Cholestyramine Therapy for

Intractable Diarrhea
M. Akram Tamer, M.D., T. Richard Santora, M.D., and Douglas H. Sandberg, M.D.
From the Department of Pediatrics, University of Miami School of Medicine, Miami, Florida 33152

ABSTRACT. Seven infants with persistent diar- orated by having exogenous microorgan-
rhea have been successfully treated with a brief isms.78
course of oral cholestyramine therapy. Two of
Since cholestyramine binds both bile
these infants had diarrhea in the form of profuse
watery ileostomy discharge. It is suggested that acids and endotoxin, the hypothesis was
the mode of action of this drug may be through formulated that cholestyramine might be
binding of endotoxin and/or bile acids in the effective in treatment of intractable infan-
intestinal lumen, thus allowing time for recovery tile diarrhea. Successful treatment with
from injury of the intestinal mucosa. Pediatrics,
oral cholestyramine of four infants with
53 : 217, 1974, CHOLESTYRAMINE, DIARBHEA-INTRAC-
TABLE, SALICYLATE KINETICS, NEONATAL PHARMA-
protracted diarrhea was initially reported
COKINETICS, PLACENTAL SALICYLATE TRANSFER. in 1972. Over a 2%-year period we now
have observed seven patients whose severe
persistent diarrhea responded to oral cho-
lestyramine administration.

METHODS AND RESULTS

The termina ileum has been shown to Seven children with persistent severe
be the major site of bile acid reabsorption. diarrhea of duration from 10 to 25 days
After excision, by-pass, or disease of the were treated with oral cholestyramine
distal ileum, increased amounts of bile ( Questran, Mead Johnson Company) for
acids reach the colonic lumen.’ Large periods of 2 to 6 days. The infants ranged
amounts of bile acids in the colon have in age from 2 to 24 weeks. Two children
been shown to have a cathartic effect which had ileostomy following intestinal resection.
may be due to either increased bowel mo- No etiology for the diarrhea was demon-
tility; to interference with water, bicar- strated in any of the seven children in spite
bonate, or sodium absorption; or to in- of extensive laboratory tests, including
creased secretion of water and sodium by blood and urine cultures and stool cultures
the colonic mucosa.3 This pathogenic for bacteria and fungi, search for parasites
process, known as cholerheic enteropathy, in stool, and immunological evaluation. The
usually responds to oral administration of latter included measurement of serum im-
cholestyramine, an insoluble quarternary munogobulins by immunodiffusion, abso-
ammonium anion exchange resin capable of lute lymphocyte counts, and evaluation of
sequestering bile acids.45 in vitro lymphoblast transformation after
Cholestyramine also has been shown to PHA stimulation. Previous unsuccess ther-
be capable of binding endotoxin.#{176} Recent apy included modalities such as parenteral
studies of mechanisms of diarrhea have ampicillin or penicillin and kanamycin, in-
presented evidence that diarrhea, in some travenous fluid replacement with no intake,
instances, may be the result of toxins elab- oral electrolyte solution, and special for-

(Received June 8; revision accepted for publication August 17, 1973).

ADDRESS FOR REPRINTS: ( M.A.T. ) Department of Pediatrics, School of Medicine, P.O. Box
875, Biscayne Annex, Miami, Florida 33152.

PEDIATRICS, Vol. 53, No. 2, February 1974

217
Downloaded from http://pediatrics.aappublications.org/ by guest on March 5, 2018
218 CHOLESTYRAMINE FOR DIARRHEA

TABLE I

CHOLESTYRAMINE THERAPY OF INTRACTABLE DIARRHEA

Response
Age Race & Duration Stools Other Cholestyramine Time
(weeks) Sex* (days) (No/day) Therapyt Treatment (days)

TB 4 NM 19 19-28 A, B, F 6gm/dayfor2days 1
KE 2 NF 10 8-10 A, B, C 6gm/dayfor2days 1
CJ 22 NM 16 7-11 A,B,E 8gm/dayfor2days 1
CM 8 NM 30 12-15 A, B, C, D 8gm/dayforsdays 2
AH 5 NM 14 10-17 A, B, C 4gm/dayfor3days 2
RH 8 NF 42 A, B, D 4 gm/day for 4 days 2
EB 24 WF 56 A, B, G, E 6 gm/day for 6 days 2

* NI, Male; F, female;, N, negro; W, white.

t A, Intravenous fluid therapy, no oral feedings; B, antibiotics, ampicillin or penicillin, and kanamycin;
C, oral electrolyte solutions; D, total intravenous feedings; E, oral Lactinex therapy; F, oral nystatin (Mycos-
tatin) therapy; G, oral elemental diet therapy.
These two patients had profuse constant watery ileostomy drainage following surgical resections for necro-
tizing enteropathy and intestinal obstruction.

mulas such as a protein hydrolysate-base electrolyte concentrations were within normal

formula ( Nutramigen ), or soybean base limits except for mild metabolic acidosis. All bac-
terial cultures including culture of ten stool speci-
formulas. Treatment with cholestyramine
mens were negative. Stool pH was repeatedly
was restricted to patients who passed 10 neutral. Parenteral fluids were administered and
or more stools per day for a period of more the infant was given
penicillin and kanamycin
than seven days. intravenously and mycostatin orally. Over the next
Table I shows the severity and protracted four days he had an average of 22 watery stools
daily. On the fifth hospital day, the patient was
nature of the diarrhea in these children.
started on oral cholestyramine therapy, 2 gm
Because the diarrhea was refractory to three times daily. The following day the number
other means of therapy, cholestyramine of stools decreased to 13, with one half described
was orally administered in modest dosages as pasty in consistency. In the second 24-hour
(4 to 8 gm/day) for a maximum of six days. period, the child had only four stools which were
well formed. He continued to have normal stools
The diarrhea decreased within one to two
and began to gain weight on the fourth day after
days and did not recur after cholestyramine beginning treatment. Diarrhea did not recur and
was discontinued. The children were given the infant was discharged on Nutramigen.
simple diets after the diarrhea stopped
Case 7
which they all tolerated satisfactorily. The
only complication of therapy encountered E.B. was a 6-month-old white female infant
admitted to the hospital with a history of profuse
was development of constipation in one in-
constant ileostomy drainage. She had had surgical
fant; this did not persist after cholestyra- resection of a Meckel’s diverticulum at three days
mine was discontinued. of age. The postoperative course was marked by
Two representative case reports are recurrent episodes of intestinal obstruction which
described in more detail. necessitated four abdominal operations. An ile-
ostomy was created at 4 months of age. She then
began to have profuse ileostomy drainage which
CASE REPORTS
resulted in repeated episodes of electrolyte im-
Case 1 balance, acidosis, and dehydration. Two seizures
TB. was a 4-week-old Negro male infant hos- were attributed to hyponatremia. She was trans-
pitalized for diarrhea of two weeks’ duration. ferred to Jackson Memorial Hospital, Miami,
Treatment during that period had been unsuc- Florida, for management of these complications.
cessful. On admission to Jackson Memorial Hospi- On admission she weighed 4.6 kg and was mod-
tal, Miami, Florida, the infant was febrile (tem- erately dehydrated. Fluids were administered in-
perature, 102 F), moderately dehydrated, and travenously and she then was given an oral
lethargic. His weight was 2.6 kg, birth weight elemental liquid diet ( Codelid) and parenteral
having been 2.7 kg. A perineal dermatitis was supplimentation with water and electrolytes. Dur-
present in association with oral candidiasis. The ing the first three hospital days there was an aver-
remainder of the physical examination was nor- age of 1,133 ml of ileostomy drainage per day.
mal. Hemogram was unremarkable and serum On the fourth hospital day therapy with Lactinex,

Downloaded from http://pediatrics.aappublications.org/ by guest on March 5, 2018

 ARTICLES 219

3 gm per day, was started. Ileostomy output on bile acids formed by bacteria present in
day 4 was 1,985 ml/24 hours. On the following
the upper small intestinal lumen were re-
day, cholestyramine, 2 gm three times daily, was
sponsible for injury to the mucosa.16 Un-
given orally. By the sixth hospital day ileostomy
output was 545 ml/24 hours, and the 24-hour conjugated bile acids are not normally
volume steadily decreased to 130 ml by the tenth present in appreciable amounts in the
hospital day. At this time, cholestyramine therapy upper small intestinal lumen. This mucosal
was discontinued. injury may then have interfered with active
On the 11th hospital
day the ileostomy output
transport of salt, water, and/or mono-
increased to hours 350 ml/24
and remained at
approximately this volume fpr the 12th to 15th
saccharides. The resulting increased intest-
day, even with reinstitution for that four-day in- inal luminal salt or monosaccharide concen-
terval of oral cholestyramine and Lactinex thera- trations could produce watery diarrhea
py. She subsequently tolerated gradual introduc- through osmotic effect. An alternative ex-
tion of Nutramigen without recurrence of the pro-
planation is that the diarrhea may have
fuse ileostomy drainage. She was discharged on
this formula and at 10 months of age showed been the result of mucosal injury from
continued satisfactory weight gain. endotoxin produced by the intestinal
microorganisms. Under these circumstances
DISCUSSION cholestyramine’s therapeutic effectiveness
Cholestyramine has been found to be results from binding of the endotoxin in
effective in controlling diarrhea associated the bowel lumen. The resulting inactivation
with loss of ileal capacity for absorption of of the endotoxin would prevent mucosal
bile acids.45 It has also been found to pre- injt.iry and perhaps also interfere with ab-
vent diarrhea in radiation-induced enteritis sorption of endotoxin into the systemic
in animals.b0 This therapeutic effect has circulation. It is, of course, possible that
been considered to be due to binding of more than one of these mechanisms may
bile acids, thus preventing their cathartic be operating in the patients who responded
effect on the colonic mucosa. However, favorably.
cholestyramine has also been reported to In this group of patients, cholestyramine
be useful in treatment of the diarrhea as- treatment for a brief period of time was ap-
sociated with acquired hypogammaglobu- parently sufficient to allow enough recovery
linemia.1’ It has also been used by Rowe of the mucosa so that after treatment was
as well as Schapiro and co-workers in suc- discontinued, the mucosa was then ade-
cessful treatment of some adult patients quately able to transport water, sugar, and
with chronic diarrhea of undetermined eli- electrolytes.
ology.’2-13 The pathophysiologic basis for The excellent response of the diarrhea
this successful therapy was not determined. to treatment in these infants suggests that
In addition, as a result of the successful use empiric short-term use of this relatively
of cholestyramine in management of choler- safe, nonabsorbable agent may be justified
heic diarrhea, it has been evaluated as in patients refractory to other therapeutic
treatment for nonspecffic tropical diarrhea measures. The use of this agent for a few
and found to be ineffective.’ In those in- days has not been associated with any seri-
stances where treatment was successful, in- ous side effects.17
terruption of cholestyramine therapy was
usually associated with recurrence of diar- SUMMARY
rhea.’5 In the patients reported here with Seven children with persistent diarrhea
utilization of a lactose-free, hypoallergic not responsive to usual modes of therapy
diet, there were no recurrences. have been successfully treated with a brief
In the two patients in this series, R. H. course of orally administered cholestyra-
and E. B., who had ileostomies associated mine. Two children had profuse watery
with profuse ileal drainage, the excellent ileostomy drainage following surgical con-
response to cholestyramine suggests that struction of an ileostomy. It is suggested
the colon is not the only site where cho- that the response to treatment was the
lestyramine exerts a therapeutic effect. In result of binding of bile acids and/or endo-
speculating about the mechanism of activ- toxin by the anion exchange resin which
ity of this drug, the following possibilities allowed recovery of the injured intestinal
were considered: one is that unconjugated mucosa.

Downloaded from http://pediatrics.aappublications.org/ by guest on March 5, 2018

220 CHOLESTYRAMINE FOR DIARRHEA

REFERENCES 10. Berk, R. N., and Seay, D. C.: Cholerheic en-

teropathy as a cause of diarrhea and death
1. Hofmann, A. F. : The syndrome of ideal dis-
in radiation enteritis and its prevention with
ease and the broken enterohepatic circula-
cholestyramine. Radiology, 104: 153, 1972.
lion : Cholerheic enteropathy ( comments).
Gastroenterology, 52:752, 1967.
11. Gleich, G. J., and Hofrnann, A. F.: Use of
cholestyramine to control diarrhea associ-
2. Archambeau, J. 0., Maetz, M., Jesseph, J. E.,
ated with acquired hypogammaglobulinemia.
et at. : Producation of diarrhea in dogs pre-
pared with a gallbladder-colon fistula. Arch.
Amer. J. Med., 51:281, 1971.
12. Rowe, G. G. : Control of diarrhea by cholesty-
Surg., 95:230, 1967.
3. Mekhjian, H. S., Phillips, S. F., and Hofmann,
ramine administration. Amer. J. Med. Sci.,
255:84, 1968.
A. F.: Conjugated bile salts block water and
13. Schapiro, R. H., Heizer, W. D., Goldfinger,
electrolyte transport by the human colon
S. E., et at.: Cholestyramine responsive
(abstract). Gastroenterology, 54: 1256, 1968.
idiopathic diarrhea (abstract). Gastroen-
4. Poley, J. R., and Hofmann, A. F. : Effective
terology, 58:993, 1970.
treatment of the diarrhea of cholerheic en-
14. McCloy, R. M., and Hofmann, A. F. : Tropical
teropathy with cholestyramine ( abstract).
diarrhea in Vietnam: A controlled study of
J. Lab. Clin. Med., 70:1024, 1967.
cholestyramine therapy. New Eng. J. Med.,
5. Hofmann, A. F., and Poley, J. R.: Cholestyra-
284:139, 1971.
mine treatment of diarrhea associated with
15. Hofmann, A. F.: Bile acid malabsorption
ileal resection. New Eng. J. Med., 281:397,
caused by ileal resection. Arch. Intern.
1969.
Med., 130:597, 1972.
6. Nolan, J. P., and Ali, M. V. : Effect of cho-
16. Shiner, J. : The effect of bile acids on the
lestyramine on endotoxin toxicity and ab-
small intestinal mucosa in man and in rats:
sorption. Amer. J. Dig. Dis., 17:161, 1972.
A light and electron microscopic study. In
7. Gorbach, S. L. : Acute diarrhea: A toxin dis-
Schiff, L., Carey, Jr., J., and Dietschy, J. D.
ease. New Eng. J. Med., 283:44, 1970.
(eds.) : Bile Salt Metabolism. Springfield,
8. Gorbach, S. L., and Khurana, 0. M. : Toxi-
Illinois: Charles C Thomas, Publisher, 1969.
genie Escherichia coti: A cause of infantile
17. Thompson, W. G. : Cholestyramine. Canad.
diarrhea in Chicago. New Eng. J. Med.,
287:791, 1972.
Med. Assoc. J., 104:305, 1971.
9. Tamer, M. A., Santora, T. R., and Sandberg,
D. H. : Cholestyramine therapy for intracta-
Acknowledgment
ble diarrhea ( abstract). Clin. Res., 20:97, Supported in part by U.S. Public Health Service
1972. Clinical Research Center Branch grant RR00261.

Downloaded from http://pediatrics.aappublications.org/ by guest on March 5, 2018

 Cholestyramine Therapy for Intractable Diarrhea
M. Akram Tamer, T. Richard Santora and Douglas H. Sandberg
Pediatrics 1974;53;217

Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/53/2/217
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its
entirety can be found online at:
https://shop.aap.org/licensing-permissions/
Reprints Information about ordering reprints can be found online:
http://classic.pediatrics.aappublications.org/content/reprints

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has
been published continuously since . Pediatrics is owned, published, and trademarked by the American
Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright ©
1974 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

Downloaded from http://pediatrics.aappublications.org/ by guest on March 5, 2018

 Cholestyramine Therapy for Intractable Diarrhea
M. Akram Tamer, T. Richard Santora and Douglas H. Sandberg
Pediatrics 1974;53;217

The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://pediatrics.aappublications.org/content/53/2/217

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has
been published continuously since . Pediatrics is owned, published, and trademarked by the American
Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright ©
1974 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

Downloaded from http://pediatrics.aappublications.org/ by guest on March 5, 2018