Postoperative Ileus. UCSF Postgraduate Course in General Surgery Maui, HI March 20, 2011

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1 Postoperative Ileus UCSF Postgraduate Course in General Surgery Maui, HI March 20, 2011 Hobart W. Harris, MD, MPH Introduction Pathophysiology Clinical Research Management Summary

2 Postoperative Ileus: Introduction Postoperative ileus (POI) is a predictable, temporary delay in gastrointestinal motility after surgery, generally lasting 2 4 days. When symptoms persist and are precipitated by a complication of surgery, e.g., anastomotic leak or intra-abdominal abscess, than this is now referred to as secondary POI; Symptoms of POI include nausea, vomiting, abdominal distention, abdominal tenderness and delayed passage of flatus and stool; sf Long considered a routine aspect of the postoperative course, POI is now identified as an important component of patient care following surgery; Prevention of POI could result in significant decrease in patient discomfort and length of stay. POI is estimated to add ~1.5 billion dollars to annual healthcare costs in the US. Postoperative Ileus: Pathophysiology Underlying mechanisms are incompletely understood and multiple factors have been identified, including; - spinal-intestinal neural reflexes - sympathetic hyperactivity (decreased parasympathetic activity) - ischemia/reperfusion injury sf endogenous & exogenous opiates - inflammatory mediators (activated leukocytes, enterocytes) - mechanical trauma - electrolyte imbalances

3 Postoperative Ileus: Pathophysiology melokinex.com/images/graph.jpg Postoperative Ileus: Pathophysiology However, the role of inflammation triggered by the physical manipulation of the intestine is now generally accepted as the key event in POI. - transient inhibition of GI motility initially described by Bayliss & Starling in 1899 (J. Physiol 1899;24:99-143); - widely recognized that not all segments of the intestine are equally affected; small intestine (24 h), stomach (24-48 h) and colon (3-5 days); sf Over the last decade there is substantial evidence that abdominal surgery triggers two different phases of POI, each with its own time course and underlying pathophysiology.

4 Postoperative Ileus: Pathophysiology Postoperative Ileus: First Neurogenic Phase laparotomy intestinal manipulation

5 Postoperative Ileus: Second Inflammatory Phase Timing of the inflammatory events triggered by abdominal surgery. Postoperative Ileus: Second Inflammatory Phase Proposed mechanism involved in the inflammatory response following intestinal manipulation. 1. mast cell activation via physical manipulation; 2. vasoactive substances alter intestinal permeability; 3. translocation of PAMPs and injury-mediated release of PAMPs activate inflammatory pathways in resident macrophages.

6 Postoperative Ileus: Impaired Intestinal Motility Mechanisms underlying the impaired contractility of the intestine following abdominal surgery. 1. activated resident macrophages release inflammatory cytokines & chemokines; 2. inflammatory mediators activate endothelial cells which upregulate adhesion molecule expression; 3. circulating leukocytes invade (diapedesis) the muscularis externa of the intestine; 4. these leukocytes and resident macrophages produce large amounts of NO and prostaglandins (PGs) which inhibit the contractile activity of intestinal smooth muscle cells. PGs also activate and increase the sensitivity of spinal afferents contributing to the generalized POI. Postoperative Ileus: Preclinical Research Potential therapeutic strategies to inhibit activation of resident macrophages and prevent POI. 1. activated resident macrophages release inflammatory cytokines & chemokines; 2. inflammatory mediators activate endothelial cells which upregulate adhesion molecule expression; 3. circulating leukocytes invade the muscularis externa of the intestine; 4. these leukocytes and resident macrophages produce large amounts of NO and prostaglandins (PGs) which inhibit the contractile activity of intestinal smooth muscle cells. PGs also activate and increase the sensitivity of spinal afferents contributing to the generalized POI.

7 Postoperative Ileus: Clinical Research Pharmacologic treatments for POI have not proven reliable, including prokinetic agents like erythromycin and metoclopramide; NSAIDs have both analgesic and anti-inflammatory roles in treating POI, but use is limited by their side effects, including GI and surgical site bleeding, and nephrotoxicity in the elderly; sf Nonselective opiod antagonists (e.g., naloxone, nalmefene) could potentially reverse effective analgesia and are not indicated for preventing/treating POI; Alvimopan, a selective opiod (mu-receptor) antagonist, was approved by the FDA in 2008 to treat POI following intestinal resection. Initial studies involving broader range of abdominal surgery patients revealed no benefit. Selected analysis and study of patients with a bowel anastomosis identified a reduction in time to resolve POI of ~12 hours without a significant reduction in LOS. Postoperative Ileus: Management Supportive Care: Intravenous fluids, correction of electrolyte abnormalities and selective use of nasogastric decompression; Epidural analgesia: shown to shorten the duration of POI, as well as improve pain control, decrease pulmonary complications and hasten recovery; Immediate feeding: early oral feeding is well tolerated by most patients in the setting of elective colorectal (Ann sf Surg 1995;222:73-77) or gynecologic surgery (Obstet Gynecol 2000;96: ). But, early feeding is not tolerated by all patients. Chewing gum: a recent meta-analysis of five randomized trials of 158 colorectal surgery patients suggests that chewing gum likely decreases time of POI (24 h) and length of stay (2 days) at very low cost to providers;

8 Postoperative Ileus: Management Chewing gum & POI Arch Surg 2008;143: Postoperative Ileus: Management Supportive Care: Intravenous fluids, correction of electrolyte abnormalities and selective use of nasogastric decompression; Epidural analgesia: shown to shorten the duration of POI, as well as improve pain control, decrease pulmonary complications and hasten recovery; Immediate feeding: early oral feeding is well tolerated by most patients in the setting of elective colorectal (Ann Surg 1995;222:73-77) or gynecologic surgery (Obstet Gynecol 2000;96: ). But, sf early feeding is not tolerated by all patients. Chewing gum: a recent meta-analysis of five randomized trials of 158 colorectal surgery patients suggests that chewing gum likely decreases time of POI (24 h) and length of stay (2 days) at very low cost to providers; Minimally invasive surgery: a systematic review of 12 randomized controlled trials (N = 4,407) comparing laparoscopic to open colectomy revealed less postoperative pain, decreased narcotic use, earlier return of bowel function and shortened LOS in the MIS patients (Br J Surg 2006;93: ).

9 Postoperative Ileus: Summary A multifactorial, inflammatory condition of the intestinal tract triggered by the physical manipulation of the bowel; Molecular pathogenesis includes the activation of resident mast cells and the subsequent production of soluble, vasoactive mediators of inflammation; Macrophage and neutrophil recruitment are central to inhibiting intestinal motility; sf Pharmacologic methods for preventing or treating POI are modestly effective at best; Chewing gum is a clinically proven, cost-effective means of treating POI and decreasing LOS; Additional preclinical and clinical research is warranted.

10 Postoperative Ileus: Pathophysiology melokinex.com/images/graph.jpg