Clinical and metabolic phenotyping of continuous versus intermittent ENteral NUTrition in ventilated adults with shock: ENNUT trial protocol

Abstract

Introduction

Critically ill patients often require enteral nutrition, but the optimal feeding strategy—continuous or intermittent—remains uncertain. While continuous enteral nutrition ensures steady nutrient delivery, it may inhibit key metabolic and cellular processes such as autophagy and ketogenesis. Intermittent enteral nutrition, by mimicking fasting periods, could activate protective pathways, potentially improving clinical outcomes. However, evidence for its efficacy and safety in intensive care units (ICUs) is limited. This study evaluates the clinical and metabolic impacts of fasting intervals during intermittent enteral nutrition compared with continuous enteral nutrition in critically ill patients.

Methods and analysis

We designed a multicenter, randomised, open-label trial across nine French ICUs, enrolling adult patients requiring mechanical ventilation and vasopressor support. Participants will receive either intermittent or continuous enteral nutrition for 7 days, with the primary endpoint being the change in the Sequential Organ Failure Assessment (SOFA) score from Day 1 to Day 7 or ICU discharge. Secondary endpoints include nutritional intake, metabolic markers, gastrointestinal tolerance, ICU-acquired infections and mortality rates. Quality of life will be assessed at discharge. A total of 174 patients will be included. Descriptive statistics will summarise group characteristics, with the Student’s t-test or the Mann-Whitney U test depending on data distribution for SOFA score change, and regression for confounders. Secondary endpoints will be analysed using regression, χ² or Fisher’s exact test, as appropriate.

Ethics and dissemination

The study protocol was approved by a French ethics committee on 24 October 2023 (Comité de Protection des Personnes Ile de France 1, Paris, France, number SI 23.03427.000435). Patients are included after providing informed consent. Results will be submitted for publication in a peer-reviewed journal.

Trial registration number

Registered on clinicaltrials.gov on 26 March 2023 (NCT06330610).

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Multicenter, randomised design to improve generalisability across intensive care unit (ICU) populations.

• Use of intermittent enteral nutrition protocols with standardised implementation procedures.

• Comprehensive metabolic phenotyping, including multi-omics analyses integrated into study methods.

• Variability in ICU practices across centres considered in site training and monitoring strategies.

• Open-label design, with potential risk of performance bias due to the inability to blind interventions.

Introduction

Importance of nutrition and potential reasons for lack of benefit in trials

Large randomised controlled trials have not demonstrated clear benefits of enteral over parenteral nutrition in patients in the intensive care unit (ICU), and some have even reported potential harm associated with enteral feeding.¹ One speculative explanation for this paradox is the continuous administration of enteral nutrition, which may not align with physiological needs. Intermittent feeding, in contrast, has shown beneficial metabolic effects in healthy populations.²

Physiological rationale for intermittent feeding

Intermittent feeding may activate protective mechanisms, such as improved protein synthesis, enhanced insulin sensitivity, preservation of circadian rhythms and stimulation of autophagy and ketogenesis, during fasting periods.^{3 4} In particular, fasting-induced activation of autophagy—a nutrient-sensitive process responsible for the clearance of intracellular debris—has garnered attention. This process, crucial for cellular repair, is inhibited by the presence of nutrients and insulin, leading to the accumulation of damaged organelles and toxic protein aggregates.⁵ Clinical data suggest that patients under stress who receive continuous and/or excessive artificial feeding may have impaired autophagy.⁶ A post hoc analysis of the Early Parenteral Nutrition Completing Enteral Nutrition in Critically Ill Patients trial demonstrated reduced muscle autophagy with early parenteral nutrition, correlating with muscle damage.⁷ Fasting-mimicking interventions could thus promote cellular repair through autophagy. In other models, intermittent fasting has shown protective effects against age-related diseases, partly via autophagy activation.⁸ Fasting also induces ketogenesis, a key metabolic adaptation that not only improves energy efficiency but also has anti-inflammatory and neuroprotective effects.9,14

Current evidence on intermittent versus continuous feeding in ICU and gaps

Despite strong physiological rationale, clinical evidence on intermittent enteral feeding in patients in the ICU remains limited. A recent analysis identified 12 heterogeneous randomised controlled trials, limiting generalisability and interpretation of findings.¹⁵ A recent multicentre Phase 2 trial found intermittent feeding to be feasible and safe, although no significant clinical differences were observed.¹⁶ Most trials were small, underpowered and lacked clinically relevant outcomes. Furthermore, many used feeding intervals (e.g., every 4 hours) that are potentially too short to trigger meaningful fasting responses.

The ideal fasting duration in the ICU remains unclear and may depend on gastrointestinal motility, which is often impaired in critical illness.¹⁷ A pilot study by Van Dyck et al observed increased ketogenesis after 4 hours of fasting and further changes in fasting markers after 12 hours, though autophagy markers were not detected.⁴ This suggests that fasting durations in existing studies may be insufficient to activate protective pathways. On the other hand, prolonged fasting intervals may increase the risk of feeding intolerance due to condensed caloric delivery. One review reported more gastrointestinal side effects with intermittent feeding,¹⁸ though other studies reported neutral or favourable safety profiles.¹⁶

Although observational and preclinical studies suggest benefits of alternating feeding and fasting, existing trials have not demonstrated clear clinical effects. This may be due to insufficient sample sizes, short fasting intervals or inclusion of less severely ill patients. Critically ill individuals, especially those in shock, are at high risk of metabolic disturbances that impact organ function.^{19 20} Multi-omics approaches and strategies integrating different biological information layers using various omics technologies, such as genomics, transcriptomics, proteomics, metabolomics and epigenomics,²¹ could achieve a comprehensive understanding of biological plasticity related to different enteral nutrition modalities.

Study objective

We hypothesise that alternating feeding and fasting in patients in the ICU may improve biological responses such as protein synthesis, insulin sensitivity and autophagy activation. This study aims to define optimal feeding protocols and fasting durations by evaluating the longitudinal clinical and metabolic effects of continuous versus intermittent enteral nutrition in critically ill patients.

Material and methods

Study design

We have designed a prospective, comparative, randomised (stratified), controlled, open-label, multicenter study (involving nine French ICUs) to compare two intervention groups. The trial is sponsored by the Centre Hospitalier Universitaire (CHU) of Rouen with external funding: the French Ministry of Health and the call for projects 2024 ‘Programme Hospitalier Interrégional de Recherche Clinique’ of the Groupement Interrégional de Recherche Clinique et d'Innovation of North-West France. The initial study protocol was approved by a French ethics committee (EC) on 24 October 2023 (Comité de Protection des Personnes Ile de France 1, Paris, France, number SI 23.03427.000435) and will be performed in accordance with the Declaration of Helsinki. The study was prospectively registered at clinicaltrials.gov on 26 March 2023 (NCT06330610).

Population and study protocol

Recruitment procedures

Patients will be recruited from nine centres in the French Northwest inter-region (ICUs at the University Hospitals of Rouen, Lille, Caen, Amiens, Elbeuf, Dieppe and Le Havre). Eligible patients will be those:

• Hospitalised in intensive care, receiving invasive mechanical ventilation for less than 48 hours, with a predicted duration of at least 48 hours.

• Supported by vasopressor amines.

• Eligible for enteral nutrition via a nasogastric tube for at least 7 days.

A total of 174 patients will be included, with 122 expected to be analysable by the study’s end. Inclusion will take place over 36 months. The planned start date is 01 June 2025, with an expected completion date of 01 June 2028.

Selection of participants

Adult patients (≥18 years) admitted to the ICU, placed on mechanical ventilation for less than 48 hours and able to undergo nasogastric feeding are eligible for inclusion. Patients must be receiving vasopressor support (epinephrine, dobutamine and/or norepinephrine), affiliated with a social security system and the patient or their designated trusted person must have read and understood the information letter and signed the informed consent form. Exclusion criteria are the presence of oesophageal varices or an obstructive syndrome contraindicating nasogastric tube placement, the impossibility to start enteral feeding within 48 hours following ICU admission, ongoing enteral nutrition for more than 1 hour at the time of inclusion, ongoing parenteral nutrition, moribund status, pregnancy or breastfeeding or legal incapacity, such as deprivation of liberty by administrative or judicial decision, guardianship or curatorship (figure 1).

Figure 1. Selection of participants. Flowchart illustrating the allocation to continuous versus intermittent enteral nutrition groups. Numbers in brackets indicate SOFA score values. D1, Day 1; ICU, intensive care unit ; MV, mechanical ventilation ; n, number ; and SOFA, Sequential Organ Failure Assessment.

Protocol description

Following their ICU admission, patients are randomised, within the first 48 hours after admission, and allocated to one of the two arms (figure 2). Randomisation will take place on the day enteral feeding begins, that is, Day 1 (D1).

Figure 2. Study design. Experimental plan detailing the continuous and intermittent enteral nutrition protocols. *% of the daily caloric intake defined according to European Society of Clinical Nutrition and Metabolism 2018 recommendations. **Adjusted body weight. ICU, intensive care unit.

Experimental group: patients will receive intermittent enteral nutrition, defined as 3 administrations of 60 min each, every 8 hours per day. In the acute phase (D1–D7), enteral nutrition (20 kcal/kg/day; protein 0.8–1.3 g/kg/day, according to European Society of Clinical Nutrition and Metabolism (ESPEN) 2018 recommendations) will be started between 24 hours after admission (H24) and 48 hours after admission (H48) of the mechanical ventilation onset for a maximum duration of 7 days, based on the adjusted weight for patients with a Body Mass Index (BMI)>30 kg/m². From D1 to D7, the total daily caloric intake—defined according to the ESPEN 2018 recommendations (D1: 25% of the calculated goal, D2: 50% of the calculated goal, D3: 75% of the calculated goal and from D4: 100% of the calculated goal)—will be divided by 3 and administered over 1 hour (60 min) according to the protocol (ie, defined daily intake÷3, every 8 hours, over 60 min). Thus, nutritional support will be interrupted every 7 hours even if the goal has not been reached. This support modality will be maintained until D7. Beyond D7, enteral nutrition administration modalities will be left to the prescriber’s discretion until patient discharge.

Control group (standard care) description: patients will receive continuous enteral support over 24 hours. In the acute phase, enteral nutrition (20 kcal/kg/day; protein 0.8–1.3 g/kg/day, according to ESPEN 2018 recommendations) will be started between H24 and H48 of the mechanical ventilation onset for a maximum duration of 7 days, based on the adjusted weight for patients with a BMI>30 kg/m². From D1 to D7, the total daily intake defined according to ESPEN recommendations will be administered continuously over 24 hours. This support will be maintained until D7 (or extubation) according to recommendations. Beyond D7, enteral nutrition administration modalities will be left to the prescriber’s discretion until the patient is extubated.

In both groups, the protocol will be discontinued on extubation, even if it occurs before D7. Enteral nutrition will be stopped at that point in order to avoid unnecessarily prolonging the use of a potentially uncomfortable and invasive nasogastric tube in patients who are clinically improving and no longer require mechanical ventilation.

The management of digestive intolerances has been defined as follows: in the presence of vomiting, indicating digestive intolerance, a prokinetic agent will be prescribed according to department habits (eg, erythromycin 100 mg/8 hours intravenously for 3–5 days) as first-line treatment. If vomiting persists, the enteral nutrition administration rate will be reduced by 50% until temporary cessation of enteral nutrition. Enteral nutrition will resume after 12 hours of digestive aspiration, following the same progression scheme (25, 50, 75 and 100% of intakes). Hourly capillary blood glucose monitoring will be performed until nutrition is resumed. Meanwhile, fluid intake will be increased with 5% glucose administration in case of reduction and/or cessation of enteral nutrition to avoid dehydration. If vomiting persists beyond D4 despite these measures, the patient will be withdrawn from the study procedure to receive another nutritional administration modality.

All other treatments will be administered according to the department’s recommendations and practices without any restriction.

Randomisation and treatment allocation

Eligible patients will be randomised into two groups: the experimental group (intermittent enteral nutrition) and the control group (continuous enteral nutrition). To minimise random imbalances, selected patients will be randomised into two equal groups, resulting in random allocation to one of the two study groups (the intermittent support group or the continuous support group). The random draw will take place at the start of enteral nutrition on D1, that is, the day after the patient’s inclusion, using balanced blocks with a 1:1 ratio and will be stratified by the Sequential Organ Failure Assessment (SOFA score on D1 based on its value,^{6 10} or,^{11 15} given the two very different administration modes of enteral nutritional support (intermittent and continuous), the study cannot be double-blind and, therefore, will be conducted as an open-label trial. The randomisation list is established within the biostatistics unit of the Rouen University Hospital, France, using the SAS (v 9.4) software before the start of the trial, and it will then be centrally stored and readable by the Clinsight software. Randomisation is fully automated and performed via the electronic Case Report Form (eCRF), specifically designed for this study. The randomisation list, generated prior to study initiation by the CHU de Rouen Biostatistics Unit using SAS software, is securely stored and inaccessible to investigators or clinical staff. At the time of enteral nutrition initiation (D1), once a patient is confirmed eligible and included, the eCRF assigns them to a treatment group (1:1 ratio) using a balanced block randomisation scheme. The investigator then receives the allocation via system-generated email, which is also sent to the sponsor. Allocation is thus centralised, concealed until assignment and reproducible, minimising bias. Importantly, the biostatistics unit holds a document describing the procedure—not the list itself—and only they have access to the full randomisation list. Investigators only receive the individual assignment at the time of inclusion. Although the study is open-label due to the nature of the interventions, measures have been taken to preserve randomisation integrity and minimise bias, including separation between the randomisation system and the clinical/data teams.

Data collection and outcome variables

Data recorded on a daily basis: follow-up visits from D1 to D7.

• Clinical data: weight, SOFA scores, mean arterial pressure (mm Hg), heart rate (per min), respiratory rate (per min), arterial oxygen saturation, urine output (mL/24 hours), temperature (°C), acquired infection, fluid balance (mL/24 hours) and therapeutic data.

• Enteral nutrition: caloric intake, protein intake, type of enteral product used and digestive tolerance.

• Laboratory work-up: inflammatory markers (procalcitonin, C-reactive protein (CRP) and complete blood count (in French: numération formule sanguine)), blood glucose, haemostasis (prothrombin time, activated partial thromboplastin time and platelets), liver markers (aspartate aminotransferase, alanine aminotransferase and bilirubin), renal function (creatinine and urea), electrolytes (sodium, potassium and phosphorus), arterial lactate and ratio of arterial oxygen tension (or pressure)/fractional inspired oxygen.

Data recorded on D1, D4 and D7:

• Albumin and prealbumin.

• Citrulline, lactate, pyruvate and ketone bodies (acetoacetate and β-hydroxybutyrate).

• Omics profiling.

  Metabolomics: tandem mass spectrometry will be used to analyse 188 metabolites using the AbsoluteIDQ p180 HR kit (Biocrates, Innsbruck, Austria) on the API 4000 QTRAP instrument (SCIEX). This kit enables the quantification of various molecules, including 21 amino acids, 21 biogenic amines, 1 hexose, 40 acylcarnitines, 90 glycerophospholipids and 15 sphingolipids.

  Proteomic analysis, including 96 proteins (Organ Damage panel), will be conducted using Olink Biomarker technology (Olink, Uppsala, Sweden).

Patients extubated before D7 will continue to be followed according to their randomisation group, and all data collected up to the point of extubation will be included in the analyses.

After ICU discharge:

• Weight, SOFA scores, duration of mechanical ventilation, duration of renal replacement therapy, duration of vasopressor support, number and type of acquired infections, length of ICU and hospital stay, presence of neuromyopathy, death and the 36-Item Short Form Survey (SF-36) score at hospital discharge.

The research end date corresponds to D90.

Metabolomic data

Metabolic monitoring will include blood glucose levels, recording both maximum and minimum values to assess glycaemic variability. Insulin administration will be quantified to calculate the Homeostatic Model Assessment (HOMA) score, serving as a surrogate marker for insulin resistance. Additionally, lactate and pyruvate concentrations will be measured daily, as they are key indicators of cellular metabolism and mitochondrial function, providing insights into the patient’s metabolic state.

On D1, D4 and D7, we will measure ketone bodies, specifically β-hydroxybutyrate and acetoacetate, to assess ketogenesis induction, which reflects a shift towards lipid metabolism during fasting periods. Citrulline levels will be used as a marker of enterocyte function and intestinal health, given its production by small intestinal enterocytes and its role in reflecting mucosal integrity. Albumin and prealbumin concentrations will be measured to evaluate nutritional status and protein synthesis dynamics, as they are commonly used indicators in clinical nutrition assessments.

Furthermore, metabolomics analyses will allow for a broader metabolic assessment. We aim to analyse 188 metabolites across various metabolic classes. Amino acids will be assessed as indicators of protein catabolism, immune function and nitrogen balance. Biogenic amines reflect oxidative stress, cellular signalling and mitochondrial activity. Acylcarnitines are markers of fatty acid oxidation and mitochondrial function, both of which are frequently disrupted in critical illness. Glycerophospholipids represent membrane integrity and inflammation, while sphingolipids are involved in apoptosis and immune regulation. This comprehensive profiling will allow us to explore alterations in energy metabolism, amino acid turnover, lipid processing and systemic stress responses in relation to the different enteral nutrition strategies. In parallel, plasma proteomic profiling will be conducted using the Olink Target 96 Organ Damage panel, which employs a proximity extension assay technology to quantify 96 proteins associated with tissue damage, inflammation, vascular injury and systemic stress. The inclusion of these biomarkers allows for a nuanced assessment of organ function and injury in the context of critical illness and nutritional interventions.

In conclusion, these comprehensive metabolic assessments will help elucidate the complex interplay between critical illness, nutritional strategies and patient outcomes.

Data collection and management

Follow-up will be conducted through access to the medical records if the patient is still in the hospital or by phone if the patient has been discharged.

Participant information will be pseudonymised in compliance with Commission Nationale de l'Informatique et des Libertés (CNIL) guidelines (data will be anonymised using a unique study ID, stored on a secure, password-protected electronic database and access will be restricted to authorised study personnel only).

Clinico-biological data will be entered into a secure online database developed by CHU de Rouen using Clinsight (Ennov Group). The data will be stored on a secure server managed by the CHU de Rouen’s Information Systems Department, with daily backups.

Data entry will be performed by physician investigators of the study or by the clinical study technician (TEC (French: Technicien d'Études Cliniques)) from each centre, using secure personal accounts. Once the database is locked, only the study’s data manager and biostatistician will access the data via a secure server.

Data entry will be supervised by the investigator and performed by team members (eg, TEC or nurse).

Primary endpoint

The primary endpoint evaluates the efficacy of intermittent enteral nutritional support during the acute phase (D1–D7 or ICU discharge) compared with continuous enteral support in reducing organ failure, defined by the delta SOFA score (D1, D7 or ICU discharge if the patient is discharged before D7) in a severely ill ICU population admitted with mechanical ventilation for less than 48 hours and vasopressor support. The SOFA score was chosen because it is a validated measure of organ dysfunction, widely used in critically ill patients, and its changes are relevant for evaluating patient outcomes in clinical trials.²²

Secondary endpoints

1. Enteral caloric intake from D1 to D7.

2. Enteral protein intake from D1 to D7.

3. Nutritional status measurements: weight/day, CRP and phosphorus levels from D1 to D7; albumin and prealbumin on D1 and D7.

4. Digestive tolerance evaluation (sign of feeding intolerance: diarrhoea, constipation, meteorism, nausea, regurgitation, vomiting, aspiration; number of events) from D1 to D7.

5. Rate of patients with at least one nosocomial infection acquired in the ICU, type of nosocomial infection and descriptive bacteriological data.

6. Other adverse events (AEs) during ICU stay.

7. Metabolic response evaluation from D1 to D7: HOMA score/day, insulin dose/day, maximum and minimum blood glucose levels/day, lactate, pyruvate, ketone bodies, metabolomic and proteomic profiles (D1, D4 and D7 if the patient is not discharged from the ICU).

8. ICU and hospital length of stay.

9. ICU-acquired neuromyopathy at ICU discharge.

10. Mortality in ICU, hospital, on D28 and D90.

11. SF-36 score (quality of life) on D90.

Statistical method

Planned number of participants to include in the research: the primary objective is to demonstrate that intermittent enteral support (3 administrations of 60 min/8 hours/day) during the acute phase (D1–D7) improves SOFA scores compared with continuous enteral support over 24 hours in patients admitted to ICU under vasopressors and requiring ventilation for at least 48 hours, with an indication for enteral nutritional support. The primary endpoint is the variation in SOFA scores between D1 (ie, inclusion date) and ICU discharge (or D7) in these patients under intermittent or continuous feeding, and the sample size is determined based on the comparison of means (Student’s t-test) of SOFA score variations measured in each group at these two times. The sample size calculation is based on the results of a study published in The Lancet in 2018,²³ which studied the effect of continuous enteral feeding in intubated and ventilated patients with organ failure. The average SOFA score was 11±3 initially. The average SOFA score was 7 after 7 days in the ICU, but without specifying the SD of this data. From the graph presented, the SOFA score range and IQR values were determined, allowing the estimation of two SDs associated with the mean SOFA score on D7. The sample size calculation is based on a 4-point decrease in SOFA with an average SOFA score of 11±3 on D1 and a SOFA score of 7±4.4 (taking the worst of the SDs calculated as described above), with an SD of the difference equal to 3.89, assuming a moderate correlation of 0.5 between SOFA values on D1 and D7. Since there is no published study on the potential benefit of intermittent nutrition on improving SOFA scores, we assume that the variance of the score variation distribution in these patients will be comparable to that observed in our study, and we base this information on the sample size calculation. A demonstration of a 2-point difference between the two groups (continuous vs intermittent enteral nutrition) seems relevant. To demonstrate this difference, given that the SD of the difference is estimated at 3.89 points, with a 5% alpha risk in bilateral formulation and a power of 80%, it is necessary to include 61 subjects per group. With the assumption of a moderate correlation of 0.5 retained for the sample size calculation, a total of 122 patients will achieve an 80% power. However, with a higher correlation or a greater difference between the two SOFA score variations, the statistical power will be significantly increased. To account for the expected 30% mortality rate with this severity level, which would reduce the statistical power of the analysis of surviving subjects on D7, and given that the type of nutrition has no impact on short-term vital prognosis, the total sample size is set at 174 subjects (87 subjects per group), which seems sufficient to conduct this study.

Significance level: a difference will be considered statistically significant if the significance level (p) is less than 5% (alpha risk=5%). The final sample size of 174 participants represents a balance between clinical expectations, such as mortality and dropout, and methodological requirements for power and outcome integrity.

Description of statistical methods

Included subjects will be described separately by group (intermittent enteral nutrition group vs continuous enteral nutrition group) using standard parameters: mean, SD, median and extreme values for quantitative variables and count and percentage for qualitative variables. For the primary endpoint, the comparison between the two groups in terms of average SOFA score variations between inclusion (D1) and ICU discharge (extubation) or 7 days after the start of nutrition (D7), in patients admitted to ICU under vasopressors and requiring ventilation for at least 48 hours, with an indication for enteral nutritional support, will be performed using the Student’s t-test or the Mann-Whitney U test, depending on data distribution. The difference in average SOFA score variations between D1 and ICU discharge (or D7) between the two treatment groups, along with its 95% CI, will be estimated. This test will be supplemented by an adjusted comparison based on a multiple linear regression model considering potential prognostic factors for SOFA score reduction, such as obesity, age and Indice de Gravité Simplifié (IGS) score. For secondary endpoints, the same method as for the primary endpoint will be used for quantitative variables (hospital stay duration, intubation duration or BMI). For qualitative variables (such as gender or mortality), the comparison will be made using the χ² test or Fisher’s exact test (depending on sample size).

For patients whose primary endpoint cannot be evaluated for reasons other than death, the minimum (or maximum) observed change in the SOFA score within the group will be assigned to reduce the gap between the groups. Subsequently, a secondary sensitivity analysis will be performed, including all randomised subjects. For patients who are alive but whose primary endpoint could not be evaluated on D7 (or before extubation), an SOFA score will be assigned as described earlier, while patients who died on D7 will be assigned the maximum SOFA score of 20. The results of the primary analysis (alive on D7 or at extubation) will be compared with those from the sensitivity analysis (all randomised subjects).

The metabolomics and proteomics data of the study will be analysed using exploratory, hypothesis-generating methods, with the goal of identifying biological pathways and molecular signatures associated with different nutritional regimens. Descriptive statistics, including mean, SD and median, will be provided for each group. To assess group comparisons, either the Student’s t-test or the Mann-Whitney U test will be employed, depending on the distribution of the data. Furthermore, multiple linear regression models will be used to adjust for relevant covariates such as age, obesity and baseline severity (IGS score). False discovery rate control will be applied to account for multiple comparisons.

Safety and study oversight

Safety, AEs, serious AEs (SAEs) and suspected unexpected serious adverse reactions

All SAEs will be reported to the sponsor.

The potential risks or complications related to enteral nutrition are as follows¹:

• Mechanical complications, such as tube obstruction, malposition or migration and nasal or oesophageal mucosal ulceration.

• Metabolic complications, including:

  • Refeeding syndrome, particularly hypophosphataemia, especially in malnourished patients. Monitoring of serum electrolytes will be essential during initiation.

  • Glucose intolerance or hyperglycaemia, which may require insulin therapy during the course of enteral feeding.

• Digestive complications, such as:

  • Diarrhoea, potentially linked to formula composition, feeding rate or concurrent antibiotic use.

  • Constipation, often related to immobility, medications (eg, opioids) or inadequate hydration.

  • Gastric stasis and meteorism, which may lead to discomfort and reduced feeding tolerance.

  • Nausea, regurgitation and vomiting, which can increase the risk of aspiration.

• Intestinal ischaemia is a rare but serious complication. The risk is heightened in patients with shock or severe haemodynamic instability due to compromised mesenteric perfusion. Clinical signs of intolerance, such as abdominal distension, worsening acidosis or increased gastric residuals, will be carefully monitored. Enteral nutrition will be interrupted if these signs suggest potential gut ischaemia and resumed once the patient is clinically stable.

• Aspiration and aspiration pneumonia are significant concerns in mechanically ventilated patients. Preventive measures, such as elevation of the head of the bed, use of prokinetics and regular assessment of gastric residual volumes, will be implemented to minimise this risk.

Expected AEs related to the principal diagnosis at ICU admission and shock state (septic, cardiogenic or hypovolaemic) are:

• Death.

• Cardiac arrest.

• Organ failure.

• Nosocomial infection.

• ICU-acquired neuromyopathy.

• Cardiac arrhythmias.

For research involving human subjects, the investigator notifies the sponsor of AEs and abnormal medical biology results defined in the protocol as determinants for evaluating the safety of participants, in accordance with reporting requirements specified in the protocol and within specified deadlines.

In accordance with French regulations, all SAEs are reported by the investigators to the sponsor, who is responsible for the pharmacovigilance of the study. The sponsor then notifies the appropriate authorities, including the regional pharmacovigilance centre and, when applicable, the EC (Comité de Protection des Personnes) and the French competent authority (Agence Nationale de Sécurité du Médicament (ANSM)). The timelines for reporting comply with regulatory requirements: life-threatening or fatal SAEs are reported immediately (within 7 days), and other SAEs within 15 days. The sponsor is ultimately responsible for ensuring timely and accurate reporting to all relevant bodies.

SAEs not subject to immediate reporting include SAEs occurring before the initiation of enteral nutrition, SAEs related to the principal diagnosis of ICU admission and shock state (septic, cardiogenic and hypovolaemic), SAEs related to underlying pathology and its treatment, SAEs related to mechanical ventilation, SAEs related to vasopressors and SAEs related to prolonged immobility.

All these events must be recorded in the eCRF and reported to the regional pharmacovigilance centres by the investigator for those related to medication(s).

Rules for termination of the study

Premature, definitive or temporary termination of the study

The study may be suspended or terminated by the sponsor or at the request of the competent authority and/or the EC, including but not limited to the following reasons:

• An unexpected frequency and/or severity of toxicity.

• New safety data.

• Insufficient recruitment of participants for the study.

• Insufficient quality of data collection.

Patients enrolled in the study will then receive care as part of standard medical practice.

Premature termination of the study procedure

Premature termination of the study procedure occurs in the event of:

• A major protocol violation.

• Vomiting lasting >4 days.

The reasons and dates for the premature termination of treatment must be documented in the eCRF. The patient will then be managed according to standard clinical practice.

Premature withdrawal from the study

Premature withdrawal may occur for the following reasons:

• Participant decision (or their legally authorised representatives). They may withdraw consent at any time without justification, retaining the right to treatment. The investigator must document the decision and reasons in the eCRF.

• Investigator decision. For participant safety (eg, SAEs or incompatible treatments), with notification to the sponsor via the withdrawal form.

• Erroneous inclusion. Decision made jointly by the investigator and sponsor.

• Participant death. Samples collected before consent will be processed as per protocol if prior consent was given by a trusted person.

Roles and responsibilities of the coordinating center

The sponsor ensures access to all study locations, source data and documents for quality control and audits. An audit may be carried out at any time by persons mandated by the sponsor and independent of those in charge of the research. The audit may apply to all stages of the study, from the development of the protocol to the publication of the results and the classification of the data used or produced as part of the study.

Investigators will provide necessary documents and data for monitoring and auditing, in compliance with regulations. Source data refers to original documents verifying the accuracy of recorded trial data.

Any modification of the protocol, which alters the management of persons taking part in the research or the benefits, risks and constraints of the research will be submitted as an amendment to the EC for approval. Once approved, the new version of the protocol and the updated consent form will be implemented. All investigators will be informed of any modification to the protocol, whether substantial or non-substantial. Investigators undertake to comply with the contents of this memorandum by signing an adherence document (principal investigator of each centre).

Discussion

The ENNUT (ENteral NUTtrition) trial aims to address a fundamental question in intensive care: the impact of intermittent versus continuous enteral nutrition in critically ill patients receiving vasopressor support. This will be achieved through a robust and multicentre methodology that will enhance the generalisability of the findings.

Indeed, feeding regimens in critically ill patients have been of increasing interest to clinicians and scientists, given the strong pathophysiological rationale and the potential benefits of intermittent feeding on the outcomes of these fragile patients. Previous randomised clinical trials comparing intermittent versus continuous enteral nutrition have shown inconsistent results.²⁴ Although continuous enteral feeding modality significantly achieved target nutrition requirements compared with the intermittent enteral feeding strategy,¹ no differences in mortality or other key secondary outcomes were demonstrated, including hospital and ICU length of stay, gastrointestinal intolerance and organ support.²⁴ On the other hand, in a recent meta-analysis of 13 randomised control trials, intermittent enteral feeding was associated with a high occurrence of feeding intolerance, including diarrhoea and abdominal distension, without beneficial effects on morbidity and mortality.¹ Based on available evidence, continuous enteral feeding may be more appropriate for patients at higher risk of feeding intolerance. The results of these meta-analyses support the current guidelines recommending continuous enteral feeding as the optimal strategy for enteral nutrition.¹⁸ Nevertheless, it has been suggested that intermittent nutrition induces various physiological and metabolic effects that could benefit critically ill patients. Continuous feeding attenuates diurnal variations in ghrelin, a hunger peptide, and in peptide YY, a satiety hormone, with pleiotropic metabolic effects,²⁵ and increases insulin resistance via inhibition of glucose transport while also impacting important cellular processes (eg, inhibiting autophagy, which leads to an accumulation of end-products of cellular damage, potentially impeding overall patient recovery).²⁶ Thus, fasting may promote autophagy, advantageously removing cellular debris (eg, from myonecrosis), which would be a beneficial effect in stress conditions.²⁷ When feeding is interrupted for an extended period, usually 14–18 hours, a cascade of cellular signalling, metabolic adaptations and neuroendocrine responses is triggered, leading to the production of ketone bodies, presumed to have multiple advantages over glucose metabolism.²⁸ In addition to ketogenesis, the low levels of circulating glucose, insulin and amino acids result in the down-regulation of the mammalian target of rapamycin and further increase the activation of autophagy and mitochondrial biogenesis.²⁹ Using metabolic profiling, Wilkinson et al found no differences in metabolomics between continuous and intermittent enteral nutrition.³⁰ This suggests that intermittent feeding (six feeds per 24 hours, each administered over 3–5 min via nasogastric tube) is unable to significantly shift metabolism in critically ill patients. A time-restricted feeding strategy might exert its beneficial effects by triggering ketone body metabolism or autophagy. However, optimal feeding duration and fasting periods are still unclear and may explain inconsistencies in clinical studies. Yet, these results do not rule out the potential benefit of intermittent feeding regimens. The clinical impact of such an intermittent feeding strategy remains unclear. Centres’ practice heterogeneity, patient follow-up and results interpretation are the main challenges for this trial. For this reason, we chose the SOFA score as the primary endpoint because of its relevance, robustness and validation in the critical care literature. The other endpoints of this trial will also cover the immediate and delayed effects of intermittent enteral nutrition, with follow-up up to 90 days and detailed quality of life analysis. This makes this study both accurate and clinically relevant to intensive and postacute care settings.

Although other limitations, such as attrition or loss to follow-up, are expected, specific measures have been implemented to minimise these risks and ensure the validity and consistency of the results. The expected results could provide insights into the current recommendations for enteral nutrition in the ICU and mitigate nutritional benefits and potential risks.

Ethics and dissemination

Patients' consent

Informed consent will be obtained in person from patients or their legally authorised representatives, following standard ICU procedures by the investigators at each centre, and recorded in the medical record. Patient and/or relative information leaflets are available in onlinesupplemental materials 15.

Ethical review board

The sponsor and investigators commit to conducting this research in accordance with the General Data Protection Regulation of 25 May 2018 and its consolidated versions; Law No. 2012-300 of 5 March 2012, related to research involving human subjects, and its consolidated versions; Law No. 2004-806 of 9 August 2004 and its consolidated versions; Good Clinical Practices (International Council for Harmonisation in its consolidated version and decision of 24 November 2006) and the Declaration of Helsinki, October 2008 version (available in full at http://www.wma.net). The research is conducted in accordance with this protocol. Except in emergencies requiring specific therapeutic actions, the investigators commit to strictly following the protocol, particularly regarding consent collection and the notification and monitoring of SAEs. The protocol was approved by a French EC on 24 October 2023 (Comité de Protection des Personnes Ile de France 1, Paris, France, number SI 23.03427.000435) and authorised by the ANSM.

Rouen University Hospital, the sponsor of this research, has subscribed to a civil liability insurance contract with XL Insurance Company SE, 61, rue Mstislav Rostropovitch, in accordance with the provisions of Article L1121-10 of the Public Health Code.

The data recorded during this research are processed at the Biostatistics Unit of Rouen University Hospital in compliance with Law No. 78-17 of 6 January 1978, related to data processing, files and freedoms, amended by Law 2004-801 of 6 August 2004 and its consolidated versions.

This research falls within the ‘Reference Methodology’ (MR-001) in application of the provisions of Article 54, paragraph 5 of the amended law of 6 January 1978, on information, files and freedoms, in its latest consolidated version. Rouen University Hospital has committed to CNIL to comply with this ‘Reference Methodology’.

Dissemination policy

Results will be reported in compliance with the relevant guidelines, published in an international peer-reviewed journal and presented at appropriate academic conferences, irrespective of the outcomes.