Sumit Ray

Senior Consultant & Vice-Chair

Critical Care & Emergency Medicine
Sir Ganga Ram Hospital
ARDS pathophysiology B Taylor Thompson et al. NEJM 2017;377:562-72.
 Mortality
Outcome
 Australian Epidemiologic study
A 28-day mortality rate of 32%
 Bersten AD, et al. Incidence of mortality of ALI and ARDS in three Australian States. AJRCCM
2002; 165:443-448

 European ALIVE Study Group

ICU mortality and hospital mortality 46% and 55% respectively
 Brun-Buisson C, et al. Epidemiology and outcome of ALI in European intensive care units:
results from the ALIVE study. Intensive Care Med 2004; 30:51-61

 LUNG SAFE Trial (5 continents,50 countries, 459 ICU’s)

Hospital mortality of 35% (Mild),40%(Moderate) & 46% (Severe)
Bellani et al. Epidemiology, patterns of care & mortality for patients of ARDS in ICU’s in 50
countries. JAMA 2016; 315(8) 788-800

-
 Baby Lung Concept
Recognised in mid-1980’s
 ARDS resulted in significant reduction in the amount of
normally aerated lung tissue
 But, with preserved areas of normal compliance  “The ‘baby
lung’ which was markedly over distended by high tidal
volumes”

Gattinoni L, Preseti A. The concept of ‘baby lung’

Intensive Care Med 1996; 17:555-75
Spectrum of Regional Opening Pressures
(Supine Position)
Opening
Pressure
Superimposed
Pressure Inflated 0

Small Airway 10-20 cmH2O

Collapse

Alveolar Collapse
(Reabsorption) 20-60 cmH2O

Consolidation 
= Lung Units at Risk for Tidal
Opening & Closure
(from Gattinoni)
 ARDS– Problems & concerns

Strain (stretch) due to over distension of compliant alveoli

leading to volutrauma. (Lung strain is the ratio of TV/FRC)
Shear stress due to complete closure & re-opening of non-
compliant alveoli (atelectrauma).
(Stress is defined as transpulmonary pressure at the end of inspiration (PTPinsp)

 High inspiratory pressures (Pplat) leading to barotrauma.

 Release of inflammatory mediators from lung (biotrauma)
 Leading to VILI(Ventilator induced lung injury)
VILI
10 university centers in the US
N =861

Labelled as Respiratory Management in Acute Lung Injury/ARDS Trial

(ARMA)

Conventional (429) Low VT (432)

Vt = 12 mls/kg Vt = 6 mls/kg
Pplat =<50cms of H2O Pplat =<30cms of H2O
PEEP based on protocol – up to 20 to 24
 ARDSnet Tidal Volume Study

Mortality: Other benefits:

Intervention group: 31% Lower duration of ventilation
Control group: 39.8% Lower incidence of non-lung
p Value: 0.007 organ failure days

NEJM 2000;342:1301-8.
Ventilator Strategies in ARDS
Objectives Strategies
Adequate ventilation of  Small V T (4-6ml/kg)
compliant alveoli  High RR (30/min)
without causing:  Allowing hypercapnia (?)
Volutrauma (PaCO2  80mm Hg)

Avoid Barotrauma
 Limit PPlat  30 cms H2O
 Pressure Control Ventilation
(± IRV) or Dual modes
PRVC/Autoflow(if needed)
From: Association Between Use of Lung-Protective Ventilation With Lower Tidal Volumes and Clinical
Outcomes Among Patients Without Acute Respiratory Distress Syndrome-A Meta-analysis
JAMA. 2012;308(16):1651-1659. doi:10.1001/jama.2012.13730

20 studies -1416 pts Low VT — 1406 pts Conventional vent

 Ventilator Strategies in ARDS
Recruitment Maneuver
Objectives Strategies
 Recruitment- opening up Recruitment maneuvers
closed, non-compliant  30-40cms CPAP for 30-40 secs
alveoli
 Series of PCV breaths-Phigh 40-
 Recruitment potential is
highest in early phase & in 50 cm H2O & PEEP of 20-35
extra pulmonary ARDS cm H2O for 2 mins
 Series of large VT=12-15 ml/kg
for 2 mins
 CT-Scan method
Recruitable lung
6 Trials = 1423 pts

Mortality
 Oxygenation

Rescue Therapies

Barotrauma
2016
 PCV at RR of 10/min

2 mins PEEP =45

Ventilator strategies in ARDS

 Objectives  Strategies
 Stop De-recruitment of  Titrated PEEP
recruited alveoli(open  Incremental in PEEP
lung), thus avoiding ‘shear
stress’(atelectrauma)  Decremental steps of PEEP
 LIP method (Amato)
 ARDS Net table
 CT scan method
 USG method
 Open Lung Ventilation Strategy
Zone of Overdistention
Volume

Safe
window

Zone of
Derecruitment
and
atelectasis

Goal is to avoid injury zones

and operate in the safe window Pressure

Froese, CCM, 1997

Adjusting PEEP
ARDS Network study
 Fixed combinations of FiO2 and PEEP
 Arterial Oxygenation Goal: PaO2=55-80
mmHg or SpO2=88-95%
FiO2 PEEP FiO2 PEEP
0.3 5 0.7 12
0.4 5 0.7 14
0.4 8 0.8 14
0.5 8 0.9 14
Brower et. 0.5 10 0.9 16
ARDS Network
NEJM
0.6 10 0.9 18
2000;342:1301- 0.7 10 1.0 20-24
1308
 Moderate/Severe ARDS Mild
Better survival

Less Rescue Therapies with High PEEP in moderate-severe ARDS

 RCT =120 ICU’s= 1010 pts
INTERVENTIONS:
Experimental group-- Lung recruitment maneuver and PEEP titration according to the
Best CRS (n = 501;) or a Control strategy of low PEEP (n = 509).
Recruitment maneuver of 45 cms H2O of PEEP → ↓ed to 35 cms later
“…an unfavorable balance between potential positive (reduction in ∆P)
and negative (increase in overdistention, hemodynamic impairment)
physiological consequences of lung recruitment and PEEP.”
“….we hypothesized that normalizing VT to CRS and using the ratio as an index
indicating the “functional” size of the lung would provide a better predictor of
outcomes in patients with ARDS than VT alone.
This ratio, termed the driving pressure (ΔP = VT/CRS).”
Derivation cohort=336 pts
Validation cohort =861 pts
Re-validation = 2365 pts
 14

RESULTS
-Among ventilation variables, ΔP was most strongly associated with survival.
- A 1-SD increment in ΔP (≈ 7 cm of H2O) was associated with increased mortality
(RR = 1.41; 95% CI 1.31 to 1.51; P<0.001),
-Even in patients receiving ―protective‖ plateau pressures and VT (RR= 1.36; 95% CI,
1.17 to 1.58; P<0.001).
-Individual changes in VT or PEEP after randomization were not independently
associated with survival; they were associated only if they were among the changes that
led to reductions in ΔP
Prone Position
 ↓ Strain
Shape Matching & Sponge Theory
Methods: 24 ARDS pts on MV with 6ml/kg PBW underwent whole lung
CT-Scans at breath-holding pressures of 5, 15 & 45 cms of H2O at PEEP of
5 & 15 cms in Supine & Prone positions →RM performed (45 cms of H2O)
before each PEEP change

Lung recruitability was defined as the difference in % of non-aerated

tissue between 5 and 45 cm H2O.
Cyclic recruitment/de-recruitment was determined by tidal changes in
% of non-aerated lung tissue
Tidal hyperinflation was determined by % of hyper-inflated lung
Results:
Supine position →↑ing PEEP from 5 to 15 cmH2O,↓non-aerated
tissue(501 to 322 gms) (P<0.001) but, ↑ tidal-hyperinflation (0.41 to
0.57 %; P=0.004)

Prone positioning further ↓ non-aerated tissue (322 to 290 gms)

(P=0.028) & ↓ tidal hyperinflation observed at PEEP 15 in supine pts

Cyclic recruitment/de-recruitment ↓ only when high PEEP & prone

positioning were applied together (4.1 to 2.9%; P= 0.003)
 Prone Position- Initial studies
 Improves oxygenation
 Allows ventilation with lower V T, pressures, FiO2
 Drainage of secretions
 Rise in PaO2 sustained after return to supine
 Problems
 Pressure ulcers, facial edema
 Lines, tubes
 CPR
 20% patients are non-responders
 Does not improve outcome in ARDS

Gattinoni et al
NEJM 2001;345:568-73.
Difference in Survival: Prone vs Supine
 PROSEVA trial

Prone= 237 / Supine=229

Damned if you do & damned if
you don’t?!
Benefits of spontaneous breathing during
invasive mechanical ventilation
 Diaphragm muscle tone:
Controlled MV → diaphragmatic muscle dysfunction & atrophy →
detectable within 18 hrs

 Pulmonary Function:
- Spontaneous breathing ↑ aeration in dependent lung , as well as ↑
lung perfusion
- Intrapulmonary shunt is ↓, V/Q matching and oxygenation ↑

 Cardiovascular Effects:
- CMV ↓ transvascular pressure & ventricular preload & afterload.
- Spontaneous breathing– does just the opposite → may ↑ or↓ CO
depending on ventricular contractility & volume status
Spontaneous Breathing Causes Injury during
Mechanical Ventilation!
 Experimental studies: mechanically ventilated rabbits with
established lung injury → vigorous spontaneous effort did not
change Pplat but did worsen injury

 “Strong spontaneous effort can injure not only the injured

lung but also the diaphragm.”*

 RCT’s support this concept in demonstrating that NM blockade

(to prevent spontaneous effort) results in improved lung function,
and increased survival in severe ARDS. **

*Goligher et al: Evolution of diaphragm thickness during mechanical ventilation: impact of

inspiratory effort. AJRCCM 2015;192:1080–1088
** Papazian et al, ACURASYS Study Investigators. Neuromuscular blockers in early ARDS N Engl J
Med 2010;363:1107–1116.
Mechanisms of Injury from Spontaneous Breathing

 Increased Lung Perfusion

 Distending Pressure & ↑Tidal Volumes

 Patient–Ventilator Asynchrony
 Increased Lung perfusion & distending pressures
Mechanical Breath Spontaneous effort

Transpulmonary pressure
(Paw-Ppl = PL)= 30-10 =20 Transpulmonary pressure
(Paw-Ppl = PL)= 30+20 =50

Transvascular pressure Transvascular pressure

(Pcap-Ppl) is low (12- 10 = 2) (Pcap-Ppl) = 8-(-20) = 28
Spontaneous effort and distribution of regional
ventilation and pleural pressure
Aerated Lung Aerated Lung Partially aerated

Insp Pl Pressure

End-expiration End-Inspiration-Spontaneous Breathing

The ―swing‖ in regional Ppl is 2-fold greater than the ―swing‖ in Pes
→indicating that diaphragm contraction results in greater distending
pressure applied to the regional lung near the diaphragm, compared with the
pressure transmitted to the remainder of the lung (i.e., Pes).
Mechanisms of Injury from Spontaneous Breathing
 In the healthy lung, changes in local Ppl, are evenly
transmitted across the lung surface; this phenomenon is
called “fluid-like” behavior

 In contrast, injured lungs exhibit “solid-like” behavior,

where a non-aerated lung region impedes the rapid
generalization of a local change in Ppl→ the lung expansion is
heterogeneous
Mechanisms of Injury from Spontaneous Breathing
 Patient–Ventilator Asynchrony

 “Double triggering”- occurrence of two consecutive inspirations after

a single respiratory effort→ leads to higher VT (> 150% of preset VT)

 “Reverse triggering” (entrainment) - in which the diaphragm is

“triggered” by ventilator-driven inspiration

More severe the ARDS, more chances of further injury with

spontaneous breathing.

Mild ARDS possibility of better lung functions with spontaneous

breathing
 Concept of mechanical power & ergotrauma

Where RR is the respiratory rate, ΔV is the tidal volume, ELrs is the

elastance of the respiratory system, I:E is the inspiratory-to-expiratory
time ratio, and Raw is the airway resistance.
The potential for mechanical power to inflict lung damage is conditional upon
multiple factors:
1. Mechanical heterogeneity of the tissue/local amplification
2. Size (capacity) of the baby lung;
3. Elasticity of the chest wall;
4. Maximal tidal stress
5. Magnitude of dynamic strain per cycle;
6. Size-adjusted driving power (plateau-PEEP) x VE x (Cexpected/Cobserved)
7. Maximum transpulmonary pressure achieved per cycle
8. Respiratory rate (RR)
9. Flow rate and contour of the delivered breath
10.PEEP level
 Extracorporeal Membrane Oxygenation

The idea is to use the extracorporeal gas-exchange to reduce VT

to ―supra-lung protective ventilation‖
Methods: UK-based multicenter trial; 180 pts, Randomized 1:1(July 2001-August 2006)
Conventional ARDS management vs Referral to ECMO

123 ECMO pts → Propensity score matching of 52 pts

Mortality did not differ between the two matched cohorts (OR= 1.48;CI, 0.68–3.23

4 RCT’s (3 with low risk of bias) =389 pts→“No statistically

significant differences in all-cause mortality at six months…..
 EOLIA Trial

Randomly assigned patients with very severe ARDS, as indicated by

one of 3 criteria —
1. PaO2/FiO2 ratio ≤ 50 mm Hg ≥ 3 hours;
2. PaO2/FiO2 < 80 mm Hg for >6 hours or
3. An ABG pH <7.25 with a PaCO2 ≥ 60 mm Hg for > 6 hours — to
receive immediate veno-venous ECMO (ECMO group) or
continued conventional treatment (control group).
Extracorporeal CO2 removal devices
Thank you!
Driving Pressures

???
Extracorporeal CO2 removal devices
Thank You!
Stress was defined as transpulmonary pressure at the end of inspiration
(PTPinsp)
Strain as the relation between TV/EELV
Atelectrauma as the difference between non-aerated lung during inspiratory
and expiratory pause in the CT scan.

DPA (Driving Pressure-Airway) = PPlat – PEEP

DPL (Driving Pressure-Lung) = PTPinp – PTPexp
459 ICUs from 50 countries across 5 continents. LUNG-SAFE Trial
RESULTS: 29 144 pts admitted, 3022 (10.4%) fulfilled ARDS criteria → 2377 pts
managed with invasive mechanical ventilation.
Methods: In a proof-of-concept study. 10 patients with lung injury & a VT > 8
ml/kg under PSV & sedation. After baseline measurements, rocuronium titrated to a
target VT of 6 ml/kg during NAVA→ patients were ventilated in PSV and NAVA
under continuous rocuronium infusion for 2 hrs
Methods: Secondary analysis of data from 787 ARDS patients enrolled in two
independent RCT’s- PROSEVA & ACURASYS

Results: Colinearity between ΔP, Crs and Pplat, which was expected as these
variables are mathematically coupled, was statistically significant.
Hazard ratios from the Cox models for day-90 mortality were :
ΔP = 1.05 (1.02–1.08) (P = 0.005),
Pplat = 1.05 (1.01–1.08) (P = 0.008)
Crs = 0.985 (0.972–0.985) (P = 0.029)
PEEP and VT were not associated with death in any model.

Conclusions: When ventilating patients with low VT , ΔP is a risk factor

for death in ARDS patients, as is Pplat or Crs.
 Driving Pressure Mechanical Power

15 cms of H2O ≤ 15 J /min

26 cms of H2O 26 ml/cms of H2O

Plateau Pressure CRS

Adjusted 90 day mortality Cut- off for survival

 Permissive Hypercapnia?
Secondary analysis of 3 prospective non-interventional cohort studies focusing
on ARDS patients from 927 intensive care units (ICUs) in 40 countries- 1899 pts
Mortality was higher even after adjusting for age, SAPS II score, RR,
PEEP, PaO2/FiO2 ratio, ∆P, Protective lung strategy, corrected minute
ventilation, and presence of acidosis
Probable causes:
1.Hypercapnia impairs innate immunity
2.Hemodynamic consequences like ↑ PA pressures & worsening RV
function are associated with worse outcomes in patients with ARDS

“Overall, the data reported here may serve as a first step towards defining
possible limits for hypercapnia. In the absence of strong evidence, our
findings may provide some guidance for reasonable limits of PaCO2 for
ARDS patients in the ICU and also for potential reassessment of the
previous assumption that severe hypercapnia is safe.”