Prolonged Postoperative Ileus After Whipple Procedure

1. Prolonged Postoperative Ileus After Whipple Procedure Richard A. Steinbrook, MD  Director of Clinical Research Department of Anesthesia, Critical Care and Pain Medicine Beth Israel Deaconess Medical Center Associate Professor Harvard Medical School Boston, Massachusetts

2. Faculty Disclosure It is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty, activity planners, content reviewers, and staff participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a person with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation has identified and resolved any and all conflicts of interest prior to the release of this activity. Richard A. Steinbrook, MD, has no financial information to disclose.

3. Educational Learning Objectives Describe the importance of improving time to gastrointestinal recovery that occurs postsurgery and consider how this affects length of hospital stay and overall quality of patient care Evaluate the evidence for therapeutic options that may improve gastrointestinal recovery postsurgery and integrate these efforts toward supporting overall surgical quality measures

4. Case Presentation • 58-year-old woman presented with painless jaundice • Abdominal CT scan: mass in head of pancreas • Past medical history: hypertension, coronary artery disease (S/P MI, S/P LAD angioplasty) • Past surgical history: tubal ligation, cholecystectomy, breast biopsy • Meds: aspirin, atenolol, diltiazem, lisinopril • Height 5 ft 4 in, weight 192 lbs, BMI 33, BP 160/80, HR 60 S/P: status post MI: myocardial infarction LAD: left anterior descending artery

5. Patient Case: Preoperative Labs Hematocrit 38.1% Platelets 258,000/μL INR 1.5 ALT 926 U/L AST 369 U/L LDH 380 U/L Alkaline phosphatase 418 U/L Total bilirubin 9.7 mg/dL Amylase 56 U/L

6. Patient Case: Surgical Procedure • Radical pancreaticoduodenectomy with insertion of a feeding jejunostomy tube • General anesthesia including fentanyl and morphine • Normothermia maintained during 12.5 hour surgery • No epidural or ketorolac because of prolonged INR

7. Patient Case: Postoperative Week 1 Initial pain control with IV morphine via PCA Bowel function returned--bowel sounds, flatus, bowel movement Oral analgesia: oxycodone and acetaminophen PCA: patient-controlled analgesia

8. Patient Case: Postoperative Week 2 • Unable to tolerate feeding via jejunostomy tube or by mouth--poor appetite, sense of abdominal fullness, nausea, vomiting • Upper GI with small bowel follow through normal To be continued…

9. What is Postoperative Ileus? • 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.

10. Delayed recovery POI Has a Major Clinical Impact • 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. Asgeirsson T, et al. J Am Coll Surg. 2010;210:228-231.

11. There Are Numerous Risk Factors for POI Extent of Bowel Manipulation Surgical Site POI is Expected to Affect Almost Every Patient Who Undergoes Abdominal Surgery Amount of Opioids Operation Time To read more about the pathogenesis of POI, click here: http://www.ncbi.nlm.nih.gov/pubmed/17909274 Resnick J, et al. Am J Gastroenterol. 1997;92:751-762. Resnick J, et al. Am J Gastroenterol. 1997;92:934-940. Senagore AJ. Am J Health-Syst Pharm. 2007;64(suppl 13):S3-S7. Senagore AJ, et al. Surgery. 2007;142:478-486. Woods MS. Perspect Colon Rectal Surg. 2000;12:57-76.

12. The Economic Burden of POI Associated with Abdominal Surgery Is Substantial Cumulative costs for coded POI (total hospitalization + readmission cost) = $1,464,167,173 Data from Premier’s Perspective Comparative Database,160 Hospitals, 2002 Goldstein J, et al. P&T. 2007;32(2):82-90.

13. There Are Multiple Preventive and Therapeutic Management Options for POI • Patient Education/Perioperative Information • Physical Options • Nasogastric tube • Early postoperative feeding • Chewing gum • Early ambulation • Surgical Technique • Laparoscopy • Pharmacologic • Epidural analgesia • NSAIDs • IV fluid restriction • Prokinetic agents • Peripheral opioid antagonists • Perioperative Care Plan(s) • Multimodal clinical pathways Luckey A, et al. Arch Surg. 2003;138:206-214.

14. 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.

15. Management Options for POI Holte K, Kehlet H. Drugs. 2002;62:2603-2615. Lobo DN, et al. Lancet. 2002;359:1812-1818 Becker G, Blum H. Lancet. 2009;373(9670):1198-1206.

16. IV Fluid Restriction Shortens LOS 250 200 150 100 50 0 Solid-Phase Gastric Emptying TimeT50 (min) Open hemicolectomy Standard group: ≥ 3 L water 154 mmol sodium/day Restricted group: ≤ 2 L water 77 mmol sodium/day More complications, longer LOS in standard group n = 10 n = 10 P = 0.028 Standard Group Restricted Group 200 150 100 50 0 Liquid-Phase Gastric Emptying TimeT50 (min) n = 10 n = 10 P = 0.017 Standard Group Restricted Group Lobo DN, et al. Lancet. 2002;359:1812-1818.

17. Routine Nasogastric Decompression Following Abdominal Surgery Is Not Indicated • 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 NG tube” Nelson R, et al. Cochrane Database Syst Rev. 2007;(3):CD004929.

18. True or False? Data from multiple studies have shown that there is no benefit for restricting postoperative oral/enteral feeding following colorectal surgery, and in fact early feeding may be advantageous. Question A) True B) False Submit

19. True A number of clinical trials have demonstrated benefits for early advancement of diet following colorectal surgery, and this is a common element of enhanced recovery protocols.

20. Oral/enteral Nutrition within 24 hours of Intestinal Surgery May Be Beneficial • 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 To read more about this meta-analysis, click here: http://www.ncbi.nlm.nih.gov/pubmed/18629592 Lewis S, et al. J Gastrointest Surg. 2009;13:569-575.

21. Early Mobilization Is Beneficial, But May Not Shorten Postoperative Ileus • Important in helping to prevent postoperative complications, ie, clots, atelectasis, or pneumonia • Ambulation thought to help increase GI blood flow and accelerate 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.

22. Gum Chewing May Decrease LOS

23. Laparoscopic Surgery Is Associated With Decreased Length of Stay • 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.

24. Which of the following best describes epidural analgesia for pain management with colorectal surgery? Question A) Multiple studies have shown that epidural analgesia is associated with reduced duration of postoperative ileus B) Use of epidural analgesia is consistently associated with reduced length of stay C) A and B Submit

25. Multiple studies have shown that epidural analgesia is associated with reduced duration of postoperative ileus Reduced duration of postoperative ileus and high quality pain relief have been demonstrated with the use of thoracic epidurals for colorectal surgeries. Interestingly, the benefits on POI have not consistently translated into significant reduction in length of hospital stay.

26. Epidural Analgesia Is Associated with Decreased Duration of Postoperative Ileus 200 Epidural local anesthetic Systemic opioid 150 Duration of Ileus (h) 100 * * * * * 50 * D C D D D D F D 0 Liu et al, 1995 Ahn et al, 1988 Wallin et al, 1986 Riwar et al, 1992 Wattwill et al, 1989 Scheinin et al, 1987 Neudecker et al, 1999 Bredtmann et al, 1990 *P < 0.05D = defecation; C = combination score (flatus and defecation); F = flatus Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.

27. Epidural Anesthesia/Analgesia Increases GI Motility Epidural local anesthetics decrease the duration of postoperative ileus after abdominal surgery1 Mechanisms by which thoracic epidural anesthesia may promote GI motility2-5: Blockade of nociceptive afferent nerves and thoracolumbar sympathetic efferent nerves Unopposed parasympathetic efferent nerves Reduced need for additional systemic opiates Increased GI blood flow Systemic absorption of local anesthetic, with analgesic and anti-inflammatory effects Jorgensen et al. Cochrane Database Syst Rev 2000;(4):CD001893. Moraca RJ, et al. Ann Surg. 2003;238:663-673. Steinbrook RA. Anesth Analg. 1998;86:837-844. Liu SS, et al. Anesthesiology. 1995;82:1474-1506. 5. Swenson BR, et al. Reg Anesth Pain Med. 2010;35:370-376.

28. Epidural Anesthesia/Analgesia Effect on Length of Stay • Epidurals • Benefits demonstrated for pain relief and duration of POI • However epidural use has not consistently translated into a significant reduction in length of stay, such as when used for laparoscopic colorectal surgeries or when combined with an enhanced recovery protocol To read more about epidural analgesia for colorectal surgery, click here: http://www.ncbi.nlm.nih.gov/pubmed/17514701 Marret E, et al. Br J Surgery. 2007;94:665-673. Zutshi M, et al. Am J Surgery. 2005;189:268-272. Werawatganon T, Charuluxanun S. Cochrane Database Syst Rev. 2005;(1):CD004088. Dennis RJ, Mills P. World J Laparoscop Surg. 2008;1:49-52.

29. Patient Case (cont) Bowel function appeared to have returned--bowel sounds, flatus, bowel movement Subsequently unable to tolerate feeding via jejunostomy tube or by mouth--poor appetite, sense of abdominal fullness, nausea, vomiting Metoclopramide plus erythromycin administered, but postoperative ileus persisted

30. Neither Metoclopramide nor Erythromycin Is Beneficial for Postoperative Ileus 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; Seta ML, et al. Pharmacotherapy. 2001;21:1181-1186; Chan DC, et al. World J Gastroenterol. 2005;11:4776-4781; Lightfoot AJ, et al. Urology. 2007;69:611-15; Bonacini M, et al. Am J Gastroenterol. 1993;88:208-211; Smith AJ, et al. Dis Colon Rectum. 2000;43:333-337.

31. Peripheral Opioid Antagonists May Be Effective for POI 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 Peripheral opioid receptor antagonists reverse GI side effects without compromising postoperative analgesia Methylnaltrexone Alvimopan Becker G, Blum HE. Lancet. 2009;373:1198-1206 Kurz A, Sessler DI. Drugs. 2003;63:649-671.Taguchi A, et al. N Engl J Med. 2001;345:935-940. Viscusi ER, et al. Anesth Analg. 2009;108:1811-1822.

32. Alvimopan Accelerated GI Recoveryin 5 Bowel Resection Studies 1.0 Alvimopan 12 mg Placebo 0.9 0.8 0.7 0.6 Estimated Probability of Achieving GI-2 Recovery 0.5 0.4 Increased risk of prolonged POI in the placebo group 0.3 0.2 0.1 0.0 0 24 48 72 96 120 144 168 192 216 240 264 Hours After End of Surgery • 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 MW, et al. Aliment Pharmacol Ther. 2008:28:312-325. FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021775s004lbl.pdf. Accessed July 2012.

33. Methylnaltrexone Is Effective for Opioid-Induced Bowel Dysfunction Methylnaltrexone accelerated GI recovery in a phase 2 study of postoperative bowel dysfunction Methylnaltrexone increased spontaneous bowel movements in constipated patients with advanced illness on chronic opioids Methylnaltrexone has not shown benefit in phase 3 trials to date for segmental colectomy or ventral hernia repair Methylnaltrexone is FDA-approved for the treatment of opioid-induced constipation in patients with advanced illness Viscusi E, et al. Anesthesiology. 2005;103:A893. Thomas J, et al. N Engl J Med. 2008;358:2332-2343. Yu CS, et al. Dis Colon Rectum.2011;54:570-578.

34. Alvimopan Is Effective for Postoperative Ileus In patients undergoing bowel resection, alvimopan Accelerated return of bowel function Reduced the time to discharge order written Reduced postoperative ileus-related morbidity Did not reverse postoperative analgesia Alvimopan is FDA-approved for accelerating GI recovery following bowel resection with primary anastomosis Benefit of alvimopan uncertain for laparoscopic procedures, with epidural analgesia, or together with NSAIDs Becker G, Blum HE. Lancet.2009;373:1198-1206. Vaughan-Shaw PG, et al. Dis Colon Rectum. 2012;55:611-620.

35. Multimodal/Fast-Track Management for Postoperative Ileus

36. What Is “Fast-Track Recovery”? • “An interdisciplinary multimodal concept to accelerate postoperative convalescence and reduce general morbidity (including POI) by simultaneously applying several interventions” • What are the appropriate choices in constructing fast-track, multimodal protocols? NG tube removal Opioid sparing Laparoscopicsurgery Laxatives, prokinetics Early feeding, fluid management Epidural anesthetics Mobilization? Mattei P. World J Surg. 2006;30:1382-1391. Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.

37. At your institution, do you manage colorectal surgery patients with an enhanced recovery (“fast-track”) protocol? Question A) Yes B) No C) Sometimes Submit

38. While the benefits of enhanced recovery protocols have been demonstrated in numerous studies, a survey of general and colorectal surgeons in the US indicated that only 30% practice in hospitals with a perioperative surgical care pathway intended to accelerate gastrointestinal recovery. To read more about the results of this survey, click here: http://www.ncbi.nlm.nih.gov/pubmed/20226899 Delaney CP, et al. Am J Surg. 2010;199:299-304.

39. Multimodal Approach White PF, et al. Anesth Analg. 2007;104:1380-1396.

40. Multimodal Approach White PF, et al. Anesth Analg. 2007;104:1380-1396.

41. In your experience, has implementation of an enhanced recovery protocol (ERP) translated into beneficial outcomes for your colorectal surgery patients? Question A) Yes B) No C) I’m not sure; it is too soon to evaluate outcomes D) Not applicable, we do not use an ERP Submit

42. In your experience, has implementation of an enhanced recovery protocol (ERP) translated into beneficial outcomes for your colorectal surgery patients? • Yes • No • I’m not sure; it is too soon to evaluate outcomes • Not applicable, we do not use an ERP

43. Benefits Associated with Multimodal Components

44. Multimodal Outcomes • Expedited gastrointestinal recovery • Earlier oral nutrition • Fewer complications • Shortened hospital LOS • Fewer readmissions • Cost minimization • Greater patient satisfaction? • Best results with epidural anesthesia/analgesia For more about enhanced recovery protocols click here: http://www.ncbi.nlm.nih.gov/pubmed/17513630 Person B, Wexner S. Curr Probl Surg. 2006;43:6-65. White PF, et al. Anesth Analg. 2007;104:1380-1396. Raue W, et al. Surg Endosc. 2004;18:1463-1468.

45. Patient Case (cont) • Radical pancreaticoduodenectomy (> 12 hr) • General anesthesia, opiate analgesia • POI > 2 weeks despite prokinetics • Post-op day 15: epidural placed at T7/8, bupivacaine, and hydromorphone • Appetite improved, diet advanced • Discharged to home on postop day 21

46. Patient Case: Take-home Points • Extensive abdominal surgery may result in prolonged POI • Opiate analgesics potentiate POI • Prokinetic drugs are not beneficial • Thoracic epidural blockade shortens the duration of POI

47. Summary Postoperative ileus has a multifactorial pathophysiology Neurogenic, inflammatory, hormonal, pharmacologic components Selective nasogastric tube use, laparoscopic surgery, epidural anesthesia/analgesia, and opioid-sparing techniques help to reduce the duration of POI Peripheral opioid receptor antagonism is a promising approach for accelerating GI recovery in patients following bowel resection Accelerating recovery of GI function improves clinical outcomes, enhances patient comfort, and reduces hospital length of stay A multimodal approach incorporating nonpharmacologic and pharmacologic options is an effective strategy for managing POI