Review Article WIENER KLINISCHE WOCHENSCHRIFT The Middle European Journal of Medicine Wien Klin Wochenschr (2008) 120/1–2: 6–17 DOI 10.1007/s00508-007-0920-2 Printed in Austria

Gastrointestinal motility in acute illness

Sonja Fruhwald, Peter Holzer, and Helfried Metzler Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria

Received August 29, 2007, accepted after revision December 19, 2007 © Springer-Verlag 2008

Einfluss akuter Erkrankungen auf die Darmmotilität intake, and an interdigestive motility pattern starting se- Zusammenfassung. Kritisch kranke Patienten lei- veral hours after a meal. Undisturbed intestinal motility den häufig unter Störungen der Darmmotilität, einerseits depends critically on a balanced interaction between in- als Folge der primären Erkrankung, welche die Aufnahme hibition and excitation, and a disturbance in this balance auf eine Intensivstation notwendig macht, andererseits leads to severe derangements of intestinal motility. The- als Komplikation des Intensivaufenthaltes. Störungen der se motility disturbances differ in clinical appearance and Darmmotilität können durch Beeinträchtigungen der mus- location but can affect all parts of the gastrointestinal kulären Funktion des Gastrointestinaltraktes, der Schritt- tract. This review focuses on select motility disturbances macherzellen des Darmes oder der nervalen Aktivität such as gastroparesis, postoperative ileus, and Ogilvie’s ausgelöst werden. Das enterale Nervensystem als neu- syndrome. Generally effective methods to treat these ronales Kontrollsystem des Darmes, enthält die größte conditions are given. Finally, we focus on special ma- Ansammlung von Nervenzellen (108 Zellen) außerhalb nagement options to prevent such motility disturbances des zentralen Nervensystems. Das enterische Nerven- or to reduce their severity. system funktioniert unabhängig vom zentralen Nerven- Key words: Intestinal motility, migrating motor com- system und generiert nach Bedarf verschiedenste Motili- plex, postoperative ileus, Ogilvie’s syndrome, and proki- tätsmuster: Die postprandiale Motilität beginnt nach der netic . Nahrungsaufnahme, die interdigestive Motilität startet ­einige Stunden nach dem Essen. Wichtig für eine unge- störte Motilität ist die balancierte Interaktion zwischen Introduction hemmenden und stimulierenden Einflüssen. Kommt The subserves a number of im- dieses Gleichgewicht aus dem Lot, sind schwere Darm- portant functions. The gut is the largest lymphoid organ motilitätsstörungen, welche sich nach ihrem klinischen and acts as a barrier to prevent abnormal absorption of Erscheinungsbild und ihrer Ausbreitung unterscheiden, intraluminal microbes and their products [1]. Its best- die Folge. Diese Übersichtsarbeit befasst sich mit dem known function, however, is digestion and absorption of Erscheinungsbild spezieller Motilitätsstörungen (Gastro- nutrients and water. In order to exert this function intes- parese, Postoperativer Ileus und Ogilvie Syndrom) sowie tinal motility is of outstanding importance. The enteric mit allgemeinen und speziellen Therapieoptionen, um die , the largest accumulation of neurons out- Häufigkeit oder den Schweregrad dieser Motilitätsstörun- side the brain, initiates and regulates these intestinal mo- gen zu reduzieren. tility patterns [2]. Most clinicians are not aware that the number of patients developing intestinal motility disturbances ex- Summary. Critical illness affects gastrointestinal ceeds all expectations. Both the acute illness itself and motility – not only as a primary problem, which brings the therapeutic interventions affect gastrointestinal motility patient to the intensive care unit (ICU), but also as a [3]. For example, gastric emptying is delayed in around complication consecutive to the ICU stay. Motility distur- 50% of mechanically ventilated patients and in about 80% bances may result from impaired function of gastrointes- of patients with head injury [4, 5]. Not surprisingly, ab- tinal muscle, pacemaker cell function and nerve activity. dominal surgery is a major contributor to intestinal motil- The most important neural control system is the enteric ity disturbances, as well as hemodynamic instability, nervous system that contains the largest collection of burns, electrolyte disorders, volume overload, and the neurons (108 cells) outside the central nervous system. need for vasoactive drugs or analgosedation [6]. All these Through its organization it can operate independently of factors weaken the natural defense of the gastrointestinal the brain and generate motility patterns according to tract, resulting in overgrowth of intestinal bacteria, in- need: a postprandial motility pattern starting after food creased epithelial permeability and bacterial translocation Fruhwald et al., Gastrointestinal motility in acute illness  leading to increased risk for systemic , sepsis stomach and progresses to the distal ileum. The interdi- and multiple organ failure [3, 7]. Efforts to prevent and gestive motility pattern consists of three different phases treat this potentially life-threatening situation include that are repeated approximately every two hours. Previ- early enteral nutrition, but the latter requires an undis- ously, only phase III was referred to as the MMC, but now turbed intestinal motility. all three phases of interdigestive motility are subsumed Recently published findings have provided new in- under this term: sights into intestinal motility patterns and possible thera- peutic interventions. The current review focuses on clini- • Phase I is a period of quiescence (45–60 min); cally important gastrointestinal motility disturbances, • Phase II is a period of irregular contractions with a evaluates underlying causes and pathophysiologic pro- duration of 30–45 min; cesses, and discusses their clinical impact and currently • Phase III is a period of regular, propulsive activity available therapeutic options. starting in the antrum of the stomach, which moves to the distal ileum within 15 minutes [12].

Normal intestinal motility The MMC is initiated entirely by the enteric nervous system, while the rhythm of phase III activity comes from The role of the enteric nervous system the interstitial cells of Cajal known as the “pacemaker Gastrointestinal motility is governed by multiple con- cells of the gut” [13]. They are present as networks of trol systems: the central, autonomic and enteric nervous cells associated with the neural plexuses within the gut systems, endocrine cells, interstitial cells of Cajal and musculature, where they are connected to each other smooth muscle [2]. We will focus here on the most im- through long processes via gap junctions [14]. Although portant control system of propulsive motility, the enteric interstitial cells of Cajal are present throughout the gas- nervous system, which is the largest collection of neurons trointestinal tract, the key pacemaker cells for normal (108 cells) outside the central nervous system. Extending phase III activity are located along the greater curvature from the esophagus to the internal anal sphincter, the of the gastric body where they initiate slow waves of neurons of the enteric nervous system are arranged in two depolarization at a frequency of three cycles per minute ganglionated nerve plexuses [2, 8]. The myenteric plexus in the stomach and 12 per minute in the small intestine is located between the longitudinal and the circular mus- [15, 16]. The MMC remains undisturbed after vagotomy cle layer and regulates mainly motility, while the submu- or sympathectomy, but is abolished in regions of the in- cous plexus between the circular muscle and the mucosa testine in which the enteric nervous system has been inter- regulates mucosal processes (electrolyte and fluid secre- rupted [17, 18]. One of the MMC-regulating peptides is tion, mucosal flow and neuroimmune interactions) motilin. Intravenous administration of this peptide or of [9]. The organization of the enteric nervous system and the motilin receptor agonist erythromycin initiates phase its ability to generate different motility patterns is inde- III activity in the antroduodenal region, while somatosta- pendent of the central nervous system [2]. This autonomy tin and other substances can initiate phase III activity in of the enteric nervous system is due to the presence of the duodenum [19]. The duration of the MMC phases local motor circuits consisting of sensory neurons (intrin- shows enormous inter- and intra-individual variability sic primary afferent neurons), interneurons, excitatory and [19]. There also seems to be a day-night rhythm, as phas- inhibitory motor neurons [10]. es I and III are more frequent during the night and, in The primary transmitters of excitatory motor neurons particular, phase III lasts longer and has a lower amplitude are acetylcholine and substance P, whereas the transmit- than during the day [20]. ters of inhibitory motor neurons are nitric oxide (NO), A normal MMC pattern, also called the “housekeeper vasoactive intestinal peptide and adenosine triphosphate of the gut”, is important for the purging of the small [2]. Inhibition of muscle activity is the dominating effect bowel. During phase III, remaining food particles and of enteric nervous system output: contraction can occur indigestible residues as well as gastrointestinal secretions only in segments in which ongoing inhibition has been are swept to the distal part of the small bowel and into switched off, while adjacent segments under continuing the colon. An undisturbed MMC may therefore play a role inhibitory input cannot contract [11]. From these organi- in protection against bacterial overgrowth of remaining zational characteristics it is obvious that normal gastro­ food particles in the small bowel [21]. An absence of the intestinal motility depends critically on a balanced inter- MMC indicates severe enteric dysfunction, while the pres- action between inhibition and excitation. A loss of in- ence of the MMC predicts a successful outcome of en- hibitory neural tone or increase in excitatory neural tone teral feeding [19, 21–23]. leads to intestinal hypermotility, while hyperactivity of inhibitory neurons or impaired function of excitatory neu- Digestive motility pattern rons causes prolonged muscle relaxation and inability to contract. Both states result in severe gastrointestinal mo- Ingestion of a meal disrupts the MMC and replaces it tility disturbances [9]. with a motility pattern that consists of accommodation, stationary motility (segmental contractions and pendular movements) and propulsive peristalsis [2]. Interdigestive motility pattern At the beginning of a meal the fundus of the stomach The migrating motor complex (MMC), now synony- relaxes. This is called accommodation and is a NO-medi- mous with the interdigestive motility pattern, starts sev- ated process, with the intention to provide space for eral hours after the end of a meal in the antrum of the ­storage of the incoming food and to give acid (HCl) and  Fruhwald et al., Gastrointestinal motility in acute illness enzymes the opportunity to initiate the digestive process and bacterial translocation. Bacterial translocation means [2, 15, 24]. Tonic contractions empty the fundus of the the passage of bacteria or bacterial products from the in- stomach and transfer the chyme via the corpus to the testine into mesenteric lymph nodes or the portal system antrum. There the chyme is triturated to small pieces due because of hyperpermeability of the intestinal barrier [1]. to coordinated contractions and relaxations of the antrum. Bacterial overgrowth and translocation can initiate a vi- When the pyloric sphincter relaxes fluid and chyme par- cious circle that leads to increased occurrence of ventila- ticles, less than 1–2 mm, pass into the duodenum, where tor associated pneumonia, systemic infections, sepsis and pancreatic lipases and proteases continue the digestive multiple organ failure [29–31]. process. Chyme particles larger than 2 mm are not able to pass the pylorus, therefore – in a period of retropulsion Gastroparesis (Table 1) – they are transported back to the proximal antrum and The three most common etiologies of this condition circle between proximal and distal antrum until they are are diabetic, idiopathic and postsurgical 32 . In gastropa- small enough to pass the pylorus 15 . [ ] [ ] resis, the stomach fails to enlarge in response to distension Comparable to the motility in the fundus-antrum re- by meals (impaired accommodation), peristaltic contrac- gion, the proximal part of the duodenum relaxes in co­ tions are weak and, unlike in the normal stomach, fail to ordination with the pylorus to receive the chyme 15 . [ ] break down particles, emulsify fats, and generate the slur- Propulsive motility – initiated by distortion of mucosal ry of nutrients and secretions known as chyme 33 . The villi or distension of the bowel wall, forwards the chyme [ ] symptoms of gastroparesis include satiety, reflux, abdom- into the small bowel. This propulsive movement involves inal pain, nausea and vomiting. However, the prevalence a contraction of the circular muscle orally and a relaxation of gastroparesis is difficult to estimate because symptoms aborally to the stimulus 2 . In the digestive motility pat- [ ] correlate incompletely with disturbances of gastric empty- tern, the peristaltic wave progresses only several centime- ing. This might explain why in tertiary medical centers ters in order to forward the chyme and distribute it the prevalence of gastroparesis is higher than in commu- throughout the small bowel, but not as far as phase III of nity centers (65 vs. 11–18%) 34 . the MMC in the interdigestive motility pattern. Stationary [ ] Gastroparesis is a frequent problem in diabetic pa- contractions consisting of pendular movements of the lon- tients (up to 75%), yet almost 50% of them are asymp- gitudinal muscle layer and segmentary contractions of the tomatic 35 . Diabetic patients show a reduced frequency circular muscle layer mix the chyme with the secretions [ ] of antral contractions, antroduodenal in-coordination and of the small intestine and bring it in contact with the pyloric spasms. Increasing blood glucose from normal mucosa to allow absorption. ranges to 230 mg/dL is associated with decreased antral The digestive pattern persists for several hours after contractions and increased pyloric contractions, both of a meal. Its duration depends mainly on the caloric load of which contribute to delayed gastric emptying 36 . The the meal – the higher, the longer – amounting to one hour [ ] main pathogenetic factors for diabetic gastroparesis are per 200 kcal as an approximate value 19, 25 . Segments [ ] vagal autonomic neuropathy and damage to the interstitial of the small intestine that are not in contact with food cells of Cajal [37, 38]. seem to maintain an interdigestive motility pattern [26].

Disturbances of gastrointestinal motility Table 1. Factors affecting gastric emptying Motility disturbances differ in clinical appearance and location, and affect the stomach, small bowel, and colon Permanent effect on gastric emptying separately or in combination. They are a common com- Diabetes mellitus plication in patients suffering from severe hemodynamic Renal insufficiency instability, multiple organ failure, intra-abdominal hyper- Functional dyspepsia tension or intra-abdominal compartment syndrome. Re- Post-vagotomy gardless of what initiates gastrointestinal motility distur- Systemic sclerosis Dermatomyositis bances, they are likely to be associated with higher mor- Myopathies bidity and mortality rates. Transient effects on gastric emptying Disturbances of the migrating motor complex Disturbances of the MMC are associated with chang- β-Adrenergic blockers es in its various phases. MMC phase I is prolonged, phase Anticholinergic drugs III is affected in duration and frequency. Peristaltic con- α2-Adrenergic agonists tractions of phase III may be retrograde rather than ante- Hyperglycemia grade, which significantly delays small bowel transit and Low potassium and magnesium levels disturbs the purging of the small bowel [27]. In patients Metabolic and respiratory acidosis suffering from gastric hypomotility the MMC starts in the Stress duodenum rather than in the antrum [28]. Pain Disturbances of the MMC are associated with reduced Head injury flushing of the luminal contents (bacteria, food remnants Postoperative ileus and cell detritus) into the colon. This results in stagnation Burns of the remaining luminal contents, microbial overgrowth Sepsis Fruhwald et al., Gastrointestinal motility in acute illness 

In the postoperative period the symptoms of gastro- dogs [48]. Incision of the skin and the muscle produces paresis can be misinterpreted as postoperative nausea and only a very short inhibition of intestinal motility, while vomiting. This has to do with the fact that the role of handling of the intestine itself causes the greatest effect. gastric hypomotility in critically ill patients is still poorly The inhibition of intestinal motility is due to sympathetic defined. In mechanically ventilated patients gastroparesis activation, because intestinal motility is completely re- is seen in about 50% of patients within 2 days after the stored when sympathetic activation fades away [48]. onset of ventilation [39]. Head injury patients are affected While under normal conditions propulsive motility is in about 80%, and in burn patients inhibition of gastric primarily controlled by the enteric nervous system, extrin- emptying is also a frequent problem [5, 40]. This large sic neuronal inhibition of intestinal motility plays an im- variation in gastroparesis rates reported in the literature is portant role in the pathogenesis of postoperative motility not well understood; it may reflect divergent degrees of disturbances. A further mechanism underlying postopera- awareness by ICU physicians or different methods used tive ileus is the neurohumoral stress response after sur- for detection. Scintigraphy is the gold standard among the gery. Neuroendocrine messengers (beta-endorphin, adre- generally accepted methods to assess gastric emptying nocorticotrophic hormone, neurotensin and catechol- [34]. The 13C breath test is an indirect measurement of amines) participate in the regulation of digestive motility. gastric emptying: Following ingestion, 13C labeled octa- There is a clear relationship between the circulating levels noic acid is absorbed in the small intestine and metabo- of these messengers, the amount of surgical stress and the 13 lized to CO2, which is detected in the exhaled air. This duration of postoperative ileus [49]. The prokinetic hor- test is acceptable only if small intestinal, pancreas, liver mone motilin, which modulates the MMC during fasting, and pulmonary function is normal [34]. Both methods are has been found to be depressed at the end of abdominal valid to evaluate the emptying of fluid and solid meals. surgery and in the immediate postoperative period. This The paracetamol test is a simple tool to assess gastric might be responsible for the reduced duration and the emptying (results stand for the emptying of fluids): After retrograde migration of phase III of the MMC. The return the administration of a single enteral dose of paracetamol of motilin to normal levels correlates with the resolution the serum concentration is measured [41]. of ileus [50, 51]. While sympathetic activation and the Given the limitations of these methods (the long dura- neurohumoral stress response have their onset immedi- tion of examination, restricted availability, breath samples ately after surgery, inflammation of the gastrointestinal or blood samples taken every few minutes over 4–6 wall develops over several hours after the surgical inter- hours), they are hardly practicable for ICU patients. A vention. This inflammatory response has been proposed to new and promising tool might be the 2D/3D ultrasono- be of importance for the maintenance of postoperative graphic assessment of antral wall motion, short-term pat- paralysis up to three days [52]. In rats, inflammation after terns of transpyloric flow and gastric emptying [42]. colonic manipulation is due to massive leukocyte recruit- ment and increased expression of mRNA for inflamma- Postoperative ileus tory mediators in the colonic musculature. This is associ- ated with an impairment of in vivo motor function and Postoperative motility disturbances are inevitable af- inhibition of in vitro smooth muscle contractility [52]. ter abdominal surgery, whereas after major non-abdomi- This postoperative inflammatory response may be a sig- nal surgery the incidence is significantly lower (2.1% af- nificant factor in the maintenance of postoperative motil- ter hip or knee arthroplasty, and 3.9% after infrarenal ity disturbances in patients after major surgery. endovascular aneurysm repair) [43, 44]. Postoperative hypomotility affects all parts of the gastrointestinal tract Etiology of prolonged postoperative ileus with different times of recovery. The stomach and the small intestine typically return to normal function within Reasons for the prolongation of postoperative ileus the first 24–48 hours. The colon is the last part of the (> 5 days) are mechanical ventilation, increased intracra- gastrointestinal tract to return to normal function, usually nial pressure, infections, sepsis or the abdominal compart- within 72 hours. Therefore the “normal” postoperative ment syndrome. Other risk factors are volume overload ileus lasts for 3–5 days after surgery, whereas prolonged and the resulting edema of the intestinal wall [53, 54]. postoperative ileus lasts longer than 5 days after surgery Further on the list are hypotension, the need for vasoactive [45]. Postoperative ileus leads to several undesirable con- drugs causing intestinal motility disturbances due to a sequences: increased postoperative morbidity and mortal- reduction of splanchnic blood flow, direct inhibitory ef- ity, delayed enteral feeding, disturbed immune function fects of catecholamines on intestinal motility and electro- and increased risk for infectious complications [6, 46, lyte disorders. 47]. Ogilvie’s syndrome Etiology of “normal” postoperative ileus The acute colonic pseudo-obstruction (Ogilvie’s syn- In patients with postoperative ileus multiple causes drome) might be a variant of critically illness-related co- are thought to lead to disturbances of the digestive as well lonic ileus [55]. In newer publications it is called an im- as the interdigestive motility pattern. One postulated cause balance in the autonomic regulation of colonic motor is subsumed in the neuronal theory: Sympathetic activa- function, leading to excessive parasympathetic suppres- tion inhibits gastrointestinal motility. The extent of sym- sion or sympathetic stimulation. These derangements can pathetic activation depends on the amount of surgical be initiated by metabolic or pharmacological factors, spi- stimulation, as demonstrated in experimental studies in nal or retroperitoneal trauma, gut ischemia, hypoxia or 10 Fruhwald et al., Gastrointestinal motility in acute illness inflammation – subsuming all factors associated with tinal transit [64, 65]. Thörn and coworkers reported clini- critical illnesses – which eventually cause atony and dila- cally relevant data from studies with healthy volunteers tation of the colon [56, 57]. [66]. They found that when was administered A large retrospective evaluation of 400 patients suf- intrathecally and intramuscularly to healthy volunteers, fering from Ogilvie’s syndrome demonstrated that non- the duration of the MMC was shortened. They further operative trauma (11%), infections (10%) and cardiac described a decrease of the propagation velocity of this diseases (10%) were the most common predisposing con- motor pattern along the gut [66]. -induced side ef- ditions [58]. The predominant symptom presented by the fects like nausea, vomiting and sedation decrease with the patients is abdominal distension that usually develops duration of opioid use. Unfortunately patients rarely de- over several days but can also occur within 24 hours [59]. velop tolerance to the constipating effects of opioids Abdominal distension is frequently associated with mild [67]. to moderate pain (up to 80%), nausea and vomiting [57, Paracetamol was demonstrated to have an inhibitory 58]. The passage of flatus and stool is undisturbed in up effect on intestinal motility in an in-vitro setting, while to 40% of patients, and bowel sounds are nearly always acetylsalicylic acid and metamizole did not [68]. The only present [57–59]. Symptoms including fever, abdominal substance class with a postulated positive effect on intes- tenderness, rigidity or peritoneal signs suggest the devel- tinal motility, especially in the postoperative period, are opment of complications such as abdominal ischemia or COX2 inhibitors [69]. Because of the increased rate of perforation. The abdominal x-ray shows a dilatation of the cardiovascular complications they are contraindicated in colon, while haustral markings are mostly normal. The patients with known cardiovascular disease or who are at small bowel is less frequently affected, but dilatation of risk for cardiovascular co-morbidities [70]. the small intestine by fluid or air may also occur [59]. Ogilvie’s syndrome is associated with a mortality rate Effective methods to treat gastrointestinal between 10–15% in patients without complications [60]. motility disturbances Risk factors for higher mortality are older age, poor clin- ical conditions and the need for surgery. In 3–15% of General therapeutic measures patients complications such as ischemia or perforation Electrolyte balance and fluid management: Therapeu- occur, and these are associated with mortality rates up to tic options to prevent the aggravation of intestinal motil- 50% [58, 60]. ity disturbances in critically ill patients include the adjust- ment of electrolyte imbalances and tailored fluid manage- Effect of analgosedation on intestinal ment. High normal plasma values of potassium and mag- motility nesium have been associated with a shorter duration of All substances used for analgosedation in critically ill intestinal paralysis. Tailored fluid management in the patients are suspect of inhibiting intestinal motility. A postoperative period as well as in critically ill patients is multimodal approach seems to be feasible, because the of ultimate importance (2–3 liters/day) [54, 71–73]. In required dose of the single substance and the dose depen- patients having surgery, an excess of salt and water may dent inhibitory effect on intestinal motility is reduced. lead to more complications than restriction of fluid. Stud- Among the substances increasingly used because of ies of the fluid balance in patients receiving nutritional their ability to induce sedation, reduce use as support have suggested that, in the perioperative period, well as requirements, and improve perioperative weight gain indicative of salt and water retention result in hemodynamic and sympathoadrenal stability, are the α2 poorer outcome [54]. Recently there has been a trend from adrenergic drugs clonidine and dexmedetomidine. They restrictive fluid management to the so-called goal directed are useful partners in an effective concept for analgo-se- fluid therapy – an individually based balance between the dation, but we should be aware that they are not devoid amount and the composition of the electrolyte solutions of adverse effects. Due to a direct inhibitory effect on to be used [72]. peristalsis and secretory processes in the gut, both sub- Early enteral feeding is an important support for the stances have a profound inhibitory effect on gastrointes- maintenance or regain of structural and functional intesti- tinal motility [61, 62]. nal integrity. The presence of nutrients in the gut leads Opioids are known for their inhibitory effect on gas- directly to increased proliferation of enterocytes. An indi- trointestinal peristalsis, as well as their efficacy to stop rect trophic effect is seen because enteral feeding stimu- , but the impact of this inhibitory effect on intes- lates the production of trophic gastrointestinal messengers tinal motility is mostly underestimated [63]. In an animal acting via autocrine, paracrine and endocrine pathways model, a quarter of the analgesic dose inhibits intestinal [34]. Enteral feeding, compared to parenteral nutrition, is motility, while one-twentieth of the analgesic dose is suf- associated with a lower rate of regional and systemic ficient to stop diarrhea [63]. This inhibitory effect is due ­infections, possibly because of reduced bacterial translo- to a reduced release of acetylcholine from the myenteric cation. Delayed gastric emptying may prevent effective plexus resulting in a decrease of peristaltic waves as well delivery of enteral nutrition [39]. as an increase in colonic tone, a delay in colonic transit, (Table 2): Fiber, lubricants, osmotic and and increased water absorption from the lumen, resulting laxatives increase stool frequency and improve in harder, drier stools. In experiments on rats, Dhasmana symptoms of constipation [74]. Dietary fiber supplements et al. and Tavani et al. demonstrated that systemic admin- (bulk laxatives) improve stool frequency and consistency istration of morphine, sufentanil, alfentanil and other opi- by increasing fecal mass [75]. These substances are avail- oids resulted in a dose-dependent decrease in gastrointes- able without physician’s prescription and are used mostly Fruhwald et al., Gastrointestinal motility in acute illness 11

Table 2. Different types of laxatives, and their onset of action water to interact more effectively with solid stool and thereby "soften" the stool [74]. Stool softeners are well Onset of action tolerated but are ineffective if fluid intake is inadequate, Bulk laxatives and they usually are ineffective when administered alone Psyllium (Psyllium seed husk) 24–72 hours [77]. Last but not least clysters are used to initiate a def- ecation reflex. Methylcellulose 24–72 hours The use of catecholamines and drugs used for anal- Wheat dextrine 24–72 hours go-sedation in critically ill patients is a double-edged Linseed products 24–72 hours sword, because most of these drugs adversely affect gas- Osmotic laxatives trointestinal motility. The undesirable inhibitory side ef- Polyethylene glycol (PEG) 2–4 days fects of opioids on intestinal motility have long been Lactulose 24–48 hours known. Recently the quaternary opioid antagonists alvi- Magnesium salts < 6 hours mopan (ADL 8-2698) and methylnaltrexone were found Sorbit 24–48 hours to antagonize the inhibitory effect of opioids on gut motil- ity, without crossing the blood-brain barrier and therefore Stimulant laxatives without antagonizing the analgesic effect of opiates. Al- Bisacodyl orally 6–12 hours vimopan was able to reduce nausea and vomiting in post- Bisacodyl suppository < 60 minutes operative patients and to restore gastrointestinal function Senna preparations 6–12 hours earlier than in control patients. Currently alvimopan is on hold because the FDA requested further safety data (http:// us.gsk.com/ControllerServlet?appId=4&pageId=402&ne wsid=1101). for chronic constipation. Osmotic laxatives are poorly The undesirable side effects of catecholamines and absorbed/nonabsorbed sugars, saline laxatives, and poly- opioids are in direct opposition to their beneficial effects. ethylene glycol, which lead to intestinal water secretion. Their use is inevitable for hemodynamic stabilization, Unwanted side effects are abdominal cramping, bloating, adequate organ perfusion pressures, as well as adequate and flatulence. Bulk and osmotic laxatives need a few pain and stress management. Therefore tailored use of days to become effective; therefore this treatment option these substances is a challenge the intensivist has to should be started as early as possible [76]. Stimulant meet. laxatives are compounds containing senna or diphenolic substances like bisacodyl (Dulcolax®) [74, 75]. Stimulant laxatives increase intestinal motility and secretion and Specific therapeutic measures exert their effect within hours of ingestion. Bisacodyl induces laxation approximately 6–12 h after oral admin- Therapeutic options for the stomach and small istration, when given as a rectal suppository the enterohe- bowel (Fig. 1) patic circulation is bypassed and the substance is effective Metoclopramide is a dopamine D2 receptor antagonist within 60 minutes [74, 75]. Side effects may be severe with central and peripheral effects, as well as a 5-HT3 abdominal cramps. receptor antagonist and a 5-HT4 receptor agonist. Meto- “Stool softeners" are surface-acting agents (lubri- clopramide increases gastric motility and has a moderate cants) and function primarily as detergents; they allow stimulant effect on the small bowel, but its prokinetic

Fig. 1. Summary of available prokinetic drugs and their site of action. Drugs in italic letters have a less pronounced positive effect 12 Fruhwald et al., Gastrointestinal motility in acute illness activity is in general limited to the proximal gut [78]. The however, is limited by desensitization to the prokinetic substance might be useful in critically ill patients but effect of the and its anti-bacterial action [85]. The seems to be ineffective in patients with postoperative ileus recommended dose should not be given for more than [79]. For patients with renal failure, the recommended three or four days. dose of 10 mg i.v. t.i.d. has to be reduced gradually; the Data on phosphodiesterase 5 inhibition with sildenafil recommended dose for hemodialysis patients is 10 mg/day are controversial. Sildenafil restores gastric emptying of [80]. Metoclopramide is effective for the short-term treat- liquids in an animal model of diabetes, suggesting a po- ment of gastroparesis for up to several weeks. tential as a therapeutic agent for diabetic gastroparesis Domperidone is a drug that acts primarily as an an- [34]. Sildenafil also reduces the dysrhythmia of the tagonist at peripheral dopamine D2 receptors. In contrast ­stomach induced experimentally by hyperglycemia in hu- to metoclopramide, the substance does not cross the mans. On the other hand, a thorough study of the effects blood-brain barrier and is therefore free of central ner- of sildenafil on human gastric sensorimotor functions vous side effects. The recommended dose is 10 mg oral- showed that the drug significantly increases postprandial ly t.i.d. gastric volume and slows liquid (though not solid) empty- Cisapride and tegaserod are both 5-HT4 receptor ing rate [88]. Sildenafil has also been demonstrated to agonists. Cisapride stimulates antral and duodenal con- inhibit interdigestive motor activity of the antrum and tractions, improves antroduodenal coordination, and ac- duodenum [89]. celerates gastric emptying and small bowel transit in , a synthetic peptide, has a sequence of 4 chronic intestinal dysmotility. However, it has been with- essential amino acids in common with somatostatin, but a drawn from use as it prolongs the QT interval in a dose- longer duration of action than somatostatin. It has been dependent manner and was associated with potentially shown to induce the MMC, but its prokinetic action on fatal cardiac arrhythmias. The efficacy of newly synthe- small bowel motility is controversial and seems to depend sized compounds derived from cisapride, such as ATI- on the dose range tested, given that higher doses (> 150 mg/ 7505, their cardiac safety and by cytochrome day) may inhibit motility [80]. P450 enzymes are currently investigated [81]. Tegaserod accelerates gastric emptying and shortens Therapeutic options for the small bowel and colon small bowel and colonic transit time [82]. Only one report (Fig. 1) demonstrates a positive effect of tegaserod on gastric Cerulein, a potent cholecystokinin-like decapeptide, emptying and vomiting in critically ill patients [83]. At the end of March 2007 tegaserod was taken from the activates cholecystokinin receptors on enteric neurons, market according to an FDA information: “Zelnorm® and stimulates small bowel motility by releasing excit- (tegaserod) is being taken off the market because a new atory transmitters such as acetylcholine and substance P. The pronounced prokinetic effect of clinically used doses safety analysis has found a higher chance of heart attack, of cerulein (0.15–0.3 g/kg/day) has been confirmed in an stroke, and worsening heart chest pain that can become a µ experimental setting 90 . An occasional side effect of heart attack in patients treated with Zelnorm® compared [ ] cerulein is the prolongation of gastric emptying, an effect to those treated with a sugar pill” (www.fda.gov/cder/ that may be compensated by metoclopramide or erythro- drug/advisory/tegaserod.htm). Meanwhile, the FDA has mycin 45 . permitted the restricted use of tegaserod for qualifying [ ] Neostigmine, an inhibitor of acetylcholine esterase patients (www.fda.gov/bbs/topics/NEWS/2007/NEW and thus an indirect cholinergic agonist, has been re- 01673.html). ported to reduce the time to first passage of gas and stool. The macrolide erythromycin stimulates gastrointesti- Interestingly, the lower the applied dose (2–2.5 mg/24 h nal motility by activating motilin receptors on smooth vs. 9.6 mg), the shorter is the time to the passage of gas muscle cells and enteric neurons to facilitate neurotrans- and stool 91, 92 . These findings are explained by mitter release 84, 85 . The effect of erythromycin on [ ] [ ] ­experimental data demonstrating a moderate prokinetic gastric motor activity is dose dependent, and the nature of effect that is limited to a narrow window of low drug its action on gastrointestinal motility seems to differ be- concentrations, while higher doses inhibit small bowel tween low and high doses 86 . Smaller doses stimulate [ ] motility 90 . MMC phase III activity, which migrates to the duodenum, [ ] while higher doses seem to induce strong contractions of the antrum, which are not propagated; consequently, duo- Specific therapeutic options for gastroparesis denal-to-cecal transit actually may be slower [87]. Eryth- The principles for management of gastroparesis in- romycin is most effective when used intravenously; there volve a correction of hydration and nutrition. For patients is some evidence of efficacy of the oral preparation in suffering from chronic gastroparesis a variety of medici- long-term use, for instance, in a 4-week trial of patients nal, endoscopic and surgical options are also available. with scleroderma. In critically ill patients, erythromycin To restore hydration and nutrition, the enteral route effectively improves gastric emptying, and there is a trend is preferable. Liquids are emptied more rapidly than sol- towards shorter times necessary for tube placement [78]. ids, and both lipids and indigestible fibers tend to delay The recommended dose is 250 mg orally b.i.d. or 1–3 mg/ gastric emptying. Therefore, small, frequent low-fat kg i.v. every 6 hours [80]. Newer studies evaluating the meals consisting of complex carbohydrates (starch-based duration of erythromycins action indicate that a dose giv- foods) are recommended to avoid gastric distention and en twice daily may be sufficient for critically ill patients the attendant symptoms of bloating, satiety, and nausea who are intolerant of enteral feeding [84]. Long-term use, [34]. Fruhwald et al., Gastrointestinal motility in acute illness 13

Specific therapeutic options for postoperative ileus tion and the inflammatory response in the smooth muscle (Table 3) [98]. An effective anesthetic approach to reduce surgery- The problem of postoperative motility disturbances induced sympathetic stimulation is epidural anesthesia. It concerns the anesthetist as well as the surgeon, both of is thought to facilitate gastrointestinal motility by block- whom have to meet the challenge of optimizing treatment ing both nociceptive afferent and thoracolumbar sympa- in order to reduce the severity and length of postoperative thetic efferent neurons, resulting in unopposed activity of ileus and its subsequent complications. parasympathetic efferent and enteric neurons [99]. This The surgeon’s sphere of influence: An appropriate applies only for the proximal colon, because the colon method to reduce the amount of surgical stress is laparo- distal to the splenic flexure and the rectum receive a para- scopic surgery, which has proven to be effective in reduc- sympathetic innervation from sacral nerve roots [99]. Sev- ing the duration of postoperative ileus 93 . Due to re- [ ] eral studies have compared epidural anesthesia with sys- duced sympathetic and neurohumoral stimulation, laparo- temic opiates, most of which attest to a faster return of scopic surgery is associated with a decrease in the dura- bowel function in the epidural anesthesia group. In two of tion of postoperative paralysis by 27–40% compared to the three studies failing to demonstrate a positive effect conventional open procedures 94, 95 . [ ] of epidural analgesia, the epidural catheter was removed Placement of a nasogastric tube does not reduce the within 24 hours [100, 101]. In the remaining study, the duration of postoperative motility disturbances as has in the epidural infusion was changed to a been demonstrated in a recent meta-analysis including narcotic agent after 24 hours [102]. In order to fully ex- more than 4000 patients 96 . Time to flatus was signifi- [ ] ploit the positive effect of epidural anesthesia, the epidu- cantly shorter in the group of patients with non-routine ral catheter must be in an optimal location. Epidurals use of nasogastric decompression. Pulmonary complica- placed at the thoracic level do in general shorten postop- tions were not significantly reduced, while the rate of erative ileus, whereas lumbar and low thoracic epidurals wound infections tended to be higher. The incidence of (lower than thoracic segment 10) are not effective. The anastomotic leakage did not differ between the two groups time gain in normalization of postoperative intestinal mo- 96 . [ ] tility achieved by epidural administration of local anes- Early mobilization has proven to have a positive in- thetics is 36 hours compared to systemic opioids. On the fluence on several aspects of postoperative recovery, but other hand, the time gain achieved with local it does not shorten the duration of postoperative ileus 93, [ and opioids given epidurally, compared to systemic opi- 97]. Other factors that have been proposed to decrease the oids, is hypothesized to be 24 hours [103]. risk of postoperative ileus are reduced dosage of paren- teral opioids and an early start of enteral nutrition [27]. The anesthetist’s sphere of influence: Anesthetic Therapeutic options for Ogilvie’s syndrome agents, particularly halothane and enflurane, have a pro- According to the current literature, daily abdominal found inhibitory action on intestinal motility [93]. Al- radiographs are state of the art to monitor colonic diam- though their effects wear off quickly once anesthesia is eters. Nasogastric tubes can help to decrease the amount discontinued, gastrointestinal motility continues to be of swallowed air and relieve vomiting, and a rectal tube ­inhibited by the surgically induced sympathetic stimula- might be helpful when colonic distension extends to the

Table 3. Parameters of the “enhanced recovery after surgery” (ERAS) concept

Preoperative management Education of the patient No preoperative fasting No forced defecation No premedication

Surgical management No stomach tube Minimal invasive surgery whenever possible

Anesthetic management Epidural anesthesia Short acting anesthetic drugs Restrictive fluid management Active (re)warming

Postoperative management Multimodal analgesic approach Early enteral feeding Early mobilization Remove lines and catheters early Prevent postoperative nausea and vomiting Stimulate intestinal motility Supervision concerning outcome and complications 14 Fruhwald et al., Gastrointestinal motility in acute illness

symptoms of abdominal distension further possibility to assess the severity of colonic disten- sion (Fig. 2) [56]. When Ogilvie’s syndrome leads to abdominal radiography abdominal hypertension and abdominal compartment syn- drome, we recommend to implement the cut off values of the World Society of the Abdominal Compartment Syn- colonic dilatation drome (WSACS) [108].

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