By Todd Cutler, MD
Faculty Peer Reviewed
A 62-year-old male is hospitalized with an acute congestive heart failure exacerbation. On hospital day three, the patient’s symptoms have significantly improved with twice daily furosemide 80mg IV. He is continued on IV diuretics and aggressive electrolyte repletion. On day five of his admission, his basic metabolic panel is significant for a creatinine of 2.3 mg/dL (increased from 1.3 on admission) and a potassium concentration of 5.9 mEq/L. His EKG is unchanged from admission. His furosemide is discontinued and he is given 15g of Kayexalate. Overnight he has a large bowel movement. The next morning his creatinine is 1.9 mg/dL and his potassium is 5.1 mEq/L.
Should Kayexalate be used in the management of hyperkalemia?
Developed in the 1930s, synthetic ion-exchange resins are insoluble polymers combined with a reactive acid group and saturated with a specific ion. Once introduced into complex solvents, the resins exchange their preloaded ions for others in the solution. Their utility was predominantly industrial until 1946 when resins were proposed as a tool for removing dietary sodium in patients with heart failure and other “edematous states.”[2,3,4] While ion-exchange resins were ultimately found to be ineffective in heart failure management, small studies showed promise in the treatment of “potassium toxicity” using a polymer called sodium polystyrene sulfonate (SPS) and marketed as Kayexalate. The exchanging of sodium for potassium within the large bowel was believed to induce gut dialysis, resulting in diminished total body potassium concentrations.
In 1961, an uncontrolled study evaluated 32 patients with renal failure. Patients received either oral or rectally administered SPS while their intake of dietary potassium was tightly controlled. Patients were treated and monitored for varying lengths of time with one patient receiving SPS three times weekly for 280 days. Over the first 24 hours, plasma potassium concentrations decreased 1.0 mEq/L and 0.8 mEq/L in patients receiving oral and rectal SPS, respectively, with a few patients developing hypokalemia. The authors also reported complete reversion of abnormal EKG findings after SPS administration.
An accompanying report in the same journal evaluated ten patients with renal failure who were treated for five days with either an SPS and sorbitol mixture or sorbitol alone. Prior to this study, it had been noted that an adverse effect of SPS was the induction of constipation leading to, in some cases, fecal impaction. A proposed solution to this problem involved the co-administration of sorbitol, an osmotic laxative, at a concentration of 70%, speeding delivery of SPS to the colon where the majority of ion-exchange activity was believed to occur while simultaneously inducing defecation – ultimately, the desired diuretic effect of the drug.
In the study, both patients who received the co-administered formulation and sorbitol alone, demonstrated decreased serum potassium concentrations. Furthermore, sodium concentrations were increased in patients who received SPS with sorbitol but not with the sorbitol control. The authors noted, “That this rise is caused by the sodium released from the resin in exchange for potassium is evident since there is no elevation of serum sodium when sorbitol is used alone,” while ultimately concluding that, “sorbitol alone is as effective as a combination of resin and sorbitol in removing potassium, or more so. However, sorbitol alone necessitated a greater volume of debilitating diarrhea. In either case the predictability of the fall in serum potassium was impressive.”
Since the 1960s, investigations into the efficacy of SPS in treating hyperkalemia have been limited. One small study in 1998 showed no changed in serum potassium concentration after a single dose of SPS or a placebo both with and without a sorbitol additive. The efficacy of SPS and any additive effect of sorbitol on serum potassium concentrations have never been elucidated in larger studies. Meanwhile, SPS became widely accepted as a means for treating hyperkalemia based on the results of uncontrolled reports and empiric observations.
While the efficacy of these drugs remains a matter of debate, their toxicities are widely recognized. Multiple reports have implicated sorbitol in the development of SPS crystals and resultant intestinal bleeding, ischemia, colitis, necrosis and bowel perforation.[9,10,11,12] In 2007, the FDA mandated a decrease in the concentration of sorbitol in the SPS formulations from 70% to 33% however episodes of ischemic colitis continued to be reported with the less concentrated mixture. In late 2009, the FDA issued a non-mandated recommended against the practice of combining SPS and sorbitol in a prepackaged mixture.  Compliance with this recommendation would result in the effective termination of current practices as most pharmacies supply SPS only in the prepackaged formulation. Furthermore, any further utilization of SPS would necessitate the co-administration of a laxative considering the drug’s known constipating effects.
While empiric evidence supports the effectiveness of SPS when used over an extended period of time, the argument remains that, in published studies, any perceived short-term effect cannot be definitively attributed to SPS due to confounding factors such as a low-potassium diet or fluid repletion. Others have suggested that apparent decreases in serum potassium concentrations after single doses of SPS may be explained by extracellular volume expansion following absorption of sodium released from the SPS resin.
The dearth of clinical evidence supporting the efficacy of SPS prompted the authors of a recent commentary in the Journal of the American Society of Nephrology to call for careful consideration before using SPS remarking, “It would be wise to exhaust other alternatives for managing hyperkalemia before turning to these largely unproven and potentially harmful therapies.”xiii The utilization of dietary restriction, diuretics, bicarbonate, beta-agonists, insulin and dextrose along with a careful investigation into the etiology of an individual patient’s hyperkalemia may obviate the perceived need for SPS administration. Until future studies clarify a role for this controversial drug, physicians should take into account the compiled evidence when weighing of the risks and benefits of SPS administration.
Special thanks to Dr. John Papadopoulus for his helpful commentary and assistance in the drafting of this article.
Kayexalate: What is it and does it work?
Commentary by Dr. John Papadopoulos
The skill to select and dose an optimal pharmacotherapeutic regimen to treat our patients develops over the course of one’s professional career and during our training. When learning about a medication, we focus on pharmacology, pharmacokinetics, potential adverse events, and data to support use in clinical practice. Unfortunately, we have a paucity of data for guidance when using medications developed and marketed before the rigor of our current drug review standards. The use of kayexalate in the management of hyperkalemia has been propagated by bedside teaching and without the rigor of evidence-based clinical trials. Dr. Cutler cogently summarizes the available literature and highlights the potential complications of kayexalate.
In my experience, kayexelate (per os and per rectum) is able to lower potassium levels modestly over the course of a few hours. It is a second-line agent that may be used when there is a need to lower total body potassium, as other interventions (except renal replacement therapies) temporarily move potassium into intracellular fluid.
Dr. Cutler is a second year resident at NYU Langone Medical Center and co-editor, pharmacology section of Clinical Correlations
Faculty Peer Reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations
Image courtesy of Wikimedia Commons
1. Cation exchange resins in the treatment of congestive heart failure. Hay SH, Wood JE Jr. Ann Intern Med. 1950 Nov;33(5):1139-49.
2. The use of a carboxylic cation exchange resin in the therapy of congestive heart failure. Feinberg AW, Rosenberg B. Am Heart J. 1951 Nov;42(5):698-709.
3. Prolonged cation-exchange resin therapy in congestive heart failure. Voyles C Jr, Orgain ES. N Engl J Med. 1951 Nov 22;245(21):808-11.
4. The effect of a cation exchange resin on electrolyte balance and its use in edematous states. Irwin L, Berger EY, Rosenberg B, Jackenthal R. J Clin Invest. 1949 Nov;28(6, Pt. 2):1403-11.
6. Management of hyperkalemia with a cation-exchange resin. Scherr L, Ogden DA, Mead AW, Spritz N, Rubin AL. N Engl J Med. 1961 Jan 19;264:115-9.
7. Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol; a preliminary report. Flinn RB, Merrill JP, Welzant WR. N Engl J Med. 1961 Jan 19;264:111-5.
8. Effect of single dose resin-cathartic therapy on serum potassium concentration in patients with end-stage renal disease. Gruy-Kapral C, Emmett M, Santa Ana CA, Porter JL, Fordtran JS, Fine KD. J Am Soc Nephrol. 1998 Oct;9(10):1924-30.
9. Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings. Abraham SC, Bhagavan BS, Lee LA, Rashid A, Wu TT. Am J Surg Pathol. 2001 May;25(5):637-44.
10. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Surgery. 1987 Mar;101(3):267-72.
11. Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol: an underrecognized condition. Rashid A, Hamilton SR. Am J Surg Pathol. 1997 Jan;21(1):60-9.
12. From hyperkalemia to ischemic colitis: a resinous way. Tapia C, Schneider T, Manz M. Clin Gastroenterol Hepatol. 2009 Aug;7(8):e46-7.
13. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? Sterns RH, Rojas M, Bernstein P, Chennupati S. J Am Soc Nephrol. 2010 May;21(5):733-5.