Protocol ID: LAS VEGAS Study Protocol Version 1.2 Amendment 1, dated 20-November-2012 Clinicaltrials.gov identifier: NCT

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1 Local Assessment of Ventilatory Management During General Anesthesia for Surgery and effects on Postoperative Pulmonary Complications: a Prospective Observational International Multi center Cohort Study Protocol ID: LAS VEGAS Study Protocol Version 1.2 Amendment 1, dated 20-November-2012 Clinicaltrials.gov identifier: NCT Sponsor/Funder: European Society of Anaesthesiology (ESA) Rue des Comédiens 24, 1000 Brussels, Belgium Phone: research@esahq.org Chief Investigator: Prof. Dr. M.J. Schultz, Professor of Experimental Intensive Care Academic Medical Center, University of Amsterdam Meibergdreef 9, C AZ Amsterdam, the Netherlands E mail: marcus.j.schultz@gmail.com International Coordinator: Sabrine N.T. Hemmes, MD Academic Medical Center, University of Amsterdam Meibergdreef 9, G AZ Amsterdam, the Netherlands Phone: E mail: lasvegas@amc.nl LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

2 Steering Committee members (in alphabetic order): Core of Steering Committee: Prof. Dr. M. Gama de Abreu University Hospital Carl Gustav Carus, Dresden, Germany S.N.T. Hemmes Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Prof. Dr. P. Pelosi IRCCS San Martino Hospital, University of Genoa, Genoa, Italy Prof. Dr. M.J. Schultz Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Biostatistician Dr. J.M. Binnekade Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Other Steering Committee members: Prof. Dr. J. Canet Hospital Universitari Germans Trias I Pujol, Barcelona, Spain jcanet.germanstrias@gencat.cat Prof. Dr. G. Hedenstierna University Hospital, Uppsala, Sweden hedenstierna@yahoo.se Prof. Dr. M. Hiesmayr Medical University, Vienna, Austria michael.hiesmayr@meduniwien.ac.at Prof. Dr. Dr. M.W. Hollmann Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands m.w.hollmann@amc.uva.nl Prof. Dr. S. Jaber Saint Eloi University Hospital, Montpellier, France s-jaber@chu-montpellier.fr Prof. Dr. G.H. Mills Sheffield Teaching Hospitals, Sheffield, U.K. Gary.Mills@sth.nhs.uk Dr. M.F. Vidal Melo Massachusetts General Hospital, Boston, U.S.A. vidalmelo.marcos@mgh.harvard.edu Dr. R. Pearse William Harvey Research Institute, London, U.K. r.pearse@qmul.ac.uk Prof. Dr. C. Putensen University Hospital, Bonn, Germany christian.putensen@ukb.uni-bonn.de Dr. W. Schmid Medical University, Vienna, Austria werner.schmid@meduniwien.ac.at Prof. Dr. P. Severgnini University of Insubria, Varese, Italy paolo.severgnini@uninsubria.it Prof. Dr. H. Wrigge University of Leipzig, Leipzig, Germany hwrigge@web.de LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

3 PROTOCOL SIGNATURE SHEET Chief Investigator and International Coordinator Name Signature Date Chief Investigator: Prof. Dr. M.J. Schultz, Professor of Experimental Intensive Care 20-Nov-2012 International Coordinator: S.N.T. Hemmes 20-Nov-2012 Sponsor: European Society of Anaesthesiology Research and Clinical Trial Coordinator Brigitte Leva 20-Nov-2012 Local Investigators (enter local details, as applicable) Name Signature Date Principal Investigator (or similar): LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

4 TABLE OF CONTENTS 1 SUMMARY Rationale Objective Study design Study population Main study parameters Nature and extent of the burden and risks associated with participation INTRODUCTION AND RATIONALE Ventilator associated lung injury Lung protective MV for acute respiratory distress syndrome Ventilatory management in short term intra operative MV Assessment of ventilatory management Assessment of pulmonary complications Aim of this study STUDY DESIGN Study Flowchart STUDY POPULATION Population Inclusion criteria Exclusion criteria Sample size calculation METHODS Study endpoints Primary study endpoint Secondary study endpoints Randomization Study procedures Data collection Withdrawal of individual subjects STATISTICAL ANALYSIS ETHICAL CONSIDERATIONS Regulation statement Ethical and Regulatory authorities approval Patient Information and Informed consent ADMINISTRATIVE ASPECTS AND PUBLICATION Handling and storage of data and documents Public disclosure and publication policy Organization REFERENCES APPENDICES LIST...23 LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

5 LIST OF ABBREVIATIONS AE Adverse Event MV Mechanical Ventilation AMC Academic Medical Center NYHA New York Heart Association ANOVA Analyses of Variance OR Operating Room ARDS Adult Respiratory Distress Syndrome OSAS Obstructive Sleep Apnea Syndrome AF Artial Fibrilation PBW Predicted Body weight ASA ASB American Society of Anesthesiologists Assisted Spontaneous Breathing PC PEEP Pressure Control Positive end expiratory pressure ASV Adaptive Support Ventilation PIN Patient Identification Number CCU Critical Care Unit PORC COPD CPAP Chronic Obstructive Pulmonary Disease Continuous Positive Airway Pressure PPC PRBC Post-operative residual curarization Post-operative pulmonary complications Packed Red Blood Cells CRF Case Report Form PSV Pressure Support Ventilation DBS Double Burst Stimulation PTC Post-tetanic count stimulation ecrf Electronic Case Report Form RM Recruitment maneuver EC ENT ESA Ethics Committee Ear, Nose & Throat European Society of Anaesthesiology QRS Complex R-R intervals SIMV EU European Union SPSS combination of three of the graphical deflections seen on a typical electrocardiogram (ECG) time between the two R waves in electrocardiogram (ECG) Synchronized Intermittent Mandatory Ventilation Statistical Package for the Social Sciences GCP Good Clinical Practice ST Single-twitch stimulation HFOV High Frequency Oscillatory Ventilation TOF ICU Intensive Care Unit VALI IRB/IEC LPMV Institutional Review board/independant Ethics Committee Lung-protective mechanical ventilation VC VT Train-of-four stimulation Ventilator associated lung injury Volume Control Ventricular Trachycardia LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

6 1 SUMMARY 1.1 Rationale Mechanical ventilation (MV) has the potential to cause so called ventilator associated lung injury (VALI). Results from randomized controlled trials of patients with acute respiratory distress syndrome (ARDS) have resulted in guidelines strongly recommending the use of pressure and volume limited MV strategies. In addition, meta-analyses suggest that patients with ARDS also could benefit from higher levels of positive end expiratory pressure (PEEP) and recruitment maneuvers. The effect of short term intra operative MV on pulmonary integrity is less well defined. International guidelines for MV of patients who are intubated and mechanically ventilated because of general anesthesia for surgery are lacking. It is unknown to what extent pressure and volume limited MV strategies, higher levels of PEEP and recruitment maneuvers are used during general anesthesia for surgery. Considering the many patients undergoing major surgical procedures worldwide each day, a small improvement in prevention of VALI could have a substantial impact on pulmonary complications. 1.2 Objective The present study aims at characterizing current mechanical ventilation practices during general anesthesia for surgery and assessing the dependence of post operative pulmonary complications on intra-operative MV settings. 1.3 Study design Prospective observational multi center international cohort study. 1.4 Study population An estimated number of 96 centers will include mechanically ventilated patients undergoing general anesthesia for surgery during a period of one week. 1.5 Main study parameters The effect of different MV settings during general anesthesia for surgery on post operative pulmonary complications will be assessed. Predefined intra operative and post operative pulmonary complications will be recorded from the medical chart up to five days after surgery. 1.6 Nature and extent of the burden and risks associated with participation In this observational study there are no risks involved for participating patients. LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

7 2 INTRODUCTION AND RATIONALE 2.1 Ventilator associated lung injury Mechanical ventilation (MV) is an essential supportive treatment for anesthesiologists and intensivists. MV, however, has the potential to aggravate or even initiate lung injury [1, 2]. MV induced overdistension of non dependent lung regions and repetitive opening and closing of dependent lung regions may lead to mechanical stress in the lungs, eventually causing lung injury [3]. 2.2 Lung protective MV for acute respiratory distress syndrome Critically ill patients requiring long term MV for lung injury have been found to benefit from lung protective MV settings. Use of pressure and volume limited MV strategies benefit critically ill patients with acute respiratory distress syndrome (ARDS) [4] and are therefore strongly recommended in international guidelines [5, 6]. Use of pressure and volume limited MV may also benefit patients at risk for ARDS [7]. Use of higher levels of positive end expiratory pressure (PEEP) to prevent tidal de recruitment of dependent lung regions has also shown to have beneficial effects [8]. Finally, it has been suggested that so called recruitment maneuvers add to the beneficial effects of PEEP [9]. 2.3 Ventilatory management in short term intra operative MV The effects of short term intra operative MV on pulmonary integrity are less well defined [10, 11]. The potential benefits of lung protective MV during general anesthesia for surgery in patients with uninjured lungs have been questioned [12, 13]. However, it has been shown that pressure and volume limited MV with the use of higher levels of PEEP attenuates pulmonary inflammation [14]. In addition, use of recruitment maneuvers has been found to improve the effectiveness of PEEP on gas exchange during intra-operative MV [15]. 2.4 Assessment of ventilatory management Little information is available on applied MV settings during general anesthesia for surgery across the world. One observational study, conducted in 28 centers in France, revealed that most patients undergoing general surgery were mechanically ventilated without PEEP and more than 40% of patients were ventilated with tidal volumes >8 ml/kg [16]. It is unclear how widespread the concept of lung protective MV is applied in other countries [17]. By performing a large observational study on current ventilator settings used in the operating room, the study has the potential to elucidate to what extent lung-protective mechanical ventilation is applied. LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

8 2.5 Assessment of pulmonary complications Pressure and volume limited MV is suggested to benefit patients who are mechanically ventilated because of general anesthesia for surgery [18]. At least one meta analysis suggests that higher levels of PEEP are beneficial intra operatively, but there is insufficient evidence whether PEEP affects post operative pulmonary complications [19]. Although use of recruitment maneuvers adds to the beneficial effects of PEEP [20], the effect on post operative pulmonary complications is uncertain. The present study also has the potential to determine the effect of specific MV settings during general anesthesia for surgery on post operative pulmonary complications. 2.6 Aim of this study The present study aims at characterizing current mechanical ventilation practices during general anesthesia for surgery and assessing the dependence of post operative pulmonary complications on intra-operative MV settings. LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

9 3 STUDY DESIGN This is a prospective observational international multi center cohort study. An outline of the trial design is given in the protocol flow chart below. 3.1 Study Flowchart Schematic diagram of trial design: procedures and stages. Mechanical Ventilation during General Anaesthesia for Surgery Enrollment in LAS VEGAS Data acquisition (day -1 or day 0) Demographic and Pre-operative data Data acquisition (day 0) Ventilatory settings Intra-operative variables Intra-operative complications CRF 1 Data acquisition (day 0 to day 5) Post-operative Pulmonary Complications Non-ICU CRF 2A ICU CRF 2B Data acquisition (day 28) Length of Hospital Stay Hospital Discharge CRF 3 LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

10 4 STUDY POPULATION 4.1 Population Assuming an inclusion of at least patients per center, it will be needed to include approximately 96 centers worldwide to reach our calculated sample size (see 4.4). Patients subjected to MV during general anesthesia for surgery will be included in a consecutive manner, during a period of one week at own choice during a time window of 8 weeks, and which will be determined in a later stage by the trial coordinator. 4.2 Inclusion criteria Age 18 years All surgical procedures requiring MV during general anesthesia for laparoscopic or non laparoscopic surgery - This includes MV performed with supra glottic devices (e.g. laryngeal mask) - This includes patients receiving MV at the onset of the procedure (e.g. ICU patients) - This includes patients who will receive one-lung ventilation during the procedure 4.3 Exclusion criteria Obstetric surgical procedures or any procedure during pregnancy Surgical procedures outside the operating room Surgical procedures involving extra corporal circulation 4.4 Sample size calculation The reported incidence of post-operative pulmonary complications varies between 2.6% [21] and 5.0% [22]. We anticipate that in order to provide a sample of at least 120 events of postoperative pulmonary complication-events an inclusion of at least patients is required. This will allow for inclusion of up to 12 covariates in a logistic regression model to analyze the effect on post-operative pulmonary complications. For a logistic regression analysis the number of events divided by the number of predictor variables should be at least 10 [23]. LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

11 5 METHODS 5.1 Study endpoints Primary study endpoint Effect of MV settings during general anesthesia for surgery on the incidence of post operative pulmonary complications (new or prolonged invasive or non-invasive mechanical ventilation, need for oxygen therapy, respiratory failure, pneumonia, ARDS, pneumothorax) Secondary study endpoints Variation of applied MV settings within centers Variation of applied MV settings between centers on an international basis Intra operative complications possibly related to MV settings (e.g. de saturation, need for unplanned RM, need for ventilatory pressure reduction, need for expiratory flow limitation, hypotension, new arrhythmias) 5.2 Randomization Not applicable 5.3 Study procedures Patients undergoing mechanical ventilation during general anesthesia for laparoscopic or non laparoscopic surgery are included during a period of 1 week from Monday at 8:00 AM to the next Monday at 7.59 AM in the center time zone. The inclusion period will be determined at a later stage by the study coordinator. Time points of data collection: Demographic data and baseline data are collected from the clinical files the day before and/or on the day of surgery MV settings, gas exchange variables and vital parameters are collected hourly during mechanical ventilation Intra-operative complications and other variables (see list below) are collected perioperatively Defined post operative pulmonary complications are recorded from the medical chart on the ward or ICU (when participating in ICU follow-up substudy; see below) on day 0 and days 1, 2, 3, 4 and 5 after surgery Length of hospital stay and in hospital death are assessed on day 28 LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

12 5.4 Data collection Data is collected on paper case report forms (CRF s), unless a local electronic system to register intra-operative and/or post-operative data is used (e.g. patient data management system). Local investigators are expected to transcribe all collected data onto an internetbased electronic CRF (web-based open source software OpenClinica). Access to the dataentry system is managed by the ESA and protected by a personalized username and password. The following information will be collected for each patient: Demographic data and baseline variables Applicability of informed consent, date of informed consent (if applicable), date of birth, gender, ethnicity/race (according to FDA Guideline [24]), height and weight, physical status, functional status, smoking status, chronic co-morbidity, respiratory infection, recent transfusion of red blood cells, history of recent mechanical ventilation within preceding 30 days (e.g. in cases of general anesthesia because of surgery or intensive care unit patients), urgency of surgery, planned duration of surgery, surgical procedure, surgical technique, pre-operative laboratory results (Hb, leukocytes, creatinine) taken no longer than 28 days before surgery (if clinically available) and peripheral oxygen saturation (SpO 2 ). Intra operative MV settings The following MV settings and monitored parameters are collected at induction and hourly intra-operatively. Ventilatory Mode (Volume Control: VC; Pressure Control: PC; Pressure Support Ventilation: PSV; Spontaneous: Spon; Other (for example HFOV, jet ventilation, SIMV)) Peak inspiratory pressure (Ppeak); cmh 2 O Plateau pressure (Pplateau); cmh 2 O (if available) Mean airway pressure (Pmean); cmh 2 O Tidal volume (actual inspired tidal volume) (TV); ml PEEP; cmh 2 O Respiratory rate (RR); / min Inspired oxygen fraction (FiO 2 ); % Use of recruitment maneuvers (RM); if yes, choose which RM is applied (most closely related to the used RM (see Appendix 1) Peripheral oxygen saturation (SpO 2 ); % End tidal fractions of CO 2 (etco 2 ); mmhg or kpa Mean arterial pressure (either invasive or non-invasive) (MAP); mmhg Heart rate (HR); bpm LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

13 Intra-operative complications Occurrences of intra operative complications possibly related to the ventilation strategy during procedure are recorded at end of surgery. Any de saturation (defined as SpO 2 < 92%) Need for unplanned recruitment maneuver (defined as ventilatory strategies aimed to restore aeration of the lungs [20]) Need for ventilatory pressure reduction (defined as ventilatory strategies aimed to lower peak and plateau pressure) New onset of expiratory flow limitation (defined as expiratory flow higher than zero at endexpiration as suggested by visual analysis of the flow curve) Hypotension (defined as SAP < 90mmHg for 3 min or longer) Need for vaso-active drugs (any vaso-active drug given to correct hypotension as defined above) Any new arrhythmias (defined as atrial fibrillation [AF], sustained ventricular tachycardia [VT], supraventricular tachycardia [SVT], or ventricular fibrillation [VF] [25]; see Appendix 1) Peri operative variables Duration of anesthesia procedure, duration of surgical procedure, breathing circuit, tube type or use of supra-glottic device, epidural anesthesia, antibiotic prophylaxis, neuromuscular monitoring, total intra operative fluid (crystalloids, colloids, albumin) and packed red blood cell requirement, Hb at end of surgery (if clinically available), temperature at end of surgery. Drug administration: Opioids, hypnotics, muscle paralysis agents, neuromuscular blockade reversal agents. Post-operative variables Post operative pulmonary complications are recorded from the medical chart on day 0 (end of surgery to 23:59 PM) and on days 1, 2, 3, 4 and 5 post-operative (each day runs from 00:00 AM to 23:59 PM). Follow up is completed on the day of discharge or on day 5 if the patient is still admitted on the ward. If a patient is admitted to the ICU, the reason for ICU admission is recorded. During ICU stay a different set of variables is recorded than during the stay on the ward. The ICU follow up is substudy; these patients are considered a sub cohort and recording of data during ICU stay is optional (see Intensive Care Unit admission section below). LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

14 On day 0 the following variables are collected on CRF 2A: Post operative residual curarization, defined as train-of-four stimulation (TOF) ratio < 0.9 [26]. - If yes, specify type of TOF monitoring used; electromyography (EMG), mechanomyography (MMG), acceleromyography (AMG) - If yes, specify if neuromuscular blockade was antagonized Invasive mechanical ventilation after discharge from the operation room - If yes; specify if MV was planned or unplanned - If unplanned; specify if ventilatory support was continuated after exit from the operation room or if patient was re-intubated Admission to ICU directly after surgery - If yes; specify if direct post-operative admission to ICU was planned or unplanned Pulmonary complications - Need for oxygen therapy (defined as supplemental oxygen administered due to PaO 2 < 60 mmhg or SpO 2 < 90% in room air). This includes oxygen supplementation given as standard care (e.g. directly after arrival in the PACU). - If yes; record FiO 2 administered (see Appendix 2 for converting table) - Respiratory failure (defined as PaO 2 < 60 mmhg or SpO 2 < 90% despite oxygen therapy, or need for non-invasive mechanical ventilation [NIV]) - If NIV is applied, specify type of interface (mask, helmet) - Pneumonia (defined by the presence of a new or progressive radiographic infiltrate plus at least two of three clinical features; fever >38 C or >100.4 F, leukocytosis or leucopenia (WBC count >12,000 cells/mm³ or <4,000 cells/mm³) and purulent secretions) [27] - ARDS (definition according to the Berlin definition of ARDS [5]) - Pneumothorax (defined as air in the pleural space with no vascular bed surrounding the visceral pleura on the chest X ray) On day 1, 2, 3, 4 and 5 the following variables will be collected: Any new admission to critical care unit Any new MV Pulmonary complications (for definitions see above) LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

15 Intensive Care Unit admission For all patients who are mechanically ventilated and/or admitted to the critical care unit during the follow-up period (day 0, 1, 2, 3, 4 or 5), the ICU admission page (page 1 of CRF2B) should be completed. Recording of further data during the follow-up days of critical care admission is optional, and can be left out by the participating centers if this workload exceeds their possibilities. The choice to leave out the critical care follow-up should be communicated with the study group. ICU admission Reason for admission to Critical Care: respiratory failure; circulatory failure; need for airway protection; need for intensive monitoring; routine care (i.e. planned admission after surgery) Cardiac or respiratory arrest prior to critical care admission. Mode of mechanical ventilation used: invasive or non-invasive MV - If non-invasive MV, specify type of interface (mask, helmet) Reason for invasive or non-invasive mechanical ventilation: respiratory failure (due to pneumonia, aspiration cardiac overload); airway protection (for fatigue, coma (Glasgow Coma Scale < 6)); post-operative MV At the first hour of ICU admission and in case of continued admission each day (during morning rounds, i.e. closest to 08:00 AM) the following variables are collected: APACHE II score [28], scored within the first 24 hours of ICU admission (in case of new admission) SOFA score (for definition see Appendix 1) Mode of mechanical ventilation used: invasive or non-invasive MV - If non-invasive MV, specify type of interface (mask, helmet) Tracheal extubation or re-intubation during the previous 24 hours MV settings Mode of ventilation; hours of controlled MV, hours of assisted MV, hours of combined controlled/assisted MV, hours of CPAP MV settings: Ppeak, Pplateau, tidal volume, PEEP, respiratory rate, inspiratory oxygen fraction Use of recruitment maneuvers (RM); if yes, choose which RM is applied (most closely related to the used RM (see Appendix 1) LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

16 Arterial blood gas values (ph, PaCO 2, PaO 2 ), taken closest to 08:00 AM Pulmonary complications: pneumonia, ARDS, pneumothorax (see definitions above) Extra-pulmonary organ failure: acute kidney failure (according to the RIFLE criteria [29]); need of renal replacement therapy; circulatory failure (defined as need for vaso-active drugs); new arrhythmias (defined as atrial fibrillation [AF], sustained ventricular tachycardia [VT], supraventricular tachycardia [SVT], or ventricular fibrillation [VF] [25]; see Appendix 1) Transfusion of fluids: packed red blood cells, fresh frozen plasma, platelets, fluid balance Discharge from critical care unit ; yes/no If discharged from critical care unit, specify reason for discharge; discharge to ward, deceased, transfer to other hospital, discharge to home Lost to follow-up. If yes, specify reason (informed consent retracted; other) If a patient is transferred back to the ward on day 0, 1, 2, 3, 4 or 5, then follow-up data collection should be continued on CRF2A. Day 28 On day 28 patient status (dead; alive discharged; alive in hospital; alive in critical care unit) and date of discharge or death (if applicable) are assessed. 5.5 Withdrawal of individual subjects A patient is left out of the study when the initial informed consent is withdrawn or not obtained. If requested by the patient the collected data will be erased/ destroyed. LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

17 6 STATISTICAL ANALYSIS The data to be collected are all part of the routine clinical care. Patient characteristics are compared and described by appropriate statistics. Student s t-test or Mann-Whitney U-tests are used to compare continuous variables and chisquared tests are used for categorical variables. Data are expressed as means (SD), medians (interquartile range) and proportions as appropriate. Comparison between and within groups are performed using one-way ANOVA and post-hoc analyses for continuous variables. Study parameters of patients receiving mechanical ventilation prior to operation and of patients undergoing one-lung ventilation during surgery are analyzed separately. Critical Care follow-up data of patients admitted to the ICU during follow-up will be analyzed separately. To identify potential factors associated with intra- and post-operative pulmonary complications univariate analyses are performed. Multivariate logistic regression model is used to identify independent risk factors for post-operative pulmonary complications [23]. A stepwise approach is used to enter new terms into the model, with a limit of p<0.05 to enter the terms. Time to event variables are analyzed using Cox regression and visualized by Kaplan-Meijer. Statistical significance is considered to be at a p value of <0.05. Where appropriate statistical uncertainty are expressed by 95% confidence levels. Statistical analyses are conducted using SPSS version 18.1 (SPSS, Inc., Chicago, IL). LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

18 7 ETHICAL CONSIDERATIONS 7.1 Regulation statement The study will be conducted according to the principles of the Declaration of Helsinki (version of 2008) and in accordance with the Medical Research Involving Human Subjects Act (WMO) [30]. Data management, monitoring and reporting of the study will be performed in accordance with the ICH-GCP Guidelines [31]. 7.2 Ethical and Regulatory authorities approval All participating centers must submit the study to the local Institutional Review Board for ethical judgment and obtain document of proof that the trial has been subject to IRB/IEC review and given approval/favorable opinion. Taking into account that all study data is recorded from medical charts and no additional data collection or patient assessment is performed, ethical approval may not be required in some centers. However, where ethical approval is required, this approval must be obtained before the start of inclusion. If authorization/approval/notification by the regulatory authority(ies) is applicable locally, this document should be obtained prior to initiation of the trial in compliance with the applicable regulatory requirement(s). 7.3 Patient Information and Informed consent If applicable; informed consent forms and any other written information to be provided to the subjects as well as advertisement for subject recruitment (if used) should be subject to IRB/IEC review and given approval/favorable opinion. If informed consent is not required by the local IRB, a waiver must be obtained from the Institutional Review Board. The study coordinator provides a template of Patient Information Sheet and Participant s Informed Consent and Authorized Informed Consent in English (see Appendix 3A, 3B, 3C). LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

19 8 ADMINISTRATIVE ASPECTS AND PUBLICATION 8.1 Handling and storage of data and documents Data is collected pseudo-anonymized; the data will be coded through a random patient identification number (PIN) generated by the electronic CRF. No patient names, patient initials or hospital patient numbers are kept on the paper CRF or collected electronically. To facilitate patient follow-up the paper CRF is provided with a coverpage: confidential patient identification form. This confidential patient identification form matches each PIN to the individual patient. After completing follow-up, this coverpage should be detached from the CRF and filed separately in a secure place. The paper CRF s should be stored behind a lock at the local site. Data will be handled confidentially and centers should keep all data stored for the length of the study and the time foreseen by local rules, but at least for a period of 10 years from the moment of the study completion. Each center will maintain an Investigator File including: protocol, IRB judgment, E.C. approval (if applicable), local investigator delegation log, local translation of informed consent form (if applicable), signed informed consent forms, etc. All handling of personal data will comply with the GCP guidelines [31]. 8.2 Public disclosure and publication policy On behalf of the Steering Committee, the ESA will act as custodian of the data. The ESA and the Steering Committee holds the right to use all pooled data for scientific and other purposes. The results of this study will be published in a peer reviewed medical journal. After publication of the primary results, on request the pooled dataset will be available for all members of the LAS VEGAS collaboration for secondary analysis, after judgment and approval of scientific quality and validity of the proposed analysis by the Steering Committee. Before submission the final version of all manuscripts related to the LAS VEGAS dataset, must be approved by the Steering Committee. All proposals of secondary analysis are encouraged. National groups may enter requests for data-access to analyze their national dataset. Individual participating site may enter requests for data-access to analyze their institutional dataset. 8.3 Organization National coordinators will be appointed in each participating country if needed. They will identify and recruit local participating centers. They will assist and train the local coordinator and monitor the conduction of the study according to ICH-GCP guidelines [31]. They will ensure that all local necessary ethical and regulatory approvals are obtained before start of patient inclusion. They will assist and validate translation of study documents (protocol, CRF, LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

20 patient informed consent form) and help coordinating data cleaning in their countries if needed. Local coordinators in individual participating centers will provide scientific and structural leadership in their center. They will ensure all local necessary ethical and regulatory approvals are obtained before start of patient inclusion. They will train and monitor their local research group, to ensure the study is conducted according to ICH-GCP guidelines [31]. They guarantee the integrity of data collection and ensure timely completion of CRF s. LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

21 9 REFERENCES 1. Putensen C, Theuerkauf N, Zinserling J, Wrigge H, Pelosi P: Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med 2009, 151(8): PMID: Tremblay LN, Slutsky AS: Ventilator-induced lung injury: from the bench to the bedside. Intensive Care Med 2006, 32(1): PMID: Slutsky AS: Lung injury caused by mechanical ventilation. Chest 1999, 116(1 Suppl):9S-15S. PMID: Burns KE, Adhikari NK, Slutsky AS, Guyatt GH, Villar J, Zhang H, Zhou Q, Cook DJ, Stewart TE, Meade MO: Pressure and volume limited ventilation for the ventilatory management of patients with acute lung injury: a systematic review and meta-analysis. PLoS One, 6(1):e PMID: The ARDS Definition Task Force. Acute respiratory distress syndrome: The Berlin definition. JAMA 2012, Jun 20;307(23): PMID: Gajic O, Frutos-Vivar F, Esteban A, Hubmayr RD, Anzueto A: Ventilator settings as a risk factor for acute respiratory distress syndrome in mechanically ventilated patients. Intensive Care Med 2005, 31(7): PMID: Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, Rana R, St Sauver JL, Lymp JF, Afessa B et al: Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 2004, 32(9): PMID: Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, Slutsky AS, Pullenayegum E, Zhou Q, Cook D et al: Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010, 303(9): PMID: Lachmann B: Open up the lung and keep the lung open. Intensive care medicine 1992, 18(6): PMID: Férnandez-Pérez ER, Keegan MT, Brown DR, Hubmayr RD, Gajic O: Intraoperative tidal volume as a risk factor for respiratory failure after pneumonectomy. Anesthesiology 2006, 105(1): PMID: Schultz MJ, Haitsma JJ, Slutsky AS, Gajic O: What tidal volumes should be used in patients without acute lung injury? Anesthesiology 2007, 106(6): PMID: Wrigge H, Uhlig U, Baumgarten G, Menzenbach J, Zinserling J, Ernst M, Dromann D, Welz A, Uhlig S, Putensen C: Mechanical ventilation strategies and inflammatory responses to cardiac surgery: a prospective randomized clinical trial. Intensive Care Med 2005, 31(10): PMID: Wrigge H, Uhlig U, Zinserling J, Behrends-Callsen E, Ottersbach G, Fischer M, Uhlig S, Putensen C: The effects of different ventilatory settings on pulmonary and systemic inflammatory responses during major surgery. Anesth Analg 2004, 98(3): PMID: Wolthuis EK, Choi G, Dessing MC, Bresser P, Lutter R, Dzoljic M, van der Poll T, Vroom MB, Hollmann M, Schultz MJ: Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents pulmonary inflammation in patients without preexisting lung injury. Anesthesiology 2008, 108(1): PMID: Rothen HU, Sporre B, Engberg G, Wegenius G, Reber A, Hedenstierna G: Prevention of atelectasis during general anaesthesia. Lancet 1995, 345(8962): PMID: Jaber S, Coisel Y, Chanques G, et al. A multicentre observational study of intraoperative ventilatory management during general anaesthesia: tidal volumes and relation to body weight. Anaesthesia. Jun PMID: LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

22 17. Blum JM, Maile M, Park PK, Morris M, Jewell E, Dechert R, Rosenberg AL: A description of intraoperative ventilator management in patients with acute lung injury and the use of lung protective ventilation strategies. Anesthesiology, 115(1): PMID: Schultz MJ: Lung-protective mechanical ventilation with lower tidal volumes in patients not suffering from acute lung injury: a review of clinical studies. Med Sci Monit 2008, 14(2):RA PMID: Imberger G, McIlroy D, Pace NL, Wetterslev J, Brok J, Moller AM: Positive endexpiratory pressure (PEEP) during anaesthesia for the prevention of mortality and postoperative pulmonary complications. Cochrane Database Syst Rev (9):CD PMID: Tusman G, Bohm SH: Prevention and reversal of lung collapse during the intraoperative period. Best Pract Res Clin Anaesthesiol, 24(2): PMID: Smetana GW, Lawrence VA, Cornell JE. Preoperative pulmonary risk stratification for noncardiothoracic surgery: systematic review for the American College of ` Physicians. Ann Intern Med, 2006:144: PMID: Canet J, Gallart L, Gomar C, Paluzie G, Valles J, Castillo J, Sabate S, Mazo V, Briones Z, Sanchis J: Prediction of Postoperative Pulmonary Complications in a Population-based Surgical Cohort. Anesthesiology 2011, 113(6): PMID: Bagley SC, White H, Golomb BA. Logistic regression in the medical literature: standards for use and reporting, with particular attention to one medical domain. J Clin Epidemiol. Oct 2001;54(10): PMID: U.S. Department of Health and Human Services. Guidance for industry collection of race and ethnicity data in clinical trials. Fed Regist Winkel TA, Schouten O, Hoeks SE, et al. Risk factors and outcome of new-onset cardiac arrhythmias in vascular surgery patients. Am Heart J. Jun 2010;159(6): PMID: Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg. Jul;111(1): PMID: American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4): PMID: Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med 1985,13(10): PubMed PMID: Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P: Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004, 8:R PMID: World Medical Association (WMA) World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects; Guideline for Good Clinical Practice E6(R1). EMEA, (CPMP/ICH/135/95); Jul LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

23 10 APPENDICES LIST Appendix 1: Definitions Appendix 2: Converting oxygen therapy from O 2 to FiO 2 Appendix 3A: Appendix 3B: Appendix 3C: Patient information Sheet English template Participant s Informed Consent English template Authorized Informed Consent English template LAS VEGAS Protocol v1.2, Amendment 1, dated 20-Nov of 23

24 Appendix 1 Definitions Definition recruitment maneuvers When a recruitment maneuver (RM) is performed, the maneuver which is most closely related to the following definition should be recorded: - Incremental PEEP: stepwise increase in PEEP at constant tidal volume, mostly in steps of 5 cmh 2 0, until peak/plateau airway pressure of above 30 cmh 2 0 is reached. PEEP is sustained for at least 3 breaths and then returned back to baseline ventilation - Tidal volume recruitment: stepwise increase in tidal volume until peak/plateau airway pressure of above 30 cmh 2 0 is reached at constant PEEP level. At least 3 breaths with the plateau pressure of above 30cmH 2 0 are performed, before returning back to baseline ventilation - Combined tidal and PEEP recruitment: PEEP and tidal volume are both stepwise increased to reach a peak/plateau pressure above 30 cmh 2 0. At least 3 breaths with the plateau pressure of above 30 cmh 2 0 are performed, before returning back to baseline ventilation - Inspiratory holds: also called CPAP maneuvers. During this kind of maneuver a positive airway pressure above 30 cmh 2 0 is applied for 10 to 30 seconds and then returned back to baseline ventilation - Sustained inflation with bag: manual hyperinflation using balloon/bag Definition new onset arrhythmias New onset arrhythmias are defined as atrial fibrillation [AF], sustained ventricular tachycardia [VT], supraventricular tachycardia [SVT], or ventricular fibrillation [VF] [24]: - Atrial fibrillation is defined by characteristic absolute irregularity of R-R intervals and concurrent loss of identifiable P waves in the ECG recordings - Ventricular tachycardia is characterized by 3 consecutive QRS complexes with a wide QRS complex at a rate of >100 beat/min and duration of >30 seconds - Supraventricular tachycardia is identified as a narrow QRS complex (<0.12 second) and a rate of >180 beat/min - Ventricular fibrillation is defined as chaotic ventricular electrical discharge with marked variability in QRS cycle length, morphology, and amplitude LAS VEGAS Appendix 1: Definitions (v1.2, 19-Mar-2013) 1 of 3

25 Definition urgency of surgery - Emergency: non-elective surgery performed when the patient's life or well-being is in direct jeopardy - Urgent: surgery required within < 48 hrs - Elective: surgery that is scheduled in advance because it does not involve a medical emergency Sequential Organ Failure Assessment score (SOFA score) The SOFA score is a six-organ dysfunction/failure score measuring multiple organ failure on a daily basis. Each organ is graded from 0 (normal) to 4 (the most abnormal) providing a daily score of 0 to 24 points. Score points Respiration PaO 2 /FiO 2 <400 <300 <200 <100 Cardiovascular Hypotension* Liver MAP <70 mmhg dopamine 5 or dobutamine in any dose with respiratory support dopamine >5 or epinephrine 0.1 or norepineph rine 0.1 with respiratory support dopamine >15 or epinephrine >0.1 or Bilirubin (mg/dl) >12.0 Renal Creatinine (mg/dl) norepinephrine or urine output <500ml/24h <200ml/24h Coagulation Platelets (*10 3 /mm 3 ) <150 <100 <50 <20 Central nervous system Glasgow Coma <6 Scale * Adrenergic agents administered for at least 1 h (doses given in μg/kg/min) or > or LAS VEGAS Appendix 1: Definitions (v1.2, 19-Mar-2013) 2 of 3

26 GCS in sedated patients must be considered as if they were not sedated. If cerebral function is estimated as normal, but the patients is sedated then GCS is 15. If patient's cerebral function is estimated to be damaged, then GCS should be estimated. RIFLE criteria; for staging of patients with acute kidney injury [29]: - Risk: GFR decrease >25%, serum creatinine increased 1.5 times or urine production of 0.5 ml/kg/hr for 6 hours - Injury: GFR decrease >50%, doubling of creatinine or urine production <0.5 ml/kg/hr for 12 hours - Failure: GFR decrease >75%, tripling of creatinine or creatinine >355 μmol/l (with a rise of >44) (>4 mg/dl) OR urine output below 0.3 ml/kg/hr for 24 hours - Loss: persistent AKI or complete loss of kidney function for more than 4 weeks - End-stage renal disease: complete loss of kidney function for more than 3 months LAS VEGAS Appendix 1: Definitions (v1.2, 19-Mar-2013) 3 of 3

27 Appendix 2 Converting oxygen therapy from O 2 to FiO 2 Method O 2 flow (l/min) Estimated FiO 2 (%) Nasal canula Nasopharyngeal catheter Face mask Face mask with reservoir LAS VEGAS Appendix 2: Converting oxygen therapy from O2 to FiO2 (v1.1, 01-Aug-2012) 1 of 1

28 Appendix 3A - Patient information Sheet LAS VEGAS study : Local Assessment of Ventilatory Management During General Anesthesia for Surgery and effects on Postoperative Pulmonary Complications: Patient information sheet Dear Sir or Madam: You are invited to participate in a research study funded by the European Society of Anaesthesiology. Before deciding whether or not to take part in this study, we would ask you to carefully read the following information which explains the study s objective and the implications of your possible participation. Study objective The main objective is to investigate which strategies used for mechanical ventilation during surgery are possibly related to pulmonary complications during the following 5 days after surgery. Study description The investigator in your center will collect information from your medical charts concerning previous illnesses, your health status, the applied mechanical ventilation strategy and other care during general anesthesia. During the following 5 days after surgery the investigator will collect information on pulmonary complications from your medical chart. What does your participation involve? Whether you decide to participate or not will not affect the medical care you are going to receive. If you decide not to take part in this study, it will not alter your treatment. The treating doctors will not modify their decisions, neither during your hospital stay nor after your discharge, because you have participated or not. LAS VEGAS Appendix 3A Patient Information Sheet (v1.1, 01-Aug-2012) 1 of 2

29 Withdrawal from the study Even though you have agreed to participate you may leave the study whenever you wish and, moreover, without having to offer any kind of explanation. You will not have to justify your decision. Privacy and use of clinical information In order to carry out the study it will be necessary to consult and make use of some of the information that appears in your medical record. Your acceptance will authorize us to consult and process the information in the following manner: Information will be stored in a computerized database for all the participants All information will be stored anonymized. All clinical information that is obtained for the study will be identified by a number. No data concerning personal identification will be stored in the database. Results of the research study The results obtained in the present study will be published in a major medical journal. In the article all participating centers will be listed and all investigators will have a copy. Finally, we would like to draw your attention to the fact that this informative consent document refers only to your participation in this study. You will have to additionally authorize your surgical intervention which you have either already been informed about or will soon be given the appropriate information. Any inquiries concerning the study should be addressed to: Hospital researcher: Telephone: Field work coordinator: Telephone: If you have any questions related to your rights as a participant in the study you can get in touch with (Hospital Ethics Committee contact): Telephone: Thank you for taking time to read this information sheet. LAS VEGAS Appendix 3A Patient Information Sheet (v1.1, 01-Aug-2012) 2 of 2

30 Appendix 3B - Participant s Informed Consent LAS VEGAS study: Local Assessment of Ventilatory Management During General Anesthesia for Surgery and effects on Postoperative Pulmonary Complications: Participant s Informed Consent I,......(first and last names of participant) Have read the LAS VEGAS Study Information Sheet for the patient. Have been able to ask questions concerning the study Have received sufficient information with respect to the study I have spoken to... (name of researcher), and understand that my participation in the study will not affect any medical care that I should receive from the hospital. I am aware that my participation is voluntary. I realise that I can withdraw from the study: Whenever I wish Without having to give any explanations Without suffering any repercussions with respect to my medical attention I freely give my consent to participate in the study. In... dated:... Signature of Participant Signature of Researcher LAS VEGAS Appendix 3B Participant s Informed Consent (v1.1, 01-Aug-2012) 1 of 1

31 Appendix 3C Authorized Informed Consent LAS VEGAS study: Local Assessment of Ventilatory Management During General Anesthesia for Surgery and effects on Postoperative Pulmonary Complications: Authorized Informed Consent (in case the patient is unable to understand the information and consent) With respect to the proposal that (first and last names of participant) participates in the previously mentioned study, I,......(first and last names) as... (relationship with participant) declare that I: Have read the information sheet provided Have been able to ask questions concerning the study Have received sufficient information with respect to the study I have also spoken to... (name of researcher), and I understand that participation in the study will not affect any medical care that the patient I am representing should receive. I am aware that his/her participation is voluntary. I realise that he/she can withdraw from the study: Whenever he/she wishes Without having to give any explanations Without suffering any repercussions with respect to his/her medical attention In my presence... (name of participant) has been given all the necessary information, appropriate to his/her level of understanding, and has agreed to participate. I freely give my consent for... (name of participant) participate in this study. to... dated:... dated: Signature of Authorized Party Signature of Researcher LAS VEGAS Appendix 3C - Authorized Informed Consent (English Template) (v1.1, 01-Aug-2012) 1 of 1