Disorders of Potassium Homeostasis

Fluid and Electrolyte Disorders

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Disorders of Potassium Homeostasis M. D. Willard, DVM, MS*

NORMAL POTASSIUM HOMEOSTASIS About 95 per cent of the total body potassium (K) is intracellular, the cell maintaining a high K concentration (about 140 mEq per L) and a low sodium concentration (about 10 mEq per L) by means of Na-K adenosine triphosphatase (ATPase) located in the cellular membrane. 5 The serum levels are the opposite, with approximately 4 to 5 mEq K per L and 145 mEq Naper L. Nonetheless, the relatively small amount of K that resides in the extracellular fluid compartment has major clinical implications. Therefore, serum K concentrations are tightly regulated by controlling the total amount of Kin the body (external balance) and by altering the relative amounts in the cell versus the blood (internal balance). Total body K (external balance) is regulated by the kidneys because K is nonselectively absorbed by the intestines (although in some cases there is increased intestinal excretion). Obligatory urinary K losses occur, which are proportional to the renal tubular flow in the distal tubules (i.e., increased flow causes increased K loss); however, aldosterone is the major modifier of renal K excretion. 40 It does this by increasing renal N a-K ATPase activity and cellular membrane permeability to K. This is a powerful means of controlling total body K, albeit not a very rapidly responding one. Aldosterone can also increase colonic K secretion in some species, probably including the dog and cat. 5 In cases of chronic excessive K intake, aldosterone is able to eliminate unneeded K; but, with acute K overload, aldosterone may be inadequate to prevent serum K concentrations from reaching toxic levels. Internal K balance is principally regulated by insulin and catecholamines, which have faster response times. 24 • 113· 123 Aldosterone is also postulated to affect internal balance, but this is uncertain. 5 Insulin facilitates cellular uptake of glucose and aminoacids, which causes cellular K sequestration. This occurs at normal resting serum insulin concentrations, but *Diplomate, American College of Veterinary Internal Medicine; Professor, Department of Small Animal Medicine and Surgery, Texas A & M University College of Veterinary Medicine, College Station, Texas Veterinary Clinics of North America: Small Animal Practice-Vol. 19, No. 2, March 1989

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whether there is insulin secretion due to hyperkalemia is uncertain. Catecholamines also cause intracellular sequestration of K, particularly stimulation of beta-2-adrenergic receptors.

PATHOPHYSIOLOGIC CONSEQUENCES OF ALTERED BLOOD POTASSIUM Both hyper- and hypokalemia can cause muscular weakness. Extracellular K is a major determinant of the cells' resting membrane potential. Hypokalemia increases the resting membrane potential, resulting in a larger difference between the resting potential and the threshold potential necessary for an action potential and muscular contraction. This means that it is more difficult to stimulate muscle fibers to contract, the net result being weakness. Additionally, hypokalemia impairs muscle capillary blood flow. Intestinal smooth muscle can also be affected with resultant ileus. 93 Cardiac muscle effects are particularly significant: Hyperpolarization at the end of repolarization leads to an increased automaticity, which may result in various arrhythmias (supraventricular and ventricular ectopics) that can be resistant to antiarrhythmic therapy (e.g., lidocaine). 83 ECG changes also occur but are less consistent: depressed T-wave amplitude, depressed S-T segment, prolonged Q-T interval, and prominent U waves. Chronic hypokalemia can also cause a true myopathy32 • 112 that may have an inflammatory component mimicking myositis. 11 Renal function may be diminished by severe hypokalemia. Although there are few reports of clinical signs in spontaneously hypokalemic dogs (e.g., polyuria-polydipsia48), recent feline data suggest that hypokalemia worsens azotemia in cats with preexisting renal disease. 31 Finally, hypokalemia may predispose dogs to alkalosis, 39 although there is conflicting data that suggest that metabolic acidosis is more likely if chloride intake is normal. 18 Regardless, failing to correct hypokalemia makes it difficult to reverse metabolic alkalosis secondary to volume depletion and hypokalemia (e.g., vomiting). Hyperkalemia increases the resting membrane potential to near threshold, which produces a weaker action potential when threshold is reached, resulting in muscle weakness. Most patients with K less than 6.5 mEq per L do not evidence signs directly referrable to the hyperkalemia but may be sick owing to uremia, glucocorticoid deficiency, or other primary disease. Patients with K greater than 7.5 mEq per L usually have signs resulting from the K. 99 Muscle weakness may be obvious (e.g., unable to stand and/ or trembling) or may mimic depression (e.g., the patient in which inability to get up is misinterpreted as depression). Many dogs with severe weakness have more noticeable signs in the rear legs, suggesting spinal cord disease, whereas cats often have cranial ventroflexion. Occasionally, esophageal regurgitation occurs owing to weakness of the esophageal striated muscle. The heart may not only be weakened but also have slowed atrioventricular conduction. 29 Spiked T waves are the first change (Fig. l); however, they are transient, usually occuring when the K is less than 6.5 mEq per L, and there are minimal clinical signs. As the K increases, there is diminution of P waves (with eventual disappearance), prolongation of the

DISORDERS OF POTASSIUM HOMEOSTASIS

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P-R interval, widening of the QRS complex, diminished R-wave amplitude, and/or bradycardia. Bradycardia is not invariable and even if present does not imply hyperkalemia unless these other changes are present. Some patients present with ventricular tachycardia. 36 The cardiotoxic effects of hyperkalemia make it important to watch for concurrent serum calcium abnormalities. Hypocalcemia weakens muscular contractions and can cause signs of hyperkalemia to be more severe and occur at lower than expected blood K concentrations. Hyponatremia and acidemia likewise potentiate the effects of hyperkalemia on the heart. 29 Rarely, very increased K concentrations (i.e., > 9.0 mEq per L) cause minimal clinical or ECG signs, 59• 110 especially if the serum sodium is normal. This has been reported in people; the author has also seen this in dogs. Measurement of potassium is indicated whenever hyperkalemia (i.e., significant acid-base abnormalities, severe renal disease or uremia, suggestive cardiac arrhythmias, muscular weakness, and when K is being supplemented) or hypokalemia (i.e., vomiting, diarrhea, muscular weakness, chronic diuretic therapy, severe acid-base abnormalities, unexplained cardiac arrythmias, diabetes mellitus, or when the patient is receiving insulin, bicarbonate, prolonged or aggressive fluid therapy, or total parenteral nutrition) is likely. It should also be performed as a screening test in any sick patient with undiagnosed dis0ase. Potassium can be measured in serum, plasma, and urine. Flame photometry, ion-specific electrodes, and "dry-reagent" methodology using a reflectance meter6 · 72 are used and give comparable results in dogs and cats. The last-named allows rapid, accurate measurement of K in any practice. Pseudohypokalemia is uncommon. It may be secondary to hyperlipidema or severe hyperproteinemia (serum total protein > 10 g per dl), but either of these rarely alters serum K to the same extent as sodium. Flame photometry and dry reagent methods 6 can be altered by these conditions, whereas ion-specific electrodes are not affected unless the machine dilutes the sample before analysis. If necessary, hyperlipidemic serum may be cleared by ultracentrifugation or polyethylene glycol. 114 Dry-reagent analysis may also have falsely decreased values owing to blood glucose levels greater than 1000 mg per dl, high serum concentrations of theophylline, and severe azotemia (BUN > 115 mg per dl). 6 The K concentration of the sample may inaccurately reflect in vivo K values. Obtaining blood through an intravenous (IV) catheter that has not been properly cleared of K-free fluids may cause the sample to have a lower K concentration than the patient. Allowing blood to clot when there are large numbers of metabolically active cells (i.e., leukamoid reactions or lymphoblastic leukemia) may allow these cells to metabolize the K in the sample, 2 although this is uncommon. Pseudohyperkalemia is more of a problem than pseudohypokalemia. Hemolysis and severe hypernatremia may falsely increase measurements with dry-reagent analysis. 6 Extreme leukocytosis 13 (probably > 100,000/ mm 3 ) and extreme thrombocytosis 52• 74 (> l,OOO,OOO/mm 3) may allow significant amounts of K to be released into the serum during the clotting

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Figure l. Electrocardiograms from dogs with abnormal serum potassium concentrations. A shows ventricular tachycardia in a dog with K > 9.0 mEq/L. B, Five minutes later, the same dog has had a spontaneous reversion to a typical pattern characterized by lack of P waves, bradycardia and short, wide R waves. C, After 55 minutes of therapy with fluids and bicarbonate the EGG shows improvement, the only remaining signs of hyperkalemia being spiked T waves and small P waves with prolonged PR intervals.

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Figure 1 (Continued). Dis a typical ECG from a dog with K = 7.0 mEq/L showing lack of P waves as the major abnormality. E, The following day the K was normal and the P waves had returned. F is an ECG from a dog with K = l. 7 mEq/L. An inexperienced clinician might confuse the wide R waves and the prolonged PR interval (i.e., 0.14 sec) with a hyperkalemic pattern.

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process. Note that very increased WBC numbers may result in artifactually increased or decreased K measurements. There is a linear relationship between the number of platelets and the degree to which the measured serum K is increased. Hemolysis generally does not alter K values in dogs or cats; however, the Akita has sufficient RBC K for hemolysis to significantly increase sample concentrations. 27 These artifacts may be circumvented by using lithium heparin tubes instead of clot tubes and rapidly separating the plasma from the serum, a procedure advisable anytime the measured K does not seem consistent with the clinical signs. Failing to properly clear an IV line of K-containing fluids and then using that line for sampling may cause inaccurate measurements as may improper sample handling that allows dehydration and subsequent concentration of solutes. Rarely, a K3 -EDTA tube will be used instead of a clot tube, resulting in artifactual hyperkalemia. Although not reported in dogs and cats, vigorous exercise immediately before (and presumably during) venipuncture will transiently increase K in humans. i 7• 72 In general, if the patient's clinical signs are consistent with the measured K value, it is appropriate to begin diagnostics and!or therapeutics immediately, although it is wise to recheck the abnormal value to ensure that it is correct. However, if the patient's signs do not seem consistent with the determined K concentration, it is mandatory to recheck the value before beginning aggressive therapy lest an artifactual measurement result in iatrogenic morbidity or mortality. Electrocardiographic analysis may be helpful (see section on Pathophysiologic Consequences) if the K determination is delayed because it must be performed by a reference laboratory. However, the changes "diagnostic" of hypokalemia are often subtle, if even present. U waves can be mistaken for T waves by the inexperienced. m More often, ectopic arrhythmias resistant to therapy are the principal ECG finding. 83 Therefore, one should not expect ECGs to allow presumptive diagnosis of hypokalemia. Hyperkalemia may be more reliably detected by ECG. However, one must remember that while finding typical ECG changes presumptively diagnoses hyperkalemia, not finding these abnormalities does not eliminate it. Sometimes repeating the ECG may diagnose hyperkalemia that was not suspected before (see Fig. 1).

HYPERKAJ.,EMIA Hyperkalemia is caused by three basic processes: increased intake, decreased excretion, and compartmental shifts from cells to the extracellular fluid. Increased intake is usually iatrogenic. Administration of K-containing drugs (i.e., potassium penicillin-G, KCl, 67 • 88 or potassium citrate35) may be responsible if too much K is given or if it is administered too fast. This is relatively common with IV KCl administration, but even the oral, slowrelease K supplements have been responsible. 60 dbcasionally, high K diets (some baby foods 37), salt substitutes (KCl), and enteral feeding solutions may be blamed. 91 Rarely, pica is responsible. 1 Whenever iatrogenic causes

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DISORDERS OF POTASSIUM HOMEOSTASIS

Table 1. Drugs that May Cause Hyperkalemia DRUG

Potassium chloride, phosphate, citrate, or K-penicillin G o,p'-DDD Potassium-sparing diuretics (spironolactone, triamterene, amiloride) Digitalis glycosides

Succinylcholine Heparin Captopril Nonsteroidal anti-inflammatory drugs (including sulindac) Cyclosporin Beta-2 antagonist drugs (even topically administered) Fluoride (hydrofluoric acid) Arginine hydrochloride Narcotics Verapamil Dantrolene Lithium Lead Progesterone Hypertonic enema Hetastarch

COMMENTS

Common cause of adding too much K to body Uncommon side effect of overdosage 'Especially if simultaneously supplementing K Massive overdosage needed to increase K; renal failure may cause digoxin concentrations to rise to sufficiently high levels to cause hyperkalemia85 Repeated administration necessary to increase K, diazepam may prevent this 44 Forms with chlorbutol inhibit aldosterone production 102 Especially in patients with renal disease (M. Miller, personal communication, 1988) Decreases renin and aldosterone Uncertain mechanism Exercise and increased K intake increase chances Severe, progressive hyperkalemia Used to treat some hyperammonemic states If cause crush injury secondary to coma Hyperkalemia due to other causes occurs more easily and cardiotoxicity is worse Reported in anesthetized dogs Rare effect in humans, may cause hypokalemia Chronic intoxication may cause hyporeninemic hypoaldosteronism Antagonizes aldosterone Rare (usually causes hypokalemia') Rare

REFERENCES

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are suspected, one should search for occult renal or adrenal disease predisposing the patient to hyperkalemia. Iatrogenic causes may also be due to other mechanisms. A list of drugs that have caused or theoretically may cause hyperkalemia is given (Table 1). Veterinarians are beginning to use many of these drugs more frequently (e.g., heparin, captopril, cyclosporin, and others) and more side effects will probably be seen. Spontaneous, severe hyperkalemia is usually due to decreased excretion, the major causes being renal and adrenal failure. 99 History, physical

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WILLARD

examination, serum chemistry profile, and urinalysis usually make it obvious that renal failure is the likely cause. Renal failure rarely causes hyperkalemia unless it is oliguric/anuric (usually acute renal failure due to drugs, nephrotoxins, and/or ischemia), but even then it is inconsistent. Postrenal obstr~c­ tion (e.g., urethral obstru~tion ii:J. cats or urinary tract rupture into the abdomen) is included in this category. Most ruptured urinary tracts are treated before hyperkalemia occurs 19 whereas many obstructed male cats will be hyperkalemic. Hyperkalemia is not necessarily prognostic but riuiy require immediate therapy. Polyuric renal failure rarely causes hyperkalemia unless the disease progresses to oliguria. However, selective damage to the renal collecting tubules and ducts in patients with otherwise moderate renal disease or failure may produce hyperkalemia because of the inability of aldosterone to perform its normal functions (i.e., end-organ unresponc siveness). Amyloidosis, renal transplantation, and systemic lupus erythematosus23· 29 are possible examples, although the last-named may also cause hyporeninemic hypoaldosteronism. 69 H ypoadrenocorticism is seen reasonably often and is easily confused with remil failure. It is classiCally found in young to middle-aged female dogs, but it may occur in dogs or cats 63 of either sex from 8 weeks of age on. 96 Familial tendencies are rarely described. 9 • 104 Untreated hypoadrenocorticism is usually characterized by obvious prerenal azotemia, hyponatremia; arid hyperkalemia. Typically, the serum Na:K ratio is less than 27:1 (and usually less than 21:1). However, expected changes may be absent if there has been recent steroid and/or fluid therapy because patients with adequate hydration and renal tubular flow can maintain normal serum I( despite lack of aldosterone. 23 Therefore, the diagnosis should always be confirmed by plasma cortisol measurements pre- and post-ACTH-stimulation because (1) adrenal failure usually has a better prognosis but requires life-long therapy different from that needed for renal failure, and (2) many patients with hyponatremia, hyperkalemia, and/or Na:K less than 27:1 do not have hypoadrenocorticism. 30 Nonetheless, therapy for hypoadrenocorticism should commence as soon as a presumptive diagnosis has been made, while awaiting results from the ACTH-stimulation test. Marked azotemia (BUN > 100 mg per dl) plus inadequately concentrated urine (specific gravity, 1.010-1.017), although supposedly diagnostic for primary renal disease, may be due to adrenal insufficiency and reverse with appropriate hormonal supplementation. 120 These findings are more likely in severely hyponatremic patients. Hypercalcemia is frequent in hypoadrenocorticism; therefore, one must be cautiou,s when eliminating adrenal failure in a patient that appears to have hypercalcemic nephropathy. "Diagnostic" features such as hypoglycemia, eosinophilia, lymphocytosis, and polycythemia, although suggestive if present, are typically absent. 38· 120 Normal serum sodium, anemia, hyperglycemia, lymphopenia, and eosinopenia occ.ur frequently enough in these patients that they should not be used to eliminate hypoadrenocorticism. Rarely, selective aldosterone deficiency29 (partial or complete) causes diagnostic confusion. This has been documented once in a dog, 119 but other dogs have had changes suggestive of this disorder, although the diagnosis was not confirmed owirig to client refusal (M. D. Willard, unpublished

DISORDERS OF POTASSIUM HOMEOSTASIS

249

data, 1988). These patients may have the same electrolyte changes seen with hypoadrenocorticism, and respond well to fluid and steroid therapy, but have normal or increased plasma cortisol values in the ACTH-stimulation test. In human beings, this is often due to the syndrome of hyporeninemic hypoaldosteronism, which is often associated with renal disease and diabetes mellitus. 28 Note: Many human diabetics have renal disease. The cause is uncertain, but prostacycline deficiency and excess atrial natriuretic factor have been suggested. 122 Diagnosis requires measurement of plasma aldosterone concentrations before and after ACTH administration. The same samples used for cortisol in the ACTH-stimulation test may be used for aldosterone. (Resting plasma aldoserone concentrations are almost valueless as there is substantial overlap between hypoadrenal and normal patients.) Although poorly documented, hyperkalemia ± hyponatremia has been found in some patients with chylothorax. Other chylothorax patients have had normal serum electrolytes but needed supplemental sodium and decreased K during therapeutic parenteral hyperalimentation. The mechanism is uncertain. When measured, plasma aldosterone concentrations before and after ACTH-administration have been greater than reference values (M. D. Willard, unpublished data, 1988). Anecdotal comments have suggested that this rarely occurs in other third space fluid accumulations (i.e., ascites and other pleural effusions) and is not due to the chylothorax per se. Perhaps decreased intravascular volume and poor renal perfusion due to the third space accumulation of fluid is responsible. Unreported in veterinary medicine, pseudohypoaldosteronism is a congenital defect in humans in whom end-organ unresponsiveness to aldosterone despite adequate or increased amounts of the hormone mimics adrenal insufficiency. 7 Shifts of K from the intracellular to the extracellular fluid compartment are usually not as significant a cause of hyperkalemia as is decreased excretion. However, they are important in that they are often ignored when they are the cause and yet considered responsible when innocent. Acidosis in particular is often proclaimed the cause of hyperkalemia; however, this is rarely the case in dogs and cats. Excess HCl (i.e., hyperchloremic metabolic acidosis with a normal anion gap) will increase movement of K into the extracellular fluid compartment whereas metabolic acidosis with an increased anion gap due to lactic acidosis from poor perfusion, ketoacidosis, or renal failure does not affect K distribution. 89 This latter type of acidosis is the most common in dogs and cats. Tissue destruction may release considerable K into the blood. Tumor lysis syndrome (the sudden destruction of massive amounts of neoplastic tissue due to chemotherapeutics resulting in hyperphosphatemia, hyperuricemia, or hyperkalemia21 ) may be responsible, although it has not been convincingly demonstrated in dogs or cats. Rhabdomyolysis may occur owing to crush-type injuries or ischemia. Both are uncommon, but traumatically exercised animals and patients that have had emboli surgically removed51 • 55 (e.g., reperfusion in cats with saddle thrombi90) may have significant hyperkalemia. Sometimes the emboli spontaneously lyse with the same result (P. D. Pion, personal communication, 1988). Occasionally,

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M. D. WILLARD

toxins (some scorpion76 and wasp80 venoms) apparently cause leakage of K from cells, although the increase in blood K can be minimal. Hypertonicity is occasionally responsible for hyperkalemia, 45• 92 especially in diabetics that have an acute surge of hyperglycemia. However, IV mannitol administration may do likewise. 23 The sudden increase in osmotic pressure· draws intracellular fluid into the extracellular compartment. This in turn causes "solvent drag" in which K is drawn or "washed out" of the cell. Spontaneous resolution will occur as the hypertonicity resolves. The clinician should recognize this and refrain from aggressive therapy for the hyperkalemia because correction of the hyperosmolality resolves the problem and additional therapy can cause severe hypokalemia. Hyperthermia similarly produces hyperkalemia56 that spontaneously resolves once the hyperthermia is corrected. Hyperkalemic periodic paralysis 29 has been suggested in one dog62 and one horse 108 but is of questionable significance in veterinary medicine. It may be considered in patients with periodic, transient bouts of hyperkalemia that have had all other causes apparently ruled out. In human beings this syndrome tends to be familial and is precipitated by exercise and cold whereas high carbohydrate meals are protective. 68 Rarely, hyperkalemia may be an idiopathic, benign disorder that apparently has a genetic basis. 77 Diagnostic Approach to Hyperkalemia The basic diagnostic approach to hyperkalemia is described in Figure 2. Whenever hyperkalemia is reported, the major concern is whether it is true or artifactual. Artifact should be suspected whenever clinical signs do not seem consistent with the laboratory value. This is important because administration of unwarranted therapy because of artifactual hyperkalemia may decrease serum K to dangerous levels. As explained earlier, an ECG may help confirm that hyperkalemia exists; however, failure to find expected changes does not eliminate mild (or occasionally severe) hyperkalemia. If the patient has a common cause of hyperkalemia (e.g., urethral obstruction in a male cat), then treatment should be instituted and the K rechecked periodically to ensure that hypokalemia does not occur. However, if the patient is not showing clinical signs of hyperkalemia, the laboratory determination should be repeated, preferrably using lithium heparin tubes for the blood samples (see Pseudohyperkalemia). Once the clinician believes that hyperkalemia is not artifactual, the history should be reviewed to eliminate iatrogenic causes. If these are implicated, they should be stopped (i.e., the therapy withdrawn) and the patient rechecked in 24 to 48 hours. However, a serum chemistry profile and urinalysis should be performed to ensure that there is not underlying disease that will worsen while waiting. Some patients with drug-induced hyperkalemia have occult renal or adrenal disease. Simultaneously, obvious causes such as urethral obstruction, ruptured urinary bladder, and hyperthermia should be sought. Likewise, if acute hypertonicity or tissue destruction has occured, one may decide to resolve that problem. and see what happens to the hyperkalemia. Many hyperkalemic patients have metabolic acidosis, but one should refrain from attrib-

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uting the electrolyte abnormality to that unless it is hyperchloremic and other causes have been eliminated. Many hyperkalemic patients will be azotemic, making renal failure and hypoadrenocorticism likely rule-outs. If the latter is at all possible, plasma cortisoland aldosterone should be measured during an ACTH-stimulation test. Renal disease that does not seem severe enough to cause hyperkalemia may confuse the diagnosis. If one is concerned that there might be endorgan unresponsiveness, eliminating other causes and determining that mineralocorticoid supplementation or furosemide administration does not alter the electrolyte values will aid in diagnosis. Hyperchloremic metabolic acidosis with normal anion gap is an uncommon cause but should be diagnosable with a chemistry profile and blood gas analysis. If all other causes have been eliminated, then hyperkalemic periodic paralysis may be considered. This syndrome can apparently be precipitated by oral administration of KCl in dosages that normal individuals tolerate readily. 62 Abnormal electromyogram findings (i.e., insertional activity, fibrillation potentials, and sharp waves) are reported in human beings. 68 Symptomatic Therapy for Hyperkalemia Specific treatment of the underlying disorder is always desired; however, therapy must often begin before the diagnosis is confirmed and specific therapy does not always lower serum K fast enough. Whenever the K is greater than 8.0 mEq per L or significant cardiotoxicity exists, fastacting symptomatic therapy is indicated, usually fluid therapy with or without bicarbonate or insulin plus glucose. (A blood sample for latter analysis should be obtained first, so that diagnostics are not confused.) If the K is less than 8. 0 mEq per L and clinical signs are mild, immediate symptomatic therapy is usually not necessary. However, if therapy is delayed, the K must be monitored closely lest sudden, unexpected hyperkalemia cause death. Emergency symptomatic therapy usually means administration of calcium gluconate or chloride, fluid therapy, sodium bicarbonate or insulin plus glucose. 118 Calcium is often discussed but seldom needed. It quickly counters the cardiotoxic effect of K for approximately 10 to 30 minutes until other therapy can decrease the blood K values. Calcium gluconate may be administered effectively (Table 2) even when the patient is normocalcemic. Calcium chloride may be used instead, but perivascular leakage may result in significant tissue sloughing. Administering calcium too quickly or giving it to patients receiving digitalis can be dangerous. Unless the patient is literally dying in front of one's eyes, there is usually enough time to use other, longer-lasting therapy. Fluid replacement is usually indicated, as most hyperkalemic patients are dehydrated. In some cases this is all the symptomatic therapy that is needed until specific therapy for the underlying problem is effective. Aggressive therapy with K-free fluids serves two purposes: rehydration, which enhances renal perfusion and increases K excretion, and dilution of the K in the blood. Lactated Ringer's solution may be used (it contains 4 mEq K per L); however, physiologic saline solution is probably best,

DISORDERS OF POTASSIUM HOMEOSTASIS

253

Table 2. Drugs That May Be Used in the Symptomatic Treatment of Hyperkalemia Fluids Calcium

Insulin plus glucose

Bicarbonate

Exchange resins

Potassium-free (or -deficient) fluids may be given to dilute serum potassium and increase renal blood flow, which will cause K excretion Carefully give 0.5-1.0 ml 10% calcium gluconate/kg IV over 10-15 min. STOP giving if bradycardia occurs or worsens. Note: This does not lower K, it only protects the heart while other therapy decreases the potassium In cats, 0.5 U regular insulin/kg plus 2 g dextrose/U of insulin, all given IV. Dogs may respond better if given larger doses (5-10 U regular insulin/kg). 54 Note: Beware of symptomatic hypophosphatemia in patients predisposed to same Best if dose is based on blood gas analysis; if this is unavailable, 1-2 mEq/kg may be given IV. Note: Care must be taken to avoid severe alkalosis or sudden shifts in diabetic ketoacidotic patients, which may be harmed by such 2.0 g sodium polystyrene sulfonate/kg, mixed with water (3--4 ml/g of resin) and divided into 3 daily doses; concurrent cathartic administration recommended. If given orally, beware of aspiration53

From Schaer M: Disorders of potassium metabolism. Vet Clin North Am 12:399--409, 1982; Willard MD: Treatment of hyperkalemia. In Kirk RW (ed): Current Veterinary Therapy IX. Philadelphia, WB Saunders, 1986, pp 94--101.

especially if the patient is hyponatremic. In fact, hypernatremic solutions were once used as symptomatic therapy. 71 Simultaneous glucose and insulin (Table 2) is effective within 15 to 30 minutes and lasts several hours. 99 Administration of glucose by itself may eventually resolve hyperkalemia, but usually requires substantial time (more than 1 hour) before endogenous insulin release has as great an effect as a pharmacologic dose of exogenous regular insulin. Repetition of this treatment within a short time may not further decrease the blood K, ostensibly because the cells have become "filled" with K. 54 Note that diabetics must not be treated too aggressively with insulin lest cerebral edema or hypophosphatemia occur. Alkalinization with sodium bicarbonate begins decreasing K within 5 to 15 minutes and lasts approximately 1 to 2 hours. (Note that it is rare that both bicarbonate and insulin/glucose are required in a patient.) However, although most hyperkalemic patients are acidotic (i.e., have renal failure or hypoadrenocorticism), some are not. Acid-base status cannot reliably be predicted without blood gas analysis or at least a total C0 2 measurement. Furthermore, severe alkalosis is just as detrimental as severe acidosis. Hence, care is warranted when using bicarbonate. Once life-threatening hyperkalemia has been controlled, specific therapy for the primary problem is needed. If the cause is not diagnosed or if there is no specific therapy for the underlying disease, long-term symptomatic therapy is necessary. Although decreasing K intake by itself is usually inadequate, it may allow other therapy to be more successful. Potassiumcontaining fluids and medications are an obvious source of K; however, some foods (e.g., milk, vegetables, and fruits 12) should also be avoided. Increased loss from the body may be promoted by diuretics (e.g., thiazides

254

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and loop diuretics such as furosemide) or mineralocorticoids. However, such medications are usually ineffective in patients with hyperkalemia due to primary renal disease. In these patients, K must be removed via exchange resins (Table 2), peritoneal dialysis, and or hemodialysis. 66 HYPOKALEMIA Hypokalemia is caused by four basic processes: decreased intake, dilution of blood K with inappropriate fluid therapy, cellular sequestration, and excessive loss from the body. In this discussion, we will principally be concerned with clinically significant hypokalemia (i.e., K < 3. 5 mEq/L). Decreased intake is rarely responsible by itself but can be significant in patients with other contributing causes. Fluid therapy with inadequate K supplementation (lactated Ringer's solution) may dilute blood concentrations and enhance renal losses, especially in anorexic patients. Iatrogenic causes include these as well as other mechanisms. Insulin therapy, total parenteral nutrition (principally when performed by persons not familar with the procedure), and bicarbonate (or similar alkalinizing therapy) may be responsible for severe hypokalemia due to cellular sequestration. Prolonged or inappropriately aggressive diuretic therapy causing loss is a more common cause. Others are mentioned in Table 3. Excessive loss is the most common spontaneous cause of which vomiting is a common reason in dogs and cats (e. g., gastric fluid has 10 to 20 mEq K per U 9 ; gastric vomiting can cause concurrent renal potassium wasting23 ). However, severe fecal K losses occur with profuse diarrhea from almost any cause as well as that due to unusual causes (e.g., radiation enteropathy15 or diarrhea due to vasoactive intestinal peptide-secreting tumor causing the "watery diarrhea and hypokalemia" syndrome of human beings 14). . Strictly renal losses are seldom suggested by the history unless marked polyuria or an osmotic diuresis 23 (e. g., diabetes mellitus) is present, and even then most polyuric patients are not severely hypokalemic. However, renal K-wasting may be due to renal insufficiency from any number of reasons and is not invariably associated with polyuria. In cats, particularly, any evidence of renal insufficiency (urine specific gravities persistently less than l. 025 or mild azotemia) may indicate renal K wasting. If in doubt, fractional urine K excretion may be determined. Cats with this syndrome often have fractional excretions greater than 14 per cent (normal less than 14 per cent) and may have severe hypokalemic myopathy. 31 Humans with hypercalcemia of malignancy often have hypokalemia due to renal K-wasting. 4 • 93 This is significant because the aggressive diuretic therapy used to lower calcium levels may also lower K. Malignancy itself (e. g., acute leukemia) can also cause hypokalemia in persons, ostensibly from renal wasting. 2 A syndrome of renal K-wasting reported in humans but not animals is Bartter' s syndrome, which is characterized by renal juxtaglomerular hyperplasia and increased plasma renin and aldosterone concentrations. 93 Another cause of renal K-wasting, renal tubular acidosis, is rarely

255

DISORDERS OF POTASSIUM HOMEOSTASIS

Table 3. Drugs that May Cause Hypokalemia DRUG

Fluid therapy Insulin Sodium bicarbonate Diuretics (thiazides or furosemide) Mineralocorticoids (desoxycorticosterone, carbenoxolone, and glycyrrhizinic acid) Nephrotoxic drugs (aminoglycosides, amphotericin-B. outdated tetracycline, and cisplatinum) Beta-2 agonist drugs

Penicillins (e.g., carbenicillin) Theophylline Soluble barium salts Thallium Nifedipine Epidural anesthesia Clay ingestion Caffeine Laxatives Exchange resins Corticosteroids Hypertonic enemas

COMMENTS

Several mechanisms: Dilution, diuresis, and failure to supply maintenance K needs Dose-related, especially in diabetics with ketoacidosis or drastically increased glucose Especially in diabetics with ketoacidosis Commonly seen and dose-related in anorexic animals Rarely seen in dogs and cats

REFERENCES

93

78 78

Hypokalemia may be seen before uremia

78, 93

Especially with newer, more potent drugs (terbutaline), effect potentiated by theophylline Only when given in large IV doses (acts as nonreabsorbable anion causing renal K wasting) Dose-related, toxic effect Toxic reaction Uncertain reasons Uncommon effect Mild effect in persons Rare cause in persons Mild effect Rare cause Rare cause Unlikely cause in dog and cat Usually a mild effect

58, 93, 103

78, 93 26, 124 93 61 117 50 46, 103 86 23, 78 78 8

From Nanji AA: Drug-induced electrolyte disorders. Drug Intel Clin Pharm 17:17~185, 1983; Raymond KH, Kunau RT: Hypokalemic states. In Maxwell MH, Kleeman CR, Narins RG (eds): Clinical Disorders of Fluid and Electrolyte Metabolism, ed 4. New York, McGrawHill, 1987, pp 519-546

associated with azotemia. Secondary to various drugs and diseases (e.g., acetazolamide, outdated tetracycline, sulfanilamide, systemic lupus erythematosus, myeloma, heavy-metal poisoning, hepatic cirrhosis, and nephrotic syndrome), this syndrome typically results in hyperchloremic metabolic acidosis with a normal anion gap. There are at least two types of renal tubular acidosis: proximal (associated with urine pH less than 6) and distal (associated with urine pH greater than 6). Diagnosis requires acid-loading or bicarbonate titration studies. ns Although rarely reported in veterinary medicine, hyperaldosteronism 16• 34 may cause hypokalemia by increasing renal losses. Currently, diagnosis is by finding expected electrolyte changes (hypernatremia and hypokalemia),

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which resolve after removal of an adrenal neoplasm. Measurement of resting or ACTH-stimulated plasma aldosterone concentrations does not appear to discriminate accurately between normal and affected animals, 119 but this may change as more experience is had with the syndrome and we learn how to correlate electrolyte values with plasma aldosterone concentrations. Hypomagnesemia is a recognized cause of potassium-wasting nephropathy in human beings. 93 This is usually identified in the patient that remains hypokalemic despite K supplementation. Such therapeutic failure is usually due to inadequate supplementation or continuing losses that exceed the amount supplemented. However, hypomagnesemia can prevent restoration of serum K concentrations despite more than adequate supplementation. The author has seen one patient that probably had this syndrome. Spontaneous causes of cellular sequestration occur but seem less common. Severe hypothermia causes hypokalemia that reverses when the hypothermia is alleviated, 65 probably because of massive catecholamine release with the beta-2 agonist effect responsible. A similar mechanism has been proposed for hypokalemia in postresuscitation patients 97 and in human fresh water near-drownings. 42 Acute respiratory alkalosis due to hepatic encephalopathy or extreme hyperventilation 33 may be responsible, but this is due to the effect of pH and should spontaneously resolve when the alkalemia is gone. Unreported in veterinary medicine, hypokalemic periodic paralysis is a poorly understood syndrome of humans in which episodic bouts of weakness are usually (but not always) associated with hypokalemia. Spontaneous resolution of the hypokalemia usually reverses the signs. There are familial predispositions in humans, and one form is associated with hyperthyroidism, 116 disappearing after resolution of the hyperthyroid state. 82 If this syndrome occurs in veterinary medicine, it will probably be diagnosed after exclusion of other known causes. Interestingly, the author has seen one hyperthyroid, hypokalemic cat that demonstrated severe weakness responsive to K supplementation. In human beings with this disease, urinary K excretion is diminished and there is no evidence of excessive fecal losses. Diagnostic Approach to Hypokalemia The first question when hypokalemia is found is whether it is real or artifactual (Fig. 3). Artifact should be considered anytime clinical signs do not correlate well with the laboratory findings. If the history suggests that hypokalemia is iatrogenic, then the suspected cause should be eliminated and the K rechecked. If hypokalemia appears to be spontaneous, one should next look for excessive loss. Gastrointestinal losses are the most common, but diabetic ketoacidosis is a significant cause. If loss appears to be the cause from the history or physical examination, then the patient should receive supplementation as needed until the primary cause is alleviated. If the hypokalemia apears to be spontaneous but the cause is not obvious, one should ascertain that the patient did not have prior vomiting, diarrhea, or urinary losses.

9 r/0

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'

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t

Do fractional urine K excretion Correct Mg and see Look for hypokalemic if K normalizes periodic paralysis, esp. with hyperthyroidism Look for leukemia or Bartter's-like syndrome

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258

M. D.

WILLARD

If there is no reason to suspect gastrointestinal losses or if the hypokalemia persists or returns after supplementation, then other causes must be sought. The first step is to request a complete blood count, serum electrolytes, glucose, creatinine, total C02 , and urinalysis. If diabetes mellitus is present, it should be considered the cause unless proved otherwise. Renal K-wasting should be sought if there is any evidence of renal dysfunction, especially in cats. If the cause is still uncertain, one should determine that the hypokalemia is persistent before more testing is done. Transient hypokalemia may be due to various problems that may spontaneously resolve or never be detected. Hyperthyroid patients should be rendered euthyroid and have the K rechecked to see if the two were related. If the cause is still unknown, hyperaldosteronism, renal tubular acidosis, hypomagnesemia, and hypokalemic periodic paralysis may be considered. Potassium supplementation should be instituted whenever the serum K is lower than 3. 0 mEq per L or the patient is symptomatic from the hypokalemia or continued losses are anticipated and the patient cannot adequately replenish K stores itself. Per os is the preferred way to administer K. Potassium-rich foods are seldom sufficient for severely deficient patients (e.g., 20 in. of banana = 20 mEq K107). Salt substitutes are more useful, often containing 50 to 60 mEq K per teaspoon. 107 There are many oral K elixirs, but many are unpalatable and unaccepted unless diluted or mixed with food. Oral elixirs have been very useful for cats with renal K-wasting in which parenteral supplementation may initially cause paradoxical lowering of the blood K. Eight to 12 mEq K (given as KCl or K gluconate) may be administered to cats daily in divided doses. 31 It has recently been noted that aggressive oral K replacement in humans is often as or more effective than the parenteral route, 41 as long as the patient is not vomiting and can absorb the K. Enteric-coated KCl tablets can cause intestinal ulceration, especially if there is slowed transit, 15 but the microencapsulated slow-release forms have minimal problems. 107 Some patients require parenteral therapy because of vomiting, anorexia, or inability to reliably be treated orally. Although subcutaneous supplementation may be done with solutions containing up to 30 mEq K per L, 12 IV therapy is usually preferred. Regardless of the form, if IV K administration is too rapid, the patient can be killed from the cardiotoxic effects. However, this is only an indication for the clinician to become familiar with K supplements, not to avoid them. Potassium chloride (KCl) is typically used because many patients have concurrent alkalosis and chloride deficiency. 107 Potassium phosphate can be used, but one must not produce hyperphosphatemia and subsequent hypocalcemia. The rate of K phosphate supplementation is based on the phosphate and is 0.01 to 0.03 mmol phosphate per kg per hour for 3 to 6 hours before rechecking the phosphorous (K phosphate usually contains 3.0 mmol phosphate per ml). When using KCl to prevent hypokalemia in an anorexic patient on IV fluids, 0.5 mEq K per kg per day is a reasonable starting dose. To replenish deficiencies, one may use general guidelines 12 or calculate the rate of K administration for each patient. It must always be remembered that K should never be administered at greater than 0.5 mEq per kg per hour. 99

DISORDERS OF POTASSIUM HOMEOSTASIS

259

The author prefers to calculate the rate of K administration for individual patients. In all but the most severely depleted patients, 0.1 to 0.2 mEq K per kg per hour is more than sufficient. Regardless of how K is supplemented, it is necessary to monitor the serum K concentrations periodically. Because the serum K concentrations do not accurately reflect total body K and because one is never sure how fast and how much K will be sequestered in cells, one cannot accurately predict how much K a given patient will ultimately need. Furthermore, despite hyperkalemia being one of the strongest stimuli for aldosterone secretion, the body cannot respond as quickly as a clinician can add K. Unsuspected renal disease may predispose to hyperkalemia. Also, beware of giving K to patients that are expected to resolve their hypokalemia spontaneously (e.g., hypothermics) lest resolution of the disease result in hyperkalemia. Therefore, it is inappropriate to supplement K without monitoring the serum concentration at least every 1 or 2 days and even more frequently if the supplementation is aggressive. SUMMARY Hypokalemia and hyperkalemia are common problems that may be artifactual, iatrogenic, or due to altered body homeostatic mechanisms. ECG may help one to recognize hyperkalemia but not hypokalemia. Excessive K supplementation is a common iatrogenic cause of hyperkalemia whereas fluid therapy is a common cause of iatrogenic hypokalemia. The most common causes of spontaneous hyperkalemia are renal failure and hypoadrenocorticism whereas the most common causes of spontaneous hypokalemia are vomiting, diarrhea, and renal wasting. Symptomatic therapy is usually done until the underlying cause(s) is resolved. REFERENCES 1. Abu-hamdam DK, Sondheimer JH, Magajan SK: Cautopyreiophagia. Am J Med 79:517519, 1985 2. Adams PC, Woodhouse KC, Adela M, et a!: Exaggerated hypokalemia in acute myeloid leukemia. Br Med J 282:1034-1035, 1981 3. Adu D, Turney J, Michael J, eta!: Hyperkalaemia in cyclosporin-treated renal allograft recipients. Lancet 2:370-371, 1983 4. Aldinger KA, Samaan NA: Hypokalemia with hypercalcemia, prevalence and significance in treatment. Ann Intern Med 87:571-573, 1977 5. Alexander EA, Perrone RD: Regulation of extrarenal potassium metabolism. In Maxwell MH, Kleeman CR, Narinus RG (eds): Clinical Disorders of Fluid and Electrolyte Metabolism, ed 4. New York, McGraw-Hill, 1987, pp 105-117 6. Ames Technical Information on Seralyzer Reflectance Photometer: A quantitative strip test for potassium in serum or plasma, 1986 7. Appiani AC, Marra G, Tirelli SA, et a!: Early childhood hyperkalemia: variety of pseudohypoaldosteronism. Acta Paediatr Scand 75:970-974, 1986 8. Atkins CE, Tyler R, Greenlee P: Clinical biochemical, acid-base, and electrolyte abnormalities in cats after hypertonic sodium phosphate enema administration. Am J Vet Res 46:980-988, 1985 9. Auge P: Addison's disease in littermates: Comp Anim Pract, Nov 1985, 43-45

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10. Battle JP, Nath KA, Sutherland DER, et al: Effects of cyclosporine on the reninangiotensin-aldosterone system and potassium excretion in renal transplant recipients. Arch Intern Med 145:505-508, 1985 11. Becker NJ, Hinman M, Giles MN, et al: Polymyositis with hypokalemia: Correction with potassium replacement in the absence of steroids. J Rheumatol 14:1042-1044, 1987 12. Bell FW, Osborn CA: Treatment of hypokalemia. In Kirk RW (ed): Current Veterinary Therapy IX. Philadelphia, WB Saunders, 1986, pp 101-107 13. Bellevue R, Dosik H, Spergel G, et a!: Pseudohyperkalemia and extreme leukocytosis. J Lab Clin Med 85:660-664, 1975 14. Bloom SR, Polak JM: Glucagonomas VIPomas and somatostatinomas. Clin Endocrinol Metab 9:285-297, 1980 15. Boley SJ, Allen AC, Schultz L, et al: Potassium-induced lesions of the small bowel. JAMA 193:81-84, 1965 16. Breitschwerdt EB, Meuten DJ, Greenfield CL, et a!: Idiopathic hyperaldosteronism in a dog. JAm Vet Med Assoc 187:841-846, 1985 17. Brown JJ, Chinn RH, Davies DL, et al: Falsely high plasma potassium values in patients with hyperaldosteronism. Br Med J 2:18-20, 1970 18. Burnell JM, Teubner EJ, Simpson DP: Metabolic acidosis accompanying potassium deprivation. Am J Physiol 27:329-333, 1974 19. Burrows CF, Bovee KC: Metabolic changes due to experimentally induced rupture of the canine urinary bladder. Am J Vet Res 35:1083-1088, 1974 20. Coggans FC: Acute hyperkalemia during lithium treatment for manic illness. Am J Psychiatry 137:860-861, 1986 21. Cohen LF, Balow JE, Macgrath IT, et al: Acute tumor lysis syndrome. Am J Med 68:486-491, 1980 22. Cooperman LH, Strobel GE, Kennell EM: Massive hyperkalemia after administration of succinylcholine. Anesthesiology 32:161-164, 1970 23. Cox M: Potassium homeostasis. Med Clin North Am 65:363-384, 1981 24. Cox M, Sterns RH, Singer 1: The defense against hyperkalemia: The roles of insulin and aldosterone. N Eng! J Med 299:525-532, 1978 25. Cummings CC, Mcivor ME: Fluoride-induced hyperkalemia: the role ofCa+ 2 dependent K+ channels. Am J Emerg Med 6:1-3, 1988 26. D'Angio R, Sabatelli F: Management considerations in treating metabolic abnormalities associated with theophylline overdose. Arch Intern Med 147:1837-1838, 1987 27. Degen M: Pseudohyperkalemia in Akitas. JAm Vet Med Assoc 190:541-543, 1987 28. DeFronzo RA: Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int 17:118134, 1980 29. DeFronzo RA: Hyperkalemic states. In Maxwell MH, Kleeman CR, Narins RG (eds): Clinical Disorders of Fluid and Electrolyte Metabolism, ed 4. New York, McGrawHill, 1987, pp 547-583 30. DiBartola SP, Johnson SE, Davenport DJ, et al: Clinicopathologic findings resembling hypoadrenocorticism in dogs with primary gastrointestinal disease. JAm Vet Med Assoc 187:60-63, 1985 31. Dow SW, Fettman MJ, LeCouteur RA, et al: Potassium depletion in cats: Renal and dietary influences. JAm Vet Med Assoc 191:1569-1575, 1987 32. Dow SW, LeCouteur RA, Fettman MJ, et al: Potassium depletion in cats: Hypokalemic polymopathy. JAm Vet Med Assoc 191:1563-1568, 1987 33. Edwards R, Winnie AP, Ramamurthy S: Acute hypocapneic hypokalemia: An iatrogenic anesthetic complication. Anesth Analg 56:786-792, 1977. 34. Eger CE, Robinson WF, Huxtable CRR: Primary aldosteronism (Conn's syndrome) in a cat; a case report and review of comparative aspects. J Small Anim Pract 24:293-307, 1983 35. Elizabeth JE, Carter NJ: Potassium citrate mixture: Soothing but not harmless? Br Med J 295:993, 1987 36. Emder P, Crawford G: Ventricular tachycardia in a neonate secondary to hyperkalaemia. Aust Paediatr J 19:112-113, 1983 37. Epperly TD: Hyperkalemia from baby food consumption. JAm Geriatr Soc 35:876-879, 1987 38. Feldman EC, Peterson ME: Hypoadrenocorticism. Vet Clin North Am 14:751-766, 1984

DISORDERS OF POTASSIUM HOMEOSTASIS

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39. Felkai F, Szenci 0, Marez I: Blood gas and acid-base values in dogs with experimentally induced hypopotassaemia. Acta Vet Hungarica 34:103-108, 1986 40. Field MJ, Berliner RW, Giebisch GH: Regulation of renal potassium metabolism. In Maxwell MH, Kleeman CR, Narins RG (eds): Clinical Disorders of Fluid and Electrolyte Metabolism, ed 4. New York, McGraw-Hill, 1987, pp 119-146 41. Fournier G, Pfaff-Poulard C, Methani K: Rapid correction of hypokalemia via the oral route. Lancet 2:163, 1987 42. Frank BS: Hypokalemia following fresh-water submersion injuries. Pediatr Emerg Care 3:158-159, 1987 43. Galler M, Folkert VW, Schlondorff D: Reversible acute renal insufficiency and hyperkalemia following indomethacin therapy. JAm Med Assoc 246:154-155, 1981 44. Giles HW: The effect of diazepam in the prevention of succinylcholine-induced hyperkalemia. Am Assoc Nurse Anesth J 54:21-22, 1986 45. Goldfarb S, Cox M, Singer I, et al: Acute hyperkalemia induced by hyperglycemia: Hormonal mechanisms. Ann Intern Med 84:426-432, 1976 46. Gonzales JJ, Owens W, Ungaro PC, et al: Clay ingestion: A rare cause of hypokalemia. Ann Intern Med 97:65-66, 1982 47. Gonzalez JJ, Werk EE, Thrasher K, et al: Renin aldosterone system and potassium levels in chronic lead intoxication. S Med J 72:433-436, 1979 48. Grauer GF, Kunze RS: Potassium depletion nephropathy and renal medullary solute washout: A case report. Calif Vet Nov 1979, 8-10 49. Gronert GA, Theye RA: Pathophysiology of hyperkalemia induced by succinylcholine. Anesthesiology 43:89-99, 1975 50. Hahn RG: Decrease in serum potassium concentration during epidural anaesthesia. Acta Anaesthes Scand 31:680-683, 1987 51. Haimovici H: Metabolic complications of acute arterial occlusions. J Cardiovasc Surg 20:349--357, 1979 52. Harmon RC, Auditore JV, Jackson DP: Studies on thrombocytosis. I. Hyperkalemia due to release of potassium from platelets during clotting. J Clin Invest 37:699-707, 1958 53. Haupt HM, Hutchins GM: Sodium polystyrene sulfonate pneumonitis. Arch Intern Med 142:379-381, 1982 54. Hiatt N, Sheinkopf JA: Treatment of experimental hyperkalemia with large dosages of insulin. Surg Gynecol Obstet 133:833-836, 1971 55. Hickey DR, Harrison L, Ramsay JG, et al: Hyperkalaemic cardiac arrest following intravenous hydralazine and propranolol therapy post-embolectomy. Can Anaesth Soc J 33:379--381, 1986 56. Honda Y, Honda N, Oda S: Physiological effects on whole body hyperthermia in dogs. Nagasaki Igakkai Zasshi 57:6-7, 1982 57. Horner JM, Hintz RL, Leutscher JA: The role of renin and angiotensin in salt-losing, 21-hydroxylase-deficient congenital adrenal hyperplasia. J Clin Endocrinol Metabol 48:776-783, 1979 58. Hurlbert BJ, Edelman JD, David K: Serum potassium levels during and after terbutaline. Anesthes Analges 60:723-725, 1981 59. Hylander B: Survival of extreme hyperkalemia. Acta Med Scand 221:121-123, 1987 60. Illingworth RN, Proudfoot AT: Rapid poisoning with slow-release potassium. Br Med J 281:485--486, 1980 61. Innis R: Thallium poisoning. Johns Hopkins Med J 142:27-31, 1978 62. Jezyk PF: Hyperkalemic periodic paralysis in a dog. JAm Anim Hosp Assoc 18:977-980, 1982 63. Johnessee JS, Peterson ME, Gilbertson SR: Primary hypoadrenocorticism in a cat. J Am Vet Med Assoc 183:881-882, 1983 64. Jorgensen LS, Genter SA, Randolf JF, et al: Electrolyte abnormalities induced by hypertonic phosphate enemas in two cats. JAm Vet Med Assoc 187:1367-1368, 1985 65. Koht A, Cane R, Cerullo LJ: Serum potassium levels during prolonged hypothermia. Intensive Care Med 9:275-277, 1983 66. Kunis CL, Lowenstein J: The emergency treatment of hyperkalemia. Med Clin North Am 65:165-175, 1981 67. Lawson DH: Adverse reactions to potassium chloride. Q J Med 43:433-440, 1974 68. Layzer RB, Lovelace RE, Rowland LP: Hyperkalemic periodic paralysis. Arch Neurol 16:455-472, 1967

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