Gut dysmotility and prokinetics

The ICU is where all organ systems have their opportunity to take a break from work, and the gut is no exception. Constipation and poor gut motility are common features of ICU stay; they are practically mandatory if you have had a severe head injury or some sort of orthopaedic trauma. There are plenty of reasons as to why one's gut might get this lazy, ranging from direct trauma (eg. a surgeon's been at it) to extensive use of opiates, consequences of electrolyte derangement, strange nasogastric diets, immobility, and peritoneal infection.

Question 9 from the first paper of 2002 is the only question which has ever asked about this topic, which is bizarre because it is something we encounter on a near-daily basis. The question wanted candidates to compare erythromycin and metaclopromide with cisapride, a drug with which they young'uns will be unfamiliar because it was withdrawn from the marked amid widespread concerns regarding its cardiotoxicity. In spite of the fact that it will likely never be seen again, the question (and the comparison table it invites as an answer) is offered here for purely historical reasons. In the future,SAQs on this topic will likely take the shape of "critically evaluate" questions. In a slightly sideways move, the college asked about constipation ( a variation on the theme of gut dysmotility) in Question 17 from the first paper of 2016.

Prokinetics Mentioned in Previous CICM SAQs

Features	Metoclopramide	Erythomycin	Cisapride
Class and mechanism	Antiemetic; Dopamine receptor antagonist Enhances gastric emptying rate and increases the tone of the oeseophageal sphincter	Macrolide antibiotic; Motilin receptor agonist, motilin release enhancer Increases the automaticity of enteric nervous system motor function	Prokinetic 5-HT4 receptor agonist Enhances oesophageal peristaltic activity, gastric emptying, intestinal propulsive activity and colonic transit (although in the wake of its discontinuation, many believe these effects were overstated).
Advantages	Low toxicity Synergistic effect with erythromycin	Low toxicity Synergistic effect with metoclopramide	None?
Adverse effects	Increased prolactin release Dystonic reactions	Allergic reactions QT prolongation	QT prolongation Significant risk of arrhythmia Numerous drug interactions

As with many topics in the Required Reading section, this chapter straddles several broad subject areas, and might have fitted equally well into the "metabolism and nutrition" section. Indeed a short blurb about prokinetics is included in the chapter on the management of inadequate nutrition and feed intolerance.  As far as published literature goes, one may find oneself buried in a gratuitous excess of data. To limit the reading to one paper would be the most sensible move.

Among the works which have informed this summary, the following were the most helpful:

• The LITFL page on prokinetics
• Nguyen, 2014:  "Pharmacological therapy of feed intolerance in the critically ills" (sic)
• Frazer et al , 2009: "Prokinetic drugs for feed intolerance in critical illness: current and potential therapies"

Definitions: the concept of acute gut injury (AGI)

In short, "acute gut injury" is what happens to your tract in the setting of critical illness. It encompasses everything, including vomiting, diarrhoea, ileus, feed intolerance, all the way up to ischaemic gut and bowel perforation. One could do worse than the 2012 ESICM statement which defined "acute gut injury" as "a malfunctioning of the GI tract in intensive care patients due to their acute illness". The definition and its associated RIFLE-esque graded staging system are arbitrary and based on clinical features, rather than hard scientific distinctions. We do not yet have a troponin-like biomarker to identify gut injury, and most of the definitions of gut dysfunction describe the disturbance in terms of what the gut does with its contents (i.e. feed intolerance, gastric residuals and diarrhoea or constipation).

Acute gut injury can be described in grades, from Grade I to Grade IV:

• Grade I = increased risk of developing GI dysfunction or failure (a self-limiting condition); for example, post-operative nausea and vomiting
• Grade II = GI dysfunction (a condition that requires interventions)- for example, feed intolerance, gastroparesis with high residuals, or diarrhoea. In short, something that would cause you to prescribe a bunch of drugs or somehow otherwise adjust your approach.
• Grade III = GI failure (GI function cannot be restored with interventions). This grade describes a situation where feed intolerance or ileus are refractory to conventional therapy (eg. prokinetics and aperients). This grade represents a situation where you would start TPN, acknowledging the failure of enteral nutrition.
• Grade IV = dramatically manifesting GI failure (a condition that is immediately life-threatening). ESICM list Ogilvie syndrome, gut ischaemia, intestinal haemorrhage and bowel perforation as examples of Grade IV acute gut injury. The defining feature of this grade is a need of emergent life-saving interventions such as laparotomy. As the authors put it, Grade IV is when "there is no proven conservative approach to resolve this situation".

Furthermore, AGI can be separated into primary gut injury (eg. peritonitis after abdominal gun shot wound) and secondary (eg. the ileus associated with septic shock, or massive opiate doses in head injury). ESICM also went on to define "feed intolerance syndrome",  intra-abdominal hypertension, abdominal compartment syndrome, and various other things. The granularity of their definitions is admirable (for instance, they take great care to discriminate between vomiting and regurgitation).

Causes of poor gut motility in the ICU

The specific problems with motility seem to be limited to the stomach, duodenum and large bowel.

• Decreased gastro-oesophageal sphincter tone
• 
  Gastroesophageal reflux
• 
  Delayed gastric emptying (high residual volumes)
• Increased (or decreased!) pyloric sphincter tone
• Retrograde duodenal peristalsis

Causes of Impaired Gut Motility in the ICU

Vascular Gut ischaemia Gut oedema Infectious Peritonitis Diverticulitis Severe sepsis Neoplastic Mesenteric "caking" of metastatic disease Hypercalcemia of malignancy Drug-induced Opiates Anticholinergics Sympathomimetics (eg. noradrenaline) Nicotine or caffeine withdrawal Nasogastric feeds

Congenital Hirschsprung's disease or aganglionosis Spina bifida Idiopathic / inflammatory / autoimmune Inflammatory bowel disease Connective tissue disease, eg. scleroderma Amyloidosis Traumatic / surgical / mechanical Post-operative ileus (from bowel handling) Increased intra-abdominal pressure Spinal injury Immobility Endocrine/metabolic Hypercalcemia Hypophosphatemia Hypokalemia Hypothyroidism Diabetes (eg. autonomic neuropathy)

Rationale for the use of prokinetics

Duh, the tract is lazy and you want to mae it move. The nurses keep bothering you about high gastric residuals, and you want to make them go away.  Beyond these valid pragmatic statements, the savvy candidate will want to write something in the "rationale" section of their "critically evaluate answer". Thus:

• Poor tolerance of gastric feeding is a reversible cause of malnutrtion among ICU patients
• Malnutrition among ICU patients is a major cause of morbidity, and is associated with an increased mortality
• Gastric distension not only contributes to poor nutrition, but is associated with aspiration and is uncomfortable for the patient, which increases sedation requirements.
• Abdominal distension due to poor gut motility can affect ventilation and act as one of the causes of slow ventilator weaning.
• Poor gut motility in critical illness is multifactorial in origin, and the specific causes may not be immediately correctable
• Thus, gut motility promoters are may reduce critical care morbidity by improving nutritional intake, increasing patient compfort and modifying aspiration risk.

Prokinetic agents

Metaclopromide and domperidone

These antidopaminergic drugs have an effect on stomach emptying and gastro-oesophageal sphincter tone. Working on the premise that gastric emptying is the major issue (small bowel motility being fairly immune to the effects of critical illness) the use of metoclopramide seems to make sense. How does it work? Jooste et al (1999) mention something about facilitating release of acetylcholine from gut cholinergic neurons, antagonism of the motility-depressing effects of dopamine and blockade of serotonergic receptors in the upper GI tract. Jooste et al performed a small-scale crossover study of metoclopramide among 10 heterogeneous patients, demonstrating that the absorption of paracetamol was improved.   However, subsequent work by Marino et al, (2003) suggests that (at least among head injury patients) metoclopramide may have no effect on gastric emptying. This was confirmed by Hersch e al (2015) whose cohort also did not benefit significantly from metoclopramide alone. In summary, it should not be used as a sole agent, as it seems to achieve nothing. The patient will probably develop dyskinesia and begin to lactate before their gastric motility improves.

Erythromycin and other macrolides

Erythromycin is a macrolide antibiotic with motilin agonist properties. Because it was the very first macrolide discovered (in the 1950s) these days pretty much everything is resistant to it, and therefore its use as an antibiotic is no longer relevant. As a prokinetic, it stimulates motilin receptors and triggers a phase of migrating myoelectric complex in the gut (Hawkyard et al, 2007). Motilin receptors are concentrated around the gastric antrum and the proximal duodenum, and this is where the effects of macrolides are most pronounced

It seems both metoclopramide and erythromycin should be used together. Erythromycin is the more potent agent of the two (Nguyen et al, 2007). There is the threat of tachyphylaxis: both agents lose their effectiveness over the first week of therapy. It is also not the only choice of motilin agonists: Ugbu et al (2015) have demonstrated that azithromycin is potentially a better prokinetic.

How much do you use? Frazer et al (2009) mention studies where laughably small 40mg doses were used with measurable effect in healthy volunteers. LITFL recommend 100mg q6h or 250mg q12h. Locally, we use more - 250mg q6h is the usual trick. Historically, up to 1g q6h has been used (that is the usual antimicrobial dose), with powerful antral contractions - but upper abdominal pain and nausea tend to accompany the improvement in gastric emptying.

Enteral naloxone

Absorption of enteral naloxone is apparently reasonably good, but it undergoes extensive first-pass metabolism and its systemic effects are limited to perhaps 1% of the enteric dose, which means it should not reverse the analgesic effects of opiates. The effect should therefore be localised to the gut; this is particularly attractive if you feel strongly that the ileus and constipation are purely opiate-related. There seems to be little in the way of complications, particularly with regard to analgesia. Gibson et al (2014) restrospectively evaluated the electronic chart records of all the patients who received enteral naloxone in the medical ICU, and found that it was free of adverse effects. These days drug companies have packaged it together with oxycodone.

Vast doses are required. The dose mentioned by Frazer et al (2009) is 8mg q6h, which probably comes from a 2003 study by Meissner et al. Those guys randomised 84 ICU patients to receive either naloxone or placebo. The opiate doses were very weird: unless I have misread Table 1, the patients were getting about 7μg/kg/hr of fentanyl, which  comes to almost 500 μg/hr for a 70kg patient. If correct, that is quite an insane amount of fentanyl, amounting to 12mg per day- well in excess of what Australian ICUs tend to use. Anyway: gastric residual volumes improved with naloxone in this massively overdosed group of patients. It is difficult to say what might have happened if the dose of opiate was more conservative (eg. locally we use a maximum of 1-2 μg/kg/hr).

Given that locally there is no formulation of naloxone available other than the 400 μg  IV formulation, the use of oral naloxone seems highly inconvenient in Australia (you'd have to open 20 ampoules four times a day). One is tempted to use methylnaltrexone just out of convenience.

Methylnaltrexone and alvimopan

This drug is a peripherally acting mu-receptor antagonist; structurally similar to naltrexone but methylated to prevent it from crossing the blood-brain barrier. Thomas et al (NEJM, 2008) found that almost 50% of chronically opiate-poisoned palliative care patients opened their bowels within 4 hours of their first dose. How much do you need? Sawh et al (2012) used doses of 0.15mg/kg to effectively reverse opiate-induced constipation in medical ICU patients, which comes to about 10.5mg for a 70kg patient. Each ampoule of Relistor is 12mg, so it seems fair not to waste the other 1.5mg (just give the lot).

Concerns have been raised about using this drug in patients with a disrupted blood-brain barrier. The head injured populatiobn have oedematous brains, where all sorts of abnormal transport is occurrig ergo, the methylnaltrexone will lose its advantage of peripheral selectivity, and might end up reversing the highly desirable central effects of opiates.

One might first counter this on purely theoretical grounds. Opiates probably do little to actually affect intracranial pressure, and there is some evidence that they may make it worse (see the chapter on ICP management), so to antagonise their effect may not do very much for your overall ICP management strategy. Moreover, that damaged macerated brain, boggy with oedema and marinaded in blood - how much of that brain is actually going to respond normally to opiates? What receptors are there for them to act upon? Difficult to say. The situation may be analogous to the damaged pancreas and its failure to respond to normal secretory signals.

Literature evidence also exists for the safety of methylnaltrexone in patients with blood brain barrier dysfunction. Taillibert et al (2005) report on the safe use of methylnaltrexone in palliative patients with brain metastases. Gordon et al (2015) have unpublished data (available as a poster) describing the safe use of methylnaltrexone in a population of patients of whom 75% were admitted with traumatic brain injury. In short, this concern is probably without foundation.

Neostigmine

The cholinergic effects of neostigmine are a brutally effective solution to the problem of critical care ileus. Van de Spoel et al (2001) used it in 30 MOSF patients, all of whom had some degree of colonic ileus. Even though five patient records were lost due to a fire, the remaining case results were fairly convincing. At a dose rate of 0.4mg/hr, neostigmine was effective at moving the bowel within the first 4-9 hours. 

Concerns are usually raised about the risk of bowel perforation. The power of neostigmine is such, they reason, that it may cause the bowel to tear itself apart, with its torn severed ends writhing around the abdomen like the arms of a wacky waving inflatable arm flailing tube man. This seems to be a sensible concern. Case reports of neostigmine-associated bowel perforation do exist (there seems to be three of them). However, it does not seem to be a dominant side-effect of the therapy. Most often, neostigmine infusion is stopped due to bradycardia.

Weird stuff, alternative prokinetics, nonphartmacological strategies

A good article exists, written by Florian Pfab and coleagues ("Alternatives to prokinetics to move the pylorus and colon",  2012). It contains a good overview of prokinetics in general, and has a nice table of different laxatives (though towards the end it trails off into wholistic granola and acupuncture).

In short:

• Dexpanthenol (15mg/kg)  - the precursor of pantothenic acid (Vitamin B5), which is in turn the precursor of Coenzyme A,  required for the synthesis of choline (and therefore acetylcholine). Theoretically, it should increase the availability of acetylcholine to the gut, therefore improving gut transit. It is very old school (Watne et al, 1963). In Australia, its availability seems to be limited to topical skin creams used for the management of nappy rash. Any attempt to administer it enterally will likely be met with raised eyebrows.
• Cisapride: 5-HT4 receptor agonist; abandoned due to cardiotoxicity
• Tegaserod: 5-HT4 receptor agonist; abandoned due to cardiotoxicity
• Aperients and laxatives
  • Coloxyl with senna
  • Bulk-forming agents, eg. Movicol
  • Osmotic agents, eg. lactulose
  • Bowel prep, eg. polyethylene glycol
  • Enemas
• Alternatives to prokinetics
  • Hydration
  • Abdominal massage
  • Nicotine patch