The efficacy and safety of prokinetics in critically ill adults receiving gastric feeding tubes: A systematic review and meta-analysis

Rong Peng; Hailong Li; Lijun Yang; Linan Zeng; Qiusha Yi; Peipei Xu; Xiangcheng Pan; Lingli Zhang

doi:10.1371/journal.pone.0245317

. 2021 Jan 11;16(1):e0245317. doi: 10.1371/journal.pone.0245317

The efficacy and safety of prokinetics in critically ill adults receiving gastric feeding tubes: A systematic review and meta-analysis

Rong Peng ^1,^2,^3,⁴, Hailong Li ^1,^2,³, Lijun Yang ⁵, Linan Zeng ^1,^2,³, Qiusha Yi ^1,^2,³, Peipei Xu ^1,^2,³, Xiangcheng Pan ^1,^2,³, Lingli Zhang ^1,^2,^3,^*

Editor: Lisa Susan Wieland⁶

PMCID: PMC7799841 PMID: 33428672

Abstract

Background

Intolerance to gastric feeding tubes is common among critically ill adults and may increase morbidity. Administration of prokinetics in the ICU is common. However, the efficacy and safety of prokinetics are unclear in critically ill adults with gastric feeding tubes. We conducted a systematic review to determine the efficacy and safety of prokinetics for improving gastric feeding tube tolerance in critically ill adults.

Methods

Randomized controlled trials (RCTs) were identified by systematically searching the Medline, Cochrane and Embase databases. Two independent reviewers extracted the relevant data and assessed the quality of the studies. We calculated pooled relative risks (RRs) for dichotomous outcomes and the mean differences (MDs) for continuous outcomes with the corresponding 95% confidence intervals (CIs). We assessed the risk of bias using the Cochrane risk-of-bias tool and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to rate the quality of the evidence.

Results

Fifteen RCTs met the inclusion criteria. A total of 10 RCTs involving 846 participants were eligible for the quantitative analysis. Most studies (10 of 13, 76.92%) showed that prokinetics had beneficial effects on feeding intolerance in critically ill adults. In critically ill adults receiving gastric feeding, prokinetic agents may reduce the ICU length of stay (MD -2.03, 95% CI -3.96, -0.10; P = 0.04; low certainty) and the hospital length of stay (MD -3.21, 95% CI -5.35, -1.06; P = 0.003; low certainty). However, prokinetics failed to improve the outcomes of reported adverse events and all-cause mortality.

Conclusion

As a class of drugs, prokinetics may improve tolerance to gastric feeding to some extent in critically ill adults. However, the certainty of the evidence suggesting that prokinetics reduce the ICU or hospital length of stay is low. Prokinetics did not significantly decrease the risks of reported adverse events or all-cause mortality among critically ill adults.

Introduction

Critical illness is usually associated with catabolic stress and increases the incidence of infection and multiple organ dysfunction, resulting in a high mortality rate. A systematic review found a strikingly high prevalence of malnutrition in intensive care unit (ICU) patients (ranging from 38% to 78%) [1]. Owing to the benefits of nutrition support with regard to reducing disease severity and favorably impacting patient outcomes, early nutrition support therapy, primarily by the enteral route, is seen as a proactive therapeutic strategy [2]. In addition, if oral intake is not possible, tube feeding through gastric access has been recommended as the standard approach to initiating enteral nutrition in critically ill adult patients [3].

However, enteral tube feeding intolerance is common in critically ill patients, especially those receiving gastric feeding [3, 4]. Blaser et al. reported that the pooled proportion of feeding intolerance was 38.3% (95% confidence interval (CI) 30.7–46.2%) [4]; besides, a meta-analysis by the European Society for Clinical Nutrition and Metabolism showed that gastric feeding intolerance was more prevalent than postpyloric feeding intolerance (25.7% vs. 3.5%, p = 0.0005) [3]. In addition, feeding intolerance is associated with elevated mortality, and seven-day feeding intolerance is an independent predictor of 60-day mortality [5]. Given the risk associated with gastric feeding intolerance, it should be treated aggressively.

The administration of prokinetics is the method most commonly used to treat gastric feeding intolerance. Among recipients of gastric feeding, 13% had been prescribed prokinetics preemptively before they developed intolerance. Approximately one-third of patients who developed feeding intolerance were treated with a prokinetic agent during their stay in the ICU [6]. Although the use of prokinetics in the ICU is common, guidelines or recommendations are little agreement on how to use prokinetics for gastric feeding intolerance in critically ill patients [2, 3, 7, 8]. One of the reasons for the different recommendations may be that the definition of feeding intolerance has changed over time, especially regarding a high gastric residual volume (GRV). A GRV of 500 mL is the recommended threshold for a diagnosis of enteral feeding intolerance in US and European critical care and nutrition society guidelines [2, 3, 9]. Although the updated European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines [3], published in 2019, provide the latest information on enteral nutrition (EN) and parenteral nutrition (PN) in critically ill adult patients, we find that some aspects of the efficacy and safety of prokinetics in critically ill patients are still unclear [10], and it is necessary to find new evidence to address these uncertainties.

On this topic, a previous meta-analysis by Lewis, K. et al. [11] examined the effects of prokinetics on feeding intolerance or high GRV and clinical outcomes. However, Lewis, K. et al. [11] defined feeding intolerance as GRV ≥150 mL, vomiting, or abdominal distention resulting in feeding interruption. This definition may be considered obsolete [12]. Some new evidence has emerged on this topic; therefore, we conducted this systematic review to determine the efficacy and safety of prokinetics for the treatment of gastric feeding intolerance in critically ill adult patients.

Methods

This systematic review and meta-analysis was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0) [13], and the reporting of our study was based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [14]. The review protocol is available on PROSPERO, registration number CRD42020157446.

Neither patients who received gastric feeding in the ICU nor their families were involved in defining the research question or the outcome measures, but they were involved in the design, providing our team with substantial useful advice regarding design ideas.

Search strategy

We searched the Medline and Embase databases as well as the Cochrane Central Register of Controlled Trials (CENTRAL) from their inception dates to November 22, 2019. We combined Medical Subject Headings (MeSH) and free text terms to identify relevant articles. An informatics expert developed our search strategies.

We also searched clinicaltrials.gov (https://clinicaltrials.gov/) and the WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/) for additional information, using the terms “critically ill patients”, and limited our search to studies labeled “completed” AND “interventional studies (clinical trials)” in which summary results were available to identify additional eligible studies. There were no language restrictions. Additionally, we used a manual search strategy to retrieve the relevant articles cited by the retrieved publications (the search strategies are reported in S1 Table).

Inclusion criteria

Trials were selected based on the following inclusion criteria: (1) the study was designed as a randomized controlled trial (RCT) comparing prokinetic treatment with a control group; (2) the population included critically ill adult patients aged ≥18 years who were admitted to the ICU and received gastric feeding tubes regardless of whether they had pre-existing feeding intolerance; (3) the intervention group received metoclopramide, erythromycin, or other prokinetic agents, such as herbal medicines or natural medicines intended to enhance gastric motility, regardless of the dose, frequency, duration or combination of prokinetics; (4) the control group received no intervention or a placebo; (5) if the gastric feeding patients with feeding intolerance had a GRV ≥500 mL and/or symptoms of nausea, vomiting, abdominal distention, regurgitation, deterioration in hemodynamics or other symptoms resulting in feeding interruption and failed to respond to interventions, regardless of whether they were in the control group or the prokinetics group, they were switched to postpyloric feeding or had gastric feeding withheld for 4–6 h [2, 3]; and (6) the outcomes included any of the following: all-cause mortality; Acute Physiology and Chronic Health Evaluation II (APACHE II) or Simplified Acute Physiology Score II; sepsis; use of an artificial airway; pneumonia; hospital or ICU length of stay; patient nutritional status (malnutrition); gastrointestinal symptoms; GRV; feeding intolerance; or side effects of the prokinetics, such as cardiovascular disorders, bronchospasm, extrapyramidal symptoms, abdominal cramps, allergic reactions and pancreas disorders. The exclusion criteria were as follows: (1) the studies had no control group; (2) the studies had no prokinetic treatment group; (3) patients were considered to have feeding intolerance if tube feeding was electively not prescribed or was stopped/interrupted for procedural reasons; (4) the studies discontinued or interrupted gastric feeding prematurely when the GRV was less than 500 mL or the patients did not have any signs of intolerance, such as nausea, vomiting, abdominal pain, abdominal distension, or deterioration in hemodynamics or overall status.

For our purposes, gastric feeding intolerance was defined as a “large” GRV (≥500 mL), the presence of gastrointestinal symptoms (vomiting, diarrhea, gastrointestinal bleeding, the presence of enterocutaneous fistulas), or inadequate delivery of EN (the energy provided by EN was less than 20 kcal/kg BW/day after 72 h of feeding attempts or less than 60% of the EN target on the fifth day) in critically ill adults receiving nutrition via gastric feeding tubes. Preventive usage of prokinetics meant that prokinetics were prescribed preemptively on the day EN was initiated and before patients presented a GRV >150 mL or symptoms of feeding intolerance. Preventive usage of prokinetics for risk meant that prokinetics were used in patients with GRVs between 150 and 500 mL before the development of intolerance. Therapeutic usage of prokinetics meant that the prokinetics were administered to patients who had developed feeding intolerance.

A reported adverse event was defined as any untoward medical occurrence or unfavorable and unintended sign, including an abnormal laboratory finding, symptom, or disease (new or exacerbated), temporally associated with the use of the study medication. The reported adverse events included abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, or measurements of vital signs), including those that worsened from baseline and were deemed clinically significant in the medical and scientific judgment of the investigator; exacerbation of a chronic or intermittent preexisting condition, including an increase in the frequency and/or intensity of the condition; new conditions detected or diagnosed after the administration of study medication even if they may have been present prior to the start of the study; and/or signs, symptoms, or clinical sequelae of a suspected interaction, such as diarrhea, nosocomial pneumonia, severe sepsis, brain herniation, cardiac arrest, or changes in the electrocardiographic QTc interval.

Risk-of-bias assessments

The methodological quality of the included RCTs was assessed independently by 2 researchers (RP, HLL) based on the Cochrane risk-of-bias criteria [13]. The seven items used to evaluate bias in each trial included randomization sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. We defined other bias as being present in the trials in which the baseline characteristics were not similar between different intervention groups. The included trials were graded as low, unclear, or high risk of bias based on the following criteria: (1) trials were considered high risk of bias if either randomization or allocation concealment was assessed as having a high risk of bias, regardless of the risk of other items; (2) trials were considered low risk of bias when both randomization and allocation concealment were assessed as having a low risk of bias and all other items were assessed as having a low or unclear risk of bias; (3) trials were considered to have unclear risk of bias if they did not meet the criteria for high or low risk of bias.

Data extraction

Two researchers (RP, HLL) independently extracted the following information from each eligible RCT: (1) general study characteristics: author name, year of publication, numbers of treatment groups and patients, trial registry number, methods for measuring gastric emptying or GRV, and the definition of feeding intolerance; (2) patient characteristics: sex, age, baseline patient information (presence or absence of pre-existing feeding intolerance, APACHE II score and nutritional status, if reported); (3) primary diseases (the medical, surgical, or neurosurgical conditions of the critically ill patients); (4) interventions: details of the prokinetic treatment group and control group (e.g., dose, frequency, duration and combination of prokinetics for treatment); and (5) outcomes: gastrointestinal symptoms, feeding tolerance, the number of participants with all-cause death, the ICU length of stay, the hospital length of stay, and the number of reported adverse events.

If the trials had more than 2 groups or used factorial designs and could be analyzed using multiple comparisons, we extracted only the information and data of interest reported in the original articles. If a trial had multiple reports, we collated all data into one study. If a trial had reports in both ClinicalTrials.gov and journal publications, we carefully checked data from these two sources for consistency. If outcome data were reported at multiple follow-up points, we used data from the longest follow-up.

Statistical analysis

The effect of prokinetics on gastrointestinal symptoms and feeding tolerance, main clinical outcomes of all-cause mortality, ICU length of stay, hospital length of stay, and reported adverse events were analyzed. We recorded data on the number of participants with each outcome event by allocated group and recorded the number of participants with compliance and the participant, who was later thought to be eligible or otherwise excluded from treatment or follow-up. Intention-to-treat (ITT) analysis was conducted. ITT analysis is a comparison of the treatment groups that include all patients as originally allocated after randomization regardless of whether treatment was initiated or completed [15]. The CONSORT (Consolidated Standards of Reporting Trials) recommends ITT analysis as standard practice [16].

We performed a meta-analysis to calculate the relative risks (RRs) or absolute risk differences (ARDs) for the dichotomous data and mean differences (MDs) for the continuous data, 95% CIs using the Mantel-Haenszel method and the inverse variance statistical method, respectively. If sufficient data were not available in the published reports or conference abstract, we contacted the authors of the paper. If the raw data were not the mean and standard deviation, the sample mean and standard deviation were estimated from the sample size, median, range and/or interquartile range [17, 18].

We tested for heterogeneity between trials using a standard Chi² test, and statistical heterogeneity between summary data was evaluated using the I² statistic. Sensitivity analysis was performed by excluding low-quality studies, trials recruiting participants with particular conditions, or trials with different characteristics from the others. When an inconsistency was detected between the RR and ARD for the same outcome, we explained the results based on the RR because the RR model is more consistent than the ARD, particularly for an intervention aimed at preventing an undesirable event [13, 19].

In our meta-analysis, a random-effects model was used. The defining feature of the random-effects model is that there is a distribution of true effect sizes, and there are two sources of variance, within-study error variance and between-study variance [20]. However, if the number of studies is very small, the statistical power will have poor precision due to the variance between studies. Although the random-effects model is still the appropriate model, the information to apply it correctly is not available. In this case, we will add the separate effects. If heterogeneity was identified (I² >40% [13]) and sufficient trials were included in the review, we investigated heterogeneity in the specified subgroups based on types of prokinetics (erythromycin, metoclopramide or other prokinetics), the use of a combination of prokinetics (yes or no), and feeding intolerance history (participants with or without pre-existing feeding intolerance before the start of the trial). Analysis was performed to assess whether the difference between the subgroups was statistically significant.

We assessed publication bias by examining funnel plots when the number of trials reporting the primary outcomes was 10 or more. However, if the number of included studies was less than 10 for a given main outcome, the funnel plot may not reliably detect evidence of departure bias. A prototypical situation that should elicit the suspicion of publication bias is when evidence is derived from a small number of studies or small sample sizes and all outcomes favor the intervention [21]. All meta-analyses were performed using RevMan version 5.3 (Cochrane Collaboration). All tests were 2-tailed, and P <0.05 was considered statistically significant.

We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to rate the certainty of evidence as high, moderate, low, or very low. RCTs begin as high-certainty evidence but can be downgraded because of the risk of bias, imprecision, inconsistency, indirectness, or publication bias. If the limitation on the evidence was considered serious, the evidence was downgraded by one level; if the limitation was considered very serious, the evidence was downgraded by two levels [22].

Results

Our initial search identified a total of 595 citations. After deduplication, 459 publications remained. The titles and abstracts of those records were screened for inclusion, and 48 reports proved potentially eligible. After full-text screening, fifteen trials met the inclusion criteria [23–37]. Five studies did not provide useful data for the quantitative synthesis (meta-analysis) [33–37]. Ultimately, 10 trials were included in the quantitative analysis [23–32]. A total of 846 patients were enrolled in the 10 RCTs, including a variety of critically ill patients with medical, surgical, and neurosurgical conditions. The details of the eligible trials are presented in Fig 1. Studies were excluded if they had a different trial design [38–42], a different intervention or a different control [43–61], or a different population [62–64] or had been registered with the Clinical Trials Registry Platform (clinicaltrials.gov or WHO ICTRP) and had been labeled “completed” but the outcomes had not been reported [65–70] (S2 Table).

The 15 eligible studies reported the use of 10 prokinetics, including metoclopramide, erythromycin, cisapride, GSK962040, mosapride and herbal medicines or natural medicines intended to enhance gastric motility (Chenxia Sijunzi decoction, ginger, fenugreek seed powder, gastrolit (Zataria multiflora), rikkunshito), respectively. Based on the outcomes measured, the studies were subdivided into those investigating effects on gastrointestinal symptoms, feeding tolerance studies, and clinical outcome studies that investigated the hospital length of stay, ICU length of stay, reported adverse events, and all-cause mortality. The details of the eligible studies are presented in Table 1.

Table 1. Characteristics of the included trials and participants.

Included Trials	Population	Treatment ^#	Main outcomes	Definition of feeding intolerance †	Prokinetic initiation timing *
Yavagal et al 2000 (India) [32]	ICU patients required placement of a nasogastric tube for >24 hrs. Mean age: 36.22 years, 61.97% male. Mean APACHE II score: 17.54.	1) Metoclopramide 10 mg NG q8h; 2) Placebo.	1) Nosocomial pneumonia; 2) Mortality.	NA	Preventive usage
Sustic et al 2005 (Croatia) [36]	Patients treated at a cardiosurgical ICU after CABG surgery, enteral feeding by nasogastric tube. Mean age: 59.5 years, 77.5% male. Mean SAPS II score: 21.	1) Metoclopramide 10 mg i.v.; 2) Control group.	1) t₊₁₅, t₊₃₀, t₊₆₀, t₊₁₂₀; 2) AUC₁₂₀; 3) C_max.	NA	Preventive usage
Nursal et al 2007 (Turkey) [29]	Traumatic brain injury patients with Glasgow Coma Scale scores of 3–11. Enteral feeding by nasogastric tube. Mean age: 43.42 years, 84.2% male Mean APACHE II score: 12.87.	1) Metoclopramide 10 mg i.v. q8h×5 days; 2) Control group, saline	1) Feeding intolerance; 2) Feeding complications; 3) AUC_60; 4) C_max; 5) Length of hospital stay; 6) Mortality.	Gastrointestinal symptoms (without GRV)	Preventive usage
Nassaji et al 2010 (Islamic Republic of lran) [28]	Surgical ICU with a nasogastric tube for more than 24 hours. Mean age: 44.88 years, 65.45% male. Mean APACHE II score: not reported.	1) Metoclopramide 10 mg NG q8h; 2) Control patients did not receive metoclopramide.	1) Nosocomial pneumonia; 2) Mortality.	NA	Preventive usage
Acosta-Escribano et al 2014 (Spain) [23]	Adult neuro-critical patients, Glasgow Coma Scores of 14 to 9 points, with ventilation indications at admission and the need for artificial enteral nutrition. Mean age: 54.53 years, 65.14% male. Mean APACHE II score: 18.53.	1) Metoclopramide 10 mg; 2) Placebo.	1) Gastrointestinal complications; 2) Gastric residual; 3) Mechanical ventilation-associated pneumonia; 4) Duration of mechanical ventilation; 5) Length of ICU stay; 6) Length of hospital stay; 7) Mortality.	Large GRV alone (>500 mL in two consecutive episodes)	Preventive usage
Rajan et al 2017 (India) [35]	Critically ill cirrhotic patients in a liver ICU with feeding intolerance.	1) Metoclopramide i.v., 2) Erythromycin i.v., 3) Placebo.	1) Mortality; 2) GRV.	Gastrointestinal symptoms including large GRV (500 mL)	Therapeutic usage
Ritz et al 2005 (Australia) [30]	Mixed medical/surgical intensive care unit patients with mechanic ventilation. Mean age: 47.49 years, 60.9% male. Mean APACHE II score: 19.	1) Erythromycin 70 mg; 2) Erythromycin 200 mg; 3) Placebo, saline (0.9%).	1) Gastric emptying coefficient; 2) Gastric half-emptying time (t_1/2).	NA	Preventive usage
Spapen et al 1995 (Belgium) [31]	Adult medical/surgical intensive care unit patients requiring prolonged mechanical ventilation and enteral feeding. Mean age: 71.10 years, 52.38% male. Mean APACHE II score: not reported.	1) Cisapride 10 mg q6h; 2) No treatment.	1) Gastric residual; 2) The mean time at which 50% of the technetium 99m-labeled test meal was eliminated from the stomach (T_1/2); 3) Mortality.	NA	Preventive usage
Heyland et al 1996 (Canada) [33]	Mechanically ventilated patients in trauma and neurosurgery ICUs. Mean age: 53.9 years, 61% male. Mean SAPS score: 9.5.	1) Cisapride 20 mg, NG; 2) An identical placebo.	1) C_max; 2) AUC₁₈₀.	NA	Preventive usage
Chapman et al, 2016 (Australia) [24]	Patients undergoing invasive mechanical ventilation in the ICU with nasogastric feeding. Mean age: 44.67 years, 83.33% male. Mean APACHE II score: 18.14.	1) GSK962040 (50 mg); 2) GSK962040 (75 mg); 3) Placebo.	1) Breath test gastric time to half emptying (BTt½); 2) Gastric emptying coefficient; 3) AUC₂₄₀, AUC₆₀; 4) C_max; 5) Adverse events.	Large GRV alone (>200 mL) at least 6 hours after commencing liquid nutrition at ≥ 40 kcal/hr	Preventive usage for risk
Mokhtari et al 2009 (Islamic Republic of lran) [34]	Adult respiratory distress syndrome (ARDS) ICU patients.	1) Ginger, 2) Placebo.	1) Feeding tolerance; 2) Ventilator-associated pneumonia; 3) ICU-free days; 4) Ventilator-free days; 5) Mortality.	Delayed gastric emptying is one of the major reasons for enteral feeding intolerance	Preventive usage
Guo JH, et al 2012 (China) [26]	Feeding with enteral nutrition in critically ill patients. Mean age: 59.49 years, 53.33% male. Mean APACHE II score: not reported.	1) Traditional Chinese medicine group: Chenxia Sijunzi decoction; 2) Western medicine group: mosapride dispersible tablets 5 mg and multienzyme tablets NG; 3) Control group: routine symptomatic treatment without any medicines to promote gastrointestinal function.	1) Time to bowel sound recovery; 2) Gas passage time by anus; 3) Bowel movement time; 4) Days in the hospital.	NA	Preventive usage
Kooshki et al 2018 (Iran) [27]	Mechanically ventilated patients, enteral nutrition with nasogastric tube in two intensive care unit centers. Mean age: 56.95 years, 51.67% male. Mean APACHE II score: 23.2.	1) Fenugreek seed powder 3 g q12h NG; 2) Routine care.	1) Diarrhea; 2) Constipation; 3) GRV; 4) Respiratory aspiration; 5) Duration of mechanical ventilation; 6) Length of stay in the hospital; 7) Length of stay in the ICU; 8) Mortality.	Gastrointestinal symptoms	Preventive usage
Tahershamsi et al 2018 (Iran) [37]	Mechanically ventilated patients hospitalized in ICU. Mean age: 63.06 years, 60.0% male. Mean APACHE II score: No report.	1) Gastrolit (Zataria multiflora) (20 drops) q8h× 4 days; 2) Placebo = water.	1) GRV.	NA	Preventive usage
Doi et al 2019 (Japan) [25]	Critically ill adult patients requiring enteral nutrition by gastric tube for at least 5 days, and all patients were treated with invasive mechanical ventilation. Mean age: 72.84 years, 77.78% male. Mean APACHE II score: 22.82.	1) Rikkunshito 5 g q8h × 5 days; 2) Rikkunshito 2.5 g q8h× 5 days; 3) No rikkunshito (control).	1) GRV; 2) The percentage of the target enteral calorie intake achieved at the fifth day; 3) The plasma levels of ghrelin; 4) ICU length of stay; 5) Hospital length of stay; 6) Adverse events; 7) Mortality.	Inadequate enteral nutrition/failure to meet the enteral nutrition target at the fifth day (<60%)	Preventive usage

Open in a new tab

NG: nasogastric tube feeding; i.v.: intravenous injection; NA: not applicable; C_max: peak paracetamol plasma levels; AUC: the area under the paracetamol concentration curve; t₊₁₅, t₊₃₀, t₊₆₀, t₊₁₂₀: plasma paracetamol concentrations at 15, 30, 60, and 120 minutes after administration of paracetamol and saline or metoclopramide in patients; SAPS, simplified acute physiology score; GRV, gastric residual volume.

# If the trials had more than 2 groups or factorial designs and permitted multiple comparisons, the subgroup in bold font was extracted in this study.

¶ The study did not provide useful data for meta-analysis.

Risk of bias

There was one trial with a low risk of bias [24], and two studies had a high risk of bias [25, 28] due to inappropriate randomization and/or allocation concealment. For the remaining 12 studies, we were unable to comprehensively evaluate the risk of bias due to the lack of information [23, 26, 27, 29–37]. (S1 Fig).

Publication bias

We checked the funnel plots of the main outcomes for asymmetry; however, we included fewer than 10 RCTs in each main outcome; therefore, that the funnel plots could not be used to reliably detect departure bias.

Main outcomes

Effect on gastrointestinal symptoms and feeding tolerance

Thirteen studies evaluated the effect of prokinetics on gastrointestinal symptoms and/or feeding tolerance in adult critically ill patients receiving gastric feeding [23–27, 29–31, 33–37]. The following main results were assessed: gastric emptying, GRV, diarrhea, constipation, feeding complications and feeding intolerance. Gastric emptying was measured by the drug model of acetaminophen absorption or the 13C-octanoic acid breath test with calculation of the gastric emptying time, gastric emptying coefficient or area under the plasma concentration-time curve. The various outcome definitions, especially for gastric tube tolerance, precluded quantitative synthesis of the data.

As a class of drugs, prokinetic agents appear to have positive effects on gastrointestinal function and feeding tolerance. Ten of the thirteen studies reported positive effects on gastric emptying and/or feeding intolerance in critically ill patients who used of prokinetic agents. However, two studies suggested that metoclopramide had no effect on decreasing gastrointestinal complications in adult neurocritical patients or critical traumatic brain injury patients. One study reported that rikkunshito did not improve the achievement of enteral calorie targets in critically ill adults (Table 2).

Table 2. Effects on gastrointestinal symptoms and feeding tolerance.

Study	Population (sample size)	Intervention	Outcome	P Value	Conclusions
Sustic et al 2005 (Croatia) [36]	Cardiosurgical patients after CABG surgery (40)	1) Metoclopramide 10 mg i.v.; 2) Control group: saline.	AUC₁₂₀; C_max. 574±296; 8.51±2.2 429±309; 5.15±2.8	0.027; 0.007	In CABG surgery patients with early enteral feeding, a single dose of intravenous metoclopramide effectively improves gastric emptying.
Nursal et al 2007 (Turkey) [29]	Traumatic brain injury patients with Glasgow Coma Scores of 3–11 (19)	1) Metoclopramide 10 mg i.v. q8h×5 days; 2) Control group: saline.	FI; feeding complications; AUC₆₀ at day 5; C_max day 5; 4/10 (40%); 5/10 (50%); 589.6±457.8; 15.8±12.9 2/9 (22.2%); 3/9 (33.3%); 560±432.9; 12.0±9.9	NS; NS; NS; NS	The results were unable to reveal any advantage of using metoclopramide in TBI patients.
Acosta-Escribano et al 2014 (Spain) [23]	Adult neuro-critical patients, Glasgow Coma Scores of 14 to 9 points (109)	1) Metoclopramide 10 mg i.v.; 2) Placebo: saline.	Incidence of gastrointestinal complications; Incidence of GRV>500 mL at day 5; 29/58 (50%); 16/58 (28%) 22/51 (45%); 11/51 (22%)	NS; NS	Metoclopramide has no effect on decreasing gastrointestinal complications in adult neuro-critical patients
Rajan et al 2017 (India) [35]	Critically ill cirrhotic patients in a liver intensive care unit (72)	1) Metoclopramide i.v.; 2) Erythromycin i.v.; 3) Placebo.	Resolution of FI; decrease in GRV beyond 24 hrs; the time to restart enteral nutrition (days) 8.7%; no report; 2.61±0.72 24%; no report; 2.20±0.91 no report; no report; 3.47±1.29	0.026; no report; 0.03	Early detection and the addition of prokinetics facilitate the resolution of FI in critically ill cirrhotic patients. Erythromycin is safe and superior to metoclopramide for early resolution of gut paralysis in critically ill cirrhotic patients.
Ritz et al 2005 (Australia) [30]	Mixed medical/surgical intensive care unit patients (35)	1) Erythromycin 70 mg i.v.; 2) Erythromycin 200 mg i.v.; 3) Placebo, saline (0.9%).	Gastric emptying coefficient; gastric half-emptying time (t_1/2) 3.8 (3.3–4.0); 98 (88–112) min 4.0 (3.6–4.2); 86 (75–104) min 2.9 (2.5–3.7); 122 (102–190) min	<0.05; <0.05	Treatment with 70 and 200 mg of intravenous erythromycin is equally effective in accelerating gastric emptying in critically ill patients. Doses as low as 70 mg (approx. 1 mg/kg) accelerate gastric emptying in critically ill patients, improving the success of enteral feeding. This effect is observed only in patients with delayed gastric emptying.
Spapen et al 1995 (Belgium) [31]	Adult medical/surgical intensive care unit patients (21)	1) Cisapride 10 mg q6h NG; 2) No treatment.	Gastric residual over one week; gastric emptying time T_1/2; 17.7±8.9 mL; 18±7 min 94.5±33.3 mL; 78±40 min	<0.001; <0.005	Gastric emptying in critically ill, sedated, and mechanically ventilated patients can be significantly improved by adding cisapride to a routine enteral feeding protocol.
Heyland et al 1996 (Canada) [33]	Mixed intensive care unit patients (72)	1) Cisapride 20 mg; 2) An identical placebo.	Differences (Day 2—Day 1) in ΔC_max; Δt_max; ΔAUC₁₈₀ 49.1±10.7; -40.8±12.0; 5534±1349 12.3±7.0; -4.2±10.4; 2832±769	0.005; 0.02; 0.09	Cisapride enhances gastric emptying in critically ill patients
Chapman et al, 2016 (Australia) [24]	Mixed intensive care unit patients (33)	1) GSK962040 (50 mg) NG; 2) GSK962040 (75 mg) NG; 3) Placebo.	Baseline vs. post gastric emptying time BTt½; AUC₂₄₀ 0.65 (0.39,0.1.08); 2.50 (1.68,3.72) 1.85 (0.82,4.15); 0.72 (0.39,1.36) 1.21 (0.68,2.15); 1.33(0.85,2.06)	No report; no report	A single enteral dose of camicinal (50 mg but not 75 mg), accelerates gastric emptying and increases glucose absorption in feeding-intolerant critically ill patients.
Mokhtari et al 2009 (Islamic Republic of lran) [34]	Critically ill adult respiratory distress syndrome (ARDS) patients (32)	1) Ginger NG, 2) Placebo.	Feeding tolerated in the first 48 hrs; feeding tolerated during the entire study period 51%; 92% 57%; 93%	<0.005; 0.42	Supplementing the diet with ginger extract in ARDS patients reduces the delayed gastric emptying risk.
Guo JH, et al 2012 (China) [26]	Mixed intensive care unit patients (80)	1) Traditional Chinese medicine group: Chenxia Sijunzi decoction; 2) Western medicine group: mosapride dispersible tablets 5 mg and multienzyme tablets NG; 3) Control group: routine symptomatic treatment without any medicines to promote gastrointestinal function.	The time to bowel sound recovery; the time to passage of gas by anus recovery; the time to bowel movement recovery 41.02±7.52^a; 49.90±6.95^a; 58.22±6.71^a 44.02±6.23^a; 51.32±5.12^a; 60.91±3.72^a 54.62±5.51; 64.68±9.47; 78.20±7.11	^aP<0.01	Chenxia Sijunzi decoction can promote severe patients’ gastrointestinal function recovery. No significant differences in each testing index were found between the traditional Chinese medicine and Western medicine groups.
Kooshki et al 2018 (Iran) [27]	Mixed intensive care unit patients (60)	1) Fenugreek seed powder 3 g q12h NG; 2) Routine care.	GRV at the 5^th day; diarrhea; constipation; respiratory aspiration at 5^th/6^th days 28.06±9.23; 1/30 (3.3%); 3/30 (10%); 1/30 (3.3%) 38.94±9.54; 6/30 (20%); 21/30 (70%); 10/30 (33.3%)	0.001; 0.04; 0.001; 0.005	Beneficial effects of fenugreek seeds on food intolerance were observed in critically ill patients.
Tahershamsi et al 2018 (Iran) [37]	Mixed intensive care unit patients (50)	1) Gastrolit (Zataria multiflora) (20 drops) q8h× 4 days; 2) Placebo = water.	GRV on the second, third, and fourth days The data could not be extracted	All P<0.0001	Gastrolit can decrease the GRV in mechanically ventilated patients
Doi et al 2019 (Japan) [25]	Mixed intensive care unit patients	1) Rikkunshito 5 g q8h ×5 days;2) Rikkunshito 2.5 g q8h×5 days;3) No rikkunshito (control).	GRV; the percentage of the target energy at the 5^th day; the target energy was achieved at the 5^th day No report; 62%; 63% No report; 40%; 38% No report; 59%; 56%	NS; NS; NS	Standard- or high-dose rikkunshito did not improve achievement of the enteral calorie target in critically ill adults.

Open in a new tab

FI, feeding intolerance; NS, not significant

^aP<0.01 compared with the control group.

Effect on hospital or ICU length of stay

The effect of prokinetics on hospital length of stay was examined by five studies [23, 25–27, 29]. These five studies, which enrolled a total of 250 patients, showed a significant difference in the hospital length of stay between the prokinetic agent-treated group and the control group (MD -3.21, 95% CI -5.35, -1.06; P = 0.003; I² = 28%) (Fig 2). Three studies evaluated the effect of prokinetics on ICU length of stay in the critical care setting [23, 25, 27]. These three studies, enrolling a total of 186 patients, showed that prokinetic agents appeared to have a positive effect on shortening ICU length of stay (MD -2.03, 95% CI -3.96, -0.10; P = 0.04; I² = 0%) (Fig 3). Additionally, the separate effects of different prokinetics on the ICU length of stay and hospital length of stay are presented in S3 Table.

Fig 2 — IV: inverse variance; CI: confidence interval.

Fig 3 — IV: inverse variance; CI: confidence interval.

Effect on reported adverse events

Seven studies reported events that met the definition of adverse events in 757 critically ill patients [23–25, 27–29, 32]. The meta-analysis showed no significant difference in the risk of reported adverse events between the prokinetic agent group and the control group (RR 1.13, 95% CI 0.92, 1.38; P = 0.25; I² = 0%) (S2 Fig).

Effect on all-cause mortality

The effect of prokinetic agents on all-cause mortality was examined by six studies in 691 critically ill patients [23, 25, 28, 29, 31, 32]. There was no significant difference in all-cause mortality between the prokinetic agent group and the control group (RR 0.96, 95% CI 0.81, 1.14; P = 0.64; I² = 0%) (S3 Fig).

Subgroup analysis

Although no significant heterogeneity was found, we performed subgroup analysis to determine whether important subgroup differences existed. In the subgroup analysis stratified by type of prokinetic agents, no significant subgroup differences were detected in the clinical outcomes of hospital length of stay, ICU length of stay, reported adverse events and all-cause mortality (S4–S7 Figs). Furthermore, no study compared the use of a combination of prokinetics to placebo or no treatment. Only one study about the preventive usage of prokinetics for risk patients investigated reported adverse events [24]. The other studies investigated the preventive usage of prokinetics in all patients. The subgroup analysis of the preventive usage of prokinetics in all patients did not show important changes in the pooled effects of the reported adverse events.

Sensitivity analysis

The sensitivity analysis, which was performed by excluding the trials with a high risk of bias [25, 28], did not show important changes in the pooled effects of hospital length of stay, ICU length of stay, reported adverse events, and all-cause mortality. (S8–S11 Figs).

Certainty of evidence

The certainty of evidence was moderate for the clinical outcome of all-cause mortality. However, the certainty of evidence was low for the clinical outcomes of ICU length of stay, hospital length of stay and reported adverse events. The details of the risk of bias and quality assessment are outlined in Table 3.

Table 3. GRADE evidence profile of the efficacy and safety of prokinetics in critically ill adult patients receiving gastric feeding tubes.

Certainty assessment							No. of patients		Effect		Certainty	Importance
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Prokinetics	Placebo	Relative (95% CI)	Absolute (95% CI)	Certainty	Importance
Effect on ICU length of stay
3	randomized trials	serious ¹	not serious ²	not serious ³	serious ⁴	none ⁵	96	90	-	MD 2.03 days lower (3.96 days lower to 0.1 days lower)	⨁⨁◯◯ LOW	IMPORTANT
Effect on hospital length of stay
5	randomized trials	serious ⁶	not serious ⁷	not serious ³	serious ⁸	none ⁵	141	109	-	MD 3.21 days lower (5.35 days lower to 1.06 days lower)	⨁⨁◯◯ LOW	IMPORTANT
Effect on reported adverse events
7	randomized trials	serious ⁹	not serious ¹⁰	not serious ³	serious ¹¹	none	105/320 (32.8%)	120/437 (27.5%)	RR 1.13 (0.92 to 1.38)	40 more RAE per 1,000 patients (from 20 fewer RAE to 100 more RAE)	⨁⨁◯◯ LOW	IMPORTANT
Effect on all-cause mortality
6	randomized trials	serious ¹²	not serious ¹³	not serious ³	not serious ¹⁴	none	114/286 (39.9%)	174/405 (43.0%)	RR 0.96 (0.81 to 1.14)	30 fewer deaths per 1,000 patients (from 100 fewer deaths to 40 more deaths)	⨁⨁⨁◯ MODERATE	CRITICAL

Open in a new tab

CI: confidence interval; RR: risk ratio; MD: mean difference; RAE: reported adverse events.

1. We downgraded the quality of evidence for risk of bias by one level. Two of three included studies had a high or unclear risk of bias.

2. We did not downgrade for inconsistency, I² = 0% and Chi² = 1.45, P = 0.48.

3. Although the studies included any critically ill patient, we did not downgrade for indirectness.

4. We downgraded the quality of evidence for imprecision by one level because the total population size is less than 400. The 95% confidence interval contained a small benefit that did not meet the clinical decision threshold (min. one day).

5. We did not downgrade for publication bias, although we could not assess this category reliably due to the small number of eligible studies. Not all included studies showed benefits of the studied intervention.

6. We downgraded the quality of evidence for risk of bias by one level. Most studies had an unclear risk of bias. In addition, one study lacked allocation concealment and blinding.

7. We did not downgrade for inconsistency, I² = 28% and Chi² = 5.52, P = 0.24.

8. We downgraded the quality of evidence by one level for imprecision because the population size is less than 400.

9. We downgraded the quality of evidence for risk of bias by one level. Most studies had an unclear risk of bias. In addition, two studies lacked allocation concealment and/or blinding.

10. We did not downgrade for inconsistency, I² = 0% and Chi² = 1.64, P = 0.95.

11. We downgraded the quality of evidence for imprecision by one level because the 95% confidence interval around the pooled effect included both no effect and appreciable harm (a relative risk increase greater than 25%).

12. We downgraded the quality of evidence for risk of bias by one level. Most studies had an unclear risk of bias. In addition, two studies lacked allocation concealment, and two studies lacked blinding.

13. We did not downgrade for inconsistency, I² = 0% and Chi² = 4.52, P = 0.48.

14. We did not downgrade for imprecision because the 95% confidence interval around the pooled effect did not include both no effect and an appreciable benefit (a relative risk reduction greater than 25%) or appreciable harm (a relative risk increase greater than 25%).

Discussion

In this systematic review, we conducted a comprehensive literature search and used objective study inclusion criteria. Fifteen studies were included in the final analysis. Because of the small sample sizes and a relatively small number of eligible studies, the pooled effects are lacking in accuracy in the quantitative analysis. Most studies (10 of 13, 76.92%) showed that prokinetic agents had beneficial effects on feeding tolerance in critically ill adults. The studies that did not show beneficial effects (3 of 13, 23.08%) investigated special populations of neuro-critical patients and critical traumatic brain injury patients taking metoclopramide and rikkunshito. Furthermore, the use of prokinetic agents in critically ill patients receiving gastric feeding may reduce the ICU or hospital length of stay, but the certainty of evidence was low due to the risk of bias and imprecision. Prokinetics did not significantly reduce the risks of reported adverse events or all-cause mortality.

In this study, we examined the effect of prokinetic agents on gastrointestinal symptoms, feeding tolerance and clinical outcomes. Compared to the control group, the group receiving prokinetics did not have a low risk of mortality; these results were the same as the results of the meta-analysis by Lewis, K. et al. [11], but our methods were different. Lewis, K. et al. [11] defined feeding intolerance as either GRV ≥150 mL, vomiting, or abdominal distention resulting in feeding interruption. This definition may be considered obsolete [12]. We defined gastric feeding intolerance as either a GRV ≥500 mL or concomitant symptoms of nausea, vomiting, abdominal distention, regurgitation or other symptoms resulting in feeding interruption in critically ill adult patients with gastric feeding tubes. We excluded studies that discontinued or interrupted gastric feeding prematurely following the disappearance of gastric feeding intolerance. Our meta-analysis included new studies that used this latest definition [23–27, 30, 31], and we identified 5 studies that investigated the administration of prokinetics, including herbal medicines/natural medicines, to critically ill adult patients with gastric feeding tubes [25–27, 34, 37].

Additionally, we found that prokinetic agents might reduce the ICU or hospital length of stay for critically ill patients receiving gastric feeding. However, the number of studies and the sample size were very small, and the certainty of the evidence was low. Furthermore, no significant difference was found between the prokinetic agent groups and placebo/no treatment groups with regard to the risks of reported adverse events and all-cause mortality. Therefore, we cannot draw a convincing conclusion that the use of prokinetics can improve clinical outcomes in critically ill adults. We recommend that more research should be conducted in this field.

This study has several limitations. First, 21 published original studies or trials registered in the International Clinical Trials Registry Platform (WHO) or clinicaltrials.gov were identified. However, 6 trials, although completed, did not have available results, which might have led to the omission of trials meeting the inclusion criteria, resulting in publication bias. Second, some included trials did not record the baseline status of feeding intolerance for all participants. The subgroup results might have been different if all individuals were evaluated. Third, we were unable to comprehensively evaluate the risk of bias in 12 studies due to a lack of information. Fourth, for each outcome, the total sample size was relatively small, which likely resulted in inadequate power to detect a difference in treatment effect. We recommend that more original studies on this topic be conducted.

Conclusion

As a class of drugs, prokinetic agents may improve gastric feeding tolerance in critically ill adults. However, the certainty of the evidence suggesting that prokinetic agents are effective at reducing the ICU or hospital length of stay is low. There was also no significant reduction in the risk of reported adverse events or all-cause mortality. Additional RCTs are needed to determine the effect of prokinetics on clinical outcomes in critically ill patients in the future.

Supporting information

S1 Table. Search strategy.

(DOCX)

Click here for additional data file.^{(29.9KB, docx)}

S2 Table. Excluded studies.

(DOCX)

Click here for additional data file.^{(22.1KB, docx)}

S3 Table. Separate effects of different prokinetic agents on hospital or ICU length of stay.

(DOCX)

Click here for additional data file.^{(15.8KB, docx)}

S4 Table. PRISMA checklist.

(DOCX)

Click here for additional data file.^{(20.1KB, docx)}

S1 Fig. Risk of bias.

(DOCX)

Click here for additional data file.^{(27.2KB, docx)}

S2 Fig. Reported adverse event outcomes.

(DOCX)

Click here for additional data file.^{(23.6KB, docx)}

S3 Fig. All-cause mortality outcomes.

(DOCX)

Click here for additional data file.^{(23.1KB, docx)}

S4 Fig. Subgroup analysis by the type of prokinetic agents for hospital length of stay outcomes.

(DOCX)

Click here for additional data file.^{(38KB, docx)}

S5 Fig. Subgroup analysis by the type of prokinetic agents for ICU length of stay outcomes.

(DOCX)

Click here for additional data file.^{(32.5KB, docx)}

S6 Fig. Subgroup analysis by the type of prokinetic agents for reported adverse event outcomes.

(DOCX)

Click here for additional data file.^{(34.1KB, docx)}

S7 Fig. Subgroup analysis by the type of prokinetic agents for all-cause mortality outcomes.

(DOCX)

Click here for additional data file.^{(33.7KB, docx)}

S8 Fig. Sensitivity analysis of hospital length of stay outcomes.

(DOCX)

Click here for additional data file.^{(23.2KB, docx)}

S9 Fig. Sensitivity analysis of ICU length of stay outcomes.

(DOCX)

Click here for additional data file.^{(22.3KB, docx)}

S10 Fig. Sensitivity analysis of reported adverse event outcomes.

(DOCX)

Click here for additional data file.^{(22.7KB, docx)}

S11 Fig. Sensitivity analysis of all-cause mortality outcomes.

(DOCX)

Click here for additional data file.^{(22.2KB, docx)}

Acknowledgments

We are grateful to all the staff in this study for their teamwork and persistent efforts, and we are also thankful to the Group of People with Highest Risk of Drug Exposure of the International Network for the Rational Use of Drugs, China, and the Evidence-Based Pharmacy Committee of the Chinese Pharmaceutical Association for providing methodological advice.

Data Availability

All data generated or analysed during this study are included in this published article.

Funding Statement

The study was supported by National Major Science and Technology Projects of China (Award Number: 2017ZX09304029, Recipient: Lingli Zhang), Sichuan Province Science and Technology Major Project (Award Number: 2017JY0067, Recipient: Lingli Zhang), the Major Project of Sichuan health committee (Award Number: 18ZD042, Recipient: Lingli Zhang), the Major Project of Sichuan Province Science and Technology in field of social development (Award Number: 20ZDYF3101, Recipient: Lingli Zhang), Sichuan Science and Technology Program (Award Number: 2020YJ0198, Recipient: Rong Peng), the Project of Education Department of Sichuan Province (Award Number: 18ZB0146, Recipient: Rong Peng), the Project of Chengdu Municipal Health Commission (Award Number: 2020088, Recipient: Rong Peng), the major Project of Affiliated Hospital of Chengdu University (Award Number: 2020YZZ04, Recipient: Rong Peng). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

1.Lew CCH, Yandell R, Fraser RJL, Chua AP, Chong MFF, Miller M. Association Between Malnutrition and Clinical Outcomes in the Intensive Care Unit: A Systematic Review [Formula: see text]. JPEN J Parenter Enteral Nutr. 2017;41(5):744–58. Epub 2016/02/04. 10.1177/0148607115625638 . [DOI] [PubMed] [Google Scholar]
2.McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159–211. Epub 2016/01/17. 10.1177/0148607115621863 . [DOI] [PubMed] [Google Scholar]
3.Singer P, Blaser AR, Berger MM, Alhazzani W, Calder PC, Casaer MP, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38(1):48–79. Epub 2018/10/24. 10.1016/j.clnu.2018.08.037 . [DOI] [PubMed] [Google Scholar]
4.Blaser AR, Starkopf J, Kirsimagi U, Deane AM. Definition, prevalence, and outcome of feeding intolerance in intensive care: a systematic review and meta-analysis. Acta Anaesthesiol Scand. 2014;58(8):914–22. Epub 2014/03/13. 10.1111/aas.12302 . [DOI] [PubMed] [Google Scholar]
5.Hu B, Sun R, Wu A, Ni Y, Liu J, Guo F, et al. Prognostic Value of Prolonged Feeding Intolerance in Predicting All-Cause Mortality in Critically Ill Patients: A Multicenter, Prospective, Observational Study. JPEN J Parenter Enteral Nutr. 2019. Epub 2019/08/21. 10.1002/jpen.1693 . [DOI] [PubMed] [Google Scholar]
6.Gungabissoon U, Hacquoil K, Bains C, Irizarry M, Dukes G, Williamson R, et al. Prevalence, risk factors, clinical consequences, and treatment of enteral feed intolerance during critical illness. JPEN J Parenter Enteral Nutr. 2015;39(4):441–8. Epub 2014/03/19. 10.1177/0148607114526450 . [DOI] [PubMed] [Google Scholar]
7.Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. Jpen. 2003;Journal of parenteral and enteral nutrition. 27(5):355–73. CN-01757915 NEW. 10.1177/0148607103027005355 [DOI] [PubMed] [Google Scholar]
8.Consensus of early enteral nutrition clinical practice in critically ill patients. Chinese Critical Care Medicine. 2018;30(8):715–21. 10.3760/cma.j.issn.2095-4352.2018.08.001 [DOI] [PubMed] [Google Scholar]
9.Reintam Blaser A, Starkopf J, Alhazzani W, Berger MM, Casaer MP, Deane AM, et al. Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines. Intensive Care Med. 2017;43(3):380–98. Epub 2017/02/09. 10.1007/s00134-016-4665-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Peng R. The efficacy and safety of administration of prokinetics improve clinical outcomes in critically ill patients is still quite unclear. Clinical Nutrition. 2020;39:307–9. 10.1016/j.clnu.2019.11.027 [DOI] [PubMed] [Google Scholar]
11.Lewis K, Alqahtani Z, McIntyre L, Almenawer S, Alshamsi F, Rhodes A, et al. The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: A systematic review and meta-analysis of randomized trials. Critical Care. 2016;20 (1) (no pagination)(259). 10.1186/s13054-016-1441-z . [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Dive A. Benefit of prokinetics during enteral nutrition: still searching for a piece of evidence. Crit Care. 2016;20(1):341 Epub 2016/10/27. 10.1186/s13054-016-1502-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Higgins JPT. Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 (updated March 2011). Cochrane Collaboration website. http://training.cochrane.org/handbook. 2011. Accessed November 22, 2017.
14.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–34. Epub 2009/07/28. 10.1016/j.jclinepi.2009.06.006 . [DOI] [PubMed] [Google Scholar]
15.Gupta SK. Intention-to-treat concept: A review. Perspect Clin Res. 2011;2(3):109–12. Epub 2011/09/08. 10.4103/2229-3485.83221 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med. 2010;7(3):e1000251 Epub 2010/03/31. 10.1371/journal.pmed.1000251 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27(6):1785–805. Epub 2016/09/30. 10.1177/0962280216669183 . [DOI] [PubMed] [Google Scholar]
18.Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135 Epub 2014/12/20. 10.1186/1471-2288-14-135 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med. 2002;21(11):1575–600. Epub 2002/07/12. 10.1002/sim.1188 . [DOI] [PubMed] [Google Scholar]
20.Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Research synthesis methods. 2010;1(2):97–111. Epub 2010/04/01. 10.1002/jrsm.12 . [DOI] [PubMed] [Google Scholar]
21.Furukawa TA, Watanabe N, Omori IM, Montori VM, Guyatt GH. Association between unreported outcomes and effect size estimates in Cochrane meta-analyses. JAMA. 2007;297(5):468–70. Epub 2007/02/08. 10.1001/jama.297.5.468-b . [DOI] [PubMed] [Google Scholar]
22.Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6. Epub 2008/04/26. 10.1136/bmj.39489.470347.AD [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Acosta-Escribano J, Almanza Lopez S, Plumed Martin L, Garcia Martinez MA, Tajadura Manjarin N. The metoclopramide effect on enteral nutrition tolerance and mechanical ventilation associated pneumonia in neuro critically ill patients. Nutricion hospitalaria. 2014;29(6):1345–51. CN-01115568. 10.3305/nh.2014.29.6.7286 [DOI] [PubMed] [Google Scholar]
24.Chapman MJ, Deane AM, O'Connor SL, Nguyen NQ, Fraser RJL, Richards DB, et al. The effect of camicinal (GSK962040), a motilin agonist, on gastric emptying and glucose absorption in feed-intolerant critically ill patients: a randomized, blinded, placebo-controlled, clinical trial https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967996/. Critical care. 2016;20(1). CN-01177110. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Doi M, Miyamoto K, Shimokawa T, Ariyasu H, Kaneko M, Yonemitsu T, et al. The effect of standard and high dose of rikkunshito on achievement of enteral nutrition target in critically ill patients: a pilot randomized controlled trial. Acute medicine and surgery. 2019. CN-01960632 NEW. [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Guo JH, Chen G, Yang SQ, Wei MH, Chen X. Clinical observation of the role of Chenxia Sijunzi decoction in promoting the recovery of gastrointestinal function in critically ill patients. Zhongguo wei zhong bing ji jiu yi xue [Chinese critical care medicine]. 2012;24(11):674–6. CN-00966946. [PubMed] [Google Scholar]
27.Kooshki A, Khazaei Z, Zarghi A, Rad M, Mohammadi HG, Tabaraie Y. Effects of fenugreek seed powder on enteral nutrition tolerance and clinical outcomes in critically ill patients: a randomized clinical trial. Biomedical research and therapy. 2018;5(7):2528–37. CN-01630190. [Google Scholar]
28.Nassaji M, Ghorbani R, Frozeshfard M, Mesbahian F. Effect of metoclopramide on nosocomial pneumonia in patients with nasogastric feeding in the intensive care unit. La revue de sante de la Mediterranee orientale / al-Majallah al-sihhiyah li-sharq al-mutawassit [Eastern Mediterranean health journal]. 2010;16(4):371–4. CN-00761902. [PubMed] [Google Scholar]
29.Nursal TZ, Erdogan B, Noyan T, Cekinmez M, Atalay B, Bilgin N. The effect of metoclopramide on gastric emptying in traumatic brain injury. J Clin Neurosci. 2007;14(4):344–8. Epub 2007/03/06. 10.1016/j.jocn.2005.11.011 . [DOI] [PubMed] [Google Scholar]
30.Ritz MA, Chapman MJ, Fraser RJ, Finnis ME, Butler RN, Cmielewski P, et al. Erythromycin dose of 70 mg accelerates gastric emptying as effectively as 200 mg in the critically ill. Intensive care medicine. 2005;31(7):949–54. CN-00528427. 10.1007/s00134-005-2663-8 [DOI] [PubMed] [Google Scholar]
31.Spapen HD, Duinslaeger L, Diltoer M, Gillet R, Bossuyt A, Huyghens LP. Gastric emptying in critically ill patients is accelerated by adding cisapride to a standard enteral feeding protocol: results of a prospective, randomized, controlled trial. Critical care medicine. 1995;23(3):481–5. CN-00111279. 10.1097/00003246-199503000-00011 [DOI] [PubMed] [Google Scholar]
32.Yavagal DR, Karnad DR, Oak JL. Metoclopramide for preventing pneumonia in critically ill patients receiving enteral tube feeding: a randomized controlled trial. Critical care medicine. 2000;28(5):1408–11. CN-00278171. 10.1097/00003246-200005000-00025 [DOI] [PubMed] [Google Scholar]
33.Heyland DK, Tougas G, Cook DJ, Guyatt GH. Cisapride improves gastric emptying in mechanically ventilated, critically ill patients. A randomized, double-blind trial. American journal of respiratory and critical care medicine. 1996;154(6 Pt 1):1678–83. CN-00135101. 10.1164/ajrccm.154.6.8970354 [DOI] [PubMed] [Google Scholar]
34.Mokhtari M, Shariatpanahi Z. Ginger extract dietary supplementation effects on delayed gastric emptying and ventilator-associated pneumonia in adult respiratory distress syndrome patients. Critical Care. 2009;1):S56 . [DOI] [PubMed] [Google Scholar]
35.Rajan V, Maiwall R, Choudhury AK, Jamwal KD, Benjamin J, Kumar G, et al. Early addition of prokinetics reverses gut paralysis and improves survival in critically ill cirrhotics-An open label placebo controlled RCT (Feed Intolerance and Treatment-FIT protocol). NCT02528760. Hepatology. 2017;66. CN-01419530. [Google Scholar]
36.Sustic A, Zelic M, Protic A, Zupan Z, Simic O, Desa K. Metoclopramide improves gastric but not gallbladder emptying in cardiac surgery patients with early intragastric enteral feeding: randomized controlled trial. Croatian medical journal. 2005;46(2):239–44. CN-00512116. [PubMed] [Google Scholar]
37.Tahershamsi F, Rezaei K, Khosravi S, Kheyri Z, Memarzadeh MR, Rafie F. Effect of oral drop gastrolit (Zataria multiflora) on gastric residual volume in mechanically ventilated patients hospitalized in the intensive care units. Journal of medicinal plants. 2018;17(68):66–73. CN-01650951. [Google Scholar]
38.Chapman MJ, Fraser RJ, Kluger MT, Buist MD, De Nichilo DJ. Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding. Critical care medicine. 2000;28(7):2334–7. CN-00298628. 10.1097/00003246-200007000-00026 [DOI] [PubMed] [Google Scholar]
39.Deane AM, Lamontagne F, Dukes GE, Neil D, Vasist L, Barton ME, et al. Nutrition Adequacy Therapeutic Enhancement in the Critically Ill: a Randomized Double-Blind, Placebo-Controlled Trial of the Motilin Receptor Agonist Camicinal (GSK962040): the NUTRIATE Study. Journal of parenteral and enteral nutrition. 2018;42(5):949–59. CN-01617154 NEW. 10.1002/jpen.1038 [DOI] [PubMed] [Google Scholar]
40.Pinilla JC, Samphire J, Arnold C, Liu L, Thiessen B. Comparison of gastrointestinal tolerance to two enteral feeding protocols in critically ill patients: a prospective, randomized controlled trial. Journal of Parenteral and Enteral Nutrition 2001;25(2):81–6. 10.1177/014860710102500281 [DOI] [PubMed] [Google Scholar]
41.Reignier J, Bensaid S, Perrin-Gachadoat D, Burdin M, Boiteau R, Tenaillon A. Erythromycin and early enteral nutrition in mechanically ventilated patients. Critical care medicine. 2002;30(6):1237–41. CN-00389663. 10.1097/00003246-200206000-00012 [DOI] [PubMed] [Google Scholar]
42.Taylor SJ, Allan K, McWilliam H, Manara A, Brown J, Greenwood R, et al. A randomised controlled feasibility and proof-of-concept trial in delayed gastric emptying when metoclopramide fails: we should revisit nasointestinal feeding versus dual prokinetic treatment: achieving goal nutrition in critical illness and delayed gastric emptying: trial of nasointestinal feeding versus nasogastric feeding plus prokinetics. Clinical nutrition ESPEN. 2016;14:1–8. CN-01446990. 10.1016/j.clnesp.2016.04.020 [DOI] [PubMed] [Google Scholar]
43.Boivin MA, Levy H. Gastric feeding with erythromycin is equivalent to transpyloric feeding in the critically ill. Critical care medicine. 2001;29(10):1916–9. CN-00374254. 10.1097/00003246-200110000-00011 [DOI] [PubMed] [Google Scholar]
44.Euctr ES. A Phase 2, Multicenter, Randomized, Double-Blind, Comparator-Controlled Study of the Efficacy, Safety, and Pharmacokinetics of Intravenous Ulimorelin (LP101) in Patients with Enteral Feeding Intolerance. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=EUCTR2016. 2016. CN-01853774.
45.Hayakawa M, Ono Y, Wada T, Yanagida Y, Sawamura A, Takeda H, et al. Effects of rikkunshito (traditional Japanese medicine) on enteral feeding and the plasma ghrelin level in critically ill patients: a pilot study. Journal of intensive care. 2014;2(1). CN-01070476. 10.1186/s40560-014-0053-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
46.Heyland DK, van Zanten ARH, Grau-Carmona T, Evans D, Beishuizen A, Schouten J, et al. A multicenter, randomized, double-blind study of ulimorelin and metoclopramide in the treatment of critically ill patients with enteral feeding intolerance: PROMOTE trial. Intensive care medicine. 2019;45(5):647–56. CN-01938933 NEW. 10.1007/s00134-019-05593-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
47.Irct201112014578N. The effect of acupuncture and traditional pharmacologic therapy on Delayed Gastric Emptying. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=IRCT201112014578N4. 2012. CN-01863905.
48.Irct201408104365N. Combination of Neostigmine and Metoclopramide to reduce gastric residual volume in mechanically ventilated ICU patients. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=IRCT201408104365N16. 2015. CN-01798093.
49.Irct201412044365N. Comparison of the effect of Neostigmine and Metoclopramide on gastric residual volume in mechanically ventilated ICU patients. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=IRCT201412044365N18. 2014. CN-01816620.
50.MacLaren R, Patrick WD, Hall RI, Rocker GM, Whelan GJ, Lima JJ. Comparison of cisapride and metoclopramide for facilitating gastric emptying and improving tolerance to intragastric enteral nutrition in critically III, mechanically ventilated adults. Clinical therapeutics. 2001;23(11):1855–66. CN-00376433. 10.1016/s0149-2918(00)89081-5 [DOI] [PubMed] [Google Scholar]
51.Makkar JK, Gauli B, Jain K, Jain D, Batra YK. Comparison of erythromycin versus metoclopramide for gastric feeding intolerance in patients with traumatic brain injury: a randomized double-blind study. Saudi journal of anaesthesia. 2016;10(3):308–13. CN-01166741. 10.4103/1658-354X.174902 [DOI] [PMC free article] [PubMed] [Google Scholar]
52.Malekolkottab M, Khalili H, Mohammadi M, Ramezani M, Nourian A. Metoclopramide as intermittent and continuous infusions in critically ill patients: a pilot randomized clinical trial. Journal of comparative effectiveness research. 2017;6(2):127–36. CN-01327651. 10.2217/cer-2016-0067 [DOI] [PubMed] [Google Scholar]
53.Nct. A Randomized, Double-Blind Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of a Single Dose of Intravenous TD-8954 Compared With Metoclopramide in Critically Ill Patients With Enteral Feeding Intolerance. https://clinicaltrialsgov/show/NCT01953081. 2013. CN-01490372.
54.Nct. Itopride in Feeding Intolerance of Critically-ill Patients Receiving Enteral Nutrition. https://clinicaltrialsgov/show/NCT03698292. 2018. CN-01663921.
55.Nguyen N, Chapman M, Fraser R, Sharley V, Kong S, Bryant L, et al. Erythromycin or metoclopramide for feed intolerance in the critically ill. Critical care. 2006;10(Suppl 1). CN-00625643. [Google Scholar]
56.Taylor S, Manara A, Brown J. Treating delayed gastric emptying in critical illness: metoclopramide, erythromycin and bedside (Cortrak[TM]) nasointestinal tube placement. Journal of the intensive care society. 2011;12(1):75–. CN-01003955. [DOI] [PubMed] [Google Scholar]
57.Yanagida Y, Hayakawa M, Yamamoto H, Wada T, Sugano M, Sawamura A, et al. Effects of rikkunshito (traditional Japanese medicine Kampo) on enteral feeding and plasma ghrelin concentration in critically ill patients: a double-blind, randomized, controlled trial. Intensive care medicine. 2013;39:S242–S3. CN-01010636. [Google Scholar]
58.Berne JD, Norwood SH, McAuley CE, Vallina VL, Villareal D, Weston J, et al. Erythromycin reduces delayed gastric emptying in critically ill trauma patients: a randomized, controlled trial. Journal of trauma. 2002;53(3):422–5. CN-00398193. 10.1097/00005373-200209000-00004 [DOI] [PubMed] [Google Scholar]
59.Meissner W, Dohrn B, Reinhart K. Enteral naloxone reduces gastric tube reflux and frequency of pneumonia in critical care patients during opioid analgesia. Critical care medicine. 2003;31(3):776–80. CN-00422940. 10.1097/01.CCM.0000053652.80849.9F [DOI] [PubMed] [Google Scholar]
60.Shariatpanahi ZV, Taleban FA, Mokhtari M, Shahbazi S. Ginger extract reduces delayed gastric emptying and nosocomial pneumonia in adult respiratory distress syndrome patients hospitalized in an intensive care unit. Journal of critical care. 2010;25(4):647–50. CN-00771992. 10.1016/j.jcrc.2009.12.008 [DOI] [PubMed] [Google Scholar]
61.Tamion F, Hamelin K, Duflo A, Girault C, Richard JC, Bonmarchand G. Gastric emptying in mechanically ventilated critically ill patients: effect of neuromuscular blocking agent. Intensive care medicine. 2003;29(10):1717–22. CN-00470263. 10.1007/s00134-003-1898-5 [DOI] [PubMed] [Google Scholar]
62.Chen JH, Hsieh CB, Chao PC, Liu HD, Chen CJ, Liu YC, et al. Effect of water-soluble contrast in colorectal surgery: a prospective randomized trial. World journal of gastroenterology. 2005;11(18):2802–5. CN-00511902. 10.3748/wjg.v11.i18.2802 [DOI] [PMC free article] [PubMed] [Google Scholar]
63.Goldhill DR, Toner CC, Tarling MM, Baxter K, Withington PS, Whelpton R. Double-blind, randomized study of the effect of cisapride on gastric emptying in critically ill patients. Critical care medicine. 1997;25(3):447–51. CN-00138391. 10.1097/00003246-199703000-00013 [DOI] [PubMed] [Google Scholar]
64.Warusevitane A, Karunatilake D, Sim J, Lally F, Roffe C. Safety and effect of metoclopramide to prevent pneumonia in patients with stroke fed via nasogastric tubes trial. Stroke. 2015;46(2):454–60. 10.1161/STROKEAHA.114.006639 . [DOI] [PubMed] [Google Scholar]
65.Tctr. Efficacy and safety of oral Erythromycin estolate in combination with Metoclopramide versus Metoclopramide mOnotherapy in mechanically ventilated patients who developed enteral feeding intolerance: a randomized double-blind controlled study. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=TCTR20171004004. 2017. CN-01884466. [DOI] [PubMed]
66.NCT02528760. To Determine the Role of Prokinetics in Feed Intolerance in Critically Ill Cirrhosis. https://clinicaltrialsgov/show/NCT02528760. 2015. CN-01580381.
67.NCT02379624. Pectin Start Early Enteral Nutritional Support in Critically Ill Patients. https://clinicaltrialsgov/show/NCT02379624. 2014. CN-01504758.
68.IRCT201610297494N24. The prophylactic effect of cuminum cyminum extract on gastric residual volume in traumatic patients under ventilator hospitalized in intensive care unit. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=IRCT201610297494N24. 2017. CN-01887634.
69.IRCT201009094722N2. The effect of Ginger extract on gastric residual volume in patients with mechanical ventilation hospitalized in intensive care unit. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=IRCT201009094722N2. 2011. CN-01849490.
70.2015/08/006111 C. Clinical trial to compare the efficacy of two oral prokinetics metoclopramide and erythromycin in non acceptance of feed in head injury patient. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=CTRI. 2015;08(006111). CN-01873462.

PLoS One. doi: 10.1371/journal.pone.0245317.r001

Decision Letter 0

Lisa Susan Wieland

19 Mar 2020

PONE-D-20-01167

The efficacy and safety of prokinetics in adult critically ill patients receiving gastric enteral nutrition: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Zhang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Both reviewers asserted that the manuscript was not technically sound, and the conclusions were not supported by the data, and both reviewers found that the text required further editing to be clearly understandable. Please see the reviewer comments for details. This manuscript would require quite a bit of revision and clarification to be suitable for further peer review and potential publication.

Specific highlights of the reviewer comments include:

Although the updated definition of feeding intolerance provides a rationale for a new examination of the question, it appears from the reviewer comments that studies without a clear definition were included (eg, Tahershamsi 2018). Please clarify why these were selected for inclusion.
It also appears from the reviewer comments that several relevant studies may have been missed. This issue could be clarified by specifying the references and exclusion criteria for the 27 studies excluded at full text. This could be done in a separate online table if necessary.
The reviewer who noted the inclusion of hospital length of stay in the Results but not in the Methods is correct. Please clarify this.
Pay attention to reviewer comments highlighting the problem with combining different interventions in the meta-analysis. For example, in the herbal group of studies, why does it make sense to combine rikkunshito and fenugreek, and why does it make sense to produce a summary estimate across all the different types of interventions? Please clarify or revise.
The reviewer comments about GRADE evaluations should be responded to. For example, imprecision is present in several analyses based on rule-of-thumb criteria for sample size (eg, at least 400 participants or 300 events in an analysis), as well as potentially based on width of the confidence interval including both benefit and lack of effect. The criteria for decisions about GRADE elements should be specified in the Methods section, and the rationale for decisions should be made clear through footnotes to Table 2.
Regarding publication bias and GRADE, it is appropriate that funnel plots were not created however the rationale for strongly suspecting publication bias in all estimates should be clarified.

In addition, I have the following comments based upon my reading of the manuscript submission:

Under funding disclosure, it is unclear whether the review was funded, and if so by whom. This needs to be specified.
The Plos ONE guidelines for systematic reviews state that: ‘Authors must also state in their “Methods” section whether a protocol exists for their systematic review, and if so, provide a copy of the protocol as supporting information and provide the registry number in the abstract.‘ Please include this information.
The review Methods should include a description of the procedures for screening of titles/abstracts and full texts.
The I-squared is not an evaluation of the statistical heterogeneity between summary data. It is an estimate of the percentage of variability in a meta-analysis that is attributable to study heterogeneity.
The choice of a random vs fixed effects model should not be based on heterogeneity according to the Cochrane Handbook and other sources. For more information on choice of models see page 105 of https://www.meta-analysis.com/downloads/Intro_Models.pdf.

==============================

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Yours sincerely,

Lisa Susan Wieland

Academic Editor

PLOS ONE

Journal requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service.

Whilst you may use any professional scientific editing service of your choice, PLOS has partnered with both American Journal Experts (AJE) and Editage to provide discounted services to PLOS authors. Both organizations have experience helping authors meet PLOS guidelines and can provide language editing, translation, manuscript formatting, and figure formatting to ensure your manuscript meets our submission guidelines. To take advantage of our partnership with AJE, visit the AJE website (http://learn.aje.com/plos/) for a 15% discount off AJE services. To take advantage of our partnership with Editage, visit the Editage website (www.editage.com) and enter referral code PLOSEDIT for a 15% discount off Editage services. If the PLOS editorial team finds any language issues in text that either AJE or Editage has edited, the service provider will re-edit the text for free.

Upon resubmission, please provide the following:

The name of the colleague or the details of the professional service that edited your manuscript
A copy of your manuscript showing your changes by either highlighting them or using track changes (uploaded as a *supporting information* file)
A clean copy of the edited manuscript (uploaded as the new *manuscript* file)

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"The study was supported by the Science and Technology Department of Sichuan Province Major

397 Project (Grant no. 2017JY0067), the National Science and Technology Major Project (Grant no.

398 2017ZX09304029) and the Major Project of Sichuan health committee (18ZD042), and the Program

399 for Yangtze River Scholars and Innovative Research Team in University (No. IRT0935).

400 Role of the Funder: The Science and Technology Department of Sichuan Province Major Project, the

401 National Science and Technology Major Project, and the Program for Yangtze River Scholars and

402 Innovative Research Team had no role in the design and conduct of the study; collection,

403 management, analysis, and interpretation of the data; preparation, review, or approval of the

404 manuscript; and decision to submit the manuscript for publication.".

i) We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

ii) Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.".

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

==============================

We would appreciate receiving your revised manuscript by May 03 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Lisa Susan Wieland

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments (if provided):

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Paragraph 115-118 needs revision. Fragment?

Line 142: end of sentence “ changes of electrocardiogram QTc interval, and so on”. Perhaps removing “and so on” will sound better or can refer to outcomes listed in the paragraph of “inclusion criteria”.

Lines 252-254: for consistency, report results fully with point estimates and 95% CIs.

Lines 256-259: what do the authors mean by “the total situation”. “And there was also no significant difference in the risk of the reported adverse events between prokinetics treatment and the control group on the total situation (RR, 1.18, 95%CI, 0.79 to 1.75, P=0.42; I2=69%).

Lines 264: can the authors explain why they deviated from their data analysis plan of conducting publication bias assessment when 10 or more studies were available (lines 181-183) but lowered the quality of evidence because publication bias was strongly suspected?

Line 271-272: “Subgroup analysis by type of prokinetics.” Fragment.

Line 275-277: When Metoclopramide did not show significant difference in the hospital length of stay compared with the control group (MD, 1.70, 95%CI, -4.75 to 8.15, P=0.61; I2=0%) (S1 Fig). Check grammar please.

Lines 283-284: repetition of 254-256.

Lines 285-286: review grammar.

Line 286-287: pooled effects for what outcome(s)?

Line 288: I think the authors mean to have the first part as a subheading “Subgroup analysis by preventive giving prokinetics or therapeutic usage of prokinetics.”

Would recommend: preventive use instead of preventive giving.

Also would recommend: “pooled effects for primary outcomes” instead of “pooled effects” at the end of sentences.

Lines 298-301: the authors deviate from statistical plan for publication bias again by downgrading for string suspicion of publication bias. Revision needed. Also in GRADE evidence profile confidence intervals for all-cause mortality, ICU and hospital length of stay and adverse events all include significant benefits and harms and yet no downgrading for imprecision was performed. Can the authors elaborate on this ? ¬¬¬For length of stay what was the unit of measurement? Days or hours? This would be important for the outcome of hospital length of stay with natural medicines. If the difference was 9 days fewer and between 18.5 and 0.8 days lower, one might consider downgrading for imprecision specially that the number of patients in that analysis is 122 only. I would strongly recommend the authors consult someone with more experience using the GRADE method.

Lines 315-318: And there was a systematic review about the definition, prevalence, and outcome of feeding intolerance in intensive care, and the result showed that there were more than 60% (40/63) of studies defining the large GRVs with the threshold less than or equal to 250 ml and about 41.7% (30/72) of studies with the sole GRVs levels to definite of feeding intolerance. Not clear and needs to be rewritten.

Lines 325-327: So, we conducted this updated systematic review and meta-analysis, we defined the gastric enteral nutrition feeding intolerance as either GRV ≥500 ml or GRV <500 ml concomitant with symptoms of nausea, vomiting, abdominal distention, regurgitation or other symptoms resulting in feeding interruption. This is not true. Only 3 of the included studies explicitly reported the cutoff for the GRV to be ≥ 500 ml (24, 31, 34) and 1 study reported > 200 ml at any time or > 500 ml/24 hours). I find this misleading.

Line 342: Lewis, K. et al [12] defined feeding intolerance as either GRV ≥150 ml, vomiting, or abdominal distention resulting in feeding interruption. This definition may be considered obsolete [13]. This is very difficult to justify given the point above when the exact amount of GRV was not reported in more than half of the studies included.

Lines 342-347 are exact repetition of lines 324-329.

Line 351: “trails” change to “trials”

Lines 352-358: I disagree with the conclusion. The heterogeneity was 95%, the confidence intervals we extremely wide (especially if this was in days) and the total number of patients is 122. This makes it extremely difficult to make any sound conclusions, contrary to the way reported by the authors.

Lines 380: I am concerned that the while the title of the ,manuscript is prokinetics, the bulk of discussion section and the conclusion is about herbal medicines as prokinetic agents. As mentioned earlier, the authors claim their cutoff for GRV was 500 ml but they included many studies without a clear cutoff and by doing that they missed many studies in Lewis et al. that included generic medicines. In addition, the authors did not include hospital length of stay as an outcome in their methods section (lines 92-101) and yet they perform this analysis and include the forest plot for it in the main manuscript.

The methods section very well written, however the other sections need significant revision of language and grammar.

Reviewer #2: The authors made a new metaanalysis on the efficacy and safety of prokinetic agents administered during enteral feeding in intensive care patients. Previous metaanalysis were already performed on thIs topic. Originality of this work may come from a revised definition for digestive feeding intolerance, which indeed corresponds to more recent experts recommendations (Gastric residual volume (GRV) above 500 mls). It has to be noted however, that even the treshold of 500 mls GRV for definition of gastric enteral feeding intolerance is challenged, and some authors now recommend against measuring any GRV during enteral nutrition in ICU patients.

I have two major concerns with that study:

- Subgroup analysis: what is the rationale of pooling studies in which different substances are administered: indeed, natural/herbal substances are not identical in these pooled studies.

- To my opinion, the conclusion (administration of herbal medicines/natural medicines may reduce hospital length of stay) is not supported by the (meta)analysis. The purpose of a metaanalysis is to pool pertinent studies in order to answer a well predefined question. The conclusion that is drawn by the authors is not really related to the initial question.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Alain-Michel Dive, CHU UCL Namur, Belgium

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Jan 11;16(1):e0245317. doi: 10.1371/journal.pone.0245317.r002

Author response to Decision Letter 0

28 Apr 2020

Dear Editors and Reviewers,

Thank you for your letter and the comments concerning our manuscript (Manuscript Number: PONE-D-20-01167). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portion are marked with the changes highlighted in yellow in the paper. The main corrections in the paper and the responds to the reviewer’s comments are as flowing:

Editors' comments:

We appreciate your generous help and your patience. We take all the comments into consideration, and revise our manuscript accordingly. We hope the revised manuscript can meet with your approval. The answers to your comments are as flowing:

1. Although the updated definition of feeding intolerance provides a rationale for a new examination of the question, it appears from the reviewer comments that studies without a clear definition were included (eg, Tahershamsi 2018). Please clarify why these were selected for inclusion.

Answer: In our study, except for feeding tolerance, the main outcomes included gastrointestinal symptoms and clinical outcomes (hospital length of stay, ICU length of stay, reported adverse events, all-cause mortality). The included studies were not based on whether the study with a clear definition of feeding intolerance. But we excluded these studies that discontinued or interrupted the gastric feeding prematurely when the GRV was less than 500 mL or the patients did not have any signs of intolerance.

2. It also appears from the reviewer comments that several relevant studies may have been missed. This issue could be clarified by specifying the references and exclusion criteria for the 27 studies excluded at full text. This could be done in a separate online table if necessary.

Answer: all the literatures had been checked again. The inclusion and exclusion studies all met the predefined criteria. And according to your advice, we added a table to explain the exclusion reason for the 27 studies. (Supp. Table 2).

3. The reviewer who noted the inclusion of hospital length of stay in the Results but not in the Methods is correct. Please clarify this.

Answer: we are very appreciated of your kindly advise. Because of our carelessness, “hospital length of stay” did not present in the Inclusion Criteria of Methods section. But the outcome of “hospital length of stay” have already been included in our plan. In the Methods section of the Data Extraction and Statistical Analysis, the outcome of “hospital length of stay” had been included. So, we amended the Methods section in manuscript. we added the outcome of “hospital length of stay” in the Inclusion Criteria of Methods section.

4. Pay attention to reviewer comments highlighting the problem with combining different interventions in the meta-analysis. For example, in the herbal group of studies, why does it make sense to combine rikkunshito and fenugreek, and why does it make sense to produce a summary estimate across all the different types of interventions? Please clarify or revise.

Answer: According to your advice, we have amended the relevant part in manuscript. In the revised manuscript, we removed the results of the combining herbal group in the meta-analysis. However, as a class of drugs, the results of the combining different types of prokinetics in the meta-analysis were reserved. Although no significant heterogeneity was found, we performed subgroup analyses to determine if there are important subgroup differences.

5. The reviewer comments about GRADE evaluations should be responded to. For example, imprecision is present in several analyses based on rule-of-thumb criteria for sample size (eg, at least 400 participants or 300 events in an analysis), as well as potentially based on width of the confidence interval including both benefit and lack of effect. The criteria for decisions about GRADE elements should be specified in the Methods section, and the rationale for decisions should be made clear through footnotes to Table 2.

Answer: we felt sorry for these mistakes. We seriously conducted the GRADE evaluation again. In the revised manuscript, the details of the risk of bias and quality assessment were outlined in Table 3, the rationale for decisions had been made clear through footnotes to Table 3.

6. Regarding publication bias and GRADE, it is appropriate that funnel plots were not created however the rationale for strongly suspecting publication bias in all estimates should be clarified.

Answer: In view of the fact that publication bias arises when investigators fail to report studies they have undertaken (typically those that show no effect). A prototypical situation that should elicit suspicion of publication bias occurs when published evidence is limited to a small number of trials, all of which are showing benefits of the studied intervention.

In the revised manuscript, the meta-analysis showed that the use of prokinetic agents in critically ill patients receiving gastric feeding may reduce ICU or hospital length of stay, there was no significant difference in the incidence of reported adverse events and all-cause mortality between prokinetic agent group and control group. Although we could not assess this category reliably due to small number of eligible studies, we did not downgrade the quality of evidence for publication bias. Because not all of included studies were showing benefits of the studied intervention in clinical outcome of ICU length of stay and hospital length of stay, respectively.

7. Under funding disclosure, it is unclear whether the review was funded, and if so by whom. This needs to be specified.

Answer: according to your advice, we have amended the relevant part in manuscript.

8. The Plos ONE guidelines for systematic reviews state that: ‘Authors must also state in their “Methods” section whether a protocol exists for their systematic review, and if so, provide a copy of the protocol as supporting information and provide the registry number in the “abstract”. Please include this information.

Answer: we have registered our protocol in https://www.crd.york.ac.uk/prospero/,

but the review is still ongoing (ID 157446).

9. The review Methods should include a description of the procedures for screening of titles/abstracts and full texts.

Answer: according to your advice, we have amended the relevant part in manuscript. The details of the eligible trials are presented in Figure 1. Reasons for excluding studies included that the study had a different trial design [41-45]; the study had a different intervention or a different control [46-64]; the study had a different population [65-67]; or the study had been registered with the Clinical Trials Registry Platform (clinicaltrials.gov or WHO ICTRP) and had been labeled “completed”, but outcomes did not report [68-73] (Supp. Table 2).

10. The I-squared is not an evaluation of the statistical heterogeneity between summary data. It is an estimate of the percentage of variability in a meta-analysis that is attributable to study heterogeneity.

The choice of a random vs fixed effects model should not be based on heterogeneity according to the Cochrane Handbook and other sources. For more information on choice of models see page 105 of https://www.meta-analysis.com/downloads/Intro_Models. pdf.

Answer: We appreciate your generous help for the references. In the revised manuscript, a random-effects model was used. However, if the number of studies is very small, the statistical power will have poor precision due to the variance between studies. Although the random-effects model is still the appropriate model, the information to apply it correctly is not available. In this case, we added the separate effects to our manuscript. If heterogeneity was identified (I2 >40%) and there were sufficient trials included in the review, we planned to investigate heterogeneity in the specified subgroups based on types of prokinetics (erythromycin, metoclopramide or other prokinetics), combination of prokinetics (yes or no), and feeding intolerance history (participants with or without pre-existing feeding intolerance before the start of the trial). Analysis was performed to assess whether the difference between the subgroups was statistically significant.

Thanks again for your help and your advice. With the help of American Journal Experts (AJE), we corrected errors in grammar and spelling in our manuscript. We also hope that the revised manuscript can meet with your approval.

Reviewers' comments:

Reviewer #1:

Thanks a lot for your very considerate advice. In the revised manuscript, there were some substantially modified in our results and conclusions sections. we removed the results of the combining herbal group in the meta-analysis. A random-effects model was used. However, if the number of studies is very small, the statistical power will have poor precision due to the variance between studies. Although the random-effects model is still the appropriate model, the information to apply it correctly is not available. In this case, we added the separate effects to our manuscript. In addition, with the help of American Journal Experts (AJE), we corrected errors in grammar and spelling in our manuscript.

we will reply your comments one by one in details.

1. Paragraph 115-118 needs revision. Fragment?

Answer: yes, we have amended the relevant part in manuscript.

In the revised essay, it is shown as follows: if the gastric feeding patients with feeding intolerance had a GRV ≥500 mL and/or symptoms of nausea, vomiting, abdominal distention, regurgitation, deterioration in hemodynamics or other symptoms resulting in feeding interruption, and if they failed to respond to intervention, then, regardless of whether they were in the control group or the prokinetics group, they were switched to postpyloric feeding or had gastric feeding withheld for 4-6 h.

2. Line 142: end of sentence “changes of electrocardiogram QTc interval, and so on”. Perhaps removing “and so on” will sound better or can refer to outcomes listed in the paragraph of “inclusion criteria”.

Answer: according to your advice, we have listed the outcomes of reported adverse events in the paragraph of “inclusion criteria”. In the revised essay, it is showed as follows: A reported adverse event was defined as any untoward medical occurrence or unfavorable and unintended sign, including an abnormal laboratory finding, symptom, or disease (new or exacerbated), temporally associated with the use of the study medication. The reported adverse events included abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, or measurements of vital signs), including those that worsened from baseline, and were deemed clinically significant in the medical and scientific judgment of the investigator; exacerbation of a chronic or intermittent preexisting condition, including an increase in the frequency and/or intensity of the condition; new conditions detected or diagnosed after the administration of study medication even if they may have been present prior to the start of the study; and/or signs, symptoms, or clinical sequelae of a suspected interaction, such as, diarrhea, nosocomial pneumonia, severe sepsis, brain herniation, cardiac arrest, or changes in the electrocardiographic QTc interval.

3. Lines 252-254: for consistency, report results fully with point estimates and 95% CIs.

Answer: Yes, in the revised manuscript, all the results were fully with point estimates and 95% CIs.

4. Lines 256-259: what do the authors mean by “the total situation”. “And there was also no significant difference in the risk of the reported adverse events between prokinetics treatment and the control group on the total situation (RR, 1.18, 95%CI, 0.79 to 1.75, P=0.42; I2=69%).

Answer: in the revised manuscript, this part had a big change in data analysis. In the outcome of reported adverse events, it is showed as follows: “Seven studies reported events that met the definition of adverse events in 757 critically ill patients [26-28, 30-32, 35]. The meta-analysis showed that there was no significant difference in the incidence of reported adverse events between the prokinetic agent group and the control group (RR 1.13, 95% CI 0.92, 1.38; P = 0.25; I2 = 0%) (Supp. Figure 2)”.

5. Lines 264: can the authors explain why they deviated from their data analysis plan of conducting publication bias assessment when 10 or more studies were available (lines 181-183) but lowered the quality of evidence because publication bias was strongly suspected?

Answer: In the revised manuscript, the meta-analysis showed that the use of prokinetic agents in critically ill patients receiving gastric feeding may reduce ICU or hospital length of stay, there was no significant difference in the incidence of reported adverse events and all-cause mortality between prokinetic agent group and control group. Although we could not assess this category reliably due to small number of eligible studies, we did not downgrade the quality of evidence for publication bias. The reasons are chiefly as follows: in view of the fact that publication bias arises when investigators fail to report studies they have undertaken (typically those that show no effect). A prototypical situation that should elicit suspicion of publication bias occurs when published evidence is limited to a small number of trials, all of which are showing benefits of the studied intervention. However, in our study, not all of included studies were showing benefits of the studied intervention in clinical outcome of ICU length of stay and hospital length of stay, respectively.

6. Line 271-272: “Subgroup analysis by type of prokinetics.” Fragment.

Answer: yes, we have amended the relevant part in manuscript.

it is showed as follows: “Although no significant heterogeneity was found, we performed subgroup analyses to determine if there are important subgroup differences. In the subgroup analysis stratified by type of prokinetic agents, there were no significant subgroup difference in the clinical outcomes of hospital length of stay, ICU length of stay, reported adverse events and all-cause mortality (Supp. Figure 4-7)”.

7. Line 275-277: When Metoclopramide did not show significant difference in the hospital length of stay compared with the control group (MD, 1.70, 95%CI, -4.75 to 8.15, P=0.61; I2=0%) (S1 Fig). Check grammar please.

Answer: In the revised manuscript, we did not report the outcome of subgroup analysis by specific drug. Because the number of studies is very small, the statistical power will have poor precision due to the variance between studies. We added a table of the separate effects of different prokinetics on the ICU length of stay and hospital length of stay in Supp. Table 3.

8. Lines 283-284: repetition of 254-256.

Answer: we have amended the relevant part in manuscript.

9. Lines 285-286: review grammar.

Line 286-287: pooled effects for what outcome(s)?

Answer: we have amended the relevant part in manuscript.

10. Line 288: I think the authors mean to have the first part as a subheading “Subgroup analysis by preventive giving prokinetics or therapeutic usage of prokinetics.” Would recommend: preventive use instead of preventive giving. Also would recommend: “pooled effects for primary outcomes” instead of “pooled effects” at the end of sentences.

Answer: yes, we accept your opinions, and we have amended the relevant part in manuscript. In the revised manuscript, this part is amended as follows: Furthermore, there was no study comparing the combination of prokinetics to placebo or no treatment. Only one study about the preventive usage of prokinetics for risk patients demonstrated the outcome of reported adverse events [27]. The others were about the preventive usage of prokinetics for all patients. The subgroup analysis result of the preventive usage of prokinetics for all patients did not show important changes in the pooled effects of the reported adverse events.

11. Lines 298-301: the authors deviate from statistical plan for publication bias again by downgrading for string suspicion of publication bias. Revision needed. Also in GRADE evidence profile confidence intervals for all-cause mortality, ICU and hospital length of stay and adverse events all include significant benefits and harms and yet no downgrading for imprecision was performed. Can the authors elaborate on this ? ¬¬¬For length of stay what was the unit of measurement? Days or hours? This would be important for the outcome of hospital length of stay with natural medicines. If the difference was 9 days fewer and between 18.5 and 0.8 days lower, one might consider downgrading for imprecision specially that the number of patients in that analysis is 122 only. I would strongly recommend the authors consult someone with more experience using the GRADE method.

Answer: we felt sorry for these mistakes. We seriously conducted the GRADE evaluation again. The result of GRADE is amended as follows: The certainty of evidence was moderate for the clinical outcome of all-cause mortality. However, the certainty of evidence was low for the clinical outcomes of ICU length of stay, hospital length of stay and reported adverse events. The details of the risk of bias and quality assessment are outlined in Table 3. The rationale for decisions had been made clear through footnotes to Table 3.

12. Lines 315-318: And there was a systematic review about the definition, prevalence, and outcome of feeding intolerance in intensive care, and the result showed that there were more than 60% (40/63) of studies defining the large GRVs with the threshold less than or equal to 250 ml and about 41.7% (30/72) of studies with the sole GRVs levels to definite of feeding intolerance. Not clear and needs to be rewritten.

Answer: yes, we have amended the relevant part in manuscript. The revised sentences are as follows: There are three methods for the treatment of gastric feeding intolerance. First, there is the most widely used method, the administration of prokinetics. Among recipients of gastric feeding, 13% had been prescribed prokinetics preemptively before they developed intolerance. Approximately one-third of patients who developed feeding intolerance were treated with a prokinetic agent during their stay in the ICU. Second, after the development of intolerance, 17% of patients received supplemental parenteral nutrition. Third, only 7.5% of patients with gastric feeding intolerance subsequently received enteral nutrition via a postpyloric feeding tube [8]. (In the revised essay, the revised sentences are in the part of “Introduction”).

13. Lines 325-327: So, we conducted this updated systematic review and meta-analysis, we defined the gastric enteral nutrition feeding intolerance as either GRV ≥500 ml or GRV <500 ml concomitant with symptoms of nausea, vomiting, abdominal distention, regurgitation or other symptoms resulting in feeding interruption. This is not true. Only 3 of the included studies explicitly reported the cutoff for the GRV to be ≥ 500 ml (24, 31, 34) and 1 study reported > 200 ml at any time or > 500 ml/24 hours). I find this misleading.

Answer: yes, we fully understand your purpose. We need to clarify the aims and objectives of our study. In this study, except for feeding tolerance, we also examined the effect of prokinetic agents on gastrointestinal symptoms and clinical outcomes. We defined gastric feeding intolerance as either GRV ≥500 ml or concomitant with symptoms of nausea, vomiting, abdominal distention, regurgitation or other symptoms resulting in feeding interruption in critically ill adult patients receiving gastric feeding tubes. We excluded studies that discontinued or interrupted gastric feeding prematurely following the disappearance of gastric feeding intolerance. Under this latest definition, our meta-analysis found some new studies [26-30, 33, 34], besides, we identified 5 studies regarding the administration of prokinetics of herbal medicines/natural medicines in patients receiving gastric feeding tube in critically ill adults [28-30, 37, 40].

14. Lines 342-347 are exact repetition of lines 324-329. Line 351: “trails” change to “trials”

Answer: Thank you for your warm reminder. We improve the quality of the English throughout our manuscript with the help of American Journal Experts (AJE).

15. Lines 352-358: I disagree with the conclusion. The heterogeneity was 95%, the confidence intervals we extremely wide (especially if this was in days) and the total number of patients is 122. This makes it extremely difficult to make any sound conclusions, contrary to the way reported by the authors.

Answer: In the revised manuscript, we were careful to generalize the conclusion of this article. we removed the results of the combining herbal group in the meta-analysis. “we found that prokinetic agents might reduce ICU or hospital length of stay in critically ill patients receiving gastric feeding. However, the number of studies and the sample size were very small, and the certainty of evidence was low. Furthermore, there was no significant difference between prokinetic agent groups and placebo/no treatment in the risk of reported adverse events and all-cause mortality. Therefore, we cannot draw a convincing conclusion that the use of prokinetics could improve clinical outcomes in critically ill adults. We recommend a more comprehensive search and further original studies on this topic”.

16. Lines 380: I am concerned that the while the title of the, manuscript is prokinetics, the bulk of discussion section and the conclusion is about herbal medicines as prokinetic agents. As mentioned earlier, the authors claim their cutoff for GRV was 500 ml but they included many studies without a clear cutoff and by doing that they missed many studies in Lewis et al. that included generic medicines. In addition, the authors did not include hospital length of stay as an outcome in their methods section (lines 92-101) and yet they perform this analysis and include the forest plot for it in the main manuscript.

The methods section very well be written. However, the other sections need significant revision of language and grammar.

Answer: your comment on the methods section is a very important recognition for our manuscript. The revised portion are marked with the changes highlighted in yellow in the paper. We hope the revised manuscript meet you’re your approval.

Reviewer #2:

Thank you for your warm reminder. Your suggestions and ideas have been highly regarded. We will reply your comments with further instructions.

The authors made a new meta-analysis on the efficacy and safety of prokinetic agents administered during enteral feeding in intensive care patients. Previous meta-analysis was already performed on this topic. Originality of this work may come from a revised definition for digestive feeding intolerance, which indeed corresponds to more recent experts’ recommendations (Gastric residual volume (GRV) above 500mls). It has to be noted however, that even the threshold of 500mls GRV for definition of gastric enteral feeding intolerance is challenged, and some authors now recommend against measuring any GRV during enteral nutrition in ICU patients.

I have two major concerns with that study:

1. Subgroup analysis: what is the rationale of pooling studies in which different substances are administered: indeed, natural/herbal substances are not identical in these pooled studies.

Answer: first, some studies have suggested that measurement of GRV provides no benefit and should no longer be recommended. However, GRV is also an indicator of feeding intolerance in many ICUs, especially in patients with a high risk of aspiration and aspiration pneumonia. Therefore, the Chinese guidelines call for caution in abandoning monitoring of GRV in some high-risk patients.

Second, after careful consideration, we agree with your advice, the natural/herbal substances are not identical in these pooled studies. In the revised manuscript, we have removed the pooled effect of the natural/herbal substances. Besides, although no significant heterogeneity was found, we performed subgroup analyses to determine if there are important subgroup differences. In the subgroup analysis stratified by type of prokinetic agents, there were no significant subgroup difference in the clinical outcomes of hospital length of stay, ICU length of stay, reported adverse events and all-cause mortality (Supp. Figure 4-7).

We found that prokinetic agents might reduce ICU or hospital length of stay in critically ill patients receiving gastric feeding. However, the number of studies and the sample size were very small, and the certainty of evidence was low. Furthermore, there was no significant difference between prokinetic agent groups and placebo/no treatment in the risk of reported adverse events and all-cause mortality. Therefore, we cannot draw a convincing conclusion that the use of prokinetics could improve clinical outcomes in critically ill adults. We recommend a more comprehensive search and further original studies on this topic.

2. To my opinion, the conclusion (administration of herbal medicines/natural medicines may reduce hospital length of stay) is not supported by the (meta)analysis. The purpose of a meta-analysis is to pool pertinent studies in order to answer a well predefined question. The conclusion that is drawn by the authors is not really related to the initial question.

Answer: we amended the relevant part in manuscript carefully. Revised portion are marked with the changes highlighted in yellow in the paper. there were some substantially modified in our results and conclusions sections.

In the revised manuscript, the conclusion was showed as follows: As a class of drugs, prokinetic agents may improve gastric feeding tolerance in critically ill adults. However, there is low certainty in the evidence that prokinetic agents are effective in reducing ICU or hospital length of stay. There was also no significant reduction in the risk of reported adverse events and all-cause mortality. Additional RCTs are needed to determine the effect of prokinetics on clinical outcomes in critically ill patients in the future.

Thank you very much for your attention and kindly advise. We hope the revised manuscript meet with your approval.

Attachment

Submitted filename: renamed_7d017.docx

Click here for additional data file.^{(40.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0245317.r003

Decision Letter 1

Lisa Susan Wieland

9 Jun 2020

PONE-D-20-01167R1

The efficacy and safety of prokinetics in critically ill adults receiving gastric feeding tubes: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Zhang,

The review is greatly improved in clarity and transparency, but requires some minor changes. Please address the comments of the reviewers and in addition:

For Line 288-289 where you state that hospital LOS was not significant I suggest you revise to use the same language as in 292-3 for ICU LOS, in that there appears to be a positive effect, unless you wish to clarify in what way the hospital LOS was not significant (clinically?)
For the outcomes of gastrointestinal symptoms and feeding tolerance, you should mention that if outcomes could not be combined by meta-analysis you summarized them narratively. You only discuss in the methods how you will use meta-analysis and then you do not meta-analyse the symptoms and tolerance outcomes, I assume because they are not appropriate to meta-analyze.
For Line 301 and the outcome of adverse events it is preferable to use the term 'risk' rather than 'incidence' as incidence implies measurement of time at risk.
For Table 3 please include the units for each outcome, e.g., days and deaths
For all forest plots, including Fig 2, Fig 3, S2Fig and S3Fig, please specify the comparison and the outcome (with units) in the header and replace the bracketed experimental and control on the x axis with a legend indicating the comparisons.

Please submit your revised manuscript by Jul 24 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Lisa Susan Wieland

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #1: I thank the authors for the significant work done to address al comments and i find the reviewed submission substantially improved.

the length of stay unit for hospital and ICU is still not clear. I assume it is days. However would be nice to have it clarified. See my original comment #11.

line 377: "We recommend a more comprehensive search and further original studies on this topic." i recommend the words "more comprehensive search" be deleted as they give the impression the authors did not perform a comprehensive search.

Reviewer #3: Thank you for the opportunity to review the revised manuscript. In this systematic review, authors evaluated the effect of prokinetics in critically ill adults on gastric feeding tube tolerance according to the updated definition. This systematic review implies that prokinetics improves tolerance of enteral feeding, and additionally provides the attractive hypothesis that prokinetics may shorten the length of ICU and hospital stay. Although authors tried to perform meta-analysis about gastric feeding tube tolerance, study diversity (e.g. various interventions and various outcome definitions) did not allow the authors data synthesis. Authors seems to revise their manuscript well according to the previous editor's and reviewers' comments.

Comments to the authors:

1. As authors state in background, the aim of this study is to evaluate the effect of prokinetics on gastric feeding tube tolerance. So, the main results of this study is the description about this effect (L273-283), not about ICU and hospital length of stay. And one of key points of this study, I believe, is the difficulty to compare results across previous studies because of various outcome definitions, and necessity of the valid measure of gastric tube tolerance in future studies. Authors should add more concise description in this paragraph (L273-283) to show the potential benefit on gastric feeding tube tolerance and clarify the abovementioned point.

2. L288-290: "Those five studies, enrolling a total of 250 patients, demonstrated that there was no significant difference in hospital length of stay ..."

Are there any significant difference between groups about the hospital length of stay? 95%CI of -5.35 to -1.06 is significant, isn't it? Please check.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: Yes: Kyohei Miyamoto

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Jan 11;16(1):e0245317. doi: 10.1371/journal.pone.0245317.r004

Author response to Decision Letter 1

26 Jun 2020

Dear Editors and Reviewers,

Thank you for your letter and the comments concerning our manuscript (Manuscript Number: PONE-D-20-01167R1). We appreciate your positive comments regarding our manuscript. Your suggestions and ideas have been carefully considered. Revised portions are marked with changes in colored fonts in the paper. We hope that the revised manuscript will meet with your approval. The main corrections in the paper and our responses to the reviewers’ comments are as follows:

Editors' comments:

The review is greatly improved in clarity and transparency, but requires some minor changes. Please address the comments of the reviewers and in addition:

1. For Line 288-289 where you state that hospital LOS was not significant I suggest you revise to use the same language as in 292-3 for ICU LOS, in that there appears to be a positive effect, unless you wish to clarify in what way the hospital LOS was not significant (clinically?)

Answer: We sincerely appreciate your thoughtful advice. This mistake was due to our carelessness in writing, and all authors sincerely apologize for this mistake. We have corrected this error. In the revised paper, the text is as follows: “These five studies, which enrolled a total of 250 patients, demonstrated a significant difference in the hospital length of stay between the prokinetic agent-treated group and the control group (MD -3.21, 95% CI -5.35, -1.06; P = 0.003; I2 = 28%) (Fig 2).”

2. For the outcomes of gastrointestinal symptoms and feeding tolerance, you should mention that if outcomes could not be combined by meta-analysis you summarized them narratively. You only discuss in the methods how you will use meta-analysis and then you do not meta-analyse the symptoms and tolerance outcomes, I assume because they are not appropriate to meta-analyze.

Answer: Yes. The various outcome definitions, especially for gastric tube tolerance, precluded quantitative synthesis of the data. According to your advice, we have amended this part in the revised manuscript as follows: “Thirteen studies evaluated the effect of prokinetics on gastrointestinal symptoms and/or feeding tolerance in adult critically ill patients receiving gastric feeding [26-30, 32-34, 36-40]. The main results obtained are as follows: gastric emptying, GRV, diarrhea, constipation, feeding complications and feeding intolerance. Gastric emptying was measured by the drug model of acetaminophen absorption or the 13C-octanoic acid breath test with calculation of the gastric emptying time, gastric emptying coefficient or area under the plasma concentration-time curve. The various outcome definitions, especially for gastric tube tolerance, precluded quantitative synthesis of the data.”

3. For Line 301 and the outcome of adverse events it is preferable to use the term 'risk' rather than 'incidence' as incidence implies measurement of time at risk.

Answer: Yes. Following your suggestion, to be more accurate, we have replaced “incidence” with “risk”.

4. For Table 3 please include the units for each outcome, e.g., days and deaths

Answer: Thank you for this comment. We have revised the manuscript to include the unit for each outcome in Table 3. We hope that this change improves the readability of the data.

5. For all forest plots, including Fig 2, Fig 3, S2Fig and S3Fig, please specify the comparison and the outcome (with units) in the header and replace the bracketed experimental and control on the x axis with a legend indicating the comparisons.

Answer: Following your suggestion, we have added “units” and “legend” to each forest plot. These changes have been made to the text to improve the readability and to clarify the interpretation of the data.

Reviewers' comments:

Reviewer #1:

1. I thank the authors for the significant work done to address al comments and i find the reviewed submission substantially improved.

Answer: Thank you for your very considerate advice; your positive comment on our manuscript is sincerely appreciated. We will reply to your comments one by one in detail.

2. the length of stay unit for hospital and ICU is still not clear. I assume it is days. However would be nice to have it clarified. See my original comment #11.

Answer: We apologize for this mistake. The unit for the lengths of hospital stay and ICU stay is “days”. We have added “units” in Table 3 in the revised manuscript. We hope that these changes improve the readability and clarify the interpretation of the data.

3. line 377: "We recommend a more comprehensive search and further original studies on this topic." i recommend the words "more comprehensive search" be deleted as they give the impression the authors did not perform a comprehensive search.

Answer: Thank you for your thoughtful reminder. We agree with your advice; the words "more comprehensive search" have been deleted in the revised manuscript.

Reviewer #3:

Thank you for the opportunity to review the revised manuscript. In this systematic review, authors evaluated the effect of prokinetics in critically ill adults on gastric feeding tube tolerance according to the updated definition. This systematic review implies that prokinetics improves tolerance of enteral feeding, and additionally provides the attractive hypothesis that prokinetics may shorten the length of ICU and hospital stay. Although authors tried to perform meta-analysis about gastric feeding tube tolerance, study diversity (e.g. various interventions and various outcome definitions) did not allow the authors data synthesis. Authors seems to revise their manuscript well according to the previous editor's and reviewers' comments.

Comments to the authors:

Answer: Thank you for your thoughtful reminder. These comments are valuable and very helpful for revising and improving our paper and provided important guiding significance for our research. According to your advice, we have amended this part in the revised manuscript as follows:

“Thirteen studies evaluated the effect of prokinetics on gastrointestinal symptoms and/or feeding tolerance in adult critically ill patients receiving gastric feeding [26-30, 32-34, 36-40]. The main results obtained are as follows: gastric emptying, GRV, diarrhea, constipation, feeding complications and feeding intolerance. Gastric emptying was measured by the drug model of acetaminophen absorption or the 13C-octanoic acid breath test with calculation of the gastric emptying time, gastric emptying coefficient or area under the plasma concentration-time curve. The various outcome definitions, especially for gastric tube tolerance, precluded quantitative synthesis of the data.

As a class of drugs, prokinetic agents appear to have positive effects on gastrointestinal function and improving feeding tolerance. Ten of the thirteen studies reported positive effects on improving gastric emptying and/or resolution of feeding intolerance in critically ill patients with the use of prokinetic agents. However, two studies suggested that metoclopramide had no effect on decreasing gastrointestinal complications in adult neurocritical patients or critical traumatic brain injury patients. One study reported that rikkunshito did not improve the achievement of enteral calorie targets in critically ill adults (Table 2).”

2. L288-290: "Those five studies, enrolling a total of 250 patients, demonstrated that there was no significant difference in hospital length of stay ..."

Are there any significant difference between groups about the hospital length of stay? 95%CI of -5.35 to -1.06 is significant, isn't it? Please check.

Answer: I apologize for this mistake. We have corrected this error. In the revised manuscript, the text is as follows: “These five studies, which enrolled a total of 250 patients, demonstrated a significant difference in the hospital length of stay between the prokinetic agent-treated group and the control group (MD -3.21, 95% CI -5.35, -1.06; P = 0.003; I2 = 28%) (Fig 2)”.

Thank you again for your attention and thoughtful advice. We hope that the revised manuscript will meet with your approval.

Attachment

Submitted filename: Response to Reviewers_Final20200625.docx

Click here for additional data file.^{(35.8KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0245317.r005

Decision Letter 2

Lisa Susan Wieland

17 Nov 2020

PONE-D-20-01167R2

The efficacy and safety of prokinetics in critically ill adults receiving gastric feeding tubes: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Zhang,

Please address the comments from the reviewer on the attachment, and consider shortening the introduction as requested.

Please submit your revised manuscript by Jan 01 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Lisa Susan Wieland

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: (No Response)

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: (No Response)

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: (No Response)

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: (No Response)

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #3: (No Response)

Reviewer #4: Minor clarifications line (see attached):

355

Also the introduction should be made more concise in this long paper.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: Yes: Kyohei Miyamoto

Reviewer #4: No

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: PONE-D-20-01167_R2_reviewer(1).pdf

Click here for additional data file.^{(1.5MB, pdf)}

PLoS One. 2021 Jan 11;16(1):e0245317. doi: 10.1371/journal.pone.0245317.r006

Author response to Decision Letter 2

6 Dec 2020

Dear Editors and Reviewers,

Thank you for your letter and the comments concerning our manuscript (Manuscript Number: PONE-D-20-01167R2). We appreciate your positive comments on our manuscript. Your suggestions and ideas have been carefully considered. The revised portions are in red font in the revised version of the paper. We hope the revised manuscript will meet with your approval. The main corrections in the paper and the responses to the reviewers’ comments are as follows:

Editors' comments:

Please address the comments from the reviewer on the attachment, and consider shortening the introduction as requested.

Answer: We are very appreciative of your advice. We have replied to the reviewers' comments in a point-by-point manner.

Reviewers' comments:

Reviewer #3:

Reviewer #3: All comments have been addressed

Answer: We appreciate your positive comments on our manuscript. Thank you for your hard work reviewing our manuscript.

Reviewer #4:

Reviewer #4: All comments have been addressed

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #4: Yes

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: Yes

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #4: Yes

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #4: Yes

6. Review Comments to the Author

Reviewer #4: Minor clarifications line (see attached):

355

Also the introduction should be made more concise in this long paper.

Answer: We appreciate your positive comments on our manuscript. Your comments were valuable when we revised and improved our paper. According to your advice, we have amended those parts in the revised manuscript. We will reply to your comments one by one in detail.

（1）Line 36: Equivocal: Continuous gastric feeding is not physiological, though possibly safer than bolus feeding (more physiological) regarding potential aspiration. Continuous intestinal feeding may be therefore actually more physiological.

Answer: We agree with you. We apologize that we did not express ourselves very clearly. We would like to present our standpoint that feeding administered in the stomach is usually considered more physiological than postpyloric feeding.

（2）Line 73: These sentences: “Some studies have suggested that measurement of GRV provides no benefit and should no longer be recommended. However, GRV is also an indicator of feeding intolerance in many ICUs.” were deleted.

Answer: Following your suggestion, we have deleted these sentences.

（3）Line 355: The negative studies (3 of 13, 23.08%) were hampered by special populations of neuro-critical patients and critical traumatic brain injury patients taking metoclopramide and by the use of the specific drug rikkunshito.

Answer: I am very sorry that we did not state it clearly. We have amended this part in the revised manuscript. It is shown as follows: “The studies that did not show beneficial effects (3 of 13, 23.08%) investigated special populations of neurocritical patients and critical traumatic brain injury patients taking metoclopramide and rikkunshito.”

（4）Also the introduction should be made more concise in this long paper.

Answer: Thank you for your reminder. These comments were very helpful for revising and improving our paper. According to your advice, we have amended this part in the revised manuscript.

Thank you again for your attention and advice. We hope the revised manuscript will meet with your approval.

Attachment

Submitted filename: REBUTTAL_LETTER_20201201.docx

Click here for additional data file.^{(33KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0245317.r007

Decision Letter 3

Lisa Susan Wieland

29 Dec 2020

The efficacy and safety of prokinetics in critically ill adults receiving gastric feeding tubes: A systematic review and meta-analysis

PONE-D-20-01167R3

Dear Dr. Zhang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Lisa Susan Wieland

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0245317.r008

Acceptance letter

Lisa Susan Wieland

2 Jan 2021

PONE-D-20-01167R3

The efficacy and safety of prokinetics in critically ill adults receiving gastric feeding tubes: A systematic review and meta-analysis

Dear Dr. Zhang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Lisa Susan Wieland

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Search strategy.

(DOCX)

Click here for additional data file.^{(29.9KB, docx)}

S2 Table. Excluded studies.

(DOCX)

Click here for additional data file.^{(22.1KB, docx)}

S3 Table. Separate effects of different prokinetic agents on hospital or ICU length of stay.

(DOCX)

Click here for additional data file.^{(15.8KB, docx)}

S4 Table. PRISMA checklist.

(DOCX)

Click here for additional data file.^{(20.1KB, docx)}

S1 Fig. Risk of bias.

(DOCX)

Click here for additional data file.^{(27.2KB, docx)}

S2 Fig. Reported adverse event outcomes.

(DOCX)

Click here for additional data file.^{(23.6KB, docx)}

S3 Fig. All-cause mortality outcomes.

(DOCX)

Click here for additional data file.^{(23.1KB, docx)}

S4 Fig. Subgroup analysis by the type of prokinetic agents for hospital length of stay outcomes.

(DOCX)

Click here for additional data file.^{(38KB, docx)}

S5 Fig. Subgroup analysis by the type of prokinetic agents for ICU length of stay outcomes.

(DOCX)

Click here for additional data file.^{(32.5KB, docx)}

S6 Fig. Subgroup analysis by the type of prokinetic agents for reported adverse event outcomes.

(DOCX)

Click here for additional data file.^{(34.1KB, docx)}

S7 Fig. Subgroup analysis by the type of prokinetic agents for all-cause mortality outcomes.

(DOCX)

Click here for additional data file.^{(33.7KB, docx)}

S8 Fig. Sensitivity analysis of hospital length of stay outcomes.

(DOCX)

Click here for additional data file.^{(23.2KB, docx)}

S9 Fig. Sensitivity analysis of ICU length of stay outcomes.

(DOCX)

Click here for additional data file.^{(22.3KB, docx)}

S10 Fig. Sensitivity analysis of reported adverse event outcomes.

(DOCX)

Click here for additional data file.^{(22.7KB, docx)}

S11 Fig. Sensitivity analysis of all-cause mortality outcomes.

(DOCX)

Click here for additional data file.^{(22.2KB, docx)}

Attachment

Submitted filename: renamed_7d017.docx

Click here for additional data file.^{(40.1KB, docx)}

Attachment

Submitted filename: Response to Reviewers_Final20200625.docx

Click here for additional data file.^{(35.8KB, docx)}

Attachment

Submitted filename: PONE-D-20-01167_R2_reviewer(1).pdf

Click here for additional data file.^{(1.5MB, pdf)}

Attachment

Submitted filename: REBUTTAL_LETTER_20201201.docx

Click here for additional data file.^{(33KB, docx)}

Data Availability Statement

All data generated or analysed during this study are included in this published article.

[pone.0245317.ref001] 1.Lew CCH, Yandell R, Fraser RJL, Chua AP, Chong MFF, Miller M. Association Between Malnutrition and Clinical Outcomes in the Intensive Care Unit: A Systematic Review [Formula: see text]. JPEN J Parenter Enteral Nutr. 2017;41(5):744–58. Epub 2016/02/04. 10.1177/0148607115625638 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref002] 2.McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159–211. Epub 2016/01/17. 10.1177/0148607115621863 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref003] 3.Singer P, Blaser AR, Berger MM, Alhazzani W, Calder PC, Casaer MP, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38(1):48–79. Epub 2018/10/24. 10.1016/j.clnu.2018.08.037 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref004] 4.Blaser AR, Starkopf J, Kirsimagi U, Deane AM. Definition, prevalence, and outcome of feeding intolerance in intensive care: a systematic review and meta-analysis. Acta Anaesthesiol Scand. 2014;58(8):914–22. Epub 2014/03/13. 10.1111/aas.12302 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref005] 5.Hu B, Sun R, Wu A, Ni Y, Liu J, Guo F, et al. Prognostic Value of Prolonged Feeding Intolerance in Predicting All-Cause Mortality in Critically Ill Patients: A Multicenter, Prospective, Observational Study. JPEN J Parenter Enteral Nutr. 2019. Epub 2019/08/21. 10.1002/jpen.1693 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref006] 6.Gungabissoon U, Hacquoil K, Bains C, Irizarry M, Dukes G, Williamson R, et al. Prevalence, risk factors, clinical consequences, and treatment of enteral feed intolerance during critical illness. JPEN J Parenter Enteral Nutr. 2015;39(4):441–8. Epub 2014/03/19. 10.1177/0148607114526450 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref007] 7.Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. Jpen. 2003;Journal of parenteral and enteral nutrition. 27(5):355–73. CN-01757915 NEW. 10.1177/0148607103027005355 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref008] 8.Consensus of early enteral nutrition clinical practice in critically ill patients. Chinese Critical Care Medicine. 2018;30(8):715–21. 10.3760/cma.j.issn.2095-4352.2018.08.001 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref009] 9.Reintam Blaser A, Starkopf J, Alhazzani W, Berger MM, Casaer MP, Deane AM, et al. Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines. Intensive Care Med. 2017;43(3):380–98. Epub 2017/02/09. 10.1007/s00134-016-4665-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref010] 10.Peng R. The efficacy and safety of administration of prokinetics improve clinical outcomes in critically ill patients is still quite unclear. Clinical Nutrition. 2020;39:307–9. 10.1016/j.clnu.2019.11.027 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref011] 11.Lewis K, Alqahtani Z, McIntyre L, Almenawer S, Alshamsi F, Rhodes A, et al. The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: A systematic review and meta-analysis of randomized trials. Critical Care. 2016;20 (1) (no pagination)(259). 10.1186/s13054-016-1441-z . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref012] 12.Dive A. Benefit of prokinetics during enteral nutrition: still searching for a piece of evidence. Crit Care. 2016;20(1):341 Epub 2016/10/27. 10.1186/s13054-016-1502-3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref013] 13.Higgins JPT. Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 (updated March 2011). Cochrane Collaboration website. http://training.cochrane.org/handbook. 2011. Accessed November 22, 2017.

[pone.0245317.ref014] 14.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–34. Epub 2009/07/28. 10.1016/j.jclinepi.2009.06.006 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref015] 15.Gupta SK. Intention-to-treat concept: A review. Perspect Clin Res. 2011;2(3):109–12. Epub 2011/09/08. 10.4103/2229-3485.83221 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref016] 16.Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med. 2010;7(3):e1000251 Epub 2010/03/31. 10.1371/journal.pmed.1000251 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref017] 17.Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27(6):1785–805. Epub 2016/09/30. 10.1177/0962280216669183 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref018] 18.Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135 Epub 2014/12/20. 10.1186/1471-2288-14-135 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref019] 19.Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med. 2002;21(11):1575–600. Epub 2002/07/12. 10.1002/sim.1188 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref020] 20.Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Research synthesis methods. 2010;1(2):97–111. Epub 2010/04/01. 10.1002/jrsm.12 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref021] 21.Furukawa TA, Watanabe N, Omori IM, Montori VM, Guyatt GH. Association between unreported outcomes and effect size estimates in Cochrane meta-analyses. JAMA. 2007;297(5):468–70. Epub 2007/02/08. 10.1001/jama.297.5.468-b . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref022] 22.Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6. Epub 2008/04/26. 10.1136/bmj.39489.470347.AD [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref023] 23.Acosta-Escribano J, Almanza Lopez S, Plumed Martin L, Garcia Martinez MA, Tajadura Manjarin N. The metoclopramide effect on enteral nutrition tolerance and mechanical ventilation associated pneumonia in neuro critically ill patients. Nutricion hospitalaria. 2014;29(6):1345–51. CN-01115568. 10.3305/nh.2014.29.6.7286 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref024] 24.Chapman MJ, Deane AM, O'Connor SL, Nguyen NQ, Fraser RJL, Richards DB, et al. The effect of camicinal (GSK962040), a motilin agonist, on gastric emptying and glucose absorption in feed-intolerant critically ill patients: a randomized, blinded, placebo-controlled, clinical trial https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967996/. Critical care. 2016;20(1). CN-01177110. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref025] 25.Doi M, Miyamoto K, Shimokawa T, Ariyasu H, Kaneko M, Yonemitsu T, et al. The effect of standard and high dose of rikkunshito on achievement of enteral nutrition target in critically ill patients: a pilot randomized controlled trial. Acute medicine and surgery. 2019. CN-01960632 NEW. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref026] 26.Guo JH, Chen G, Yang SQ, Wei MH, Chen X. Clinical observation of the role of Chenxia Sijunzi decoction in promoting the recovery of gastrointestinal function in critically ill patients. Zhongguo wei zhong bing ji jiu yi xue [Chinese critical care medicine]. 2012;24(11):674–6. CN-00966946. [PubMed] [Google Scholar]

[pone.0245317.ref027] 27.Kooshki A, Khazaei Z, Zarghi A, Rad M, Mohammadi HG, Tabaraie Y. Effects of fenugreek seed powder on enteral nutrition tolerance and clinical outcomes in critically ill patients: a randomized clinical trial. Biomedical research and therapy. 2018;5(7):2528–37. CN-01630190. [Google Scholar]

[pone.0245317.ref028] 28.Nassaji M, Ghorbani R, Frozeshfard M, Mesbahian F. Effect of metoclopramide on nosocomial pneumonia in patients with nasogastric feeding in the intensive care unit. La revue de sante de la Mediterranee orientale / al-Majallah al-sihhiyah li-sharq al-mutawassit [Eastern Mediterranean health journal]. 2010;16(4):371–4. CN-00761902. [PubMed] [Google Scholar]

[pone.0245317.ref029] 29.Nursal TZ, Erdogan B, Noyan T, Cekinmez M, Atalay B, Bilgin N. The effect of metoclopramide on gastric emptying in traumatic brain injury. J Clin Neurosci. 2007;14(4):344–8. Epub 2007/03/06. 10.1016/j.jocn.2005.11.011 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref030] 30.Ritz MA, Chapman MJ, Fraser RJ, Finnis ME, Butler RN, Cmielewski P, et al. Erythromycin dose of 70 mg accelerates gastric emptying as effectively as 200 mg in the critically ill. Intensive care medicine. 2005;31(7):949–54. CN-00528427. 10.1007/s00134-005-2663-8 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref031] 31.Spapen HD, Duinslaeger L, Diltoer M, Gillet R, Bossuyt A, Huyghens LP. Gastric emptying in critically ill patients is accelerated by adding cisapride to a standard enteral feeding protocol: results of a prospective, randomized, controlled trial. Critical care medicine. 1995;23(3):481–5. CN-00111279. 10.1097/00003246-199503000-00011 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref032] 32.Yavagal DR, Karnad DR, Oak JL. Metoclopramide for preventing pneumonia in critically ill patients receiving enteral tube feeding: a randomized controlled trial. Critical care medicine. 2000;28(5):1408–11. CN-00278171. 10.1097/00003246-200005000-00025 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref033] 33.Heyland DK, Tougas G, Cook DJ, Guyatt GH. Cisapride improves gastric emptying in mechanically ventilated, critically ill patients. A randomized, double-blind trial. American journal of respiratory and critical care medicine. 1996;154(6 Pt 1):1678–83. CN-00135101. 10.1164/ajrccm.154.6.8970354 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref034] 34.Mokhtari M, Shariatpanahi Z. Ginger extract dietary supplementation effects on delayed gastric emptying and ventilator-associated pneumonia in adult respiratory distress syndrome patients. Critical Care. 2009;1):S56 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref035] 35.Rajan V, Maiwall R, Choudhury AK, Jamwal KD, Benjamin J, Kumar G, et al. Early addition of prokinetics reverses gut paralysis and improves survival in critically ill cirrhotics-An open label placebo controlled RCT (Feed Intolerance and Treatment-FIT protocol). NCT02528760. Hepatology. 2017;66. CN-01419530. [Google Scholar]

[pone.0245317.ref036] 36.Sustic A, Zelic M, Protic A, Zupan Z, Simic O, Desa K. Metoclopramide improves gastric but not gallbladder emptying in cardiac surgery patients with early intragastric enteral feeding: randomized controlled trial. Croatian medical journal. 2005;46(2):239–44. CN-00512116. [PubMed] [Google Scholar]

[pone.0245317.ref037] 37.Tahershamsi F, Rezaei K, Khosravi S, Kheyri Z, Memarzadeh MR, Rafie F. Effect of oral drop gastrolit (Zataria multiflora) on gastric residual volume in mechanically ventilated patients hospitalized in the intensive care units. Journal of medicinal plants. 2018;17(68):66–73. CN-01650951. [Google Scholar]

[pone.0245317.ref038] 38.Chapman MJ, Fraser RJ, Kluger MT, Buist MD, De Nichilo DJ. Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding. Critical care medicine. 2000;28(7):2334–7. CN-00298628. 10.1097/00003246-200007000-00026 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref039] 39.Deane AM, Lamontagne F, Dukes GE, Neil D, Vasist L, Barton ME, et al. Nutrition Adequacy Therapeutic Enhancement in the Critically Ill: a Randomized Double-Blind, Placebo-Controlled Trial of the Motilin Receptor Agonist Camicinal (GSK962040): the NUTRIATE Study. Journal of parenteral and enteral nutrition. 2018;42(5):949–59. CN-01617154 NEW. 10.1002/jpen.1038 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref040] 40.Pinilla JC, Samphire J, Arnold C, Liu L, Thiessen B. Comparison of gastrointestinal tolerance to two enteral feeding protocols in critically ill patients: a prospective, randomized controlled trial. Journal of Parenteral and Enteral Nutrition 2001;25(2):81–6. 10.1177/014860710102500281 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref041] 41.Reignier J, Bensaid S, Perrin-Gachadoat D, Burdin M, Boiteau R, Tenaillon A. Erythromycin and early enteral nutrition in mechanically ventilated patients. Critical care medicine. 2002;30(6):1237–41. CN-00389663. 10.1097/00003246-200206000-00012 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref042] 42.Taylor SJ, Allan K, McWilliam H, Manara A, Brown J, Greenwood R, et al. A randomised controlled feasibility and proof-of-concept trial in delayed gastric emptying when metoclopramide fails: we should revisit nasointestinal feeding versus dual prokinetic treatment: achieving goal nutrition in critical illness and delayed gastric emptying: trial of nasointestinal feeding versus nasogastric feeding plus prokinetics. Clinical nutrition ESPEN. 2016;14:1–8. CN-01446990. 10.1016/j.clnesp.2016.04.020 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref043] 43.Boivin MA, Levy H. Gastric feeding with erythromycin is equivalent to transpyloric feeding in the critically ill. Critical care medicine. 2001;29(10):1916–9. CN-00374254. 10.1097/00003246-200110000-00011 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref044] 44.Euctr ES. A Phase 2, Multicenter, Randomized, Double-Blind, Comparator-Controlled Study of the Efficacy, Safety, and Pharmacokinetics of Intravenous Ulimorelin (LP101) in Patients with Enteral Feeding Intolerance. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=EUCTR2016. 2016. CN-01853774.

[pone.0245317.ref045] 45.Hayakawa M, Ono Y, Wada T, Yanagida Y, Sawamura A, Takeda H, et al. Effects of rikkunshito (traditional Japanese medicine) on enteral feeding and the plasma ghrelin level in critically ill patients: a pilot study. Journal of intensive care. 2014;2(1). CN-01070476. 10.1186/s40560-014-0053-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref046] 46.Heyland DK, van Zanten ARH, Grau-Carmona T, Evans D, Beishuizen A, Schouten J, et al. A multicenter, randomized, double-blind study of ulimorelin and metoclopramide in the treatment of critically ill patients with enteral feeding intolerance: PROMOTE trial. Intensive care medicine. 2019;45(5):647–56. CN-01938933 NEW. 10.1007/s00134-019-05593-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref047] 47.Irct201112014578N. The effect of acupuncture and traditional pharmacologic therapy on Delayed Gastric Emptying. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=IRCT201112014578N4. 2012. CN-01863905.

[pone.0245317.ref048] 48.Irct201408104365N. Combination of Neostigmine and Metoclopramide to reduce gastric residual volume in mechanically ventilated ICU patients. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=IRCT201408104365N16. 2015. CN-01798093.

[pone.0245317.ref049] 49.Irct201412044365N. Comparison of the effect of Neostigmine and Metoclopramide on gastric residual volume in mechanically ventilated ICU patients. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=IRCT201412044365N18. 2014. CN-01816620.

[pone.0245317.ref050] 50.MacLaren R, Patrick WD, Hall RI, Rocker GM, Whelan GJ, Lima JJ. Comparison of cisapride and metoclopramide for facilitating gastric emptying and improving tolerance to intragastric enteral nutrition in critically III, mechanically ventilated adults. Clinical therapeutics. 2001;23(11):1855–66. CN-00376433. 10.1016/s0149-2918(00)89081-5 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref051] 51.Makkar JK, Gauli B, Jain K, Jain D, Batra YK. Comparison of erythromycin versus metoclopramide for gastric feeding intolerance in patients with traumatic brain injury: a randomized double-blind study. Saudi journal of anaesthesia. 2016;10(3):308–13. CN-01166741. 10.4103/1658-354X.174902 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref052] 52.Malekolkottab M, Khalili H, Mohammadi M, Ramezani M, Nourian A. Metoclopramide as intermittent and continuous infusions in critically ill patients: a pilot randomized clinical trial. Journal of comparative effectiveness research. 2017;6(2):127–36. CN-01327651. 10.2217/cer-2016-0067 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref053] 53.Nct. A Randomized, Double-Blind Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of a Single Dose of Intravenous TD-8954 Compared With Metoclopramide in Critically Ill Patients With Enteral Feeding Intolerance. https://clinicaltrialsgov/show/NCT01953081. 2013. CN-01490372.

[pone.0245317.ref054] 54.Nct. Itopride in Feeding Intolerance of Critically-ill Patients Receiving Enteral Nutrition. https://clinicaltrialsgov/show/NCT03698292. 2018. CN-01663921.

[pone.0245317.ref055] 55.Nguyen N, Chapman M, Fraser R, Sharley V, Kong S, Bryant L, et al. Erythromycin or metoclopramide for feed intolerance in the critically ill. Critical care. 2006;10(Suppl 1). CN-00625643. [Google Scholar]

[pone.0245317.ref056] 56.Taylor S, Manara A, Brown J. Treating delayed gastric emptying in critical illness: metoclopramide, erythromycin and bedside (Cortrak[TM]) nasointestinal tube placement. Journal of the intensive care society. 2011;12(1):75–. CN-01003955. [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref057] 57.Yanagida Y, Hayakawa M, Yamamoto H, Wada T, Sugano M, Sawamura A, et al. Effects of rikkunshito (traditional Japanese medicine Kampo) on enteral feeding and plasma ghrelin concentration in critically ill patients: a double-blind, randomized, controlled trial. Intensive care medicine. 2013;39:S242–S3. CN-01010636. [Google Scholar]

[pone.0245317.ref058] 58.Berne JD, Norwood SH, McAuley CE, Vallina VL, Villareal D, Weston J, et al. Erythromycin reduces delayed gastric emptying in critically ill trauma patients: a randomized, controlled trial. Journal of trauma. 2002;53(3):422–5. CN-00398193. 10.1097/00005373-200209000-00004 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref059] 59.Meissner W, Dohrn B, Reinhart K. Enteral naloxone reduces gastric tube reflux and frequency of pneumonia in critical care patients during opioid analgesia. Critical care medicine. 2003;31(3):776–80. CN-00422940. 10.1097/01.CCM.0000053652.80849.9F [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref060] 60.Shariatpanahi ZV, Taleban FA, Mokhtari M, Shahbazi S. Ginger extract reduces delayed gastric emptying and nosocomial pneumonia in adult respiratory distress syndrome patients hospitalized in an intensive care unit. Journal of critical care. 2010;25(4):647–50. CN-00771992. 10.1016/j.jcrc.2009.12.008 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref061] 61.Tamion F, Hamelin K, Duflo A, Girault C, Richard JC, Bonmarchand G. Gastric emptying in mechanically ventilated critically ill patients: effect of neuromuscular blocking agent. Intensive care medicine. 2003;29(10):1717–22. CN-00470263. 10.1007/s00134-003-1898-5 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref062] 62.Chen JH, Hsieh CB, Chao PC, Liu HD, Chen CJ, Liu YC, et al. Effect of water-soluble contrast in colorectal surgery: a prospective randomized trial. World journal of gastroenterology. 2005;11(18):2802–5. CN-00511902. 10.3748/wjg.v11.i18.2802 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0245317.ref063] 63.Goldhill DR, Toner CC, Tarling MM, Baxter K, Withington PS, Whelpton R. Double-blind, randomized study of the effect of cisapride on gastric emptying in critically ill patients. Critical care medicine. 1997;25(3):447–51. CN-00138391. 10.1097/00003246-199703000-00013 [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref064] 64.Warusevitane A, Karunatilake D, Sim J, Lally F, Roffe C. Safety and effect of metoclopramide to prevent pneumonia in patients with stroke fed via nasogastric tubes trial. Stroke. 2015;46(2):454–60. 10.1161/STROKEAHA.114.006639 . [DOI] [PubMed] [Google Scholar]

[pone.0245317.ref065] 65.Tctr. Efficacy and safety of oral Erythromycin estolate in combination with Metoclopramide versus Metoclopramide mOnotherapy in mechanically ventilated patients who developed enteral feeding intolerance: a randomized double-blind controlled study. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=TCTR20171004004. 2017. CN-01884466. [DOI] [PubMed]

[pone.0245317.ref066] 66.NCT02528760. To Determine the Role of Prokinetics in Feed Intolerance in Critically Ill Cirrhosis. https://clinicaltrialsgov/show/NCT02528760. 2015. CN-01580381.

[pone.0245317.ref067] 67.NCT02379624. Pectin Start Early Enteral Nutritional Support in Critically Ill Patients. https://clinicaltrialsgov/show/NCT02379624. 2014. CN-01504758.

[pone.0245317.ref068] 68.IRCT201610297494N24. The prophylactic effect of cuminum cyminum extract on gastric residual volume in traumatic patients under ventilator hospitalized in intensive care unit. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=IRCT201610297494N24. 2017. CN-01887634.

[pone.0245317.ref069] 69.IRCT201009094722N2. The effect of Ginger extract on gastric residual volume in patients with mechanical ventilation hospitalized in intensive care unit. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=IRCT201009094722N2. 2011. CN-01849490.

[pone.0245317.ref070] 70.2015/08/006111 C. Clinical trial to compare the efficacy of two oral prokinetics metoclopramide and erythromycin in non acceptance of feed in head injury patient. http://wwwwhoint/trialsearch/Trial2aspx?TrialID=CTRI. 2015;08(006111). CN-01873462.

PERMALINK

The efficacy and safety of prokinetics in critically ill adults receiving gastric feeding tubes: A systematic review and meta-analysis

Rong Peng

Hailong Li

Lijun Yang

Linan Zeng

Qiusha Yi

Peipei Xu

Xiangcheng Pan

Lingli Zhang

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Search strategy

Inclusion criteria

Risk-of-bias assessments

Data extraction

Statistical analysis

Results

Fig 1. Literature search and screening process.

Table 1. Characteristics of the included trials and participants.

Risk of bias

Publication bias

Main outcomes

Effect on gastrointestinal symptoms and feeding tolerance

Table 2. Effects on gastrointestinal symptoms and feeding tolerance.

Effect on hospital or ICU length of stay

Fig 2. Forest plot for hospital length of stay outcomes.

Fig 3. Forest plot for ICU length of stay outcomes.

Effect on reported adverse events

Effect on all-cause mortality

Subgroup analysis

Sensitivity analysis

Certainty of evidence

Table 3. GRADE evidence profile of the efficacy and safety of prokinetics in critically ill adult patients receiving gastric feeding tubes.

Discussion

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Lisa Susan Wieland

Roles

Author response to Decision Letter 0

Decision Letter 1

Lisa Susan Wieland

Roles

Author response to Decision Letter 1

Decision Letter 2

Lisa Susan Wieland

Roles

Author response to Decision Letter 2

Decision Letter 3

Lisa Susan Wieland

Roles

Acceptance letter

Lisa Susan Wieland

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases