Postgrad Med J 2011 Dushianthan 612 22

Acute respiratory distress syndrome and acutelung injury

A Dushianthan,1 M P W Grocott,1,2 A D Postle,3 R Cusack1

ABSTRACTAcute respiratory distress syndrome (ARDS) is a lifethreatening respiratory failure due to lung injury froma variety of precipitants. Pathologically ARDS ischaracterised by diffuse alveolar damage, alveolarcapillary leakage, and protein rich pulmonary oedemaleading to the clinical manifestation of poor lungcompliance, severe hypoxaemia, and bilateral infiltrateson chest radiograph. Several aetiological factorsassociated with the development of ARDS are identifiedwith sepsis, pneumonia, and trauma with multipletransfusions accounting for most cases. Despite theabsence of a robust diagnostic definition, extensiveepidemiological investigations suggest ARDS remainsa significant health burden with substantial morbidity andmortality. Improvements in outcome following ARDS overthe past decade are in part due to improved strategies ofmechanical ventilation and advanced support of otherfailing organs. Optimal treatment involves judicious fluidmanagement, protective lung ventilation with low tidalvolumes and moderate positive end expiratory pressure,multi-organ support, and treatment where possible ofthe underlying cause. Moreover, advances in generalsupportive measures such as appropriate antimicrobialtherapy, early enteral nutrition, prophylaxis againstvenous thromboembolism and gastrointestinal ulcerationare likely contributory reasons for the improvedoutcomes. Although therapies such as corticosteroids,nitric oxide, prostacyclins, exogenous surfactants,ketoconazole and antioxidants have shown promisingclinical effects in animal models, these have failed totranslate positively in human studies. Most recently,clinical trials with b2 agonists aiding alveolar fluidclearance and immunonutrition with omega-3 fatty acidshave also provided disappointing results. Despite thesenegative studies, mortality seems to be in decline due toadvances in overall patient care. Future directions ofresearch are likely to concentrate on identifying potentialbiomarkers or genetic markers to facilitate diagnosis,with phenotyping of patients to predict outcome andtreatment response. Pharmacotherapies remainexperimental and recent advances in the modulation ofinflammation and novel cellular based therapies, such asmesenchymal stem cells, may reduce lung injury andfacilitate repair.

INTRODUCTIONAcute respiratory distress syndrome (ARDS), andits milder form acute lung injury (ALI), are a spec-trum of lung diseases characterised by a severeinflammatory process causing diffuse alveolardamage and resulting in a variable degree of venti-lation perfusion mismatch, severe hypoxaemia, andpoor lung compliance.1 Patients with ARDS are

often mechanically ventilated during the course oftheir illness. Morbidity and mortality remains highand early recognition of patients is a vital step inproviding appropriate care. Due to the broad rangeof precipitating conditions, patients can present toany medical or surgical specialty with acute respi-ratory deterioration. Prompt appropriate manage-ment with intensive care unit (ICU) provision isessential to improve outcome. The objectives ofthis review are to provide a clinical approach tothe diagnosis and management of ARDS, clarifycurrent definitions and their shortcomings, andevaluate the clinical evidence for established andproposed treatment strategies.

DEFINITIONARDS was first reported by Ashbaugh et al in1967.2 They described a rapid onset of tachypnoeaand hypoxaemia, with loss of lung compliance andbilateral infiltrates on chest radiograph, in other-wise healthy young individuals. Although theARDS precipitating illnesses differed betweenpatients, they had similar clinical and pathologicalfeatures.2 Differentiating pulmonary oedemasecondary to heart failure from ARDS was difficult,and in the subsequent decades, the pulmonaryartery catheter was widely used to measurepulmonary artery wedge pressure to facilitatediagnosis and management. Furthermore, theadvent of the specialty of intensive care medicineresulted in improved survival and enabled greaterunderstanding of ARDS. However, much of thisearly work is difficult to interpret due to the lack ofa consistent definition of ARDS.The American-European Consensus Conference

(AECC) proposed a definition, which is now widelyaccepted as a simple diagnostic tool for patientcharacterisation and research trial conduct. Thereare three diagnostic criteria for ARDS: the presenceof acute severe hypoxaemia (defined as a ratio ofarterial oxygen tension over fractional inspiredoxygen (PaO2/FiO2) <200 mm Hg (26.7 kpa)), bilat-eral infiltrates on chest radiography (CXR), and theabsence of raised pulmonary artery wedge pressure(table 1).3 If the PaO2/FiO2 is >200 mm Hg(26.7 kPa) and <300 mm Hg (40 kPa), the criteriafor ALI are met.AECC diagnostic criteria are a relatively crude

screening tool for identifying patients with ARDS,and are recognised to have limitations relating tospecificity and reproduciblity.6 The degree ofacuteness is not defined by the AECC criteria;however, <72 h from the onset of the precipitatingcause is used by many as an arbitrary diagnostictime frame. Furthermore, the degree of hypoxaemiacan vary depending on the amount of positive end

1Critical Care Research Unit,Southampton UniversityHospital, Southampton, UK2Division of DevelopmentalOrigins of Health and Disease,School of Medicine, Universityof Southampton, SouthamptonUniversity Hospitals,Southampton, UK3Division of Infection,Inflammation and Immunity,School of Medicine, Universityof Southampton, SouthamptonUniversity Hospital,Southampton, UK

Correspondence toDr A Dushianthan, CE 93, MP24, E-Level, Centre Block,Southampton UniversityHospital, NHS Trust, TremonaRoad, Southampton SO16 6YD,UK; [email protected]

Received 26 January 2011Accepted 5 May 2011Published Online First4 June 2011

612 Postgrad Med J 2011;87:612e622. doi:10.1136/pgmj.2011.118398

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expiratory pressure (PEEP) applied, which can either include orexclude the diagnosis in individual patients.7 8 Radiographicinterpretation of ARDS criteria also lacks sensitivity and speci-ficity, with large inter-observer variability among critical carephysicians.9 10 Pulmonary artery catheterisation for ARDS isnow rarely performed in the UK and exclusion of cardiogenicpulmonary oedema clinically can be difficult as both conditionsmay co-exist. The correct diagnosis hinges on evaluatingpatients in all three aspects of the diagnostic criteria, but evenwith these deficiencies, the criteria have nevertheless helped toidentify a cohort of patients with ARDS and allowed focusedresearch trials since 1994. Despite the advantages of this simpledefinition, caution needs to applied in grouping patients withvarying underlying aetiology, and hence disease progression.Invariably, a heterogeneous group of conditions are clusteredtogether in clinical trials and this may partly explain the reasonfor many negative results. Rigorous assessment and manage-ment of the underlying clinical condition is an essentialcomponent of the management approach of patients withARDS.

Other notable diagnostic criteria for ARDS are Murray’s LungInjury Score (LIS) and the Delphi consensus criteria. In 1988Murray et al proposed a scoring system with three physiologicalvariables: hypoxaemia, lung compliance and applied PEEP; anda fourth radiological variable: the extent of alveolar consolida-tion (table 1).4 Although used widely as an adjunct to the AECCdefinition in many clinical trials, LIS is now generally supersededby the AECC criteria. The limitations of the AECC definition ledto the Delphi consensus exercise in 2005, by Ferguson et al. Thisincorporates additional variables such as compliance, and precisecriteria for acute onset and predisposing factors (table 1).5 Whenall three diagnostic methods were evaluated against a study withpostmortem findings, Delphi consensus criteria and LIS had

better specificity but sensitivity was higher with AECC criteria,although the differences were not statistically significant.11

EPIDEMIOLOGYIncidenceThe estimated incidence of ARDS and ALI varies due to thelimitations of the diagnostic criteria which result in heteroge-neous populations being identified. A study of critical care unitsin the USA in 2005 estimated the incidence of ARDS to be58/100 000 person years with 141 500 new cases per year and anannual death rate of 59 000 per year.12 European estimates aremore conservative, ranging between 4.2 and 13.5/100 000 personyears.13 14 In the UK there are no prospective population basedstudies. The Intensive Care National Audit and Research Centre(ICNARC) database, which produces a case mix report ofpatients admitted to ICUs, does not record data that would berequired to accurately identify patients with ARDS. In Scotlandin 2003, an audit study reported the incidence of ARDS to be16/100 000 per year.15

MortalityReported mortality rates vary widely. A pooled mortality esti-mate from a recent systematic review suggests that themortality for ARDS is between 36e44%, with little change overthe two decades up to 2006.16 In contrast to this, the ARDSNetwork clinical trials conducted over the last two decadesshow a clear decline in mortality among their study populationsbetween 1997 and 2009 (figure 1)22 although the potential forselection bias needs to be considered when interpretingmortality data from clinical trials as opposed to observationalstudies. The reasons for the reported decline in mortality arenot clear. Several factors may have contributed, including theintroduction of permissive hypercapnia and protective lung

Table 1 Diagnostic criteria for ARDS

Defining components AECC criteria3 Murray’s Lung Injury score* (LIS)4 Delphi consensus5

1) Onset Acute onset Not defined Rapid onset <72 h

2) Chest radiography Bilateral infiltrates seen onfrontal chest radiograph

Alveolar consolidationNo consolidation, score 01 quadrant, score 12 quadrant, score 23 quadrant, score 34 quadrant, score 4

Bilateral airspace disease involving $2 quadrants onfrontal chest radiography

3) Hypoxaemia (mm Hg) PaO2/FiO2 #200 PaO2/FiO2 $300 Score 0PaO2/FiO2 225e299 Score 1PaO2/FiO2 175e224 Score 2PaO2/FiO2 100e174 Score 3PaO2/FiO2 <100 Score 4

PaO2/FiO2 <200

4) Exclusion of hydrostaticpulmonary oedema

Pulmonary artery wedge pressureof #18 mm Hg or no clinical evidenceof left atrial hypertension

Not defined No clinical evidence of congestive cardiac failure

5) Compliance Not defined $80 ml/cm H2O, score 0$60e79 ml/cm H2O, score 1$40e59 ml/cm H2O, score 2$20e39 ml/cm H2O, score 3#19 ml/cm H2O, score 4

Static inspiratory system compliance <50 ml/cm H2O

6) PEEP Not defined $5, score 06e8, score 19e11, score 212e14, score 3$15, score 4

>10

7) Predisposition Not defined Not defined Direct or indirect factor associated with lung injuryz*For LIS divide the aggregate sum by the number of components that were used: no lung injury, score 0; mild to moderate, score 0.1e2.5; severe lung injury, score >2.5.yAirspace disease is defined as the presence of one or more of the following: (1) air bronchograms, (2) acinar shadows (nodular opacities 4e10 mm in diameter with poor margination), (3)coalescence of acinar shadows, (4) silhouette sign (loss of definition of the heart border or hemidiaphragmdexcluding that caused by lobar collapse.zClinical syndromes associated with ARDS: (1) Direct lung injury: pneumonia, aspiration of gastric contents, fat emboli, near drowning, inhalational injury, reperfusion pulmonary oedema aftertransplantation, or pulmonary embolectomy; (2) Indirect lung injury: sepsis, severe trauma with shock and multiple transfusions, cardiopulmonary bypass, transfusions of blood products, andsevere burns.AECC, American-European Consensus Conference; ARDS, acute respiratory distress syndrome; PaO2/FiO2, ratio of arterial oxygen tension over fractional inspired oxygen; PEEP, positive endexpiratory pressure.

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ventilation as well as improved supportive measures such asearly antibiotics, ulcer and thrombosis prophylaxis, betterfluid management, and improved nutritional and other organsupport.23

Patients with ARDS frequently have multi-organ failure, andthe majority of patients die from sepsis syndrome with multi-organ failure rather than intractable respiratory failure. Ina study analysing the causes of death in ARDS patients, only16% of deaths were attributed to respiratory failure. Most of thedeaths in the first 3 days were due to the underlying illness, andwhen they occurred later they were most frequently due tosepsis syndrome.24

Aetiology and risk factorsARDS has many causes. Sepsis from both pulmonary and non-pulmonary origin accounts for the majority of cases.12 Commonaetiological insults are documented in table 2. Mortality variesaccording to the aetiology, with trauma patients fairing betterthan patients with sepsis.12 Genetic predisposition may influ-ence clinical outcome and many candidate genes have beenidentified.25 Chronic alcohol abuse,26 27 age, chronic liver disease,

immunosuppression,14 and obesity28 are all associated with thedevelopment of ALI, whereas diabetes mellitus appears to beprotective.29 It is unclear whether this is due to diabetes per se orthe anti-inflammatory effect of insulin. Ethnic variations inmortality and outcome with higher reported mortality in blackpopulations are well recognised, and this was thought to be dueto an increased severity of illness at presentation.30

Morbidity after survivalPatients who survive any critical illness frequently have signifi-cant psychological and physical morbidity. Although lungfunction parameters tend to recover well in ARDS patients,residual physical limitations and a poor quality of life arecommon.31 Depression, anxiety and post-traumatic stressdisorder (PTSD) are also very common; even after 8 years,psychiatrist diagnosed PTSD is reported in up to a quarter ofpatients.32 Risk factors for depression at 1 year are alcoholdependence, female gender and younger age; risk factors fordeveloping anxiety are lower PaO2/FiO2 ratio and duration ofmechanical ventilation.33 Cognitive impairment with reducedmemory, attention and task execution is also common.34 Suchmorbidity has a significant economic burden and the develop-ment of physical and psychological rehabilitation strategies areimportant to improve outcome in ARDS/ALI survivors.

PATHOPHYSIOLOGYARDS/ALI is characterised by an overwhelming inflammatoryprocess leading to alveolar epithelial and vascular endothelialinjury in the lung which can be infective and non-infective inorigin. During the initial acute phase of ARDS there is alveolarflooding with protein-rich fluid due to increased vascularpermeability. Alveolar epithelial injury of type I cells contributesto the pulmonary oedema and the breakdown of this epithelialbarrier exposes the underlying basement membrane, predis-posing to bacteraemia and sepsis. Injury to type II alveolar cellsleads to impaired surfactant synthesis and metabolism resultingin increased alveolar surface tension and alveolar collapse.1

Histopathologically there is diffuse alveolar damage withneutrophil infiltration, alveolar haemorrhage, and hyalinemembrane formation.35 The acute phase is followed by a fibro-proliferative phase in some with various degrees of fibrosis,neovascularisation and later resolution.36 However, these stagescan often overlap. Vascular injury and remodelling may lead topulmonary arterial hypertension which may compromise rightventricular function, exacerbating hypoxaemia and leading topoor clinical outcome.1

Neutrophils play a critical role in the pathogenesis of ALI/ARDS and when activated release harmful mediators includingcytokines, proteases, reactive oxygen species, and matrixmetalloproteinases leading to further damage.37 Certain cyto-kines such as interleukin 1 (IL1), IL6, IL8, and tumour necrosisfactor (TNF) are pro-inflammatory and may exacerbate lunginjury.Coagulation cascade abnormalities are characteristic in ALI/

ARDS with an imbalance in both pro- and anticoagulationfactors. For example, protein C concentrations are low in plasmaand lung oedema fluid in ARDS patients.38 These abnormalitiesmay offer potential therapeutic targets for patients withALI/ARDS in the future.

DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC TOOLSMany respiratory conditions can mimic ARDS and attemptsshould be made to exclude other causes of respiratory failure toensure appropriate treatment. Box 1 shows other potential

Figure 1 Observed 60 day mortality from ARDS Network clinical Trialsfrom 1997 to 2009. ARMA, Acute Respiratory Distress SyndromeManagement with Lower versus Higher Tidal Volume (ARMA-6 patientsreceived Vt of 6 ml/kg) (ARMA-12 patients received Vt of 12 ml/kg)17;ALVEOLI, Assessment of Low tidal Volume and Elevated End-expiratoryVolume to Obviate Lung Injury18; FACTT, Fluid and Catheter TreatmentTrial19; ALTA, Albuterol for the Treatment of ALI20; OMEGA, Omega-3Fatty acid, Gamma-Linolenic Acid, and Antioxidant Supplementation inthe Management of ALI or ARDS.21 Adapted with permission fromSpragg et al.22

Table 2 Clinical conditions associated with aetiology of ARDS(adapted from Ware and Matthay 2000 with permission)1

Direct lung injury Indirect lung injury

Common causes Common causes

PneumoniaAspiration of gastric contents

SepsisSevere trauma with shock andmultiple transfusions

Less common causes Less common causes

Pulmonary contusionFat emboliNear drowningInhalational injuryReperfusion pulmonary oedema aftertransplantation or pulmonary embolectomy

Cardiopulmonary bypassDrug overdoseAcute pancreatitisTransfusion of blood products

ARDS, acute respiratory distress syndrome.


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diagnoses with similar clinical findings. The following investi-gative tools are generally utilised to facilitate the diagnosis andmanagement of patients with ARDS.

ImagingThe diagnosis of ARDS is clinical and hinges upon the recogni-tion of a precipitating cause, with radiological and laboratoryparameters to aid diagnosis. CXR is a cheap and helpful tool forthe diagnosis of ARDS and to exclude other common conditionscausing hypoxaemia which require alternative treatments.Typical changes on CXR are bilateral patchy infiltrates. Thesemay take time to evolve and are non-specific and recognition issubject to significant inter-observer variability.9 10 Cardiomegaly,bilateral upper lobe vascular diversion and effusions are moresuggestive of cardiac failure than ARDS.39

CTscanning can be used to differentiate ARDS from other lesscommon conditions and interstitial processes, and may preventinvasive investigations such as open lung biopsy which are veryrarely used. CT is also more specific than plain chest radiograph.Since CT imaging in ARDS has become more common, thehomogeneous distribution of the disease suggested by the plainchest radiograph has been disputed. Dependent areas have beenshown to be affected more than the apices.40 CT has also beenused for quantitative evaluation of lung recruitment manoeu-vres.40 The major disadvantage of CT scan is the risks involvedwith patient transfers. Other disadvantages are a larger radiationdose than CXR and the associated cost.

Positron emission tomography with (18F) fluorodeoxyglucose(FDG-PET) detects inflammatory cells and can assess lunginflammation.41 At present this is a research tool and does nothave a clinical role. Future use of this non-invasive technique inroutine practice for the management of ARDS patients is likelyto be severely limited primarily due to lack of resources.

Ultrasonography is a helpful tool that can be performed at thebedside without radiation exposure. Thoracic ultrasound iswidely used for diagnostic and therapeutic intervention inpatients with pleural effusions and pneumothoraces. The valueof ultrasonography as a method for assessment in lung recruit-ment following application of PEEP is promising and furtherstudies are needed to evaluate this.42

Bronchoalveolar lavageBronchoalveolar lavage (BAL) is used in patients with ARDS toimprove targeting of antimicrobial therapy. This is usually a welltolerated procedure in critically ill patients but can be associated

with transient worsening of hypoxaemia and haemodynamicinstability.43 Occasionally BAL may not be practical in severehypoxaemic patients. Quantitative BAL involves using largervolumes of saline (100e300 ml) and is rarely performed due topractical issues of patient stability and the lack of appropriateprocessing and analysis facilities in most hospital laboratories. InARDS, the lavage fluid is usually very cellular and predominatedby neutrophils in the early stages.44 Eosinophils may be presentat later stages, but if present in a high proportion in the earlystages of the disease may suggest eosinophilic pneumonia.Lymphocytosis, if present disproportionally, suggests hypersen-sitivity pneumonitis or cryptogenic organising pneumonia.45

Diffuse alveolar haemorrhage may mimic ARDS and in thisinstance BAL can be diagnostic. BAL is a particularly useful toolin identifying atypical pathogens in immunocompromisedpatients with lung injury. BAL is also helpful as a research toolto study novel inflammatory markers from bronchial fluid andmay provide insights into potential therapeutic targets in thefuture. Transbronchial and open lung biopsies are reserved forpatients with atypical presentation who need histologicalconfirmation and are rarely performed.

Haemodynamic monitoring and assessmentPulmonary artery catheters (PAC) were widely used in ICUsfollowing their development in the early 1970s. They were usedto assist in the diagnosis of ARDS and to guide fluid manage-ment. Although AECC criteria endorsed the pulmonary arteryocclusion pressure as one of the components of the diagnosticcriteria for ARDS,3 PAC readings are subject to significant inter-observer variability and therefore erroneous interpretations.46

While PAC has been used by many to guide management inARDS, there is no evidence to suggest routine use improvesoutcome.47 Due to this lack of evidence, difficulty in interpre-tation of measurements, risks of procedure and the developmentof other less invasive techniques have resulted in the decline ofPAC usage over recent years.Other less invasive haemodynamic monitoring procedures

such as oesophageal Doppler aortic velocimetry and arterialwave form analysis using lithium (LiDCO) or thermodilution(PiCCO) provide alternatives to PAC in the guidance of fluidmanagement in critically ill patients. The utility of these in themanagement of ARDS patients has not been evaluated inrandomised controlled trials.Transthoracic echocardiography is a rapid non-invasive tool

for the assessment of cardiac function that may provide addi-tional information in the management of ARDS patients.Although very useful in some cases, images are often of limitedquality and diagnostic accuracy in ventilated patients.48

BiomarkersVarious inflammatory mediators that reflect epithelial andendothelial injury, inflammation and coagulation abnormalitiesin ALI have been investigated as potential biomarkers to assistdiagnosis and prognostication in ALI. These include IL6, IL8,tumour necrosis factor receptor-1 (TNFR-1), von Willebrandfactor (VWF), surfactant protein D (SP-D), intercellular adhesionmolecule-1 (ICAM-1), protein C, and plasminogen activatorinhibitor-1 (PAI-1). Although some of these biomarkers correlatewith mortality, ventilator free days and duration of organfailure, none of the currently available biomarkers are rigorousenough for clinical outcome prediction. When used in combi-nation with clinical variables, plasma IL8 and SP-D are betterpredictors of clinical outcome than any single biomarker orclinical parameter alone.49 Brain natriuretic peptide (BNP) may

Box 1 Differential diagnosis of acute respiratory distresssyndrome

< Acute cardiogenic pulmonary oedema< Other causes of flash pulmonary oedema:

– Renal artery stenosis– High altitude– Drugs (eg, naloxone)– Head injury

< Lymphangitis carcinomatosa< Pulmonary veno-occlusive diseases< Pulmonary vasculitis< Acute presentation of idiopathic interstitial lung diseases< Acute hypersensitivity pneumonitis< Acute eosinophilic pneumonia


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have diagnostic value, and at lower levels may help to excludecardiogenic pulmonary oedema.50

TREATMENTThe treatment of ARDS involves general supportive measuresnecessary for all critically ill patients (eg, infection control, earlyenteral nutrition, stress ulcer prophylaxis, and thrombopro-phylaxis) combined with focused ventilatory strategies andappropriate treatment of the underlying conditions. There areno effective pharmacological therapies for ARDS. The followingsection is a review of key therapies that have been trialled inpatients with ARDS and ALI. Table 3 illustrates the adoptedtreatment strategies for patients with ARDS/ALI in currentclinical practice.

VentilationLow tidal volume ventilation/protective ventilationThe main supportive therapy for ARDS is positive pressuremechanical ventilation which helps to ensure adequate oxygen-ation. Early ventilation strategies involved volume controlledventilation with tidal volume (Vt) of 10e15 ml/kg to achieve‘normal’ arterial blood gases. However, ventilation itself cancause lung injury. A landmark trial conducted in the late 1990sby the ARDS Network compared conventional Vt of 12 ml/kgwith low Vt of 6 ml/kg and permissive hypercapnia. A 9%absolute mortality reduction was found in the low Vt ventilationgroup along with reduced pulmonary and circulating inflamma-tory cytokines.17 In this study, Vt was calculated based on idealbody weight (IBW) with targeted plateau pressures of <30 cmH2O and permissive hypercapnia. This study produced a signifi-cant impact in our current ventilatory practices and has beenconfirmed by a subsequent study in which patients who wereventilated with higher Vt and lower PEEP had increased ICU andhospital mortality.51 A recent trial in patients with respiratoryfailure without ALI also demonstrated low Vt ventilation to beprotective, preventing ALI and associated with a reduction in the

release of inflammatory cytokines. This study was stopped earlydue to an increased incidence of lung injury in patients ventilatedwith higher Vt.52 Taken together, these studies demonstrate theimportance of using lower Vt to ventilate the injured lung asopposed to aiming to normalise blood gases variables.Earlier concerns of a possible need for increased sedation and

haemodynamic compromise, requiring increased cardiovascularsupport in patients ventilated with low Vt, prevented manyphysicians from practising this strategy. However, studiesaddressing these concerns have shown that low TV ventilationis a safe strategy and should be adopted in the management ofpatients with ARDS/ALI.53e55

The level of PEEPThe optimal level of PEEP in ventilated patients with ARDS/ALIremains controversial. PEEP helps to recruit alveolar units andreduces alveoli collapse due to alveolar flooding and therebyreduces ventilation perfusion mismatch. The level of PEEPneeded to achieve optimal recruitment without causing alveolarover-distension and damage is not established. Three large clin-ical trials conducted to determine ‘best PEEP ’ in patients withALI showed clinical improvement but no mortality benefit whenusing high PEEP in comparison with low PEEP (14 cm H2O vsapproximately 8 cm H2O).18 56 57 A meta-analysis of thesetrials confirmed this finding of no mortality benefit, butwhen patients with ARDS were analysed separately (PaO2/FiO2

<200 mm Hg) there was a statistically significant improvementin survival in the higher PEEP group.58

The percentage of potentially recruitable lung is variableamong patients and in the absence of recruitable lung, applica-tion of higher levels of PEEP may be harmful. This may partlyexplain the results of these clinical trials.59 Methods that havebeen utilised to assess recruitability and the response to PEEPinclude CT of the thorax,60 determination of oesophageal pres-sure,61 and thoracic ultrasound.62 Due to the heterogeneousnature of this disease, the response to PEEP should be

Table 3 Current therapeutic strategies available for the management of patients with ARDS/ALI (general supportive measures are not included)

Measures Indication Benefit Caution

Lung protective ventilation with:

1) Low tidal volume (6 ml/kg)2) Moderate PEEP as per ARDSNetwork guidance47

3) Plateau pressure of <30 cm H2O

All ARDS/ALI patients Improves mortalityReduces circulating inflammatory cytokines

Potential for de-recruitmentMay need increased sedationHaemodynamic deterioration

Prone positioning Severe hypoxaemia Improves oxygenationMay provide survival benefit in patients withsevere ARDS

Pressure soresEndotracheal tube displacementNursing issues

High frequency oscillatory ventilation Severe hypoxaemia Improves oxygenation May produce higher mean pulmonaryairway pressures (mPaws) and riskof pneumothoraxMay need heavy sedation with paralysisCardiovascular instability

Conservative fluid strategies All ARDS/ALI patients Improves lung functionReduces the duration of mechanical ventilation

Renal failure

Low dose early corticosteroids Early ARDSSevere hypoxaemia

Improves oxygenationMay provide survival benefit

ICU myopathy and neuropathyDo not give after 14 days of onsetRisk of infection

ECMO Severe ARDSRelatively contraindicated inpatients with high pressureventilatory support for >7 days

May improve survival when patients transferredto a dedicated centre

Risks of haemorrhage (in particular ICH),risk of large invasive linesPractically challengingPatient transfer to specialist unit

ALI, acute lung injury; ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; ICH, intracranial haemorrhage; ICU, intensive care unit; PEEP, positive endexpiratory pressure.


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individually assessed when applying higher PEEP, and the utilityof various methods as predictors of recruitability in day-to-daypractice needs to be established. The ARDS Network hasdeveloped a grid of applicable PEEP according to oxygenationwhich is a valuable guide for estimation of PEEP required.18

Recruitment manoeuvresWhile low tidal volume ventilation is lung protective, it mayexacerbate lung atelectasis and worsen hypoxia. Various alveolarrecruitment manoeuvres have been used to open or recruitcollapsed alveoli. These involve either a steady or rapid increasein PEEP or inspiratory holds to increase transpulmonarypressures. A systematic review of 1185 patients suggestedsignificant improvement in oxygenation after a recruitmentmanoeuvre. This effect, however, was transient and frequentcomplications were observed including hypotension and associ-ated desaturation.63 Although recruitment manoeuvres canimprove oxygenation without causing cardiovascular compro-mise or barotraumas, they need to be individualised, and thelack of standardisation remains a major issue in assessing thistreatment modality.

High frequency oscillatory ventilationHigh frequency oscillatory ventilation (HFOV) is an uncon-ventional way of ventilation whereby a piston pump oscillatesat a frequency of 3e10 Hz, generating pressure swings leading tosmall Vt with a high respiratory rate. The mean airway pressureis slightly higher than in conventional ventilation, but thepressure differences throughout the respiratory cycle are smaller.The small Vt generated, coupled with higher mean airwaypressures, provide continued alveolar recruitment. HFOV istherefore an intuitively attractive method of ventilating ARDSpatients.64 However, to date there are few studies involvingsmall numbers of patients comparing HFOV to conventionalventilation. A recent meta-analysis suggested a trend towardsmortality benefit and more ventilator free days. The results ofthis analysis need to be interpreted cautiously as the main studycontributing to the meta-analysis used high Vt in the controlgroup rather than current lung protection ventilation tech-niques.65 A large multicentred clinical study (OSCAR) iscurrently underway, which may indicate whether there isa definitive role of HFOV in patients with ARDS. In themeantime, HFOV remains as a rescue mode of ventilation forpatients with severe hypoxaemic ARDS.

Partial liquid ventilationPartial liquid ventilation (PLV) is a unique method of ventilationwhere the lungs are partially filled with an inert liquid calledperflourocarbon which has a superior oxygen dissolving capacityto blood and facilitates gaseous exchange. Patients are mechan-ically ventilated in the usual way. Although there is improve-ment in gaseous exchange and reduced lung injury in animalmodels with PLV,66 a randomised controlled trial failed toshow any mortality benefit in ARDS patients.67 This is nota recommended ventilation strategy for ALI/ARDS patients.

Extracorporeal membrane oxygenationIn the UK extracorporeal membrane oxygenation (ECMO) isonly performed by specialised centres. ECMO involves oxygen-ation of the patient’s blood outside the body via a membraneoxygenator which acts as an artificial lung, allowing adequategaseous exchange without vigorous mechanical ventilation. Anearlier study conducted in the 1970s showed no survival benefit,with overall mortality exceeding >90%.68 A UK clinical trial

(CESAR) randomised eligible patients with ARDS to ‘conven-tional’ treatment in the referring centre or transfer to thespecialist centre for ECMO. This study showed a survivaladvantage in the ECMO group (63% for ECMO vs 47% forcontrols).69 However, the study was criticised for not havinga standardised protocol management for the control group andbecause some patients in the treatment arm did not receiveECMO. The major risks associated with ECMO are the risks oftransfer of seriously ill patients, complications of large borevascular access, and bleeding due to anticoagulation. CurrentlyECMO remains an option as a rescue therapy for patientswith refractory hypoxaemia. Its use is likely to be limited tospecialised centres.

Prone positioningProne positioning results in a consistent improvement inoxygenation in patients with hypoxic respiratory failure. Thepossible mechanisms for improved oxygenation are: recruitmentof dependent lung units, redistribution of blood flow to themore unaffected lung regions, reducing ventilation perfusionmismatch,70 minimising compression of lung from anteriormediastinal structures,71 and facilitation of respiratory secretionclearance. Four large randomised controlled trials have consis-tently shown improvements in oxygenation without survivalbenefit or reduction in duration of ventilation.72 A recent meta-analysis performed by Gattinoni et al suggests survival benefitin a subgroup of patients with severe ARDS (PaO2/FiO2 <100mm Hg). They concluded that prone positioning should beconsidered for patients with severe hypoxaemia includingARDS.73 The common adverse effects of prone positioning arepressure sores and tube displacement. Prone positioning maybe considered in patients with severe ARDS to improveoxygenation in centres with capable nursing expertise.

Pharmacological therapiesPharmacotherapies have a very limited role in the managementof ARDS. So far there is no effective medical treatment thatimproves survival for adult patients with ARDS, althoughexogenous surfactant is beneficial in the paediatric population.

Neuromuscular agentsNeuromuscular agents (NMA) can be used to improve patienteventilator synchrony and assist mechanical ventilation inpatients with severe hypoxaemia. There is evidence that usingNMA in patients with severe ARDS (PaO2/FiO2 <150 mm Hg)improves oxygenation and reduces inflammatory cytokines.74 75

A phase IV randomised controlled trail comparing cis-atracuriumwith placebo for 48 h in patients with severe ARDS (PaO2/FiO2

<150 mm Hg) showed improved adjusted 90 day survival rateand increased ventilator fee days in the cis-atracurium groupwithout significant increase in muscle weakness.76 It is not clearwhether the observed benefit was due to neuromuscularparalysis alone, possible additional anti-inflammatory effects, ora possible reduction in oxygen consumption. Paralysing patientswith NMA can be associated with critical care neuromyopathy,longer weaning times, longer ICU stays, and a higher mortalityand they therefore need to be used cautiously.77 From thisevidence, it is not possible to recommend routine use of NMAbeyond the usual indications. Further studies are necessary toevaluate the routine use of NMA in ARDS/ALI.

VasodilatorsInhaled nitric oxideInhaled nitric oxide (NO) is an endogenous vasodilator. Wheninhaled it reduces V/Q mismatch and improves oxygenation by


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selective pulmonary vasodilatation in alveolar units that areventilated.78 It has been used in clinical trials in patients withhypoxic ventilatory failure, ALI, and ARDS. Inhaled NO alsoreduces elevated pulmonary vascular resistance in patientswith ARDS.79 Adverse effects of inhaled NO are meth-aemoglobinaemia, cytotoxic nitrogen products (nitrogendioxide), and renal failure.80 A Canadian survey in 2004 reportedthat up to 30% of critical care physicians were using inhaled NOin selected patients with ARDS,81 suggesting widespread usageas rescue therapy despite the lack of evidence. A Cochranereview of 14 clinical trials with 1303 patients (which includedthree paediatric and one combined adult and paediatric study)showed only a transient improvement in oxygenation with nosurvival benefit or increase in ventilator free days. Furthermore,no improvement was seen in secondary outcomes such as lengthof ICU or hospital stay, and increased renal impairment wasnoted in the inhaled NO treated group.82 Current use isdeclining due to the poor outcome data and escalating costs ofusing inhaled NO. Its use is not recommended as routinetherapy but may be considered for improvement of oxygenationin patients with refractory hypoxaemia.

ProstanoidsProstacyclins are arachidonic acid derivatives that causepulmonary vasodilatation and are used to treat patients withprimary pulmonary hypertension. They have additional immu-nomodulatory effects such as reducing neutrophil adhesion,and inhibition of neutrophil, macrophage and platelet activa-tion.83 Nebulised prostacyclin (PGI2) has comparable effects inimproving oxygenation, pulmonary vasodilatation and shuntreduction when compared with inhaled NO.84 Improvedoxygenation has been seen in a paediatric study,85 but this hasnot yet been demonstrated in adult patients with ARDS.

Intravenous prostaglandin (PGE1) has been evaluated ina Cochrane systematic review which identified seven studiesincluding a total of 697 patients. These studies were difficult tocompare due to protocol and drug formulation differences, butno mortality benefit was seen and more hypotension, arrhyth-mias and hypoxia occurred in the study group.86 Clinicallyprostanoids are rarely used and not recommended for routinepractice.

Anti-inflammatory agentsSteroidsARDS is characterised by a profound inflammatory processfollowed by fibro-proliferative changes; using steroids to reducethis inflammation or to moderate the fibrotic recovery is anobvious approach that has been tried in several clinical studies.The dose of corticosteroids, duration of treatment, and thetiming of initiation in both prevention and treatment of ARDShas been evaluated. Studies of ARDS prevention for at riskpatients suggest that there is no preventative effect conferred bythe use of high dose short duration courses of steroids.87 Highdose short duration steroids also have no mortality benefit inearly ARDS.88 In a phase III study, the ARDS Network inves-tigators assessed the effect of steroids in the late stage fibroticphase of ARDS (after 7 days of onset) and again showed nomortality benefit in the treatment group, with a highermortality in patients treated 14 days after onset.89 A studyby Meduri et al showed improved ICU mortality, LIS, lowerinfection rate, and shorter duration of mechanical ventilationand ICU stay when low dose corticosteroids were commenced inthe early stages of ARDS. However, this study was limited bysmall numbers and methodological issues, including a 2:1

randomisation allocation ratio and frequent crossovers. More-over, an increased number of patients with catecholaminedependent shock in the treatment group may have biased themortality outcome in this group.90

Further larger randomised controlled trials are needed to assessthe effect of low dose corticosteroids in patients with earlyARDS. From the available evidence, corticosteroids are notindicated for prevention, but low dose steroids (1e2 mg/kgmethylprednisolone) may be considered in patients with severeearly (<72 h) ARDS. The dose titration and the duration oftreatment remains a contentious issue. While prolonged use ofcorticosteroids may moderate fibrotic recovery, this should bebalanced against the deleterious effects of steroids. It is notrecommended to initiate corticosteroids beyond 14 days afterthe onset of ARDS.

KetoconazoleKetoconazole is an imidazole based antifungal medication whichinhibits the synthesis of thromboxane A2, a potent vasocon-strictor involved in platelet aggregation and neutrophil recruit-ment.91 It is also known to reduce alveolar macrophageinflammatory mediator92 and was therefore assessed for itsrole as an anti-inflammatory agent in ARDS. Although earlypreventive studies suggested benefit,93 94 a phase III studyconducted in 2000 by the ARDS Network showed no improve-ment in mortality or secondary outcome measures.95 Ketoco-nazole is not recommended for the treatment of ARDS/ALI.

Lysofylline and pentoxifyllinePentoxifylline is a phosphodiesterase inhibitor and lisofylline isa pentoxifylline derivative with anti-inflammatory properties.Lisofylline reduces elevated circulating oxidised free fatty acidslevels, seen in patients with ARDS, and inhibits neutrophilaccumulation as well as reducing pro-inflammatory cytokines(TNFa, IL1, and IL6). While animal studies showed promisingresults, a phase II/III study conducted by the ARDS Networkshowed no treatment benefit and a trend towards increasedmortality in patients treated with lisofylline.96 This is notrecommended as treatment for ARDS/ALI.

Sivelestat (neutrophil elastase inhibitor)Neutrophil elastase secreted by activated neutrophils is thoughtto play an important role in endothelial damage and changes invascular permeability during ALI. Sivelestat is an inhibitor ofneutrophil elastase and was studied in a phase II/III randomisedcontrolled trial (STRIVE). Mortality was increased in the treat-ment arm and the study was stopped prematurely.97 Depelestatis another neutrophil elastase inhibitor currently being assessedin ARDS patients in a phase II study, the results of whichare expected soon. Neutrophil elastase inhibitors remain anexperimental therapy while further results are awaited.

AntioxidantsOxygen free radicals produced by activated neutrophils andmacrophages are thought to play an important role in theinflammatory pathways that lead to cell damage in patientswith ARDS. Glutathione is an antioxidant which is produced inthe liver, the levels of which are reduced in alveolar fluid inpatients with ARDS.98 Glutathionine levels can be replenishedby supplementation with its precursor N-acetylcysteine. Severalsmall studies have demonstrated no mortality benefit with theuse of N-acetylcysteine in ALI and ARDS patients.86

Fluid management and alveolar fluid clearanceOptimal fluid management is an essential step in the resusci-tation of critically ill patients. While it is important to maintain


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an adequate intravascular pressure to perfuse major organs,raised capillary hydrostatic pressure from excess fluid therapycan lead to worsening of pulmonary oedema in patients withARDS.99 Positive fluid balance is associated with worse clinicaloutcomes in patients with ARDS.100 A phase III studyconducted by the ARDS Network compared liberal versusconservative fluid strategy in patients with ALI. Despiteshowing no difference in mortality between the groups, theconservative group had improved oxygenation, LIS, and short-ened duration of mechanical ventilation without any increase inother organ failures.19 We recommend a conservative fluidmanagement approach, once resuscitation is complete, with theaim being to achieve cumulative neutral balance withoutcompromising cardiovascular and renal variables. Some patientsaccumulate a significant positive fluid balance during theresuscitation phase, and use of diuretics (after resolution ofhaemodynamic instability) to achieve a sustained negativebalance may be valuable. Careful monitoring of renal functionand other indices of perfusion is important if this strategy isadopted.

The resolution of ARDS depends on the adequate clearance ofthe alveolar oedema. Defective alveolar fluid clearance is asso-ciated with decreased survival in ARDS patients.101 102 The roleof b2 agonists in assisting alveolar fluid clearance has beeninvestigated using salbutamol in ARDS patients. A small studydemonstrated reduced extravascular lung water and a trendtowards survival benefit.103 The effect of b2 agonists in ARDS/ALI has been further investigated in phase II/III multicentrestudies in the USA with aerolised albuterol (ALTA) and in theUK with intravenous salbutamol (BALTI-2). Both studies werestopped prematurely. Preliminary data suggest that b2 agonistsprovide no survival benefit in ARDS/ALI and in fact may beassociated with increased mortality.20 b2 agonists are notrecommended as part of therapy for patients with ARDS/ALI.

ImmunonutritionNutritional input has been increasingly valued in critically illpatients and early enteral nutrition is generally advised.Manipulation of nutrition with supplementation of fish oilbased omega-3 fatty acids, eicosapentanoic acid (EPA), docosa-hexaenoic acid (DHA), and gamma-linolenic acid (GLA) inborage oil are thought to reduce arachidonic acid availability forthe generation of inflammatory pathways. Supplementationwith EPA and GLA has resulted in alveolar neutrophilde-recruitment, improved gaseous exchange, and reduction induration of mechanical ventilation.104 A recent systematicreview to assess immunonutrition in critically ill patients

showed significant reduction in mortality, secondary infectionsand length of hospital stay with fish oil based immunonutritionin the ICU setting.105

A recent phase III clinical trial conducted by the ARDSNetwork supplementing omega-3 fatty acids, GLA and antioxi-dants in patients with ALI (OMEGA) showed no mortalitybenefit.21 Further trials are currently underway to assess theeffect fish oil in ARDS patients. This form of nutrition remainsexperimental and further studies are needed to elucidate theeffects of various types of immunonutrition for inflammatorymodulation in patients with ARDS/ALI.

Exogenous surfactantsPulmonary surfactant is a complex mixture of phospholipids,proteins and neutral lipids produced by alveolar type II cells.Surfactant helps to maintain alveolar surface tension and is alsoinvolved in the host immune response.106 Bronchial lavagesurfactants recovered from patients with ARDS show changes inphospholipids composition and decreased levels of surfactantproteins.107e109 A number of clinical trials have tested thehypothesis that administration of exogenous surfactant confersclinical benefit in adult patients with ARDS, but in contrast tothe literature in newborns and children, no mortality benefit hasbeen demonstrated.110 Limitations of these studies includeinsufficient surfactant delivery, lack of incorporation of hydro-philic surfactant proteins and, possibly most importantly, notargeting of populations who might be most likely to benefit (eg,where there is reduced production rather than inactivation orincreased breakdown due to hydrolysis and/or oxidation). Noveltechniques utilising stable isotope labelling of surfactantprecursors, to assess surfactant synthesis and metabolism,111

open up the possibility of characterising and targeting patientswith reduced synthesis who may most likely benefit fromexogenous surfactant. However, at present exogenous surfactanthas no added value in the management of adult patients withARDS.

Mesenchymal stem cellsMesenchymal stem cells (MSC) are bone marrow derived stemcells with a capacity to differentiate into many cell types. Theirtherapeutic importance is under investigation in many diseasesincluding lung injury. In animal models with lung injury,intravenous MSC lead to favourable outcome with reduction ininflammation, pro-inflammatory cytokines and lung oedema. Inex vivo human lung models of endotoxin induced lung injury,administration of MSC resulted in improved alveolar fluidclearance with quantitative increase in keratinocyte growth

Table 4 Potential therapies for ALI/ARDS under clinical evaluation

Therapy Action

1. Anti-tissue factor antibody To reduce procoagulant activity and inflammation

2. CytoSorb haemoperfusion device for IL6 Removal of IL6 and hence reduce inflammation

3. Depelestat (neutrophil elastase inhibitor) Anti-inflammatory

4. Fish oil Immunonutrition

5. Granulocyte macrophage colony stimulating factor Promoting alveolar epithelial cell proliferation and repair

6. Nebulised heparin To reduce pulmonary coagulation activation and vascularpermeability

7. Interferon b To reduce vascular leakage

8. Insulin Anti-inflammatory

9. Keratinocyte growth factor To promote alveolar epithelial proliferation and repair

10. P38 a mitogen-activated protein kinase inhibitor Anti-inflammatory

11. Statins Anti-inflammatory

ALI, acute lung injury; ARDS, acute respiratory distress syndrome.


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factor (KGF). KGF is a cytokine and a potent mitogen whichspecifically acts on epithelial cells, and in lung injury models it isprotective and induces type II cell proliferation and oedemaclearance.112 Human studies with MSC are still awaited. Asingle centre phase II study is underway to assess the effect ofintravenous KGF in ALI patients.

DIFFICULTIES WITH ARDS TRIALS AND FUTURE DIRECTIONSPharmacological clinical trials in ARDS are limited by theheterogeneous nature of patients and the lack of direct trans-lational animal models that adequately represents ARDS path-ogenesis in humans. Subgroups of patients have been foundto benefit from certain therapies in patients with severeARDS,58 73 74 but so far no medical treatment has been shown toimprove overall survival. Nevertheless, future ARDS therapies

may involve single or combination treatments that involvetargeting inflammatory pathways at various levels, minimisingvascular dysfunction and oxidative lung injury, and improvingalveolar fluid clearance. Cell based therapies with MSC arecurrently under evaluation and show promising results in animalmodels.112 Statins, insulin and interferon b are also currentlyunder evaluation in clinical trials (table 4).

CONCLUSIONSARDS remains a major health burden. Mortality remains highwith significant physical and psychosocial morbidity. Thera-peutic strategies remain sparse and ongoing trials will hopefullyprovide further information on future potential treatments. Onthe other hand, the future looks exciting. Investigators are likelyto concentrate on manipulating inflammatory pathways andoptimising repair of lung tissue while preventing the develop-ment or progression of ALI/ARDS. Improved characterisation ofsubgroups of patients within this heterogeneous populationmay also lead to advances.

MULTIPLE CHOICE QUESTIONS (TRUE (T)/FALSE (F): ANSWERSAFTER THE REFERENCES)1. In patients with ARDS, mechanical ventilation with low

tidal volume improves survival2. Lymphocytes are predominant cells in bronchoalveolar lavage

of patients with early ARDS3. Respiratory failure is the most common cause of death in

ARDS4. Prone positioning improves oxygenation in ARDS5. Exogenous surfactant therapy improves oxygenation and

survival rates in patients with ARDS

Competing interests None.

Provenance and peer review Not commissioned; externally peer reviewed.

REFERENCES1. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med

2000;342:1334e49.2. Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults.

Lancet 1967;2:319e23.3. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus

Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trialcoordination. Am J Respir Crit Care Med 1994;149(3 Pt 1):818e24.

Main messages

< ARDS is a clinical syndrome characterised by severehypoxaemic respiratory failure.

< Despite limitations, the AECC diagnostic criteria is a simplescreening tool for patient identification.

< Assessment of the underlying condition with appropriatetreatment is an essential part of management strategy.

< Lung protective ventilation with low tidal volume (6 ml/kg),moderate PEEP and plateau pressure limitation <30 cm H2Oimproves patient survival.

< General supportive measures are likely to have contributed insurvival benefit and should not be overlooked.

< A conservative fluid management strategy should be adopted.< Severe ARDS patients may have beneficial effects from the

measures such as recruitment manoeuvres, prone positioning,higher PEEP, and transfer to a specialist centre in difficultcases (eg, ECMO).

Current research questions

1. Effective identification of useful biomarkers and geneticmarkers for diagnosis, phenotypic characterisation, andprognostic assessment.

2. Role of various inflammatory pathways and possible targetsfor treatmentdfor example, insulin, statin, depelestat, anti-IL1, etc.

3. Use of stem cells for epithelial and endothelial repair.4. The use of potent mitogenic cytokines such as KGF and

GM-CSF in epithelial repair and effective alveolar oedemaclearance.

5. Modulation of procoagulant activity in the lung.6. Newer surfactant preparations:

< withstanding hydrolysis or breakdown< in certain phenotypes (eg, intrinsic vs extrinsic or patients

with reduced synthesis)< use of potential carriers to improve delivery

7. Effective removal of cytokines from whole blood viacytoabsorb haemoperfusion to reduce inflammation.

8. The clinical effects of various immunonutrition on ARDS/ALI.9. The clinical effectiveness of the newer lung assisting devices

in advanced lung protective ventilation.

Key references

< Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratorydistress in adults. Lancet 1967;2:319e23.

< Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions,mechanisms, relevant outcomes, and clinical trial coordina-tion. Am J Respir Crit Care Med 1994;149(3 Pt 1):818e24.

< The Acute Respiratory Distress Syndrome Network.Ventilation with lower Vt as compared with traditional Vt foracute lung injury and the acute respiratory distress syndrome.N Engl J Med 2000;342:1301e8.

< Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparisonof two fluid-management strategies in acute lung injury.N Engl J Med 2006;354:2564e75.

< Briel M, Meade M, Mercat A, et al. Higher vs lower positiveend-expiratory pressure in patients with acute lung injury andacute respiratory distress syndrome: systematic review andmeta-analysis. JAMA 2010;303:865e73.


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ANSWERS

1. T2. F3. F4. T5. F

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2011 87: 612-622 originally published online June 4,Postgrad Med J A Dushianthan, M P W Grocott, A D Postle, et al. acute lung injuryAcute respiratory distress syndrome and

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