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ACS Chapter Meeting Content

ACS Chapter Meeting Content. The Evolving Multimodal Management Plan for Postoperative Ileus: Improving Time to Bowel Recovery. Educational Activity Learning Objectives. Describe the prevalence, pathophysiology, and defining criteria for postoperative ileus (POI)

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ACS Chapter Meeting Content

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  1. ACS Chapter Meeting Content The Evolving Multimodal Management Plan for Postoperative Ileus: Improving Time to Bowel Recovery

  2. Educational Activity Learning Objectives • Describe the prevalence, pathophysiology, and defining criteria for postoperative ileus (POI) • Distinguish evidence-based therapeutic options for the management of POI • Describe how to implement a multimodal management plan in your institution for patients undergoing bowel resection procedures to improve time to bowel recovery

  3. Postoperative Ileus Management Council Definition of POI • Transient cessation of coordinated bowel motility after surgical intervention, which prevents effective transit of intestinal contents and/or tolerance of oral intake Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.

  4. Primary POI: Response by Different Intestinal Segments Average time to resolution of POI after major abdominal surgery1-3 Small intestine: 0-24 hours Stomach: 24-48 hours Colon: 48-120 hours • Luckey A, et al. Arch Surg. 2003;138:206-214. • Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:121-132. • Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.

  5. Pathophysiology of POI: Multifactorial • The major causes of POI • Surgical trauma and manipulation of the bowel • Other surgeries such as hysterectomy, knee, thoracic • Stress • Stimulation of GI opioid receptors by endogenous and exogenous opioids • POI has been generally regarded as a usual and inevitable response to surgery Kehlet H, Holte K. Am J Surg. 2001;182 (5A Suppl):3S–10S. Holte K, Kehlet H. Drugs. 2002;62:2603-2615.

  6. Pathogenesis of POI Is Multifactorial Sympathetic Nervous System1,2Inhibitory neural reflexes Enteric Nervous System2 Nitric oxide Vasoactive intestinal peptideSubstance P Neuropeptide and Hormonal Factors1,2Calcitonin gene-related peptide,endogenous opioid peptides, corticotropin-releasing factor Multiple Pathways Inflammatory Mediators1,2Macrophage and neutrophil infiltration, IL-1, IL-6 Pharmacologic2 Exogenousopioids IL = interleukin 1. Luckey A, et al. Arch Surg. 2003;138:206-214. 2. Behm B, et al. Clin Gastroenterol Hepatol. 2003;1:71-80.

  7. Control Laparotomy 1 Eventration 0.8 Running Compression 0.6 Contractility 0.4 0.2 0 0 0.1 1 10 100 300 Bethanechol uM Effect of Surgical Manipulation Leukocyte infiltration into intestinal mucosa Intestinal contractility * P < 0.05 800 * * 600 * 400 * 200 0 Control Running Compression Eventration Laparo... Kalff J, et al. Ann Surg. 1998;228:652-663.

  8. Inhibitory Effects of Opioids on Bowel Function Brix-Christensen V, et al. Int J Cardiol. 1997;62:191-197. Yoshida S, et al. Surg Endosc. 2000;14:137-140. Kalff JC, et al. Ann Surg. 1998;228:652-663. Cali R, et al. Dis Colon Rectum. 2000;43:163-168.

  9. Risk Factors for Postoperative Ileus • Abdominal surgery • Surgical technique • Prolonged opioid analgesia • Preexisting gastrointestinal disease • Physiological stress from surgery • Physical inactivity pre/post surgery Senagore A. Am J Health-Syst Pharm. 2007;64(S13):S3-7.

  10. Delayed recovery Clinical Impact of POI • Increased postoperative pain • Increased nausea and vomiting • Increased risk of aspiration • Prolonged time to regular diet • Delayed wound healing • Increased risk of malnutrition/catabolism • Prolonged time to mobilization • Increased pulmonary complications • Prolonged hospitalization • Increased health care costs Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S. Leslie JB. Ann Pharmacother. 2005; 39:1502-1510. Behm B, Stollman N. Clin Gastroenterol Hepatol. 2003;1:71-80.

  11. How Long Can POI Last? Figure from Steinbrook RA. Contemp Surg. 2005; March(suppl):4-7. Wolff B, et al. Ann Surg. 2004;240:728-734.

  12. POI and Abdominal Surgery 25 20 15 Coded POI (%) 10 5 0 Abdominal Hysterectomy Large Bowel Resection Small Bowel Resection Chole- cystectomy Nephro- ureterectomy Other Procedures Appendectomy HCFA Data 1999-2000 Delaney C, et al. Clinical Consensus Update in General Surgery. 2006.

  13. Economic Burden of POI • Nasogastric (NG) intubation • IV hydration • Additional nursing care • Lab tests • Increased hospital days Livingston E, Passaro E Jr. Dig Dis Sci. 1990;35:121-132. Collins TC, et al. Ann Surg. 1999;230:251-259. Sarawate CA, et al. Gastroenterology. 2003;124:A-828.

  14. Postoperative Ileus: Economic Consequences and Length of Stay (LOS) • Prolonged POI at an Academic Medical Center (ICD-9 codes 564.4 and 997.4) • Total of 83 patients (total abdominal hysterectomy & hemicolectomy) Salvador CG, et al. P&T. 2005;30:590-595.

  15. Indications for Readmission Surgical site septic complications (SSSC) 24% 20% Ileus/small bowel obstruction (SBO) Medical complications 23% 33% Other Kariv Y, et al. Am J Surg. 2006;191:364-371.

  16. Factors Associated With Readmission Cause RD = readmission within 30 days of discharge SSSC: surgical site septic complications; SBO: small bowel obstruction Kariv Y, et al. Am J Surg. 2006;191:364-371.

  17. Options to Reduce LOS • Change discharge criteria • Change postoperative care plans • Altered surgical technique • Laparoscopy vs Open • Different incisions • Enhance postoperative recovery • Better analgesia • “Anti-ileus” adjuncts • Early ambulation

  18. Current Management Strategies for Postoperative Ileus

  19. Preventive and Therapeutic Management Options for POI Physical Options Nasogastric tube Early postoperative feeding Early ambulation Surgical Technique Laparoscopy Psychological Perioperative Information Anesthesia and Analgesia Epidural NSAIDs Pharmacologic Prokinetic agents Opioid (PAMOR) antagonists Other agents Perioperative Care Plan(s) Multimodal clinical pathways Fluid/sodium restriction? PAMOR = peripherally acting µ-opioid receptor antagonist Luckey A, et al. Arch Surg. 2003;138:206-214.

  20. Management Options for POI Holte K, Kehlet H. Drugs. 2002;62:2603-2615. Behm B, Stollman N. Clin Gastroenterol Hepatol. 2003;1:71-80. Luckey A, et al. Arch Surg. 2003;138:206-214.

  21. Prophylactic Nasogastric Decompression Following Abdominal Surgery • Meta-analysis • 33 Studies, N = 5,240 patients • Patients without routine NG tube use had: • Earlier return of bowel function (P < 0.00001) • Decrease in pulmonary complications (P = 0.01) • Trend toward increase risk of wound infection (P = 0.22) • Shorter length of stay • No difference in anastomotic leak between patients with vs without NG tubes (P = 0.70) • “Routine nasogastric decompression does not accomplish any of its intended goals and should be abandoned in favor of selective use of the nasogastric tube” Nelson R, et al. Cochrane Database Syst Rev. 2007;Jul 18;(3):CD004929.

  22. Early Oral/Enteral Nutrition Within 24 Hours of Intestinal Surgery • Meta-analysis of 13 clinical trials, N = 1,173 patients • Mortality – reduced with early post-op feeding • RR (95% CI): 0.41 (0.18, 0.93) • Data suggestive of reduced • Wound Infections – RR (95% CI): 0.77 (0.48, 1.22) • Pneumonia - RR (95% CI): 0.76 (0.36, 1.58) • Length of Stay - RR (95% CI): -0.60 (-0.66, -0.54) • Anastomotic Dehiscence – little evidence of benefit or harm • RR (95% CI): 0.69 (0.36, 1.32) • Overall conclusion: no benefit for restricting postoperative oral/enteral nutrition Lewis S, et al. J Gastrointest Surg. 2009;13:569-575.

  23. Mobilization and Postoperative Ileus • Important in helping to prevent postoperative complications, ie, clots, atelectasis, or pneumonia • Ambulation thought to help increase blood flow to the GI and speed up recovery from POI • Lack of studies showing any effect of mobilization (alone) to stimulate bowel function and decrease duration of POI Waldhausen J, et al. Ann Surg. 1990;212:671-677.

  24. Controlled Rehabilitation with Early Ambulation and Diet (CREAD)Laparotomy & Intestinal Resection • Compared with traditional postoperative care: • CREAD patients spent less total time in the hospital following surgery (5.4 vs 7.1 days, P = 0.02) • Patients < 70 years had greater benefits than overall study group • No adverse effect on patient satisfaction, pain scores, complications, or readmission rates • Increased surgeon experience with CREAD associated with improved outcome N = 31 CREAD patients N = 33 traditional postop care patients Delaney C, et al. Dis Col Rect. 2003;46:851-859.

  25. Surgical Technique - Laparoscopy • Duration of ileus is shortened after less invasive surgery • Progression to a solid diet and discharge is faster • Several studies have shown favorable results • Possible rationale • Reduced surgical trauma leads to less sympathetic activation and inflammation • Smaller incisions, less pain (therefore less opiate use) • Earlier ambulation, earlier tolerance of feeding, less NGT use Holte K, Kehlet H. Drugs. 2002;62:2603-2615. Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.

  26. . Laparoscopic Open RCT: Laparoscopy vs Open Surgery 120 100 80 60 40 20 0 * Duration of Ileus (h) * * D D F F Lacy et al. (1995) Schwenk et al. (1998) Milsom et al. (1998) Leung et al. (2000) *P < 0.05 D = defecation; F = flatus; RCTs = randomized clinical trials. Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493. Kehlet H, Holte K. Am J Surg 2001;182(5A suppl):3S-10S.

  27. Intraoperative Measures:Laparoscopic Surgery • Meta-analysis of 22 trials (n= 2965) of colorectal surgery • Reduced blood loss of 71.8 mL (95% CI, 30.8-113 mL; P = 0.0006) • Reduced postoperative pain by 9.3/100 (95% CI, 5.4-13.2; P < 0.0001) • Earlier flatulence by 1 day (95% CI, 0.76-1.3; P < 0.0001) • Earlier bowel movement by 0.9 days (95% CI, 0.74-1.13; P < 0.0001) • Lessened ileus (RR = 0.40 95% CI, 0.22-0.73; P = 0.003) • Reduced wound infections (RR = 0.56 95% CI, 0.39-0.89; P = 0.002) • Shortened hospital length of stay (LOS) by 1.5 days (95% CI, 1.12-1.94; P < 0.0001) Schwenk W, et al. Cochrane Database Syst Rev. 2005;CD003145.

  28. Management Options for POI Holte K, Kehlet H. Drugs. 2002;62:2603-2615. Behm B, Stollman N. Clin Gastroenterol Hepatol. 2003;1:71-80. Luckey A, et al. Arch Surg. 2003;138:206-214. Becker G, Blum H. Lancet. 2009;373(9670):1198-1206..

  29. Epidural Thoracic Anesthetics • Epidural (epi) anesthesia with local anesthetics (LA) • Suppression of inhibitory neural responses • Randomized trials demonstrate decreased POI duration compared with systemic opioids • epi-LA vs systemic opioid =  POI • epi-LA vs epi-opioid =  POI • epi-LA/opioid vs systemic opioid =  POI (less than epi-LA) • Location of catheter important: thoracic application more effective than lumbar or low-thoracic Jorgensen H, et al. Br J Anaesthesia. 2001;87:577-583. Steinbrook R. AnesthAnalg.1998;86:837-844. Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493. Jorgensen H, et al. Cochrane Database Syst Rev. 2001;(1):CD001893.

  30. Epidural Analgesia and Duration of Postoperative Ileus *Compared with systemic analgesic regimens; IPAA: ileal pouch anal anastomosis Adapted from Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.

  31. Opioid-Sparing Analgesia • Nonsteroidal anti-inflammatory drugs (NSAIDs) • Reduce prostaglandin production • Randomized, double-blind study of morphine PCA ± ketorolac in 79 colorectal surgeries showed 29% less morphine use, earlier first bowel movement (1.5 [0.7-1.9] vs 1.7 [1-2.8] days, P < 0.05), and earlier ambulation (2.2 ± 1 vs. 2.8 ± 1.2 days, P < 0.05) with NSAID use • Similar results in other surgeries and epidural route • Concerns: platelet inhibition (bleeding) • Cyclooxygenase-2 (COX-2) Inhibitors • Similar results as NSAIDs; safety? • Surveys indicate patients prefer inadequate pain relief over adequate analgesia with associated bowel dysfunction Person B, Wexner S. Curr Probl Surg. 2006;43:6-65. Chen JY. Acta Anaesthesiol Scand. 2005;49:546-551.

  32. Effect of Metoclopramide on POI 120 100 80 60 40 20 0 Metoclopramide Placebo Duration of Ileus (h) I D F Jepsen et al. (1986) Cheape et al. (1991) Tollesson et al. (1991) Jepsen S, et al. Br J Surg. 1986;73:290-291. Cheape JD, et al. Dis Colon Rectum. 1991;34:437-441. Tollesson PO, et al. Eur J Surg. 1991;157:355-358. Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493. D = defecation; F = flatus; I = ingestion of solid food

  33. POI: Peripheral Opioid Antagonism Most patients require opioids Opioids inhibit GI propulsive motility and secretion; the GI effects of opioids are mediated primary by µ-opioid receptors within the bowel Naloxone and naltrexone reduce opioid bowel dysfunction but reverse analgesia An ideal POI treatment is a peripheral opioid receptor antagonist that reverses GI side effects without compromising postoperative analgesia Alvimopan Methylnaltrexone Kurz A, Sessler DI. Drugs. 2003;63:649-671.Taguchi A, et al. N Engl J Med. 2001;345:935-940.

  34. CH3 + Methylnaltrexone: A Novel, Quaternary -Opioid Receptor Antagonist NaltrexoneN-methylnaltrexone • Poorly lipid soluble, does not penetrate the BBB, not demethylated to significant extent in humans • Does not antagonize the central (analgesic) effects of opioids or precipitate withdrawal Foss JF. Am J Surg. 2001;182 (5ASuppl):19S-26S.

  35. Methylnaltrexone: MNTX 203 Methods • Phase 2 study for reduction of postoperative bowel dysfunction • Randomized, double-blind, placebo-controlled • 65 patients undergoing segmental colectomy • MNTX 0.3 mg/kg or placebo i.v. • First dose within 90 min of end of surgery, then every 6 hr • Up to 24 hr after GI recovery, max of 7 days • GI recovery: tolerated solid food plus bowel movement (BM) Viscusi E, et al. Anesthesiology. 2005;103:A893.

  36. 200 180 160 * 140 120 * MNTX N = 33 100 Time (hours) * Placebo N = 32 80 60 40 20 0 Full Liquids 1st BM GI Recovery Discharge Actual Eligible Discharge Methylnaltrexone: Phase 2 Results *P < 0.05 Viscusi, E et al. Anesthesiology. 2005;103:A893.

  37. Methylnaltrexone for POI: Phase 3 Studies Segmental colectomy1,2 and ventral hernia repair3 • Treatment: IV methylnaltrexone (12 or 24 mg) or placebo every 6 hours • Primary endpoint: Reduction in time to recovery of GI function compared with placebo • Results: Treatment did not achieve primary or secondary endpoints4-6 1. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00387309. Accessed March 2009. 2. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00401375. Accessed March 2009. 3. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00528970. Accessed March 2009. 4. Available at: http://www.wyeth.com/news/archive?nav=display&navTo=/wyeth_html/home/news/pressreleases/2008/ 1205322072160.html. Accessed March 2009. 5. Available at: http://www.progenics.com/releasedetail.cfm?ReleaseID=311785. Accessed March 2009. 6. Available at: http://www.progenics.com/releasedetail.cfm?ReleaseID=370543. Accessed July 2009.

  38. Fentanyl Alvimopan: A Novel, Quaternary-Opioid Receptor Antagonist Moderately Large MW (461 Da) Alpha vimu opioid peripheral antagonist Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S.

  39. Alvimopan • Peripherally acting µ-opioid receptor antagonist1 • Highly selective for µ-opioid receptor over  and κ receptors1,2 • Higher potency at µ-opioid receptor than morphine and methylnaltrexone2 • Because of large molecular weight and polarity, does not readily cross the blood-brain barrier; thus, does not block central opioid receptors2 • Phase I, phase II, and phase III trials have been completed3-8 • FDA approval May 20089 • Azodo IA, et al. Curr Opin Investig Drugs. 2002;3:1496-1501. • Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S. • Taguchi A, et al. N Engl J Med. 2001;345:935-940. • Wolff BG, et al. Ann Surg. 2004;240:728-735. • Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. • Viscusi E, et al. Surg Endosc. 2006;20:67-70. • Ludwig K, et al. Arch Surg. 2008;143:1098-1105. • Buchler M, et al. Aliment Pharmacol Ther. 2008;28:312-325. • FDA approval available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed March 2009.

  40. Alvimopan for POI - Phase 3 Clinical Trial Summary GI-3: later time of first tolerated solid food and time for first flatus or bowel movement; GI-2: later time of first tolerated solid food and time for bowel movement; DOW: time to discharge order written All studies conducted in North America except 001, which was conducted in Europe and New Zealand • Wolff BG, et al. Ann Surg. 2004;240:728-735. • Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. • Viscusi E, et al. Surg Endosc. 2006;20:67-70. • Ludwig K, et al. Arch Surg. 2008;143:1098-1105. • Buchler M, et al. Aliment Pharmacol Ther. 28:312-325.

  41. Alvimopan POI Phase 3 Study Design Placebo BID Alvimopan 6 mg BID Randomization Treatment until discharge or up to 7 days Alvimopan 12 mg BID Pre-op dose ≥ 30 min and < 5 hrs before surgery Endpoints: GI-2, GI-3, Time to discharge order written, safety Surgery Upper and Lower GI Recovery GI-3: later time of first tolerated solid food and time for first flatus or bowel movement; GI-2: later time of first tolerated solid food and time for bowel movement

  42. Alvimopan Phase 3 Studies – GI Recovery 140 Placebo 6 mg Alvimopan 12 mg Alvimopan § 120 § # * # # * 100 * 80 Time to GI-2 (hours) 60 40 20 0 Study 313 Study 302 Study 308 Study 314 Study 001 Wolff BG, et al. Ann Surg. 2004;240:728-735. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. Viscusi E, et al. Surg Endosc. 2006;20:67-70. Ludwig K, et al. Arch Surg. 2008;143:1098-1105. Buchler M, et al. Aliment Pharmacol Ther. 28:312-325. *P < 0.001; #P < 0.01; §P < 0.02; Studies 313, 302, 308 include bowel resection and hysterectomy; Studies 314, 001 bowel resection only

  43. Alvimopan Phase 3 Studies: Discharge Orders Written Study 313 Study 302 Study 308 Study 314 Study 001 0 -5 -10 Reduction in Time to Discharge Order Written Compared with Placebo (hours) P = 0.008 P < 0.001 -15 P = 0.015 P < 0.001 -20 P = 0.003 6 mg Alvimopan 12 mg Alvimopan -25 Studies 313, 302, 308 include bowel resection and hysterectomy; Studies 314, 001 bowel resection only All studies conducted in North America except 001, which was conducted in Europe and New Zealand

  44. Alvimopan Bowel Resection Pooled Analysis P value 1.28 0.001 < 0.001 GI-3 1.38 Alvimopan 6 mg Alvimopan 12 mg 1.34 GI-2 < 0.001 < 0.001 1.46 1.37 < 0.001 < 0.001 Ready for HD 1.48 1.36 < 0.001 < 0.001 DOW 1.43 0 0.5 1 1.5 2 2.5 In favor of placebo In favor of alvimopan GI-3: later time of first tolerated solid food and time for first flatus or bowel movement; GI-2: later time of first tolerated solid food and time for bowel movement; HD: ready for hospital discharge based on GI recovery; DOW: discharge order written Delaney C, et al. Ann Surg. 2007;245:355-363. Studies 302, 308, 313

  45. Alvimopan POI-Related MorbidityBowel Resection Pooled Analysis‡ 18 16 Placebo N = 695 14 Alvimopan 12 mg N = 714 12 10 * Patients (%) * 8 6 * 4 * 2 0 Overall POM Post-op NGT Overall POI POI Complications Resulting in Prolonged Stay POI Complications Resulting in Readmission Insertion Complications POM: postoperative morbidity; NGT: nasogastric tube; POI: postoperative ileus *P≤ 0.001 ‡Studies 302, 308, 313, 314 Wolff B, et al. J Am Coll Surg. 2007;204:609-616.

  46. Alvimopan Safety Treatment-emergent Adverse Events Reported in ≥ 3% Alvimopan-treated Patients and for Which the Rate for Alvimopan was ≥ 1% than Placebo Worldwide POI Safety Population Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009.

  47. Alvimopan for POI Summary • Treatment of patients undergoing bowel resection with alvimopan compared with placebo: • Accelerated return of bowel function • Reduced the time to discharge order written • Reduced postoperative ileus-related morbidity • Alvimopan did not reverse postoperative analgesia • Alvimopan was well tolerated; adverse events were similar between placebo and alvimopan treatment groups

  48. Alvimopan for Opioid-induced Bowel Dysfunction (OBD) • 12-month study in patients taking opioids for chronic non-cancer pain • Alvimopan (0.5 mg) or placebo BID • More reports of myocardial infarction in patients treated with alvimopan (1.3%) compared with placebo (0) • Serious cardiovascular adverse events in patients at high risk for cardiovascular disease • Myocardial infarction did not appear to be linked to duration of dosing • Not observed in other alvimopan studies, including POI studies in patients undergoing bowel resection (12 mg dose BID for up to 7 days) • Causal relationship between alvimopan and myocardial infarction has not been established Available at: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01838.html; http://www.gsk.com/media/pressreleases/2007/2007_04_09_GSK1012.htm. Accessed March 2009.

  49. Alvimopan for POI: Formulary Considerations • E.A.S.E.™ Program • Distribution Program for ENTEREG® (alvimopan) • Alvimopan is available only to hospitals that enroll in the E.A.S.E. Program. To enroll in the E.A.S.E. Program, the hospital must acknowledge that hospital staff who prescribe, dispense, or administer alvimopan have been provided the educational materials on: • Limiting the use of alvimopan to short-term, inpatient use • Patients will not receive more than 15 doses of alvimopan • Alvimopan will not be dispensed to patients after they have been discharged from the hospital • Hospital will not transfer alvimopan to unregistered hospitals E.A.S.E.: Entereg Access Support and Education. Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009.

  50. Multimodal/Fast Track Management for Postoperative Ileus

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