The document discusses the significance of driving pressure in the management of patients with acute respiratory distress syndrome (ARDS), emphasizing its correlation with survival outcomes. It presents a series of studies and observations that indicate the need to monitor driving pressure rather than solely relying on plateau pressure during mechanical ventilation. Key findings suggest that tidal volume does not act as a mediator in improving patient outcomes, which challenges traditional one-size-fits-all ventilation strategies.

1. Why Driving-Pressure Matters
Marcelo B. P. Amato
University of São Paulo, Brazil
DasSMACC, Berlin, June 2017

2. Special Article
Driving Pressure and Survival in the Acute
Respiratory Distress Syndrome
Marcelo B.P. Amato, M.D., Maureen O. Meade, M.D., Arthur S. Slutsky, M.D.,
Laurent Brochard, M.D., Eduardo L.V. Costa, M.D., David A.
Schoenfeld, Ph.D., Thomas E. Stewart, M.D., Matthias Briel, M.D., Daniel
Talmor, M.D., M.P.H., Alain Mercat, M.D., Jean-Christophe M. Richard, M.D.,
Carlos R.R. Carvalho, M.D., and Roy G. Brower, M.D.
N Engl J Med
Volume 372(8):747-755
February 19, 2015

3. São Paulo, Brazil

4. São Paulo, Brazil

5. São Paulo, Brazil
Leptospira Interrogans

6. Bleeding....

7. ?
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9. VOLUME 338 February, 5 NUMBER 6
1998

10. (cmH2O)
PDriving
(cmH2O)
PPlat Alv
(cmH2O)
Auto PEEP
CRS
(mL / cmH2O)
8.4
19.9
0.3
20.9
ΔP

12. Dreyfuss et al (1988) Am Rev Respir Dis;137: 1159-1164
Volutrauma or Barotrauma ?
Neither of both….
(Transpulmonary)
Driving
pressures !!

13. LIM 09 - HCFMUSP
Mental Experiment….
( Einstein’s elevator )

14. 35 cmH O2
P =p l
15
spulmonary:
20 cmH O2
P =p l
-5
35 cmH O2
Transpulmonary:
40 cmH O2
VT
CRS
DV
DV
DP
DP
VT = 400 mL VT = 400 mL
PTP = 4 PTP = 36
VT is
important?
Crs = 10Crs = 50 (CCW = 100)
Scale your VT….
VT = 400 mL
∆P = 8 cmH2O
VT = 400 mL
∆P = 40 cmH2O
Lung-size
ERS = EL+ ECW
( 1 / CRS) = (1 / CL) + (1 / CCW)
Patient 1: CL = 100; PL = 400/100 = 4 cmH2O
Patient 2: CL = 11; PL = 400 / 11 = 36 cmH2O
During controlled MV,
If ∆PL (Transpulmonary) increases,
Þ ∆P increases…..

15. LIM 09 - HCFMUSP
Anesthesia
Left-Lung
Ventilation
VT = 6 mL/kg
PPLAT = 29 cmH2O
PEEP = 0 cmH2O
DP = 29 cmH2O !!!!!

16. Amato et al.
1998
(N = 53)
Brochard et al.
Brower et al.
Stewart et al.
1998-1999
(N = 288)
ARDSnet
2000
(N = 861)
Alveoli
2004
(N = 545)
Express
LOVS
Talmor et al.
2008
(N = 1811)
TOTAL
2013
(N = 3562)
time1998 2012

17. Because of terrible offenses to God ,
Sisyphus was condemned to repeat forever
the same meaningless task of pushing an
enormous rock up a mountain, only to see it
roll down again…

18. 0 1 2 3 4 5
0
10
20
30
40
0 1 2 3 4 5
0
10
20
30
40
30
20
40
10
0
1.4
1
0.7
Airwaypressure(cmH2O)AdjustedRelatibveRisk)
N = 3080
MultivariateRisk

19. 123456
0
10
20
30
40
123456
0
10
20
30
40
30
20
40
10
0
1.4
1
0.7
Airwaypressure(cmH2O)AdjustedRelatibveRisk)
N = 3080
?

20. 0 1 2 3 4 5
0
10
20
30
40
0 1 2 3 4 5
0
10
20
30
40
?
30
20
40
10
0
1.4
1
0.7
Airwaypressure(cmH2O)AdjustedRelatibveRisk)
N = 3080
MultivariateRisk

21. 1. Cyclic vs. Absolute deformation
…watch your ∆P , not PPLAT

22. 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

23. 1. Cyclic vs. Absolute deformation
…watch your ∆P , not PPLAT
2. Pressure swings vs. Volume swings ?
( ∆P or ∆V ) ?

24. LIM 09 - HCFMUSP
Grafico driving pressure

25. LIM 09 - HCFMUSP
Grafico driving pressure

26. DRIVING-PRESSURE
5
10
15
20
25
30
35
PLATEAU-PRESSURE
0
5
10
15
20
25
30
35
RESAMPLING : MATCHED PPLAT , QUINTILES OF DP
0 1 2 3 4 5 6
RELATIVE-RISK(adjusted)
0.6
0.8
1.0
1.2
1.4
1.6
Plateau–Pressure
(cmH2O)
Resampling: matched PPLAT , decreasing quintiles of ∆P
Decreasing ∆P
P < 0.0001
?
Driving-Pressure
RelativeRisk
(multivariate)

27. TIDAL-VOLUME
4
6
8
10
12
14
PLATEAU-PRESSURE
0
5
10
15
20
25
30
35
RESAMPLING : MATCHED PPLAT , QUINTILES OF VT
0 1 2 3 4 5 6
RELATIVE-RISK(adjusted)
0.6
0.8
1.0
1.2
1.4
1.6
Resampling: matched PPLAT , decreasing quintiles of VT
Decreasing VT
P = 0.92
?
TIDAL-VOLUME
Plateau–Pressure
(cmH2O)
RelativeRisk
(multivariate)

28. P < 0.0001
Odds-ratioforBarotrauma
(adjusted*)
*: pre-adjusted for age, APACHE/SAPS risk, arterial-pH, P/F ratio and study-trial
(multivariate logistic regression where both ∆P and VT co-participate in Model-1)
Odds for Barotrauma across quintiles of ∆P or VT:
- Combined population of ARDS ( N = 3080 )
Figure 2d:
4 8 12 16 20 24 28
0.6
1.0
1.4
1.8
2.2
P < 0.0001
Driving-pressure (∆P, cmH2O)
Odds-ratioforBarotrauma
(adjusted*)
*: pre-adjusted for age, APACHE/SAPS risk, arterial-pH, P/F ratio and study-trial
(VT and ∆P co-participating in model-1 )
4 6 8 10 12
0.6
1.0
1.4
1.8
2.2
P = 0.87
Tidal-Volume (VT , mL/kg.PBW)
Odds-ratioforBarotrauma
(adjusted*)
*: pre-adjusted for age, APACHE/SAPS risk, arterial-pH, P/F ratio and study-trial
(VT and ∆P co-participating in model-1)
Driving-pressure (∆P, cmH2O)
4 8 12 16 20 24 28
Tidal-Volume (VT , mL/kg[PBW] )
4 6 12108
P < 0.0001 P = 0.87

29. DP = marker of severity of ALI ?
DP = DV
Crs

30. DP = disease-∆P + superimposed-∆P
LOW Crs Randomization
(changes in ventilator settings)
P < 0.0001 P < 0.0001
Mediation Analysis
- intuition -

31. related to
randomization
related to baseline
compliance
(severity of disease)
{
Highest decile
of compliance
{
Lowest decile2nd to 9th deciles…
25
45
5
Drivingpressure(cmH2O)
Control arm
Treatment
Average exposure to ΔP Observed Risk ( across decile
B. Variations in ΔP driven by differences in baseline lung compliance
A. The two main components of ΔP variation:
pliance
9
10
Treatment arm
Control arm
Lowest decile
of compliance 2nd to 9th deciles… Highest decile
P < 0.0001
related to
randomization
related to baseline
compliance
(severity of disease)
{
Highest decile
of compliance
{
Lowest decile2nd to 9th deciles…
25
45
5
Drivingpressure(cmH2O)
Control arm
Treatment
Average exposure to ΔP Observed Risk ( acros
B. Variations in ΔP driven by differences in baseline lung compliance
A. The two main components of ΔP variation:
pliance
9
10
Treatment a
Control arm
Lowest decile
of compliance 2nd to 9th deciles… Highest decile
P < 0.0
related to
randomization
related to baseline
compliance
(severity of disease){
Highest decile
of compliance
{
Lowest decile2nd to 9th deciles…
25
45
5
Drivingpressure(cmH2O) Control arm
Treatment
Average exposure to ΔP Observed Risk ( acros
B. Variations in ΔP driven by differences in baseline lung compliance
A. The two main components of ΔP variation:
nce
10
Treatment a
Control arm
Lowest decile
of compliance 2nd to 9th deciles… Highest decile
related to
randomization
related to baseline
compliance
(severity of disease){
Highest decile
of compliance
{
Lowest decile2nd to 9th deciles…
25
45
5
Drivingpressure(cmH2O) Control arm
Treatment
Average exposure to ΔP Observed Risk ( across d
B. Variations in ΔP driven by differences in baseline lung compliance
A. The two main components of ΔP variation:
liance
9
10
Treatment arm
Control arm
Lowest decile
of compliance 2nd to 9th deciles… Highest decile

32. Disciplina de Pneumologia - InCor HC FMUSP
Causality and Mediation

33. Causality
Cause Effect
• If the cause is withheld… Counterfactual outcome
(≠ real outcome)
No
effect
• Precedes the effect
Hernán MA & Robins JM . Causal Inference 2012

34. Lung transplantation for Mr. Marty
( performed 4 years ago )
Michael J. Fox
But what if he had not received the lung ??
He is alive today!!Dr. Emmett
(Christopher Lloyd)

35. Counterfactual outcome
2017
2013

36. Causality
Cause Effect
• Precedes the effect
• Counterfactual outcome ≠ Real outcome
Hernán MA & Robins JM . Causal Inference 2012
• But, in real life, there is only one
real outcome per individual….
No
effect
• Counterfact is not observable….

37. Average causal effect
Interchangeability Principle
( Simultaneous conterfactual outcome )
Hernan & Robins Causal Inference Chapman & Hall/CRC, 2015
Treatment Controls

38. Mediation
Hernan & Robins Causal Inference Chapman & Hall/CRC, 2015
Increase
PEEP
Improved
Oxygenation
Recruit
many alveoli
Mediator must be within the causal pathway....
Cause
(Intervention)
Mediator
Effect
Same causality principles....

39. Mediation
Hernan & Robins Causal Inference Chapman & Hall/CRC, 2015
Increase
PEEP
Improved
Oxygenation
Recruit
many alveoli
Cause
(Intervention)
Effect
Conterfactual:
No
effect
Mediator
What if the mediator was blocked (did not change) ?
No
recruitment
The only possibility:
Direct effect ?

40. Mediation
Hernan & Robins Causal Inference Chapman & Hall/CRC, 2015
Increase
PEEP
Recruit
many alveoli
Cause
(Intervention)
Effect
Conterfactual:
Mediator
What if the mediator was blocked (did not change) ?
No
recruitment
Preferentialy not !!
( Complete mediation )

41. Mediation
Hernan & Robins Causal Inference Chapman & Hall/CRC, 2015
Cause
(Intervention)
Effect
Conterfactual:
Mediator
What if the mediator was blocked (did not change) ?
Protective package:
• ¯VT
• ¯PPLAT
• ­PEEP
• ­RR
• ­PaCO2
Improved
Survival
Decrease in
∆P
How to block the
effects of mediator?
Randomization

42. Regression language
Pre-ajusting a survival regression model for a
covariate (e.g. the mediator, or ∆P)….
Is equivalent to observe…
The effects of an intervention (e.g. randomization)
in an alternative model where ∆P has the same
value for all individuals

43. Mediation
Cause
(Intervention)
Effect
Conterfactual:
Mediator
What if the mediator was blocked (did not change) ?
Direct effect ?
Protective package:
• ¯VT
• ¯PPLAT
• ­PEEP
• ­RR
• ­PaCO2
Improved
Survival
Decrease in
∆P
How to block the
effects of mediator?
Multivariate
Model
Preferentialy not !!
( Complete mediation )
Mediator

44. Lower ΔP
IC95%: 0.48 « 0.75; P < 0.0001
P = 0.004
P = 0.46 (N.S.)

45. Lower VT
RR = 0.59; P = 0.009
P = 0.67 (N.S.)

46. Conclusions:
1. Tidal Volume (VT ) did not work out as a
mediator in these trials!
2.A target-VT (PBW), is just good on average to
patients. But it is a “one-size-fits-all approach”
(potentially deleterious - nor optimized for
individuals)

47. 35 cmH O2
P =p l
15
spulmonary:
20 cmH O2
P =p l
-5
35 cmH O2
Transpulmonary:
40 cmH O2
VT
DP
VT = 400 mL VT = 400 mL
PTP = 5 PTP = 30
Crs = 10Crs = 50
How it works..….
Lung-size

48. Thank you !