PEEP after EPVent-2 & ART: Now What?!

Jeremy R. Beitler, MD, MPHCenter for Acute Respiratory FailureColumbia University

• Speaking fees from Hamilton Medical

• Research Funding:• NIH

• ATS Foundation

Disclosures

High vs. Low PEEP in ARDS

LOVS Trial. JAMA 2008ARDSNet ALVEOLI Trial. NEJM 2004

Respiratory Mechanics-based PEEP

Express Trial. JAMA 2008 ART Trial. JAMA 2017

PL = Pairway – Ppleural

Lung Mechanics-based PEEP

Beitler et al. Clin Chest Med. 2016;37:633-646

Could adjusting PEEP to maintain Pairway ≥ Ppleural prevent atelectrauma?

p = 0.13

Difference in 28d mortality after adjusting for APACHE-II:RR 0.46 (95%CI 0.19-1.0); p = 0.049

EPVent Trial

PES-guided PEEP vs. empiric low PEEP

EPVent-2 Trial

PES-guided PEEP vs. empiric high PEEP

What Happened?

If PL < 0 signifies atelectrauma, negligible difference over first few days in EPVent2

PL Separation in EPVent1 vs. EPVent2

EPVent2EPVent1

FiO2

Control Arm 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

EPVent PEEP 5 5-8 8-10 10 10-14 14 14-18 20-24

EPVent2 PEEP 5-10 10-18 18-20 20 20 20-22 22 22-24

EPVent2 Not a Validation Study of EPVent1

EPVent2 asked a different research question:PES-guided PEEP vs. empirical high PEEP

FiO2

Control Arm 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

EPVent2 PEEP 5-10 10-18 18-20 20 20 20-22 22 22-24

EPVent2 “Control” Arm Nothing Like Usual Care

LUNG-SAFEEPVent2 Control Arm

PEEP & ARDS Severity

Briel et al. JAMA. 2010;303:865-873

PaO2:FiO2 ≤ 200 mmHg PaO2:FiO2 201-300 mmHg

Possible InterpretationHigh PEEP (without aggressive decremental PEEP trial) is superior to low PEEP in moderate-severe ARDS

Following are preliminary results

Heterogeneity of Treatment Effect

1.0

0.8

0.6

0.4

0.2

0

6050403020100

1.0

0.8

0.6

0.4

0.2

0

6050403020100

PES-guided PEEP

Empirical PEEP

PES-guided PEEP

Empirical PEEP

P = 0.03 P = 0.08

Surv

iva

l Pro

ba

bili

ty

Time (days) Time (days)

Lower APACHE Higher APACHE

Test for interaction term: p < 0.01

Attributable Risk of Death in ARDS

Illness Severity

Pro

bab

ility

of

Dea

th

EPVent2 enrolled low PaO2:FiO2 (≤ 200)

• HTE analysis: benefit with lower APACHE

ARDS attributable risk

Non-ARDS attributable risk

0.2

0.4

0.6

0.8

1.0

• Sepsis• Baseline morbidity

Examples:

Attributable Risk of Death in ARDS

Illness Severity

Pro

bab

ility

of

Dea

th

EPVent2 enrolled low PaO2:FiO2 (≤ 200)

• HTE analysis: benefit with lower APACHE

ARDS attributable risk

Non-ARDS attributable risk

0.2

0.4

0.6

0.8

1.0

Attributable Risk of Death in ARDS

Illness Severity

Pro

bab

ility

of

Dea

th

EPVent2 enrolled low PaO2:FiO2 (≤ 200)

• HTE analysis: benefit with lower APACHE

ARDS attributable risk

Non-ARDS attributable risk

0.2

0.4

0.6

0.8

1.0

Possible InterpretationPES-guided PEEP improves survival when risk of death is mostly due to ARDS

HTE Analysis in ART

∆PAW and PL may yield Different PEEP values

Change in Airway Driving Pressure

Ch

ange

in E

nd

-exp

irat

ory

PL

-15 -10 0 +20

-15

-10

-5

0

+5

+20

+25

+15

+10

+25+5 +10 +15-5

ß = -0.13 (95% CI -0.31 to 0.05)P = 0.16R2 = 0.01

More work to be done

Back to Physiology

-10

0

10

20

30

P=0.56

PL values have Intrinsic MeaningP

L(c

m H

2O

)

PL at Total Lung Capacity in Health =20-25 cm H2O

Physiologic FRC

Normal end-insp. stress

-10

0

10

20

30

P=0.56

PEEP Competing EffectsP

L(c

m H

2O

)

6 ml/kg∆P 12

Atelectrauma

Overdistension

PL at Total Lung Capacity in Health =20-25 cm H2O

6 ml/kg∆P 12

6 ml/kg∆P 18 6 ml/kg

∆P 10

Prevent atelectrauma(PL end-exp)

Exacerbate overdistension(PL end-insp)

Physiologic FRC

Normal end-insp. stress

-10

0

10

20

30

P=0.56

PEEP Competing EffectsP

L(c

m H

2O

)Prevent atelectrauma

(PL end-exp)

Exacerbate overdistension(PL end-insp)

Atelectrauma

Overdistension

6 ml/kg∆P 18 4 ml/kg

∆P 126 ml/kg∆P 18 6 ml/kg

∆P 16

PL at Total Lung Capacity in Health =20-25 cm H2O

Physiologic FRC

Normal end-insp. stress

Ideal PEEP ≠ Higher PEEP

27

Ideal PEEP ≠ Lower PEEP

Ideal PEEP titration:Minimum Stress ApproachMust account for competing effects of mitigating atelectrauma and exacerbating overdistension with higher PEEP

Thank you

Jeremy R. Beitler, MD, MPH

jrb2266@cumc.columbia.edu

Additional Slides for Q&A

Separation in PEEP & PL in EPVent2

• Huge range in end-inspiratory PL

for a given…

• Plateau pressure

PL versus Plateau Pressure

Beitler et al. Crit Care Med. 2016;44:91-99.

PL versus Tidal Volume

Beitler et al. Crit Care Med. 2016;44:91-99.

• Huge range in end-inspiratory PL

for a given…

• Plateau pressure

• Tidal volume

PL versus Driving Pressure

Beitler et al. Crit Care Med. 2016;44:91-99.

• Huge range in end-inspiratory PL

for a given…

• Plateau pressure

• Tidal volume

• Driving pressure

Model Marginal R2 Variable of Interest P-value

Log(sRAGE) = Expiratory-PL + Day 14.2% Expiratory PL 0.04

Log(sRAGE) = Inspiratory-PL + Day 15.5% Inspiratory PL < 0.01

Log(sRAGE) = Inspiratory-PL +Expiratory-PL + Day

15.6% Inspiratory PL

Expiratory PL

< 0.010.50

Log(sRAGE) = dPL + Day 14.4% dPL 0.02

PL & Alveolar Epithelial Injury

Beitler, Talmor, for the EPVent2 Investigators. Unpublished data.

Log(sRAGE) = PEEP + Day 13.2% PEEP 0.41

Log(sRAGE) = Pplat + Day 13.4% Pplat 0.13

Log(sRAGE) = dPairway + Day 13.6% dPairway 0.06

• PEEP effect on atelectrauma trivial in non-ZEEP era• No trial has proven definitively one strategy is superior to another

• High PEEP better than low PEEP in moderate-severe ARDS• PES provides added safety assurance

• PES-guided PEEP improves survival when ARDS-attributable risk of death is high

Possible Interpretations

PL and Airway Opening Pressure

Pairway

Ppleural

Volume

Flow

Original data, unpublished. Courtesy of D Talmor.

Setting PEEP to PL

PES = 28 cmw

PAW = 17 cmwPAW

Flow

PES

PL

Flow = 0 L/min

PL = -11 cmw

PES = 31 cmw

PAW = 31 cmw

Flow = 0 L/min

PL = 0 cmw

Baseline On PES-guided PEEP Protocol

End-Inspiratory Values

PAW

Flow

PES

PL

Baseline On PES-guided PEEP Protocol

PES = 31 cmw

PAW = 31 cmw

Flow = 0 L/min

PL = 0 cmw

PES = 38 cmw

PAW = 46 cmw

Flow = 0 L/min

PL = 8 cmw

PL and Airway Opening Pressure

PAW

PES

Volume

Original data, unpublished. Courtesy of D Talmor.Slide courtesy of D. Talmor

Atelectrauma: Role for PEEP?

Beitler et al. Clin Chest Med. 2016;37:633-646.

Cressoni et al. AJRCCM. 2014;189:149-158.

Bilek et al. JAP. 2003;94:770-783.

• PEEP effect on atelectrauma trivial in non-ZEEP era• No trial has proven definitively one strategy is superior to another

Possible Interpretations

PEEP

Inju

ry d

ue

to

Ate

lect

rau

ma

0 5 10 15 20 25

Inju

ry d

ue

to

Ove

rdis

ten

sio

n

Lower APACHE ≤ 27(n = 99)

Higher APACHE > 27(n = 101)

P-value

Age 57 (42 to 67) 58 (47 to 67) 0.36

Weight, kg 85.4 (72.0 to 110.3) 77.8 (69.0 to 96.5) 0.02

Body mass index, kg/m2 31.1 (26.4 to 39.7) 28.3 (24.8 to 33.4) 0.01

APACHE-II 21 ± 4 33 ± 4 < 0.01

Vasopressors at baseline, no. (%) 45 (45.5%) 69 (68.3%) < 0.01

PaO2:FiO2 95 (75 to 132) 86 (69 to 119) 0.20

Airway driving pressure, cmH2O 13 (10 to 15) 13 (10 to 14) 0.80

PES at end-expiration, cmH2O 16 (12 to 19) 16 (13 to 18) 0.34

PL at end-expiration, cmH2O -1 (-4 to 2) -1 (-3 to 1) 0.81

Randomization to PES-guided PEEP 51 (51.5%) 51 (50.5%) 0.89

Heterogeneity of Treatment Effect

Differential Response to Treatment by Baseline Illness Severity in EPVent2

Lower APACHE Higher APACHE P for interactionPES-guided Empirical PES-guided Empirical

Mortality at day 28 8 (15.7) 13 (27.1) 25 (49.0) 17 (34.0) 0.04

Mortality at day 60 10 (20.0) 19 (39.6) 28 (54.9) 18 (36.0) < 0.01

Mortality at 1 year 14 (28.0) 22 (45.8) 30 (60.0) 22 (45.8) 0.02

Ventilator-free days* 21 (6 to 24) 17.5 (0 to 24) 0 (0 to 21) 17.5 (0 to 22) < 0.01

Shock-free days* 20 (11 to 23) 18 (0 to 22) 3 (0 to 18) 16 (0 to 20) < 0.01

Acute kidney injury requiring renal replacement therapy*

8 (15.7) 9 (18.8) 13 (25.5) 23 (46.0) 0.34

Data presented as no. (%) or median (IQR).

* Through day 28

Higher vs. Lower PEEP in Other Trials

47Briel et al. JAMA. 2010;303:865-873

PaO2:FiO2 ≤ 200 mmHg PaO2:FiO2 201-300 mmHg

Pro

bab

ility

of

Surv

ival

Ideal PEEP titrationMust account for competing effects of mitigating atelectrauma and exacerbating overdistension with higher PEEP

PEEP research:

where good

ideas go to

die.

Which PEEP strategy did

these fools attempt to study

this time?

Bring out your dead!

I’m not dead yet!