Acute Respiratory Distress Syndrome Has management changed in the last Decade? Ram E. Rajagopalan, MBBS, AB (Int Med) AB (Crit Care) Head, Department of Critical Care Medicine SUNDARAM MEDICAL FOUNDATION Chennai

X-Ray in Early ARDS Homogeneous pulmonary infiltrates CT Ratio <.55 Homogeneous pulmonary infiltrates Non-central distribution of oedema Normal cardiac size

Gattinoni et al. Intensive Care Med. 1986; 12: 137-42. CT in Early ARDS A thirty-year-old observation Pl. effusion “Preservation of normal lung regions” Pulmonary edema Dependent collapse Maunder et al. JAMA 1986; 255:2463-5. Gattinoni et al. Intensive Care Med. 1986; 12: 137-42.

“It is Sponge Lung!!” Lung superimposed h pressure Density x h Gravity dependent atelectasis Density x h *Int Care Med 1986; 12: 137-42. **AJRCCM 2002; 165: 1647–53.

The “Baby lung” ARDS Lung has “normal” & unaerated / partially aerated alveoli “Normal” segments inflate easily Unaerated segments distend poorly High pressure Slow response Normal lung segments may be over-inflated when ventilated with traditional tidal volumes

Tidal Volume in ARDS Low (6cc / Kg) vs. ‘traditional’ (12 cc/Kg) n = 432 vs. 429 N Engl J Med 2000; 342: 1301-8.

P-V relationship in ARDS Pressure Volume UIP LIP Beside avoiding large Vt……

Alveolar Collapse Pressure Volume

“Volutrauma & Atelectrauma” Non-dependent bullae are probably due to alveolar overdistension Dependent bullae are due to alternating opening & closing of the airway Gattinoni et al. AJRCCM 2001; 164: 1701-11.

Limiting Injury: “Lung Protective Ventilation” Pressure Volume PEEP LIMIT Pr. or Vol.

ARDSnet: High vs. Low PEEP NEJM 2004; 351: 327-36.

Variability in Recruitable Lung Recruitable lung (% of total) N Engl J Med 2006;354:1775-86. Supports prior physiological studies* The “anatomical” (CT) extent of potentially recruitable lung is very variable *AJRCCM 2005; 171: 1002-1008.

Problems with ARDSnet approach Significant “Recruitable” Lung volume Sparse “Recruitable” Lung volume Identification of the potentially recruitable ARDS lung becomes important PEEP Opens alveoli Benefits patient Hyperinflates lung Harms patient No Effect; a l’ARDSnet

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) _

…K PEEP induced asymmetrical expansion Homogenize the Lung! If the alveolar distension is made more homogeneous…… …K PEEP induced asymmetrical expansion

The Prone Position Prone Supine

Prone Position Improves Oxygenation PaO2 / FiO2 Ratio Rajagopalan et al; Ind. J. Crit. Care Med. 1999; 3(1): 73-5.

Deforming Pressures in ARDS Lung Superimposed Pressure But…. Superimposed pressure is altered by…..

Deforming Pressures in ARDS Heart & Mediastinum Abdominal contents & caudal diaphragm; “Pincers”

Effect of Heart & Mediastinum 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 AJRCCM 2000;161:1660-5

Restriction of anterior chest makes wall compliance homogeneous Chest Wall Compliance Supine Prone Mobile anterior chest wall allows preferential ventilation of ventral lung Restriction of anterior chest makes wall compliance homogeneous

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

Gattinoni: Prone Trial 2001 n = 152/ 152; 6-hours prone/day; 10 days P/F <200 on 5 PEEP; <300 on 10 PEEP No effect of Prone Positioning (?) SUPINE PRONE Gattinoni et al N Engl J Med 2001; 345:568-73

Mancebo; Long Proning RCT of 136 patients 76 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 study Supine posture J mortality AJRCCM 2006; 173: 1233-9.

2013: Prone Works! 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%) N Engl J Med 2013 doi: 10.1056/ NEJMoa1214103

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 60 cm recruitment PEEP + 25 26 patients 60 cm recruitment PEEP + 25 40 cm recruitment + PEEP above LIP No recruitment PEEP + 5 AJRCCM 2006;174: 268 – 78.

Effects in Clinical Trials Systematic review of clinical trials of RM Average effects of RM on oxygenation is +ve Inadequate data on sustenance of effect Sustained mPaw is important AJRCCM 2008; 178: 1156-63

Sustaining high mPaw Rationale for HFOV Time mPaw HFO PCV Rationale for HFOV Conventional ventilation translates into higher and prolonged peak Paw which may be more detrimental to normal alveoli

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

Outcomes with HFOV OSCILLATE stopped p 548 pts OSCAR n=795 OSCILLATE

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 lung They are not ‘normal’ Regional heterogeneity will persist even after “opening” the lung AJRCCM 2009; 180: 415 - 23

Vt: How low… do we go? 2/3 1/3 In patients with ARDS (Vt 6ml / Kg); Non aerated Poor aeration Normal Hyperinflated In patients with ARDS (Vt 6ml / Kg); 1/3 show significant hyperinflation with Inspiration (tidal) 1/3 AJRCCM 2007; 175: 160–166.

Tidal Hyperinflation: Predictors Tidal No Hyperinflation 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 AJRCCM 2007; 175: 160–166.

Optimal tidal volumes Mortality Tidal volume 12 cc / kg RIP Mortality Tidal volume RIP 12 cc / kg 4cc/kg 6cc/kg 12cc/kg

Pump-driven veno-venous ECMO Lung “rested”: Peak Paw = 20-25 cm H2O PEEP = 10-15 cm H2O RR = 10 FiO2 = 0.3 CESAR trial

ECMO: The CESAR study 90 randomized to transfer to ECMO site 90 left on conventional Rx Not ARDS only (~90%) “Murray score” >3 ph <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 63% vs. 47% (p=0.03) Lancet 2009; 374; 1351-63 Survival: 82% vs. 59% vs. 54% 63% vs. 47% (p=0.03) “ECMO group” “Control”

CESAR; Other concerns No difference in rescue modalities Poor conventional care Lancet 2009; 374; 1351-63

CESAR; Sensitivity Analysis 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 clear The benefits of expert care is obvious Lancet 2010; 375: 550-1

PECLA; A Caution “Pumpless Extra-corporeal Lung Assist” A lot of abuse of “pumpless” systems is on the rise They are effective for CO2 removal, not oxygenation

Eicosanoid Metabolism 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 n=272 (stopped for futility) W-3 supplements trending to worse outcome compared to low-fat, high-CHO feed JAMA 2011; 306: 1574-81

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