Q: have heard and read that chewing gum may be a possible treatment to reduce POI. Are there data supporting the use of chewing gum for POI? Should I recommend this therapy in our bowel resection patients if appropriate? What "dose" should we use?

A: The use of chewing gum to reduce POI is an interesting therapy that deserves some attention. Although the exact mechanism is unknown, it is thought that chewing gum as a type of sham feeding may stimulate the cephalic-vagal mechanism and bowel motility. There have been at least 7 fully published, randomized, controlled clinical trials evaluating the use of chewing gum to reduce POI.¹ Some studies have shown chewing gum to be beneficial, and others have not.

Schuster et al² evaluated 34 patients who underwent elective sigmoid colon resection for recurrent diverticulitis or cancer. Patients were preoperatively consented and randomized to receive chewing gum (n = 17) or no chewing gum (n = 17) postoperatively, in addition to standard postoperative care. Patients chewed one stick of sugarless gum three times a day beginning on postoperative day 1 and continued until bowel function returned. Standard postoperative care included analgesia via epidural or subcutaneous local anesthetic infusion pump + PCA, and mobilization began on postoperative day 1. The analgesic treatments and parenteral narcotics/morphine administered were similar in both groups. Compared to the control group, patients who received chewing gum had significantly shorter time to flatus (80.2 ± 19.1 hours vs. 65.4 ± 14.8 hours, P = 0.05), first bowel movement (89.4 ± 24 hours vs. 63.2 ± 5.4 hours, P = 0.04), and length of stay (6.8 ± 1.4 days vs. 4.3 ± 0.4 days, P = 0.01). No major complications were reported, and one patient in the control group developed POI requiring therapy with a nasogastric tube for 2 days. No patients were readmitted in the 1-month follow-up period.²

Noble et al¹ performed a systematic review and meta-analysis of clinical trials evaluating chewing gum for POI. Their analysis included randomized, controlled trials of patients who underwent elective intestinal surgery where chewing gum with standard postoperative care was compared to standard care without gum. They included 437 patients from 7 published studies, along with 2 published abstracts. The studies mainly included patients who underwent colon resection for cancer, although one study included patients with diverticulitis, and another included patients who underwent radical cystectomy with ileal conduit. Sugarless chewing gum was administered beginning on postoperative day 1, and in most studies it was chewed three times a day for > 5 minutes to 60 minutes. In one study patients chewed gum four times daily, and in another study patients chewed gum every 2 to 4 hours. Chewing gum was continued until oral intake or until hospital discharge. Their combined results demonstrated that chewing gum was associated with a significant reduction in time to first flatus (-14 hours, 95% CI -20 to -8 hours, P < 0.001), time to first bowel movement (-23 hours, 95% CI -32 to -15 hours, P < 0.001), and hospital length of stay (-1.1 days, 95% CI -1.9 to -0.2 days, P = 0.016). Overall, chewing gum appeared to be well tolerated and the reported adverse effects were similar when compared to control patients. There are limitations to this meta-analysis that should be noted. The trials included had small sample sizes (18–102 patients), there was evidence of between-study heterogeneity for all outcomes (especially length of stay), and results were heavily influenced by one trial.¹

Another meta-analysis that included 5 of the same trials demonstrated similar results as above, although the difference in length of stay did not achieve statistical significance (except when excluding studies where patients received stomas).³ Collectively, these data suggest that the use of chewing gum 3 to 4 times a day for up to 60 minutes after intestinal surgery may be of benefit.^1,3 A large, prospective, well-designed clinical trial (prospective, randomized, blinded, placebo-controlled) is needed to definitively evaluate the effectiveness of chewing gum to reduce POI and length of stay after intestinal surgery.

In my opinion, sugarless chewing gum is inexpensive, safe, and there are data suggesting it may be of benefit. I would consider using sugarless chewing gum routinely in patients who have undergone intestinal surgery if deemed safe to do so by the attending surgeon, and if the patient does not have a contraindication to chewing gum (eg, anatomical defect, swallowing defect, dentures or poor dentition, etc.). If used, I would recommend starting on postoperative day 1 with a "dose" of 1 stick chewed for 15 to 60 minutes three to four times a day until recovery of bowel function and initiation of oral intake.

References

1. Noble EJ, Harris R, Hosie KB, Thomas S, Lewis SJ. Chewing gum reduces postoperative ileus? A systematic review and meta-analysis. Int J Surg. 2009;7:100-105.
2. Schuster R, Grewal N, Greaney GC, Waxman K. Chewing gum reduces ileus after elective open sigmoid colectomy. Arch Surg. 2006;141:174-176.
3. Purkayastha S, Tilney HS, Darzi AW, Tekkis PP. Meta-analysis of randomized studies evaluating chewing gum to enhance postoperative recovery following colectomy. Arch Surg. 2008;143:788-793.

Q: Patients who undergo surgery often receive large volumes of crystalloid solutions during resuscitation. This combined with a reduced ability to excrete fluid and sodium can lead to significant tissue edema, including in the intestine, which can contribute to a delayed return of bowel function after intestinal surgery. Are there any data suggesting that fluid restriction can reduce POI and enhance recovery of bowel function?

A: There are data demonstrating that excess fluid and sodium is associated with delayed recovery of gastrointestinal function, increased incidence of complications, and increased length of hospital stay. However, there are few prospective, randomized, controlled trials that specifically evaluated the effect of water and sodium balance on the recovery of bowel function after intestinal surgery (I am only aware of one such trial). Lobo et al¹ evaluated 20 patients undergoing elective hemicolectomy or sigmoidectomy for cancer. Patients were randomized equally to receive either standard fluid therapy (≥ 3 liters of fluid and ≥ 154 mEq of sodium daily) or restricted fluid therapy (≤ 2 liters of fluid and ≤ 77 mEq of sodium daily) in the postoperative period. Fluid therapy in the restricted group was controlled by the investigators, while fluid therapy in the standard group was controlled by the treating physicians. Decisions about discontinuation of fluids and advancing diet were made by the treating physicians. Compared to patients who received standard fluid therapy, patients in the restricted fluid group had lower estimated median net fluid balance (+ 0.2 liters vs. + 3.7 liters, P < 0.0001), median time to passing flatus (3 days vs. 4 days, P = 0.001), bowel movement (4 days vs. 6.5 days, P = 0.001), enteral intake (4 days vs. 6.5 days, P = 0.002), and length of stay (6 days vs. 9 days, P = 0.001). Interestingly, there were fewer patients who developed adverse events in the restricted fluid group as compared to standard fluid group (1 patient vs. 7 patients, P = 0.01). The investigators also evaluated liquid-phase and solid-phase gastric emptying on postoperative day 4, and these were both significantly shorter in the restricted fluid group. This study was limited by a small sample size, and there was no blinding in the postoperative period. Although the optimal fluid management (eg, exact limit/volume, preferred fluid, duration) is not known, this study would suggest that maintaining euvolemia while avoiding dehydration and electrolyte abnormalities may improve time to recovery of bowel function after colon resection.¹

Reference

1. Lobo DN, Bostock KA, Neal KR, et al. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: A randomized controlled trial. Lancet. 2002;359:1812-1818.

Q: Based on studies I have read, and information posted here previously by Dr. Kraft, it appears that prokinetic agents are not effective in preventing or reducing POI. It appears that there were some data suggesting cisapride, a serotonin type 4 (5-HT₄) receptor agonist, may be effective for POI, but this agent was removed from the market due to adverse cardiac events. Tegaserod is a 5-HT₄ selective partial agonist that was previously approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in women 55 years old and younger. Are there any data or ongoing studies evaluating tegaserod for the treatment of POI?

A:Tegaserod was withdrawn from the market in 2007 due to the results of a safety analysis that demonstrated patients treated with tegaserod had a higher risk of stroke and heart attack. Tegaserod is only available in emergency situations and with authorization from the Food and Drug Administration (FDA).

I am not aware of any published or ongoing studies evaluating tegaserod for POI. One published report described 3 critically ill patients with gastroparesis who were treated successfully with tegaserod after failing other treatment (eg, metoclopramide).¹ However, this was published prior to the aforementioned safety analysis and removal from the market, and it is unknown if tegaserod would be effective for POI.

At this time, tegaserod should not be used for POI given the significant safety concerns, withdrawal from the market, limited emergency use requiring FDA authorization, and lack of data. It seems unlikely that tegaserod will be studied further for POI.

Reference

1. Bahn HL, MacLean C, Topp T, Hall R. The use of tegaserod in critically ill patients with impaired gastric motility. Clin Pharmacol Ther. 2005;77:583-586.

Q: I have been following the POI Expert On-Call series and have found it very interesting and informative. I am wondering if there are any newly published data regarding POI that you would recommend along with the other information and references published here?

A: Earlier this year, Dr. Anthony Senagore and his colleagues published an evaluation of the financial impact of operationally-defined POI (or what I would call a more "practical" definition of POI).¹ They evaluated 186 patients admitted over a one-year period who underwent an elective colectomy. They defined primary POI as 3 episodes of emesis in 24 hours and return to NPO and/or insertion of a nasogastric (NG) tube, secondary POI as associated with an intra-abdominal complication, and delayed POI as readmission for gastrointestinal failure (without radiological or surgical identification of a bowel obstruction). All patients received the same postoperative care with an "Enhanced Recovery Protocol". The investigators found that 38 (20.4%) patients developed primary POI, 7 (3.8%) patients developed secondary POI, and 141 (75.8%) patients did not develop POI. Nineteen (50%) of patients with primary POI required reinsertion of an NG a tube. Compared to secondary POI patients, primary POI patients had longer duration of narcotic use, longer time to first feeding, and longer length of hospital stay (LOS). The average overall costs per patient were significantly higher for patients with primary or secondary POI compared to patients without POI ($15,914 vs. $17,311 vs. $8,316, P < 0.05). POI patients accounted for 24% of the total study population, yet they accounted for 38% of the total costs. Average LOS was significantly longer in patients with primary POI compared with patients who developed secondary POI or who did not develop POI (8.9 days vs. 7 days vs. 4 days, respectively; P < 0.05). There were a total of 27 (14.6%) readmissions within 30 days, and delayed POI was the most common reason (9 of 27 patients; 33%). Average cost per readmission was not significantly different in patients with delayed POI compared to readmissions for other reasons ($3546 vs. $6670, respectively). These data show that operationally-defined POI occurs frequently after colon resection, and it is associated with a significant increase in LOS and overall hospital costs per admission.¹ This study is consistent with previously published data, further emphasizing that preventing or reducing POI could lead to improved clinical and economic outcomes.

Reference

1. Asgeirsson T, El-Badawi KI, Mahmood A, Barletta J, Luchtefeld M, Senagore AJ. Postoperative ileus: It costs more than you expect. J Am Coll Surg. 2010;210:228-231.

Q: Are there any potential future drug therapies being evaluated for POI?

A: There are several agents currently being investigated for treatment of GI transit abnormalities (primarily constipation or gastroparesis). Some of these agents could be promising future therapies for POI.

Lubiprostone is the first approved drug from a new class of compounds called prostones (bicyclic fatty acid prostaglandin E₁ derivatives).¹ Lubiprostone increases intestinal fluid secretion and GI transit by activating chloride channels in the GI epithelium. The drug is approved in the US for the treatment of chronic idiopathic constipation in adults, but there are no studies evaluating this compound for the prevention/treatment of POI.

Drugs that act as agonists at the serotonin type 4 (5-HT₄) receptor can enhance GI motility, and they are promising prokinetic agents that could also be evaluated for POI. Cisapride was a 5-HT₄ receptor agonist that was an effective prokinetic agent, and there were some published data for treatment of POI. However, cisapride was withdrawn from the market due to adverse cardiac events.

Prucalopride is a 5-HT₄ receptor agonist that is being evaluated for chronic constipation. A large, prospective, randomized, placebo-controlled study demonstrated that prucalopride was effective in the treatment of severe chronic constipation, and had no significant effect on QTc.² There are no clinical studies of prucalopride for POI.

Mosapride is also a 5-HT₄ receptor agonist that is available outside of the US (eg, Japan). Mosapride was evaluated for POI in a small (n = 40), placebo-controlled study of patients after hand-assisted laparoscopic colectomy.³ All patients received multimodal care after surgery. Compared to patients who received placebo, patients who received mosapride had reduced time to first bowel movement (48.5 hours vs 69.3 hrs, P = 0.0149) and shorter LOS (6.7 days vs 8.4 days, P = 0.0398). There was no QTc prolongation reported. This could be a promising therapy for POI, but currently mosapride is not available in the US.

Motilin is a GI peptide that stimulates motilin receptors, causing contraction of GI smooth muscle directly and through release of acetylcholine (primarily in the proximal GI tract). Atilmotin, a peptide analogue, is a motilin agonist currently under investigation as a prokinetic agent.⁴ Other motilin agonists are also currently being evaluated in clinical trials.⁵

Two potentially promising drug classes for treating POI are the ghrelin receptor agonists and tachykinin receptor antagonists. Ghrelin is a peptide hormone synthesized in and secreted from the gastric mucosal cells, and its actions stimulate food intake, gastric emptying, and intestinal motility.^6,7 Two compounds have been studied in a rat model of morphine-induced ileus,^8,9 and clinical trials of other agents are ongoing.⁵

TZP-101 is the first of a new class of ghrelin agonists being evaluated for its prokinetic effects. A randomized, placebo-controlled, phase 2b dose-ranging trial of TZP-101 for management of POI after partial colectomy was recently published.¹⁰ Adult men and women (18–80 years old) weighing ≤ 100 kg and undergoing open partial colectomy with primary anastamosis were included in the study. Patients were excluded if they had a history of severe underlying conditions, if they were undergoing colostomy or ileostomy creation, total colectomy, low anterior resection, surgery for complete bowel obstruction, or laparoscopic procedure. All patients were scheduled for “fast-track” postoperative care (including removal of NG tube at the end of surgery, oral liquids and ambulation encouraged on postoperative day #1, and solid food offered on postoperative day #2), and were expected to receive systemic opioids as part of their postoperative pain management (PCA was allowed but not required). Doses of TZP-101 were evaluated over a range of 20 mcg/kg to 600 mcg/kg, administered as a 30-minute infusion once daily. Treatment began within 1 hour of the conclusion of surgery, and continued until the patient had their first bowel movement, the patient was discharged from the hospital, or treatment for 7 postoperative days (whichever occurred first). Patients were not allowed to receive prophylactic antiemetics or medications that interacted with cytochrome P450 3A4 or that prolonged QT interval. The primary endpoint was recovery of bowel function (time from end of surgery until first bowel movement); there were several secondary endpoints including time to tolerating solid food and first bowel movement (latter of the two), proportion of patients achieving the primary or secondary endpoint within 72 hours, readiness for hospital discharge (based on GI function), and safety analyses. A total of 236 patients were randomized, and 202 (86%) completed the study. The time to first bowel movement was accelerated in all groups receiving TZP-101, with the 80 mcg/kg dose established as the low-efficacious dose and the 480 mcg/kg dose demonstrated as the most efficacious dose. Compared to the placebo group, the median time to first bowel movement was significantly shorter in patients who received the 80 mcg/kg dose (-20.75 hours, HR 1.65, P = 0.03) and the 480 mcg/kg dose (-23.25 hours, HR 1.61, P = 0.04). Time to the latter of first bowel movement and tolerating solid food was also significantly shorter in patients receiving TZP-101 80 mcg/kg and 480 mcg/kg vs placebo. Readiness for hospital discharge was significantly accelerated in patients receiving TZP-101 480 mcg/kg vs. placebo (approximately 20 hours sooner, HR 1.69, P = 0.03). These results persisted when evaluating the effects of several covariates (age, gender, weight, opioid use, and factors related to surgery). TZP-101 appeared to be well tolerated and safety profiles were similar between treatment and placebo groups. The most common adverse effects were nausea and vomiting, and there appeared to be a lower incidence in the treatment groups (all doses combined). Serious treatment-emergent adverse effects occurred in 22 patients (13%) receiving TZP-101 and in 6 patients (9%) receiving placebo. Three patients in the treatment groups died (PE occurring 1 day after the last dose, sepsis occurring 22 days after the last dose, and due to coronary artery disease occurring 27 days after the last dose). TZP-101 did not appear to cause any significant ECG changes or changes in serum glucose concentrations.¹⁰ TZP-101 appears to be a promising compound for the management of POI.

Tachykinins (eg, substance P, neurokinins) appear to act as neurotransmitters in the GI tract and affect regulation GI motility.¹¹ A study of 3 tachykinin receptor antagonists in a rat model of POI demonstrated an improvement in GI transit with each agent alone, as well as with a combination of 2 of the agents.¹²

References

1. Ambizas EM, Ginzburg R. Lubiprostone: A chloride channel activator for treatment of chronic constipation. Ann Pharmacother. 2007;41:957-964.
2. Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med. 2008;358:2344-2354.
3. Narita K, Tsunoda A, Takenaka K, et al. Effect of mosapride on recovery of intestinal motility after hand-assisted laparoscopic colectomy for carcinoma. Dis Colon Rectum. 2008;51:1692-1695.
4. Park MI, Ferber I, Camilleri M, et al. Effect of atilmotin on gastrointestinal transit in healthy subjects: a randomized, placebo-controlled study. Neurogastroenterol Motil. 2006;18:28-36.
5. www.clinicaltrials.gov. Accessed July 2010.
6. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone releasing acylated peptide from stomach. Nature. 1999;402:656-660.
7. DeWinter BY, DeMan JG, Seerden TC, et al. Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus in mice. Neurogastroenterol Motil. 2004;16:439-446.
8. Poitras P, Polvino WJ, Rocheleau B. Gastrokinetic effect of ghrelin analog RC-1139 in the rat: Effect on post-operative and on morphine induced ileus. Peptides. 2005;26:1598-1601.
9. Venkova K, Fraser G, Hoveyda HR, Greenwood-Van Meerveld B. Prokinetic effects of a new ghrelin receptor agonist TZP-101 in a rat model of postoperative ileus. Dig Dis Sci. 2007;52:2241-2248.
10. Popescu I, Fleshner PR, Pezzullo JC, et al. The ghrelin agonist TZP-101 for management of postoperative ileus after partial colectomy: A randomized, dose-ranging, placebo-controlled clinical trial. Dis Colon Rectum. 2010;53:126-134.
11. Goyal RK, Hirano I. The enteric nervous system. N Engl J Med. 1996;334:1106-1115.
12. Ciechanownicz R, Sein-Anand J, Chodorowski Z, et al. Salutary effects of tachykinin receptor antagonists in a rat model of postoperative ileus. J Surg Res. 2006;133:197-202.

Q: We are in the process of adding alvimopan to our hospital formulary, and we are working with one of our surgeons to develop criteria for appropriate use. Currently, we are considering limiting the use to open bowel resection patients receiving systemic opioids for analgesia, and limiting use to a maximum of 15 doses in the inpatient setting. Are these criteria appropriate? Are there other criteria we should consider?

A: This is an important issue to address. Alvimopan is indicated to accelerate the time to upper and lower GI recovery after partial large or small bowel resection with primary anastomosis.¹ Based on the published clinical data, patients undergoing open bowel resection surgery with primary anastomosis who receive systemic opioids for postoperative analgesia are most likely to benefit from alvimopan therapy. It is important to develop criteria so that alvimopan is used appropriately and to optimize the potential benefits.

Alvimopan use should be limited to the inpatient hospital setting. Patients could only receive a maximum of 15 doses of alvimopan in the clinical trials for POI, and this limit should be applied to use in the inpatient setting as well. Results from a long-term safety study of alvimopan 0.5 mg twice daily for the treatment of opioid-induced bowel dysfunction (OBD) demonstrated a higher number of patients who developed myocardial infarction.² Patients who experienced a cardiovascular event were older or had established cardiovascular disease, and these were higher in the alvimopan group compared with placebo.² No imbalance in severe adverse events was observed in patients from POI clinical trials, but the duration of follow-up was limited to < 2 weeks post-discharge for the majority (> 95%) of these patients.² Because of these observations, the FDA required implementation of a Risk Evaluation and Mitigation Strategy (REMS) to assure the safe use of alvimopan. Hospitals that perform bowel resection surgeries must enroll in the Entereg^® Access Support and Education (E.A.S.E.) program in order to procure and use alvimopan.³ By enrolling in this program, hospitals attest that they will provide education to health care staff involved in ordering, dispensing, or administering alvimopan, that they will limit alvimopan use to the inpatient setting, that patients will receive no more than a maximum of 15 doses, and that alvimopan will not be transferred to a hospital that is not registered with the E.A.S.E. program. Ongoing evaluation of patients who receive alvimopan is essential to assess for any further adverse effects.

Other criteria for use to consider include:

• Avoid alvimopan use in patients receiving opioids prior to surgery: alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days before surgery. Patients receiving therapeutic doses of opioids were excluded from the clinical trials of alvimopan. Because alvimopan is a peripherally-acting mu-opioid receptor antagonist, administration of a 12 mg dose could result in adverse GI effects in patients taking chronic opioid therapy.
• Require patients to receive the preoperative dose of alvimopan: use of a preoperative dose was part of all published clinical trials of alvimopan for POI, and there are no data describing the efficacy of alvimopan if the preoperative dose is omitted.
• Use of alvimopan only for open-bowel resection surgery: all of the clinical trials of alvimopan have included patients undergoing open-bowel resection, but the labeled indication does not specify the surgical technique (open vs laparoscopic). There are no published data evaluating the efficacy of alvimopan in patients undergoing laparoscopic bowel resection surgery. Given that patients who undergo laparoscopic surgical procedures typically have less postoperative pain and less analgesic/opioid requirement, one could conclude that alvimopan may be less effective in this situation.
• Use alvimopan only in patients receiving systemic opioids for analgesia after surgery: patients in the clinical trials of alvimopan received opioid therapy via patient-controlled analgesia for postoperative pain control. Because alvimopan is a peripherally-acting mu-opioid receptor antagonist, one could conclude that alvimopan may be less effective in patients who are not receiving systemic opioids.
• Incorporate alvimopan into existing multimodal care plans/accelerated care pathways (or consider establishing such pathways): published data suggest that use of a standardized multimodal care plan after bowel resection can reduce length of stay. In addition, a standardized care plan was used for all patients in the clinical trials of alvimopan (both treatment and placebo groups).

References

1. FDA. Entereg Prescribing Information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021775s004lbl.pdf. Accessed July 2010.
2. US FDA Advisory Committee Briefing Document. Entereg^® (alvimopan) Capsules for Postoperative Ileus. http://www.fda.gov/ohrms/DOCKETS/ac/08/briefing/2008-4336b1-02-Adolor.pdf. Accessed July 2010.
3. FDA. NDA 21-775 Entereg (alvimopan) Risk Evaluation and Mitigation Strategy. http://www.fda.gov/downloads/Drugs/DrugSafety/
   PostmarketDrugSafetyInformationforPatientsandProviders/ucm129511.pdf. Accessed July 2010.

Q: Alvimopan is approved to reduce the time to GI recovery after bowel resection surgery, and we are considering adding it to our hospital formulary. However, we are concerned about the potential cost of this agent. Are there any data assessing the potential cost impact or benefit of alvimopan?

A: As discussed last month, there is a growing body of literature suggesting that postoperative ileus (POI) definitely represents a financial burden to hospitals and the health care system. Certainly reducing patient discomfort and improving patient satisfaction with care is very important. However, we must carefully weigh the potential benefits of any drug therapy against the potential costs. Those benefits may go beyond the individual patient; reducing the duration of POI can also reduce hospital lengths of stay (LOS) and reduce overall costs. Therefore, I believe when assessing POI outcomes, it is important to look at all costs and potential savings (not just the cost of the medication).

With that said, there is only one published study and one published abstract that I am aware of that have specifically evaluated the potential economic impact of alvimopan for POI.^1,2 The study was a pooled analysis of data from bowel resection patients from the phase III North American trials of alvimopan for POI. The authors estimated patient hospital costs using hospital discharge data from Premier's Perspective Comparative Database, as well as data from the US Census Bureau Statistical Abstract (represents average cost per patient to community hospitals). The cost of alvimopan was estimated at $62.50 per 12 mg dose (based on published wholesale acquisition cost), and cost of placebo was assumed to be $0. The analysis demonstrated that patients who received alvimopan had a mean LOS that was 1 day shorter than those who received placebo (6.6 days vs 7.6 days, respectively, P < 0.001; estimated from calendar day of surgery to calendar day of discharge). Patients in the alvimopan group received a mean of 8.9 doses. Based on the estimated number of doses and LOS, and using the estimated hospital cost data, use of alvimopan was associated with an overall reduction of total hospital costs of $879–$977 ($879 using cost estimates from Perspective Comparative Database cost estimates; $977 using cost estimates from the US Census Bureau Statistical Abstract).²

An abstract presented at the American Society of Health System Pharmacists Midyear Clinical Meeting in December 2009 described one hospital's use of alvimopan over a 6-month period.² These authors demonstrated alvimopan use for open bowel resection was associated with a reduction in LOS of 1.2 days, and a reduction in overall hospital costs of $1042. These results are similar to the results of the analysis described above. These data suggest that alvimopan use is associated with a reduction in overall hospital costs if patient LOS can be reduced.

References

1. Bell TJ, Poston SA, Kraft, MD, et al. Economic analysis of alvimopan in North American phase III efficacy trials. Am J Health Syst Pharm. 2009;66:1362-1368.
2. Banares LW, Absher RK, Gerkin TM, Roh JM. Effect of alvimopan on postoperative length of stay in patients undergoing partial bowel resection: A 6-month medication use evaluation. American Society of Health-System Pharmacists Midyear Clinical Meeting. Poster 3-118. Las Vegas, NV. December 2009.

Q: Should early PO or enteral nutrition (EN) be encouraged after abdominal or bowel resection surgery? Should EN be a part of a multimodal care plan?

A: It is well known that malnutrition is associated with increased morbidity and mortality in surgical patients.¹ It is also well accepted that oral or EN is preferred over parenteral nutrition (PN) when providing nutritional support therapy to patients.² The potential benefits of providing early oral nutrition or EN to surgical and critically ill patients (within 24–36 hours) include reducing catabolism, improving immune function, reducing infectious complications, and promoting anabolism and wound healing.^3,4 A recent meta-analysis of 13 randomized controlled trials with over 1100 patients compared the effect of early oral nutrition or EN (within 24 hours of GI surgery) versus "traditional" nutrition management on several outcomes.⁴ The results of this analysis suggested that early nutrition was associated with reduced mortality, reduced length of stay, and a trend toward reducing wound infections and pneumonia. There also appeared to be no evidence of benefit or harm of early feeding with respect to anastomotic dehiscence. The main conclusion the authors emphasized is that there is "no obvious benefit" to routinely keeping patients NPO after GI surgery.⁴

Some studies evaluating the effect of early EN on recovery of bowel function after surgery suggest this treatment may reduce the duration of POI, but other studies have not shown a benefit.⁵ Early feeding is often used with other treatment modalities for the treatment/prevention of POI after abdominal surgery, so it is unclear if early oral feeding or early EN alone can reduce POI. However, evidence in the literature demonstrates that early feeding can be done safely, and can reduce morbidity and mortality. Therefore, early oral nutrition or EN should be encouraged routinely after GI surgery, and should be considered as part of a multimodal care plan.

References

1. Kudsk KA, Tolley EA, DeWitt RC, et al. Preoperative albumin and surgical site identify surgical risk for major postoperative complications. J Parenter Enter Nutr. 2003;27:1-9.
2. A.S.P.E.N. Board of Directors and The Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enter Nutr. 2002;26(Suppl 1):1SA-138SA.
3. Marik PE, Zaloga GP. Early enteral nutrition in acutely ill patients: A systematic review. Crit Care Med. 2001;29:2264-2270.
4. Lewis SJ, Andersen HK, Thomas S. Early enteral nutrition within 24 hours of intestinal versus later commencement of feeding: A systematic review and meta-analysis. J Gastrointest Surg. 2009;13:569-575.
5. Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg. 2000;87:1480-1493.

Q: I have read that many surgeons and experts believe that postoperative ileus (POI) contributes to prolonged length of stay (LOS) for abdominal surgery patients, and is a significant financial burden to the health care system. Are there published studies or data that support or refute these statements?

A: This is an important question to address. There is a growing body of literature demonstrating that POI results in prolonged LOS and represents a significant financial and resource burden to the health care system. Some studies have demonstrated that POI increases the average LOS by ~2–8 days and result in an increase in average hospital costs of approximately $4,000–$12,000 (US) per patient.^1-5 Not only can POI increase LOS and estimated costs, but there is an increase in resource utilization.⁶ Patients who require further treatment for POI will likely use more medications (eg, antiemetics, analgesics) or supportive care (eg, parenteral nutrition) and require increased nursing care. Prolonging LOS could prevent other admissions to the hospital, potentially decreasing revenue. In addition, POI is one of the leading causes of readmission after abdominal surgery.^7,8 The estimated hospital cost per readmission in patients who have POI has been estimated at $9000 more than patients who do not have POI.² The overall annual cost of POI to the health care system in the US has been estimated to be as much as $1.47 billion (US).² Reducing POI could result in reduced LOS and decreased hospital costs and resource utilization.

There are challenges in documenting the impact of POI on the health care system. POI is generally considered an inevitable response after abdominal surgery and therefore may not be documented in all patients unless it is prolonged or severe. Furthermore, there are no specific International Classification of Diseases, 9th edition (ICD-9) codes for POI. Several codes that may be associated with POI include 560.1 (paralytic ileus), 564.4 (postoperative functional disorder), and 997.4 (digestive complication, not elsewhere classified), and these have been used by investigators in an attempt to identify patients with POI. However, this method could identify patients with a prolonged or more severe ileus, or it could miss patients who have POI but did not have it documented in the medical record.

References

1. Salvador CG, Sikirica M, Evans A, et al. Clinical and economic outcomes of prolonged postoperative ileus in patients undergoing hysterectomy and hemicolectomy. P & T. 2005;30:590-595.
2. Goldstein JL, Matuszewski KA, Delaney CP, et al. Inpatient economic burden of postoperative ileus associated with abdominal surgery in the United States. P & T. 2007;32:82-90.
3. Sarawate CA, Lin SJ, Walton SM, et al. Economic burden of postoperative ileus (POI) in Abdominal Surgical Procedures. Gastroenterology. 2003;124:A828.
4. Saunders WB, Bowers B, Moss B, et al. Recorded Rate and Economic Burden Associated with Postoperative Ileus (P440E, abstract 30346). Presented at the 39th Annual American Society of Health-System Pharmacists Midyear Clinical Meeting. Orlando, FL: 2004 Dec 8.
5. Senagore A, Delaney C, Wang PF, et al. Economic burden and risk factors associated with ICD-9 coded postoperative ileus (POI): Results from US hospital data during 2002. Program and abstracts of the American Society of Colon and Rectal Surgeons 2005 Annual Meeting; April 30-May 5, 2005; Philadelphia, PA. Podium presentation, S22, p 165.
6. Bosio RM, Delaney CP, Senagore AJ. Economic impact of POI and prolonged length of stay. Semin Colon Rectal Surg. 2005;16:235-238.
7. Kiran RP, Delaney CP, Senagore AJ, et al. Outcomes and prediction of hospital readmission after intestinal surgery. J Am Coll Surg. 2004;198:877-883.
8. Kariv Y, Wang W, Senagore AJ, et al. Multivariable analysis of factors associated with hospital readmission after intestinal surgery. J Am Coll Surg. 2006;191:364-371.

Q: One of our surgeons has used methylnaltrexone to treat severe refractory opioid-induced constipation in some of her patients with success. She inquired about using methylnaltrexone for prevention or treatment of postoperative ileus (POI). Has methylnaltrexone been studied for POI? Is it effective?

A: Methylnaltrexone is a peripherally-active mu-opioid receptor antagonist, and a subcutaneous dosage form has been approved by the US Food and Drug Administration (FDA) for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care and when the response to laxative therapy has not been sufficient.¹ An intravenous form of methylnaltrexone has also been studied for POI. The results of a Phase II trial of methylnaltrexone for POI in patients undergoing segmental colectomy demonstrated promising results, but this has only been published in abstract form.² Methylnaltrexone significantly accelerated the time to toleration of full liquids, time to first bowel movement, and time to discharge eligibility. Patients in the methylnaltrexone also had a shorter time to toleration of solid food, GI recovery, and actual discharge, but these endpoints did not reach statistical significance.

Intravenous methylnaltrexone was evaluated in at least three Phase III studies for the treatment of POI, including patients undergoing segmental colectomy^3,4 and ventral hernia repair.⁵ However, methylnaltrexone was not shown to be superior to placebo with respect to the primary or secondary outcomes (did not achieve statistical significance).^6-8 These studies have not yet been published, and these preliminary results are only available in press release form. Based on these results, methylnaltrexone does not appear to be effective for the treatment of POI and should not be used for this indication until further data are available.

References

1. FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021964s006lbl.pdf. Accessed June 2010.
2. Viscusi E, Rathmell J, Fichera A et al. A double-blind, randomized, placebo-controlled trial of methylnaltrexone (MNTX) for post-operative bowel dysfunction in segmental colectomy patients. Anesthesiology.2005;103:A893.
3. Study evaluating IV methylnaltrexone for the treatment of postoperative ileus. http://www.clinicaltrials.gov/ct2/show/NCT00387309. Accessed June 2010.
4. Study of intravenous (IV) methylnaltrexone bromide (MNTX) in the treatment of postoperative ileus (POI). http://www.clinicaltrials.gov/ct2/show/NCT00401375. Accessed June 2010.
5. A study evaluating IV MOA-728 for the treatment of POI in subjects after ventral hernia repair. http://www.clinicaltrials.gov/ct2/show/NCT00528970. Accessed June 2010.
6. Wyeth and Progenics announce preliminary clinical trial results for RELISTOR oral and intravenous formulations. http://www.wyeth.com/irj/portal/news/archive?nav=display&navTo=/wyeth_html/home/
   news/pressreleases/2008/1211465152818.html. Accessed June 2010.
7. Wyeth and Progenics announce preliminary clinical trial results for RELISTOR oral and intravenous formulations. http://www.progenics.com/releasedetail.cfm?ReleaseID=311785. Accessed June 2010.
8. Progenics pharmaceuticals reports fourth quarter and year-end results and corporate update. http://www.progenics.com/releasedetail.cfm?ReleaseID=370543. Accessed June 2010.

Q: I work with a gastrointestinal surgery service that performs many bowel resection surgeries each year. We often have patients who have prolonged recovery of bowel function and develop postoperative ileus (POI). We usually provide supportive care, but I am wondering if prokinetic medications are effective for POI?

A: The two prokinetic medications available in the US that have been studied for POI are metoclopramide and erythromycin. Metoclopramide is a dopamine and serotonin receptor antagonist, and it enhances the response to acetylcholine in the upper gastrointestinal (GI) tract, thereby increasing gastric emptying and upper GI motility. Metoclopramide has been evaluated in several randomized, controlled trials for the treatment of POI after abdominal surgery, but overall the data suggest that it is not effective in reducing POI.^1,2

Erythromycin is a motilin receptor agonist, and this stimulates the migrating motor complex (MMC) that occurs through the stomach and small intestine in the fasted state. Erythromycin has only been evaluated for POI in a few studies.^3-5 Overall, erythromycin has not been shown to improve time to bowel recovery after abdominal surgery and does not appear to be effective for POI. Because the highest density of motilin receptors are found in the more proximal portions of the GI tract, motilin agonists such as erythromycin may not be the optimal agents for the treatment of POI.¹

References

1. Bungard TJ, Kale-Pradhan PB. Prokinetic Agents for the Treatment of Postoperative Ileus in Adults: A Review of the Literature. Pharmacotherapy. 1999;19:416-423.
2. Seta ML, Kale-Pradhan PB. Efficacy of metoclopramide in postoperative ileus after exploratory laparotomy. Pharmacotherapy. 2001;21:1181-1186.
3. Bonacini M, Quiason S, Reynolds M, et al. Effect of intravenous erythromycin on postoperative ileus. Am J Gastroenterol. 1993;88:208-211.
4. Smith AJ, Nissan A, Lanouette NM, et al. Prokinetic effect of erythromycin after colorectal surgery. Dis Colon Rectum. 2000;43:333-337.
5. Lightfoot AJ, Eno M, Kreder KJ, et al. Treatment of postoperative ileus after bowel surgery with low-dose intravenous erythromycin. Urology. 2007;69:611-615.

Q: Several of our surgeons who perform open abdominal surgeries routinely prescribe laxatives (eg, bisacodyl) for their patients after surgery, but a few of the surgeons do not. Are laxatives effective for postoperative ileus (POI)? Should we routinely recommend the use of laxatives to treat/prevent POI?

A: Laxatives and stool softeners are often used in the postoperative period for the treatment of constipation associated with opioid use. Patients who are receiving opioid therapy should be monitored closely for constipation, and they should be provided some sort of a bowel regimen to treat or prevent constipation (eg, docusate, bisacodyl, senna, or polyethylene glycol).

With respect to POI, there are at least 2 studies documenting the effectiveness of bisacodyl suppositories in patients undergoing colon surgery. In one double-blind, randomized, controlled study,¹ 20 patients undergoing elective colectomy were randomized to receive bisacodyl 10 mg suppository or placebo suppository on postoperative day (POD) #3 if they had not yet had a spontaneous defecation. If there was no response to the first suppository, one additional suppository was given 12 hours later. Time to defecation was significantly shorter in the treatment group vs. placebo group (P < 0.001). On POD #3, all 10 patients in the treatment group defecated vs 2 of 10 patients in the placebo group. Five of the remaining 8 patients in the placebo group defecated on POD #4, and the remaining 2 patients on POD #5. Patients in the control group did receive twice as much morphine as patients in the treatment group; however, there was no clear correlation between the amount of morphine received and the time to defecation. The mean length of stay (LOS) was 8.5 ± 2.7 days in the treatment group vs 10.4 ± 5.3 days in the placebo group (P = NS).

In a more recent double-blind, randomized, controlled study,² 200 patients undergoing elective colorectal resection (open or laparoscopic) were randomized to receive bisacodyl 10 mg tablets by mouth twice daily or placebo (using the same capsule); data from 169 patients were analyzed. Treatment began on the day prior to surgery, and continued until POD #3. Mean time to achieve the composite endpoint of GI-3 (the later time of first flatus, first bowel movement, and first solid food tolerated) was significantly shorter in the bisacodyl group vs. placebo group (3.4 ± 1.7 days vs 4.0 ± 1.6 days, P = 0.007), and this was primarily due to shorter mean time to first bowel movement (3.1 ± 1.9 days vs 4.2 ± 2.1 days, respectively, P = 0.001). There were no significant differences observed in other outcomes or in adverse events.

Overall, laxative therapy with bisacodyl appears to be a promising therapy for treatment of POI in patients undergoing colon resection. Bisacodyl may be recommended if considered safe by the treating surgeon. If it is used, consider beginning therapy on the day prior to surgery (based on the largest prospective, randomized, controlled study published to date). Further studies are needed to determine if bisacodyl is effective for POI after other types of abdominal surgery, and to determine if other laxatives may be effective for POI after abdominal surgery.

References

1. Wiriyakosol S, Kongdan Y, Euanorasetr C, Wacharachaisurapol N, Lertsithichai P. Randomized controlled trial of bisacodyl suppository versus placebo for postoperative ileus after elective colectomy for colon cancer. Asian J Surg. 2007;30:167-172.
2. Zingg U, Miskovic D, Pasternak I, et al. Effect of bisacodyl on postoperative bowel motility in elective colorectal surgery: A prospective, randomized trial. Int J Colorectal Dis. 2008;23:1175-1183.

Q: I am a busy clinical surgeon in a community hospital, and I want to provide the best care for my patients. There is interest in shortening hospital length of stay for patients undergoing colon resections, but I don’t want to compromise the quality of care. How might I go about achieving this goal?

A: The quality of care does not need to be compromised in trying to achieve a reduced length of stay. The optimal way to do this is to recruit the help and expertise of all personnel and specialties involved in the care of your patients. I suggest that you and your administration organize a committee of people whose sole objective is to achieve this goal. The committee should be composed of nurses from the admitting area, operating and recovery room nurses, pharmacists, anesthesiologists, floor nurses, and surgeons. It truly requires a multidisciplinary approach. The process starts before the patient even enters the hospital and involves educating him/her about what will transpire and what the expected milestones are with respect to recovery. The admission nurses must administer certain medications before surgery that are intended to hasten recovery and reduce complications. The anesthesiologists may initiate a pain management program that is intended to provide satisfactory analgesia while reducing narcotic load. The surgeon should focus on performing minimally invasive, minimally traumatic surgery. The floor nurses should keep in mind a time schedule for certain milestones that are essential for recovery.

Q: What are your recommendations regarding mechanical bowel preparation for colorectal surgery?

A: For decades it was felt that the colon should be "prepped" for surgery in order to reduce the incidence of infection and several schemes were devised to achieve that goal. It generally involved oral medications that required either ingestion of large volumes of liquid or foul-tasting alternatives. A salty, low volume alternative was used for years and seemed to be tolerable but it proved to be harmful to the kidneys. There hasn’t been a suitable bowel cleansing regimen devised that is both completely safe and easy to consume. Consequently, research efforts were directed toward investigating whether omitting a bowel cleansing achieved satisfactory outcomes for surgical patients. Based on these studies, it is reasonable to omit a bowel "prep" and it is certainly within the standard of care to do so, however, many surgeons still cling to old practices and continue to prepare their patients with colon-cleansing regimens.

Q: I have read about several ways to reduce hospital stay for my patients undergoing bowel surgery. Is there a single intervention that clearly stands above the rest that I should concentrate on?

A: While one could look at several individual, separate, and independent interventions and try to draw conclusions, it is far preferable to focus on a "concept" or "goal" and then employ various means to achieve that goal. With respect to patients undergoing bowel surgery, that goal should be to find ways to minimize the effects of narcotic usage while maintaining patient comfort and satisfaction. It is very simple. With that goal in mind, a fast-track protocol can be generated. Cumulative narcotic levels affect bowel function, with higher utilization producing more gut dysfunction. Narcotic utilization can be lessened by administering non-steroidal anti-inflammatory (NSAID) medications such as ketorolac which also works to reduce the inflammatory effect of surgical manipulation. Epidural analgesics can lower the dose of systemic opioids needed to achieve pain control. NSAID administration and epidural catheter insertion are done before the patient leaves the operating room. Laparoscopic surgery generally involves smaller incisions and may lower the time needed for parenteral opioids. Peripherally-acting opioid antagonists such as alvimopan act to block the gut affects of narcotics but do not cross the blood brain barrier. In this way, pain control and patient satisfaction are not compromised. In summary, the important concepts to focus on are ways to lessen the effects of systemic opioids and provide less traumatic surgery.

Q: I recently did a screening colonoscopy on a 58-year-old gentleman and found a fairly small cancer on the right side of his colon. A CT scan showed that there was no evidence of metastatic disease and his overall medical condition is suitable for general anesthesia and surgery. We have several respectable surgeons in town, some of whom perform laparoscopic resections for cancer. Does this approach really accelerate recovery of intestinal function?

A: It is generally held that laparoscopic approaches reduce the duration of postoperative ileus; however, there are many other factors that must be considered. Only approximately 10% of colectomies in the country are performed laparoscopically for various reasons, therefore availability is an issue. Also, there is a significant learning curve with this technology and the surgeon may or may not be comfortable with advanced procedures such as this. What is important is that the surgeon does his/her best job at following proper oncologic principles in the conduct of the operation even if this requires an open operation. While most reports comparing laparoscopic versus open surgery cite hastened GI recovery with laparoscopy, this is not universally the case. Short length of stay can be realized even with open surgery if a fast-track protocol is utilized, narcotics are minimized, and other measures tried that have been proven to be beneficial.

Reference

Rea J, et al. Utilization of laparoscopic colectomy in the United States before and after the clinical outcomes of surgical therapy (COST) study group trial. Dis Colon Rectum. 2010;53(4):16.

Q: Following colectomy, how long does postoperative ileus last and what does it mean if it is prolonged?

A: Cessation of bowel propulsive activity is normally expected for a period of approximately three days after which patients will pass flatus, stool, and demonstrate progressive tolerance of their diet. If a patient never achieves these milestones despite the passage of several days, there could be a septic focus in the abdomen, such as an abscess or anastomotic leak and these conditions must sought for. If a patient does achieve these milestones, only to later develop distention, vomiting, and lack of stool or gas, the possibility of a postoperative bowel obstruction from adhesive disease must be considered. Although clinical differences between an ileus and an adhesive obstruction may not be clinically and readily apparent, they are nevertheless treated the same initially with intravenous fluids, nasogastric suction, and nutrition.

Q: I am planning to operate on a young man for ileocecal Crohn's fistulas. He is extremely fearful of having a nasogastric tube placed but I was always taught that they are essential for proper care of the postoperative patient. Am I correct?

A: The routine use of nasogastric tubes for the postoperative bowel resection patient is no longer considered essential. Routine placement benefits only 1 in 20 patients so treated. Rather, they are used selectively and perhaps should be considered for the patient undergoing a lengthy operation during which time there was extensive bowel manipulation or lysis of adhesions. Avoiding NG tubes does not predispose to more anastomotic complications as was feared and may actually help avoid pulmonary complications. Most fast-track protocols do not employ the routine use of NG tubes.

Q: Our hospital physical therapists are adamant that early ambulation of the surgical patient shortens the duration of postoperative ileus and is therefore essential. Is this true?

A: It has never been conclusively proven that early ambulation shortens the duration of postoperative ileus. However, early ambulation may still be in the patient's best interest because of a reduced risk of thromboembolic events and improved pulmonary function. In addition, frequent ambulation is a component of most enhanced recovery protocols.

Q: Some of my patients have asked about the enteric nervous system. I would like to give them a brief explanation. Can you help?

A: Neural regulation of the GI tract involves both intrinsic and extrinsic control systems. The enteric nervous system (ENS) is the intrinsic neural network that plays a critical role in the coordination of GI motility, secretion, and blood flow. The ENS processes sensory information, regulates neural reflex activity, and coordinates complex motor patterns in the GI tract. The ENS functions to a large extent independent of the central nervous system (CNS) and because of its complex interconnecting neural networks and sophisticated functions, the ENS is often referred to as the brain in the GI tract. The neuronal cell bodies of the ENS are grouped in ganglia located in the myenteric plexus and the submucosal plexus. Three types of neurons mediate ENS functions: sensory neurons, interneurons, and motor neurons. Enteric sensory neurons (also referred to as intrinsic primary afferent neurons) respond to chemical and mechanical stimuli via receptors in the intestinal epithelium, mucosa, and muscle. Interneurons serve an integrating function between sensory and motor neurons and between different motor neurons. Excitatory and inhibitory motor neurons act on effector cells including smooth muscle cells, epithelial cells, glands, and blood vessels resulting in rhythmic, coordinated GI muscle contraction and movement of luminal contents, as well as secretory and endocrine functions.

Extrinsic neural pathways modulate gut motility through connections with the ENS. Sensory information is transmitted to the CNS via spinal and vagal afferent nerves. Parasympathetic efferent pathways have a stimulatory effect on bowel activity, whereas efferent sympathetic activity has an inhibitory effect on GI motility. Interestingly, part of the systemic response to surgery includes sympathetic nervous system activation. Laparotomy and extensive bowel manipulation result in sympathetic hyperactivity, which exerts a greater effect on the GI tract than parasympathetic input, contributing to decreased motility.

References

• Goyal RK, Hirano I: The enteric nervous system. N Engl J Med. 1996;334:1106-1115.
• Wood JD, Alpers DH, Andrews PL: Fundamentals of neurogastroenterology. Gut. 1999;45(suppl 2):II6-II16.
• Costa M, Brookes SJ, Hennig GW: Anatomy and physiology of the enteric nervous system. Gut. 2000;47(suppl 4): iv15-19;discussion iv26.
• Viscusi E, Gan TJ, Leslie J, et al. Peripherally acting mu-opioid receptor antagonists and postoperative ileus: mechanisms of action and clinical applicability. Anesth Analg. 2009;108:1811-1822.

Q: How do I know if patients are developing symptoms and signs of postoperative ileus (POI) and do plain abdominal x-rays or blood tests help in the diagnosis?

A: POI typically develops when there is a prolonged cessation of bowel motility beyond the normal recovery process following abdominal surgery. The signs and symptoms may include the following:

• Abdominal pain and cramping
• Abdominal distension
• Absence of bowel sounds
• Tympany on abdominal percussion
• Delayed passage of flatus and stool
• Increased nausea and vomiting
• Tachycardia and oliguria due to sequestration of fluid in the gut
• Delay in resuming oral intake and possible need for parenteral nutrition
• Delayed absorption of oral medications
• Delayed nourishment resulting in hypoalbuminemia, poor wound healing, and reduced immune function
• Delay in postoperative mobilization

There is not a diagnostic test used for definitive diagnosis of POI. Plain radiograph may be helpful although it is not necessary for the diagnosis of POI. It may demonstrate dilated air-filled loops of small and large bowel, however this is a nonspecific finding and not unique to POI. Computerized axial tomography (CT) and/or upper GI contrast studies as well as endoscopy are useful when it is necessary to differentiate an ileus from mechanical bowel obstruction. Laboratory studies are usually unremarkable but may demonstrate metabolic acidosis.

Q: I had a patient who underwent an open abdominal procedure. He was provided with opioid patient-controlled analgesia (PCA) for postoperative pain control. On subsequent postoperative days, he needed fairly large doses of opioids to control his pain. Is there a dose relationship between opioid and the incidence of opioid-related adverse events?

A: It is widely known that while opioids are potent analgesics, their use can result in significant side effects. Examples of opioid side effects include nausea, vomiting, pruritus, constipation, urinary retention, drowsiness, delirium, and respiratory depression. There is an increasing body of literature that correlates the amount of opioid use in the perioperative period and the incidence of opioid-related side effects. In a study investigating the use of cyclooxygenase 2 (COX-2) specific inhibitors in reducing opioid requirement, Gan et al showed a dose response relationship between opioid doses and opioid-related symptoms distress scores (SDS). The SDS takes into account the incidence, severity and clinical meaningfulness of opioid-related side effects as experienced by the patients.

In another study, Cali et al conducted a prospective evaluation of 40 patients undergoing uncomplicated colectomy who received morphine by PCA for postoperative pain control. There was a statistically significant positive correlation between the amount of morphine used and the time to return of bowel function, as measured by bowel sounds, time to first passage of flatus and time to first bowel movement There was also a correlation between return of bowel function and hospital length of stay.

References

1. Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21:185-211.
2. Gan TJ, Joshi GP, Zhao SZ, Hanna DB, Cheung RY, Chen C. Presurgical intravenous parecoxib sodium and follow-up oral valdecoxib for pain management after laparoscopic cholecystectomy surgery reduces opioid requirements and opioid-related adverse effects. Acta Anaesthesiol Scand. 2004;48:1194-1207.
3. Cali RL, Meade PG, Swanson MS, Freeman C. Effect of morphine and incision length on bowel function after colectomy. Dis Colon Rectum. 2000;43:163-168.

Q: One of my colleagues suggests that I should insert an epidural in a patient who is having an open colectomy. He read recently that epidural pain management helps postoperative recovery and hastens bowel function. What are the advantages of epidural use and does it decrease the incidence of postoperative ileus?

A: Epidural is the insertion of a catheter in the epidural space commonly performed for postoperative pain management in patients undergoing moderate to major surgery. There are many advantages of epidural anesthesia/analgesia in the perioperative period.

Clinical studies with epidural analgesia have demonstrated an improvement in surgical outcome as a result of beneficial effects on pulmonary function, reduction of the surgical stress response, and improved analgesia. A literature review by Moraca et al reported significant reduction in perioperative cardiac morbidity (~30%), pulmonary infections (~40%), pulmonary embolism (~50%), ileus (~2 days), acute renal failure (~30%), and blood loss (~30%) with epidural anesthesia/analgesia.

Substantial experimental and clinical evidence suggests that epidural anesthesia/analgesia is safe for patients undergoing bowel resections with anastomoses. In addition, studies in animals and humans have demonstrated that thoracic epidural anesthesia with local anesthetics during surgical stimulation maintains intestinal mucosal blood flow and gastric mucosal pH at physiologic levels compared with controls treated with general anesthetics. It has been hypothesized that the increased mucosal blood flow may promote anastomotic healing. In fact, retrospective cohort controlled studies suggest that regional anesthetic techniques were associated with a beneficial effect on anastomotic healing rates.

The proposed mechanisms by which thoracic epidural anesthesia may promote GI motility include blockade of nociceptive afferent nerves, blockade of thoracolumbar sympathetic efferent nerves, unopposed parasympathetic efferent nerves, reduced need for postoperative opiates, increased GI blood flow, and systemic absorption of local anesthetic.

However, it is important to note that there are complications associated with the use of epidurals. Such potential complications may range from transient paresthesias (< 10%) to epidural hematomas (0.0006%).

References

1. Liu SS, Carpenter RL, Mackey DC, et al. Effects of perioperative analgesic technique on rate of recovery after colon surgery. Anesthesiology. 1995;83:757-765.
2. Moraca RJ, Sheldon DG, Thirlby RC. The role of epidural anesthesia and analgesia in surgical practice. Ann Surg. 2003;238:663-673.
3. Ogilvy AJ, Smith G. The gastrointestinal tract after anaesthesia. Eur J Anaesthesiol Suppl. 1995;10:35-42.
4. Ryan P, Schweitzer SA, Woods RJ. Effect of epidural and general anaesthesia compared with general anaesthesia alone in large bowel anastomoses. A prospective study. Eur J Surg. 1992;158:45-49.
5. Steinbrook RA. Epidural anesthesia and gastrointestinal motility. Anesthes Analg. 1998;86:837-844.

Q: A 55-year-old female patient scheduled for hemicolectomy for removal of a tumor is concerned about postoperative bowel complications. She has multiple allergies and does not want to receive too many drugs to prevent bowel dysfunction. Are there any non-pharmacologic methods that have been shown to improve postoperative bowel dysfunction?

A: There are a number of nonpharmacologic interventions that have been utilized in the prevention and management of postoperative ileus (POI). Some of them have been shown to be beneficial while others are supported by less evidence. Among the options are:

• Early oral feeding. Recent studies have demonstrated modest efficacy of early feeding in the postoperative period and it appears to be well tolerated in many patients.
• Psychological and preoperative preparation. A single study found a positive benefit for preoperative suggestion (psychological preparation) in decreasing time to flatus and hospital discharge. It is inexpensive and does not have much downside.
• Laparoscopic surgery. Minimally invasive surgery (laparoscopy) minimizes surgical stress and tissue damage, and greatly diminishes the incidence and severity of postoperative ileus (POI). This may be partly the result of the need for less pain medication, which typically is implemented with opioids.
• Early ambulation. Early ambulation has not been found to reduce the duration of POI, but is effective in preventing other postsurgical complications, especially pulmonary and thrombotic complications.
• Nasogastric suction. NG tubes have long been advocated for the relief of POI, but have not been found to be effective in reducing the duration of POI; indeed, they may contribute to further morbidity.
• Gum chewing. Chewing gum has been evaluated in a number of randomized controlled trials. A recent meta-analysis demonstrated moderate improvement in enhancing bowel function after colorectal surgery and the authors recommended adding this modality in routine practice.
• Acupuncture. Although acupuncture can affect bowel motility, its use in reducing the incidence of POI has not been demonstrated.

References

1. Behm B, Stollman N. Postoperative ileus: etiologies and interventions. Clin Gastroenterol Hepatol. 2003;1:71-80.
2. Holte K, Kehlet H. Postoperative ileus: progress towards effective management. Drugs. 2002;62:2603-2615.
3. Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg. 2003;138:206-214.
4. Mattei P, Rombeau JL. Review of the pathophysiology and management of postoperative ileus. World J Surg. 2006;30:1382-1391.
5. Thomas J. Opioid-induced bowel dysfunction. J Pain Symptom Manage. 2008;35:103-113.
6. Cavusoglu YH, Azili MN, Karaman A, et al. Does gum chewing reduce postoperative ileus after intestinal resection in children? A prospective randomized controlled trial. Eur J Pediatr Surg. 2009;19:171-173.
7. Vasquez W, Hernandez AV, Garcia-Sabrido JL. Is gum chewing useful for ileus after elective colorectal surgery? A systematic review and meta-analysis of randomized clinical trials. J Gastrointest Surg. 2009;13:649-656.
8. Meng ZQ, Garcia MK, Chiang JS, et al. Electro-acupuncture to prevent prolonged postoperative ileus: a randomized clinical trial. World J Gastroenterol. 2010;16:104-111.

Q: I have a 65-year-old patient who is scheduled for an open left hemicholectomy. He has a long history of chronic pain and is taking hydrocodone and paracetamol (Vicodin) on a regular basis. He suffers from constipation related to his opioid use. How do I best manage his pain postoperatively?

A: Food intake elicits a reflex response that is propulsive in action. A recent review of 7 studies comparing early enteral feeding with the traditional approach to postoperative feeding found that ileus tended to resolve earlier with early enteral feeding, reaching statistical significance in a few of the studies.

A meta-analysis by Lewis et al of 11 studies comparing different feeding techniques was undertaken involving 837 patients. Early feeding was associated with a reduced risk of any type of infection and reduction in mean hospital length of stay. Risk reductions were noted for anastomotic dehiscence, wound infection, pneumonia, intra-abdominal abscess, and mortality, but these failed to reach significance. In this analysis, early feeding was associated with an increased risk for vomiting.

Presently, the introduction of a multimodal rehabilitation program (that may include surgical stress reduction, epidural anesthesia/analgesia, opioid-sparing analgesia, limited use of NG tubes, early oral feeding, and enforced mobilization) is an effective technique to reduce postoperative ileus in abdominal procedures.

References

1. Andersen HK, Lewis SJ, Thomas S. Early enteral nutrition within 24h of colorectal surgery versus later commencement of feeding for postoperative complications. Cochrane Database Syst Rev. 2006:CD004080.
2. Dervenis C, Avgerinos C, Lytras D, Delis S. Benefits and limitations of enteral nutrition in the early postoperative period. Langenbecks Arch Surg. 2003;387:441-449.
3. DiFronzo LA, Yamin N, Patel K, O'Connell TX. Benefits of early feeding and early hospital discharge in elderly patients undergoing open colon resection. J Am Coll Surg. 2003;197:747-752.
4. Kawamura YJ, Kuwahara Y, Mizokami K, et al. Patient's appetite is a good indicator for postoperative feeding: a proposal for individualized postoperative feeding after surgery for colon cancer. Int J Colorectal Dis. 2010;25:239-243.
5. Moiniche S, Bulow S, Hesselfeldt P, Hestbaek A, Kehlet H. Convalescence and hospital stay after colonic surgery with balanced analgesia, early oral feeding, and enforced mobilisation. Eur J Surg. 1995;161:283-288.
6. Petrelli NJ, Cheng C, Driscoll D, Rodriguez-Bigas MA. Early postoperative oral feeding after colectomy: an analysis of factors that may predict failure. Ann Surg Oncol. 2001;8:796-800.
7. Reissman P, Teoh TA, Cohen SM, Weiss EG, Nogueras JJ, Wexner SD. Is early oral feeding safe after elective colorectal surgery? A prospective randomized trial. Ann Surg. 1995;222:73-77.
8. Ryan JA, Jr., Page CP, Babcock L. Early postoperative jejunal feeding of elemental diet in gastrointestinal surgery. Am Surg. 1981;47:393-403.
9. Lewis S, Egger M, Sylvester P, Thomas S. Early enteral feeding versus ‘nil by mouth' after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. Br Med J. 2001;323:1-5.
10. Schwenk W, Bohm B, Haase O, Junghans T, Muller JM. Laparoscopic versus conventional colorectal resection: a prospective randomised study of postoperative ileus and early postoperative feeding. Langenbecks Arch Surg. 1998;383:49-55.
11. Stewart BT, Woods RJ, Collopy BT, Fink RJ, Mackay JR, Keck JO. Early feeding after elective open colorectal resections: a prospective randomized trial. Aust N Z J Surg. 1998;68:125-128.

Q: I am trying to develop a standardized care pathway for my bowel resection patients. I have read different things about fluid management. Some studies advocate a restricted fluid regimen; others promote goal-directed fluid therapy. What is best in terms of GI recovery and why?

A: The literature in this respect is confusing. A large body of literature has demonstrated that goal-directed fluid administration improves gastrointestinal (GI) function, reduces major and minor GI adverse events and other complications, and reduces length of hospital stay.^1-3 Other studies comparing different intraoperative volumes of fluid administered showed that smaller volumes were better than larger volumes in the recovery of GI function.^4-6 Holte et al, however, demonstrated that larger volumes are associated with better GI and pulmonary functions when compared with smaller volumes of intraoperative fluid administration.⁷

The discrepancy of results can be explained as follows:

1. The definitions of the volume of fluid. Published studies used the terms "restricted," "liberal," "dry," "wet" and "standard" regimen and the definitions of these terms vary in different studies. For example, the volume administered in the "restricted" group in one study is similar to the volume administered in the "standard" or "liberal" group in another study. In the goal-directed studies, the volumes in the goal-directed group versus the standard of care group also vary between studies. Since the volume status of each patient varies at the start of surgery and the fluid requirement is different between patients, close monitoring of the dynamic hemodynamic variables, eg, cardiac output or stroke volume, in addition to the traditional variables, eg, heart rate, blood pressure and urine output, is essential to better manage the patient's fluid need during the perioperative period. Holte et al in the conclusion of one study wrote, "...future studies should focus on the effect of individualized goal-directed fluid administration strategies rather than fixed fluid amounts on postoperative outcome." ⁸
2. The type of fluid used. Published studies have used different type of fluids, colloid, crystalloids, fluid with balanced versus unbalanced (saline based) electrolytes.^4-6 This can cause confusion as different fluids have different physiological effects on postoperative patients. There is much evidence that crystalloid does not stay within the plasma vascular space for any significant length of time and the solution moves to the interstitial fluid compartment within minutes after administration.⁹ This can result in significant interstitial edema and hence may compromise bowel recovery and symptoms of postoperative nausea and vomiting.¹⁰ In a review by Chappell, ¹¹ postoperative weight gain was closely associated with the volumes of crystalloid infused. The administration of large volumes of saline-based solutions has the tendency to cause hyperchloremic acidosis and may result in organ including bowel dysfunction. ¹²

My perioperative fluid administration recommendations are:

1. Avoid crystalloid excess by using a combination of colloid and crystalloid, colloid to maintain plasma volume and a modest volume of crystalloid for insensible loss.
2. Consider minimally or noninvasive cardiac output monitoring to better guide fluid administration. This can cause confusion as different fluids have different physiological effects on postoperative patients. There is much evidence that crystalloid does not stay within the plasma vascular space for any significant length of time and the solution moves to the interstitial fluid compartment within minutes after administration.⁹ This can result in significant interstitial edema and hence may compromise bowel recovery and symptoms of postoperative nausea and vomiting.¹⁰ In a review by Chappell, ¹¹ postoperative weight gain was closely associated with the volumes of crystalloid infused. The administration of large volumes of saline-based solutions has the tendency to cause hyperchloremic acidosis and may result in organ including bowel dysfunction. ¹²

References

1. Giglio MT, Marucci M, Testini M, Brienza N. Goal-directed haemodynamic therapy and gastrointestinal complications in major surgery: a meta-analysis of randomized controlled trials. Br J Anaesth. 2009;103:637-646.
2. Gan TJ, Soppitt A, Maroof M, et al. Goal-directed intraoperative fluid administration reduces length of hospital stay after major surgery. Anesthesiology. 2002;97:820-826.
3. Kimberger O, Arnberger M, Brandt S, et al. Goal-directed colloid administration improves the microcirculation of healthy and perianastomotic colon. Anesthesiology. 2009;110:496-504.
4. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al. Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg. 2003;238:641-648.
5. Lobo SM, Salgado PF, Castillo VG, et al. Effects of maximizing oxygen delivery on morbidity and mortality in high-risk surgical patients. Crit Care Med. 2000;28:3396-3404.
6. Nisanevich V, Felsenstein I, Almogy G, Weissman C, Einav S, Matot I. Effect of intraoperative fluid management on outcome after intraabdominal surgery. Anesthesiology. 2005;103:25-32.
7. Holte K, Klarskov B, Christensen DS, et al. Liberal versus restrictive fluid administration to improve recovery after laparoscopic cholecystectomy: a randomized, double-blind study. Ann Surg. 2004;240:892-899.
8. Holte K, Foss NB, Andersen J, et al. Liberal or restrictive fluid administration in fast-track colonic surgery: a randomized, double-blind study.[Erratum appears in Br J Anaesth. 2008 Feb;100(2):284]. Br J Anaesth. 2007;99:500-508.
9. Lamke LO, Liljedahl SO. Plasma volume changes after infusion of various plasma expanders. Resuscitation. 1976;5:93-102.
10. Moretti E, Robertson KM, El-Moalem H, Gan TJ. Intraoperative colloid administration reduces postoperative nausea and vomiting and improves postoperative outcomes compared with crystalloid administration. Anesth Analg. 2003;96:611-617.
11. Chappell D, Jacob M, Hofmann-Kiefer K, Conzen P, Rehm M. A rational approach to perioperative fluid management. Anesthesiology. 2008;109:723-740.
12. Wilkes NJ, Woolf R, Mutch M, et al. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. Anesth Analg. 2001;93:811-816.

Q: How does alvimopan work to reduce the duration of postoperative ileus (POI) and how well does it work?

A: Alvimopan is a newly-approved, peripherally-acting µ-opioid receptor antagonist. It antagonizes the peripheral effects of opioids on GI motility and secretion by competitively binding to GI tract µ-opioid receptors. Because of its charged molecule, it does not cross the blood-brain barrier, and hence it does not reverse the central analgesic effects of µ-opioid agonists. Thus, it reduces the peripheral side effects of opioids without reducing analgesic effects. It is available as an oral route of administration and is commenced before surgery and continued after surgery (alvimopan is only available for in-hospital use, 12 mg administered 30 minutes to 5 hours prior to surgery followed by 12 mg twice daily, for up to 7 days with a maximum of 15 doses).

The safety and efficacy of alvimopan have been evaluated in multiple placebo-controlled trials. Treatment of bowel resection patients with alvimopan (12 mg) was associated with significant acceleration of GI recovery (defined as later time of 1st tolerated solid food and time to 1^st bowel movement) and reduced time to discharge orders written compared with placebo treated patients.^1-6

References

1. Büchler MW, Seiler CM, Monson JR, et al. Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study. Aliment Pharmacol Ther. 2008;28:312-25.
2. Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48:1114-1125; discussion 1125-116; author reply 1127-1129.
3. Delaney CP, Wolff BG, Viscusi ER, et al. Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase III studies. Ann Surg. 2007;245:355-363.
4. Ludwig K, Enker WE, Delaney CP, et al. Gastrointestinal tract recovery in patients undergoing bowel resection: results of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway. Arch Surg. 2008;143:1098-1105.
5. Senagore AJ, Bauer JJ, Du W, Techner L. Alvimopan accelerates gastrointestinal recovery after bowel resection regardless of age, gender, race, or concomitant medication use. Surgery. 2007;142:478-486.
6. Viscusi ER, Gan TJ, Leslie JB, et al. Peripherally acting mu-opioid receptor antagonists and postoperative ileus: mechanisms of action and clinical applicability. Anesth Analg. 2009;108:1811-1822.

Q: I have a patient who is having a bowel surgery and is concerned about postoperative ileus. How common is postoperative ileus and what are the risk factors?

A: Postoperative ileus (POI) is the impairment of gastrointestinal motility after intraabdominal surgery or other non-abdominal surgeries. It may present as nausea and vomiting, absence of passage of flatus or stool. The abdomen can be distended with pain and discomfort. POI is expected to affect almost every patient who undergoes abdominal surgery. It becomes abnormal when it is prolonged.

The incidence varies depending on the procedure, ranging from 15% in large bowel surgery to about 20% in small bowel surgery.

There are a number of factors that influence the incidence of POI, including neurogenic, hormonal, inflammatory, and pharmacologic components. Important factors include the surgical site and the extent of bowel resection and bowel manipulation. Prolonged operation time also increases the risk. A patient's pre-existing conditions, such as systemic infection or sepsis are also factors. The use of opioids is directly related to the incidence and duration of POI. Studies have shown an almost linear correlation.

Q: I have a 65-year-old patient who is scheduled for an open left hemicholectomy. He has a long history of chronic pain and is taking hydrocodone and paracetamol (Vicodin) on a regular basis. He suffers from constipation related to his opioid use. How do I best manage his pain postoperatively?

A: This is indeed a challenging case with respect to postoperative pain management. Patients who present with chronic pain often have an increased level of postoperative pain following surgery. There will be acute pain on chronic pain.

Given the presence of chronic pain with long-term opioid therapy, I would recommend an epidural for perioperative pain control. The epidural is inserted preoperatively at the lower thoracic level in between the 11th and 12th interspinous space. Following a test dose to ascertain correct placement, a bolus dose of hydromorphone 0.6 to 0.8 mg may be administered via the epidural route. Postoperative epidural infusion may be accomplished with 0.125% bupivacaine with 10 mcg/mL of hydromorphone at a rate of 6 to 8 mL/hr.

A standard general anesthetic is advised with the use of opioid and inhalational agent. A dose of ketorolac 15 mg may be administered intravenously to reduce the use of opioid intra- and postoperatively.

The epidural may be kept in place until the patient establishes bowel function, when pain management may then be converted to oral opioid containing analgesics.