colloid SIADH osmotic pressure in which intravascular fluid migrates to Pseudohyponatremia the tissue (edema results). The low plasma volume causes SIADH, syndrome of inappropriate arginine vasopressin hormone AVP to be produced, causing fluid retention and resulting secretion. in dilution of Na+. This compensatory mechanism is also 18698_ch16_p346-374.indd 350 28/11/12 12:00 PM  CHAPTER 16 n ELECTROLYTES 351 20 mmol/d, water retention may be a result of nephrotic Table 16-4 Causes Of Hypernatremia syndrome, hepatic cirrhosis, or CHF.7 Water imbalance can occur as a result of excess Excess Water Loss water intake, as with polydipsia (increased thirst). The Diabetes insipidus increased intake must be chronic before water imbalance Renal tubular disorder occurs, which may cause mild or severe hyponatremia. Prolonged diarrhea In a normal individual, excess intake will not affect Na+ levels. SIADH causes an increase in water retention Profuse sweating because of increased AVP (ADH) production. A defect Severe burns in AVP regulation has been associated with pulmonary Decreased Water Intake disease, malignancies, central nervous system (CNS) dis- Older persons orders, infections (e.g., Pneumocystis carinii pneumonia), or trauma.7 Pseudohyponatremia can occur when Na+ is Infants measured using indirect ion-selective electrodes (ISEs) Mental impairment in a patient who is hyperproteinemic or hyperlipidemic. Increased Intake or Retention An indirect ISE dilutes the sample prior to analysis and Hyperaldosteronism as a result of plasma/serum water displacement; the ion levels are falsely decreased. (For detailed information Sodium bicarbonate excess on the theory of water displacement with indirect ISEs, Dialysis fluid excess consult Chapter 5.) Hyponatremia can also be classified according to plasma/serum osmolality (Table 16-3). Because Na+ is a major contributor to osmolality, both levels can assist Hyponatremia with a normal osmolality may be a in identifying the cause of hyponatremia. There are result of a high increase in nonsodium cations as three categories of hyponatremia—low osmolality, nor- listed in Table 16-4. In multiple myeloma, the cationic mal osmolality, or high osmolality.4 Most instances of γ-globulins replace some Na+ to maintain the electroneu- hyponatremia occur with decreased osmolality. This may trality; however, because it is a multivalent cation, it has be a result of Na+ loss or water retention, as previously little affect on osmolality. mentioned. Pseudohyponatremia, as mentioned earlier, may also be seen with in vitro hemolysis, considered the most common cause for a false decrease.4 When Classification Of Hypo­ red blood cells (RBCs) lyse, Na+, K+, and water are Table 16-3 natremia By Osmolality released. Na+ concentration is lower in RBCs, resulting With Low Osmolality in a false decrease. Hyponatremia with a high osmolality is associated with hyperglycemia. The elevated levels Increased sodium loss of glucose increase the serum osmolality and cause a Increased water retention shift of water from the cells to the blood, resulting in With Normal Osmolality a dilution of Na+. Increased nonsodium cations Symptoms of hyponatremia. Symptoms depend on the Lithium excess serum level. Between 125 and 130 mmol/L, symptoms Increased γ-globulins—cationic (multiple myeloma) are primarily gastrointestinal (GI). More severe neu- ropsychiatric symptoms are seen below 125 mmol/L, Severe hyperkalemia including nausea and vomiting, muscular weakness, Severe hypermagnesemia headache, lethargy, and ataxia. More severe symptoms Severe hypercalcemia also include seizures, coma, and respiratory depression.7 Pseudohyponatremia A level below 120 mmol/L for 48 hours or less (acute hyponatremia) is considered a medical emergency.8 Hyperlipidemia Serum and urine electrolytes are monitored as treatment Hyperproteinemia to return Na+ levels to normal occurs.9 Pseudohyperkalemia as a result of in vitro hemolysis Treatment of hyponatremia. Treatment is directed at With High Osmolality correction of the condition that caused either water loss Hyperglycemia or Na+ loss in excess of water loss. In addition, the onset of hyponatremia—acute or chronic (less than or more Mannitol infusion than 48 hours)—and the severity of hyponatremia are 18698_ch16_p346-374.indd 351 28/11/12 12:00 PM  352 PART 2 n CLINICAL CORRELATIONS AND ANALYTIC PROCEDURES considered in treatment. Conventional treatment of HYPERNATREMIA (150 mmol/L) hyponatremia involves fluid restriction and providing TABLE 16-5 RELATED TO URINE OSMOLALITY hypertonic saline and/or other pharmacologic agents that may take several days to reach the desired effect and may Urine Osmolality 700 mOsm/kg tor antagonist, has been found to be an effective treat- Loss of thirst ment for euvolemic or hypervolemic hyponatremia. Insensible loss of water (breathing, skin) Conivaptan has been approved by the U.S. Food and Gastrointestinal loss of hypotonic fluid Drug Administration for use in the United States and blocks the action of AVP in the collecting ducts of the Excess intake of sodium nephron, thus decreasing water reabsorption.10 This AVP, arginine vasopressin hormone. AVP receptor antagonist tends to restore Na+ levels within 24 hours.5 Euvolemic hypernatremia is associ- ated with SIADH, hypothyroidism, and adrenal insuf- fiency.6 Hypervolemic hyponatremia is associated with liver cirrhosis with ascites, CHF, and overhydrated Water loss through the skin and by breathing (insen- postoperative patients.8 Conivaptan is not an effective sible loss) accounts for about 1 L of water loss per day in treatment with hypovolemic hyponatremia because adults. Any condition that increases water loss, such as the increased water loss would accentuate the volume fever, burns, diarrhea, or exposure to heat, will increase depletion problem.10 the likelihood of developing hypernatremia. Commonly, hypernatremia occurs in those persons who may be Hypernatremia thirsty but who are unable to ask for or obtain water, Hypernatremia (increased serum Na+ concentration) such as adults with altered mental status and infants. results from excess loss of water relative to Na+ loss, When urine cannot be fully concentrated (e.g., in neo- decreased water intake, or increased Na+ intake or reten- nates, young children, older persons, and certain patients tion. Hypernatremia is less commonly seen in hospital- with renal insufficiency), a relatively lower urine osmo- ized patients than hyponatremia.7 lality may occur. Loss of hypotonic fluid may occur either by the kidney Chronic hypernatremia in an alert patient is indica- or through profuse sweating, diarrhea, or severe burns. tive of hypothalamic disease, usually with a defect in the Hypernatremia may result from loss of water in diabe- osmoreceptors rather than from a true resetting of the tes insipidus, either because the kidney cannot respond osmostat. A reset osmostat may occur in primary hyper- to AVP (nephrogenic diabetes insipidus) or because aldosteronism, in which excess aldosterone induces mild AVP secretion is impaired (central diabetes insipidus). hypervolemia that retards AVP release, shifting plasma Diabetes insipidus is characterized by copious pro- Na+ upward by approximately 3 to 5 mmol/L.1 duction of dilute urine (3 to 20 L/d). Because people Hypernatremia may be from excess ingestion of salt with diabetes insipidus drink large volumes of water, or administration of hypertonic solutions of Na+, such hypernatremia usually does not occur unless the thirst as sodium bicarbonate or hypertonic dialysis solutions. mechanism is also impaired. Partial defects of either AVP Neonates are especially susceptible to hypernatremia release or the response to AVP may also occur. In such from this cause. In these cases, AVP response is appro- cases, urine is concentrated to a lesser extent than appro- priate, resulting in urine osmolality of greater than priate to correct the hypernatremia. Excess water loss 800 mOsm/kg (Table 16-5). may also occur in renal tubular disease, such as acute tubular necrosis, in which the tubules become unable to Symptoms of hypernatremia. Symptoms most commonly fully concentrate the urine. involve the CNS as a result of the hyperosmolar state. The measurement of urine osmolality is necessary These symptoms include altered mental status, leth- to evaluate the cause of hypernatremia. With renal loss argy, irritability, restlessness, seizures, muscle twitching, of water, the urine osmolality is low or normal. With hyperreflexes, fever, nausea or vomiting, difficult res- extrarenal fluid losses, the urine osmolality is increased. piration, and increased thirst. Serum Na+ of more than Interpretation of the urine osmolality in hypernatremia is 160 mmol/L is associated with a mortality rate of 60% shown in Table 16-5. to 75%.7 18698_ch16_p346-374.indd 352 28/11/12 12:00 PM  CHAPTER 16 n ELECTROLYTES 353 Treatment of hypernatremia. Treatment is directed at Na+ Electrode correction of the underlying condition that caused the Internal Plastic clip water depletion or Na+ retention. The speed of cor- filling solution rection depends on the rate with which the condition developed. Hypernatremia must be corrected gradually because too rapid a correction of serious hypernatremia (≥160 mmol/L) can induce cerebral edema and death; the maximal rate should be 0.5 mmol/L/h.1 Vinyl wire to connector Determination of Sodium Specimen Na+ Internal Plastic Serum, plasma, and urine are all acceptable for Na+ glass reference body measurements. When plasma is used, lithium heparin, electrode ammonium heparin, and lithium oxalate are suitable anti- FIGURE 16-2 Diagram of sodium ion-selective electrode with glass coagulants. Hemolysis does not cause a significant change capillary membrane. (Courtesy of Nova Biomedical, Waltham, MA.) in serum or plasma values as a result of decreased levels of intracellular Na+. However, with marked hemolysis, levels may be decreased as a result of a dilutional effect. membranes cause poor selectivity, which results in poor Whole blood samples may be used with some analyz- reproducibility of results. A routine maintenance of these ers. Consult the instrument operation manual for accept- ISEs requires removal of this protein buildup to ensure ability. The specimen of choice in urine Na+ analyses is quality results. a 24-hour collection. Sweat is also suitable for analysis. Vitros analyzers (Ortho-Clinical Diagnostics) use a Sweat collection and analysis are discussed in Chapter 29. single-use direct ISE potentiometric system. Each dispos- Methods able slide contains a reference and measuring electrode Through the years, Na+ has been measured in vari- (Fig. 16-3). A drop of sample fluid and a drop of refer- ous ways, including chemical methods, flame emission ence fluid are simultaneously applied to the slide, and spectrophotometry, atomic absorption spectrophotom- the potential difference between the two is measured, etry (AAS), and ISEs. Chemical methods are outdated which is proportional to the Na+ concentration.11 because of large sample volume requirements and lack of precision. ISEs are the most routinely used method in Reference Ranges See Table 16-6.3 clinical laboratories. The ISE method uses a semipermeable membrane to Potassium develop a potential produced by having different ion con- centrations on either side of the membrane. In this type Potassium (K+) is the major intracellular cation in the of system, two electrodes are used. One electrode has a body, with a concentration 20 times greater inside the constant potential, making it the reference electrode. The cells than outside. Many cellular functions require that difference in potential between the reference and measur- the body maintain a low ECF concentration of K+ ions. ing electrodes can be used to calculate the “concentra- As a result, only 2% of the body’s total K+ circulates in tion” of the ion in solution. However, it is the activity of the plasma. Functions of K+ in the body include regula- the ion, not the concentration that is being measured (see tion of neuromuscular excitability, contraction of the Chapter 5). Most analyzers use a glass ion-exchange mem- heart, ICF volume, and H+ concentration.1 brane in its ISE system for Na+ measurement (Fig. 16-2). The K+ concentration has a major effect on the con- There are two types of ISE measurement, based on sample traction of skeletal and cardiac muscles. An elevated preparation: direct and indirect. Direct measurement plasma K+ decreases the resting membrane potential provides an undiluted sample to interact with the ISE (RMP) of the cell (the RMP is closer to zero), which membrane. With the indirect method, a diluted sample decreases the net difference between the cell’s resting is used for measurement. There is no significant differ- potential and threshold (action) potential. A lower than ence in results, except when samples are hyperlipidemic normal difference increases cell excitability, leading to or hyperproteinemic. Excess lipids or proteins displace muscle weakness. Severe hyperkalemia can ultimately plasma water, which leads to a falsely decreased measure- cause a lack of muscle excitability (as a result of a higher ment of ionic activity in millimoles per liter of plasma, RMP than action potential), which may lead to paralysis whereas the direct method measures in plasma water or a fatal cardiac arrhythmia.1 Hypokalemia decreases cell only. In these cases, direct ISE is more accurate. excitability by increasing the RMP, often resulting in an One source of error with ISEs is protein buildup on the arrhythmia or paralysis.1 The heart may cease to contract membrane through continuous use. The ­protein-coated in extreme cases of either hyperkalemia or hypokalemia. 18698_ch16_p346-374.indd 353 28/11/12 12:00 PM  354 PART 2 n CLINICAL CORRELATIONS AND ANALYTIC PROCEDURES 1. Upper slide mount 2. Paper bridge 3. Ion-selective membrane Methyl monensin 4. Reference layer NaCl Buffer at pH 5.6 5. Silver, silver chloride layer 6. Support layer 7. Lower slide mount FIGURE 16-3 Schematic diagram of the ion-selective electrode system for the potentiometric slide on the Vitros. (Courtesy of OCD, a Johnson & Johnson company, Rochester, NY.) K+ concentration also affects the H+ concentration in change in the plasma K+ concentration because excess K+ the blood. For example, in hypokalemia (low serum K+), is normally excreted in the urine. as K+ is lost from the body, Na+ and H+ move into the Three factors that influence the distribution of K+ cell. The H+ concentration is, therefore, decreased in the between cells and ECF are as follows: (1) K+ loss fre- ECF, resulting in alkalosis. quently occurs whenever the Na+, K+-ATPase pump is inhibited by conditions such as hypoxia, hypomagne- Regulation semia, or digoxin overdose; (2) insulin promotes acute Renal function related to tubular reabsorption and secre- entry of K+ into skeletal muscle and liver by increasing tion is important in the regulation of potassium balance. Na+, K+-ATPase activity; and (3) catecholamines, such Initially, the proximal tubules reabsorb nearly all the K+. as epinephrine (β2-stimulator), promote cellular entry of Then, under the influence of aldosterone, additional K+ K+, whereas propanolol (β-blocker) impairs cellular entry is secreted into the urine in exchange for Na+ in both of K+. Dietary deficiency or excess is rarely a primary the distal tubules and the collecting ducts. Thus, the cause of hypokalemia or hyperkalemia. However, with a distal nephron is the principal determinant of urinary K+ pre-existing condition, dietary deficiency (or excess) can excretion. Most individuals consume far more K+ than enhance the degree of hypokalemia (or hyperkalemia). needed; the excess is excreted in the urine but may accu- mulate to toxic levels if renal failure occurs. Exercise K+ uptake from the ECF into the cells is important K+ is released from muscle cells during exercise, which in normalizing an acute rise in plasma K+ concentration may increase plasma K+ by 0.3 to 1.2 mmol/L with mild due to an increased K+ intake. Excess plasma K+ rapidly to moderate exercise and by as much as 2 to 3 mmol/L enters the cells to normalize plasma K+. As the cellular with exhaustive exercise. These changes are usually K+ gradually returns to the plasma, it is removed by uri- reversed after several minutes of rest. Forearm exercise nary excretion. Note that chronic loss of cellular K+ may during venipuncture can cause erroneously high plasma result in cellular depletion before there is an appreciable K+ concentrations.12 Hyperosmolality Hyperosmolality, as with uncontrolled diabetes mellitus, Reference Ranges For causes water to diffuse from the cells, carrying K+ with TABLE 16-6 the water, which leads to gradual depletion of K+ if kid- Sodium ney function is normal. Serum, plasma 136–145 mmol/L Urine (24 h) 40–220 mmol/d, varies Cellular Breakdown with diet Cellular breakdown releases K+ into the ECF. Examples are severe trauma, tumor lysis syndrome, and massive Cerebrospinal fluid 136–150 mmol/L blood transfusions. 18698_ch16_p346-374.indd 354 28/11/12 12:00 PM  CHAPTER 16 n ELECTROLYTES 355 Table 16-7 Causes Of Hypokalemia in healthy persons, decreased intake may intensify hypo- kalemia caused by use of diuretics, for example. Gastrointestinal Loss Increased cellular uptake of potassium is encountered Vomiting in alkalemia and with elevated levels of insulin via thera- Diarrhea peutic treatment of diabetes. Both alkalemia and insulin increase the cellular uptake of K+. Because alkalemia Gastric suction promotes intracellular loss of H+ to minimize elevation Intestinal tumor of intracellular pH, both K+ and Na+ enter cells to pre- Malabsorption serve electroneutrality. Plasma K+ decreases by about Cancer therapy—chemotherapy, radiation therapy 0.4 mmol/L per 0.1 unit rise in pH.1 Insulin promotes the entry of K+ into skeletal muscle and liver cells. Because Large doses of laxatives insulin therapy can sometimes uncover an underlying Renal Loss hypokalemic state, plasma K+ should be monitored care- Diuretics—thiazides, mineralocorticoids fully whenever insulin is administered to susceptible Nephritis patients.1 A rare cause of hypokalemia is associated with a blood sample from a leukemic patient with a signifi- Renal tubular acidosis cantly elevated white blood cell count. The K+ present in Hyperaldosteronism the sample is taken up by the white cells if the sample is Cushing’s syndrome left at room temperature for several hours.13 Hypomagnesemia Acute leukemia Symptoms of hypokalemia. Symptoms (e.g., weakness, fatigue, and constipation) often become apparent as Cellular Shift plasma K+ decreases below 3 mmol/L. Hypokalemia can Alkalosis lead to muscle weakness or paralysis, which can interfere Insulin overdose with breathing. The dangers of hypokalemia concern all Decreased Intake patients, but especially those with cardiovascular disor- ders because of an increased risk of arrhythmia, which may cause sudden death in certain patients. Mild hypo- kalemia (3.0 to 3.4 mmol/L) is usually asymptomatic. Clinical Applications Treatment of hypokalemia. Treatment typically includes Hypokalemia oral KCl replacement of K+ over several days. In some Hypokalemia is a plasma K+ concentration below the instances, intravenous (IV) replacement may be indicat- lower limit of the reference range. Hypokalemia can ed. In some cases, chronic mild hypokalemia may be cor- occur with GI or urinary loss of K+ or with increased rected simply by including food in the diet with high K+ cellular uptake of K+. Common causes of hypokalemia content, such as dried fruits, nuts, bran cereals, bananas, are shown in Table 16-7. Of these, therapy with thiazide- and orange juice. Plasma electrolytes are monitored as type diuretics is the most common.13 GI loss occurs treatment to return K+ levels to normal occurs. when GI fluid is lost through vomiting, diarrhea, gastric suction, or discharge from an intestinal fistula. Increased Hyperkalemia K+ loss in the stool also occurs with certain tumors, mal- The most common causes of hyperkalemia are shown absorption, cancer therapy (chemotherapy or radiation in Table 16-8. Patients with hyperkalemia often have an therapy), and large doses of laxatives. underlying disorder, such as renal insufficiency, diabe- Renal loss of K+ can result from kidney disorders tes mellitus, or metabolic acidosis, that contributes to such as K+-losing nephritis and renal tubular acidosis hyperkalemia.12 For example, during administration of (RTA). In RTA, as tubular excretion of H+ decreases, K+ KCl, a person with renal insufficiency is far more likely excretion increases. Because aldosterone promotes Na+ to develop hyperkalemia than is a person with normal retention and K+ loss, hyperaldosteronism can lead to renal function. The most common cause of hyperkalemia hypokalemia and metabolic alkalosis.1 Hypomagnesemia in hospitalized patients is due to therapeutic K+ admin- can lead to hypokalemia by promoting urinary loss istration. The risk is greatest with IV K+ replacement.12 of K+. Mg2+ deficiency also diminishes the activity of In healthy persons, an acute oral load of K+ will Na+, K+-ATPase and enhances the secretion of aldo- briefly increase plasma K+ because most of the absorbed sterone. Effective treatment requires supplementation K+ rapidly moves intracellularly. Normal cellular pro- with both Mg2+ and K+.1 Renal K+ loss also occurs with cesses gradually release this excess K+ back into the acute myelogenous leukemia, acute myelomonocytic plasma, where it is normally removed by renal excretion. leukemia, and acute lymphocytic leukemia.13 Although Impairment of urinary K+ excretion is usually associated reduced dietary intake of K+ rarely causes hypokalemia with chronic hyperkalemia.1 18698_ch16_p346-374.indd 355 28/11/12 12:00 PM  356 PART 2 n CLINICAL CORRELATIONS AND ANALYTIC PROCEDURES TABLE 16-8 CAUSES OF HYPERKALEMIA gradually released from erythrocytes during storage, often causing elevated K+ concentration in plasma supernatant. Decreased Renal Excretion Patients on cardiac bypass may develop mild eleva- Acute or chronic renal failure (GFR < 20 mL/min) tions in plasma K+ during warming after surgery because Hypoaldosteronism warming causes cellular release of K+. Hypothermia causes movement of K+ into cells. Addison’s disease Diuretics Symptoms of hyperkalemia. Hyperkalemia can cause Cellular Shift muscle weakness, tingling, numbness, or mental con- fusion by altering neuromuscular conduction. Muscle Acidosis weakness does not usually develop until plasma K+ Muscle/cellular injury reaches 8 mmol/L.1 Chemotherapy Hyperkalemia disturbs cardiac conduction, which can Leukemia lead to cardiac arrhythmias and possible cardiac arrest. Plasma K+ concentrations of 6 to 7 mmol/L may alter the Hemolysis electrocardiogram (ECG), and concentrations more than Increased Intake 10 mmol/L may cause fatal cardiac arrest.1 Oral or intravenous potassium replacement therapy Artifactual Treatment of hyperkalemia. Treatment should be imme- diately initiated when serum K+ is 6.0 to 6.5 mmol/L or Sample hemolysis greater or if there are ECG changes.12 To offset the effect Thrombocytosis of K+, which lowers the resting potential of myocardial Prolonged tourniquet use or excessive fist clenching cells, Ca2+ may be given to reduce the threshold potential of myocardial cells. Therefore, Ca2+ provides immediate GFR, glomerular filtration rate. but short-lived protection to the myocardium against the effects of hyperkalemia. Substances that acutely shift K+ back into cells, such as sodium bicarbonate, glucose, or insulin, may also be administered. K+ may be quickly If a shift of K+ from cells into plasma occurs too removed from the body by use of diuretics (loop), if rapidly to be removed by renal excretion, acute hyperka- renal function is adequate, or sodium polystyrene sulfo- lemia develops. In diabetes mellitus, insulin deficiency nate (Kayexalate) enemas, which bind to K+ secreted in promotes cellular loss of K+. Hyperglycemia also con- the colon. Hemodialysis can be used if other measures tributes by producing a hyperosmolar plasma that pulls fail.12 Patients treated with these agents must be moni- water and K+ from cells, promoting further loss of K+ tored carefully to prevent hypokalemia as K+ moves back into the plasma.1 into cells or is removed from the body. In metabolic acidosis, as excess H+ moves intracellu- larly to be buffered, K+ leaves the cell to maintain electro- Collection of Samples neutrality. Plasma K+ increases by 0.2 to 1.7 mmol/L for Proper collection and handling of samples for K+ analysis each 0.1 unit reduction of pH.1 Because cellular K+ often is extremely important because there are many causes of becomes depleted in cases of acidosis with hyperkalemia artifactual hyperkalemia. First, the coagulation process (including diabetic ketoacidosis), treatment with agents releases K+ from platelets, so that serum K+ may be 0.1 to such as insulin and bicarbonate can cause a rapid intra- 0.7 mmol/L higher than plasma K+ concentrations.2 If the cellular movement of K+, producing severe hypokalemia. patient’s platelet count is elevated (thrombocytosis), serum Various drugs may cause hyperkalemia, especially in K+ may be further elevated. Second, if a tourniquet is left patients with either renal insufficiency or diabetes melli- on the arm too long during blood collection or if patients tus. These drugs include captopril (inhibits angiotensin- excessively clench their fists or otherwise exercise their converting enzyme), nonsteroidal anti-inflammatory forearms before venipuncture, cells may release K+ into agents (inhibit aldosterone), spironolactone (K+-sparing the plasma. The first situation may be avoided by using a diuretic), digoxin (inhibits Na+–K+ pump), cyclosporine heparinized tube to prevent clotting of the specimen and (inhibits renal response to aldosterone), and heparin the second by using proper care in the drawing of blood. therapy (inhibits aldosterone secretion). Third, because storing blood on ice promotes the release Hyperkalemia may result when K+ is released into the of K+ from cells,14 whole blood samples for K+ determina- ECF during enhanced tissue breakdown or catabolism, tions should be stored at room temperature (never iced) especially if renal insufficiency is present. Increased cel- and analyzed promptly or centrifuged to remove the cells. lular breakdown may be caused by trauma, administra- Fourth, if hemolysis occurs after the blood is drawn, tion of cytotoxic agents, massive hemolysis, tumor lysis K+ may be falsely elevated—the most common cause of syndrome, and blood transfusions. In banked blood, K+ is artifactual hyperkalemia. Slight ­hemolysis (≈50 mg/dL of 18698_ch16_p346-374.indd 356 28/11/12 12:00 PM  CHAPTER 16 n ELECTROLYTES 357 hemoglobin) can cause an increase of approximately 3% Reference Ranges For while gross hemolysis (>500 mg/dL of hemoglobin) can Table 16-9 Potassium cause an increase of up to 30%.2 Serum 3.5–5.1 mmol/L Determination of Potassium Plasma Males: 3.5–4.5 mmol/L Specimen Females: 3.4–4.4 mmol/L Serum, plasma, and urine may be acceptable for analy- Urine (24 h) 25–125 mmol/d sis. Hemolysis must be avoided because of the high K+ content of erythrocytes. Heparin is the anticoagulant of choice. Whereas serum and plasma generally give similar ­ owever, it is involved in maintaining osmolality, blood h K+ levels, serum reference intervals tend to be slightly volume, and electric neutrality. In most processes, Cl− higher. Significantly elevated platelet counts may result shifts secondarily to a movement of Na+ or HCO3−. in the release of K+ during clotting from rupture of these Cl− ingested in the diet is almost completely absorbed cells, causing a spurious hyperkalemia. In this case, by the intestinal tract. Cl− is then filtered out by the plasma is preferred. Whole blood samples may be used glomerulus and passively reabsorbed, in conjunction with some analyzers. Consult the instrument’s opera- with Na+, by the proximal tubules. Excess Cl− is excreted tions manual for acceptability. Urine specimens should in the urine and sweat. Excessive sweating stimulates be collected over a 24-hour period to eliminate the influ- aldosterone secretion, which acts on the sweat glands to ence of diurnal variation. conserve Na+ and Cl−. Methods Cl− maintains electrical neutrality in two ways. First, As with Na+, the current method of choice is ISE. For Na+ is reabsorbed along with Cl− in the proximal tubules. ISE measurements, a valinomycin membrane is used to In effect, Cl− acts as the rate-limiting component, in that selectively bind K+, causing an impedance change that Na+ reabsorption is limited by the amount of Cl− avail- can be correlated to K+ concentration. KCl is the inner able. Electroneutrality is also maintained by Cl− through electrolyte solution. the chloride shift. In this process, CO2 generated by cel- lular metabolism within the tissue diffuses out into both Reference Ranges the plasma and the red cell. In the red cell, CO2 forms See Table 16-9.3 carbonic acid (H2CO3), which splits into H+ and HCO3− (bicarbonate). Deoxyhemoglobin buffers H+, whereas the Chloride HCO3− diffuses out into the plasma and Cl− diffuses into Chloride (Cl−) is the major extracellular anion. Its the red cell to maintain the electric balance of the cell precise function in the body is not well understood; (Fig. 16-4). Peripheral Plasma Erythrocyte tissue cell O2 O2 O2 (Internal respiration) HHbCO2 HHb 4 Dissolved 5 HbO2– PrCO2 dCO2 CO2 2 3 6 C.A. CO2 CO2 CO2 + H2O H+ + HCO3– HCO3 – + Na+ (Metabolism) +H2O + + 7 H+HCO3 K+ + Cl– Cl– 1 + Protein H-protein + HCO3 FIGURE 16-4 Chloride shift mechanism. See text for details. (Reprinted with permission from Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. 2nd ed. Philadelphia, PA: WB Saunders; 1994.) 18698_ch16_p346-374.indd 357 28/11/12 12:00 PM  358 PART 2 n CLINICAL CORRELATIONS AND ANALYTIC PROCEDURES Clinical Applications Bicarbonate Cl− disorders are often a result of the same causes that Bicarbonate is the second most abundant anion in the disturb Na+ levels because Cl− passively follows Na+. ECF. Total CO2 comprises the bicarbonate ion (HCO3−), There are a few exceptions. Hyperchloremia may also H2CO3, and dissolved CO2, with HCO3− accounting occur when there is an excess loss of HCO3− as a result for more than 90% of the total CO2 at physiologic pH. of GI losses, RTA, or metabolic acidosis. Hypochloremia Because HCO3− composes the largest fraction of total may also occur with excessive loss of Cl− from prolonged CO2, total CO2 measurement is indicative of HCO3− vomiting, diabetic ketoacidosis, aldosterone deficiency, measurement. or salt-losing renal diseases such as pyelonephritis. A HCO3− is the major component of the buffering sys- low serum level of Cl− may also be encountered in condi- tem in the blood. Carbonic anhydrase in RBCs converts tions associated with high serum HCO3− concentrations, CO2 and H2O to H2CO3, which dissociates into H+ and such as compensated respiratory acidosis or metabolic HCO3−. alkalosis. CO2 + H2O ←→ H2CO3 ←→ H+ + HCO3− CA CA Determination of Chloride Specimen (Eq. 16-3) Serum or plasma may be used, with lithium heparin being the anticoagulant of choice. Hemolysis does not where CA is carbonic anhydrase. HCO3− diffuses out of cause a significant change in serum or plasma values as the cell in exchange for Cl− to maintain ionic charge neu- a result of decreased levels of intracellular Cl−. However, trality within the cell (chloride shift; see Fig. 16-4). This with marked hemolysis, levels may be decreased as a process converts potentially toxic CO2 in the plasma to result of a dilutional effect. an effective buffer: HCO3−. HCO3− buffers excess H+ by Whole blood samples may be used with some ana- combining with acid, then eventually dissociating into lyzers. Consult the instrument’s operation manual for H2O and CO2 in the lungs where the acidic gas CO2 is acceptability. The specimen of choice in urine Cl− analy- eliminated. ses is 24-hour collection because of the large diurnal Regulation variation. Sweat is also suitable for analysis. Sweat collec- Most of the HCO3− in the kidneys (85%) is reabsorbed by tion and analysis are discussed in Chapter 29. the proximal tubules, with 15% being reabsorbed by the Methods distal tubules. Because tubules are only slightly perme- There are several methodologies available for measuring able to HCO3−, it is usually reabsorbed as CO2. This hap- Cl−, including ISEs, amperometric-coulometric titra- pens as HCO3−, after filtering into the tubules, combines tion, mercurimetric titration, and colorimetry. The most with H+ to form H2CO3, which then dissociates into commonly used is ISE. For ISE measurement, an ion- H2O and CO2. The CO2 readily diffuses back into the exchange membrane is used to selectively bind Cl− ions. ECF. Normally, nearly all the HCO3− is reabsorbed from Amperometric-coulometric titration is a method using the tubules, with little lost in the urine. When HCO3− is coulometric generation of silver ions (Ag+), which com- filtered in excess of H+ available, almost all excess HCO3− bine with Cl− to quantitate the Cl− concentration. flows into the urine. In alkalosis, with a relative increase in HCO3− com- Ag2+ + 2Cl− → AgCl2 (Eq. 16-2) pared with CO2, the kidneys increase excretion of When all Cl− in a patient is bound to Ag+, excess or HCO3− into the urine, carrying along a cation such as free Ag+ is used to indicate the endpoint. As Ag+ accu- Na+. This loss of HCO3− from the body helps correct pH. mulates, the coulometric generator and timer are turned Among the responses of the body to acidosis is an off. The elapsed time is used to calculate the concentra- increased excretion of H+ into the urine. In addition, tion of Cl− in the sample. The digital (Cotlove) chlorid- HCO3− reabsorption is virtually complete, with 90% of ometer (Labconco Corporation) uses this principle in the filtered HCO3− reabsorbed in the proximal tubule Cl− analysis. and the remainder in the distal tubule.1 Reference Ranges Clinical Applications See Table 16-10.3 Acid–base imbalances cause changes in HCO3− and CO2 levels. A decreased HCO3− may occur from metabolic aci-  Reference Ranges For dosis as HCO3− combines with H+ to produce CO2, which Table 16-10 Chloride is exhaled by the lungs. The typical response to metabolic Plasma, serum 98–107 mmol/L acidosis is compensation by hyperventilation, which low- ers pco2. Elevated total CO2 concentrations occur in met- Urine (24 h) 110–250 mmol/d, varies with diet abolic alkalosis as HCO3− is retained, often with increased 18698_ch16_p346-374.indd 358 28/11/12 12:00 PM