A multicenter, randomized, double-blind study of ulimorelin and metoclopramide in the treatment of critically ill patients with enteral feeding intolerance: PROMOTE trial

Abstract

Purpose: Enteral feeding intolerance (EFI) is a frequent problem in the intensive care unit (ICU), but current prokinetic agents have uncertain efficacy and safety profiles. The current study compared the efficacy and safety of ulimorelin, a ghrelin agonist, with metoclopramide in the treatment of EFI.

Methods: One hundred twenty ICU patients were randomized 1:1 to ulimorelin or metoclopramide for 5 days. EFI was diagnosed by a gastric residual volume (GRV) ≥ 500 ml. A volume-based feeding protocol was employed, and enteral formulas were standardized. The primary end point was the percentage daily protein prescription (%DPP) received by patients over 5 days of treatment. Secondary end points included feeding success, defined as 80% DPP; gastric emptying, assessed by paracetamol absorption; incidences of recurrent intolerance (GRV ≥ 500 ml); vomiting or regurgitation; aspiration, defined by positive tracheal aspirates for pepsin; and pulmonary infection.

Results: One hundred twenty patients were randomized and received the study drug (ulimorelin 62, metoclopramide 58). Mean APACHE II and SOFA scores were 21.6 and 8.6, and 63.3% of patients had medical reasons for ICU admission. Ulimorelin and metoclopramide resulted in comparable %DPPs over 5 days of treatment (median [Q1, Q3]: 82.9% [38.4%, 100.2%] and 82.3% [65.6%, 100.2%], respectively, p = 0.49). Five-day rates of feeding success were 67.7% and 70.6% when terminations unrelated to feeding were excluded, and there were no differences in any secondary outcomes or adverse events between the two groups.

Conclusions: Both prokinetic agents achieved similar rates of feeding success, and no safety differences between the two treatment groups were observed.

Keywords: Enteral feeding intolerance; Gastric residual volume; Metoclopramide; PROMOTE; Ulimorelin; Volume-based feeding.

Fig. 1

Primary end point of the trial, the % daily protein prescription achieved through enteral nutrition on days 1 through 5 and on individual study days. The results are expressed as median [1st quartile, 3rd quartile]. High median %DPP rates are noted on each of the study days commencing with day 1. Median percentages for days 1–5 and the totals for the 5 days include all patients dosed (ulimorelin 62, metoclopramide 58), imputing values for patients with missing data, as discussed in “Methods.” No significant differences were noted between treatment groups over the 5 days of study drug administration or any of the study days (Wilcoxon signed rank test). The shaded area represents ≥ 80% DPP achieved

Fig. 2

Rates of a feeding success, b episodes of recurrent EFI (GRV ≥ 500 ml), c vomiting or regurgitation and d a positive tracheal aspirate for pepsin on each of the study days, days 1–5, and over the 5 days of the study. Totals, days 1–5, represent the percentages of patients who achieved feeding success over the 5 study days or the total numbers of patients who experienced one or more episodes of EFI recurrence, vomiting or regurgitation, or a positive tracheal aspirate for pepsin on any of the 5 study days, as the percentage of patients dosed. The proportions on individual days are expressed as the percentages of subjects remaining in the trial each day [n = 62, 58, 52, 49 and 38 (ulimorelin) and 58, 56, 53, 51 and 46 (metoclopramide), days 1 through 5, respectively]. None of the differences between treatment groups were statistically significant (chi-squared test). While the daily proportions of patients with feeding success increased, in part because of the declining number of patients remaining in the trial, daily declines are evident in the percentages of patients who experienced EFI recurrence or a positive tracheal aspirate for pepsin