Skip to main content

Prokinetic agents in critical care

Abstract

Prokinetic agents are commonly used in intensive care, mainly to aid in early enteral feeding. The present commentary reviews some of the recently published papers and highlights the lack of a sizable evidence base, as well as the possible importance of euglycaemia in this important clinical area.

Introduction

Early enteral feeding is now recognized as one of the fundamentals of critical care practice [1,2,3,4]. Enteral nutrition (EN) increases gut blood flow, thereby protecting the gastric mucosa [5,6]. Early feeding results in fewer septic complications, decreased catabolic response to injury, decreased stress ulceration in the ventilated patient, improved gut immune function and improved wound healing [3,4,7,8]. Successful enteral feeding relies on intact gastrointestinal motility, which is frequently impaired in the critically ill.

Prokinetic agents have a valuable role to play in this situation. A recent review by Booth and coworkers [9] with an accompanying editorial [10] in Critical Care Medicine systematically reviewed the evidence for the use of gastrointestinal promotility drugs in critical care. The context of the review was that promotility agents may improve tolerance to EN, and reduce gastroesophageal reflux and pulmonary aspiration; they therefore have the potential to improve outcomes of critically ill patients. The authors appear to have conducted a comprehensive search of the available literature over the preceding two decades. The studies were then methodologically assessed for their quality using a previously described scoring system, with attempts made to contact the primary investigators for further information where this was thought necessary.

The review scrutinized 18 studies involving a total of 908 individuals. A significant proportion of the review examined the role of prokinetics in aiding tube placement, whereas the remainder looked at the effects of cisapride, erythromycin and metoclopramide on gut transit/feeding tolerance. (For a summary of the actions of those agents, see Table 1.) Cisapride is currently unavailable in many countries because of cardiac toxicity [11].

Table 1 Summary of features and actions of cisapride, erythromycin and metoclopramide

A breakdown of the reviewed studies is shown in Table 2. If we exclude the studies on tube placement, those with endpoints that involved patient outcomes and those gastrointestinal transit studies that involved cisapride alone, then we are left with only six studies (highlighted in Table 2 with asterisks), involving 80 patients, that examined agents that are available as prokinetics in contemporary practice. The review justified the inclusion of cisapride because there are currently new generation agents undergoing trials; however, it failed to mention that the studies on the new motilin receptor agonists (macrolide derivatives), such as ABT-229, have yielded disappointing results [12,13]. The authors suggested that we should be more cautious with our use of erythromycin, given the increasing incidence of antibiotic resistance, and suggested 20 mg metoclopramide as first-line treatment. This dose appears to have little scientific basis because only one of the tube placement studies [14] used it; the review stated that a dose of 20 mg was used in the gastrointestinal transit study conducted by Jooste and coworkers [15], but it actually employed a 10 mg dose. The value of the review is that it highlights the lack of any large methodolical studies on which to base treatment recommendations.

Table 2 Summary of studies of gastrointestinal promotility drugs

In view of recent critical care trials, it is disappointing that neither the review nor the editorial mentioned the effect of hyperglycaemia on gastric function. It is now recognized that increasing blood glucose in both diabetic patients and normal individuals has a reversible effect on gastrointestinal motor function [16,17]. Also of note is that the gastrokinetic effects of erythromycin were attenuated in healthy individuals when their blood glucose concentrations were increased from approximately 4 to 15 mmol/l [18].

Another study [19], published in June 2002 in Critical Care Medicine (too late for inclusion in the review by Booth and coworkers [9]), examined the effects of erythromycin in ventilated patients. It adds considerably to the body of evidence by studying 40 patients randomly assigned to either placebo or erythromycin 250 mg four times daily in 50 ml 5% dextrose. Enteral feeding was commenced at 500 ml/day on the first day, and was increased in 500-ml steps to a maximum of 2000 ml/day. Residual gastric volume (RGV) was measured at 6-hour intervals and feed was discontinued if RGV exceeded 250 ml or the patient vomited. The treatment group exhibited a significant decrease in RGV for the first 3 days of feeding and a significant decrease in the number of patients who were unable to tolerate EN (35% versus 70%).

The ideal dosing of erythromycin still requires clarification; the above regimen produced satisfactory outcomes, but similar results might have been achieved with twice daily dosing [20]. Erythromycin involves two different pathways [21], and its effects are known to vary with dosing. A low dose (40 mg) induces a premature activity front at the antral level, migrating caudally to the small intestine, and is possibly mediated by activation of an intrinsic cholinergic pathway. Higher doses (200–350 mg) induce a prolonged period of strong antral activity that is not followed by phase 1 and does not migrate caudally, and is possibly mediated via a pathway that involves activation of a muscular receptor [22]. The recent cloning of the motilin receptor may help to clarify the correct dose from a molecular level [23].

Metoclopramide may well be more efficacious at a dose of 20 mg, but currently there is no evidence to support this in the absence of an adequately powered and randomized study. On current evidence, the best dose is probably 10 mg intravenously three times daily.

This important everyday area of practise noticeably lacks an evidence base. Perhaps the current move in many units to more aggressive blood sugar control, which requires a more constant source of glucose, will provide the impetus for the much needed further work in patients who are euglycaemic.

Abbreviations

EN:

EN = enteral nutrition

RGV:

RGV = residual gastric volume.

References

  1. 1.

    Miskovitz P: Gastric prokinetic motility therapy to facilitate early enteral nutrition in the intensive care unit. Crit Care Med 2002, 30: 1386-1387. 10.1097/00003246-200206000-00046

    Article  PubMed  Google Scholar 

  2. 2.

    Marik PE, Zaloga GP: Early enteral nutrition in acutely ill patients: A systematic review. Crit Care Med 2001, 29: 2264-2270.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Zaloga GP: Early enteral nutritional support improves outcome: hypothesis or fact? Crit Care Med 1999, 27: 259-261. 10.1097/00003246-199902000-00024

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Heyland DK, Cook DJ, Guyatt GH: Enteral nutrition in the critically ill patient: a critical review of the evidence. Intensive Care Med 1993, 19: 435-442.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Hadfield RJ, Sinclair DJ, Houldsworth PE, Evans TW: Effects of enteral and parenteral nutrition on gut mucosal permeability in the critically ill. Am J Respir Crit Care Med 1995, 152: 1545-1548.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Saito H, Trocki O, Alexander JW, Kopcha R, Heyd T, Joffe SN: The effect of route of nutrient administration on the nutritional state, catabolic hormone secretion, and gut mucosal integrity after burn injury. JPEN J Parenter Enteral Nutr 1987, 11: 1-7.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Kudsk KA, Minard G, Wojtysiak SL, Croce M, Fabian T, Brown RO: Visceral protein response to enteral versus parenteral nutrition and sepsis in patients with trauma. Surgery 1994, 116: 516-523.

    CAS  PubMed  Google Scholar 

  8. 8.

    Moore FA, Feliciano DV, Andrassy RJ, McArdle AH, Booth FV, Morgenstein-Wagner TB, Kellum JM Jr, Welling RE, Moore EE: Early enteral feeding, compared with parenteral, reduces postoperative septic complications: the results of a meta-analysis. Ann Surg 1992, 216: 172-183.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  9. 9.

    Booth CM, Heyland DK, Paterson WG: Gastrointestinal promotility drugs in the critical care setting: a systematic review of the evidence. Crit Care Med 2002, 30: 1429-1435. 10.1097/00003246-200207000-00005

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Tisherman SA, Marik PE, Ochoa J: Promoting enteral feeding 101. Crit Care Med 2002, 30: 1653-1654. 10.1097/00003246-200207000-00044

    Article  PubMed  Google Scholar 

  11. 11.

    Wysowski DK, Bacsanyi J: Cisapride and fatal arrhythmia. N Engl J Med 1996, 335: 290-291. 10.1056/NEJM199607253350416

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Tack J, Peeters T: What comes after macrolides and other motilin stimulants? Gut 2001, 49: 317-318.

    PubMed Central  CAS  PubMed  Google Scholar 

  13. 13.

    Talley NJ, Verlinden M, Geenen DJ, Hogan RB, Riff D, McCallum RW, Mack RJ: Effects of a motilin receptor agonist (ABT-229) on upper gastrointestinal symptoms in type 1 diabetes mellitus: a randomised, double blind, placebo controlled trial. Gut 2001, 49: 395-401. 10.1136/gut.49.3.395

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  14. 14.

    Whatley K, Turner WW Jr, Dey M, Leonard J, Guthrie M: When does metoclopramide facilitate transpyloric intubation? JPEN J Parenter Enteral Nutr 1984, 8: 679-681.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Jooste CA, Mustoe J, Collee G: Metoclopramide improves gastric motility in critically ill patients. Intensive Care Med 1999, 25: 464-468. 10.1007/s001340050881

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Jones KL, Kong MF, Berry MK, Rayner CK, Adamson U, Horowitz M: The effect of erythromycin on gastric emptying is modified by physiological changes in the blood glucose concentration. Am J Gastroenterol 1999, 94: 2074-2079. 10.1016/S0002-9270(99)00336-6

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Kong MF, Horowitz M: Gastric emptying in diabetes mellitus: relationship to blood-glucose control. Clin Geriatr Med 1999, 15: 321-338.

    CAS  PubMed  Google Scholar 

  18. 18.

    Jones KL, Berry M, Kong MF, Kwiatek MA, Samsom M, Horowitz M: Hyperglycemia attenuates the gastrokinetic effect of erythromycin and affects the perception of postprandial hunger in normal subjects. Diabetes Care 1999, 22: 339-344.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Reignier J, Bensaid S, Perrin-Gachadoat D, Burdin M, Boiteau R, Tenaillon A: Erythromycin and early enteral nutrition in mechanically ventilated patients. Crit Care Med 2002, 30: 1237-1241. 10.1097/00003246-200206000-00012

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Chapman MJ, Fraser RJ, Kluger MT, Buist MD, De Nichilo DJ: Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding. Crit Care Med 2000, 28: 2334-2337.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Coulie B, Tack J, Peeters T, Janssens J: Involvement of two different pathways in the motor effects of erythromycin on the gastric antrum in humans. Gut 1998, 43: 395-400.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  22. 22.

    Tack J, Janssens J, Vantrappen G, Peeters T, Annese V, Depoortere I, Muls E, Bouillon R: Effect of erythromycin on gastric motility in controls and in diabetic gastroparesis. Gastroenterology 1992, 103: 72-79.

    CAS  PubMed  Google Scholar 

  23. 23.

    Feighner SD, Tan CP, McKee KK, Palyha OC, Hreniuk DL, Pong SS, Austin CP, Figueroa D, MacNeil D, Cascieri MA, Nargund R, Bakshi R, Abramovitz M, Stocco R, Kargman S, O'Neill G, Van Der Ploeg LH, Evans J, Patchett AA, Smith RG, Howard AD: Receptor for motilin identified in the human gastrointestinal system. Science 1999, 284: 2184-2188. 10.1126/science.284.5423.2184

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Warren L Doherty.

Additional information

Competing interests

None declared.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Doherty, W.L., Winter, B. Prokinetic agents in critical care. Crit Care 7, 206 (2003). https://doi.org/10.1186/cc1849

Download citation

Keywords

  • enteral feeding
  • erythromycin
  • hyperglycaemia
  • intensive care
  • metolopramide
  • prokinetic agent