APPENDIX 1 Appendix 1. Complete respiratory protocol. First 24 hours: All patients with ARDS criteria were ventilated during 24 hours with low V T (6-8 ml/kg predicted body weight (PBW)) (NEJM 2000; 342 (18): 1301-8 / Am rev Respir Dis 1981;123:659-64), inspiratory plateau pressure limited at 30 cmh 2 O, initial ventilator rate of 30 breaths/min adjusted to maintain a ph goal of 0 to 7.45 to a maximum of 35 breaths/min, fraction of inspired oxygen (FiO 2 ) ensuring arterial oxygen saturation (SaO 2 ) 88-95% or arterial partial pressure of oxygen (PaO 2 ) of 55-80 mmhg, and PEEP level that permitted the best oxygenation with the lowest FiO 2 without adverse hemodynamic effects. In case of a plateau pressure greater of 30 cmh 2 O with V T of 6 ml/kilogram PBW, it was allow to reduce V T 1 ml/kg PBW if necessary until 4 ml per kilogram PBW; in that case, plateau pressure limit was set at 35 cmh 2 O. After 24 hours: if they meet all inclusion criteria, they were randomized into two s: FiO 2 -driven- PEEP or a compliance-guided. Randomization was performed in blocks of 10 using sealed envelopes. In FiO 2 -driven-peep, PEEP was set based on the patient FiO 2 according to the PEEP strategy reported in the ARDSNet study (NEJM 2000; 342 (18): 1301-8). In FiO 2 -driven-peep, PEEP was set based on the patient FiO 2 according to the PEEP strategy reported in the ARDSNet study (NEJM 2000; 342 (18): 1301-8). In compliance-guided, PEEP level was set daily, according to the method described by Suter (Chest 1978; 73:158-62). Static compliance (Cst) was calculated at different levels of PEEP at a constant V T of 6-8 ml/kg PBW. Cst was determined by dividing V T by the difference between the pressure at the end of inflation hold (2 seconds) and the PEEP, at series of incrementally values for end-expiratory pressure, beginning at 5 cmh 2 O and steps of 2 cmh 2 O, without an upper PEEP titration limit. The maximum value of Cst in individual patients was considered as the best PEEP. If two PEEP level compliance was identical we choose the ones who gets the lower plateau pressure. All the patients received sedatives and analgesics at the time of PEEP setting, and some patients were on treatment with muscle relaxants due to ARDS and mechanical ventilation, not specifically to measure autopeep or plateau pressure. PEEP level was set once daily in the morning while the patient was under mechanical ventilation until weaning was started, according the study. Intrinsic PEEP was measured before and after each change in PEEP; inspiratory time was adjusted to prevent its occurrence.
Table A. Ventilation Protocol: respiratory parameters. Tidal volume goal Pre-randomization (first 24 hours) 6-8 ml/kg of predicted body weight Post-randomization FiO 2 -driven-peep Compliance-guided 6-8 ml/kg of predicted body 6-8 ml/kg of predicted weight body weight Plateau pressure limit Inspiration: expiration relation Ventilator rate (breaths/min) < 30 cmh 2 O < 30 cmh 2 O < 30 cmh 2 O 1:2 1:2 1:2 30 rpm initial, adjusted according ph Adjusted according ph Adjusted according ph ph goal 0 7.45 0 7.45 0 7.45 Oxygenation goals - PaO 2 55-80 mmhg 55 80 mmhg 55 80 mmhg - SaO 2 88-95% 88-95% 88-95% PEEP The one that permits the best oxygenation without hemodynamic adverse effects * Combinations of PEEP and FiO 2 (NEJM 2000; 342 (18): 1301-8) Depending on the FiO 2 applied (see below) Depending on the best compliance FiO 2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1 PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-20-22-24
Appendix 2. Weaning protocol. Weaning Protocol FiO 2 < 0,4 y PEEP < 5 cmh 2 O? Patient has spontaneous breathing efforts? Haemodinamically stable? CPAP TRIAL Set CPAP 5 cmh 2 O, PS 0 cmh 2 O and FiO2 0,5 Yes RR < 35 bpm for 5 minutes No PRESSURE SUPPORT TRIAL Set PEEP 5 cmh2o, FiO 2 0,5 y PS based on RR during CPAP trial CPAP trial not tolerated Return to previous CMV ventilador settings. Reassess next morning RR < 25 bpm Set 10 cmh 2 O RR 26-35 bpm Set PS 20 cmh 2 O RR < 35 rpm and SaO 2 > 88% without respiratory distress? No Yes Decrease PS by 2-5 cmh 2 O every 10-15 min PS 5 cmh 2 O, PEEP 5 cmh 2 O y FiO 2 0,5 reached with RR < 35 rpm and SaO 2 > 88% without respiratory distress? Yes No Extubation or spontaneous ventilation tracheostomy End of weaning protocol PS trial not tolerated Return to previous CMV ventilador settings. Reassess next morning Abbreviations: CPAP: Continuous Positive Airway Pressure. PS:Pressure Support Ventilation. RR : Respiratory rate. BPM : breath per minute. CMV: Controlled Mechanical Ventilation.
Appendix 3. ARDS etiology. ARDS etiology. FiO 2 -driven-peep (n = 36) Compliance-guided (n= 34) Direct lung injury: 24 (66,7%) 15 (44,1%) Pulmonary infection 18 (75%) 13 (86,6%) Severe chest trauma 3 (12,4%) 1 (6,7%) OP * 1 (4,2%) Aspiration of gastric contents 1 (4,2%) Diffuse alveolar hemorrhage 1 (4,2%) 1 (6,7%) Indirect lung injury: 12 (33,3%) 19 (55,9%) Sepsis 8 (66,7%) 11 (57,8%) Acute pancreatitis 3 (25%) 3 (15,8%) Multiple blood transfusions 3 (15,8%) Drug overdose 1 (5,3%) Others 1 (5,3%) Severe nonthoracic trauma 1 (8,3%) Results are shown as number of patients and porcentage. * OP: crytogenetic organizing pneumonia. Others: dermatomyositis.
Appendix 4. Respiratory variables during the study. Respiratory Variables during the study. Basal 6 hours 24 hours FiO 2 - driven- PEEP P value FiO 2 - driven- PEEP P value FiO 2 - driven- PEEP Minute ventilation Respiratory rate (cicles/min) Peak pressure Plateau pressure 12.1 12.9 0.15 11.5 12.6 0.09 12.4 12.8 0.43 23 +1 25 +1 0.30 25 +1 26 +1 0.26 25 +1 26 +1 0.52 38.1 38.2 +1.3 0.90 37.1 +1.4 36.2 +1.0 0.68 38.1 +1.2 36.1 +1.2 0.16 31.9 +1.6 28.3 +1.2 0.13 30.1 +2.4 2 +1.3 0.17 29.1 +1.8 27.0 0.16 PEEP * 10 (8-14) 10 (10-12) 0.71 10 (10-14) 11 (10-13) 0.82 10 (10-13) 12 (10-13) 0.40 Compliance 29.1 +1.6 33.8 +2.2 0.08 29.6 +2.1 35.3 +2.5 0.80 31.0 +2.2 37.0 +2.9 0.10 (ml/cmh 2 O) PaO 2 /FiO 2 (mmhg) 133.3 +6.5 146.3 +6.7 0.12 139.5 + 144.2 +7.5 0.56 150.1 +8.2 167.7 +11.0 0,17 ph 4 +0.01 3 +0.01 0.47 2 +0.01 2 +0.01 0.12 3 +0.01 2 +0.01 0.74 48 hours 72 hours 7 days Minute ventilation 12.6 +0.1 13.6 +0.1 0.36 12.5 12.9 0.57 13.9 +0.6 13.1 +0.6 0.30 Respiratory rate 26 +1 26 +1 0.53 26 +1 26 + 1 0.70 26 +1 24 +1 0.11 (cicles/min) Peak pressure 37.4 36.5 +1.7 0.36 36.7 35.2 0.66 35.7 +2.9 32.2 +2.2 0.18 Plateau pressure 28.6 27.1 +1.2 0.69 28.9 +1.8 26.4 +1.4 0.39 29.7 +2.4 24.0 +2.1 0.07 PEEP * 10 (8-12) 10 (9-13) 0.40 10 (8-12) 10 (8-12) 0.30 10 (6-12) 8 (6-12) 0.46 Compliance 32.2 +2.7 40.4 +7.4 0.29 31.4 +2.3 45.3 +9.1 0.14 33.6 +3.8 45.1 +5.4 0.08 (ml/cmh 2 O) PaO 2 /FiO 2 (mmhg) 164.0 +9.0 189.0 +13.0 0.11 176.3 +10.3 196.0 +15.1 0.25 180.1 +11.0 191.1 +13.0 0.56 ph 3 +0.01 5 +0.01 0.33 6 +0.01 6 +0.01 0.74 6 +0.02 9 +0.01 0.16 14 days 21 days 28 days Minute ventilation 12.9 13.3 0.80 13.3 13.9 0.68 11.3 +1.2 11.2 +1.5 0.94 Respiratory rate 25 +1 24 +2 0.71 23 +2 21 +1 0.38 22 +2 19 +3 0.35 (cicles/min) Peak pressure 37.8 +2.4 34.2 +2.1 0.29 33.5 +2.3 33.5 +1.3 0.74 24.5 +4.4 30.0 +5.7 0.30 Plateau pressure 29.4 +3.8 26.3 +2.1 0.27 24.2 +2.3 24.7 +1.3 0.88 19.5 +2.7 24.5 +4.3 0.30 PEEP * 8 (6-13) 8 (6-10) 0.46 6 (4-10) 9 (6-10) 0.23 6 (5-8) 8 (6-12) 0.24 Compliance 30.1 +4.1 37.6 +5.5 0.28 34.6 +5.2 41.0 +4.7 0.39 56.4 +14.6 49.9 +11.0 0.75 (ml/cmh 2 O) PaO 2 /FiO 2 (mmhg) 194.3 +16.7 203.9 +21.6 0.71 245.6 +15.8 230.6 +32.0 0.66 278.6 +24.6 26 +40.1 0.80 ph 7 +0.02 7.41 +0.02 0.13 7.43 +0.02 9 +0.03 0.29 9 +0.02 6 +0.02 0.25 Data are presented as mean + standard deviation, except the marked ones with * that are presented as median (interquartile range). Abbreviations: PEEP: Positive end-expiratory pressure. PaO 2 /FiO 2 : ratio to the partial pressure of arterial oxygen to the fraction of inspired oxygen. P value
Appendix 5. Hemodynamic variables during the first 72 hours of study. 6 h 24 h 48 h 72 h Hemodynamic variables during the first 72 hours of study MAP (mmhg) HR (beats/min) RAP (mmhg) CO PAWP (mmhg) PVR (d/seg/cm-5) p p p p p p Basal 86.8 <0.01 97.1 +3.8 0.21 15.6 0.54 7.1 0.50 15.1 0.33 206.95 0.15 PEEP +1.7 + 0.8 +0.6 +2.4 76.8 +2.1 103.5 + 3.4 14.2 + 0.6 7.6 14.1 183.8 +25.8 PEEP PEEP PEEP PEEP 82.7 +1.6 80.5 83.6 +1.8 83.6 +2.3 88.3 80.4 +3.0 87.2 86.2 +2.4 0.36 0.98 0.30 0.75 101.3+4.2 0.22 15.2 108.2 +3.9 13.7 102.0+4.1 0.41 13.3 +0.6 106.6 +3.9 14.3 96.9 +3.6 0.45 13.2 +0.6 100.8 +3.7 13.9 96.4 +3.9 0.90 13.9 96.9 +3.5 14.9 0.76 0.41 0.64 0.72 7.9 7.7 +0.3 6.7 7.5 +6.7 0.34 0.49 0.32 0.79 16.4 15.2 14.6 15.7 + 0.7 15.5 15.1 18.1 +1.6 17.6 +1.3 0.28 0.31 0.75 0.83 170.4 +18.9 178.4 +19.2 160.6 +14.3 182.1 +20.1 177.0 +21.9 162.8 +21.1 151.9 +23.7 166.8 +35.6 Data are presented as mean + standard deviation. Abbreviations: h: hours. MAP: mean arterial pressure. HR: heart rate. RAP: right atrium pressure. CO: cardiac output. PAWP: pulmonary artery wedge preseure. PVR: pulmonary vascular resistance. 0.14 0.25 0.46 0.45
Appendix 6. Sedation. Sedation: dosages of drugs administered by study day. Opioids (mg/h) Midazolam (mg/h) Propofol (mg/h) Others* n (%) Muscle relaxants*α n (%) p p p p p Basal FiO 2 -driven- 3.3 0.78 9.9 0.48 44.9 0.30 9 0.56 14 0.80 PEEP +0.3 +21.1 (25%) (39%) 3.2 8.9 86.4 +33.7 6 (18%) 12 (35%) 24 h FiO 2 -driven- 3.2 0.45 9.1 0.33 38.4 0.25 7 0.99 12 0.80 PEEP +15.1 (19%) (33%) 2.8 +0.3 7.9 71.1 +24.3 7 (21%) 13 (38%) 48 h FiO 2 -driven- 3.6 0.17 9.3 0.08 58.1 0.32 5 0.99 14 0.31 PEEP +26.9 (14%) (40%) 2.8 +0.3 6.9 96.3 +24.9 4 (12%) 9 (27%) 72 h FiO 2 -driven- 3.6 0.56 8.1 0.84 56.7 0.28 6 0.48 9 0.9 PEEP +0.6 +21.8 (17%) (26%) 3.2 7.8 100.1 +25.9 3 (9%) 10 (30%) 7 d FiO 2 -driven- 2.9 0.39 7.8 0.71 67.9 0.18 4 0.72 6 0.36 PEEP +1.3 +19.7 (13%) (19%) 3.8 8.5 +1.7 128.5 +36.9 5 (19%) 8 (31%) 14 d FiO 2 -driven- 3.6 0.09 10.9 0.03 123.1 0.53 1 0.58 2 0.64 PEEP +1.5 +0.1 (6%) (12%) 2.1 5.5 +1.8 57.9 +44.2 2 (14%) 3 (21%) 21 d FiO 2 -driven- 3.2 0.40 11.2 0.22 15.8 0.41 3 0.58 0 PEEP +1.3 +2.9 +0.2 (30%) (0%) 1.8 5.3 93.9 +36.9 1 (12%) 0 (0%) 28 d FiO 2 -driven- 1.7 0.63 11.2 0.27 4.9 0.52 2 0.60 0 PEEP +2.9 +0.1 (40%) (0%) 2.2 4.5 +1.5 125.2 +75.1 3 (43%) 0 (0%) Figure shows the mean doses of opioids, midazolam and propofol used at each time of the study in milligrams per hour, and the number of patients requiring other sedatives and muscle relaxants. Data are presented as mean + standard deviation, except the marked ones with * that are presented as number of patients (percentage). Others: Expresses the number of patients requiring other sedatives used in the sedation of these patients, fentanyl, tramadol, Thalamonal (fentanyl-droperidol), etomidate. α Muscle relaxants: Expresses the number of patients requiring muscle relaxation by intravenous infusion. Abbreviations: h: hours; d: days.