5/9/2015 Disclosures Novel Therapies in ARDS Research funding: - PDF document

5/9/2015 Disclosures Novel Therapies in ARDS  Research funding: NIH, FDA, Amgen Jeff Gotts, MD/PhD UCSF Critical Care Medicine and Trauma CME May 9 th , 2015 Overview  The Berlin Definition  Neuromuscular blockers for ARDS  Proning in ARDS: PROSEVA trial  Statins in ARDS  Weaning  Low Tidal Volumes for Everyone?  Future therapies:  PETAL Network  Mesenchymal stem cells 1

5/9/2015 The Berlin Definition  ARDS is defined by consensus criteria  Last updated in 1994 by the American-European Consensus Conference  While AECC definition has served well, group of investigators met in 2011 to reconsider the definition  Goal of clarifying some aspects of AECC criteria ARDS Definition Task Force, JAMA 2012 ARDS Definition Task Force, JAMA 2012 Berlin Definition: Clarifications from AECC Berlin Definition vs. AECC Definition Definition  Preserves the central features of prior definition:  Acute onset = within one week of known insult  PaO2/FiO2 ratio < 300  Recommends assessment of cardiac function (e.g. echocardiogram) if no  Bilateral radiographic opacities not primarily due to heart failure known ARDS risk factor  Elimination of term “acute lung injury”  Clarifies that ARDS may co-exist with volume overload  Mild ARDS: PaO2/FiO2 ratio 201-300  Several additional features were considered for inclusion but ultimately  Moderate ARDS: PaO2/Fio2 ratio 101-200  Severe ARDS: Pao2/Fio2 ratio ≤ 100 discarded, as they did not add predictive value:  Patients with ARDS must be on positive pressure ventilation with PEEP ≥ 5 cm  Radiographic severity, respiratory compliance, high PEEP, and high minute H20 ventilation  CPAP allowed for mild ARDS only ARDS Definition Task Force, JAMA 2012 ARDS Definition Task Force, JAMA 2012 2

5/9/2015 Berlin Definition: Summary Overview   Essential elements of definition unchanged  Neuromuscular blockers  Elimination of term “ALI”   Increased recognition of co-occurrence of ARDS and volume overload   Requirement for PEEP is most significant change   May limit applicability to early ARDS in non-ventilated patients and to  resource-limited settings    ARDS Definition Task Force, JAMA 2012 Neuromuscular Blockers: Cisatracurium for Early Severe ARDS Key Points  N=340  Mechanism of benefit unclear  P:F ratio < 150 on PEEP ≥ 5  Within 48 h of presentation  ? Decrease in VILI  Survival curves separate late  Cisatracurium for 48 h  No increase in neuromyopathy observed  Bolus followed by infusion of 37.5 mg/hr  Trial may be too small to detect this  HR for death 0.68 (0.48-0.98,  Reinforces clinical practice of many senior intensivists p=0.04)  Consider when dyssynchrony is an issue  Repeat trial needed before extending to all severe ARDS Papazian L et al. N Engl J Med 2010;363:1107-1116 3

5/9/2015 Overview    Proning: PROSEVA trial       Gattinoni L, et al . Anesthesiology 1991;74:15-23 Slide c/o L. Brochard Meta-analysis of Prone Positioning Suggests ?Benefit in Severe ARDS Gattinoni et al. NEJM 2001 Guérin et al. JAMA 2004 Mancebo et al. AJRCCM 2006 Abroug F, et al . CC 2011 4

5/9/2015 PROSEVA: Proning Protocol: Important Details Inclusion and Exclusion Criteria  INCLUSION CRITERIA:  EXCLUSION CRITERIA:  Randomized 474 patients  Criteria for cessation of daily  Age ≥ 18 years  Pregnancy  DOSE OF PRONING: proning:  Intubated for ARDS < 36  Facial trauma  P/F ≥ 150  Time from randomization to first PP = 55 hours  Unstable spines or long bone  55 minutes  ARDS according to AECC  PEEP ≤ 10 fractures criteria for minimum 12-24  PP daily duration = 17  3 hours  FiO2 ≤ 0.60  Patient already on iNO or hours  All patients ventilated with lung ECMO  All criteria persist after at least 4 hrs  AND severity criteria at  MAP < 65 (vasopressor protective ventilation that time in supine position resistant)  PaO2/FiO2 < 150 with FIO2  Vast majority of pts were on  0.6 + PEEP  5 cm H2O + VT 6 ml/kg IBW vasopressors NEJM 2013 NEJM 2013 Primary outcome: 28-d Mortality * SOFA score, vasopressors, and NMB differed significantly NEJM 2013 NEJM 2013 5

5/9/2015 Survival Should we prone all our patients?  PROSEVA replicates trends seen in some prior proning studies  Magnitude of difference much greater than in prior studies, for unclear reasons  More complications in supine group than expected (e.g. 13% incidence of cardiac arrest)  Control mortality near expected for this severity  Centers were highly experienced with proning: No adverse events attributed to repositioning  Video available on NEJM.org  Most patients were treated with neuromuscular blockers  Study authors: “Needs to be replicated” JAVA NEJM 2013 Overview Statins: Ineffective for VAP   Multicenter RCT in France   Patients on mechanical ventilation for at least 2 days and suspected of  having VAP using clinical score  Statins  Simvastatin 60 mg vs. placebo   Started on same day as antibiotics   Stopped for futility after enrollment of 300 patients   Planned to enroll 1000 patients    Mortality 21% in simvastatin group, 15% in placebo; p=0.10 Papazian, JAMA 2013 6

5/9/2015 More & More Crowded in the Graveyard Statins: Ineffective for ARDS of ARDS Pharmacotherapies  N-actetylcysteine  Ibuprofen  Statins for Acutely Injured Lungs in Sepsis trial  Procysteine  Activated Protein C  Multicenter RCT in US, NHLBI ARDS Network  Glutamine  Ketoconazole  Patients with ARDS and suspected/confirmed infection plus SIRS  Antioxidants  Beta agonists  Lisophylline  Glucocorticoids  Rosuvastain 40 mg/20 mg vs. placebo  Stopped for futility after 745 patients enrolled  PGE1  Surfactant  No difference in mortality or ventilator-free days  PMN elastase  Statins  KGF inhibitors ARDS Network, NEJM 2014 Overview     Patients transferred to LTACH for weaning from  prolonged ventilation (>21 days)  Weaning  Randomized to either weaning with pressure support   or trach collar   Took 10 years to enroll 500 patients  Jubran A et al, JAMA 2013 7

5/9/2015 Trial Protocol Details  Began with 5 day “screening procedure”  Pts placed on trach collar  Those who did not develop respiratory distress during 5 days were considered weaned = 160 of the 500 patients!  Trach collar group: Max 12 hrs on first day  Rested on ACVC overnight  On day 3, trial of up to 24 hours of TC  Pressure support group:  Assessed three times daily for decrease in PSV settings  Decrease of 2 cm H20 when possible, no more than 6 cm/day  Once PSV < 6 cm H20 for at least 12 hrs, trial TC Jubran A et al, JAMA 2013 Jubran A et al, JAMA 2013 Weaning Study: Major Findings Overview   About 1/3 of patients transferred to LTACH for weaning were  immediately weaned   For the rest, trach collar trials superior to pressure support gradual  reduction   No difference in mortality between two groups  Low Tidal Volumes for Everyone?  51-55% at 6 months, 63% at 1 year   Unblinded, long duration of trial   Jubran A et al, JAMA 2013 8

5/9/2015 Low Tidal Volumes for Everyone? Low Tidal Volumes in OR  Multicenter double blind trial  400 adults undergoing abdominal surgery  Randomized to lung protective ventilation (including PEEP, recruitment  20 articles  2822 participants maneuvers) or nonprotective ventilation (10-12 cc/kg, 0 PEEP, no recruitment  Risk ratio for ARDS 0.33 maneuvers)  Composite endpoint: Major pulmonary and non-pulmonary complications (95% CI 0.23-0.47)  Number needed to treat = 11  Endpoint occurred in 10.5% of lung-protective group vs. 27.5% of controls;  Risk ratio for mortality 0.64 p=0.001 (95% CI 0.46-0.89)  Decrease in rates of intubation post-op, hospital LOS Serpa Neto A et al, JAMA 2012; Ferguson ND et al, JAMA 2012 Futier et al, NEJM 2013 Overview New ARDS Network  Focused on prevention and early treatment   PETAL:   Prevention and Early Treatment of Acute Lung Injury    New network of 12 centers including UCSF beginning  July 2014   Future therapies:  PETAL Network  Mesenchymal stem cells 9

5/9/2015 Mesenchymal Stem (Stromal) Cells Current Proposals Include: • Proning in moderate-severe ARDS • Protocolized analgesia, sedation management • Vitamin C • Cisatracurium (to suppress spontaneous breaths) • GM-CSF for septic shock  Discovered in bone marrow 1968 (supporting cell of hematopoietic stem cell niche); capacity to make mesodermal tissues  Allogeneic administration: Don’t differentiate but do modulate function of multiple organs and cell types; anti-inflammatory MSCs Restore Alveolar Fluid Clearance in MSCs Reduce Pulmonary Edema in a 24-Hour Sheep Model of Severe ARDS Explanted Human Lungs Damaged with Intrabronchial LPS 10 9 † 8 Alveolar Fluid Clearance (%/h) 30 Wet/Dry Ratio † 7 * # 6 20 5 4 3 10 2 * 1 * 0 0 Control Normal Lung MSC MSC CM PlasmaLyte (n=7) MSC-Low (n=7) MSC-High (n=4) Fibroblasts Asmussen et al, Thorax 2014 Lee et al. PNAS 2009 LPS 10