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In medicine (endocrinology), hypoaldosteronism refers to decreased levels of the hormone aldosterone. There are several causes for this condition, including primary adrenal insufficiency, congenital adrenal hyperplasia, and medications (certain diuretics, NSAIDs, and ACE inhibitors). This condition may result in hyperkalemia, which can be serious medical condition. It can also cause hyponatremia.

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Hyperkalemia in the Patient Receiving Specialized Nutrition Support
From JPEN: Journal of Parenteral and Enteral Nutrition, 3/1/04 by Dickerson, Roland N

In this issue of JPEN, Rivard and associates1 report an alternative solution to reducing potassium content of enteral feeding solutions for hyperkalemic patients. Hyperkalemia may be a more prevalent problem for patients receiving specialized nutrition support than generally realized. In 1 series of 100 patients given specialized enteral nutrition support, hyperkalemia (as defined by a serum potassium concentration of >5 mEq/L) occurred in 40% of patients.2 It is important that clinicians first evaluate the significance of the hyperkalemia and then identify potential etiologies before embarking upon substantial changes to the patient's enteral nutritional regimen.

Pseudo- or factitious hyperkalemia must be excluded.3 Red blood cell hemolysis is the most common culprit for pseudohyperkalemia in hospitalized patients. A secondary cause of pseudohyperkalemia stems from the in vitro leaching of potassium from leukocytes and platelets. A small amount of potassium normally moves out of leukocytes and platelets during coagulation that is usually not very clinically relevant in normal subjects. However, for patients with substantial leukocytosis (white blood cells >100,000 cells/mm^sup 3^) or thrombocytosis (platelets >400,000 cells/mm^sup 3^), these abnormalities may lead to spurious elevations in serum potassium. It has been suggested that serum potassium will be falsely increased by ~0.15 mEq/L for every 100,000 cells per mm^sup 3^ above normal in patients with thrombocytosis.4

The next step in interpretation of hyperkalemia is to evaluate its clinical relevancy (eg, signs and symptoms). One of the most relevant methods is to observe the patient's electrocardiogram (ECG) tracings to look for evidence of changes caused by hyperkalemia (eg, peaking of the T wave among other ECG changes).5

Examination of the arterial blood pH would also be pertinent as during acidosis, hydrogen ions move into the cell to be buffered, whereas potassium ions move out, resulting in an increase in the serum potassium concentration. A general rule suggests for every 0.1 change in pH, the serum potassium concentration will change in the opposite direction by ~0.6 mEq/L. Despite this commonly used rule, it is pertinent to point out that the range of change of serum potassium for each 0.1 change in pH was quite large at 0.3 to 1.3 mEq/L.6 Therefore, if the patient had an acute acidemic episode and was aggressively being treated for that acidemia, then treatment of the hyperkalemia might be more conservative.

The presence of hyperkalemia usually indicates an imbalance between intake and excretion. Hyperkalemia in hospitalized patients is most often multifactorial in origin.7 When evaluating hyperkalemia, it is necessary to determine the potassium intake received by the patient and identify all potential sources for exogenous potassium. This would include IV fluids, intermittent electrolyte doses, parenteral feeding, and enteral feeding. Subtle sources of potassium that might be overlooked include red blood cell transfusion, salt substitutes,8 and some medications such as penicillin G potassium.9 Packed red blood cells transfused after 10 or more days of storage may contain up to 7.5 to 13 mEq/L of potassium.10 Salt substitutes contain 49 to 70 mEq of potassium per teaspoon, whereas penicillin G (potassium) contains 1.7 mEq of potassium per 1 million units. Use of these sources of potassium in patients at risk for development of hyperkalemia have led to fatal hyperkalemia in some patients.9,11

Renal impairment, pharmacotherapy that reduces urinary potassium excretion, advancing age, and diabetes are pertinent predisposing factors for the development of hyperkalemia.7 Reduced renal excretion of potassium can occur during renal impairment or failure and is the most common cause of hyperkalemia in hospitalized patients.7 Clinicians often use serum creatinine along with other clinical markers to evaluate renal function. However, use of the serum creatinine concentration alone as a marker of renal function may be erroneous, particularly in the elderly. Because creatinine is released from muscle mass and the elderly have a decreased muscle mass, a "normal serum creatinine concentration" in an elderly patient may actually reflect some level of renal impairment. For example, a serum creatinine concentration of 1 mg/dL in a 20-year-old, 72-kg man would lead to an estimated creatinine clearance (by the Cockroft-Gault equations12) of 120 mL/min. The same serum creatinine concentration of 1 mg/dL in a 70-year-old, 72-kg man would result in an estimated creatinine clearance of 70 mL/min. However, renal potassium homeostasis in the elderly is altered beyond just a reduction in creatinine clearance. The aldosterone response to an elevated serum potassium level is blunted because of depressed renin-angiotensin levels in the elderly.13 In audition, there is a decline in renal distal tubular function with decreased ability for disposal of potassium and acid loads.14 Despite these alterations, it is still unlikely that these renal neurohormonal changes alone would result in significant hyperkalemia.14 However, when combined with other predisposing factors such as underlying renal or cardiovascular disease that alters renal perfusion (eg, congestive heart failure) or pharmacotherapy that potentially decreases urinary potassium excretion, then the elderly patient becomes high risk for developing hyperkalemia.14-17

Patients requiring specialized nutrition support may have disorders that predispose the patient to hyperkalemia. For example, patients with advanced diabetes are known to have juxtaglomerular sclerosis and low plasma renin concentrations.18 Diabetic patients with mild to moderate renal insufficiency are particularly prone to developing hyporeninemic hypoaldosteronism leading to hyperkalemia.19 Insulin-dependent diabetic patients could have a relative insulin deficiency with hyperglycemia, resulting in a shift of intracellular potassium into the extracellular space.20 Tissue catabolism, particularly in response to rhabdomyolysis or chemotherapy or major trauma, may also lead to hyperkalemia, particularly in the presence of renal impairment.

Pharmacotherapy has long been known to be a principal factor in the pathogenesis of hyperkalemia in many hospitalized patients.10,17,21-24 Potassium-sparing diuretics that reduce the urinary excretion of potassium such as triamterene, spironolactone, and amiloride can result in significant hyperkalemia.25 Angiotensin-converting enzyme inhibitors (captopril, lisinopril, enalapril, etc.) have been shown to cause hyperkalemia in up to 6% of patients with normal renal function, but hyperkalemia becomes increasingly more common (5% to 50%) in patients with renal insufficiency.25 To a lesser extent, the angiotensin-II receptor blockers (cardesartan, losartan, etc) may also be involved in inducing hyperkalemia.10 The use of nonsteroidal anti-inflammatory agents (NSAIDS; eg, ibuprofen, indomethacin) that alter renal blood flow and decrease the synthesis of prostaglandins that are involved in the synthesis of aldosterone can also cause hyperkalemia.26 Up to 46% of hospitalized patients treated with indomethacin developed an increase in serum potassium concentration or developed significant hyperkalemia.27 The more selective cyclo-oxygenase-2 inhibitors may not cause hyperkalemia as prevalently as NSAIDs;10 however, they may still potentially increase serum potassium concentration.10 Heparin has been shown to induce aldosterone suppression and decrease the number and affinity of angiotensin-II receptors in the adrenal zona glomerulosa, with resultant increases in serum potassium.28 The increase in serum potassium is usually between 0.2 and 1.7 mEq/L and usually does not occur until after a few days of heparin therapy. These increases in serum potassium concentration may occur even with low doses of heparin used for subcutaneous deep venous thrombosis prophylaxis (eg, 5000 units twice daily).29,30 Significant and more prevalent (8% to 19%) hyperkalemia secondary to heparin required the presence of risk factors for alterations in potassium homeostasis (eg, renal failure or diabetes) in addition to the heparin therapy.28-30 Trimethoprim, when used in high doses in the treatment of Pneumocystis carinii pneumonia, has been shown to induce hyperkalemia by reducing urinary potassium excretion because of its pharmacologic similarity to amiloride and triamterene.31,32 A 50% incidence of mild hyperkalemia (serum potassium concentration >5 mEq/L) and 10% incidence of severe hyperkalemia (serum potassium concentration >6 mEq/L) has been reported in HIV-infected patients receiving high-dose trimethoprim.32 However, reports of hyperkalemia in patients receiving conventional doses of trimethoprim for the elderly population or in those with concurrent renal impairment have also been emerging.33-35 Other drugs such as pentamidine,36 octreotide,37,38 [beta] adrenergic blockers (eg, propranolol),39 tacrolimus,40 cyclosporine,41 [alpha] adrenergic agonists (eg, phenylephrine),42 and aminocaproic acid43 may also increase serum potassium concentrations at therapeutic doses, particularly when used in combination with other pharmacotherapies or in patients with renal impairment.

Many of these pharmacotherapies, particularly when combined or when used in an at-risk patient, can lead to life-threatening hyperkalemia.44,45 Thus, it is imperative that the clinician examine the patient's pharmacotherapy and evaluate whether alternative therapy that does not alter potassium homeostasis can be implemented in lieu of the potential offending agent.

After evaluation of all of these considerations, the clinician should assess potassium content of the enterai feeding solution provided to the patient. Depending on the severity of the hyperkalemia, the enterai feeding content (without any additional potassium additives) may need to be addressed sooner. Rivard and associates1 mixed 2 different concentrations of sodium polystyrene sulfonate to the enterai formula for 20 minutes and then allowed the mixture to settle out over 24 hours. The potassium content of the supernatant was decreased by 25% to 36%.

There are much easier and more practical methods to deal with the potassium content of enterai feeding. Using our enterai nutritional products formulary at the Regional Medical Center at Memphis, we will make the assumption that the patient requires a 1 kcal/mL high-protein polymeric formula at 100 mL/h to provide 2400 total kcals/day and 148 g protein/day. This feeding will result in a potassium intake of 110 mEq/d. If we change the formula to a half-strength 2 kcal/mL polymeric formula and add 15 g of protein powder to each liter at a rate of 100 mL/h, the patient will receive 2544 total kcals/day and 144 g of protein/day but with only 43 mEq of potassium/day. If the higher dose of sodium polystyrene sulfonate were added to the original 1 kcal/mL polymeric high-protein formula, the potassium content would be reduced to ~70 mEq/day in contrast to our method at 43 mEq/day. For a patient not requiring a high-protein intake, the conversion is even simpler. A patient requiring 1 kcal/mL, modest protein-containing, polymeric formula from our hospital formulary at 90 mL/h will provide 2289 kcal, 97 g of protein, and 101 mEq of potassium per day. Our concentrated 2 kcal/mL formula at 45 mL/h (or half-strength 2 kcal/mL formula at 90 mL/h) will provide 2160 kcal, 97 g protein, and 38 mEq of potassium per day. Both of these case scenarios resulted in a 60% reduction in potassium intake, which is a greater reduction in potassium content than the method proposed by Rivard et al.1 Another alternative to reducing potassium intake, using enterai formulas from our formulary, would be the use of a half-strength 2 kcal/mL formula designed for patients with renal failure. These formulas contain very low concentrations or no electrolytes. However, protein supplementation to achieve the desired protein intake might be somewhat tedious in this scenario as additional protein powder would be added to the diluted feeding and supplemental bolus doses of protein may be required.

Another concern with the method of Rivard et al1 is that their technique resulted in a significant increase in sodium content (242% to 324%) of the enteral feeding. Many patients with hyperkalemia have impaired renal function and possibly have edema from the inability to excrete water and sodium. For example, the patient with advanced cirrhosis with ascites and edema who has an actual weight of 90 kg compared with a dry weight of 60 kg is likely to develop worsening edema and ascites when given a sodium-enriched enterai feeding formula.

A final concern with the method of Rivard et al1 is that they allowed 24 hours for the particulate matter in the formula to settle before decanting. Bacterial contamination of enterai feeding is an established concern among many institutions.46-49 Some institutions have developed strict policies regarding hang time, tubing changes, and preparation techniques and have adopted closed-container systems for delivery for enterai nutrition whenever possible. Although storage during the formula settling process was likely done in a refrigerated setting, there is likely an increased risk for bacterial contamination and growth with the manipulation of the formulas on 2 separate occasions.

The premise of Rivard et al1 was that this method was adopted when there was no clear alternative enterai feeding formula to provide comparable clinical benefit to the specialty formula used in a particular patient population. Given those constraints, this method might be useful in those selected hyperkalemic patients where an alternative "nonspecialized" formula may potentially lead to an inferior clinical outcome. However, it is imperative that strict evidence-based guidelines be developed for use of that particular specialized formula50 and the advantages and disadvantages of this novel technique be carefully considered before its implementation in a given hospitalized patient.


1. Rivard AL, Raup SM, Beilman GJ. Sodium polystyrene sulfonate used to reduce the potassium content of a high protein enterai formula: a quantitative analysis. JPEN. 2004;28:76-78.

2. Vanlandingham S, Simpson S, Daniel P, Newmark SR. Metabolic abnormalities in patients supported with enterai tube feeding. JPEN. 1981;5:322-3244.

3. Wiederkehr MR, Moe OW. Factitious hyperkalemia. Am J Kidney Dis. 2000;36:1049-1053.

4. Graber M, Subramani K, Corish D, Schwab A. Thrombocytosis elevates serum potassium. Am J Kidney Dis. 1988;12:116-120.

5. Webster A, Brady W, Morris F. Recognising signs of danger: ECG changes resulting from an abnormal serum potassium concentration. Emerg Med J. 2002;19:74-77.

6. Burnell JM, Villamil MF, Uyeno BT. Effect in humans of extracellular pH change in relationship between serum potassium concentration and intracellular potassium. J Clin Invest. 1956; 35:935-939.

7. Acker CG, Johnson JP, Palevsky PM, Greenberg A. Hyperkalemia in hospitalized patients: causes, adequacy of treatment, and results of an attempt to improve physician compliance with published therapy guidelines. Arch Intern Med. 1998;158:917-924.

8. Riccardella D, Dwyer J. Salt substitutes and medicinal potassium sources: risks and benefits. J Am Diet Assoc. 1985;85:471-474.

9. Mercer CW, Logic JR. Cardiac arrest due to hyperkalemia following intravenous penicillin administration. Chest. 1973;64: 358-359.

10. Perazella MA. Drug-induced hyperkalemia: old culprits and new offenders. Am J Med. 2000;109:307-314.

11. Hoye A, Clark A. Iatrogenic hyperkalaemia. Lancet. 2003;361: 2124.

12. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.

13. Mulkerrin E, Epstein FH, Clark BA. Aldosterone responses to hyperkalemia in healthy elderly humans. J Am Soc Nephrol. 1995;6:1459-1462.

14. Biswas K, Mulkerrin EC. Potassium homoeostasis in the elderly. QJM. 1997;90:487-492.

15. Perazella MA. Trimethoprim is a potassium-sparing diuretic like amiloride and causes hyperkalemia in high-risk patients. Am J Ther. 1997;4:343-348.

16. Luckey AE, Parsa CJ. Fluid and electrolytes in the aged. Arch Surg. 2003;138:1055-1060.

17. Mayan H, Kantor R, Farfel Z. Trans-tubular potassium gradient in patients with drug-induced hyperkalemia. Nephron. 2001;89: 56-61.

18. Perez GO, Lespier L, Knowles R, Vaamonde CA. Potassium homeostasis in chronic diabetes mellitus. Arch Intern Med. 1977; 137:1018-1022.

19. DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int. 1980;17:118-134.

20. Goldfarb S, Cox M, Singer I, Goldberg M. Acute hyperkalemia induced by hyperglycemia: hormonal mechanisms. Ann Intern Med. 1976;84:426-432.

21. Nanji AA. Drug-induced electrolyte disorders. Drug Intell Clin Pharm. 1983;17:175-185.

22. Brass EP, Thompson WL. Drug-induced electrolyte abnormalities. Drugs. 1982;24:207-228.

23. Rimmer JM, Horn JF, Gennari FJ. Hyperkalemia as a complication of drug therapy. Arch Intern Med. 1987;147:867-869.

24. Moore ML, Bailey RR. Hyperkalaemia in patients in hospital. N Z Med J. 1989;102:557-558.

25. Hu Y, Carpenter JP, Cheung AT. Life-threatening hyperkalemia: a complication of spironolactone for heart failure in a patient with renal insufficiency. Anesth Analg. 2002;95:39-41.

26. Tan SY, Shapiro R, Franco R, Stockard H, Mulrow PJ. Indomethacin-induced prostaglandin inhibition with hyperkalemia: a reversible cause of hyporeninemic hypoaldosteronism. Ann Intern Med. 1979;90:783-785.

27. Zimran A, Kramer M, Plaskin M, Hershko C. Incidence of hyperkalaemia induced by indomethacin in a hospital population. BMJ. 1985;291:107-108.

28. Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med. 1995;98:575-586.

29. Busch EH, Ventura HO, Lavie CJ. Heparin-induced hyperkalemia. South Med J. 1987;80:1450-1451.

30. Orlando MP, Dillon ME, O'Dell MW. Heparin-induced hyperkalemia confirmed by drug rechallenge. Am J Phys Med Rehabil. 2000;79:93-96.

31. Greenberg S, Reiser IW, Chou SY, Porush JG. Trimethoprimsulfamethoxazole induces reversible hyperkalemia. Ann Intern Med. 1993;119:291-295.

32. Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of trimethoprim-induced hyperkalemia. Ann Intern Med. 1993;119:296-301.

33. Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med. 1996;124:316-320.

34. Marinella MA. Trimethoprim-induced hyperkalemia: an analysis of reported cases. Gerontology. 1999;45:209-212.

35. Perazella MA, Mahnensmith RL. Trimethoprim-sulfamethoxazole: hyperkalemia is an important complication regardless of dose. Clin Nephrol. 1996;46:187-192.

36. Lachaal M, Venuto RC. Nephrotoxicity and hyperkalemia in patients with acquired immunodeficiency syndrome treated with pentamidine. Am J Med. 1989;87:260-263.

37. Sargent AI, Overton CC, Kuwik RJ, Varcelotti JR, Deppe SA. Octreotide-induced hyperkalemia. Pharmacotherapy. 1994;14: 497-501.

38. Brown RO, Hamrick KD, Dickerson RN, Lee N, Parnell DH Jr, Kudsk KA. Hyperkalemia secondary to concurrent pharmacotherapy in a patient receiving home parenteral nutrition. JPEN. 1996;20:429-432.

39. Berglund G, Andersson O, Larsson O, Wilhelmsen L. Antihypertensive effect and side-effects of bendroflumethiazide and propranolol. Acta Med Scand. 1976;199:499-506.

40. Woo M, Przepiorka D, Ippoliti C, et al. Toxicities of tacrolimus and cyclosporin A after allogeneic blood stem cell transplantation. Bone Marrow Transplant. 1997;20:1095-1098.

41. Kamel KS, Ethier JH, Quaggin S, et al. Studies to determine the basis for hyperkalemia in recipients of a renal transplant who are treated with cyclosporine. JAm Soc Nephrol. 1992;2:1279-1284.

42. Williams ME, Rosa RM, Suva P, Brown RS, Epstein FH. Impairment of extrarenal potassium disposal by alpha-adrenergic stimulation. N Engl J Med. 1984;311:145-149.

43. Perazella MA, Biswas P. Acute hyperkalemia associated with intravenous epsilon-aminocaproic acid therapy. Am J Kidney Dis. 1999;33:782-785.

44. Schepkens H, Vanholder R, Billiouw JM, et al. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med. 2001;110:438-441.

45. Hay E, Derazon H, Bukish N, Katz L, Kruglyakov I, Armoni M. Fatal hyperkalemia related to combined therapy with a COX-2 inhibitor, ACE inhibitor and potassium rich diet. J Emerg Med. 2002;22:349-352.

46. Fagerman KE. Limiting bacterial contamination of enteral nutrient solutions: 6-year history with reduction of contamination at two institutions. Nutr Clin Pract. 1992;7:31-36.

47. Fagerman KE, Paauw JD, McCamish MA, Dean RE. Effects of time, temperature, and preservative on bacterial growth in enteral nutrient solutions. Am J Hasp Pharm. 1984;41:1122-1126.

48. Paauw JD, Fagerman KE, McCamish MA, Dean RE. Enteral nutrient solutions: limiting bacterial growth. Am Surg. 1984;50: 312-316.

49. de Leeuw IH, Vandewoude MF. Bacterial contamination of enteral diets. Gut. 1986;27(Suppl 1):56-57.

50. McCowen KC, Bistrian BR. Immunonutrition: problematic or problem solving? Am J Clin Nutr. 2003;77:764-770.

Roland N. Dickerson, PharmD

University of Tennessee Health Science Center, Memphis, Tennessee

Received for publication October 31, 2003.

Accepted for publication November 11, 2003.

Correspondence: Roland N. Dickerson, PharmD, University of Tennessee College of Pharmacy, 26 S. Dunlap St., Memphis, TN 38163.

Copyright American Society for Parenteral and Enteral Nutrition Mar/Apr 2004
Provided by ProQuest Information and Learning Company. All rights Reserved

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