INTENSIVE CARE
Acute respiratory distress
syndrome
Tapan Parikh aka Parmar
David Pilcher
Abstract
Acute respiratory distress syndrome (ARDS) is a heterogeneous lung
disease that is triggered by pulmonary and non-pulmonary pathol-
ogies. It predominantly causes hypoxaemic respiratory failure and
can lead to significant morbidity and mortality. Although ARDS re-
mains underdiagnosed, 24% of mechanically ventilated patients in
intensive care units and 33% of coronavirus disease (COVID-19) pa-
tients admitted to the hospital are reported to have ARDS. Despite
recent advances in treatment, mortality remains at more than 30%
for all ARDS patients and 43% for severe ARDS.
The pathophysiology is complex and involves acute pulmonary and
systemic inflammation, alveolar oedema, and de-recruitment which
lead to ventilation-perfusion mismatch, reduced lung compliance
and hypoxaemia. Similarities in the pathophysiology of COVID-19
ARDS outnumber differences from non-COVID-19 ARDS. Inhomoge-
neous distribution of transpulmonary pressure variation throughout
the lungs in ARDS increases the risk of patient self-inflicted lung injury
and ventilator-associated lung injury.
Stratifying ARDS patients as per Berlin definition can help to recog-
nize ARDS early, identify resource requirements and plan appropriate
management. Treating the underlying cause, lung-protective ventila-
tion and supportive care are the mainstays of clinical management.
Multiple rescue therapies, novel treatments, and methods of facili-
tating individualized ventilation have been described but many require
further validation; and appropriate patient selection is warranted.
Keywords Acute respiratory distress syndrome; ARDS; COVID-19;
ECMO; individualized ventilation; intensive care; lung-protective
ventilation; P-SILI; pathophysiology; rescue therapies
Royal College of Anaesthetists CPD Skills Framework: Intensive care
medicine and emergency management; airway and resuscitation
Introduction
Acute respiratory distress syndrome (ARDS) is a heterogeneous
lung disease that can lead to significant morbidity and mortality
among critically ill patients including patients infected with severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) respon-
sible for the recent coronavirus disease (COVID-19) pandemic.
Tapan Parikh aka Parmar MD DNB is a Transitional year trainee of
College of Intensive Care Medicine and currently works at the Alfred
Hospital ICU, Melbourne, Australia.
David Pilcher MBBS FRACP FCICM is a senior Intensive Care Specialist
at the Alfred Hospital, Melbourne, Australia and is the Chair of the
Australian and New Zealand Intensive Care Society (ANZICS) Centre
for Outcome and Resource Evaluation.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 23:10
Learning objectives
After reading the article, you should be able to:
C define acute respiratory distress syndrome (ARDS), describe the
complex pathophysiology, and identify aetiologies and risk fac-
tors for poor prognosis
C categorize ARDS patients in different severity and able to explain
ventilatory management including lung-protective ventilation
and non-ventilatory management
C discuss appropriateness of patient selection for various rescue
and novel therapies and debate about utility of components of
individualized ventilation
Despite recent advances in the understanding of pathophysiology,
investigations and treatment, ARDS remains significantly under-
diagnosed and mortality remains high. Lung-protective ventila-
tion and treating the underlying cause have been the mainstay of
treatment. Prone positioning, veno-venous extracorporeal mem-
brane oxygenation (VV ECMO) and neuromuscular blockade are
sometimes deployed with uncertain clinical benefits. The patho-
physiology of COVID-19 pneumonitis marginally differs, howev-
er, most of the principles of treatment are similar.
Definition and scoring system
ARDS was first reported in a case series of 12 patients from
Denver in 1967. The American European Consensus Conference
(AECC) in 1994 defined ARDS as the acute onset of hypoxaemia
(the ratio of partial pressure of arterial oxygen to fraction of
inspired oxygen [PaO2/FiO2]
200 mmHg), with bilateral in-
filtrates on chest X-ray, in the absence of left atrial hypertension.
The sensitivity of this definition remained reasonable at 84%, but
the specificity was significantly lower at only 51%.1
Due to issues with the validity of this definition, a consensus
process was developed (an initiative of the European Society of
Intensive Care Medicine endorsed by the American Thoracic
Society and the Society of Critical Care Medicine), which pro-
duced the Berlin definition of ARDS in 2012. This underwent
independent peer-review and endorsement by the same
societies.1
The final version of the Berlin definition includes the four key
diagnostic criteria:
1. Acute onset: within 7 days of a defined trigger
2. Degree of hypoxia: a PaO2:FiO2 ratio of <300 mmHg (40 kPa)
on at least 5 cmH2O of positive end-expiratory pressure
(PEEP).
3. Bilateral lung infiltrates seen on either chest X-ray or
computed tomography scan
4. Not fully explained by cardiac failure or fluid overload.
ARDS is further subcategorized into mild, moderate, or severe
categories according to PaO2/FiO2 ratio and these are listed in
Table 1. Mortality increased with stages of ARDS from mild
(27%; 95% CI, (24e30%)), to moderate (32%; 95% CI, (29
e34%)) to severe (45%; 95% CI, (42e48%)). Similarly, the
duration of mechanical ventilation increased as the severity of
ARDS increased from mild (5, interquartile [IQR], 2e11) to
moderate (7, IQR, 4e14) and severe (9, IQR, 5e17).2
635 Ó 2022 Published by Elsevier Ltd.
 INTENSIVE CARE
Compared with the AECC definition, the final Berlin definition
had better predictive validity for mortality. The Berlin definition
does not include underlying aetiology, lacks a direct measure of
lung injury, and does not allow early identification. The PaO2/
FiO2 cut-offs for ‘severity’ of 100, 200 and 300 mmHg are arbitrary
and poorly validated. The PaO2/FiO2 ratio itself depends on other
factors such as PEEP, inspiratory/expiratory time ratio, and FiO2.
The PaO2/FiO2 ratio is widely accepted as part of the ARDS
definition, provides categorization of severity for ARDS and is
simpler to calculate than other scores such as the oxygen index
(OI, based on mean airway-pressure (Pmaw) and PaO2/FiO2
ratio), extravascular lung water index (EVLWI), and sequential
organ failure assessment (SOFA). However, the last three scores
have better prognostic capabilities in terms of 28-day mortality
compared to PaO2/FiO2 ratio.3
The lung injury prediction score (LIPS) identifies patients who
are unlikely to develop ARDS with a negative predictive value
(LIPS <4) of 97%. Murray Score >3, which is based on the level
of PEEP, PaO2/FiO2 ratio, the dynamic lung compliance, and the
degree of radiographic infiltration is commonly used as a quali-
fying threshold for support with ECMO. These scores address the
Berlin definition lack of utility in early recognition of ARDS and
deciding the treatment modality.
Epidemiology and outcomes
An international, multicentre, prospective cohort study (Lung
safe) published in 2016 demonstrated that the period prevalence
of ARDS was 10.4 and 23.4% of all patients requiring MV. Clinical
recognition rates ranged from 51.3% for mild ARDS to 78.5% for
severe ARDS.3 Additionally, a growing number of ARDS patients
are managed by high-flow nasal cannula (HFNC) support. Hence,
the actual incidence of ARDS may be higher. Overall hospital
mortality in ARDS is more than 30% rising to 43% in moderate to
severe ARDS. However, it remains unclear how much of the re-
ported mortality can be attributed to ARDS as opposed to under-
lying cause and other comorbidities.4 The cause of death is more
commonly sepsis and multiple organ failure than respiratory
failure. About 50% of patients remain burdened by functional
limitations or psychological and cognitive impairment at 2 years.4
As of 20 March 2022, over 468 million confirmed cases and
over 6 million deaths have been reported globally due to COVID-
19 infection. Overall, 33% of hospitalized patients with COVID-
19 infection developed ARDS.5
Aetiologies and risk factors
The most common risk factors are pneumonia and non-
pulmonary sepsis. New causes such as vaping product use-
Classification of acute respiratory distress syndrome
(ARDS) as per Berlin definition
Severity of ARDS PaO2:FiO2 ratio (mmHg) PaO2:FiO2 ratio (kPa)
Mild 200e300 26.6e40
Moderate 100e200 13.3e26.6
Severe <100 <13.3
Table 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE 23:10
associated lung injury, have emerged. Patients with diabetes
and women are less likely to develop ARDS. However, for pa-
tients with severe persistent ARDS, women have higher mortality
than men. The attributable risk of any singular genetic poly-
morphism to ARDS risk or outcome seems minimal.6 See Table 2
for precipitants and differential diagnosis.
Pathophysiology
Microbial or cell injury products from pulmonary and non-
pulmonary sources cause activation of alveolar macrophages.
This releases cytokines that activate circulating neutrophils, and
release further inflammatory molecules leading to not only
pathogen killing, but also injury to the alveolar endothelial
eepithelial barrier. Due to dysfunction of the surfactant
secreting Alveolar type II pneumocytes and reduced lymphatic
clearance, the alveolar space fills with an inflammatory cell-rich
proteinaceous oedema fluid (exudative phase). This causes
alveolar collapse and de-recruitment.
In the proliferative phase of ARDS, various mechanisms
including neutrophil apoptosis, interstitial matrix reformation,
and regrowth of alveolar epithelium result in clearance of path-
ogens, repair, and restoration of normal function. If the prolif-
erative phase is impaired or prolonged, ongoing inflammation
and fibroblast proliferation ultimately lead to the long-term
consequence of fibrosing alveolitis (fibrotic phase of ARDS) in
some patients.
Gas exchange impairment in ARDS
Alveolar oedema and de-recruitment cause reduced ventilation-
to-perfusion (V/Q) ratio. Increased FiO2 can improve oxygena-
tion. However, pulmonary vascular injury and intrapulmonary
shunting leading to high V/Q ratio, maybe unresponsive to
increased FiO2. Diffusion limitation plays a minimal part in
impaired oxygenation.
CO2 elimination is also affected which may be addressed by
raising minute ventilation. Hypercapnia with protective lung
ventilation is better accepted since the landmark ARDSNet study
showed mortality reduction when a low tidal volume (TV) (6 ml/
kg) was used versus a high TV (12 ml/kg).
Regional differences in ventilation and blood flow
The dorsal and basilar regions of the lung are predominately
affected by oedema, consolidation, and shunting, especially in
the supine position.
Heterogeneity of regional ventilation is larger in the supine
position due to more compressive effect of the lung and soft
tissue weight on basilar lung regions and greater regional pleural
pressure differences in the supine position.
The pulmonary circulation is less affected by gravitational
forces and positioning. Blood flow is higher in posterior and
caudal lung regions, and hence, prone positioning which im-
proves ventilation in these areas is associated with significant gas
exchange improvement in most patients with ARDS.
Respiratory mechanics in ARDS
Lung parenchyma is formed of interdependent alveoli, which
prevent overdistension during inspiration and collapse during
expiration. In ARDS, lung compliance is reduced due to alveolar
oedema and de-recruitment. The ‘baby lung’ concept/term is
636 Ó 2022 Published by Elsevier Ltd.
 INTENSIVE CARE
Precipitants of acute respiratory distress syndrome and differential diagnosis
Common precipitants Less common precipitants
Pneumonia (bacterial and viral are the most Smoke inhalation
common, compared to mycobacterial and Drowning
fungal) E-cigarette use
Non-pulmonary sepsis Multiple transfusion of blood products
Aspiration of gastric contents
Ischaemia-reperfusion injury
Pancreatitis
Non-cardiogenic shock
Severe trauma or high-risk surgery
Drug overdose
Table 2
used to indicate the reduced size of aerated lung. This is physi-
ological rather than anatomical because compliance changes
over the course of the disease and due to various treatment
manoeuvres. This variation creates heterogeneity of distending
pressures which form a penumbra of at-risk lung units of alveoli.
ARDS may be associated with airway obstruction due to
inflammation and thickening of the distal small airways’ wall.
This leads to expiratory flow limitation and increased airway
resistance which improves with PEEP but not with
bronchodilators.
Pathophysiology of ventilator-induced lung injury
(VILI)
VILI associated with high lung volumes is due to alveolar over-
distension (barotrauma/volutrauma). Volutrauma and baro-
trauma may lead to pneumothorax, pneumomediastinum, and
air embolism in ARDS. Lung-protective ventilation may not be
adequately protective when accounting for delivered TV to
nonaerated parts of the lung.
Cyclic opening and closing of collapsed (atelectatic) but
recruitable lung units during TV contribute to lung injury and is
termed as atelectrauma. It causes parenchymal shear injury and
may be prevented with higher PEEP in some patient subsets.
Other aetiologies include patient self-inflicted lung injury (P-
SILI) and biotrauma. Biotrauma represents generation of proin-
flammatory mediators that drive ongoing lung injury and cause
systemic organ dysfunction.
Patient self-inflicted lung injury
Increased work of breathing as a response to impaired gas ex-
change can lead to heightened respiratory efforts and increased
negative intrapleural pressure in both diseased and at-risk lung
regions even when TV and plateau pressures are limited. This
can lead to regional over-distension of alveoli and atelectrauma.
Spontaneous ventilation has beneficial effects in preventing res-
piratory muscle atrophy, reducing sedation and facilitating early
mobilization. However, when deciding whether to continue with
spontaneous ventilation or to instigate invasive ventilation, cli-
nicians should take the following factors: the amount of respi-
ratory drive and effort; the severity of ARDS; the patient’s clinical
trajectory; and the search for non-respiratory causes of increased
ANAESTHESIA AND INTENSIVE CARE MEDICINE 23:10 637
Differential diagnoses
Vasculitis
Diffuse alveolar haemorrhage
Drug-induced pneumonitis
Organizing pneumonia
Hypersensitivity pneumonitis
Acute eosinophilic pneumonia
Acute exacerbation of interstitial lung disease
Malignancy
respiratory drive, such as metabolic acidosis or uncontrolled
pain.
Pathophysiology of COVID-19 lung injury
Pathophysiological similarities of ARDS from COVID-19
compared to other causes outnumber any differences. The
virus enters type 2 alveolar cells through host angiotensin-
converting enzyme 2 (ACE-2) receptor which leads to release
of various cytokines (cytokine storm). This attracts neutrophils,
CD4 and CD8 T cells which counteract viruses but also lead to
subsequent inflammation and lung injury. The thrombotic ten-
dency causing pulmonary vasculature micro- and macro-throm-
bosis increase the severity of respiratory failure. In many ways,
the advent of COVID-19 as a trigger for ARDS has reopened many
questions on the pathophysiology of ARDS itself.7
Risk factors for poor prognosis
Studies have depicted many risk factors, but no single factor or
scoring system has been proven to be superior to others. Risk
factors are listed in Table 3.
Prognostic factors for poor long-term outcomes also include
treatment such as low TV, prone position or ECMO intervention
and number and severity of complications.
Management
General principles
Early recognition of the underlying cause and its treatment is of
paramount importance to prevent and treat ARDS. A better un-
derstanding of mechanical ventilatory support, prevention of
VILI and good supportive care are essential in managing patients
with ARDS.
Ventilatory strategies
Lung-protective ventilation is the mainstay of ventilatory
management to prevent VILI. The ARDSNet study respiratory
management arm (ARMA) trial was a randomized multicentre
study conducted by ARDSNet investigators, which compared a
ventilation strategy of lower TV (6 ml/kg) to 12 ml/kg TV in
ARDS and demonstrated considerable reduction of hospital
mortality and duration of mechanical ventilation when a lower
TV strategy coupled with targeting plateau pressure less than
Ó 2022 Published by Elsevier Ltd.
 INTENSIVE CARE

Risk factors for poor prognosis in acute respiratory distress syndrome (ARDS)
Patient related Disease related Treatment related

Age (>60% mortality in patients age>85) Severity of hypoxaemia Positive fluid balance
Comorbidities such as cancer, Pulmonary vascular dysfunction Steroids prior to ARDS
immunosuppression, chronic liver failure High severity of illness score Red blood cell transfusions
Lower mortality in Obese Non-traumatic cause of the ARDS Late intubation

Table 3

30e32 cmH2O was used. Plateau pressure may decrease as the
duration of time spent at end-inspiratory occlusion lengthens,
likely due to delayed recruitment of additional lung volume via
surfactant spread and alveolar pendelluft. Pendelluft is defined
as redistribution of gas from a more recruited nondependent
lung region to a less recruited dependent lung region due to
differences in time constant (compliance X resistance)
when there is no inhalation or exhalation. Hence, a shorter
end-inspiratory occlusion plateau pressure should be
considered.
Low TV ventilation can cause hypercapnia, double triggering
and dyssynchrony. To control hypercapnia, a relatively high
respiratory rate should be adopted first. However, it increases the
risk of dynamic hyperinflation.
PEEP and inspiratory:expiratory ratio: adjustment of PEEP is
an important strategy to improve oxygenation in patients with
ARDS. No single strategy has proven to be ideal. In the ARMA
trial, PEEP levels in the range 5e24 cmH2O were used, with
dynamic changes to PEEP in combination with FiO2. High PEEP
is more advantageous in moderate to severe ARDS in terms of
reducing mortality rates. Low TV ventilation itself is less bene-
ficial in ARDS when implemented without high PEEP4,8
Other methods to optimize PEEP include:
 adjustment of PEEP to either optimal SpO2 or static
compliance, with or without preceding recruitment
manoeuvres
 set PEEP at 2 cmH2O above the lower inflection point of
pressure-volume loop which represents the pressure where
maximum alveoli are thought to be recruited
 dynamic PEEP titration to achieve lower driving pressure
(<15 cmH2O)
 transpulmonary pressure-guided PEEP, especially
in situations of reduced non-pulmonary compliance such
as in abdominal hypertension and morbid obesity
 optimizing PEEP by various methods in electrical
impendence tomography (EIT), a non-invasive bedside
tool that monitors real-time distribution of ventilation.
The driving pressure (DP ¼ TV/CRS(static compliance of the respi-
ratory system) or plateau pressure-PEEP) estimates TV adjusted to
functional lung size and driving pressure >19 cmH2O has been
associated with increased mortality rates. It is unclear whether
DP is superior to other methods to set PEEP.9 The dynamic
adjustment of PEEP to ensure low plateau pressure is more
important than the level of PEEP itself.
Complications of high PEEP include:
 decreased right ventricular preload
 raised right ventricular afterload and pulmonary vascular
resistance
 increased dead space due to reduced blood flow in West
zone 1 and impaired CO2 elimination.
Modifying the inspiratory:expiratory ratio with prolonged
inspiratory time leads to prolonged high mean airway pressure
and improved oxygenation.
Oxygenation targets: the optimal strategy for supplemental ox-
ygen is still controversial and remains unknown. Studies have
failed to show the reproducibility of benefits or harms of either
liberal or conservative oxygenation targets.
Different ventilator modes: There is limited evidence for the
superiority of any ventilator mode over the others. For example,
airway pressure release ventilation (APRV) is a mode of venti-
lation that involves maintaining a continuous high positive
pressure for most of the cycle with intermittent release phases,
while allowing for spontaneous respiration. Only low-quality
evidence favours APRV over synchronized intermittent manda-
tory ventilation (SIMV) to reduce duration of mechanical venti-
lation and length of intensive care unit (ICU) stay when applied
early in patients with ARDS.
Rescue therapies
Recruitment manoeuvres improve lung compliance and gas
exchange by expanding collapsed alveoli. Various methods have
been used. Some of them include increasing TV gradually in
volume-controlled ventilation, or up-titrating PEEP while main-
taining driving pressure until a peak inspiratory pressure of at
least 40 cmH2O is reached in pressure control ventilation. A large
randomized controlled trial has shown that titration of PEEP to
respiratory compliance with recruitment manoeuvres is associ-
ated with increased mortality. Recruitment manoeuvres can
provide a temporary advantage at the expense of increased
sedation requirements, decreased cardiac preload, increased risk
of VILI, and possibly worsening oxygenation by promoting
perfusion of poorly ventilated areas. The search for a better target
population is needed which could include patients with ARDS
who have a higher potential of reaping the benefits of recruit-
ment manoeuvres rather than experiencing adverse effects.
Prone positioning is now a widely accepted and utilized tool for
the management of ARDS.
Various randomized, controlled trials including a metanalysis
and the PROSEVA trial which compared early application of
prone positioning for at least 16 hours to conventional supine

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 INTENSIVE CARE
positioning among patients with moderate to severe ARDS
showed significant reduction in 28-day and 90-day mortality.
Improved survival is predominantly because of reduction of VILI
due to more even distribution of volume than due to improved
oxygenation.10 Other advantages are improved secretion clear-
ance and respiratory mechanics.
Despite the benefits, the rate of use of prone position was as
low as 16% in patients with severe ARDS in the large prospective
epidemiologic Lung safe study.4
Factors associated with low implementation of prone ventila-
tion include under recognition of ARDS, logistical difficulties, and
fear of complications. Complications of prone positioning include
increased intraabdominal or intracranial pressure, pressure in-
juries, ETT obstruction or dislodgement, difficult monitoring and
performing procedures and delay in the instigation of ECMO.10
Extracorporeal membrane oxygenation: VV ECMO improves
oxygenation and CO2 clearance and may reduce ventilator
induced lung injury by allowing the reduction in the intensity of
mechanical ventilation. The CESAR trial demonstrated higher
survival without disability in the ECMO group versus the control
group (67% vs 43%) whereas The EOLIA trial revealed a non-
statistically significant reduction in mortality in the ECMO
group (35% vs 46%), despite a high rate of crossover to ECMO in
the control group. Extracorporeal Life Support Organization
(ELSO) guidelines recommend that patients with severe ARDS
and refractory hypoxaemia (PaO2/FiO2 <80 mm Hg), or severe
hypercapnic respiratory failure (pH <7.25 with a PaCO2
60 mmHg), should be considered for ECMO after optimal
conventional management including a trial of prone positioning
and in the absence of contraindications.11 Selecting patients for
ECMO can be challenging and inclusion criteria vary between
hospitals. Severity and aetiology of the respiratory failure are key
factors to be considered. Maximizing traditional therapies for
ARDS before initiation of ECMO, early transfer to the ECMO
centre, earlier use of ECMO, protocolize care and weaning from
ECMO are of paramount importance. ARDS patients treated with
ECMO experienced less psychological morbidity and impairment
of health-related quality of life.10
As per ELSO Registry report, estimated in-hospital mortality
90 days after VV ECMO support was 37.4% post-pandemic and
40% pre-pandemic. While COVID-19 ECMO run duration (18
e20 days) may be longer than in non-COVID-19 ECMO patients
(12 days), published mortality appears to be similar in the two
groups.12
Inhaled pulmonary vasodilators: the benefit of nitric oxide
(iNO) is to improve oxygenation by improving V/Q because of
selective vasodilation of ventilated lung regions, rather than a
reduction in pulmonary artery pressure and right ventricle
afterload. Its use is associated with infrequent complications
such as renal toxicity, methaemoglobinemia and rebound pul-
monary hypertension. Minimization and frequent re-evaluation
of the dose and monitoring of complications are essential.
Studies have failed to show survival benefits. However, given a
favourable benefit-risk ratio with adequate monitoring, iNO may
be justified in severe ARDS when prone positioning and opti-
mization of mechanical ventilation do not correct hypoxaemia.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 23:10
Supportive therapies
Conservative fluid therapy: implementation of a conservative
lung strategy in patients with ARDS without contraindications can
reduce the length of ICU and hospital stay and reduce duration of
mechanical ventilation. Also, early diuretic use in ARDS is inde-
pendently associated with lower hospital mortality.10
Sedation and neuromuscular blocking agents (NMBAs):
sedation and analgesia are used in patients with ARDS to
improve tolerance to mechanical ventilation and decrease oxy-
gen consumption. Using sedation scales such as the Richmond
Agitation-Sedation Scale (RASS) may help clinicians meet seda-
tion goals more effectively, reducing the likelihood of over or
under-sedation.
NMBAs can benefit patients with ARDS by reducing lung
injury caused by patient-ventilator dyssynchrony and P-SILI. The
ACURASYS trial investigated early use of NMBAs in patients with
ARDS and revealed improved 90-day mortality and increased
ventilator-free days. In contrast, the Re-evaluation of Systemic
Early Neuromuscular Blockade (ROSE) trial revealed no out-
comes benefits with early use of NMBAs at 3, 6, and 12 months.
A panel of international experts suggested against the routine
use of an NMBA infusion in adults with ARDS before optimizing
mechanical ventilation, assessing ARDS severity and who
tolerate ventilation using lighter sedation. They recommended
the use of NMBA infusion for up to 48 hours for patients whom
clinicians determine that they require ongoing deep sedation, to
facilitate lung-protective ventilation.13
Corticosteroids: studies in the last two decades have conflicting
results regarding improvement in outcomes (ventilator-free days,
ICU length of stay) with early steroid use.
In the recent DEXA-ARDS trial, patients with moderate-severe
ARDS who received steroids (20 mg dexamethasone daily for
5 days followed by 10 mg daily for 5 days) had lower 60 days all-
cause mortality rates more ventilator-free days. Randomized
Evaluation of COVID-19 Therapy (RECOVERY) trial showed
benefit from dexamethasone therapy in COVID-19 in 28 days
mortality especially the patients who were mechanically venti-
lated and had symptoms for >7 days.
Due to the heterogeneity of clinical presentation and compli-
cations of steroids, an individualized approach is suggested,
where steroids are given to patients most likely to benefit such as
in ARDS with septic shock, COVID-19 and PaO2/FiO2 ratio <200;
withheld in patients at higher risk for harm such as trauma,
influenza; and considered on a case-by-case basis among patients
with intermediate risks/benefits.14
Recent research and conflicts in ARDS
Individualized mechanical ventilation
A personalized mechanical ventilation approach for patients with
ARDS based on lung physiology and morphology, ARDS aeti-
ology, lung imaging, and biological phenotypes may improve
ventilation practice and outcome.
Novel methods of safe TV and dynamic PEEP titration
Adaptive support ventilation, an automated closed-loop mode of
ventilation, may provide the best combination of TV and
639 Ó 2022 Published by Elsevier Ltd.
 INTENSIVE CARE
respiratory rate (RR), to achieve the lowest work of breathing
combined with the lowest driving pressure (DP).
Functional residual capacity (FRC) is severely decreased in
ARDS. End-expiratory lung volume (EELV) is FRC plus lung
volume increased by the applied PEEP. Measurement using the
modified nitrogen multiple breath washout technique may help
titrate PEEP and TV and allow determining dynamic lung strain
(TV over EELV).9
Transpulmonary pressure and electrical impedance
tomography (EIT) guided PEEP
Transpulmonary pressure (PL), the distending force of the lung, is
the difference between airway (PAW) and pleural pressure (PPL),
which is estimated by oesophageal pressure (PES). In recent trials,
PL guided adjustment of PEEP was found to be superior in
improving oxygenation especially in patients with high abdominal
pressure such as obesity and reducing rescue therapies such as
ECMO. Better survival was observed when PEEP was titrated
closer to 0 cmH2O of transpulmonary pressure.9,15
EIT uses electric currents by placing electrodes on the tho-
rax to image the changes in air content in the lungs and
evaluate regional differences in ventilation patterns. This may
be used to set PEEP level. It is unknown whether EIT improves
outcomes.
Determine suitability for recruitment manoeuvres
A bedside approach to estimate recruitability has recently been
proposed by abruptly dropping PEEP with an increase in expired
volume. The difference between expired volume and the volume
predicted by compliance at low PEEP estimates the recruited
volume by PEEP. This recruited volume divided by the pressure
change estimates the compliance of the recruited lung; the ratio
of the compliance of the recruited lung to the compliance at low
PEEP measures the recruitment-to-inflation ratio. The higher the
recruitment-to-inflation ratio is, the higher the potential for lung
recruitment is.10
Imaging
Imaging techniques may help to identify different lung
morphology and response to ventilation strategies. Chest CT al-
lows quantitative analysis of lung: normally aerated, poorly
aerated, and non-aerated tissue. Two main chest CT phenotypes,
lobar attenuations (focal findings) and diffuse (non-focal find-
ings) have been proposed. Recruitment manoeuvres yield less
hyperinflation in patients with non-focal CT morphology. A
recent trial found no differences in outcome between standard
lungeprotective ventilation in focal ARDS and personalized
ventilation (openelung strategy with high PEEP, recruitment
manoeuvres and rescue prone positioning). Patients who were
misclassified in the personalized ventilation group had a higher
mortality rate.
Biological phenotype
Studies demonstrated that the different phenotypes (hyper-
inflammatory and hypoinflammatory) had a differential or even
opposite response to PEEP, fluid management, and simvastatin
treatment The stratification of ARDS patients according to phe-
notypes is promising but requires validation before it can be
translated into to the clinical setting.9
ANAESTHESIA AND INTENSIVE CARE MEDICINE 23:10
Timing of intubation
Late intubation, use of non-invasive ventilation (NIV) in severe
ARDS and possibly P-SILI are associated with high mortality.
Conversely, with the growing use of high-flow nasal oxygen, the
proportion of ARDS patients who never require intubation or
require mechanical ventilation later in the course of illness is
increasing. Hence, the decision on timing of intubation should be
taken on a case-by-case basis considering other clinical and lo-
gistic factors.16
Timing of spontaneous breathing
There are risks of developing P-SILI, patient-ventilator dyssyn-
chrony, under assistance and impaired gas exchange with
spontaneous breathing on mechanical ventilation versus the risk
of developing ventilator-induced diaphragm dysfunction (VIDD)
and complications of excessive PEEP during controlled ventila-
tion, sedation and/or paralysis. These factors other than the
PaO2/FiO2 ratio may need to be considered when deciding about
weaning to spontaneous breathing.
Airway occlusion pressure (P0.1) is a non-invasive measure
for estimating respiratory drive during mechanical ventilation
with spontaneous breathing, P0.1 is defined as the negative
airway pressure occurring during the first 0.1 seconds of an
occluded inspiration. Small P0.1 (1.0 cmH2O), indicates the weak
effort which can lead to weaning failure, while large P0.1
(4.0 cmH2O) indicates the strong patient’s inspiratory effort
which may be associated with P-SILI.17 Further validation form
randomized studies is warranted.
Extra corporeal carbon dioxide removal (ECCO2R)
ECCO2R is a strategy that has been proposed as a rescue therapy
and is a means of facilitating ultra-protective lung ventilation
(UPLV) for patients with ARDS. Appropriate patient selection is
important. Clinical outcome benefits are yet to be proven in
randomized studies.
Scope of future research and unmet needs
Risk prediction models
There has been a growing interest in developing predictive tools
to foresee who is more likely to develop ARDS and predict tra-
jectory and complications after developing it. This would allow
more targeted therapies. It is difficult to establish specific tool as
ARDS is a heterogenous disease and mortality also depends on
the underlying cause. Recently, a mortality prediction model for
ARDS that included age, APACHE III score and biomarkers
(surfactant protein D, and interleukin 8) was published. A ma-
chine learning model based novel variable [PaO2/(FiO2PEEP)]
for patients on PEEP 5 cmH2O has also been proposed to predict
severity over time after ARDS onset and bridge the gaps of the
Berlin definition. These may be useful tools for the identification
of high-risk patients for recruitment into clinical trials, or for risk
adjusted comparisons of outcomes between centres. These tools
need to be validated further to be used in clinical settings.18
Disease modifying agents and adjunctive
pharmacotherapies
Various drug therapies have been investigated including
inhaled adrenomedullin for intubated patients with ARDS,
inhaled b-agonists, corticosteroids, epithelial sodium channels
640 Ó 2022 Published by Elsevier Ltd.
 INTENSIVE CARE
activators in alveolar epithelial cells and mesenchymal stem cell
therapies. None of them has been adequately studied in ran-
domized, well-powered trials and approved for use yet.
Long term outcomes
Despite advances in the care of critically ill patients, survivors of
ARDS experience significant long-term sequelae and high mor-
tality (41%) in the first year beyond the initial critical illness
which is higher than in many non-ARDS critical illnesses.19
Common morbidities seen in survivors of ARDS are cognitive
and psychological impairment, reduced exercise capacity, muscle
wasting, pulmonary function impairments, as well as reduced
quality of life and ongoing healthcare utilization.
More trials focused on therapeutic tools to prevent, limit, or
treat long-term sequels and increasing understanding of the long-
lasting effects of ARDS and the most effective management are
needed.
Summary
ARDS is a syndrome caused by pulmonary and non-pulmonary
pathologies and leads to predominantly hypoxaemic respiratory
failure. COVID-19 infection has contributed significantly to the
recent cases. Stratification to different severity groups is impor-
tant to ensure appropriate resource use and plan treatment.
Lung-protective ventilation, treating underlying cause and sup-
portive management are of paramount importance. Appropriate
patient selection is essential when rescue and novel therapies are
planned to be used. A
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