Management of Gastrointestinal Hypomotility in the Hospitalized Patient

Gastrointestinal (GI) motility is a complex process that involves vagal control, myenteric nervous input, locally acting substances, and enteric-specific peptides. In response to various stimuli, excitatory substances (e.g., acetylcholine acting on M₃ receptors, serotonin acting on 5-HT₄ receptors, substance P acting on neurokinin-1 receptors) cause smooth muscle contraction. Other substances (e.g., nitric oxide, vasoactive intestinal peptide, somatostatin, norepinephrine acting on β₂ receptors, neuropeptide Y) cause smooth muscle relaxation. The coordinated constriction and relaxation results in propulsion of the ingesta in an aborad direction, a process known as peristalsis.

Ghrelin, a hormone released from ghrelin cells in the stomach, can increase GI motility. Conversely, cholecystokinin released from I-cells in the duodenum and jejunum can delay gastric emptying. Dopamine (via D₂ receptors) can inhibit acetylcholine release and therefore decrease GI motility. Motilin acts in the GI tract during the interdigestive period to activate migrating motor complexes (MMCs), resulting in motility during fasting.^1-3

Gastrointestinal hypomotility (GIHM) describes both delayed gastric emptying and ileus. GIHM has been reported to affect more than 50% of critically ill humans.¹ Although incidence among hospitalized dogs and cats has not been reported, GIHM is thought to be common.

GIHM may result from primary GI disease or be secondary to systemic disease. Common causes of GIHM in dogs and cats include parvoviral enteritis, postoperative GIHM, inflammatory bowel disease, GI ulceration, neoplasia, gastric dilatation–volvulus, sepsis, pancreatitis, opioid administration, and systemic inflammation.¹ One study involving healthy dogs found that hospitalization alone results in delayed gastric emptying.⁴ Possibly implicated in the pathogenesis of GIHM are medication administration (especially opioids and vasopressors), tissue handling during surgery, loss of antropyloroduodenal coordination, gut edema, inflammation, nitric oxide–induced enteric paralysis, increased cholecystokinin, and altered MMCs.^1,2,5

Identification of GIHM may be based on clinical signs supportive of altered motility, including abdominal pain, nausea, vomiting, regurgitation, anorexia, abdominal distension, and documentation of ingesta in the stomach despite prolonged fasting. It should be considered only after mechanical ileus has been ruled out. Diagnosis of GIHM is often based on abdominal ultrasonography findings. Gastric and intestinal dilation and GI contractile activity can be measured to determine hypomotility. Serial ultrasonography evaluations may enable more comprehensive evaluation of gut motility. The role of quantifying gastric residual volumes in the diagnosis of GIHM remains unclear. Left untreated, GIHM may result in regurgitation, aspiration pneumonia, reflux esophagitis, abdominal pain, lack of nutrition, increased intra-abdominal pressure, and bacterial translocation from the GI tract.^1,2

Pharmacologic Interventions for GIHM

Metoclopramide

Mechanism of action: Metoclopramide is both an antiemetic and prokinetic. Its antiemetic effects likely result from dopamine antagonism (predominantly D₂) and serotonin 5-HT₃ antagonism, and its prokinetic effects likely result from dopamine antagonism and serotonin 5-HT₄ agonism. In dogs, metoclopramide has been shown to increase the rate of gastric emptying.^1,6 The prokinetic effects are usually ascribed to its effects on the stomach; however, older research suggests that metoclopramide may also stimulate small intestinal smooth muscle contraction.⁷ In cats, metoclopramide has similarly been shown to increase the rate of gastric emptying.⁸

Administration: The ideal dose for metoclopramide is unknown. It is commonly administered as a constant-rate infusion (CRI) at a rate of 2 mg/kg/day, which may be preceded by a 0.5 mg/kg bolus. Alternatively, metoclopramide may be administered as an intermittent bolus (0.2 to 0.5 mg/kg SC or IM). However, some studies have shown that these doses may not be sufficient to produce prokinetic effects.⁹ Instead, much higher rates may be needed (1 mg/kg bolus followed by 1 mg/kg/h in the perianesthetic period).¹⁰ In addition, some research indicates that dosing may be breed dependent.¹¹ The author typically administers a 0.5 mg/kg IV bolus followed by a 2 mg/kg/day CRI but will titrate to 8 mg/kg/day if needed based on persistence of the ileus. Oral formulations do exist; however, the short half-life of metoclopramide requires frequent dosing, and oral dosing may not be ideal for patients with GIHM.

Adverse reactions: At high doses, metoclopramide may cause extrapyramidal signs (e.g., aggression, restlessness, hypersalivation, muscle spasms or rigidity). If these signs are recognized, treatment with a benzodiazepine or antihistamine will usually lead to their resolution.¹

Cisapride

Mechanism of action: Cisapride is thought to work predominantly by increasing acetylcholine release, serotonin 5-HT₁ and 5-HT₃ antagonism, and serotonin 5-HT₄ and 5-HT₂ agonism. Through those mechanisms, cisapride increases the rate of gastric emptying, improves gastroduodenal coordination, augments small intestinal motility (effects on jejunal propulsion and jejunal nervous activity), and increases colonic motility.^1,5,12

Administration: Cisapride is only available in compounded oral formulations and is typically administered at 0.5 to 1 mg/kg PO (or via a feeding tube) q8h.

Adverse reactions: Cisapride was withdrawn from the human market due to its propensity to prolong the QT interval. Although this effect has not been demonstrated in clinical veterinary medicine, cisapride should be used cautiously in dogs and cats at risk for QT prolongation.¹

Macrolide Antibiotics

Mechanism of action: Macrolide antibiotics (e.g., erythromycin, azithromycin) stimulate motilin receptors, which act during the interdigestive period to stimulate phase III MMC activity, resulting in increased gastric and small intestinal motility in humans and dogs. Cats have motilin receptors throughout their GI tract but do not have phase III MMC activity; therefore, macrolides seem to work directly on motilin receptors to stimulate smooth muscle contraction in cats.^2,13

Administration: The described prokinetic dose for azithromycin in cats is 3.5 mg/kg IV or PO q24h and in dogs is 2 mg/kg IV or PO q8h.^2,13 Erythromycin may be used in patients of both species at a dose of 0.5 to 1 mg/kg IV or PO q8h.¹⁴ Studies in humans have demonstrated the equivalence of the prokinetic effects of azithromycin and erythromycin. Because of the cost, availability, safety profile, longer duration of action, and more favorable side effect profile, the author uses azithromycin rather than erythromycin.^15,16

Adverse reactions: Side effects are rare, although retrograde peristalsis has been documented with higher doses of erythromycin. However, use of macrolide antibiotics may contribute to the development of antimicrobial resistance in human and veterinary medicine. In addition, erythromycin (but not azithromycin) is an inhibitor of cytochrome P450 enzymes; therefore, the clinician must be aware of possible drug interactions.¹

Enteral Naloxone

Mechanism of action: In intensive care units, opioids are commonly prescribed, either postoperatively or for visceral pain associated with severe ileus. In addition, in critically ill patients, endogenous opioids may also be released. Opioids inhibit acetylcholine release, resulting in GIHM. Administration of naloxone via a feeding tube may inhibit the local actions of endogenous and exogenous µ-agonist opioids, resulting in reduced gastric reflux, without blocking the systemic effects of opioids.^1,17,18

Administration: For humans, administration of 8 mg (of the injectable formulation) via a feeding tube q6h has been described.¹⁸ For refractory ileus in dogs and cats, the author has used 0.1 mg/kg q6h via nasogastric tube.

Adverse reactions: Although administration of naloxone could result in decreased analgesia, this effect is unlikely due to naloxone’s high rate of first-pass metabolism.¹⁷

Other Interventions for GIHM

Nonpharmaceutical Interventions

A mainstay for the treatment of GIHM is early enteral nutrition; for patients who are not eating, nasogastric tube placement should be considered. Small, frequent, liquid meals that are low in calories, low in fat, and low in protein are likely to most significantly increase the rate of gastric emptying.^1,2 The measurement and removal of gastric residual volumes are likely not helpful for either diagnosing or treating GIHM. In dogs, higher gastric residual volumes are not associated with vomiting, regurgitation, or aspiration pneumonia. Currently, the relationship between high gastric residual volumes, outcome, and management of GIHM is unclear.^1,2,19-21

Avoiding overhydration is essential as it will increase intestinal edema and worsen GIHM. To avoid gut edema associated with the overuse of crystalloids, use of natural or synthetic colloids and hypertonic saline should be considered. Electrolyte imbalances should be corrected to exclude electrolyte disturbances as a cause of altered motility. Ambulation has long been recommended to encourage gut motility; however, studies demonstrating the benefit during the acute phase are lacking. Electroacupuncture may increase gastrointestinal motility in veterinary patients, although the mechanisms are unclear.^22-25

Other Medications

Ghrelin agonists are thought to have prokinetic effects through stimulation of the vagus nerve.²⁵ The effects of capromorelin on GI motility are currently unknown. Other medications, including lidocaine,²⁶ ranitidine,^27,28 and maropitant,²⁹ have shown no effect on GI motility. Bethanechol has been shown to increase antral contractility in dogs, cats, and humans; however, in humans, the increased contractions do not result in an increased rate of gastric emptying or propulsion of gastric material.^30,31 Neostigmine may increase intestinal motility, including in dogs.^32-34 However, the use of bethanechol and neostigmine cannot be recommended without further evidence. There is some evidence that an herbal supplement, rikkunshito, may have prokinetic activity in dogs through effects on ghrelin and 5-HT₃ receptors.³⁵

Recent studies in humans have shown that combination therapy with prokinetic agents with different mechanisms of action may reduce signs associated with GIHM and optimize gastric emptying.^36,37 At the start of treatment for GIHM in dogs and cats, the author commonly initiates both metoclopramide and azithromycin.

As discussed above, pure µ-opioid agonism is associated with GIHM. Using a multimodal analgesic approach, including peripheral nerve blocks, epidural catheters, and secondary agents, should be strongly considered.^1,38 Administration of buprenorphine instead of a pure µ-opioid agonist may also be considered because it has minimal effect on GI smooth muscle.³⁹

Summary

GIHM can be hard to diagnose in dogs and cats in the absence of an experienced ultrasonographer. Treatment for GIHM should be multimodal, and doses should be titrated to the individual patient. Clinicians should be aware of potential side effects of prokinetics, especially those associated with high-dose metoclopramide.