ESPEN Congress Brussels Dietary and pharmacological therapy of Intestinal Failure. Bernard MESSING

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1 ESPEN Congress Brussels 2005 Dietary and pharmacological therapy of Intestinal Failure Bernard MESSING

2 Dietary and pharmacological therapy of Intestinal Failure Professeur Bernard MESSING HOPITAL LARIBOISIERE 2, rue Ambroise Paré Paris Cédex 10 SERVICE D HÉPATOGASTROENTEROLOGIE ET D ASSISTANCE NUTRITIVE Approved centre for Home Parenteral Nutrition bernard.messing@lrb.aphp.fr Intestinal Failure ESPEN Chairmen : M. Hiele & M.Staun

3 Dietary and pharmacological therapy of Chronic Intestinal Failure (CIF) Diet : Nutrients : Enteral Drugs : Liquids, solids Prot (AA) Fat vs Complex CHO Tube feedding according to type of CIF* Hormonal factors : Growth Hormone (GH) Glucagon Like Peptide 2 (GLP2) * Short Bowel Syndrome (anatomical), CIPO (functional) CIF

4 SBS treatment: : per & post.op phase Main goal: hydration, electrolyte / mineral balances -Per.op: Avoid gastric emptying delay with hyper hydration* - Post.op : After the postoperative ileus, losses due to diarrhea, gastric tube and stoma can be up to 10 liters/day - with high Na ( mmol/l) concentration -, especially when restarting feeding - A precise monitoring is needed: - daily BW and hydration status - Fluid supplies & losses - Electrolyte/mineral samples (plasma: twice/wk, urine daily, intestinal effluents : when changing regimen) * Lobo DN et al Lancet 2002;359:

5 Clinical fates of SBS Intestinal failure the reduction in the functioning gut mass induces increased losses with negative balances - Electrolytes: - Minerals: - Macronutrients: - Micronutrients: Water & Na, K Mg Protein/Fat Vit & metals hours, days Ca & K days, weeks months wk to mos 20% of short bowel patients who do not require PN for macronutrient balance still require iv fluid.* * J Nightingale: Proceedings Nutr Society 1994,53,373.

6 - Parenteral nutrition is able to attenuate body weight and fat-free mass depletion, and to improve long term survival (Gouttebel, 1986). SBS treatment : postoperative phase - Fluid and electrolyte monitoring is needed several times /day until equilibrium status is obtained (Vanderhoof, 1997) - Gastric hypersecretion gastrique contributes to water and electrolyte losses. IV Anti H2 receptors antagonists or proton pump inhinitors are needed. Octreotide can be usefull for secretory diarrhea (Nightingale, 1993). - Parenteral nutrition must be initiated early, on a separate venous access.

7 Crenn et al Gut 2004

8 SBS and Hyperphagia In 90 adult studied patients hyperphagia was documented : - in 81% of cases : > 1.5 fold the BEE 41% : REE = % : REE = % : REE = Hyperphagia was negatively related to : - Fat absorption p < BMI p < Was not braked by PN (39 no PN, 51 with HPN) Intake in % of BEE : 2.0±0.6 (± PN) [ ] Crenn et al : Gut 2004,53(9):

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10 3 main anatomical types of SBS - type of anastomose - I, Enterostomy II, Jéjuno-colic III, Jéjuno-ileal Liquids be aware of too much fat Solids : Fat ad libitum Complex carbohydrates ad libitum

11 SBS with IF 2 MAINSTAY DIETETIC RULES: FIRST : SOLID FOODS ad libitum NO SPARE REGIMEN IMPLEMENT & PROMOTE HYPERPHAGIA (similar % of absorption) Lipids (LCT) : type* I proteins : types I, II et III complex carbohydrates (colonic fermentation) : types II et III Type of anastomosis : I entérostomy, II : jéjuno-colic, III : Jéjuno-ileal BM02

12 SBS with IF 2 MAINSTAY DIETETIC RULES: Second : beware liquids especially in SGC type I : sodas, coca : osmotic diarrhea Milk 300 ml : osmotic diarrhea eau plate : sécrétory diarrhea Establish intraluminal isoosmolarity : Salt tablets, réhydration solution +++ BM02

13 Dietary counselling for short-bowel syndrome a Entérostomy b Jéjuno-colonic Fractionated meals ++ +/- Drinks appart from meals? no no Rehydration solution c +++ +/- Salt alone (+ 30% losses)++ ++ CHO alone (or milk) 500 ml/d 750 ml/d Tap water ml/d Rich CHO meals Rich lipidic meals ++ 33% of E MCT +/- + Hyperphagy diet BM. 6th EAGE Modified 04 a Remnant small bowel 200 cm. b 24 h output 600 cc. C OMS in g/l: ClNa 3.5; CO 3 HNa 2.5; KCl 2.5; Glucose 20g, H 2 O 1000 cc.

14 SBS with CIF : drug treatment Optimisation of absorption: Gastric hypersecretion: PPI, no peptic ulcer Slowing transit time: Loperamide, Codeine... Both effects: short-term use of octreotide (if colon -) on long-term: escape & antitrophic effect Biliary salt :? Ox bile, Cholylsarcosine* Preventive treatment of potential complications: Bone: calcium & Mg salts & Vit D metabolites Liver cholestasis & gallbladder lithiasis : Ursodeoxycholate? Preventive Cholecystectomy: up to 45% of gallstones Renal oxalate stones [up to 25%] if + colon: Ca salts Treat BO if dysmotility with Antibiotics > gram - bacilli * Fortran Gastro 1982; Basaeus Scand J Gastro 1986; Little Dig Dis Sci 1992.

15 Management of HPN : examples In SBS, solid oral free hyperalimentation should be encouraged instead of restrictive regimens In SBS, attempt to re establish colonic continuity should always be discussed In SBS with secondary anorexia, enteral nutrition through tube or gastrostomy may decrease PN dependence BM.04

16 SBS treatment: : adaptative phase Main goal: maintain nutritional status and promote intestinal adaptation - Gastrostomy can be performed at surgery if : - remaining small bowel is < 1 m - and previous oral intake is poor (Messing 1997) - Continuous EN was first shown to promote adaptation in a 51-patient series (Levy, 1988) * EN given on day 14 made it possible to interrupt PN after 36 days * Digestive autonomy was obtained within 87 days, more rapidly when remaining SB was > 80 cms.

17 Net absorption: comparison between 3 mode of enteral feeding in SBS Tube n = 16 Oral n = 16 Tube +oral n = 9 Kcal /d 2404 ± ± ± 621 Total Calories (%) 82 ± 12* 65 ± ± 8* Lipids (%) 69 ± 25 * 41 ± ± 19* Proteins (%) 72 ± 13** 57 ± ± 10** Glucids (%) 95 ± 4 88 ± ± 7 SBS 4 type I and 12 type II: post duodenal remnant: 76 ±35 cm, colon 45 ± 29% * For total calories & lipids : p<0.001, ** for proteins p<0.01 in tube alone and tube + oral versus oral F. Joly et al ESPEN 2005 (P057)

18 Gain in net absorption per day with tube or tube + oral versus oral alone in SBS % absorbed Gain if same intake: with tube feeding + 17% Kcal with tube + oral + 10% Kcal Increased intake: Net gain : In % REE x 1.5 In protein (g/kg) : Kcal Kcal 38 ± 13% 0.5 ± Kcal Kcal 58 ± 12% 0.5 ± 0.2 Joly F et al : ESPEN 2005 (P057)

19 Pharmacological therapy of Chronic Intestinal Failure (CIF) due to Very Short Bowel Syndrome Hormonal factors : - Recombinant human Growth Hormone (GH)* - Glucagon Like Peptide 2 (GLP2) Aim : -to up regulate the physiological adaptive processes which can develop only* in the presence of : - Maximal food intake - Absence of malnutrition

20 CUD (%) rhgh Placebo 100% p<0,04 80% p<0,004 60% p<0,05 NS* 40% 75% 54% 66% 20% 40% 39% 25% 31% 18% 0% Calories Azote Lipides H de C * Non significatif Comparaison of net absorption (%) of Energy & macronutriments on rhgh versus placebo n = 12 (moy. ± SE). Seguy et al Gastro 2003;124:

21 Characteristic of 12 HPN dependent SBS Patients rh.gh : 0,05 mg.kg/.d. Randomized, placebo-controlled, cross over study 2 Periods of 3 weeks, 1 week wash out The 15% gain in net absorption was : 430 ± 80 Kcal.d p < This gain represented : 19 ± 8% of BEE x 1.5* * Energy balance equilibrium in SBS type II or III Messing et al : Gastro 1991;100: Seguy et al Gastro 2003;124:

22 rhgh in SBS PN-dependent adults A randomized D.Blind, Placebo-controlled study 41 aged 50±15 yr, 4.6 yrs since resection SB remnant lenght: 73cm; 5 type I (no colon) design : 3 parallel groups after 2-wk diet equilibrium: -diet + P : - diet + oral Gln (30g/d) 4 wk - diet + Gln + rhgh 0.10 mg/kg/j Primary end point : Change in weekly PN volume* - [wk 6 - wk 2] (*PN, hydration, iv lipids) Second : change in kcal and PN frequency Byrne TA et al, JPEN, 2003, 27: S17 (A)

23 rhgh in SBS PN-dependent adults Decrease in PN volume PN kcal PN frequency wk needs L/wk /wk N/wk diet+gln 3.8± ± ±0.9 n=9 diet+rhgh 5.8±3.8* 4323±1855* 3.0±1.8* n=9 diet+gln 7.7± ± ±1.4 + rhgh n=16 * mean ± SD p<0.05; p<0.01 vs diet,gln group Adverse events : limb pains, tissue turgor, GI symptoms. Byrne TA et al, JPEN, 2003, 27: S17 (A)

24 A first long term treatment (6 to 12 weeks) with low dose of rhgh (0.05 mg /Kg /d s.c) in 11 SBS type II (jejuno colonic anastomosis) HPN dependent 5 (2-7) cycles / wk: Was associated with few minor transiant side effects and permitted to decrease significantly the HPN dependence : from 1 to 3 [3(1-3)] cycle per week, 3 weaned off, 8 reduced, with no erosion of the LBM assessed with DEXA. This change was greater than the placebo effect, the latter being associated with a loss of lean body mass. Messing et al ESPEN 2005 P116

25 rhgh and weaning off SBS-HPN The expected effect is a minimum 15% to a maximum 45% reduction PN-dependency* this can benefit patient - no previous cancer - with a less than 50% PN-dependence (< 4 infusions/wk) at a cost of maintenance treatment** with colonic survey due to an increased risk of adenomas : OR 3(2-6) in inappropriate GH secretion patients FDA approved at 0.10 mg/kg/d during one month at the end of the year 2003 * Seguy et al Gastro 2003 & Messing et al ESPEN 05 ** personal unpublished data, GUT 2003 BM.04

26 SBS patients in whom treatment with r-hgh is more likely to be successful. Well nourished Diet and medications optimized Able to take in adequate enteral nutrients and fluids Treatable co-morbid diseases controlled Presence of a colon No history of Crohn s disease E Steiger, B Messing et al Am J Gastro Submitted

27 Increased secretion of proglucagonrelated peptides (PGDPs) and intestinal villus hyperplasia Gleeson et al.; Endocrine tumor in kidney affecting small bowel structure, motility and absorptive function. Gut 1971 However, the identity of the specific intestinal PGDP with intestinotrophic activity proved elusive

28 GLP2 400 ug x 2/d sc. 35 d in SGC type 1 SBS (iléon- Colon -*) entérostomy, 6/8 Crohn. - 4 HPN - 83 cm jejunal remnant - 4 ileal resection (106 cm) Résults (comparison before, end of trt) : - Total absorption : + 3.5±4.0% p <.04 - Protein absorption : + 4.7±5.4% p <.04 - Stool weight : - 11±12% p <.04 - Lean mass Gain : + 2.9±1.9Kg p < Solid Gastric emptying :+ 30±16 mn p<.05 - Crypt prolif/ht villi : 5 et 6/8 respectively *déficit in post prandial GLP-2. Jeppesen et al: Gastro 2001; 120:

29 3-week sc.glp2 analogue* in 16 SBS patients Teduglutide, a dipeptidyl peptidase IV resistant GLP2, mg/kg/d. Teduglutide* increased absolute (+743 (477) g/day; p<0.001) and relative (+22 (16)%; p<0.001) wet weight absorption, urine weight (+555 (485) g/day; p<0.001), and urine sodium excretion (+53 (40) mmol/day; p<0.001). Teduglutide decreased faecal wet weight (-711 (734) g/day; p = 0.001) and faecal energy excretion (-193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy (n=10),were significantly increased: villus height (+38 (45)%; p = 0.030), crypt depth (+22 (18)%; p = 0.010), and mitotic index (+115 (108)%; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity (n=6). The most common side effects were enlargement of the stoma nipple and mild lower leg oedema. Comparison before and last 3-d, Return to baseline after 3 wk Jeppesen PB, et al Gut Sep;54(9):

30 Promote absorption in IF-SBS patients Implement Effect Hyperphagia : no major decrease in % absorbed Enteral : + 20% (700 kcal/d) : 38% of TEE rhgh*: + 15% (400 kcal/d) : 20% of TEE nglp2** : + 5% (100 kcal/d) : 7% of TEE rhglp2 : + 10% (200 kcal/d) : 10% of TEE rhgh/igf-1 + rhglp2 :? (Not done, great hope) * 3 to 4 Wk treatment (0.05 to mg/kg/d); ** Electrolytes & Prot; - 20% in stool wet weight BM.0905

31 Conclusions Dietary education is of primary importance and oral hyperphagia is a necessary goal. GE & mineral, nutritional treatments are also very important. Education is needed to increase a probably poor compliance. Enteral nutrition could be used in the subset of patients who are poor eaters. Cocktail of enterotrophic factors showed promise.

32 5 add slides For discussion If needed

33 Net digestive energy balance of Short Bowel patients End-enterostomy 1 Jejuno(ileo)colonic anastomosis 2 Oral intake; Kcald 2500 ( ) 3100 ( ) Fecal losses: Kcal 1400 ( ) 970 ( ) Percent of absorption 44 (-10,+75) 67 (41-85) Net absorption: Kcald 1100 (-200,+2800) 2130 ( ) Net absorption: % of BEE 80 (-20, +200) 150 (55-330) Fecal output: Kg 3.8( ) 1.4( ) 1 Nightingale et al: Lancet 90;336: Messing et al: GE 91;100: 1502

34 GH and Intestine Animal experiments : - Intestinal résection + hypophysectomy Taylor Bet al. Eur J Clin Invest Transgénic mice surexprimant GH Ulshen MH et al. Gastroenterology Intestinal résection < 80% (rat & mini pig) + GH Benhamou PH et al. J Pediatr Surg Intestinal résection 80% (rat) + GH ± Gln Zhou X et al. J Surg Research 2001 In human : - Brush border vésicules + rhgh Inoue Y et al. Ann Surg rhgh + Glutamine + fibers (non controled : SGC+NPAD) Byrne TA et al. JPEN 1995 BM.04

35 Effect of GLP2 in animals Induction of epithelial proliferation in non-resected mice Drucker et al Proc Natl Acad SCI USA 1996 RNA, protein, BB enzymes normal /g of bowel wt Brubaker et al. Am J Physiol Inhibition of insulin stimulated antral motility in pigs Weiderman et al Scand J Gastro 98 GLP2 Induces additional, but reversible, Intestinal Growth in rats Adapted to Intestinal Resection B. Hartmann, et al. Gastroenterology 03 (A) BM.04

36 Jeppesen et al. Gut 1999;45: Gut 2000

37 Physiology of GLP-2 secretion Enteral nutrition GIP vagus GRP Gastric emptying and secretion Mucosal growth in intestines K-cells L-cells in terminal ileum and colon GLP-2 GIP ~ Glucose-dependent Insulinotrophic Peptide GRP ~ Gastrin Releasing Peptide