Still a Place for Metoclopramide as a Prokinetic Drug in Critically Ill Patients?

Neurologic adverse reactions, including extrapyramidal disorders, dyskinesia, dystonia, convulsions, hypertonia, and tremors.4 The reported occurrence of tardive dyskinesia ranges from <0.01%–23%.5 High occurrence is attributed to chronic use (months to years) of approximately 30 ± 10 mg/d metoclopramide6 and concerns mostly older (60 ± 22 years) women.5 Of an estimated 15.9 million metoclopramide prescriptions in the United Kingdom from 1967–1982, extrapyramidal symptoms were reported with an incidence of 0.003%.7 Occurrence of akathisia is related to the rate of intravenous (IV) metoclopramide administration. After a bolus injection over 2 minutes, 24.7% experienced akathisia, which was reduced to 5.8% in patients receiving the same dose in a 15-minute infusion.8 Cardiac adverse reactions, including shock, hypotension, cardiac arrest, tachycardia, bradycardia, hypertension, cardiorespiratory arrest, and circulatory collapse.4 Evidence is solely based on case reports.4 Delayed gastric emptying is commonly encountered in the ICU and may be present in 50%–60% of all ICU patients.910-11 A recent retrospective analysis in ICUs in 21 countries demonstrated an enteral feed intolerance in 30.5% of patients after a median of 3 days on enteral nutrition. A prokinetic drug was administered in 37.9% of cases, primarily metoclopramide and erythromycin far less frequently.12 Metoclopramide is extensively used as an IV prokinetic drug to treat delayed gastric emptying and facilitate early enteral feeding. However, metoclopramide is not officially registered for this specific indication in critically ill patients. The commonly used metoclopramide dosage in the ICU setting is 10 mg 4 times daily.9 As tachyphylaxis to metoclopramide frequently occurs after a few days of treatment, IV erythromycin 200 mg twice daily can be added to enhance the prokinetic effects and decrease tachyphylaxis.13 Early combination therapy of erythromycin and metoclopramide has been shown to be more effective than single administration of either drug.13 Limited information is available on metoclopramide dosing in renal failure. In the United States, it is recommended to reduce the dose by 50% when creatinine clearance is 10–40 mL/min. In Europe, however, dose reduction is recommended when creatinine clearance is 60 mL/min and lower.1415-16 Therefore, we recommend following local dosing guidelines. Since the volume of distribution of metoclopramide is high, metoclopramide is only minimally removed by hemodialysis or peritoneal dialysis, and no supplemental dose is necessary after dialysis. During continuous renal replacement therapy, 50% of the normal dose can be prescribed.1415-16 At present, in many countries, the only available alternative to metoclopramide is IV erythromycin. Erythromycin is generally considered effective, and some investigators suggest that erythromycin is even more effective than metoclopramide as a single prokinetic agent.11,17 Commonly, 200 mg IV erythromycin twice daily is used, but doses of 70 mg might be effective as well.18 Use of erythromycin as a single agent may be hampered by the occurrence of tachyphylaxis within a few days and because of the concerns regarding its cardiac effects (QTc prolongation) and the potential emergence of antibiotic resistance.9,11 Besides erythromycin, no other alternatives are currently available. However, several new agents are being developed but have not been studied as extensively in critically ill patients compared with metoclopramide and erythromycin (Table 1). Adjusting the maximum daily dose to 10 mg thrice daily or no more than 0.5 mg/kg body weight/d according to the recommendations of the EMA should decrease the risk of neurologic and other adverse reactions associated with metoclopramide.3 However, evidence supporting the effectiveness of this dose in critically ill patients is scarce, since most studies among these patients investigated the effects of 10 mg every 6 hours.9 One study did investigate metoclopramide 10 mg thrice daily in the prevention of pneumonia in ICU patients who received nasogastric enteral feeding. Although metoclopramide at this dose did delay the onset of pneumonia, it was not clinically significant, as the risk of pneumonia and mortality was not reduced.26 Therefore, adjusting the metoclopramide dosage according to the recommendations of the EMA cannot be recommended as there is lack of evidence supporting this dosage regimen in critically ill patients. Efficacy has only been shown in studies using 10 mg qid. A decrease in the response to a drug after repeated administration is called tachyphylaxis. Increasing the dose of the drug may be able to restore the original response. Tachyphylaxis was addressed in 2 studies.13,17 Over time, all treatments became less effective with treatment failure (ie, tachyphylaxis occurring after 2, 3, and 6½ days for metoclopramide, erythromycin, and combination therapy, respectively). Desensitization, downregulation, and endocytosis of neurohumoral receptors have been proposed as mechanisms underlying the occurrence of tachyphylaxis. Combination therapy might be more effective because of the complementary actions of both prokinetics in delaying tachyphylaxis and the multiple mechanisms underlying delayed gastric emptying. However, the relevance is unclear, as it did not improve survival or reduce the length of hospital stay. The power of these studies may be insufficient to demonstrate significance.13,17 At present, the only available alternative to metoclopramide is erythromycin. Both agents are often used as a strategy to improve gastric emptying and improve patient outcomes.9 Some new prokinetic agents appear promising but will not be available in the near future. We recommend to continue the off-label use of metoclopramide and not to exceed a daily dose of 10 mg qid. Patients should be monitored closely for clinical evidence of side effects and the occurrence of tachyphylaxis to maximize patient safety and facilitate successful treatment. Erythromycin should be added if intolerance to enteral feeding persists with the use of metoclopramide as a single therapy. Although combination therapy should not be used beyond 7 days, both agents should be considered if no improvement occurs after 24–48 hours because of the potential for developing tachyphylaxis. If the combination does not work, an alternative route of feeding such as postpyloric feeding should be considered. In case of renal failure, the dose of metoclopramide should be adjusted. Since neurologic and cardiac side effects have been rarely reported in critically ill patients and clinical experience is large, we recommend to continue the off-label use of metoclopramide in critically ill patients to improve gastric emptying in patients with high gastric residual volumes to enhance enteral feeding. To limit side effects, a slow infusion rate and dosages not exceeding a daily dose of 10 mg metoclopramide qid is recommended, and dosages should be adjusted in case of renal failure. Combination therapy with erythromycin is more effective. For reasons of tachyphylaxis and safety, a maximum duration of 7 days for either drug or the combination is recommended. In case of treatment failure, a postpyloric feeding tube should be considered. This update is brought to you by the Critical Care Nutrition Team and is posted on its website as a nutrition information byte (NIBBLE) at www.criticalcarenutrition.com.

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