Alveolar Recruiment for ARDS TrialAlexandre 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. 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, OtávioBerwanger, Carlos R. R. Carvalho.

• Data Monitoring Committee: Gordon Guyatt, Niall Ferguson, Stephen Walter.

• Funding: PROADI - Brazilian Ministry of Health.

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

Background

Intensive Care Med 2014;40:1227–1240

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.

Design

Lung recruitment maneuver and titrated

PEEP

Central randomization

28-day follow-up and 6-month follow-up

Low-PEEP (ARDSNet strategy)

Moderate-severe ARDS <72 hours’ duration

3 hours under ARDSNet mechanical ventilation

PaO2 : FIO2 ≤ 200 after 30 minutes with FiO2

100% and PEEP≥10cmH2O

Low-PEEP group (ARDSNet)

• Mode: volume-controlled

• Tidal volume: 6mL/kg of PBW, (adjusted between 4 and 6 mL/kg)

• Plateau pressure ≤30cmH2O

• Respiratory rate up to 35 bpm

• PEEP and FiO2 adjusted according to the ARDSNet table to maintain SpO2 88 to 95% or PaO2 55 to 80mmHg

FiO2 30% 40% 40% 50% 50% 60% 70% 70% 70% 80% 90% 90% 90% 100%

PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24

Lung recruitment and PEEP titrated according to the best static compliance group

Time (minutes)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

70

60

50

40

30

20

10

0

Air

way

pre

ssu

re(c

mH

2O

)

25

3035

23

P=15cmH2O

PEEP titrationNew

recruitment

Maintenance ventilation with optimal PEEP

2017

14

Lung recruitment

11

35

Except for lung RM and titrated PEEP all other MV settings equal between groups

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

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

0.042• 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)

Sites

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

Flow of patients

2077 Patients assessed for eligibility

1013 Randomized

863 Were ineligible147 Eligible but were not enrolled54 Excluded due to unknown reason

512 Allocated to the low-PEEP

512 Received assigned treatment501 Allocated to receive lung recruitment maneuver

and titrated PEEP 480 Received assigned treatment

21 Did not receive lung recruitment14 Hypotension3 Pneumothorax4 Other reasons

501 Included in primary outcome analysis

0 Were lost to 28-day follow-up

509 Included in primary outcome analysis

3 Withdrew consent and were excluded from analysis

Baseline characteristics

CharacteristicLung recruitment maneuver

with PEEP titration group (n=501)

Low-PEEP group(n=509)

Age, mean (SD), y 51.3 ± 17.4 50.6 ± 17.4

Female sex, % 37.5 37.5

SAPS3 score 63.5 ± 18.1 62.7 ± 18.1

No. of non-pulmonary organ failures 2.4 ± 1.2 2.4 ± 1.2

Septic shock, % 67.1 65.0

Cause of ARDS

Pulmonary, % 62.5 61.5

Extrapulmonary, % 37.5 38.5

Prone position, % 10.2 9.9

Time since onset of ARDS 22.5 ± 19.1 22.0 ± 18.6

Tidal volume

5.0

5.2

5.4

5.6

5.8

6.0

6.2

6.4

6.6

0 1h 1d 3d 7d

Tid

alvo

lum

e (m

l/kg

)

Lung recruitment and titrated PEEP

Low-PEEP

PEEP

89

101112131415161718

0 1h 1d 3d 7d

PEE

P (

cmH

2O

) Lung recruitment and titrated PEEP

Low-PEEP

PaO2 : FIO2

100

120

140

160

180

200

220

240

260

280

0 1h 1d 3d 7d

PaO

2:F

IO2

Lung recruitment and titrated PEEP

Low-PEEP

Driving Pressure

10.5

11.5

12.5

13.5

14.5

0 1h 1d 3d 7d

Dri

vin

gp

ress

ure

(cm

H2O

)

Lung recruitment and titrated PEEP

Low-PEEP

Primary Outcome: 28-Day Mortality

0

25

50

75

0 4 8 12 16 20 24 28

Days after randomization

Mo

rtal

ity,

%

Lung recruitment and titrated PEEP

Low-PEEP

Hazard ratio, 1.20 (95% CI, 1.01 to 1.42); P=0.041

4th Day

6-Month Mortality

0

25

50

75

0 30 60 90 120 150 180

Days after randomization

Mo

rtal

ity,

%

Lung recruitment and titrated PEEP

Low-PEEP

Hazard ratio, 1.18 (95%CI, 1.01 to 1.38); P=0.04

Secondary Outcomes

OutcomeLung Recruitment and Titrated PEEP

(n=501)

Low-PEEP (n=509)

AbsoluteDifference

(95% CI)

P value

Pneumothorax requiring drainage within 7 days, % 3.2 1.2 2.0 (0.0 to 4.0) 0.03

Barotrauma within 7 days, % 5.6 1.6 4.0 (1.5 to 6.5) 0.001

No. of ventilator-free days from day 1 to day 28, d 5.3 ± 8.0 6.4 ± 8.6 -1.1 (-2.1 to -0.1) 0.03

Length of hospital stay, d 25.5 ± 32.3 26.2 ± 31.7 -0.7 (-4.6 to 3.3) 0.74

Briel 2010: 7.7% 6.5%

Exploratory Outcomes

Outcome

Lung Recruitment and

Titrated PEEP (n=501)

Low-PEEP (n=509)

Absolutedifference(95% CI)

P value

Death within 7 days, % 31.9 25.5 6.4 (0.6 to 12.2) 0.03

Death with refractory hypoxemia within 7 days, % 9.0 10.0 -1.0 (-4.9 to 2.8) 0.59

Death with refractory acidosis within 7 days, % 13.6 11.0 2.6 (-1.7 to 6.8) 0.25

Death with barotrauma within 7 days, % 1.4 0.0 1.4 (0.2 to 2.6) 0.007

Commencement/increase of vasopressors or hypotension

within 1 hour, %34.8 28.3 6.5 (0.5 to 12.4) 0.03

Refractory hypoxemia (PaO2 < 55mmHg) within 1 hour, % 1.6 2.0 -0.4 (-2.2 to 1.5) 0.81

Severe acidosis (pH < 7.10) within 1 hour, % 13.1 10.9 2.2 (-2.0 to 6.5) 0.29

Briel 2010: 3.8% 3.5%

Effect on 28-Day Mortality in Subgroups

Subgroup P Value for Interaction

PaO2 : FIO2

≤ 100 mmHg 0.33

> 100 mmHg

SAPS 3

< 50 0.42

≥ 50

Type of ARDS

Extrapulmonary 0.15

Pulmonary

Duration of ARDS

≤ 36h 0.63

> 36h to <72h

Position

Supine 0.21

Prone

0.33 0.50 0.75 1.00 1.25 2.00 3.00

Favors Low-PEEPFavors LR maneuver

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.

Available at jama.com and on The JAMA Network Reader at

mobile.jamanetwork.com

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

Discussion…..

What went Wrong ??

Driving Pressure

10.5

11.5

12.5

13.5

14.5

0 1h 1d 3d 7d

Dri

vin

gp

ress

ure

(cm

H2O

)

Lung recruitment and titrated PEEP

Low-PEEP

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;372:747-755

Differences in ∆P = 1.5 cmH2O

→ ~ 6-7% reduction in relative risk

Baseline mortality of 50%

→ Treatment mortality ~47%

→ Sample size = 12.000 patients!

Four mistakes:

1. Effect-size vs. Sample Size

2. Control Group (back-fire)

3. Not-individualized (trully)

4. VCV during the long assisted-phase

The study design assumed a Hazard Ratio of 0.75

for the treatment arm….

→ this would require differences in ∆P = - 6 cmH2O

ARMA 2000: ≠∆P = -8 cmH2O

Amato 1998: ≠∆P = -14 cmH2O

LOW PEEP - ART – day 1

ART (Low PEEP arm)

Alveoli Express Lovs

25

15

10

5

20

0

AlveoliMédia = 8.9

FiO2 – day 1

ALVEOLI– day1

PEE

P –

DA

Y 1

Média = 7.1P

EEP

–D

AY

1

FiO2 – day 1

EXPRESS– day1

PEE

P –

DA

Y 1

FiO2 – day 1

PaO2 > 80PaO2 ≤ 80

PaO2 > 150

ART – day1(FIO2 that should be used, according to ARDSNet table)

PEE

P –

DA

Y 1

jamanetwork.com

Available at jama.com and on The JAMA Network Reader at mobile.jamanetwork.com

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

Open Chest Cardiac Surgery

• Coronary Artery Bypass Surgery

• Valvular repair

• Combined

• 85% of ECMO (~90 min)

Grade 3 Grade 4 Grade 5 Grade 0 Grade 1 Grade 2

55 75 20 4

41 79 35 8

3

Patients (%)

0 20 40 60 80 100

Modified Score of Pulmonary Complications

(No symptoms) ( Death )

Moderate-RS(N = 163)

Intensive-RS(N = 157)

P = 0.003

Day1

Art Lovs

0.5 0.6 0.7 0.8

10

30

50

Pa

w (

cm

H2O

)

0.5 0.6 0.7 0.8-1

00

05

0

Flo

w (

l/m

in)

0.5 0.6 0.7 0.8

-20

02

00

Vo

lum

e (

ml)

0.5 0.6 0.7 0.8

05

10

15

Time (min)

DZ

(m

l/kg

)

Patient enrolled: set VT = 6 mL/kg – High PEEP (~16 cmH2O)Breath stacked breaths : VT = 10-12 mL/kg and PPLAT = 45cmH2O (Peak ~ 55 cmH2O)

*

*: Ventilator display showing VT = 420 mL (~6 mL/kg)

4.8 4.9 5.0 5.1 5.2

10

15

20

25

30

Pa

w (

cm

H2O

)

4.8 4.9 5.0 5.1 5.2

-40

-20

02

0

Flo

w (

l/m

in)

4.8 4.9 5.0 5.1 5.2

02

46

81

2

Time (min)

DZ

(m

l/kg

)

Patient ventilated with set VT = 6 mL/kg – under Low PEEPBreath stacked breaths : VT = 12 mL/kg and PPLAT = 28 cmH2O

0.8 1.0 1.2 1.4 1.6 1.8 2.0

02

04

06

080

Pa

w (

cm

H2O

)

0.8 1.0 1.2 1.4 1.6 1.8 2.0

-60

-20

02

04

0

Flo

w (

l/m

in)

0.8 1.0 1.2 1.4 1.6 1.8 2.0

-10

010

20

30

Time (min)

DZ

(A

U)

6 mL/kg

15 mL/kg

Patient ventilated with: VT = 6 mL/kg – under High PEEP (~19 cmH2O)Breath stacked breaths generating VT = 15 mL/kg and PPLAT = 45-50 cmH2O (Peak ~70 cmH2O)

And now?

ICU death - adjusted for baseline covariates prespecified

(APACHE, age, P/F ratio, arterial pH)

1st PET 2nd PET

Sagital

Coronal

Axial

Slice ViewHigh PEEP Group

1st PET 2nd PET

Low PEEP Group

0.022

Ki (m

in-1

)

0.000

18F-FDG

uptake scale

RCT are bad to test isolatedmechanisms,

unless the expected effect-size isenormous...

This is why we need predictiveenrichment!!!

Thank you !

Thanks the patients and families

P11P P12P P13PP11A P12A P13A

GROUPS

Methods

P16A P15P

SHAM

VILI(3 hours)

VILI+

40 hs of

protective V

(ARDSnet)

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

O2 desaturation 20.5

Bradycardia or tachycardia (HR <60bpm or >150bpm) 2.6

Other 3.8

Titrated PEEP, cmH2O 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

Lung recruitment and PEEP titration – before protocol changes

Effect on Subgroups

Subgroup P Value for Interaction

PaO2 : FIO2

≤ 100 mmHg 0.33

> 100 mmHg

SAPS 3

< 50 0.42

≥ 50

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

0.33 0.50 0.75 1.00 1.25 2.00 3.00

Effect on primary outcome, by site

Effect by site

Learning curve

Alveolar recruitmentwith 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) 0.540

7th to last center patient 145/255 (56.9%) 122/248 (49.2%) 1.26 (0.96 to 1.66)

Sensitivity Analyses

28-Day Mortality

• Cox proportional hazards model with adjustment for age, SAPS3, and PaO2:FIO2

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.

Limitations

• Not blinded

• Subphenotypes not determined

• Response to a PEEP dose in both groups – would allow subgropsanalysis 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