Objectives of the Working Group
The aim was to identify the main problems contributing to high mortality in adults and children who are potential candidates for intestinal transplantation and provide recommendations on how these can be corrected. In addition clinical scenarios associated with a higher rate of mortality in patients with long-term intestinal failure and dependency on parenteral nutrition (PN) were reviewed.
The target audience is all key participants involved in the management of intestinal failure including patients, physicians, allied health professionals including specialist nurses, pharmacists and dieticians, payors (funding agencies), and PN providers.
The background to this working group is the notably high annual death rate of death on the waiting list for intestinal transplantation which is 306 per 1000 patient years which is twice that of heart-lung candidates and three times that of liver transplant candidates (1, 2). The unpredictable evolution of lethal intestinal failure associated liver disease (IFALD) and the lack of size matched donors, especially in children, are major factors in the high waiting list mortality. A high percentage of adult and pediatric transplant referrals have already developed severe liver complications by the time they are assessed and require a combined liver-intestine transplant (2). Undoubtedly, late consideration of intestinal transplantation and lack of clarity of referral criteria have been part of the reason for this waiting list mortality historically. Factors that may contribute to late referral include a lack of awareness of programs with advanced strategies for intestinal failure management (i.e. intestinal rehabilitation and transplantation), and a lack of clear consensus criteria for when to refer to these centers. Although previous attempts to establish such criteria (3) seem to have had some success (2), their effectiveness in decreasing intestinal transplant wait-list mortality has yet to be fully realized. Better communication between referring units and centers with a comprehensive expertise in intestinal failure management, including intestinal rehabilitation and transplantation (4) is needed to facilitate more timely referral.
The differences between children and adults will be discussed later, but the key features are that children are much more likely to develop liver disease and experience acute liver-related complications requiring intervention (i.e. stomal bleeding) (5) whereas adults more typically experience the long-term attritional effects of venous access problems, mild perturbations of liver function, low level malnutrition (body mass index 15–18), and episodic catheter related blood stream infections (6, 7). This sometimes creates a false sense of security regarding the very real potential for lethal decompensation, perhaps resulting in indecision as to when to proceed with small bowel transplantation.
Mortality in PN dependent intestinal failure patients, whether or not they are being considered for intestinal transplant, is clearly a problem in some groups, for example, those with radiation enteritis experiencing a mortality of 50% (6) and microvillous inclusion disease and some other causes of protracted diarrhea experiencing almost 100% mortality by the age of 10 years (8). However, other groups of patients such as those with Crohn's disease maintain very good outcomes with 85% survival or more over 5 years (6, 9–11). Reports in the literature addressing mortality in PN-dependant intestinal failure patients are conflicting for two main reasons: there are very few population based registries and where such registries exist (6, 11–13), the criteria used to identify cause of death are not standardized and in many cases are subjective. The following definitions have been agreed by the working party and applied in this document wherever possible.
- Intestinal failure is defined as the inability of the alimentary tract to digest and absorb sufficient nutrients to maintain normal fluid balance, growth and health.
- Intestinal failure center is a center possessing a multiprofessional team with nurse specialist, gastroenterologist, pharmacist, dietician, surgeon, stoma therapist, psychologist who are capable of training patients and families for home PN and supervising home PN either directly or through shared care with referring physician or commercial home care provider.
- Intestinal rehabilitation, an active and time-sensitive process that attempts to optimize the function of the remaining intestine using medical, surgical and nutritional strategies with the goal of subsequently weaning PN completely or partially.
- Parenteral nutrition failure is defined by three criteria: (a) the failure to maintain an acceptable protein-energy or hydration status despite optimizing PN, (b) the incompatibility with survival over the foreseeable future without hospitalization for the management of complications, (c) the development of PN related complications (IFALD, loss of venous access, recurrent catheter related blood stream infections [CRBSI], or metabolic complications).
- IFALD is further subdivided into early/mild, established/moderate, and late/severe, after other causes of liver injury have been excluded.
- Early IFALD is defined as a persistent elevation of liver enzymes alkaline phophatase and γ-glutamyl transferase×1.5 above upper limit reference range which persist for more than or equal to 6 months in adults and more than or equal to 6 weeks in children. Total bilirubin will be less than 3 g/L, and hepatic ultrasound will show an echogenic appearance. If a liver biopsy is performed, up to 25% of liver parenchyma will demonstrate steatosis or up to 50% portal tracts will show fibrotic changes.
- Established IFALD is defined as alkaline phophatase and γ-glutamyl transferase greater than 1.5× above normal range (in children the γ-glutamyl transferase may be low because of poor enteropathetic recirculation of bile acids). The total bilirubin 3 to 6 g/L, and abdominal ultrasound shows grossly echogenic liver associated with enlarged spleen, biliary sludge with or without gall stones. A liver biopsy will show significant steatosis (>25%) and fibrosis affecting more than 50% of portal tracts.
- Late IFALD is defined by liver function tests (transaminases and alkaline phophatase with or without γ-glutamyl transferase) more than 3× above the normal range. The total bilirubin is more than 6 g/L, and is associated with signs of a chronic inflammatory state with or without hypersplenism, as the platelet count is less than 100×109. The international normalized ratio is worse than 1.5, and spider naevi, ascites, varices, gastrointestinal bleeding from erosions or varices are present to varying degrees. If a liver biopsy is performed, considerable fatty change may be present with areas of intense fibrosis. Cirrhosis is unusual but individual lobes of the liver may show different degrees of fibrosis and distortion of architecture.
- Critical loss of venous access is defined as when more than 2 of veins suitable for a feeding catheter become occluded, or where positioning of feeding catheter can only be achieved with the aid of complex interventional radiological or surgical techniques (the use of the femoral vein is not considered ideal and if a patient requires such access, this would constitute critical loss of venous access).
- Fluid balance problems occur in PN dependant patients, but no satisfactory definition exists. As a rule of thumb, adults and children who require regular hospitalization (more than once per month) to manage fluid balance problems are defined as having fluid balance problems.
- Impaired quality of life is defined by three criteria: (a) by self assessment in validated semi-quantitative questionnaire, (b) prolonged hospitalization (more than 4 weeks in any 1 year) or recurrent hospitalizations (more than four admissions per year or 12 total admissions involving at least one night in hospital), (c) pain intense enough to require regular narcotic analgesics.
- CRBSI is defined as the presence of microorganisms in the blood of patients with an indwelling catheter (includes infection originating directly from the feeding catheter and those originating from other sources within the body, such as infection derived from a compromised intestinal tract).
A panel of experts in intestinal failure, assessment of candidates for small bowel transplantation, and small bowel transplantation was convened by Dr. Farmer and the scientific organizing committee of the Xth International Small Bowel Transplant Symposium. Literature from 1990 to 2007 was reviewed and 63 relevant articles were identified. The working party discussed the published articles in a structured format and produced this document as a synthesis of proceedings. The group noted that there is a paucity of randomized controlled trials in this area and therefore many of the views expressed in this document are the result of expert opinion.
Risk Factors for Mortality in Children While on Parenteral Nutrition
Several studies of the natural history of intestinal failure in children have been published and these report overall mortality ranging from 13.5% (13) to 16% (8) to 5% in a cohort of patients from which patients fulfilling criteria for small bowel transplantation had been excluded (14). But there are “at risk groups” whose underlying disease, age, vulnerability to CRBSI, development of co-morbidity such as liver dysfunction, merit early referral to an intestinal failure and rehabilitation center and include all children who are still on PN 6 weeks after starting PN. Factors which have been shown to be especially indicative of high risk of poor outcome in chronic intestinal failure are shown in Table 1.
In recent years, a range of nontransplant options for managing complications of intestinal failure have been described (4). This has led to the recognition of the role of the well resourced multidisciplinary team in minimizing complications (15–18) and in some cases reducing the patients' dependency on intravenous PN (19). Management strategies have been well described elsewhere (10, 20–22), but include the medical (23–26), dietetic (27, 28), and surgical treatments (4, 29–33). Referral criteria are summarized in Table 2.
Risk Factors for Mortality in Children While on Waiting List for Small Bowel Only and Combined Liver and Small Bowel Transplantation
The consequences of late referral are well described: life expectancy was less than 6 months in children with plasma bilirubin in excess of 12 mg/dL, and less than 8 weeks in children with varices and a coaguaopathy (5), and only 30% survived 12 months in patients with hepatic cirrhosis (34). The late referrals combined with the difficulty of matching up donor organs especially in children, has resulted in waiting list deaths of 50% to 60% (1, 35). The poor condition of these transplant candidates correlates with the 3 years posttransplant survival of approximately 50%, which contrasts with 3-year survival of 70% to 80% patients who do not have liver failure at the time of transplantation (36) (Table 3).
To reduce mortality on the transplant waiting list earlier referral that is at a point when the above risk factors are identified but before they are fully manifested is recommended. This view is summarized in Table 4.
Risk Factors for Mortality in Adults While on Parenteral Nutrition
The natural history of intestinal failure and dependency on PN has been evaluated in several large studies from Italy, France, Netherlands, United Kingdom, and the United States (6, 7, 9–11, 37–39), which cumulatively indicate that the majority of patients can survive long periods on home PN especially if a specialist nutritional care is involved either directly or in collaboration with the patient's local team (40, 41). But some of these studies also identify “high at risk groups” who merit early referral to an intestinal failure rehabilitation unit with either a small bowel transplant center or has close links with one (9, 42). This high risk group of adults include hospitalized patients and those with poor quality of life because of narcotic dependency (43) and those with deteriorating liver disease (i.e. moderate IFALD or worse—see definitions earlier). The effect of age on survival while receiving HPN is not straightforward. Most authors report increased mortality rates with increasing age (9–11, 37, 39), but Lloyd et al. (6) suggested a quadratic relationship between age and survival, with the younger age groups also at higher risk. This is also apparent when comparing mortality on PN with standardized mortality ratios according to age groups (6). Also venous thromboses are often stochastic events and it may be possible to maintain a last remaining access point for many years without complication. Nevertheless, such a position is tenuous and such patients should be considered high risk and under the close supervision of an intestinal failure rehabilitation center with good links to a transplant team (see also Table 5).
Risk Factors for Mortality in Adults While on Waiting List for Small Bowel Only and Combined Liver and Small Bowel Transplantation
Although an adult listed for small bowel transplant has a better chance of receiving a graft than a pediatric patient, the waiting list mortality in both adult and pediatric transplant candidates greatly exceeds that of all other organs. Candidates waiting for intestine only transplants have relatively low mortality, but those requiring both intestine and liver account for the majority of the waiting list deaths. In 1999, the death rates quoted by United Network for Organ Sharing for patients awaiting liver transplantation alone was 138 (deaths per 1000 patient years waiting) compared with 231 for adults aged 18 to 34 and 353 for adults aged 35 to 39 awaiting a liver and small bowel transplant (44). The significant discrepancy in the waiting list mortality and the fact that United Network for Organ Sharing status did not seem to accurately predict mortality in home PN patients with complications especially liver disease, indicates that the criteria applied for allocating organs in liver disease of other etiologies cannot be used in intestinal transplant candidates. This realization led to an amendment in model for end-stage liver disease (MELD) and pediatric end-stage liver disease (PELD) scores to adjust for IFALD (see later). The impact of these modifications has yet to be fully evaluated but does seem to have produced some improvement in waiting list mortality in some centers (Dr. D. Sudan, Nebraska Medical Centre, personal communication, 2007).
As with children, the risk factors for mortality in adults while awaiting an intestinal transplant are clearly the onset of liver disease and the need for combined organs. In addition narcotic dependency and chronic hospitalization have also been reported, although these factors may simply reflect the presence of complicated or advanced intestinal failure (see also Table 6).
Review of Prognostic Scores
From the foregoing it is apparent that the definitions for PN related complications and the criteria for referral for consideration of small bowel transplantation are quite subjective and vary within and between countries, and different health care systems. Over the years attempts have been made to devise objective scoring systems to define disease severity or predict mortality. These include the criteria described by Malatack et al. (45) in 1987 for pediatric liver disease to a pediatric hepatology dependency score used in pediatric patients with a wide range of illness not just those listed for transplant (46), and more recently, the adoption of MELD and PELD scoring systems in the United States (47). Although it is generally accepted that the MELD system has been implemented successfully and is now a powerful audit tool, the transplant community has expressed less confidence in PELD as an accurate predictor of pretransplant mortality in children (48, 49). It is also apparent that MELD and PELD do not predict waiting list mortality in the liver-intestinal candidates and for that reason, it has recently been agreed that an additional 10% estimated mortality risk is added to the score of intestinal transplant candidates who require a combined liver and bowel graft (50). Consideration is also being given to directing the smaller donor livers (if suitable as a composite graft with the intestine) to infants listed for both organs rather than for liver transplant alone (51). This critical evaluation of MELD and PELD will continue and it is to be hoped that ultimately the factors which correlate with pretransplant mortality will emerge more clearly. However, with such a restricted range of variables under consideration (bilirubin, albumin, coagulation, and age) this scoring system is unlikely to inform the referral criteria for patients with intestinal failure to intestinal failure rehabilitation centers and for small bowel transplantation, thus it remains a priority that such data are identified through registries and other systematic means of collecting data.
Both the PELD and MELD scoring systems have been developed to estimate the severity of disease when there is liver disease present. However, for patients with intestinal failure without liver failure there is no validated scoring system and the identification of patients with a poor prognosis is more difficult. Despite the inherent limitations of a scoring system, this would be useful to develop for this patient group.
There is a need to identify causes of pretransplant mortality based on more objective criteria and definitions. Articles addressing the issue of pretransplant mortality were presented at the Xth International Small Bowel Transplantation Symposium and using these it will be possible to develop consensus on a useful risk factors which could be combined to provide a prognostic index for survival in patients with intestinal failure.
All participants of the working group agreed that national registries for PN dependent patients with intestinal failure, supported by intestinal rehabilitation centers and their local referring units need to be established. It was acknowledged that it was incumbent on the established well-resourced intestinal failure rehabilitation centers to work collaboratively with the totality of the “medical” community (i.e. patients, physicians, allied health professionals, PN providers, payors/funding agencies) to facilitate ongoing data collection for the registry and to facilitate timely usage of their available expertise (8, 41, 52).
- Primary care givers should establish a link with intestinal failure programs early.
- Collaboration with intestinal rehabilitation centers should be initiated for intestinal failure patients if PN requirements anticipated to be more than 50% at 3 months from initiating therapy.
- Intestinal failure programs need to include intestinal rehabilitation and intestinal transplantation or have active collaborative relationship with centers that perform intestinal transplantation.
- National registers for intestinal failure patients should be established and participation by prescribers of PN solutions should be expected.
- Until the data on the natural history of PN dependant failure patients are available, the criteria for proceeding to listing for intestinal transplantation should be defined at the individual centers who will normally be guided by the consensus criteria (3) published in 1999.
There are still many unresolved questions about IFALD in adults and children, and, the relatively large number of centers managing a handful of cases hinders elucidation of the natural history of complications, from liver disease, to catheter care, to the composition of PN solutions. The establishment and strong support for national intestinal failure databases is a key recommendation of this group. Funding of multicenter studies and the adoption of universally accepted standards of care in relation to sepsis rates, incidence of liver dysfunction and mortality would improve outcomes in long term intestinal failure and small bowel transplantation.
The authors thank Dr. Marvin Ament, Director of Pediatric nutritional support team, UCLA, USA, Dr. Girish Gupte, Birmingham Children's Hospital, UK, Professor Bernard Messing, Hopital Beaujon, Clichy, France, Dr. Darius Mirza, The Queen Elizabeth Hospital, Birmingham, UK, and Dr. Jeremy Woodward, Addenbrookes Hospital, Cambridge, UK, for their valuable contribution to the discussions at the workshop and review of the literature.
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