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. 2005;294(22):2889-2896 (doi:10.1001/jama.294.22.2889)JAMA

Eddy Fan; Dale M. Needham; Thomas E. Stewart

Respiratory Distress SyndromeVentilatory Management of Acute Lung Injury and Acute

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CLINICIAN’S CORNERCLINICAL REVIEW

Ventilatory Managementof Acute Lung Injury andAcute Respiratory Distress SyndromeEddy Fan, MD

Dale M. Needham, MD, PhD

Thomas E. Stewart, MD

FOR NEARLY 4 DECADES SINCE THE

acute respiratory distress syn-drome (ARDS) was first de-scribed,1 research has been on-

going in an effort to improve theoutcome of this critical illness. Acuterespiratory distress syndrome is char-acterized by the acute onset of hypox-emia and bilateral infiltrates on chestradiography in the absence of left atrialhypertension. Various pulmonary (eg,pneumonia) and nonpulmonary (eg,pancreatitis) risk factors are associ-ated with ARDS.2 Mortality rates rangefrom26% to 74%, with most deaths at-tributed to associated conditions, such

as sepsis and multisystem organ fail-ure, rather than hypoxemia alone.2-6

Some survivors of ARDS have reducedquality of life with physical, neurocog-nitive, and emotional morbidity.7-10

The original ARDS case series1 out-lined a number of clinical features thatwere later incorporated into more for-mal definitions of this syndrome(TABLE 1).11-13 In 1994, the American-European Consensus Conference(AECC) definition was developed andis used widely by clinicians and re-

searchers.13

Under this definition, acutelung injury (ALI) is designated for pa-tients with significant hypoxemia (par-tial pressure of arterial oxygen to frac-tion of inspired oxygen[PaO2 /FIO2] ratio

300),while ARDS represents the sub-set of ALI patients with the most se-vere lung injury (PaO2 /FIO2 ratio200).Using these definitions, ALI and ARDSare relatively common with annual in-cidences estimated at 20 to 50 and 15

to 30 cases per 100 000 persons, re-spectively.2,3

No specific pharmacologic therapyhas proved effective for ALI or ARDS,and therapy is largely supportive withthe use of mechanical ventilation.11 Per-haps themost important advance in ALIand ARDS research has been the recog-nition that mechanical ventilation, al-

thoughnecessary to preservelife, canpo-tentiate or directly injure the lungsthrough a variety of mechanisms col-

Author Affiliations: InterdepartmentalDivision of Criti-calCare Medicine andDepartment of Medicine, Uni-versity of Toronto and University Health Network and

Mount SinaiHospital, Toronto, Ontario, (Drs Fan andStewart) and Division of Pulmonary and Critical CareMedicine, JohnsHopkins University, Baltimore, Md (Dr Needham).Corresponding Author: ThomasE. Stewart, MD,Uni-versity HealthNetwork/MountSinai Hospital, 600Uni-versity Ave, Suite 18-206, Toronto, Ontario, CanadaM5G 1X5 ([email protected]).ClinicalReview Section Editor: Michael S. Lauer, MD.We encourage authors to submit papers for consid-eration as a “Clinical Review.” Please contact Mi-chael S. Lauer, MD, at [email protected].

Context The acute lung injury and acute respiratory distress syndrome are criticalillnesses associated with significant morbidity and mortality. Mechanical ventilation isthe cornerstone of supportive therapy. However, despite several important advances,the optimal strategy for ventilation and adjunctive therapies for patients with acutelung injury and acute respiratory distress syndrome is still evolving.

Evidence Acquisition To identify reports of invasive ventilatory and adjunctive thera-pies in adult patients with acute lung injury and acute respiratory distress syndrome,we performed a systematic English-language literature search of MEDLINE (1966-2005) using the Medical Subject Heading respiratory distress syndrome, adult , andrelated text words, with emphasis on randomized controlled trials and meta-analyses.EMBASE and the Cochrane Central Register of Controlled Trials were similarly searched.The search yielded 1357 potential articles of which 53 were relevant to the study ob- jectives and considered in this review.

Evidence Synthesis There is strong evidence to support the use of volume- andpressure-limited lung-protective ventilation in adult patients with acute lung injury andacute respiratory distress syndrome. The benefit of increased levels of positive end-expiratory pressure and recruitment maneuvers is uncertain and is being further evalu-ated in ongoing trials. Existing randomized controlled trials of alternative ventilationmodes, such as high-frequency oscillation and adjunctive therapies, including inhalednitric oxide and prone positioning demonstrate no significant survival advantage. How-ever, they may have a role as rescue therapy for patients with acute respiratory dis-

tress syndrome with refractory life-threatening hypoxemia.Conclusions Volume- and pressure-limited ventilation strategies should be used inmanaging adult acute lung injury and acute respiratory distress syndrome patients.Further research is needed to identify barriers to widespread adoption of this strategy,as well as the role of alternative ventilation modes and adjunctive therapies.

JAMA. 2005;294:2889-2896 www.jama.com

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©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, December 14, 2005—Vol 294, No. 22 2889








lectively referred to as ventilator-associatedlung injury.14-16 Thesemecha-nisms include exposure to high inflationpressures or overdistention (baro-trauma or volutrauma),17 repetitive op-ening and closing of alveoli (atelec-

trauma),

18

and mechanotransductionresulting in up-regulated cytokine re-lease and a systemic inflammatory re-sponse (biotrauma).19 The lungs of pa-tientswith ALIor ARDS areparticularlyprone to ventilator-associated lung injury because they are heterogeneouslyaffected, as demonstrated in computed

tomographystudies (FIGURE).20 Asare-sult, some areas of the lung (often de-pendent regions) are atelectatic, con-solidated, less compliant, and thus lessavailable for ventilation while otherareas (usually nondependent regions)

appear and behave normally. Under-standing this heterogeneity has led tothe “baby lung” concept, which sug-gests that, overall, a markedly re-duced volume of lung is available forventilation in ALI or ARDS, effec-tively, a functionally baby-sized lungwithin an adult-sized body.21,22 Conse-

quently, mechanical ventilation can re-sult in barotrauma or volutraumawhenvolumes and pressures meant for theentire lung are forced into only a smallportion of functional lung. In addi-tion, shear forces at the interface be-

tween the open and closed lung unitsresult in atelectrauma. Both of thesetypes of injury also can lead to releaseof cytokines from the lung and have ad-verse systemic effects, contributing tothe development of multisystem or-gan failure.18,19

This improved understanding of ALIand ARDS and ventilator-associatedlung injury has been important in de-signinglungprotectivemechanical ven-tilation strategies aimed at attenuat-ing ventilator-associated lung injuryandimproving outcomes. Suchstrategies for

the invasive ventilatory managementof adult ALI and ARDS have recently beentested in a number of important clini-cal trials, which we review in this ar-ticle. In addition, we discuss alterna-tive invasive ventilatory modes andadjunctive therapies, with a focus onthose that we believe are widely avail-able for clinical use in adults at thepresent time. We also highlight recentcontroversies and suggest areas forfuture research.

Table 1. Diagnostic Criteria for ARDS

Source Oxygenation Chest Radiograph Other Criteria

Petty and Ashbaugh,11

1971

Cyanosis refractoryto oxygen therapy

Diffuse alveolarinfiltrates on frontalchest radiograph

Impaired pulmonarycompliance

Marked difference ininspired vs arterialoxygen tensions

Murray et al,12

1988Hypoxemia (PaO2 /FIO2 ),

by quintilesNo. of quadrants

of alveolarconsolidationon frontal chestradiograph

PEEP and respiratorysystem compliance(by quintiles)

Preexisting direct orindirect lung injury

Nonpulmonary organdysfunction

Bernard et al,13

1994 ALI, PaO2 /FIO2 300,

regardless of PEEP level ARDS, PaO2 /FIO2 200,

regardless of PEEP level

Bilateral infiltrates onfrontal chestradiography

PCWP18 mm Hgif measured orno clinical evidenceof left atrialhypertension

Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; PaO2 /FIO2, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; PCWP, pulmonary capillary wedge pressure; PEEP, positive end-expiratory pressure.

Figure. Typical Chest Radiograph and Computed Tomographic Scan of a Patient With Acute Respiratory Distress Syndrome

A B

A, The chest radiograph shows bilateral pulmonary infiltrates that appear to be diffuse. B, A computed tomographic scan of the thorax from the same patient dem-onstrates that the distribution of the bilateral infiltrates is predominantly in dependent regions with more normal-appearing lung in nondependent regions.

MANAGEMENT OF ACUTE LUNG INJURY AND ARDS

2890 JAMA, December 14, 2005—Vol 294, No. 22 (Reprinted) ©2005 American Medical Association. All rights reserved.








EVIDENCE ACQUISITIONTo assist with this review, we system-atically searched MEDLINE (1966 toSeptember 2005), using the MedicalSubjectHeadingrespiratorydistresssyn-drome, adult, and related text words

(acute respiratory distress syndrome,acute lung injury, respiratory distress syn-drome, adult respiratory distress syn-drome, ALI, or ARDS). The search re-sults were limited to English language,human subjects, randomized con-trolled trials, and meta-analyses.EMBASE and the Cochrane CentralRegister of Controlled Trials were alsosimilarly searched. This strategy re-sulted in 1357 potentially relevant ar-ticles for which citations, abstracts, orboth were reviewed. Bibliographies of all selected articles and review articles

were hand searched for additional rel-evant articles. Studies evaluating non-invasive ventilation, pharmacologictherapies(not part of a mechanical ven-tilation strategy), and small, explor-atory randomized trials (50 pa-tients) were excluded. To provide afocused and pragmatic review, we alsoexcluded studies of therapies that webelieved were not widely available forclinical use in adults at thepresent time(eg, exogenous surfactant and extra-

corporeal membrane oxygenation). Atotal of 53 articles met our criteria andwere considered in this review.

EVIDENCE SYNTHESIS

Conventional Lung

Protective-Ventilation

Conventional lung-protective ventila-tion involves strategies designed to miti-gate further lung injury in patients withALIor ARDS using a standard mechani-cal ventilator. Five randomized con-trolled trials23-27 and 3 meta-analy-ses28-30 have evaluated lung-protectiveventilation compared with conven-tional approaches,using a varietyof vol-ume- and pressure-limited strategies(TABLE 2). Three of the randomizedtrials, with sample sizes of 52 to 120patients, did not find a difference in

mortality between the treatment andcontrol arms.24-26 One study by Amatoet al23 used higher positive end-expiratory pressure(PEEP) and recruit-ment maneuvers in conjunction withpressure- and volume-limited ventila-tion in the intervention group. Thisstudy was stopped early, enrolling 53of 58 patients,after demonstrating a sig-nificant reduction in 28-day mortal-ity. However, there was no significantdifference in mortality at hospital dis-

charge, and a high mortality rate (71%)in the control group may have ac-countedfor the survival difference. Nev-ertheless, this trial strongly suggestedthat ventilatory strategies could im-pact mortality, and theresults in thein-

tervention group generated interest-ing hypotheses that have been pursuedin subsequent studies. The largest trialof volume- and pressure-limited ven-tilation was conducted by the ARDSNetwork (ARDSNet).27 This trial of 861patients demonstrated a 9% absolutedecrease in mortality (31% vs 40%;P =.007) when patients with ALI orARDS receiving mechanical ventila-tion have reduced tidal volumes (tar-getof 6 mL/kg of predictedbody weightwith a range of 4-8 mL/kg dependingon plateau pressure and pH) and re-

duced pressures (plateau pressure, mea-sured after a 0.5-second end-inspira-tory pause,30 cm H2O).

Three meta-analyses28-30 of these 5clinical trials have been performed.23-27

The first meta-analysis concluded thatthe control groups of the 2 trials, whichdemonstrated a survival advan-tage,23,27 did not reflect the “standardof care” and were likely responsible forthe mortality difference.28 In addition,the authors suggested that thelow tidal

Table 2. Trials of Volume- and Pressure-Limited Ventilation in Acute Lung Injury and Acute Respiratory Distress Syndrome

Study Participants

Source

ARDSNetwork,27

2000 Amato et al,23

1998Brochard et al,24

1998Stewart et al,25

1998Brower et al,26

1999

No. 861 53 116 120 52

Mean age, y 52 35 57 59 49

Target intervention Tidal volume, mL/kg 6 vs 12 PBW 6 vs 12 ABW 6-10 vs 10-15 DBW 8 vs 10-15 IBW 8 vs 10-12 PBW

Plateau pressure,cm H2O

30 vs 50 20 vs unlimited 25-30 vs60 30 vs 50* 30 vs 45-55

Actual intervention† Tidal volume, mL/kg 6.2 vs 11.8 384 vs 768‡ 7.1 vs 10.3 7.0 vs 10.7 7.3 vs 10.2

Plateau pressure,cm H2O

25 vs 33 30 vs 37 26 vs 32 22 vs 27 25 vs 31

Outcomes mortality, % 31 vs 40§ 38 vs 71 47 vs 38¶ 50 vs 47# 50 vs 46#

P value .007 .001 .38 .72 .61

Abbreviations: ABW, actual body weight; DBW, dry body weight; IBW, ideal body weight, calculated as 25 m2; PBW, predicted body weight, calculated as 50 plus 0.91 (height incentimeters minus 152.4) for men or 45.5 plus 0.91 (height in centimeters minus 152.4) for women.

*Represents peak inspiratory pressure rather than plateau pressure.†Mean values at earliest recorded time point are reported and represent lung-protective vs control ventilation groups.‡Tidal volume available in milliliters only.§Mortality at hospital discharge or at 180 days.||28-Day mortality.¶60-Day mortality.#In-hospital mortality.










volumes used in the interventiongroupof the ARDSNet trial may be harm-ful.28 This meta-analysis has been criti-cized as having important methodologi-cal flaws, such as inappropriatelygrouping the individual trial re-

sults.

29-31

In addition, its findings arecontradicted by 2 subsequent meta-analyses,29,30 which suggested that vol-ume-limited ventilation, particularly inthe setting of elevated plateau pres-sure (30 cm H2O), has a short-termsurvival benefit. One meta-analysisalsoconcluded that decreased tidal vol-umes may be advantageous below athreshold level (7.7 mL/kg pre-dicted body weight).30

In many instances, lung-protectiveventilation may lead to an elevation of arterial carbon dioxide, referred to as

permissive hypercapnia. Although acutehypercapnic respiratory acidosis hasmany potential adverse effects, the ex-tent to which a more controlled sub-acute elevation of carbon dioxide isharmful remains uncertain.32 In fact,some evidence indicates that permis-sive hypercapnia is relatively be-nign.32 At present, there are few data toinform physicians on a clinically rel-evant threshold of hypercapnia, acido-sis, or both that require specific inter-ventions, such as increasing effective

ventilation, decreasing carbon diox-ide production, or using buffer therapy(eg, bicarbonate). Of note, theARDSNetstudy27 investigators useda stepwise ap-proach of increasing respiratory rates(to a maximum of 35 breaths/min), al-lowing bicarbonate infusions (at thephysicians’ discretion), and increas-ing tidal volumes for the managementof acidosis.

Other important consequences of lung-protective ventilation possibly in-clude worsened oxygenation and the

need for increased sedation or analge-sia compared with patients receivingconventional ventilation. Of note, pa-tients in the intervention arm of theARDSNet study had reduced oxygen-ation in the first few days but im-proved survival.27 Furthermore, a re-cent analysisof a subsetof theARDSNetstudy revealed no significant differ-

ences in sedation or analgesia use be-tween lung-protective and conven-tional mechanical ventilation groups.33

However, the effect of any potential in-crease in sedation or analgesia use inpatients receiving lung-protective ven-

tilation requires further study.In addition to pressure and volumelimitation, higher PEEP and the use of recruitment maneuvers may be impor-tant components of a lung-protectiveventilation strategy. Recruitment re-fers to the dynamic process of reopen-ing collapsed alveoli through an inten-tional increase in transpulmonarypressure, which may be achievedthrough a variety of mechanisms, suchas a transient high continuous posi-tive airway pressure (eg, 40 cm H2O for40 seconds).34 Human studies evaluat-

ingrecruitment maneuvers have yieldedvariable results.35-39 Such factors as thetype (eg, primary vs secondary) andstage (eg, early vs late) of ALI or ARDSand recruitment technique used maybe important determinants of re-sponse.40-42 The optimal pressure, du-ration, and frequency of recruitmentmaneuvers has not been defined andtested in clinical trials. Of note, thesafety of recruitment maneuvers alsore-quires careful evaluation. Althoughtransient oxygen desaturation and hy-

potension are the most common ad-verse effects, other clinically signifi-cant events, such as barotrauma (eg,pneumothorax), arrhythmia, and bac-terial translocation, may occur.38,43

The isolated effect of higher PEEPand recruitment maneuvers could notbe determined in the small trial byAmato et al.23 A much larger study,known as the ALVEOLI trial,44 wasconducted by ARDSNet to investigatethi s i ssue. Thi s study pr o v i dedvolume- and pressure-limited lung-

protective ventilation to all studypatients and evaluated the effect onmortality of higher PEEP (12-24 cm vs5-24 cm H2O) in the treatment group.In addition, recruitment maneuverswere conducted in patients random-ized to the higher PEEP group byapplying a pressure of 35 to 40 cmH2O for 30 seconds to assess the effect

on oxygenation. After evaluating thefirst 80 patients, recruitment maneu-vers demonstrated only a modesteffect on oxygenation with no differ-ence in the requirement for oxygen-ation support (ie, PEEP or FIO2) and

were not continued for the remainderof the study.39 The study was stoppedearly, due to futility, after enrollmentof 549 of 750 patients. There was nosignificant difference in in-hospitalmortality, even after adjusting forimportant imbalances in baseline char-acteristics between the study groups(higher, 25.1% vs lower, 27.5% PEEP;95% confidence interval [CI], −3.6%to 8.4%; P=.47). However, some havesuggested that a true effect may havebeen missed due to stopping the studyearly.45 Alternatively, a beneficial effect

of higher PEEP in some (recruitable)patients may have been negated by adetrimental effect in other (nonre-cruitable) patients. These issuesrequire further investigation.

Alternative Ventilatory Approaches

to Lung Protection

The precise role of alternative methodsof ventilation, such as high-frequencyventilation (ie, jet, oscillation, and per-cussive ventilation) and airway pres-sure release ventilation, hasnot been es-

tablished. High-frequency ventilationallows for higher mean airway pres-sures that may be advantageous forlungrecruitment. In addition, it also allowsfor markedly reduced tidal volumes (1-3mL/kg) compared with conventionalventilation, which may further reduceventilator-associated lung injury.46,47

Airway pressure release ventilation notonly provides higher mean airwaypres-sures but also allows for spontaneousbreathing, which may be associatedwith better gas exchange, hemody-

namics, and reduced sedation re-quirements.48

Of these alternative ventilatorymodes, only high-frequency oscilla-tory ventilation (HFOV) has been stud-ied in moderately sized randomizedtrials.49 In a trial of 148 patients com-paring HFOV with conventional me-chanical ventilation with respect to key










adverse outcomes (eg, new airleak, in-tractable hypotension), there were nosignificant differences between groups.Mortality was examined as a second-ary outcome, with a nonsignificantlower 30-day mortality in the HFOV

group (37% vs 52%, P=.10). This find-ing must be interpretedwith caution be-cause the conventional ventilation pro-tocol did not use the current standardfor volume- and pressure-limited lungprotective ventilationand the study wasnot powered to assess mortality. A sec-ond trial of 61 ARDS patients compar-ing HFOV with conventional mechani-cal ventilation also revealed nosignificant differences in survival with-out supplemental oxygen or ventila-tory support (HFOV vs conventionalventilation 32% vs 38%; adjusted odds

ratio, 0.80; 95% CI, 0.22-2.97; P =.79),or other secondary end points.50 How-ever, a post hoc analysis revealed thatpatients with the most severe hypox-emia had a trend toward a benefit fromHFOV.

Adjunctive Therapies to

Lung-Protective Ventilation

Adjunctive therapies are cointerven-tions that may result in improved out-comes when combined with lung-protective ventilatory strategies. Prone

positioning and inhaled nitric oxide are2 adjunctive therapies that are cur-rently widely available and have beenstudied in large randomized trials of adult patients with ALI or ARDS.

The use of prone positioning withmechanical ventilation was first de-scribed in 1974.51 Placing the patientin a prone position has potential physi-ological benefits, including the recruit-ment of dorsal (nondependent) atelec-tatic lung units, improved respiratorymechanics, decreased ventilation-

perfusion mismatch, increased secre-tion drainage, reduced and improveddistribution of injurious mechanicalforces, and improved fit of the lungswithin the thorax.52

There are3 randomized trialsof pronepositioning in adults with ALI orARDS.53-55 In the first study, 304 pa-tients were randomly assigned either to

the supine or the prone position for atleast 6 hours per day over a 10-day pe-riod.53 Although oxygenation signifi-cantly improved in the prone group,there was no significant difference inmortality or any secondary outcome. A

post hoc analysis of the most severelyill patients revealed decreased mortal-ity for patientsrandomly assigned to theprone position (relative risk [RR, 0.54;95% CI, 0.32-0.90) at day 10, but thisbenefit did not persist beyond inten-sive care unit discharge. The secondstudy randomized 791 patients (48%with ALI or ARDS) to supine or pronepositioning for at least 8 hours per dayand also demonstrated improved oxy-genation withouta survival benefitat 28days (supine, 31.5%vsprone 32.4%;RR,0.97; 95% CI, 0.79-1.19; P=.77).54 This

second trial revealed a significantlyhigherrate ofadverse eventsin thepronegroup, including selective (right or leftmainstem bronchus) intubation, endo-tracheal tube obstruction, and pres-sure sores. The third study of prone po-sitioning in ARDS, was stopped early(133 of 200 patients) due to problemswith enrolment. It revealed a large, butstatistically insignificant, difference in in-tensive care unit mortality between the2 groups (supine, 58.6% vs prone,44.4%, P=.43).55

Inhaled nitric oxide provides selec-tive vasodilation in ventilated lungunitsthus improving ventilation-perfusionmismatch, hypoxemia, and pulmo-nary hypertension.56 This therapy hasbeen studied in 6 randomized, placebo-controlled trials of adults with ALI orARDS.57-62 None of these studies dem-onstrated a sustained benefit. A Coch-rane meta-analysisof more than 500 pa-tients (80% adults) concluded thatinhaled nitric oxide led to a transientimprovement in oxygenation for up to

72 hours but no survival benefit (RR,0.98; 95% CI, 0.66-1.44).63 After thismeta-analysis was completed, the larg-est trial of inhaled nitric oxidewaspub-lished.62 This study randomly as-signed 385 nonseptic patients with ALIor ARDS to receive either continuouslow-dose inhaled nitric oxide at 5 ppmor placebo. The results of this trial were

consistent with earlier studies in dem-onstrating only transient improve-ments in oxygenation without a sig-nificant mortality benefit (nitric oxide,23% vs placebo 20%, P =.54).

CURRENT UNRESOLVED

QUESTIONS ANDPERSONAL PERSPECTIVE

Current ALI and ARDS Definition

and Clinical Trials

Despite a strong physiological ratio-nale, many therapies for ALIand ARDShave not led to a significant survivalbenefit when tested in large clinicaltrials. It is possible that the case defi-nition of ALI and ARDS may have con-tributed to this. The current American-European Consensus Conferencedefinition has important limitations in

its reliability and validity. First, thePaO2 /FIO2 ratio that defines hypox-emia does not consider theeffect of ven-tilatory settings (eg, PEEP) or adjunc-tive therapies(eg, inhaled nitric oxide),which can have an important acute in-fluence on PaO2, nor does it considerwhether a patient meets ALI or ARDScriteria.64-66 Thus, variation in ventila-tion practices across institutions maylead to systematic differences in defin-ing this disease entity for clinical stud-ies and patient management. Second,

there is only moderate interobserveragreement in interpreting the chest ra-diograph for ARDS, and ventilator set-tings also can influence the degree of infiltrates appearing on the radio-graph.13,67 Finally, in comparison to au-topsy findingsof nonsurvivors, a single-center study demonstrated onlymoderate accuracy of the ARDS defi-nition.68 Refinement of thecurrent defi-nition of ALIand ARDS to achieve morehomogeneous patient populations maybe beneficial in order to detect a sig-

nificanttreatmenteffect in clinical trialsof ALI and ARDS therapies. However,a more restrictive definition also mayexclude patients who may potentiallybenefit from a particular intervention.Further consideration of the currentALI and ARDS definitions are neces-sary before potentially important thera-pies are rejected as nonbeneficial.










Widespread Adoption of the

ARDSNet Ventilation Protocol

Given that the ARDSNet study27 pro-vided the only ventilationprotocol thathad a significant and sustained short-term mortality benefit, we believe

patients with ALI or ARDS would ben-efit if all institutions used a lung-protective ventilation protocolbased onthisvolume-and pressure-limited strat-egy. AlthoughtheARDSnet protocolcanbe successfully implemented in clini-cal practice,69 widespread adoption hasnot rapidly occurred.70-73 One possibleexplanation for this finding is a per-ception by caregivers that implemen-tation could be harmful to patients,73

despite the lack of evidence to supportthis notion.

Some argue that adoption of the ex-

act ARDSNet protocol (available atwww.ardsnet.org) may be unnecessaryand use of other modes of ventilation,which achieve similar volume andpres-sure limitations (ie, tidal volume 4-8mL/kg predicted body weight and pres-sure30cmH2O), may be equally ben-eficial.74 Such alternate volume- andpressure-limitedprotocols may be easierto implement and follow, especially if they are already consistent with localpractice patterns. However, the use of custom-made protocols, which may

seem logical, shouldbe approached withcaution, for it remainsunclear what spe-cific aspect of the ARDSNet protocolconfers the survival advantage. For in-stance, a secondary analysis of theARDSNetdata75 suggested thattidal vol-ume reduction even benefited patientswith safe plateaupressuresof 31 cm H2O

or less of water, meaning that pressure-limited ventilation, without concomi-tant volume-limitation, may be detri-mental. Irrespective of this controversyas to whether the exact ARDSNet pro-

tocol shouldbe adopted, theexistingevi-dence (including 2 meta-analyses of alltrials) supports that clinicians shouldchange their practice and adopt vol-ume-and pressure-limited ventilationforpatients with ALI or ARDS. As addi-tional evidence emerges, ongoing reas-sessment and evolution of these proto-cols will be necessary.

Role for Rescue Therapy

There are many alternative ventila-tory approaches and adjunctive thera-pies that have some evidence of short-term physiological benefit, but noconsistent evidence for a survival ad-

vantage when studied with large ran-domized trials. Consequently, decid-ing the exact role of such therapies inmanaging individual patients is diffi-cult. One approach is to completelyavoid all of these therapies outside of clinical trials until their efficacy hasbeenadequately demonstrated. Assum-ingtheir physiological benefit andsafetyhave been appropriately evaluated inprior human studies, another ap-proach is to limit use of these thera-pies to well-defined rescue situationsin which a patient is deemed to be fail-

ing, or at risk of harm, from conven-tional ventilation. In these instances,rescue therapy maybe consideredto po-tentially avoid significant morbidity ormortality. However, the controversyliesin determining which rescue thera-pies should be used (either alone or incombination) and at what point theyshould be initiated and terminated. Forexample, preliminary data suggest thatearlier institution of HFOV may por-tend a better prognosis76 andthat theremay be synergistic benefits of combin-

ing different rescue modalitiesfor ARDSpatients with severe,life-threatening hy-poxemia.77,78 Although some proto-cols have been reported,79 there is in-sufficient evidence to support thesuperiority of any particular approachto rescue therapy. Whenever possible,such patients should be considered fortransfer to institutions with signifi-cant experience in ALI and ARDS man-agement to allow further expert evalu-ation and treatment. Additionalresearch is needed to build on the an-

ecdotal evidence supporting the ben-efit of rescue therapies for the most se-verely ill patients with ALI or ARDS.

Conclusions and

Future Considerations

Recognition that mechanical ventila-tion, although life-saving, can contrib-ute to patient morbidity and mortality

has been the most important advancein the management of patients with ALIand ARDS. Volume- and pressure-limited ventilation clearly leads to im-proved patient survival. The role of re-cruitment maneuvers, higher levels of

PEEP, or both remaincontroversial andare the subject of 2 ongoing multi-center clinical trials (ExPress trial[France], LOVS trial [Canada, Austra-lia, and Saudi Arabia]). At this time, useof alternative modes of ventilation (eg,HFOV) andadjunctivetherapies (eg, in-haled nitric oxide and prone position-ing) should be limited to future clini-cal trialsandrescuetherapy for patientswith ALI or ARDS with life-threaten-ing hypoxemia failing maximal con-ventional lung-protective ventilation.

Although agreement on the current

definition of ALI and ARDS has been afundamental step forward in researchand clinical practice, further refine-ment is required to ensure that the ef-ficacy of new andexisting therapies areevaluated in the most appropriate pa-tient population.

Finally, after decades of ALI andARDS research, it is important to en-sure widespread uptake of efficaciousvolume- and pressure-limitedmechani-cal ventilation. It is critical that clini-cians who treat patients with ALI or

ARDS reassess their current ventila-tion strategies, assimilate the availableevidence, and modify their practices toensure the highest quality of care andbest outcomes for their patients. Un-derstanding the existing barriers to useof lung-protective ventilation andmeth-ods for increasing implementation of current research findings are impor-tant opportunities for future study.

Financial Disclosures: None reported.Funding/Support:Dr Needham is supportedby theCa-nadian Institutes of Health Research (Clinician-Scientist Award), Royal College of Physicians and Sur-

geons of Canada (Detweiler Fellowship),and grant P050HL 73994-01 from the National Institutes of Health.Role of the Sponsor: None of the funding organiza-tions or sponsors had any role in the design and con-ductof the study; the collection, management, analy-sis,or interpretation ofthe data; orpreparation,review,or approval of the manuscript.Acknowledgment: We thank A. Slutsky, MD, Inter-departmental Division of Critical Care Medicine andDepartment of Medicine, and A. Detsky, MD, PhD,Department of Medicine, both at the University ofToronto, Toronto, Ontario, and C. Soong, MD, De-










partment of Medicine, William Osler Health Center,Etobicoke, Ontario, for their review of early drafts ofthis article.

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Art may be served by morality: it can never be its ser-vant. For the principles of art are eternal, while theprinciples of morality fluctuate with the spiritual ebband flow of the ages.

—Arthur Symons (1865-1945)








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