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 SchoolBoston, Massachusetts

Prolonged Postoperative Ileus After Whipple Procedure

Faculty DisclosureIt 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.

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

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 60S/P: status postMI: myocardial infarctionLAD: left anterior descending artery

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

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

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

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…

• Transient cessation of coordinated bowel motility after surgical intervention, which prevents effective transit of intestinal

contents and/or tolerance of oral intake

What is Postoperative Ileus?

Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.

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

Delayed recovery

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.

There Are Numerous Risk Factors for POI

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.

Systemic Infec-tions Patient Health

Extent of Bowel Manipulation

Surgical Site

Amount of Opioids

Operation Time

POI is Expected to Affect Almost

Every Patient Who Undergoes

Abdominal Surgery

To read more about the pathogenesis of POI, click here: http://www.ncbi.nlm.nih.gov/pubmed/17909274

The Economic Burden of POI Associated with Abdominal Surgery Is Substantial

Goldstein J, et al. P&T. 2007;32(2):82-90.

Data from Premier’s Perspective Comparative Database,160 Hospitals, 2002

Coded POI Without Coded POITotal number of procedures (%) 142,026 (8.5%) 1,519,663 (91.5%)

Average length of stay (days) 11.5 5.5

Cost per hospital stay $18,877 $9,460

Number of readmissions (%) 5,113 (3.6%) 304 (0.02%)

Cumulative costs for coded POI (total hospitalization + readmission cost) = $1,464,167,173

There Are Multiple Preventive and Therapeutic Management Options for POI

Luckey A, et al. Arch Surg. 2003;138:206-214.

PharmacologicEpidural analgesiaNSAIDsIV fluid restrictionProkinetic agentsPeripheral opioid

antagonists

Perioperative Care Plan(s)Multimodal clinical

pathways

Patient Education/Perioperative Information

Physical OptionsNasogastric tubeEarly postoperative feedingChewing gumEarly ambulation

Surgical TechniqueLaparoscopy

Management Options for POINonpharmacologic Options

Management Potential Mechanism CommentsNG tube Gastric/small bowel

decompressionHelps symptoms of POI, but no evidence NG tubes reduce duration of POI; may increase pulmonary postoperative complications

Early feeding or chewing gum

Stimulates GI motility by eliciting reflex response and stimulating release of hormonal factors

Appears safe, well tolerated; some, but not all, studies suggest decrease in POI

Early ambulation

Possible mechanical stimulation; possible stimulation of intestinal function

No significant change in duration of POI, but may decrease other postoperative complications

Laparoscopic surgery

Decreased opiate requirements, decreased pain, less abdominal wall trauma, less intestinal manipulation

Most studies find decreased duration of 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.

Management Options for POIPharmacologic Options

Treatment or Prevention

Potential Mechanism Comments

Epidural anesthesia with local anesthetics

Inhibits sympathetic reflex at cord level; opioid-sparing analgesia; anti-inflammatory effects of local anesthetics

Several RCTs suggest benefit in preventing POI; most effective when inserted at thoracic level

NSAIDs Opiate-sparing analgesia, inhibits COX-mediated prostaglandin synthesis

Probable benefit; COX-2selective medications need further evaluation

IV fluid restriction

Positive salt & water balance delays return of GI function

Fewer complications, shorter LOS with fluid restriction

Metoclopramide Dopamine antagonist, cholinergic agonist

Majority of RCTs suggest no benefit

Peripherally selective mu-receptor antagonists

Block enteric mu-receptors and minimize opiate effects on GI function, without impacting CNS-mediated analgesia

Clinical trials with alvimopan demonstrate reduced duration of POI, decreased time to discharge order written

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.

IV Fluid Restriction Shortens LOS

Open hemicolectomy

Standard group:≥ 3 L water154 mmol sodium/day

Restricted group:≤ 2 L water77 mmol sodium/day

More complications, longer LOS in standard group

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Standard Group Restricted Group

Solid-Phase Gastric Emptying TimeT50 (min)

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Standard Group Restricted Group

Liquid-Phase Gastric Emptying TimeT50 (min)

Lobo DN, et al. Lancet. 2002;359:1812-1818.

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.

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.

Submit

Question

A) True

B) False

A. 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.

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

Lewis S, et al. J Gastrointest Surg. 2009;13:569-575.

To read more about this meta-analysis, click here:http://www.ncbi.nlm.nih.gov/pubmed/18629592

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.

Gum Chewing May Decrease LOSMeta-analysis Patient

Population Time to flatus Time to BM Comments

Chan MK, et al. Dis Colon Rectum. 2007;50:2149-2157.

5 trials, 158 colorectal surgeries

20.8 hours faster (95% CI, 8.9-32.6; P = 0.0006)

33.3 hours faster (95% CI, 15.7-50.8; P = 0.0002)

Shortened LOS by 58.9 hours (95% CI, 42.3-74.4; P < 0.0001)Fewer complications (OR = 0.45; 95% CI, 0.2-1; P = 0.05)

Purkayastha S, et al. Arch Surg. 2008;143:788-793.

5 trials, 158 abdominal surgeries

15.8 hours faster (95% CI, 4.8-26.6; P = 0.005)

26.4 hours faster (95% CI, 10.1-43; P = 0.002)

Trend toward shortened LOS by 30 hours

Vasquez W, et al. J Gastrointest Surg. 2009;13:649-56

6 trials, 244 colorectal surgeries

14 hours faster (95% CI, 4.6-23.5; P < 0.05)

25 hours faster (95% CI, 7.7-42.3; P < 0.05)

Trend toward shortened LOS by 26.2 hours

De Castro S, et al. Dig Surg. 2008;25:39-45.

5 trials, 158 colorectal surgeries

20 hours faster (95% CI, 13-27; P < 0.05)

29 hours faster (95% CI, 19-39; P < 0.05)

Trend toward shortened LOS by 31.2 hours

Noble EJ, et al. Inter J Surg. 2009;7:100-105.

9 trials, 437 intestinal resections

14 hours faster (95% CI, 8-20; P = 0.001)

23 hours faster (95% CI, 15-32; P < 0.001)

Shortened LOS by 26.4 hours (95% CI, 4.8-45.6; P = 0.016)

Fitzgerald JE, Ahmed I. World J Surg. 2009;33:2557-2566.

7 trials, 272 gastrointestinal surgeries

12.6 hours faster (95% CI, 3.7-21.5; P = 0.005)

23.1 hours faster (95% CI, 11.9-34.3; P < 0.001)

Trend toward shortened LOS by 23.9 hoursSimilar complication rates

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.

Which of the following best describes epidural analgesia for pain management with colorectal surgery?

Submit

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

A. 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.

Epidural Analgesia Is Associated with Decreased Duration of Postoperative Ileus

*P < 0.05D = defecation; C = combination score (flatus and defecation); F = flatusHolte K, Kehlet H. Br J Surg. 2000;87:1480-1493.

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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

1. Jorgensen et al. Cochrane Database Syst Rev 2000;(4):CD001893.2. Moraca RJ, et al. Ann Surg. 2003;238:663-673.3. Steinbrook RA. Anesth Analg. 1998;86:837-844.4. Liu SS, et al. Anesthesiology. 1995;82:1474-1506.5. Swenson BR, et al. Reg Anesth Pain Med. 2010;35:370-376.

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

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.

To read more about epidural analgesia for colorectal surgery, click here: http://www.ncbi.nlm.nih.gov/pubmed/17514701

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

Neither Metoclopramide nor Erythromycin Is Beneficial for Postoperative Ileus

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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.

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.

Alvimopan Accelerated GI Recoveryin 5 Bowel Resection Studies

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Alvimopan 12 mgPlacebo

1. Wolff BG, et al. Ann Surg. 2004;240:728-735.2. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. 3. Viscusi E, et al. Surg Endosc. 2006;20:67-70.4. Ludwig K, et al. Arch Surg. 2008;143:1098-1105.5. 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.

Increased risk of prolonged POI in the placebo group

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.

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.

Multimodal/Fast-Track Management for Postoperative Ileus

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?

Opioid sparing

Laparoscopicsurgery

Early feeding,fluid

managementMobilization?

Epidural anesthetics

Laxatives, prokinetics

NG tuberemoval

Mattei P. World J Surg. 2006;30:1382-1391. Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.

At your institution, do you manage colorectal surgery patients with an enhanced recovery (“fast-track”) protocol?

Submit

Question

A) Yes

B) No

C) Sometimes

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.

Delaney CP, et al. Am J Surg. 2010;199:299-304.

To read more about the results of this survey, click here: http://www.ncbi.nlm.nih.gov/pubmed/20226899

Multimodal Approach

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

Intraoperative Components

Anesthesia to optimize surgery and recovery

Local anesthesia/analgesia (or thoracic epidural) if possible

Laparoscopic surgery if possible (gentle handling of tissue)

Multimodal Approach

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

Postoperative Components

Remove NG tube

Start oral feedings early

Minimize opioids

Ambulate

Discharge criteria

In your experience, has implementation of an enhanced recovery protocol (ERP) translated into beneficial outcomes for your colorectal surgery patients?

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

Question

In your experience, has implementation of an enhanced recovery protocol (ERP) translated into beneficial outcomes for your colorectal surgery patients?A. YesB. NoC. I’m not sure; it is too soon to evaluate

outcomesD. Not applicable, we do not use an ERP

Benefits Associated with Multimodal Components

Management Approach Benefit

Limited nasogastric tube use Allows resumption of oral intake

Early oral/enteral feedingCounteracts catabolismImproves immune functionHastens wound healing

Early ambulation Helps to prevent post-op complications such as clots, atelectasis, pneumonia

Laparoscopic surgery

Reduced manipulation and trauma of the bowel leads to less sympathetic activation and inflammation, reduced pain and associated opiate use, earlier ambulation, reduced need for nasogastric tube, earlier resumption of diet

Epidural anesthesia/analgesia

Synergistically block inhibitory sympathetic reflexes; epidural analgesia reduces opioid adverse effects

Opioid-sparing analgesia Minimizing the use of opiates reduces associated GI effects; anti-inflammatory effects of NSAIDs

Peripheral opioid antagonism Reverse GI side effects of opioids without compromising postoperative analgesia

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

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.

For more about enhanced recovery protocols click here: http://www.ncbi.nlm.nih.gov/pubmed/17513630

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

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

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