Conference Report _ _ _ _ _ _ _ _ _ __ Mechanisms of Acute Respiratory Failure Prepared by JOHN F. MURRAY, M.D., and the staff of the DIVISION OF LUNG DISEASES, NATIONAL HEART, LUNG AND BLOOD INSTITUTE

FOREWORD A workshop on "Mechanisms of Acute Respiratory Failure" was sponsored by the Division of Lung Diseases of the National Heart, Lung and Blood Institute on October 20 and 21, 1976, at Stouffers Inn, Arlington, Va. Thirty investigators attended and discussed the definition and mechanisms of acute lung injury and responses of the lung to injury. Dr. John F. Murray was the conference chairman. The following report summarizes the participants' presentations, discussions, and recommendations. INTRODUCTION AND DEFINITION Acute respiratory failure is usually defined on the basis of alterations in arterial blood gas composition: an arterial Po 2 < 60 mm Hg andjor an arterial Pco2 > 50 mm Hg. These abnormalities are clearly nonspecific and can be produced by disturbances in the control of breathing (e.g., drug overdose), by impaired function of airways (e.g., acute bronchial asthma), and by disorders of the lung parenchyma (e.g., lobar pneumonia). This workshop dealt with the type of acute respiratory failure termed adult respiratory distress syndrome (ARDS), a disorder that results from diffuse injury to the alveolar capillary membranes. To date, ARDS can be defined only in terms of a clinical syndrome. (J) It is usually found in association with a serious illness that requires hospitalization but often does not involve the lungs initially. (2) There is usually a latent period after hospitalization of several hours to a few days during which respiratory involvement is minimal or absent. (3) After the latent period, acute respiratory failure develops that may progress relentlessly and cause the patient's death.

It is difficult to collect reliable data about ARDS because of inherent difficulties in establishing the diagnosis of such an ill-defined disorder. The Division of Lung Disease Task Force estimated that 150,000 cases occur each year and emphasized that many of these were young, previously healthy persons. The over-all mortality rate is similarly impossible to obtain because the actual incidence is unknown. Of the 90 patients enrolled in the Extracorporeal Membrane Oxygenator (ECMO) Study, most of whom can be said to have had ARDS, only 8 survived (91 per cent mortality). Data from the same 9 centers participating in the ECMO program revealed that of the 600 patients who received mechanically assisted ventilation with inspired 0 2 concentrations of greater than 50 per cent, which includes a high percentage of patients with ARDS, more than 75 per cent died. At San Francisco General Hospital during the past 3 years, 119 patients (7 per cent of all combined admissions to the Respiratory and Surgical Intensive Care Units) were diagnosed as having ARDS; of these, 53 per cent died. Thus, the available data indicate that the incidence of the disorder is appreciable and that once ARDS develops, the prognosis is poor. On the basis of histologic examination, studies using dextran molecules of known molecular weight, and analysis of secretions collected from the respiratory tract, it has been concluded that a major consequence of the diffuse injury to the lung parenchyma is increased permeability of the capillary endothelium. The resulting edema of the interstitial spaces and alveolar spaces provides a straightforward explanation for the ob-

AMERICA:-/ REVIEW OF RESPIRATORY DISEASE, VOLUME 115, 1977

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served derangements in blood gases (chiefly, hypoxia from right-to-left shunting of blood) but does not satisfactorily exp!ain the remarkable alterations in the mechanical properties of the injured lung. In some cases of ARDS, the cause of the diffuse lung injury is known (extensive viral infection, widespread fat emboli, and inhalation or aspiration of corrosive chemical substances), but in most cases it is not. The first portion of the workshop examined possible cellular, humoral, and other mechanisms that might cause diffuse lung injury and initiate the sequence of events that culminates in ARDS; the second portion was a review of the known structural and functional responses to such injury; and the final portion was a general discussion of acute lung injury that was focused on identifying promising subjects for future investigation and formulating specific recommendations for further basic and clinical research. POSSIBLE MECHANISMS OF ACUTE LUNG INJURY Polymorphonuclear leukocytes. The inflammatory response of the lung involves the polymorphonuclear leukocyte (PMN), which contains 4 well-defined lysosomal proteases (cathepsin D, cathepsin G, collagenase, and elastase). Mechanisms have been outlined defining particulate or soluble immunologic stimuli that provoke the selective release of lysosomal enzymes from PMN. The stimuli that provoke release of the enzymes include complement components C5a and C3b, aggregated immunoglobulins, endotoxins, and others. It is possible that substances implicated in the pathogenesis of ARDS could provoke the release of proteases by generating C5a and C3b. The released proteases could result in damage to the pulmonary vascular endothelium. The contents of PMN can be released in a number of ways: (I) cell death; (2) perforation from within, causing release of cytoplasmic and lysosomal enzymes; (3) regurgitation during feeding; and (4) reversed endocytosis. The first two methods involve death of the cell, whereas the latter two involve lysosomal enzyme release from viable PMN. The latter two are relevant to the pathogenesis of immune tissue injury. Regurgitation during feeding occurs when PMN consume insoluble immune complexes that form vacuoles that merge with primary lysosomes and release lysosomal hydrolases and inflammatory

materials into the surrounding tissues. The PMN remain viable, but their lysosomal contents have been released to act on surrounding tissues. Reversed endocytosis involves the adherence of and stimulation by immune complexes on the surface of the PMN; this causes the selective release of their lysosomal enzymes into the tissue surroundingthePMN. Lysosomal release of enzymes can be enhanced with cyclic guanine monophosphate, cholinergic agonists, phorbol myristate acetate, deuterium oxide, and concanavalin A. Enzyme release is inhibited by cyclic adenosine monophosphate, theophylline, prostaglandin E, cholera toxin, histamine, ,a-adrenergic agonists, colchicine, and vinblastine. Cytochoalasin B-treated PMN are unable to ingest particles but can release or secrete lysosomal enzymes when particles come into contact with their surfaces. It is possible that cortisol stabilizes lysosomal membranes against immunoglobulin- and complement-stimulated release of enzymes. It is important to understand the mechanisms of surface binding of ligands and receptors. Aggregated but not native IgG, C3b, and C5a enhance the stickiness of ligands and cells and in turn promote lysosomal hydrolase release and generation of superoxide radicals. In patients with acute pancreatitis and cardiopulmonary bypass who developed ARDS, but not in those who did not, excess C3b was found in the bloodstream. Platelets and proteolytic enzymes. The possible roles of platelet and plasma proteolytic enzymes in the pathogenesis of diffuse lung injury were discussed. It was suggested that diffuse parenchymal lung injury is a result, at least in part, of surface-activated proteolysis and platelet aggregation. The mediators released lead to a combination of the inflammatory reaction, tissue destruction, and thrombosis. Endothelial cells become damaged, and, if severe enough, the cells become detached, exposing the subendothelial surface. Platelets will begin adhering to the exposed collagen and change from disc shape to rounder shape with pseudopods. Collagen, adenosine diphosphate, and thrombin act as mediators of platelet aggregation. At higher concentrations of adenosine diphosphate, the p:atelets become irreversibly aggregated. Thrombin is required to release lysosomal enzymes from platelets. Platelets contain 3 types of granules: (1) dense granules containing serotonin and nucleotides, (2) lysosomal gran-

CONFERENCE REPORT

ules containing lysosymes, and (3) "peculiar" granules containing fibrinogen and heparin releasing factor. Collagenase is released very early, probably incident with changes in the platelet surface membrane. Platelets have the ability with mild activation to release tissue-destroying proteolytic enzymes. The activation of platelets can (1) occlude lung capillaries by formation of platelet aggregates, (2) release enzymes such as collagenase and elastase leading to tissue destruction, and (3) release prostaglandins and serotonin mediating local vascular reactivity, and an activator of C5 forming C5a, a chemotactic peptide. All these humoral mediators could potentially cause or exacerbate ARDS. The plasma proteolytic enzymes are involved in 4 systems: coagulation, fibrinolysis, kinin formation, and complement. The regulation of the systems is related in a complex way, having a common initiating factor (Factor XII or Hageman factor) and common inhibitors. These systems comprise a network that mediates, in part, the vascular responses necessary for hemostasis (coagulation and fibrinolytic systems), vasodilatation (kinin-forming system, complement, and clotting factors), inflammation, and host defense (complement system). Factor XII is activated in vivo upon exposure to the subendothelial basement membrane-containing collagen. Fragments broken off the molecule during production of activated Factor XII enhance formation of kallikrein, the enzyme that acts on kininogen to liberate bradykinin. Bradykinin can reproduce many features of the inflammatory response, including vasodilatation, increased capillary permeability, pain, and chemotactic stimuli. Two plasma kinases inactivate bradykinin in plasma. Bradykinin is rapidly broken down by the endothelial cells lining the pulmonary capillary bed. Activated Factor XII not only triggers formation of kinins but also initiates intravascular coagulation via the thrombin pathway. Thrombin cleaves fibrinogen to yield fibrinopeptide A and B, which forms the fibrin clot. Increased coagulation liberates two important mediators, thrombin, which causes fibrin deposition, and fibrinopeptide A, which acts as a vasoconstrictor of both systemic and pulmonary vessels. Activated Hageman factor is also involved in the fibrinolytic system, resulting in the conversion of plasminogen to plasmin, the fibrinolytic enzyme. Both kallikrein and plasmin help to

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catalyze their own formation by acting back on Factor XII. Plasmin acts on many substrates, including the conversion of C3 to C3a, which has chemotactic and permeability increasing properties. Plasmin also acts on casein and hemoglobin and may contribute directly to lung tissue destruction. Plasmin can act on fibrinogen to form a series of breakdown products with anticoagulant properties; it also can directly convert kininogen to bradykinin and may be able to activate kallikrein. These products can be measured immunologically and provide evidence of fibrin deposition with subsequent fibrinolytic activity. In pulmonary embolism a marked elevation of fibrin split products occurs that may be of diagnostic value. It has been demonstrated that the activated Hageman factor is relatively weak in initiating the formation of kallikrein and plasmin, but a portion of the preactivated Hageman factor is quite potent. It was found that a high molecular weight kininogen accelerates the initial rate of cleavage of prekallikrein by activated Hageman factor. The pathways of coagulation, fibrinolysis, and kinin formation are all integrated and interact successively in cascade fashion. The initiating pathways are mutually dependent and result in inflammatory change and tissue destruction. There are not only accelerating factors and positive feedbacks but also naturally occurring effective inhibitors. Because most of the enzymes involved are serine proteases, the most effective inhibitors are protease inhibitors. The humoral mediators produced by plasma and platelet proteolytic enzymes are integrated to participate in the inflammatory reactions as well as tissue destruction and thrombosis that may underlie acute diffuse lung injury. As the roles of these humoral mediators are better defined, specific pharmacologic interactions may be useful in controlling this syndrome. Mast cells. Mast cells are plentiful in normal human lungs and are found in airways and the adventitia of blood vessels. Mast cells have been implicated in the pathogenesis of immediate (type 1) immunologic reactions after sensitization by IgE (reagenic antibody) that binds to the surface of the cell. In the presence of specific antigen, a cascade of reactions involving cyclic nucleotides ensues that results in the liberation of (1) preformed mediators (histamine, eosinophilic chemotactic factor of anaphylaxis, neutrophilic chemotactic factor anaphylaxis, and, in some species, heparin and serotonin), and (2)

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newly formed mediators (slow-reacting substance of anaphylaxis and platelet aggregating factor). Mast cells have receptors for substances besides IgE, such as j3-adrenergic agonists, histamine, prostaglandins, and, possibly, acetylcholine, all of which can modulate mediator release. Nonimmunologic stimuli, such as physical injury and chemical reactions, can cause mast cells to release their mediators. Humoral substances. During biologic reactions such as coagulation, fibrinolysis, kinin formation, complement activation, and platelet aggregation, numerous humoral substances are elaborated. Some of these-histamine, slow-reacting substance of anaphylaxis, kinins, and enzymes-are known to increase permeability or cause cell injury. However, none has been convincingly implicated in the pathogenesis of ARDS, although it is now possible to measure some of these substances. Studies in animals were described in which single humoral substances, believed possibly to be involved in the pathogenesis of ARDS, were injected or infused intravenously, usually with unimpressive results. However, the failure to demonstrate a full-blown ARDS-type response to the injection of a single substance does not exclude a role for that compound, because other substances besides the one tested are probably produced in the in vivo reaction, the presence of activator and inactivator substance(s) and the concentration at the site of release and activity are likely to be extremely important determinants of the over-all response in patients. Pharmacologic intervention. Because the distribution of receptors on cells is not random, drugs can be designed that can affect the function of particular cells and not others. Thus, pharmacologic manipulation of some processes involved in the pathogenesis would be possible provided we knew where we wanted drugs to work and what we wanted them to do. Present uncertainties concerning the specific mechanisms of injury, the source of the agents that cause lung damage, and the sites of the reaction limit rational pharmacologic treatment of ARDS. Oxygen toxicity. One of the organs most susceptible to 0 2 toxicity and subsequent injury is the lung. Animals placed in an atmosphere of 100 per cent 0 2 may develop lesions acutely (3 to 4 days) or chronically (4 to 8 weeks). The pathologic changes associated with 0 2 toxicity include (1) pulmonary edema, (2) atelectasis,

(J) pulmonary vascular lesions, (4) transient pleural effusion, (5) bullous lesions, (6) lesions of the type I alveolar cell during the first few days with subsequent increase in number of type II cells, (7) tracheobronchitis, and (8) pulmonary fibrosis. The mechanism by which 0 2 damages the cell is uncertain. It is possible that free radicals may play a role. Hydrogen peroxide and lipid peroxides have been suggested as harmful intermediates of 0 2 metabolism. The severity of 0 2 toxicity is related to Po 2 , age, and species of the animal. Levels of 0 2 above 60 per cent should be considered dangerous for normal lungs. In the injured lung, lower levels of 0 2 may be dangerous. Factors that could lower the safe level of 0 2 are (1) infection, (2) concurrent injury, (J) impaired cellular repair mechanisms (e.g., irradiation and chemotherapeutic agents), and (4) drugs (e.g., toxins, steroids, paraquat). The subject of 0 2 tolerance was also discussed. It has been shown that rats exposed to 85 per cent 0 2 at l atmosphere can better tolerate an atmosphere of 100 per cent 0 2 than animals without prior exposure. Oxygen tolerance may develop because of a change in enzyme activities. In some strains of rats exposed to 85 per cent 0 2 , the lungs have been found to have a 45 per cent increase in superoxide dismutase and almost a doubling of glucose-6-phosphate dehydrogenase (G6PD). Changes in enzyme concentration correlated with tolerance, or lack of it, to subsequent exposure to l atm of 0 2 . The increase in G6PD may protect the lung from 0 2 toxicity by providing nicotinamide adenine dinucleotide phosphate that leads to reduction of oxidants or is used to synthesize cell components. Superoxide dismutase catalyzes the dismutation of the superoxide anion, a potentially toxic-free radical. Experiments were described in which it was shown that rats given a-napthylthiourea had an increased 0 2 tolerance. It was believed that this could be attributed to an increase in the enzyme activity of G6PD. Supplemental doses of vitamin E also increased tolerance to 0 2 • It was suggested that this occurs by vitamin E acting as a scavenger of free radicals. Lungs tolerant to l atm of 0 2 produced increased quantities of lactate. This suggests that the availability of high-energy phosphate from glycolysis is another mechanism involved in 0 2 tolerance. The role of steroids on recovery from 0 2 tox-

CONFERENCE REPOR r

icity was considered. Hydrocortisone will decrease the weight of lungs recovering from 0 2 toxicity faster than lungs not given corticosteroids. Steroids also have been shown to potentiate the increase in surfactant production during recovery from 0 2 Role of intrapulmonary nerves. There are motor (efferent) nerves to pulmonary arteries and veins but none to capillaries. These are mainly sympathetic fibers, and innervation of blood vessels by the parasympathetic nerves is poorly documented. Vasomotor changes in ARDS could occur from neural effects on arteries, veins, or both, and the possibility of separate control systems must be considered. However, the actual contribution of neural activity to the pathogenesis of ARDS is not understood and the evidence is conflicting. It is possible that there is some tonic vagal activity that protects the lung. Parasympathetic motor fibers apparently innervative smooth muscles in airways, mucous glands, and (possibly) type II cells. Virtually all of the remaining nerves are afferent fibers from J -receptors, other C-fibers, stretch receptors, and rapidly adapting irritant receptors. Thus, although it is difficult to demonstrate a ro!e for efferent pulmonary nerves in the production of acute lung injury, once injury has occurred a large number of afferent fibers are presumably activated and take part in secondary responses.

RESPONSE TO INJURY: STRUCTURAL ABNORMALITIES

Contribution of Oxygen Evidence was presented to suggest that the administration of high concentrations of 0 2 is responsible for many of the major patho!ogic changes of ARDS: thickening of septal walls, hyaline membranes, and the deposition of collagen along alveolar ducts. The presence of hyaline membranes tended to decrease with time and the presence of fibrosis to increase with time. It is possible that the membranes might serve as a matrix over which collagen is deposited. Additional morphologic evidence was presented to support the prevailing view that breathing high concentrations of 0 2 is not a sine qua non to the development of ARDS. Degranulated platelets and PMN were found associated with histologic abnormalities of type II and endothelial lesions in lung biopsies from patients

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having cardiopulmonary bypass and, at autopsy, in patients who died from ARDS. Early pulmonary abnormalities in experimentally induced 0 2 toxicity in rats were interstitial edema and changes in the capillary endothelial cells. In chronic 0 2-induced injury in monkeys, there were decreased numbers of capillaries, interstitial thickening, epithelial thickening, and hyperplasia of type II cells. These were, in part, reversib!e after weaning the animals back to room air. Other studies in animals have shown that after extensive damage to type I alveolar epithelial cells, the epithelial surface is repaired by a marked proliferation of type II cells. Autoradiographic studies in rats with damaged lungs show that after intravenuous injections of 3H-thymidine, the type II cells have a high index of labeling, whereas the type I cells remain essentially unlabeled; this is evidence that type I cells do not undergo mitotic division. New type I cells are produced by differentiation of type II cells that, accordingly, must be considered the progenitor of the epithelial surface, both during fetal development and after many kinds of diffuse lung injury.

Structural Changes in ARDS Acute ARDS. There was alveolar edema with fibrin strands and leukocyte debris, extensive damage to type I epithelial cells but little evidence of damage to type II cells, endothelial cell damage, and interstitial edema. Subacute ARDS. There was persistent damage to the capillary endothelium and proliferation of type II cells with beginning evidence of squamous transformation. Chronic ARDS. Findings differ depending on whether death is from a nonrespiratory complication or progressive respiratory failure. In the former there was further transformation toward normal; in the latter there was variable thickening of the interstitium with infiltration of lymphocytes, fibroblasts, and other cells; the air-blood barrier was thickened, chiefly because of changes in the epithelial layer; in some cases there was interstitial fibrosis. RESPONSE TO INJURY: FUNCTIONAL ABNORMALITIES Increased permeability. A common feature of ARDS is pulmonary microemboli. Thus, the effect of microemboli on the water and protein

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balance of the pulmonary microvascular bed was discussed. Previous experiments on cats by other investigators were described in which 75 per cent of the lung tissue was removed, forcing all the cardiac output through the remaining 25 per cent of the pulmonary vascular bed. The overperfused tissue became edematous. More recent studies in dogs showed that when glass beads or thrombin were used to block the pulmonary vascular bed, the lungs also became edematous. This may also be the mechanism of high altitude pulmonary edema in which it is hypothesized that the hypoxia causes nonuniform precapillary vasoconstriction that forces the cardiac output through a smaller and smaller portion of the pulmonary vascular bed with the result that the overperfused areas become edematous. Experiments on anesthetized sheep were de· scribed in detail in which lung lymph was collected during pulmonary embolization. The pulmonary vascular bed was embolized with glass beads, mineral oil, or fibrin clots until the pulmonary vascular resistance increased 3-fold. The lung lymph flow increased as the pulmonary vascular bed was obstructed. The increase in lung lymph flow correlated better with the increase in pulmonary vascular resistance than with changes in pulmonary vascular pressures. Because the lung lymph protein flux increased in proportion to fluid flux, the pulmonary edema is caused by increased microvascular permeability. The same response was seen for all 3 types of emboli. At autopsy, gravimetric studies showed a 15 per cent increase in the extravascular water content of the embolized lungs compared to the lungs from control animals. Possible explanations for the increased permeability are that (I) the increase in linear velocity of blood flow through the perfused vessels physically damages the pulmonary microvascular endothelium, or (2) mediators are released with resulting chemically induced injury to the microvasculature. In the discussion concerning experimental models of pulmonary edema, two points were stressed: (I) that the increase in water content of the lung does not explain satisfactorily the marked decrease in compliance of the lung that occurs in ARDS, and (2) that the use of positive end-expiratory pressure has now been shown by several groups of investigators not to decrease the amount of extravascular water in the lung that forms after a given experimental intervention.

Changes in mechanical properties. Remarkable changes in the mechanical properties of the lung occur during the evolution of ARDS. Previously reported and new experiments on the effects of repeated inflation at a constant tidal volume of the isolated lung on the pressurevolume curve of the lung were summarized. In addition, the effects of manipulations such as ventilation with 100 per cent N 2 , changing temperature, prolonged refrigeration, and the instillation of aerosolized hydrochloric acid were described; the modifying influence of end-expiratory pressure, corticosteriods, and albumin on the mechanical properties, weight gain, and gas exchange capabilities of the injured lung were reviewed. In general, the use of corticosteroids and albumin in huge doses was physiologically beneficial when given concomitantly with the hydrochloric acid. The use of end-expiratory pressure at a given level had effects that were both advantageous and disadvantageous (e.g., 15 em H 2 0 positive end-expiratory pressure was associated with the least right-to-left shunt of blood but the highest gain in weight and worst shift in pressure-volume relationships). RECOMMENDATIONS The conference participants agreed (I) that ARDS is an important clinical disorder with high mortality and socioeconomic cost, and, hence, efforts directed to prevention, early diagnosis, and improved treatment are warranted, and (2) that sufficient research questions have been formulated for which there are available means of solution to recommend that the National Heart, Lung and Blood Institute initiate a comprehensive investigative program. Furthermore, as emphasized by the presentations and discussions at the conference, close collaboration among clinicians, pathologists, physiologists, other basic scientists, and epidemiologists is essential. Thus, the research program envisioned is broad in scope and content and interdisciplinary in organization. The definable problems fall roughly into 3 categories-clinical, pathologic, and experimental-but the considerable overlap among these underscores the need for a broadly based approach.

Clinical More reliable clinical data concerning inci· dence, mortality, natural history, and effects of treatment can be collected and evaluated.

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Recommendation: That several interested and knowledgeable physicians involved in critical care be organized into a cooperative study group charged with the following responsibilities: (a) To prepare a satisfactory working definition of ARDS. (b) To develop a system of reporting that will allow collection of data in a prospective manner to define the natural history of the disorder, to assess the incidence of ARDS in certain high-risk patient groups (drug overdose with shock, multiple nonthoracic trauma, gramnegative sepsis), and to determine the mortality rate and cause of death. (c) To develop tests for the purpose of making the diagnosis at an early stage before advanced clinical, roentgenographic, and physiologic abnormalities have occurred. Such studies might include methods of detecting the excessive amounts of extravascular water in the lung, the rate at which radiolabeled protein equilibrates in the lung tissue spaces, the concentrations of biochemical substances (e.g., C3b, or converting enzyme) that are released into the bloodstream by the d;Imaged lung, or the impaired function of the injured endothelial surface (e.g., conversion of angiotensin I to angiotensin II). (d) To evaluate in a controlled fashion, once patients can be diagnosed accurately and early, the effects of current controversial aspects of therapy (e.g., corticosteriods, albumin, and diuretics). (e) To determine the contribution of the recognizable hematologic syndrome, which some patients develop, to the pathogenesis and progression of ARDS. Related questions concern whether the lung disorder initiates intravascular coagulation or whether lung damage results from microemboli induced by a clotting disturbance arising elsewhere in the body. Do alterations of blood components lead to endothelial or other cellular damage in the lung and other organs? Pathologic Although data concerning the pathology of ARDS are being generated in a few centers throughout the world, it is important that more information be obtained, particularly on the relationship between the pathologic findings and the clinical, radiologic, and physiologic abnormalities. Recommendation: That a pathology center be developed to which suitable biopsy and autopsy specimens can be sent for light and electron

microscopy and quantitative examinations. The objective of the investigators should be: (a) To correlate the pathologic findings with the clinical and pertinent laboratory data at the time the biopsy was obtained (or the patient died) to provide an integrated understanding of the structure-function abnormalities in ARDS. (b) To determine if there are pathologic changes in other organs besides the lung and the sequence of injury and repair in all involved organs. (c) To analyze the contribution of 0 2induced injury to the pathologic changes in ARDS by correlating the structural abnormalities with the duration and concentration of 0 2 administered. (d) To study the extent to which microembolism of platelet-fibrin aggregates, fat emboli and release of fatty acids, and breakdown of formed elements of the blood contribute to the pathology of ARDS.

Experimental Basic research on ARDS has been severely hampered by the lack of a suitable animal model or models. This, in turn, is related in part to uncertainties about the spectrum of abnormalities that are being reproduced; however, sufficient clinical and pathologic information is available to provide a basis for increased attempts to simulate the clinical disorder in animals. Recommendation: That efforts be directed toward developing animal models of the ARDS that will allow assessment of the physiologic and pathologic consequences of the reaction of the lung to injury. The models should recapitulate the essential abnormalities and the time course of ARDS. To encompass the multiple variables and provide a suitable number of animals for study, it is likely that different animal species, including primates, will need to be studied. Once one or more animal models are available, research can progress in the following directions: (a) To investigate the mechanism(s) of injury that characterize ARDS and to analyze the respective roles of endothelial versus epithelial sites of injury in producing a given spectrum of responses. (b) To study the mechanisms that enhance or retard the ability of type II cells to regenerate and to differentiate into type I cells. Similarly, to discover !10w endothelial and other cells in the lung react to injury and their capacity for repair. (c) To assess the effects of 0 2 in different con-

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centrations on cells after they are damaged. Can the lung be "conditioned" to reduce the effect of 0 2 toxicity, and what role does such condi· tioning have in ARDS. (d) To discover the mechanism(s) that trigger cellular proliferation and fibrosis, hallmarks of the end-stage ARDS lungs. Because obliteration ·of the normal structure of the lung characterizes the irreversible stage of ARDS, potential control of this triggering process could prove to be important in management. (e) To study the presence of hematologic abnormalities that may precede or follow acute lung injury and to document the role played by changes in the formed elements of the blood in the pathogenesis of ARDS. (f) To evaluate the effect that lung injury associated with ARDS has on the metabolic and nonrespiratory functions of the lung. To develop tests of any abnormalities in the nonrespiratory functions that occur after injury that might be useful in the early diagnosis of ARDS. (g) To determine the mechanisms responsible for the remarkable changes in the lung mechanics that occur in ARDS. Studies in animal models can differentiate the contributions of changes in tissue and surface forces, the importance of foam, ate:ectasis, and airway closure, and the role of humorally mediated or reflex changes in producing the abnormalities in mechanical properties.

(h) To correlate quantitative pathologic changes with physiologic abnormalities at stages during the evolution of the responses to lung injury. (i) To perform neurophysiologic studies to sort out the contribution of ]-receptors and other receptors that should be activated after lung injury to determine whether there are early changes in the pattern of breathing that might be useful diagnostically.

WORKSHOP PARTICIPANTS Robert H. Bartlett Lynn H. Blake Kurt J. Bloch Kenneth Brigham Fred Cheney John A. Clements Robert W. Colman James Crapo Matthew B. Divertie Barry A. Gray J. Donald Hiil Thomas F. Hornbein Gary L. Huber Theodor Kolobow Claude Lenfant Kenneth Melmon

John F. Murray Hannah Peavy Solbert Permutt Thomas L. l'eLy Phillip C. Pratt Peter Ramwell Robert Rodvien .James P. Shinnick J\I ichael Snider Norman C. Staub Donald F. Tierney Carol Vreim Ewald R. Weibel Gerald \Veissmann John Widdicombe James W. Wilson