ards: an evidence-based update. by mac sweeney

Rob Mac SweeneySMACCgold 2014

rob@criticalcarereviews.com / @critcarereviews

ARDS An Evidence Based Update

Disclosure• Research funding from Northern Ireland Health and Social Care

Research and Development Board• Research into ARDS biomarkers

• http://www.criticalcarereviews.com/index.php/smacc-2014

References

Rob Mac SweeneySMACCgold 2014

rob@criticalcarereviews.com / @critcarereviews

ARDS An Evidence Based Update

A Condition That….

1. can’t diagnose2. of limited use3. no specific treatment for4. people don’t die from

……….. doesn’t actually exist

Wikimedia Commons

Wikimedia Commons

Wikimedia Commons

Causes

Pulmonary • Pneumonia• Pulmonary contusion• Inhalational injury• Aspiration• Fat embolism• Near Drowning

Extra-Pulmonary • Extra-pulmonary sepsis• Trauma• Burns• Acute Pancreatitis• Massive Transfusion• Drug overdose

Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome

Original Description • Case Series of 12

Original Description • Syndrome of

• Severe Dyspnoea• Tachypnoea• Cyanosis refractory to oxygen therapy• Loss of lung compliance• Benefit with PEEP• Possible benefit with steroids• Diffuse alveolar infiltration

Acute Lung Injury

ALI ARDS

300 – 200 mmHg < 200 mmHg

40 – 26.6 kPa < 40 kPa

Acute Respiratory Distress Syndrome

mild moderate severe

< 300 mmHg < 200 mmHg

< 40 kPa < kPa 26.6

< 100 mmHg

< kPa 13.3

Wikimedia Commons

Definition

Prediction

Clinical Utility

Autopsy Timing

Definition

Prediction

Clinical Utility

Autopsy

Timing Oedema

Timing

Definition

Prediction

Clinical Utility

Autopsy

Timing Oedema PaO2/FiO2

Radiograph InfiltratesOedemaOrigin

Definition

Prediction

Clinical Utility

Autopsy

Timing Oedema PaO2/FiO2

OxygenationOxygenation

Definition

Prediction

Clinical Utility

Autopsy

Timing Oedema PaO2/FiO2

Infiltrates

Infiltrates

Infiltrates

Definition

Utility

Clinical Utility

Autopsy

Timing Oedema PaO2/FiO2

Infiltrates

Infiltrates

Definition

Utility

Clinical Utility

Autopsy

Timing Oedema PaO2/FiO2 Infiltrates

Temporality

Temporary

Temporality

Definition

Utility

Clinical Utility

Autopsy

Timing Oedema PaO2/FiO2 Infiltrates

Clinical Use

Temporary Reality

ClinicalReality

Definition

Utility

Clinical Utility

Autopsy

Timing Oedema PaO2/FiO2 Infiltrates

Temporary

ClinicalConsequence

Recognition

Recognition

Reality

Definition

Utility

Mortality

Autopsy

Timing Oedema PaO2/FiO2 Infiltrates

Temporary Recognition Reality

Definition

Utility

Mortality

Autopsy

Timing Oedema PaO2/FiO2 Infiltrates

Temporary

Severity

Cause

Recognition

Cause

Reality

Definition

Utility

Mortality

Autopsy

Timing Oedema PaO2/FiO2 Infiltrates

Temporary

Severity

Cause Prediction

Recognition

Prediction

Reality

Definition

Utility

Mortality

Autopsy

Timing Oedema PaO2/FiO2 Infiltrates

Temporary

Severity

Cause Prediction

Recognition Reality

Definition

Utility

Mortality

Autopsy

Timing Oedema PaO2/FiO2 Infiltrates

Temporary

DiffuseAlveolarDamage

Cause Prediction

DAD

Recognition Reality

Source: Wikimedia Commons

50%

50%

One in Two

DAD

ARDS

DAD

ARDS

Pneumonia No Lesion

Abscess

COPD

DAD

ARDS

Pneumonia No Lesion

Abscess

COPD Cancer

DAD

ARDS

Pneumonia No Lesion

Abscess

COPD Cancer

DAD

ARDS

Pneumonia No Lesion

Abscess

COPD Cancer

DAD

ARDS

Pneumonia No Lesion

Abscess

COPD Cancer

DAD

ARDS

Pneumonia No Lesion

Abscess

COPD Cancer

DAD

ARDS

Pneumonia No Lesion

Abscess

COPD Cancer

DADPEBleedingFibrosisPOTB

ARDS

DAD

ARDS

DAD

NON - DAD

ARDS

ARDS

NON - ARDS

ARDS

NON - ARDS

Therapy

General

ARDS

NON - ARDS

Therapy

DADSpecific

ARDS – A Condition That….

1. can’t diagnose (we can’t agree to diagnose)2. of limited use (doesn’t change management)3. no specific treatment for (getting to it)4. people don’t die from (mostly)

5. doesn’t actually exist (half the time)

ARDS – A Condition That….

1. can’t diagnose (we can’t agree to diagnose)2. of limited use (doesn’t change management)3. no specific treatment for (getting to it)4. people don’t die from (mostly)

5. doesn’t actually exist (half the time)

ARDS – A Condition That….

1. can’t diagnose (we can’t agree to diagnose)2. of limited use (doesn’t change management)3. no specific treatment for (getting to it)4. people don’t die from (mostly)

5. doesn’t actually exist (half the time)

ARDS – A Condition That….

1. can’t diagnose (we can’t agree to diagnose)2. of limited use (doesn’t change management)3. no specific treatment for (getting to it)4. people don’t die from (mostly)

5. doesn’t actually exist (half the time)

ARDS – A Condition That….

1. can’t diagnose (we can’t agree to diagnose)2. of limited use (doesn’t change management)3. no specific treatment for (getting to it)4. people don’t die from (mostly)

5. doesn’t actually exist (half the time)

ARDS – A Condition That….

1. can’t diagnose (we can’t agree to diagnose)2. of limited use (doesn’t change management)3. no specific treatment for (getting to it)4. people don’t die from (mostly)

…….doesn’t actually exist (half the time)

?

Therapeutic Evidence-Base

Timing InfiltratesOedema PaO2/FiO2

Temporary Function Clinical

Severity Mortality

DAD

?

Ventilatory Adjuncts

Haemodynamics

Drugs

ECMO

Ventilation

Tidal Volume • 861 ARDS patients (P/F < 300 cm H20)

• 6 ml/kg & Pplt ≤ 30 cm H20 versus

• 12 ml/kg & Pplt ≤ 50 cm H20 • 9% absolute risk reduction in 28 day

mortality

Tidal Volume • 150 critically ill mechanically

ventilated patients

• 6 ml/kg vs 10 ml/kg

Development of ARDS• 2.6% versus 13.5%; p = 0.01

Tidal Volume • 400 patients undergoing major

abdominal surgery

• 10-12 ml/kg & ZEEP & no recruitment versus• 6-8 ml/kg & PEEP 6-8 cm H20 & RM

• Postoperative Respiratory Support• 5% vs 17% • RR 0.29 (95% CI 0.14 to 0.61)

Oscillate

• 548 ARDS patients • PaO2/FiO2 < 200 cmH20• Fi02 > 0.5

In-hospital mortality • HFOV 47% vs Control 35% (RR 1.33; 95% CI 1.09 to 1.64; P = 0.005)

Oscar

• 548 ARDS patients • PaO2/FiO2 < 200 cmH20• PEEP > 5 cmH20

30 day mortality• HFOV 41.7% vs Control 41.1%• Difference 0.6%, 95% CI −6.1 to 7.5

Haemodynamics

Drugs

ECMO

Ventilation

Ventilatory Adjuncts

Haemodynamics

Drugs

ECMO

Ventilation

ACURASYS Study

• 340 ARDS patients• PaO2/FiO2 < 150 mmHg

Adjusted Mortality at Day 90 • NMB: 31.6% vs placebo: 40.7%• HR 0.68 (95% CI 0.48 to 0.98; P = 0.04)

PROSEVA Study

• 466 ARDS patients • PaO2/FiO2 < 150 cmH20

28 day mortality• Prone: 16% vs Control 32.8%

Unadjusted 90-day mortality• Prone: 23.6% vs supine 41.0%

Prone Ventilation

• 4 RCTS• 1,573 patients

In the most hypoxaemic• 486 patients• PaO2/FiO2 < 100 mmHg• absolute mortality reduction 10%

(6% to 21%)

Ventilatory Adjuncts

NMBs

Drugs

ECMO

Ventilation

Prone

Ventilatory Adjuncts

Fluids

Drugs

ECMO

Ventilation

FACTT Study

• 1000 patients with ALI• 0 ml vs 7000 ml fluid balance at day 7

60 Day Mortality• Conservative: 25.5% vs liberal 28.4%

95% CI difference −2.6 to 8.4 %, P=0.3

FACTT Study

• 1000 patients with ALI• 0 ml vs 7000 ml fluid balance at day 7

60 Day Mortality• Conservative: 25.5% vs liberal 28.4%

95% CI difference −2.6 to 8.4 %, P=0.3

FACTT Study

• 1000 patients with ALI• 0 ml vs 7000 ml fluid balance at day 7

60 Day Mortality• Conservative: 25.5% vs liberal 28.4%

95% CI difference −2.6 to 8.4 %, P=0.3

Ventilatory Adjuncts

Fluids

Fluids CVC

ECMO

Ventilation

Ventilatory Adjuncts

Fluids

Drugs

ECMO

Ventilation

Drugs

Drugs

Clinically Tested1. NMBs √2. Steroids ?3. Surfactant X4. β2 agonists X5. Diuretics ?6. Ketoconazole X7. Activated Protein C X8. Nitric Oxide X9. Silvelestat X10. Lisofylline X11. Pharmaconutrients X

Drugs

Clinically Tested1. NMBs √2. Steroids ?3. Surfactant X4. β2 agonists X5. Diuretics ?6. Ketoconazole X7. Activated Protein C X8. Nitric Oxide X9. Silvelestat X10. Lisofylline X11. Pharmaconutrients X

Clinically Untested1. Prostacyclin2. Almitrine3. Ibuprofen4. N-Acetylcysteine5. Mucolytics6. Albumin

Drugs

Clinically Tested1. NMBs √2. Steroids ?3. Surfactant X4. β2 agonists X5. Diuretics ?6. Ketoconazole X7. Activated Protein C X8. Nitric Oxide X9. Silvelestat X10. Lisofylline X11. Pharmaconutrients X

Clinically Untested1. Prostacyclin2. Almitrine3. Ibuprofen4. N-Acetylcysteine5. Mucolytics6. Albumin

Next Wave1. Statins2. Aspirin3. ACEI / ARB4. Macrolides5. Insulin6. Vitamin D7. Antibodies• Complement• Interleukins

8. Stem cells9. Growth factors10. Gene therapy

Drugs

Clinically Tested1. NMBs √2. Steroids ?3. Surfactant X4. β2 agonists X5. Diuretics ?6. Ketoconazole X7. Activated Protein C X8. Nitric Oxide X9. Silvelestat X10. Lisofylline X11. Pharmaconutrients X

Clinically Untested1. Prostacyclin2. Almitrine3. Ibuprofen4. N-Acetylcysteine5. Mucolytics6. Albumin

Next Wave1. Statins2. Aspirin3. ACEI / ARB4. Macrolides5. Insulin6. Vitamin D7. Antibodies• Complement• Interleukins

8. Stem cells9. Growth factors10. Gene therapy

ALTA Study

• 282 patients with ALI• Aerosolized albuterol vs saline

Ventilator-free days • albuterol 14.4 vs control 16.6 d• 95% CI difference –4.7 to 0.3 d; P =

0.087Hospital death • albuterol 23.0% vs control 17.7%• 95% CI difference –4.0 to 14.7%, P=0.30

BALTI 2 Study

• 326 ARDS patients • PaO2/FiO2 < 200 mmHg

• IV salbutamol vs placebo

28 day mortality• salbutamol: 34% vs Control 23%• RR 1 47, 95% CI 1 03 to 2 08∙ ∙ ∙

Nitric Oxide

Severe ARDS • n = 329, six trials• RR 1.01; 95% CI 0.78 to 1.32; p = 0.93

Mild to Moderate ARDS• n = 740, seven trials• RR1.12, 95% CI 0.89 to 1.42; p = 0.33

Ventilatory Adjuncts

Fluids

Drugs

ECMO

Ventilation

Ventilatory Adjuncts

Fluids

Drugs

ECMO

Ventilation

ECMO

CESAR STUDY• 170 patients with severe respiratory

failure

6 month mortality outcome• ECMO centre 63% vs referral 47%• RR 0·69; 95% CI 0·05 to 0·97, p=0·03

ECMO

ANZICS H1N1 ECMO Case Series• 2009 influenza A(H1N1) - associated

ARDS• 68 patients

• Median PaO2/FiO2 56 (48-63) mmHg• 71% survival

Ventilatory Adjuncts

Fluids

Drugs

ECMO

Ventilation

Ventilatory Adjuncts

Fluids

Drugs

ECMO

Ventilation

Ventilatory Adjuncts

Fluids

Drugs

ECMO

Ventilation

Ventilatory Adjuncts

Fluids

Drugs

ECMO

Ventilation

Ventilatory Adjuncts

Fluids

Drugs

ECMO

Ventilation

Ventilatory Adjuncts

Fluids

Drugs

ECMO

Ventilation

To Summarise

1. The positive studies would likely be positive in any critical care condition

2. The negative studies are probably negative because they have been studied in any critical care condition (i.e. ARDS) rather than the specific condition that they are intended for (i.e. DAD)

To Summarise

1. The positive studies would likely be positive in any critical care condition

2. The negative studies may be negative because they have been studied in any critical care condition (i.e. ARDS) rather than the specific condition that they are intended for (i.e. DAD)

To Summarise

1. The positive studies would likely be positive in any critical care condition

2. The negative studies may be negative because they have been studied in any critical care condition (i.e. ARDS) rather than the specific condition that they are intended for (i.e. DAD)

To Summarise

1. The positive studies would likely be positive in any critical care condition

2. The negative studies may be negative because they have been studied in any critical care condition (i.e. ARDS) rather than the specific condition that they are intended for (i.e. DAD)

ARDS – A Condition That….

1. can’t diagnose2. of limited use3. no specific treatment for4. people don’t die from

…….doesn’t actually exist

Final Thoughts

1. ARDS studies need to be able to identify alveolar injury

2. Did the AECCC prevent us from adequately investigating some therapies?

3. Are critical care syndromes really of any use?

http://www.flickr.com/photos/furlined/6744550629

References at: www.criticalcarereviews.com/SMACC

Autopsy Case Series

• 712 Autopsies

• 356 ARDS patients

• 159 had DAD (45%)

• 75% of severe ARDS had DAD