Mortality and economics in short bowel syndrome

Best Practice & Research Clinical Gastroenterology Vol. 17, No. 6, pp. 931 –942, 2003 doi:10.1053/ybega.2003.415, www.elsevier.com/locate/jnlabr/ybega

4 Mortality and economics in short bowel syndrome J. Schalamon

MD

Assistant Professor

J. M. Mayr Associate Professor

M. E. Ho¨llwarth*

MD

Professor and Head Department of Paediatric Surgery, University of Graz, Medical School, Auenbruggerplatz 34, A-8036 Graz, Austria

The incidence of patients with short-bowel syndrome (SBS) has increased over the years due to progress of intensive care medicine and parenteral nutrition techniques. These techniques have significantly improved the prognosis of neonates, children and adults who have lost major parts of their intestinal tract. Long-term survival is possible and does not depend primarily on the length of the remaining bowel but on complications such as parenteral nutrition-associated cholestasis, recurrent septicaemia, central venous catheter infections, and the motility of the remaining intestine. Thus, the overall related mortality in infants with SBS ranges from 15 to 25%, and in adults from 15 to 47%, depending on the age of the patients, the underlying disease, and the duration on total parenteral nutrition. Home parenteral nutrition (HPN) significantly decreases the complication rate and improves the psychological situation of the patient. Additionally, HPN reduces in-hospital cost significantly. Nevertheless, the annual costs/patient are between $100 000 and $150 000. The mortality rate of SBS patients on HPN is about 30% after 5 years, which is still lower than the 5-year survival rate of intestinal grafts, and it is about equal to patients’ survival after intestinal transplantation. However, the overall costs of a successful intestinal transplantation are already lower after 2 years when compared with the cost of a prolonged HPN programme. Key words: short-bowel syndrome; mortality; economics; home parenteral nutrition; central venous catheter; motility; intestinal transplantation.

The term ‘short bowel’ was defined by Rickham as a small intestinal remnant of 30% or less, which equals a maximum of 75 cm of normal small-bowel length in a full-term neonate.1 Thus, adult ‘short bowel’ results when less than 150 –200 cm of small intestine remain after extensive resection. The resulting ‘short-bowel syndrome’ (SBS) is defined by most authors as a state of significant maldigestion and malabsorption * Corresponding author. Tel.: þ43-316-385-3762; Fax: þ43-316-385-3775. E-mail address: [email protected] (M. E. Ho¨llwarth). 1521-6918/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.

932 J. Schalamon, J. M. Mayr and M. E. Ho¨llwarth

requiring a prolonged period of parenteral nutrition. This parenteral nutrition enables normal growth and development, prevents dehydration and permits the replacement of electrolytes, vitamins and trace elements following extensive loss of the small bowel. The definition of SBS includes patients with congenital deficiencies or surgical resection of small-bowel segments, and those who are suffering from malabsorption due to a functional loss of absorptive surface area, for example, after abdominal radiation injury.2 The prevalence of SBS has increased in recent decades, and progress in intensive care medicine has improved the initial prognosis of patients who have lost major parts of their small intestinal tract. However, the real incidence of SBS is difficult to determine because all forms of reduced small-bowel length/function associated with a malabsorption syndrome are included. Mughal and Irving3 estimated that severe SBS cases remaining dependent on long-term parenteral nutrition amount to two new patients per one million of the population/year. According to Wallander et al4, the incidence of extreme SBS in the neonatal age group lies around 3 – 5 per 100 000 births per year. The introduction of long-term parenteral nutrition in the 1960s by Dudrick et al and by Wilmore and Dudrick revolutionized the management of patients with SBS.5,6 Parenteral nutritional support allows time while intestinal adaptation takes place—the process by which the bowel remnants regain an increased absorptive surface area and capacity. However, the cost of providing long-term parenteral nutrition in either hospital patients or by home parenteral nutrition (HPN) is substantial. The long-term survival rates of patients with SBS—as well as the probability of returning to enteral nutrition—have significantly improved over recent decades. The clinical outcome of older children and adults is often a reflection of the underlying disease. Complications such as severe liver failure and/or recurrent sepsis expose infants and small children to life-threatening problems, and often represent major obstacles for long-term survival. Each little step forward towards a successful outcome in SBS patients is difficult to achieve, and progress follows an exponential curve in regard to time and cost. This chapter summarizes evidence from the literature in regard to the mortality rates and actual survival expectations, and analyses the economical aspect of long-term parenteral nutritional support as well as intestinal transplantation in patients with SBS.

MORTALITY Newborns and infants The impact of intestinal remnant length Most cases of SBS occur in the neonatal age group, due either to prenatal diseases (intrauterine vascular injury to the intestinal tract, intrauterine volvulus or gastroschisis with volvulus of the prolapsed bowel), or to postnatally acquired diseases necessitating extensive small-bowel resection (necrotizing enterocolitis or volvulus), or they are caused by genetically determined motility disorders (total aganglionosis, chronic intestinal pseudoobstruction or congenital short bowel).2 The final outcome of a patient with SBS depends not only on the length of the remaining small bowel but also on the presence or absence of the ileum, the ileo-cecal valve and/or major parts of the colon, and the underlying disease. In 1955 Potts stated that long-term survival is possible in newborns if more than 40 cm of the small bowel remains, while mortality reaches 50% in infants with 15 –40 cm of remaining small bowel, especially in the absence of the ileocecal valve (ICV).7 In 1972 Wilmore predicted a good

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outcome for infants with at least 15 cm jejuno-ileum with the ICV, or 40 cm of jejuno-ileum without the ICV.8 In the 1980s, Caniano et al expected an 86% survival and eventual enteral alimentation in neonates with extensive SBS, despite significant morbidity.9 In 1991 Goulet et al retrospectively analysed a group of 87 children with SBS and found an overall survival rate of 80%. In regard to the length, 92% of those infants with a small intestinal remnant between 40 and 80 cm survived, in contrast to 66% surviving babies with less than 40 cm. While the presence of the ICV influenced survival only in the period before 1980, both length and ICV (with adjacent ileum) had a significant influence on the time required for adaptation and enteral nutrition.10 Galea et al concluded in 1992 that neonates with a remaining jejuno-ileal segment of more than 20 cm with an intact ICV, or more than 30 cm without an ICV, should be considered salvageable.11 These results correspond closely with two retrospective long-term analyses at the end of the 1990s, of neonates with SBS which revealed an overall survival rate close to 80%.12,13 In 1999, Mayr et al showed that all babies with a jejunoileal length between 30 and 60 cm, as well as all children with preserved ICV survived, while four out of five with less than 30 cm and four out of nine without ICV died.12 Most of the recent reports in the literature confirm the older evidence that the remaining intestinal length together with the presence of the ICV are crucial factors for survival. Additionally, it is well known that salvage of the ileum—possibly together with a significant amount of the colon— contributes significantly to the long-term outcome owing to the high adaptation abilities of the ileum in contrast to the relatively lower adaptation potential of the jejunum. Babies with a congenital short bowel represent a special subgroup of patients with a mortality rate up to 80%. This rare but genetically determined malformation is characterized by a short small intestine of between 30 and 40 cm and a severely disturbed motility.14 In 1983 Postuma et al described a long-term survivor with only 13 cm of small bowel due to neonatal midgut volvulus; the parenteral nutrition was discontinued at 21 months of age.15 In the same year, Kurz and Sauer reported the case of a long-term survivor with 10 cm of jejunum and 1 cm of ileum, and an intact ICV and colon, who was eventually weaned from parenteral nutrition after 3 years of treatment.16 Georgeson et al presented a case of a newborn with 6 cm of small bowel distal to the papillae who was successfully treated with two lengthening procedures.17 Despite these single reports of a favourable outcome of babies with very little small bowel remnants between 6 and 13 cm of length, one must conclude that survival and/or weaning from parenteral nutrition in infants with less that 20 cm of residual intestinal Table 1. Survival rates of patients with SBS and main causes of death. Author

Year

Patients

Deaths

Main cause of death

Grosfeld et al18 Caniano et al9 Goulet et al10 Galea et al11 Mayr et al12 Coran et al13 Anagnostopoulos et al19 Messing et al20 Thakur et al21

1986 1989 1991 1993 1999 1999 1999 1999 2002

60 14 87 50 17 22 59 144 (adults) 17

9 2 16 14 4 5 12 36 13

Sepsis Liver failure Sepsis Sepsis Liver failure Liver failure Sepsis Sepsis Liver failure

Survival (%) 85 86 82 78 76 77 80 75 76

934 J. Schalamon, J. M. Mayr and M. E. Ho¨llwarth

length continue to occur only in very few patients. The overall mortality rate in infants related to SBS ranges from 15 to 25% (Table1).9 – 13,18 – 21 Infants with an extreme SBS and intestinal remnants shorter that 15 – 20 cm, especially without the ICV and with little colon, will most likely die within their first year of life due either to sepsis or parenteral-nutrition-associated cholestasis (PNAC), or to other metabolic disorders. Intestinal transplantation is a valid option for those desperate cases. The impact of complications Neonates and infants need a high caloric nutrition to provide for adequate development and growth. These high-energy loaded parenteral solutions may cause a continuous decrease in bile flow after a few weeks, leading to severe cholestatic liver injury and finally to irreversible cirrhosis. Thus, PNAC is common in children with SBS, with neonates and small infants having the highest incidence.2 The exact aetiology of PNAC has not been definitely established, but enzyme deficiencies, toxic phytosterols in the lipid solutions, the lack of enteral stimulation or a deficiency of bile acid transport proteins, and the translocation of enteric bacteria, toxins, and sepsis have all been widely discussed in the literature.22 – 25 Beath et al have shown that one of the most important factors for cholestasis is prematurity, and PNAC developed in only 15% of infants older than 38 weeks of gestation.26 In this study sepsis was associated in 30% with an increase in serum bilirubin, while enteral starvation and duration of TPN did not correlate with the development of cholestasis. Coran et al and Teitelbaum et al reported that a direct bilirubin level greater than 4 mg/dl for more than 6 months is associated with significant mortality.13,27 An increase of total bilirubin after 6 months of life indicates either a bad prognosis or the early need for intestinal transplantation. The predominant complications of 15 non-survivors in three series of SBS patients were cholestatic liver insufficiency or septicaemia within 13 months after the primary resection or surgical therapy.9,12,28 The ability to provide long-term parenteral feeding through a central venous line is one of the major achievements in modern medicine. Disadvantages of long-term parenteral nutrition include the risk of bacterial contamination of the inserted catheter. Although infants are more prone to recurrent catheter sepsis, all age groups may be affected. Thus, additionally to the above mentioned problem of PNAC in small infants, long-term central venous lines are significantly associated with recurrent complications due to thrombosis of the catheter and sepsis, due either to translocated enteric organisms or to skin-derived bacteria. Terra et al showed that patients with remaining small bowel shorter than 50 cm have a higher frequency of catheter-related sepsis, particularly by enteric microorganisms. The authors considered this as evidence of the occurrence of bacterial translocation and its role in the pathogenesis of catheterrelated sepsis in patients with SBS receiving HPN.29 The incidence of septic episodes is reported in children on HPN with 2.1 per 1000 central venous catheter days (CVCD) on average, with a 0.83 rate in children younger than 2.1 years and 4.3 in older children.30 The highest infection rates were observed in children with the poorest outcome: 5.4 per 1000 CVCD in SBS children who died versus 3.3 per 1000 CVCD in survivors.31 In a collective review of 64 SBS infants described by Galea et al, the mortality related to parenteral nutrition in children was 5%.11 The impact of motility In addition to the impact of length of the intestinal remnants and parenteral nutrition associated complications, a disturbed motility of the bowel remnants is probably

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the most crucial factor determining the post-operative course, the incidence of sepsis, and the final outcome of babies with SBS. Failure or significant delayed propulsion of chyme—due either to a primary motility disorder, or secondarily to enormously dilated bowel loops—causes bacterial overgrowth, translocation of bacteria and toxins into the portal and systemic circulation, recurrent septicaemia, and finally cholestasis and liver failure. In a study by Mayr et al, babies with fatal outcome had poor propulsive peristalsis as evidenced by radiological investigations. Moreover, impaired intestinal motility as well as a complicated clinical course occurred more frequently in babies with congenital anomalies (gastroschisis and intestinal atresia) than in those with acquired diseases such as necrotizing enterocolitis or volvulus.12 It is well known that intestinal motility may be severely impaired over a long time in neonates with gastroschisis and/or atresia. Likewise, dysmotility is a major problem in patients with chronic intestinal pseudo-obstruction (CIPO) who need to be repeatedly re-admitted due to severe metabolic disorders and septicaemia. Both complications eventually cause the fatal outcome within a time-frame that correlates closely with the severity of the motility disorder. Individual differences in the quality of intestinal motility may explain why some infants and adults survive with little or no complications despite a minimal bowel length, while others with even longer bowel remnants suffer from recurrent complications and may finally pass away. Infants without significant motility disorders who survive the first 6 –9 months in a stable condition without severe complications are called ‘self-selected survivors’ and definitely have a better outcome. Older children and adults Extensive intestinal resections leading to SBS are less frequently required in older children and adults. Indications may include severe Crohn’s disease, traumatic avulsion of the intestinal tract and/or mesenteric artery, mesenteric vascular accidents due to emboli, arterial or venous thrombosis, intestinal tumours, or radiation injury. In adults, a remnant small bowel length of less than 50 cm, end-enterostomy or arterial infarction are all related to an increased mortality. A small bowel length of less than 100 cm is highly predictive of permanent intestinal failure, while neither parenteral nutrition dependence nor age are significantly associated with increased mortality.20 The study of Cavicchi et al on 90 patients showed a 84% probability of survival in patients on HPN and younger than 41 years of age, compared with a 53% survival rate for older patients. This study summarized all causes of death, including the underlying disease.32 Complications and repeated re-hospitalization in adult SBS patients are most often caused by the underlying diseases—Crohn’ disease, CIPO, carcinoma—which may finally lead to death. In a survey including 228 adult patients, complications were attributed in 48% to re-hospitalization; among those in whom catheter-related sepsis accounted for 61%, metabolic disorders for 27%, venous access thrombosis for 12%.33 Williams et al estimated the catheter-related sepsis rate to be between 0.3 and 1.3 per 1000 CVCD.34 Howard and Malone found in a large survey of more than 9000 adult patients on HPN, that only 5% of the deaths were related to therapy complications.35 Messing et al confirmed these results in an investigation with 124 adult patients, and reported a mortality rate of 6% related to parenteral nutrition side-effects.20 Excessive caloric administration in adults is often followed by a reversible liver steatosis, but rarely by a cholestatic injury with irreversible cirrhosis.36 The incidence of end-stage liver disease in patients receiving prolonged HPN was estimated by

936 J. Schalamon, J. M. Mayr and M. E. Ho¨llwarth

Guglielmi et al to be 15 –20%.37 Chan et al retrospectively analysed the charts of 42 adult patients with SBS with a total of 283 person-years (mean 6.7 years) of HPN. Six (14.3%) suffered from end-stage liver disease and died 10.8 ^ 7.1 months after the initial bilirubin elevation. While no progression to end-stage liver disease was found in five younger patients with duodenocolostomy, three of the six SBS-patients with fatal outcome suffered from Crohn’s disease, two patients had superior mesenteric artery thrombosis and pancreatitis, and one had sarcoma. The authors concluded that the combination of chronic inflammation and the SBS appears to be necessary for the development of end-stage liver disease with prolonged HPN in adults.38 These results confirm the above mentioned evidence that recurrent infectious diseases, due to bacterial translocation, exogenous catheter infection or chronic inflammation, represent a major cofactor in the pathogenesis of cholestasis in SBS patients. Home parenteral nutrition The concept of HPN significantly decreased the complication rate, improved the psychological situation of the patients, and beneficially supported the development of all age groups. Chan et al have shown that total parenteral nutrition (TPN) can be the sole nutritional support in adults with minimal remaining small intestine and without the development of hepatic dysfunction for up to 20 years, provided that the patients are otherwise well and have no sign of chronic inflammatory diseases.38 One-year and 4year survival rates are 94 and 80% of all patients in the USA receiving HPN for SBS.35 The overall survival rate of HPN patients with benign diseases is up to 70% at 5 years, but it is noteworthy that mortality directly related to HPN itself accounts only for 5 –15% of the deaths.20,33,35,38,39 In a study by Cavicchi et al, 53 out of 90 (59%) children and adults were still on HPN between 6 and 198 month (mean 45 months); during this period, 10 had been weaned and 27 (30%) died. Four deaths were related to the primary disease, six to PNAC, and seven died of sepsis (catheter-related in some cases).32

ECONOMICS In most patients with SBS, the intestinal adaption process restores digestion and absorption of nutrients to an extent that parenteral nutrition can be finally discontinued. Andorsky et al showed that the duration of the need for parenteral nutrition in neonates with SBS was significantly correlated with the length of residual small bowel, while the presence of an ICV or the frequency of catheter-related infections were not.40 In contrast, Goulet et al found in a retrospective analysis of 87 infants with SBS that the presence of ICV had a significant influence on the time required for intestinal adaptation and weaning from TPN.10 In a study by Wilmore et al on adult patients, the ratio between bowel length and body weight appeared to be the most discriminating predictor to the patient becoming independent from parenteral nutrition: an initial ratio . 0.5 cm jejuno-ileal length/kg body weight predicts an 80% chance to come off TPN, using their therapeutic regimen of a modified diet, growth hormone and glutamine.41 However, intestinal capacities for adaptation are limited. In infants, no significant further intestinal adaptation can be expected after a maximum of 36 –48 months.42 The adaptive potential is even more reduced in older children and adults, and permanent intestinal failure must be expected after a 24-month period of parenteral nutrition.43

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These patients remain at least partially on long-term HPN, or they elect for an intestinal transplantation procedure. Economics and home parenteral nutrition HPN was introduced in the USA in the 1970s. Once 50% of the required calories are tolerated well by enteral diet, a home nutrition programme can be introduced. The HPN improves living conditions for the patient, and the negative effects of hospitalization can be prevented by parenteral nutrition in a family environment at home.44 HPN is an expensive therapy, particularly with regard to treatment periods of up to 20 years in adult patients. Nevertheless, HPN reduces the health care costs significantly when compared with in-hospital treatment. Moreover, families primarily concerned with HPN reported a clear improvement in this quality of life after discharge from hospital.45 By 1992 it was estimated that 40 000 patients were on HPN in the USA.46 The European Registry indicates an incidence of four HPN cases per 106 adults and a prevalence of six new cases per 106 inhabitants per year. Some 18% of all cases of HPN in the British Registry are children.31 In 1997, children accounted in seven European countries for about 22% of the total HPN population.43 Economic appraisals of paediatric HPN programmes are not available but they may be similar to costs/patient in adults. A first study in 1978 totaled the average annual costs per adult patient on HPN in the USA as $19 700 compared with $73 720 for parenteral nutrition as an in-hospital patient.47 Over a 12-year time-frame (1970 – 1982), HPN resulted in a net savings of $19 232 per patient and an increase in survival, adjusted for quality of life, of 3.3 years.48 In 1990, Bisset et al estimated the costs of HPN versus in-hospital parenteral nutrition for children as £30 000 and £100 000 per patient and year, respectively,.49 In 1992 the average cost/patient/year was estimated to be $100 000, and in 2002, $150 000.35,50 Once discharged from hospital, the constant help of a nutrition team/nurse is necessary. The overall annual cost for the nutritionsupporting nurse was estimated by Curtas et al to be $2070.51 A cost-utility analysis of HPN by Richards and Irving52 performed in the early 1990s estimated the savings for home versus hospital parenteral nutrition in 64 adult patients for a median duration of 4 years to be £170 506. Thus, the HPN programme offers not only an improved quality of life when compared with an inpatient situation, but significantly reduces the cost to the health services.53 The annual cost for parenteral nutrition in the author’s institution is approximately $205 000 in hospital compared to $90 000 for HPN. The hospital costs were calculated according to the information provided by the hospital finance department and include the cost of procedures, hospitalization (surgical ward and intensive care unit, including medical staff), parenteral nutrition-solutions, medical equipment and laboratory testing. For calculation of HPN costs, the cost for daily care (nutritionsupport nurse, disposable supplies, nutrition-solution) and follow-up referrals (cost of hospital and laboratory-testing) were considered. Similar to our data, the cost-benefit of HPN compared to in-patient hospital care is between 50 and 75% in other studies.52,54 Richards and Irvine demonstrated in their cost-utility analysis that the longer a patient survives on HPN the more cost-effective the treatment becomes.52 Catheter-related sepsis is the most important factor which influences the cost of HPN owing to the need for hospitalization.53 The latter has been estimated by Puntis to be $10 000 per episode corresponding to 10 –15 days of hospital treatment. Melville

938 J. Schalamon, J. M. Mayr and M. E. Ho¨llwarth

et al showed that the catheter survival and the sepsis rates are lower if the central line is used at home compared to in-hospital treatment. Therefore, considerable cost savings can be achieved if the patients are treated as soon as possible at home.55 Furthermore, the use of antiseptic-impregnated central venous catheters is recommended to reduce the rate of line-infections, and to decrease the mortality rate.56 Finally, the introduction of a clinical practice guideline to standardize the indication and the use of parenteral nutrition have also been shown to be cost-effective.57 Economic aspects of intestinal transplantation Most infants and adults with SBS can eventually be weaned from parenteral nutrition. However, patients with extreme SBS as well as patients with life-threatening complications may benefit from bowel or liver/bowel transplantation (BTx or LBTx).58,59 According to Goulet et al60, neonates with less than 40 cm small intestinal length and absent ICV have a 40% probability of remaining on indefinite parenteral nutrition. Prospects in adults are even less encouraging. Even in the presence of an intact colon and ICV, older patients with less than 35 cm of jejunum have only a 50% chance for weaning from parenteral solution.61 Referral for BTx or LBTx is indicated in cases with progressive liver disease, recurrent catheter-associated sepsis, impending loss of central venous access (two out of the four major major standard veins in infants and four out of six standard access sites in children), and extreme short bowel with less than 10 –20 cm remnant, respectively.58,62 The number of potential candidates for BTx in a British study was estimated to be two/year/106 inhabitants, including adults and children.63 Patient and graft survival rates have been reported from the Pittsburg group, with 72% of patients alive at 1 year and 55% at 5 years (graft: 66% and 48%, respectively).64 Other transplant centres report very similar results.65,66 The overall patient survival rate achieved by the Omaha group in a 7-year experience was 70% for BTx and 60% with LBTx.36 In a recently published investigation, the 5-year patient survival rate improved to 80%.67 Compared to parenteral nutrition, intestinal transplantation is more cost effective either with or without liver transplantation. The cost in Austria for BTx is estimated to be $35 000, and $45 000 for combined LBTx, including a 30-day hospital stay. AbuElmagd and Bond recently assessed the average cost of TPN as more than $150 000 per patient year, and noted a cost effectiveness of BTx by the second year after surgery.50 The costs for living-related BTx have been estimated for donor work-up and hospitalization to be $16 000, the average cost for hospitalization of the recipient was $113 000, and the yearly cost for follow-up was $3900, respectively. Based on these data, living-related BTx becomes cost-effective from the first year post-transplant when compared with HPN.68

SUMMARY Extensive loss of small bowel is the most common cause of SBS. The physiological process of intestinal adaptation aims to regain digestive and absorptive capacities, but the SBS patient may need months or even years of parenteral nutritional support. Some 80 –85% of newborns and infants with SBS, and more than 53– 85% of adults without malignancies, may be finally weaned from parenteral nutrition. The remaining mortality

Mortality and economics 939

rate refers either to the underlying disease (mostly in adults) or to complications such as PNAC and catheter-related complications and septicaemia. Impaired intestinal motility and stasis of chyme is a significant risk factor leading to bacterial translocation and sepsis. Despite the fact that HPN programmes are cost effective when compared with in-hospital treatment, the average annual cost/patient/year amounts to $100 000 – $150 000. Thus, intestinal transplantation (with or without simultaneous liver transplantation) is a valuable option in patients with severe complications or extreme short bowel remnants. Recent 5-year survival rates of BTx have been reported between 60 and 80%. The average cost for BTx may become lower in the second year when compared to HPN.

Practice points † PNAC, sepsis and inflammations are the life-threatening complications in SBS patients † disturbed motility and stasis of chyme cause massive bacterial translocation and sepsis † HPN improves quality of life and reduces cost † intestinal transplantation has long-term results similar to those of HPN, but it is cheaper

Research agenda † the pathogenesis of PNAC needs further research and clarification † the mechanisms of bacterial translocation need to be defined † further progress in immunosuppression after intestinal transplantation is necessary † the optimal balance of parenteral solutions for neonates and infants is not available

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