Acute Respiratory Distress SyndromeHas management changed in the last Decade?

Ram E. Rajagopalan,MBBS, AB (Int Med) AB (Crit Care)

Head, Department of Critical Care MedicineSUNDARAM MEDICAL FOUNDATION

Chennai

CT Ratio <.55

X-Ray in Early ARDS

Homogeneous pulmonaryinfiltrates

Non-central distributionof oedema

Normal cardiac size

Pl. effusion

CT in Early ARDS

Maunder et al. JAMA 1986; 255:2463-5.Gattinoni et al. Intensive Care Med. 1986; 12: 137-42.

“Preservation of normallung regions”

Pulmonary edema

Dependent collapse

A thirty-year-old observation

“It is Sponge Lung!!”

“Sponge Lung”* Gravity dependent atelectasis

Lung superimposedpressure

Density x h

h

*Int Care Med 1986; 12: 137-42.**AJRCCM 2002; 165: 1647–53.

The “Baby lung”

Unaerated segments distend poorly High pressure Slow response

Normal lung segments may be over-inflated when ventilated with traditional tidal volumes

ARDS Lung has “normal” & unaerated / partially aerated alveoli

“Normal” segments inflate easily

Tidal Volume in ARDSLow (6cc / Kg) vs. ‘traditional’ (12 cc/Kg)

N Engl J Med 2000; 342: 1301-8.

n = 432 vs. 429

P-V relationship in ARDS

Pressure

Volume

LIP

UIP

Beside avoiding large Vt……

Alveolar Collapse

Pressure

Volume

“Volutrauma & Atelectrauma”

Non-dependent bullae areprobably due to alveolaroverdistension

Dependent bullae are dueto alternating opening &closing of the airway

Gattinoni et al. AJRCCM 2001; 164: 1701-11.

Pressure

Volume PEEP LIMIT Pr. or Vol.

Limiting Injury: “Lung Protective Ventilation”

ARDSnet: High vs. Low PEEP

NEJM 2004; 351: 327-36.

FiO2 LoPEEP HiPEEP0.3 5 140.4 5 14-160.5 8-10 15-18-200.6 10 200.7 12-14 200.8 14 20-220.9 14-18 221.0 18-24 22-24

1.0

0.5

00 10 20 30 40 50 60

Prob

abili

ty

Days

Survival

Discharge

1.0

0.5

00 10 20 30 40 50 60

1.0

0.5

00 10 20 30 40 50 60

Prob

abili

ty

Days

Survival

Discharge

n = 549

Variability in Recruitable Lung

*AJRCCM 2005; 171: 1002-1008.

The “anatomical” (CT) extent of potentially recruitable lung is very variable

Supports prior physiological studies*

A B

0

5

10

15

20

25

-5 0 5 10 15 20 25 30 35 40 45 50 55 60

A B

n

Recruitable lung (% of total)

N Engl J Med 2006;354:1775-86.

Problems with ARDSnet approach

PEEP

Significant“Recruitable”Lung volume

Sparse“Recruitable”Lung volume

Opens alveoliBenefits patient

Hyperinflates lungHarms patient

No Effect; a l’ARDSnet

Identification ofthe potentiallyrecruitable ARDSlung becomes important

Heterogeneous effect of Paw Ptp (not Pairway ) correlates c EELV

A uniform airway pressure causes heterogeneous lung expansion because of pleural pressure D

The range of Ppleura J with lung injury

May result in significant over-distension of the ventral lung (A)

_

Homogenize the Lung!

If the alveolar distension is made more homogeneous……

…K PEEP induced asymmetrical expansion

The Prone Position

Supine Prone

Prone Position Improves Oxygenation

Rajagopalan et al; Ind. J. Crit. Care Med. 1999; 3(1): 73-5. 0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

3 0 0

3 5 0

Pre P = 0.0232 Best Prone

83.8 + 27.3 torr 160.9 + 75.6 torr

PaO

2 / F

iO2 R

atio

Deforming Pressures in ARDS

LungSuperimposed

Pressure

But….Superimposed pressureis altered by…..

Deforming Pressures in ARDS

Heart & Mediastinum

Abdominal contents & caudal diaphragm;

“Pincers”

Effect of Heart & Mediastinum

AJRCCM 2000;161:1660-5

The weight of the heart and mediastinum exaggerates the gravitational collapse esp. on the left lung

In the prone position the entire mass is supported on the sternum and chest wall with no intervening lung

Chest Wall Compliance

Mobile anterior chest wall allows preferential ventilation

of ventral lung

Restriction of anterior chest makes wall compliance

homogeneous

Supine Prone

Uniform V/Q matching

Contrary to popular belief, pulmonary blood flow may not be gravity dependent (“C”)

Prone Positioning The Great Equalizer!

Decreases deforming forces (abdominal ‘pincers’ & heart)

Homogenizes chest wall compliance

Homogenizes ventilation & V/Q matching

AJRCCM 2000;161:1660-5AJRCCM1998; 157: 387-93AJRCCM 1998; 157: 1785-90

Gattinoni: Prone Trial 2001n = 152/ 152; 6-hours prone/day; 10 daysP/F <200 on 5 PEEP; <300 on 10 PEEP

No effect of Prone Positioning (?)

SUPINE

PRONE

Gattinoni et alN Engl J Med 2001; 345:568-73

Mancebo; Long ProningRCT of 136 patients76 were in prone position Aimed for 20 hrs/ day (obtained 17 hrs)Average duration of 10 days

Mortality K 58% to 43% (p=0.12)Multivariate analysis:

Higher SAPS II score, Days ventilated before studySupine posture J mortality

AJRCCM 2006; 173: 1233-9.

2013: Prone Works!

N Engl J Med 2013doi: 10.1056/ NEJMoa1214103

n = 466

P/F <150 (avg: 100)

Proned >16 hrs. (averaged 17hrs.)

Mortality:28 days: 16% (v. 32.8%)90 days: 23.6% (v. 41%)

Recruitment Homgenizes!

Recruitment, the application of a high Ptp, can make the alveolar distension more homogeneous

Can K PEEP induced asymmetry of distension

Lung Recruitment

No recruitment PEEP + 5 40 cm recruitment + PEEP above LIP 60 cm recruitment PEEP + 25AJRCCM 2006;174: 268 – 78.

26 patients

Effects in Clinical Trials

AJRCCM 2008; 178: 1156-63

Systematic review of clinical trials of

RMAverage effects of RM on oxygenation is +ve

Inadequate data on sustenance of effectSustained mPaw is important

Sustaining high mPaw

Conventional ventilation translates into higher and prolonged peak Paw which may be more detrimental to normal alveoli

Paw

Time

mPaw HFO

mPaw PCVRationale for

HFOV

Gas exchange in HFOV

Oxygenation is determined by mean Paw

High Frequency Oscillation

N Engl J Med 2013. DOI: 10.1056/NEJMoa1215554

N Engl J Med 2013. DOI: 10.1056/NEJMoa1215716

OSCILLATE

Outcomes with HFOV

OSCAR

OSCILLATE stopped p 548 ptsOSCAR n=795

Is HFOV ineffective? One-size fits all approach No scope for titration in OSCILLATE No accounting of D in recruitability No prior recruitment in OSCAR

Were the patients ill enough to benefit? P/F ratio <200 for inclusion

Or too late; delayed inclusion in study

Greater need for sedation & HD issues

Study-related issues may account for the negative results, or…

‘Baby lung’ & Recruited lungThey are not ‘normal’

AJRCCM 2009; 180: 415 - 23Regional heterogeneity will persist even after “opening” the lung

Vt: How low… do we go?

Non aeratedPoor aerationNormalHyperinflated

2/3

1/3

AJRCCM 2007; 175: 160–166.

In patients withARDS (Vt 6ml / Kg);

1/3 show significanthyperinflation with Inspiration (tidal)

Tidal Hyperinflation: Predictors

AJRCCM 2007; 175: 160–166.

Tidal NoHyperinflation Hyperinflation

P plat: 28.9+0.9 25.5+0.9 p=0.006

P/F: 102+24 149+34 p=0.0008

Eins L Wt 1912+206 1541+386 p=0.008

% non-aerated 27+14.3 16.1+7.7 p=0.002

% normal 39.1+19.8 68.2+11.3 p=0.003

% hyperinflat 23.3+10.1 3.0+2.2 p=0.01

Tidal hyperinflation is an independent predictor of inflammation and ventilator-free days

Optimal tidal volumes

12 cc / kg

RIP

Mor

talit

y

Tidal volume

4cc/kg 6cc/kg 12cc/kg

RIP

Pump-driven veno-venous ECMO

Lung “rested”:

Peak Paw = 20-25 cm H2OPEEP = 10-15 cm H2ORR = 10FiO2 = 0.3

CESAR trial

ECMO: The CESAR study90 randomized to transfer to ECMO site90 left on conventional Rx

Not ARDS only (~90%)

“Murray score” >3ph <7.20 (J CO2)

Death or severe disability at 6 months

Power adjustments made post-hoc; reduced n from 240 to 180!

Lancet 2009; 374; 1351-63

ECMO: The CESAR study

“ECMO group” “Control”Survival: 82% vs. 59% vs. 54%

63% vs. 47% (p=0.03)

Lancet 2009; 374; 1351-63

CESAR; Other concerns

Lancet 2009; 374; 1351-63

No difference in rescue modalities

Poor conventional care

CESAR; Sensitivity Analysis

Lancet 2010; 375: 550-1

Considering poor baseline care even a small J in survival in the conventionally treated patients would “annul” benefits of ECMO

2 less deaths would make results NS

Conclusion: The benefits of ECMO not clearThe benefits of expert care is obvious

PECLA; A Caution

A lot of abuse of “pumpless” systems is on the rise

They are effective for CO2 removal, not oxygenation

“Pumpless Extra-corporeal Lung Assist”

Eicosanoid Metabolism

linoleic acid (LA) - linolenic acid (ALA)C18:2-6 C18:3-3

arachidonic acid (AA)C20:4-6

eicosapentanoic acid (EPA)C20:5-3

docosahexanoic acid (DHA)C22:6-3

cyclic endoperoxids LTA4 LTA5

TXA2 TXA3 PGI2 PGI3 LTB4 LTB5 LTC4 LTC5

linoleic acid (LA) - linolenic acid (ALA)C18:2-6 C18:3-3

arachidonic acid (AA)C20:4-6

eicosapentanoic acid (EPA)C20:5-3

docosahexanoic acid (DHA)C22:6-3

cyclic endoperoxids LTA4 LTA5

TXA2 TXA3 PGI2 PGI3 LTB4 LTB5 LTC4 LTC5

W-6 W-3

W-3 fatty acids produce

eicosanoids with lower

inflammatory potential

The Formula

W-3 Fatty Acids in ARDS

3 RCTs included (author’s own paper too)

K Mortality OR: 0.40 (0.24-0.68) ventilation SMD: 0.56 (0.32-0.79) new organ failure OR: 0.17 (0.08-0.34) ICU stay SMD: 0.51 (0.27-0.74)

Establishes efficacy of specific formula (Oxepa ®) JPEN 2008; 32: 596-605

ARDSnet: W-3 Fatty Acids

JAMA 2011; 306: 1574-81

W-3 FA Supplement

W-3 supplements trending to worse outcome compared to low-fat, high-CHO feed

JAMA 2011; 306: 1574-81

n=272(stopped for futility)

Thank you for your patient

listening!