Erythromycin for Promoting the Postpyloric Placement of Feeding Tubes: A Systematic Review and Meta-Analysis

Critically ill patients can benefit from enteral nutrition with postpyloric feeding tubes, but the low success rate limits its wide use. Erythromycin could elevate the success rate of tube insertion, but its clinical efficiency still remains controversial.  Included studies must be RCTs which assessed the success rate of postpyloric feeding tube insertion using erythromycin.  284 patients were enrolled in six studies. Meta-analysis showed that erythromycin significantly increases the rate of successful postpyloric feeding tube placement (RR 1.45, 95% CI (1.12, 1.86)) and did not increase the risk of adverse effects (RR 2.15, 95% CI (0.20, 22.82)). Subgroup analysis showed that unweighted feeding tubes (RR 1.47, 95% CI (1.03, 2.11)) could significantly increase the success rate. Country of study, intravenous route of erythromycin, and year of participant enrollment did not influence these results.  Erythromycin significantly increases the success rate of postpyloric feeding tube placement. This suggests that erythromycin can be used as an auxiliary method to improve the success rate of bedside insertion.

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title: Gastrointestinal dysmotility: evidence and clinical management
abstract: Purpose of reviewGastrointestinal dysmotility and dysfunction underlie our difficulties in providing adequate nutrition by the enteral route to our critically ill patients. Recent findingsRecent studies have quantified gastric emptying and nutrient absorption. Slow gastric emptying is common and probably mediated by cholecystokinin and reduced active ghrelin concentrations. The cause of impaired nutrient absorption is not yet fully understood but may be related to small intestinal blood flow and/or mucosal factors. The absorption of the different macronutrients may be affected in different ways both by critical illness and by therapies. A better understanding of this may optimize the design of nutrient formulations in the future. New treatment modalities for gastrointestinal dysfunction are being investigated and include small intestinal feeding, nonpharmacological options such as acupuncture, and drugs including novel motilin receptor agonists, and opioid antagonists. SummaryWe are gradually developing a better understanding of how the gut works during critical illness, which has implications for optimizing the delivery of nutrition and thereby improving nutritional and clinical outcomes.

title: Enteral nutrition-related gastrointestinal complications in critically ill patients: a multicenter study. The Nutritional and Metabolic Working Group of the Spanish Society of Intensive Care Medicine and Coronary Units.
abstract: To evaluate the frequency of gastrointestinal complications (GICs) in a prospective cohort of critically ill patients receiving enteral nutrition and to assess its effect on nutrient administration and its relationship to the patient's outcome.



Multicenter, prospective cohort study.



Thirty-seven multidisciplinary intensive care units (ICUs) in Spain.



Prospective cohort of 400 consecutive patients admitted to the ICU and receiving enteral nutrition.



Noninterventional, follow-up study.



Enteral nutrition-related GICs and their management were defined by consensus before data collection. A set of variables related to enteral nutrition administration and the presence of GICs was recorded. During the 1-month study period, 400 patients were enrolled, and a total of 3,778 enteral feeding days were analyzed. The mean time of enteral nutrition was 9.6+/-0.4 days. Mean elapsed time from ICU admission to the start of enteral feeding was 3.1+/-0.2 days. A total of 265 patients (66.2%) received a standard polymeric formula, and 132 (33.8%) received a disease-specific one. Enteral feeds were administered mainly through a nasogastric tube (91%). One or more GICs were presented by 251 patients (62.8%) during the feeding course. The frequency of each particular GIC was as follows: high gastric residuals, 39%; constipation, 15.7%; diarrhea, 14.7%; abdominal distention, 13.2%; vomiting, 12.2%; and regurgitation, 5.5%. Enteral nutrition withdrawal as a consequence of noncontrollable GICs occurred in 15.2% of patients. The volume ratio (expressed as the ratio between administered and prescribed volumes) was calculated daily and was used as an index of diet administration efficacy. Patients with GICs had a lower volume ratio than did patients without GICs (63.1+/-1.20% vs. 93.3+/-0.3%) (p < .001), a longer length of stay (20.6+/-1.2 vs. 15.2+/-1.3 days) (p < .01), and higher mortality (31% vs. 16.1%) (p < .001).



The frequency of enteral nutrition-related GICs in critically ill patients is high. High gastric residuals is the most frequent GIC. These complications decreased nutrient intake and, if persistent, could expose the patients to undernutrition. Enteral feeding gastrointestinal intolerance seems to have an evolutive effect in prolonging the ICU stay and increasing patient mortality.

title: Clinical costs of feeding tube placement.
abstract: Although small-bore tube placement is common, insertion can lead to serious complications. We investigated the use of radiographs, fluoroscopy, feeding tubes, and complications associated with blind feeding-tube placement.



The electronic and paper records of adult patients receiving a small-bore feeding tube in 2005 were retrospectively reviewed for the following variables: demographics, desired location (gastric or postpyloric), number of radiographs, number of tubes per individual, time interval between medical prescription, tube placement and delivery of the diet, complications, transport for fluoroscopy, and hospital location of placement (intensive care unit vs floor).



We identified 1822 tubes placed into 729 patients (male: 449, 61.6%; female: 280, 38.4%; median age: 59 years old, range 18-98). All tubes were placed by nurses unless fluoroscopically placed in radiology or placed after head and neck surgery in the operating room. An average of 2.5 (range 1-20) tubes was used per patient. A total of 2696 radiographs were obtained for an average of 3.7 (range 0-32) films per patient and 1.5 (range 0-11) per feeding tube. Successful placement was higher for intragastric (93.3%) than for postpyloric position (60.4%; p < .001). Fluoroscopy was needed in 18.6% of the patients, mostly for postpyloric insertion (p < .001). Respiratory tree misplacement occurred in 23 (3.2%) patients; 9 (1.2%) had a pneumothorax and 4 (0.5%) died. Patients with a malpositioned feeding tube underwent more tube insertions (6.8 +/- 5.4; range 2-20) than patients without complications (2.2 +/- 1.8; range 1-18; p < .001).



The incidence of airway misplacement of feeding tubes (3.2%) at a major tertiary referral university hospital was alarming. Mandatory radiographs may eliminate the risk of respiratory administration of feedings but not misplacements. The associated costs of radiographs, unsuccessful placements, fluoroscopy, and complications are significant. A solution to this problem will require focused attention and development of specific protocols, possibly using new technologies.

title: Prokinetics in gastroparesis.
abstract: Prokinetic agents are medications that enhance coordinated gastrointestinal motility and transit of content in the gastrointestinal tract, mainly by amplifying and coordinating the gastrointestinal muscular contractions. In addition to dietary therapy, prokinetic therapy should be considered as a means to improve gastric emptying and symptoms of gastroparesis, balancing benefits and risks of treatment. In the United States, metoclopramide remains the first-line prokinetic therapy, because it is the only approved medication for gastroparesis. Newer agents are being developed for the management of gastroparesis. This article provides detailed information about prokinetic agents for the treatment of gastroparesis.

title: Erythromycin facilitates postpyloric placement of nasoduodenal feeding tubes in intensive care unit patients: randomized, double-blinded, placebo-controlled trial.
abstract: To determine whether administration of erythromycin (E) could facilitate passage of a nasoenteric feeding tube into the duodenum for postpyloric feedings, this randomized, double-blind, placebo-controlled trial was performed.



Fifty-seven patients were accrued from the surgical intensive care units (ICUs) of a tertiary-care university hospital. Patients enrolled were categorized as to the presence or absence of diabetes mellitus (DM). Those patients without DM were then subdivided into those with normal or depressed mental status. The three groups, normal (NMS), depressed mental status (DMS), or diabetes mellitus (DM), were then randomized independently to receive either E or placebo (P), followed by blind placement of a feeding tube. Tube placement was verified by an abdominal radiograph.



Overall, the rate of postpyloric placement was 61% (19/31) in the E group, significantly better than 35% (9/26) in the P group (p < .05). In patients with NMS, the success rate with E was improved (64%, 9/14) compared with that with P (9%, 1/11) (p < .0005). In the DMS group, there was a 50% success rate (6/12) with E versus 63% (5/8) with P (not significant [NS]). In the DM group, 80% (4/5) of the patients had placement of the tube in the duodenum with E and 43% (3/7) with P (NS).



These data suggest that, overall, E is effective in facilitating placement of a nasoenteric feeding tube into the duodenum in ICU patients. It is clearly beneficial in those patients with normal mental status and may be useful in patients with diabetes mellitus.

title: Motility agents for the placement of weighted and unweighted feeding tubes in critically ill patients
abstract: ObjectiveTo determine if successful attempts at feeding tube placement into the small bowel could be increased with the use of a weighted end or by pre-treatment with a drug to increase gastric motility. prospective randomized control study, double blinded for a drug study drug, in a population of critically ill patients.SettingA 635-bed acute care hospital in Philadelphia, PatientsEighty-three patients in the critical care setting randomized into four groups receiving either parenteral normal saline (NS) 100 cc, erythromycin (EMY) 200 mg, or metoclopramide (MET), 10 mg, 30 min prior to attempted tube placement with either a weighted (WEI) (57 patients) or unweighted tube (UNW) (26 patients).ResultsWhen analyzed for number of attempts prior to successful tube placement into the stomach there was a signficant difference between the unweighted and weighted groups: 2.08±1.03 attempts vs 1.51±0.94,P≤0.015. Duodenal migration at 24 h was demonstrated in three patients in the NS/UNW group and in two patients in the NS/WEI group as compared to no patients in either the EMY/WEI or the MET/WEI groups (p≤0.025, Fisher's exact test).ConclusionsThese data demonstrate that the use of weighted feeding tubes decreases the number of attempts required to achieve gastric intubation, but that motility agents given prior to tube insertion do not augment advancement of the feeding tube beyond the stomach and may in fact hinder placement into the duodenum.

title: Intravenous erythromycin facilitates bedside placement of postpyloric feeding tubes in critically ill adults: A double-blind, randomized, placebo-controlled study*
abstract: ObjectiveTo evaluate the efficacy of intravenous erythromycin as a method to facilitate feeding tube placement into the small intestine in critically ill patients. DesignDouble blind, randomized, controlled trial. SettingMedical and surgical intensive care units in an academic medical center. PatientsProspective cohort of 36 consecutive adults requiring intensive care unit care and enteral tube feeding for nutritional support. InterventionInfusion of a single dose of intravenous erythromycin (500 mg) or saline before placement of 10-Fr feeding tubes using a standardized active bedside protocol. Measurements and Main ResultsWe determined the success rate of feeding tube placement into or beyond the second portion of the duodenum and the time required for this procedure by experienced nurses. The feeding tube was considered to be postpyloric when the tip was in the second portion of the duodenum or beyond. The predictive value of a serial step-up in gastrointestinal aspirate pH from ≤5.0 to ≥6.0 was also determined. Use of intravenous erythromycin significantly improved the rate of feeding tube placement into the duodenum or jejunum (erythromycin group, 13 of 14 patients or 93% vs. the control group, 12 of 22 patients or 55%;p < .03). Erythromycin administration also significantly decreased the procedure time from 25 ± 3 to 15 ± 2 mins (p < .04). Feeding tube placement into either duodenum or jejunum was confirmed in all 18 patients with a pH step-up from ≤5.0 to ≥6.0. ConclusionA single bolus dose of intravenous erythromycin facilitates active bedside placement of postpyloric feeding tubes in critically ill adult patients.

title: Erythromycin to promote bedside placement of a self-propelled nasojejunal feeding tube in non-critically ill patients having pancreatitis: a randomized, double-blind, placebo-controlled study.
abstract: Postpyloric enteral feeding often requires endoscopic or fluoroscopic placement of a feeding tube. Self-propelled feeding tubes are designed to facilitate spontaneous migration into the jejunum. This study aimed to assess the rate of success and time to migrate a self-propelled feeding tube to jejunal position using erythromycin, a prokinetic agent.



Non-critically ill patients with pancreatitis who required jejunal enteral feeding were included. A self-propelled nasoenteric feeding tube was placed into the stomach using either placebo or erythromycin. At 24 and 48 hours after initial placement, an abdominal x-ray was taken to determine the position of the tube.



Forty subjects were included and randomized. After 48 hours, there was no difference in the rates of success between placebo 56% (9/16) and erythromycin 50% (10/20) (P = .71).



Self-propelled feeding tubes migrated into the jejunum in 53% of the subjects within 48 hours. However, this study failed to determine any benefit of erythromycin in terms of success or time to migrate to jejunal position using a self-propelled feeding tube. Selection of subjects without impaired motility and tachyphylaxis may have contributed to clinical failure of erythromycin as a prokinetic agent in this study.

title: Erythromycin and metoclopramide improves the success rate of post-pyloric placement of the spiral distal end nasal-enteral feeding tubes.
abstract: To determine whether intravenous infusion of erythromycin or metoclopramide can improve the success rate of post-pyloric placement of the spiral distal end nasal-enteral feeding tubes in critically ill patients. One hundred and twenty critically ill patients were randomly divided into 3 groups.250 mg erythromycin and 10 mg of metoclopramide were given intravenously to patients in the erythromycin group and metoclopramide group before tube insertion respectively,and the dosages were repeated after 12 hours,while no gastrointestinal prokinetic agent was given to other patients as control group.24 hours later,an abdominal radiography was obtained at the bedside to locate the position of the feeding tube. The success rate of tube placement was 74.3%(29/39)in the erythromycin group,and 71.8%(28/39)in the metoclopramide group,both significantly higher than that 42.8%(18/42)in the control group(P0.05).Conclusion Intravenous infusion of erythromycin or metoclopramide can improve the success rate of post-pyloric placement of the spiral distal end nasal-enteral feeding tubes in critically ill patients.

title: Efficacy of erythromycin for postpyloric placement of feeding tubes in critically ill children: a randomized, double-blind, placebo controlled study.
abstract: Erythromycin enhances gastric emptying and has been suggested to facilitate nasoenteric feeding tube placement in adults. Our primary objective was to evaluate the effect of erythromycin on the transpyloric passage of feeding tubes in critically ill children, and second, to evaluate the effect of erythromycin on the distal migration of duodenal feeding tubes.



Seventy-four children were randomly assigned to receive erythromycin lactobionate (10 mg/kg) IV or equal volume of saline placebo 60 minutes before passage of a flexible weighted tip feeding tube. Abdominal radiographs were obtained 4 hours later to assess tube placement. If the tube was proximal to the third part of the duodenum, two additional doses of erythromycin/placebo were administered 6 hours apart. Those receiving additional doses had repeat radiographs 14 to 18 hours after tube placement.



The number of postpyloric feeding tubes was similar in the erythromycin and placebo treated groups 4 hours after tube insertion (23/37 vs 27/37, p = .5). Of those with prepyloric tubes at 4 hours, none in the erythromycin group and 3 in the placebo group had the tube migrate to the postpyloric position by 14 to 18 hours (p < .05). Of those with postpyloric tubes proximal to the third part of the duodenum at 4 hours, additional doses of erythromycin did not cause more tubes to advance further into the intestine than did placebo (p = .6).



Erythromycin does not facilitate transpyloric passage of feeding tubes in critically ill children. The distal migration of duodenal tubes further into the small bowel is also not enhanced by erythromycin.

title: Erythromycin as a prokinetic agent: a prospective, randomized, controlled study of efficacy in nasoenteric tube placement.
abstract: Erythromycin, a macrolide antibiotic, has been shown to mimic the effects of the polypeptide motilin in the gastrointestinal tract. To determine whether erythromycin ethylsuccinate elixir would facilitate the transpyloric passage of a standard nasoenteric feeding tube once the tube was placed into the stomach, 20 patients were randomized to receive erythromycin or standard therapy.



Twenty patients (ages 45-78), mean age 63 yr, all male, had 43-inch nasoenteric tubes placed and were randomized to receive erythromycin ethylsuccinate elixir (400 mg/5 ml per os every 8 h for three doses) through the feeding tube or to receive standard therapy that involved no drug intervention.



Three placements resulted in immediate transpyloric passage. This represented 3/21 (14%) with immediate passage. One patient dropped out after initial tube placement. The remaining 17 patients had initial tube placement in the stomach; of these, eight were randomized to receive erythromycin and nine to receive standard therapy. Six of the eight nasoenteric tubes in the erythromycin group achieved transpyloric passage in 1 day. Zero of the nine nasoenteric tubes in the standard therapy group achieved transpyloric passage in 1 day (p = 0.0023, Fisher's exact test).



This study demonstrates that erythromycin ethylsuccinate elixir improves the success of transpyloric feeding tube passage in 1 day and is superior to the standard therapy, which consists of no drug intervention.

title: Bedside placement of nasojejunal tubes: a randomised-controlled trial of spiral- vs straight-ended tubes.
abstract: The success rate of unguided nasojejunal feeding tube insertion is low, thus often requiring endoscopic or radiological assistance. The spiral end of the Bengmark nasojejunal tube is supposed to aid post-pyloric placement, but no comparative trial has been performed.



Patients requiring nasojejunal feeding were randomised to have either Medicina (straight) or Bengmark (spiral) nasojejunal tube placed after stratification into those with normal gastric emptying or clinical evidence of delayed gastric emptying. Nasojejunal tubes were placed at the bedside in a standard fashion without radiological guidance by the same person for pre- and/or post-operative feeding. Bolus intravenous metaclopromide (10mg) was given prior to insertion in the abnormal gastric emptying group. Abdominal radiographs were obtained at 4 and 24h, and the primary end-point was jejunal placement at 24h.



Forty-seven patients were randomised of which 17 (11 straight, 6 spiral) could not tolerate the nasojejunal tube. Of the 30 remaining patients, 16 had normal gastric emptying. In patients with normal gastric emptying, successful placement at 24h was achieved in 78% (spiral tube), vs 14% (straight tube) (P=0.041). In the abnormal gastric emptying group, success rates were 57% and 0%, respectively (P=0.07).



Spiral nasojejunal tubes are preferable to straight tubes for bedside unguided post-pyloric feeding in patients with normal gastric emptying.

title: Comparison of Metoclopramide and Erythromycin in the Treatment of Diabetic Gastroparesis
abstract: To compare the effects of erythromycin and metoclopramide on gastric emptying and symptoms of gastroparesis in diabetic patients with delayed gastric emptying.  The study group consisted of 13 patients with symptoms of severe gastroparesis and delayed gastric emptying. Gastric emptying was evaluated using a radionuclide method, and gastrointestinal symptoms were scored. The patients were given either erythromycin (250 mg 3 times/day) or metoclopramide (10 mg 3 times/day) in random order for 3 wk, and after a washout period of 3 wk they were crossed-over to the other medication for another 3 wk. Parameters of gastric emptying were assessed before treatment and after both erythromycin and metoclopramide administration.  The half-time of gastric emptying in diabetic subjects was 110 (77–120) min before treatment. At 60 and 90 min, the median value of residual isotope activity was 66.5 (55–83.5) and 55% (43–74.3), respectively. The half-time decreased to 55 min (28.6–115) after 3 wk of treatment with erythromycin and percentages of meal retention in the stomach at 60 and 90 min were 49.9 (38.4–70) and 40.5% (29.7–60), respectively. After taking metoclopramide, the median value of half-time was 67 min (15–115) and percentages of meal retention at 60 and 90 min were 51 (34.5–93.9) and 42% (24–71.2), respectively. When compared with baseline values a significant difference in gastric emptying parameters was found after both erythromycin and metoclopramide. A significant improvement of the total score for gastrointestinal symptoms was observed with both drugs, but this improvement was more pronounced with erythromycin.  Erythromycin, a macrolide antibiotic and a motilin receptor agonist, appears to stimulate intestinal motility and seems to be an alternative agent for the treatment of gastroparesis caused by diabetic autonomic neuropathy.

title: Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding
abstract: To evaluate the effect of intravenous erythromycin on gastric emptying and the success of enteral feeding in mechanically ventilated, critically ill patients with large volume gastric aspirates.  Prospective, double-blind, randomized, and placebo-controlled trial.  General intensive care unit in a university hospital.  Twenty critically ill, mechanically ventilated patients intolerant of nasogastric feeding (indicated by a residual gastric volume of ≥250 mL during feed administration at ≥40 mL/hr).  After a gastric aspirate of ≥250 mL, which was discarded, the enteral feeding was continued at the previous rate for 3 hrs. Intravenous erythromycin (200 mg) or placebo was then administered over 20 mins. The residual gastric contents were again aspirated and the volume was recorded 1 hr after the infusion began.  Gastric emptying was calculated as volume of feed infused into the stomach over 4 hrs minus the residual volume aspirated. Mean gastric emptying was 139 ± 37 (±sem) mL after erythromycin and −2 ± 46 mL after placebo (p = .027). Nasogastric feeding was successful in nine of ten patients treated with erythromycin and five of ten who received placebo 1 hr after infusion (chi-square p = .05).  In critically ill patients who have large volumes of gastric aspirates indicating a failure to tolerate nasogastric feeding, a single small dose of intravenous erythromycin allows continuation of feed in the short term.

title: Erythromycin as a prokinetic agent in preterm neonates: a systematic review
abstract: It often takes several days or even weeks to establish full enteral feeds (FEFs) in preterm, especially extremely low birthweight neonates because of feed intolerance related to gastrointestinal hypomotility. Clinical trials of erythromycin as a prokinetic agent in preterm neonates have reported conflicting results.  To systematically review the efficacy and safety of erythromycin as a prokinetic agent in preterm neonates.  Only randomised controlled trials in preterm neonates (gestation ⩽37 weeks) were considered eligible for inclusion. The primary outcome was the time to reach FEFs of 150 ml/kg/day. The secondary outcomes included the incidence of erythromycin related adverse effects such as diarrhoea, cardiac arrhythmias, and hypertrophic pyloric stenosis. No restrictions were applied on the dose (low: 3–12 mg/kg/day; antimicrobial: ⩾12 mg/kg/6–8 hours) and route (oral or intravenous) and mode (prophylactic or rescue) of administration. The standard methodology for systematic reviews was followed. A subgroup analysis was preplanned based on the dose and mode of drug administration.  Seven trials (three prophylaxis, four rescue) with various doses, routes and modes of administration, and durations of erythromycin treatment and different results were found to be eligible for inclusion in the analysis. Meta-analysis could not be performed, as specific data were either inadequate or not available.  The conflicting trial results may be explained by differences in dose and route and mode of administration of erythromycin and in gastrointestinal motor responses in the presence of different feeding conditions—for example, fasting v fed state, intermittent v continuous feeds. Gestational and postnatal ages during erythromycin treatment are also important.

title: The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta-analysis of randomized trials
abstract: BackgroundIntolerance to enteral nutrition is common in critically ill adults, and may result in significant morbidity including ileus, abdominal distension, vomiting and potential aspiration events. Prokinetic agents are prescribed to improve gastric emptying. However, the efficacy and safety of these agents in critically ill patients is not well-defined. Therefore, we conducted a systematic review and meta-analysis to determine the efficacy and safety of prokinetic agents in critically ill patients.MethodsWe searched MEDLINE, EMBASE, and Cochrane Library from inception up to January 2016. Eligible studies included randomized controlled trials (RCTs) of critically ill adults assigned to receive a prokinetic agent or placebo, and that reported relevant clinical outcomes. Two independent reviewers screened potentially eligible articles, selected eligible studies, and abstracted pertinent data. We calculated pooled relative risk (RR) for dichotomous outcomes and mean difference for continuous outcomes, with the corresponding 95 % confidence interval (CI). We assessed risk of bias using Cochrane risk of bias tool, and the quality of evidence using grading of recommendations assessment, development, and evaluation (GRADE) methodology.ResultsThirteen RCTs (enrolling 1341 patients) met our inclusion criteria. Prokinetic agents significantly reduced feeding intolerance (RR 0.73, 95 % CI 0.55, 0.97; P = 0.03; moderate certainty), which translated to 17.3 % (95 % CI 5, 26.8 %) absolute reduction in feeding intolerance. Prokinetics also reduced the risk of developing high gastric residual volumes (RR 0.69; 95 % CI 0.52, 0.91; P = 0.009; moderate quality) and increased the success of post-pyloric feeding tube placement (RR 1.60, 95 % CI 1.17, 2.21; P = 0.004; moderate quality). There was no significant improvement in the risk of vomiting, diarrhea, intensive care unit (ICU) length of stay or mortality. Prokinetic agents also did not significantly increase the rate of diarrhea.ConclusionThere is moderate-quality evidence that prokinetic agents reduce feeding intolerance in critically ill patients compared to placebo or no intervention. However, the impact on other clinical outcomes such as pneumonia, mortality, and ICU length of stay is unclear.