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Journal of Parenteral and Enteral Nutrition
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Original Communications

Erythromycin vs Metoclopramide for Facilitating Gastric Emptying and Tolerance to Intragastric Nutrition in Critically Ill Patients

Robert MacLaren, PharmD, FCCM, FCCP1, Tyree H. Kiser, PharmD1, Douglas N. Fish, PharmD, FCCP, FCCM1 and Paul E. Wischmeyer, MD2

From the 1 Department of Clinical Pharmacy, School of Pharmacy, and the 2 Department of Anesthesiology, School of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado.

Address correspondence to: Robert MacLaren, PharmD, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, Academic Office 1, L15-1421, 12631 East 17th Avenue, PO Box 6511, Aurora, CO 80045; e-mail: rob.maclaren{at}uchsc.edu.

Background: The purpose of this study is to evaluate erythromycin vs metoclopramide for facilitating gastric emptying and tolerance to intragastric enteral nutrition (EN). Methods: Twenty critically ill patients with a gastric residual >150 mL while receiving EN were randomized to receive 4 intravenous doses of erythromycin 250 mg or metoclopramide 10 mg, each administered every 6 hours. Acetaminophen 975 mg was administered enterally at baseline and after the fourth dose. Acetaminophen peak plasma concentration (Cmax), concentration at 60 minutes (C60), time to Cmax (Tmax), and area under the concentration-time curve from 0 to 60 minutes (AUC0-60) were determined. Residual volumes and feeding rates were recorded. Results: Compared with baseline, erythromycin increased Cmax (9.5 ± 6.1 mg/L to 17.7 ± 11.9 mg/L, P < .01), C60 (5.4 ± 3.5 mg/L to 12.9 ± 7.6 mg/L, P < .01), and AUC0-60 (3.5 ± 3.0 mg·h/L to 12.5 ± 8.7 mg·h/L, P < .01), while metoclopramide increased only AUC0-60 (4.4 ± 2.8 mg·h/L to 9.5 ± 3.8 mg·hr/L, P < .05). Neither agent significantly reduced Tmax. Both erythromycin and metoclopramide reduced residual volumes (122 ± 48 mL to 36 ± 48 mL, P < .01, and 103 ± 88 mL to 21 ± 23 mL, P < .05, respectively) and allowed increased feeding rates (17 ± 23 mL/h to 45 ± 21 mL/h, P < .05, and 14 ± 17 mL/h to 44 ± 22 mL/h, P < .05, respectively). Conclusions: Both agents facilitate tolerance to intragastric EN, but erythromycin may be more effective than metoclopramide for enhancing gastric motility.

Key Words: erythromycin • metoclopramide • gastric motility • enteral nutrition • gastric residual • intensive care • critical illness

Initiating enteral nutrition (EN) soon after patients are admitted to the intensive care unit (ICU) reduces GI permeability, infectious complications, mortality, ICU or hospital length of stay, and cost compared with delayed initiation.1-4 Expert practice guidelines recommend, when feasible, initiating EN within the first 24 hours of ICU admission.5-8 Unfortunately, critically ill patients are frequently intolerant to intragastric EN as a result of GI motility dysfunction.9-15 The incidence of intolerance is 43%–63%, with the development of high gastric residual volumes (GRVs) accounting for 30%–51% of cases.16-25 Patients with intolerance are less likely to achieve goal caloric intake, stay longer in the ICU, and have higher mortality rates.16,17,25 In addition, aspiration may be associated with GI motility dysfunction26-29 and EN intolerance.5-8,25,27-31

Gastric emptying abnormalities associated with critical illness are multifactorial in origin but are related to gastric antrum dysfunction causing dyskinetic propagation of contractions through the duodenum.9-15 Many clinicians use GRV monitoring, along with an abdominal physical examination, to assess GI function.5-8,27-33 Current therapeutic options for managing elevated GRV are limited to altering the EN regimen, starting a prokinetic agent, switching EN administration from intragastric to postpyloric, or initiating parenteral nutrition. Of these options, treatment with a prokinetic agent is considered first-line therapy.5-8,10,11,27-36 Cohort studies demonstrate that approximately 22% of critically ill patients receive a prokinetic agent to facilitate EN.23,24 Erythromycin and metoclopramide are the most commonly used agents. Placebo-controlled studies have demonstrated these 2 prokinetic agents accelerate gastric motility in critically ill patients.37-46 Few studies have compared these 2 agents,47-49 and no study has used an objective measurement of gastric emptying to compare multiple doses of these 2 agents in patients with intolerance. The purpose of this study is to comparatively evaluate erythromycin and metoclopramide after multiple doses for promoting gastric emptying, as assessed by the acetaminophen absorption method,50,51 and facilitating tolerance to intragastric EN.


   Materials and Methods
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Materials and Methods
Results
 Discussion
 
Patients
The protocol was reviewed and approved by the Institutional Review Board of the University of Colorado at Denver and Health Sciences Center. Patients were enrolled from 1 of 3 ICUs (16-bed medical ICU, 16-bed surgical ICU, or 8-bed neurosurgical ICU). Written informed consent and Health Insurance Portability and Accountability Act authorization were obtained from each patient or next of kin.

Critically ill, mechanically ventilated patients between the ages of 18 and 85 years who were intolerant to continuous nasogastric or orogastric administration of EN were eligible for study enrollment. Intolerance was defined as a single aspirated GRV ≥150 mL unless this GRV was measured within 4 hours of enteral administration of contrast media, sterile water, or medications.52 Patients were required to have an 18-Fr large-diameter gastric tube in place over the study period.

Patients were ineligible for enrollment if any of the following were present: administration of erythromycin or metoclopramide within 24 hours of study eligibility; concurrent administration of medications that may interact with erythromycin, metoclopramide, or acetaminophen to potentially cause a severe adverse drug event; known anaphylactic reactions or other severe adverse events to erythromycin, metoclopramide, or acetaminophen; GI hemorrhage or bowel surgery within 24 hours of eligibility; malabsorptive GI disease (obstruction, perforation, short-bowel syndrome, or Crohn's disease); abnormal liver function as defined by liver transplantation or the presence of 2 of the following: transaminases ≥3 times the upper limit of normal, prothrombin time ≥2 times the upper limit of normal, or total bilirubin ≥3 times the upper limit of normal; renal dysfunction requiring active renal replacement therapy; hemodynamic instability defined by a mean arterial pressure <65 mm Hg despite fluid resuscitation and the administration of IV infusions of dopamine >10 µg/kg/min, norepinephrine, epinephrine, or phenylephrine; blood depletion within 12 hours of study eligibility defined by the presence of a hemoglobin count <6.5 g/dL or hematocrit <0.22 and not replaced with packed red blood cells; pregnant women or women suspected of being pregnant; or severe obesity defined by actual body weight ≥150% of ideal body weight.

Study Design
As outlined by an institution-specific EN administration protocol that existed prior to initiating this study, EN is started as early as possible in critically ill patients based on physician discretion and after consultation with an ICU dietitian. The protocol starts gastric EN at a rate of 20 mL/h, with increases of 20 mL/h every 8 hours until the goal rate is achieved. GRVs are assessed every 4 hours. The protocol stipulates that EN be discontinued for 4 hours after the development of intolerance and then restarted at half the previous rate, increased by 10 mL/h every 8 hours as tolerated. Volumes <150 mL are returned, and half the volume is returned for GRVs ≥150 mL.

Consenting patients were randomized by a random numbers table to receive either erythromycin 250 mg infused over 30 minutes or metoclopramide 10 mg by IV bolus, each administered every 6 hours for a total of 4 doses. The study was not blinded. The time of administration was recorded.

Prior to enrollment, correct antral positioning of the gastric feeding tube was determined radiographically. This was confirmed twice daily by auscultating over the stomach after injecting air through the 18-Fr large-diameter gastric tube. If possible, intragastric EN support was continued during the course of study drug administration. The decision to begin parenteral nutrition support was determined by the attending physician or nutritionist. The bedside nurse measured aspirated GRV before each prokinetic dose using the aspiration-by-syringe technique through the 18-Fr large-diameter gastric tube. GRVs were not returned for assessments done immediately prior to acetaminophen administration. Otherwise, GRVs <150 mL were returned, and half the volume was returned for GRVs ≥150 mL.

Acute Physiology and Chronic Health Evaluation (APACHE) III score was assessed for the 24-hour periods before enrollment and after study completion. The use of agents (dopamine, opioids, cathartics) affecting gastric motility were recorded but not controlled for by the study protocol. Bowel movements were recorded.

Laboratory Procedures
The acetaminophen absorption method was used to assess gastric emptying function. Studies in critically ill patients have demonstrated that acetaminophen absorption (plasma concentration at 60 minutes [C60] and area under the plasma concentration-time curve from 0 to 60 minutes [AUC0-60]) correlate significantly with gastric emptying.50,51 Both peak plasma concentration (Cmax) and time to peak concentration (Tmax) have been validated as markers of gastric emptying and showed gastric motility dysfunction at baseline with enhanced emptying after prokinetic therapy.37-42,47,53,54 Six hours before the first dose of prokinetic agent (baseline) and 30 minutes after the fourth dose was finished being administered, patients received 975 mg of enteral acetaminophen as 30 mL of undiluted syrup (32.5 mg/mL) followed by 20 mL of sterile water to flush the 18-Fr gastric tube (the tube was not flushed prior to acetaminophen administration). The exact time of administration was recorded by the bedside nurse and verified by a study investigator. Gastric contents were emptied and discarded immediately prior to acetaminophen administration, and EN was temporarily discontinued during blood collection. Venous blood samples of 3 mL in volume were obtained from an indwelling catheter by a study investigator immediately prior to and 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after acetaminophen administration. Blood samples were collected in test tubes without heparin and transported on ice. Plasma was separated by centrifugation for 15 minutes at 3000 rpm. Plasma samples were placed in labeled polyethylene vials, frozen at –80°C immediately after processing, and kept frozen until assay. Acetaminophen concentrations were determined in duplicate by a fluorescence polarization assay (TDxFLx; Abbott Diagnostics, Chicago, IL) as described elsewhere47 and the mean concentration at each time point used for pharmacokinetic analysis. Noncompartmental analysis of acetaminophen concentrations with WinNonlin version 5.0.1 (Pharsight Corporation, Mountain View, CA) was used to determine Cmax, C60, Tmax, the area under the concentration-time curve from 0 to 360 minutes (AUC0-360), and AUC0-60.

Statistical Analyses
For a power of 0.8 and a significance level of .05, 8 patients were required in each prokinetic group to show a difference of 5 mg/L in C60, assuming standard deviations of 3.5 mg/L.53 A previous randomized, crossover study of single doses of erythromycin and metoclopramide showed erratic acetaminophen absorption for 2 (20%) of 10 patients.47 Therefore, 10 patients were enrolled into each prokinetic group. All statistical analyses used SAS (version 9.1; SAS Institute, Cary, NC). Statistical analysis of pharmacokinetic parameters, volume of gastric residuals, volume of EN, and APACHE III score between study groups used the t test or Mann-Whitney U test for parametric data and nonparametric data, respectively. Statistical analysis of pharmacokinetic parameters and APACHE III score for each study group compared with baseline used the Wilcoxon matched pair test. Reductions in GRV over time and increased feeding rates over time were analyzed using Friedman's repeated-measures ANOVA of ranks using Dunn's test for comparison with baseline GRVs and feeding rates. Statistical significance was defined as P < .05. All data are reported as mean ± standard deviation unless stated otherwise.


   Results
Top
Materials and Methods
 Results
Discussion
 
A total of 20 patients were enrolled, 10 in each group. All patients were included in the final analysis. Study groups were similar with respect to patient demographics (Table 1), clinical characteristics (Table 1), and nutrition-related variables (Table 2). All patients had the head of the bed elevated >30°. One patient in the metoclopramide group received concurrent parenteral nutrition. For each group, baseline APACHE III scores were similar to APACHE III scores at study completion (Table 1). All patients had an aspirated GRV ≥150 mL at the time of eligibility (Table 2); 6 patients had GRVs ≥250 mL. Seventeen patients also had at least 1 GRV >100 mL in the 24 hours preceding enrollment.


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  		Table 1. Patient Demographics and Clinical Characteristics (n = 10/group)

 

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  		Table 2. Nutrition-Related Variables

 

Baseline acetaminophen pharmacokinetic parameters were highly variable but similar between groups (Table 3). Compared with baseline values, erythromycin significantly increased Cmax, C60, AUC0-360, and AUC0-60, whereas metoclopramide increased only AUC0-60. Both agents reduced Tmax by approximately 50%, although neither was statistically significant. Once adjusted for absorption rates, no differences existed between groups or within groups for any other pharmacokinetic parameter, including elimination rates.


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  		Table 3. Pharmacokinetic Variables

 

Compared with baseline, both agents significantly reduced aspirated GRV (Table 4). The maximum feeding rates achieved during the study period were similar (Table 4). EN feeding rates were significantly increased in both groups (Table 4), and goal feeding rates were achieved in 4 (40%) erythromycin patients and 3 (30%) metoclopramide patients over the 4-dose study regimen. Failure of therapy over time was not observed in any patient. During the study period, 7 (70%) patients receiving erythromycin and 4 patients receiving metoclopramide had bowel movements. Three erythromycin patients and 1 metoclopramide patient had diarrhea. No serious adverse events were observed during the study period. One erythromycin patient developed elevated transaminases of 4- to 5-fold the upper limit of normal within 24–48 hours after the study was completed. These levels resolved over the course of the ICU stay.


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  		Table 4. Aspirated Gastric Residual Volumes (GRV) and Feeding Rates During Study Period

 


   Discussion
Top
Materials and Methods
 Results
 Discussion
 
The most important results of this study are that only erythromycin consistently demonstrated enhanced gastric emptying using the acetaminophen absorption method, but both erythromycin and metoclopramide facilitated tolerance to intragastric EN. Both agents increased AUC0-60 from baseline, but only erythromycin enhanced Cmax, C60, and AUC0-360. While not statistically significant, both agents shortened Tmax by similar lengths of time. Therefore, both agents increased the extent of absorption to increase AUC0-60, but only erythromycin expedited the rate of absorption to increase C60 and Cmax over baseline. Of note, metoclopramide was associated with increased C60 and Cmax values, but the magnitude of change from baseline was less than that of erythromycin, resulting in statistically insignificant results. Seventeen study patients would be needed in the metoclopramide group to show a difference in C60 from baseline given the amount of change and variation found after 10 subjects were enrolled in this study. Of clinical importance is that GRV decreased over the study duration, the extent of reduction similar between agents. Concurrently, EN feeding rates increased with no differences between erythromycin and metoclopramide.

While several placebo-controlled studies have demonstrated that both erythromycin and metoclopramide accelerate gastric motility in critically patients,37-46 only 3 of these studies enrolled patients with EN intolerance.38,45,46 Two studies investigated IV erythromycin (either 250 mg every 6 hours administered indefinitely or a single dose of 200 mg), and 1 study investigated IV metoclopramide (10 mg every 6 hours for 36 hours). Both studies of erythromycin found that GRVs were reduced and EN feeding rates increased when compared with placebo. The metoclopramide study did not demonstrate significant changes. Neither erythromycin study objectively measured gastric emptying, whereas metoclopramide showed a trend toward increased AUC0-60 using the acetaminophen absorption method.

To our knowledge, our study is only the second multiple-dose evaluation directly comparing erythromycin and metoclopramide for the treatment of intolerance to intragastric EN.48 Nguyen et al48 conducted a randomized study of erythromycin 200 mg administered intravenously twice daily and metoclopramide 10 mg administered intravenously 4 times daily in 90 patients with GRVs exceeding 250 mL and found that treatment with erythromycin reduced GRVs and resulted in more patients successfully fed. The same investigators showed that combination therapy with erythromycin and metoclopramide significantly reduced GRVs and facilitated caloric intake compared with erythromycin alone.49 Neither study, however, objectively assessed gastric emptying. While our study is limited by the small number of subjects, our gastric emptying results corroborate their clinical findings and the results of placebo-controlled studies to suggest that erythromycin is more effective than metoclopramide as a prokinetic agent in critically ill patients with intolerance to intragastric EN.

Unequal efficacies of erythromycin and metoclopramide may be expected since these agents act differently. Erythromycin enhances motilin to facilitate contractility in the gastric antrum and duodenum, whereas metoclopramide acts as a selective dopamine2 antagonist and enhances peristaltic contractility of the esophagus, gastric antrum, duodenum, and jejunum.15,27 The etiology of motility irregularities in the critically ill may be related to alterations of the interstitial cells of Cajal, which are concentrated in the gastric antrum and act as the pacemaker of GI motility or disturbances of the migrating motor complex (MMC) from abnormal vagal and hormonal innervations.9-15,28 Whether these agents have different activities on the interstitial cells of Cajal located in the gastric antrum or on the neurohormonal innervations of the MMC has not been studied.

An interesting finding by Nguyen et al48 was that therapy failure to both agents, defined as the return of elevated gastric residual volumes resulting in unsuccessful feeding, seemed to develop over a course of 7 days. Tolerance to either agent was not apparent in our study, but the short study duration may have prevented this observation. The duration of our study was based on the number of doses that were anticipated as needed to demonstrate improved gastric emptying as evidenced by residual volumes.47 The length of therapy with a prokinetic agent varies based on the clinical scenario, but it is reasonable to attempt discontinuation once the EN feeding rate has been maintained at goal for 24–48 hours.28 Therefore, most patients should require therapy for only 3–5 days rather than the 7 days that was studied by Nguyen et al. Of note, the volume of residual needed for eligibility was 100 mL less in our study and the daily erythromycin dose used was 2.5-fold greater than that used by Nguyen et al. While not studied, some recommendations suggest that metoclopramide at a dose of 20 mg is more effective than 10 mg, and dose escalation may be attempted when patients remain intolerant to EN at lower doses.10,11,27-33 Whether multiple higher doses of either agent are more effective or reduce the likelihood of tolerance is unknown, but a single IV dose of erythromycin 70 mg is equally as effective as 200 mg at accelerating gastric emptying in critically ill patients.44 Also, if higher volumes of gastric residuals are refractory to treatment, it seems reasonable to initiate therapy with a prokinetic agent when volumes are moderately elevated (eg, 150-200 mL) rather than excessively elevated (eg, ≥250 mL). We chose ≥150 mL to define intolerance because we have demonstrated that this volume is associated with delayed gastric emptying compared with ICU patients with minimal GRVs.52 Additional studies are needed to investigate the GRV that defines intolerance and requires treatment.

Enteral dosing of these agents is easier to administer and minimizes cost. However, both erythromycin and metoclopramide require systemic absorption to be active, so it is plausible that the activity of these agents, when administered by the enteral route, is hampered by impaired gastric emptying. IV administration of erythromycin has been shown to be more effective than enteral administration in patients with diabetic gastroparesis.47 Two studies have investigated enteral administration of prokinetic agents in critically ill patients with evidence of EN intolerance.47,53 A randomized, crossover study of single doses found metoclopramide to be more effective than erythromycin at enhancing gastric emptying.47 A double-blind, randomized study of 7 doses found that metoclopramide was more effective than cisapride at enhancing gastric emptying and facilitating tolerance to EN.53 Therefore, erythromycin should be administered intravenously, whereas metoclopramide appears to be effective when administered enterally or intravenously. Further evaluations of these pharmacodynamic differences, and their potential cost implications, are warranted.

Similar to the results of other studies, we found that both agents reduced GRV compared with baseline, and feeding rates were concurrently increased.37-48 Maximum feeding rates achieved were similar with erythromycin and metoclopramide. This suggests that nutrition-related outcomes are similar despite experimental differences of gastric empting between the 2 groups. Explanations for this discrepancy include the use of a protocol to guide EN administration, the lack of clinical correlation between GRV and gastric emptying function, and too few subjects in our study to demonstrate clinical differences. Our EN protocol advances the feeding rate provided that GRVs are maintained at <150 mL. Therefore, similar maximum feeding rates are expected as long as GRVs are relatively low. The variability associated with assessing GRVs and the many factors that may influence gastric emptying has created a clinical controversy regarding the validity of using GRVs for assessing gastric emptying.5-8,27-33 Several studies have found no associations between GRVs of 50–150 mL and experimental methods of assessing gastric emptying.28,29 In contrast, several studies demonstrate that GRVs of 150–200 mL are indicative of gastric emptying dysfunction and may even represent a risk factor for aspiration.25,55,56 Therefore, until proven otherwise, residual volumes of 150–200 mL should be used to define intolerance.

In summary, this study demonstrates that erythromycin is effective for accelerating gastric emptying in patients with intragastric EN intolerance and that both erythromycin and metoclopramide facilitate feeding with intragastric EN when GRVs exceed 150 mL. Additional studies are needed to confirm our results with delineation of clinical outcomes and investigation of pharmacologic, pharmacodynamic, and cost differences. In addition, studies are needed to define the relationship between GRV and aspiration and the use of prokinetic agents to reduce the occurrence of aspiration.57 In addition, concerns of enhancing the emergence of macrolide resistance, particularly with respect to the Streptococcus species, when erythromycin is used as prokinetic therapy need to be evaluated.58,59 Of note, Clostridium difficile–induced diarrhea does not appear to be associated with erythromycin prokinetic therapy.60

The results were presented as a poster at the Society of Critical Care Medicine 37th Critical Care Congress in Honolulu, Hawaii, in February 2008. The authors would like to thank James Landzinski and Phillip Owen for their help with subject identification and blood collection.


  
Top
Materials and Methods
 Results
 Discussion
 
Financial disclosure: This study was supported by a grant provided by the American Association of Colleges of Pharmacy. The authors do not have any financial interests (eg, employment, consultancies, stock ownership, honoraria, expert testimony) in the materials or subject matter dealt with in this article.

Received for publication October 5, 2007. Accepted for publication March 3, 2008.

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Journal of Parenteral and Enteral Nutrition, Vol. 32, No. 4, 412-419 (2008)
DOI: 10.1177/0148607108319803
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