Management of ileus and adhesions (Proceedings)

Although there has been a substantial increase in our understanding of postoperative complications in recent years, the treatments remain very much the same. For ileus, these treatments include decompression of the stomach, replacement of fluid and electrolyte losses with parenteral fluids, and use of a variety of prokinetic agents. For adhesions, treatments include anti-inflammatory medications and antibiotics, although some of the newer physical agents such as carboxymethylcellulose offer new modalities for combating this problem. However, in order to make further advances in treatment of these problems, a close appraisal of the clinical and basic science literature is warranted so that new therapies can be based on an understanding of the mechanisms that result in ileus and adhesions.

Clinical aspects of postoperative ileus

Postoperative ileus in the horse is essentially a syndrome related to abnormal small intestinal motility because it is identified on the basis of proximal gastrointestinal reflux. Thus, although there are horses with abnormal large intestinal motility following colic surgery, the term postoperative ileus has not included these cases in most studies. This is because abnormal small intestinal motility, with the attendant reflux of stomach contents, is readily recognized as an important cause of postoperative mortality. Recent studies indicate that the prevalence of ileus amongst horses with signs of colic taken to surgery for abdominal exploration ranges from 10% to over 40% depending upon the study population and the criteria for defining cases of ileus. The criteria for defining ileus vary widely. For example, one study regarded any horse with >2L reflux to have postoperative ileus, whereas another study defined cases of postoperative ileus as horses with >20L during a 24-hour period, or >8L during any single refluxing event. However, it is likely that these studies are evaluating a similar population of horses, with differing levels of severity, since horses had other important features of the syndrome of postoperative ileus, including an increase in heart rate and signs of colic. Risk factors for postoperative ileus can be grouped into two important categories: those related to the degree of circulatory shock, and those related to surgery. For example, elevated heart rate and packed cell volume in the preoperative period place horses at risk of postoperative ileus, and small intestinal surgery, particularly involving strangulating obstruction, place horses at risk of postoperative ileus. These groups of factors have been consistently linked in two studies using multiple logistic regression analyses, suggesting that the degree of shock and the nature of the intestinal lesion are intimately linked, and combine to place horses at risk of postoperative ileus.

Not all studies suggest such a high prevalence of postoperative ileus, which may relate to differences in disease management. For instance, Freeman and coworkers were able to show that of horses taken to surgery for small intestinal disease, only 10% developed postoperative ileus. One key management factor that may differ from other hospitals was early re-feeding, where horses were offered water and small amounts of hay within 18-24-hours of the completion of surgery. Conversely, many surgeons will hold horses off feed for at least 24-hours before contemplating a return to feed. The work by Freeman and coworkers suggests that this is not optimal. Regardless of prevalence data, postoperative ileus appears to contribute significantly to postoperative mortality. The percentage of horses that die in the postoperative period from ileus ranges from 9 to 43%. Considering that these deaths are all short-term deaths (within the period of the initial hospitalization), postoperative ileus is one of the major reasons for a substantial drop in survival noted in the early postoperative period. These deaths are typically elective (euthanasia at the owners request or surgeon's recommendation), and usually relate to the inability to manage the degree of shock associated with continued copious reflux, or the requirement for additional surgical procedures in order to evaluate recurrent colic in the face of ileus. One study noted that in horses undergoing small intestinal surgery, the occurrence of postoperative ileus was the single greatest risk factor for death (horses with ileus were 29-fold more likely to die than horses without ileus).

Clinical aspects of adhesions

As with postoperative ileus, abdominal adhesions are more of a problem in horses with small intestinal disease, although they can occur following surgery of the large colon. One important study by Baxter and co-workers showed that in horses taken to surgery for small intestinal disease, 22% had a clinical problem with adhesions that required repeat laparotomy or euthanasia. Only one of the horses that had a clinical problem with adhesions survived, highlighting the difficulty of treating this condition once it has occurred. Interestingly, 70% of the horses requiring surgical intervention because of adhesions were re-operated within 60-days of the original surgery. Therefore, it is reasonable to inform owners of the risks of adhesion formation following small intestinal surgery, but it is also worthwhile indicating that approximately 70% of the time, the problem will be evident within the first 60-days.

Evidence of adhesions can include more subtle signs than overt need for repeat laparotomy or euthanasia. A number of horses will have intermittent colic following small intestinal surgery that is not associated with reflux and which starts approximately 3-5 days following surgery. This form of postoperative colic is likely attributable to early adhesion formation in many cases. Abdominocentesis can be performed along with ultrasound in order to gain additional information. On ultrasound, thickening of the wall of the small intestine, or fibrin tags may be noted. On abdominocentesis, the most important factor to rule out is septic peritonitis. All horses are expected to have intra-abdominal evidence of inflammation following surgery, but some horses additionally have evidence of intra- or extracellular bacteria . Evidence of bacteria indicates the need for abdominal lavage.

New research findings related to development of ileus and adhesions

In the area of ileus, the majority of recent advances have been made by a group studying a rodent model of postoperative ileus. In this model, selective manipulation of the small intestine, similar to that encountered during exploratory laparotomy, results in inflammatory cell infiltration in the longitudinal and circular muscle layers, and the myenteric neural plexus. During the development of inflammation, a number of cytokines and pro-inflammatory enzymes are activated. Perhaps of most clinical interest is up-regulation of inducible nitric oxide synthase (iNOs) and cyclooxygenase-2 (COX-2). Both have been shown to be upregulated in strangulated equine small intestine. These enzymes elaborate nitric oxide and prostanoids respectively, which have documented roles in reducing, or disrupting, intestinal motility, and are potential therapeutic targets. In equine intestine, it is likely that although strangulated small intestine is resected when it is encountered, remaining small intestine contains similar evidence of inflammation as that in the rodent models. Furthermore, patients with simple obstruction of the small intestine also undergo substantial intestinal manipulation. Thus, although markedly inflamed intestine is resected, the residual intestine may be inflamed as a result of surgical manipulation and inflammation extending beyond the borders of the resected intestine. The latter has already been demonstrated in one study in which intestinal neutrophil infiltration was noted at the margins of resected small intestine, most prominently at the oral resection margin. This is important because in small intestinal surgery, the oral resection margin is typically regarded as 'clean' because the total length of the small intestine allows for ample resection margins in most cases. Thus, what we are likely dealing with in horses with postoperative ileus is extensive neuromuscular inflammation, with release of mediators that disrupt motility. This is in contrast to earlier theories on the syndrome, which suggested a more global effect of extra intestinal neural pathways.

Similar inflammatory mechanisms likely exist for the formation of adhesions. Studies by Sullins and co-workers have shown that adhesions can be induced by both ischemia and distension in foals. Gross and histologic evidence of adhesions were noted within 10-days of the initial surgery. Histologically, fibrous tissue was noted in the outer layer of the serosa. Additional studies have evaluated the histologic appearance of the intestinal resection margins of resected intestine from natural cases of small intestinal strangulating obstruction. These studies have revealed a preferential infiltration of the serosa with neutrophils, most notably at the proximal resection margins. Presumably, the latter is indicative of injury induced by distension within intestine proximal to an obstruction. However, it is likely that this early neutrophil infiltration sets off a cascade of events leading to formation of fibrous adhesions. Thus, interrupting early inflammation will be critical to prevention of abdominal adhesions.

Management of ileus and adhesions

In general, clinicians should realize that they are treating postoperative inflammatory events localized within the small intestine. For postoperative ileus, this means that treatments solely aimed at increasing motility via various neural mechanisms, such as metoclopramide or erythromycin, are likely to have limited success because they do not treat the primary cause of the problem, which is inflammation. Treatment with lidocaine continues to make good sense because although the mechanism of this medication was first thought to be related to blockade of inhibitory neural pathways, it is now becoming clear that lidocaine is an anti-inflammatory agent. This is because lidocaine inhibits neural reflex arcs that serve to recruit neutrophils. More specifically, it has been shown that activation of sensory nerves can in turn activate inflammatory cells such as mast cells, and these cells are then capable of releasing neutrophilic chemoattractants. Although this remains to be evaluated in horses, it makes sense to treat horses early in the postoperative period (such as immediately following surgery) in order to take advantage of any anti-inflammatory effects. Other anti-inflammatory medications also include anti-oxidant medications, which prevent generation of chemoattractants in experimental studies, just as they prevent onset of reperfusion injury. An example is DMSO, although this agent has not been evaluated for its ability to reduce neuromuscular inflammation. However, DMSO at a dosage of 20mg/kg IV has been shown to prevent adhesion formation, possibly as a result of reduce serosal inflammation. Additional treatments should include non-steroidal anti-inflammatory drugs, which could be replaced by COX-2 inhibitors in the future, considering up-regulation of this enzyme in injured intestine, and medications aimed at inhibiting iNOs.

In a recent clinical study concerning adhesions, the use of the non-steroidal anti-inflammatory drug flunixin, combined with broad-spectrum antibiotics (penicillin and gentamicin) was shown to reduce the incidence of adhesions. Further studies concerning reduction of the incidence of adhesions indicate efficacy for use of topical carboxymethylcellulose (CBMC) and hyaluronate. These agents can be applied in two ways, both of which have been shown to reduce adhesion formation. They can be used as solutions, and placed on the bowel during and after the surgical procedures. Alternatively, CBMC-hyaluronate membranes are commercially available for placement on an area deemed at risk of adhesion formation, such as an anastomosis. An on-going epidemiological study at NC State University suggests that both of these agents have a protective effect from early evidence of adhesions (postoperative colic), and can be used together for maximal effect.