Gastrointestinal complications of renal transplantation. 2. The colon STUART D. ARCHIBALD, MD, FRCS[C]; DENNIS W. JIRSCH, MD, M SC, PH D, FRCS[C]; ROBERT A. BEAR, MD, FRCP[C], FACP

In 95 consecutive cases of cadaveric renal transplantation followed up for I to 83 months (mean 23.1 months) seven colonic complications developed in seven patients; these Included ischemic colitis in three, colonic perforation in two, fecal impaction in one and appendicitis in one. Except for appendicitis all the complications occurred within 2.5 months of transplantation and were not related to the patient's age, sex, blood group, or use of cigarettes or alcohol, the duration of hemodialysis before transplantation, the tissue match or the number of infusions of immunosuppressive medication. Two patients died, but not of the complication. In the management of free colonic perforation prompt resection or exteriorization, with avoidance of intraperitoneal suture lines, and continuous postoperative peritoneal lavage may be lifesaving. Early surgical intervention and creation of a colostomy in one of the cases of ischemic colitis proved helpful.

precoce et Ia creation d'une colostomie dans un des cas de colite isch6mique se sont av6r6es utiles.

Renal allotranspiantation and antirejection therapy are associated with numerous gastrointestinal complications. Major colonic complications are among the most serious of these, often threatening the patient's survival.' Since the data on such complications are sparse and fragmented, we reviewed the experience at St. Michael's Hospital, Toronto with 95 consecutive cases of cadaveric renal transplantation. This material, along with relevant English-language reports, was analysed to determine the frequency, significance and appropriate treatment of these complications. Methods At our centre renal transplantation is performed in selected patients2 by the same surgical team using standard surgical techniques. CurrentDans 95 cas cons6cutifs de greffe d'un rein cadav6rique surveill6s pendant ly immunosuppressive therapy conI A 83 mois (23.1 mois en moyenne) sists of daily maintenance doses of sept complications affectant le c8lon prednisone (100 mg tapered to 15 mg sont apparues chez sept patients; by 1 year) and azathioprine (2 to 3 ceci comprend trois cas de colite mg/kg of body weight) and five inisch6mique, deux de perforation du travenous infusions of 750 mg of colon, un de fecalome et un d'appenmethylprednisolone and 400 mg of dicite. A l'exception de l'appendicite, cyclophosphamide during the first 21 toutes les complications sont survenues days after transplantation, and as moms de 2.5 mois aprAs Ia greffe needed thereafter to control rejection. et n'etaient pas reli6es a l'ige, au Twelve of the first renal transplant sexe, au groupe sanguin ou & l'usage de Ia cigarette ou d'alcool, au temps recipients received no infusions, but cumulatif pass6 sous hemodialyse only oral therapy with prednisone avant Ia greffe, a Ia compatibilite and azathioprine. tissulaire du greffon pour le receveur The charts of all recipients of ou au nombre de perfusions de cadaveric renal transplants from medicaments immunosuppresseurs. November 1969 to June 15, 1977 Deux patients sont d6c6des, mais pas were reviewed. All patients were foldes complications. Dans le traitement lowed up for at least 4 months or d'une perforation colique libre une until death or graft loss occurred. resection ou l'ext6riorisation rapide, The frequency, clinical significance en evitant les lignes de suture Intraperitoneales, et le lavage periton6al and management of each colonic continu en postop6ratolre peuvent sauver complication was noted. Correlations Ia vie. Une intervention chirurgicale were sought between the development of such complications and the From the departments of surgery and patient's age, sex, blood group and medicine (nephrology), St. Michael's use of cigarettes and alcohol, the Hospital and the University of Toronto Reprint requests to: Dr. Dennis W. Jirsch, duration of hemodialysis before 30 Bond St., Toronto, Ont. MSB 1W8 transplantation, the tissue match and

the number of infusions of immunosuppressive medication after transplantation. Results The 95 patients' ages ranged from 18 to 59 years (mean 38.1 years); 69 were men and 26 were women (male:female ratio 2.7:1). The overall mortality was 19% and the proportion with graft loss was 25% for the entire follow-up period (mean 23.1 months). Seven colonic complications occurred in seven patients (Table I); the rate of such complications was therefore 7%. Each of these patients had received the current high-dose immunosuppressive regimen. Two (29%) of the seven died; the mortality for such complications in the entire series of patients was therefore 2%. Except for one case of acute appendicitis occurring 20.5 months after transplantation, all coIonic complications presented in the first 2.5 months (mean 1.5 months) after transplantation. Between the transplant patients with colonic complications and those without, there was no significant difference in age (39.7 v. 36.7 years), tissue match (mean HLA match 1.4 in each group), duration of hemodialysis before transplantation (approximately 15 months each) or duration of follow-up after transplantation (25.8 v. 22.9 months). All the patients in whom colonic complications developed were men except for the patient with appendicitis. Cigarette and alcohol use was comparable in the two groups, as was the distribution of blood types.

CMA JOURNAL/DECEMBER 9, 1978/VOL. 119 1301

Since all patients received five intravenous infusions of immunosuppressive medication in the first 3 weeks after transplantation and additional infusions during rejection episodes, the mean of 5.9 infusions from the time of transplantation until the development of complications in the group with colonic complications was not considered to be significantly different from the mean of 6.0 for the group without complications. Since the number of patients with each complication was small and complications occurred at various intervals after transplantation, it was impossible to isolate, for each complication, a control group with which to compare the total amount of steroid received. Colonic perforation Perforation, the most common previously reported colonic complication of renal transplantation, occurred in two of our patients. Case 1: A 50-year-old man known to have sigmoid diverticula before transplantation presented with fever, abdominal pain, a tender mass in the left lower quadrant and spreading peritonitis 2 months after transplantation. He had just received an infusion of immunosuppressive medication for threatened graft rejection. With the provisional diagnosis of diverticulitis with perforation the prednisone close was reduced to 15 mg/d, azathioprine was discontinued, and cephalothin and gentamicin were administered. Emergency laparotomy within 12 hours of onset of the acute symptoms revealed that feculent pus from a perforated parasigmoid abscess was disseminated throughout the pentoneal cavity, but the precise site of perforation could not be identified. A right transverse-loop colostomy and continuous postoperative pentoneal lavage with high-flow pentoneal dialysis solution were established.3 Peritoneal lavage was stopped on the third day of convalescence, but outflow sump drains were left in situ for a further 14 days. Antibiotics were discontinued by the 30th day. Allograft function was maintained throughout. The patient was discharged 54 days after the operation. Maintenance therapy consisted of prednisone, 15 mg/d. With prophylactic administration of cephalothin, elective resection

and end-to-end anastomosis of the sigmoid colon was performed 10 months later. The colostomy was closed without further difficulty an additional 2 months later. Case 2: A 33-year-old man with no known gastrointestinal disease was still in hospital 6 weeks after transplantation because of poor renal function. While he was receiving 40 mg of prednisone and 50 mg of azathioprine daily, midabdominal pain developed; it worsened over 4 hours and was exacerbated by movement. Examination disclosed a rigid abdomen, with no bowel sounds. The patient was afebrile. Free intraperitoneal air was demonstrated roentgenographically, and a provisional diagnosis of perforated peptic ulcer was made. Intravenous administration of gentamicin and clindamycin was started. The daily dose of prednisone was reduced to 15 mg and azathioprine was discontinued. At emergency laparotomy 9 hours after onset of the symptoms free intrapenitoneal feces and a perforation 6 cm in diameter in an otherwise healthy sigmoid colon were found. The abdominal cavity was irrigated and the involved portion of the sigmoid colon was exteriorized as a colostomy, then continuous postoperative lavage and drainage were established. Lavage was discontinued after 43 hours and the sump drain was removed on the eighth postoperative day. The patient went home and was readmitted 4 months later for elective closure of the colostomy; cephalothin, given systemically, was used prophylactically and the maintenance dose of prednisone was reduced from 25 to 7.5 mg/d. An abscess extending from the left subphrenic space along the left paracolic space towards the pelvis developed 3 months later and was incised and drained. The patient was taking prednisone, 75 mg/d, because of an acute rejection episode 5 days earlier. The daily dose of prednisone was reduced to 10 mg and azathioprine was discontinued for the next 12 days. Antibiotic therapy included penicillin, clindamycin and gentamicin. Feces began to drain from the drain site 3 weeks later. A fistulogram showed a tract to the previous colostomy closure site. Fecal drainage failed to diminish when the patient was given an elemental diet for 3

1302 CMA JOURNAL/DECEMBER 9, 1978/VOL. 119

weeks, and a proximal right transverse-loop colostomy was performed. The fistula was reduced to a sinus, which still opened into the colon 27 months later. Ischemic colitis This complication occurred preterminally in two patients. One, a 49-year-old man, presented with failing renal function, and overwhelming sepsis and pneumonia, which resulted in death 9 days later. During the 6 days prior to death, immunosuppressive medications were discontinued, and minor colonic bleeding occurred throughout the last 3 days. At autopsy the colonic mucosa showed superficial ischemic ulceration mainly on the right side, without large-vessel occlusion. The other patient who died, a 50-year-old man, also had sepsis and pneumonia. Azathioprine was discontinued and prednisone, 15 mg/d, was given for 17 days. After 1 month massive rectal bleeding occurred and the daily dose of prednisone was reduced to 50 mg. Sigmoidoscopic examination revealed no discrete bleeding lesion, and angiography showed patent colonic vessels with no identifiable bleeding point. Blood was transfused, but the patient died of sepsis and respiratory failure 7 days later. At autopsy the splenic flexure and descending colon showed ischemic colitis without perforation. In both of these cases life-threatening pneumonia precluded operative intervention. Both had minimal abdominal complaints, and in neither did ischemic colitis contribute significantly to death. A third patient had ischemic colitis after transplantation. In this 27year-old man left-sided abdominal pain and massive rectal bleeding developed 3 days after the fifth infusion of immunosuppressive medication. The daily dose of prednisone was immediately reduced to 20 mg and azathioprine was discontinued. The patient's condition deteriorated over the next 24 hours, and peritonitis developed. The descending and the sigmoid colon were edematous but viable, with good mesenteric flow. A right transverse-loop colostomy was performed to decrease colonic activity and increase blood flow in the compromised bowel. A second laparotomy 48 hours later showed diminution of edema, and recovery was uneventful.

Fecal impaction In one previously reported case4 fecal impaction in the right colon presented as small-bowel obstruction. The patient, a 28-year-old man, required repeated colonic lavage and enema administration in the first 3 weeks after transplantation. Normal bowel function returned after the antihypertensive agent clonidine hydrochloride was discontinued. The graft was rejected, but the patient remained well, without bowel complaints, and later underwent successful transplantation. Appendicitis A 43-year-old woman, receiving 15 mg of prednisone and 125 mg of azathioprine daily, presented with fever, nausea, vague abdominal discomfort, diffuse abdominal tenderness and a normal leukocyte count 20.5 months after renal transplantation. Diagnosis was delayed 24 hours because of diagnostic uncertainty; however, at laparotomy a perforated appendix was removed. The peritoneal cavity was irrigated and the skin and subcutaneous tissues were left open, without drains. Cephalothin and gentamicin were administered postoperatively. Following healing of a superficial wound infection, the skin was closed without complication. Discussion A classification of colonic complications following renal transplantation as derived from published reports is shown in Table II. From these reports the overall frequency of these complications was 2.3%, and the overall mortality 70%.

Perforation was the most frequently reported colonic problem following renal transplantation.1'1'9""2'16'0 In the reports reviewed by us1'1'7'1"8 colonic perforation occurred in 0.7% of 3084 cases of renal transplantation and the overall mortality was almost 90%; there were no survivors among the patients with nonoperatively treated or unrecognized perforation.1'9"0 Sigmoid diverticula, as in those not undergoing transplantation21 and in one of our patients, were the site of most (60%) of the perforations; no known underlying lesion was identified in most of the other cases of perforation, although in several instances perforation was probably due to unrecognized colonic injury at the time of transplantation."9'17 The patient with colonic perforation usually has fever, acute or chronic abdominal pain, and local or generalized peritonitis. In some cases rectal bleeding, abdominal distension or a change in bowel habit occurs. Less commonly, colonic perforation presents more subtly, with malaise, lethargy, encephalopathy or abnormal abdominal roentgenograms. Unfortunately, physical signs and symptoms are often masked by immunosuppressive therapy or by the presence of a tender renal allograft undergoing rejection. Most authors believe that immunosuppressive medications, particularly steroids, are an important factor in colonic perforation. Steroid therapy thins lymphoid tissue in the bowel, thus diminishing resistance to bacterial invasion,5"6 slows the turnover of mucosal cells,1 and decreases the reparative activity of fibroblasts.'8'. Colonic perforations have been found in patients treated systemically with

steroids who have not received a transplantY27 Once colonic perforation is diagnosed, immediate optimum treatment consists of reduction of the dose of immunosuppressive medications and intravenous administration of fluids and antibiotics. Prompt exteriorization of the perforation or resection of the perforated segment and creation of a double-barrelled colostomy was performed in our patients and in the few previously reported survivors.'0'16'17 Primary anastomosis must be avoided except when bowel preparation and elective resection of a local perforation in an uncontaminated field can be done.'0 High-volume peritoneal lavage may be beneficial in postoperative management.3"6 Unfortunately, even when these principles are adhered to, postoperative mortality is high. Prevention of colonic perforation in renal transplant recipients is the ideal. Because colonic diverticular disease probably predisposes to perforation after transplantation, we now believe it important to give a barium enema and obtain roentgenograms of the colon before transplantation. Prophylactic colon resection should be considered in selected cases when previous diverticulitis has been managed nonoperatively. Careful attention to bowel preparation before transplantation and bowel regularity after the operation is essential to avoid constipation and the risk of perforation. In the studies we reviewed, ischemic colitis occurred in 0.6% of 2434 cases of renal transplantation"5'7'9 and the mortality was more than 70%. As in our cases, approximately 50% of the reported cases

CMA JOURNAL/DECEMBER 9, 1978/VOL. 119 1303

occurred within 2 weeks after transplantation, and nearly 90% within 4 months. A number of factors may predispose renal transplant recipients to ischemic colitis. Persons with renal failure are subject to premature advanced atheromatous disease and are therefore predisposed to ischemic colitis.10 Many have heart failure, are being treated with digitalis and have relative intestinal hypoperfusion, which may be exacerbated during an operation.u Retroperitoneal dissection during renal transplantation may compromise colonic collateral circulation.. Precipitating factors in the early period after transplantation include hypotension, ileus-induced coIonic distension (resulting in reduced colonic blood flow) and decreased gut motility due to uremia and constipation. In some cases treatment of transplant rejection with increased immunosuppression has been followed by ischemic colitis.8'13 When such treatment includes irradiation of the transplanted kidney the possibility of colonic radiation injury exists, although the doses of radiation used are generally below the threshold for bowel injury.39 Finally, acute pancreatitis, which is reported to occur in about 2% of kidney transplant recipients,30 may be complicated by mesenteric thrombosis, with resultant ischemic colitis.31 In our cases of ischemic colitis none of these factors could be incriminated, and the cause remains unexplained. Clinical features of ischemic colitis include fever, abdominal distension, abdominal pain, rectal bleeding, which may be massive, diarrhea and occasionally paralytic ileus. Three radiologic views of the abdomen should be obtained, then a barium enema should be given so that characteristic features of ischemic colitis can be sought. Once the diagnosis of ischemic colitis has been made clinically and radiologically, close clinical observation, with repeated roentgenography as required, is mandatory. Angiography and colonoscopy may be helpful. A judicious operation, as in one of our cases and in other reported cases,6"5 may be lifesaving. As with colonic perforation, prevention is the ideal. Avoidance of hypotension during transplantation, in the early postoperative period and during postoperative hemodialysis is important.

Cation-exchange enemas have been causally linked to ischemic colitis by some observers,1' and should be avoided if possible. Two colonic complications not identified in our series are colonic ulceration and necrotizing or pseudomembranous enterocolitis. Together they have been reported in 0.5% of 2434 cases of renal transplantation and have been associated with a mortality of more than 90% *1,3,7-13,30 Colonic ulceration has been reported in association with cytomegalovirus infection in debilitated31 or immunosuppressed32 patients, although the importance of the virus in the occurrence of the ulceration is uncertain. In four reported cases of colonic ulceration after transplantation various organisms, including actinomyces,3 varicella virus,5 Candida10 and cytomegalovirus," were suspected as causative agents on the basis of histologic study of the ulcers post mortem. Simple isolated benign colonic ulcers in otherwise healthy patients, usually occurring in the cecum and diagnosed by the exclusion of other causes of colonic ulceration, have been recognized.. These ulcers, which are histologically similar to colonic ulcers occurring in patients with high concentrations of circulating adrenal corticosteroid hormones,3. usually cause hemorrhage or perforation. In one case hemorrhage from such a cecal ulcer after transplantation was controlled with a brief course of selective vasopressin infusion,3 but fatal cecal perforation occurred 1 month later. Most of the patients had deteriorating renal function and presented with colonic hemorrhage and diarrhea; the mortality was 100%. Aldrete and colleagues1' reported a case of ulcerative colitis first presenting after renal transplantation. The term enterocolitis as used here includes pseudomembranous enterocolitis and necrotizing enteritis. This entity presents with fever, abdominal distension and pain, and diarrhea, and sigmoidoscopic examination shows discrete white plaques overlying friable, superficially ulcerated mucosa. Pathologic specimens show pseudomembranes made up of necrotizing mucosal glands and blood cells enmeshed in fibrin, with an underlying superficial mucosal ulcer and submucosal edema.37 Enterocolitis has been noted following many types

1304 CMA JOURNAL/DECEMBER 9, 1978/VOL. 119

of operations, particularly abdominal procedures, and in nonoperative conditions such as uremia, malignant tumours, congestive heart failure with or without myocardial infarction, and chronic colonic obstruction.374 Drugs implicated in the development of pseudomembranous enterocolitis include clindamycin,41 ampicillin,43'43 tetracycline,43 chloramphenicol,43 lincomycin43'" and corti.costeroids. The pathologic changes are considered by most to be caused by gut ischemia,4347 although some disagree with this.40 For a number of reasons renal transplant recipients are at risk for enterocolitis. They receive antibiotic and steroid therapy, have uremia, undergo major operations and suffer the stresses of other complications such as hemorrhage from the upper gastrointestinal tract and sepsis.6 Once enterocolitis is diagnosed clinically and endoscopically, treatment consists of discontinuing antibiotics if possible and reducing greatly the daily steroid dose. The prognosis remains poor, however. Fecal impaction after renal transplantation is unusual in that it often affects the right colon.4'6'9 It may develop rapidly in the early period after transplantation9 or present as smallbowel obstruction,4'6 or be the culmination of chronic constipation.20 Clinical findings include abdominal distension and discomfort, as well as a change in bowel habit. Impaction has been related to inhibition of vagal motor activity secondary to uremia (which explains the peculiar anatomic distribution) and to use of nonabsorbable antacids (particularly magnesium and aluminum hydroxide gel with magnesium trisilicate),'3'46 immunosuppressive medications.' cationexchange . and antihypertensive medications.4 The risk of impaction is increased by inadequate preoperative bowel preparation, postoperative ileus, dehydration and bed rest. Proper treatment is necessary to prevent colonic perforation, and consists of early postoperative ambulation, adequate hydration, avoidance of obstipating medications and use of enemas or colonic lavage or both. In our patient, impaction resolved only after clonidine hydrochloride was discontinued.4 Operation is required to treat refractory . and colonic perforation.13

The final complication noted, acute appendicitis, has been sporadically reported in renal transplant recipients. These reports re-emphasize the dangers of infective or inflammatory lesions in patients whose immune response has been suppressed, for most of them describe preoperative progression to gangrene or perforation. Diagnosis is often difficult in the face of minimal or atypical symptoms and signs, and the condition is often confused with such entities as fecal impaction or the presence of a tender right renal allograft associated with graft rejection. Increased disability may result from delayed appendectomy, and further difficulties may occur secondary to poor healing of the appendiceal stump.1" Conclusion Serious colonic complications in renal transplant recipients must be considered grave, since they are not rare, are difficult to diagnose and treat, and are associated with high morbidity and mortality. There is considerable overlap in the clinical presentation of many of the complications, which makes correct diagnosis difficult. Diagnosis and treatment of these complications demands a high degree of suspicion, clinical acumen and cooperation between physician and surgeon. Prevention will assume greater importance as our knowledge of risk factors increases. We thank Drs. M. Johnson and M.B. Goldstein for permitting their patients to be included in this study. References 1. HADJIYANNAKIS EJ, EVANS DB, SMELLIE WAB, et al: Gastrointestinal complications after renal transplantation. Lancet 2: 781, 1971 2. KJELLSTRAND CM, SIMMONS RL, BUSELMEIER RJ, et al: Renal transplantation: recipient selection, medical management, and dialysis, in Transplantation, 1st ed, NAJARIAN JS, SIMMONS RL (eds), Lea & Febiger, Philadelphia, 1972, pp 418-45 3. Cuiuwi. DJ: Continuous peritoneal lavage. Surg Gynecol Obstet 135: 951, 1972 4. Bn.R R, STEER K: Pseudo-obstruction of the bowel due to clonidine. Br Med 1 1: 197, 1976 5. PENN I, BRETrSCHNEIDER L, SIMPSON K, et al: Major colonic problems in human homotransplant recipients.

Arch Surg 100: 61, 1970 6. PENN I, GROTH CG, BRETrSCHNEIDER L, et al: Surgically correctable intra-

abdominal complications before and after renal homotranspiantation. Ann Surg 168: 865, 1968 7. Powis SJA, BARNES AD, DAWSONEDWARDS P, Ct al: Ileocolonic problems after cadaveric renal transplantation. Br Med J 1: 99, 1972 8. ARVANITAKIS C, MALEK G, UEHLING

D, et al: Colonic complications after renal transplantation. Gastroenterology 64: 533, 1973 9. BERNSTEIN WC, NIVATVONGS 5, TALLENT MB: Colonic and rectal com-

plications of kidney transplantation in man. Dis Colon Rectum 16: 255, 1973 10. MISRA MK, PINKUS GS, BIRTCH AG,

et al: Major colonic diseases complicating renal transplantation. Surgery 73: 942, 1973

11. ALDRETE JS, STERLING WA, HATH-

AWAY BM, et al: Gastrointestinal and hepatic complications affecting patients with renal allografts. Am I

Surg 129: 115, 1975

12. JULIEN PJ, GOLDBERG HI, MARGULIS

AR, et al: Gastrointestinal complications following renal transplantation. Radiology 117: 37, 1975 13. AGUILO JJ, ZINCKE H, WooDs JE, et al: Intestinal perforation due to fecal impaction after renal transplantation. I Urol 116: 153, 1976 14. LEAPMAN SB, VIDNE BA, Burr KM, et al: Elective and emergency surgery in renal transplant patients. Ann Surg 183: 266, 1976 15. MARGOLIS DM, ETHERIDGE EE, GARZA.

GARZA R, et al: Ischemic bowel disease following bilateral nephrectomy or renal transplant. Surgery 82: 667, 1977 16. AARON KE, DAILEY TH: Survival after colonic perforation of a patient with a transplanted kidney. Report of a case. Dis Colon Rectum 17: 103, 1974 17. DELORIMIER AA, BELZER FO, KOUNTZ

SL, et al: Simultaneous bilateral nephrectomy and renal allotransplantation for bilateral Wilms' tumor. Surgery 64: 850, 1968 18. DEMLING RH, SALVATIERRA 0, BELZER

FO: Intestinal necrosis and perforation after renal transplantation. Arch Surg 110: 251, 1975 19. MATOLO NM, GARFINKLE SE, WOLFMAN EF JR: Intestinal necrosis and perforation in patients receiving immunosuppressive drugs. Am I Surg

132: 753, 1976 20. PETERSON R: Gastrointestinal abnormalities in renal homotransplant patients. I Can Assoc Radiol 27: 240, 1976 21. LozoN AA, DUFF JH: Acute perforation of the colon. Can I Surg 19: 48, 1976 22. CANTER JW, SHORn PE: Acute perforation of colonic diverticula associated with prolonged adrenocorticosteroid therapy. Am I Surg 121: 46, 1971 23. FEIN BT: Perforation and inflammation of diverticula of the colon sec-

ondary to long-term adrenocortico-

steroid therapy for bronchial asthma and pulmonary emphysema. South Med 1 54: 355, 1961 24. RENSH.AW TS, PHELPS DB: Perforation of colonic diverticula. A lifethreatening postoperative complication in patients receiving long-term corticosteroid therapy. I Bone Joint Surg [Am] 54: 1070, 1972 25. STERIOFF 5, ORRINGER MB, CAMERON

JL: Colon perforation associated with steroid therapy. Surgery 75: 56, 1974 26. WARSHAw AL, WELCH JP, OTTINGER LW: Acute perforation of the colon associated with chronic corticosteroid therapy. Am J Surg 131: 442, 1976 27. FERRER MI, BRADLEY SE, WHEELER HO, et al: The effect of digoxin in

the splanchnic circulation in ventricular failure. Circulation 32: 524, 1965

28. PERLOFF U, CHON H, PETRELLA EJ, et al: Acute colitis in renal allograft

recipient. Ann Surg 183: 77, 1976 29. GILLIEs M, SKYRING A: Gastrointestinal complications of radiotherapy.

Australas Radiol 11: 254, 1967 30. JOHNSON WC, NABSETH DC: Pancreatitis in renal transplantation. Ann Surg

171: 309, 1970 31. WOLFE BM, CHERRY JD: Hemorrhage

from cecal ulcers of cytomegalovirus infection: report of a case. Ann Surg

177: 490, 1973 32. SIMMONS RL, LoPEZ C, BALFOUR H

JR, et al: Cytomegalovirus: clinical virological correlations in renal transplant recipients. Ann Surg 180: 623,

1974 33. SMITHWICK W us, ANDERSON RP, BALLINGER WF is: Nonspecific ulcer of

the colon. Arch Surg 97: 133, 1968 34. BARRON ME: Simple nonspecific ulcer of the colon. Arch Surg 17: 355, 1928

35. SAUTTER RD, ZIFFREN SE: Adrenocortical steroid therapy resulting in unusual gastrointestinal complications.

Arch Surg 79: 346, 1959 36. SUTHERLAND D, FRECH RS, WElL R, et al: The bleeding cecal ulcer: pathogenesis, angiographic diagnosis, and nonoperative control. Surgery 71: 290,

1972 37. BIRNBAUM D, LAUFER A, FREUND M: Pseudomembranous enterocolitis; a clinicopathologic study. Gastroenterol-

ogy 41: 345, 1961 38. JAFFE RH, LAING DR: Changes of the digestive tract in uremia; patho-

logic anatomic study. Arch intern Med 53: 851, 1934 39. MASON EE: Gastrointestinal lesions

occurring in uremia. Ann Intern Med

37: 96, 1952

40. GOULSTON

SJM,

MCGOVERN

VJ:

Pseudo-membranous colitis. Gut 6: 207, 1965

41. TEDESCO FJ, BARTON RW, ALPERS

DH: Clindamycin-associated colitis: a

prospective study. Ann Intern Med 81:

429, 1974 42. KEATING JP, FRANK AL, BARTON LL,

et al: Pseudomembranous colitis associated with ampicillin therapy. Am I Dis Child 128: 369, 1974

continued on page 1309

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Ludiom Il® ..de 6. GANT NF, MADDEN JD, CHAND S, et al: Metabolic clearance rate of dehydroisoandrosterone sulfate. 6. Studies of eclampsia. Ibid, p 327 7. SINGLEY T, MADDEN JD, CHAND 5, et al: Metabolic clearance rate of dehydroisoandrosterone sulfate. 7. Effect of lateral versus supine recumbency. Ibid, p 419 8. B.LISLE

S,

OSATHANONDH

R,

TUL-

CHINSKY D: The effect of constant infusion of unlabeled dehydroepiandrosterone sulfate on maternal plasma androgens and estrogens. J Gun Endocrinol Metab 45: 544, 1977 9. MADDEN JD, SIITERI PK, MACDONALD PC, et al: The pattern and rates of metabolism of maternal plasma dehydroisoandrosterone sulfate in human pregnancy. Am J Obstet Gynecol 125: 915, 1976 10. MACDONALD PC, GANT NF, PORTER JC: Relationship of placental blood flow to the placental clearance of maternal plasma dehydroisoandrosterone sulfate (DS) through estradiol (PC-DSE2) (abstr 135). Gynecol Invest 8: 90, 1977 11. KELLER PJ, BAERTSCHI U, BADER P, et al: Biochemical detection of fetoplacental distress in risk pregnancies. Lancet 2: 729, 1971 12. GUMMERUS M: The DHEA-S loading test in the evaluation of fetoplacental

function. Acta Obstet Gynecol Scand 53: 319, 1974 13. STRECKER JR, LAURITZEN C: Load-test for fetoplacental function with DHEAS and determination of plasma by radioimmunoassay. Acta Endocrinol [Suppi] (Kbh) 184: 159, 1974 14. KUNZUG HJ, GEIGER W, GWUZDZ P: Effect of DHEA-S on the plasma level of estrone, estradiol- 1713, and estriol in the last trimester of pregnancy. Ibid, p 160 15. FRASER IS, LEASK R, DRIFE J, et al: Plasma oestrogen levels following intravenous injection of dehydroepiandrosterone sulphate in the third trimes-

ter of pregnancy. Br J Obstet Gynaecol 82: 252, 1975 16. KLOPPER A, JANDIAL V: The conver-

sion of dehydroepiandrosterone to estrogen: a dynamic placental function test. Eur J Obstet Gynecol Reprod Biol 5: 93, 1975 17. KORDA AR, CHALLIS JJ, ANDERSON

ABM, et al: Assessment of placental function in normal and pathological pregnancies by estimation of plasma oestradiol levels after injection of dehydroepiandrosterone sulphate. Br J Obstet Gynaecol 82: 656, 1975 18. KLOPPER A, VARELA-TORRES R, JAN-

DIAL V: Placental metabolism of dehydroepiandrosterone sulphate in normal pregnancy. Br I Obstet Gynaecol 83: 478, 1976 19. TULCHINSKY

D,

OSATHANONDH

R,

FINN A: Dehydroepiandrosterone sulphate loading test in the diagnosis of complicated pregnancies. N Engi J Med 294: 517, 1976 20. TABET T, HEINRICHS WL: Diagnosis of placental sulfatase deficiency. Am J Obstet Gynecol 124: 409, 1976

Brief prescribing information. Indications Endogenous depressive illness, including the depressed phsse 21. OSATHANONDH R, CANICK 5, RYAN KS, of manic-depressive illness (bipolar depression) and et al: Placental sulfatase deficiency: a involutional melancholia Selected patients suffering depressive neurosis. Contraindicatlons case study. I Clin Endocrinol Metab severe Ludiomil (maprotiline) should not be used concom43: 208, 1976 itantly with monoamine oxidase inhibitors; at least fourteen days should elapse between discontinuing 22. HENSLEIGH PA, TULCHINSKY D, FAINone of the interacting drugs and replacing it with the STAT T: Antepartum identification of other. Ludiomil is contraindicated in patients with existing severe hepatic or renal damage, a history of fetal adrenal hypoplasia (abstr 19). severe blood dyscrasias, narrow angle glaucoma, conPresent. au 25. congr.s annuel de Ia vulsive disorders and during the acute recovery phase myocardial infarction. Not recommended for Society for Gynecologic Investigation, following use in children. Use in Pregnancy Safe use of Ludiomil during pregnancy and lactation has not been estabAtlanta, Ga, le 15 au 18 mars, 1978 lishe therefore, it should not be administered to 23. THOUMSIN H: Exploration Dynamique women of childbearing potential or nursing mothers unless the benefits outweigh the possible hazards. par le Test au DHEA-S de la Produc- Warnings Extreme caution should be used when tion Oestrog.nique au Cours de jije Ludiomil (maprotiline) is given to patients with known cardiovascular disease including a history of myocarTrirnestre de la Gestation. Applications dial infarction, arrhythmias and/or ischemic heart Cliniques et Modalit.s d'lnterpr.tation, disease. Use with caution in hyperthyroid patients or on thyroid medication, and in patients with a these de doctorat, universit. de Liege, those history of urinary retention, particularly in the pres1977 ence of prostatic hypertrophy. Close supervision and careful adjustment of dosage is required when administering Ludiomil with anticholinergic or sympathomimetic drugs. Patients requiring concomitant treatGASTROINTESTINAL ment for hypertension should not be given antihyperCOMPLICATIONS tensives of the adrenergic-neurone inhibitor type, such as guanethidine. Activation of psychosis in schizophrenic patients, hypomanic or manic episodes continued from page 1305 in patients with cyclic disorders have occurred with 43. SCRAPIRO RL, NEWMAN A: Acute en- tricyclic antidepressants. The use of an antipsychotic drug these latter two conditions is recommended terocolitis. A complication of anti- shouldin they occur in the course of Ludiomil adminisbiotic therapy. Radiology 108: 263, tration. Precautions Seriously depressed patients must carefully be supervised due to the possibility of 1973 suicide. Patients should be warned that their reto alcoholic beverages or other CNS depres44. MARTIN EW: Serious gastrointestinal sponses sants may be exaggerated. Patients should also be toxicity due to clindamycin and linco- cautioned against performing potentially dangerous tasks that require mental alertness and good physical mycin. FDA Drug Bull Jan-Mar 1975, coordination. Periodic blood cell counts and liver p2 function tests are recommended with prolonged Prior to elective surgery, Ludiomil should be 45. MARSTON A: The bowel in shock. The therapy. discontinued for as long a period as clinically feasible. role of mesenteric arterial disease as Adverse reactions The following adverse reactions have reported either with Ludiomil or the tria cause of death in the elderly. Lancet cyclic been antidepressant drugs: Neurological: numbness, 2: 365, 1962 tingling, paresthesias of extremities, incoordination, ataxia, tremors, peripheral neuropathy, extrapyramidal 46. MORSON BC, DAWSON IMP: Vascular symptoms, seizures, alteration in EEG patterns, disorders, in Gastrointestinal Pathol- nitus. Behavioral: confusional states (especially in tinthe elderly) with hallucinations, disorientation, delusions; ogy, Blackwell, London, 1972, p 339 anxiety, restlessness, agitation, insomnia and night47. PENNER A, BERNHEIM Al: Acute post- mares, hypomania, mania, exacerbation of psychosis, decrease in memory, feelings of unreality, weakness operative enterocolitis: a study on the and fatigue, drowsiness, dizziness, urinary frequency. dry mouth and, rarely, associated subpathologic nature of shock. Arch Autonomic: lingual adenitis; blurred vision, disturbances of acPathol 27: 966, 1939 commodation, mydriasis; constipation; paralytic ileus; urinary retention, delayed micturition, dilation of the 48. BRETTSCHNEIDER L, MONAFO W, Ostract, perspiration, flushing. Cardiovascular: BORNE DP: Intestinal obstruction due urinary hypotension, hypertension, congestive heart failure, palpitation, myocardial infarction, arto antacid gels: complication of med- tachycardia, rhythmias, block, stroke and syncope. Hematoical therapy for gastrointestinal bleed- logic: boneheart marrow depression including agranulocytosis, eosinophilia, purpura and thrombocytopenia ing. Gastroenterology 49: 291, 1965 may occur as an idiosyncratic response. 49. HOLMES XX: in Experience in Renal and differential counts should be performedLeukocyte in any patient who develops fever and sore throat during the Transplantation, STARZL TE (ed), therapy; the drug should be discontinued if there is Saunders, Philadelphia, 1964, p 24 evidence of pathological neutrophil depression. Gastrointestinal: nausea or vomiting, anorexia, epigastric distress, diarrhea, bitter taste, stomatitis, abdominal cramps, black tongue, dysphagia, increased salivation, altered liver function. Endocrine: gynecomastia in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, impotence, testicular swelling, elevation or depression of blood sugar levels, weight gain or loss. This list is an acknowledgement of Allergic or toxic: skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive exposure to books received. It does not precllude sunlight); edema (general or of face and tongue); drug review at a later date. fever, obstructive jaundice, nasal congestion. Dosage Adults Outpatients: initially 25 mg t.i.d., may be inin increments of 25-50 m. to a maximum of 50 BASIC PHARMACOLOGY IN MEDICINE. creased mg q.i.d. Hospital patients: initially 50 m g b.i.d. or Edited by Joseph R. DiPalma. 420 pp. t.i.d., may be increased in increments of 25-50 mg to a Illust. McGraw-Hill Book Company, New maximum of 300 mg daily. Elderly patients: generally mg t.i.d. or qid. Maintenance: dosage may be York; McGraw-Hill Ryerson Limited, 25 gradually reduced 75 mg daily or less. A single daily Scarborough, Ont., 1976. $21.60. ISBN dose of 75 mg to to 150 mg at bedtime can be given by virtue of the long half-life of Ludiomil. This would en0-07-01701 0-X sure better patient compliance and may obviate the need for hypnotics. Supplied Tablets containing BLAKISTON'S GOULD MEDICAL DIC- maprotiline hydrochloride, film coated, slightly biconTIONARY. 3rd ed. Arthur Osol, chairman vex: 25 mg, light orange marked CIBA one side and DP of the editorial board. 1828 pp. Illust. on other; 50 mg, orange marked CIBA on one side and ER on other; 75 mg, coral, scored, marked CIBA on one McGraw-Hill Book Company, New York; side and FS on other. Bottles of 50 and 500 tablets. McGraw-Hill Ryerson Limited, Scarbo- Product Monograph supplied on request. References rough, Ont., 1972. $27.60. ISBN 0-07- 1. Trick, KL.K.: Double-Blind Comparison of Maprotiline (Ludiomil5) with Amitriptyline in the Treat005683-8 ment of Depressive Illness. J. mt. Med. Research, Vol. 3, Suppl. 2,1975. Edited by J.E. Murphy, Cambridge CARE FOR THE INJURED CHILD. The Medical Publications Ltd., England. pp. 67-70 2. Surgical Staff. The Hospital for Sick Mathur, G.N.: A Double-Blind Coin parat lye Clinical of Maprotiline (Ludiomil5) and Amitriptyline. J. Children, Toronto, Canada. 444 pp. Illust. Trial mt. Med. Research, Vol. 3, Suppl. 2,1975. Edited by The Williams & Wilkins Company, Balti- J.E. Murphy, Cambrid9e Publications Ltd., more, Maryland; Burns & MacEachern England. pp. 71-743. Singh,Medical A.N., Saxena, B.: Maproti(Ludiomil,5 CIBA 34,276-BA) and Imipramine in Limited, Don Mills, Ont., 1975. $35.50. line Depressed Outpatients: A Double-Blind Clinical ISBN 0-683-08025-3 Study. Current Therapeutic Research, Vol. 19, No. 4, April, 1976.4. Product Monograph-Ludiomil5 continued on page 1314

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Gastrointestinal complications of renal transplantation. 2. The colon.

Gastrointestinal complications of renal transplantation. 2. The colon STUART D. ARCHIBALD, MD, FRCS[C]; DENNIS W. JIRSCH, MD, M SC, PH D, FRCS[C]; ROB...
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