What must be monitored in patients on enteral feeding?

Enteral feedings are safely tolerated by most patients. When complications occur, gastrointestinal disturbances are most frequently encountered, followed by mechanical and metabolic complications. Nurses can prevent many of the problems associated with enteral feeding through careful monitoring. Based on the current literature, the authors make the following recommendations: 1. All patients receiving tube feedings should be placed on a protocol that provides guidelines for (a) confirming correct tube placement; (b) preventing/managing tube obstruction; (c) handling and selecting formulas; (d) administering formulas; and (e) monitoring patients. 2. Fine-bore tubes are easily misplaced or dislodged; ensure correct positioning both before and during feeding. Food coloring should be added to all feedings to help detect aspiration/tube displacement. 3. Multiple factors can cause diarrhea in tube-fed patients and, therefore, require periodic assessment. These factors include concomitant drug therapy; malnutrition/hypoalbuminemia; formula-related factors (for example, lactose content, osmolality); and bacterial contamination. 4. Urine sugar and acetone levels should be checked every 6 hours (until stable). Vital signs and fluid intake and output should be determined every 8 hours, and weight should be measured on a daily basis. Serum electrolytes, blood urea nitrogen, and glucose levels should be determined daily, until serum levels stabilize. Weekly measurements of trace elements should be made to ensure adequate mineral replacement. 5. Use a controller pump to administer continuous feedings at a constant rate or to administer formulas that are viscous. Flush feeding tubes with water every 4 hours during continuous feedings, after giving intermittent feedings, after giving medications, and after checking for gastric residuals. If tube obstruction occurs, attempt to irrigate the tube with either water or cola. 6. Select feedings that contain appropriate nutrient sources, caloric density, and osmolality; handle feedings in a way that minimizes bacterial contamination. 7. Ongoing nutritional assessments are necessary to provide information about the overall adequacy of the enteral feeding in restoring or maintaining nutrition.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To investigate the clinical efficacy and safety of monitoring GRV during enteral nutrition.

Malnutrition leads to an increase in medical expenses, increased length of hospital stays, and poor patient prognosis. Up to 40% of in‐hospital patients are affected by "disease‐related malnutrition," which is a specific type of malnutrition caused by concomitant disease (Cederholm 2017; Nutrition Day). To achieve target energy for hospitalized patients who are at risk of malnutrition, it is important to take pre‐emptive measures. However, in some people with acute illness, oral intake of food may not provide the necessary nutritional value due to various reasons (Gomes 2017; Weimann 2017). The reasons may include appetite loss due to acute illness, nausea, vomiting, early satiety, and difficulty in swallowing. This issue is especially relevant in critically ill patients, since oral intake is severely affected in such cases for reasons including the need for mechanical ventilation, gastrointestinal surgery, or unconsciousness. Patients under such conditions have higher mortality rates (Esteban 2013; Rubenfeld 2005), and it is imperative for medical care providers to explore the best interventions to maintain proper nutritional status, especially since nutritional management has recently been emphasized as an important determinant of patient survival (Reintam 2017). Critically ill patients also show highly variable metabolic and immune responses to injury or illness (Shaw 1993; Wanzer 1989). Inflammatory conditions result in increased glycogenolysis, protein catabolism, and fatty acid degradation, and insufficient nutrient intake causes depletion of organ proteins, ultimately leading to malnutrition, and increased risk of infection and death (Reintam 2017).

Under these circumstances, enteral nutrition (EN) (enteral tube feeding) or parenteral nutrition (PN) (the delivery of calories and nutrients into a vein) can compensate for nutritional intake until oral intake becomes satisfactory (Bounoure 2016). Patients with reduced nutrient intake from the gastrointestinal tract have an increased risk of infection because of reduced gut integrity and the physiologic stress response (McClave 2009b). Because of the better outcomes regarding infection, recent national guidelines backed by randomized controlled trials (RCTs) or systematic reviews, or both, have consistently suggested that EN should be used preferentially over PN in hospitalized patients who require non‐oral nutrition therapy, excluding cases where EN is contraindicated (CCPG 2015; JSICM 2017; McClave 2016a; McClave 2016b; Reintam 2017). A recent Cochrane Review of all types of nutrition support in hospitalized patients reported that EN may alleviate serious adverse events (Feinberg 2017).

A large number of microorganisms exist in the gastrointestinal tract, and the gastrointestinal mucosa acts as a barrier against microbial infection. Furthermore, immune tissue known as the Peyer's patches located in the gastrointestinal mucosa plays a preventive role against bacterial contamination of the body (Reintam 2012). It has been proposed that when nutrients do not flow in the gastrointestinal tract, the gastrointestinal mucosa becomes atrophied, leaving the individual susceptible to infection due to the reduced interaction between the gut and the systemic immune response, and leads to poor prognosis in critically ill patients (McClave 2009b). In particular, for critically ill patients with highly variable metabolic and immune response to injury or illness, early nutrition intake via the intestinal tract, that is enteral feeding, is highly important. Many studies have suggested that in such patients, early enteral feeding reduces the rate of infection and mortality (McClave 2009b). Currently available clinical practice guidelines recommend that early EN should be administrated to patients, especially to those in the intensive care unit (ICU) (Reintam 2017).

Enteral feeding is a riskless, useful, and generally well‐tolerated approach applied in patients with normal gastrointestinal (GI) tract and function (Zanetti 2016). The human GI tract has many roles, including digestion and absorption of nutrients and water, regulating the growth of intraluminal microorganisms, while maintaining barrier control, secretion, and endo/paracrine and immunologic functions. For proper GI functioning, perfusion, secretion, movement, and co‐ordinated intestinal microbial interaction are essential (Reintam 2012).

In hospitalized patients, GI function is often impaired because of pre‐existing disease (e.g. diabetes mellitus, vagotomy, myopathies); acute disease (e.g. shock, pancreatitis, spinal cord injury, trauma, abdominal surgery, burn); medication (e.g. sedatives, opioids, anticholinergics, vasopressors); or electrolyte abnormalities (e.g. hyperglycemia, hypokalemia) (Deane 2007; Zanetti 2016). The severity of existing disease is thought to be the main reason for GI dysfunction, and may influence the occurrence and degree of complications due to enteral nutrition (Deane 2007; Nguyen 2008); the sympathetic nervous system predominates over the parasympathetic nervous system, leading to reduced gastrointestinal peristalsis and reduced absorption capacity in the digestive tract, with a concomitant increase in enteral nutrient stagnation time in the stomach. Gastrointestinal dysfunction is a common event during critical illness, with an incidence rate of 63%, and can emerge as part of multi‐organ failure (Montejo 1999; Reintam 2012).

Gastrointestinal dysfunction is often an obstacle to EN. Feeding intolerance (FI) signifies GI dysfunction, and manifests as a result of motility and absorption disorders of GI tract, frequently leading to reduced EN intake (Elke 2015; Zanetti 2016). Incidence of FI is about 27% in general ward patients, and about 36% in ICU patients (Gungabissoon 2015; Wang 2017). A systematic review of observational studies showed that in comparison with patients without FI, those with FI presented with higher infectious complications and ICU mortality, and longer ICU stays (Blaser 2014).

The leading cause of FI is delayed gastric emptying. Gastric emptying can be assessed by various methods, such as scintigraphy, paracetamol absorption test, ultrasound, refractometry, breath test, and gastric impedance monitoring (Moreira 2009). In clinical practice, however, it is usually assessed by measuring the gastric residual volume (GRV). Gastric residual volume is the amount of liquid drained from a stomach following administration of enteral feed; this liquid consists mainly of infused nutritional formula or water, and secreted GI juice. Gastric residual volume is measured either by aspiration using a syringe, or by gravity drainage to a reservoir (Elke 2015). Though GRV can easily vary depending on the method of drainage, patient's position, amount of gastric juice, kind of tube (large/small diameter, pored/non‐pored), and position of tube tip (Bartlett 2015; Metheny 2005), it is the preferred clinical indicator of gastric emptying because of its simplicity.

Monitoring GRV involves obtaining frequent GRV measurements and employing appropriate interventions in patients with large GRVs. Gastric residual volume monitoring (monitoring of residual volume of the enteral nutrients including digestive juices) is an essential component of EN patient care and aids in preventing complications due to EN (McClave 2009a; Metheny 2012). In healthy adults and patients with mild illness, seven to nine liters of digestive juices are secreted daily (Jeejeebhoy 1977; Jeejeebhoy 2002). Most of these juices are absorbed by the small bowel, while approximately 500 mL reaches the colon and 150 g remains in the stools. Administering additional enteral nutrients in patients with increased GRVs may cause aspiration and an increase in intra‐abdominal pressure, which increases the risk of respiratory and circulatory failure, and intestinal necrosis. For this reason, it is particularly important to monitor GRV in the early stages of administration of enteral nutrition, especially in critically ill patients. Frequency of GRV measurement (e.g. every six hours) and the intervention strategy for large GRVs (e.g. if GRV is above 500 mL, hold feeding for two hours and re‐check GRV) is usually decided as per institution‐specific protocols and needs of the inpatient population (Bounoure 2016). Gastric residual volume is usually monitored in the ICU during nasogastric feeding or gastrostomy tube. Gastric residual volume monitoring is a well‐established and common nursing practice in the ICU. Metheny reported that about 97.1% of critical care nurses reported GRV measurements in the United States (Metheny 2012). Optimal GRV monitoring involves standardization of several parameters, and the following aspects have been studied so far: the frequency of monitoring (Reignier 2013; Williams 2014), comparison of the methods of managing GRV to prevent complications (Booker 2000), and whether the remaining contents of the stomach should be returned to the stomach or discarded (Julien 2009; Williams 2010).

Feeding intolerance is highly prevalent and is associated with worse outcomes, especially in critically ill patients. It is thus imperative to standardize assessment of GI function and a bedside examination of the abdomen (JSICM 2017; McClave 2016a). Gastric residual volume monitoring is considered to be a simple and effective method of monitoring FI, and a recent systematic review showed that a large GRV was used to define FI in 83% of studies (Blaser 2014). The main purpose of monitoring GRV is to improve safety in patients receiving EN. The administration of more enteral nutrients via the feeding tube while the stomach is already full (a high GRV) is not advisable in patients with reduced GI tolerance. In such cases, the residual gastric fluid is refluxed from the stomach into the esophagus, causing vomiting, and ultimately increasing the risk of aspiration pneumonitis caused by aspiration of the vomit (McClave 2009a). Aspiration pneumonitis is a severe complication that not only prolongs hospital stays but also increases mortality rates and the expense of hospitalization (Hayashi 2014). Hence, monitoring the GRV is considered an important procedure.

Gastric residual volume monitoring may enable clinicians to identify patients with delayed gastric emptying earlier, and deploy strategies to minimize the adverse effects of FI. The strategies to minimize FI include the use of prokinetic agents, postpyloric feeding, and pausing/decreasing EN (Elke 2015). Enteral nutrition protocols including interventions for cases with large GRVs may help achieve goal rate and prevent aspiration (Metheny 2010; Racco 2012). According to a national survey in the United States, almost 70% of critical care nurses used 200 mL or 250 mL as threshold levels for interrupting EN, and 80% of the nursing personnel measured GRV every four hours (Metheny 2012).

However, apart from the aforementioned benefits, monitoring the GRV has several disadvantages (Edwards 2000). Gastric residual volume monitoring is unnecessary intervention because of the lack of evidence of efficacy of GRV monitoring in some cases, and may result in an increase in the time taken to reach the target amount of enteral nutrients because of interrupted feeding (Edwards 2000). Digestive juices are included in the residual contents of the stomach, and it is possible that important electrolytes and digestive enzymes are discarded along with the residual contents of the stomach, which might lead to electrolyte imbalances and poor digestion. Furthermore, GRV monitoring must be confirmed manually primarily by a nurse, and increases other costs of patient care as well (e.g. requirement of additional syringes). Unnecessary monitoring of the GRV therefore contrarily increases nursing burden, which may lower the quality of medical care.

Although GRV monitoring has been part of the recommendations for critical care for decades, the importance and clinical relevance of routine GRV monitoring has been frequently questioned.

In recent years, GRV monitoring has been routinely performed as per institution‐specific protocols in all patients receiving EN (Reintam 2017). However, as mentioned above, it has been suggested that routine monitoring of the GRV may increase the workload of nurses, thereby delaying treatment for other patients. Insufficient nursing care may also be a consequence of increased nursing burden. Furthermore, it is thought that the interruption of feeding for monitoring of the GRV increases time taken to reach the feeding goal, and also increases the risk of infection caused by malnutrition from insufficient energy intake and reduced usage of the gastrointestinal tract (Reintam 2017).

Recent RCTs of GRV monitoring may be classified into three categories: 'higher versus lower GRV threshold,' 'not monitoring versus routine monitoring GRV,' and 'regular versus variable time interval of monitoring GRV.' Two RCTs showed that increasing the threshold levels of GRV leading to pause/decrease of EN from 200 mL to 400 mL or 500 mL did not increase the occurrence of regurgitation, aspiration, or pneumonia (McClave 2005; Montejo 2010). Results from one RCT and one before‐after study indicated that discontinuation of GRV monitoring improved delivery of EN without compromising patient safety (Poulard 2010; Reignier 2013). There were no significant differences in pneumonia incidence between GRV‐monitored and GRV‐unmonitored groups in these two trials. One RCT showed that a lower frequency of GRV monitoring was associated with more vomiting, but was not associated with worse outcomes including pneumonia (Williams 2014). Furthermore, GRV monitoring may result in tube clogging, improper discontinuation of EN, waste of medical resources including nursing time, and decreased supply of EN (Powell 1993).

Even among the national guidelines, most of which are for critically ill patients, recommendations on GRV monitoring vary. The American College of Gastroenterology and Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition (SCCM/ASPEN) recommend against GRV monitoring (McClave 2016a; McClave 2016b). The Canadian Critical Care Society and Canadian Critical Care Trials Group recommend a GRV monitoring frequency of once every four to eight hours (CCPG 2015). The SCCM/ASPEN and the Japanese Society of Intensive Care Medicine suggest that holding EN for GRVs less than 500 mL in the absence of other signs of intolerance should be avoided (JSICM 2017; McClave 2016a). The European Society of Intensive Care Medicine suggests delaying EN if the GRV is above 500 mL per six hours (Reintam 2017).

No adequately powered studies have to date demonstrated the best way to assess GRV, and no systematic review has shown the risk‐benefit analysis of monitoring GRV in a general population of hospitalized patients. Gastric residual volume monitoring may also increase mortality rates, and therefore exploring the best methods for monitoring the GRV may reduce unnecessary interventions, ensure patient safety, and reduce costs. Since different methods to monitor the GRV exist, there is an immediate need for studies to look into the following aspects.

1. Is GRV monitoring necessary?

2. If monitoring is performed, is frequent monitoring of GRV needed?

3. Does lower GRV affect the reduction of complications during enteral nutrition?

4. Should the residual contents of the stomach be discarded or returned to the stomach after the monitoring procedure?

To investigate the clinical efficacy and safety of monitoring GRV during enteral nutrition.

Types of studies

We will include all randomized controlled trials (RCTs) and randomized cross‐over trials (first period only) in the review.

We will also include cluster‐RCTs if the number of clusters or the average size of each cluster, the outcome data ignoring cluster design for the total number of individuals, and an estimate of intracluster (or intraclass) correlation coefficient (ICC) are available.

No restrictions will be placed on the language of publication when searching the electronic databases. We will include studies published as abstract only, and unpublished data.

Types of participants

We will include all adults (aged 18 years or older) receiving enteral nutrition via a nasogastric tube or a gastrostomy tube, with a diagnosis of any disease type and in all settings (ICU, non‐ICU, or outpatient).

Types of interventions

We will include trials comparing the following interventions in which the 'intervention group' receives any type of strict monitoring for GRV during enteral nutrition: frequency and stringency of monitoring (because the influence of GRV during enteral nutrition will be considered in relation to monitoring frequency); the upper limit of GRV before intervention is required to reduce the volume; and intervention strategy for aspirated residual gastric fluid. We will include all methods of GRV monitoring (i.e. by aspiration/drainage from a nasogastric or a gastrostomy tube, by ultrasound examination, or by computed tomography (CT) scan). We will designate the minimum intervention period as 24 hours and the maximum as 14 days. It is expected that the dose of EN that does not cause complications in the acute stage will be about 7 days, and that the observation period of 14 days is appropriate when including EN in the chronic phase. We will consider the following interventions and comparisons.

1. More frequent monitoring of GRV versus less frequent monitoring (greater than or equal to eight hours versus less than eight hours)

2. Frequent monitoring of GRV versus no monitoring (less than or equal to 12 hours versus no monitoring)

3. The higher threshold for GRV at the time of aspiration versus the lower threshold at the time of aspiration (greater than or equal to 500 mL per six hours versus less than 500 mL per six hours) (Reintam 2017).

4. Returning the aspirated/drained GRV versus discarding it.

5. Protocol‐based enteral nutrition strategy that includes criteria related to GRV versus protocol‐based enteral nutrition strategy that does not include criteria related to GRV or non‐protocol‐based enteral nutrition strategy.

Types of outcome measures

Primary outcomes

1. Mortality (at the end of follow‐up; up to 28 days)

Secondary outcomes

1. Pneumonia (we will accept the authors' definition including ventilator‐associated pneumonia and hospital‐acquired pneumonia, and follow‐up from the day the EN is initiated until it is discontinued; up to 28 days)

2. Length of hospital stay

3. Vomiting (we will accept the authors' definition and follow‐up from the day that EN is initiated until it is discontinued)

4. The number of hours to reach the target calories per day in EN

5. Gastric residual volume (we will accept the authors' definition)

6. Adverse events (we will accept the authors' definition)

The selection of the above clinical outcomes was based on the optimal method of GRV monitoring as per the needs of patients and healthcare providers.

Reporting of the outcomes listed here will not be an inclusion criterion for the review.

Electronic searches

We will conduct a literature search to identify all published and unpublished RCTs in all languages. We will translate non‐English language papers and fully assess them for potential inclusion in the review as necessary.

We will search the following electronic databases:

1. Cochrane Central Register of Controlled Trials (CENTRAL;Appendix 1 );

2. MEDLINE via Obid (1966 to present; Appendix 2);

3. Embase (1988 to present; Appendix 3); and

4. CINAHL (Cumulative Index to Nursing and Allied Health Literature) (1982 to present; Appendix 4).

Searching other resources

We will check the reference lists of all primary studies and review articles for additional references. We will contact authors of identified trials in order to locate other published and unpublished studies. We will also contact manufacturers and experts in the field.

We will search for errata or retractions from eligible trials on PubMed (www.ncbi.nlm.nih.gov/pubmed) and report the date this was done in the review.

Grey literature databases

1. Health Management Information Consortium (HMIC) database (//www.ovid.com/site/catalog/databases/99.jsp)

2. National Technical Information Service (NTIS) database (//classic.ntis.gov/products/ntis‐database/)

3. OpenGrey (//www.opengrey.eu)

4. PsycEXTRA (//www.apa.org/pubs/databases/psycextra)

Clinical trials registers and trial result registers

We will also conduct a search of clinical trial registers/trial result registers.

1. US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov)

2. Current Controlled Trials metaRegiser of Controlled Trials (mRCT)

   1. The WHO trial search portal for studies worldwide (//apps.who.int/trialsearch)

   2. The UKCTG for studies recruiting in the UK (//www.ukctg.nihr.ac.uk/default.aspx)

3. EU Clinical Trials Register (www.clinicaltrialsregister.eu)

4. World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/trialsearch)

Selection of studies

Two review authors (NK, RY) will independently screen the titles and abstracts of all studies identified as a result of the search, and code them as 'retrieve' (eligible, potentially eligible, or unclear) or 'do not retrieve.' We will retrieve the full text of study reports or publications, and two review authors (NK, RY) will independently screen the full texts and identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. Any disagreements will be resolved through discussion for by consulting a third review author (SA) if necessary. We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will record the selection process in sufficient detail to construct a PRISMA flow diagram and 'Characteristics of excluded studies' table.

Data extraction and management

We will use a standard data collection form for study characteristics and outcome data that has been piloted on at least one study in the review. One review author (HY) will extract study characteristics from the included studies. We will extract the following study characteristics.

1. Methods: study design, total duration of the study and run‐in period, number and locations of study centers, study setting, withdrawals, and date of study.

2. Participants: N, mean age, age range, sex, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria, and exclusion criteria.

3. Interventions: intervention method, comparison method, concomitant medications, and excluded medications.

4. Outcomes: specified and collected primary and secondary outcomes, and time points reported.

5. Notes: funding details for the trial and notable conflicts of interest of trial authors.

Two review authors (RY, SA) will independently extract outcome data from the included studies. We will report in the 'Characteristics of included studies' table if outcome data were reported in an unusable manner. Any disagreements will be resolved by consensus or by involving a third review author (NK). One review author (HY) will copy the data from the data collection form into the Review Manager 5 file (Review Manager 2014). We will double‐check that data have been entered correctly by comparing the study reports with the presentation of data in the systematic review. A second review author will spot‐check study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Two review authors (NK, RY) will independently assess the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreements will be resolved by discussion or by involving a third review author (HY). We will assess risk of bias according to the following domains.

1. Random sequence generation

2. Allocation concealment

3. Blinding of participants and personnel

4. Blinding of outcome assessment

5. Incomplete outcome data

6. Selective outcome reporting

7. Other bias

We will grade each potential source of bias as high, low, or unclear, and provide a quote from the study report and justification for our judgment in the 'Risk of bias' table. We will summarize the 'Risk of bias' judgments across studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary, for example risk of bias for unblinded outcome assessment may be very different for all‐cause mortality than for a patient‐reported pain scale. Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome, as part of the GRADE methodology.

Assesment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

We will analyze dichotomous data (such as the rate of the mortality, pneumonia, vomiting, and adverse event) as risk ratios with 95% confidence interval (CI), and continuous data (such as length of hospital stay, number of hours to reach the target calorie levels, and GRV) as mean difference (MD), or standardized mean difference (SMD) with 95% CI if different scales have been used. For rate outcomes, results will be expressed as rate ratio with 95% CI. We will ensure that higher scores for continuous outcomes have the same meaning for the particular outcome, explain the direction to the reader, and report where the directions were reversed if this was necessary (Review Manager 2014).

We will undertake meta‐analyses only where this is meaningful, that is if the treatments, participants, and the underlying clinical question have a high degree of similarity and are conducive to data pooling.

A common way that trialists indicate they have skewed data is by reporting medians and interquartile ranges. When we encounter this, we will note that the data are skewed and consider the implication of this. If the data are skewed, we will not perform a meta‐analysis, but will provide a narrative summary instead.

Where multiple trial arms are reported in a single trial, we will include only the relevant arms. If two comparisons (e.g. frequent monitoring of GRV less than 4 hours versus between 4 and 8 hours and more than 8 hours) must be entered into the same meta‐analysis, we will halve the control group to avoid double‐counting.

Unit of analysis issues

For dichotomous data of cluster‐RCTs, we will account for the design effect, and calculate effective sample size and number of events using the ICC, the average cluster size for dichotomous data, and adjusted standard errors if they have been reported, as described in Sections 16.3.3 and 16.3.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If the ICC has not been reported, we will use the ICC of similar studies as a substitute. For continuous data only, the sample size will be reduced, while means and standard deviations will remain unchanged (Higgins 2011).

For randomized cross‐over trials, we will only include data from the first period. If we identify and include multiple‐arm studies, we will include only the relevant arms.

In order to avoid double‐counting of events, we will consider how to report adverse events (i.e. as single events or included in a group of events). For count data (number of times events occur in a participant patient more than once), we will use the counts of rare events as a rate ratio and the counts of more common events as continuous data. Otherwise, we will use dichotomous data with participants as the unit of analysis.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and to obtain missing numerical outcome data as indicated (e.g. when a study is identified as an abstract only). If we are unable to obtain the information from the investigators or study sponsors, we will impute the mean from the median (i.e. consider median as the mean) and the standard deviation from the standard error, interquartile range, or P values, according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will assess the impact of including such studies using a sensitivity analysis. If we are unable to calculate the standard deviation from the standard error, interquartile range, or P values, we will impute standard deviation as the highest standard deviation in the remaining trials included in the outcome, fully aware that this method of imputation might decrease the weight of the studies in the meta‐analysis of mean difference, and shift the effect towards 'no effect' for standardized mean difference.

Assessment of heterogeneity

We will use the I² statistic to measure heterogeneity among trials in each analysis (Higgins 2003). If we identify substantial heterogeneity as per the Cochrane Handbook for Systematic Reviews of Interventions (greater than 50% to 60%), we will explore the heterogeneity by prespecified subgroup analysis (Higgins 2011). We will also assess heterogeneity by evaluating whether there is an acceptable overlap of confidence intervals.

Assessment of reporting biases

If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible publication bias. We will use the Egger's test to determine the statistical significance of the reporting bias (Egger 1997). We will consider P < 0.05 to be a statistically significant reporting bias.

Data synthesis

We will use the random‐effects model by default. For testing the robustness of our findings regardless of which method was chosen, we will conduct a sensitivity analysis for primary outcomes using fixed‐effect models. In case of divergence between the two models, we will present both results; otherwise, we will present only results from the random‐effects model.

'Summary of findings' table

We will create a 'Summary of findings' table with the following outcomes: mortality, pneumonia, and length of hospital stay. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of the evidence based on the studies that contributed data to the meta‐analyses for each outcome, classifying the quality as high, moderate, low, or very low. We will use the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), employing GRADEpro GDT software (GRADEpro GDT). We will justify all decisions to downgrade or upgrade the quality of the evidence in the footnotes, and provide comments to aid the reader's understanding of the review where necessary. We will consider whether there is additional outcome information that was not incorporated into the meta‐analyses, note this in the comments, and state if it supports or contradicts the information from the meta‐analyses.

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses for the primary outcomes.

1. Participant subsets (ICU, non‐ICU, or outpatient)

2. Participants with a high severity of illness score as defined by validated severity scales specific to critically ill patients, such as the Acute Physiology and Chronic Health Evaluation (APACHE), Simplified Acute Physiology Score (SAPS), or the Sequential Organ Failure Assessment (SOFA)

3. Participants with obesity (as defined in each of the included studies)

4. The methods used for monitoring GRV, such as aspiration from a nasogastric tube or a gastrostomy tube, ultrasound examination, and CT scans.

We will use the following outcomes in subgroup analysis.

1. Mortality (at end of follow‐up)

2. Pneumonia (we will accept the authors' definition and follow‐up from the day the EN is initiated until it is discontinued)

3. Vomiting (we will accept the authors' definition and follow‐up from the day that EN is initiated until it is discontinued)

We will use Cochran's Q test for subgroup difference to test for subgroup interactions.

Sensitivity analysis

We will perform sensitivity analysis to assess the robustness of our conclusions for the primary outcomes. This will involve the following.

1. Comparison based on our 'Risk of bias' assessment of included studies. We will exclude studies at high risk of selection bias.

2. Comparison of results from a fixed‐effect model versus results from a random‐effects model

3. Excluding trials for which mean or standard deviation or both were imputed

Reaching conclusions

We will only base our conclusions on findings from the quantitative or narrative synthesis of studies included in this review. We will avoid making recommendations for practice; our implications for research will give the reader a clear sense of the needed focus of future research and remaining uncertainties in the field.

We acknowledge the help and support of the Cochrane Upper Gastrointestinal Diseases Review Group. The authors would also like to thank the following editors and peer referees who provided comments to improve the protocol: Sarah Rhodes, Sana Alkhawaja, and Marilyn Walsh and to Lisa Winer for copy editing the protocol.

The methods section of this protocol is based on a standard template used by the Cochrane Gastrointestinal and Pancreatic Diseases Review Group.

1. exp enteral nutrition/

2. exp Intubation, Gastrointestinal/

3. ((stomach or gastric or gastro* or intragastric or nasogastr* or naso‐gasstric or nasal or nose or duoden* or nasoduoden* orogastric or jejun* or nasojejun* or esophagus or fine bore or Ryles or "PEJ" or "PEG" or bowel* or intestine* or intestinal or gastrointestinal or postpylor* or post‐pylor* or transpylor* or trans‐pylor* or nasoenter* or gavage or enteral or enteric) adj3 (feed* or fed or feeding or tube* or intubat* or tubal or nutrition*)).tw,kw.

4. ((feeding or fed or feed) adj3 (tube* or intubat* or tubal)).tw,kw.

5. (g‐tube* or ng‐tube* or j‐tube* or nj‐tube*).tw.

6. or/1‐5

7. (((gastric or stomach) and (residual or residue or volume or capacity)) or "GRV").af.

8. exp Gastric Emptying/

9. ((gastric or stomach) adj (emptying or evacuation)).tw,kw.

10. or/7‐9

11. 6 and 10

12. remove duplicates from 11

1. exp enteral nutrition/

2. exp Intubation, Gastrointestinal/

3. ((stomach or gastric or gastro* or intragastric or nasogastr* or naso‐gasstric or nasal or nose or duoden* or nasoduoden* orogastric or jejun* or nasojejun* or esophagus or fine bore or Ryles or "PEJ" or "PEG" or bowel* or intestine* or intestinal or gastrointestinal or postpylor* or post‐pylor* or transpylor* or trans‐pylor* or nasoenter* or gavage or enteral or enteric) adj3 (feed* or fed or feeding or tube* or intubat* or tubal or nutrition*)).tw,kw.

4. ((feeding or fed or feed) adj3 (tube* or intubat* or tubal)).tw,kw.

5. (g‐tube* or ng‐tube* or j‐tube* or nj‐tube*).tw.

6. or/1‐5

7. (((gastric or stomach) and (residual or residue or volume or capacity)) or "GRV").af.

8. exp Gastric Emptying/

9. ((gastric or stomach) adj (emptying or evacuation)).tw,kw.

10. or/7‐9

11. 6 and 10

12. randomized controlled trial.pt.

13. controlled clinical trial.pt.

14. random*.ab.

15. placebo.ab.

16. trial.ab.groups.ab.

17. drug therapy.fs.

18. or/12‐18

19. exp animals/ not humans.sh.

20. 19 not 20

21. 11 and 21

1. exp enteric feeding/

2. exp stomach tube/

3. exp nasogastric tube/

4. exp nose feeding/

5. tube feeding/

6. ((stomach or gastric or gastro* or intragastric or nasogastr* or naso‐gasstric or nasal or nose or duoden* or nasoduoden* orogastric or jejun* or nasojejun* or esophagus or fine bore or Ryles or "PEJ" or "PEG" or bowel* or intestine* or intestinal or gastrointestinal or postpylor* or post‐pylor* or transpylor* or trans‐pylor* or nasoenter* or gavage or enteral or enteric) adj3 (feed* or fed or feeding or tube* or intubat* or tubal or nutrition*)).tw,kw.

7. ((feeding or fed or feed) adj3 (tube* or intubat* or tubal)).tw,kw.

8. (g‐tube* or ng‐tube* or j‐tube* or nj‐tube*).tw.

9. or/1‐8

10. exp residual volume/

11. (((gastric or stomach) and (residual or residue or volume or capacity)) or "GRV").af.

12. exp stomach emptying/

13. ((gastric or stomach) adj (emptying or evacuation)).tw,kw.

14. or/10‐13

15. 9 and 14

16. (random: or placebo: or double‐blind:).mp.

17. clinical trial:.mp.

18. blind:.tw.

19. 16 or 17 or 18

20. 15 and 19

1. (MH "Enteral Nutrition")

2. (MH "Intubation, Gastrointestinal")

3. TI ( stomach or gastric or gastro* or intragastric or nasogastr* or naso‐gasstric or nasal or nose or duoden* or nasoduoden* orogastric or jejun* or nasojejun* or esophagus or fine bore or Ryles or "PEJ" or "PEG" or bowel* or intestine* or intestinal or gastrointestinal or postpylor* or post‐pylor* or transpylor* or trans‐pylor* or nasoenter* or gavage or enteral or enteric ) OR AB ( stomach or gastric or gastro* or intragastric or nasogastr* or naso‐gasstric or nasal or nose or duoden* or nasoduoden* orogastric or jejun* or nasojejun* or esophagus or fine bore or Ryles or "PEJ" or "PEG" or bowel* or intestine* or intestinal or gastrointestinal or postpylor* or post‐pylor* or transpylor* or trans‐pylor* or nasoenter* or gavage or enteral or enteric )

4. TI ( feed* or fed or feeding or tube* or intubat* or tubal or nutrition* ) OR AB ( feed* or fed or feeding or tube* or intubat* or tubal or nutrition* )

5. S3 AND S4

6. TI ( feeding or fed or feed ) OR AB ( feeding or fed or feed )

7. TI ( tube* or intubat* or tubal ) OR AB ( tube* or intubat* or tubal)

8. S6 AND S7

9. TI ( g‐tube* or ng‐tube* or j‐tube* or nj‐tube* ) OR AB ( g‐tube* or ng‐tube* or j‐tube* or nj‐tube* )

10. S1 OR S2 OR S5 OR S8 OR S9

11. TI (((gastric or stomach) and (residual or residue or volume or capacity)) or "GRV") OR AB (((gastric or stomach) and (residual or residue or volume or capacity)) or "GRV")

12. TI ( (gastric or stomach) and (emptying or evacuation) ) OR AB ( (gastric or stomach) and (emptying or evacuation) )

13. S11 OR S12

14. S10 AND S13

15. (MH "Randomized Controlled Trials")

16. TI ( random* or placebo* or blind* or double blind* ) OR AB ( random* or placebo* or blind* or double blind* )

17. S15 OR S16

18. S14 AND S17

Conceiving the protocol: HY, NK, RY, HT, YT, TA, SA, and YK.

Designing the protocol: HY, NK, RY, HT, YT, TA, SA, and YK.

Co‐ordinating the protocol: HY, HT, YT, and YK.

Designing search strategies: Yuhong (Cathy) Yuan.　

Writing the protocol: HY, SA, HT, YT, and YK.

Providing general advice on the protocol: HY, SA, HT, YT, and YK.

Securing funding for the protocol: HY, HT, YT, and YK.

Performing previous work that was the foundation of the current study: HY, SA, HT, YT, and YK.

HY: no declarations of interest

NK: no declarations of interest

RY: no declarations of interest

SA: no declarations of interest

TA: no declarations of interest

HT: no declarations of interest

YT: no declarations of interest

YK: no declarations of interest