J Am Soc Nephrol 9: 1924-1930. 1998

Effect of Single Dose Resin-Cathartic Therapy on Serum Potassium Concentration in Patients with End-Stage Renal Disease

CHRISTINE GRUY-KAPRAL, MICHAEL EMMETT, CAROL A. SANTA ANA, JACK L. PORTER, JOHN S. FORDTRAN, and KENNETH D. FINE Departnzent of Internal Medicine, Baylor Universirs’ Medical Center, Dallas, Texas.

Abstract. Hyperkalemia in patients with renal failure is fre- slightly (0.4 mEqIL) during the I 2-h experiment. This rise was quently treated with a cation exchange resin (sodium polysty- apparently abrogated by some of the regimens that included rene sulfonate, hereafter referred to as resin) in combination resin; this may have been due in part to extracellular volume with a cathartic, but the effect of such therapy on serum expansion caused by absorption of sodium released from resin. potassium concentration has not been established. This study Phenolphthalein regimens were associated with a slight rise in evaluates the effect of four single-dose resin-cathartic regimens serum potassium concentrations (similar to placebo); this may

and placebo on 5 different test days in six patients with chronic have been due to extracellular volume contraction produced by renal failure. Dietary intake was controlled. Fecal potassium high volume and sodium-rich diarrhea and acidosis secondary output and serum potassium concentration were measured for to bicarbonate losses. None of the regimens reduced serum 12 h. Phenobphthalein alone caused an average fecal potassium potassium concentrations, compared with baseline levels. Be- output of 54 mEq. The addition of resin caused an increase in cause single-dose resin-cathartic therapy produces no or only insoluble potassium output but a decrease in soluble potassium trivial reductions in serum potassium concentration, and be- output; therefore, there was no significant effect of resin on cause this therapy is unpleasant and occasionally is associated total potassium output. Sorbitol plus resin caused less potas- with serious complications, this study questions the wisdom of sium output than phenolphthalein plus resin. On placebo ther- its use in the management of acute hyperkabernic episodes. apy, the average serum potassium concentration increased

The usual regimen used to treat acute hyperkalernia in patients serum potassium concentration fell over a period of several with renal failure includes administration of a cation exchange days, the study did not discriminate between the effects of resin (sodium polystyrene sulfonate, Kayexalate#{174}, hereafter resin-sorbitol, hypertonic glucose, or the extremely low potas- referred to as resin), together with a cathartic, usually sorbitol sium diet. In the era of chronic hemodialysis, it has become (1-6). The cathartic is believed to facilitate resin binding of common practice to administer single doses of resin-cathartic potassium by ensuring that the resin has adequate contact with in the management of acute hyperkalemia. However, as before, potassium-containing gastrointestinal secretions. Independent the efficacy of resin-cathartic therapy for acute hyperkabemia of any facilitory effect on resin binding of potassium, the has not been clarified due to the simultaneous use of other cathartic also causes loss of soluble potassium in diarrheal fluid potassium-lowering treatments, including glucose and insulin (I ,2,7). Presumably, therefore, the resin and the cathartic act in infusions, sodium bicarbonate, and/or f32-agonists. a synergistic manner to remove potassium from the body. In a previous experiment in healthy subjects (9), we found Moreover, the cathartic may prevent resin-induced constipa- that gastrointestinal excretion of potassium was greater after tion or fecab impaction ( 1,8). phenobphthalein-docusate (hereafter referred to as phenol- The early study (1 ) that introduced resin-cathartic therapy phthalein) than after sorbitol, and that addition of resin to either was carried out before the advent of chronic hemodiabysis. laxative caused only modest additional fecal potassium excre- Hyperkalemic patients were treated for several days with re- tion. The subjects used in that experiment had normal renal peated doses of resin-sorbitol and with a diet consisting of 50% function, and they were given potassium intravenously to pre- dextrose in water or Karo syrup and ginger ale. Although vent a net loss of potassiurn frorn the body. Therefore, this earlier study did not address whether resin-cathartic regimens could reduce the serum potassium concentration. Because a benefit of resin-cathartic therapy has not been Received October 20, 1998. Accepted March 9, 1998. clearly established, and because this therapy is unpleasant, Correspndence to Dr. Kenneth D. Fine, Baylor University Medical Center, poorly tolerated, and occasionally results in significant or even 2nd Floor HOB. 3500 Gaston Avenue Dallas, TX 75246. fatal complications 1,6,8, 10- 16), we performed a controlled l()46-6673/090l0- I924503.00/0 ( Journal of the American Society of Nephrology study on the effect of several single-dose resin-cathartic regi- Copyright 0 1998 by the American Society of Nephrology rnens in patients with end-stage renal disease. We analyzed the J Am Soc Nephrol 9: 1924-1930. 1998 Resin-Cathartics and Serum K Concentration 1925

effect of these regimens on serum potassium concentration and Table 1. Treatment regimens on the amount of potassium that is removed from the body. Placebo: 8 gelatin capsules with 500 ml of water Sodium polystyrene sulfonate: 30 g of resin with 500 ml of Materials and Methods water Patients Phenolphthalein-docusate: 8 tablets” with 500 ml of water Six patients with chronic renal failure maintained on hemodialysis Phenolphthabein-docusate plus resin: 8 tablets,” 30 g of resin volunteered for the study. This research was approved by the Institu- with 500 ml of water tional Review Board for Human Protection of Baylor University Sorbitol plus resin: 60 g of sorbitob, 30 g of resin with 500 Medical Center. and informed consent was obtained. ml of water

a Given as Correctol#{174}; each tablet contains 65 mg of yellow Protocol phenolphthalein and 100 mg of docusate sodium. The patients underwent five studies on five separate experimental days, with at least I wk between each study. Patients were studied 2 d after a dialysis treatment and I d before their next dialysis session. In Results random order, they were treated with one of the five regimens listed 12-Hour Fecal Output of Potassium after Cathartic in Table I . Four hours after treatment, the patients ingested a standard Regimens meal containing 15.2 ± 2.2 mEq of sodium and 21.4 ± 1.4 mEq of Average results are shown in Table 2. Total fecal potassium potassium. No other foods or beverages (including water) were con- output after phenolphthalein alone was 54 mEq; of this sumed during the study. Intravenous fluid was not administered. amount, 46 mEq (85%) was dissolved in stool water, and the Serum potassium concentration was measured just before, and at 4, 8, and 12 h after treatment; a free-flowing peripheral vein was used remainder was insoluble. When 30 g of resin was ingested rather than the vascular access to avoid risk of access damage. Stools together with phenolphthalein, I 7 g of resin (57% of the were collected for I 2 h after each treatment to quantify fecal potas- ingested dose) was excreted; this was associated with an I 1 sium, sodium, and resin output. The patients did not excrete any urine mEq average rise in the output of insoluble potassium (P < during the experimental periods. 0.05). However, addition of resin was also associated with a 21 rnEqfL reduction in soluble potassium concentration and with a 17 mEq fall in soluble potassium output (P values not Analytical Methods and Calculations significant). The resin-induced rise in insoluble potassium out- Water and solid content of stool were measured by weighing before put was offset by the fall in soluble potassium output, and resin and after lyophilization. Sodium and potassium concentrations were therapy therefore did not increase total potassium excretion. measured by flame photometry. Calcium and magnesium concentra- The ingestion of sorbitol and 30 g of resin resulted in the tions were measured by atomic absorption spectroscopy. Soluble stool cation outputs were calculated as the product of the stool supernatant fecal excretion of only 9.3 g of resin (3 1 % of the ingested cation concentration and the grams of total fecal water (determined by dose). Fecal excretion of total potassium was less with sorbitol lyophilization of stool). Total stool output of cations was calculated as plus resin than with phenolphthalein plus resin, in agreement the product of stool weight and cation concentration of an acid- with an earlier study in healthy subjects (9). digested stool sample. Insoluble cation output is the difference be- tween total and soluble cation output. Plasma concentrations of chlo- 12-Hour Fecal Output of Sodium after Cathartic ride, bicarbonate, and glucose were measured by automated analysis. Regimens Stool resin concentration was estimated by measuring stool cation As shown in Table 2, when patients ingested phenobphtha- binding capacity. First, all cation binding sites in an aliquot of stool were lein alone, fecab sodium output existed almost exclusively in converted to the lithium form by suspending the stool in a concentrated the soluble state. When 30 g of resin was ingested with phe- solution (I mol/L) of lithium chloride. Unbound lithium was removed by nobphthalein, fecal output contained 1 7 g of resin, and there repeated washing and centrifugation. The precipitate was then suspended in water, and concentrated potassium chloride was added to displace the was a marked increase in fecal excretion of both soluble and bound lithium. The amount of lithium released into water, measured by insoluble sodium. After sorbitol plus resin, the fecal output atomic absorption spectroscopy, is equal to the mEq of cation binding contained less resin and less sodium than when phenolphtha- sites of stool. The resin content of a 12-h stool collection in mEq is the 1cm plus resin was ingested. product of the stool cation binding capacity and the 12-h stool weight. Thirty grams of resin contains I 20 rnEq of sodium. To the Since each gram of resin binds 4 mEq of cations, the weight of resin in extent that other cations are bound by resin, an equivalent stool is calculated by dividing stool cation binding capacity in mEq by 4. amount of sodium is released from resin and becomes part of When known amounts of resin were added to stool in vitro, recovery was the soluble intraluminal sodium pool. Therefore, the sodium 96 to 100%. When subjects ingested laxatives without resin, this method content of the resin needs to be included when the effect of the yielded an average stool cation binding content of 0.34 mEq (0.09 g) per various treatments on sodium balance is calculated. When 12-h stool. Thus, stool without resin has minimal cation binding capacity. phenolphthalein alone was ingested, fecal sodium output was 80 mEq, so there was a negative sodium balance of 80 mEq. Statistical Analyses When phenolphthalein plus resin was ingested, sodium intake A one-way repeated measures ANOVA was used with a Bonferroni was 1 20 mEq, fecal sodium output was 190 mEq, and there t test. A P value 0.05 was considered statistically significant. was a negative sodium balance of 70 mEq. On the other hand, 1926 Journal of the American Society of Nephrology J Am Soc Nephrol 9: 1924-1930. 1998

Table 2. Fecal excretion of water, monovalent electrolytes, and resin in six patients with end-stage renal disease, in response to three resin-cathartic regimen&’

Phenolphthalein Sorbitol plus P Value by Parameter Phenolphthalein plus Resin Resin ANOVA

No. of bowel movements (no./12 h) 3.7 ± 1 5.7 ± I 5.0 ± 1 0.155 Stool weight (g/12 h) 891 ± 177 1 195 ± 193 859 ± 175 0.422 Stool water (g/12 h) 801 ± 155 1089 ± 185 773 ± 168 0.408 Stool solids (g/12 h) 96 ± 22 106 ± 13 87 ± 8 0.708 Soluble K cone. (mEqIL) 50 ± 9 29 ± 6 37 ± 14 0.051 K output total (mEq/l2 h) 54 ± 19 49 ± 10 31 ± 4 0.174 K output soluble (rnEq/l2 h) 46 ± 16 29 ± 6 19 ± 2 0.082 K output insoluble (rnEq/l2 h) 9 ± 3b 20 ± 5 12 ± 2 0.015 Soluble Na cone. (mEqfL) 93 ± 7b 130 ± 6C 66 ± 1 1 <0.001 Na output total (mEq/l2 h) 80 ± 16b 190 ± 33C 67 ± 16 0.002 Na output soluble (mEq/l2 h) 75 ± 15k’ 144 ± 28C 51 ± 1 1 0.006 Na output insoluble (mEq/l2 h) 6 ± 46 ± 4C 16 ± 5 <0.001 Soluble Cl cone. (rnEqIL) 58 ± 2 65 ± 6C 23 ± 3 <0.001 Cl output soluble (mEq/12 h) 48 ± 11 79 ± b5C 17 ± 4 0.009 Soluble HCO1 cone. (mEqIL) 42 ± 7 47 ± 6C 20 ± 5 0.005 HCG1 output soluble (mEq/l2 h) 36 ± 1 1 59 ± 17 18 ± 7 0.085 Resin output (g/12 h) 0.4 ± 0#{149}2b 17.0 ± l.lc 9.3 ± 2.1 <0.001

a Results are given as mean ± SEM. cone., concentration. h Statistically significant differences (P < 0.05 by Bonferroni corrected a’test) between phenolphthalein alone and phenolphthalein plus resin.

C Statistically significant differences (P < 0.05 by Bonferroni corrected t test) between phenolphthalein plus resin and sorbitol plus resin.

with sorbitol plus resin, sodium intake was 120 mEq, fecal in diarrheal fluid induced by phenolphthalein. Resin caused an sodium output was 67 rnEq, and there was a positive sodium increase in the insoluble outputs of all four cations. Assuming that balance of 53 rnEq. With resin alone, there was no fecal these increments in insoluble cation outputs were due to binding sodium output, so there was a positive sodium balance of 120 to excreted resin, the amount of different cations bound to ex- rnEq. (The 15 rnEq sodium content of the meal was not creted resin can be calculated. According to this analysis, the order included in these balance calculations because it was small and of binding was Na > K > Ca > Mg. Total cation binding was was a constant in all arms of the experiment.) 3.70 mEq/g of excreted resin, close to the known cation binding sites on the resin (4 mEq/g). Ammonium probably accounts for Calculation of Cations Bound to Excreted Resin after the difference (7). Resin binding of potassium was 0.65 mEq K/g, Ingestion of Phenolphthalein plus Resin a value that is almost identical to the resin binding ratio of 0.66 Table 3 summarizes the effect of resin on the output of cations mEq KJg observed in our previous study of healthy subjects (9).

Table 3. Calculation of cations bound to excreted resin after ingestion of phenolphthabein plus resin

Parameter K Na Ca Mg

Insoluble output (mEq/12 h) phenolphthalein 9 5 121 23 phenolphthalein + resin 20 46 1 29 27 z 11 41 8 4 resin binding (mEq/g)” 0.65 2.41 0.47 0.24 Soluble concentration (mEqfL) phenolphthalein 50 93 16 17 phenolphthalein + resin 29 130 6 4 Soluble output (mEq/l2 h) phenolphthalein 45 75 9 15 phenolphthalein + resin 29 144 5 4

a Seventeen grams of resin were excreted in the I 2-h collection after phenolphthalein plus resin. Resin binding per gram of excreted resin was calculated by dividing the increment in insoluble cation output after resin plus phenolphthalein () by 17. J Am Soc Nephrol 9: 1924-1930, 1998 Resin-Cathartics and Serum K Concentration 1927

When exposed to equal concentrations of cations in vitro, resin treatment regimen. Glucose concentrations fell equally on all has a higher affinity for divalent than for monovalent cations. treatments, from approximately 107 mg/dl at zero time to However, in this in vivo study, resin excreted in stool was bound approximately 89 mg/dl at 1 2 h. Serum bicarbonate concen- mainly to sodium and potassium. This can be explained by the trations are shown in the first part of Table 4; treatments that much higher concentration of soluble monovalent than divalent included phenolphthalein caused serum bicarbonate concentra- cations in diarrheal stool, as shown in Table 3. Although total tions to fall. calcium output greatly exceeded total potassium output, the con- centration of soluble potassium greatly exceeded the concentra- Serum Potassium Concentration tion of soluble calcium. Similar calculations are not possible for The second part of Table 4 provides mean values for serum resin binding after ingestion of sorbitol plus resin, because we did potassium concentration before and at 4, 8, and 12 h after the not study the effect of sorbitol alone. various therapies. On placebo there was a tendency for serum potassium concentration to rise slightly during the 12-h period 12-Hour Fecal Output of Chloride and Bicarbonate of observation. None of the resin-cathartic regimens caused a after Cathartic Regimens fall in average serum potassium concentration, compared with Table 2 shows that the concentrations and outputs of soluble pretreatment values. However, treatments with resin alone and chloride and bicarbonate were higher with phenolphthalein resin plus sorbitol were associated with smaller average in- plus resin than with phenolphthalein alone. This can be ex- creases than were observed with placebo therapy. By contrast, plained by the much higher output of soluble sodium, related to phenolphthalein alone and phenolphthalein plus resin were the high sodium content of resin. The concentrations and associated with slight rises in average serum potassium con- outputs of soluble chloride and bicarbonate were much higher centration, similar to those associated with placebo therapy. with phenobphthalein plus resin than with sorbitob plus resin. Figure 1 shows serum potassium concentration in each pa- This can be explained by the fact that phenolphthalein elicits tient, before and after each treatment and placebo. The serum diarrhea by stimulating secretion of electrolytes, whereas sor- potassium concentrations before the various treatments ranged

bitol elicits diarrhea because of the osmotic effect of a poorly from 3.4 to 5.7 mEq/L. There was no evidence that the serum absorbed nonelectrolyte. potassium concentration was more likely to fall (in association with resin-cathartic regimens) when the initial serum potas- Changes in Body Weight sium concentration was in the hyperkalemic range. There was Body weight was measured before and at the end of the 12-h no significant correlation between changes in serum potassium experiment. Average body weight did not change on placebo and bicarbonate concentration, either on test days when pa-

(74.7 to 74.7 kg), increased slightly with resin alone ( = +0.2 tients took phenolphthalein (r = 0. 1 1, P = 0.74) or on all test kg), fell with phenolphthalein alone ( = -0.8 kg), fell with days combined (r = 0.01, P = 0.96). There also was no phenolphthalein plus resin (= -0.8 kg), and fell to a lesser significant correlation between the output of potassium in stool

extent with sorbitol plus resin ( = -0.3 kg). and the change in serum potassium concentration during the 12-h experiment. However, the changes in serum potassium Serum Concentrations of Sodium, Chloride, concentration were inversely correlated with changes in body

Bicarbonate, and Glucose weight (r = 0.42, P = <0.02), i.e. , weight loss was associated There was no change in average levels of sodium or chloride with a rise in serum potassium concentration and weight gain between 0 and 12 h, and concentrations were similar after each with a fall in serum potassium concentration. Moreover, the

Table 4. Average serum bicarbonate and potassium concentrations in patients with end-stage renal failure before and after various treatments”

Serum Bicarbonate Serum Potassium Co ncentration (mEqIL) Concentration (mEqIL) Group hour 0 hour 12 hour 0 hour 4 hour 8 hour 12

Placebo 25 ± 1 22 ± I 4.32 ± 0.33 4.44 ± 0.43 4.57 ± 0.34 4.71 ± 0.35 Resin 24 ± 1 23 ± 1 4.21 ± 0.27 4.26 ± 0.25 4.29 ± 0.29 4.29 ± 0.27 Phenolphthalein 26 ± I 21 ± 1” 4.24 ± 0.38 4.60 ± 0.53 4.50 ± 0.38 4.62 ± 0.50 Phenolphthalein + resin 23 ± 2 20 ± 1 4.35 ± 0.26 4.42 ± 0.41 4.57 ± 0.43 4.65 ± 0.42 Sorbitol + resin 24 ± 1 24 ± 1 4.27 ± 0.38 4.31 ± 0.44 4.30 ± 0.42 4.28 ± 0.43

a Results are given as mean ± SEM. In one of the six patients, we were not able to obtain a blood sample at all of the four sampling periods on the test days he received placebo and phenolphthalein alone. Therefore, none of his serum values was included in the mean results for these two treatments. However, individual results for serum potassium concentration on all six patients are shown in Figure 2. None of the differences in serum potassium concentration was statistically significant. I, p < 0.05 for effect of phenolphthalein alone on serum bicarbonate concentration. 1928 Journal of the American Society of Nephrology J Am Soc Nephrol 9: 1924-1930, 1998

Placebo effort to study higher, and relatively equilibrated serum potas- sium concentrations. Consequently, longer test periods would 6 have been very difficult to undertake. 5 In patients with end-stage renal disease, induction of secre- 4 .tEE:::E;;:.o.*_ 8 hours tory diarrhea with 520 mg (8 tablets) of phenobphthabein caused w 3 E an average excretion of 54 mEq of potassium via the gastro- 2 intestinal tract within 12 h. Although larger doses of phenol- 1#{149} phthalein would probably promote greater volumes of diarrhea,

_ 0 hours 12 hours this would likely have a minimal impact on stool potassium excretion because the diarrheal fluid potassium concentration Resin alone Phenolphthaleln alone decreases as diarrhea volume increases ( 17-20). For the pur- 7. 7 poses of removing potassium from the body via the intestine, 6 6 small doses of cathartics on sequential days, aiming for pro- 5 tracted small volume diarrhea containing a high concentration S. 4 ..$ --. of potassium, would probably be more efficacious than large 3 single-dose regimens that induce a brief period of high volume 2 ii diarrhea containing a low concentration of potassium. In other 1 words, we believe that 2 L of diarrhea over 4 d would remove U i 0 hours 12 hours 0 hours 12 hours more potassium than 2 L of diarrhea in I day. The addition of 30 g of resin to the phenolphthalein regimen

Phenolphthaleln + resin Sorbltol + resin caused an increase in fecal excretion of insoluble potassium, 7. but did not increase excretion of total potassium. (Total potas- 6 sium is defined as the sum of insoluble and soluble potassium.) 5 Several factors probably contributed to this result. First, only 17 g of resin (57% of the orally ingested dose) was excreted in E3 the 12-h stool collection. Second, the excreted resin bound 2 potassium at a ratio of 0.65 mEq K/g resin, a value that is almost identical to the resin binding ratio of 0.66 mEq K/g , , observed in our previous study of healthy subjects (9). How- 0 hours 12 hours 0 hours 12 hours ever, these values are lower than the binding ratio of approx- Figure 1. Serum potassium concentration (mEqfL) in each patient imately 1 mEq KJg resin reported in the absence of diarrhea with end-stage renal failure before and 12 (or 8) h after various (7,2124).’ The reduced resin potassium binding after resin- treatments. cathartic therapy is probably due to the bower potassium and higher sodium concentration of diarrheal cobonic fluid (17-20) as opposed to the higher potassium and lower sodium concen- changes in serum potassium concentration were inversely cor- trations of cobonic fluid in the absence of diarrhea (25,26). related with sodium balance (r 0.48, P < 0.007), i.e., Third, the addition of resin to phenobphthalein was associated negative sodium balance was associated with a rise in serum with a reduction in the fecal output of soluble potassium, which potassium concentration and positive sodium balance with a offset the increase in fecal insoluble potassium excretion pro- fall in serum potassium concentration. duced by resin. One possible explanation for this observation is Additional calculations revealed that there was no statisti- that rapid transit through the colon in association with diarrhea cabby significant correlation between the initial serum potas- did not allow electrochemical equilibration of potassium across sium concentration and the amount of potassium excreted in the colonic mucosal membrane, so that potassium bound by stool in response to cathartics (with or without resin). resin within the cobonic lumen was not replaced by potassium diffusing from blood into the colonic lumen. Discussion Sorbitol plus resin produced less fecal potassium excretion Fecal Potassium Excretion than phenolphthalein plus resin. This is due primarily to the Phenolphthabein was selected as the prototype cathartic be- fact that osmotic diarrhea induced by sorbitol contains less cause our previous study in healthy subjects revealed that the potassium (and sodium) than the secretory diarrhea induced by secretory diarrhea induced by phenolphthalein produced greater fecal excretion of potassium with less unpleasant side effects than the osmotic diarrhea produced by sorbitol (9). In a This value for expected binding ratio in the absence of diarrhea is derived addition, resin combined with hypertonic sorbitol has been from studies with other resins (carboxylic cation exchange resin in the hydro- implicated as a cause of colonic necrosis and perforation (14- gen. ammonium, sodium. or calcium cycle; or sodium polystyrene sulfonate as a coarse powder) rather than from studies with finely ground sodium polysty- 16). A test period of I 2 h was selected as a reasonable time rene sulfonate (Kayexalate#{174}). For the latter. we could find no data on the frame to evaluate therapy for acute hyperkalemia. Each study binding ratio in the absence of diarrhea. either in healthy subjects or in patients was initiated 2 d after the patient’s last dialysis session in an with renal failure. J Am Soc Nephrol 9: 1924-1930, 1998 Resin-Cathartics and Serum K Concentration 1929 phenolphthalein (18 -20). Furthermore, the amount of resin tracts extracellular volume and would tend to increase serum recovered in the I 2-h stool specimen after sorbitol plus resin potassium concentration. This would mitigate the effect of was only about half that recovered after phenolphthalein plus stool potassium losses in diarrheal fluid. Sorbitol induces an resin. This is probably due to delayed gastric emptying of osmotic diarrhea, which does not contain a high concentration insoluble resin produced by hypertonic solutions (9). Conse- of sodium, and therefore is less apt to induce volume contrac- quently, the wave of diarrhea generated by sorbitol precedes tion. We found that the changes in serum potassium concen- the resin through the gastrointestinal tract (9,24). This physical tration were inversely correlated with the changes in body and temporal separation of sorbitol from the resin, within the weight and with sodium balance and this supports this hypoth- gastrointestinal tract, will mitigate one of the potential benefits esis. of the combination, i.e., the prevention of resin-induced con- The bicarbonate concentration in diarrhea fluid induced by stipation and fecal impaction (1,8). phenolphthalein is higher than that of serum, and the serum As noted, 13 and 2 1 g of resin were not recovered in the 12-h bicarbonate concentration fell after phenolphthalein therapy. A stool collection after the ingestion of phenolphthalein plus reduction in serum bicarbonate would shift potassium from the resin and sorbitol plus resin, respectively. Unexcreted resin that intracellular to the extracellular space. Acidosis is therefore remains in the stomach or small bowel would bind potassium another possible explanation for the slight increase in serum poorly, because of the low potassium and relatively high hy- potassium concentration with phenolphthalein therapy. How- drogen or sodium concentrations in these organs (23,24). As ever, there was no correlation between changes in serum po- resin moves into the colon it would bind additional potassium tassium and bicarbonate concentrations when results from phe- (presumably up to a ratio of approximately 1 mEq K/g resin), nolphthalein test days were analyzed, or when all test days but the time lag would mitigate its efficacy for the acute were analyzed as a group. Although this does not exclude management of hyperkalemia. acidosis as a contributing factor to the rise in serum potassium concentration after phenolphthalein, it may suggest that this is Serum Potassium Concentration less important than the volume changes discussed in the pre- An evaluation of the effect of resin-cathartic therapy on vious paragraph. serum potassium concentration requires that all other factors It is interesting to compare these results with resin-cathartic are held constant. It was possible to do this in our experiment therapy to a previous study on the effect of hemodialysis on because we studied patients with end-stage renal disease who serum potassium concentration. Hou et a!. found that the serum had normal or modestly increased serum potassium concentra- potassium concentration fell from approximately 5. 1 to ap- tions and therefore did not need the multiple drugs that are used proximately 3.1 mEq/L when 80 mEq of potassium was re- to treat severe hyperkalemia. The dietary intake of potassium moved from the body by hemodialysis. One hour after termi- was controlled, and one arm of the experiment consisted of nating dialysis, the serum potassium concentration had risen to treatment with a placebo so that spontaneous changes in serum approximately 3.7 mEqfL (28). Several factors probably con- potassium concentrations could be assessed. tribute to the differences in the serum potassium response to On placebo there was a tendency for the serum potassium cathartics (± resin) and hemodialysis. First, on average hemo- concentration to rise slightly (average rise 0.4 mEqfL) during dialysis removes twice as much potassium in one-third the the 12-h period of observation. None of the resin-cathartic time. Second, hemodialysis removes potassium directly from regimens caused a fall in serum potassium concentration, com- the plasma (and extracellular fluid), whereas potassium re- pared with baseline levels. However, resin alone and sorbitol moved by cathartics (± resin) originates from several sources. plus resin were not associated with as much rise in serum In addition to removal of potassium from the extracellular potassium concentration as was observed with placebo therapy. fluid, some of the potassium removed by resin-cathartic ther- Unexpectedly, phenolphthalein alone and phenolphthalein plus apy is probably already present in the colon and predestined for resin were associated with small increases in serum potassium excretion in stool, some originates in the meal, and some may concentration, even though they removed more potassium from be removed from mucosal cells lining the gastrointestinal tract. the body than other regimens. This paradox might be due to the Third, the fall in serum potassium concentration caused by effect of the various treatments on extracellular fluid volume. hemodialysis is due not only to external removal of potassium, Thirty grams of resin contains 120 mEq of sodium. Resin but also to a shift of potassium from the extracellular to binding of other cations (hydrogen, magnesium, calcium, po- intracellular fluids. Hemodialysis will infuse bicarbonate and tassium, etc.) releases an equivalent amount of sodium. The glucose and elevate catecholamine levels (29), each of which amount of sodium released may be substantial. For example, promote intracellular potassium movement. The specific con- previous studies have indicated that the resin releases virtually tribution of potassium removal by hemodialysis to the hemo- all of its sodium in the stomach, as it is quantitatively con- dialysis-associated reduction in serum potassium concentration verted to the hydrogen form (27). Released sodium becomes is unknown. part of the soluble intraluminal sodium poo1 and is subject to With this background, we can speculate on why fecal ex- active absorption into the extracellular fluid. Therefore, resin cretion of up to 54 mEq of potassium, in response to resin- therapy (alone or in combination with sorbitol) could dilute cathartic therapy, had such a small effect on the serum potas- serum potassium by expanding extracellular volume. Phenol- sium concentration in our patients. First, the experimental phthalein induces a sodium-rich secretory diarrhea, which con- protocol included the ingestion of a meal containing 21 mEq of 1930 Journal of the American Society of Nephrology J Am Soc Nephrol 9: 1924-1930. 1998 potassium; therefore, net gastrointestinal excretion of potas- Fordtran IS: Effect of three laxatives and a cation exchange resin sium averaged only 33 mEq. Second, as noted above, some of on fecal sodium and potassium excretion. Gastroentero/ogv I08: this 33 mEq may have arisen from the potassium pool seques- 752-760, 1995 tered in cobonic contents, rather than from body fluids. Third, 10. Berlyne GM, lanabi K, Shaw AB: Dangers of resonium A in the treatment of hyperkalemia in renal failure. Lancet I: 167-169, a loss of 33 mEq of potassium is trivial compared with the total I966 potassium in the body, which amounts to approximately 3000 II . Schroeder ET: Alkabosis resulting from combined administration mEq. And fourth, cathartics that induce secretory diarrhea may of a “nonsystemic” antacid and a cation-exchange resin. Ga.stro- produce some degree of extraceblular volume contraction and enterologv 56: 868-874. 1969 acidosis, which would tend to elevate serum potassium the 12. Ohlsson A, Hosking M: Complications following oral adminis- concentration. tration of exchange resins in extremely low-birth-weight infants. It would be impossible to study the effect of resin-cathartic Eur J Pediatr 146: 571-574, 1987 therapy alone in patients with hazardous degrees of hyperka- 13. Haupt HM, Hutchins GM: Sodium polystyrene sulfonate pneu- bemia because in such instances it would be unethical to with- monitis. Arch Intern Med 142: 379-381, 1982 hold other treatments that reduce the serum potassium concen- 14. Gerstman BB, Kirkman R, Platt R: Intestinal necrosis associated tration. However, we know of no evidence in previous with postoperative orally administered sodium polystyrene sul- publications suggesting that the effect of a potassium-lowering fonate in sorbitol.Am J Kidney Dis 20: 159-161, 1992 therapy is dependent on the initial serum potassium concen- 15. Rashid A, Hamilton SR: Necrosis of the gastrointestinal tract in tration. Moreover, in our study, there was no tendency for uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol. Am J Surg Patho/ 21 : 60-69, 1997 resin-cathartic therapy to reduce the serum potassium concen- 16. Roy-Chaudhury P. Meisels IS. Freedman S. Steinman TI, Steer tration to a greater degree in patients who had moderate de- M: Combined gastric and ileocecab toxicity (serpiginous ulcers) grees of hyperkalemia than in patients whose serum potassium after oral Kayexabate in sorbitol therapy. Am J Kidney Dis 30: concentrations were normal. Therefore, we believe that the 120-122, 1997 effect of single-dose resin-cathartic therapy in patients with 17. Watten RH, Morgan FM. Songkhla YN, Vanikiati B, Phillips hazardous hyperkalemia would be the same as the effect we RA: Water and electrolyte studies in cholera. J C/in Invest 38: observed in the present study, which was little or no change in 1879-1889, 1959 serum potassium concentration. Our data do not rule out a 18. Fordtran IS: Speculations on the pathogenesis of diarrhea. Fed clinically significant serum potassium-lowering effect of Proc 26: 1405-1414, 1967 chronic resin-cathartic therapy, as used originally by Flinn et 19. Fine KD, Krejs GI, Fordtran IS: Diarrhea. In: Gastrointestina/ al. (1). Disease: Pathophysiology, Diagnosis, Management, 5th Ed., ed- ited by Sleisenger MH, Fordtran IS, Philadelphia, W. B. Saun- Acknowledgments ders, 1993, pp 1043-1072 This work was supported by U.S. Public Health Service Grant 20. Agarwab R, Afzalpurkar R, Fordtran IS: Pathophysiology of 5-ROl -DK37I 72-05 from the National Institute of Diabetes, Digestive potassium absorption and secretion by the human intestine. Gas- and Kidney Diseases and by the Southwest Digestive Disease Foun- troentero/ogv 107: 548 -57 1, 1994 dation. The authors thank Diana Santa Ana for preparing the manu- 2 1. Greenman L. Peters IH, Mateer FM, Weigand FA, Wilkins D, script. 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