Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Futier E, Constantin J-M, Paugam-Burtz C, et al. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med 2013;369: DOI: /NEJMoa (PDF updated October 10, 2013.)

2 Table of contents Supplementary appendix List of IMPROVE trial investigators 3 Acknowledgments 3 Inclusion criteria 4 Exclusion criteria 5 Trial settings for intraoperative ventilation 5 Trial definitions for postoperative complications 6 Protocol violations 8 Handling of missing data 8 Figure S1. Time-to-event curve for non-invasive or invasive ventilation for postoperative acute respiratory failure within 30 days after surgery 9 Figure S2. Time-to-event curve for postoperative pneumonia within 30 days after surgery 10 Figure S3. Time-to-event curve for postoperative ALI/ARDS within 30 days after surgery 11 Figure S4. Time-to-event curve for postoperative sepsis, severe sepsis and septic shock within 30 days after surgery 12 Table S1. Univariate and multivariate analysis of factors associated with the primary outcome 13 Table S2. More details on intraoperative procedures 16 Table S3. Unadjusted and adjusted analyses for outcomes 18 Table S4. Unadjusted and adjusted analyses for outcomes excluding patients with the higher risk for postoperative pulmonary complications 21 Table S5. Postoperative gas Exchange 24 References 25 2

3 Intraoperative PROtective VEntilation (IMPROVE) trial investigators Steering Committee: Emmanuel Futier, Samir Jaber, Jean-Michel Constantin, Catherine Paugam-Burtz, Emmanuel Marret, Marc Beaussier, Jean-Yves Lefrant, Bernard Allaouchiche. Trial Management Committee: Emmanuel Futier, Jean-Michel Constantin Scientific Committee: Emmanuel Futier, Samir Jaber, Jean-Michel Constantin, Marc Leone Trial Monitoring and Research Coordinators: Dominique Morand, Sandrine Saugues, Julien Pascal, Fabrice Kwiatkowski Data Monitoring and Safety Committee: Elie Azoulaz, Karim Asehnoune, Lise Laclautre Perrier Statistical and data coordination: Bruno Pereira Writing Committee: Emmanuel Futier, Samir Jaber, Jean-Michel Constantin Participating sites and investigators: Estaing Hospital, Clermont-Ferrand, France: E Futier, JM Constantin, JE Bazin, A Petit, A Gérard, O Cherbis Saint Eloi Hospital, Montpellier, France: S Jaber, D Verzilli, A De Jong, M El Kamel Beaujon Hospital, AP-HP, Paris, France: C Paugam-Burtz, M Eurin, A Neuschwander Tenon Hospital, AP-HP, Paris, France: E Marret, ML Brulé, J de Montblanc, JF Perrier, O Szymkiewicz Saint Antoine Hospital, AP-HP, Paris, France: M Beaussier, C Gutton Edouard Herriot Hospital, Lyon, France: B Allaouchiche, C Le Goff, A Challan-Belval Caremeau Hospital, Nîmes, France: J Ripart, JY Lefrant Acknowledgments We wish to thank all patients who participated in the study, and the clinical and research staff at all trial sites, without whose assistance the IMPROVE study would never have been completed. We would especially like to thank Mervyn Singer for his valuable advice during the preparation of the manuscript. We also wish to thank the monitors of the trial, in particular Dominique Morand and Sandrine Saugues at the Direction de la Recherche Clinique (DRC), Clermont-Ferrand University Hospital for coordinating the monitoring of the trial. 3

4 Inclusion criteria 1. All adult patients older than 40 years (and < 90 years) 2. Scheduled for planned laparoscopic or non-laparoscopic major abdominal surgery 3. With an expected duration of 2 hours 4. With a preoperative risk index 1 for postoperative pulmonary complications of 2 5. And informed consent obtained 6. And valid affiliation to the Social Security System Preoperative risk index 1 Risk factor Point Value Type of surgery Abdominal aortic aneurysm repair 15 Upper abdominal 10 Age 80 years years years years 4 Functional status Totally dependent 10 Partially dependent 6 Weight loss > 10% in past 6 months 7 History of chronic obstructive pulmonary disease 5 General anesthesia 4 Impaired sensorium 4 History of cerebrovascular accident 4 Blood urea nitrogen level < 2.86 mmol/l (< 8 mg/dl) mmol/l (22 30 mg/dl) mmol/l ( 30 mg/dl) 3 Transfusion > 4 units 3 Emergency surgery 3 Steroid use for chronic condition 3 Current smoker within 1 year 3 Alcohol intake > 2 drinks/d in past 2 weeks 2 Risk Class Risk Class 1 Risk Class 2 Risk Class 3 Risk Class 4 Risk Class points points points points > 55 points 4

5 Exclusion criteria 1. Mechanical ventilation of >1 hour within the last 2 weeks before surgery 2. Body mass index 35 kg/m 2 3. Acute respiratory failure (pneumonia, acute lung injury or acute respiratory distress syndrome) 4. Emergency 5. Sepsis or septic shock 6. Progressive neuromuscular illness 7. Intra-thoracic surgery 8. Pregnancy 9. Refusal to participate Trial settings for intraoperative ventilation Patients were randomly assigned to receive either non-protective (non-protective ventilation group) or lung protective (lung-protective ventilation group) mechanical ventilation throughout the surgical procedure. Patients in the non-protective ventilation group had a tidal volume of 10 to 12 ml per kilogram predicted body weight, zero PEEP and no recruitment maneuver. Patients in the lung-protective ventilation group had a tidal volume of 6 to 8 ml per kilogram predicted body weight, a PEEP level of 6 to 8 cm of water and recruitment maneuvers. Recruitment maneuvers consisted of a continuous positive airway pressure of 30 cm of water for 30 sec, and were applied immediately after tracheal intubation and every 30 min thereafter until the end of surgery. Predicted body weight (PBW) was calculated according to a predefined formula with: x (centimeters of height 152.4) for males and x (centimeters of height 152.4) for females. In each group, patients were ventilated using the volume-controlled ventilation strategy using an anesthesia ventilator: 1. Avance (Datex-Ohmeda, General Electric, Helsinki, Finland) 2. Aisys (Datex-Ohmeda, General Electric, Helsinki, Finland) 3. Primus (Dräger, Lübbeck, Germany) In each group, attending anesthesiologists were advised to use an inspired oxygen fraction (F I O 2 ) below 0.5 and to maintain oxygen saturation 95%. The inspiratory to expiratory time ratio was set at 1:2, with a respiratory rate adjusted to maintain normocapnia (end-tidal carbon dioxide concentration of mmhg). Main Ventilator settings Lung-protective Ventilation group Non-protective Ventilation group Tidal volume, ml/kg PBW PEEP, cmh 2 O Recruitment maneuver After intubation and every 30 min No Recruitment maneuvers were standardized among centers and performed as follows: 1. Pressure Support Ventilation (PSV) mode 2. Positive End-expiratory Pressure (PEEP) set to 30 cm of water 3. Inspiratory gas flow set to the highest value 4. Duration of the maneuver = 30 sec 5

6 In case of desaturation (defined as a peripheral oxygen saturation of less than 92%), a rescue therapy was proposed and consisted of increasing F I O 2 to 100% in the both groups until oxygen saturation had reached the target value (oxygen saturation 95%), and applying PEEP and/or recruitment maneuver in the group assigned to non-protective ventilation. Trial definitions for postoperative complications Postoperative pulmonary complications were scored using a grade scale 2 ranging from 0 to 4, with grade 0 representing the absence of any pulmonary complication and grades 1 through 4 representing successively the worse forms of complications. Grade scale for postoperative pulmonary complications. 2 Grade 1 - Cough, dry - Microatelectasis: abnormal lung findings and temperature > 37.5 C without other documented cause; results of chest radiograph either normal - Dyspnea, not due to other documented cause Grade 2 - Cough, productive, not due to other documented cause - Bronchospasm: new wheezing or pre-existent wheezing resulting in change therapy - Hypoxemia - Atelectasis: radiological confirmation plus either temperature > 37.5 C or abnormal lung findings - Hypercarbia, transient, requiring treatment, such as naloxone or increased manual or mechanical ventilation Grade 3 - Pleural effusion, resulting in thoracentesis - Pneumonia, suspected: radiological evidence without bacteriological confirmation - Pneumonia, proved: radiological evidence and documentation of pathological organism by Gram stain or culture - Pneumothorax - Re-intubation postoperative or intubation, period of ventilator dependence (non-invasive or invasive ventilation) 48 hours Grade 4 Ventilatory failure: postoperative non-invasive ventilation dependence 48 hours, or re-intubation with subsequent period of ventilator dependence 48 hours Postoperative hypoxemia was defined as a PaO 2 < 60 mmhg or SpO 2 < 90% on room air. Pneumonia was suspected upon the presence of new and/or progressive pulmonary infiltrates on chest radiograph plus two or more of the following criteria: - Fever 38.5 C or hypothermia <36 C - Leukocytosis 10 WBC/mm 3 or leukopenia < 4000 WBC/mm 3 - Purulent sputum and/or new onset or worsening cough or dyspnea Atelectasis was defined as lung opacification with shift of the mediastinum, hilum or hemidiaphragm towards the affected area and compensatory overinflation in the adjacent nonatelectatic lung. 6

7 The SIRS criteria were (we used the most deranged value recorded after surgery): 1. Core temperature > 38 C or <36 C. (Core temperature was rectal or tympanic). If oral, inguinal or axillary temperatures were used, 0.5 C were added to the measured value. 2. Heart rate > 90 beats per minute. If patient had an atrial arrhythmia, record the ventricular rate. If patients have a known medical condition or are receiving treatment that would prevent tachycardia (for example, heart block or beta blockers), they must meet two of the remaining three SIRS criteria. 3. Respiratory rate > 20 breaths per minute or a PaCO 2 < 32 mmhg (4.3 kpa) or mechanical ventilation for an acute process. 4. White Blood Cell (WBC) count of >12 x 10 9 /l or < 4 x 10 9 /l. Sepsis was defined as a 1. Defined focus of infection and 2. At least two systemic inflammatory response syndrome (SIRS) criteria. Defined focus of infection was indicated by either an organism grown in blood or sterile site, or an abscess or infected tissue (e.g. pneumonia, peritonitis, urinary tract, vascular line infection, soft tissue, etc.). Severe sepsis was defined by sepsis plus at least one organ failure, hypotension or hypoperfusion. Septic shock was sepsis-induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities. 7

8 Protocol violations Four hundred patients were included in the modified intention-to-treat analysis and were followed up to 30 days after surgery. One patient in the traditional ventilation group received the lung-protective ventilation strategy, and was analyzed in the group to which he was assigned. Handling of missing data Missing baseline variables (Table 1): No missing values. We had full data sets on all 400 patients. Missing intraoperative procedures (Table 2): No missing values. We had full data sets on all 400 patients. Missing outcome data: For the primary outcome measure and most of the secondary outcomes, we had full data sets on all 400 patients. There were missing data for following secondary outcomes measures (Table 4): - ph - PaO 2 - PaCO 2 - HCO SaO 2 Multiple imputation method was performed using command mi from software STATA. mi impute assumes that missing data are missing at random; that is, missing values do not carry any extra information about why they are missing than what is already available in the observed data. mi replaces missing values with multiple sets of simulated values to complete the data, applies standard analyses to each completed dataset, and adjusts the obtained parameter estimates for missing-data uncertainty. The objective of mi is not to predict missing values as close as possible to the true ones but to handle missing data in a way resulting in valid statistical inference. Pattern has been considered with parameters used on multivariate analysis: randomization group, stratification variables (center, use of epidural analgesia), sex, preoperative risk index for postoperative pulmonary complications, duration of surgery (ranging from 2-4 hours, 4-6 hours or 6 hours) and blood transfusion. The number of patients where the measurements were documented in source data is presented. Mean (±SD) values and p-values are given for data obtained after missing-data imputation (N = in each randomization group). Analyses on complete data were also carried out and confirm results presented. 8

9 Figure S1. Kaplan-Meier curve estimates of the probability for requiring intubation or non-invasive ventilation for postoperative acute respiratory failure within 30 days after surgery between the lung non-protective ventilation group and the lung protective ventilation group. (P<0.001, log-rank test). Probability of event Non-protective ventilation Protective ventilation No. at risk Days since surgery Non-protective ventilation Lung protective ventilation

10 Figure S2. Kaplan-Meier curve estimates of the probability for postoperative pneumonia within 30 days after surgery between the lung nonprotective ventilation group and the lung protective ventilation group. (P<0.001, log-rank test). Probability of event Non-protective ventilation Protective ventilation No. at risk Days since surgery Non-protective ventilation Lung protective ventilation

11 Figure S3. Kaplan-Meier curve estimates of the probability for postoperative ALI/ARDS within 30 days after surgery between the lung non-protective ventilation group and the lung protective ventilation group. (P=0.018, log-rank test). Probability of event Non-protective ventilation Protective ventilation No. at risk Days since surgery Non-protective ventilation Lung protective ventilation

12 Figure S4. Kaplan-Meier curve estimates of the probability for postoperative sepsis, severe sepsis and septic shock within 30 days after surgery between the non-protective ventilation group and the lung protective ventilation group. (P=0.003, log-rank test). Probability of event Non-protective ventilation Protective ventilation No. at risk Days since surgery Non-protective ventilation Lung protective ventilation

13 Table S1. Univariate and multivariate analysis of factors associated with the primary outcome. Characteristic Yes (N = 76) Primary outcome Univariate Analysis No (N = 324) Odds ratio (95%CI) P Value Odds ratio* (95%CI) Multivariate Analysis P Value Odds ratio** (95%CI) Randomization group Lung protective ventilation 21 (10.5) 179 (89.5) 0.31 ( ) < ( ) < ( ) < Traditional mechanical ventilation 55 (27.5) 145 (72.5) 1.00 Patient-specific risk factors Age (year) no. (%) (8.7) 42 (91.3) (13.0) 94 (87.0) 1.56 ( ) 1.39 ( ) (20.6) 104 (79.4) 2.73 ( ) 1.96 ( ) (26.3) 73 (73.7) 3.74 ( ) 3.72 ( ) (29.4) 12 (70.6) 4.37 ( ) 5.32 ( ) 0.05 Gender no. (%) Male 59 (24.9) 178 (75.1) 2.85 ( ) < ( ) ( ) Female 17 (10.4) 146 (89.6) 1.00 Body mass index kg/m ± ± ( ) 0.26 Predicted body weight kg 66.0± ± ( ) 0.02 Preoperative Risk index no. (%) < Risk class 2 24 (11.9) 177 (88.1) Risk class 3 46 (24.6) 141 (75.4) 2.41 ( ) 1.73 ( ) 0.07 Risk class 4 6 (50) 6 (50) 7.37 ( ) 7.42 ( ) Smoker no. (%) Yes 27 (26.7) 74 (73.3) 1.86 ( ) ( ) No 49 (16.4) 250 (83.6) 1.00 Alcohol intake Yes 9 (29.0) 22 (71.0) 1.84 ( ) 0.14 P Value

14 No 67 (18.2) 302 (80.8) 1.00 Functional dependence Yes 8 (50.0) 8 (50.0) 4.65 ( ) ( ) 0.03 No 68 (17.7) 316 (82.3) 1.00 COPD Yes 11 (27.5) 29 (72.5) 1.72 ( ) 0.15 No 65 (18.1) 295 (81.9) 1.00 Weight loss > 10% Yes 24 (28.6) 60 (71.4) 2.03 ( ) 0.01 No 52 (16.5) 264 (83.5) 1.00 Chronic use of steroid Yes 1 (9.1) 10 (90.9) 0.42 ( ) 0.70 No 75 (19.3) 314 (80.7) 1.00 Laparoscopic surgery no. (%) Yes 10 (13.2) 75 (23.1) 0.50 ( ) 0.06 No 66 (86.8) 249 (76.9) 1.00 Cancer diagnosis no. (%) Yes 70 (21.9) 249 (78.1) 3.56 ( ) No 6 (7.4) 75 (92.6) 1.00 Factors related to intraoperative patient management Epidural analgesia no. (%) Yes 31 (19.4) 129 (80.6) 1.04 ( ) 0.88 No 45 (18.7) 195 (81.3) Duration of surgical procedure 2-4 hours 19 (12.6) 132 (87.4) 1.00 < hours 27 (17.9) 124 (82.1) 1.51 ( ) 1.21 ( ) ( ) 0.67 >6 hours 28 (32.9) 57 (67.1) 3.41 ( ) 3.02 ( ) ( ) Blood transfusion no. (%) Yes 26 (36.6) 45 (63.4) 3.37 ( ) < ( ) ( ) 0.03 No 47 (14.6) 274 (85.4) 1.00 Blood transfusion Number of unit 1.1± ± ( ) < 0.001

15 Blood losses (ml) median (interquartile range) 500 ( ) 250 ( ) 1.00 ( ) < Volume of fluids (ml) median (interquartile range) Crystalloid 3000 ( ) 0 ( ) 1.00 ( ) < Colloid 1000 ( ) 500 ( ) 1.00 ( ) Need for vasopressor no. (%) Yes 23 (29.9) 54 (70.1) 2.19 ( ) No 52 (16.3) 268 (83.7) 1.00 Plus-minus values are means±sd. COPD denotes chronic obstructive pulmonary disease and PPC postoperative pulmonary complications. Two models were considered for the logistic regression analysis: first considering each patient-specific risk factor for predicting postoperative pulmonary complications in the preoperative risk index (*), and second, using the multifactorial risk index (**). 1 The criterion for entering variables tested in the model were selected if P<0.10 and according to clinical significant parameters. 2 Preoperative risk index of postoperative pulmonary complications. 1 The risk index ranges from class 1 to class 5, with higher risk class indicating higher risk of complications. Patients having a risk class of 2 or more were eligible for participation. Ten patients had both laparoscopic and non-laparoscopic procedures (intraoperative conversion from laparoscopic to open surgery)

16 Table S2. More details on intraoperative procedures. Variable Non-protective Ventilation group (N = ) Lung Protective Ventilation group (N = ) P Value Tidal volume ml 719.0± ±75.6 <0.001 Tidal volume ml per kilogram PBW* 11.1± ±0.8 <0.001 PEEP cmh 2 O median (interquartile range) At baseline 0 (0 0) 6 (6 8) <0.001 End of surgery 0 (0 0) 6 (6 8) <0.001 Recruitment maneuver median (interquartile range) 0 (0 0) 9 (6 12) <0.001 Peak pressure cmh 2 O At baseline 20.1± ± End of surgery 20.6± ± Plateau pressure cmh 2 O At baseline 16.1± ± End of surgery 16.6± ±2.6 <0.001 Respiratory system compliance ml/cmh 2 O At baseline 48.4± ± End of surgery 45.1± ±26.7 <0.001 F I O 2 % 47.2± ± Volume of fluids median (interquartile range) Crystalloid L 2.0 ( ) 1.5 ( ) 0.47 Colloid L 0.5 ( ) 0.5 ( ) 0.97 Duration of surgery no. (%) hours 76 (39.6) 75 (38.5) 4-6 hours 75 (39.1) 76 (38.9) >6 hours 41 (21.3) 44 (22.6) Duration of mechanical ventilation min 344± ± Time to extubation min 31 (20 60) 30 (20 60) 0.61 Anesthetic drug no. (%) 0.45 Desflurane inhalation 157 (78.5) 163 (81.5) Sevoflurane inhalation 43 (21.5) 37 (18.5) Neuromuscular blocking agent no. (%) 0.45 Atracurium 81 (40.9) 74 (37.2) Cis-atracurium 117 (59.1) 125 (62.8) Intravenous opioid no. (%) 0.19 Sufentanil 160 (80.0) 170 (85) Remifentanil 40 (20.0) 30 (15) Blood loss ml median (interquartile range) 300 ( ) 300 ( ) 0.29 Blood transfusion no. (%) 37 (18.5) 34 (17.0) 0.79 Need for vasopressor no. (%) 42 (21.1) 35 (17.7) 0.45 Epidural analgesia no. (%) 77 (38.5) 83 (41.5)

17 Values are displayed as mean±sd unless otherwise stated. F I O 2 denotes inspired oxygen fraction, PBW predicted body weight, PEEP positive end-expiratory pressure. Detailed on intraoperative procedures are given in Table S2 in the Supplementary Appendix. * Predicted body weight was calculated as x [height (centimeters) 152.4] for males and x [height (centimeters) 152.4] for females. Duration of surgery is the time between skin incision and closure of the incision. Time to extubation is the time between the end of surgery and successful extubation. Criteria for extubation after surgery were: recovery of a spontaneous ventilation with an expired tidal volume between 5-8 ml/kg, respiratory rate between breaths/min, absence of residual neuromuscular blockade (assessed by a T4/T1 ratio 90%), peripheral oxygen saturation 95%, stable hemodynamics and a body temperature 36 C 17

18 Table S3. Unadjusted and adjusted analyses for outcomes. Variable Outcome Non-protective Ventilation group (N = ) Lung Protective Ventilation group (N = ) Unadjusted Relative Risk (95% CI) P Value* Adjusted Relative Risk (95% CI) P Value Primary outcome to Day 7 no. (%) 55 (27.5) 21 (10.5) 0.38 ( ) < ( ) Composite outcome to Day 30 no. (%) 58 (29.0) 25 (12.5) 0.43 ( ) < ( ) <0.001 Secondary outcome measures Pulmonary complications to Day 7 no. (%) Grade (15.0) 25 (12.5) 0.69 ( ) ( ) 0.16 Grade 3 42 (21.0) 10 (5.0) 0.24 ( ) < ( ) <0.001 Atelectasis to Day 7 no. (%) 34 (17.0) 13 (6.5) 0.38 ( ) ( ) Pneumonia to Day 7 no. (%) 16 (8.0) 3 (1.5) 0.19 ( ) ( ) ALI or ARDS to Day 7 no. (%) 6 (3.0) 1 (0.5) 0.17 ( ) ( ) 0.14 Need for invasive ventilation to Day 7 no. (%) 7 (3.5) 2 (1.0) 0.29 ( ) ( ) 0.26 Need for non-invasive ventilation to Day 7 no. (%) 29 (14.5) 9 (4.5) 0.31 ( ) ( ) Pulmonary complications to Day 30 no. (%) Grade (15.0) 25 (12.5) 0.70 ( ) ( ) 0.17 Grade 3 42 (21.0) 12 (6.0) 0.29 ( ) < ( ) <0.001 Pneumonia to Day 30 no. (%) 18 (9.0) 3 (1.5) 0.17 ( ) ( ) ALI or ARDS to Day 30 no. (%) 8 (4.0) 1 (0.5) 0.12 ( ) ( ) 0.07 Need for invasive ventilation to Day 30 no. (%) 13 (6.5) 3 (1.5) 0.23 ( ) ( ) Need for non-invasive ventilation to Day 30 no. (%) 29 (14.5) 11 (5.5) 0.38 ( ) ( ) Extra-pulmonary complications to Day 7 no. (%) SIRS 100 (50.0) 86 (43.0) 0.86 ( ) ( ) 0.37 Sepsis 29 (14.5) 13 (6.5) 0.45 ( ) ( )

19 Severe sepsis or septic shock 9 (4.5) 8 (4.0) 0.89 ( ) ( ) 0.47 Extra-pulmonary complications to Day 30 no. (%) SIRS 103 (51.5) 86 (43.0) 0.83 ( ) ( ) 0.26 Sepsis 36 (18.0) 16 (8.0) 0.44 ( ) ( ) Severe sepsis or septic shock 11 (5.5) 8 (4.0) 0.73 ( ) ( ) 0.83 Surgical complications to Day 30 no. (%) Surgical site infection 15 (7.5) 9 (4.5) 0.60 ( ) ( ) 0.11 Intra-abdominal abscess 15 (7.5) 11 (5.5) 0.73 ( ) ( ) 0.49 Anastomotic leakage 44 (22.0) 24 (12.0) 0.54 ( ) ( ) Need for reoperation 20 (10) 15 (7.5) 0.75 ( ) ( ) Day mortality no. (%) 7 (3.5) 6 (3.0) 0.86 ( ) ( ) 0.83 Service utilization Mean Difference (95% CI) Mean Difference (95% CI) Days in hospital median (interquartile range) 13 (8 20) 11 (8 15) (-4.04 to -0.47) (-4.17 to -0.72) Days in ICU median (interquartile range) 7 (4 9) 6 (4 8) (-6.87 to 3.91) (-4.98 to 7.40) 0.69 Treatment-related adverse events Intraoperative hypotension no./total no. of recruitment procedures (%) Unadjusted Relative Risk (95% CI) Adjusted Relative Risk (95% CI) 0/8 (0.0) 29/1729 (1.7) NA NA NA NA Pneumothorax no. (%) 2 (1.0) 4 (2.0) 2.00 ( ) ( ) 0.18 Adjustment was performed for stratification variables (epidural analgesia and study center) and preoperative risk index for postoperative pulmonary complications, sex gender, duration of surgery and blood transfusion. * The Hochberg procedure was used to adjust for multiple testing of components of the composite primary outcome. The primary outcome measure was a composite of major pulmonary (defined as pneumonia or need for invasive or non-invasive ventilation for acute respiratory failure) and extra-pulmonary (defined as sepsis, septic shock or death) complications to Postoperative day 7. ALI denotes acute lung injury, CI 19

20 confidence intervals, ARDS acute respiratory distress syndrome, ICU intensive care unit, NA not applicable, SIRS systemic inflammatory response syndrome. All postoperative complications are defined according to consensus criteria (for details, see Supplementary Appendix). Postoperative pulmonary complications are scored using a grade scale 2, with 0 representing the absence of any pulmonary complication and grades 1 through 4 representing successively worse forms of pulmonary complications (for details, see Supplementary Appendix). Tracheal intubations for reoperation due to surgical complications were not used did not qualify as a postoperative pulmonary complication. 20

21 Table S4. Unadjusted and adjusted analyses for outcomes excluding patients with the higher risk (preoperative risk index of class 4 or more) for postoperative pulmonary complications (N=6 in each group) Variable Outcome Non-protective Ventilation group (N = 194) Lung Protective Ventilation group (N = 194) Unadjusted Relative Risk (95% CI) P Value* Adjusted Relative Risk (95% CI) Primary outcome to Day 7 no. (%) 51 (26.3) 19 (9.8) 0.37 ( ) < ( ) Composite outcome at Day 30 no. (%) 54 (27.8) 23 (11.9) 0.43 ( ) < ( ) Secondary outcome measures Pulmonary complications to Day 7 no. (%) Grade (15.4) 23 (11.8) 0.65 ( ) ( ) 0.11 Grade 3 39 (20.1) 10 (5.2) 0.26 ( ) < ( ) <0.001 Atelectasis to Day 7 no. (%) 32 (16.5) 13 (6.7) 0.41 ( ) ( ) Pneumonia to Day 7 no. (%) 16 (8.3) 3 (1.6) 0.19 ( ) ( ) ALI or ARDS to Day 7 no. (%) 6 (3.1) 1 (0.5) 0.17 ( ) ( ) 0.14 Need for invasive ventilation to Day 7 no. (%) 7 (3.6) 2 (1.0) 0.29 ( ) ( ) 0.26 Need for non-invasive ventilation to Day 7 no. (%) 27 (13.9) 9 (4.6) 0.33 ( ) ( ) Pulmonary complications to Day 30 no. (%) Grade (19.4) 23 (12.6) 0.65 ( ) ( ) 0.12 Grade 3 39 (20.1) 12 (6.2) 0.31 ( ) < ( ) <0.001 Pneumonia to Day 30 no. (%) 18 (9.3) 3 (1.6) 0.17 ( ) ( ) ALI or ARDS to Day 30 no. (%) 8 (4.1) 1 (0.5) 0.13 ( ) ( ) 0.07 Need for invasive ventilation to Day 30 no. (%) 12 (6.2) 3 (1.6) 0.25 ( ) ( ) Need for non-invasive ventilation to Day 30 no. (%) 27 (13.9) 11 (5.7) 0.41 ( ) ( ) 0.01 Extra-pulmonary complications to Day 7 no. (%) P Value 21

22 SIRS 97 (50.0) 83 (42.8) 0.86 ( ) ( ) 0.33 Sepsis 28 (14.4) 12 (6.2) 0.43 ( ) ( ) 0.03 Severe sepsis or septic shock 7 (3.6) 8 (4.1) 1.14 ( ) ( ) 0.35 Extra-pulmonary complications to Day 30 no. (%) SIRS 100 (51.6) 83 (42.8) 0.83 ( ) ( ) 0.23 Sepsis 35 (18.0) 15 (7.7) 0.43 ( ) ( ) Severe sepsis or septic shock 9 (4.6) 8 (4.1) 0.89 ( ) ( ) 0.70 Surgical complications to Day 30 no. (%) Surgical site infection 15 (7.7) 9 (4.6) 0.60 ( ) ( ) 0.11 Intra-abdominal abscess 15 (7.7) 10 (5.2) 0.67 ( ) ( ) 0.36 Anastomotic leakage 44 (22.7) 24 (12.4) 0.54 ( ) ( ) Need for reoperation 19 (9.8) 14 (7.2) 0.74 ( ) ( ) Day mortality no. (%) 6 (3.1) 5 (2.6) 0.83 ( ) ( ) 0.99 Service utilization Mean Difference (95% CI) Mean Difference (95% CI) Days in hospital median (interquartile range) 13 (8 20) 11 (8 15) (-4.17 to -0.50) (-4.41 to -0.89) Days in ICU median (interquartile range) 7 (4 9) 6 (4 8) (-7.12 to 4.05) (-4.98 to 7.40) 0.69 Treatment-related adverse events Intraoperative hypotension no./total no. of recruitment procedure (%) Unadjusted Relative Risk (95% CI) Adjusted Relative Risk (95% CI) 0/8 (0.0) 29/1693 (1.7) NA NA NA NA Pneumothorax no. (%) 2 (1.1) 4 (2.1) 2.00 ( ) ( ) 0.18 Adjustment was performed for stratification variables (epidural analgesia and study center) and preoperative risk index for postoperative pulmonary complications, sex gender, duration of surgery and blood transfusion. * The Hochberg procedure was used to adjust for multiple testing of components of the composite primary outcome. 22

23 The primary outcome measure was a composite of major pulmonary (defined as pneumonia or need for invasive or non-invasive ventilation for acute respiratory failure) and extra-pulmonary (defined as sepsis, septic shock or death) complications to Postoperative day 7. ALI denotes acute lung injury, CI confidence intervals, ARDS acute respiratory distress syndrome, ICU intensive care unit, NA not applicable, SIRS systemic inflammatory response syndrome. All postoperative complications are defined according to consensus criteria (for details, see Supplementary Appendix). Postoperative pulmonary complications are scored using a grade scale 2, with 0 representing the absence of any pulmonary complication and grades 1 through 4 representing successively worse forms of pulmonary complications. Tracheal intubation for reoperation due to surgical complications was not recorded as a pulmonary complication. 23

24 Table S5. Gas Exchange after Extubation and at Postoperative Day 1. Variable ph Non-protective Ventilation group (N = ) No. Assessed Value Lung Protective Ventilation group (N = ) P Value No. Assessed Value After extubation (0.05) (0.05) 0.02 Day (0.05) (0.05) 0.92 PaO 2 mmhg After extubation (46.6) (53.5) 0.66 Day (27.2) (28.5) 0.17 PaCO 2 mmhg After extubation (5.3) (4.6) 0.03 Day (5.0) (4.8) 0.17 HCO - 3 mmol/liter After extubation (2.6) (2.9) 0.35 Day (2.7) (2.5) 0.90 SaO 2 % After extubation (3.4) (3.2) 0.96 Day (3.3) (2.8) 0.04 Values are displayed as mean±sd. PaO 2 denotes arterial partial pressure of oxygen, PaCO 2 arterial partial pressure of carbon dioxide, SaO 2 arterial saturation of oxygen. Number of patients where the measurements were documented in source data. All gas exchange were measured on room air (F I O 2 = 0.21) after tracheal extubation. Gas exchange were measured on room air (F I O 2 = 0.21) unless peripheral oxygen saturation was below 95%. At Postoperative Day 1, 270 patients received oxygen: 142 (71%) patients and 128 (64%) patients in the traditional ventilation group and in the lung-protective ventilation group, respectively (P=0.14). Median oxygen concentration was 2.25 l/min (interquartile range, 1.5 to 3.0) in the traditional ventilation group and 2.0 l/min (interquartile range, 1.5 to 3.0) in the lung-protective ventilation group (P=0.11). 24

25 References 1. Arozullah AM, Khuri SF, Henderson WG, Daley J. Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Ann Intern Med 1;135: Hulzebos EH, Helders PJ, Favie NJ, et al. Preoperative intensive inspiratory muscle training to prevent postoperative pulmonary complications in high-risk patients undergoing CABG surgery: a randomized clinical trial. JAMA 6;296: Malek MH, Berger DE, Coburn JW. On the inappropriateness of stepwise regression analysis for model building and testing. Eur J Appl Physiol 7;101: