Aetiology

Previous studies in animal models have suggested two major mechanisms involved in the development of POI: neurogenic and inflammatory mechanisms both related to the surgical procedure itself (BOECKXSTAENS and DE JONGE 2009). These two mechanisms probably combine in causing POI with different time frames, considerable overlap, and possible interactions (BAUER et al. 2002). A third component discussed in the development of POI, is the effect of different drugs (e.g.

anaesthetics) on the motility of the intestine after surgery (KEHLET 2008). However,

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the effects of volatile anaesthetics is short lasting and therefore only of marginal importance. Perioperative use of sedatives as alpha-2-agonists (e.g detomidine) can affect the motility of the gastro-intestinal-tract and gastric emptying (SUTTON et al.

2002). The combined use of ketamine and xylazine for induction of anaesthesia in horses resulted in a complete loss of intestinal motility for 3-6 hours (SINGH et al.

1996). The use of post-operative opioids as pain treatment has a greater impact on the gastro-intestinal motility, with a delayed gastric emptying and prolonged intestinal transit after administration of morphine (BOSCAN et al. 2006) or butorphanol (SELLON et al. 2004).

3.2.2.1 Neurogenic phase

The normal function of the gastrointestinal tract is dependent on the coordination of activating parasympathetic stimuli and inhibition though sympathetic activation.

Through hyperactivation of the autonomic nerve system in the early postoperative phase with an increased sympatheticus activity the motility of the intestine is decreased (MIEDEMA and JOHNSON 2003). The degree of inhibition of motility is dependent on the severity of the stimuli, with only a short-term inhibition of motility after skin incision and laparotomy through activation of a low-threshold adrenergic inhibitory pathway (BOECKXSTAENS and DE JONGE 2009). This probably involves a spinal loop with afferent splanchnic nerves synapsing in the spinal cord and efferents travelling back to the entire intestinal tract, abolishing the motility of the entire gastrointestinal tract (LIVINGSTON and PASSARO 1990). In contrast, more intense stimuli such as handling and manipulation of the intestine lead to an activation of high-threshold supraspinal pathways with a much longer inhibition of intestinal motility (BARQUIST et al. 1996, BOECKXSTAENS et al. 1999). This includes activation of additional pathways actively mediated by the brainstem. After transmission of afferent signals to the brainstem, the signals trigger an increased autonomic output to the neurons of the intermediolateral column of the thoracic cord to the location of sympathetic preganglionic neurons. Activation of these nerves subsequently inhibits the motility of the entire gastro-intestinal tract through the effect of secreted noradrenaline on adrenergic receptors and subsequently inhibition of the

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migrating motor complexes (MMC) (SAGRADA et al. 1987, BOECKXSTAENS and DE JONGE 2009). Additionally, intense stimulation of the splanchnic afferents triggers an inhibitory non-adrenergic, vagally mediated pathway (THE et al. 2005).

The role of neurogenic activation for the development of POI is important, but is not the only contributing factor as it cannot explain the long-lasting dysfunction of the intestinal motility in some cases (PANTELIS and KALFF 2007).

The “first” or neurogenic phase usually ceased at the end of surgery (BOECKXSTAENS and DE JONGE 2009).

3.2.2.2 Inflammatory phase

In 1978 FIORAMONTI and RUCKEBUSCH observed two phases of inhibition of intestinal activity in dogs and sheep after abdominal surgery. The first phase consisted of complete inhibition of electrical spiking activity during and after surgery, which transiently ceased after the end of surgery. The second phase of inhibition was observed 3-4h after surgery with the duration being dependent on the nature of surgery, with a long-lasting reduction (48-72h) of spiking activity after resection of the small intestine in dogs and sheep (BUENO et al. 1978a). It could be demonstrated, that an inhibitory neural pathway mediated the first phase; however the exact origin of the second phase was unclear.

KALFF et al. (1998) suggested that the timeframe of the second phase of POI correlates with an activation and infiltration of inflammatory cells in the intestinal wall.

Intestinal manipulation resulted in the activation of macrophages and subsequent release of cytokine and chemokine with an influx of leukocytes approx. 3-4h after surgery. Other authors demonstrated an interaction between the immune system, the autonomic nervous system and the muscular function of the gastrointestinal tract (BOECKXSTAENS et al. 2009, DE WINTER and DE MAN 2010, WEHNER et al.

2012).

Discussed mediators involved in the pathogenesis of inflammatory-mediated ileus include nitric oxide (NO) and prostaglandins (DE WINTER and DE MAN 2010). The inducible form of NO synthase (iNOS) has been suggested to mediate LPS-induced motility disturbances in mice models of sepsis-induced ileus (DE WINTER et al.

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2002, 2005) and in surgically induced POI (KALFF et al. 2000). There was evidence, that the effects of iNOS on motility disturbances in septic induced ileus were partly mediated by NO-mediated oxidative stress mechanisms, by the use of anti-oxidant molecules (DE WINTER et al. 2005). In a study by SCHWARZ et al. (2001) surgical manipulation of the intestine of rats resulted in an expression of COX-2 mRNA and proteins within resident muscularis macrophages, together with an increased prostaglandin level in the peritoneal fluid and in the circulation. The expression of COX-2 mRNA was associated with a decrease of jejunal circular muscle contractility in-vitro and increased gastrointestinal transit time. Both of these could be alleviated pharmacologically by the use of a selective COX-2 inhibitor (DFU ( phenyl-2(5H)-furan one)). In humans, KALFF et al. (2003) also demonstrated an expression of COX-2 mRNA in the muscularis externa of jejunal specimens after prolonged abdominal surgery (approx. 3h). In addition to the local effect on gastrointestinal motility, prostaglandins are suggested to modulate afferent nerve signalling from the intestine to the spinal cord and higher brain centres, Thereby modulating sensitivity disturbances and pain signalling pathways (WANG et al. 2005).

Manipulation of small intestine in rodents resulted decreased contractility compared to control specimens, which was accompanied by an accumulation of neutrophilic granulocytes, monocytes and mast cells in the muscularis externa and an activation of resident macrophages (KALFF et al. 1998).

Another study by KALFF et al. (2003) investigated the initiation of an inflammatory response within the human intestinal muscularis externa intraoperatively. Numerous macrophages within the intestinal muscularis externa with an expression of increased lymphocyte immunreactivity were shown after prolonged abdominal surgery (approx.

3h). This was correlated with a time-dependent expression of intestinal cytokines and enzymes (IL-6, IL-1, TNF-α, iNOS and COX-2 mRNAs). In cases of re-laparotomy 24 or 48 h after the first laparotomy, a leukocytic infiltration (neutrophils and monocytes) primarily recruited to the circular muscle layer was observed in the jejunal specimens. This was not identified in the early specimens (30 min after incision) from the first surgery. The muscle strips after re-laparotomy also demonstrated a marked

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decrease of in-vitro spontaneous activity and response of circular muscle to stimulation with bethanechol.

Type and severity of mechanical manipulations can induce various degrees of intestinal inflammation, as has been documented in rodents (KALFF et al. 1998, 1999 a,b, 2000, SCHWARZ et al. 2001, 2004, WEHNER et al. 2007), mice (THE et al. 2005), pigs (HIKI et al. 2006), and human beings (de JONGE and THE 2004, KALFF et al. 2003, THE et al. 2008).