Gastrointestinal Complications After Cardiac Transplantation Potential Benefit ofEarly Diagnoses and Prompt Surgical Intervention
J. K. KIRKLIN, M.D., A. HOLM, M.D., J. S. ALDRETE, M.D., C. WHITE, R.N., and R. C. BOURGE, M.D.
Acute gastrointestinal (GI) illnesses are unusual but potentially fatal complications following cardiac transplantation. A retrospective study was performed to analyze the frequency, etiology, and severity of GI complications and the potential impact of early diagnosis and prompt surgical intervention when appropriate. Between 1981 and July 1, 1988, 31 GI complications (pancreatic, 6; colonic, 6; gastroduodenal, 6; biliary, 5; esophageal, 3; appendical, 2; hernia, 2; and splenic, 1) occurred in 26 patients undergoing 32 cardiac transplants. Complications were most common (14 of 31 patients, 45%) within the first 30 days after transplantation. Seventeen GI complications were treated medically (2 deaths), 2 with elective surgery and 12 with emergent operations (3 deaths). The overall mortality rate was 16%. All patients who underwent emergent operations within 3 days of onset of symptoms survived; the mean interval of onset between symptoms and operation in the nonsurvivors was 10 ± 3.8 days. We infer that among patients requiring urgent surgical intervention, successful outcome is enhanced by intense surveillance for early symptoms, prompt diagnostic evaluation, and early surgical intervention.
From the University of Alabama at Birmingham, Birmingham, Alabama
abama at Birmingham. During this period, 31 major GI complications occurred in 26 patients undergoing 32 cardiac transplants. There were 21 men and 5 women with an age range of 21 to 64 years (median, 44 years). Twentyfive patients underwent orthotopic cardiac transplantation and one patient had heterotopic transplantation. Five patients underwent a second transplant and one a third. Although the first 17 patients in this experience received only azathioprine and prednisone to maintain immunosuppression, all patients experiencing major GI complications received cyclosporine and prednisone, with or without azathioprine. All hospital and outpatient records were reviewed and all potential GI complications were identified. A major GI complication was defined as any gastrointestinal illness that required hospitalization and specific medical or surgical treatment. Simple diarrhea and/or gastroenteritis were excluded. The usual statistical methods were used to determine the likelihood that differences were due to chance.
A CUTE GASTROINTESTINAL (GI) illnesses are unusual but potentially fatal complications following cardiac transplantation, particularly when surgical intervention is required." A high mortality rate has generally been attributed to the need for emergent abdominal surgery after cardiac transplantation.' To investigate the frequency, etiology, and severity of GI complications and the potential impact of early diagnosis of intra-abdominal disease and prompt surgical intervention when appropriate, a retrospective analysis was performed.
Timing of GI Complications The GI complications occurred at a median of 58 days after cardiac transplantation (range, 1 day to 3.6 years). Complications were most common (14 of 31 complications, 45%) within the first 30 days after transplantation. Fifty per cent occurred within 2 months of transplantation and 75% occurred by 1 year (Fig. 1).
Materials and Methods Between 1981 and July, 1988, 151 patients underwent 169 cardiac transplant operations at the University of AlPresented at the 101st Annual Meeting of the Southern Surgical Association, Hot Springs, Virginia, December 3-6, 1989. Address reprint requests to J. K. Kirklin, M.D., University of Alabama at Birmingham, Department of Surgery, 739 Zeigler Bldg., UAB Station, Birmingham, AL 35294. Accepted for publication December 28, 1989.
Associated Morbid Events The most frequent associated morbid event was acute allograft rejection. A total of 241 treated rejection episodes
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days or a treated rejection episode, or both) was present in 58% (18 of 31) of GI complications. In 13% (4 of 31) of GI complications there was a major infectious episode in the preceding 30 days.
Percentile Interval (days) 4 10% 12 25% 58 50% 331 75% 90% 658
Interval (days) from Transplant to GI Complication
FIG. 1. Frequency distribution curve for GI complications (n = 31) after cardiac transplantation (UAB; 1981-July 1988). The curve depicts the percentage of patients whose interval from transplant to complication was < the stated interval in days.
occurred during the study period, of which 4% (10 of 241 episodes) were associated with a subsequent GI complication within 30 days. Thirty-two per cent (10 of 31) of the GI complications had an associated rejection episode within the preceding 30 days. Recent augmented immunosuppression (either by transplantation within 30 TABLE 1. Gl Complications After Cardiac Transplantation: UAB, 1981 to July, 1988
Surgical Rx Medical
Appendical Appendicitis Carcinoid with perforation Biliary Cholecystitis Cholangitis Colonic Cecal volvulus CMV colitis Diverticulitis Pseudomembranous colitis Pseudoobstruction Toxic megacolon Esophagitis Hernia Diaphragmatic Umbilical Pancreatitis Gastroduodenal Bleeding duodenal ulcer Bleeding gastritis Gastritis Perforated duodenal ulcer Spleen Infarct Total
GI COMPLICATIONS AFTER CARDIAC TRANSPLANTATION
The overall mortality related to a GI complication was 16% (5. of 31 complications; 70% Confidence Limits, 9% to 26%) (Table 1). The mortality rate was similar in patients undergoing medical treatment (2 of 17 patients, 12%) and surgical therapy (3 of 14 patients, 21%)(p = 0.4). The two deaths in the medically treated group occurred in patients suffering from profound low cardiac output. One patient developed intermittent upper GI bleeding and the other acute hemorrhagic pancreatitis. The three deaths in the group undergoing emergent surgical therapy were all associated with multisystem failure.
Interval from Onset of Symptoms to Emergent Surgical Intervention Among patients undergoing emergent surgical intervention for a GI complication (Table 2), the interval from the onset of GI symptoms to emergent surgery was considerably shorter in surviving patients compared to nonsurviving patients (1.1 ± 0.48 days vs. 10 ± 3.8 days, p = 0.0005). All but two surviving patients received prompt surgical intervention within 48 hours of the development of symptoms. In contrast, two of three nonsurviving patients had a delay in excess of 10 days before surgical intervention (Table 3).
TABLE 2. Emergent Operations for GI Complications: UAB, 1981 to July 1988
1 1 1 1 1 (1)
3 1 4 (1)
Appendical perforation (carcinoid) Appendicitis Bleeding duodenal ulcer Cecal volvulus
Cholangitis 1 2 (1) I
1 (1) 1 2
1 17 (2)
Numbers in parentheses indicate deaths associated with the complication. UAB, University of Alabama.
Cholecystitis Necrotizing pancreatitis Necrotizing pancreatitis Perforated duodenal ulcer Toxic megacolon *
Appendectomy Appendectomy Oversewing of ulcer,* vagotomy and plyoroplasty Cecal resection Peracutaneous biliary decompression followed by cholecystectomy and choledochoduodenostomy Cholecystectomy 85% pancreatectomy,t gastrostomy, jejunostosomy, extensive drainage Debridement and drainage Omentopexyt Subtotal colectomyt
Patient died after subsequent GI complication.
t Death associated with this complication.
UAB, University of Alabama.
KIRKLIN AND OTHERS
TABLE 3. GI Complications After Cardic Transplantation Emergent Surgical Therapy (n = 12): UAB, 1981 to July 1988 Interval (Days) Between Onset of Symptoms and Operation
Complication Cholecystitis Cholangitis* Bleeding ulcert Appendicitis Cecal volvulus Necrotizing pancreatitis
Perforated ulcer Toxic megacolon
0 0 3 4 0 1 0
4 13 13
Rejection Rejection Multisystem failure Multisystem failure Multisystem failure
* Percutaneous biliary decompression followed by elective cholecystectomy and choledochoduodenostomy. t Patient died after subsequent GI complications.
Discussion Acute gastrointestinal complications after cardiac surgery without immunosuppression are rare (less than 1% requiring operation),5 but the reported operative mortality rate has been as high as 40%.5 In this setting the development of such complications as pancreatitis, GI bleeding, ischemic bowel, and acute cholecystitis are likely to be, in part, related to acute cardiac dysfunction and low cardiac output during the early period following operation.5 Patients who develop profound acute cardiac failure after cardiac transplantation, occasionally complicated by multisystem dysfunction, appear particularly vulnerable to the development of lethal gastrointestinal complications. In the experience reported here, all five fatalities related to gastrointestinal complications occurred in the setting of profound cardiac failure, often with multisystem
dysfunction. The obligatory immunosuppression required for transplantation appears to provide an additional milieu for the development of serious gastrointestinal complications.6-'0 The deleterious effects of steroids, azathio-
prine,6'7 and cyclosporine' have been implicated in the predisposition to GI complications. As noted in this experience, patients following renal transplantation appear to be particularly vulnerable to GI complications after a period of augmented immunosuppression for the treatment of acute allograft rejection.6'7 In the presence of lifethreatening GI complications after renal transplantation, immediate decrease in steroid dosage and cessation of azathioprine have been recommended, along with appropriate medical and prompt surgical therapy, as the critical therapeutic maneuvers to provide the maximal chance for survival.6 Unfortunately after cardiac transplantation,
Ann. Surg. - May 1990
massive reduction of immunosuppression is not a realistic option when GI complications develop because there is no effective support technique, such as renal dialysis, available for irreversible cardiac rejection. Thus the GI medical and surgical teams must be able to effectively manage these complications without major reduction in immunosuppressive therapy. Complications of gastroduodenal ulceration, pancreatitis, acute biliary pathology, and colonic disease were most frequently encountered in this experience. The wellknown association of chronic steroid therapy and gastroduodenal ulcerations may contribute to upper GI bleeding or ulcer perforation."7 Cytomegalovirus may be an etiologic factor in acute perforation of upper gastrointestinal ulcerations.' Pancreatitis has been described as an important complication of renal7 and cardiac transplantation.4"I In the azathioprine era of renal transplantation, acute pancreatitis was associated with a reported mortality rate of 50%. " The pathogenesis of steroid-related pancreatitis is unclear, but a mechanism of vascular occlusion similar to avascular necrosis of bones in the presence of chronic steroid therapy has been suggested.4" 2 Pancreatitis has been temporally associated with augmentation of steroid therapy,'3 azathioprine therapy,'4"15 and cytomegalovirus infection.'6"17 Cholelithiasis and acute cholecystitis or cholangitis has been reported following cardiac transplantation,l and cyclosporine therapy may contribute to gallstone formation.'8 Colonic complications in the immunosuppressed patient," 6 occasionally with perforation, have been associated with steroid therapy, cytomegalovirus, 1920 and lymphoproliferative disorders.2'2 Our analysis suggests that survival following major gastrointestinal complications after cardiac transplantation is favorably influenced by prompt diagnosis and early surgical intervention. There is often a tendency to procrastinate in the preoperative surgical decision making of this complex and often critically ill group of patients. Delay, we believe, is rarely advised and often fatal. An aggressive policy of early surgical intervention has also been recommended by Steed and colleagues,' Nghiem,6 and others. The chances for survival appear greatest when GI operations have been performed within 48 hours of the onset of symptoms.
Inferences From this analysis, we would make the following inferences: * Major GI complications occur most frequently during the first post-transplant month after cardiac transplantation and are often associated with other morbid events that may mask subtle signs of GI pathology. * With early diagnosis and prompt therapy, mortality rates are low.
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GI COMPLICATIONS AFTER CA RDIAC TRANSPLANTATION
* Among patients requiring urgent surgical intervention, successful outcome is enhanced by intense surveillance for early symptoms, prompt diagnostic evaluation, and early surgical intervention (usually within 48 hours), even in the presence of acute cardiac or multisystem dysfunc-
tion. References 1. Steed DL, Brown B, Reilly JJ, et al. General surgical complications in heart and heart-lung transplantation. Heart and Heart Lung Transplantation 1985; 98:739-745. 2. Oaks TE, Pennock JL, Myers JL, Wisman CB. Survival following rupture of a pancreatic abscess in a heart transplant recipient. J Heart Transplant 1986; 5:148-53. 3. Sinnott JT, Cullison JP, Rogers K. Treatment of cytomegalovirus gastrointestinal ulceration in a heart transplant patient. J Heart Transplant 1987; 6:186-8. 4. Aziz S, Bergdahl L, Baldwin JC, et al. Pancreatitis after cardiac and
cardiopulmonary transplantation. Surgery 1985; 97:653-660. 5. Aranha GV, Pickleman J, Pifarre R, et al. The reasons for gastrointestinal consultation after cardiac surgery. Am Surg 1984; 50: 301-304. 6. Nghiem DD, Corry RJ. Colorectal perforation in renal transplant recipients. Am Surg 1983; 45:554-557. 7. Aldrete JS, Sterling WA, Hathaway BM, et al. Gastrointestinal and hepatic complications affecting patients with renal allografts. Am J Surg 1975; 129:115-124. 8. Faro ES, Corry RJ. Management of surgical gastrointestinal complications in renal transplant recipient. Arch Surg 1979; 114310-12.
DISCUSSION DR. HUNTER MCGuIRE, JR. (Richmond, Virginia): Our VA hospital in Richmond has done 193 heart transplants and only five have required surgery for acute GI complications. There were two patients with colon perforation who survived, two cases of severe pancreatitis with one fatal abscess, and one small bowel infarct patient who died of a stroke. About a dozen patients have returned for readmission for elective cholecystectomies and they have behaved like any other uncomplicated cholecystectomies in young, healthy patients. We agree with Dr. Aldrette, as we always do, and join him in urging general surgeons to have no reticence or fear of doing the right operation at the right time in patients who have had heart transplants. Except in the very rare case of acute rejection, these patients have ASA class I hearts and they do remarkably well if treated quickly and correctly. DR. ROBERT MENTZER (Buffalo, New York): I would like to compliment Dr. Aldrete and his colleagues on a fine presentation and for bringing to our attention the observation that nongastrointestinal morbid events in heart transplant patients may mask GI pathology and early diagnosis and treatment may lower the mortality. Like other medical centers, we recognize that, although GI complications occur infrequently after open heart surgery, such complications can be lethal. At our own institution in the past year and a half, 25 of 1686 (or 1.5%) of the patients who underwent coronary bypass surgery developed significant GI complications. Among those who underwent GI surgery, the mortality rate was eight times greater than what we would have predicted for patients without heart disease. Because cardiac transplantation is associated with an even higher GI-related mortality rate, we decided to test the hypothesis that
9. Hubbard SG, Riving BA, Lucas BA, et al. Acute abdomen in the transplant patient. Am Surg 1980; 46:116-120. 10. Merrell SW, Scott AA, Nelson EW, et al. Major abdominal complications following cardiac transplantation. Arch Surg 1989; 124: 889-894. 11. Johnson WC, Nabseth DC. Pancreatitis in renal transplantation. Ann Surg 1970; 171:301-313. 12. Briggs WA, Hampers CL, Merrill JP, et al. Aseptic necrosis in the femur after renal transplantation. Ann Surg 1972; 175:282-289. 13. Corrodi P, Knoblauch M, Binswanger U, et al. Pancreatitis after renal transplantation. Gut 1975; 16:285-289. 14. Broe PJ, Cameron JL. Azathioprine and acute pancreatitis. Studies with an isolated perfused canine pancreas. J Surg Res 1983; 34: 159-163. 15. Nogueira JR, Freedman MA. Acute pancreatitis as a complication of Imuran therapy in regional enteritis. Gastroenterology 1972; 62:1040-1041. 16. Tilney NL, Collins JJ Jr, Wilson RE. Hemorrhagic pancreatitis, a fatal complication of renal transplantation. N Engl J Med 1966; 274:1051. 17. Case records of the Massachusetts General Hospital. Case 15, 1973. N Engl J Med 1974; 288:780. 18. Kahan BD, VanBuren CT, Flechners S, et al. Clinical and experimental studies using cyclosporine in renal transplantation. Surgery 1985; 97:125. 19. Bramwell NH, Davies RA, Koshal A, et al. Fatal gastrointestinal hemorrhage caused by cytomegalovirus duodenitis and ulceration after heart transplantation. J Heart Transplant 1987; 6:303-306. 20. Sinnott JT, Cullison JP, Rogers K. Treatment of cytomegalovirus gastrointestinal ulceration in a heart transplant patient. J Heart Transplant 1987; 6:186-188. 21. Starzl TE, Porter KA, Iwatsuki S, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporinsteroid therapy. Lancet 1984; 1:583-587.
these complications may be related to a low flow state and that heart transplant patients are actually at a lower risk of developing GI complications when compared to patients with advanced cardiomyopathy. To date we have studied 127 patients with severe cardiomyopathy who were referred for transplantation and 31 who underwent transplantation during the same time period. Patients were identified as having significant GI disease if they had signs and symptoms, laboratory, radiographic, or endoscopic confirmation, or if they were surgically treated for a GI problem. As you can see from this slide, while the incidence of significant GI complications in the transplanted group was high, the overall incidence of pancreaticobiliary and gastric duodenal complications in the transplant cohort was significantly less than in the pretransplant group. What is not shown on this slide is that the transplant patients seemed to have a lower mortality rate associated with GI operations. We interpret these data to suggest that low cardiac output is indeed the underlying mechanism responsible for many of these complications. The questions I would like to ask Dr. Aldrete's group are: (1) do you have any evidence that a low flow state associated with prolonged cardiopulmonary bypass occurred in any of your patients? (2) Do you have any evidence that the patients who sustained rejection manifested a significant reduction in cardiac output? (3) And finally, because a number of transplant patients in your study did have biliary complications, would you comment on the reliability of using HIDA scans and ultrasonography in patients who were NPO and who had gastrointestinal problems? DR. HILLIARD F. SEIGLER (Durham, North Carolina): A number of years ago we looked at this question concerning renal allograft recipients and found that the GI complications were, for the most part, steroid driven. We had the appropriate donor recipient combinations for evaluation, which, of course, you won't have in heart transplants in that we had living related donor recipient pairs that had no steroids to compare. We found that when we analyzed all groups the most significant variable