Therapy Erythromycin is more effective than metoclopramide in the treatment of feed intolerance in critical illness.
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Summary
Posted By:	Gordon S Doig
E-Mail:	Gordon.Doig@EvidenceBased.net
Posted Date:	29 1 2007
Title:	Erythromycin is more effective than metoclopramide in the treatment of feed intolerance in critical illness.
Authors:	Nguyen NQ, Chapman MJ, Fraser RJ, Bryant LK, Holloway RH.
Reference:	Crit Care Med. 2007 Feb;35(2):483-489.
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	OBJECTIVE: This study aimed to a) compare the efficacy of metoclopramide and erythromycin in the treatment of feed intolerance in critical illness; and b) determine the effectiveness of "rescue" combination therapy in patients who fail monotherapy. DESIGN: Randomized controlled trial. SETTING: Level III mixed medical and surgical intensive care unit. PATIENTS: Ninety mechanically ventilated, medical patients with feed-intolerance (gastric residual volume >/=250 mL). INTERVENTIONS: Patients received either metoclopramide 10 mg intravenously four times daily (n = 45) or erythromycin 200 mg intravenously twice a day (n = 45) in a double-blind, randomized fashion. After the first dose, nasogastric feeding was commenced and 6-hourly nasogastric aspirates were performed. If a gastric residual volume >/=250 mL recurred on treatment, open-label, combination therapy was given. Patients were studied for 7 days. Successful feeding was defined as 6-hourly gastric residual volume <250 mL with a feeding rate >/=40 mL/hr. MEASUREMENTS AND MAIN RESULTS: Demographic data, blood glucose levels, and use of inotropes, opioids, and benzodiazepines were similar between the two groups. After 24 hrs of treatment, both monotherapies reduced the mean gastric residual volume (metoclopramide, 830 +/- 32 mL to 435 +/- 30 mL, p < .0001; erythromycin, 798 +/- 33 mL to 201 +/- 19 mL, p < .0001) and improved the proportion of patients with successful feeding (metoclopramide = 62% and erythromycin = 87%). Treatment with erythromycin was more effective than metoclopramide, but the effectiveness of both treatments declined rapidly over time. In patients who failed monotherapy, rescue combination therapy was highly effective (day 1 = 92%) and maintained its effectiveness for the study duration (day 6 = 67%). High pretreatment gastric residual volume was associated with poor response to prokinetic therapy. CONCLUSIONS: In critical illness, erythromycin is more effective than metoclopramide in treating feed intolerance, but the rapid decline in effectiveness renders both treatments suboptimal. Rescue combination therapy is highly effective, and further study is required to examine its role as the first-line therapy.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Unsure. Although the authors report the study as being a "two-way randomized, double-blind, parallel-group study" they do not explicitly report how the ranomisation sequence was administered. We cannot be certain that allocation concealment was maintained.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	No. It was reported that 107 patients were enrolled but 17 were excluded from the primary analysis. Although the authors report that 9 patients were excluded from one group and 8 were excluded from the other, they do not report reasons for exclusion by study group. For example, the authors report that 9 patients were 'excluded' due to early recovery (a good outcome), 7 were excluded due to death (a bad outcome) and 1 was excluded due to a massive GI bleed (also bad). A true intention to treat analysis would include all patients randomised, and could assume good 'values' for patients with known good outcomes and bad 'values' for patients with a known bad outcome. Note- On closer inspection, it appears that 108 patients were enrolled and randomised and 18 were excluded. An additional patient was considered 'withdrawn' from the study due to a contraindication to a study drug (Myasthenia gravis). Since this patient was enrolled and randomised, under the principle of ITT, this patient should have been withdrawn from treatment but not withdrawn from the study. This patient should have been considered as a 'poor' outcome in the primary analysis and their poor outcome should have been attributed to the group to which they were originally randomised.
2b. Were patients analyzed in the groups to which they were randomized?
	No. Due to 17% (18/108) of randomised patients being excluded from the primary analysis, and with a failure to report the groups to which each patient had originally been randomised to, it is difficult to claim that patients were analysed in the groups to which they were originally assigned.
3. Were patients, health workers, and study personnel blind to treatment?
	Although it is stated that both groups received QID dosing, it is not explicitly stated that the syringes were blinded. Erythromycin may have a slight red tint. Most syringes would not hide this red tint.
4. Were the groups similar at the start of the trial?
	Uncertain. Although Table 2 presents the baseline balance for the 90 patients reported in the analysis presented, Table 2 should have included baseline measures for all 108 randomised patients.
5. Aside from the experimental intervention, were the groups treated equally?
	Uncertain. I cannot find caloric intake or EN volumes reported by study day.
What are the Results?
1. How large was the treatment effect?
	Due to the high proportion of missing outcomes, the reported results should be interpreted with caution. The sample size calcuation for this study was based on finding a 20% reduction in the 'rate of successful feeding'. Therefore, the 'rate of successful feeding is the primary outcome. Authors claim the 'rate of successful feeding' was significantly higher for erythromycin on Day 1: 87% vs 63%, (p-value not reported by authors. P=0.01 calculated by Gord) On day 7, there was no significant difference: 31% vs 16%,(p-value not reported by authors. P=0.15 calculated by Gord) Note - the p-value reported by the authors as indicating 'more successful feeding at all time points' appears to be from a time-to-event analysis and thus simply represents a 'longer duration of successful feeding'. Erythromycin may provide a longer median time to failure of one day... however if this time-to-event analysis is indeed intended as the primary analysis there is no sound justification for excluding patients who failed to reach day 7. Time-to-event analysis was developed to allow the handling of patients who are 'censored'. In other words, a time-to-event analysis is able to use information form patients who do not complete the entire study.
2. How precise was the estimate of the treatment effect?
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	Uncertain at this time.
2. Were all clinically important outcomes considered?
	No. ICU based RCTS should consider it mandatory to report clinically meaningful outcomes (mortality, ICH LoS and Hospital LoS) on all patients. Even if the study is not powered to detect a difference in these outcomes, they are essential in supporting clinical decisions.
3. Are the likely treatment benefits worth the potential harms and costs?
	Unknown at this time.
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