the adult respiratory distress syndrome: definition and prognosis ...

British Journal of Anaesthesia 1990; 65: 107-129

THE ADULT RESPIRATORY DISTRESS SYNDROME:DEFINITION AND PROGNOSIS, PATHOGENESISAND TREATMENT

J. P. WIENER-KRONISH, M. A. GROPPER AND M. A. MATTHAY

The Adult Respiratory Distress Syndrome(ARDS) was first described in a British journal byAshbaugh and colleagues [3] more than 20 yearsago. Since that time, a considerable body ofknowledge about ARDS has emerged from bothclinical and experimental work, but much moreneeds to be learned about the basic mechanismsthat regulate the initial inflammatory response,and about the factors that regulate the repairprocess in the lung.

This review has four objectives. First, we willcritically examine the classic definition of ARDSand determine whether an expanded definitionwould provide a more workable approach fordetermining prognosis and guiding therapy forpatients with acute lung injury. Second, althoughthe pathophysiology of ARDS has been welldescribed, we will review a number of newdevelopments in our understanding of the extentof lung and pleural involvement in ARDS. Third,both clinical and experimental studies have pro-vided a long list of possible mechanisms thatcould be responsible for the pathogenesis of acutelung injury in man. We shall review some of themost promising developments in both clinical andbasic research that shed new light on themechanisms of acute lung injury and repair. Ourfinal objective will be to review the status ofcurrent treatment for ARDS and to discuss newtreatments that may become available in the nextfew years.

DEFINITION, EPIDEMIOLOGY AND PROGNOSIS OF

ARDS

In 1967, Petty described ARDS as a syndrome ofacute respiratory failure characterized by non-

cardiogenic pulmonary oedema with severehypoxaemia caused by right-to-left intra-pulmonary shunting secondary to atelectasis andair space filling from oedema fluid [3]. The chestradiograph showed diffuse pulmonary infiltrates,and there was a decrease in lung compliance; thelungs required higher than normal airway pres-sures to inflate them to a normal tidal volume.

Although this clinical description was veryuseful, there is now a need for a more com-prehensive definition. First of all, the hetero-geneity of both the inciting clinical disorders andthe variability of the clinical course of ARDS hasbeen better appreciated. For example, the im-portance of non-pulmonary organ failure, in-dependent of respiratory failure, has been recog-nized increasingly as a major cause of death inpatients who develop acute lung injury. Also, theprognosis for recovery depends on the associatedclinical disorder: ARDS associated with sepsishas a 90% mortality, while ARDS associated withfat embolism has a 10% mortality.

The incidence of ARDS has been difficult toestablish. In 1977, it was estimated that therewere 150000 cases of ARDS annually in theUnited States with a mortality of approximately50-60% [80]. Recently, Webster, Cohen andNunn reported a much lower incidence in theUnited Kingdom [112]. The American estimatepredicted an annual incidence of 0.6/1000,whereas the British study predicted an incidenceof 0.05/1000. A prospective study in the CanaryIslands reported an incidence of 0.02 to 0.04/1000,with a mortality of approximately 70 % [ 110]. Thedifferences in the reported incidences of ARDSreflect in part the various criteria used for making

KEY WORDSLung: adult respiratory distress syndrome.

JEANINE P. WIENER-KRONISH, M.D.; MICHAEL A. GROPPER,M.D., PH.D.; MICHAEL A. MATTHAY, M.D.; Departments ofAnesthesia and Medicine, Cardiovascular Research Institute,University of California, San Francisco, California, U.S.A.

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108 BRITISH JOURNAL OF ANAESTHESIA

the diagnosis. In order to determine the trueincidence of acute lung injury, it is important tostandardize the definition and provide a morequantitative scoring system that includes bothpulmonary and non-pulmonary organ function.

Therefore, we proposed an expanded definition[81] and this was endorsed by Dr Petty [90]. Wewill describe the three parts of the definition insome detail and we will also refer to the recentclinical and epidemiological studies that led to theformulation of this expanded definition.

Acute lung injury scoring system

The first part of the definition includes asemiquantitative method for scoring acute lunginjury derived in part from criteria used by otherinvestigators [38, 88]. The scoring involves a four-point system. First, the impairment of oxygen-ation is quantified by the ratio of the arterialoxygen tension to the fraction of inspired oxygen.Second, the chest radiograph is scored on a four-point system: if the chest radiograph is clear, then

no points are assigned; one to four points areassigned for consolidation in the four lung zones.A radiologist is not needed to grade the film.Third, respiratory system compliance can becalculated (if the trachea is intubated) by dividingthe tidal volume by the plateau airway pressureminus the positive end-expiratory pressure(PEEP). The fourth criterion reflects the PEEP.This is important for at least two reasons: PEEPobviously influences oxygenation, and the PEEPthat is required provides some indication of theseverity of respiratory failure. With this four-point scoring system, we classify acute lung injuryas mild to moderate (0.1 to < 2.5) or severe(^ 2.5) (table I) [81]. Using this scoring system ina prospective investigation of the sepsis syndrome,we found that severe lung injury or fully de-veloped ARDS occurred in 25% of 40 patientswho had sepsis; however, another 35% of thepatients had only mild to moderate lung injury[113]. Thus this scoring system provides a broaderview of the spectrum of acute lung injury that

TABLE I. Components of the lung injury score

1. Chest radiograph scoreNo alveolar consolidationAlveolar consolidation in one quadrantAlveolar consolidation in two quadrantsAlveolar consolidation in three quadrantsAlveolar consolidation in all four quadrants

2. Hypoxaemia score

•PaoV-Flo,P*o,/Flo,

3. Respiratory system compliance score(when ventilated)

ComplianceComplianceComplianceComplianceCompliance

4. PEEP score (when ventilated)PEEPPEEPPEEPPEEPPEEP

The final value is obtained by dividing the aggregatesum by the number of components that were used:

No lung injuryMild-to-moderate lung injurySevere lung injury (ARDS)

Value

—————

225-299175-224100-174< 100

> 80 ml/cm H,O60-79 ml/cm H,O40-59 ml/cm H,O20-39 ml/cm H,O< 19 ml/cm H,O

< 5 cm H,O6-8cmH,O

9-11 cmH.O12-14 cm H,O> 15 cm H,O

Score

01234

u1234

01234

01234

00.1-2.5>2.5


ARDS 109

occurs after sepsis. It also provides a semi-quantitative method for following the physio-logical variables in patients with acute lung injury.

Clinical disorders associated with ARDS

The second part of the definition requires thatthe clinical disorders) associated with the de-velopment of ARDS be identified. Recent epi-demiological studies of ARDS have been com-pleted at a number of centres [38, 88]. Theseprospective studies identified sepsis syndromeand gastric aspiration as die two clinical disordersmost commonly associated with ARDS (table II).Other clinical disorders associated with a risk fordeveloping ARDS include shock of any aetiology,major trauma, multiple transfusions, severe acutepancreatitis, drug overdose, pneumonia and neardrowning [96, 113]. The risk of developing ARDSincreases with the number of clinical disordersthat occur in the same patient. In addition, thetime course for the development of ARDS afterthe onset of the clinical disorder has beenexamined. Overall, acute lung injury developedwithin 24 h in 80 % of patients at risk whoultimately developed ARDS. Subsequently, wecarried out a prospective study of 40 patients withsepsis syndrome. We found that ARDS developedafter sepsis in less than 6 h in many patients [113].These findings have important therapeutic im-plications. It had been hoped that early treatmentcould be instituted to attenuate the severity of theacute lung injury. It may be difficult to achieve

Sepsis isassociated with

this objective, however, because the intervalbetween the inciting clinical event and thedevelopment of acute respiratory failure is usuallyless than 24 h.

the most common clinical disorderthe development of ARDS:

20-40% of patients with sepsis develop thesyndrome. As injury to the pulmonary endo-thelium occurs early in experimental sepsis, wehypothesized that increased concentrations of vonWillebrand factor (vWF) antigen, a product ofboth the systemic and pulmonary endothelium,might identify the patients with sepsis who woulddevelop acute lung injury. We found that a plasmavWF-antigen concentration > 450 % of controlhad a sensitivity of 92 % and a specificity of 77 %for predicting acute lung injury. In addition, if apatient had non-pulmonary organ failure at thetime of entry to the study (by definition, nolung injury could be present at this time) as wellas a plasma vWF-antigen > 450 %, then there wasan 80 % likelihood for the patient to develop lunginjury and not survive [96].

The relationship between ARDS and sepsis hasbeen investigated by other groups. In one study,if a patient had clinical evidence of infection andhad positive blood cultures but the site of infectioncould not be identified before death, then thesource of infection was usually found in theabdomen at postmortem [7]. In contrast, whenpatients had negative blood cultures with clinicalsepsis, the postmortem examination showed that

TABLE II. Incidence of ARDS following clinical risks (includes only those patients with a single riskevent, not those with multiple risks). (Modified from data in [39] and [88])

Clinical condition

SepsisBacteraemiaSepsis syndrome

Aspiration of gastric contentsFractureMultiple transfusions

10 units/24 h10 units/6 h

Cardiopulmonary bypassBurnPneumonia in I CXIDisseminated intravascular coagulationPulmonary contusionNear-drowningPancreatitisProlonged hypotension

Incidence

Washington

—5/13(38%)7/23(30%)1/12(8%)

—4/17(24%)

————

5/29(17%)2/31/10/1

of ARDS

Colorado

9/239(4%)—

16/45(36%)2/38(5%)

9/197(5%)—

4/237(2%)2/87(2%)

10/84(12%)2/9(22%)

————



TABLE III . Direct causes of death in patients vrith ARDS and control subjects. * Three patients with sepsis and respiratory failureas contributing cause, one patient with respiratory failure as indirect cause, t Sepsis present as a contributory cause in all patients.

% Sepsis present as a contributory cause in one patient. {Reproduced, with permission, from [79])

Irreversible

(direct cause)

SepsisCardiacRespiratoryCentral nervous systemHaematological statusHaemorrhagic shockHepatic

ARDS

Early mortality(» =

(%)

30101030

0200

= 10)

(«)

3113

—2

—

group

Late(n

(%)

36231818400

mortality= 22)

(»)

85*4t4t1——

Early(n

(%)

1240

5212200

Non-ARDS

mortality= 25)

(n)

31

—1335

—

group

Late mortality(n =

(%)

5037

33303

= 30)

(n)

1512*

101

—1

the origin of the infection was usually in the lung.Subsequently, Montgomery and co-workers [79]reported that both early and late mortality inpatients with ARDS was related primarily tosepsis. The actual cause of death in the first 3 daysafter the onset of ARDS was respiratory failure inonly 10% of the patients. In fact, although theincidence of respiratory failure as a cause of deathincreased to 18% in those who died after 3 days,most of these patients had a complicating pneu-monia (table III). Another study reported that theoverall survival rate was only 29 % in a group of129 patients with ARDS [99]. Infection was muchmore common in non-survivors, and the lung andabdomen were again the most common sites ofinfection. Even when the patients received anappropriate course of antibiotics, the outcome wasstill poor (table IV).

Aspiration of gastric contents is another clinicaldisorder frequently associated with ARDS. Todetermine the extent of lung injury secondary togastric aspiration, one study examined the prog-nostic value of gas exchange data in patients whohad suffered an episode of gastric aspiration [16].The authors measured arterial blood-gas tensionsin 44 patients within 1 h after aspiration, andcalculated the ratio of arterial oxygen tensionmeasured to the alveolar oxygen tension delivered.If the ratio was 0.5 or less, mortality was 48%; ifthe ratio was greater than 0.5, mortality was 14%(P < 0.05). Thus by examining the initial oxy-genation data, it was possible to assess theprognosis of patients with ARDS from gastricaspiration.

The adult respiratory distress syndromedevelops also after major trauma. In some trauma

TABLE IV. Outcome determinants in ARDS. $ Includespatients with known site of infection only. \Chi-square

contingency analysis. (Adapted, with permission, from [99])

All study patientsInfection

PresentAbsent

Antibiotic therapy^AdequateInadequate

Number

129

10821

6913

Survivors

No.

37

2314

203

(%)

29

2167

2923

\P

patients, acute lung injury occurs in associationwith lung contusion or within the first 24 h of thetrauma if severe hypotension occurs, emergencysurgical treatment is required, or multiple trans-fusions are administered [88]. ARDS develops inother trauma patients when they develop sepsissyndrome several days after the initial trauma. Intrauma victims with long bone fractures, the fatembolism syndrome and ARDS may develop[97]. Those that develop ARDS secondary to fatemboli have a much better prognosis than patientswho develop ARDS following sepsis or immedi-ately after major trauma, hypotension and surgicaltreatment. In ARDS patients with fat emboli,supportive treatment with mechanical ventilationshould result in a greater than 90% survival [97].

A number of other clinical disorders may beassociated with the development of ARDS, in-cluding drug overdoses with aspirin, opioids,tricyclic antidepressants or barbiturates. Patientsmay develop acute lung injury from hypotension,concomitant gastric aspiration, or from direct


ARDS 111

lung injury from the ingested drug itself. Cardio-pulmonary bypass is another important clinicalcondition associated with the development ofacute lung injury. At our institution, the prognosisfor ARDS following cardiopulmonary bypass isbetter than from other causes of acute lung injury[120]. In contrast, ARDS developing after bonemarrow transplantation has a nearly 100% mor-tality [83].

Thus the clinical disorder or disorders that leadto the development of acute lung injury clearlyinfluence the patient's prognosis for recovery.Therefore, the second part of the expandeddefinition requires that the associated clinicaldisorders should be specified, so that a morerealistic assessment of the prognosis can beestablished at the onset of ARDS.

Non-pulmonary organ failure

The third part of the definition specifies thefailure of organs other than the lung. Theimportance of non-pulmonary organ failure hasbeen increasingly recognized in ARDS patients(fig. 1). Cardiovascular abnormalities were over-looked in the early descriptions of ARDS. In fact,an early requirement for the diagnosis of ARDSwas the exclusion of cardiac disease. The literaturesuggests, however, that as many as 20% ofpatients with acute ARDS have concomitantcardiac disease [78, 129]. Because patients with

acute and chronic cardiac failure have a higherrisk of infection, it is reasonable to suppose thatthey may have a higher chance of developingARDS and may have a worse prognosis because oftheir poor cardiac function. Furthermore, sepsiscan cause a decrease in left and right ventricularfunction [18, 57,85]. The decrease in ejectionfraction tends to occur after the onset of sepsis andmay resolve over a period of 7-10 days. Thesesepsis-induced cardiac abnormalities cannot beidentified using a pulmonary arterial catheter;consequently, a radionuclide study is required tomeasure the decrease in ejection fraction [85].Furthermore, stroke volume in this situation isnot improved by increasing the intravascularvolume [84].

Concomitant hepatic failure and ARDS areassociated with an especially poor prognosis.Hepatic failure in the face of acute lung injurycarries an almost 100% mortality [98]. In fact,any combination of three organs that have failedfor more than 7 days carries a 98% mortality[61].

An example of the value of this new definitionis provided by the study by Fowler and co-workers [39]. They reported that there were threevariables at the onset of ARDS that correlatedwith a particularly poor outcome. Patients withARDS had a mortality rate greater than 80% ifthe patient's initial pH remained less than 7.4

Renal: 40-55%

Gastrointestinal: 7-30%

Hepatic 12-95%

Haematological 0-26%

CNS 7-30%

Cardiac 10-23%

FIG. 1. Incidence of non-pulmonary organ failure in patients who have ARDS. Abnormalities are mostconsistently observed in the kidneys. However, hepatic dysfunction has also been reported in as many

as 95% of patients with ARDS. (Reproduced, with permission, from [30].)



TABLE V. Criteria for expanded definition of acute lung injury

I. Severity of acute lung injuryArterial oxygenation (.P&ot/Fi0JChest radiographStatic lung complianceLevel of positive end-expiratory pressure

II. Associated clinical disorders)Sepsis (microbiology, anatomical site)Aspiration (type)Major traumaDrug overdoseCardiopulmonary bypassOthers (bone marrow transplant)

III. Systemic organ functionAcid-base statusRenal functionHaematological abnormalitiesHepatic functionCentral nervous system functionCardiovascular function

after the trachea was intubated and the lungsventilated mechanically, if the initial serum con-centration of bicarbonate was less than20 mmol dl"1, and if the initial concentration ofblood urea nitrogen was greater than23 mmol litre-1 (65 mg dJ"1)- The ARDS patientswith these findings had an 80% mortality,compared with 40% mortality in the ARDSpatients without these abnormalities. This is agood example of how systemic factors mayinfluence outcome and why it is important tocharacterize a patient's pulmonary and non-pulmonary clinical status to develop a reliableprognostic system.

The three major categories in the expandeddefinition of ARDS [81] are summarized in tableV. We believe that a more quantitative definitionof pulmonary and non-pulmonary organ failureincluding the associated clinical disorders iscritical for establishing the actual incidence ofARDS and for determining the prognosis forrecovery [2, 6, 8].

PATHOPHYSIOLOGY OF ARDS

In the early phase of acute respiratory failure fromacute lung injury, patients typically have severealveolar oedema with large numbers of inflam-matory cells, primarily neutrophils, in the airspaces and interstitium of the lung. Initially, theoedema fluid has a high concentration of protein(75-95 % of plasma protein concentration) whichis characteristic of an increased-permeability

oedema [34]. Also, one group of investigatorsmeasured a rapid clearance of i.v. injected 131I-albumin into the air spaces in patients with sepsisand acute lung injury [2]. Other methods formeasuring lung microvascular permeability inARDS patients have not yet been sufficientlyreliable to be useful clinically [116]. Ultra-structural studies of the lungs from patients whodied in the first 24 h after developing ARDSshowed evidence of lung endothelial injury,presumably leading to the capillary leak and theincreased-permeability pulmonary oedema [4](fig. 2).

The early experimental studies of acute lunginjury focused primarily on the injury to thepulmonary endothelium. However, morphologi-cal studies by Bachofen and Weibel in 1977 alsoshowed considerable epithelial injury in patientsdying of ARDS in the acute phase (fig. 2) [4].Epithelial injury is now emerging as a veryimportant component of the acute lung injurysyndrome, partly because injury to the epitheliumlowers the threshold for alveolar flooding andresults in a substantial deterioration in gasexchange.

In fact, a recent clinical study in patients withARDS has demonstrated that the presence orabsence of normal alveolar epithelial function, asmeasured by sequential measurements of theconcentration of protein in pulmonary oedemafluid, may be an important prognostic indicator inARDS patients [120]. If patients can reabsorbexcess alveolar oedema within the first 12 h afterdeveloping pulmonary oedema, alveolar epithelialfunction is reasonably intact. Patients in thiscategory had an excellent chance for recoveryfrom their acute respiratory failure and an ex-cellent chance of survival overall. In contrast,patients who had no change in their pulmonaryoedema fluid protein concentration in the first12 h after the onset of mechanical ventilation (andtherefore did not reabsorb any of the excessalveolar liquid), had a much higher mortality.

At first, airway abnormalities were not identi-fied as an important feature of ARDS. Pulmonaryfunction studies of ARDS survivors demonstratedthat a large proportion of the patients whorecovered from this disease had nearly normalpulmonary function. However, some patients withno prior history of smoking and no history ofasthma did develop reactive airway disease afterrecovery from ARDS [52,89]. Experimentalstudies have demonstrated that gram-negative


ARDS 113

FIG. 2. Ultrastructure of a lung specimen, showing the alveolar septum with extensive epithelialdestruction in a 19-yr-old woman who died after 4 days of fulminant capillary leakage as a result ofsepticaemia. Note the irregularly swollen and damaged endothelium. Also note that there is loss of theepithelial cell-lining in some areas where the basement membrane is exposed to the alveolar space. A =Alveolar space; BM = denuded basement membrane; C = capillary; EC = intravascular erythrocyte;EN = swollen endothelial cell; HM = hyaline membrane; LC = intravascular leukocyte. (Reproduced,

with permission, from [5].)

endotoxaemia causes substantial airway constric-tion in sheep, which suggests that this mechanismof airway constriction may also occur during thepatient's stay in hospital [102]. Broncho-constriction is mediated by thromboxane and canbe inhibited by cyclo-oxygenase block utilizingindomethacin [102]. Clinical studies have con-firmed some of these experimental findings;airway resistance was increased in 50 % of patientswith ARDS in one hospital [122].

There is an equal incidence (approximately40%) of pleural effusion in patients with hydro-static or increased permeability pulmonaryoedema [1, 119]. It has been established thatapproximately 20-25 % of the excess lung waterin acute pulmonary oedema that accumulates inthe first few hours from increased permeabilityoedema drains into the pleural space and is clearedfrom the thoracic cavity by pleural lymphatics[117]. More lung oedema drains through thepleural space than through the lung lymphatics inexperimental studies of respiratory distress syn-drome in newborn lambs [12]. Thus the pleuralspace is an important route for the clearance of asignificant fraction of pulmonary oedema fluid.

The interstitium of the lung becomes involvedduring the sub-acute phase of ARDS, approxi-mately from day 5 to day 10 after lung injury.Some patients develop an accelerated fibrosingalveolitis. Ultrastructural studies have shown animpressive proliferation of alveolar type II epi-

thelial cells, providing a new epithelial lining,apparently in response to injury of the type Ialveolar epithelial cells in the acute phase. Thereis a pronounced increase in fibroblast and collagenformation in the interstitium (fig. 3) [71]. Themechanisms for these responses to the acute lunginjury are not understood, but there is con-siderable interest in investigating the role offibroblast and epithelial growth factors that maybe released from alveolar macrophages and othercells in the lung.

Lung destruction occurs during the chronicphase of ARDS (10-14 days after the syndromehas developed). There is considerable evidence oflung destruction, emphysema and pulmonaryvascular obliteration, in addition to areas ofintense fibrosis. In this chronic phase, patientsusually do not have as severe an oxygenationdefect as they did in the acute phase when therewas flooding of the air spaces with protein-richoedema fluid. In the subacute and chronic phases,oxygenation usually improves and the require-ments for PEEP may decline. The patientscontinue to have a large deadspace and require avery high minute ventilation, in excess of 15-20litre, to maintain a normal arterial carbon dioxidetension. During this phase of the disease, there isstill decreased lung compliance which may besecondary to the pulmonary fibrosis and in-sufficient surface active material.

Most patients do not die during the acute phase



FIG. 3. Ultrastnicture of a lung specimen from a patient about 1 week after near drowning, showing thehistological features of the subacute stage of the adult respiratory distress syndrome. The septum iswidened by interstitial oedema (ED), fibres and cells (double arrows) and an almost continuous layer ofbulky epithelial cells resembling type II cells (EP2). The single bold arrows refer to areas of fusedendothelial and epithelial basement membrane. The patient had persistent sepsis from an abdominal

source for 1 week. (Reproduced, with permission, from [5].)

of lung injury [79]: they survive to develop thesubacute and chronic phases of ARDS whensecondary pulmonary and non-pulmonary infec-tions determine the outcome. Nosocomial pneu-monia is a common complicating problem inpatients with ARDS, particularly during thesubacute phase [23,62]. The highest risk ofinfection appears to be during the first 6-10 daysafter the initiation of ventilation [62]. The mech-anism for increased host susceptibility to infectionis not well understood. Some studies of alveolarmacrophage function have not shown any majoralteration. One explanation may be that destruc-tion of lung tissue results in an impairment ofboth blood supply and lymphatic drainage, and tothe presence of cellular debris and plasma in theair spaces, predisposing these areas to bacterialgrowth. Since airway abnormalities have alsobeen identified in some patients, it may be thatmucociliary transport is impaired as well. Thiscould result in the retention of secretions and agreater chance of developing pneumonia.

Recent studies of ARDS survivors have foundthat patients who were bacteraemic during theirillness had a greater decrease in their diffusingcapacity after they recovered. There was nocorrelation between pulmonary function and theduration of mechanical ventilation, the inspired

concentration of oxygen or the period for whichthey required supplementary oxygen [89]. Theseresults suggest that sepsis, not the requiredsupportive care with supplementary oxygen,mechanical ventilation and PEEP, may be theprimary factor influencing the magnitude oflung injury. However, another study showeda correlation between impaired post-ARDSpulmonary function and the maximal pulmonaryarterial pressure, lung compliance and themaximal PEEP required during the patient'sillness [41].

PATHOGENESIS OF ARDS

The co-existence of ARDS and sepsis is associatedwith a very poor prognosis. Consequently, thisSection will focus on the mechanisms of acute lunginjury following endotoxaemia, bacteraemia andsepsis.

Infusions of live Pseudomonas bacteria intosheep that had lung lymph fistulae caused amarked increase in lung vascular permeability asreflected by an increase in protein-rich lung lymphflow [15]. E. coli endotoxin was shown to producea similar pattern of lung endothelial injury insheep, with an increase in protein-rich lung lymphflow within 2-4 h after the administration [76].


ARDS 115

Other experiments have shown that both cellularand humoral factors are important in the patho-genesis of the early and late phases of endothelialinjury after i.v. administration of endotoxin [102].However, i.v. administration of endotoxin doesnot consistently cause pulmonary alveolaroedema, does not appear to cause alveolar epi-thelial injury [118] and does not fully replicate theadult respiratory distress syndrome. Nonetheless,endotoxin may play a role in ARDS, sincedetectable concentrations of endotoxin have beenmeasured in patients who have ARDS [86].Endotoxin studies in various animal models havebeen useful in examining the host response toinjury and in identifying those resident lung cellsand mediators which contribute to the acute lunginjury seen in clinical septicaemia.

NeutrophilsThere is abundant evidence to suggest that

neutrophils play a role in the initial lung damagein patients who develop ARDS. Large numbers ofneutrophils collect in the lung in the early phaseof lung injury. In eight of 10 patients whosubsequently developed ARDS there was per-ipheral leucopenia with a white blood cell countless than 4200 cells mm"3. Of 30 patients with asimilar risk of ARDS but who did not develop thesyndrome, only four had the same level ofleucopenia [106]. The implication was that per-ipheral leucopenia was associated with ARDSbecause neutrophils accumulated in the lung.Furthermore, some investigators have reportedthe development of ARDS in patients with severeneutropenia after chemotherapy [74, 93]. How-ever, another group of investigators evaluated 116patients with bacteraemia but did not find arelationship between leucopenia and the devel-opment of ARDS [35]. In the experimentalstudies of endotoxin-induced acute lung injury,peripheral neutropenia is a common finding, butneutropenia is not invariable or necessary for thedevelopment of ARDS after sepsis.

Some investigators have reported that, inpatients with ARDS, neutrophils are in a func-tionally and metabolically activated state.Zimmerman and associates [127] reported thatchemotactic responses of neutrophils in patientswith ARDS were increased more than two-foldcompared with neutrophils from control patients.Also, these investigators found an increase ingeneration of chemoluminescence by neutrophilsfrom ARDS patients, suggesting that these granu-

locytes were likely to generate increased quantitiesof active oxygen metabolites [127, 128]. However,another group of investigators has reported morerecently that neutrophils from the systemic andpulmonary arterial blood of patients with ARDSare not activated and did not respond morevigorously to chemotactic stimuli [91]. Therefore,the state of activation of the neutrophils in ARDSremains uncertain.

Neutrophil function can be divided into fourphases: adherence, chemotaxis, phagocytosis andtriggering of postphagocytic intracellular eventsdesigned to kill ingested micro-organisms. Whenneutrophils are incubated in plasma from septicshock patients, the neutrophils display increasedadherence, implicating a soluble factor in theplasma [109]. Neutrophils from patients withbacteraemia have depressed chemotaxis [50] andit is important to recognize that depressed neu-trophil chemotactic responses may be observedafter the neutrophils have secreted their intra-cellular contents. In general, most investigatorsconsider that these defects in phagocytosis occurbecause of the deficiencies of antibody, comp-lement or the decrease in the number of neutro-phils that occur in the patients that develop severesepticaemia [50].

One possible mechanism of neutrophil-de-pendent acute lung injury is that activatedneutrophils sequester in the pulmonary circu-lation and release toxic oxygen products, pro-teolytic enzymes and products of the arachidoniccascade to injure the lung. Hallgren and associates[44] have reported that activated neutrophils andeosinophils are present in patients with ARDS,demonstrating increased circulating concentrationsof lactoferrin and eosinophilic cationic protein,which are products of these activated cells.McGuire and colleagues [67] found increasedproteolytic activity attributable to neutrophilelastase in lavage fluid taken from the lungs ofpatients with ARDS—another product of acti-vated neutrophils. Another group of investigatorshas reported that the neutrophils in the air spacesof the lungs of ARDS patients have reducedoxidative metabolism compared with normalcontrols, suggesting that they may already havebeen activated [91].

In summary, there are probably both neutrophil-dependent and neutrophil-independent mechan-isms responsible for lung injury. The issue ofneutrophil-related lung injury will be exploredfurther in the sections considering the role of


116

oxidants and proteases in mediating tissue injuryin the lung.

Platelets and coagulation abnormalities

Platelet abnormalities have been identified inpatients with ARDS. In a study of septic patientsat risk for developing ARDS, a platelet count lessthan 100000 mm"' was associated with increasedrisk of ARDS. This study also demonstrated thatthere was considerable platelet sequestration inthe reticuloendothelial system in such patients[35].

Patients at high risk for the development ofARDS but who do not develop the syndrome mayalso have coagulation and platelet abnormalities.In patients at risk for developing ARDS, 51%had thrombocytopenia, but did not progress todevelop ARDS [106]. Another series [20] foundthat 50 % of the patients at risk for developingARDS had thrombocytopenia but did not developthe syndrome. Furthermore, several investigatorshave been unable to demonstrate platelet seques-tration or disseminated intravascular coagulationin patients who have developed ARDS [31, 100].It is clear that coagulation disorders, includingthrombocytopenia and microthrombosis, can beassociated with ARDS; however, these disordersare also found in patients with sepsis and majortrauma who do not develop ARDS. While plateletand coagulation abnormalities may be associatedwith the pathogenesis of acute lung injury, thesefactors are not reliable, specific predictors for thedevelopment of ARDS.

Although it has been difficult to implicate plate-lets and the coagulation system in the initial phaseof acute lung injury, recent investigations suggestan important role for local abnormalities in coa-gulation and fibrinolytic pathways that probablypredispose to deposition of fibrin in the air spacesof the lung. These studies may account for thefrequent finding of hyaline membranes and otherprecipitated proteins in the alveoli of patientswith ARDS (fig. 4). Idell and colleagues [51] haverecently reported that the bronchoalveolar lavagefluid from patients with ARDS contained in-hibitors of the extrinsic coagulation pathway.They also found depressed fibrinolysis that wasnot the result of a local insufficiency of plasmin-ogen, but rather of inhibition of both plasmin andplasminogen activator. These are important obser-vations, because precipitation of protein in the airspaces of the lung may be one of the reasons whyrecovery from acute lung injury may be pro-

BRITISH JOURNAL OF ANAESTHESIA

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FIG. 4. Ultrastructure of a lung specimen from a 17-yr-oldwoman, who died of complications that included the adultrespiratory distress syndrome 3 days after a traffic accident,showing an alveolar entrance ring (AER) covered by a hyalinemembrane (HM) composed of condensed plasma protein andfibrin strands (F). Qose contact of hyaline membrane to theepithelial basement membrane (BM) is restricted to an areaof destroyed epithelial lamina. (Reproduced, with permission,

from [5].)

tracted. We have shown that soluble protein canbe removed readily from the air space of the lungover a period of 6 days, as may occur underconditions of hydrostatic pulmonary oedema [9].However, in the case of acute lung injury, proteinprecipitates in the air spaces and makes it moredifficult for the cellular debris and protein to beremoved. Clearance pathways in acute lung injurymay depend on the phagocytosis of protein bymacrophages and the slow removal of proteinthrough lymphatics and capillaries.

Mononuclear cells

Considerable attention has recently been fo-cused on the possible contribution of monocytesto lung injury because of the discovery that they


ARDS 117

are an important source of cytokines that maycause secondary lung injury. For example, mono-cytes release tumour necrosis factor, which repro-duces much of the septic shock syndrome whengiven i.v. Monocytes also produce a variety ofinterleukins which may amplify the inflammatoryresponse. Furthermore, alveolar macrophages se-crete a variety of factors that recruit neutrophils tothe air spaces of the lung and could potentiallycontribute to lung injury. In the past 5 years, anentirely new lung cell has been discovered, theintravascular lung macrophage, which may beimportant in modulating lung injury [111]. Thereare important species differences in the wayintravascular macrophages respond to variousstimuli, including their response to live bacterialorganisms and endotoxin. A recent report indi-cates that intravascular macrophages do exist inthe human lung and are estimated to exceed thetotal number of alveolar macrophages [27]. Therelease of intracelluar products of intravascularmacrophages may contribute to the increase in thelung endothelial or epithelial permeability andcontribute to lung injury in ARDS. Furtherprogress must await success in isolating this cell inexperimental studies and evaluating its contribu-tion to lung injury under a variety of experimentalconditions.

Endothelial cells

In vitro studies have suggested that endotoxinapplied to endothelial cells directly affects endo-thelial monolayer permeability in the absenceof leucocytes or monocytes [14, 47]. Structuralstudies of these endothelial monolayers show thatthe cells undergo contraction, become pyknoticand finally die [77]. These endothelial cells releasesignificant amounts of prostacyclin [77]. Also, thepermeability of the endothelial layers increaseswith the application of endotoxin [47, 77]. Morein vivo studies are needed to test the mechanismsof injury suggested by these in vitro cell culturestudies of the pulmonary endothelium.

Epithelial cells

Pathological studies have demonstrated thatepithelial cell injury is prevalent in septic patientswho die in the first 24-48 h after developingARDS (fig. 2) The function of the alveolarepithelial barrier may be a very important in-dicator of the severity of acute lung injury inpatients with acute ARDS and may be a prog-nostic indicator [120].

For many years, investigators have consideredthe possibility that some of the abnormalities inARDS patients could be the result of decreasedproduction of surfactant, production of an ab-normal surface acting material, or inactivation ofthe surface acting material by the presence ofprotein-rich oedema in the air spaces of the lungduring ARDS [45, 54]. There is still no conclusiveevidence regarding the contribution of abnor-malities in surfactant secretion or function as acause of the physiological abnormalities. How-ever, some of the data from studies in neonatesusing exogenous surfactant as treatment suggest arole for surfactant [54]. Clinical trials in theU.S.A. are beginning to treat patients withaerosolized surfactant in the hope that it mayimprove lung compliance, improve oxygenationand result in a shorter duration of mechanicalventilation.

The alveolar epithelium is responsible for theactive removal of excess liquid from the air spacesof the lung by an active sodium transport system[69, 73]. In fact, both in vitro and in vivo studieshave demonstrated that, in some species, thesodium transport system can be accelerated bytreatment with beta-adrenergic agonists [10, 22].Although it is intriguing to speculate that theclearance of alveolar liquid might be acceleratedin patients with pulmonary oedema, more studiesare needed to determine the relative rates ofalveolar liquid clearance in man compared withother species and also to determine if epithelialcells in man are responsive to beta-adrenergicagonists.

Nevertheless, these data have provided im-portant new information regarding epithelial cellsand their critical role in both the recovery fromacute lung injury and the removal of oedema fluidfrom the air spaces of the lung. The role of thealveolar epithelium in protein removal from theair spaces is unknown. Recent in vivo studies fromour laboratory have demonstrated that the re-moval of soluble protein from the air spaces of thelung occurs relatively rapidly (1 % per hour) inunanaesthetized sheep; these studies may be moreapplicable to patients recovering from hydrostaticoedema than those recovering from ARDS,because much of the protein in the air spaces ofpatients with acute lung injury is insoluble. Moreinformation is needed to determine how insolubleprotein is removed from the air spaces, and howepithelial injury changes these removal patterns.

Finally, the mechanism for injury to the alveolar



epithelium must be identified. While endotoxinreadily injures the lung endothelium, experimentaldata from our laboratory indicate that even highdoses of endotoxin do not injure the epithelialbarrier [118]. In contrast, live organisms do injurethe alveolar epithelial barrier, causing an increasein permeability to protein [121]. The mechanismfor this injury must be established, to permita bener understanding of the factors causing acuteepithelial lung injury.

Complement systemActivation of the complement cascade has long

been thought to be an important mechanism inthe pathogenesis of acute lung injury. In par-ticular, C3a and C5a are potent chemotacticfactors for neutrophils, and both have been foundin the bronchoalveolar lavage fluid obtained frompatients with ARDS [94]. Several recent ex-perimental studies have implicated complementas potentially important in the pathogenesis oflung injury. Specifically, a study in baboonsdemonstrated that anti-C5a antibody could at-tenuate the lethal effects of live E. coli organismsif given prophylactically [103]. Clinical studiesmeasuring complement activation in plasma havefound that concentrations of C5a are indeedincreased in patients with sepsis, but do notpredict the development of lung injury. However,in one study, concentrations of C5a correlatedbetter with hypotension and metabolic acidosisthan with the eventual development of acute lunginjury [9]. Complement activation is clearly partof the pathophysiological process during sepsisleading to endothelial injury in both the systemicand pulmonary circulations, but complementactivation alone may not be sufficient for thedevelopment of lung injury.

Prostaglandins/leukotrienesThe metabolites of arachidonic acid metabolism

have been investigated extensively in a numberof experimental models for their potential role inmediating acute lung injury. In experimentalmodels where E. coli endotoxin is administered,cyclo-oxygenase products have been identified asmediating the initial pulmonary hypertension aswell as the airway constriction that occurs afterthe infusion of endotoxin in sheep [102]. Con-versely, treatment with indomethacin inhibitsthe pulmonary hypertension. The late phaseresponse, when lung vascular permeabilityincreases, is temporally associated with the elabor-

ation of a variety of lipoxygenase mediators, notcyclo-oxygenase products. However, specificblock of the lipoxygenase receptors does notclearly prevent the increase in permeability.Studies measuring mediators in bronchoalveolarlavage fluid and in pulmonary oedema fluid fromARDS patients have reported the presence ofsubstantial quantities of leukotriene D4 [72]. Thismediator has been shown to cause bronchocon-striction and vasoconstriction. The prostaglandinsand leukotrienes are, therefore, undoubtedly in-volved in mediating some of the hypoxaemiaassociated with acute lung injury, but have notbeen clearly identified as major factors in thedevelopment of increased vascular permeability.Clinical studies in progress are evaluating thepotential role of ibuprofen, a compound thatinhibits prostaglandin metabolism and also has astabilizing effect on neutrophils. The preliminaryresults of those studies indicate a mild improve-ment in oxygenation in some patients with ARDS[68].

Oxygen radicalsOxidant-induced lung injury has emerged as a

new focus for clinical and basic science investiga-tions of acute lung injury. Consequently, manyinvestigators have studied anti-oxidant andoxygen radical scavengers in an effort to attenuateacute lung injury [49]. Toxic oxygen productsmay be produced by a variety of mechanisms,including the activation of phagocytes and pla-telets. High inspired fractions of oxygen inpatients in whom the trachea is intubated may bean additional source of toxic oxygen radicals.Finally, reperfusion of hypoxic tissue may wellresult in an additional oxidant burden.

The lung contains specific mechanisms forinactivation of oxygen radicals that are found bothintracellularly and extracellularly (fig. 5). With-in mitochondria, cytochrome oxidase reducesoxygen to water and acts as a sink for free radicals.Superoxide dismutase, catalase and glutathioneperoxidase act together to minimize the con-centrations of toxic oxygen products. Antioxidantactivity is also found in vitamins A, E and C.

Specific treatments have been studied inattempts to attenuate oxidant lung injury inmodels of acute lung injury. It is well known thatactivation of neutrophils results in the generationof toxic oxygen products. It has also been shownthat neutrophils are attracted to the lung inlarge numbers in many types of lung injury.


ARDS 119

Using air emboli as a model of ARDS, Flick andcolleagues [37] found that pretreatment of sheepwith catalase attenuated transvascular liquid andprotein flux, as measured by lung lymph flow, byapproximately 50%. The same group has re-ported that administration of superoxide dis-mutase also decreased the effects of air embolismon lung injury [38]. Furthermore, Bernard andcolleagues [8] reported that N-acetylcysteineattenuated the severity of acute lung injury inunanaesthetized sheep given E. coli endotoxin. N-acetylcysteine is an oxygen radical scavenger andalso may have a direct effect on neutrophils.

An important consideration in any anti-oxidantenzyme therapy is the fact that these largemolecules do not cross cellular membranes to asignificant extent. Therefore, their effect might belimited in terms of modifying the intracellularenvironment. However, in the case of cellularinjury with increased cellular membrane per-meability, exogenous administration of theseagents could be beneficial. Finally, one mustconsider the teleological basis of oxygen radicalgeneration. A respiratory burst of neutrophils isan integral aspect of host defence against inspiredmicro-organisms. Since sepsis is the leading causeof death in ARDS, caution must be exercised inlimiting those host defences.

Proteases

Proteolytic enzymes are important products ofmononuclear cells and granulocytes that have thecapacity to cause tissue injury. The tissue damageobserved in the acute phase of ARDS with thesubsequent fibrosis that occurs in the subacuteand chronic phases highlights a possible role for

proteases in the pathophysiology of acute lunginjury. Enzymes such as elastase, plasminogenactivator, plasmin and hyaluronidase can degradethe extracellular matrix, leading to increasedvascular permeability through interruption ofstructural integrity. More importantly, degra-dation of the cell surface and basement membraneglycoproteins such as proteoheparin sulphatehave been shown to disrupt the surface anioniccharge and have been associated with increasedmicrovascular permeability [104]. Trypsin, col-lagenase and elastase are all active in the chronicphase of ARDS when extensive fibrosis occurs.However, recent clinical studies have indicatedthat there is an excess of antiproteases present inthe air spaces of patients with ARDS, suggestingthat protease-related injury may not be a sufficientexplanation for much of the lung injury [75].

Interestingly, on the basis of recent experi-mental and clinical work, there is a growinginterest in a possible interaction between elastasesand toxic oxygen radicals. In a recent review,Weiss [114] described an innovative mechanismwhereby neutrophils could co-operatively usechlorinated oxygen to penetrate multiple anti-proteinase barriers, thereby allowing elastase toattack susceptible tissues within the inflammatoryfocus (fig. 6). This hypothesis could be useful inexplaining a synergistic interaction of both oxygenradicals and elastases in mediating acute lunginjury. It has been shown in recent in vitro studiesthat neutrophils can generate and use bothhypochlorous acid (HOC1) and N-chloramines tooxidize the surrounding alpha-1 proteinase in-hibitor at a rate that permitted the elastasedischarged from neutrophils to solubilize the

ROH

Other sourcesof oxidants

FIG. 5. A hypothetical antioxidant role for platelets and erythrocytes in the protection of endothelial cellsfrom oxidant-induced injury. (Reproduced, with permission, from [49].)


1:20 BRITISH JOURNAL OF ANAESTHESIA

E Elastase \_E Complex

L J o1-PI0x

Complex

FIG. 6. The left half of the figure shows neutrophil oxidants creating a zone of oxidized al-proteinaseinhibitor (a l -PI) that allows released elastase (E) to attack and degrade tissues. Because oxidized a l -proteinase inhibitor (al-PIo,) can inhibit elastase only inefficiently, the enzyme may also be detected.The right half of the figure shows an alternative setting: only a small portion of the surrounding a l -proteinase inhibitor is oxidized, thus ensuring the efficient regulation of the released elastase. In eithersetting, proteolysis can occur to a limited degree subjacent to the neutrophil. (Reproduced, with

permission, from [114].)

extracellular matrix [115]. Although neutrophilsrapidly inactivate alpha-1 proteinase inhibitor invitro, it should be recalled that elastase in vivomust still contend with both alpha-2 macro-globulin and secretory leucoproteinase inhibitor.Recent interesting studies indicate that bothalpha-2 macroglobulin and secretory leuco-proteinase inhibitor can be oxidatively inactivatedby activated neutrophils. Thus all three com-ponents of the anti-elastase shield are potentiallysensitive to oxidative attack. Only if neutrophilsare prevented from generating H0C1 can theantiproteinases remain active, in which case theyare able to prevent tissue damage almost com-pletely. Further in vitro and in vivo work will beneeded to explore this hypothesis, but it mayprovide an important new advance in our under-standing of the interaction of neutrophils, toxicoxygen radicals and proteases in mediating lunginjury in patients with sepsis, gastric aspiration,or both.

Tumour necrosis factor and other cytokines

Tumour necrosis factor (TNF) is a peptideelaborated by mononuclear cells in response toendotoxin, interleukin-2 and several other mito-gens. Tracy and colleagues [108] found thatinfusion of recombinant TNF into dogs repro-

duced the physiological changes normally seenwith endotoxin, including hypotension, metabolicacidosis and death. TNF has been reported to beincreased in some patients with sepsis [26]. Also,increased concentrations of TNF were found inchildren with meningococcaemia and severe in-fectious purpura [43]. Furthermore, Tracy andcolleagues [107] attempted to attenuate septicshock by developing monoclonal antibodies toTNF which were used to immunize passivelybaboons which were then subsequently chal-lenged with lethal doses of i.v. live E. coliorganisms. This treatment was effective when theantibody was administered 2 h before the injectionof live organisms, with complete protection fromshock and organ failure, but the treatment was noteffective if the antibody was given at the time theorganisms were administered. TNF is clearly apotent, important mediator of septic shock, but itsspecific role in acute lung injury requires furtherevaluation.

Summary of pathogenesis

Much has been learned about the complexinteraction of circulating and resident lung cellsand how they may cause acute lung injury in man.The list of possible mediators released, bothlocally in the lung and systemically, has grown


ARDS 121

TABLE VI. Mechanisms for injury and repair in ARDS, 1990

Circulating cells:

Resident lung cells:

Possible mediators:

PlateletsNeutrophilsMonocytes? LymphocytesIntravascular macrophagcsAlveolar macrophagcsEpithelial cells—Type IIFibroblastsComplement systemProstaglandinsOxygen radicalsProteasesTumor necrosis factorOther cytokines

in the past decade. Further basic and clinicalresearch will help to clarify how these factorsinteract as mechanisms for lung injury and repairin patients with ARDS (table VI).

CURRENT AND FUTURE MANAGEMENT STRATEGIES

Current and future therapy for ARDS may beseparated into five separate categories.

Control of infection and its complications

The first and foremost issue to consider in themanagement of ARDS patients is the earlydiagnosis, treatment and prevention of infection.We have already reviewed the importance ofsepsis as a cause of ARDS, in addition to itsrole in determining ultimate outcome after theacute phase of ARDS has subsided. It is impor-tant to reduce nosocomial infection by goodhandwashing, by wearing gloves, by removalof unnecessary intravascular or urinary cathetersand prevention of skin ulcers, and to search forsurgically treatable infections. If there is a positiveblood culture and an unknown source for thebacteraemia, then surgical exploration of theabdomen is frequently helpful [7]. More recentsuggestions for the prevention of nosocomialinfections in critically ill patients include selec-tive decontamination which involves the ad-ministration of non-absorbable antibiotics orallyand topically to the oropharynx, in addition to theadministration of i.v. antibiotics. Although mor-tality was not significantly affected, the incidenceof late nosocomial pulmonary infections was de-creased in the patients who received selectivedecontamination [63]. These patients did not haveARDS, so the applicability of this study to ARDS

patients is unclear. However, a study of theadministration of non-absorbable and i.v. anti-biotics to baboons that had acute lung injury didresult in a decrease in the number of organismsfound in pulmonary specimens obtained at post-mortem [56]. Three regimens were found to beeffective: topical polymixin and i.v. penicillin orgentamicin; topical gentamicin and i.v. penicillinor gentamicin; topical and i.v. gentamicin andpenicillin. When antibiotics were not ad-ministered, polymicrobial pneumonia occurred inall animals [55]. The role of prophylactic anti-biotics and decontamination regimens in patientswho have ARDS is currently being investigated.

Immunotherapy is, perhaps, the most promisingnew therapeutic option for preventing and treat-ing infection in patients with ARDS. Severalstudies have demonstrated that active and passiveimmunization using a rough mutant of thechemotype of Salmonella minnesota and theRC chemotype, J5 mutant, of E. coli, protectednormal and granulocytopenic animals againstchallenges using heterologous Gram-negativebacteria or lipopolysaccharide (LPS) (endotoxin)[24, 66, 125]. In the clinical trials by Zeigler andBaumgartner, administration of antisera to E. coliJ5 as treatment or prophylaxis to patients withGram-negative bacteraemia resulted in a sub-stantial decrease in mortality [6, 126].

However, more recent investigations usingmonoclonal IgG antibodies have produced in-consistent clinical benefit [123, 125]. McCabe andcolleagues [65] attempted to explain these differ-ences by comparing the protective activity ofIgM and IgG immunoglobulin classes in post-immunization sera from rabbits and humans.They found that IgM induced protection similarto that observed for whole post-immunizationsera, whereas post-immunization IgG aloneafforded no greater protection than saline. Theseresults were confirmed in a study by Calandra andcolleagues [17] in which human IgG antibody toE. coli J5 was compared with a standard IgGpreparation in the treatment of 71 patients withGram-negative shock. The mortality was 50 % inboth groups.

Another study by McCabe further exploredthese issues by investigating the effects of avaccine prepared from boiled, acetone-precipitated Salmonella minnesota R595, an Rechemotype mutant [28]. The vaccine was ad-ministered to 122 healthy volunteers and titres of



antibody to the Re LPS, the basal core structureof endotoxin, increased in a dose-responsivefashion. Sera were harvested from theseimmunized volunteers and mice were passivelyimmunized. Although passive immunization pro-vided protection against gram-negative bacteriaand endotoxin, there was no correlation betweenthe degree of protection and the antibody titres toRe LPS, suggesting another immunodeterminantmay be involved. Therefore, more research isneeded to determine the protective factor in thesera raised against these non-virulent bacteria.The clinical role of immunotherapy will dependon isolating the key protective factors in serumand then administering them as early as possibleto patients at high risk of Gram-negative infectionor in the very early phase of Gram-negative sepsis.

Methods for improving gas exchange

There has been a continuing interest in newmethods of mechanical ventilation for patientswith severe respiratory failure from ARDS.However, such interest may be somewhat mis-guided, since many studies have shown thatmortality in most ARDS patients can beattributed to uncontrolled infection and multi-organ failure, not primarily to respiratory failure[79].

In the extracorporeal membrane oxygenation(ECMO) study published in the early 1970s, acontrol group was treated with conventionalmechanical ventilation while ECMO-treatedpatients received lower tidal volumes and hadlower mean airway pressures [124]; the incidenceof barotrauma and mortality was the same in thetwo groups. Subsequently, some investigatorsadvocated PEEP, up to 40-50 cm H2O, with theobjective of reducing the intrapulmonary shuntfraction [59]. Although there was some initialenthusiasm that the increased PEEP improvedsurvival in ARDS, the studies were uncontrolled.In fact, Nelson and colleagues [82] reportedresults of a randomized study of increased vsmoderate PEEP and found no significant dif-ference between the groups in terms of durationof mechanical ventilation or overall mortality.Finally, a prospective trial of the prophylactic useof 8 cm H2O of PEEP in patients at high risk fordeveloping ARDS showed no benefit in pre-venting acute lung injury [87]. There is noevidence that PEEP hastens the recovery fromlung injury, prevents the development of lunginjury or reduces extravascular lung water. Alv-

eolar oedema is primarily absorbed by an activesodium transport pump which does not dependon the mode of ventilation or the airway pressure[53].

In the early 1980s, there was considerableinterest in high frequency ventilation, partlybecause patients' lungs could be ventilated atlower peak airway pressures, which some in-vestigators thought might cause less barotraumaand less ventilation-induced lung injury. How-ever, subsequent work demonstrated that oxy-genation with high frequency ventilation isstrongly influenced by the mean airway pressure,especially in patients with ARDS [95]. Significantimprovement in oxygenation could be achievedwith high frequency jet ventilation (HFJV), butonly if this was associated with an increase inmean airway pressure, which in turn often had adetrimental effect on venous return and cardiacoutput. Furthermore, a well designed pros-pective, randomized study of 309 patientsshowed that there was no significant difference inthe total duration of intensive care or survival inpatients managed with HFJV compared withconventional ventilation [19].

There has also been interest in other forms ofventilatory support, most notably the use ofpressure-controlled, inverse-ratio ventilation.One retrospective study reported 31 patients withsevere ARDS in whom conventional volume-controlled ventilation was ineffective [105]. Theauthors reported that use of pressure-controlledinverse-ratio ventilation was associated with asignificant reduction of minute ventilation, peakairway pressure and PEEP, and a slight im-provement in oxygenation. However, there was asignificant increase in mean airway pressure, andpneumothoraces developed in six of the 31patients treated with pressure-controlled, inverse-ratio ventilation. Overall mortality for the 31patients with ARDS in this study was 77%. Thestudy demonstrated the feasibility of this alterna-tive method, but certainly did not indicate animproved outcome. In fact, until a prospectivecontrol trial is completed, clinicians should notuse experimental modes of ventilation in patientswith ARDS because they may in fact worsenoutcome, particularly if mean airway pressure ismarkedly increased.

Some 15 years ago, a prospective studyevaluated the possible value of ECMO as a meansof resting the lungs and providing oxygenationand elimination of carbon dioxide for patients


ARDS 123

with severe ARDS [124]. That study showed nosurvival benefit using this technique. More re-cently, an uncontrolled Italian study reportedfavourable results with veno-veno extracorporealmembrane carbon dioxide removal in 47 patientswith ARDS [40]. Although those results wereencouraging, ECMO-treated patients cannot becompared with historical controls. Therefore, theNational Institute of Health in the United Stateshas sponsored a prospective study centred in theUniversity of Utah in Salt Lake City to evaluateveno-veno ECMO as a treatment for ARDS. Theresults of that study are not yet complete, but todate the data show no difference between thecontrol and ECMO-treated groups. Any newventilation techniques must be subjected to thesame prospective evaluation that would be re-quired for a new drug [70].

Our current recommendation is that patientswith acute respiratory failure in ARDS beventilated with either assist-control ventilation orintermittent mandatory ventilation with judiciousvalues of PEEP, usually between 5 and 18 cmHjO. It seems reasonable to decrease the frac-tional inspired oxygen to less than 1.0 and ifpossible to 0.5. This is not always possible if thepatient's respiratory function is very poor. Thereare very few experimental or clinical data toprovide guidelines as to which patients will sufferfrom oxygen toxicity. Since most patients do notdie from overwhelming respiratory failure, itseems reasonable to ventilate their lungs with anaccepted conventional mode of ventilation withmoderate PEEP.

Most studies show that surfactant replacementcan improve lung compliance, although usuallythere is no definite effect in reducing the degree ofinflammation or the degree of lung oedema[33, 48, 54]. Conceivably, surfactant replacementcould improve lung compliance and allowpatients' lungs to be ventilated at a smallerinspired oxygen concentration, with weaningfrom mechanical ventilation earlier than is cur-rently possible. Surfactant has been shown to beinactivated by the presence of protein. This couldbe a problem with its administration during theactive phase of ARDS [54]. Prospectiverandomized trials will be needed to demonstratethat surfactant replacement therapy really isuseful in decreasing the duration of mechanicalventilation or decreasing mortality.

Limiting or decreasing pulmonary oedema

An important objective in treating patients withARDS is to attempt to minimize the degree ofpulmonary oedema. The primary mechanism forpulmonary oedema in patients with ARDS can beattributed to the increase in lung vascular andepithelial permeability. Nevertheless, modest in-creases in pulmonary vascular pressures, par-ticularly left atrial pressure, will worsen the degreeof pulmonary oedema [92]. One study did findthat increasing amounts of lung oedema wereassociated with a higher mortality [32]. However,as another clinical study suggested, this resultmay reflect the fact that the more ill septic patientsrequire administration of a greater volume of i.v.fluids to maintain their arterial pressure [101].Thus increased extravascular lung water andincreased body weight may simply reflect theincreased vascular leak and extravascular accumu-lation of fluid in these patients. Standard clinicalpractice is to limit the increase in left atrialpressure as much as possible by judicious ad-ministration of fluids, to use diuretics if thepatient is haemodynamically stable, and to avoidthe infusion of large volumes of colloid that wouldincrease left atrial pressure.

Improving systemic oxygen delivery

In many patients with ARDS, hypotensioncomplicates the early phase of acute respiratoryfailure. In some patients, the hypotension may beattributed to hypovolaemia because of the com-bination of a systemic and pulmonary capillaryleak syndrome as well as a PEEP-induced re-duction of venous return. Therefore, modestvolume expansion is the first treatment in thesepatients. Pre-existing heart disease is commonand may require treatment with vasopressors andeven afterload reduction with vasodilators [78,129]. Co-existing sepsis may also affect cardiacfunction and overall circulatory responses[18, 25, 57, 85]. Dopamine can be used to supportthe arterial pressure and increase cardiac output.Even if invasive haemodynamic monitoring withpulmonary arterial catheterization is used, it isimportant for the clinician to rely on evidence ofend-organ perfusion to evaluate the effects oftherapy in terms of urine flow, arterial pH andmental status.

There has been considerable interest in thepossibility that increasing oxygen delivery mayhelp improve the survival rate among patients



with ARDS, particularly those with sepsis. Thereis evidence that many patients with ARDS orsepsis also have occult tissue hypoxaemia asmanifested by an increased oxygen consumptionwhen oxygen delivery is increased [11]. Improvedoxygen delivery in these patients may also im-

-prove organ perfusion and thereby reduce theincidence of multi-organ failure. However, noclinical studies have confirmed this hypothesis. Inone study, cardiac output and oxygen consumptionin patients with sepsis were improved by vaso-pressor therapy, but mortality was no better thanin patients treated with i.v. fluids alone [42].Further studies are required to evaluate thebenefit of therapy directed at improving oxygendelivery in patients with ARDS.

Attenuation of pulmonary or systemic injury

The mainstay of current therapy is to reducepulmonary injury by decreasing the inspiredoxygen concentration to approximately 50% assoon as possible, with the judicious use of PEEPand optimal tidal volume. One study was able toshow in an experimental model of lung injury that50% oxygen did not produce additive toxicity[21]. In general, the clinician must balance thepotentially toxic effects of increased concentrationsof oxygen against increased PEEP which maycause barotrauma or decreased venous return. Itseems reasonable to make every effort to wean thepatient from 100% oxygen as soon as possible,partly because absorption atelectasis can beavoided if there is some nitrogen in the inspiredgas mixture. Experimentally, most studies report-ing severe oxygen toxicity have used 100%

oxygen. We recommend that patients' Fi0 bereduced to 0.9 as soon as possible. Furtherreductions in the concentration of oxygen shouldbe a major goal, providing that PEEP greater than15-18 cm HjO is not required. In addition, theacceptable Pa^ depends somewhat on the patient'sunderlying medical problems. If the patient hascoronary artery disease, a Pa^ between 10 and12 kPa is reasonable, whereas if the patient has noevidence of heart disease then PaOj between 8 and9 kPa should be adequate, as oxygen saturationwill be greater than 90 % in this range.

A number of drugs have been evaluated in thehope that one or more would be useful astreatment for reducing the severity of lung injury.Corticosteroids, oxygen radical scavengers, prosta-glandin inhibitors, anti-TNF antibodies and otheranti-inflammatory agents have been shown toreduce the severity of early lung injury. How-ever, in a number of these studies, the drug wasadministered as prevention and not as a treatment.Even in patients to whom treatment was ad-ministered after the onset of lung injury, the timeinterval between the administration of treatmentand the onset of lung injury was relatively brief.

Although corticosteroids have been shown toreduce lung injury experimentally, a number ofclinical studies have now shown that there is nobenefit to most patients with ARDS [64]. How-ever, Webster and colleagues found a benefit intheir U.K. series [112]. Corticosteroids have notbeen shown to be beneficial in terms of morbidityor mortality in patients with sepsis [13]. Inaddition, there have been some recent studiesusing pentoxifylline, an anti-inflammatory agent,

TABLE VII. Summary of current and future treatment of ARDS

1.

2.

3.

4.

5.

Current

Infection: prevention, earlydiagnosis and treatment

Improve gas exchange, reducebarotrauma: PEEP

Limit or decrease pulmonaryoedema: diuretics, lowest leftatrial pressure

Improve tissue oxygen delivery:volume, vasopressorsAttenuate pulmonary or systemicinjury: decrease fraction ofinspired oxygen

Future

ImmunotherapySelective decontamination

Improved ventilatory modesSurfactant therapy

Beta-adrenergic agonists

Vasodilators

ECMO (venous bypass)Oxygen radical scavengersAnti-TNF antibodiesPentoxifylline


ARDS 125

to attenuate endothelial leak in acute lung injury[46j 116]. However, pentoxifylline is a vasodilatorand some of its effect on endothelial leak maydepend on this property. Conceivably, pentoxy-fylline, prostaglandin inhibitors or anti-oxidanttherapy may be useful in limiting the degree ofendothelial permeability in acute lung injury. Also,there has been some enthusiasm for the treatmentof patients with antibodies specific to circulatingmediators of sepsis and lung injury. As men-tioned, one experimental study showed that anti-TNF antibodies could prevent the occurrence ofshock and death in baboons given live E. coliorganisms [107]. However, for this treatment tobe effective, it was necessary to administer theantibody 2 h before the administration of live E.coli organisms! There has been some interest alsoin monoclonal antibodies to the adherence-pro-moting leucocyte glycoprotein, CD 18, as amethod for reducing systemic organ injury. Lunginjury was not attenuated, but functions of otherorgans were improved [29]. Treatment with thistype of therapy might also make the host signifi-cantly more susceptible to infection. Many moreexperimental and clinical studies will be neededif the safety and efficacy of these new therapeuticapproaches are to be confirmed.

Finally, recent work has suggested the in-volvement of a variety of polypeptide growthfactors in the fibrosing alveolitis of ARDS [58].Conceivably, specific therapy to inhibit unre-strained fibroblast proliferation after the onset ofacute lung injury could attenuate the severity ofthe subacute to chronic phases of ARDS. How-ever, development of this type of therapy and itsapplication to a clinical setting will require muchmore basic research and then careful testing inclinical studies.

A summary of currently accepted modes oftherapy for ARDS is provided in table VII.Possible future approaches are also listed. Arealistic evaluation of any new treatment regimenwill depend on a careful assessment of the extentof lung injury (table I), the associated clinicaldisorders and the extent of non-pulmonary organfailure (table V). As mortality is greatest inpatients with sepsis-induced ARDS, this is thegroup of patients that could benefit most from newtreatment regimens—particularly advances in im-munotherapy which might improve host defencesand attenuate systemic and pulmonary injury.

ACKNOWLEDGEMENTS

We appreciate the help of Sanja Djulac in the preparation ofthis manuscript.

The work was supported in part by a grant from theNational Institute of Health Pulmonary Vascular SCORHL19155.

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