Ri 趙基安 Supervisor VS 葉育彰

1. Gastrointestinal motility and prokinetics in the critically illCurrent Opinion in Critical Care 2007, 13:187–194 Ri趙基安 Supervisor VS葉育彰

2. Introduction • Early enteral administration of nutrition is currently considered to be best practice • 50~60% of critically ill patients have delayed gastric emptying • The aetiologies of abnormal UGI motor activity remain unclear; related: pre-existing comorbidities, admission diagnoses, drugs, electrolyte abnormalities including hyperglycaemia, recent surgery, shock, and circulating cytokines

3. Sequelae of abnormal UGI motility: ☆ poor nutrition ☆ bacterial colonization of the gastrointestinal tract ☆ gastro-esophageal reflux ☆ esophagitis ☆ gastrointestinal bleeding ☆ pulmonary aspiration ☆ ventilator-associated pneumonia

4. Current treatment for abnormal UGI motility has major limitations • Better understanding  target therapy new agents

5. Upper gastrointestinal motility in health • Lower esophageal sphincter tone prevents reflux of food, acid and bile • Proximal stomach functions as a reservoir and an important determinant of liquid gastric emptying; nutrient redistribution • Antro-pyloro-duodenal motility: Contractions can be localized or propagated (antegrade or retrograde)

6. Chyme into the duodenum  nutrient receptor feedback  fundal relaxation, decrease in fundic and antral contractions, increased pyloric activity  slow gastric emptying • Fasting motility consists of migratory motor complexes, which are divided into 3 phases: ☆Phase I: quiescence ☆Phase II: variable period of irregular contractile activity ☆Phase III: short period (5~10 min) of intense, frequent, regular contractions (motilin receptor) clear bowel

7. Gastrointestinal motility control: mixture of neural and humoral mechanisms • Interstitial cell of Cajal  fluctuated RMP  rhythm of smooth muscle activity • Neural and humoral mechanisms  to or not to initiate a mechanical contraction • Intrinsic: myenteric plexus • Extrinsic: parasympathetic↑; sympathetic↓ • CCK, released in response to nutrients  slow gastric emptying

8. Gastric emptying in the critically ill • Delayed gastric emptying occurs frequently in critical illness • Gastric residual volumes  surrogate marker to determine the success or failure of nasogastric nutrition, and the risk of regurgitation and aspiration • The incidence of delayed gastric emptying in the critically ill appears to be affected by age, illness severity, and admission diagnosis

9. Delayed gastric emptying is more frequent in: ☆Burns ☆multiple trauma (with and without head injury) ☆severe sepsis ►80% head injuries (IICP associated) ►Hyperglycemia delays gastric emptying (pre- existing DM doesn’t affect)

10. Drugs administered in ICU, particularly inotropes and those used for sedation, may impact on gastrointestinal motility • Opiates μreceptors  may contribute to abnormal upper gastrointestinal motor function • Neuromuscular blockers  no effect

11. High levels of circulating catecholamines commonly seen  negative effect • Adrenaline reduces gastric emptying by a β-adrenergic effect • Dopamine reduces antral contractions and slows orocaecal transit • High-dose catecholamines may reduce the prokinetic effect of erythromycin • Anticholinergics and calcium channel blockers

12. Upper gastrointestinal motility abnormalities in the critically ill

13. Esophageal dysmotility • Reflux oesophagitis occurs in approximately 50% of patients  hemorrhage, microaspiration  ventilator-associated pneumonia. • Lower esophageal sphincter tone is reduced or absent in mechanically ventilated patients  free oral flow of gastric contents

14. Gastric dysmotility • Motor disturbances have been described in all regions of the stomach. ★Proximal stomach • Fundic wave frequency is reduced • Subsequent recovery of nutrient-induced relaxation to baseline is markedly delayed

15. ★Whole stomach • Intragastric meal distribution is abnormal • Proximal gastric meal retention  GE reflux ★Distal stomach • Antral motor activity is greatly reduced • Pyloric activity is increased • Exaggeration in response to the presence of nutrients in the duodenum

16. Duodenal dysmotility • Frequency of duodenal contractions is relatively well • Organization of duodenal activity is abnormal • 50% of these contractions are retrograde in critically ill

17. Control mechanisms • During fasting, ghrelin and peptide YY (PYY) concentrations are abnormal • Nutrient-stimulated concentrations of cholecystokinin and PYY are markedly elevated  delayed gastric emptying

18. Intestinal absorption • Glucose absorption is substantially reduced in the critically ill • Fat absorption may also be reduced • The reasons for impaired absorption are unclear

20. Therapeutic options

21. Cisapride • 5-HT4 agonist  Acetylcholine increase in enteric nervous system (parasympathomimetic)  increase esophageal sphincter tone and gastric emptying • Limited use due to enteral formulation and the risk of cardiac arrhythmias

22. Metoclopramide • Widely used in ICU • Antagonizes the inhibitory effect of dopamine on motility; weak 5-HT3 antagonist • Less effective than erythromycin • With repeated administration tachyphylaxis develops • Ineffective and contraindicated in patients with head injuries

23. Erythromycin • Low doses (1~3 mg/kg IV) of erythromycin act as a motilin agonist, triggering phase 3-like activity in the stomach and small intestine • In critically ill, itincreases antral motility, accelerates gastric emptying and improves the success of feeding • Efficacy reduced after 7-day use • Cardiac toxicity (use low dose:70 vs 200mg) and bacterial resistance

24. Combination therapy • Combination of erythromycin and metoclopramide for failure of nasogastric feeding, both as first-line treatment and after the failure of monotherapy, is superior to either drug alone and with less tachyphylaxis

26. Novel drug therapies

27. 5-HT4 receptor agonists • Activation of the 5-HT4 receptor is important in the initiation of peristalsis ☆Tegaserod • A selective, 5-HT4 receptor partial agonist • Improve gastric hypomotility in a small number of critically ill patients • Ischemic colitis?

28. μreceptor antagonists • Opiates slow gastric emptying  opiate antagonist ☆Naloxone • administered directly into the gut  avoid antagonism of the central effects of parenteral opiates • improves the success of feeding and reduces ventilator-associated pneumonia

29. ☆Alvimopan • High affinity for μreceptors • Does not cross the blood–brain barrier • No effect on gastric emptying • hastened gut recovery and shortened time to hospital discharge in patients after bowel resection or hysterectomy

30. Cholecystokinin receptor antagonists • Elevated cholecystokinin levels slow gastric emptying and motility and are associated with feed intolerance in critically ill patients ☆Dexloxiglumide • Selective and highly potent CCK-1 receptor antagonist • Inhibits gallbladder contraction, • Improves lower oesophageal sphincter function, • Hastens colonic transit. • Potential treatment

31. Postpyloric feeding • As small intestinal motor function appears to be relatively preserved, successful feeding may be achieved with postpyloric feeding tubes • Blind placement  often failure • Radiological or endoscopic support are required • Postpyloric tubes v.s. intravenous erythromycin  failed nasogastric feeding and unresponsive to prokinetics

32. Conclusion • New insights into the pathophysiology underlying failed enteral feeding • Commonly used prokinetics have limited efficacy • New agents are yet to undergo systematic clinical evaluation in the critically ill • Real time localization of the path of the tube • Use of frictional nasal jejunal feeding tubes