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Electronic Supplementary Material

Supplement to: Li Bassi G and Panigada M. et al. RANDOMIZED, MULTI-CENTER TRIAL OF LATERAL TRENDELENBURG VERSUS SEMI-RECUMBENT BODY POSITION FOR THE PREVENTION OF VENTILATOR-ASSOCIATED PNEUMONIA

Supplementary Material | 1

RANDOMIZED, MULTI-CENTER TRIAL OF LATERAL TRENDELENBURG VERSUS SEMI-RECUMBENT BODY POSITION FOR THE PREVENTION OF VENTILATOR-ASSOCIATED PNEUMONIA

THE GRAVITY-VAP TRIAL

Electronic Supplementary Material

Table of Contents

ELECTRONIC SUPPLEMENTARY METHODS 6

ADDITIONAL METHODS 7

DECISION TO TERMINATE THE TRIAL AT THE SECOND PRE-SPECIFIED INTERIM ANALYSIS 10

DECISION TO INCLUDE AN ADDITIONAL NEUROLOGICAL EVALUATION OF PATIENTS UPON DISCHARGE FROM THE INTENSIVE

CARE UNIT 11

STATISTICAL ANALYSIS 12

SAMPLE SIZE 12

RANDOMIZATION 12

REVISED STATISTICAL PLAN OF ANALYSIS 12

Rationale for revised statistical plan of analysis 12

FINAL STATISTICAL ANALYSIS PLAN (SAP) 12

Descriptive analysis 12

Primary and secondary outcomes 12

Primary outcome (Efficacy analysis) 12

A. Incidence risk 12

B. Incidence rate 13

C. Competing risk analysis 13

D. Efficacy and Safety based on adherence analysis (Complier Average Causal Effect – CACE) 13

Secondary outcomes 13

A. Clinical suspected VAP 13

B. Mortality 14

C. Length of mechanical ventilation 14

D. Length of ICU and hospital stay 14

E. Use of sedatives, opioids and neuromuscular blocking drugs 14

F. Use of antibiotics 14

G. Secondary bacterial infections 14

H. Nutritional support 14

I. Adverse events 14

L. Nursing feasibility and workload 15

Subgroup analysis 16

Feasibility analysis 16

General comments 16

Statistical plan amendment 16

Sub-group analysis 16

ELECTRONIC SUPPLEMENTARY RESULTS 18

TABLE E1: COLLABORATING CENTERS 19

TABLE E2 COMPETING RISK ANALYSIS OF THE PRIMARY OUTCOME 20

TABLE E3: VENTILATOR-ASSOCIATED PNEUMONIA CAUSATIVE PATHOGENS 21

TABLE E4: CAUSES OF DEATH IN THE INTENSIVE CARE UNIT 22

TABLE E5: COMPLIER AVERAGE CAUSAL EFFECT ANALYSES OF LATERAL-TRENDELENBURG VERSUS SEMIRECUMBENT POSITION

TABLE E6: BACTEREMIA AND OTHER INFECTIONS 24

TABLE E7: DAYS ON SEDATIVES, OPIOIDS, NEUROMUSCULAR BLOCKING AGENTS DURING THE 14-DAY STUDY AND DOSES

ACCORDING TO STUDY GROUPS 25

TABLE E8: DAYS ON ANTIMICROBIALS DURING THE 14-DAY STUDY AND DOSES ACCORDING TO STUDY GROUPS 26

TABLE E9: NUTRITION AND CALORIE INTAKE 27

TABLE E10: NURSING FEASIBILITY AND WORKLOAD OF THE INTERVENTIONS BY NURSES IN PATIENTS WHO WERE PLACED IN

THE RANDOMIZED POSITIONS 28

TABLE E11: NEUROLOGICAL EVALUATION UPON DISCHARGE FROM THE INTENSIVE CARE UNIT 29

TABLE E12: POST-HOC INTERACTION EXPLORATORY ANALYSES FOR THE EFFECT OF THE POSITION ON MAIN OUTCOMES

BETWEEN PATIENTS WITHOUT [N=206] AND WITH [N=189] PULMONARY INFILTRATES UPON ENROLLMENT 30

ELECTRONIC SUPPLEMENTARY FIGURE LEGENDS 32

FIGURE E1: RECRUITMENT RATE 33

FIGURE E2: REASONS FOR CHANGING POSITION FROM LATERAL-TRENDELENBURG TO SEMI-RECUMBENT 34

FIGURE E3: PROPORTION OF TIME IN EACH POSSIBLE BODY POSITION PER STUDY TIME AND PER RICHMOND AGITATION

SEDATION SCORE. 35

FIGURE E4: NURSING FEASIBILITY AND WORKLOAD 36

ELECTRONIC SUPPLEMENTARY METHODS

Additional Methods

Participants and settings

We conducted a prospective, multicenter, randomized, controlled trial of lateral Trendelenburg versus semirecumbent body position in mechanically ventilated patients for the prevention of ventilator-associated pneumonia (Gravity-VAP Trial). The Gravity-VAP trial was done in 18 hospitals (see electronic supplementary table E1) in five countries (Spain, Italy, Germany, Croatia, United States of America). The study protocol, which is available as on-line supplementary material, was initially approved by the ethics committees at Fondazione Cà Granda in Milan, Italy and Hospital Clinic, Barcelona, Spain, which were the coordinating centers, and later at each participating institution. Patients 18 years old of age or older, expected to be invasively mechanically ventilated for at least 48 hours were assessed for enrolment, within 6 hours from endotracheal intubation. We excluded patients who were enrolled in another interventional trial; who underwent endotracheal intubation longer than 12 hours, during the previous 30 days; with documented bronchiectasis; with pulmonary aspiration before or during intubation; cystic fibrosis; increased intracranial pressure, brain edema or any medical condition that could increase intracranial pressure; heart failure with impairment of the daily activities (Class III-IV of the New York Heart Association); spinal cord injury; body mass index > 35; grade IV intra-abdominal pressure or compartment syndrome; pregnant women and patients with orthopaedic problems who could not be kept in the study positions. According with local ethical regulations, prior or delayed informed written consents were obtained from the patients or their next of kin. The trial was overseen by an independent data and safety monitoring (DSMB) committee. At the first feasibility/safety interim analysis, due to low rate of inclusion for the time of enrolment, the protocol was amended to allow inclusion of patients within 12 hours of tracheal intubation.

Randomization and interventionsRandomizationFor randomization of patients, we used an interactive web-based randomization system accessible at the study website (www.gravityvaptrial.org). A statistician with no further role in study implementation created a randomization schedule, stratified by center. Investigators at each institution were blinded to the randomization block length (10 patients) and microbiology laboratory personnel were blinded to group assignments.

Assessment upon inclusionUpon inclusion, the following parameters were collected:

- Age- Sex- The Acute Physiology and Chronic Health Evaluation II (APACHE II), which is based on data regarding

physiological function that were obtained during the first 24 hours after admission to the ICU, ranges from 0 to 60, with higher scores indicating greater severity of illness. The total score, which is based on acute physiology, age, and severe coexisting illnesses, ranges from 0 to 71, with higher scores indicating greater severity of illness

- Coexisting illnesses- Type of admission- Reason of admission- Toxic habits- Stress ulcer prophylaxis

Proton pump inhibitor Histamine H2-receptor antagonists Others

- Systemic antibiotics - Oral decontamination- Selective digestive decontamination, SDD- Parenteral nutrition- Enteral nutrition- Subglottic aspiration - Nasotracheal intubation

- Richmond agitation-sedation score (RASS) upon inclusion, which is used for routine neurological assessments in the intensive care unit. RASS is a 10-point scale with discrete criteria, with four levels of agitation (+1 to +4), one level for calm and alert state (0), and 5 levels of sedation (−1 to −5).

- Arterial partial pressure of oxygen per inspiratory fraction of oxygen ratio (PaO2/FiO2) ratio upon inclusion

- Positive end-expiratory pressure, PEEP - Endotracheal tube internal cuff pressure after intubation upon inclusion - Pulmonary infiltrate upon inclusion

o Noneo Unilateral Righto Unilateral Lefto Bilateral

- Arterial pressure upon inclusion - Serum creatinine upon inclusion - Glasgow Coma Scale prior to induction for endotracheal intubation, which is a scale evaluating: Eye

response (No eye opening; Eye opening in response to pain stimulus; Eye opening to speech; Eyes opening spontaneously). Verbal response (No verbal response; Incomprehensible sounds. Inappropriate words. Confused. Oriented. Motor response (No motor response; adduction of arm to pain stimulation; flexion of arm to pain stimulation; Withdrawal from pain; Localizes pain; Obeys commands). Glasgow coma scale ranges from 3 to 15, with lower scores indicating a reduced level of consciousness. Motor scores range from 1 to 6, with lower scores indicating a reduced motor response.

InterventionsLATERAL TRENDELENBURG POSITION:In the lateral-Trendelenburg group, the patients were positioned similarly to the recovery position. First, the air-mattress was fully inflated. Then, the arm closest to the attending nurse was placed straight out from the body. The far arm was positioned with the back of the hand close to the near cheek. The patient's far knee was grabbed and bended. Protecting the head with one hand, the patient was gently rolled toward the attending nurse by pulling the far knee over the bed. Thus, the patient was positioned in a 60-degree semi-lateral position. Then, the head was slightly tilted up. The hand was positioned close to the cheek, never underneath. A pillow was positioned behind the chest and close to the dependent forearm in order to prevent compression of the axillary artery. An imaginary line from the sternal notch to the mouth, passing through the middle of the trachea was used as a surface landmark. The endotracheal tube, exiting the mouth, was also oriented a few degrees below horizontal to allow drainage of respiratory secretions. Every 6 hours, patients were rotated from one side to the other. In each participating institution, a comprehensive 1-day workshop was held before patient enrolment to distribute educational materials and describe the study positions with presentations, videos, web-based frequently asked questions and bedside training. The workshop was targeted to nurses, respiratory therapists and physicians.

SEMI RECUMBENT POSITION: In the semirecumbent group, patients were supine, with the head of the bed elevated at least 30 degrees. In the SRP group, patients were supine, with the head of the bed elevated ≥ 30°. Active humidification of respiratory gases was used in all patients. Study positions were encouraged until extubation or 14 days of MV.

It was strongly recommended to not use sedative and neuro-muscular blocking drugs to increase compliance to the randomized positions. Any change in position was recorded. Also, every 6 hours, the attending nurse monitored the head of the bed and Trendelenburg angle indicator to record the angulation. Early discontinuation of the study was allowed in case of death, transfer to another department/hospital or unexpected circumstances that did not allow monitoring of the patient's position. VAP preventive protocols, already implemented prior to the beginning of the trial, were not modified during the course of the study.

OutcomesPrimary OutcomeThe primary outcome was incidence of VAP, within the first 14 days of tracheal intubation, confirmed by quantitative culture of bronchoalveolar lavage (BAL) or mini-BAL or secretions collected through a protected

specimen brush (PSB). VAP was clinically suspected by the attending physician on duty when a new radiographic lung infiltrate was present, following 48 hours of tracheal intubation, and 2 or more of the following clinical criteria of new pulmonary infection were present:

1. Fever (T≥38 ºC) or hypothermia (T<35ºC)2. Leukocytosis (WBC>10000/ml) or leucopenia (WBC<4000/ml)3. Purulent tracheal aspirates

Then, VAP was microbiologically confirmed if quantitative cultures of BAL or mini-BAL fluids yielded ≥ 104 colony-forming units (cfu)/ml, or when samples obtained via PSB yielded ≥ 103 cfu/ml.

Secondary OutcomesSecondary and tertiary outcomes included all-cause mortality at 28 days, in the intensive care unit (ICU) and hospital; length of ICU and hospital stay; duration of MV; use of sedatives, analgesics, and antibiotics. We computed antibiotics' daily defined doses (DDDs), lorazepam and morphine equivalents, and propofol dosage. We assessed feasibility and safety of the interventions, including frequency of adverse events (AEs) and serious adverse events (SAEs). Finally, nurses’ feasibility and workload were self-reported through questionnaires given to the attending nurse upon patient ICU discharge, and compared between lateral-Trendelenburg and the semi-recumbent position groups. Of note, after inclusion of 137 patients the DSMB recommended an additional neurological evaluation upon patient discharge from the ICU.

Decision to terminate the trial at the second pre-specified interim analysis

In October 2015, the data safety monitoring board (DSMB), which consisted of three experienced scientists and physicians, with noteworthy expertise in randomized clinical trials:

Antonio Anzueto, MD, PhD. University of Texas Health Science Center at San Antonio, 111E 7400 Merton Minter Blvd, San Antonio, Texas 78230 USA

Francesco Blasi, MD, PhD Pulmonary Medicine Section, Department of Physiopathology, University of Milan, via F. Sforza 35, 20122, Milan Italy

Tobias Welte, MD, PhD Department of Pulmonary Medicine, Hannover Medical School, Hannover, German

and an epidemiologist:(Dario Consonni, MD, PhD, University of Milan, via F. Sforza 35, 20122, Milan Italy)

was granted a mandate to perform a formal interim analysis for efficacy and safety. At the time of the interim analysis, complete follow-up-data were available for 401 patients. In preparation of the interim analysis, all data of the included 395 patients were offered for endpoints assessment to the epidemiologist. The DSMB comprehensively evaluated efficacy endpoints and safety data, in particular intensive care unit, hospital, 28-day mortality and adverse events. to stop the study for low incidence of VAP in the control group, lack of benefits in any major secondary outcome and adverse events in the LTP group. The trial steering committee adopted the DSMB advice, specifically due to the lower-than-expected incidence of VAP in the control group. Patient enrolment was therefore stopped.

Decision to include an additional neurological evaluation of patients upon discharge from the intensive care unit

In March 2014, the DSMB, evaluated the findings of an animal study to assess the neurological effects of the lateral-Trendelenburg position. This laboratory trial was conducted at the Division of Animal Experimentation of the Department of Pulmonary and Critical Care Medicine, Hospital Clinic, Barcelona. This study was part of our continuous efforts to evaluate benefits, safety and indications of the lateral-Trendelenburg position, as a preventive measure for critically ill patients. We compared gross findings and cerebral histological patterns associated with the use of the semi-recumbent (10 animals) and Trendelenburg positions (7 animals) in pigs on invasive mechanical ventilation for 72 hours, and at risk of developing VAP. None of the animals in Trendelenburg position developed VAP; whereas 80% of the animals in semi recumbent had VAP. Trendelenburg position was associated with a significant increase in mean arterial pressure, due to blood volume centralization and absence of infection. Upon gross examination, we found higher venous engorgement in the brains of animals in the Trendelenburg group, in comparison with animals in semi recumbent. Additionally, in animals positioned in Trendelenburg, the dentate gyrus, within the hippocampus, showed increased signs of cell apoptosis (data not published yet).

Based on these results, we held a conference call on Wednesday, March 26, 2014. During this conference call, magnetic resonance imaging of 2 patients, enrolled in the lateral-Trendelenburg group were also evaluated. The DSMB members agreed that the results of the animal study were marginal, and limited by the applied experimental methods. In particular, the higher mean arterial pressure, the closure of the jugular vein (which is tied up upon insertion of the Swan-Ganz catheter) and absence of prevention of deep venous thrombosis with heparin, likely increased the risk of neurological injury in the Lateral-Trendelenburg group. This was also corroborated by the absence of any vascular abnormality, confirmed by MRI, in 2 of the patients positioned in the lateral-Trendelenburg position at the Policlinico di Milano and Hospital Clinic.Nevertheless, the DSMB members recommended improving the neurological monitoring of patients enrolled into the trial. In particular, upon intensive care unit discharge, the principal investigator addressed the following questions:1) Did the patient develop unexplained neurological complications, such as impairment in consciousness or delayed regain of consciousness after discontinuation of sedatives/analgesics; focal impairments in motor or sensor function; seizures? Yes/No or I do not know2) If yes, please describe in detail the condition3) Was neuroimaging ordered to evaluate this condition? Yes or No4) If yes, did the neuroimaging detect signs of current ischemia, infarction or hemorrhage?5) Please describe in details the results of the neuroimaging tests

These data were thoroughly evaluated during every DSMB meetings for the remaining time of the study.

Statistical analysis

Sample size

Incidence of VAP from May 2008 to May 2009 for each center comprising the Gravity-VAP Network, divided by type of intensive care unit, were pooled together (Table 8, Gravity VAP trial protocol version 2.1.1). The analysis has shown an overall incidence of VAP of 15.2%. We designed this study to detect a 50% reduction in incidence of VAP from 15 to 7.5 %. We calculated that approximately 800 patients (400 for each group) should be enrolled to detect a 50% reduction in VAP for a statistical power of 90% with a 2- sided significance alpha level of 0.05.

Randomization

Lists of randomization were designed by a coordination center at the Epidemiology Unit of the Policlinico di Milan, Italy. The principal investigator of each unit randomized the patients through the official website of the trial (www.gravityvaptrial.org). Allocation to lateral-Trendelenburg or Semi-recumbent arm was performed by fixed blocks of 10 patients and stratified by recruiting site.

Revised statistical plan of analysis

Rationale for revised statistical plan of analysisAfter the decision to stop the trial, upon the second pre-specified interim analysis by the DSMB, the trial steering committee decided to revise the statistical plan of analysis (SAP), prior to granting full access to the study data. An epidemiologist (OTR), Otavio Tavares Ranzani, who had been collaborating with the group since 2008, was invited to revise the original statistical analysis plan, under the supervision of the main trial statistician, Dario Consonni. The decision to revise the SAP was aimed at assuring an independent, unbiased analysis, because no formal statistical plan of analysis was published before the trial was stopped. The revised SAP was discussed with the principal investigators and the trial statistician, and after final approval of the revised SAP, the database was retrieved from the trial website, checked and fully analyzed.

Final Statistical Analysis Plan (SAP)

Descriptive analysisContinuous variables will be reported as means ± standard deviations or medians and 25-75% interquartile ranges. The frequency distribution of continuous variables will be evaluated by plotting histograms and Shapiro-Wilk tests. Categorical variables will be reported as proportions. Baseline variables will be compared between study groups to assess randomization performance and baseline balance between arms. Given that any difference in baseline characteristics are consequences of chance due to randomization, we will not perform any statistical testing for baseline comparison between arms1-4. For purposes of study time and time-to-event analyses, ‘Day 0’ will be considered the day of randomization.Primary and secondary outcomesAll analyses will be conducted in accordance with the intention-to-treat principle and in accordance to the CONSORT statement2 for comparison between two randomized study groups. We will not conduct adjusted analysis for the primary and secondary outcomes, except for variables defined a posteriori.

Primary outcome (Efficacy analysis)The primary outcome of the Gravity-VAP Trial will be the incidence of ventilator-associated pneumonia within the first 14 days of intubation, confirmed by quantitative microbiology analysis of either bronchoalveolar lavage (BAL) or mini-BAL fluids or secretions collected through protected specimen brush (PSB).A. Incidence riskThe incidence risk of microbiologic confirmed VAP will be compared as the proportion of patients who developed VAP in the lateral-Trendelenburg position group, in comparison with the proportion of patients who developed VAP

in the semi-recumbent position group. We will estimate the effects of the study intervention by unadjusted relative risk and its 95% confidence interval; then through the Fisher’s exact test.B. Incidence rateThe incidence rate of microbiologic confirmed VAP in the lateral-Trendelenburg position group will be also computed and compared with the incidence rate of microbiologic confirmed VAP in the semi-recumbent position group. Incidence rates will be reported as number of events per 1.000 ventilator-days. We will estimate the effect by unadjusted relative rates and its 95% confidence interval; then by the Fisher’s exact test. The Center of Disease Control recommends measuring the incidence of VAP in terms of rates over an appropriate denominator population that best reflects the risk of developing VAP, namely, per 1,000 ventilator-days. Indeed, incidence rates are a complementary measure of VAP frequency, because VAP is a disease that occur during mechanical ventilation. C. Competing risk analysisIn a sensitivity analysis of our data, we will consider the informative censoring that may occur on follow-up, by using competing risk analysis. Indeed, the occurrence of VAP can be biased by the presence of competing events 5-7, specifically death or extubation, which compete with VAP diagnosis, ultimately precluding its occurrence or dramatically changing its risk. For instance, a critically ill patient, at high risk of VAP, could die during the time on mechanical ventilation, but before the onset of VAP. Traditional methods of time-to-event analysis, e.g. the Kaplan-Meier estimators, would consider patients who died while receiving mechanical ventilation as non-informative censoring, resulting in biased estimates6,8,9. Likewise, patients who are extubated had an informative censoring, because occurrence of VAP is limited within the time on mechanical ventilation. Thus, in this sensitivity analysis, within the first 14 days of study, patients will be considered under risk (“exposure time”) until the occurrence of VAP, or until occurrence of one of the two competing events (death while receiving mechanical ventilation or extubation, whichever come first), or censored within 14 days (study time).

In the competing risk analysis, two complementary approaches can be used for estimation of the measure of effect to an exposure6-9. When aiming causal/etiological questions, the cause-specific hazard ratio is the most appropriated method8-10. When aiming prediction or risk, the sub-distributional hazard ratio is indicated (Fine and Gray model)8,9. Also, reporting both measures is recommended for better understanding of the cumulative incidence function (CIF), because the CIF is the result of the cause-specific hazard rate for each competing event6,8,9.In conclusion, to estimate the effect of the intervention in the incidence of microbiologic confirmed VAP (“causal question”), taking into account the two competing events, we will estimate the unadjusted cause-specific hazard ratio using the Cox proportional hazards model7-9. The proportionality assumption will be assessed through inclusion of a time-dependent interaction into the model and by plotting the Schoenfeld's residuals. We will also report the unadjusted sub-distribution hazard ratios using the Fine and Gray model.D. Efficacy and Safety based on adherence analysis (Complier Average Causal Effect – CACE)In an intention-to-treat study design, after randomization, it may occur that some of the patients may be not compliant to the randomized intervention. Importantly, “per-protocol” or “as-treated” analyses are limited by important post-randomization selection bias, because these approaches do not respect the intention-to-treat principle and the strengths of the randomization11-14. Yet, although the standard intention-to-treat analysis could be conservative for efficacy, it does not take into account the non-compliant patients, and could result in biased estimates, specifically for safety12,14,15. In order to respect the intention-to-treat principles and comprehensively evaluate the measure of effect of treatment in compliant patients, we will apply the Complier Average Causal Effect (CACE) approach, using instrumental variable analysis and principal stratification11-14,16,17. In a randomized experiment, the randomized arm can indeed perform as an instrumental variable, which has direct association with the treatment (lateral-Trendelenburg versus semi-recumbent positions) and only affect the outcome, through its association with the treatment15. In patients randomized in the lateral-Trendelenburg position, we will define ‘compliers’ those who stayed for a specific period of time in the lateral-Trendelenburg position, within the first 2 days of study time. In particular, we will compute the median percentage of time spent in the randomized position and we will apply this value to define the complier population. In patients in the lateral-Trendelenburg group, we will not not expect crossover to the semirecumbent position; therefore, the condition of monotonicity will be achieved18. We will estimate the complier average causal effect for the incidence of microbiologic confirmed VAP, by using standard instrumental variables analysis, with generalized method of moments19.Secondary outcomesA. Clinical suspected VAPThe incidence risk of clinical suspected VAP will be compared as the proportion of patients who had clinical suspicious of VAP in the lateral-Trendelenburg position group, versus the proportion of patients with clinical

suspicion of VAP in the semi-recumbent position. We will estimate the effect by unadjusted relative risk and its 95% confidence interval, followed by the Fisher’s exact test. The incidence rate of clinical suspected VAP in the lateral-Trendelenburg position group will be also compared with the incidence rate of clinical suspected VAP in the semi-recumbent position group, and will be reported as number of events per 1.000 ventilator-days. We will estimate the effect by unadjusted relative rates and its 95% confidence interval, followed by the Fisher’s exact test. B. MortalityAll-cause ICU and hospital mortality will be compared between patients in lateral-Trendelenburg and semi-recumbent position. We will estimate the effect by unadjusted relative risk and its 95% confidence interval, followed by the Fisher’s exact test. Also, we will compare the proportion of patients who died by all causes, up to 28-days after randomization, between lateral-Trendelenburg and the semi-recumbent position group. We will estimate the effect by unadjusted relative risk and its 95% confidence interval, followed by the Fisher’s exact test. Kaplan-Meier curves will be plotted and compared using the log rank test for 28-days survival comparison. As reported above, we will also compute the complier average causal effect for ICU, hospital and 28-day mortality.C. Length of mechanical ventilationDays under mechanical ventilation will be reported as median and 25-75% interquartile range. We will compare the median of all paired differences between observations in the lateral-Trendelenburg and semi-recumbent position groups and its 95% confidence interval (Hodges-Lehmann method)20,21. The between-group analysis will be performed using the Wilcoxon rank-sum test.D. Length of ICU and hospital stayICU and hospital length of stay will be reported as median and 25-75% interquartile range. We will estimate the effect by the median of all paired differences between observations in the lateral-Trendelenburg and semi-recumbent position groups and its 95% confidence interval (Hodges-Lehmann method)20,21. The comparison between lateral-Trendelenburg and semi-recumbent position groups will be performed using the Wilcoxon rank-sum test.E. Use of sedatives, opioids and neuromuscular blocking drugsDuration of sedative use, sedative free-days, within the first 14-day of the study time, lorazepam equivalents dose per day, propofol dose per day, duration of opiates use, 14-day study time opiates free-days, morphine equivalents dose per day and duration of neuromuscular blocking drugs use will be reported as median and 25-75% interquartile range. We will estimate the effect by the median of all paired differences between observations in the lateral-Trendelenburg and semi-recumbent position groups and its 95% confidence interval (Hodges-Lehmann method)20,21. The comparison between lateral-Trendelenburg and semi-recumbent position groups comparison was will be performed using the Wilcoxon rank-sum test. The proportion of patients who received at least one day of neuromuscular blocking drugs treatment will be compared between groups through the Fisher’s exact test.F. Use of antibioticsWe will compare the number of patients who received at least one day of antimicrobial treatment between groups, through the Fisher’s exact test. The duration of antimicrobial treatment within the first 14 days, study time antimicrobials free days, daily defined dose (DDD) and DDD per day will be reported as median and 25-75% interquartile range. We will estimate the effect by the median of all paired differences between observations in the lateral-Trendelenburg and semi-recumbent position groups and its 95% confidence interval (Hodges-Lehmann method)20,21. The comparison between groups will be performed using the Wilcoxon rank-sum test.G. Secondary bacterial infectionsThe occurrence of secondary bacterial infections, other than VAP, such as ventilator-associated tracheobronchitis (VAT), infection of the abdomen, urinary tract, skin and soft tissue, central line or unknown source and others, and occurrence of bacteraemia will be compared between groups through the Fisher’s exact test.H. Nutritional supportWe will compare the number of patients who received at least one day of nutritional support (enteral, parenteral or both) between lateral-Trendelenburg and the semi-recumbent position group through the Fisher’s exact test. The total amount of kilo-calories per day within the first 14 days will be reported as median and 25-75% interquartile range. We will estimate the effect by the median of all paired differences between observations of patients in lateral-Trendelenburg and semi-recumbent position and its 95% confidence interval (Hodges-Lehmann method)20,21. The comparison between lateral-Trendelenburg and semi-recumbent position groups will be performed using the Wilcoxon rank-sum test.I. Adverse eventsThe occurrence of serious adverse events and occurrence of new pressure ulcer, endotracheal tube displacement, central venous line loss, drain tubes displacement, endotracheal tube obstruction, vomiting and nasogastric tube

displacement will be compared between lateral-Trendelenburg and the semi-recumbent position groups, through the Fisher’s exact test.L. Nursing feasibility and workloadNursing feasibility and workload surveyed through self-questionnaires will be compared between lateral-Trendelenburg and the semi-recumbent position groups, through the Fisher’s exact test.

Subgroup analysisNo subgroup analysis will be specified a priori.

Feasibility analysisWe will evaluate the proportion of patients who were never positioned in the randomized position during the study period (14 days). The time in each of the following positions and any change in position will be continuously monitored by the attending nurses: lateral-Trendelenburg, semi-recumbent, supine and prone. We will compute the proportion of daily time in each position as follows: Time in X position (hour:min)/1440 min. Of note, for patients undergoing mechanical ventilation only for a segment of the day, i.e. extubated patients, the denominator will be the cumulative time during the day, while on mechanical ventilation. The percentage of time will be reported as mean and 95% confidence interval and median and 25-75% interquartile range. We will compare the compliance to lateral-Trendelenburg and semi-recumbent position between groups using the Wilcoxon rank-sum test, in those patients who were positioned any time to the randomized positions. We will assess the compliance to the randomized position over time and per Richmond Agitation Sedation Score, considering hours in that positions as counts and modelling through a multilevel mixed-effects Poisson or negative-binomial regression, depending on the presence of over-dispersion. The model will include a random intercept per each patient.

General commentsUnless otherwise specified, categorical variables will be compared using the Fisher’s exact test and continuous variables will be compared using Wilcoxon rank-sum test or unpaired t-tests, as appropriate. All tests will be two-sided with significance levels set at P < 0.05 and with no correction for multiplicity. All analysis will be conducted in the Stata version 13.1 (Stata Corporation LP, College Station, TX, USA).

Statistical plan amendmentAfter a comprehensive evaluation of the findings of aforementioned analyses, the steering committee agreed to cluster the patients into 2 groups, based on the presence or absence of pulmonary infiltrates at baseline. The rationale for this analysis was based on the well-recognized challenges in the diagnosis of VAP, through standard clinical variables and chest radiographs. Indeed, a new pulmonary infiltrate could be difficult to detect in patients with a abnormal chest radiograph at baseline.

Sub-group analysisIn a post hoc subgroup analysis, we will assess whether the effects of the interventions (Lateral-Trendelenburg position vs Semi-recumbent position) on the primary outcome and mortality rates interact with the presence or absence of pulmonary infiltrates at baseline. We will use the Mantel-Haenszel test for homogeneity. For the secondary outcomes duration of mechanical ventilation, ICU and hospital stay, the interaction will be tested by modeling a negative-binomial regression model.

References:1. Altman DG, Dore CJ. Randomisation and baseline comparisons in clinical trials. Lancet 1990;335:149-53.2. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152:726-32.3. Roberts C, Torgerson DJ. Understanding controlled trials: baseline imbalance in randomised controlled trials. BMJ 1999;319:185.4. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 Explanation and Elaboration: Updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol 2010;63:e1-37.5. Reignier J, Mercier E, Le Gouge A, et al. Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial. JAMA 2013;309:249-56.6. Wolkewitz M, Cooper BS, Bonten MJ, Barnett AG, Schumacher M. Interpreting and comparing risks in the presence of competing events. BMJ 2014;349:g5060.7. Wolkewitz M, Vonberg RP, Grundmann H, et al. Risk factors for the development of nosocomial pneumonia and mortality on intensive care units: application of competing risks models. Crit Care 2008;12:R44.8. Andersen PK, Geskus RB, de Witte T, Putter H. Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol 2012;41:861-70.9. Lau B, Cole SR, Gange SJ. Competing risk regression models for epidemiologic data. Am J Epidemiol 2009;170:244-56.10. Bhaskaran K, Rachet B, Evans S, Smeeth L. Re: Helene Hartvedt Grytli, Morten Wang Fagerland, Sophie D. Fosså, Kristin Austlid Taskén. Association between use of β-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2013.01.007.: beta-blockers and prostate cancer survival--interpretation of competing risks models. Eur Urol 2013;64:e86-7.11. Angrist JD, Imbens GW, Rubin DB. Identification of Causal Effects Using Instrumental Variables. Journal of the American Statistical Association 1996;91:444-55.12. Sussman JB, Hayward RA. An IV for the RCT: using instrumental variables to adjust for treatment contamination in randomised controlled trials. BMJ 2010;340:c2073.13. Barnard J, Frangakis CE, Hill JL, Rubin DB. Principal Stratification Approach to Broken Randomized Experiments. Journal of the American Statistical Association 2003;98:299-323.14. Hernan MA, Hernandez-Diaz S. Beyond the intention-to-treat in comparative effectiveness research. Clin Trials 2012;9:48-55.15. Greenland S. An introduction To instrumental variables for epidemiologists. Int J Epidemiol 2000;29:1102.16. Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in critically ill adults. N Engl J Med 2014;371:1673-84.17. Halpern SD, French B, Small DS, et al. Randomized trial of four financial-incentive programs for smoking cessation. N Engl J Med 2015;372:2108-17.18. Hernan MA, Robins JM. Instruments for causal inference: an epidemiologist's dream? Epidemiology 2006;17:360-72.19. Rassen JA, Schneeweiss S, Glynn RJ, Mittleman MA, Brookhart MA. Instrumental variable analysis for estimation of treatment effects with dichotomous outcomes. Am J Epidemiol 2009;169:273-84.20. Young P, Saxena M, Bellomo R, et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med 2015;373:2215-24.21. Lehmann EL. Nonparametric Confidence Intervals for a Shift Parameter. 1963:1507-12.

ELECTRONIC SUPPLEMENTARY RESULTS

Table E1: Collaborating Centers

Number Institution Location Intensive Care Unit Type Hospital Type* Principal Investigator Intensivist-In-Chief

1 Policlinico di Milano Milan, Italy Medical-Surgical A Mauro Panigada Luciano Gattinoni

2 Ospedale Nuovo del Mugello Italy Medical-Surgical B Vieri Parrini Roberto Oggioni

3 Gruppo Ospedaliero San Donato Italy Surgical A Hassan Kandil Andrea Ballotta

4 Hospital Clinic Spain Pulmonary A Gianluigi Li Bassi Antoni Torres5 Arcispedale S.Maria Nuova Italy Medical-Surgical B Giovanni Salati Antonino Pistilli6 Ospedale S.Giovanni Bosco Turin, Italy Medical-Surgical B Paola Selvaggi Sergio Livigni7 Policlinico San Matteo Pavia, Italy Medical-Surgical B Alessandro Amatu Giorgio Iotti8 Policlinico di Modena Modena, Italy Medical-Surgical A Emanuela Biagioni Massimo Girardis

9 Ospedale Città di Sesto San Giovanni

Sesto San Giovanni, Italy Medical-Surgical B Mirella Furia Gabriella Moise

10 Ospedale San Gerardo Monza, Italy Medical-Surgical A Alberto Zanella Antonio Pesenti11 Policlinico Gemelli Rome, Italy Medical-Surgical A Giovanna Mercurio Massimo Antonelli

12 Azienda Ospedaliera Universitaria di Parma Parma, Italy Medical-Surgical A Antonietta Costa Maria Luisa Caspani

13 Azienda Ospedaliera Unversitaria di Parma Parma, Italy Surgical A Fernanda Tagliaferri Maria Barbagallo

14 Azienda Ospedaliera Unversitaria di Parma Parma, Italy Cardio-Surgical A Tullio Manca Antonella Vezzani

15 University Hospital Frankfurt Frankfurt, Germany Surgical A Lindau Simone Patrick Meybohm

16 University Hospital Center Zagreb Zagreb, Croatia Medical A Jaksa Babel Vladimir Gasparovic

17 Ospedale Santa Chiara Trento, Italy Medical-Surgical B Marco Cavana Edoardo Geat

18 Massachusetts General Hospital Boston, MA, USA Surgical A Lorenzo Berra Jeanine Wiener-Kronish

*Hospitals were classified as follows: A, hospitals, being general hospitals providing facilities for giving instruction to medical students of any university, as evidenced by a written agreement between the hospital and the university with which it is affiliated, and providing post-graduate education leading to certification or a fellowship in one or more of the medical specialties; B, hospitals, being general hospitals having not fewer than 100 beds

Table E2 Competing risk analysis of the primary outcome

Event Cause-specific HR (95% CI)*

Cause-specificP-value

Sub-distribution HR (95% CI) ¶

Sub-distribution

P-Value

Measure of effect on microbiologic confirmed VAP‡

0.13(0.02-1.00) 0.050 0.13

(0.02-1.02), 0.052

Measure of effect on weaning/extubation

0.94(0.72-1.23) 0.659 0.98

(0.76-1.27) 0.881

Measure of effect ondeath while receiving MV§

0.99(0.63-1.56) 0.975 1.03

(0.66-1.61) 0.891

Of note, for the competing risk analysis, we considered two competing events, which would hinder detection of VAP occurrence: extubation and death while receiving mechanical ventilation *HR hazard ratio and 95% confidence interval (CI)¶ Sub-distribution hazards ratio from the Fine and Gray model.‡VAP ventilator associated pneumonia§ MV mechanical ventilation.

Table E3: Ventilator-associated pneumonia causative pathogens

Etiologic factor Semi-recumbent(8/201) No.

Lateral-Trendelenburg(1/194) No.

Staphylococcus aureus 4Klebsiella pneumoniae 3

Pseudomonas aeruginosa 2Escherichia coli 2

Haemophylus influenzae 1

VAP was caused by more than a pathogen in 3 patients. In 2 cases, by Staphylococcus aureus and Klebsiella pneumoniae; in 1 case, Staphylococcus aureus and Escherichia coli were concomitantly isolated

Table E4: Causes of death in the intensive care unit

Cause of death Semi-recumbentPosition (n=47)

Lateral-TrendelenburgPosition (n=59)

P-value

Refractory multiple organ dysfunction 26 (55.3%) 33 (55.9%) 0.87Refractory pulmonary failure 9 (19.2%) 13 (22.0%)

Refractory cardiovascular failure 9 (19.2%) 7 (11.9%)Central nervous system catastrophic

event 1 (2.1%) 3 (5.1%)

Cardiac arrest 1 (2.1%) 1 (1.7%)

Among the patients who did not survive, there was only 1 missing cause of death, in a patient randomized to the semi-recumbent position.

Table E5: Complier average causal effect analyses of lateral-Trendelenburg versus semirecumbent position

Risk difference (95% CI)* P value

Primary Outcome

Microbiologic confirmed VAP† -7.6% (-14.0, -1.1) 0.021

Secondary Outcomes

Intensive care unit mortality 14.2% (-4.9, 33.4) 0.145

Hospital mortality 12.6% (-7.8, 33.0) 0.227

28-day mortality 9.9% (-9.5, 29.3) 0.315

Of note, compliers were defined patients who were kept in the randomized position for at least 50% of the study time within the first 2 days. * CI, confidence interval † VAP, ventilator-associated pneumonia

Table E6: Bacteremia and other infections

Semi-recumbent(n=201)

Lateral-Trendelenburg

(n=194)RR (95% CI)* P value

Bacteremia 20 (10.0%) 19 (9.8%) 0.98 (0.54-1.79) 0.99Incidence of other infections

No. (%) 24 (11.9%) 36 (18.6%) 1.55 (0.96-2.51) 0.07

Pulmonary ‡ No. (%) 11 (5.5%) 17 (8.8%) 1.60 (0.77-3.33) 0.24Abdominal No. (%) 2 (1.0%) 1 (0.5%) 0.52 (0.05-5.67) 0.99

Catheter-associated urinary tract No. (%)** 4 (2.0%) 10 (5.2%) 2.59 (0.83-8.12) 0.11

Skin and soft tissue No. (%) 1 (0.5%) - - >0.99Catheter-related blood

stream infection No. (%)‡‡ 3 (1.5%) 9 (4.6%) 3.11 (0.85-11.31) 0.08

Unknown source No. (%) - 4 (2.1%) - 0.06Other No. (%) 3 (1.5%) 4 (2.1%) 1.38 (0.31-6.09) 0.72

*RR, risk ratio; CI, confidence interval ‡ All other potential pulmonary infections, i.e. ventilator-associated tracheobronchitis, viral or fungal infections, except ventilator-associated pneumonia. Ventilator-associated tracheobronchitis was clinically suspected by the attending physician on duty when, ≥ 48 hours following tracheal intubation, two or more clinical criteria of new pulmonary infection were present in a patient without a new pulmonary infiltrate at the chest radiograph: a) fever (T≥38 ºC) or hypothermia (T<35ºC); leukocytosis (WBC>10000/ml) or leucopenia (WBC<4000/ml); purulent tracheal aspirates. Diagnosis of VAT was ultimately microbiologically confirmed if quantitative cultures of tracheal secretions yielded ≥ 105 colony-forming units (cfu)/ml.** Catheter-related blood stream infection was defined as an infection in a patient with at least one of the following signs or symptoms: fever (≥38 ºC), chills, or hypotension and pathogen(s) identified from blood withdrawn from a bloodstream catheter –unrelated to an infection at another site – and from blood withdrawn from another peripheral vein.

Table E7: Days on sedatives, opioids, neuromuscular blocking agents during the 14-day study and doses according to study groups

(n=194)RR or RD (95% CI)* P

SedativesMedian ICU free sedative

days No. (IQR) ‡ 2 (0-6) 3 (1-5) 0 [-1-0] 0.98

Median duration of sedation (days) No. (IQR) 3.0 (2-7) 3.0 (2-7) 0 [0-1] 0.52

Median lorazepam equivalents (mg/day)

(IQR)46.7 (20.8-120.0) 58.0 (28.0-124.2) 6.4 [-7.5-22.7] 0.37

Propofol dose (mg/day) (IQR) 1393 (627-2345) 1661 (826-2700) 210 [-65-483] 0.13

OpioidsMedian ICU free opioids

days No. (IQR) 2.5 (0-6) 3.0 (0-5) 0 [-1-0] 0.79

Median duration of opiates use (days) No.

(IQR)3 (2-7) 3 (2-7) 0 [0-1] 0.71

Morphine equivalents (mg/day) (IQR) 112 (30-217) 119 (31-234) 4.7 [-11.5-31.7] 0.56

Neuro-muscular blocking drugsPatients undergoing

neuromuscular blocking drugs No. (%)

64 (31.8%) 58 (29.9%) 0.94 (0.70-1.26) 0.74

Median days on neuromuscular blocking

drugs No. (IQR)0 (0-1) 0 (0-1) 0 [0-0] 0.90

*RR, risk ratio or RD, risk difference CI, confidence interval‡ ICU, intensive care unit; IQR, interquartile range

Table E8: Days on antimicrobials during the 14-day study and doses according to study groups

(n=194)RR or RD (95% CI)* P

Patients undergoing antimicrobial therapy

during the study No.(%)167 (83.1%) 157 (80.9%) 0.97 (0.89-1.07) 0.98

Median ICU antimicrobial free days (days) No. [IQR]

‡§2 [0-5] 2 [0-4] 0 [0-0] 0.95

Median duration of antimicrobial therapy

(days) No. (IQR) ‡4 [1-8] 4 [1-8] 0 [-1-1] 0.77

Daily defined dose 8 [2-22] 10.2 [2-23.1] 0.1 [-1-2.5] 0.53

Daily defined dose per day 2 [1-3] 2.1 [0.8-3.3] 0 [-0.2-0.4] 0.76

*RR, risk ratio or RD, risk difference; CI, confidence interval ‡ IQR, interquartile range§ ICU, intensive care unit

Table E9: Nutrition and calorie intake

(n=194)RD (95% CI)* P

Type of Nutrition (None/Enteral/Parental)

No. (%)

44 (21.9) / 110 (54.7)/ 47 (23.4)

45 (23.2) / 94 (48.5)/ 55 (28.4) NA 0.42

Median calorie intake per day (IQR) ‡ 1246 (900-1800) 1357 (1000-1966) 133 [-16-284] 0.08

Median calorie intake per day only enteral nutrition

(IQR) ‡1082 (730-1500) 1135 (795-1517) 50 (-79-193) 0.41

Median calorie intake per day only parental nutrition (IQR) ‡

1162 [754-1578] 1142 [900-1354] 5 [-196-200] 0.97

*RD, risk difference; CI, confidence interval ‡ IQR, interquartile range

Table E10: Nursing Feasibility and workload of the interventions by nurses in patients who were placed in the randomized positions

Semi-recumbent(n=185)No. (%)

Lateral-Trendelenburg(n=160)No. (%)

P-Value

Feasibility <0.001Very Difficult 1 (0.5%) 22 (13.8%)

Difficult 11 (6.0%) 57 (35.6%)Not Sure - 3 (1.9%)

Easy 96 (51.9%) 64 (40.0%)Very Easy 77 (41.6%) 14 (8.8%)

Workload <0.001Extremely High 2 (1.1%) 26 (16.3%)

High 12 (6.5%) 65 (40.6%)Not Sure 1 (0.5%) 2 (1.3%)

Low 94 (51.1%) 57 (35.6%)Extremely Low 75 (40.8%) 10 (6.3%)

There were 20 missing surveys (9 and 11 in patients in the semirecumbent and lateral-Trendelenburg position groups, respectively)

Table E11: Neurological evaluation upon discharge from the intensive care unit

Semi-recumbent position Group No. (%)

(n=135)

Lateral-Trendelenburg Group No. (%)

(n=129)P value

Did the patient develop unexplained neurological

complications?0.162

No 127 (94.1%) 118 (91.5%)Yes 0 4 (3.1%)*

Not sure/I don’t know 8 (5.9%) 7 (5.4%)

* In only one patient, neurologic imaging detected signs of current ischemia, infarction or hemorrhage, this occurrence was reported as a serious adverse event, possibly associated with the intervention

Table E12: Post-hoc interaction exploratory analyses for the effect of the position on main outcomes between patients without [n=206] and with [n=189] pulmonary infiltrates upon enrollment

Subgroup Semirecumbent*Lateral-

Trendelenburg†

Risk Ratio or Risk Difference

(95%CI) II

P value for heterogeneity

Patients on antibiotics already upon

randomization No. (%)

Without Pulmonary Infiltrate 58 (52.3) 52 (54.7) NANA

With Pulmonary Infiltrate 83 (92.2) 89 (89.9) NA

Incidence of microbiologically

confirmed VAP No. (%)‡

Without Pulmonary Infiltrate 8 (7.2%) 1 (1.1%) 0.15 (0.02-1.15)NA

With Pulmonary Infiltrate 0 0 NA

Microbiologically confirmed VAP per

1000 Ventilator Days (No. 95% CI) ‡ II

Without Pulmonary Infiltrate 16.48 (8.24-32.95) 2.35 (0.33-16.70) 0.14 (0.01-1.07)

With Pulmonary Infiltrate 0 0 NA

Incidence of clinically suspected VAP No.

(%)‡

Without Pulmonary Infiltrate 14 (12.6%) 5 (5.3%) 0.42 (0.16-1.12)0.04

With Pulmonary Infiltrate 7 (7.8%) 13 (13.1%) 1.69 (0.71-4.04)

Clinically suspected VAP* per 1000

Ventilator Days (No. 95% CI) ‡II

Without Pulmonary Infiltrate 29.38 (17.40-49.61)

12.29 (5.11-29.52) 0.42 (0.12-1.23)

0.04With Pulmonary Infiltrate 11.72 (5.59-24.58) 20.12 (11.69-

34.66) 1.72 (0.64-5.09)

Median duration of MV (IQRs) (days) §**

Without Pulmonary Infiltrate 3 [2-7] 3 [2-7] 0 (-1.00 – 1.00) §

0.14With Pulmonary Infiltrate 7 [3-12] 6 [3-13] 0 (-1.00 – 2.00) §

Median duration of ICU stay (IQRs) (days)

¶††

With Pulmonary Infiltrate 10 [5-17] 9 [5-17] 0 (-3.00 – 2.00) §

Median duration of hospital stay (IQRs)

(days)

0.44With Pulmonary Infiltrate 20 [11-34] 16 [8-29] -4 (-9.00 – 1.00)

ICU Mortality No. (%)††

Hospital Mortality No. (%)

Without Pulmonary Infiltrate 31 (27.9%) 22 (23.2%) 0.83 (0.52-1.33)

28-Day Mortality No. (%)

* Patients in the semirecumbent position without [n=111] and with [n=90] pulmonary

infiltrates

† Patients in the lateral Trendelenburg position without [n=95] and with [n=99] pulmonary

infiltrates

‡ VAP, ventilator associated pneumonia

§ Risk difference

II CI, confidence interval

** MV, mechanical ventilation; IQRs interquartile ranges

†† ICU, intensive care unit

Electronic Supplementary Figure Legends

Figure E1: Recruitment rateFrom December 2010 until April 2012 patients were recruited only in the coordinating centers, Fondazione Cà Granda in Milan, Italy and Hospital Clinic, Barcelona, Spain. Then, recruitment was extended to several collaborating centers, until the end of the study in June 2015. Most of the centers were in Italy, with one center each in Spain, Germany, United States and Croatia

Figure E2: Reasons for change in position from lateral-Trendelenburg to semi-recumbent Throughout the study, nurses reported reasons for any change in position. Of note, patients were often not compliant to the position, specifically when awaken.

Figure E3: Proportion of time in each possible body position per study time and per Richmond Agitation Sedation Score (RASS). A: Percentage of time in each body position per study days of patients randomized into the lateral-Trendelenburg group. The time in lateral-Trendelenburg position varied throughout the study time (p<0·01). In particular, patients were more adherent to the intervention during the first days of the study. B: Percentage of time in each body position per study time of patients randomized into the semirecumbent position. The time in semirecumbent position did not change throughout the study time (p=0·49). C: Percentage of time in each body position per RASS score of patients randomized into the lateral-Trendelenburg position. The time in lateral-Trendelenburg position varied among RASS scores (p<0·01). D: Percentage of time in each body position per RASS score of patients randomized into the semirecumbent position. The time in semirecumbent position did not vary among RASS scores (p=0·82). Error bars depict standard errors.

Figure E4: Nursing Feasibility and WorkloadSurvey of lateral-Trendelenburg position nursing feasibility and workload per clusters of cumulative number of enrolled patients per center. A: Nursing feasibility. Of note, we found a slight trend toward improved nursing feasibility throughout the clusters of enrolled patients (p=0.50), suggesting that nurses' experience in patient positioning had some effect on nursing feasibility. B: Nursing workload. Conversely, nursing workload was not affected by nurses' experience in patient positioning (p=0.80).

Figure E1: Recruitment rate

Figure E2: Reasons for changing position from lateral-Trendelenburg to semi-recumbent

Figure E3: Proportion of time in each possible body position per study time and per Richmond Agitation Sedation Score.

Figure E4: Nursing Feasibility and Workload

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