Alveolar Recruiment for ARDS Trial

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1 Alveolar Recruiment for ARDS Trial Alexandre Biasi Cavalcanti HCor Research Institute For the ART Investigators

Trial Organization Coordination: HCor Research Institute (Sao Paulo, Brazil). Support: Brazilian Research in Intensive Care Network (BRICNet). Steering Committee: Alexandre Biasi Cavalcanti, Érica A.

2 Trial Organization Coordination: HCor Research Institute (Sao Paulo, Brazil). Support: Brazilian Research in Intensive Care Network (BRICNet). Steering Committee: Alexandre Biasi Cavalcanti, Érica A. Suzumura, Ligia N. Laranjeira, Denise M. Paisani, Lucas P. Damiani, Hélio P. Guimarães, Edson R. Romano, Maria M. Regenga, Luzia N. T. Taniguchi, Cassiano Teixeira, Roselaine P. Oliveira, Flavia R. Machado, Fredi A. Diaz-Quijano, Marcelo B. P. Amato, Otávio Berwanger, Carlos R. R. Carvalho. Data Monitoring Committee: Gordon Guyatt, Niall Ferguson, Stephen Walter. Funding: PROADI - Brazilian Ministry of Health.

3 Background Functional lung size is decreased in ARDS VILI overdistention and atelectrauma Open lung approach: lung recruitment maneuvers and titrated PEEP Systematic reviews suggest reduction in mortality

4 Background Intensive Care Med 2014;40:

6 Objective To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate-to-severe ARDS compared to a conventional low-peep strategy.

7 Design Moderate-severe ARDS <72 hours duration 3 hours under ARDSNet mechanical ventilation PaO 2 : FIO after 30 minutes with FiO 2 100% and PEEP 10cmH 2 O Central randomization Lung recruitment maneuver and titrated PEEP Low-PEEP (ARDSNet strategy) 28-day follow-up and 6-month follow-up

8 Low-PEEP group (ARDSNet) Mode: volume-controlled Tidal volume: 6mL/kg of PBW, (adjusted between 4 and 6 ml/kg) Plateau pressure 30cmH 2 O Respiratory rate up to 35 bpm PEEP and FiO 2 adjusted according to the ARDSNet table to maintain SpO 2 88 to 95% or PaO 2 55 to 80mmHg FiO 2 30% 40% 40% 50% 50% 60% 70% 70% 70% 80% 90% 90% 90% 100% PEEP

9 Airway pressure (cmh 2 O) Lung recruitment and PEEP titrated according to the best static compliance group Lung recruitment PEEP titration New recruitment P=15cmH 2 O Maintenance ventilation with optimal PEEP Time (minutes) Except for lung RM and titrated PEEP all other MV settings equal between groups

10 Outcomes Primary outcome 28-day mortality Secondary outcomes Length of ICU and hospital stay 28-day ventilator-free days Pneumothorax requiring drainage within 7 days Barotrauma within 7 days ICU, in-hospital and 6-month mortality

11 Statistical Analysis Sample size: Event driven trial 520 events (28-day deaths) 90% power to detect hazard ratio 0.75 with type I error of 5% Statistical analysis: Intention-to-treat principle Two interim analysis (DMC): significance level for final primary outcome analysis was Cox proportional hazards model for primary outcome (28-day mortality) and 6- month mortality Categorical outcomes: chi-squared tests Continuous outcomes: generalized linear models (with Gamma or Poisson distribution)

12 Sites 120 sites in 9 countries: Brazil, Argentina, Colombia, Italy, Malaysia, Poland, Portugal, Spain, Uruguay

13 Flow of patients 2077 Patients assessed for eligibility 1013 Randomized 863 Were ineligible 147 Eligible but were not enrolled 54 Excluded due to unknown reason 501 Allocated to receive lung recruitment maneuver and titrated PEEP 480 Received assigned treatment 21 Did not receive lung recruitment 14 Hypotension 3 Pneumothorax 4 Other reasons 0 Were lost to 28-day follow-up 501 Included in primary outcome analysis 512 Allocated to the low-peep 512 Received assigned treatment 3 Withdrew consent and were excluded from analysis 509 Included in primary outcome analysis

14 Baseline characteristics Characteristic Lung recruitment maneuver with PEEP titration group (n=501) Low-PEEP group (n=509) Age, mean (SD), y 51.3 ± ± 17.4 Female sex, % SAPS3 score 63.5 ± ± 18.1 No. of non-pulmonary organ failures 2.4 ± ± 1.2 Septic shock, % Cause of ARDS Pulmonary, % Extrapulmonary, % Prone position, % Time since onset of ARDS 22.5 ± ± 18.6

15 Tidal volume (ml/kg) Tidal volume Low-PEEP Lung recruitment and titrated PEEP 0 1h 1d 3d 7d

16 PEEP (cmh 2 O) PEEP Low-PEEP Lung recruitment and titrated PEEP 0 1h 1d 3d 7d

17 PaO 2 : FIO 2 PaO 2 :FIO Lung recruitment and titrated PEEP Low-PEEP 0 1h 1d 3d 7d

18 Driving pressure (cmh 2 O) Driving Pressure Low-PEEP Lung recruitment and titrated PEEP 0 1h 1d 3d 7d

19 Mortality, % Primary Outcome: 28-Day Mortality 75 4 th Day Lung recruitment and titrated PEEP 50 Low-PEEP 25 Hazard ratio, 1.20 (95% CI, 1.01 to 1.42); P= Days after randomization

20 Mortality, % 6-Month Mortality 75 Lung recruitment and titrated PEEP 50 Low-PEEP 25 0 Hazard ratio, 1.18 (95%CI, 1.01 to 1.38); P= Days after randomization

21 Secondary Outcomes Outcome Lung Recruitment and Titrated PEEP (n=501) Low-PEEP (n=509) Absolute Difference (95% CI) P value Pneumothorax requiring drainage within 7 Briel days, 2010: % % % 2.0 (0.0 to 4.0) 0.03 Barotrauma within 7 days, % (1.5 to 6.5) No. of ventilator-free days from day 1 to day 28, d 5.3 ± ± (-2.1 to -0.1) 0.03 Length of hospital stay, d 25.5 ± ± (-4.6 to 3.3) 0.74

22 Exploratory Outcomes Outcome Lung Recruitment and Titrated PEEP (n=501) Low-PEEP (n=509) Absolute difference (95% CI) Death within 7 days, % (0.6 to 12.2) 0.03 Death with refractory hypoxemia within 7 days, % (-4.9 to 2.8) 0.59 Death with refractory acidosis within 7 days, % (-1.7 to 6.8) 0.25 Death with barotrauma within 7 days, % (0.2 to 2.6) Commencement/increase of vasopressors or hypotension within 1 hour, % Briel 2010: 3.8% 3.5% P value (0.5 to 12.4) 0.03 Refractory hypoxemia (PaO 2 < 55mmHg) within 1 hour, % (-2.2 to 1.5) 0.81 Severe acidosis (ph < 7.10) within 1 hour, % (-2.0 to 6.5) 0.29

23 Effect on 28-Day Mortality in Subgroups Subgroup P Value for Interaction PaO2 : FIO2 100 mmhg 0.33 > 100 mmhg SAPS 3 < Type of ARDS Extrapulmonary 0.15 Pulmonary Duration of ARDS 36h 0.63 > 36h to <72h Position Supine 0.21 Prone Favors Low-PEEP Favors LR maneuver

24 Conclusions In patients with moderate-to-severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients.

vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome Published online

25 Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome Published online September 27, 2017 Available at jama.com and on The JAMA Network Reader at mobile.jamanetwork.com

26 Discussion.. What went Wrong??

Driving pressure (cmh 2 O) Driving Pressure 14.5 13.

28 Driving pressure (cmh 2 O) Driving Pressure Low-PEEP Lung recruitment and titrated PEEP 0 1h 1d 3d 7d

29 Relative Risk of Death in the Hospital versus ΔP in the Combined Cohort after Multivariate Adjustment. Amato MBP et al. N Engl J Med 2015;372:

30 Differences in P = 1.5 cmh 2 O ~ 6-7% reduction in relative risk Baseline mortality of 50% Treatment mortality ~47% Sample size = patients!

31 Four mistakes: 1. Effect-size vs. Sample Size 2. Control Group (back-fire) 3. Not-individualized (trully) 4. VCV during the long assisted-phase

32 The study design assumed a Hazard Ratio of 0.75 for the treatment arm. this would require differences in P = - 6 cmh 2 O ARMA 2000: Amato 1998: P = -8 cmh 2 O P = -14 cmh 2 O

33 LOW PEEP - ART day Alveoli Express Lovs ART (Low PEEP arm)

34 PEEP DAY 1 ALVEOLI day1 Alveoli Média = 8.9 FiO 2 day 1

35 PEEP PEEP DAY DAY 1 1 FiO day 1 EXPRESS day1 Média = 7.1

36 PEEP DAY 1 ART day1 (FIO 2 that should be used, according to ARDSNet table) PaO 2 80 PaO 2 > 80 PaO 2 > 150 FiO 2 day 1

AC Leme and coauthors Effect of Intensive vs Moderate Alveolar Recruitment Strategies Added to Lung-Protective Ventilation on Postoperative Pulmonary

37 AC Leme and coauthors Effect of Intensive vs Moderate Alveolar Recruitment Strategies Added to Lung-Protective Ventilation on Postoperative Pulmonary Complications: A Randomized Clinical Trial Published online March 21, 2017 Available at jama.com and on The JAMA Network Reader at mobile.jamanetwork.com jamanetwork.com

38 Open Chest Cardiac Surgery Coronary Artery Bypass Surgery Valvular repair Combined 85% of ECMO (~90 min)

Modified Score of Pulmonary Complications P = 0.

39 Modified Score of Pulmonary Complications P = Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 (No symptoms) ( Death ) Intensive-RS (N = 157) Moderate-RS (N = 163) Patients (%)

41 Day1 Art Lovs

42 Patient enrolled: set V T = 6 ml/kg High PEEP (~16 cmh 2 O) Breath stacked breaths : V T = ml/kg and P PLAT = 45cmH 2 O (Peak ~ 55 cmh 2 O) Paw (cmh 2 O) DZ (ml/kg) Flow (l/min) Volume (ml) * *: Ventilator display showing V T = 420 ml (~6 ml/kg) Time (min)

43 DZ (ml/kg) Flow (l/min) Paw (cmh 2 O) Patient ventilated with set V T = 6 ml/kg under Low PEEP Breath stacked breaths : V T = 12 ml/kg and P PLAT = 28 cmh 2 O Time (min)

44 DZ (AU) Flow (l/min) Paw (cmh 2 O) Patient ventilated with: V T = 6 ml/kg under High PEEP (~19 cmh 2 O) Breath stacked breaths generating V T = 15 ml/kg and P PLAT = cmh 2 O (Peak ~70 cmh 2 O) ml/kg 6 ml/kg Time (min)

46 And now?

47 ICU death - adjusted for baseline covariates prespecified (APACHE, age, P/F ratio, arterial ph)

51 Ki (min -1 ) Slice View High PEEP Group 1 st PET 2 nd PET Low PEEP Group 1 st PET 2 nd PET Coronal 18 F-FDG uptake scale Sagital Axial 0.000

52 RCT are bad to test isolated mechanisms, unless the expected effect-size is enormous... This is why we need predictive enrichment!!!

53 Thank you! Thanks the patients and families

54 P11A P12A P13A Methods P11P P12P P13P GROUPS P16A P15P SHAM VILI (3 hours) VILI + 40 hs of protective V (ARDSnet)

55 Lung recruitment Characteristic Lung Recruitment Maneuver with PEEP Titration Group (n=501) Maximum alveolar recruitment maneuver, % Completed 80.2 Interrupted 15.6 Not attempted 4.2 Reason for interrupting alveolar recruitment maneuver, % Hypotension 73.1 O 2 desaturation 20.5 Bradycardia or tachycardia (HR <60bpm or >150bpm) 2.6 Other 3.8 Titrated PEEP, cmh 2 O 16.8 Alveolar recruitment maneuver repeated between day 1 and day 7, No. of events(%) No 62.7 Once 19.0 Twice 9.2 Three or more times 9.2

56 Lung recruitment and PEEP titration before protocol changes

57 Effect on Subgroups Subgroup P Value for Interaction PaO2 : FIO2 100 mmhg 0.33 > 100 mmhg SAPS 3 < Type of ARDS Extrapulmonary 0.15 Pulmonary Duration of ARDS 36h 0.63 > 36h to <72h Position Supine 0.21 Prone Protocol modification Before 0.89 After

58 Effect on primary outcome, by site Effect by site

59 Learning curve Alveolar recruitment with titrated PEEP Low-PEEP Hazard ratio (95% CI) P First 6 center patients 50/105 (47.6%) 49/105 (46.7%) 1.09 (0.69 to 1.71) th to last center patient 145/255 (56.9%) 122/248 (49.2%) 1.26 (0.96 to 1.66)

60 Sensitivity Analyses 28-Day Mortality Cox proportional hazards model with adjustment for age, SAPS3, and PaO 2 :FIO 2 Hazard ratio, 1.22; 95% CI, 1.03 to 1.45; P=0.02. Post-hoc frailty Cox model Hazard ratio,1.21; 95% CI, 1.02 to 1.44; P=0.03.

61 Limitations Not blinded Subphenotypes not determined Response to a PEEP dose in both groups would allow subgrops analysis according to PEEP responsiveness Long duration (2011 to 2017) care of ARDS may have changed Complex intervention not possible to ascribe effects exclusively to lung recruitment maneuver or titrated PEEP

Driving Pressure. What is it, and why should you care?

Driving Pressure. What is it, and why should you care? Driving Pressure What is it, and why should you care? Jonathan Pak MD March 2, 2017 Lancet 1967; 290: 319-323 Traditional Ventilation in ARDS Tidal Volume (V T ) = 10-15 ml/kg PBW PEEP = 5-12 cm H 2 O