# Protocol for a prospective cohort study on the use of clinical nutrition and assessment of long-term clinical and functional outcomes in critically ill adult patients

M Hiesmayr, A Csomos, K Dams, G Elke, W Hartl, O Huet, L J Krzych, H Kuechenhoff, M Matejovic, Z A Puthucheary, et al.

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## To cite this version:

M Hiesmayr, A Csomos, K Dams, G Elke, W Hartl, et al.. Protocol for a prospective cohort study on the use of clinical nutrition and assessment of long-term clinical and functional outcomes in critically ill adult patients. Clinical Nutrition ESPEN, 2021, 43, pp.104 - 110. 10.1016/j.clnesp.2021.01.048. hal-04941852

HAL Id: hal-04941852

https://hal.univ-brest.fr/hal-04941852v1

Submitted on 12 Feb 2025

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Protocol

Protocol for a prospective cohort study on the use of clinical nutrition and assessment of long-term clinical and functional outcomes in critically ill adult patients☆

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M. Hiesmayr a, *, A. Csomos b, K. Dams c, G. Elke d, W. Hartl e, O. Huet f, L.J. Krzych g, H. Kuechenhoff h, M. Matejovic i, Z.A. Puthucheary j, O. Rooyackers k, R. Tetamo l, I. Tjäder m, C. Vaquerizo n

ARTICLE INFO

Article history:
Received 31 July 2020
Accepted 15 January 2021

Keywords:
ICU
Clinical nutrition
Functional status
Parenteral
Enteral

SUMMARY

**Background and aims:** Limited data are available on the impact of clinical nutrition over the course of critical illness and post-discharge outcomes. The present study aims to characterize the use of nutrition support in patients admitted to European intensive care units (ICUs), and its impact on clinical outcomes. Here we present the procedures of data collection and evaluation.

**Methods:** Around 100 medical, surgical, or trauma ICUs in 11 countries (Austria, Belgium, Czech Republic, Germany, France, Hungary, Italy, Poland, Spain, Sweden, United Kingdom) participate in the study. In defined months between November 2019 and April 2020, approximately 1250 patients are enrolled if staying in ICU for at least five consecutive days. Data from ICU day 1–4 are collected retrospectively, followed by a prospective observation period from day 5–90 after ICU admission. Data collection includes patient characteristics, nutrition parameters, complications, ICU and hospital length of stay, discharge status, and functional outcomes. For data analysis, the target is 1000 patients with complete data. Statistical analyses will be descriptive, with multivariate analyses adjusted for potential confounders to explore associations between nutritional balance and change in functional status, time-to-weaning from invasive mechanical ventilation, time to first clinical complication, and overall 15, 30 and 90-day survival.

**Ethics and dissemination:** This non-interventional study was reviewed and approved by the ethics committee of the Medical University Vienna, Vienna, Austria (approval number 1678/2019), and the respective ethical committees from participating sites at country and/or local level, as required. Results

<footnote>ª Division of Cardiac, Thoracic, Vascular Anesthesia and Intensive Care, and Center for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Spitalgasse 23, Vienna, Austria</footnote>

<footnote>ᵇ MH EK Honvedkorhaz, Budapest, Hungary</footnote>

<footnote>ᶜ Department of Critical Care Medicine, Antwerp University Hospital, University of Antwerp, Edegem, Belgium</footnote>

<footnote>ᵈ Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany</footnote>

<footnote>ᵉ Klinik Fuer Allgemeine, Viszeral-, und Transplantationschirurgie, Klinikum der Universitaet, Campus Grosshadern, Ludwig-Maximilians-Universität</footnote>

<footnote>Muenchen, Munich, Germany</footnote>

<footnote>f CHRU la Cavale Blanche, Brest, France</footnote>

<footnote>g Medical University of Silesia, Katowice, Poland</footnote>

<footnote>h Statistisches Beratungslabor, Institut Fuer Statistik Ludwig-Maximilians-Universitaet Muenchen, Germany</footnote>

<footnote>i First Medical Department, Faculty of Medicine in Pilsen, Charles University and University Hospital in Pilsen, Czech Republic</footnote>

<footnote>j Barts Health (Royal London) & Queen Mary University of London, London, England, UK</footnote>

<footnote>k Klinik Vetenskap, Intervention Och Teknik, Anestesi, Karolinska Institut, Stockholm, Sweden</footnote>

<footnote>l Ospedale Civile di Guastalla (Reggio Emilia), Italy</footnote>

<footnote>m Karolinska University Hospital, PMI Huddinge, Stockholm, Sweden</footnote>

<footnote>n Department of Intensive Care Medicine, Fuenlabrada University Hospital (Hospital Universitario de Fuenlabrada), Madrid, Spain</footnote>

<footnote>* Current study status: First patient included on November 5th, 2019. Data collection finalized on July 31st, 2020. Statistical analysis started in November 2020.</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail addresses: michael.hiesmayr@meduniwien.ac.at (M. Hiesmayr), csomos.akos@hm.gov.hu (A. Csomos), karolien.dams@uza.be (K. Dams), gunnar.elke@uksh.de (G. Elke), whartl@med.uni-muenchen.de (W. Hartl), olivier.huet@chu-brest.fr (O. Huet), lkrzych@sum.edu.pl (L.J. Krzych), kuechenhoff@stat.uni-muenchen.de (H. Kuechenhoff), matejovic@fnplzen.cz (M. Matejovic), z.puthucheary@qmul.ac.uk (Z.A. Puthucheary), olav.rooyackers@ki.se (O. Rooyackers), romanotetamo@me.com (R. Tetamo), inga.tjader@sl.se (I. Tjäder), clara.vaquerizo@salud.madrid.org (C. Vaquerizo).</footnote>
will be shared with investigators on a country level, and a publication and results presentation at the 2021 ESPEN Congress is planned.

Trial registration: ClinicalTrials.gov identifier NCT04143503.

© 2021 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Abbreviations

<table><tr><td>LOS</td><td>Length Of Stay</td></tr><tr><td>ICU</td><td>Intensive Care Unit</td></tr><tr><td>EN</td><td>Enteral Nutrition</td></tr><tr><td>SPN</td><td>Supplemental Parenteral Nutrition</td></tr><tr><td>RCT</td><td>Randomized, Controlled Trial</td></tr><tr><td>CI</td><td>Confidence Interval</td></tr><tr><td>SPIRIT</td><td>Standard Protocol Items: Recommendations for Interventional Trials</td></tr><tr><td>BMI</td><td>Body Mass Index</td></tr><tr><td>SD</td><td>Standard Deviation</td></tr><tr><td>SAP</td><td>Statistical Analysis Plan</td></tr><tr><td>CRRT</td><td>Continuous Renal Replacement Therapy</td></tr></table>

<table><tr><td>ESPEN</td><td>European Society of Clinical Nutrition and Metabolism)</td></tr><tr><td>CPAx</td><td>Chelsea Physical Assessment tool</td></tr><tr><td>HAI</td><td>Healthcare-associated infection</td></tr><tr><td>eCRF</td><td>electronic Case Report Form</td></tr><tr><td>ID</td><td>Identification</td></tr><tr><td>IMC</td><td>Intermediate Care unit</td></tr><tr><td>SOFA</td><td>Sequential Organ Failure Assessment score</td></tr><tr><td>APACHE II</td><td>Acute Physiology and Chronic Health Evaluation score, second revision</td></tr><tr><td>NUTRIC</td><td>NUTrition Risk In Critically ill score</td></tr><tr><td>BW</td><td>Body Weight</td></tr><tr><td>BIC</td><td>Bayesian Information Criterion</td></tr><tr><td>IRB</td><td>Institutional Review Board</td></tr><tr><td>ICMJE</td><td>International Council of Medical Journal Editors</td></tr></table>

# 1. Introduction

Malnutrition is associated with adverse clinical and economic consequences, including an increased risk of complications [1,2], a decreased quality of life [3,4], and increased costs due to a longer hospital length-of-stay (LOS), higher re-admission rate, and greater resource utilization [2]. Adequate nutrition is essential to support recovery of hospitalized patients, particularly those with critical illness, as the auto-aggressive reactions induced by an exaggerated systemic inflammatory response lead to a significant loss of lean body mass [5–7]. This loss is associated with an increased risk of infection, impaired wound healing, prolonged duration of mechanical ventilation, increased LOS in the ICU, and ultimately increased mortality [8–11].

The optimal timing, amount, and route of clinical nutrition in critically ill patients remains a matter of debate. Current guidelines recommend early initiation of EN in hemodynamically stable patients who are unable to maintain oral intake [8,9,12,13, 14]. However, EN alone is often insufficient to meet caloric and protein requirements [4,15–17]. Indeed, studies in patients with critical illness suggest that usually only up to 50–70% of caloric requirements can be successfully provided in the practice by EN [18–21] with additional evidence supporting the use of Supplemental PN (SPN) to significantly improve caloric and protein intake [11,22].

Several RCTs have examined the effect of calorie intake during the acute phase of critical illness, either as a primary target or as incidental finding to another scientific objective. A recent review thoroughly discussed these studies, which had also been incorporated into 11 meta-analyses [12]. The evidence of a positive impact of clinical nutrition over outcomes related to critical illness is inconsistent, with the unfavorable results of some RCTs being possibly valid only for specific subgroups of critically ill patients.

Observational studies, which may be less selective in terms of patient inclusion criteria, have also been subject to substantial

criticism because of inherent major methodological weaknesses, such as confounding by indication, or ignoring the time-dependent nature of the variable of interest (nutrition). Consequently, they have yielded as well quite contradictory results. A summary of the results from those observational trials is provided within the guidelines for clinical nutrition in critical care medicine of the German Society for Nutritional Medicine [12].

A recent, large retrospective study tried to overcome statistical limitations of preceding observational studies. This analysis evaluated the associations between daily caloric intake and short-term survival in 9661 critically ill patients, using novel statistical approaches [23]. Three categories for caloric intake were defined in a pragmatic manner: category I <30% of target, category II 30–70%, and category III >70%. The investigators found that those patients in category I, who were only provided minimal amounts of calories throughout the first 11 nutrition days (about 1.0 kcal/kg day) presented an increased risk of dying during the first 30 days after ICU admission, compared to those provided a mild, hypocaloric nutrition. Additionally, no substantial hazard change was detected when a delayed or an early, near target calorie intake was compared to an early, mildly hypocaloric nutrition (Hazard Ratio 0.71 (95% confidence interval [CI], 0.54 to 0.94) and 0.56 (95% CI, 0.38 to 0.82), respectively). A major limitation of this study, however, was that collection of survival status ended at the time of hospital discharge: hence, in order to evaluate survival on day 30, more than half of the patients required assumptions on survival status.

Patients who survive acute critical illness often experience impaired physical function and prolonged rehabilitation. Observational studies have identified several predictors of functional outcome, including age, LOS in the ICU, and duration of mechanical ventilation [24,25]. While it is highly likely that nutrition and recovery of physical function are related to each other, the available evidence is limited. Randomized studies examining the effect of a variable protein intake [26–31] mostly did not show beneficial effects, however they were limited as well by a variety of factors
such as a large number of missing values, the absence of an intention-to-treat analysis (ignorance of dying patients), and a highly variable follow-up time.

After reviewing the limited evidence available, we designed this study in order to validate the hypothesis of a positive relation between the intensity of clinical nutrition and functional recovery in critically ill patients, particularly those with a longer stay, as well as the impact of clinical nutrition over complications and survival. The primary objective of the study is to characterize the current use of clinical nutrition in critically ill patients hospitalized in European ICUs with a minimum LOS of five consecutive calendar days, and their nutritional balance, including caloric and protein balance. Secondary objectives are to describe the association between the nutritional balance and clinical outcomes, including the change in functional status from before ICU admission to days 15, 30 and 90 following ICU admission and time to weaning from invasive mechanical ventilation. The association of nutritional balance with the time to first nosocomial infection and overall 15, 30, and 90-day survival time. Potential predictors of nutritional deficits (both caloric and protein) will also be evaluated.

## 2. Methods

The EuroPN Survey is a multinational, exploratory, observational cohort study in critically ill adults treated in the ICU for at least 5 consecutive days. It will be conducted in 115 participating sites in 11 countries (Austria, Belgium, Czech Republic, France, Germany, Hungary, Italy, Poland, Spain, Sweden, and the United Kingdom), with a pre-defined screening month in each country. The protocol for this observational study follows the recommendations from the SPIRIT reporting Guidelines [32].

The study schematic in Fig. 1 includes exemplary patient scenarios, to illustrate the selection criteria for initial screening.

For each enrolled patient, part 1 of the study is a retrospective observation period, defined as the period from ICU admission through day 4. Demographic, clinical, and nutritional data for the first four days in the ICU will be retrieved from the patient's medical chart after confirmation of eligibility and written informed consent or requirements from local ethical committee (EC) have been fulfilled.

Part 2 of the study is a prospective observation period, with data collection commencing on day 5 after ICU admission. On day 5, patient's functional status reflecting status before ICU admission will be estimated by interviewing the patient, the patient's legally acceptable representative, or the patient's care giver, where

applicable. Alternatively, relevant information can also be extracted from the admission status documented in the medical records. Nutrition and clinical parameters will be collected daily from day 5 until ICU discharge or death, or for a maximum of 15 days for patients who are still in the ICU on day 15. Telephone interviews with the patient, the patient's legally acceptable representative, or the patient's care giver will be conducted on days 15, 30 and 90 after ICU admission to assess functional status, survival, and readmission(s) to the ICU and hospital. For patients who are still in the ICU or hospital on these days, functional status will be assessed in person by study site personnel.

In case the sample size is not reached, additional screening months can be performed in the previously selected sites to increase recruitment; nevertheless, patients can only be enrolled once in the study.

According to the observational study design, patients will receive standard medical care throughout the study period, as per the clinical judgement of their treating healthcare practitioner.

### 2.1. Selection of study population

#### 2.1.1. Inclusion criteria

* Critically ill adult male and female patients (age between 18 and 95 years)

* BMI of ≥18.5 kg/m2 and ≤45 kg/m2

* Hospitalized in academic, university, regional, or community hospitals with a medical, surgical, or trauma ICU

* Hospitalized in a medical, surgical, or trauma ICU for at least five consecutive calendar days, and admitted to the ICU either during the pre-defined screening month, or maximally 4 days before start of the screening month

#### 2.1.2. Exclusion criteria

* Burns

* Pre-existing neuromuscular or psychiatric disorders, or severe hypoxic brain injury or neurological diagnosis at the time of ICU admission precluding proper assessment of functional status

* Home nutritional support at the time of ICU admission,

* Chronic invasive or non-invasive ventilatory support before ICU admission

* Patients admitted to the ICU for palliative care

<figure><img src="image_4.png" /><figcaption>**Fig. 1. Study schematics.** Patients with a minimum ICU LOS of 5 days and admitted in the ICU during the pre-defined period of one month will be enrolled in the study, including those admitted up to 4 days before its start. Clinical and nutrition data are collected during a maximum of 15 days while in the ICU. Four different patient scenarios are presented to illustrate eligible patients. Each "◆" symbol indicates an assessment timepoint for follow-up (15, 30 and 90 days after ICU admission). ICU = Intensive care unit, LOS = Length of stay.</figcaption></figure>
* Concurrent enrolment in a nutrition-related interventional study at the time of screening

* Having a legal representative already in place before ICU admission

Before any data collection, written informed consent to participate in the study will be obtained by the investigator, either from the patient or their legally acceptable representative, as per requirements of their local/national ethical committee.

## 2.2. Sample size calculation

A sample size of 1000 patients was determined based on feasibility considerations. Since it was expected to include a minimum of 12 patients per site, those participating countries with a higher number of sites could consequently provide more patients to the sample, which might not be necessarily related to the size and population of that country.

To compensate for an estimated 20% rate of incomplete data ascertainment, a total of approximately 1250 patients will be recruited to achieve the objective of 1000 patients with complete data.

The confidence interval (CI) for the relative cumulative nutritional balance (%) can be calculated as the mean ± z(1-α/2) × σ/√n, where z (1-α/2) equals 1.96 for a significance level of α = 0.05, σ is the SD and n is the sample size. With a sample size of 1000, the precision of the two-sided 95% CI for nutritional balance is 0.06 times the SD. Based on a previous comparable study conducted in Latin America [25], a SD for nutritional balance of 40% is realistic; therefore, a precision of 2.5% can be achieved.

In order to minimize the limitations from previous observational studies, we plan to adhere to a strict follow-up protocol, as well as to use advanced statistical methods. Nevertheless, since the frequency and nature of missing data cannot be foreseen, alternative approaches for the statistical testing will be also evaluated, and the resulting method will be specified in a Statistical Analysis Plan (SAP). The estimated precision corresponding to the actual number of patients with complete data will be provided in the final publication, in the event that the target sample size of 1000 patients with complete data is not met.

Due to the exploratory nature of statistical testing in the present study, no adjustment of the type I error will be performed. In addition, drop-outs during Part 2 (prospective observation period) will not be replaced.

## 2.3. Outcome measures

A list of the outcomes of interest is provided in Table 1.

## 2.4. Data analysis plan

All data collected during the study will be recorded in a specifically designed eCRF by designated site staff and will be stored in a study-specific database within an electronic data management system compliant with the Good Automated Manufacturing Practice guidelines, version 5.0 (GAMP 5; INES, IQVIA, Paris, France). All patient data will be pseudonymized and coded with a unique patient identification (ID) number generated by the electronic data management system. The database will comply with all applicable national, regional, and local regulations regarding patient data protection and records retention. Data analyses will be performed using SAS statistics software (SAS Institute Inc., Cary, NC) and R statistical software.

### 2.4.1. Description of variables

Continuous variables will be described by the number of patients with valid/missing observations, mean, SD, median, minimum and maximum values. In addition, two-sided 95% CI will be computed for the caloric and protein balance variables, including the proportion of patients in each of the defined balance categories. For non-normally distributed data the median and interquartile range will be calculated. Categorical variables will be described by the number of patients with valid/missing observations and by frequencies and related percentages per class level. All data will be summarized, and analyses will be performed at regional (i.e. overall for the European region), as well as at national level.

The primary endpoint nutritional balance, including absolute, relative and cumulative caloric and protein balance will be calculated based on the caloric and protein intake from the information provided by the investigators compared to targets published by ESPEN [8].

All variables will be analyzed descriptively, including but not limited to: proportion of patients transitioned to step-down/IMC unit, ward, home, rehabilitation center, nursing home/residential care or other; requirements of vital support (sedation, muscle paralysis, vasopressors, antimicrobials, ventilatory support, renal replacement therapy); use of physiotherapy (active, passive or both, up to maximum 15 days from ICU admission); severity of complications, measured by change from baseline SOFA [36] score value; number of days with delirium; proportion of patients with identified risk of malnutrition at admission; predicted mortality

<table><caption>**Table 1**
Study outcomes.</caption><thead><tr><th></th><th>Outcome</th><th>Description</th></tr></thead><tbody><tr><td>Primary outcomes</td><td>Caloric and protein intake and balance</td><td>The primary endpoint is defined as the 95% CI of the nutritional balance, up to a maximum of 15 days from ICU admission. For these calculations, both the actual caloric and protein intake from nutritional (PN, EN, ON/ONS) and non-nutritional (e.g. Propofol, citrate from continuous renal replacement therapy (CRRT), or dextrose solutions) sources will be considered, as reported in each patient's medical chart.<sup>a</sup> Targets for the balance calculation will be based on the recommendations made by the recent ESPEN guideline [8].</td></tr><tr><td>Secondary outcomes</td><td>Functional status<br>Interruptions<br>Time to weaning from invasive mechanical ventilation</td><td>IMS [33] and CFS [34] score values obtained and changes from status before ICU admission to days 15, 30, and 90.<sup>c</sup> CPAx score [35] will be considered as optional<br>Reasons for not allowing, stopping, and interrupting clinical nutrition, and number of days without clinical nutrition<br>Impact of clinical nutrition during ICU stay on the duration of invasive mechanical ventilation</td></tr><tr><td>Tertiary outcomes</td><td>Overall mortality<br>Clinical complications</td><td>Impact of clinical nutrition during ICU stay on the Overall 15, 30, and 90-day survival time<br>Impact of clinical nutrition during ICU stay on the development of Hospital-Acquired Infection (HAI).</td></tr></tbody></table>

**Notes.**

ON: Planned oral nutrition caloric intake will be divided according to the expected percentage per meal, and accounted using plate diagrams.

<footnote><sup>a</sup> For propofol 1.1 Kcal per ml, dextrose 4 Kcal per g, clevidipine 2 Kcal per ml; and citrate 2.5 Kcal per g.</footnote>

<footnote><sup>c</sup> For all scores, local-language versions will be provided to each participating site.</footnote>
based on APACHE II score at admission; re-admission to ICU/Hospital (for patients discharged before follow-up days 15, 30 and 90); and modified NUTRIC score [37], calculated from parameters assessed within 24 h following ICU admission.

### 2.4.2. Multivariable analysis of outcomes

Linear mixed-effect models with repeated measures will be used to assess predictors associated with daily absolute caloric intake (kcal/kg BW), daily absolute protein intake (g/kg BW), daily caloric balance (kcal/kg BW), and daily protein balance (g/kg BW). To account for possible nonlinear relationships flexible penalized spline will be applied. Continuous predictor variables to be analyzed using penalized splines will include those variables assessed at baseline level (not at daily level).

Outcomes will be assessed for all patients on a daily basis during ICU stay, excluding discharge date, due to the potential risk of using partial nutritional data depending on discharge time. The study site will be included in the analysis as a separate variable and defined as random effect.

The list of predictor variables to be considered for all the analyses with nutritional outcomes includes: Assessment of patients by nutrition support team, nutritional needs regularly assessed for patients, age, sex, type of ICU admission I (surgical/non-surgical), type of ICU admission II (elective/emergency), main reason for ICU admission (leading diagnosis), APACHE II score, patient at risk of malnutrition, number of days without nutrition until the preceding day, number of days with stopped or interrupted nutrition until the preceding day, SOFA score [36], number of days on invasive mechanical ventilation until the preceding day, and limited medical support.

The strength of the associations between selected predictor variables and outcome variables will be characterized using regression coefficient and 95% CI.

### 2.4.3. Multivariable analysis of the functional and clinical outcomes

Changes in functional status and absolute functional status values will be analyzed using a linear mixed-effect model. Potential predictors will be included in the model as fixed effects (considering that all response options are covered by the variable), except for study site, which will be included as a random effect. Except nutrition variables, only those predictors registered up to day 5 will be included in the main analysis.

Only patients alive at the corresponding timepoint (15, 30 and 90 days after ICU admission) will be included in the model, deceased patients at the corresponding timepoint will be excluded. Due to the high correlation between daily average cumulative caloric intake and daily average cumulative protein intake, four separate models will be performed, one for each predictor: cumulative and absolute caloric intake and balance, and cumulative and absolute protein intake and balance. Nutrition variables will be treated as the variables of interest.

The list of potential predictors for these analyses includes age, sex, body weight, type of ICU admission (I), Type of ICU admission (II), main reason for ICU admission, severe comorbidities at ICU admission, APACHE II, unintentional weight loss during the past 6 months, SOFA score [36], HAI, delirium, sedation, invasive mechanical ventilation, physiotherapy, prior functional status, limited medical support, and GI-tract function.

A forward selection method will be used to identify the variables finally included in the model with Bayesian information criterion (BIC).

The strength of the associations between predictor variables and outcome variables will be characterized using regression coefficients and 95% confidence intervals.

### 2.4.4. Time-to-event multivariable analysis

The following three time-to-event models will be performed:

* Time to weaning, addressing the impact of nutrition received during ICU stay on the duration of invasive mechanical ventilation. For this analysis, a penalized estimation of complex, nonlinear exposure-lag-response Cox proportional hazard model, defining death while still being intubated as a competing event

* Time to first HAI: For this analysis, a penalized estimation of complex, nonlinear exposure-lag-response Cox proportional hazard model, defining ICU discharge without a new infection before the end of the observation period as a competing event will be used. Death before day 15 in the ICU cannot be assumed independent of HAI and thus we will consider two approaches in a sensitivity analysis, death considered as independent or as HAI at the day of death. The HAI observation period ends for all patients at day 15, or at day of death or ICU discharge.

* Survival: The same statistical approach described for time to weaning from invasive mechanical/time to first HAI will also be used to analyze overall survival until day 15, day 30 and day 90, assuming death as the event of interest. For death follow-up until day 90 is planned for all patients and loss of follow-up is the only competing event.

Except nutrition variables, only predictors registered up to day 5 will be included in the main analysis.

The list of potential predictors includes age, sex, body weight, type(s) of ICU admission (I), type of ICU admission (II), main reason for ICU admission, comorbidities at ICU admission, APACHE II, unintentional weight loss during the past 6 months, categorized cumulative absolute caloric intake and relative caloric balance, categorized cumulative absolute protein intake and relative protein balance, SOFA score [36], HAI, delirium, sedation, physiotherapy, prior functional status, limited medical support, and GI-tract function.

Results will be modelled to an artificial nutrition plan, and plan comparisons will be done to estimate associations of different nutrition plans with the outcome. Plans will be designed based on available patterns in the data and intake will be categorized according to either the absolute value, or to the relative value (reference is ESPEN target). Like in the multivariate analysis for functional and clinical outcomes, four separate analyses will be done for protein and calorie intake (mutual exclusion).

All data analyses will be performed using SAS statistics software (SAS Institute Inc., Cary, NC) as well as R (R Foundation for Statistical Computing, Vienna, Austria). All analyses will be performed in a manner consistent with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

## 3. Ethics and dissemination

This study protocol was reviewed and approved by the ethics committee of the Medical University Vienna, Vienna, Austria (approval number 1678/2019). Additionally, it was reviewed and approved by the respective Ethics Committee (EC) and Institutional Review Board (IRB) for each participant country and site, when deemed appropriate by applicable regulations. Amendments, if any, will be timely submitted for EC/IRB approval, and communicated to all responsible parties.

The identity of patients will be considered confidential and will not be revealed or published under any circumstances; all provisions of laws governing personal data protection will be observed. Patient data recorded in the eCRF will be documented pseudonymously using de-identified patient ID codes; only designated
authorized staff at each participating site will have access to identifiable data. For all other parties involved in data management and analysis, data access will be limited to non-identifiable patient data.

A patient's identity may not be revealed without the explicit written permission of both the patient and the patient's physician. Should the exceptional circumstance of needing to reveal a patient's identity due to legal obligation or for the purpose of an audit to evaluate data quality, the study responsible parties will ensure compliance of all applicable statutes and guidelines pertaining to patient confidentiality.

In addition to the present publication, details from the study have been made publicly available through databases for study disclosure (ClinicalTrials.gov study identifier NCT04143503).

As of today, this cohort study represents the largest data collection initiative for gathering real world evidence relevant to clinical nutrition and its effect over the clinical outcomes of critically ill patients with an ICU LOS ≥5 days treated in European ICUs. Therefore, we plan to disseminate its results in national and international conferences, and submit for publication, with authorship following the ICMJE recommendations (http://www.icjme.org/recommendations). Additionally, since the results will be submitted to the EC and/or the IRB at the participating sites upon completion of the study, it is also planned to have derivatives country-specific publications in national and regional journals, and to present the results will be presented in local congresses and published in national journals.

## Authors' contributions

M. Hiesmayr acts as the corresponding author, being responsible for the final review of the manuscript and its submission.

W. Hartl and H. Kuechenhoff provided advise for the methods section and during the elaboration of the statistical analysis plan.

C. Akós, K. Dams, G. Elke, O. Huet, L. Krzych, M. Matejovic, Z. Puthucheary, O. Rooyackers, R. Tetamo, I. Tjader, C. Vaquerizo had an equal contribution to the elaboration of this protocol and the review of the subsequent manuscript.

The Authors would also like to highlight the contribution and technical support from the teams of Fresenius Kabi during the conceptualization of this study, and for the preparation and submission of this manuscript.

## Funding statement

This study is sponsored, funded and logistically supported by Fresenius Kabi Deutschland, GmbH, Else-Kroner-Strasse 1, D-61352 Bad Homburg v. d. H., Germany. The sponsor has no influence over data collection and/or its interpretation.

## Declaration of competing interest

M. Hiesmayr has received lecture fees and travel support from Fresenius Kabi, Nestlé, Baxter, SSPC, consulting fees from Fresenius from Fresenius Kabi, and unrestricted research grants from Baxter and Fresenius Kabi to Medical University Vienna.

M. Matejovic has received lecture fees from Fresenius Kabi, Baxter, Nutricia and consulting fees and travel support from Fresenius Kabi.

C. Vaquerizo has received lecture fees and travel support from Fresenius Kabi, Nestlé Healthcare Nutrition, Abbott Nutrition and Vegenat Nutrisens, and consulting fees from Fresenius Kabi and Vegenat Nutrisens.

G. Elke has received lecture fees and travel support from Fresenius Kabi, Baxter and consulting fees and travel support from Cardinal Health, Fresenius Kabi and Nutricia.

K. Dams has received lecture fees from Fresenius Kabi, Baxter, Nestlé and consulting fees and travel support from Fresenius Kabi.

The rest of the authors have no conflicts of interest to declare in relation with this study.

## Acknowledgements

The Authors would like to acknowledge the contribution of the following persons during the development of this study protocol: Prof. Dr. Martin Westphal, MD, Dr. Petra Loedige, MD, Dr. Eva Fries-Schaffner, Dr. Jean-Marc Lohse, Dr. Steffen Benzing, Dr. Martín Hernández-González, MD, Dr. Melanie Streicher, Mrs. Jenny Pham, M. Sc., Mrs. Silke Gerrath, M. Sc., Mr. Xieran Li, M. Sc., Dr. Rosa Abele, Dr. Margot Crucet Peregrino, Prof. Dr. John Stover, MD, Mrs. Claudia Miranda-Foca-Fuchs, MSc., Prof. Jean-Francois Baron, MD, Prof. Thomas Lescot, MD, Dr. Anna Mallol, Mrs. Anne-Sophie Tepenier.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.clnesp.2021.01.048.

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