Acute Respiratory Distress Syndrome

Bilateral diffuse inflammatory lung injury characterised by loss of aerated lung tissue and reduced pulmonary compliance. Various diagnostic criteria exist, the Berlin Criteria requires all of:

The Berlin criteria were updated in 2023 to remove the reliance on ABG and radiography, and include the use of HFNO. Whilst this makes the definition more widely available, it also weakens discrimination of an already over-broad definition and so further limits the utility of the concept of ARDS.

Acute onset
Within 7 days of known precipitant.
Bilateral radiographic opacities
Consistent with pulmonary oedema. Can be on:
- XR
- CT
- Ultrasound
  With a well-trained operator
Non-hydrostatic
Not related to an ↑ PCWP. If access to the following equipment is available, then it is present despite:
- Intubation
- NIV with CPAP ⩾5cmH₂O
- HFNO ⩾30L/min
Hypoxia
ARDS is graded by severity of hypoxia into:
- Mild
  - PaO₂/FiO₂: 200-300
  - SpO₂/FiO₂ <315 with SpO₂ <97%
- Moderate
  PaO₂/FiO₂: 100-200.
- Severe
  PaO₂/FiO₂: <100.

The PaO₂:FiO₂ (P:F) and SpO₂:FiO₂ and (S:F) ratios quantify the degree of hypoxia relative to the degree of oxygen supplementation.

They are calculated as:

\(P/F = {PaO_2 \over FiO_2}\)
\(S/F = {SpO_2 \over FiO_2} \times 1000\)

Where:

\(PaO_2\) is in mmHg
\(FiO_2\) is a decimal (0-1)

Epidemiology and Risk Factors

Significant regional variation, in part due to different definitions. In general, ARDS:

Represents ~10% of ICU admissions
- ~25% of those requiring mechanical ventilation
Cases are reasonably spread across all severities:
- ~30% are mild
- ~45% are moderate
- ~25% are severe

Pathophysiology

Acute phase consists of a combination of:

Alveolar-capillary barrier damage
Bidirectional leakage of fluid and protein:
- Plasma protein into alveolus
  Causing pulmonary oedema.
- Alveolar protein into plasma
  Surfactant and other alveolar proteins.
Inflammatory infiltrate
Large ↑ in:
- Alveolar macrophages
  Usually dominant cell in health.
- Alveolar neutrophils
  Rare in health (~1% of cells), become superabundant (~90%) in ARDS.
Surfactant dysfunction
Epithelial cell damage alters cellular production of inflammatory mediators and ↑ water egress into the alveolus, as well as production of dysfunctional surfactant.

The late (>5 days) phase is characterised by fibrosing alveolitis.

Aetiology

Precipitants of ARDS
Direct	Indirect
Pneumonia	Sepsis
Aspiration	Trauma
Contusion	Massive transfusion
Fat embolism	Pancreatitis
Drowning	CPB
Inhalational injury
Reperfusion injury

Clinical Manifestations

Diagnostic Approach and DDx

Investigations

Management

Principles of management are:

Early identification and treatment of cause
Avoidance of further lung injury

Specific therapy:

Pharmacological
- Steroids
  Likely ↓ mortality and ventilator duration.
  - Indications depend on cause, and include:
    - Primarily infective
    - Steroid-responsive
      Organising pneumonias.
    - Moderate-severe ARDS that fails standard therapies
  - Consider:
    - Dexamethasone 10mg IV OD
    - Methylprednisolone
  - Pure glucocorticoid preferable to mineralocorticoid
    Avoids sodium and water retention.
Physical
- Proning
  Significant improvement in hypoxia by:
  - Recruiting dorsal lung
  - Improving V/Q matching

Meduri Protocol for Methylprednisolone Dosing
Time	Dose
Load	1 mg/kg
Day 1-14	1 mg/kg/day
Day 15-21	0.5 mg/kg/day
Day 22-25	0.25 mg/kg/day
Day 26-28	0.125 mg/kg/day
Note: If the patient extubates during day 1-14, advance to day 15 of the schedule

Proning is a cornerstone of ARDS management, and is covered in detail under Proning.

Supportive care:

B
- Lung protective ventilation
  - Appropriate PEEP
    Often titrated to a PEEP-FiO₂ table. Considerations:
    - The disease and degree of recruitable lung is highly heterogenous and often over-distension and under-recruitment will occur together
    - Higher PEEP is associated with better outcomes in more severe disease, and worse outcomes in milder disease
    - Inadequate PEEP tends to cause under-recruitment and hypoxia
    - Excessive PEEP tends to cause over-distension, ↑ lung stress, and reduced cardiac output
    - Ideally, PEEP maintains lung volume at FRC thereby:
      - Maximally recruiting available alveoli
      - Spreading V_T over a greater number of alveoli
      - Reducing Pip
      - Deceasing Barotrauma and volutrauma
  - Appropriate FiO₂
    High FiO₂ is associated with diffuse alveolar damage. FiO₂ should be titrated (in combination with PEEP adjustment):
    - Down to <0.6 (as able)
    - Aiming SpO₂ >90%
  - Permissive hypercapnoea
  - Avoid:
    - Volutrauma
      AimV_T4-6mL/kg predicted body weight.
    - Barotrauma
      Aim Pplat <30cmH₂O.
      - The plateau pressure is a substitute for the transpulmonary pressure, which reflects the actual elastic distending pressure of the lung
        
        Measurement of the transpulmonary pressure can be performed with an oesophageal balloon, which allows the chest wall and lung elastance to be separated (rather than measuring the elastance of the respiratory system as a whole)
      - This may be still be excessive (or inadequate) in patients at extremes of chest wall elastance
- Neuromuscular blockade
  - No evidence of benefit for routine use
  - Appropriate for:
    - Ventilator dyssynchrony despite deep sedation
    - Very poor lung compliance preventing lung protective ventilation
  - Advantages
    - ↓ PTHx rate
    - Predicate of proning
  - Disadvantages
    - Requires deep sedation
    - ↑ Haemodynamic instability
- iNO
  Appropriate to trial for hypoxaemia refractory to traditional ventilation, for:
  - Short periods
  - As a bridge to proning or ECMO
- VV ECMO
E
- Early mobilisation
G
- Stress ulcer prophylaxis
- Feeding
H
- DVT prophylaxis

One reasonable approach to PEEP-setting is identifying the level where DO₂ (i.e., the product of arterial oxygen content and cardiac output) is maximal. Determining this point at the bedside is, of course, difficult.

Disposition:

Marginal and Ineffective Therapies

High-Frequency Oscillatory Ventilation
↑ Mortality compared to lung protective ventilation strategies.
Recruitment manoeuvres
Recruitment improves oxygenation by ↑ number of ventilated alveoli. However, following a recruitment manoeuvre:
- Over-inflation of previously normal lung occurs
  May be harmful.
- Oxygenation may improve
  Predominantly early ARDS with a lower baseline PEEP.
- Haemodynamic instability may occur
  Due to large changes in VR.

Recruitment manoeuvres are covered in more detail under Recruitment.

Anaesthetic Considerations

Complications

Prognosis

Death
Improving with better preventative care and ↓ VILI. Mortality varies on:
- Severity:
  - ~35% mild
  - ~40% moderate
  - ~45% severe
- Cause and comorbidities:
  - ↓ In trauma
  - ↑ In elderly, chronic or acute organ failures, and sepsis
Chronic lung disease
Pulmonary function tests normalise in 6-12 months.
Persistent critical illness
↑ In survivors of ARDS compared to non-ARDS ICU patients.
- Functional impairment persists in young survivors of severe disease

Key Studies

Lung Protective Ventilation:

ARMA (2000)
- 861 non-pregnant Americans with ARDS of any grade (P/F <300) without neuropathy, chronic lung disease, or severe burns
- Multicentre (10) randomised trial
- Low tidal volume ventilation vs. “traditional” high tidal volume ventilation
  - Low tidal volume ventilation
    - VCV at 6mL/kg V_T
    - Pplat <30cmH₂O
  - “Traditional” ventilation
    - CVC with 12mL/kg V_T
    - Pplat <50cmH₂O
- Significant ↓ mortality (39.8% vs. 31%) in low tidal volume ventilation group

The ARMA trial also included a ketoconazole arm, which was stopped early for lack of efficacy. It has not been included in this summary.

ARMA: Titration Protocol
FiO₂	PEEP (cmH₂O)
0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0 1.0	5 5 8 8 10 10 10 12 14 14 14 16 18 18 20-24
Move up or down the table to target one of: PaO₂ 55-80mmHg If most recent. SpO₂ 88-95%

Open Lung Approach:

Combination of high PEEP and recruitment manoeuvres to prevent alveolar collapse, and thereby:
- ↓ VILI
- ↓ Atelectotrauma
- ↑ Oxygenation
(Appropriately) high PEEP is generally well established as safe and effective, the role of recruitment manoeuvres is unclear
ART (2017)
- ~1000 adults with moderate-severe ARDS requiring mechanical ventilation, without high risk of barotrauma or escalating vasoactive requirements
- Multicentre (120!), unblinded, allocation concealed, block randomised trial
- Open lung vs. control
  - Open lung
    - PCV with driving pressure of 15cmH₂O
    - Muscle relaxation applied
    - Staircase recruitment up to PEEP of 45cmH₂O
    - PEEP down-titrated in 3cmH₂O increments, with measurement of static compliance at leach level
      Level with highest lung compliance noted.
    - Further recruitment at PEEP 45cmH₂O of PEEP
    - New PEEP set to level at maximal compliance + 2cmH₂O
  - Control
    - Conventional ARDSnet ventilation
  - Both groups managed with VCV at 6mL/kg with safe lung ventilation
  - Refractory hypoxaemia managed with proning, iNO, or VV ECMO
  - Pressure support attempted once PEEP <14cmH₂O
- ↑ Mortality in open lung group (55.3% vs 49.3%, p=0.04)
- Secondary outcomes showed the open lung group had ↑ 6 month mortality, ↓ ventilator free days, and more pneumothoraces requiring drainage
- Compliance in open lung group did not significantly ↑ following recruitment
- Recruitment manoeuvre had to be abandoned in 15% due to hypotension or hypoxia
- Most patients only had one recruitment manoeuvre
- Indiscriminate aggressive recruitment manoeuvres are harmful in moderate-severe ARDS, but this does not rule out benefit in select subgroups

Muscle Relaxation:

Lung protective ventilation aims to ↓ VILI by ↓ barotrauma and Pip
NMBA bypass any ventilator dyssynchrony and may improve chest wall compliance
ACURASYS (2010)
- 340 French adults intubated with ARDS for <48 hours with a P/F ratio <150mmHg
- Multicentre (20), double-blind, block randomised trial
- 80% power to detect 15% ↓ ARR (!) in 90 day mortality assuming control mortality of 50%
- Cisatracurium vs. placebo for 2 days
  - Cisatracurium
    15mg bolus then 37.5mg/hr.
  - Placebo
  - All patients received VCV and ARDSnet ventilation with 6-8mL/kg V_T
- Significant ↓ in adjusted 90 day mortality (Hazard Ratio 0.68, CI 0.48-0.98)
- Underpowered due to lower than expected control mortality
- Secondary outcomes:
  - No difference in actual mortality (32% vs. 41%)
  - ↓ Barotrauma in cisatracurium group
  - ↑ Organ failure days in cisatracurium group
ROSE (2019)
- 1006 Americans with moderate-severe ARDS (P/F <150), with several appropriate exclusions including BMI >100
- Multi-centre (48), unblinded, block randomised trial
- 1408 patients provide 90% power for 9% ↓ mortality, based on control group mortality of 35%
- Deep sedation and paralysis vs. light sedation for average 48 hours
  - Intervention
    - Deep sedation
    - Cisatracurium
      15mg bolus then 37.5mg/hr.
  - Control
    - Light sedation
    - 25% received NMBA
  - Sedation to RASS 0 to -1
  - Managed with high PEEP
- Stopped early for futility
- No change in mortality (42.5% vs 42.8%)
- Secondary outcomes: ↑ Cardiac SAE in intervention group
- 80% of screened patients excluded, with a large number already receiving NMBA

Other:

PROSEVA (2013)
- 474 Europeans with ARDS (PF <150mmHg), intubated for <36 hours at inclusion
- Multicentre (experienced proning units), assessor-blinded, RCT
- 456 patients gives 90% power for 15% ARR from control mortality of 60%
- Randomised to proning vs. supine
  - Proning
    16 consecutive hours for 28 days, or until improvement.
  - Standardised ventilation and weaning strategy
- Significant ↓ mortality (16% vs. 33%, OR 0.42 (0.26-0.66), NNT 6) in proning group
- Over 2000 patients were not screened

PROSEVA was the definitive trial on proning.

ARMA (2000)
- 861 non-pregnant Americans with ARDS of any grade (P/F <300) without neuropathy, chronic lung disease, or severe burns
- Multicentre (10) randomised trial
- Low tidal volume ventilation vs. “traditional” high tidal volume ventilation
  - Low tidal volume ventilation
    - VCV at 6mL/kg V_T
    - Pplat <30cmH₂O
  - “Traditional” ventilation
    - CVC with 12mL/kg V_T
    - Pplat <50cmH₂O
- Significant ↓ mortality (39.8% vs. 31%) in low tidal volume ventilation group

The ARMA trial also included a ketoconazole arm, which was stopped early for lack of efficacy. It has not been included in this summary.

ARMA: Titration Protocol
FiO₂	PEEP (cmH₂O)
0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0 1.0	5 5 8 8 10 10 10 12 14 14 14 16 18 18 20-24
Move up or down the table to target one of: PaO₂ 55-80mmHg If most recent. SpO₂ 88-95%

DEXA-ARDS (2020)
- 277 non-pregnant, non-lactating adult Spaniards intubated for moderate-severe ARDS undergoing active treatment
- Without COPD, heart failure, or other immunosuppressants
- Assessor (not clinician) blinded, multicentre (17) randomised trial, stratified by centre
- 80% power to detect ↓ from 9 to 7 ventilator free days, and 15% ↓ (!) in 60 day mortality assuming control mortality of 48%
- Dexamethasone vs. usual care
  - Dexamethasone group
    - 20mg IV OD from day 1-5
    - 10mg IV OD from day 6-10
- Significant ↑ in ventilator-free days (12.3 vs 7.5)
- Secondary outcomes of 60 day mortality, ICU mortality, duration of mechanical ventilation, P/F ratio all favoured dexamethasone group
- Most patients not proned
- Most patients had pneumonia or sepsis
- Control group mortality lower than anticipated

References

Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.
Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. The Lancet Respiratory Medicine. 2020;8(3):267-276. doi:10.1016/S2213-2600(19)30417-5
Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. New England Journal of Medicine. 2019;380(21):1997-2008. doi:10.1056/NEJMoa1901686
Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2017;318(14):1335-1345. doi:10.1001/jama.2017.14171
Papazian L, Forel JM, Gacouin A, et al. Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome. New England Journal of Medicine. 2010;363(12):1107-1116. doi:10.1056/NEJMoa1005372
Guérin C, Reignier J, Richard JC, et al. Prone Positioning in Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2013;368(23):2159-2168. doi:10.1056/NEJMoa1214103
Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, et al. Methylprednisolone Infusion in Early Severe ARDS: Results of a Randomized Controlled Trial. Chest. 2007 Apr 1;131(4):954–63.