State-of-the-art colorectal disease: postoperative ileus

Postoperative ileus (POI) is a common problem encountered by surgeons after abdominal and even non-abdominal surgery [1]. Although physicians are quite familiar with this condition there is a lack of a precise clinical definition [2]. It is generally understood as a disruption of the regularly orchestrated, propulsive activity of the gastrointestinal tract after surgery. To a certain extent, this is considered as a normal, self-limited response to an operation. But sometimes prolonged paralysis occurs, leading to abdominal distension, nausea, and vomiting with the consequence of intolerance of oral food intake and delayed time to hospital discharge [3]. Multiple definitions have been used in the literature; most commonly, the absence of bowel movement and cessation of oral food intake longer than postoperative day 4 are the cutoff for prolonged POI [4]. But there is a broad variety in authors’ opinions about an adequate gastrointestinal recovery time. Additionally, prolonged POI must be differentiated from other complications such as early postoperative bowel obstruction, perforation, or intraabdominal abscess formation [5] which might present similarly but require a surgical intervention. As with the definition, the incidence of POI varies in surgical literature ranging from around 10% up to 27% of patients who are affected [6‐8]. This does not only have a consequence for their wellbeing but is also related with higher morbidity and complications as well as a prolonged hospital stay and consecutively has a severe economic impact [5]. Recent data from New Zealand describe a significant increase by 71% of hospital costs in patients with prolonged ileus [9]. In the USA, the economic burden of POI was an estimated 750 million $ per year [10]. Therefore, POI remains a key issue for surgeons, patients, and society alike.

The underlying mechanisms of POI are a complex interaction of inflammation, neural reflexes, neurohumoral pathways, and pharmacologic effects. While interstitial cells of cajal (ICC) provide the rhythmicity of gut motility by their pacemaker activity, the enteric nervous system is the key player in influencing gut motility with mediation by parasympathetic and sympathetic pathways [11, 12]. It has been demonstrated that manipulation of the gut leads to a leukocyte infiltration into the intestinal mucosa reflecting an inflammatory response which leads to an impaired muscle contractility [13, 14]. Further, animal studies revealed that a network of resident macrophages plays a central role in orchestrating this inflammation [15, 16] involving numerous cytokines but also prostaglandins by inducing the expression of cyclooxygenase-2 (COX-2) as well as NO [17]. Moreover, the release of proinflammatory cytokines and chemokines by the enteric nervous system add to that effect [18, 19]. Recently, research focused on the population of enteric glial cells. They modulate neural activity in the enteric nervous system and can be activated by mechanical forces that initiate a neuro-inflammatory process [20]. Preclinical research of our group demonstrated an IL-1 receptor-type 1 (IL1R1) and P2X2-dependend effect on POI [19]. Figure 1 provides a current understanding of the neuro-immune interactions in gastrointestinal dysmotility. Yet, not all mechanisms of action and their dependencies are fully understood. Furthermore, noxious stimuli of the surgical procedure trigger inhibitory neural reflexes by splanchnic afferents which are also mediated by supraspinal pathways, thus increasing sympathetic activity with reduced gut motility [11]. Aside from these noradrenergic facilitated effects, neurohumoral peptides such as nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) also seem to act as inhibitory neurotransmitters leading to impaired intestinal motility [21]. Finally, the μ-receptor-mediated decrease of motility due to postoperative analgesia with opioids is a familiar contribution in maintaining POI [22].

The identification of predisposing factors associated with POI could allow for a targeted surveillance or even prophylaxis for patients at risk. Most meta-analyses searching for independent risk factors for POI have been published in a certain surgical field, commonly in patients undergoing colorectal surgery. The varying definition of POI hinders comparability of single studies and conclusions thereof [23]. For gastrointestinal surgery, male sex, creation of a stoma, respiratory comorbidities, and duration of surgery > 3 h were identified as independent risk factors as summarized in Table 1 [4, 23, 24]. One of the key factors contributing to POI is the surgical technique. It has been demonstrated that open surgery in contrast to minimally invasive surgery (MIS) significantly increases the probability of POI with odds ratios (OR) ranging from 1.97 to 6.37. Additionally, perioperative need for blood-transfusion and liberal crystalloid infusion contributes to POI [5, 7]. Predictive scores to identify the risk of POI have only been established in small- to medium-sized cohorts and have yet to be validated in clinical use [5, 25]. Furthermore, any factor (e.g., pharmacologic treatment, comorbidities) that reduces gastrointestinal motility per se can contribute to the risk for prolonged POI.

The main clinical features of POI are abdominal distension, nausea and vomiting, and the absence of flatus or stool passage. While there might be mild tenderness on palpation, usually, no muscular defense is present in clinical examination. Laboratory tests typically show no specific alterations [26, 27]. As postoperative complications like intra-abdominal infections and anastomotic leakage are also associated with POI, any patient with prolonged ileus should be closely monitored and these complications should always be ruled out [26].

The risk factors collected over the years of POI research and the growing understanding of its pathophysiology have led to various prevention strategies. Those that have a promising effect on POI development are summarized in Table 2 and will be reviewed in this section. Some of them have been integrated in fast-track protocols. Their multimodal approach is to reduce or even prevent the undesirable side effects of patients’ pathophysiologic reactions to the surgical trauma and perioperative management [40]. Fast-track programs have gained popularity over the past two decades, yet their influence on POI has still to be investigated. Data suggest a beneficial effect on length of stay, time to defecation, and complications in patients treated under those regimens [41, 42] although it remains unclear which components account for the improvement.

It has to be stated that once prolonged POI has manifested, there is no evidence-based therapeutic approach. Prokinetic substances like metoclopramide, erythromycin, and acetylcholinesterase-inhibitors such as neostigmine are widely used in clinical routine without showing a benefit in clinical symptoms or shortening POI in a Cochrane analysis [82]. Also, the oral administration of gastrografin, a hyperosmolar contrast agent, has no significant effect in resolving the symptoms of POI [83, 84]. Considering the multifactorial pathophysiology with a complex interaction of neuro-immune mechanisms and apparent inflammation of the muscularis externa, it is not surprising that a prokinetic agent fails to restore intestinal motility. The treatment of patients with manifest POI is of supportive manner only. This includes decompression of a distended intestine in patients with persistent vomiting via insertion of a nasogastric tube and parenteral nutrition depending on the duration of POI. Furthermore, isotonic crystalloids and potassium should be substituted intravenously to maintain normovolemia and balanced electrolytes [85].

In summary, the incidence of POI remains high in patients even in the era of MIS and fast-track programs and is a burden for both patients and society. A Delphi approach within the Association of Coloproctology of Great Britain and Northern Ireland even stated POI to be in the high priority list of non-cancer related clinical problems [86]. A lot of research has been conducted regarding the pathophysiology and possible treatments. Current approaches focus either on advancing the understanding of promising prevention strategies, as we have discussed above or on new aspects of POI pathophysiology. Enteric glia and their IL1-receptor signaling pathways are an experimental target to influence neuroinflammation, yet clinical trials have not been initiated. In addition, prucalopride, a 5-HT4 receptor agonist reducing intestinal inflammation and vagus nerve stimulation, might provide treatment strategies if future studies demonstrate their safety and efficacy [20]. While there is certain evidence for single therapeutic options, these often fail to prove successful in meta-analyses. The reason lies within the studies itself. As stated in the introduction, there is no general definition of POI or prolonged POI which impedes comparability of acquired results due to varying endpoints. Some authors focused on that problem and tried to define parameters that best reflect restitution of gastrointestinal transit [87]. Also, a Delphi study found consensus to define POI [88]. Despite these efforts, the endpoints defined so far depend on soft criteria and often solely rely on patients’ compliance (e.g., time to first flatus, toleration of solid food). It is even unclear whether they are reliable criteria to assess the duration and severity of POI [89].

Efforts in POI research should focus on the development of reliable and, at its best, objective criteria allowing for qualitatively better studies and their comparability [90]. In our opinion, this is the only way to tackle the challenging clinical problem of POI.