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Postoperative ileus (POI) is the most common gastrointestinal (GI) motility disorder managed by surgeons in their clinical practice. The definition, pathophysiology, prevention, diagnosis and management of POI are still not determined. An expert consensus defined POI as a ‘transient cessation of coordinated bowel motility after surgical intervention, which prevents effective transit of intestinal contents and/or tolerance of oral intake’.1 Primary POI is a physiological response that occurs in almost all patients following abdominal surgery and is usually spontaneously resolved by the 5th postoperative day after open laparotomy and by the 3rd day after laparoscopic surgery.1 The small intestine recovers its normal motility 8–24 h after surgery; the stomach, 24–48 h and the colon from 72 h, the left colon being the last to recover.2 As most surgeons wait for GI function recovery before allowing patients to be fed, POI has become the main cause of delayed hospital discharge after abdominal surgery. In addition, 19–25% of patients will develop prolonged primary ‘paralytic’ POI following major intestinal surgery.1 ,2 The clinical picture of primary POI ranges from oligosymptomatic patients to a full symptom cluster including abdominal pain, nausea and vomiting, abdominal distension and bloating, delayed passage of flatus and stool, and inability to progress to an oral diet. Diagnosis of POI relies on identification of these clinical features but diagnosis by abdominal auscultation for return of bowel sounds or passage of flatus is inaccurate, and instrumental exploration non-existent.1 ,2 A composite clinical endpoint (GI-2), defined by time to tolerability of solid food and time to first bowel movement, has been proposed as a reliable marker of the end of POI.1 An objective technique to monitor postoperative GI motility should be developed to facilitate research and patient care. Prolonged primary POI causes additional postoperative morbidity with increased pain and catabolism, reduced immunity and enhanced risk of nosocomial infections, pulmonary complications, poor wound healing and anastomotic leaks. Due to the resulting prolonged hospitalisation, higher healthcare resource utilisation and higher readmission and reoperation rates, POI presents a health and economic burden.1 ,2 The prevention, early identification and treatment of POI is therefore essential to improve surgical care.
POI is caused by the interplay of multiple factors including: (a) neurogenic mechanisms with overactivation of sympathetic pathways; (b) inhibition of GI motility by opioid analgesics; and (c) intestinal inflammatory response to bowel manipulation and surgical trauma. Inhibitory neurogenic mechanisms mediate the immediate-early phase of POI and are stepwise activated depending on the intensity of the nociceptive stimuli. Initially, skin incision and laparotomy activate somatic fibres which in turn activate spinal adrenergic reflexes. Then, manipulation of intestinal or peritoneal afferents activates supraspinal pathways, which include the activation of hypothalamus and the dorsal vagal complex and central release of corticotropin-releasing factor.1 ,3 These boost descendent spinal pathways, enhancing the sympathetic inhibitory drive to the gut via splanchnic nerves3 and an inhibitory vagal pathway mediated by peripheral release of nitric oxide (NO).4 Animal studies showed that corticotropin-releasing factor antagonists can prevent POI.3 In addition, high thoracic epidural anaesthesia has been clinically shown to reduce POI by blocking both the afferent and efferent arms of these inhibitory reflexes and by improving splanchnic blood flow.1 ,2 Stimulation of parasympathetic pathways by early enteral nutrition or sham feeding (gum chewing) can also improve motility and balance the effects of the autonomic nervous system in POI.3 ,4 Endogenous opioids released during surgical stress response and exogenous opioids used as major postoperative analgesics are also major contributors to impaired GI motility in POI.1 ,5 Opioids activate µ-receptors in the enteric nervous system, inhibiting the release of neurotransmitters involved in peristalsis. There are two possible strategies to avoid these negative effects. Alvimopan and methylnaltrexone selectively block enteric µ-receptors and do not cross the blood-brain barrier, avoiding the negative effects of opioids on POI while not interfering with the effect of endorphins or opioid analgesics on the central nervous system.1 ,2 ,5 Alternatively, opioid-sparing analgesia using non-steroidal anti-inflammatory drugs during the postoperative period also helps prevent POI.2
The inflammation of the intestinal muscularis caused by the extent of surgical bowel manipulation will determine the duration and severity of inhibition of GI motility during POI. This prolonged inflammatory phase of POI is initiated by mediators released from damaged tissue or by luminal bacterial products such as lipopolysaccharide crossing an impaired GI mucosal barrier.4 These ‘damage signals’ activate inducible NO synthase and cyclooxygenase-2 pathways in macrophages residing in the muscularis externa. Activated macrophages release NO and prostaglandins which directly inhibit neuromuscular function.1 ,5 Bowel manipulation also evokes mediator release from peritoneal mast cells possibly via primary afferents releasing calcitonin gene-related peptide and Substance P.4 Macrophage-derived and mast cell-derived cytokines and chemokines enhance inflammation, recruit additional circulating leucocytes, impair muscle contractility, reduce release of neurotransmitters and can even cause tissue damage.4 ,6 Due to their multiple involvement in POI, mast cells and macrophages are strategic targets. Mast cell stabilisation with ketotifen or doxantrazole, and macrophage inhibition with semapimod improved the inflammatory-dysmotility component of POI in a clinical trial7 and an animal study.8 Van Bree et al 9 investigated the therapeutic effect of a novel spleen tyrosine kinase inhibitor GSK143 on cultured mast cells and macrophages and in mouse POI. Their in vitro results demonstrate that GSK143 can inhibit mediator release from mast cells evoked either by Substance P or by IgE crosslinking, indicating broad inhibition of mediator release. GSK143 also prevented lipopolysaccharide-induced macrophage activation, indicated by the decreased expression and release of proinflammatory mediators. In the mouse small bowel, GSK143 reduced the manipulation-induced production of proinflammatory, macrophage-derived cytokines. Finally, GSK143 improved intestinal transit and reduced recruitment of neutrophils and monocytes to the muscularis externa of the manipulated bowel.9 The inhibitory effects of GSK143 on mast cell and on macrophage are interesting as simultaneous targeting of both cell types might counteract their synergistic actions in POI pathophysiology, enhancing treatment.
Management of POI has changed over the last decade from a ‘supportive strategy’ during bowel rest, to an ‘active strategy’ aimed at identifying, preventing and treating all the perioperative factors contributing to POI. The integrated multimodal ‘fast track’ approach includes routine use of minimally invasive techniques such as laparoscopy, thoracic epidurals, opioid-sparing analgesia, avoidance of fluid overload, restricted use of nasogastric tubes and promotion of early postoperative oral feeding.1 ,2 ,10 Inflammation-related dysmotility during POI has been addressed only recently and its prevention and treatment have not yet been incorporated into clinical practice. The article of van Bree et al suggests that drugs targeting this relevant factor causing POI should be introduced in the multimodal perioperative care of our surgical patients as soon as possible.
Contributors Both authors JR and PC wrote the review/comment.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Commissioned; externally peer reviewed.