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An Analysis of the Long-Term Complications of Intestine Transplant Recipients

Posted on: Thursday, 23 December 2004, 03:01 CST

Background-One-year survival rates for intestine transplant recipients have increased to 70%, but it is believed that the complications following the procedure do not diminish after the first year as is seen in other forms of solid-organ transplantation.

Objective-To review the ongoing medical requirements of an increasing number of long-term survivors of intestinal transplantation.

Method-A retrospective medical chart review was completed on all patients who received intestinal transplantation at the University of Nebraska Medical Center from September 1990 through March 2003. One hundred forty-six transplantations were performed on 128 patients-53 intestinal, 70 liver/intestinal, and 23 intestinal with liver and pancreas or kidney.

Results-Seventy-six patients survived longer than 365 days and form the study group. Major reasons for readmissions were infections, gastrointestinal complications, dehydration, and rejection. The average number of rehospitalizations per patient per year remained constant. Death in patients with more than 365 days survival (N=23) was the result of sepsis (56%) and multiple other complications (44%).

Conclusion-The number of readmissions each year per patient remains constant and medical problems remain complex and life threatening. Patients with intestinal transplantation will continue to require regular expert follow-up care and careful attention to even the smallest medical problem even years following transplantation. (Progress in Transplantation. 2004; 14:277-282)

In the early 1990s, long-term survival following intestinal transplantation was rare and there were few reports documenting these patients in the literature.12 Throughout the last decade, long- term survival rates continued to improve and intestinal transplantation has become an established therapy for patients with life-threatening complications of intestinal failure.15 Overall, long-term survival is reported at approximately 50%; however, since 1995, advances in surgical technique, clinical skill, and immunosuppressive therapy have improved 1 -year patient survival to more than 70% in most experienced centers.5,6 Thus, intestinal transplant center professionals find themselves dealing with progressively increasing numbers of long-term survivors of intestinal transplantation. There are several reports examining the perceived improvement of quality of life of these patients.7,8 Several articles quote survival rates and provide outcome statistics at 1,3, 5, and even 10 years after transplantation. These documents have little detail concerning the cause of death or the ongoing medical requirements of long-term survivors of intestinal transplantation.1,3,4,9

Follow-up of long-term survivors of intestinal transplantations at the University of Nebraska Medical Center remains intense and does not diminish over time. Persistent feedback is required from the transplant team to families and local medical providers and frequently the patient requires transfers back to our facility for medical care. This pattern is dissimilar to that seen in liver transplant recipients; in these patients, the morbidity and mortality rates are very low after the immediate postoperative period.2 In an attempt to clarify these impressions, a retrospective chart study of long-term intestinal transplant recipients was undertaken to review the cause of death and number of rehospitalizations, length of stay, and admitting diagnosis of these patients.

Objective

The objective of this article is to examine longterm outcomes after intestinal transplantation at the University of Nebraska Medical Center by reviewing rehospitalization, length of stay, admitting diagnosis, patient survival, and cause of death. By understanding these issues we will be better able to counsel patients, families, and local physicians on the potential for long- term complications and to plan for allocation of resources to provide for long-term follow-up to patients.

Method

A retrospective medical chart review including review of our medical electronic database was completed with approval from the internal review board on all patients who received intestine transplants at the University of Nebraska Medical Center from September 1990 through March 2003. This review included admissions to the University of Nebraska Medical Center and admissions to local medical facilities. Information regarding admissions to other hospitals was often obtained from patients' families and local physicians, as well as discharge summaries when available. The patient charts were then further reviewed for admitting and discharge diagnosis, length of stay, graft survival, and cause of death.

Results

One hundred forty-six intestinal transplantations were performed in 128 patients from September 1990 through March 2003. Of these, 50 patients died less than 1 year after transplantation. Two patients were lost to follow-up. Seventy-six patients remained to form the study group; 32 patients received isolated intestinal transplantation, 32 received combined liver and intestinal transplantation, 11 patients received pancreas in addition to liver and intestinal transplants, and 1 patient received liver, intestine, pancreas, and kidney transplants. Nine of these patients underwent retransplantation (Table 1).

Twenty-three patients died at more than 365 days after transplantation. Survival for these patients ranged from 368 to 2293 days (6.2 years), with a median survival after transplantation of 563 days. The most common cause of death occurring in 56% of the patients was from sepsis. Sepsis occurred in 8 patients with an intact or functioning graft either after longterm survival from their initial transplantation or following retransplantation. In 4 cases, death from sepsis occurred following chronic or severe rejection. These deaths occurred following graft explantation and may be related to the treatment received for the severe rejection that led to explantation. Death from sepsis also occurred in 2 patients who had other abdominal surgical procedures performed after transplantation for lysis of adhesions and bowel obstruction (Table 2).

Table 1 Retransplant patients

Table 2 Cause of death of first-time transplant recipients

Rehospitalizations and Admitting Diagnosis

Seventy-six patients were reviewed for events during the second year after transplantation. The subject groups reviewed for each subsequent year were smaller for the third, fourth, and beyond the fifth year, the group's size was 56, 43, and 32 patients, respectively. The range of posttransplant survival days reviewed was up to 4428 days (11 years).

The number of rehospitalizations per patient per year remained relatively stable over the study period (Table 3). Patients were rehospitalized an average of 3.6 times during the second year after transplantation and between 2 to 3 times per year in the subsequent periods. The median length of the hospital stay per patient decreased from 8 days in the second postoperative year to 4 days at more than 5 years. Nearly half (45%) of all the hospital admissions were for fewer than 7 days, but even after 5 years prolonged admissions continued to occur.

Discharge diagnosis for readmission in each postoperative period is shown in the Figure. In the second year after transplantation, infectious complications accounted for 117 of 258 readmissions. Although the absolute and relative number of admissions for infections falls in following years, infections remain the major diagnosis for readmission in all periods. Infections included those due to bacterial, viral, and fungal pathogens. Diagnoses for gastrointestinal complications included gastrointestinal diarrhea not due to rejection, intestinal biopsies without findings of rejection or virus, stomal prolapse of the bowel, colitis, and episodes of constipation. In the second year, there were 54 admissions for gastrointestinal complications; although declining to 45 readmissions in the third year, readmissions for gastrointestinal complications did not decline noticeably in subsequent years. Thirtyfive patients were hospitalized for dehydration in year 2. These episodes of dehydration were not from intestinal fluid losses because these cases were placed in the categories of rejection, infection, or gastrointestinal complications. Again, the number of hospitalizations declined to 12 in third year but then remained stable thereafter. Rejection accounted for 18 readmissions in the second year. Episodes of rejection decreased to 8 in the third year following transplantation but did not decrease notably in the succeeding years. Most importantly, several of the later episodes of rejection were severe and resulted in graft loss and/ or patient death.

Table 3 Rehospitalizations of intestinal transplant recipients

Other diagnostic categories included pulmonary and renal complications, further surgical procedures, and hematology and oncology diseases, mostly posttransplant lymphoproliferative disease. Multiple admissions occurred for several patients with chronic lung disease. The lengths of stay were long and readmissions were frequent. Two patients had renal failure and required kidney transplantation. Nearly 20 patients were admitted for surgical procedures, such as bowel obstruction, lysis of adhesions, and fistula repair or ileostomy stomal takedow\n, over the review period. Two of these patients died following surgical procedures. Posttransplant lymphoproliferative disease occurred in 2 patients and plasmacytoma occurred in 1 patient. One patient died from lymphoma. Patients who required treatment for posttransplant lymphoproliferative had numerous admissions for treatment and central catheter infections. Although these final categories made up few readmissions in comparison to the other large groups, there were still long lengths of stay and morbidity associated with these diagnoses.

Discharge diagnoses by posttransplant year

Discussion

A limitation of this study may be that the information collected reflects information received from patients, local physicians, and chart review and not always from discharge summaries. Some patients may have been admitted for more than 1 diagnosis and though effort was made to determine the actual cause of admission in some instances, some diagnoses may overlap. All patients who had survived longer than 5 years were placed in the 5 years and greater category, not selecting for individual years after 5.

More than 45% of all admissions were 7 days or fewer; many of these were for 24 to 48 hours. There were frequent admissions for procedures that normally would be considered outpatient treatments for other patients such as tonsillectomies, tympanoplasties, or replacement of gastro-jejunal feeding tubes. Because of the complexity of these patients, local physicians are often reluctant to treat them as they would their other patients. As small bowel transplant recipients become more familiar to local physicians caring for our patients, these procedures may be done more often in an outpatient setting.

There were also frequent admissions in the past for fever workup, fluid rehydration, and liver or intestinal biopsies. However, at this time, in our center, febrile but otherwise asymptomatic patients are evaluated in an outpatient setting. Initial antibiotic therapy can be instituted and patients may remain in the outpatient setting awaiting final culture results if their medical condition allows. In the same manner, fluid therapy for dehydration can be provided in the outpatient treatment center or via home infusion therapy. Intestinal or liver biopsy is most often done as an outpatient procedure and the patient is admitted only if it is indicated by his or her condition or if rejection is diagnosed. This reflects the increasing experience in caring for intestinal transplant recipients.

This report constitutes the largest review of longterm hospital admissions in intestinal transplant recipients presented to date. The ability to discuss long-term complications is, in itself, recognition that long-term survival is now to be expected in intestinal allograft recipients and has established itself as the standard of care for patients with life-threatening complications of intestinal failure. The major causes for of readmission, namely infection, gastrointestinal complications, dehydration, and rejection, are discussed individually.

Infections

Infections are reported as the most common complication following intestinal transplantation.39 Patients have little protection from infection in the face of severe rejection. The mucosal protection of the bowel is lost, bacterial translocation occurs and treatment of rejection with increased immunosuppression leaves the immune system defenseless. Patients who undergo retransplantation and are already receiving immunosuppressive therapy are at greater risk of infection, particularly when they receive higher levels of immunosuppression associated with the immediate posttransplant period. The high number of infections in long-term survivors of intestinal transplantation is likely a result of continued high levels of immunosuppression when compared to other long-term solid- organ transplant survivors.2 Admissions for infection included fever of undetermined origin, infectious gastroenteritis, upper respiratory infections, urinary tract infections, and most importantly infections associated with indwelling central catheters. In all patients, parenteral nutrition had been discontinued, but permanent central catheters may be in place for long-term fluid replacement or replaced for treatment of other medical conditions such as de novo malignancy. The causative pathogens included a variety of viral, bacterial, and fungal organisms. In all periods, infection was the largest diagnostic category for readmissions; after the second year, a large reduction in the number of admissions for infections of all types existed.

In every instance, fever in an intestinal transplant recipient must be taken seriously and the source conscientiously sought particularly in those with central venous access. The number of deaths that occurred from sepsis certainly implies that. Consideration must be given for obtaining blood, urine, and other cultures as indicated by the clinical condition as well as test for specific viruses, including Epstein-Barr virus, cytomegalovirus, other herpes viruses, adenovirus, respiratory syncytial virus, and influenza. Consideration should also be given to empiric therapy with broadspectrum antibiotics or intravenous antiviral therapy while awaiting culture results.

Gastrointestinal Complications

The category of gastrointestinal complications included readmissions for placement of feeding tubes, gastrointestinal bleeding, pancreatitis, constipation, colitis, partial bowel obstruction, specific food intolerance, and treatment of bacterial overgrowth. Maintaining enterai feeding access may remain a concern for intestinal transplant recipients for years following transplantation. Although every attempt is made to get patients to eat normally, in many cases enterai tube feeding is the only form of nutrition for 2 or more years after transplantation, especially in young children,10,11 so feeding tubes must be replaced promptly to prevent dehydration and loss of nutrition. Gastrojejunal and jejunal tubes may need to be placed endoscopically or in an interventional radiology setting. When these cannot be scheduled for 1 to 2 days, the patient is often admitted to be supported with intravenous fluids until the procedure can be accomplished. Gastrointestinal bleeding must be evaluated immediately after the symptom is reported; it can be a sign of acute and severe graft rejection,12,13 although no patients in this report presented with gastrointestinal bleeding due to rejection. The causes of gastrointestinal bleeding noted were from anastomotic bleeding, gastric ulcer, or stomal irritation. Repeated episodes of pancreatitis were noted in a patient who had been explanted and had a short duodenal slump with gastric drainage. Colitis was a repeated problem in a small child who received a transplant for tufting enteropathy. There were several isolated episodes of ileus or partial bowel obstruction that were treated with nasogastric decompression and temporary bowel rest. Patients were admitted for evaluation of failure to thrive if they had decrease in weight gain and height, or loss of muscle mass. These patients generally were found to have bacterial overgrowth, specific food intolerance, or dietary noncompliance. None of the admissions for gastrointestinal complications led to death; however, they did prompt immediate intervention to prevent further morbidity.

Dehydration

Readmissions for dehydration were most often indicated by increased serum urea nitrogen and creatinine levels and hemoconcentration. These admissions were not due to intestinal losses. In this study, patients who were found to have enteritis or rejection that led to dehydration were entered into the appropriate categories. Dehydration in this category was most often attributed to leaking from enterai feeding tubes, enterai pump malfunction, patient noncompliance, or excessive insensible fluid losses without adequate fluid replacement during periods of hot weather. Fluid therapy was initiated as soon as possible via the intravenous or enterai route. Dehydration is significant in any patient taking an immunosuppressive drug because of the nephrotoxic effects, but can be particularly detrimental to intestinal transplant recipients. Significant dehydration may cause hypovolemia and decreased blood flow to the intestinal graft. In severe cases, this has been thought to contribute to intestinal ischemia, which has resulted in partial or complete loss of the allograft.

Rejection

Although accounting for few readmissions throughout the study period, the occurrence of acute or chronic allograft rejection is arguably the most devastating morbidity after intestinal transplantation. Although modern immunosuppressive protocols have appeared to decrease episodes of acute rejection in the immediate posttransplant period, the frequency of late rejection remained constant throughout the sludy period. Reports of patients suffering late acute rejection and chronic rejection, in isolated intestinal transplant recipients, have resulted in high rates of explantation.14,15 In this study, 4 deaths could be attributed to infectious causes that appear to be precipitated by intestinal rejection and the treatment thereof. There should be a low threshold for proceeding to intestinal biopsy any time an intestinal recipient presents with increased fecal output. This may be more difficult to accomplish if the patient is no longer at the transplant center, but it is still necessary. Therefore, it is important to maintain a close relationship with the gastroenterologist who is following the patient locally. Research continues to identify less-invasive methods to readily identify rejection in intestinal transplant recipients, but at present a tissue diagnosis is required.16

Conclusion

This study does confirm the high frequency of readmission of long- term intestinal transplant recipients. Each set of patient blood work data, each \phone call from the patient, family and local physician must be evaluated and acted upon, most often requiring further intervention and follow-up. Serious complications can still threaten patients' lives, even 5 to 10 years after transplantation.

Intestinal transplantation has become the accepted treatment for patients who have complications of intestinal failure. However, this has to be seen as a trade-off for the chronic illness of intestinal failure with complications leading to death for the chronic illness of intestinal transplantation." The number of radmissions each year per patient remains constant and medical problems remain complex and life threatening. Patients with intestinal transplantation will continue to require regular expert follow-up care and careful attention to the smallest medical problem years following transplantation.

Acknowledgments

The authors gratefully acknowledge the editorial assistance of Laurel Williams, RN, MSN, CCTC, and Debra Sudan, MD, and the technical support of Tina Rackley, administrative assistant.

References

1. Farmer DG, McDiarmid SV, Yersiz H, et al. Outcome after intestinal transplantation: results from one center's 9-year experience. Arch Sarg. 2001 ;9:1027-1031.

2. Horslen S, Sudan D. Long-term outcomes in small bowel transplantation: survival, nutrition, growth and quality of life. Curr Opin Org Transplant. 2003;8:202-208.

3. Abu-Elmagd K, Reyes J, Bond G, et al. Clinical intestinal transplantation: a decade of experience at a single center. Annu Surg. 2001 ;234:404-416.

4. Nishida S, Levi D, Kato T, et al. Ninety-five cases of intestinal transplantation at the University of Miami. J Gastrointest Surg. 2002;6:233-239.

5. Pirenne J, Koshiba T, Coosemans W, Herman J, Van Damme- Lombacrt R. Recent advances and future prospects in intestinal and multi-visceral transplantation. Pediatr Transplant. 2001;5:452-456.

6. Reyes J, Mazariegos G, Geoffrey MD, et al. Pediatric intestinal transplantation: historical notes, principles and controversies. Pediatr Transplant. 2002;6:193-207.

7. Sudan D, Horslen S, Botha J, et al. Quality of life after pediatric intestinal transplantation: the perception of pediatric recipients and their parents. Am J Transplant. 2004;3:407-413.

8. Rovera GM, Dimartini A, Schoen RE, Rakela J, Abu-Elmagd K, Graham TO. Quality of life of patients after intestinal transplantation. Transplantation. 1998;9:1131-1145.

9. Langnas A, Chinnakotla S, Sudan D, et al, Intestinal transplantation at University of Nebraska Medical Center: 1990- 2001. Transplant Proc. 2002;3:958-960.

10. Iyer K, Horslen S, Iverson A, et al, Nutritional outcome and growth of children after intestinal transplantation. J Pediatr Surg. 2002;3:464-466.

11. Nucci AM, Barksdale EM Jr, Beserock N, et al. Long-term nutritional outcome after pediatric intestinal transplantation. J Pediatr Surg. 2002;3:460-463.

12. Andersen D, Zabrocki A, Brown C, et al. Intestinal transplantation in pediatric patients: part two; the immediate postoperative period. J Gastroenterol Nurs. 2001;23:201-209.

13. Kosmach-Park B. Intestinal transplantation in pediatric patients. Prog Transplant. 2002;2:970-113.

14. Garrido V, Bond GJ, Mazariegos G, et al. Late severe rejection of intestinal allografts: risks and survival outcome. Transplant Proc. 2001;1-2:1556-1557.

15. Iyer KJ, Srinath C, Horslen S, et al. Late graft loss and long-term outcome after isolated intestinal transplantation in children. J Pediatr Surg. 2002;2:151-154.

16. Mittal NK, Tzaskis AG, Kato T, Thompson JF, Current status of small bowel transplantation in children: update 2003. Pediatr Clin North Am. 2003;6:1419-1433.

Deborah A. Andersen, RN,

BSN, CCTC,

Simon Horslen, MD

University of Nebraska Medical Center, Omaha, Neb

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Copyright North American Transplant Coordinators Organization Dec 2004

Source: Progress in Transplantation

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