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1 1 Supplementary Online Content Leme AC, Hajjar LA, Volpe MS, et al. Effect of intensive vs moderate alveolar recruitment strategies added to lung-protective ventilation on postoperative pulmonary complications: a randomized clinical trial in hypoxemic patients with hypoxemia after cardiac surgery. JAMA. doi: /jama efigure 1. Systolic, Diastolic and Mean Blood Arterial Pressures During and After the Recruitment Maneuvers efigure 2. Heart Rate During and After the Recruitment Maneuvers efigure 3. Mean Arterial Blood Pressure (Mean and Individual Values) During and After the First Recruitment Maneuver efigure 4. Ventilation Maps (Obtained by Electrical Impedance Tomography) After the Recruitment Maneuvers efigure 5. Daily Evolution of Worst Pulmonary Complications First-Five Postoperative etable 1. Respiratory and Gas Exchange Data During the Four-Hour Period Of Ventilation etable 2. Hemodynamic Data During the Four-Hour Period of Ventilation etable 3. Daily Use of Aided Lung Expansion With Positive-Pressure Mask Ventilation emethods. Details on Statistics and Methods This supplementary materi al has been provided by the authors to give readers additional information about their work.

2 2 1. efigure 1: Arterial blood pressures during the first and second (4 hours later, before extubation) recruiting maneuvers Legend: Mean values (symbols) and 95% CI (error bars) for invasive arterial pressure measurements. T1, T2 and T3 refer to measurements taken immediately after each of the three inflation-cycles of recruiting maneuvers (each cycle lasting 60-seconds in the Intensive-RM, or 30 seconds in the Moderate-RS, with PEEP/CPAP levels of 30cmH 2 O and 20cmH 2 O, respectively). Soon afterwards (1min to 5min after the maneuvers), patients received assist/control ventilation to obtain V T of 6 ml/kg,pbw, inspiratory time of 1 second, minimum respiratory-rate to maintain PaCO 2 between mmhg, and PEEP levels set at 13cmH 2 O or 8 cmh2o (Intensive-RS and Moderate-RS, respectively). At baseline, all patients were ventilated under PEEP = 5cmH 2 O. P-values represent the significance of the interaction-term between strategy and time, when considering the short interval between baseline and T3 (P<.001), or a longer interval between baseline and 5 min (marginal significance). A comparison between-arms, only considering the measurements after the maneuvers (1min to 5 min), showed no difference between the two groups (P>0.34 for all comparisons). Tests were performed by repeated-measures ANOVA, with contrast comparison between baseline and T3 or between baseline and 5 minutes. The number of patients presented in the figures was 153 and 157 (Intensive-RS group and Moderate-RS group, respectively).

3 3 2. efigure 2: Heart rate during the first and second (4 hours later) recruiting maneuvers Legend: Mean values (symbols) and 95% CI (error bars) for heart rate. T1, T2 and T3 refer to measurements taken immediately after each of the three inflation-cycles of the recruiting maneuvers (each cycle lasting 60-seconds in the Intensive-RM, or 30 seconds in the Moderate-RS, with PEEP/CPAP levels of 30cmH 2 O and 20cmH 2 O, respectively). Soon afterwards (1min to 5min), patients received assist/control ventilation adjusted to obtain V T of 6 ml/kg,pbw, inspiratory time of 1 second, minimum respiratory-rate to maintain PaCO 2 between mmhg, and PEEP levels set at 13cmH 2 O or 8 cmh2o, in the Intensive-RS and Moderate-RS, respectively). At baseline, all patients were ventilated at PEEP = 5cmH 2 O. P-values represent the significance of the interaction-term between strategy and time, considering the time-interval indicated. Tests were performed by repeated-measures ANOVA, with contrast comparison between baseline and T3 or between baseline and 5 minutes. The number of patients presented in the figures was 153 and 157 (Intensive-RS group and Moderate-RS group, respectively). The number of patients presented in the figures was 153 and 157 (Intensive-RS group and Moderate-RS group, respectively).

4 4 3. efigure 3: Mean Arterial Blood Pressure (mean and individual values) during the first recruiting maneuver Intensive RS Moderate RS Arterial Blood Pressure (mmhg) baseline RM1 RM2 RM3 1min 1 3min 3 min 5min 5 min baseline RM1 RM2 RM3 1min 1 min 3min 3 min 5min 5 min T1 T2 T3 T1 T2 T3 Inflation-cycles Inflation-cycles Legend: Mean values (red symbols) with standard deviation (red error bars) and individual values (dark gray lines) for mean arterial pressure (invasive measurements). T1, T2 and T3 refer to measurements taken immediately after each of the three inflation-cycles of recruiting maneuvers (each cycle lasting 60-seconds in the Intensive-RM, or 30 seconds in the Moderate-RS, with PEEP/CPAP levels of 30cmH 2 O and 20cmH 2 O, respectively). Although ensuring that all patients received the 3 cycles of lung inflation, not rarely, the cycles were aborted after 15 seconds (~20% cases), especially in the second and third cycles, in order to avoid excessive drops in blood pressure. In the exceptional cases where the patient could not tolerate a minimum of 15 seconds of lung inflation, we waited for 5 min, stabilized the patient, and repeated the inflation cycle. The dashed lines indicate the threshold of 60 mmhg, used to guide abort (or not) the maneuver. Soon afterwards (1min to 5min after the maneuvers), patients received assist/control ventilation to obtain V T of 6 ml/kg,pbw, inspiratory time of 1 second, minimum respiratory-rate to maintain PaCO 2 between mmhg, and PEEP levels set at 13cmH 2 O or 8 cmh2o (Intensive-RS and Moderate-RS, respectively). At baseline, all patients were ventilated under PEEP = 5cmH 2 O. The number of patients presented in the figures was 153 and 157 (Intensive-RS group and Moderate-RS group, respectively).

5 5 4. efigure 4: Distribution of regional lung ventilation during the mechanical ventilation in the intensive care unit, after randomization. A C 2 U/L ratio = 4.7 (Moderate-RS) B Upper / Lower ratio Moderate-RS P = Intensive-RS 0.25 Baseline After Randomiz. Before Extubation U/L ratio = 0.5 (Intensive-RS) Legend: Electrical Impedance Tomography (EIT) analysis of the last 33 consecutive patients enrolled in the trial (Intensive-RS = 19, Moderate = 14). Panel A: representative EIT map of ventilation (cross section at 4-5 th intercostal space) of a patient submitted to Moderate-RS (5 minutes later), exhibiting insufficient ventilation in dependent lung regions, a typical finding in patients with massive postoperative atelectasis. Air and ventilation are forced to occur in the anterior, non-dependent lung regions, as pointed out by high U/L ventilation-ratio (above 1:1). The yellow line represents the mid-position between anterior and posterior half of the thoracic section. U/L represents the Upper to Lower ratio of regional ventilation. Panel B: representative map of ventilation of a patient submitted to Intensive-RS (5 min later), exhibiting mainly dependent lung ventilation, a typical finding when there is consistent reversal of postoperative atelectasis (the dependent lung zones, once recruited, present larger regional compliance). Here, the U/L ventilation-ratio decrease to below 1:1. Panel C: Evolution of the U/L ventilation-ratios along the time, for each study-arm. From baseline (PEEP = 5cmH2O) to before-extubation, the intensive-rs caused a much larger increase in dependent lung-compliance and ventilation. P-value represents the significance of the interaction term between strategy and time (repeated-measures ANOVA). At baseline, all patients were ventilated under PEEP = 5, with a mean U/L ratio above 1:1 in both arms. 5. efigure_5: Daily evolution of worst pulmonary complications first-five postoperative days

6 6 Daily pulmonary complications (%) (P.O. Days) Intensive-RS Moderate-RS grade 0 (no complications) grade 1 (e.g. simple atelectasis) grade 2 (e.g. hypoxemia plus abnormal lung findings) grade 3 (e.g. pneumonia, intense NIV need) grade 4 (e.g. intubation > 48hs) grade 5 (death) Legend: Daily incidence of worst postoperative pulmonary complications for each day. Complications were graded from 0 to 5, according to objective criteria defined in the appendix, adapted from previous publications, where: Grade-0 means no symptoms; Grade-1 means one of the following: dry cough; abnormal lung findings and temperature > 37.5 C with normal chest radiograph; dyspnea without other documented cause; Grade-2 means two items of the following: productive cough; bronchospasm; Hypoxemia (SpO2 90%) at room air; atelectasis with gross radiological confirmation (concordance of 2 independent experts) plus either temperature > 37.5 C or abnormal lung findings; hypercarbia (PaCO2 > 50 mmhg) requiring treatment; Grade-3 means one of the following: pleural effusion resulting in thoracentesis; pneumonia (strictly defined, see supplement); pneumothorax; extended noninvasive ventilation (strictly required, see supplement); reintubation lasting less than 48 hours; Grade-4 means mechanical ventilation 48 hours, which was prolonged after ICU arrival, or needed because of reintubation; Grade-5 means hospital death. P.O.: Post-operative days. The overall shift in the distribution of scores was analyzed by ordinal regression, stratified by each day, with the Intensive-RS showing a consistent shift in scores towards lower levels; with P=0.006 after multiplicity correction (original P < 0.001).

7 7 5. etable 1. Respiratory and gas exchange data* Variables Baseline 15 min after 1º RM 4 hours 15 min after 2º RM P-Value betweenfactor P-Value interactionfactor V T (ml) Moderate-RS (N=155) 365 (76) 370 (85) 364 (80) 369 (82) Intensive-RS (N=144) 369 (89) 375 (92) 374 (97) 377 (94) V T (ml/pbw) Moderate-RS (N=155) 6.0 (0.9) 6.1 (1.0) 6.0 (1.0) 6.1 (1.1) Intensive-RS (N=144) 6.1 (1.4) 6.1 (1.3) 6.1 (1.4) 6.2 (1.4) Plateau pressure (cmh 2 O) Moderate-RS (N=156) 14.6 (2.2) 16.1 (2.1) 16.4 (2.1) 15.9 (2.2) <0.001 <0.001 Intensive-RS (N=147) 15.3 (3.2) 19.6 (2.3) 20.6 (2.6) 19.1 (2.4) Driving pressure (cmh 2 O) Moderate-RS (N=156) 9.6 (2.2) 8.1 (2.1) 8.4 (2.1) 7.9 (2.2) <0.001 <0.001 Intensive-RS (N=147) 10.3 (3.2) 6.6 (2.3) 7.6 (2.6) 6.1 (2.4) C RS (ml/cmh 2 O) Moderate-RS (N=155) 42.3 (12.8) 50.0 (15.5) 47.9 (14.5) 52.6 (17.8) <0.001 <0.001 Intensive-RS (N=144) 41.6 (12.7) 64.6 (19.4) 54.9 (17.1) 68.4 (19.0) Arterial ph Moderate-RS (N=151) 7.32 (0.66) 7.27 (0.71) 7.31 (0.65) 7.30 (0.74) < < Intensive-RS (N=142) 7.32 (0.62) 7.31 (0.64) 7.34 (0.55) 7.34 (0.69) PaCO 2, mmhg Moderate-RS (N=151) 42.8 (5.9) 49.7 (9.0) 43.9 (8.0) 47.3 (9.0) < < Intensive-RS (N=142) 43.3 (6.2) 45.4 (7.3) 41.6 (6.2) 41.9 (7.4) PaO 2 /FiO 2 Moderate-RS (N=151) 183 (37) 236 (68) 231 (74) 239 (74) < < Intensive-RS (N=142) 181 (35) 344 (74) 348 (69) 362 (67) Abbreviations: RM, recruitment maneuver, V T, Tidal volume; PBW, Predicted-body weight; C SR, compliance of respiratory system; PaCO 2, Partial pressure of arterial carbon dioxide; PaO 2, Partial pressure of arterial oxygen; FiO 2, inspired oxygen fraction. Data are presented as mean (SD)*. Tests for significance were performed by repeated-measures ANOVA, using two factors (group-strategy and time), including interaction terms.

8 8 6. etable 2: Hemodynamic data during the four-hour period of ventilation * Variables 1 hour 2 hours 3 hours 4 hours P between factor P interaction factor Heart rate, bpm Moderate-RS (N=156) 101 (16) 103 (15) 104 (16) 105 (15) Intensive-RS (N=148) 101 (14) 104 (15) 104 (17) 105 (17) SAP, mmhg Moderate-RS (N=156) 133 (25) 131 (25) 126 (22) 125 (22) Intensive-RS (N=148) 132 (25) 130 (26) 125 (22) 125 (22) DAP, mmhg Moderate-RS (N=156) 70 (12) 69 (11) 67 (11) 67 (12) Intensive-RS (N=148) 70 (13) 69 (12) 68 (11) 69 (11) MAP, mmhg Moderate-RS (N=156) 91 (16) 88 (14) 86 (13) 86 (15) Intensive-RS (N=148) 89 (16) 88 (14) 86 (13) 87 (12) During the four-hour period of ventilation 7 patients in the Intensive-RS and 2 patients in the Moderate-RS presented PAM < 60 mmhg (P = 0,080). Abbreviations: SAP, Systolic arterial pressure; DAP, diastolic arterial pressure; MAP, Mean arterial pressure. *Data are presented as mean (SD) unless otherwise indicated. Tests for significance were performed by repeated-measures ANOVA, using two factors (group-strategy and time), including interaction terms.

9 9 etable 3. Use of aided lung expansion with positive-pressure mask. Postoperative Day Intensive-RS (N= 157) Moderate-RS (N= 163) P value 1 st 138 (88%) 138 (85%) 0,515 2 nd 111 (71%) 125 (77%) 0,203 3 rd 8 (5%) 24 (15%) 0,005 4 th 7 (5%) 19 (12%) 0,023 5 th 7 (5%) 14 (9%) 0,176 Tests for significance were performed by Chi-squared tests, not adjusted for multiplicity of comparisons.

10 10 emethods II) DETAILS ON METHODS: 1. Study register The study protocol was approved by the local ethics and research committee (Comitê de Ética para Análise de Projetos de Pesquisa CAPPesq, number 0913/08) and written informed consent was obtained from all the participants. The study protocol was registered at ClinicalTrials.gov (NCT ). 2. Surgical and anesthetic techniques Preoperative medication consisted of midazolam (0.1 to 0.2 μg/kg given orally 30 minutes before surgery). Anesthesia was induced with fentanyl (3-5 μg/kg), midazolam (0.05 μg/kg), etomidate ( μg/kg), and pancuronium bromide (0.1 μg/kg). Anesthesia was maintained with isoflurane in oxygen, and fentanyl as needed. During cardiopulmonary bypass, additional doses of midazolam and pancuronium were administered as required. All patients were monitored with an arterial and central venous catheter; some also received a pulmonary artery catheter. After tracheal intubation, all patients received invasive mechanical ventilation with intermittent positive pressure with a tidal volume of 8 ml/kg, positive end-expiratory pressure of 5 to 8 cm H 2 O, and fraction of inspired oxygen of 0.6 to 1 to keep arterial oxygen saturation above 95%. Nitroglycerin and sodium nitroprusside were administered intravenously as vasodilators, dobutamine as an inotrope, and norepinephrine and epinephrine as vasopressors. In all patients, blood glucose levels were kept below 160 μg/dl (to convert to mmol/l, multiply by ), using continuous intravenous insulin if needed. Methylprednisolone (10 μg/kg) and cefuroxime (750 μg) were administered intravenously at induction of anesthesia. All surgical procedures were undertaken through a median sternotomy. In all patients, clopidogrel and oral anticoagulants were stopped at least 5 days before surgery. All patients received 5 g of ε-aminocaproic acid, an antifibrinolytic, at induction of anesthesia and an additional 1 g/h until the end of surgery. Anticoagulation was established with an initial dose of 500 IU/kg of heparin injected into the central venous line before initiation of bypass, with a target activated clotting time of 480 seconds. Additional heparin was given intermittently to titrate clotting times during bypass. At the end of bypass, heparin was reversed by protamine chloride in a 1:1 ratio, with additional protamine given as required to return the activated clotting time to preoperative values. Coagulation profiles and platelet counts were obtained after heparin reversal. Significant intraoperative bleeding associated with platelet disorders or coagulopathy were treated using platelets, fresh frozen plasma, or cryoprecipitate. Surgeons performed a hemostasis review. Cell salvage was not used. A centrifugal pump (Medtronic Biomedicus; Medtronic, Minneapolis, Minnesota) was used for bypass. An extracorporeal circuit containing a microporous polypropylene membrane oxygenator (Braile; São José do Rio Preto, São Paulo, Brazil) with an integrated venous cardiotomy reservoir was used. The oxygenator was primed with 1500 ml of lactated Ringer solution, 20% (1 g/kg) mannitol, and 2500 units of unfractionated heparin. During bypass, a mild hypothermic temperature management strategy (32 C to 34 C) with α-stat blood gas management was used in all patients. During bypass, nonpulsatile flow was maintained at 2.0 to 2.4 L/min per square meter, and mean arterial pressure varied from 60 to 90 mm Hg. Myocardial preservation was achieved by intermittent antegrade cold crystalloid cardioplegia. Cardioplegia was repeated every 30 minutes during the cross-clamping period. Fluid management was accomplished with lactated Ringer solution and adjusted according to filling pressures, diuresis, and cardiac output. Albumin or hydroxyethyl starch (130/0.4) could be administered if considered necessary. Patients were transferred to the ICU before recovery from anesthesia while still receiving mechanical ventilation. Source: Hajjar et al. 1.

11 11 3. Score of Postoperative Pulmonary Complications Postoperative pulmonary complications were scored using a grade scale ranging from 0 to 5, with grade zero representing absence of complications, grades 1 to 4 representing increasing (worsening) levels of complications, and grade 5 representing death before hospital discharge. This score was adapted from Kroenke et al. 2, Hulzebos et al. 3 and Futier et al. 4. Grade 1 Grade 2* Grade 3 Grade 4 Grade 5 - Cough, dry Postoperative pulmonary complications score - Microatelectasis: abnormal lung findings and temperature > 37.5 C without other documented cause; normal chest radiograph - Dyspnea, not due to other documented cause - Cough, productive, not due to other documented cause - Bronchospasm: new wheezing or pre-existent wheezing resulting in a change in therapy - Hypoxemia (SpO 2 90%) at room air - Atelectasis: gross radiological confirmation (concordance of 2 independent experts) plus either temperature > 37.5 C or abnormal lung findings - Hypercarbia (PaCO 2 > 50 mmhg), requiring treatment - Pleural effusion, resulting in thoracentesis - Pneumonia: radiological evidence (concordance of 2 independent experts) plus clinical symptoms (two of the following: leucocytosis or leucopenia, abnormal temperature, purulent secretions), plus either a pathological organism (by Gram stain or culture), or a required change in antibiotics - Pneumothorax - Noninvasive ventilation, strictly applied to those with all of the following: a) oxygen saturation (SpO 2 ) lower than 92% under supplemental oxygen; b) need of supplemental oxygen >5 L/min; and RR 30 bpm - Re-intubation postoperative or intubation, period of ventilator dependence (non-invasive or invasive ventilation) 48 hours - Ventilatory failure: postoperative ventilator dependence exceeding 48 hours, or reintubation with subsequent period of ventilator dependence exceeding 48 hours - Death before hospital discharge * We only classified as grade 2 if two or more items in the grade 2 were present.

12 12 References 1. Hajjar LA, Vincent JL, Galas FR, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. Oct ;304(14): Kroenke K, Lawrence VA, Theroux JF, Tuley MR. Operative risk in patients with severe obstructive pulmonary disease. Arch Intern Med. May 1992;152(5): Hulzebos EH, Helders PJ, Favie NJ, De Bie RA, Brutel de la Riviere A, Van Meeteren NL. Preoperative intensive inspiratory muscle training to prevent postoperative pulmonary complications in high-risk patients undergoing CABG surgery: a randomized clinical trial. JAMA. Oct ;296(15): Futier E, Constantin JM, Paugam-Burtz C, et al. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. The New England journal of medicine. Aug ;369(5):