Con Position: APRV should be used in ARDS Timothy Scialla, MD Assistant Professor Division of Pulmonary and Critical Care Duke University 09/07/2017

COI disclosure slide I am a co-investigator for on-site clinical research trials sponsored by: GSK AstraZeneca Sanofi Genentech NHLBI

ARDS epidemiology 190,000 cases / year in the USA Mortality 40% 50% Moderate (PaO2/FiO2 100-200) 25% Severe (PaO2/FiO2 < 100) Mortality 40% Early (underlying cause) Late (sepsis / nosocomial pneumonia /MODS) Ventilatory failure (ie. Hypoxemia) uncommon High Morbidity (cognitive, psychological, physical)

The ARDS Industrial Complex Nearly 2 decades of well-funded research Multiple large randomized trials Pharmacotherapy Ventilator strategies Hemodynamic monitoring/management Lessons learned Heterogeneous disease process Different ARDS phenotypes Few successes Extensive Animal Studies

Studies with mortality benefit ARMA trial Neuromuscular blockade in ARDS Prone positioning in ARDS All three: Avoid ventilator-induced lung injury

The ventilator is an agent of harm Risk of overdistension injury 12 12 Lung volume 6 6 6 6 Risk of atelectasis injury Time

Lung Protective Strategies “Low VT” strategy Minimize stress and strain Limit VT and plateau pressure (<30cm H20) “Open Lung” strategy: recruiting nonaerated lung regions Keep open with adequate levels of PEEP. Minimize hyperinflation and atelectrauma with alveolar recruitment.

ARDS Network Low vs. Traditional VT P=0.007 6 ml/kg 12 ml/kg Absolute risk reduction = 9% (31% vs 40% mort) Relative risk reduction = 22% Lower oxygenation Worse ventilation ARDS Network NEJM 2000

Lung Protective Ventilation and Knowledge Translation Needham et al Lung Protective Ventilation and Knowledge Translation Needham et al. BMJ. 2012 180/485 patients (37%) never had LPV 417/485 (86%) adherent 50% or less Prospective cohort of patients with ALI 13 ICUs at 4 hospitals in Baltimore 485 patients Primary outcome was 2 year survival 64% of patients died at 2 years. 30 day mortality was 44%. 90 day mortality was 52%. 1 year was 62%. 100% adherence to LPV associated with 8% absolute risk reduction. 50% adherence with 4%

NMB in early ARDS. Papazian et. al. NEJM. 2010 340 patients randomized Sedative: Ramsey Level = 6 (very very sedated) Cisatracurium group: 15mg bolus followed by continuous infusion for 48hrs Open label 20mg IV bolus of cisatracurium allowed in either group if Pplat>32. Adjusted Cox regression model: HR 0.68 (95% CI, 0.48 to 0.98; p=.04) Adjustments made for PaO2/FiO2; Pplat, SAPS II

Open Lung Strategy: Metaanalysis: High vs Low PEEP. Higher PEEP (n=1136) Low PEEP (n=1163) Higher PEEP: better PaO2 transiently (same at day 7) Higher PEEP:  Pplat; PEEP Briel et al. JAMA. 2010

Why these results? Responders Nonresponders Applied lower (12hours) and higher PEEP (12hours) strategy from ALVEOLI trial to 19 patients Found nine recruiters Alveolar recruitment, decreased lung elastance, better oxygenation Nonrecruiters: worse lung elastance. Grasso et al. High vs Low PEEP. AJRCCM. 2005.

HFO: The perfect scenario Risk of overdistension injury Lung volume Rapid oscillations of a diaphragm Results in active insp and expiration Little pressure to distal airways (Vt) Decouple oxygenation & ventilation O2 depends on mPaw CO2 depends on Hz and P Mechanism of Gas transport Bulk flow Cardiac oscillation Molecular diffusion Risk of atelectasis injury Time 13

Risk of overdistension injury Risk of atelectasis injury Avoid this Risk of overdistension injury Lung volume Risk of atelectasis injury Time 14

HFOV: Our curiosity with this mode has come to an end OSCILLATE trial 548 patients HFO group Increased sedation/paralytics More pressors/high mean airway pressures Less refractory hypoxemia Increased mortality? N=146 P=.08 Ferguson et al. NEJM. 2013

Prone Positioning in ARDS: Mount Everest in Kansas Recruited more severely hypoxemic patients Prone group with higher PaO2:FiO2 ratio at days 3 and 5 Prone group had lower Pplatrs lower at days 3 and 5 NNT to prevent one death was 6 466 patients 16 vs 32% 28-day mortality. HR 0.39 12-24 hours stabilization period before final inclusion Stop proning if after 4hrs in supine position ratio> 150 with PEEP 10 and FiO2 60% 28 days of proning possible Guerin et al. NEJM. 2013

Pleural pressure in dependent and non-dependent regions More homogenous ventilation. Less collapse in dependent zones. Fessler and Talmor. Respiratory Care. 2010

APRV: Evidence & Limitations Limited, small, mostly trauma patients One RCT: APRV vs LOVT Intubated trauma patients at risk for ARDS LOVT = SIMV (VT = 6ml/kg PS=10 cm H20) Limitations At Phigh: spont breaths can add to strech Plow to Phigh: shearing/atelectrauma N=31 N=32 LOVT= low tidal volume ventilation Maxwell et al. J Trauma. 2010

↑ Mean Airway Pressure ≠ ↑ PaO2/FiO2

Conclusions 2 decades of extensive prospective studies APRV = 1 very small RCT (negative study) Longer time on ventilator No improvements in oxygenation Trend towards more sedation! Low tidal volume ventilation is GOLD STANDARD Severe cases Neuromuscular blockage Prone ventilation Neither requires tertiary care center/ high technology

Sage Advice from the master