Sumit Ray Senior Consultant & Vice-Chair Critical Care & Emergency Medicine Sir Ganga Ram Hospital

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.

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 Mortality 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 Collapse 10-20 cmh 2 O Alveolar Collapse (Reabsorption) Consolidation 20-60 cmh 2 O 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 noncompliant 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 V T (432) Vt = 12 mls/kg Pplat =<50cms of H2O Vt = 6 mls/kg Pplat =<30cms of H2O PEEP based on protocol up to 20 to 24

ARDSnet Tidal Volume Study Mortality: Intervention group: 31% Control group: 39.8% p Value: 0.007 Other benefits: Lower duration of ventilation Lower incidence of non-lung organ failure days NEJM 2000;342:1301-8.

Ventilator Strategies in ARDS Objectives Adequate ventilation of compliant alveoli without causing: Volutrauma Strategies Small V T (4-6ml/kg) High RR (30/min) Allowing hypercapnia (?) (PaCO 2 80mm Hg) Avoid Barotrauma Limit P Plat 30 cms H 2 O 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 V T 1406 pts Conventional vent

Ventilator Strategies in ARDS Recruitment Maneuver Objectives Recruitment- opening up closed, non-compliant alveoli Recruitment potential is highest in early phase & in extra pulmonary ARDS Strategies Recruitment maneuvers 30-40cms CPAP for 30-40 secs Series of PCV breaths-p high 40-50 cm H2O & PEEP of 20-35 cm H2O for 2 mins Series of large V T =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 Stop De-recruitment of recruited alveoli(open lung), thus avoiding shear stress (atelectrauma) Strategies Titrated PEEP Incremental in PEEP Decremental steps of PEEP LIP method (Amato) ARDS Net table CT scan method USG method

Open Lung Ventilation Strategy Volume Zone of Overdistention Zone of Derecruitment and atelectasis Safe window Goal is to avoid injury zones and operate in the safe window Pressure Froese, CCM, 1997

Adjusting PEEP ARDS Network study Brower et. ARDS Network NEJM 2000;342:1301-1308 Fixed combinations of FiO2 and PEEP Arterial Oxygenation Goal: PaO 2 =55-80 mmhg or SpO 2 =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 0.5 10 0.9 16 0.6 10 0.9 18 0.7 10 1.0 20-24

Moderate/Severe ARDS Better survival Mild 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 C RS (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 V T to C RS 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 V T alone. This ratio, termed the driving pressure (ΔP = V T /C RS ). 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 H 2 O) 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 V T (RR= 1.36; 95% CI, 1.17 to 1.58; P<0.001). -Individual changes in V T 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

Shape Matching & Sponge Theory Strain

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 H 2 O 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 PaO 2 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

Prone= 237 / Supine=229 PROSEVA trial

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 Transvascular pressure (Pcap-Ppl) is low (12-10 = 2) Transpulmonary pressure (Paw-Ppl = PL)= 30+20 =50 Transvascular pressure (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 R aw 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 CO 2 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. DP A (Driving Pressure-Airway) = PPlat PEEP DP L (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 V T were not associated with death in any model. Conclusions: When ventilating patients with low V T, 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 C RS 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, PaO 2 /FiO 2 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.