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Pharmacotherapy for Prevention andTreatment of Acute RespiratoryDistress SyndromeCurrent and Experimental Approaches

Karen J. Bosma,1,2,3 Ravi Taneja2,3,4 and James F. Lewis1,3,5

1 Department of Medicine, Division of Respirology, The University of Western Ontario, London,

Ontario, Canada

2 Critical Care Western, The University of Western Ontario, London, Ontario, Canada

3 London Health Sciences Centre, London, Ontario, Canada

4 Department of Anesthesia & Perioperative Medicine, The University of Western Ontario, London,

Ontario, Canada

5 St. Joseph’s Health Centre, London, Ontario, Canada

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12561. Pathophysiology and Clinical Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12562. Supportive Care and Salvage Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12603. Current and Experimental Pharmacological Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1262

3.1 Prevention of Acute Respiratory Distress Syndrome (ARDS) in Patients at Risk . . . . . . . . . . . . . . . 12623.1.1 Ketoconazole. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12623.1.2 ACE Inhibitors and Angiotensin II Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . 12653.1.3 Thiazolidinediones (Peroxisome Proliferator Activated Receptor-g Agonists) . . . . . . . . . . 12653.1.4 Tetracycline-Related Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12663.1.5 Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12663.1.6 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12673.1.7 Recombinant Human Platelet-Activating Factor Acetylhydrolase . . . . . . . . . . . . . . . . . . 1267

3.2 Treatment of Established ARDS: Acute and Exudative Phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12673.2.1 b2-Adrenergic Receptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12673.2.2 Exogenous Surfactant Replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12683.2.3 Antioxidants and Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12703.2.4 Modulation of Neutrophil Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12713.2.5 Other Immunomodulating Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12723.2.6 Activated Protein C. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12743.2.7 HMG-CoA Reductase Inhibitors (Statins) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1275

3.3 Treatment of Established ARDS: Fibroproliferative Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12753.3.1 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1275

4. Potential for Future Clinical Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12764.1 Lessons Learned from Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1277

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1277

REVIEWARTICLEDrugs 2010; 70 (10): 1255-1282

0012-6667/10/0010-1255/$55.55/0

ª 2010 Adis Data Information BV. All rights reserved.

Abstract The acute respiratory distress syndrome (ARDS) arises from direct andindirect injury to the lungs and results in a life-threatening form of respiratoryfailure in a heterogeneous, critically ill patient population. Critical care tech-nologies used to support patients with ARDS, including strategies for me-chanical ventilation, have resulted in improved outcomes in the last decade.However, there is still a need for effective pharmacotherapies to treat ARDS, asmortality rates remain high. To date, no single pharmacotherapy has proveneffective in decreasing mortality in adult patients with ARDS, although exo-genous surfactant replacement has been shown to reduce mortality in thepaediatric population with ARDS from direct causes. Several promisingtherapies are currently being investigated in preclinical and clinical trials fortreatment of ARDS in its acute and subacute, exudative phases. These includeexogenous surfactant therapy, b2-adrenergic receptor agonists, antioxidants,immunomodulating agents and HMG-CoA reductase inhibitors (statins). Re-cent research has also focused on prevention of acute lung injury and acuterespiratory distress in patients at risk. Drugs such as captopril, rosiglitazoneand incyclinide (COL-3), a tetracycline derivative, have shown promising re-sults in animal models, but have not yet been tested clinically. Further researchis needed to discover therapies to treat ARDS in its late, fibroproliferativephase. Given the vast number of negative clinical trials to date, it is unlikely thata single pharmacotherapy will effectively treat all patients with ARDS fromdiffering causes. Future randomized controlled trials should target specific,more homogeneous subgroups of patients for single or combination therapy.

Acute lung injury (ALI) and the acute res-piratory distress syndrome (ARDS) arise fromdirect or indirect injury to the lungs, and resultsin a life-threatening form of respiratory failure.ALI/ARDS is both common and serious:6.5–8.5% of patients admitted to an intensive careunit (ICU) will be diagnosed with ALI orARDS,[1-3] and approximately one-quarter toone-half of these patients will succumb to thisdisease process.[1,4-6] Over the past 40 years,ARDS has been the focus of extensive basicscience and clinical research, although no singlepharmacotherapy has been shown to reducemortality in a large, randomized, controlled,multicentre trial of adult patients. The reasonsfor this are manifold, and include issues of dos-ing, route of administration and timing of thevarious interventions tested. More importantly,however, may be the nature of the disorder itself:the diagnosis of ARDS envelops a heterogeneousgroup of patients with varying causes and patho-physiological mechanisms at work. The notionthat a therapeutic agent that can successfully altera single biological target in an animal model of

ALI will reduce mortality in all patients withARDS may be unrealistic. Nonetheless, there isreason for hope on the scientific horizon.

Recent advances have been made in ourunderstanding of the pathophysiological mech-anisms underlying ALI/ARDS, leading to theidentification of potential novel targets forpharmacological intervention. Some therapiesare best aimed at preventing the development ofARDS, while others treat the syndrome as it un-folds or aid in its resolution. The challenge lays inidentifying the subgroup of patients most likelyto benefit from such focused therapy. This paperreviews the current experimental and existingapproaches to managing ARDS, highlightingthe pathophysiological basis for their use andpotential for future clinical development.

1. Pathophysiology and Clinical Course

ALI may occur following a direct insult to thepulmonary system such as aspiration of gastriccontents, bacterial pneumonia or viral pneumo-nitis (e.g. H1N1 influenza virus), or an indirect

1256 Bosma et al.

ª 2010 Adis Data Information BV. All rights reserved. Drugs 2010; 70 (10)

insult such as the systemic inflammatory responseassociated with pancreatitis, sepsis or multipletrauma. Table I shows common direct and in-direct causes of ALI/ARDS. Whether this ‘firsthit’ to the lung is direct or indirect, a pulmonaryinflammatory response may occur, which often isadaptive and self-limited. However, when cou-pled with repeated ‘hits’ to the lung from insultssuch as injurious mechanical ventilation or othersecondary processes such as hypotension, a cycleof intense inflammation and worsening pulmon-ary injury ensues. The ‘multiple hit’ theory ofARDS progression also provides a frameworkfor studying the disease process (figure 1).

Clinically, ALI manifests as bilateral airspacedisease observed on chest radiograph and hy-poxaemia, such that the ratio of partial pressureof arterial oxygen to fraction of inspired oxygen(PaO2/FiO2) is greatly reduced. According to the1994 American European Consensus Conference(AECC) definition, a chest radiograph consistentwith pulmonary oedema and a PaO2/FiO2 ratio<300 is sufficient to diagnose ALI in the setting ofan inciting pulmonary insult and the absence ofcongestive heart failure. The aforementionedcriteria but with a PaO2/FiO2 ratio <200 is clas-sified as ARDS.[8] Although differentiated by theAECC definition, ALI and ARDS are oftengrouped together for the purpose of clinical trialenrolment and are treated as a single entitythroughout this review.

Although not all patients follow the sameclinical course, progression of ALI/ARDS may

be considered along a pathophysiological time-line of early, mid and late phases, with consider-able overlap between these phases. Table IIsummarizes the pathogenetic mechanisms atwork during each phase, linking each biologicalpathway to a potential drug therapy. A generaloverview of the pathophysiology of ARDS isprovided here, with more detailed descriptionsof the specific biologic pathways discussed insections 3.1–3.3 as they pertain to each potentialpharmacological therapy.

The early phase, within the first 72 hours ofthe inciting lung injury, is characterized by in-flammatory damage to the alveolar-capillarybarrier. This results in increased vascular per-meability, leading to interstitial and alveolaroedema as proteinaceous fluid fills the alveolarspace. This inflammation-induced pulmonaryoedema disrupts normal gas exchange and in-creases the work of breathing, leading to res-piratory failure and the need for mechanicalventilation. Mechanical ventilation itself maycause secondary insult to the already inflamedoedematous alveoli. During each tidal breathinduced by mechanical ventilation, unstable al-veoli undergo cyclical collapse and shearingopen, termed ‘atelectrauma’. Furthermore, thenon-collapsed alveolar units may receive a

Table I. Direct and indirect causes of acute lung injury/acute res-

piratory distress syndrome

Direct causes Indirect (systemic) causes

Bacterial pneumonia

Viral pneumonitis

High-risk viruses:

SARS coronavirus

H1N1 influenza A virus

Gastric aspiration

Blunt thoracic trauma with lung

contusion

Near drowning

Smoke inhalation

Meconium aspiration (infants)

Sepsis

Pancreatitis

Surface burns

Drug overdose

Transfusion-related acute

lung injury

Severe trauma (without

contusion)

Cardiopulmonary bypass

SARS = severe acute respiratory syndrome.

Death

Secondary insult

Initial insult

Recovery

Recovery

Multi-organfailure

ARDS

PneumoniaAspirationSepsisMulti-traumaPancreatitisBrain injury

MechanicalventilationShockInfection

Inflamed lung

Normal lung

Recovery

Fig. 1. ‘Multiple hit’ theory of acute respiratory distress syndrome(ARDS) progression. The ‘first hit’ to the lung incites a pulmonaryinflammatory response, which, when coupled with repeated ‘hits’ tothe lung from injurious mechanical ventilation or other secondaryinsults, may lead to the pathological manifestations of ARDS. Themost common cause of death in ARDS is multiple organ dysfunctionsyndrome (reproduced from Bosma et al.[7] [2007], with permission).

Pharmacotherapy for ARDS 1257


greater proportion of the delivered tidal volume,leading to damage due to overdistention or ‘volu-trauma’. Further breakdown of the endothelial-

epithelial barrier may occur with atelectraumaand volutrauma, along with the release oflocal proinflammatory mediators which further

Table II. Pathophysiology of acute respiratory distress syndrome (ARDS)a

Mechanism Pathophysiological process Potential therapeutic approachb

Early (0–72 hours)a

Damage to alveolar-capillary barrier Capillary endothelial cell damage ACE inhibitors, ARBs, GM-CSF

Alveolar epithelial cell damage GM-CSF

Alveolar oedema formation Protein leak into alveoli

Fluid accumulation in alveoli b2-Agonists, GM-CSF, diuretics

Neutrophil recruitment Mediated by increased NF-kB activity PPAR-g agonists

Mediated by increased ICAM-1 expression

Neutrophil activation Release proteases:

MMPs Incyclinide

HNE Incyclinide, HNE inhibitors

defensins

Release AA metabolites:

thromboxanes Ketoconazole

leukotrienes

prostaglandins

Modulation of neutrophil activation Prostaglandin E1

Early-Mid (0–7 days)a

Delayed neutrophil apoptosis

Intra-alveolar hyaline membrane formation

Oxidant stress Increased oxygen free radical production N-acetylcysteine, a-tocopherol, ascorbic acid

Decreased glutathione levels N-acetylcysteine

Increased inflammatory mediators General Corticosteroids, statins

Specific:

PAF rhPAF acetylhydrolase

eicosanoids from omega-6 FA Omega-3 FA supplementation

phosphatidic acid-1a Lisofylline

IL-8 Anti-IL-8 monoclonal antibody

TNFa Anti-TNFa monoclonal antibody

Disruption of surfactant system Surfactant impaired function/increasedmetabolism

Exogenous surfactant replacement

Activation of complement

Activation of coagulation cascade Decreased plasma protein-C levels Drotrecogin alfa

Late (8–28 days)a

Organization and fibrosis Proliferation of type II alveolar cells Corticosteroids

Organization of alveolar exudates

Interstitial collagen-rich matrix formation

Alveolar fibrosis/destructiona Mechanisms causing pulmonary dysfunction may occur simultaneously and overlap in different stages of ARDS.

b See text for details.

AA= arachidonic acid; ARB = angiotensin receptor antagonist (blocker); FA= fatty acid; GM-CSF = granulocyte macrophage colony-

stimulating factor; HNE = human neutrophil elastase; ICAM-1 = intercellular adhesion molecule-1; IL-8 = interleukin-8; MMPs =matrix

metalloproteinases; NF-kB =nuclear factor-kB; PAF =platelet-activating factor; PPAR-g = peroxisome proliferator activated receptor-g;rhPAF = recombinant human PAF; TNFa = tumour necrosis factor-a.

1258 Bosma et al.


propagate this cycle of ventilator-exacerbatedlung injury.[7]

As inflammation ensues, neutrophils are re-cruited to the lung. Damaged endothelial cellsexhibit increased activity of the transcriptionfactor nuclear factor-kB (NF-kB), which up-regulates the surface expression of intercellularadhesion molecule (ICAM)-1. ICAM-1 mediatesleukocyte adhesion and migration across the en-dothelium to the alveolar epithelium. Activatedneutrophils release proteases, such as matrixmetalloproteinases (MMP) and neutrophil elas-tase (NE), which further damage the alveolar-capillary membrane.[9] Activated neutrophils alsocontain high levels of arachidonic acid,[10] whichis metabolized into leukotrienes, prostaglandinsand thromboxanes. Leukotrienes attract moreneutrophils, prostaglandins are proinflammatorymediators, and thromboxanes play a role invasoconstriction and platelet and leukocyte ag-gregation. Neutrophil recruitment and activationmay be an adaptive physiological response to in-jury, or may incite a vicious cycle of inflamma-tion and further damage.[9]

At this stage, patients may recover from theinitial insult, with clearance of the pulmonaryoedema and restoration of the barrier betweencapillary endothelial and alveolar epithelial cells,or may progress to the exudative or mid phaseof ARDS. It is not fully understood why twopatients exposed to the same insult may havecompletely different clinical courses; however,genetic factors,[11] co-morbid illnesses such asdiabetes mellitus and alcohol addiction,[12] nu-tritional status, medications and exposure tofurther insults are all likely to play a role. Un-derstanding the host and environmental factorsthat place a patient at high risk of progressing tothe exudative phase of ARDS will facilitateidentification of targets for earlier intervention.

The exudative or subacute phase typically oc-curs over the 3–7 days following the initial insult.Pathologically, this mid phase is characterized byformation of intra-alveolar hyaline membranesrich in plasma proteins, fibrin and cellular deb-ris.[13] A biopsy of the lungs at this stage will showdiffuse alveolar damage and, clinically, the lungshave poor compliance with ongoing gas exchange

problems including hypoxaemia and elevateddead space fraction. The inflammatory milieuwithin the alveoli, coupled with the cyclicalopening, stretching and collapsing of alveoli viamechanical ventilation, initiates a number ofpathogenic pathways in concert or in series.These include disruption of surfactant functionand metabolism, ongoing neutrophil recruitmentand activation, along with increased expres-sion and release of inflammatory mediators, im-balance of oxidant and antioxidant activity, andactivation of complement and coagulation cas-cades. Each of these pathways is further discussedto provide context for the drugs or therapiesaimed at ameliorating these various mechanisms(see section 3).

Interestingly, only a minority of patients willsuccumb to severe hypoxaemia or hypercarbia, asthe major source of mortality is not the pulmon-ary injury per se, but rather the occurrence ofmultiple organ failure. In this setting, the injuredlung may represent a rich source of inflammatorymediators that could contribute to the develop-ment of multi-organ failure. For example, stressfailure and necrosis of the endothelial-epithelialbarrier may allow various inflammatory media-tors, bacteria and endotoxins to quickly spreadfrom the lungs into the systemic circulation.Indeed, it is this de-compartmentalization ofinflammatory mediators from the lungs into thecirculation that is felt to lead to cell apoptosis indistal organs,[14] and ultimately multiple organdysfunction syndrome (MODS) [figure 2].[15]

Once MODS develops, disease is often irrever-sible and mortality may increase significantly to60–98%, the latter occurring when three or moreorgans are involved for a period of more than7 days.[15-17] Thus, a key to developing noveltherapies that will reduce mortality in ARDS willbe identification of the cellular and molecularmechanisms by which ARDS leads to MODS.

Survivors of the first week of ALI/ARDS mayenter the late phase of the disorder, known as thefibroproliferative phase. During days 8–28, theexudates and hyaline membranes become orga-nized, and fibrosis may become apparent. Type IIalveolar cells proliferate and line the alveolarwalls, fibroblasts migrate and differentiate into



myofibroblasts in the interstitial and alveolarspaces, and a collagen-rich extracellular matrix islaid down in the interstitium.[13] Alveoli may bedestroyed, pulmonary vascular area may be re-duced and chronic inflammation is generallypresent. Patients in the fibroproliferative phaseof ARDS may slowly recover, or may fail towean from mechanical ventilation and succumbto complications of a lengthy critical illness orpre-existing co-morbid illnesses. Pharmaceuticalinterventions for late ARDS must interrupt thefibrosing alveolitis and aid in resolution, re-modelling and repair of injured lungs.[13] Often,therapies that might be beneficial during the earlyphase of lung injury are started too late in thecourse of the disease, when fibrosis is alreadyestablished, muting their potential efficacy. When

tested specifically for the late fibroproliferativephase of ARDS, anti-inflammatory therapieshave yielded disappointing results. Basic scienceresearch examining mechanisms of idiopathicpulmonary fibrosis may illuminate therapeuticpathways for fibroproliferative ARDS, but fur-ther work is required in this area.

2. Supportive Care and SalvageTherapies

Although no pharmacological therapies havebeen proven to reduce mortality in large, ran-domized controlled trials (RCTs) involving adultpatients, it appears that improvements in sup-portive care have reduced mortality to someextent. For example, mortality estimates ranged

Alveolar-capillary barrier disruption• Increased permeability pulmonary oedema• Surfactant disruption

Pulmonary inflammation• Neutrophil migration and activation• ↑ Cytokines, ↑ oxygen radicals• Epithelial/endothelial cell damage

Systemic inflammation• ↑ Inflammatory mediators in circulation• Impairment of organ function

MOF

ARDS

↑ Cytokines

↑ Cytokines

Fig. 2. Progression of acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Initially, inflammatory damage to thealveolar-capillary barrier results in increased vascular permeability, leading to interstitial and alveolar oedema as proteinaceous fluid fills thealveolar space. There, the proteinaceous fluid interferes with the function and metabolism of the endogenous surfactant system. Coupled withthis, neutrophils that infiltrate lungs are subsequently activated and represent an important source of inflammatory mediators and oxygen freeradicals, inducing further epithelial and endothelial cell damage and an altered host immune response. Newly secreted mediators and/or spill-over of inflammatory mediators from the lung into the systemic circulation ultimately contribute to the development of MOF. Inflammatorymediators released from organs such as the liver, heart and kidney return to the lung via the systemic circulation and may contribute to furtherpulmonary inflammation. Thus, each new insult to the pulmonary system accelerates the acute lung injury cycle (reproduced from Bosmaet al.[7] [2007], with permission).

1260 Bosma et al.


from 55% to 65% as reported in the literature inthe 1980s and early 1990s[18-21] to more recentestimates of 32–46% in observational epidemio-logical studies[1,2] and 25–31% in large clinicaltrials.[5,6] Although this mortality reduction mayin part reflect differences in diagnostic criteriaused post publication of the 1994 AECC defini-tion, undoubtedly the largest impact has beenthe move to more ‘protective’ strategies of me-chanical ventilation.

In 2000, the National Institutes of Health-sponsored ARDS Network (ARDSnet) trial in-volving low tidal volume ventilation was pub-lished, and now constitutes the standard of carefor patients with ALI and ARDS. This trialcompared a traditional tidal volume of 12mL/kgwith a lower tidal volume of 6mL/kg in 861patients and reported a mortality reduction from40% in the control arm to 31% in the treatmentarm.[5] These results definitively ended the debatefuelled by three previous inconclusive smallertrials regarding lower versus conventional tidalvolumes. In terms of furthering ALI/ARDSresearch, several lessons have been learned fromthis landmark study. First, ARDSnet was set upto conduct well designed, large, phase III studieswith a concerted effort to optimize patient en-rolment through involvement of many centres inan organized and cohesive group.[22] This enableda study sufficiently powered to realize a mortalitydifference to be conducted within a reasonabletimeframe, and pointed the way for other simi-larly structured ARDS research networks to be-come established. Second, the treatment arm wasassociated with lower oxygenation values thanthe conventional arm, highlighting the potentialdanger of relying on oxygenation or other phy-siological parameters as surrogates for mortality.Third, this study demonstrated that a non-pharmacological intervention could alter mor-tality, indicating that future RCTs need to becarefully standardized in all aspects of supportivecare in both treatment and control arms.

One potential caveat ensuing from this studyhas been the assumption that any additionalproven therapy would reduce mortality across apopulation as heterogeneous and diverse as thatenrolled in the ARDSnet low tidal volume trial.

This approach may be misguided, as subsequentstudies have demonstrated differences betweenpatients with direct and indirect causes ofALI/ARDS in responsiveness to specific thera-pies.[23,24] Research is ongoing to determinewhether newer modes of mechanical ventilation,such as high-frequency oscillation (HFO), canfurther improve outcomes in ARDS relative tothe ARDSnet low tidal volume strategy.[25] Inaddition, other aspects of supportive care havebeen evaluated in large clinical trials, some con-ducted by ARDSnet, and have proven effective inreducing morbidity associated with criticalillness. These include cautious fluid manage-ment,[26,27] adequate nutrition,[28] prevention ofventilator associated pneumonia,[29-32] prophy-laxis for deep venous thrombosis[33] and gastriculcers,[34] weaning of sedation and mechanicalventilation as early as possible,[35] and physio-therapy and rehabilitation.[36] A recent reviewof all patients enrolled in ARDSnet studiesbetween 1996 and 2005 showed that these ad-vancements in critical care (aside from lower tidalvolume ventilation) are likely responsible for theimproved survival in ALI/ARDS patients inclinical trials noted over the last decade.[37]

Additional modalities used as ‘rescue thera-pies’ for the ARDS patient at risk of succumbingto severe hypoxaemia or respiratory acidosishave also been tested, including nitric oxide,prone positioning, HFO and extracorporealmembrane oxygenation (ECMO). Nitric oxide[38]

and prone positioning[39,40] have not been shownto reduce mortality or duration of mechanicalventilation in patients with ALI/ARDS, and aretherefore not recommended for routine use.However, combined together, these therapiesmay provide a sustained improvement in oxyge-nation for patients with severe hypoxaemiaand a mortality benefit for patients who are fail-ing conventional mechanical ventilation strate-gies.[39-41] A clinical trial of HFO for routine careof patients with ARDS is currently underway,but existing evidence supports its use as salvagetherapy if instituted early for patients failingconventional ventilation,[42] and may have ad-ditive benefits when combined with nitric oxideand prone positioning.[43] Finally, ECMO has



recently been studied in the CESAR trial (seetable III for a list of trial acronyms).[44] This studyshowed that transferring adult patients with se-vere but potentially reversible respiratory failure,whose Murray score exceeds 3.0 or who have apH of <7.20 on optimum conventional manage-ment, to a centre with an ECMO-based manage-ment protocol, significantly improved survivalwithout severe disability. Recent evidence sug-gests ECMO is also useful for rescue therapy foradults with severe ARDS due to H1N1-influenzaA virus infection.[45]

3. Current and ExperimentalPharmacological Treatments

Pharmacological treatments for ALI/ARDSmay be employed prior to the onset of ARDS orin the early,mid or late phases of ARDS (table IV).Accordingly, their purpose may be to preventALI in those at risk, mitigate the pathogenicmechanisms responsible for the cycle of lunginjury and systemic inflammation in establishedARDS, or aid in lung healing and repair. Sometherapies, such as corticosteroids, have been stu-died for prevention of ARDS, treatment of early

ARDS and treatment of late ARDS, and arediscussed within each context.

3.1 Prevention of Acute Respiratory DistressSyndrome (ARDS) in Patients at Risk

The concept that ARDS may be prevented inthose at high risk after an inciting insult is notnew, but is one that is garnering greater attentionin the scientific literature in recent years. Since nopharmacological agent has proven effective intreating established ARDS in adults, attentionhas turned to prophylactic treatment to preventthe development of ARDS in those at highestrisk. Of course, any pharmacotherapy that isinitiated prior to the diagnosis of disease musthave a very high benefit to risk ratio and be costeffective. As such, it should have the followingattributes: (i) be low risk, without serious adverseeffects; (ii) be easily and widely applicable; and(iii) be relatively inexpensive. Drug classes stu-died for ARDS prevention include imidazoles(e.g. ketoconazole), ACE inhibitors, thiazolidi-nediones (e.g. rosiglitazone), chemically modifiedtetracycline derivatives, antioxidants, and corti-costeroids and other immunomodulating agents.

3.1.1 Ketoconazole

Over 20 years ago, the first clinical trialexamining prophylactic use of ketoconazole toprevent ARDS in patients at risk was pub-lished.[46] The rationale for using ketoconazole,an antifungal drug with anti-inflammatory prop-erties, was as follows. As mentioned in section 1,patients with ARDS have increased levels of ara-chidonic acid metabolites in their bronchoalveolarfluid.[10,87] Metabolism of arachidonic acid leadsto the production of leukotrienes, prostaglandinsand thromboxanes. Thromboxane A2 is a potentvasoconstrictor, and is involved with platelet andleukocyte aggregation, while leukotrienes actas powerful chemokines to attract neutrophils.Ketoconazole is an antifungal agent of the imida-zole class which selectively blocks thromboxanesynthetase. Ketoconazole also inhibits 5-lipoxy-genase, the enzyme necessary to generate leu-kotrienes, and inhibits procoagulant activity.[55]

In addition to showing promise in preclinical

Table III. Clinical trial acronyms

Acronym Definition

ALTA Albuterola to Treat Acute Lung Injury

BALTI-1 Beta-Agonist Lung Injury Trial

CARDS Calfactant for direct Acute Respiratory Distress

Syndrome

CESAR Conventional Ventilatory Support versus

Extracorporeal Membrane Oxygenation for

Severe Adult Respiratory Failure

CORTIFLU Low Doses Corticosteroids as Adjuvant

Therapy for the Treatment of Severe H1N1 Flu

KARMA Ketoconazole and Respiratory Management in

ALI and ARDS

LARMA Lisofylline and Respiratory Management in the

treatment of ALI and ARDS

LaSRS Late Steroid Rescue Study

SAILS Statins for Acutely Injured Lungs From Sepsis

STIP Statin Trial for Influenza Patients

STRIVE Sivelestat Trial in ALI Patients Requiring

Mechanical Ventilation

a Salbutamol.

1262 Bosma et al.


Table IV. Pharmacotherapy studied for prevention or treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)a

Pharmacological agent Class Current evidence

[SC/MC, phase

(no. of patients/trial)]

Outcome References

Prevention of ALI/ARDSKetoconazole Imidazole 3 SC clinical trials (n = 71,

54, 40)

Reduced incidence of

ARDS

46-48

Captopril ACE inhibitor Animal model Reduced severity of ARDS 49

Rosiglitazone PPAR-g agonist Animal model Reduced severity of ARDS 50

Incyclinide (COL-3) Tetracycline derivative Animal model Reduced incidence of

ARDS

51

a-Tocopherol, ascorbic acid Antioxidants 1 SC clinical trial (n = 595) No risk reduction for

ARDSb

52

Methylprednisolone Corticosteroid 4 SC clinical trials (n = 81,75, 304, 42), MA

No risk reduction for

ARDSc

53

rhPAF-acetylhydrolase Indirect cytokine inhibitor 1MC clinical trial, phase IIb

(n= 127)No risk reduction for ARDS 54

Treatment of established ARDS: acute and exudative phases

Ketoconazole Imidazole 1 MC clinical trial (n =234) No mortality reduction 55

Salbutamol (intravenous) b2-Agonist 1 SC clinical trial (n= 40) Reduced extravascular

lung water

56

Salbutamol (aerosolized) b2-Agonist 1 MC clinical trial (n =279) No reduction in ventilator-

free days

57

Exosurf� Surfactant (aerosolized) 1 MC clinical trial, phase III

(n= 725)No mortality reduction 58

Survanta� Surfactant (instilled) 1 SC clinical trial, phase II

(n= 59)No safety concerns 59

Venticute� rSP-C surfactant (instilled) 2 MC clinical trials, phase

III (n= 448, 800)No mortality reductiond 23,60

Calfactant (Infasurf�) Surfactant (instilled) 1 MC clinical trial

[paediatric] (n = 153)Mortality reduction 61

N-acetylcysteine, oxothiazolidine

(Procysteine�)

Antioxidants 2 MC, 1 SC clinical trials

(n= 46, 61, 66)No mortality reduction 62-65

Omega-3 fatty acids, a-tocopherol,ascorbic acid

Antioxidants 2 MC clinical trials, phase

III, II (n =272, 98)No mortality reduction 66-68

Sivelestat Neutrophil elastase

inhibitor

2 MC clinical trials, phase

III (n= 492, 230)No mortality reduction 69,70

Depelestat Neutrophil elastase

inhibitor

Animal model, phase IIe Reduced lung

inflammation

71

TLC-C-53 (Ventus�) Prostaglandin 2 MC clinical trials, phase

III (n= 350, 102)No mortality reduction 72,73

Molgramostim Colony-stimulating factor 1 SC, 1 MC clinical trials,

phase II (n =10,132e)Improved oxygenation;

results not published

74,75

Lisofylline Cytokine inhibitor 1 MC phase II/III clinicaltrial (n = 235)

No mortality reduction 76

Anti-IL-8 monoclonal antibody Cytokine inhibitor Animal model Reduced pulmonary

oedema

77,78

Methylprednisolone Corticosteroid 2 MC clinical trials

(n= 99, 91)Conflicting results 79,80

Hydrocortisone Corticosteroid Post hoc analysis of 1

clinical trial (n= 177)No mortality reductionf 81

Continued next page



animal studies, when given prophylactically topatients at risk of developing ARDS, ketocona-zole has been shown to reduce the incidence ofsevere ARDS in three small trials.

A 1988 study of 71 patients admitted toa surgical ICU showed that in the grouptreated prophylactically with oral ketoconazole200mg/day, 2 of 35 patients (6%) ultimatelydeveloped ARDS, whereas 11 of 36 (31%)patients in the control group developed ARDS(p < 0.01).[46] Similar results followed in a 1993study of 54 patients with septic shock admitted toa surgical ICU, where the incidence of ARDS inthe group treated with ketoconazole 400mg/daywas 15% (4 of 26 patients) compared with64% (18 of 28 patients) in the control group(p = 0.002), and mortality was 15% versus 39%,respectively (p = 0.05).[47] Although both of thesestudies were conducted prior to the 1994 AECCdefinition, ARDS was strictly defined in theaforementioned studies, including a PaO2/FiO2

ratio <150 or intrapulmonary shunt >20% inpatients requiring mechanical ventilation andwho had diffuse infiltrates on chest radiographwithout clinical evidence of heart failure aspulmonary arterial occlusion pressures were<18mmHg. Building on the results of these two

studies, Sinuff and colleagues[48] developed prac-tice guidelines for prophylactic ketoconazole use,and tested the implementation and efficacy ofthese guidelines in two ICUs (one control and oneactive comparator). They reported a significantlydecreased incidence of ARDS in the ICU popu-lation receiving ketoconazole prophylaxis, al-though mortality was equivalent within the twounits.[48]

In 2000, ARDSnet published the KARMAstudy evaluating oral ketoconazole versus place-bo for patients within 36 hours of an establisheddiagnosis of ALI or ARDS according to the 1994AECC definition.[55] The study was stopped earlyafter enrolment of 234 patients for failing to showa difference in mortality or ventilator-free days.Of note, this study was designed to look at earlytreatment of ALI/ARDS rather than preventionof ARDS in patients at risk, and therefore did notnecessarily negate the findings of the three pre-vious smaller studies. Furthermore, a problemidentified in the KARMA study was that eventhough blood ketoconazole concentrations wereadequate, urinary metabolites of thromboxanewere not affected, raising the possibility that theproper dose to achieve an anti-inflammatory ef-fect was not given. However, since the KARMA

Table IV. Contd

Pharmacological agent Class Current evidence

[SC/MC, phase

(no. of patients/trial)]

Outcome References

Drotrecogin alfa Anticoagulant 1 MC clinical trial, phase II

(n= 75)No mortality reduction 82

Rosuvastatin Statins 2 cohort studies (n = 196,178)

No mortality reduction 83,84

Treatment of established ARDS: fibroproliferative phase

Methylprednisolone Corticosteroid 2 MC clinical trials

(n= 24, 180)No mortality reductiong 85,86

a Excluding salvage therapies for severe hypoxaemia.

b Reduced risk of multiple organ dysfunction syndrome but not ARDS.

c Potentially increased risk of ARDS and death.

d Mortality reduction in subgroup of patients with direct cause of ARDS.

e Results not yet published.

f Mortality reduction in subgroup of patients with ARDS, septic shock and relative adrenal insufficiency.

g No mortality reduction in larger study, n =180 (LaSRs).

IL-8 = interleukin-8; MA=meta-analysis; MC =multicentre; PPAR-c = peroxisome proliferator activated receptor-g; rhPAF = recombinant

human platelet-activating factor; rSP-C = recombinant surfactant protein-C; SC = single-centre.

1264 Bosma et al.


study showed no difference in mortality, widelyconsidered the most important endpoint toachieve, further research on ketoconazole forALI/ARDS ceased.[55] Additionally, ketoconazolehas numerous drug interactions and requires anacidic milieu to be absorbed via the enteral route,making routine use in the ICU complicated.

Further research should examine whether otherdrugs in the imidazole class given intravenouslyhave similar anti-inflammatory properties, andalso establish the inflammatory dose-responsecurve for ALI/ARDS. In addition, although theconcept that prevention of ARDS will definitelylead to decreasedmortality is intuitive, this still hasto be proven in large multicentre clinical trials.The authors are unaware of any studies beingconducted in this area presently.

3.1.2 ACE Inhibitors and Angiotensin II ReceptorAntagonists

Angiotensin-converting enzyme (ACE) isproduced in the lungs and is responsible forconverting angiotensin I into angiotensin II, apeptide active in vasoconstriction and sodium-fluid balance to maintain blood pressure homeo-stasis. ACE inhibitors and angiotensin II recep-tor antagonists (blockers; ARBs) are classes ofdrugs commonly used to treat hypertension, andprevent progression of diabetic nephropathyin patients with diabetes. ACE inhibitors alsohelp to preserve vascular structure and function,by exerting a protective effect on endothelialcells. Endothelial cell damage is the catalyst forthe inflammatory and coagulation cascades acti-vated in ALI/ARDS. Thus, the protection ofendothelial cells offered by ACE inhibitors mayhave a beneficial role in ARDS.[49]

Studies in transgenic mice have shown thatACE, angiotensin II and angiotensin II receptortype 1a may promote lung injury, whereas ACE2,a close homologue of ACE, and angiotensin IIreceptor type 2 may protect against severe lungdysfunction in models of ARDS.[88] The ACEinhibitor captopril has been shown to preventsevere lung injury in an oleic acid-induced modelin rats. In this model, captopril reduced expres-sion of ICAM-1 in lung tissue, indicating a pro-tective effect on endothelial cells, diminished

activity of tissue plasminogen activator, involvedin coagulation, and blocked NF-kB, the major sig-nal transduction pathway that regulates the ex-pression of multiple early-response genes relatedto inflammation.[49] In humans, two small cohortstudies have demonstrated that polymorphismof the ACE gene increases susceptibility to thedevelopment of ARDS and its outcome.[89,90]

Two additional studies, published only in ab-stract form to date, have examined the associa-tion between ACE inhibitor use and ARDS. Aretrospective cohort study of 1423 adult criticallyill patients found that 5.5% of patients developedARDS after hospital admission, and that pre-existing, long-term use of an ACE inhibitor orARB was associated with decreased risk ofARDS development, after adjusting for predis-posing conditions (odds ratio [OR] 0.49; 95% CI0.25, 0.94; p= 0.03).[91] The second abstract, acase-control study nested within a prospectivecohort of 1553 critically ill patients at risk forARDS, reported that patients on ACE inhibitorshad a lower prevalence of respiratory failure onadmission to ICU, but not lower incidence ofARDS after adjusting for confounders on multi-variate analysis. However, among patients whodeveloped ARDS, ACE inhibitor use was asso-ciated with lower mortality (adjusted hazard ra-tio 0.66; 95% CI 0.45, 0.99).[92] The associationsobserved in these clinical studies is consistentwith preclinical animal data, but requires furtherresearch prior to being applicable clinically.[90]

3.1.3 Thiazolidinediones (Peroxisome ProliferatorActivated Receptor-c Agonists)

Peroxisome proliferator activated receptors(PPARs) are ligand-activated transcription factorsrelated to thyroid hormone, steroid and retinoidreceptors.[50] There are three isoforms: PPAR-g,PPAR-a and PPAR-b/d. PPAR-g plays a centralrole in glucose homeostasis. Thiazolidinediones, aclass of oral antidiabetic drugs, are synthetic li-gands for PPAR-g. Synthetic PPAR-g agonistsalso have anti-inflammatory properties, inhibit-ing proinflammatory cytokine production andmacrophage activation in vitro.[93,94] This action ismediated in part by antagonizing the activityof transcription factor NF-kB. When activated,



NF-kB induces overexpression of inflammatorycytokines such as tumour necrosis factor (TNF)-a,which in turn induces upregulation of ICAM-1expression, as well as recruitment and activationof immune cells. ICAM-1, expressed on the sur-face of endothelial cells, mediates leukocyte ad-hesion and migration through endothelium intotissues. The anti-inflammatory properties of thi-azolidinediones have been demonstrated in vivoin murine models of inflammatory bowel dis-ease[95] and rheumatoid arthritis.[96] Rosiglita-zone is the most potent selective PPAR-g of thethiazolidinediones.

Prophylactic administration of rosiglitazonehas been shown to attenuate ALI in an animalmodel of pancreatitis-associated ALI.[50] In thisstudy, rosiglitazone was dissolved and givenintravenously to rats 30 minutes prior to induc-tion of acute pancreatitis by sodium taur-ocholate. Compared with control group rats withacute pancreatitis and its associated lung injury,prophylactic administration of rosiglitazone re-sulted in a significantly lower histological pulmon-ary injury score, reduced pulmonary expressionof TNFa and ICAM-1 messenger RNA, anddecreased lung tissue myeloperoxidase activity, ameasure of neutrophil infiltration in the lung.[50]

This suggests that prophylactic rosiglitazone mi-tigates the ALI associated with acute pancreatitisby its anti-inflammatory effect. Unfortunately,the safety of rosiglitazone has recently beenquestioned due to its augmentation of sodiumand water retention, leading to increased in-cidence of congestive heart failure in diabeticpatients placed on this drug long-term.[97,98]

Thus, further animal studies are needed to confirmthe effects of rosiglitazone in acute pancreatitisand evaluate potential complications related toits use, prior to proceeding to human studies.

3.1.4 Tetracycline-Related Compounds

During the early phase of lung injury, neu-trophils are recruited into the pulmonary vascu-lature and activated to release proteases, such asMMPs and NE, which damage the alveolar-capillary membrane,[51] resulting in further releaseof inflammatory mediators. A single laboratoryin the State University of New York (New York,

NY, USA) has demonstrated in various animalmodels that blocking the proteases NE, MMP-2and MMP-9 with a unique modified tetracyclinecan prevent the increased pulmonary vascularpermeability that ultimately leads to ARDS.

The same group has developed a ‘two-hit’porcine model of sepsis plus gut ischaemia-reperfusion injury that parallels the insidiousonset of sepsis-induced ARDS in humans. In thismodel, anaesthetized Yorkshire pigs undergocross-clamping of the superior mesenteric arteryfor 30 minutes to induce intestinal ischaemia,followed by intraperitoneal placement of a faecalblood clot. Pigs are then awakened, extubatedand taken to an animal ICU for 48 hours ofcontinuous observation, where they receive in-travenous fluids, broad-spectrum antibacterialsand pain control medications. When thePaO2/FiO2 ratio falls below 250, pigs are anaes-thetized and placed back on mechanical ventila-tion with tidal volumes of 10mL/kg. In thismodel, they demonstrated that prophylactic ad-ministration of a synthetic, nonantimicrobial de-rivative of tetracycline called incyclinide (COL-3;CollaGenex Pharmaceuticals), prevented the de-velopment of both ARDS and septic shock.[51]

Incyclinide has not yet been tested in any humanstudies of ARDS prevention; however, the com-plex model developed by this group contains allthe elements of a clinically relevant animal modeland, therefore, these results show potential forphase II studies.

3.1.5 Antioxidants

Oxidative stress is associated with develop-ment of ARDS and MODS via direct tissueinjury. Nathens and colleagues[52] examined theeffect of antioxidant supplementation using a-tocopherol and ascorbic acid in critically illsurgical patients. In a prospective RCT of 595surgical ICU patients (mainly victims of trauma),they found antioxidants did not reduce the risk ofdeveloping ARDS, but did decrease the risk ofdeveloping MODS, and shortened duration ofmechanical ventilation and length of ICU stay.[52]

Antioxidants supplementation and nutritionalstrategies are now being studied for critically illpatients with early signs of MODS,[99] but not

1266 Bosma et al.


specifically for ARDS prevention. Antioxidantsand nutrition have also been studied for treat-ment of ARDS, and are further discussed in thiscontext in section 3.2.3.

3.1.6 Corticosteroids

Given that excessive and protracted inflamma-tion is the overriding principle responsible for thevarious pathophysiological mechanisms leadingto ARDS, broad and potent anti-inflammatorydrugs, such as corticosteroids, would seem to be arational choice for prevention. Four RCTs, pub-lished between 1985 and 1988, have examined theuse of corticosteroids to prevent the onset ofARDS in patients at risk. A recent meta-analysisof these studies demonstrated that preventivecorticosteroids may actually increase the risk ofdeveloping ARDS in critically ill adults.[53] Fur-thermore, the meta-analysis suggested a weaklyincreased risk of death associated with preventivecorticosteroid therapy in those patients whoultimately developed ARDS. Thus, corticoster-oid therapy is not recommended for preventingARDS in those at risk. Corticosteroid therapyhas also been extensively studied for the treat-ment of established disease in the early and latephases, and is discussed further in these contexts(see the Corticosteroids subsection of section3.2.5 and section 3.3.1).

3.1.7 Recombinant Human Platelet-ActivatingFactor Acetylhydrolase

Platelet-activating factor (PAF) is a potentproinflammatory mediator that is degraded bythe enzyme PAF acetylhydrolase. Recombinanthuman PAF acetylhydrolase (rhPAF-AH; epafi-pase) was studied in a phase IIb RCT to preventARDS in septic patients.[54] 127 patients withsevere sepsis were randomized to receive rhPAF-AH 1mg/kg, rhPAF-AH 5mg/kg or placebo. Theincidence of ARDSwas not different amongst thethree groups, but 28-day all-cause mortality wassignificantly decreased in the 1mg/kg treatmentgroup compared with placebo (21% vs 44%;p= 0.03). Therefore, although rhPAF-AH doesnot appear to be an effective prophylactic treat-ment for ARDS, it may hold promise for treat-ment of severe sepsis.

3.2 Treatment of Established ARDS: Acute andExudative Phases

The majority of research to date has focusedon treating ARDS once the diagnosis is estab-lished. Although many studies are designed totreat ‘early ARDS’, with randomization occur-ring within 48 hours of diagnosis, these studiesalso likely capture many patients in the exudativephase of ARDS with intra-alveolar hyalinemembranes and histological diffuse alveolar da-mage at the time of enrolment. This problemarises in part because the diagnostic criteria forARDS are subjective and lack sensitivity andspecificity when compared with pathologicaldiagnosis.[100] Thus, timing an interventionat a certain point after ‘diagnosis’ could resultin the patient receiving treatment in the early,mid or even late pathophysiological stage ofALI/ARDS. Some more recent studies are nowtargeting time after intubation rather than timeafter diagnosis to achieve more uniform timing ofintervention. However, since the acute and exu-dative phases occur along a continuum and arenot generally distinguished clinically, therapiestargeting these phases will be considered con-comitantly. Therapies currently under investiga-tion for early and/or exudative ARDS includethose targeting the disrupted surfactant system,oxidative stress and antioxidant activity, neu-trophil recruitment and activation, expressionand release of inflammatory mediators, activa-tion of the coagulation cascade, and micro-vascular injury and leak. Treatment of the overallinflammatory response with agents such ascorticosteroids has also been studied and is dis-cussed. Finally, the only drugs specifically tar-geting resolution of the alveolar oedema of theacute phase are b2-adrenergic receptor agonists(b2-agonists).

3.2.1 b2-Adrenergic Receptor Agonists

Clearance of alveolar oedema depends onthe balance between oedema formation and re-absorption. The rate of fluid reabsorption de-pends on the active transport of sodium andelectrolytes; water follows in the direction of thetransported electrolytes. The active transport of



salt and water occurs via epithelial sodiumchannels induced via Na+/K+ adenosine triphos-phatase (ATPase).[101] b2-Agonists are thought toincrease alveolar fluid clearance via two possiblemechanisms: (i) increasing the levels of intracell-ular cyclic adenosine monophosphate, which inturn upregulates Na+/K+ ATPase, causing in-creased sodium transport across alveolar type IIcells; and (ii) reducing alveolar-capillary perme-ability, thereby decreasing oedema formation.Preliminary animal and ex vivo studies demon-strated the potential of b2-agonists to acceleratethe rate of alveolar fluid clearance.[102,103]

A small, single-centre RCT randomized 40patients with ALI/ARDS to receive intravenoussalbutamol (albuterol) 15 mg/kg/h or placebo for7 days.[56] The primary endpoint of BALTI-1 wasextravascular lung water measured by the single-indicator transpulmonary thermodilution system(PiCCO�; Pulsion Medical Systems) at day 7.Patients in the salbutamol group had lower ex-travascular lung water and plateau pressures, al-though oxygenation did not differ between thetreatment and placebo groups. This latter findingwas perhaps due to the vasodilatory effects ofb2-agonists contributing to shunting of oxygenin the capillary bed. There was no difference in28-day mortality or ventilator-free days, althoughthe study was not sufficiently powered to detect adifference in these endpoints.[56] Funded by theMedical Research Council, the same investi-gators in the UK are now conducting BALTI-2,using the same intravenous salbutamol protocolas in BALTI-1, but powered to detect clinicallyimportant outcomes.[104] It will be interesting todetermine if the physiological benefits observedin BALTI-1 confer a reduction in 28-day all-cause mortality in BALTI-2.

Aerosolized b2-agonists have fewer systemicadverse effects than intravenous preparations.The National Heart, Lung and Blood Institute(NHLBI), in conjunction with ARDSnet, con-ducted a study of an aerosolized b2-agonist, theALTA study.[105] The study was stopped for fu-tility at the first interim analysis after enrolling279 patients.[57] There was no difference in theprimary outcome of ventilator-free days to day28. This study may have been negative for the

following reasons: (i) delivery of nebulized drugto lung injury sites may have been suboptimal, aswas the case with aerosolized surfactant; and/or(ii) less severely ill patients with ALI (rather thanARDS with more severe hypoxaemia) may retainadequate alveolar fluid clearance without the needfor upregulation with b2-agonists. Sixty-day mor-tality in the ALTA study was 19.7% comparedwith a 28-day mortality of 60% in the severely illgroup of patients who received physiological ben-efit from intravenous salbutamol in BALTI-1.[106]

3.2.2 Exogenous Surfactant Replacement

Exogenous surfactant administration has beenvery successful in treating and preventing neo-natal respiratory distress syndrome (nRDS).Given the physiological and pathological simila-rities between nRDS and ARDS, exogenoussurfactant therapy has been under investigationfor treatment of ALI/ARDS for over a decade.Although clinical trial results have been largelydisappointing, recent studies show promise. Thestrong scientific rationale for targeting the dis-rupted surfactant system, as well as lessons learntfrom previous trials, therefore merit furtherattention.

Endogenous surfactant is composed of 90%lipids (mainly phosphatidylcholine and phos-phatidylglycerol) and 10% proteins. The role ofendogenous surfactant in the healthy lung is todecrease surface tension and thereby prevent al-veolar collapse. In addition, surfactant plays arole in suppressing inflammation and scavengingfree oxygen radicals. Four apoproteins have beenidentified, termed surfactant protein (SP)-A, -B,-C and -D.Whereas the presence of either or bothof the hydrophobic surfactant proteins SP-B and-C are important for the biophysical function ofsurfactant, the hydrophilic proteins SP-A and -Dperform the various host defence roles, includingmodulation of leukocytes, enhancement of thefunction of phagocytic cells[107] and regulation ofthe host’s immune system.[108,109]

In ALI, disruption of the endogenous surfac-tant system occurs by a number of mechanisms:injury to alveolar type II cells results in abnormalsynthesis and secretion of surfactant, serum pro-teins that leak into the airspace interfere with

1268 Bosma et al.


surfactant function, serine endopeptidase andphospholipase A2 cause degradation of surfac-tant, and, finally, mechanical ventilation, partic-ularly with high tidal volumes, causes conversionof functional surfactant aggregate forms intodysfunctional forms. Without optimal surfactantfunction, there is high surface tension at the al-veolar surface in a non-uniform pattern withinthe lung leading to alveolar instability and col-lapse. The presence of bacteria within the air-space may also release and activate endotoxins, aprocess that is augmented in the presence of anabnormal surfactant system. Based on the func-tional importance of the endogenous surfactantsystem in the normal lung and, more importantly,the consequences of an altered surfactant systemin ALI/ARDS, there is good rationale to considerexogenous surfactant administration as a ther-apeutic intervention in these patients.[109]

In 1996, a phase III, double-blind RCT testedan aerosolized, synthetic surfactant calledExosurf� (Glaxo Wellcome) in 725 patients withsepsis-induced ARDS.[58] This study showed nosignificant difference in overall survival, durationof mechanical ventilation or oxygenation be-tween the treatment groups and standard care. Itwas postulated that this lack of efficacy was dueto a low level of alveolar deposition of the aero-solized preparation and/or due to the absence ofsurfactant proteins in the preparation.[23] Cur-rently, this surfactant preparation is not beingevaluated for patients with ALI/ARDS and is nolonger marketed in the US.

Shortly afterwards, a smaller, open-labelphase II clinical trial evaluated tracheal instilla-tion of a liquid bolus of the natural bovine extractsurfactant, Survanta� (Ross Laboratories), inpatients with severe ARDS.[59] There was a trendtoward decreased mortality in the group ofpatients receiving up to four doses of phospho-lipids 100mg/kg surfactant compared with thepatients in the control group (18.8% vs 43.8%;p= 0.075), and no safety concerns were identified.However, Survanta� contains only very smallamounts of SP-B. Coupled with concerns re-garding resource limitations, no further clinicaltrials of this exogenous surfactant preparationfor adults with ARDS have been performed.

Recognizing the importance of surfactant-specific proteins brought progress to clinical sur-factant research. In 2004, results were publishedfor two phase III clinical trials evaluating effect ofa liquid, recombinant SP-C (rSP-C) surfactant,Venticute� (Nycomed), instilled intratracheally inpatients with established ARDS.[23] The two stu-dies enrolled a total of 448 patients within 24 hoursof diagnosis of ARDS and were powered to showa difference in ventilator-free days. Althoughoxygenation was significantly better during the24-hour treatment period in the surfactant group,there were no significant differences noted in thenumber of ventilator-free days or in 28-day survi-val.[23] A post hoc analysis demonstrated thatpatients with ‘direct’ causes of ARDS (i.e. pneu-monia, witnessed aspiration of gastric contents orboth) had a mortality benefit with surfactanttreatment compared with standard care. A follow-up meta-analysis pooling results of five multi-centre studies of rSP-C confirmed this finding: thesubgroup of patients with severe ARDS due topneumonia or aspiration had decreased mortalitywhen treated with rSP-C (26.3% vs 39.3% in theusual care group; p= 0.018).[24] Subsequently, aprospective phase III RCT evaluating effect ofVenticute� in 1200 patients with pneumonia oraspiration of gastric contents was conducted.The study was terminated at 800 patients due tofutility. Neither these results nor the potentialreasons for futility have been published to date.[60]

Calfactant (Infasurf�, ONY Inc.) is a modifiednatural surfactant produced by extracting thephospholipids, neutral lipids and surfactant-specific proteins SP-B and SP-C from newborncalf lungs. In in vivo animal lung studies, calfac-tant has shown greater surface activity thanExosurf� and Survanta�,[110-113] and the highestlevel of resistance to inactivation due to its highratio of protein SP-B to phospholipids.[114-116]

From 2000 to 2003, calfactant was used in amulticentre study of ALI/ARDS in the paedia-tric population 1 week (full-term infants) to21 years of age. Overall, calfactant significantlyimproved oxygenation and reduced mortality(19% vs 36%; p = 0.03), although the greatestimpact was observed in the subgroup of pa-tients with direct ALI/ARDS while calfactant



had little effect in patients with indirect ALI orARDS.[61]

Indeed, calfactant is the first and only phar-macological agent to demonstrate a mortalitybenefit for treatment of ALI/ARDS. It is of note,however, that this study differs from other adultstudies in that the majority of paediatric patientshad direct causes of ARDS and the most com-mon cause of death was respiratory failure,whereas adult studies have included a largerproportion of patients with indirect causes, suchas sepsis, wherein the most common cause ofdeath is multi-organ failure. Based on thoseencouraging results, Pneuma Pharmaceuticalsbegan conducting a large phase III multicentreRCT of calfactant for direct ARDS (origin ofARDSmust be infectious pneumonia, aspiration,near drowning, smoke inhalation without pul-monary burn or inhaled industrial gas) in adultsand children. A total of 880 patients in two con-secutive studies of patients under 12 and over12 years of agewas planned.However, after the firstinterim analysis in January 2010, the paediatricarm of the study was stopped for futility due to anunexpectedly low mortality rate. Recruitment inthe adult arm (ages 12–85 years) is continuing asthe interim analysis did not reveal futility or anysafety concerns (Wilson D, University of VirginiaHealth Sciences Center, Charlottesville, VA,USA, personal communication).[117]

3.2.3 Antioxidants and Nutrition

Since reactive oxygen species also contributeto the tissue damage incurred in ALI, antioxidanttherapies have also been investigated as ther-apeutic options for established disease. N-acetyl-cysteine (NAC) is a commercially availableantioxidant approved for the treatment of para-cetamol (acetaminophen) toxicity. NAC is aprecursor for glutathione, an antioxidant presentin normal lungs and deficient in bronchoalveolarlavage fluid from ALI/ARDS patients. Ad-ditionally, because of its thiol group, NAC canscavenge reactive oxygen species such as hydro-gen peroxide and superoxide anion. In an RCT of46 patients, NAC and oxothiazolidine carboxy-late (Procysteine�, Clintec Technologies Inc.),another glutathione precursor, were studied for

their combined effect in ALI/ARDS but failedto reduce mortality compared with placebo,[62]

negating promising results of three prior smallstudies.[63-65]

Interestingly, recent evidence suggests thatgenetic diversity may explain variable respon-siveness to NAC. Glutathione-S-transferases(GSTs) are enzymes from a complex, multigenefamily with important roles in oxidative stresspathways. A study byMoradi and co-workers[118]

demonstrated that deletion of specific GST genepolymorphisms correlated with mortality andthat treatment with NAC significantly loweredmortality in these subgroups of patients. Theseresults suggest that patients with GST gene dele-tions are more vulnerable to oxidative stresscontributing to ARDS and may be in greaterneed of antioxidant therapy.[118]

Antioxidant supplementation to enteral nu-trition rich in omega-3 fatty acids has also beeninvestigated for patients with ALI/ARDS. Whilethe rationale for nutritional antioxidants such asvitamins E and C is to reduce the oxidative stresspresent in ALI, the purpose of the omega-3 fattyacids is to reduce production of proinflammatorymediators. Eicosanoids, such as prostaglandins,thromboxanes and leukotrienes, derived fromomega-3 fatty acids are generally much lessproinflammatory than those derived from omega-6 fatty acids. Since omega-6 fatty acids competewith omega-3 fatty acids for the same rate-limitingenzymes in the production of eicosanoids, dietswith a high proportion of omega-6 fats arethought to be proinflammatory and prothrom-botic. Examples of polyunsaturated omega-3fatty acids are a-linolenic acid, eicosapentaenoicacid and docosahexaenoic acid.[119]

A phase II study enrolling 98 patientswith ALI compared an antioxidant enteral feed-ing formula containing eicosapentaenoic acid,g-linolenic acid and antioxidant vitamins withplacebo, and observed improved oxygenation,reduced pulmonary inflammation, fewer days ofmechanical ventilation and fewer non-pulmonaryorgan failures in the treatment arm, althoughthere was no difference in mortality between thisapproach and the control group.[66] ARDSnetproceeded to conduct the OMEGA study, a

1270 Bosma et al.


phase III study examining efficacy of omega-3and antioxidant supplementation to enteral nu-trition. The study was stopped for futility, butresults have not yet been published.[67,68]

3.2.4 Modulation of Neutrophil Activity

Several therapies aimed at modulating neutro-phil activity have been studied. To understandwhy previous clinical trials have been negativeand highlight potential targets for novel therapies,it is important to understand the role of neutro-phils in propagating lung injury and MODS.

Polymorphonuclear neutrophils (PMNs) formthe first line of defence against invading patho-gens, and neutropenia or defective neutrophilfunction predisposes the host to increased mor-bidity. Extensive clinical and experimental datasupport the role of the activated neutrophil in thepathogenesis of organ injury in sepsis. The lung isparticularly vulnerable. Postmortem studies ofpatients with ARDS show massive pulmonaryaccumulation of neutrophils, with the highestcounts in non-survivors.[120] The pathologicalimpact of neutrophils may be due to their acti-vation, transmigration or delayed apoptosis.However, neutrophil-independent mechanismsof ALI must also exist, since ARDS has beendescribed in neutropenic patients.

Neutrophil Activation

Neutrophil kinetics in the pulmonary circula-tion differ substantially from that of micro-vascular beds in the systemic circulation. Thepulmonary circulation harbours a large in-travascular reservoir of leukocytes, mainly neu-trophils, referred to as the ‘marginated pool’.[121]

This marginated pool may equal or even exceedthe pool of circulating neutrophils and exchangeswith the latter as an ongoing phenomenon. Thus,it is important to appreciate that circulatingneutrophils, when isolated for experimental ana-lysis, may not represent the characteristics of theentire population of neutrophils in the blood-stream. Intravital microscopic studies have re-vealed that, in contrast to the systemic circulationwhere neutrophil sequestration is almost ex-clusively confined to the venular compartment,the major site of neutrophil retention in the lung

is the alveolar capillary bed.[122] Neutrophil acti-vation can also lead to cytoskeletal changes thatreduce cell deformability and slow their transittime through the alveolar capillaries. Since oneof the earliest manifestations of ARDS is accu-mulation of large numbers of neutrophils in thealveolar capillaries, it is possible that the accu-mulation of neutrophils may initiate selectivecapillary blockade and arteriovenous shuntingleading to hypoxia seen in ARDS.

NE inhibitors

Activated neutrophils also produce humanNE (HNE), a protease capable of producingtissue damage by means of its degradation ofelastin, fibronectin, laminin, collagen and pro-teoglycans. Normally, protease inhibitors impedeNE, but in the setting of an overwhelming inflam-matory response, neutrophils generate reactiveoxidants that inactivate endogenous protease in-hibitors, leaving the activity of HNE unchecked.This may lead to increased pulmonary inflamma-tion and endothelial cell permeability.[9] Sivelestat(Elaspol�, ONO Pharmaceuticals) is a competi-tive inhibitor of NE. It was launched in Japanafter a phase III study demonstrated reducedICU stay and improved pulmonary function inpatients with ALI associated with the systemicinflammatory response syndrome (SIRS).[70] How-ever, the STRIVE study[69] was terminated earlyafter randomizing 492 patients from 105 sitesin six countries, when the Data and Safety Mon-itoring Board found a trend to increased mor-tality at 180 days. Final analysis revealed nodifference in 28-day all-cause mortality (26% inboth groups) or number of ventilator-free daysbetween the treatment group and controls.

EPI-HNE-4 or depelestat (Debiopharm S.A.) isanother HNE inhibitor currently under develop-ment for treatment of inflammatory pulmonarydiseases, including ALI. In a repeated lung injuryrat model depelestat administration afforded a sig-nificant protective effect on lung compliance andalveolar inflammation at day 14 compared with thecontrol group.[71] A phase II study examining safetyand efficacy of intravenous depelestat for patientswith ARDS has been completed, but results havenot yet been published.[123]



Neutrophil Transmigration

Neutrophil margination allows for a mole-cular interaction between the cell surfaces of theneutrophil and endothelial cell to occur. Subse-quently, as a consequence of cell surface integrinsand their ligands, neutrophils undergo adhesionwith endothelial cells. Following adherence,neutrophils must pass through the endothelialmonolayer, interstitial tissue and alveolar epi-thelium to reach the alveolar space. Passage oflarge numbers of activated neutrophils can causeepithelial damage, sloughing and increased per-meability both due to mechanical force exertedby neutrophil pseudopodia as well as due to re-lease of toxic substances such as proteinases (e.g.elastases, cationic peptides, defensins, oxidantsandMMPs).[9] While there are conflicting reportson the effects of elastase on increased epithelialpermeability, cationic peptides such as defensinscan cause both epithelial and endothelial cell in-jury. Defensin levels have been found to begreatly elevated in patients with ARDS and theirlevels correlate with the severity of lung in-jury.[124] Neutralizing its effects could be im-portant in the management of ARDS. Ongoingresearch is examining if defensins can be used toidentify patients with ALI at an early stage.[125]

Delayed Apoptosis of Neutrophils

Once egressed into the extravascular space,neutrophils cannot return to the circulation andtheir elimination is dependant upon their clear-ance by apoptosis and subsequent recognition andelimination by macrophages and other phagocyticcells. Normally, neutrophils are terminally differ-entiated cells with a terminal half-life of 5–6 hoursin vivo. Upon completion of their lifespan, neu-trophils institute a programme of cell death knownas ‘apoptosis’ and are then removed from thecirculation by the liver and spleen. Apoptosis, asopposed to necrosis, is believed to be crucial forresolution of inflammation as it does not result inloss of cell membrane integrity and bystander tis-sue damage by release of intracellular enzymes,proteases and reactive oxygen species.[126]

Expression of neutrophil apoptosis is delayedin ARDS.[127] This is not an unexpected finding,especially since PMN apoptosis is delayed in

other critically ill patients with sepsis, trauma andburns.[128,129] Apoptosis of neutrophils may be animportant consequence in determining the extentof lung injury. For example, it has been shownthat the induction of neutrophil apoptosis by theadministration of dead Escherichia coli prior toreperfusion resulted in significant improvementin lung injury.[130] Induction of neutrophil apop-tosis in the alveolar space has the potential forresolution of inflammation in ARDS, and canbe carried out in a number of ways that couldinclude multiple strategies such as ligation of Fas,activation of proapoptotic caspases and mod-ulation of mitogen-activated protein kinases ortranscription factors such as NF-kB. Hasteningneutrophil apoptosis in the alveolar space mayalso decrease the probability of secondary ne-crosis and further tissue damage in ARDS. It isintriguing that no significant differences werefound between the expression of neutrophilapoptosis in patients at risk and those with est-ablished ARDS, nor did the extent of apoptoticinhibition correlate with overall outcome inARDS.[131] Therefore, while it is well establishedthat ARDS is associated with accumulation oflarge numbers of neutrophils in alveolar spaces,their contribution to the severity of ARDS inhumans remains uncertain.

In summary, targeting neutrophil responses inARDSmay have therapeutic potential. However,as has been learnt from various ALI and sepsistrials in the past, simple strategies to controldysregulated neutrophil behaviour may not beeffective. Rather, key stages of neutrophil func-tion and kinetics may need to be identified indifferent clinical phases of ARDS, and selectiveimmunomodulation strategies may need to beidentified for individual patients.

3.2.5 Other Immunomodulating Agents

In addition to modulation of neutrophilfunction, there are other facets of the immuneand inflammatory response currently under in-vestigation as potential therapeutic targets fortreatment of ARDS. These include modulation ofmacrophage activity with granulocyte macro-phage colony-stimulating factor (GM-CSF), in-hibition of inflammatory mediators and broad

1272 Bosma et al.


suppression of the inflammatory response withcorticosteroids.

Prostaglandin Administration

Although most prostaglandins are proin-flammatory mediators, prostaglandin E1 (PGE1)has potential beneficial effects in ALI, specificallydue to its ability to modulate neutrophil activa-tion. However, exogenous PGE1 is associated withseveral adverse effects and patient intolerance dueto haemodynamic instability has been observed.TLC-C-53 (Ventus�; The Liposome Company) isa liposomal dispersion of PGE1. The developmentof PGE1 in liposomal form may potentiate its rolein neutrophil downregulation, improve peripheraldelivery of the drug to the lung and decreasesystemic adverse effects, thus providing a goodrationale for testing in humans.[73]

A phase III trial of 350 patients with ARDSrandomized to intravenous TLC-C-53 at esca-lating doses for 7 days versus placebo found nodifference in duration of mechanical ventilationor 28-day mortality between the treatment andcontrol groups, although treatment was asso-ciated with accelerated improvement in oxyge-nation.[72] However, more than 50% of patientsrequired a dose reduction due to hypotensionor hypoxaemia. Interestingly, those patients whotolerated and received at least 85% of the full dosehad a shorter duration of mechanical ventilation.A subsequent multicentre phase III trial of TLC-C-53 in 102 ARDS patients[73] demonstrated nodifferences in time to liberation from the venti-lator or 28-day mortality; the trend to shorterduration of hypoxaemia in the treatment groupfailed to reach statistical significance.

Granulocyte Macrophage Colony-StimulatingFactor

GM-CSF has been shown to stimulate pha-gocytosis and oxidative functions of host defenceneutrophils, monocytes and macrophages.[74]

In addition to its systemic actions, GM-CSFmay also influence pulmonary host defence bymodulating alveolar macrophage function andsurfactant metabolism. As noted, apoptosis ofneutrophils is an important mechanism by whichthese cells are cleared from inflamed lung regions,thereby facilitating resolution of inflammation.

Although both granulocyte colony-stimulatingfactor and GM-CSF are thought to inhibit neu-trophil apoptosis, in animal models of lung in-jury, GM-CSF has been shown to help restorecapillary barrier integrity,[132] preserve alveolarepithelial function and improve alveolar fluidclearance.[133] A pilot study of 45 patientswith ARDS undergoing serial bronchoalveolarlavage found that patients who survived ARDShad higher concentrations of GM-CSF in thebronchoalveolar lavage fluid on day 1 thanpatients who died.[134] The authors speculatedthat GM-CSF might improve survival byprolonging the neutrophil lifespan in the alveoliand/or inducing proliferation of alveolar macro-phages, thereby improving host defence andreducing infectious complications in this setting.

In a phase II trial, molgramostim (Schering-Plough), a recombinant human GM-CSF, wasgiven intravenously at a low dose (3 mg/kg) for5 days to ten patients with severe sepsis andsepsis-related pulmonary dysfunction (defined asa PaO2/FiO2 ratio of <287 with a pulmonary in-filtrate on chest radiograph).[74] The primaryoutcome was 30-day survival, and secondaryoutcomes included oxygenation, occurrence ofARDS and degree of organ dysfunction at day 5.There was no difference in 30-day survival be-tween the treatment and placebo groups, butoxygenation improved in the GM-CSF group.ARDS was present in four of ten patients in theGM-CSF group on study entry, but resolved intwo of these patients by day 5, whereas in theplacebo groupARDSwas present in three patientson study entry and five patients on day 5. Organdysfunction was similar between the two groups,with no change between study entry and day 5.

From July 2004 to July 2009, the NHLBI en-rolled patients who had been diagnosed withALI/ARDS for at least 3 days into a phase IIRCT of recombinant GM-CSF (sargramostim[Leukine�], Genzyme Corporation) versus pla-cebo.[75] The primary outcome was the number ofventilator-free days during days 1–28. Secondaryoutcomes included measures of lung epithelialcell integrity, alveolar macrophage function,changes in severity of respiratory gas exchange,non-respiratory organ failure and incidence of



ventilator-associated pneumonia. This study hasbeen completed, but results have not yet beenpublished.[75]

Cytokine Inhibitors

Cytokines are glycoproteins that act as mes-sengers to cell surface receptors to promote ordiminish the inflammatory cascade. Specificcytokines are observed in high amounts in thebronchoalveolar lavage fluid of patients withARDS, and are thought to play an importantrole in propagating lung injury. Unsaturatedphosphatidic acid plays an important role inintracellular signalling leading to neutrophilaccumulation within the lungs, as well as pro-inflammatory cytokine expression and cell mem-brane oxidation, all of which leads to lung tissuedamage.[135] Lisofylline (Cell Therapeutics) is acytokine inhibitor that impedes synthesis ofphosphatidic acid-1a and, therefore, was thoughtto hold potential for treatment ofARDS.However,ARDSnet stopped a phase II/III trial, the LARMAstudy, for futility after the first interim analysisfailed to demonstrate any difference in 28-daymortality, ventilator-free days, organ failures orlevels of circulating free fatty acids.[76] Interleukin(IL)-8 is another potent chemoattractant forneutrophils, observed in high levels in patientswith early ARDS[136] and associated with in-creased mortality.[137] Anti-IL-8 monoclonalantibody has been shown to reduce pulmonaryoedema and neutrophil accumulation in animalmodels of ARDS[77,78] but has not yet been testedin humans. Finally, TNFa has long been rec-ognized as an important proinflammatorycytokine in ARDS, but more recent evidencesuggests that it actually plays a dichotomous rolein both contributing to permeability oedema butalso increasing alveolar fluid clearance capacity.Monoclonal anti-TNFa antibodies have beentested in patients with sepsis with disappointingresults.[138] Given its dual role in alveolar oedemaformation and resorbtion, a more sophisticatedapproach than simply blocking all TNFa activityis likely to be required in ARDS.

Corticosteroids

Studies examining the efficacy of corticoster-oids for acute exudative ARDS have shown

conflicting results. In 1987, Bernard et al.[80]

published results of a study of 99 patients withARDS randomized to high-dose pulse methyl-prednisolone (30mg/kg every 6 hours for24 hours) or placebo. There was no difference in45-day mortality (60% vs 63%; p=nonsignificant)but the confidence intervals were wide, suggestingthat the study may have been underpowered todetect a small difference in a population withheterogenous outcomes. In 2007, Meduri andcolleagues[79] published their results of 91 patientswith severe early ARDS (<72 hours) from fivehospitals randomized to methylprednisolone1mg/kg/day for 28 days versus placebo. Theyfound corticosteroids significantly reduced ICUmortality (21% vs 43%; p = 0.03), duration ofmechanical ventilation and length of ICU stay.[79]

Annane et al.[81] published a post hoc analysisof 177 ARDS patients enrolled in an RCT oflow-dose corticosteroids in septic shock. Patientsin the treatment group received hydrocortisone50mg every 6 hours plus fludrocortisone 50mg/dayfor 7 days. Although there was no mortality dif-ference for ARDS patients overall, ARDS patientswith relative adrenal insufficiency and septic shockhad significantly reduced mortality when treatedwith low-dose hydrocortisone (53% vs 75% in theplacebo group; p = 0.01).[81] The use of cortico-steroids for acute exudative ARDS remains con-troversial, although the evidence is more definitivefor corticosteroid treatment initiated late for fibro-proliferative ARDS (see section 3.3.1). A studyexamining low doses of corticosteroids as adjuvanttherapy for lung injury associated with H1N1 in-fluenza virus (CORTIFLU) is planned.[139]

3.2.6 Activated Protein C

Microvascular injury and coagulation playcritical roles in the pathogenesis of ALI. Plasmaprotein C levels are decreased in patients withALI, and are associated with higher mortalityand fewer ventilator-free days.[82] Recombinanthuman activated protein C (rhAPC; drotrecoginalfa; Eli Lilly) was tested in a phase III clinical trialof patients and demonstrated a significant mor-tality reduction from 30% to 24% in patients withsevere sepsis.[140] A phase II study was sponsoredby the NHLBI to determine if drotrecogin alfa

1274 Bosma et al.


increased ventilator-free days in patients withALI (patients with severe sepsis were excluded).The study was terminated by the Data SafetyMonitoring Board. Although drotrecogin alfasignificantly increased plasma protein C levelsand decreased pulmonary dead space fraction,there was no significant difference in the numberof ventilator-free days or in 60-day mortality (5 of38 vs 5 of 37 patients, respectively; p= 1.0).[82]

3.2.7 HMG-CoA Reductase Inhibitors (Statins)

HMG-CoA reductase inhibitors, commonlyknown as statins, have recently been proposedas a treatment for ALI/ARDS. The rationalefor this is based on animal models suggestingthat statins can attenuate organ dysfunction byreducing vascular leak and inflammation.[84] Aprospective cohort study in Ireland showed anonsignificant trend towards lower odds of deathin ARDS patients receiving a statin during theirICU admission (OR 0.27, 95% CI 0.06, 1.21;p= 0.09).[83] However, a recently published retro-spective cohort study from the Mayo Clinic(Rochester, MN, USA) showed no differencein mortality or organ dysfunction in ARDSpatients treated with statins.[84] STIP is currentlyenrolling patients admitted to an ICU with res-piratory distress and a PaO2/FiO2 ratio <300 dueto the H1N1 pandemic strain of influenza.[141]

Patients in this trial will be randomized toreceive rosuvastatin 20mg/day or placebo for21 days. Since this is a specific subpopulationof patients with ALI, findings from this studymay not be generalizable to other ALI subgroups.The SAILS trial (also rosuvastatin 20mg/day vsplacebo) is also planned but not yet open forrecruitment.[142]

3.3 Treatment of Established ARDS:Fibroproliferative Phase

Patients who survive the early and exudativephases of ARDS generally enter a period fromweek 1 to 3 consisting of fibroproliferation andorganization of exudative debris within theairspace. This fibroproliferative relatively ‘late’phase either slowly resolves or progresses tofibrosis. During this phase, patients are at risk

of dying from other complications such asMODS, or may fail to wean from mechanicalventilation due to severely impaired respiratorymuscle and lung function. Those who success-fully wean off mechanical ventilation may haveresidual pulmonary fibrosis and reduced exercisecapacity.

For resolution to occur, removal of in-flammatory cells, cellular debris, and soluble andinsoluble proteins needs to take place. As notedin section 3.2.4, apoptosis of neutrophils facil-itates resolution of inflammation. Monocyte andmacrophage phagocytic clearance of apoptoticcells appears to be an important mechanism bywhich neutrophils are cleared from inflamed lungregions. Soluble proteins are likely to be primarilyremoved via paracellular diffusion, but removal ofinsoluble proteins appears to depend on the func-tion of alveolar macrophages. Mechanisms in-volved in remodelling of hyaline membranes andrestoration of a functional alveolar-capillary bar-rier are incompletely understood at present, buttherapeutic interventions aimed at modulationof phagocytosis/apoptosis are being evaluated.To date, far less research has targeted this laterphase of the disease, as most trials have focused onearlier preventative processes.

3.3.1 Corticosteroids

Fibroproliferative ARDS is characterized byongoing inflammation. In addition to being tes-ted for prevention of ARDS, and treatment of theearly and mid exudative phases, corticosteroidshave also been tested for efficacy in reversing thefibrosing alveolitis of the late phase of ARDS. Astudy by Meduri and colleagues[86] examined theeffect of prolonged methylprednisolone therapy(2mg/kg/day for 32 days) on 24 patients withsevere ARDS that was unresolved after 7 days ofrespiratory failure. Although this study demon-strated a significant hospital mortality benefit(2 of 16 patients [12%] in the corticosteroid groupdied vs 5 of 8 [62%] in the placebo group), thesignificance of these findings was controversialfor two reasons: the calculated sample size todemonstrate a 30% absolute difference inmortalitywas 99 patients but the study was terminated earlyafter enrolment of 24 patients, and the mortality



in the placebo group was slightly higher thananticipated.[86]

To shed further light on this issue, ARDSnetspecifically designed a study to focus on the latefibrotic stage of the disease, called LaSRS.[85]

This study examined the role of corticosteroids in180 patients in the late phase (>7 days from onset)of persistent ARDS. Methylprednisolone, dosedat 2mg/kg/day for 14 days followed by taperingdoses until day 25, was compared with placebo.There was no difference in 60- or 180-day mor-tality rates. Methylprednisolone improved oxy-genation, respiratory system compliance andblood pressure, resulting in an increased numberof ventilator-free and shock-free days; however, ahigher rate of neuromuscular weakness and, ifinitiated more than 14 days after the onset ofARDS, a significant increased mortality wasobserved in themethylprednisolone group. There-fore, despite the improvement in cardiopulmon-ary physiology, methylprednisolone does notimprove overall mortality in ARDS and is notrecommended for treatment of late ARDS.

Given these results, the convincing lack of effi-cacy for prevention of ALI prior to diagnosis andthe lack of evidence of benefit in the early phase,corticosteroids cannot be recommended for routinetreatment of ALI/ARDS at any stage, at this time.Furthermore, it may prove to be exceedingly diffi-cult to determine which individual patient mightbenefit from corticosteroids and at what specificpoint to intervene.

4. Potential for Future ClinicalDevelopment

Clearly, the current status of treatment optionsfor patients with ALI/ARDS is suboptimal. Atthis time, the clinical management of patients withALI/ARDS involves supportive therapy only.This primarily includes low stretch or ‘lung pro-tective’ mechanical ventilation, conservative fluidmanagement and adequate nutritional support.Although the term ‘supportive’ may sound some-what discouraging, these are important observa-tions, not only because they impact on the outcomeof patients with ALI/ARDS but also because theyshould be embraced and implemented as ‘standard

care’ for this patient population. Furthermore, anynew therapy being tested should be compared withoptimal ‘standard care’. Other methods proposedto offer greater protection to the lungs while pro-viding mechanical support to respiration includeHFO and ECMO. Studies into these modes areongoing.

Although supportive therapies have reducedmortality, there is still significant need forimprovements. Previous studies have providedimportant insight into the pathophysiology ofALI/ARDS. Research is ongoing into thera-pies to prevent ALI/ARDS in those at risk,treat it early in its course or aid in its resolution.Each of these goals is associated with specificchallenges.

Demonstrating that a prophylactic interventionreduces mortality, morbidity and is cost effective ischallenging at best. This is most likely to occurwhen the risk of acquiring the disease is high, theoutcome of the disease is uniformly devastatingand treatment for the disease is nonexistent. Forsome critically ill patients at risk for ARDS, thismay be the case. However, the diagnosis ofALI/ARDS encompasses a very heterogeneouspopulation, with incompletely understood riskfactors and non-uniform, diverse outcomes. Thegreatest likelihood of success for prophylactictherapy will come when we have further delin-eated the subgroups at highest risk of dyingfrom ALI/ARDS and have accurate diagnostictests to identify these patients. For ALI/ARDS,specifically targeting the pathogenic mechanismsresponsible for the increased risk of death inthese patient subgroups would theoretically be highyield. Basic science research identifying geneticpolymorphisms of patients with highest mortalityor greatest need for specific therapies shows greatpromise in this regard, but is not yet clinicallyapplicable. Until then, validating biomarkers andclinical indicators for poor prognosis inALI/ARDSshould remain a primary research goal.

Finding therapies to treat ARDS in its latefibroproliferative phase is also in great need. Toooften patients survive the early and mid phase ofARDS only to succumb to complications in thelate phase or undergo withdrawal of life supportas they are unable to be weaned from mechanical

1276 Bosma et al.


ventilation. Research into mechanisms of idio-pathic pulmonary fibrosis may help identifycommon pathways to target for therapy. To date,the majority of research has focused on treatingALI/ARDS in its earlier stages, in the hope thatthe disease process may be reversed prior to thepatient entering the fibroproliferative phase.

4.1 Lessons Learned from Research

Progress in finding therapies to treat estab-lished ARDS has been slow and hampered by along series of negative clinical trials. However,there are several lessons to be learned from theseRCTs. First, a ‘one-size-fits-all’ approach has notworked for pharmacotherapy for ARDS. In thissense, the syndrome of ALI/ARDS may belikened to cancer. Cancer as a broad term sig-nifies the uncontrolled replication of abnormalcells, but there are specific chemotherapeutictreatments for specific types of cancer, dependingon its origin. Some treatments may be effectivefor more than one type of cancer, but not forother types, and the magnitude of the benefitmight vary according to the type and stage ofdisease. Oncologists would not design a trial en-rolling all patients with differing types of cancerand expect to find a single drug that shows asurvival benefit. Yet, that is what has been at-tempted with several large ARDS trials. Recentstudies have demonstrated that direct ARDS islikely to respond differently than indirect ARDS,and in fact within these broad categories, patho-genesis may differ. Therefore, different therapiesmay need to be developed for specific aetiologiessuch as sepsis-related ARDS, SIRS-relatedARDS and various direct causes of ARDS.

Second, a well designed negative RCT does notnecessarily mean that the therapy tested should beabandoned. It means that the therapy is likely tonot be appropriate for widespread application.However, just because a drug does not work forevery ARDS patient does not necessarily meanit should not be used for anyone with ARDS.For example, there is no evidence for treating allpatients with acute ARDS with corticosteroids,but there is evidence that treating ARDS patientswith relative adrenal insufficiency and septic shock

with low doses of hydrocortisone is likely to bebeneficial. Similarly, nitric oxide should not rou-tinely be applied to all patients with ALI/ARDS,but may be useful in refractory hypoxaemia,particularly in conjunction with other ventilationrescue strategies.

Third, a negative RCT should potentially leadto further research so that we can gain furtherinsight as to why the therapy failed to yield aclinical benefit. Thomas Edison, when asked whyhe pursued his quest to invent a functional andpractical light bulb after innumerable failed at-tempts, is reported to have replied, ‘‘I have notfailed. I’ve just found 10000 ways that won’twork’’. ARDS research should take us from benchto bedside and back to the bench again. Basicscience can help us understand basic mechanismsof disease, discover why a therapy failed, thenprovide new ideas to apply to the clinical realm.RCTs are necessary to prove benefit and quantifyrisk prior to changing clinical practice. Since weare in urgent need of therapies to treat ALI/ARDS, it is necessary that RCTs continue to ad-vance our clinical care. However, these RCTs needto be well founded in basic biology and physiologyresearch, and focused on specific hypothesesregarding mechanisms of disease. Continuing toconduct large clinical trials on heterogeneouspatients with ALI/ARDS from multiple aetiolo-gies will not only prove ineffective but also addenormous cost to the healthcare system.

The most significant and promising findingfrom anRCT to date is that calfactant, the naturalbovine surfactant rich in Sp-B and -C, reducesmortality in ALI from 36% in the control arm to19% in the paediatric population. Indeed, calfac-tant is the first and only pharmacological agent todemonstrate a mortality benefit for treatment ofALI/ARDS. The ongoing CARDS study willattempt to reproduce that finding in adults withdirect causes of ARDS.[117] This trial is continuingenrolment after the first interim analysis, with atarget completion date of March 2011.

5. Conclusion

Great gains have been made in providing sup-portive management to patients with ALI/ARDS.



Ongoing and future research efforts will provideimportant insights into the complex patho-physiologies involved and may provide furtherrationale for patient-specific therapies and/orcombination therapies targeting the variousmechanisms contributing to this disorder. Un-derstanding who is at greatest risk of succumbingto ALI/ARDS and establishing the optimal timeto intervene will be essential to improving mor-tality for this syndrome.

Acknowledgements

The authors thank JeanetteMikulic for her assistance withpreparation of the manuscript. No sources of funding wereused to assist in the preparation of this review. The authorshave no conflicts of interest that are directly relevant to thecontent of this review.

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Correspondence: Dr Karen J. Bosma, Assistant Professor,Department of Medicine, University Hospital, 339 Wind-ermere Road, London, Ontario, Canada N6A 5A5.E-mail: [email protected]

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