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|Restoring GI Autonomy to Intestinal Failure Patients|
Kishore Iyer, MBBS, FRCS, FACS
Director, Intestinal Transplantation, Mount Sinai Medical Center, New York, New York
This is an adaptation of a talk given by Dr. Iyer at Albany Medical Center on April 19, 2007.
The current algorithm for managing intestinal failure due to short bowel seems to follow a predictable pattern. The patient has a catastrophic gastro-intestinal (GI) event leading to major intestinal resection. Hopefully the patient recovers and early on in this process parenteral nutrition (PN) is initiated. If the patient does well, then he or she goes home to continue on PN at home (i.e., HPN). If the patient does not do well and develops complications related to PN, either immediately or at some future point, he or she is likely to be referred to a transplant center.
There are several disadvantages in this approach. First, there is no early recognition of patients at high risk for developing PN complications. Second, nationally, the majority of these PN-dependent patients are managed by a physician who has neither the time nor the expertise to administer an adequate level of care or take the steps to gradually wean the patient from PN. An effort to wean is a necessary, but not easy process.
Intestinal RehabilitationI have for some time embraced a somewhat different approach. Instead of consigning the PN-dependent patient to benign indifference or neglect and then transplant, I prefer adopting a more formal approach to intestinal rehabilitation. This approach incorporates all of the available therapies—nutrition, medical, and in some cases, specialized surgical procedures—in an attempt to wean a patient off PN if possible. Where weaning is not possible, the goal then becomes prevention of PN complications. The hope is that only a very, very small minority—perhaps less than 1 percent of all patients in whom PN is initiated—will ultimately require intestinal transplantation.
There is outcome data available from large national databases both in North America and Europe that allows us to think about which type of patient may come to intestinal transplantation. This is more likely in adults who have less than 50 cm of small bowel, or children with less than 30 cm, especially if they have no ileum, iliocecal valve, or colon. The HPEN registry and European data show, for patients with non-malignant diagnoses on long-term HPN, one- and four-year survival rates on the order of 95 percent and 80 percent respectively can be accomplished. The results from smaller, single-center series, UCLA, Alabama, Omaha, Denver, and Paris, are similar. It is important to note that this data indicates survival that is accomplished in patients managed by experts in the field working at the best centers; this may not, therefore, be the survival that all patients are enjoying. Nevertheless, it is clear that excellent survival outcomes are possible in the majority of patients on PN. It is because of these data that the standard of care today for the patient with irreversible intestinal failure remains PN and indications for intestinal transplantation have become the presence of irreversible intestinal failure along with the onset of life-threatening complications of PN.
The Course of EvaluationMy own approach to the patient with intestinal failure is to ask myself, is this failure permanent? To answer this, I look at etiology, residual bowel length, residual anatomy, residual motility, and a history of enteral tolerance.
If the intestinal failure does not appear to be permanent but the patient is still on PN, I would emphasize enteral nutrition (EN) via diet, or via tube if need be, in the hope of speeding intestinal adaptation, and follow up with close monitoring and good nutritional and medical care. If adaptation occurs, and the patient weans from PN, well and good; if not, I go back and ask again, is this intestinal failure permanent?
If "permanent” intestinal failure appears likely, I would still optimize PN and aggressively pursue EN. If such a patient is stable, not a lot more needs to be done as long as stability is maintained. In children, growth is an issue and must be monitored. Many of these patients, particularly children, will eventually undergo intestinal adaptation.
If the patient is not stable on PN, the cause of his or her instability needs to be pinpointed. Complications of PN leading to instability should lead to a reassessment of the bowel anatomy. Many patients with short bowel syndrome have markedly dilated bowel. The reasons are not always completely clear; it may be a compensatory mechanism for the loss of length or it may be a function of poor vascularity. Also they may have areas of narrowing and disturbed motility. In these circumstances, overgrowth with abnormal bacteria may be occurring, worsening the absorptive function. Probiotics and cycled antibiotics often help, but eventually a surgical modification of the bowel may be needed. I would resort to one of the series of procedures that we call autologous gastrointestinal reconstruction (AGIR). These include:
If instability is caused by liver disease in the setting of irreversible PN-dependence, we would implement an aggressive protocol for the management of PN-associated liver disease while simultaneously evaluating the patient for transplant, again in the hope of performing an isolated intestinal transplant. There is increasing support for the idea that PN-associated liver disease may have a multi-factorial origin. Attention to the many risk factors may allow reversal of PN-associated liver disease in some patients, as we have previously reported.
Our protocol checks for other factors that may cause hepatic dysfunction, including viruses, medications, alcohol, or gall bladder disease. We check for unrecognized sepsis and for anatomical dysfunction that may cause bacterial overgrowth (labeled SBBO, for small bowel bacterial overgrowth, on figure 1). We make every effort to feed via the gut to the limit of tolerance and back down PN as much as possible, lowering or completely withdrawing parenteral lipids. There is evidence that plant-derived fat (soy bean oil) and possibly plant-derived cholesterol (sitosterol) given intravenously cause liver inflammation. There seems to be a beneficial effect from the use of intravenous fish oil emulsion. This data must still be viewed as preliminary and the parenteral fish oil emulsion is not currently approved in the United States by the FDA for clinical use.
(See "HPN-Associated Liver Disease in Infants” article a for details.)
Benefits of Early ReferralSince the vast majority of patients with intestinal failure on long-term PN are managed by physicians who do not have the time or the expertise to closely look after them, it is surprising that more patients are not ultimately labeled as having PN failure and referred to a transplant center.
Unfortunately, from a transplant center’s point of view, referrals that are made to transplant centers are often very, very late. Last year, based on national data, over 68 percent of short bowel patients who were listed for intestinal transplant were also listed for liver replacement. There is no other transplant area (i.e., kidney, heart, liver, lungs) managed by a single organ transplant in which the physician waits for a second organ to fail before considering transplant referral. Conversely, from the primary physician’s point of view there is concern—legitimate in some instances—that earlier referrals are sometimes transplanted prematurely and possibly inappropriately.
The burning question facing intestinal transplant today is: Should intestinal failure patients with PN complications get preemptive, isolated intestinal transplant before end-stage liver disease, or should we wait until advanced liver disease mandates combined liver-intestinal transplant?
There is a growing body of data that can inform this discussion. Data from the Paris group of Bernhard Messing suggests that most patients who have at least 100 cm of functioning small bowel will be able to come off PN. In contrast, adult patients who have less than 50 cm of small bowel and have been on PN for five years are very unlikely to come off PN. If such a patient is starting to develop significant liver problems, then perhaps referral should be made sooner rather than later. The question really is what is meant by "significant” liver problems. Most patients on long-term PN develop some biochemical evidence of liver dysfunction [alkaline phosphatase and transaminase enzymes twice normal value] but the development of severe liver failure is comparatively rare (perhaps 5 percent of all adults on very long-term PN, although more frequent in children). Perhaps the move to refer should be made when liver function tests start to worsen (increased bilirubin and prolonged clotting time).
Why are these issues important? Jonathan Fryer and colleagues have studied data on the mortality of patients on the waiting list for intestinal and liver transplants compiled from the Scientific Registry of Transplant Recipients (SRTR). The mortality rate for those awaiting combined liver-intestinal transplant is much higher than for those awaiting isolated intestinal transplant. These studies show that between 30 and 50 percent of patients awaiting combined liver-intestinal transplants will not make it to the transplant. Furthermore, in most centers that contribute to the international registry, survival appears to be better after isolated intestinal transplant compared to combined liver-intestinal transplant.
Advanced liver disease is still the most common indication for intestinal transplant. However, early referrals in patients with liver disease can often allow for reversal of liver disease, and avoid the need for combined liver–small bowel transplant.
The FutureTransplant centers are expanding their therapeutic horizons beyond transplant; there is growing recognition of the need to provide a high level of expertise in all aspects of intestinal failure management—HPN and reconstruction surgery, as well as transplant. Such centers need robust infrastructures with adequate levels of support in order to care for these complex patients properly.
There is a wide range in the percentage of patients who are seen at the different transplant centers who end up receiving an intestinal transplant. Some centers are transplanting a small percentage of all patients they see, others are transplanting 90 percent of the patients they see. This disparity needs to be explained. Perhaps the explanation is as simple as a given center having an interest only in transplantation, as opposed to another center that offers and explores the entire spectrum of therapies for a given patient.
Clearly intestinal transplant still has a long way to go. But we are learning, and getting better. More recent data shows that close to 90 percent of patients survive to the one-year post-transplant mark, and survival at five years is approaching 50 to 60 percent. From a transplant surgeon’s perspective, the hope is that earlier referral of patients will lead to improvement in these outcomes.
The goal is to provide the right transplant to the right patient at the right time. To use a cliché, in caring for a patient with intestinal failure, we have many tools in a box, with transplant being the proverbial sledge hammer. It is true that we don’t need the sledge hammer for every task. However, to wait too long for referral to an intestinal failure center is to risk reaching a point where no tool, not even the hammer, can fix the problem.