EFFECT OF 9-a-FLUOROHYDROCORTISONE ON THE ILEAL EXCRETA OF ILEOSTOMIZED SUBJECTS

Transcription

1 GASTROENTEROLOGY 1972 by The Williams & Wilkins Co. Vol. 62, No. 2 Printed in U. S. A. EFFECT OF 9-a-FLUOROHYDROCORTISONE ON THE ILEAL EXCRETA OF ILEOSTOMIZED SUBJECTS PHIT.IP KRAMER, M.D., AND RUVEN LEVITAN, M.D. The Evans Memorial Department of Clinical Research, University Hospital and the Gastroenterology Department, New England Medical Center Hospitals, Tufts University Medical School, Boston, Massachusetts, and the Veterans Administration West Side Hospital, The Abraham Lincoln School of Medicine, University of Illinois, Chicago, Illinois Sodium deprivation, produced by sodium restriction or loss, results in a fall in the sodium and a rise in the potassium content of ileal excreta of ileostomized subjects. An endogenous aldosterone secretion has been postulated. To determine whether similar changes could be induced by exogenous mineralocorticoids, 9-a-fluorohydrocortisone, 2 mg per day by mouth, was administered to 5 subjects with stable ileostomy function who had had total colectomies for ulcerative colitis. Balance techniques were used. Contrary to the response seen with sodium deprivation, the 24-hr excretion of sodium was unaffected but mean potassium excretion and concentration in the ileal excreta increased (P < 0.01) in patients receiving 9-a-fluorohydrocortisone. A significant fall in the mean urinary sodium (P = 0.03) but not in the mean potassium output occurred indicating that the renal and small intestinal responses to exogenous oral 9-a-fluorohydrocortisone differed in our subjects. In 1 additional subject who was probably sodium-depleted, a decrease in the mean ileal sodium excretion (milliequivalents per day) occurred while the sodium concentration rose during 9-a-fluorohydrocortisone administration. The mea,n urine sodium excretion showed a further fall from control levels in this patient while the mean potassium excretion rose. It is, therefore, possible that exogenous mineralocorticoids in sodium-deprived individuals with ileostomies may be of therapeutic value by aiding them to conserve salt. A decrease in the sodium and a rise in the potassium content of the ileal excreta in ileostomized subjects has been observed when sodium deprivation was produced by excessive sodium losses 1 or Received February 8, Accepted October 14, Address requests for reprints to: Dr. Philip Kramer, University Hospital, 750 Harrison Avenue, Boston, Massachusetts This investigation was supported by the United States Public Health Service Research Grant AM from the National Institute of Arthritis and Metabolic Diseases. Dr. Levitan was supported by Research Grant sodium restriction. 2 Gallagher et al. 1 postulated that these changes in the composition of ileal effluent were in response to an endogenous aldosterone secretion stimulated by the sodium depletion. If this suggestion is correct, it would appear that the response of the human small in- AM from the National Institute of Arthritis and Metabolic Diseases and Veterans Administration Medical Research Funds. Dr. Levitan's present address is: Gastroenterology Section, Department of Medicine, Veterans Administration West Side Hospital, The Abraham Lincoln School of Medicine, University of Illinois, Chicago, Illinois. 235

2 236 KRAMER AND LEVITAN Vol. 62, No.2 testine to mineralocorticoids is similar to that of the kidney, salivary glands, and colon. A variety of corticosteroids has been administered to human ileostomized subjects to determine whether the foregoing postulation could be confirmed. 3-5 Additional observations were recorded during metabolic studies while patients had been receiving steroids as part of a therapeutic regimen. 6, 7 The findings of these investigations have not always agreed. Furthermore, only limited conclusions could be reached because either ileal sodium and potassium concentration were measured over an 8-hr period per day, or because the patients were not in a steady state having recently undergone a colectomy. No studies have been published to indicate whether mineralocorticoids affect the 24-hr excretion of electrolytes in subjects with stable ileostomy fu'nction who are ingesting a normal diet. Such investigations would yield data of physiological interest and also could have therapeutic implications. Ileostomized individuals are chronic intestinal sodium wasters and are readily susceptible to additional sodium deprivation If mineralocorticoids produce significant ileal sodium retention then they could be used in patients with ileostomies as an adjunctive measure in the treatment and prevention of excessive ileal sodium losses. We, therefore, administered 1 to 2 mg of 9-a-fluorohydrocortisone orally in divided doses to subjects with long-standing ileostomies to determine the effect upon the ileal excreta collected during 24-hr periods. Methods Seven subjects with ileostomies for ulcerative colitis participated in this study (table 1). Three of them, M. 0., R. B., and R. D., lived at home while conducting their normal activities; the technique used has been previously described. 2, 8 These subjects consumed the same daily diet which contained 200 mg or 9 meq per day of sodium and they added 9.0 g of sodium chloride supplied in envelopes to their meals. Metabolic principles were adhered to in the handling of the food. The remaining patients were hospitalized on a metabolic ward and ingested the same diet daily which was supervised by dietitians and contained the same quantity of sodium. Both groups were studied in a similar fashion. There was a minimal 3-day control period followed by a 3- to 4-day test period during which 1 to 2 mg of 9-a-fluorohydrocortisone were given orally in divided doses daily and then a repeat control period of 3 to 4 days. Initially the effect of 1 mg per day in 2 subjects was investigated but because the results were not in keeping with our expectations, i.e., the failure of a sodium response, we increased the dose to 2 mg per day. During the I-mg per day study, 0.2 mg was administered every 4 hr for five doses; the amount per dose was simply doubled during the 2-mg study. Both the ileal excreta and urine were collected in 24-hr batches in plastic ileostomy bags and sodiumfree plastic bottles respectively, the collections starting at the same hour each day. The excreta were analyzed for total weight, sodium and potassium concentration, while the urine was analyzed for volume, sodium, and potassium. A Baird flame photometer, KY-l, and an AutoAnalyzer were used to measure the sodium and potassium. The results were statistically evaluated by comparing the control and test period for each individual and applying the paired t-test. The mean control and test period findings for the group plus 1 SD were also calculated and are shown to simplify presentation of the results. Results The effect of 9-a-fluorohydrocortisone on the ileal excreta and urine are summarized in tables 1. and 2 and figure 1. Subject M. J. is discussed separately because she was probably sodium-depleted rather than in a stable state. Marked variations were observed in the daily ileal and urinary excretion in each subject and between subjects. The serum electrolytes (sodium and potassium) remained within normal limits throughout the study. Effect of 1 mg per day (2 Subjects) Ileal excreta. In the 2 subjects (R. D., M. 0.) studied, the daily total weight, sodium concentration (milliequivalents per liter), and daily sodium output (milliequivalents per day) were unchanged. However, the potassium concentration showed a daily rise in both subjects (R. D.,

3 . February a-FLUOROHYDROCORTISONE ON ILEOSTOMY EXCRETA 237 TABLE 1. Summary of data on ileostomy subjects Duration of Dose of 9- Small intes- Subject Sex Age ileostomy Type of study a -fluorohydro- tinal X-rays cortisone/day yr yr mg M.O o F 36 8 Home 2 Normal 1 R. E. 0. M 28 6 Home 1 Normal R. D M 40 6 Home 2 Normal M.L.... F 36 4 Hospital 2 Normal W. M " o. M 42 2 Hospital 2 Normal R. Bo M 27 1'/2 Hospital 2 Normal M. J. _ o - F 28 5 Hospital 2 Normal TABLE 2. Effect of 2 mg, perorally of 9-a-fluorohydrocortisone on ileal excreta and urine of 5 subjects with stable ileostomy function (group A) and subject M J a Periods Ileal excreta Wet weight Sodium Potassium Volume Sodium Potassium Urine glday meq ld~y meqlliter meqlday meqlliter ml meqlday meqlliter meqlday meqlliter Group A Control ±108.0 ± 47.9 ± 17.7 ± 2.95 ± 3.42 ±175.0 ± 54.8 ±46.9 ± 17.6 ±46.9 During 9-afluorohydrocortisone ±301.0 ± 49.4 ±26.8 ± 3.06 ± 4.18 ±168 ± 21.4 ±19.4 ± 15.2 ±34.4 P valuea <0.01 < 0.01 =0.03 =0.03 Subject M. J. Control ±185.4 ± 20.1 ± 25.4 ± 4.4 ±5. 7 ±340.7 ± 3.8 ±3.2 ± 9.9 ±8.2 During 9-afluorohydrocortisone ±587.0 ±19.3 ±5.0 ±4.0 ±2.6 ±488.7 ± 1.3 ±0.46 ± 4.0 ±67.6 a Results are expressed as mean ± 1 SD. P value given only where significant changes occur. mean control, 7.4 ± 0.2 meq per liter and 11.4 meq per liter on the 4th test day, P < 0.02; M. 0., mean control, 12.0 ± 1.3 meq per liter and 19.6 meq per liter on the 4th test day, P <0.05). After the drug was discontinued the potassium concentration returned to control levels. A parallel change in the daily potassium excretion occurred in R. D. (control was 4.3 ± 0.2 meq per day and 6.7 meq per day on the 4th test day, P < 0.001). In M. 0., the potassium was 7.8 meq per day on the 3rd day but 5.0 meq per day on the 4th day of mineralocorticoid administration with a mean control value of 3.8 ± 0.3 meq per day, P < Urine. The volume, sodium, and potassium content were unchanged in subject M. 0., whereas in subject R. D. the sodium concentration and daily sodium excretion decreased while the potassium concentration and daily output rose (P values of 0.05 to for the sodium and potassium changes). Effect of 2 mg per Day (5 Subjects) Ileal excreta. Total weight. In 2 subjects (R. Bo. and M. L.) a decrease in total

4 238 KRAMER AND LEVITAN Vol. 62, No.2 24,If CXlNTROL PERIOO 2nd CXlNTROL PERIOO DAYS FIG. 1. Graph of group mean daily potassium concentration and excretion during control periods and the administration of 2.0 mg per day of 9-a-fluorohydrocortisone, perorally. There is a daily rise in the mean potassium concentration while the mineralocorticoid is given. The effect is still present on the 1st day of the second control period, the concentration thereafter falling to the previous control levels. The mean potassium excretion (milliequivalents per day) during mineralocorticoid administration rose, then plateaued, and then fell to previous control levels after the drug was discontinued. The brackets enclose the mean ± 1 SD. weight occurred while in the other 3 (M. 0., R. B., W. M.) an increase was observed; therefore, the change for the entire group was not significant. The group mean during the control period was ± per day and ± per day during the test period. Sodium excretion. Neither the sodium concentration (milliequivalents per liter) nor the daily sodium excretion (milliequivalents per day) were affected by the mineralocorticoid. The mean group sodium concentration was ± 17.1 meq per liter in the control period and ± 26.8 meq per liter during the drug period; the group mean daily sodium excretion during these periods was ± 47.9 meq per day and ± 49.4 meq per day respectively. Potassium excretion. ' In every subject the mean potassium concentration increased when the mineralocorticoid was given, the difference between the group and test period displaying a P value of

5 February l-FLUOROHYDROCORTISONE ON ILEOSTOMY EXCRETA 239 <0.01 (table 2). The daily group mean potassium concentrations showed a steplike rise on the steroid (fig. 1). They were still elevated on the 1st day after the 9-a-fluorohydrocortisone was discontinued, presumably because the drug was still exerting an effect, and thereafter fell to control levels. The group mean for the control period was ± 3.42 meq per liter and ± 4.18 meq per liter during the drug period. The daily potassium excretion did not demonstrate the same day to day increase although in 3 subjects (M. 0., R. B., W. M.) there was such a trend. On the 1st day of drug ingestion the mean excretion for the group was 8.6 ± 3.7 meq per day, on the 2nd day ± 4.6 meq, on the 3rd day ± 3.2 meq, and ± 5.6 meq on the 4th day. The mean control results were 6.84 ± 2.95 meq per day and ± 3.06 meq per day while the drug was being given with a P value of <0.01. Urine. The mean daily urine output also fluctuated widely but was not significantly affected by the 9-a-fluorohydrocortisone. Although a wide range of mean sodium concentration and daily sodium excretion were observed, there was a significant difference between the mean control values (83.6 ± 46.9 meq per liter and ± 54.8 meq per day respectively) and those of the drug periods (38.98 ± 19.4 meq per liter and ± 21.4 meq per day respectively) P = Therefore, renal tubular absorption of sodium increased with mineralocorticoid administration. No significant increase in potassium concentration occurred (control ± 46.9 meq per liter, test ± 34.4 meq per liter) or in the daily potassium excretion (control ± meq per day, test ± meq per day). Results in Subject M. J. (Table 2) Subject M. J. was asymptomatic and therefore was originally in the study. However, it became apparent during this investigation that she was probably sodiumdepleted despite the oral ingestion of 9.0 g of sodium chloride because the urine sodium excretion was less than 10 meq per day. 1 The 9-a-fluorohydrocortisone produced a decrease in the mean wet weight of ileal excreta, mean urine volume, mean ileal and urinary sodium excretion. The mean sodium output decreased from a control value of ± 20.1 meq per day to 71.0 ± 19.3 meq per day while the mean concentration rose from 82.5 ± 25.4 to ± 5.0 meq per liter. Although the mean potassium output decreased the mean potassium concentration increased from 14.3 ± 5.7 to 17.0 ± 2.0 meq per liter. Both the mean urinary potassium excretion and co~centration increased. When analyzed statistically none of the changes produced by the mineralocorticoid were calculated as being significant. Discussion The oral administration of 9-a-fluorohydrocortisone to subjects with stable ileostomy function produced a progressive increase in the potassium excretion and concentration in the ileal excreta. This change was observed whether these subjects received 1 or 2 mg of the mineralocorticoid or were studied at home or on a metabolic ward. The sodium content of the ileal excreta was not affected. On the other hand, the sodium concentration and daily sodium output decreased in the urine, indicating that the orally administered 9-a-fluorohydrocortisone was absorbed in our subjects. These findings are at variance from those described in the literature on the effect of adrenocorticoids on human ileal excreta and therefore small intestinal function. Brooke 6 reported a decrease in volume, sodium concentration, and daily sodium output of ileal effluent in cortisonetreated patients. However, these conclusions were reached by comparing the results of patients receiving cortisone with those who were not. These patients had been recently operated upon and therefore had unstable ileostomy function and the data were not analyzed statistically. Furthermore, the sodium concentrations of 200 to 400 meq per liter suggested that the results were not valid. Smiddy et al. 7 found that cortisone-treated patients in

6 240 KRAMER AND LEVITAN Vol. 62, No.2 the immediate postoperative period showed less volume and sodium losses in the ileal effluent than untreated patients but these parameters gradually increased to normal values in spite of continued steroid therapy. The comments previously mentioned, except for the high sodium concentrations, also apply to this investigation. In another study by Hasner,4 cortisol and cortisone produced a fall in sodium concentration and a rise in potassium concentration in ileal excreta collected for an 8-hr period per day; daily 24-hr excretion was not mentioned. Goulston et al. 3 determined the effect of 2 mg of 9-a-fluorohydrocortisone upon the sodium and potassium concentration of ileal excreta collected between 11 PM to 7 AM. The Na: K ratio decreased from control values in the same individual. Only the ratios were published and not the actual sodium and potassium concentrations. A small increase in the potassium concentration in itself could result in a marked change in the ratio without the sodium concentration being altered. Because of their method of study, daily outputs of electrolytes could not be measured. D-Aldosterone given intravenously over a 20-min period had no effect on the ileal excreta in 4 ileostomized patients investigated by the metabolic balance technique. 5 According to Shields et al. 9 D-aldosterone is rapidly inactivated and when given as a single rapid infusion would not be likely to exert any influence on the intestine. However, in unpublished observations by Goulston and Levitan, D aldosterone did not al ter ileal excreta when administered intravenously over several hours. Our results in human subjects are similar to those obtained by Shields et al. 9 in acute experiments in dogs with isolated small intestinal loops. D-Aldosterone was given as a continuous intravenous infusion and produced a net secretion of potassium into the intestinal lumen. As a consequence, the potassium concentration was increased. Net water and sodium transport were unaffected. These authors also suggested that increased adrenocortical activity could cause significant excessive potassium losses. Although there was a significant trend toward such losses in our ileostomized subjects, it was of small magnitude. Of interest is the difference in response between the kidney and small intestine to mineralocorticoids. Thus, there was a decrease in the sodium concentration and output in the urine, a response we expected in the ileal excreta but which did not occur. Although some of the subjects were studied at home while others were investigated in a metabolic ward, the results were similar. This finding is further evidence that a carefully supervised metabolic study on ileostomized subjects can be performed with the subjects living at home. It would appear from our investigation on subjects with stable ileostomy function that oral mineralocorticoids would not be of value in altering ileal sodium losses; renal sodium losses, however, may be further decreased. Yet in our sodiumdepleted subject, M. J., (table 2) the mean ileal daily sodium excretion decreased 37.4 meq per day from control values while 2 mg of 9-a-fluorohydrocortisone was administered. A further decrease in the mean urinary sodium excretion occurred and the mean urinary potassium excretion rose over control levels. These changes and the fact that the mean ileal sodium concentration rose suggests that a mineralocorticoid effect did occur. However, the differences between the control and drug period were not statistically significant. During the mineralocorticoid administration the measured parameters showed, in addition to normal variations, progressive alterations favoring a drug effect. As a consequence of all these factors, large values for the standard deviation were obtained thereby making significant statistical changes unlikely. After the 9-afluorohydrocortisone was discontinued the ileal electrolytes returned toward previous control levels. Exogenous oral mineralocorticoids as administered by us and endogenous mineralocorticoid which resulted from body sodium deprivation differed in their

7 February a-FLUOROHYDROCORTISONE ON ILEOSTOMY EXCRETA 241 effect upon the small intestinal handling of ileal sodium and potassium. We have no explanation for this disparity in results. The differences could be due to type of mineralocorticoid, the mode of administration, or the dose relationship. Two milligrams of 9-a-fluorohydrocortisone is 20 to 40 times the amount necessary to treat Addison's disease, the therapeutic dose being 0.05 to 0.1 mg per day. Fifty to 150 Jig per day of aldosterone is secreted normally by the adrenal cortex; under conditions of low sodium intake, i.e., 8 to 14 meq per day approximately 300 to 2400 Jig per day may be secreted. 10 Two milligrams of 9-a-fluorohydrocortisone has the approximate electrolyte effect up to 4000 Jig per day of aldosterone (Dr. James C. Melby, personal communication). It would appear that the dose we administered should be more than adequate; failure of absorption did not occur because a renal effect was noted. We would have to postulate but without any evidence that exogenous mineralocorticoid does not entirely simulate the physiological response of the body homeostatic mechanisms to sodium deprivation. REFERENCES 1. Gallagher ND, Harrison DD, Skyring AP: Fluid and electrolyte disturbances in patients with long-established ileostomies. Gut 3: , Kramer P: The effect of varying sodium loads on the ileal excreta of human ileostomized subjects. J Clin Invest 45: , Goulston K, Harrison DD, Skyring AP: Effect of mineralocorticoids on the sodium/potassium ratio of human ileostomy fluid. Lancet 2: , Hasner E: Electrolyte excretion in the urine, saliva, and ileostomy fluid after administration of cortisol and cortisone and postoperatively. Acta Chir Scand (suppl 343) : , Levitan R, Goulston. K: Water and electrolyte content of human ileostomy fluid after d-aldosterone administration. Gastroenterology 52: , Brooke BN: Ileostomy chemistry. Dis Colon Rectum 1:3-14, Smiddy FG, Gregory SD, Smith lb, et al: Fecal loss of fluid, electrolytes, and nitrogen in colitis before and after ileostomy. Lancet 1:14-19, Kramer P, Kearney MM, Ingelfinger FJ: The effect of specific foods and water loading on the ileal excreta of ileostomized human subjects. Gastroenterology 42: , Shields R, Mulholand AT, Elmslie RG: Action of aldosterone upon the intestinal transport of potassium, sodium and water. Gut 7: , Laragh JH, Sealey JE, Sommers SC: Patterns of adrenal secretion and urinary excretion of aldosterone and plasma renin activity in normal and hypertensive subjects. Circ Res 18, 19 (suppl 1): , 1966