ARDS Andrew Stewart ST5 Breakfast Club – May 2017

Plan History

Definition

Pathophysiology

Management: what works / what doesn’t

History

History

1960s - USA

David Ashbaugh (right) -> Thoracic surgeon

Thomas Petty (left) -> Respiratory Physician

Chief Residents at University of Colorado Medical Centre

The first description

Case series – 12 patients admitted to general ICU

Very similar respiratory syndromes

Differing trigger conditions

ARDS: - acute - bilateral infiltrates - reduced pulmonary compliance - persistent hypoxaemia

Publication

NEJM: rejected the manuscript..! ‘documentation of inappropriate and dangerous ventilator management’

• Also rejected by….

• JAMA • American Journal of Surgery

Finally..

The Lancet

Summer – 1967

Springboard for global research

Ashbaugh DG et al. The Lancet 1967; 2(7511):319-323

Definitions

Murray – Lung Injury Score (LIS)

1988

LIS – provides assessment of severity

4 criteria - alveolar infiltration - hypoxaemia - PEEP - compliance

Each criteria scored… /4

Downsides: compliance not routinely measured + no cardiogenic/overload criteria

Used in conjunction with modern day definitions

Murray et al. Am rev Respir Dis 1988; 138:720-723

LIS

American – European Consensus conference AECC

Published 1994

North American / European joint committee

ARDS: - acute - bilateral opacities - PCWP < 18 / no evidence of LA HTN - PF ratio < 200 (ARDS) < 300 (ALI)

But: Acute? Infiltrates? and - PCWP: rarely measured + unreliable

Bernard et al. Am J Resp crit care 1995; 149:818-824

Berlin Definition - ESICM

Published in 2012

Aims to address controversies with AECC def.

ARDS: - Acute (within 7 days of known trigger) - bilateral opacities on either CXR/CT (not explained by other pathology) - Oedema not fully explained by cardiac/overload - PF ratio: <100 (severe) 100-200 (mod) 200-300 (mild) with PEEP applied

ARDS definition task force. JAMA 2012; 307: 2526-2533

Ongoing difficulties…

What quantifies bilateral infiltrates? (even the experts aren’t sure…)

Complex pathology v simplistic diagnostic criteria

No biomarker

If it’s not severe, does it really matter..?

Pathophysiology

TRIGGER EXUDATIVE FIBRO PROLIFERATIVE RESOLUTION

Obligatory science slide

Trigger Dys–regulated inflammatory response

WBC activation cytokine release (IL 1,6 + TNF)

Inflammation affects lung parenchyma

Specifically; all layers of blood gas barrier

Oedema formation: alveolar + interstitial

Type 2 cells reduced surfactant

Fibroblast proliferation + hyaline membranes

Causes

DIRECT - Pneumonia - Inhalation - Aspiration

INDIRECT - Sepsis - SIRS - Transfusion

ARDS phenotypes

Indirect / direct causes

Damage occurs across full width of ACM.

But -> Insult is not equal.

Direct ARDS: greater damage to epithelium

Indirect ARDS: greater damage to endothelium

‘Distinct Molecular Phenotypes of direct v indirect ARDS’

Hypothesis – direct ARDS: greater epithelial injury

953 patients in total (multi-centre)

Biomarkers: surfactant protein D (direct) angiopoeitin 2 (indirect)

Found higher levels of respective direct/indirect biomarkers

may allow targeting of future novel therapies

Calfee et al Chest 2015 jun;147:1539-48

Management

Management

What’s in: - Lung protective ventilation (!) - Early neuromuscular blockade - Appropriate fluid management - Early proning - ECMO

What’s out: - beta2agonists - steroids (at least for now…) - Nitric Oxide - HFOV

Lung Protective Ventilation

ARMA Lower tidal volume ventilation in ARDS

NEJM – May 2000

Multi – centre RCT -> 10 hospitals across US

1990s – LPV proven to reduce mortality in animals

Conflicting data from 4 human studies

ARMA aimed to provide clarity

Hypothesis: lower VTs / reduced lung stretch

Brower RG et al. NEJM 2000; 363:1107-1116

Method

Enrollment: 1996 – 1999

861 patients

TREATMENT CONTROL

Volumes based on PBW / Ventilation: volume control with AC

- 6ml/kg VTs - 12ml/kg VTs - plat < 30 - plat <50

Results

Terminated early

Treatment arm; 22% reduction in mortality

Also: reduced: vent days, days with MOF + LOS

Reduced IL – 6 levels

LPV: required higher Fi02/PEEP (days 1,2,3)

Why so successful..?

Larger difference in VTs (6 -> 12ml/kg) compared to previous studies.

Resp acidosis – treated with bicarb / Increased MV (therefore ?patients less acidotic than prev studies.

So – should we treat acidosis early…?

- should we use volume control ventilation..?

NM blockade

ACURASYS Neuromuscular blockade in early

ARDS

NEJM – September 2010

Large MC RCT -> 40 ICUs across France

No intervention (since ARMA) shown to improve survival

Could early use of cisatracurium reduce mortality? less dys-synchrony: reduced stretch/VILI

Papazian et al. NEJM. 2010; 363:1107-1116

Method

340 patients randomised - Mechanical ventilation - ARDS + PF ratio <150 - < 48 hours from Dx

TREATMENT CONTROL - MR: bolus + IVI - Placebo

Infusions continued for 48 hours…

Results

Treatment arm: - Reduced 90 day mortality (31.6 v 40.7%) - More vent free days - Less barotrauma

No stat significant difference in ICUAW

Likely mechanism: improved patient/vent synchrony -> better LPV…

Fluid Management

FACTT Fluid and catheters treatment trial

Authors recognised; optimal fluid Mx not known

A balancing act: -> Systemic perfusion v pulmonary function

Hypothesis – running ‘dry’ likely better for chest, but may worsen non – pulmonary organ function…

2006: MC RCT – 20 US hospitals (ARDSnet)

Wiedemann et al. NEJM. 2006; 354:2564-2575

Method

1000 patients randomised to receive either: -> Liberal (CVP 10-14) -> Conservative (CVP <4)

Crucially - Only enrolled after CVS ‘stable’ (average 43 hours from Dx)

Assessed every 4 hours for 7 days

Interventions via strict protocol to achieve target

2ndry Ix – further randomised to either CVC/PAC

Bottom Line

Conservative strategy: - Fewer ventilator days - Reduced ICU LOS - Better gas exchange

However – no mortality benefit @ 60 days

No increase in non – pulmonary organ failure

‘Conservative’ group: actually ‘even’ rather than negative balance…

Proning

PROSEVA Proning severe ARDS patients

Proning- makes sense….

Most ARDS is posterior /inferior

Proning should improve perfusion to healthy lung parenchyma

Multiple studies demonstrated improved numbers

No mortality benefit -> until PROSEVA

Typical CXR

Typical CT…

Posterior Infiltrate ->

PROSEVA

NEJM – 2013

27 participating ICUs – Spain and France

All were experience in proning

466 patients in total

Inclusion: early (<36hrs) + PF ratio <150

Proned – at least 16 hours

Claude G et al. NEJM 2013; 368:2159 - 2168

Results

23 day mortality: 16% (prone) v 32.8% (supine)

90 day mortality: 23.6% (p) v 41% (s)

No major difference in complications

All units – at least 5 years experience in proning

Early application of prolonged proning improves mortality in patients with ‘severe’ ARDS

ECMO

CESAR Conventional therapy v ECMO for patients

with SRF

2009 Lancet - RCT

180 patient enrolled across UK

Inclusion: SRF with Murray score > 3

Pneumonia + ARDS most common Dx

Randomised: vv ECMO v standard LPV

Outcome measure: 6 month survival without significant disability

Results

ECMO – 63% v LPV – 47% (6mo survival)

22 patients in ECMO group improved prior to Tx

ECMO -> longer ICU and hospital stay

ECMO – a viable option for refractory SRF

Steroids

Steroids The controversy rages on..

Steroids should….in theory….. be of some benefit?

Current literature – very conflicting

Not in routine use at present

Methylprednisolone – drug of choice

Studies

No role for prevention (4 RCTs in 1970s/80s)

Early use at high dose -> worsens mortality (Bernard et al 1987)

2006 – Steinburg et al (ARDS net) - Late, low dose, prolonged course - Fewer vent days / but no mortality benefit - not recommended for routine use

Higher levels of pro – collagen peptide 3 (BAL) in those responding well to steroids….

Bottom Line

May be of benefit – unresolving fibro – proliferative ARDS.

Low dose, prolonged infusions of M – pred

More data needed before routine use

Beta 2 Agonists

BALTI trials

Summary

High mortality syndrome

Good management improves outcome

Diagnosis -> Berlin criteria

Murray score -> sometimes used in conjunction

In: LPV / Fluid Mx / NMB / Proning / ECMO

Out: Beta2 agonists / HFOV / steroids (for now!)

Thank you