Search

Patients with short bowel syndrome have significant fluid losses. This represents a significant management problem, especially in patients with minimal residual intestine. We determined whether clonidine, an alpha2-adrenergic agonist, is effective in decreasing fecal water and sodium (Na) losses in patients with proximal jejunostomy. Eight parenteral nutrition (PN)-dependent subjects (3 men, 5 women), aged 49.9+/-10.2 years, with a residual small bowel length of 71.8+/-152.0 cm that ended in a jejunostomy, were studied.Subjects were admitted to the North-western General Clinical Research Center (GCRC) for a 2-day equilibrium period while receiving a self-selected 100 g fat diet with protein 1.5 g/kg/d and 30 kcal/kg/d and 1 L/d of oral rehydration solution. A D-xylose test was performed after an overnight fast. On days 3-5, all stool and urine were collected for volume, weight, fat, nitrogen, energy, sodium, magnesium, potassium, and calcium. Meals were provided in duplicate and the equivalent portions consumed by each patient were analyzed for fluid volume, fat, nitrogen, energy, sodium, magnesium, calcium, and potassium in order to calculate nutrient balances. At the conclusion of the stool and urine collections (day 6), a clonidine (0.3 mg) patch was applied to the shoulder. Subjects were restudied after 1 week.Daily fecal volume and weight were 4.514+/-1.769 L/d and 4394+/-1727 g/d, respectively, at baseline. Five subjects were net "secretors" in that excreted fecal volume exceeded oral intake. Fecal volume decreased by 427+/-562 mL/d (8.9%, p=.07). Fecal weight decreased by 438+/-527 g/d (9.4%, p=.05). Urine volume correspondingly increased by 747+/-1934 mL (18.9%, p=not significant [NS]). The increase in urine output was weakly and negatively correlated with the decrease in fecal volume and weight (r=-0.37 and -0.41, respectively, p=NS). Oral fluid intake decreased slightly from 3.328+/-1.246 L/d baseline to 3.203+/-1.119 L/d with clonidine therapy (-3.8%, p=NS). Fecal Na loss was significantly decreased from baseline (887+/-996 mg/d, 11.2+/-12.3%; p=.036). This was not related to decreased oral Na intake, which actually increased from baseline (3.799+/-2.271 g/d) to 3.933+/-1.314 g/d after clonidine therapy (p=NS). No patient developed hypotension.Our results show the transdermal administration of clonidine is associated with a modest but clinically significant decrease in fecal output in patients with short bowel syndrome and high-output proximal jejunostomy that require chronic parenteral fluid infusion. This is accompanied by decreased fecal Na loss.

Rejection remains a major obstacle to successful small bowel transplantation in humans, irrespective of the immunosuppressants. Previous large animal studies have not used quadruple immunosuppression (with high-dose intravenous cyclosporine A [CSA]) for induction, followed by triple immunosuppression for maintenance therapy. Nor have immunosuppressive doses been comparable to clinical solid organ transplants. We studied, in 78 nonrelated outbred pigs, the effect of quadruple immunosuppression (including horse anti-pig thymocyte globulin [ATG] and high-dose intravenous CSA) on the incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 19) pigs were nonimmunosuppressed. Group B (n = 20) received quadruple immunosuppression: pig ATG (10 mg/kg/day x 10 days), intravenous CSA (3.0 mg/kg/day), prednisolone (2 mg/kg/day), and azathioprine (2.5 mg/kg/day); prednisolone and azathioprine were each reduced by 50% on posttransplant Days 8 and 15. Trough CSA levels were > or = 400 ng/ml for the first 7 days posttransplant, > 200 ng/ml thereafter. Recipient pigs underwent resection of large and small bowel; orthotopic transplants (proximal duodenojejunostomy, distal ileostomy) were done with systemic vein drainage. We developed a scoring system (no, mild, moderate, severe rejection) to grade the extent of both interstitial and vascular rejection: biopsies were obtained daily from the ileostomy. Rejection-free graft survival at posttransplant Days 7, 10, and 14 was 32, 26, and 16% in the nonimmunosuppressed group versus 95, 90, and 85% in the immunosuppressed group (P < 0.0001). Rejection grades were significantly better over the whole observation period in immunosuppressed pigs: interstitial rejection was not present in up to 67% of all daily biopsy specimens. Rejection was present in all specimens of nonimmunosuppressed pigs. Vascular rejection was uncommon (incidence < 10%) in both groups. Isolated vascular rejection without interstitial rejection was not found. Graft-versus-host reaction was noted in both groups in the skin only; liver and native bowel were not involved. We conclude that quadruple immunosuppression with pig ATG and high-dose intravenous CSA for induction effectively prevents moderate and severe rejection in this model. Since clinical transplant complications (rejection, lymphomas) have persisted under FK 506 treatment, our immunosuppressive regimen should be considered an alternative for bowel transplantation in humans to prevent early rejection.

Diet may play an important role in the management of patients with short bowel syndrome who have colon in continuity. However, macronutrient absorption has not been well characterized, and the most appropriate dietary constituents have not been well defined.To define carbohydrate absorption characteristics in patients with short bowel syndrome and determine the potential role of pectin as a dietary substrate.The authors studied the effect of a custom pectin-based supplement in 6 subjects (3 male/3 female) aged 29-67 years with jejunocolonic anastomosis, 4 of whom required long-term parental nutrition. Small intestinal absorption capacity, macronutrient and fluid balance, gastrointestinal transit time, and energy consumption were measured.Data showed that 53% nitrogen, 50% fat, and 32% total energy were malabsorbed. In contrast, the majority (92%) of total carbohydrate was utilized. Fecal short-chain fatty acids (SCFAs) were increased, an indication of increased fermentation. Although only 4% of starch was recovered in stool, it is indicative of considerable starch malabsorption, thus providing the main carbohydrate substrate, for colonic bacterial fermentation. In contrast, nonstarch polysaccharide was a relatively minor fermentation substrate with only 49% utilized. Eighty percent of the pectin was fermented. Supplementation was associated with increased total SCFAs, acetate, and propionate excretion. There was a trend observed toward greater fluid absorption (-5.9% ± 54.4% to 26.9% ± 25.2%) following pectin supplementation. Nonsignificant increases in gastric emptying time and orocolonic transit time were observed.Despite malabsorption, starch is the primary carbohydrate substrate for colonic bacterial fermentation in patients with short bowel syndrome, although soluble fiber intake also enhances colonic SCFA production.

Alterations in mesangial and endothelial cell production of vasoactive substances may be a contributing factor to the decreased renal blood flow and glomerular thrombosis associated with FK506 nephrotoxicity. In preliminary studies Rapamycin (RAPA) appears to induce fewer renal side-effects than FK506, although further documentation is required. In this study, the effects of FK506 and RAPA on release of prostacyclin, a vasodilator, and endothelin, a vasoconstrictor, were investigated in cultured rabbit mesangial and endothelial cells. In general, the effects of both RAPA and FK506 on the basal or stimulated release of prostacyclin (as measured by release of its stable metabolite, 6-keto-PGF1 alpha) or endothelin from mesangial cells and endothelial cells were similar with the following exceptions: RAPA resulted in a significant (p < 0.05) increase in the release of prostacyclin (PGI2) from endothelial cells, while in contrast, FK506 resulted in a significant decrease in the release of this analyte from these cells. The similar effects both drugs have on release of vasodilatory and vasoconstrictor substances in vitro does not explain the differences in renal side-effects of the drugs in vivo.

Heterotopic heart transplants were performed on 50 New Zealand white rabbits. Groups of 5 rabbits were randomly assigned to receive, through an intravenous route, rapamycin (RAPA) or cyclosporine at the following doses: RAPA (0.05, 0.1, 0.5, and 1.0 mg/kg/day); CsA (5.0, 10.0, and 15.0 mg/kg/day). Drug vehicle and saline controls were also included. Trough blood concentrations were monitored in both RAPA- and CsA-treated groups on a weekly basis throughout the study. Biochemical assessment of renal and liver function was performed at the beginning and end of the study. Animals receiving RAPA exhibited excellent allograft survival; only two animals in the lowest dosage group (0.05 mg/kg/day) rejected their grafts. In contrast, no rejection occurred in the CsA-treated groups. Animals that rejected their grafts were maintained on the drug until the endpoint of the study was reached at 60 days posttransplant to monitor drug induced side-effects. In some instances animals were sacrificed prior to this time due to infectious and other complications. No significant changes in renal or liver function were noted in the RAPA-treated group, while in the group of animals receiving the highest dose of CsA (15.0 mg/kg/day) a significant decrease in creatinine clearance was noted. A correlation was shown to exist between dose and the trough concentrations of both drugs. The whole-blood concentrations of RAPA that resulted in maximal efficacy with minimal toxicity was in the range of 10-60 micrograms/L. Rabbits having trough whole-blood concentrations of < 10 micrograms/L rejected their grafts. A much wider therapeutic range for CsA (50-300 micrograms/L) was noted. The results suggest that RAPA is as efficacious as CsA in prevention of allograft rejection in the animal model tested. The therapeutic monitoring of trough blood concentrations of RAPA, as with CsA, may be useful in guiding dosage adjustments to maximize the immunosuppressive efficacy while minimizing drug-induced side-effects.