红霉素和甲氧氯普胺单独或联合用于危重症患者成功喂养的有效性和安全性：系统评价和网络荟萃分析。

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【Abstract】 BACKGROUND: The comparative effectiveness and safety of erythromycin, metoclopramide, and their combination for enteral nutrition in critically ill patients remain uncertain. This network meta-analysis (NMA) synthesized available evidence. METHODS: A systematic search of seven electronic databases (Embase, PubMed, Web of Science, Cochrane Library, CNKI, Wanfang, VIP) from inception to February 6, 2026, was conducted with no language restrictions. Standard Cochrane methods were used for study selection, data extraction, and risk of bias assessment. A frequentist NMA was performed using STATA 18.0 with the mvmeta package. Effect estimates were calculated as odds ratios (OR) for binary outcomes and mean differences (MD) for gastric residual volume (GRV), each with 95% confidence intervals (CI). Random-effects models were used throughout. The surface under the cumulative ranking curve (SUCRA) was used to rank interventions. Sensitivity analyses excluded two pediatric studies. Certainty of evidence was assessed using the CINeMA framework (GRADE for NMA). RESULTS: Seventeen studies (2,654 patients) were included. For feeding success (5 trials), combination therapy was most effective [SUCRA 100.0%; OR vs. erythromycin 3.03 (1.90-4.83); vs. metoclopramide 4.89 (3.01-7.93)]. For postpyloric intubation success (10 trials), no significant pairwise differences were found; combination therapy ranked highest (SUCRA 76.4%) but with very wide confidence intervals. GRV change (3 trials) showed no significant differences. For any reported AEs (12 trials), placebo (SUCRA 80.0%) and metoclopramide (65.6%) had the most favorable safety profiles, while combination therapy ranked worst (7.5%). The certainty of evidence was moderate for feeding success, low to moderate for AEs, and very low for postpyloric intubation success and GRV. CONCLUSION: Combination therapy may be the most effective for feeding success, though based on small trials. Metoclopramide had a better safety profile. No significant differences were observed for postpyloric intubation success or GRV. These preliminary findings require confirmation in larger, well-designed trials. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD420251247900. 【Background】 Current guidelines from the American Society for Parenteral and Enteral Nutrition (ASPEN) recommend early enteral nutrition (EN) as the primary approach for critically ill patients with stable hemodynamics, normal gastrointestinal function, and inadequate oral intake (). Research has shown that initiating EN within 24 h may be associated with reduced gastrointestinal permeability, infection complications, mortality, ICU stays, and overall treatment costs (, ). However, gastric motility dysfunction in these patients often leads to feeding intolerance (FI), with rates ranging from 43 to 63% (–). Critically ill children also frequently experience gastric dysmotility, with delayed gastric emptying reported in up to 50% of pediatric ICU patients (). The ASPEN guidelines define EN intolerance based on clinical signs and symptoms observed during daily monitoring, such as abdominal distension, emesis, diarrhea, or unexplained abdominal pain, and discourage routine GRV monitoring in the absence of these signs (). In contrast, the ESPEN guidelines provide specific quantitative criteria, including gastric residuals >500 mL, worsening abdominal distention or pain, nausea or vomiting ≥3 times/day, diarrhea > 3 times/day or > 500 mL/day, intra-abdominal pressure > 20 mmHg, or the need to reduce or stop EN due to persistent gastrointestinal symptoms for more than 24 h (). Among these patients, 15–30% have gastric emptying abnormalities (–). FI and gastric motility dysfunction may hinder caloric intake, are associated with increase aspiration risk due to mechanical ventilation (–), prolong ICU stays, and increase mortality risk (, , ). Several guidelines suggest prioritizing postgastric-pyloric feeding for patients with FI, reflux, or aspiration risks (, ), but clinical success rates are low, which may be largely attributable to gastric motility issues and gastric emptying abnormalities (). Gastric emptying abnormalities in critically ill patients stem from multiple factors, including dysfunction of the gastric antrum, which may disrupts normal gastric contraction propagation to the duodenum (–, ). Gastrointestinal function is assessed by monitoring the gastric residual volume (GRV) and performing physical abdominal examinations (, , ). Treatment options for increasing the GRV include modifying the EN plan, using prokinetic drugs, switching from intragastric to postpyloric EN, or starting parenteral nutrition. Prokinetic drugs are often considered a preferred therapy (–, –) and are essential for increasing the success rate of postpyloric feeding tube placement (). Approximately 22% of critically ill patients use prokinetic drugs to enhance enteral nutrition absorption, with erythromycin and metoclopramide being the most common (, ). Erythromycin, a macrolide antibiotic, promotes gastric emptying by activating the motilin receptor, whereas metoclopramide improves gastrointestinal motility by blocking dopamine receptors (, ). Studies have shown that erythromycin reduces the GRV by 75%, metoclopramide by 47%, and combined treatment can reduce the GRV by 92% (). However, these agents are not without risks. Erythromycin has been associated with dose-related gastrointestinal adverse events (e.g., nausea, vomiting, diarrhea) and QTc interval prolongation, which may increase the risk of cardiac arrhythmias (). Metoclopramide can cause extrapyramidal symptoms, including acute dystonic reactions and akathisia, particularly in younger patients and at higher doses (). Previous studies have reported conflicting opinions on the effectiveness of monotherapy versus combination regimens (, ), indicating that efficacy may vary depending on patient condition and administration method. In addition, prokinetic agents are also used as a rescue strategy to facilitate postpyloric feeding tube placement. OuYang et al. reported 57.5% success for erythromycin, 50.3% for metoclopramide, and 76% for combined treatment in postpyloric catheterization (), suggesting a potential synergistic effect. Child studies also have shown that administering metoclopramide intravenously may improve the success rate of bedside blind peristaltic gastrostomy tube insertion in critically ill children (). In clinical practice, treatment strategies are often multimodal, and patient responses vary, highlighting the need for a comprehensive evidence synthesis approach. Prior meta-analyses on prokinetics in this population have notable limitations: one focused solely on erythromycin monotherapy using pre-2013 data (), while another confirmed erythromycin’s prokinetic effect but included only a single placebo-controlled trial for metoclopramide and did not utilize network meta-analysis (). Neither analysis could rank multiple interventions or estimate the comparative effectiveness of combination therapy versus monotherapy in the absence of head-to-head trials. Our network meta-analysis addresses this gap by synthesizing direct and indirect evidence for erythromycin, metoclopramide, their combination, placebo, and blank control within a unified framework. Furthermore, although gastric residual volume (GRV) is widely used to assess feeding intolerance, its correlation with gastric emptying and aspiration risk is poor, and recent guidelines (, ) no longer recommend routine GRV monitoring. This controversy further supports the use of a composite endpoint—successful feeding—rather than isolated GRV thresholds. Accordingly, this study employs network meta-analysis to evaluate the efficacy and safety of the three prokinetic regimens, providing additional evidence to inform clinical decision-making. 【Methods】 This systematic review and meta-analysis was performed following the PRISMA 2020 guidelines (). The protocol number that we registered on the PROSPERO is CRD420251247900. 【Literature search】 Based on the PICOS framework, we established inclusion and exclusion criteria and identified relevant articles that met these criteria. To identify studies on erythromycin and/or metoclopramide for treating abnormal gastric emptying in critically ill patients, we conducted a comprehensive search of the following seven databases from their inception to February 6, 2026: Embase, PubMed, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, and China Science and Technology Journal Database (VIP Database). The search strategy combined MeSH terms and free text, incorporating keywords such as “Erythromycin,” “Metoclopramide,” and “Critical Illness.” The specific search strategies used in each database and their corresponding results are presented in . Two researchers independently conducted the literature search and screening. Any disagreements regarding the included studies were resolved through discussion. 【Eligibility criteria】 Eligibility criteria for study selection in this review: (1) Population: Patients admitted to the intensive care unit (ICU) and currently receiving or scheduled to receive enteral nutrition. There were no restrictions on the types of critical illnesses or intubation methods for enteral nutrition. (2) Intervention and Control: Studies comparing any of the following interventions were eligible for inclusion: erythromycin monotherapy, metoclopramide monotherapy, combination therapy with erythromycin and metoclopramide, placebo, and blank control; (3) Results: At least one of the primary or secondary outcomes was reported in the included studies. The primary outcome was successful feeding rate, defined as a gastric residual volume (GRV) decreased below the safety threshold used in each original study, combined with the absence of clinical symptoms of feeding intolerance. Secondary outcomes included: (1) postpyloric intubation success rate, defined as radiologically confirmed tube tip position beyond the pylorus; (2) change in GRV before and after treatment, calculated as the difference between post-treatment and baseline values; and (3) any reported adverse events (any AEs), defined as any unfavorable medical occurrence documented in the original trials, irrespective of attribution to the study drug. (4) No restrictions were imposed regarding study design, publication language or publication status. The exclusion criteria were as follows: (1) Meetings, reviews, case reports, and protocols were excluded; (2) Duplicate published studies or datasets. 【Data extraction】 The data extraction process was carried out by two independent investigators who operated separately. Any discrepancies were resolved through discussion. The investigators extracted both basic characteristic data and outcome data from studies that met the predefined inclusion criteria. The basic characteristic data included the following elements: author(s) of the article, year of publication, research design, research location, type of severe condition, sample size, average age, proportion of male participants, types of prokinetic drugs (erythromycin monotherapy, metoclopramide monotherapy, or combination therapy), single dosage, and research findings. The efficiency and safety outcomes included the successful feeding rate, postpyloric intubation success rate and any AEs. 【Risk of bias assessment】 The quality of the included randomized controlled trials (RCTs) was assessed via the “Cochrane Risk of Bias Assessment Tool Version 2 (RoB2) (), whereas nonrandomized studies were evaluated via the “Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I)” tool (). Two independent assessors performed the quality assessments separately, addressing any disagreements through discussion. The RoB2 tool encompasses five domains, with risks of bias in each domain and overall classified as “low risk,” “some concerns,” or “high risk.” The ROBINS-I tool assesses the quality of nonrandomized intervention studies across seven aspects, with the results categorized into five levels: low risk, moderate risk, serious risk, critical risk, and no relevant information. 【Statistical analysis】 Within the frequentist framework (), all analyses and visualizations were conducted in STATA (version 18.0) using the mvmeta package and its associated tools. Effect estimates for the dichotomous outcomes—feeding success, post-pyloric tube success, and any AEs rate—were calculated using odds ratios (ORs), which are presented with 95% confidence intervals (CIs). For the continuous outcome, GRV change, mean difference (MD) was used because the original studies reported the outcome using the same units and measurement methods; we extracted the change from baseline to the final measurement time point (typically day 7 or study endpoint), calculated as post-treatment minus baseline when only separate values were reported, and imputed the variance using a correlation coefficient of 0.5. Heterogeneity was assessed using I2 (with values > 50% indicating high heterogeneity) and the between-study standard deviation τ (and τ2), estimated from a random-effects model. To evaluate the consistency assumption, we performed a global inconsistency test (design-by-treatment interaction, χ2 test) and local node-splitting analysis for each closed loop. A non-significant p-value (p > 0.05) was considered supportive of consistency. The efficacy and safety of the various interventions was then ranked using the surface under the cumulative ranking curve (SUCRA). Two-sided P < 0.05 was considered to indicate statistical significance. Small-study effects and potential publication bias were evaluated using comparison-specific funnel plots. To assess the potential impact of including two pediatric trials (, ), a sensitivity analysis by repeating the network meta-analysis after excluding these studies were performed. To further illustrate the incidence of any AEs across different gastric motility regimens, we qualitatively summarized the types and numbers of any AEs reported in previous monotherapy and combination therapy studies. 【Transitivity assumption and assessment of effect modifiers】 The validity of network meta-analysis relies on the transitivity assumption, which requires that the distribution of potential effect modifiers is comparable across different treatment comparisons within the network (). To evaluate the plausibility of transitivity, we compared the following study-level characteristics that may act as effect modifiers across pairwise comparisons: (1) patient population (adults vs. children), (2) severity of illness (APACHE II or equivalent scores), (3) use of concomitant medications (sedatives, opioids, vasopressors), (4) erythromycin dosage, (5) definition of outcome measures (e.g., GRV thresholds for feeding success, radiological criteria for postpyloric placement), and () intervention protocols (route, timing, and duration of administration). The distributions of these characteristics were tabulated and visually inspected for systematic differences across comparisons. Formal inconsistency tests were also performed for each outcome (reported in the respective sections) to provide statistical support for the consistency assumption. 【GRADE assessment】 The certainty of evidence for each network meta-analysis estimate was assessed using the Confidence in Network Meta-Analysis framework (CINeMA), which operationalizes the GRADE approach for network meta-analysis. Five domains were evaluated: risk of bias, inconsistency, indirectness, imprecision, and publication bias. No upgrading factors—such as large effect, dose-response gradient, or plausible residual confounding that would reduce the effect—were applied, as the data did not support them. For each comparison, the overall certainty was rated as high, moderate, low, or very low. 【Results】 【Study selection】 A total of 1,284 records were identified through database searching (PubMed: 112; Embase: 247; Cochrane Library: 84; Web of Science: 321; CNKI: 35; WanFang: 83; VIP: 402), and an additional 3 records were identified through reference searching, giving a total of 1,287 records. After the removal of 241 duplicate records, 1,046 records remained for title and abstract screening. Based on the screening, 1,008 records were excluded for the following reasons: case report (n = 1), meta-analysis or review article (n = 46), and irrelevant population or outcomes (n = 961). The full texts of the remaining 38 articles were retrieved for detailed assessment. Of these, 20 articles were excluded for not reporting the outcomes of interest, and 1 was excluded as a duplicate publication. Ultimately, 17 studies (, –, , –) met the inclusion criteria and were included in this systematic review and network meta-analysis. The study selection process was illustrated in . To ensure the authenticity of the data and the reproducibility of the research results, we included English versions of the abstracts from the Chinese studies, along with traceable literature website information, in . Flowchart of study selection. 【Study characteristics and assessment of the transitivity assumption】 The publication years of the 17 included studies ranged from 1995 to 2025. The studies were conducted in several countries, including China (n = 7), the United States (n = 6), Australia (n = 2), Thailand (n = 1), and India (n = 1). Most studies (n = 16) were RCTs, while one study was a retrospective trial. The sample sizes varied considerably across the studies, ranging from 20 to 777 participants, with a total of 2,654 critically ill patients included across all the studies. The proportion of male participants ranged from 51.4 to 84.3%, with several studies reporting more than 60% male representation. The mean age of the participants ranged from approximately 1.8–69.1 years, with most studies focusing on adult populations, except for those by Gharpure et al. () and Ketsuwan et al. (), which included pediatric cohorts. The interventions evaluated included erythromycin, metoclopramide, combination therapy (erythromycin + metoclopramide), placebo, or a blank control. Dosages varied across studies, with erythromycin dosages ranging from 70 mg to 500 mg, metoclopramide from 10 mg to 20 mg, and combination therapy from 0.25 mg/kg to 250 mg + 10 mg. The study characteristics are summarized in . Characteristics of the included studies. RCT, randomized controlled trial; ERY, erythromycin; MET, metoclopramide; COMB, combination therapy; AEs, adverse events; GRV, gastric residual volume. Data are mean ± SD or median (range). “/” = not reported. Blank control = no prokinetic intervention. Dickerson 2009 was retrospective; all others were RCTs. Pediatric studies: Gharpure 2001 and Ketsuwan 2021. Safety outcomes: any reported AEs (see for details). *: Total enrolled 324 patients including a naloxone arm not part of the network; only 243 patients in the three intervention groups (metoclopramide, erythromycin, combination) were included in the NMA. &:Combination group data were used only for qualitative safety description and were not included in the feeding success network meta-analysis as a parallel treatment node. Based on these characteristics, this study further assessed the transitivity assumption of the network meta-analysis by comparing the distribution of key potential effect modifiers across treatment comparisons, including patient age (pediatric vs. adult), erythromycin dosage, disease severity (APACHE II or equivalent scores), and outcome definitions (e.g., GRV thresholds for feeding success, radiological criteria for postpyloric placement). These distributions are detailed in . While some variability was observed—particularly in age and dosage—no systematic imbalance was identified that would obviously favor one treatment comparison over another. Formal inconsistency tests performed for each outcome (see the respective sections) were all non-significant (p > 0.05), providing statistical support for the consistency assumption. However, given the limited number of studies, the potential impact of