Clinical Acute Lung Injury and Acute Respiratory Distress ... · Clinical Acute Lung Injury and Acute Respiratory Distress Syndrome Matthay et al. 141 causes included major surgery

Clinical Acute Lung Injury and Acute Respiratory Distress SyndromeMichael A. Matthay, MDTokujiro Uchida, MDXiaohui Fang, MD

AddressCritical Care Medicine, University of California, San Francisco, 505 Parnassus Avenue, Campus Box 0624, San Francisco, CA 94143-0624, USA.E-mail: [email protected] Treatment Options in Cardiovascular Medicine 2002, 4:139–149Current Science Inc. ISSN 1092-8464Copyright © 2002 by Current Science Inc.

IntroductionClinical acute lung injury is the most important cause ofnoncardiogenic pulmonary edema. In contrast tocardiogenic or high-pressure pulmonary edema, theprimary cause can be explained by an increase in lungvascular permeability leading to the accumulation ofprotein-rich edema in the interstitial and air spaces ofthe lung. In contrast to cardiogenic pulmonary edema,the mechanism cannot be explained by elevated pulmo-nary venous pressure from left ventricular dysfunction,valvular disease, or intravascular volume overload.Currently, the accepted terminology is to refer to this

type of pulmonary edema as clinical acute lung injuryand acute respiratory distress syndrome (ALI/ARDS) [1•].Although several clinical disorders are associated withthe development of ALI/ARDS [1•,2–4], sepsis is themost common and the most lethal cause, probablybecause the lung injury is more severe [1•,3,5•] and theextent of nonpulmonary organ dysfunction is greater[1•,6]. This article considers recent advances in estab-lishing more uniform definitions, clinical features,pathogenesis and resolution, and important newadvances in the treatment of ALI/ARDS.

Opinion statementThis article provides a description of the clinical disorders associated with the develop-ment of acute noncardiogenic pulmonary edema, better known as clinical acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS). Much has been learned about the mechanisms by which the lung is injured in patients with sepsis, pneumonia, aspiration of gastric contents, and following major trauma. In the last 5 years, major progress has been made in the treatment of patients with ALI/ARDS. A lung protective ventilatory strategy with a low tidal volume (6 mL/kg/predicted body weight) in conjunction with a plateau pressure limit of 30 cm H20 attenuated the severity of clinical lung injury and reduced mortality by 22%. Ironically, after years of searching for anti-inflammatory treatments for ALI/ARDS, it turns out that a lung protective ventilatory strategy has proven to be the most efficacious anti-inflammatory treatment ever discovered for ALI/ARDS. However, it is still possible that pharmacologic treatments also may enhance survival. For example, a recent report that activated protein C reduces mortality in patients with sepsis raises hope that the incidence and severity of sepsis-induced ALI/ARDS may be reduced by treatment with this agent that has both anti-inflammatory and anticoagulant properties. Also, therapy directed at hastening the resolution of lung injury by increasing the functional recovery of the alveolar epithelium may be of value, both in diminishing the fibroproliferative phase of ALI/ARDS as well as accelerating the resolution of alveolar edema.

140 Cardiopulmonary Disease

DEFINITIONSAn international conference was convened in 1994 todevelop uniform definitions that would facilitateclinical care, clinical research, and testing of potential ther-apeutic strategies for the prevention and treatment of ALI/ARDS. The conference included clinicians and academi-cians from North America and Europe [7]. This grouprecognized that the adult respiratory distress syndromedevelops in children and accordingly the term for theclinical syndrome was modified to the acute respiratorydistress syndrome. The consensus conference also made adistinction between ALI and ARDS. ALI is characterized byan acute onset; a ratio of partial pressure of oxygen in theblood to fraction of inspired oxygen (PaO2/FiO2) lessthan 300 mm Hg, regardless of the presence or absence ofpositive end expiratory pressure (PEEP); bilateral infil-trates on chest radiograph; and a pulmonary artery occlu-sion pressure less than 18 mm Hg, when measured, or noclinical evidence of left atrial hypertension. ARDS isdefined using all of these criteria, except that the PaO2/FiO2 was less than 200 mm Hg, regardless of the presenceor absence of PEEP. Although there are some limitations tothese definitions [1•], they have worked remarkably wellin facilitating clinical research and clinical trials in the last7 years. Interestingly, the initial severity of oxygenation isnot a major independent predictor of outcome. Patientswho develop ALI with a PaO2/FiO2 ratio between 200 mmHg and 300 mm Hg have a similar mortality to patientswho present with a PaO2/FiO2 ratio less than 200 mm Hg[2,3] with the possible exception of patients with lunginjury from trauma [8].

CLINICAL PRESENTATIONThe initial clinical presentation of ARDS initially wasdescribed by Petty et al. [9]. The patient usually has

tachypnea with a respiratory rate greater than 20breaths per minute with an increase in the work ofbreathing, and some patients are cyanotic, particularlyif they are not receiving supplemental oxygen. The chestradiograph shows patchy opacities that may not besymmetrical (Fig. 1). The measurement of arterial bloodgases, in particular the PaO2/FiO2 ratio, is required toestablish the diagnosis of ALI or ARDS. Other pulmo-nary abnormalities in patients with ALI/ARDS includean increased shunt fraction and increased dead-spaceventilation. Recent preliminary work from our institu-tion indicates that the dead-space fraction is elevated toalmost 60% on the first day of diagnosis, and a mark-edly elevated dead space fraction may identify patientswho are less likely to survive [10]. As lung injury andedema progress, pulmonary compliance decreases.Measurement of the pulmonary arterial wedge pressuremay be needed in some patients to differentiatebetween ALI/ARDS and cardiogenic pulmonary edema.A pulmonary arterial wedge pressure more than 18 mmHg suggests that the respiratory failure and pulmonaryedema may be from cardiac insufficiency or intravascu-lar volume overload, although it is possible that mildelevations of the pulmonary arterial wedge pressuremay occur in some patients with lung injury, either as aresult of overzealous fluid administration or justintrinsic cardiac dysfunction [11].

PREDISPOSING FACTORS OF ACUTE RESPIRATORY DISTRESS SYNDROMENumerous predisposing factors have been associatedwith ALI/ARDS [12,13]. Depending on the nature of thereporting hospital, the most common causes of ALI/ARDS are pneumonia, sepsis, aspiration of gastriccontents, and major trauma [5•]. Other less common

Figure 1. Chest radiograph from a patient with acute respiratory distress syndrome secondary to sepsis syndrome. Note the bilateral diffuse infiltrates. The heart size is normal, suggesting noncardiogenic pulmonary edema.

Table 1. Clinical disorders associated with ALI and ARDS

Pulmonary disordersPneumonia

BacterialFungalViral

Aspiration of gastric contentsMajor trauma, contusionNear-drowning

Extrapulmonary disordersSepsisTrauma with multiple transfusionsCardiopulmonary bypassDrug overdoseAcute pancreatitisBlood product transfusions

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

Clinical Acute Lung Injury and Acute Respiratory Distress Syndrome Matthay et al. 141

causes included major surgery with multiple bloodproduct transfusions, fat emboli, acute pancreatitis,drug overdoses, smoke inhalation, and major burns(Table 1). When a patient has more than one risk factorfor developing ALI/ARDS, the incidence increasessignificantly [13]. Sepsis is associated closely with thedevelopment of ARDS. Approximately 20% to 40% ofpatients with sepsis syndrome develop ARDS. Theinciting factor leading to clinical lung injury in sepsissyndrome is probably endothelial injury [14].

PATHOLOGY AND PATHOGENESISPathologically, ALI/ARDS is characterized by a protein-rich edema fluid that is usually associated with a largeinflux of neutrophils into the interstitium and distalairspaces of the lung [15]. There is injury to the lungendothelium and in many patients there is evidence ofalveolar epithelial injury as well. The pathology isdescribed as diffuse alveolar damage that includesalveolar epithelial cell injury, acute inflammatory cellinfiltration, proteinaceous alveolar and interstitialedema fluid, alveolar hyaline membranes, type IIpneumocyte proliferation, and varying degrees of intra-alveolar and interstitial fibrosis (in the later stages of thesyndrome) [16,17]. Cellular damage occurs in ALI/ARDS with the influx of inflammatory cells and damageto the endothelium and epithelium.

The importance of endothelial injury and perme-ability to the formation of pulmonary edema in ALI/ARDS has been well established for many years. Morerecently, the critical importance of epithelial injury toboth the development of and recovery from ALI/ARDShas been better appreciated [1•,18,19•]. The degree ofalveolar epithelial injury is an important predictor ofoutcome in ALI/ARDS [19•,20].

The loss of epithelial integrity in ALI/ARDS hasseveral major consequences. First, under normalconditions the epithelial barrier is much less permeablethan the endothelial barrier [18]. Thus, epithelial injurycontributes to alveolar flooding. Second, loss of epithe-lial barrier integrity and injury to type II cells disruptsthe normal function of epithelial ion and fluid trans-port, impairing the removal of edema fluid from thealveolar space [19•,20]. Third, injury to type II cellsreduces surfactant production and turnover, contribut-ing to the surfactant abnormalities characteristic of ALI/ARDS [21]. Fourth, loss of epithelial barrier propertiesin pneumonia can lead to septic shock [22]. Finally, ifinjury to the alveolar epithelium is severe, disorganizedor insufficient epithelial repair may lead to a fibrosingalveolitis [23].

Neutrophil-dependent lung injury Many clinical andexperimental studies have provided circumstantial anddirect evidence for neutrophil-mediated injury in ALI/ARDS. Histologic studies of early ALI/ARDS show a

marked accumulation of neutrophils in the lung [15–17]. Neutrophils predominate in the pulmonary edemafluid and bronchoalveolar lavage fluid from patients[24], and many animal models of ALI are neutrophildependent. The mechanisms of neutrophil sequestra-tion and activation and neutrophil-mediated lunginjury have been reviewed [25].

New evidence raises the question of whether neutro-philic inflammation in ALI/ARDS is the cause or theresult of lung injury. ALI/ARDS may develop in patientswith profound neutropenia [26], and some animalmodels of acute lung injury are neutrophil indepen-dent. Clinical trials using granulocyte colony-stimulat-ing factor to increase the numbers and activation stateof circulating neutrophils in severe pneumonia did notincrease lung injury [27]. Also, the neutrophil plays acritical role in host defense in ALI/ARDS, especially inpneumonia and sepsis. This may explain in part whytreatments that use anti-inflammatory strategies largelyhave been unsuccessful. In some causes of ALI, such asaspiration of gastric contents, experimental studiesstrongly support a major role for the neutrophil in theinitial phase of lung injury [28].

Other proinflammatory mechanisms A complex networkof cytokines and other proinflammatory compounds ini-tiate and amplify the inflammatory response in ALI/ARDS. Proinflammatory cytokines may be producedlocally in the lung by inflammatory cells, lung epithelialcells, and fibroblasts [24]. There is evidence that indicatesthat it is not simply the production of proinflammatorycytokines that is important in ALI/ARDS but rather thebalance between proinflammatory and anti-inflam-matory mediators. Several endogenous inhibitors ofproinflammatory cytokines have been described, includ-ing interleukin (IL)-1 receptor antagonist, soluble tumornecrosis factor receptor, autoantibodies to IL-8, and anti-inflammatory cytokines such as IL-10 and IL-11. A betterunderstanding of the role of cytokines in ALI/ARDS willbe gained in the future through studies of the biologicactivity of specific cytokines [29] rather than by measur-ing the static levels by immunologic methods.

Ventilator-induced lung injury Experimental evidenceindicates that mechanical ventilation at high volumesand pressures can injure the lung [30], causing increasedpermeability pulmonary edema in the uninjured lung[31,32] and enhanced edema formation in the injuredlung [5•]. Initial theories to explain these deleteriouseffects focused on capillary stress failure due to alveolaroverdistention. More recently, cyclic opening and closingof atelectatic alveoli during mechanical ventilation hasbeen shown to cause lung injury independent of alveolaroverdistention. Alveolar overdistention coupled with therepeated collapse and reopening of alveoli can initiate aproinflammatory cytokine cascade [33].


In patients with ALI/ARDS, ventilation at traditionaltidal volumes (10 to 15 mL/kg) may overdistend non-injured alveoli, perhaps promoting further lung injury,inhibiting resolution and contributing to multisystemorgan failure [33]. The failure of traditional ventilatorystrategies to prevent end expiratory closure of atelectaticalveoli also may contribute to lung injury. These concernsstimulated a number of clinical trials of protective ventila-tory strategies to reduce alveolar overdistention andimprove recruitment of atelectatic alveoli [1•]. Interest-ingly, a recent study found that a protective ventilatorystrategy could reduce both the pulmonary and systemiccytokine response in patients with ALI/ARDS [34•].

Other mechanisms of injury Like any form of inflam-mation, ALI/ARDS is a complex process in which multi-ple pathways can propagate or inhibit lung injury [1•].For example, abnormalities of the coagulation systemoften develop with small vessel platelet-fibrin thrombiand impaired fibrinolysis. This pathway is of particularinterest in view of the new published report that phar-macologic inhibition of the coagulation cascade withrecombinant human activated protein C can diminishmortality is patients with sepsis [35•,36]. Also, abnor-malities of surfactant production, composition, andfunction probably contribute to alveolar collapse andgas exchange abnormalities [21].

Fibrosing alveolitis Following the acute or exudativephase of ALI/ARDS, some patients have an uncomplicatedcourse with rapid resolution [1•,37]. Others progress tofibrotic lung injury, which is observed histologically asearly as 5 to 7 days after the onset of ALI/ARDS [38]. Thealveolar spaces become filled with mesenchymal cells andtheir products along with new blood vessels. The biopsyfinding of fibrosing alveolitis correlates with an increasedmortality from ALI/ARDS [39]. Levels of procollagen IIIpeptide, a precursor of collagen synthesis, are elevated inthe alveolar compartment very early in the course of ALI/ARDS, even at the time of intubation and mechanical ven-tilation [29,40,41]. Furthermore, the early appearance ofprocollagen III in the alveolar space identifies patientswith a higher mortality [40,41].

RESOLUTION OF ALI/ARDSStrategies that enhance resolution may ultimately be asimportant as treatments that attenuate early inflam-matory lung injury. Alveolar edema is removed by theactive transport of sodium and chloride from the distalairspaces into the lung interstitium [42]. Water followspassively, probably through transcellular waterchannels, the aquaporins, located primarily on type Icells. However, the presence of water channels is notrequired to maximize the rate of alveolar fluidclearance. In clinical studies of ALI/ARDS, alveolar fluidclearance occurs surprisingly early, often measurablewithin the first few hours after intubation and mechan-ical ventilation [19•,20]. Intact alveolar fluid clearanceportends a better outcome as measured by oxygenation,duration of mechanical ventilation, and survival(Fig. 2) [19•,20].

Treatment

• Improvement in the supportive care of ALI/ARDS patients may have contrib-uted to the recent decline in mortality [43]. The care of any patient with ALI/ARDS should include a careful search for the underlying cause with particular attention to treatable infections such as sepsis or pneumonia. Appropriate treatment with antimicrobial agents or surgical treatment of abdominal infections should be promptly instituted. The prevention and early treatment of nosocomial infections is critical because patients frequently die from uncontrolled infection [6]. Adequate nutrition with enteral feeding is

Figure 2. Percentage of patients with three categories of alveolar fluid clearance: impaired (< 3% per hour), submaximal (≥ 3% per hour, < 14% per hour) or maximal (≥ 14% per hour). Alveolar fluid clearance was measured during the first 4 hours after intubation and mechanical ventilation in 79 patients with acute lung injury or the acute respiratory distress syndrome. Solid columns show the percentage of 79 patients in each group. Adapted from Ware and Matthay [19•].


preferred because this route does not carry the serious risk of line sepsis from parenteral nutrition [44]. Prevention of gastrointestinal bleeding and thromboembolism is also important [45].

• Improved understanding of the pathogenesis of ALI/ARDS has led to testing of several novel treatment strategies. An important advance has been the establishment of the National Institutes of Health (NIH)-supported ALI/ARDS network, which now includes 20 university medical centers [1•,34•]. This network has established the infrastructure for implementing well designed, multicenter, randomized trials of potential new therapies.

• A recent review provides a detailed update on treatment of ALI/ARDS with an emphasis on both current established treatment modalities as well as potential future therapeutic options that require more evaluation [46]. This section briefly reviews the most important therapeutic approaches, beginning with a discussion of mechanical ventilation.

• The most appropriate mode of mechanical ventilation in patients with ARDS has been controversial since the syndrome was first described. Although the tidal volume in normal individuals at rest is 6 to 7 mL/kg, historically, 12 to 15 mL/kg was recommended in ALI/ARDS, in part because higher tidal volumes were associated with an improvement in arterial oxygenation. However, the use of this relatively high tidal volume in conjunction with elevated airway pressures has been implicated in propagating the lung in ALI/ARDS. Interestingly, the possibility of ventila-tor-associated lung injury was first considered in the 1970s, leading to the 1974 extracorporeal membrane oxygenation trial, in which ventilation was reduced to 8 to 9 mL/kg, although there was no specific guidelines for limiting airway pressures [47]. However, this strategy failed to improve mortality, as did a later trial of extracorporeal carbon dioxide removal [48].

• Recently, a multicenter trial of 6 mL/kg versus 12 mL/kg tidal volume in 861 patients was completed by the NIH ALI/ARDS Network [34•]. In the low tidal volume arm, the plateau pressure was limited to 30 cm H2O and a detailed protocol was used to adjust FiO2 and PEEP levels in all patients. Mortality was reduced by 22% in the low tidal volume arm, a finding of considerable importance. This constitutes the first large multicenter trial with convincing evidence that a specific therapy for ARDS can reduce mortality. In addition, the trial provides evidence for the clinical signifi-cance of ventilator-associated lung injury and establishes a well-defined protocol for ventilating patients with ALI/ARDS against which future ventilator strategies can be compared. The details of this protocol are summarized briefly in Table 2 [34•].

• There also has been considerable interest in the optimal level of PEEP in patients with ALI/ARDS. It was noted early on that the application of PEEP in patients with ALI/ARDS can improve oxygenation, allowing a reduced FiO2. The best documented effect of PEEP on lung function is an increase in functional residual capacity [49], probably from recruitment of collapsed alveoli [50]. Although lung injury can be prevented in rats using prophylactic PEEP [30], the prophylactic use of 8 cm H20 PEEP in patients at risk for ARDS was not successful [51].

• Some investigators have used an open-lung approach to ventilate patients with ALI/ARDS [52]. In addition to a low tidal volume and pressure-controlled inverse-ratio ventilation, the protocol included raising the level of PEEP above the lower inflection point on a pressure-volume curve for each patient in an attempt to ensure adequate recruitment of atelectatic

Mechanical ventilation


lung. With this approach, mortality was reduced. However, the adoption of this mode of ventilator care cannot yet be recommended for several reasons. First, this study was small and involved only a single center. Second, mortality in the conventional ventilation arm was unusually high (71%), suggesting that this high tidal volume arm may have been especially injurious. Furthermore, the mortality difference was only apparent at 28 days; survival to hospital discharge was equivalent. Third, a reliable mea-surement of the lower inflection point on the pressure volume curve is tech-nically difficult and requires sedation and paralysis. In spite of these issues, the study by Amato et al. [52] raises the possibility that improved alveolar recruitment with higher levels of PEEP than were used in the NIH ALI/ARDS Network study might further reduce ventilator associated lung injury.

• A number of alternative approaches to conventional mechanical ventila-tion also have been proposed, including prone ventilation [1•], but have not yet proven beneficial. Future trials of low tidal volume combined with higher levels of PEEP are being carried out to assess the potential value of increasing lung recruitment in the presence of the low tidal volume approach. Also, some investigators would like to test the value of intermit-tent recruitment maneuvers designed to periodically inflate the lungs of patients with ALI/ARDS. These strategies need to be evaluated in careful clinical trials. There is considerable interest in the potential value of prone ventilation, although one recent study found no benefit of prone ventilation in patients with ARDS [53].

• The rationale for restricting fluid administration in patients with ALI/ARDS is to decrease pulmonary edema. Animal studies indicated that there was less edema fluid formation in acute lung injury if left atrial pressure was lowered [54]. Some clinical studies have supported this hypothesis [55]. Currently, a randomized trial of fluid management based on pulmo-nary artery catheter versus central venous pressure monitoring is being car-ried out by the NIH ALI/ARDS Network. While awaiting these results, a reasonable objective is to maintain the intravascular volume at the lowest level consistent with adequate systemic perfusion as assessed by metabolic acid/base balance and renal function. If systemic perfusion cannot be maintained with restoration of intravascular volume, as in septic shock,

Table 2. NIH ARDS Network lung protective ventilation strategy for patients with ALI/ARDS

Variables Protocol

Ventilator mode Volume assist controlTidal volume ≤ 6 mL/kg predicted body weight*Plateau pressure ≤ 30 cm H2OVentilation set rate/pH goal 6 to 35 breaths per minute, adjusted to achieve arterial pH ≥ 7.3 if possibleInspiratory flow, I:E Adjust flow to achieve I:E of 1:1–1:3Oxygenation goal 55 ≤ PaO2 80 ≤ mm Hg or 88 ≤ SpO2 ≤ 95%FiO2/PEEP (mm Hg) combination 0.3/5, 0.4/5, 0.4/8, 0.5/8, 0.5/10, 0.6/10, 0.7/10, 0.7/12, 0.7/14, 0.8/14, 0.9/14,

0.9/16, 0.9/18, 1.0/18, 1.0/22, 1.0/24

*Predicted body weight for male patients = 50 + (2.3 × [height in inches – 60]) or 50 + (0.91 × [height in centimeters – 152.4]); predicted body weight for female patients = 4.5 + (2.3 × [height in inches – 60]) or 4.5 + (0.91 × [height in centimeters – 152.4]).ALI/ARDS—acute lung injury and acute respiratory distress syndrome; FiO2—fraction of inspired oxygen; NIH—National Institutes of Health; PaO2—partial pressure of oxygen in the blood; PEEP—positive end respiratory pressure; SpO2—oxyhemoglobin saturation by pulse oximetry.Data from the NIH ARDS Network [34]; see this article for additional information on protocol.

Fluid and hemodynamic management


vasopressors are indicated to restore end-organ perfusion and normalize oxygen delivery. However, based on several negative clinical trials, supranormal levels of oxygen delivery cannot be recommended [56].

Surfactant therapy• Because of the success of surfactant replacement in the neonatal respiratory

distress syndrome [57], surfactant replacement has been proposed as a treatment for the surfactant abnormalities of ALI/ARDS. However, a synthetic surfactant preparation (Exosurf; GlaxoSmithKline, Research Triangle Park, NC) had no impact on oxygenation, duration of mechanical ventilation, or survival [58]. There are several possible explanations for the negative results. The surfactant was delivered as an aerosol, and less than 5% may have reached the distal airspaces. Also, Exosurf, a protein-free phospholipid preparation, may not be the most appropriate surfactant replacement in people with ALI/ARDS.

• The evaluation of newer surfactant preparations that contain recombinant surfactant proteins is underway and new modes of instillation are being tested, including tracheal instillation and bronchoalveolar lavage. The results of some of these clinical trials will be available in the near future.

Inhaled nitric oxide and other vasodilators• Nitric oxide is a potent vasodilator that can be delivered to the pulmonary

vasculature by inhalation without causing systemic vasodilation. Although observational studies suggested that inhaled nitric oxide might be benefi-cial in patients with ALI/ARDS [59], randomized, double-blinded studies have been discouraging. In a phase II study, there was no difference in mortality or number of days alive off mechanical ventilation with inhaled nitric oxide in patients with ALI/ARDS [60]. Improvements in oxygenation were modest and not sustained, and pulmonary arterial pressure showed only a minor drop on the first day of treatment. Also, a recent phase III study of inhaled nitric oxide for ALI/ARDS showed no effect on mortality or the duration of mechanical ventilation [61]. Thus, inhaled nitric oxide cannot be recommended for routine treatment of ALI/ARDS, but may be useful as a rescue therapy in patients with refractory hypoxemia.

• Several less selective vasodilators, including nitroprusside, hydralazine, prostaglandin E1, and prostacyclin, also have not been beneficial [1•].

Glucocorticoids and other anti-inflammatory strategies• Recognition of the inflammatory nature of the lung injury in ALI/ARDS

prompted interest in anti-inflammatory treatments, particularly glucocorticoids. However, glucocorticoids given before the onset or early in the course of ALI/ARDS had no benefit [1•].

• More recently, glucocorticoids have been used to treat the later fibrosing alveolitis stage. Encouraging results were reported in a small randomized trial of 24 patients [62]. A larger randomized, multicenter trial by the NIH ALI/ARDS Network of high-dosage methylprednisolone for ALI/ARDS of at least 7 days duration has enrolled more than 100 patients. Because high-dosage methylprednisolone may increase the incidence of infection, its routine use in patients with established ALI/ARDS cannot be recom-

Pharmacologic treatment


mended until results of a large multicenter trial are available. A short course of high-dosage glucocorticoids can be considered as rescue therapy in patients with severe nonresolving ALI/ARDS.

• In addition to glucocorticoids, other anti-inflammatory interventions designed to interrupt the process of ALI have been investigated without success. The failure of these anti-inflammatory strategies may reflect the complexity and redundancy of the inflammation in ALI, or the inability to deliver these agents early enough in the course of ALI/ARDS.

• The recognition of the importance of the resolution phase of ALI/ARDS has stimulated interest in strategies to hasten recovery from lung injury. Experimentally, the removal of pulmonary edema fluid from the alveolar space can be enhanced by both catecholamine-dependent and catechola-mine-independent mechanisms, including inhaled and systemic beta agonists [42]. One experimental study demonstrated that inhaled beta agonists can accelerate the resolution of alveolar edema in sheep and rats with hydrostatic pulmonary edema [63] as well as in animal models of lung injury [64,65]. Beta agonists are appealing for clinical ALI/ARDS because they are already in wide clinical use and lack serious side effects, even in critically ill patients [66]. Also, preliminary data from our institution indicate that aerosolized beta agonists given by routine approach in mechanically ventilated patients results in therapeutic levels in the pulmonary edema fluid [67].

• An additional approach to enhancing the resolution of ALI/ARDS is to accelerate re-epithelialization of the injured alveolar barrier. Alveolar epithelial type II cell proliferation is controlled by a number of epithelial growth factors, including keratinocyte growth factor. Experimentally, administration of keratinocyte growth factor can protect against lung injury [68], probably due in part to enhanced alveolar type II cell proliferation, increased alveolar fluid clearance, antioxidant effects, and a reduction in lung endothelial injury [1•]. There is also recent evidence that keratinocyte growth factor makes alveolar epithelial cells more resistant to mechanical deformation [69]. These findings raise the question of whether an epithelial specific growth factor could be used to accelerate the resolution of ALI/ARDS.

Acknowledgment

• This work was supported by NIH grant HL51856. We would like to thank Rebecca Cleff for help in preparing this manuscript.

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Clinical Acute Lung Injury and Acute Respiratory Distress ... · Clinical Acute Lung Injury and Acute Respiratory Distress Syndrome Matthay et al. 141 causes included major surgery