Outcomes From Severe ARDSManaged Without ECMO

Roy Brower, MD

Johns Hopkins University

Critical Care Canada Forum

Toronto

November 1, 2016

Severe ARDS

• Berlin Definition 2012• P:F ratio ≤ 100 mm Hg

• Prevalence: 28% of ARDS patients

• Mortality: 45% (95% CI: 42-48 %)

• LUNG-SAFE 2016 • P:F ratio ≤ 100 mm Hg

• Prevalence: 23.4% of patients

• Mortality: 46.1% (95% CI: 41.9-50.4)

Interventions for Severe ARDS

• Lung-protective ventilation

• Infection management

• Fluid management

• Neuromuscular blockade

• Prone positioning

• ECMO?

The ECMO Argument

Appeal of ECMO

• Physiologic rationale

• Preserve life • Buy time for treatment and

healing

• “Lung rest”

Downside of ECMO

• May only prolong death

• Invasive, complications

• Resource-intensive

• Expensive

Early RCTs in ECMO

Zapol et al. JAMA 1979Morris et al. AJRCCM 1994

ECMO Volumes: 1988-2013

Bartlett, RH J Am Coll Surg 2014

2009

JAMA 2009

68 Patients With H1N1-Influenza-ARDS

PaO2/FiO2 56 (48-63)

PEEP 18 (15-20)

ALI Score 3.8 (3.5-4.0)

Mortality 25%

Davies et al. JAMA 2009

JAMA 2009

68 Patients With H1N1-Influenza-ARDS

PaO2/FiO2 56 (48-63)

PEEP 18 (15-20)

ALI Score 3.8 (3.5-4.0)

Mortality 25%

Age 34 (27-43)

Comorbidity 8%

Davies et al. JAMA 2009

2009: CESAR Trial

Surv

ival

(%

)

• Conventional group• 90 patients• Death: 45%

• ECMO center• 90 patients• 68 received ECMO• Death: 33%

P= 0.027

2009: CESAR TRIAL

Treatment Conventional “ECMO”

Volume/Pressure limited ventilation at any time 70% * 93% *

Time under low volume/pressure strategy 15.0 days * 23.9 days *

Steroids 64% * 84% *

MARS (Liver Assist) 0% * 17% *

Transport to High-Volume Center 0% 100%

* p< 0.05

Noah. JAMA, 2011

Pham. AJRCCM 2013

Objective

Characterize the features and outcomes of patients with severe ARDS who met criteria for ECMO at other institutions

but were managed with usual care

Criteria for ECMO ConsiderationOur Criteria Brodie Criteria ELSO Criteria

HypoxemiaPaO2/FiO2 ratio < 100 despite levels of PEEP > 10 cm H2O for at least 6 hours

PaO2/FiO2 ratio < 80 despite high levels of PEEP (typically 15-20 cm H2O) for at least 6 hrs

Consider when PaO2/FiO2 < 150 on FiO2 > 90% or ALI score 2-3Indicated when PaO2/FiO2 < 100 on FiO2 > 90% and/or ALI score 3-4 despite optimal care > 6 hrs

HypercapniaPCO2 > 50 with arterial pH < 7.15 or venous pH < 7.12

pH < 7.15 despite best accepted standard of care with MV

CO2 retention on mechanical ventilation despite high Pplat > 30 cm H2O

High plateau pressurePplat > 35 cm H2O with either tidal volume ≤ 6 ml/kg PBW or arterial pH < 7.15

Excessive plateau pressures:Pplat > 35-45 cm H2O despite best accepted standard of care with MV

Other: Severe air leak, need for intubation in patient on transplant list, sudden cardiac or respiratorycollapse (PE, blocked airway, unresponsive to optimal care)

Brodie and Bachetta, NEJM 2011 ELSO Website, Dec 2013

Methods

• Prospective Observational Study

• Daily screening of JHH MICU census from February 2014 – June 2015 for patients with severe ARDS + ECMO consideration criteria

• 46 patients identified

• 5 patients received ECMO

Patient characteristicsN = 46

Age 51.02 (17.18)

Female Gender 22 (47.8)

APACHE II 27.57 (7.40)

SOFA 12.59 (3.94)

ARDS Risk Factor

Pneumonia 28 (60.8)

Non-Pulmonary Sepsis 13 (28.2)

Aspiration 2 (4.3)

Pancreatitis 1 (2.2)

Blood Product Transfusion 1 (2.2)

Other 2 (2.2)

PaO2/FiO2 60.5 (33)

FiO2 100 (30)

PEEP 14.15 (4.41)

Pplat 34.49 (5.78)

PCO2 67.5 (27)

pH 7.15 (0.11)

Tidal Volume 5.23 (0.88) *Stats reported as mean (SD), median (IQR), or number(%)*Other Cause of ARDS – Diffuse Alveolar Hemorrhage

Overall:46 patientsAverage 51 yearsSOFA 12.6P/F 60.5Low VT 5.23 cc/kg PBWMortality: 56%

Contraindications to ECMOOur Criteria Brodie Criteria ELSO Criteria

Anticoagulation contraindicated Anticoagulation contraindicated CNS hemorrhage, recent or expanding

High pressure ventilation > 7 days High pressure ventilation > 7 days MV at high settings (FiO2 > 0.9, Pplat> 30) for > 7 days

High FiO2 requirement (>0.8) > 7 days

High FiO2 requirement (>0.8) > 7 days

Major pharmacologic immunosuppression (ANC < 400)

Limited potential benefit for ECMO Limited potential benefit for ECMO Limited potential benefit for ECMO

Limited vascular access

All Patients (n = 46) Eligible for ECMO (n = 25) Not Eligible for ECMO (n = 16)

Age 51.02 (17.18) 53.48 (14.28) 51.19 (18.9)

Female 22 (47.8%) 14 (56%) 5 (31.2%)

APACHE II 27.57 (7.40) 28.88 (7.43) 27.38 (7.3)

SOFA 12.59 (3.94) 13.2 (3.62) 11.62 (4.61)

Pneumonia 28 (60.8%) 16 (64%) 8 (50%)

PaO2/FiO2 60.5 (33) 66 (35) 57.5 (25.5)

FiO2 100 (30) 90 (30) 95 (30)

PEEP 14.15 (4.41) 14 (6) 12 (5.5)

Pplat 34.49 (5.78) 32 (6) 34.5 (6)

PCO2 67.5 (27) 61 (20) 70.5 (24.5)

pH 7.15 (0.11) 7.16 (0.12) 7.16 (0.10)

Tidal Volume 5.23 (0.88) 5.32 (0.77) 5.56 (0.62)

Mortality 27 (56%) 11 (44%) 12 (75%)

*Stats reported as mean (SD), median (IQR), or number(%)

Clinical Course and Outcomes

All Patients (n = 46) Eligible for ECMO (n = 25) Not Eligible for ECMO (n = 16)

Rescue Therapies 22 (52) 12 (48) 5 (31)

Neuro Blockade 21 (45.6) 12 (48) 5 (31.2)

Prone 7 (15) 3 (12) 1 (6.2)

Inhaled vasodilator 1 (2) 1 (4) 0

ICU LOS 15 (18) 13 (16.5) 20 (27)

Hospital LOS 21.5 (22) 21 (22) 22 (28.5)

Mortality 27 (56%) 11 (44%) 12 (75%)

*Stats reported as median (IQR), or number(%)

Predicting ECMO Survival“RESP Score”

RESP Score Risk Class Survival

≥ 6 I 92%

3-5 II 76%

-1 to 2 III 57%

-5 to -2 IV 33%

≤ -6 V 18%

Schmidt et al AJRCCM 2014Schmidt et al, AJRCCM 2014

RESP Score

All Pts Eligible Not Eligible

RESP score 0 (4) 1 (4) -1 (6)

Survival 44% 56% 25%

Schmidt et al, AJRCCM 2014

Conclusions

• Survival in ECMO eligible patients managed without ECMO comparable to survival predicted with ECMO

• ECMO may not improve outcomes in population of severe ARDS patients

• Need good randomized controlled trials• Which patients?

• When?

• How?

ECMO Complications

Ventetuolo and Muratore AJRCCM 2014

RCTs of Interventions We Believed In(but were not working)

• Flecainide for arrhythmia suppression (NEJM, 1991)

• Engineeered molecules for sepsis (1990s)

• Milrinone for acute CHF (JAMA 2002)

• Nesiritide for acute CHF (JAMA 2005)

• Surfactant for ARDS (NEJM 2004; AJRCCM 2011)

• Higher PEEP for ARDS (NEJM 2006; JAMA 2008)

• Intra-aortic Balloon Pump for M.I. with shock (NEJM 2012)

• HFOV for ARDS (NEJM 2013)

• Glutamine for oxidant stress in critically ill (NEJM 2013)

• Pulmonary Artery Catheters for:• High risk surgery (NEJM 2003)• Critically ill (Lancet 2005)• Shock or ARDS or both (JAMA 2003)• ARDS (NEJM 2006)

Thank You

ECMO patients

ECMO patients (n = 5)

Age 29 (7)

APACHE II 21.6 (2.30)

SOFA 12.6 (3.21)

Pneumonia 4 (80%)

PaO2/FiO2 49 (9)

FiO2 100 (0)

PEEP 18 (4)

Pplat 44 (5)

pCO2 102.20 (29.34)

pH 7.15 (0.10)

Tidal Volume 3.76 (0.70)

Days on MV 6.4 (2.88)

ECMO patients (n = 5)

Rescue Therapies 5 (100%)

Paralytic 4 (80)

Prone 3 (60)

iNO 0

ICU LOS 8 (5)

Hospital LOS 30 (17)

RESP score 0 (2)

Mortality 4 (80)

*Stats reported as mean (SD), median (IQR), or number(%)

Coming Enlightenment?

• EOLIA: ECMO to rescue Lung Injury in severe ARDS• Multi-national, multi-center• Randomized, controlled

• VV-ECMO with “lung rest” • Vent:FiO2 0.3-0.6; PEEP ≥ 10 cm H2O; Pplat <10

• Conventional ARDS management • Pplat < 28-30 cm H2O

• Cross-over to ECMO for refractory hypoxemia

• Primary Endpoint: Mortality at Day 60

Inclusion criteria :ARDS defined as:• Intubation and mechanical ventilation for ≤ 6 days• Bilateral pulmonary infiltrates c/w edema• PaO2/FiO2 ratio < 200 mm Hg• Absence of clinical evidence of elevated LAPOne of the 3 following criteria of disease severity:• PaO2/FiO2 < 50 mm Hg with FiO2 ≥ 80% for > 3 hrs,

despite optimization of MV (Vt set at 6 ml/kg and trial of PEEP ≥ 10 cm H2O) and despite possible adjunctive therapies (NO, recruitment maneuvers, prone position, HFO ventilation, almitrine infusion)

• PaO2/FiO2 < 80 mm Hg with FiO2 ≥ 80% for > 6 hrs, despite optimization of MV and despite possible recourse to adjunctive therapies

• pH < 7.25 for > 6 hours (with RR increased to 35/min) resulting from MV settings adjusted to keep Pplat ≤ 32 cm H2O (first, tidal volume reduction by steps of 1 mL/kg to 4 mL/kg then PEEP reduction to a minimum of 8 cm H2O.

EOLIA: Inclusion/Exclusion

Exclusion Criteria:• Intubation and mechanical ventilation for ≥ 7 days• Age < 18 years• Pregnancy• Weight > 1 kg/cm or BMI > 45 kg/m²• Chronic respiratory insufficiency treated with oxygen

therapy of long duration and/or long-term respiratory assistance

• Cardiac failure requiring veno-arterial ECMO• Previous history of heparin-induced thrombopenia• Malignancy with fatal prognosis within 5 years• Patient moribund on the day of randomization or has a

SAPS II > 90• Non drug-induced coma following cardiac arrest• Irreversible neurological pathology, for example, flat EEG

tracing cerebral herniation• Decision to limit therapeutic interventions• ECMO cannula access to femoral vein or jugular vein

impossible.• CardioHelp device not immediately available

Adult ECMO at Johns Hopkins• Formal ECMO program started in 2014

• C. Sciortino, Surgical Director

• S. Stephens, Medical Director

• 3-ECMO

• 2014: • 37 runs (VV and VA)

• 7 deaths (3 ARDS)

• 2015 (to date): • 13 runs (VV and VA)

• 3 deaths (1 ARDS)

• Projected 2015 volume: 52 runs

ECMO for ARDS: the JHH ExperienceSince January, 2014

All Survivors Non-Survivors

Patients (%) 7 3 (43%) 4 (57%)

Median Age (Range) 30 (23-78) 37 (24-63) 28.5 (23-78)

Mean APACHE II (SD) 27 (7.4) 33.5 22

Mean SOFA (SD) 10.3 (3.7) 10 10.5

Changing ECMO Indications

Bartlett, RH J Am Coll Surg 2014

2009

H1N1 Patients Managed Without ECMO

• 168 critically ill patients with H1N1• 81% mechanically ventilated at ICU admission

• Mean age 32.3 years

• Only 4.2% of patients placed on ECMO

• 17.3% mortality

Kumar et al, JAMA 2009

2009 H1N1 Influenza

CESAR Trial

Peek et al Lancet 2009; 374:1351-63

• 180 adults with severe ARDS

– ALI Score >3.0 or

– Hypercapnia with pH < 7.20

– For < 7 days

• Randomized to either:

– Conventional Management at home hospital: 90 patients

– Referral to a single tertiary center for consideration of ECMO: 90 patients