466
SCIENCE & PRACTICE
Scientific perspectives
on
adult
respiratory distress
syndrome JOHN E. REPINE The adult respiratory distress syndrome (ARDS) is often thought to be common, to have a single pathogenetic mechanism, and to have no effective treatment. Although patients do die from ARDS, its true incidence remains unknown. Some estimates put the number of new cases of ARDS each year in the USA at about 150 000 with a 50% death rate. However, the severity of ARDS may vary widely and improvements in intensive care may have increased the incidence of ARDS substantially in recent years. The notion of a final common pathway, through which diverse precipitating insults act to cause lung inflammation, microvascular injury, and progressive hypoxaemia, is an attractive one because it offers hope of specific interventions. Unfortunately, it is not consistent with the evidenced1 Clinical management is discussed in the companion paper by Macnaughton and Evans, but it must be said from the start that no pharmacological strategy has produced impressive results. Methylprednisolone2 and prostaglandin E13have shown no benefit in trials; the glutathione agonist N-acetylcysteine has seemed promising, but there is no evidence that it lessens mortality or improves functional indices.4 Clearly, we need more basic knowledge of the syndrome, and in this brief paper I review some of the principal hypotheses now under investigation. ARDS can be defmed both pathophysiologically and clinically. The clinical definition is given in the next article, but in my account I shall use acute non-cardiogenic oedematous lung injury, so as to include some indication of the processes leading to pulmonary damage.
Theories and influences
Complement and free radicals Evidence that neutrophils contribute to ARDS has accumulated rapidly.s ARDS lungs are populated by large numbers of neutrophils, many of which are adjacent to damaged endothelium (fig 1).6 In addition, the blood and bronchopulmonary lavage fluid contain mediators that can activate neutrophils in vitro and cause lung inflammation when given to laboratory animals. The blood neutrophils of ARDS patients show enhanced oxidative metabolism in vitro; and activated neutrophils promote damage and fluid leakage in isolated lungs and lung endothelial cell monolayers. Lastly, the acute oedematous lung injury in animals injected with neutrophil activators can be lessened by neutrophil depletion. Neutrophils might contribute to lung injury by release of oxygen radicals and elastase. ARDS patients have abovenormal amounts of oxidised antiproteases in lung lavage fluid and increased quantities of hydrogen peroxide in their breath.7 Although oxidants are produced by other cells, including macrophages and endothelial cells, elastase is derived only from neutrophils. Isolated lungs perfused with
stimulated normal neutrophils are damaged, whereas neutrophils from patients with chronic granulomatous disease, which are essentially normal except for their inability to make oxygen radicals, have no such effects. Elastase-induced injury is most striking after previous exposure to oxidants. In isolated lungs not subjected to oxidants, elastase is free from toxicity except in concentrations so high that they are unlikely to be achieved in vivo.8
Fig 1-Section from an ARDS lung showing accumulation of neutrophils and erythrocytes.
Neutrophil recruitment is probably initiated by release of chemotactic agents from lung cells that seem to be stimulated by airway insults, complement components, or endotoxin (fig 2). Neutrophils then accumulate near endothelial cells, to which they attach themselves.9 Lung neutrophil sequestration alone may not increase lung permeability. Neutrophils can transiently increase in the lung without causing damage.1o Neutrophil priming may be an important prerequisite for lung damage. One stimulus would preactivate the neutrophil so that it was more responsive to a second stimulus that caused release of amplified oxygen radicals and degranulation. Neutrophils from the blood or lungs of ARD S patients are in some cases activated and in other cases depressed.ll,12 Such differences might reflect priming or exhaustion of neutrophils. The interactions between the neutrophil and the endothelial cell are increasingly complex (fig 3).13 When all possible influences (table), together with the primary, secondary, and tertiary responses, are considered, the notion of a final common pathway is clearly unsatisfactory. ADDRESS Webb-Waring Lung Institute, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box C321, Denver, Colorado 80262, USA (Prof John E. Repine, MD)
467
POTENTIAL CONTRIBUTORY FACTORS IN ARDS
Complement Oxygen radicals Proteases (elastase) Endotoxin Eicosanoids (thromboxanes, Platelet-activating factor
prostaglandins, leukotrienes)
Cytokines (TNF,* interleukins, endothelin) Growth factors Kallikreins (kinins) Fragment D *Tumour necrosis factor
Fig 2-Factors influencing progression to ARDS.
neutrophil is an obvious target for therapy. Some approaches are highly specific and focus on neutralising a single agent-eg, elastase inhibitors and free-radical scavengers. Antioxidants may limit not only direct but also The
indirect effects of oxygen radicals, such as those that are mediated through enhancement of elastase toxicity, stimulation of thromboxane, or other oxygen-metabolite dependent processes (fig 3). Alternative, more general approaches, involve prevention of neutrophil adherence or secretion. 14,15 Another aspect of free-radical-induced tissue injury is that related to ischaemia-reperfusion.16 Localised vascular clotting and shunting might lead to localised ischaemiareperfusion events. The mechanisms responsible for reperfusion injury are unknown. According to the xanthine oxidase (XO) hypothesis, ischaemia causes conversion of xanthine dehydrogenase (XD) to XO with catabolism of ATP hypoxanthine (a substrate for XO). Reperfusion provides the oxygen necessary for superoxide (0) and hydrogen peroxide (H202) formation. In the presence of iron (Fe), these metabolites form highly toxic oxygen species, such as hydroxyl radicals (-OH). These events have
Fig 3-Neutrophil-endothelial cell interactions in ARDS. XD =xanthine oxidase; MPO= myeloperoxidase; GSH =glutathione. O2= superoxide anion.
468
been reported in several systems where XO inhibitors-eg, tungsten or allopurinol--or oxygen-radical scavengers protect against reperfusion damage. Neutrophils also contribute to injury following ischaemia-reperfusion insults by oxygen radical and other mechanisms." Supranormal amounts of XO have been found in blood from patients with ARDS, and XO is increased in lungs compared with hearts in rabbits. Release of XO may provide a marker of endothelial damage, since it is normally concentrated in endothelium. Distribution of this enzyme via the circulation may account for inflammation and injury at distant sites in the lung or other organs.18 Multiple organ failure after the onset of ARDS carries a poor prognosis. This catastrophe may be due to the same systemic processes that damage the lung; in solid organs the ill-effects might show themselves later because permeability defects are not so harmful to function.1
Endotoxaemia The observation that the amount of lymph in sheep lungs increased after injection of gram-negative bacteria or endotoxin suggested that endotoxin might be involved in the pathogenesis of ARDS.19 The effects of endotoxin on the lung closely resemble the findings in the ARDS lung. Endotoxin independently stimulates neutrophil and endothelial injury in vitro. Endotoxin may also have a protective effect on the lung. Rats pretreated with small doses of endotoxin are resistant to both hyperoxia-induced fatal acute oedematous lung injury and ischaemia-reperfusion injury. The alveolar epithelial lining fluid of ARDS patients shows high antioxidant activity.2O Use of monoclonal antibodies should clarify whether the role of endotoxin is fundamental.21 Cytokines are also potentially important mediators in ARDS. Tumour necrosis factor (TNF) is likely to be involved in ARDS that accompanies sepsis and shock. TNF promotes neutrophil adherence by increasing surface glycoproteins, c3bi, and interleukin-1. TNF may also affect tissue procoagulant activity and contribute to thrombosis and clotting of small vessels. TNF causes pulmonary oedema in rats,22 and treatment with anti-TNF monoclonal antibodies prevents septic shock and lethal bacteraemia. TNF also has protective properties .23,24 Interleukins may also be detrimental or protective.23
PAF, a product of all the suspected inflammatory cells, is likely to mediate some of the effects of ARDS.25 To date, PAF has not been measured in blood or lavage fluid of ARDS patients; the assay is difficult. Surfactant Surfactant defects may likewise be an important influence in ARDS. Defective surfactant activity may result from wash-out or dilution after lung fluid accumulation, protein denaturation by oxidants, or injury to the type II pneumocyte. Abnormalities in surfactant could increase alveolar surface tension, and thereby promote atelectasis and interstitial fluid accumulation. Profound hypoxaemia would ensue. The ability to stimulate surfactant production and to give surfactant into airways opens exciting prospects, though it is possible that the additional surfactant would be inactivated by the inflammatory process. Some of these issues are discussed in the accompanying article.
Future
The pathogenesis of ARDS is multifactorial. Are certain individuals prone to the development of ARD S? There may be unrecognised intrinsic differences in host responses. Investigative techniques are not always specific and better laboratory animal models are needed.26 Species differences may exist. For instance, elastase may be different in different species and, as a result, the effectiveness of an elastase inhibitor in one animal may not predict its effectiveness in man. Moreover, experiments in animals, where the insult is short-lasting, may present a misleading picture for man, in whom the insult is persistent. Moreover, in man there are often several insults, such as shock and secondary infection, whereas usually only a single insult is tested in animal models. ARDS is a complicated disease process; unfortunately, this complexity has prevented any substantial progress in drug therapy. I fear that few effective treatments will become available until we have a much better basic understanding of the pathogenetic mechanisms leading to ARDS. Such developments will have important implications for other inflammatory disorders. We thank Ms text of this
are
located in the
J. D. Smith for her expert preparation of the graphics and
paper. Dr Polly Parsons kindly provided the lung section from the
ARDS patient.
Alveolar macrophages
Macrophages
challenges
lung
and
can
release
radicals, proteases, cyclo-oxygenase and lipoxygenase derivatives, and cytokines. Macrophages also release chemotaxins, adherence-promoting factors, and neutrophil secretagogues. A causal link between pulmonary oxygen
damage and these factors has not been established. Lipid mediators Many changes that are found in lungs of ARDS patients could be attributable to lipid-derived factors, such as eicosanoids and platelet-activating factor (PAF). These factors influence vascular reactivity and augment inflammation. For instance, thromboxane is a potent vasoconstrictor that has been found in high concentrations in lung lavages from ARDS patients. Leukotrienes are increased in lavages of ARDS patients; leukotriene B4 has chemotactic activity for neutrophils, eosinophils, and monocytes and could contribute to ARDS by increasing phagocytic cell recruitment.
REFERENCES
JE, Christman JW. Mechanisms and mediators of the adult respiratory distress syndrome. Clin Chest Med 1990; 11: 621-32. 2. Bernard GR, Luce JM, Sprung CL, et al. High dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 1987; 317: 1565-70. 3. Bone RC, Slotman G, Maunder R, et al. Randomized double-blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome. Chest 1989; 96: 114-19. 4. Bernard GR, Swindell BB, Meredith MJ, Carroll FE, Higgins SB. Glutathione (GSH) repletion by N-acetylcysteine in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1989; 139: 1. Rinaldo
221A. 5.
Repine JE, Beehler CJ. Neutrophils and adult respiratory distress syndrome: two interlocking perspectives in 1991. Am Rev Respir Dis 1991; 144: 251-52. JE, Davis WB, Holter JR, Mohammed JR, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome: clinical and pathophysiologic significance. Am Rev Respir Dis 1986,
6. Weiland
133: 218-25. 7.
Sznajder JI, Fraiman A, Hall JB, et al. Increased hydrogen peroxide in the expired breath of patients with acute hypoxemic respiratory failure. Chest 1989; 96: 606-12.
469
8. Baird BR, Cheronis JC, Sandhaus RA, Berger EM, White CW, Repine JE. O2 metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs. J Appl Physiol 1986; 61: 2224-29. 9. Worthen GS, Schwab B, Elson EL, Downey GP. Mechanics of stimulated neutrophils: cell stiffening induces retention in capillaries. Science 1989; 245: 183-84. 10. Martin TF, Pistorese BP, Chi EY, Goodman RB, Matthay MA. Effects of leukotriene B4 in the human lung: recruitment of neutrophils into the alveolar spaces without a change in protein permeability. J Clin Invest 1989; 84: 1609-19. 11. Zimmerman GA, Renzetti AD, Hill HR. Functional and metabolic activity of granulocytes from patients with adult respiratory distress syndrome. Am Rev Respir Dis 1983; 127: 290-300. 12. Martin TR, Pistorese BP, Hudson LD, Maunder RJ. The function of lung and blood neutrophils in patients with the adult respiratory distress syndrome. Implications for the pathogenesis of lung infections. Am Rev Respir Dis 1991; 144: 254-62. 13. Mulligan MS, Hevel JM, Marletta MA, Ward PA. Tissue injury caused by deposition of immune complexes is L-arginine dependent. Proc Natl Acad Sci USA 1991; 88: 6338. 14. Riva CM, Morganroth ML, Ljungman AG, et al. Iloprost inhibits neutrophil-induced lung injury and neutrophil adherence to endothelial monolayers. Am J Respir Cell Mol Biol 1990; 3: 301-09. 15. Leff JA, Baer JW, Kirkman JM, Bodman ME, Ostro MJ, Repine JE. Post-injury treatment with liposome-encapsulated prostaglandin E1 decreases acute edematous lung injury ("ARDS") in rats given interleukin-1 intratracheally. Clin Res (in press). 16. Kennedy TP, Rao NV, Hopkins C, Pennington L, Tolley E, Hoidal JR. Role of reactive oxygen species in reperfusion injury of the rabbit lung. J Clin Invest 1989; 83: 1326-35.
17. Linas
SL, Shanley PF, Wittenberg D, Berger E, Repine JE. Neutrophils ischemia-reperfusion injury in isolated perfused rat kidneys. Am J Physiol 1988; 24: 728-35. 18. Terada LS, Dormish JJ, Leff JA, Willingham IR, Repine JE. Circulating accentuate
xanthine oxidase mediates lung neutrophil sequestration following mesenteric ischemia. Clin Res 1989; 37: 145A. 19. Brigham KL, Bowers RE, Haynes J. Increased sheep lung vascular permeability caused by Escherichia coli endotoxin. Circ Res 1979; 45: 292-97. 20. Lykens M, Davis WB, Pacht E. Increase in alveolar epithelial fluid antioxidant activity in ARDS. Clin Res 1988; 36: 508A. 21. Bernard GR, Grossman JE, Campbell GD, Gorelick KJ. Multicentre trial of a monoclonal anti-endotoxin antibody (XOMEN E-5) in gram negative sepsis. Chest 1989; 96: 137A. 22. Ferrari-Baliviera E, Mealy K, Smith RL. Tumor necrosis factor induces adult respiratory distress syndrome in rats. Arch Surg 1989; 124: 1400-05. 23. White CW, Ghezzi P, Dinarello CA, Caldwell SA, McMurtry IF, Repine JE. Recombinant tumor necrosis factor/cachectin and interleukin I pretreatment decreases lung oxidized glutathione accumulation, lung injury and mortality in rats exposed to hyperoxia. J Clin Invest 1987; 79: 1868-73. 24. Alexander HR, Sheppard BC, Jensen JC, et al. Treatment with recombinant tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis. J Clin Invest 1991; 88: 34-39. 25. Braquet P, Hosford D. The potential role of platelet-activating factor (PAF) in shock, sepsis and adult respiratory distress syndrome (ARDS). Prog Clin Biol Res 1989; 308: 425-39. 26. Flick MR. Mechanisms of acute lung injury: what have we learned from experimental animal models?. Clin Care Clin 1986; 2: 455-70.
Management of adult respiratory distress syndrome
The adult respiratory distress syndrome (ARDS) was first characterised in 1967.1 A wide range of both direct and indirect pulmonary insults can lead to the high-permeability pulmonary oedema that characterises this condition with mortality rates varying from 50-90%.2 ARDS is now recognised as the pulmonary component of a generalised disorder of endothelial structure and function brought on most commonly by trauma or sepsis and resulting in failure of multiple organ systems (the multiple organ failure
syndrome).
Diagnosis Clinical criteria The diagnosis of ARDS is mainly clinical and criteria vary between centres (table). The effects of pulmonary endothelial damage range from mild respiratory impairment to the overwhelming pulmonary oedema that characterises ARDS.3 Murray and colleagues have described a scoring system that categorises patients according to their underlying condition and quantifies the severity of lung injury from chest radiographic appearances, degree of hypoxaemia, requirement of positive end-expiratory pressure (PEEP), and thoracic compliance.4 This system allows ARDS to be defmed more precisely and could be a valuable method of assessing disease progression.
Haemodynamic measurements The insertion of a balloon-tipped pulmonary artery catheter allows pulmonary artery occlusion pressure and cardiac output
be monitored. These data and blood gas from arterial and mixed venous blood enable oxygen delivery (D02) and peripheral
measurements
samples
to
uptake (V02) to be calculated. Several studies have an abnormal relation between D02 and V02 in some patients with ARDS and sepsis.5,6 At rest, V02 is normally independent of DOz as long as the latter is maintained above a critical level, but oxygen consumption becomes delivery dependent above this threshold in ARDS, oxygen
identified
such that the oxygen extraction ratio (V02/D02) remains (fig 1). The mechanisms underlying this observation are poorly understood, but it has been interpreted as evidence of occult tissue hypoxia and has been associated with a high mortality. An increased plasma lactate concentration, which may reflect an imbalance between metabolic requirements and DOz, could be a useful marker of oxygen-uptake supply dependency.7 constant
ADDRESS Department of Clinical Physiology, Anaesthesia, and Intensive Care, National Heart and Lung Institute, Royal Brompton National Heart and Lung Hospital, Sydney Street, London SW3 6NP, UK (P D. Macnaughton, MRCP, T. W. Evans, MD).
Correspondence to Dr T
W Evans.
SCIENCE & PRACTICE
Scientific perspectives
on
adult
respiratory distress
syndrome JOHN E. REPINE The adult respiratory distress syndrome (ARDS) is often thought to be common, to have a single pathogenetic mechanism, and to have no effective treatment. Although patients do die from ARDS, its true incidence remains unknown. Some estimates put the number of new cases of ARDS each year in the USA at about 150 000 with a 50% death rate. However, the severity of ARDS may vary widely and improvements in intensive care may have increased the incidence of ARDS substantially in recent years. The notion of a final common pathway, through which diverse precipitating insults act to cause lung inflammation, microvascular injury, and progressive hypoxaemia, is an attractive one because it offers hope of specific interventions. Unfortunately, it is not consistent with the evidenced1 Clinical management is discussed in the companion paper by Macnaughton and Evans, but it must be said from the start that no pharmacological strategy has produced impressive results. Methylprednisolone2 and prostaglandin E13have shown no benefit in trials; the glutathione agonist N-acetylcysteine has seemed promising, but there is no evidence that it lessens mortality or improves functional indices.4 Clearly, we need more basic knowledge of the syndrome, and in this brief paper I review some of the principal hypotheses now under investigation. ARDS can be defmed both pathophysiologically and clinically. The clinical definition is given in the next article, but in my account I shall use acute non-cardiogenic oedematous lung injury, so as to include some indication of the processes leading to pulmonary damage.
Theories and influences
Complement and free radicals Evidence that neutrophils contribute to ARDS has accumulated rapidly.s ARDS lungs are populated by large numbers of neutrophils, many of which are adjacent to damaged endothelium (fig 1).6 In addition, the blood and bronchopulmonary lavage fluid contain mediators that can activate neutrophils in vitro and cause lung inflammation when given to laboratory animals. The blood neutrophils of ARDS patients show enhanced oxidative metabolism in vitro; and activated neutrophils promote damage and fluid leakage in isolated lungs and lung endothelial cell monolayers. Lastly, the acute oedematous lung injury in animals injected with neutrophil activators can be lessened by neutrophil depletion. Neutrophils might contribute to lung injury by release of oxygen radicals and elastase. ARDS patients have abovenormal amounts of oxidised antiproteases in lung lavage fluid and increased quantities of hydrogen peroxide in their breath.7 Although oxidants are produced by other cells, including macrophages and endothelial cells, elastase is derived only from neutrophils. Isolated lungs perfused with
stimulated normal neutrophils are damaged, whereas neutrophils from patients with chronic granulomatous disease, which are essentially normal except for their inability to make oxygen radicals, have no such effects. Elastase-induced injury is most striking after previous exposure to oxidants. In isolated lungs not subjected to oxidants, elastase is free from toxicity except in concentrations so high that they are unlikely to be achieved in vivo.8
Fig 1-Section from an ARDS lung showing accumulation of neutrophils and erythrocytes.
Neutrophil recruitment is probably initiated by release of chemotactic agents from lung cells that seem to be stimulated by airway insults, complement components, or endotoxin (fig 2). Neutrophils then accumulate near endothelial cells, to which they attach themselves.9 Lung neutrophil sequestration alone may not increase lung permeability. Neutrophils can transiently increase in the lung without causing damage.1o Neutrophil priming may be an important prerequisite for lung damage. One stimulus would preactivate the neutrophil so that it was more responsive to a second stimulus that caused release of amplified oxygen radicals and degranulation. Neutrophils from the blood or lungs of ARD S patients are in some cases activated and in other cases depressed.ll,12 Such differences might reflect priming or exhaustion of neutrophils. The interactions between the neutrophil and the endothelial cell are increasingly complex (fig 3).13 When all possible influences (table), together with the primary, secondary, and tertiary responses, are considered, the notion of a final common pathway is clearly unsatisfactory. ADDRESS Webb-Waring Lung Institute, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box C321, Denver, Colorado 80262, USA (Prof John E. Repine, MD)
467
POTENTIAL CONTRIBUTORY FACTORS IN ARDS
Complement Oxygen radicals Proteases (elastase) Endotoxin Eicosanoids (thromboxanes, Platelet-activating factor
prostaglandins, leukotrienes)
Cytokines (TNF,* interleukins, endothelin) Growth factors Kallikreins (kinins) Fragment D *Tumour necrosis factor
Fig 2-Factors influencing progression to ARDS.
neutrophil is an obvious target for therapy. Some approaches are highly specific and focus on neutralising a single agent-eg, elastase inhibitors and free-radical scavengers. Antioxidants may limit not only direct but also The
indirect effects of oxygen radicals, such as those that are mediated through enhancement of elastase toxicity, stimulation of thromboxane, or other oxygen-metabolite dependent processes (fig 3). Alternative, more general approaches, involve prevention of neutrophil adherence or secretion. 14,15 Another aspect of free-radical-induced tissue injury is that related to ischaemia-reperfusion.16 Localised vascular clotting and shunting might lead to localised ischaemiareperfusion events. The mechanisms responsible for reperfusion injury are unknown. According to the xanthine oxidase (XO) hypothesis, ischaemia causes conversion of xanthine dehydrogenase (XD) to XO with catabolism of ATP hypoxanthine (a substrate for XO). Reperfusion provides the oxygen necessary for superoxide (0) and hydrogen peroxide (H202) formation. In the presence of iron (Fe), these metabolites form highly toxic oxygen species, such as hydroxyl radicals (-OH). These events have
Fig 3-Neutrophil-endothelial cell interactions in ARDS. XD =xanthine oxidase; MPO= myeloperoxidase; GSH =glutathione. O2= superoxide anion.
468
been reported in several systems where XO inhibitors-eg, tungsten or allopurinol--or oxygen-radical scavengers protect against reperfusion damage. Neutrophils also contribute to injury following ischaemia-reperfusion insults by oxygen radical and other mechanisms." Supranormal amounts of XO have been found in blood from patients with ARDS, and XO is increased in lungs compared with hearts in rabbits. Release of XO may provide a marker of endothelial damage, since it is normally concentrated in endothelium. Distribution of this enzyme via the circulation may account for inflammation and injury at distant sites in the lung or other organs.18 Multiple organ failure after the onset of ARDS carries a poor prognosis. This catastrophe may be due to the same systemic processes that damage the lung; in solid organs the ill-effects might show themselves later because permeability defects are not so harmful to function.1
Endotoxaemia The observation that the amount of lymph in sheep lungs increased after injection of gram-negative bacteria or endotoxin suggested that endotoxin might be involved in the pathogenesis of ARDS.19 The effects of endotoxin on the lung closely resemble the findings in the ARDS lung. Endotoxin independently stimulates neutrophil and endothelial injury in vitro. Endotoxin may also have a protective effect on the lung. Rats pretreated with small doses of endotoxin are resistant to both hyperoxia-induced fatal acute oedematous lung injury and ischaemia-reperfusion injury. The alveolar epithelial lining fluid of ARDS patients shows high antioxidant activity.2O Use of monoclonal antibodies should clarify whether the role of endotoxin is fundamental.21 Cytokines are also potentially important mediators in ARDS. Tumour necrosis factor (TNF) is likely to be involved in ARDS that accompanies sepsis and shock. TNF promotes neutrophil adherence by increasing surface glycoproteins, c3bi, and interleukin-1. TNF may also affect tissue procoagulant activity and contribute to thrombosis and clotting of small vessels. TNF causes pulmonary oedema in rats,22 and treatment with anti-TNF monoclonal antibodies prevents septic shock and lethal bacteraemia. TNF also has protective properties .23,24 Interleukins may also be detrimental or protective.23
PAF, a product of all the suspected inflammatory cells, is likely to mediate some of the effects of ARDS.25 To date, PAF has not been measured in blood or lavage fluid of ARDS patients; the assay is difficult. Surfactant Surfactant defects may likewise be an important influence in ARDS. Defective surfactant activity may result from wash-out or dilution after lung fluid accumulation, protein denaturation by oxidants, or injury to the type II pneumocyte. Abnormalities in surfactant could increase alveolar surface tension, and thereby promote atelectasis and interstitial fluid accumulation. Profound hypoxaemia would ensue. The ability to stimulate surfactant production and to give surfactant into airways opens exciting prospects, though it is possible that the additional surfactant would be inactivated by the inflammatory process. Some of these issues are discussed in the accompanying article.
Future
The pathogenesis of ARDS is multifactorial. Are certain individuals prone to the development of ARD S? There may be unrecognised intrinsic differences in host responses. Investigative techniques are not always specific and better laboratory animal models are needed.26 Species differences may exist. For instance, elastase may be different in different species and, as a result, the effectiveness of an elastase inhibitor in one animal may not predict its effectiveness in man. Moreover, experiments in animals, where the insult is short-lasting, may present a misleading picture for man, in whom the insult is persistent. Moreover, in man there are often several insults, such as shock and secondary infection, whereas usually only a single insult is tested in animal models. ARDS is a complicated disease process; unfortunately, this complexity has prevented any substantial progress in drug therapy. I fear that few effective treatments will become available until we have a much better basic understanding of the pathogenetic mechanisms leading to ARDS. Such developments will have important implications for other inflammatory disorders. We thank Ms text of this
are
located in the
J. D. Smith for her expert preparation of the graphics and
paper. Dr Polly Parsons kindly provided the lung section from the
ARDS patient.
Alveolar macrophages
Macrophages
challenges
lung
and
can
release
radicals, proteases, cyclo-oxygenase and lipoxygenase derivatives, and cytokines. Macrophages also release chemotaxins, adherence-promoting factors, and neutrophil secretagogues. A causal link between pulmonary oxygen
damage and these factors has not been established. Lipid mediators Many changes that are found in lungs of ARDS patients could be attributable to lipid-derived factors, such as eicosanoids and platelet-activating factor (PAF). These factors influence vascular reactivity and augment inflammation. For instance, thromboxane is a potent vasoconstrictor that has been found in high concentrations in lung lavages from ARDS patients. Leukotrienes are increased in lavages of ARDS patients; leukotriene B4 has chemotactic activity for neutrophils, eosinophils, and monocytes and could contribute to ARDS by increasing phagocytic cell recruitment.
REFERENCES
JE, Christman JW. Mechanisms and mediators of the adult respiratory distress syndrome. Clin Chest Med 1990; 11: 621-32. 2. Bernard GR, Luce JM, Sprung CL, et al. High dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 1987; 317: 1565-70. 3. Bone RC, Slotman G, Maunder R, et al. Randomized double-blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome. Chest 1989; 96: 114-19. 4. Bernard GR, Swindell BB, Meredith MJ, Carroll FE, Higgins SB. Glutathione (GSH) repletion by N-acetylcysteine in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1989; 139: 1. Rinaldo
221A. 5.
Repine JE, Beehler CJ. Neutrophils and adult respiratory distress syndrome: two interlocking perspectives in 1991. Am Rev Respir Dis 1991; 144: 251-52. JE, Davis WB, Holter JR, Mohammed JR, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome: clinical and pathophysiologic significance. Am Rev Respir Dis 1986,
6. Weiland
133: 218-25. 7.
Sznajder JI, Fraiman A, Hall JB, et al. Increased hydrogen peroxide in the expired breath of patients with acute hypoxemic respiratory failure. Chest 1989; 96: 606-12.
469
8. Baird BR, Cheronis JC, Sandhaus RA, Berger EM, White CW, Repine JE. O2 metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs. J Appl Physiol 1986; 61: 2224-29. 9. Worthen GS, Schwab B, Elson EL, Downey GP. Mechanics of stimulated neutrophils: cell stiffening induces retention in capillaries. Science 1989; 245: 183-84. 10. Martin TF, Pistorese BP, Chi EY, Goodman RB, Matthay MA. Effects of leukotriene B4 in the human lung: recruitment of neutrophils into the alveolar spaces without a change in protein permeability. J Clin Invest 1989; 84: 1609-19. 11. Zimmerman GA, Renzetti AD, Hill HR. Functional and metabolic activity of granulocytes from patients with adult respiratory distress syndrome. Am Rev Respir Dis 1983; 127: 290-300. 12. Martin TR, Pistorese BP, Hudson LD, Maunder RJ. The function of lung and blood neutrophils in patients with the adult respiratory distress syndrome. Implications for the pathogenesis of lung infections. Am Rev Respir Dis 1991; 144: 254-62. 13. Mulligan MS, Hevel JM, Marletta MA, Ward PA. Tissue injury caused by deposition of immune complexes is L-arginine dependent. Proc Natl Acad Sci USA 1991; 88: 6338. 14. Riva CM, Morganroth ML, Ljungman AG, et al. Iloprost inhibits neutrophil-induced lung injury and neutrophil adherence to endothelial monolayers. Am J Respir Cell Mol Biol 1990; 3: 301-09. 15. Leff JA, Baer JW, Kirkman JM, Bodman ME, Ostro MJ, Repine JE. Post-injury treatment with liposome-encapsulated prostaglandin E1 decreases acute edematous lung injury ("ARDS") in rats given interleukin-1 intratracheally. Clin Res (in press). 16. Kennedy TP, Rao NV, Hopkins C, Pennington L, Tolley E, Hoidal JR. Role of reactive oxygen species in reperfusion injury of the rabbit lung. J Clin Invest 1989; 83: 1326-35.
17. Linas
SL, Shanley PF, Wittenberg D, Berger E, Repine JE. Neutrophils ischemia-reperfusion injury in isolated perfused rat kidneys. Am J Physiol 1988; 24: 728-35. 18. Terada LS, Dormish JJ, Leff JA, Willingham IR, Repine JE. Circulating accentuate
xanthine oxidase mediates lung neutrophil sequestration following mesenteric ischemia. Clin Res 1989; 37: 145A. 19. Brigham KL, Bowers RE, Haynes J. Increased sheep lung vascular permeability caused by Escherichia coli endotoxin. Circ Res 1979; 45: 292-97. 20. Lykens M, Davis WB, Pacht E. Increase in alveolar epithelial fluid antioxidant activity in ARDS. Clin Res 1988; 36: 508A. 21. Bernard GR, Grossman JE, Campbell GD, Gorelick KJ. Multicentre trial of a monoclonal anti-endotoxin antibody (XOMEN E-5) in gram negative sepsis. Chest 1989; 96: 137A. 22. Ferrari-Baliviera E, Mealy K, Smith RL. Tumor necrosis factor induces adult respiratory distress syndrome in rats. Arch Surg 1989; 124: 1400-05. 23. White CW, Ghezzi P, Dinarello CA, Caldwell SA, McMurtry IF, Repine JE. Recombinant tumor necrosis factor/cachectin and interleukin I pretreatment decreases lung oxidized glutathione accumulation, lung injury and mortality in rats exposed to hyperoxia. J Clin Invest 1987; 79: 1868-73. 24. Alexander HR, Sheppard BC, Jensen JC, et al. Treatment with recombinant tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis. J Clin Invest 1991; 88: 34-39. 25. Braquet P, Hosford D. The potential role of platelet-activating factor (PAF) in shock, sepsis and adult respiratory distress syndrome (ARDS). Prog Clin Biol Res 1989; 308: 425-39. 26. Flick MR. Mechanisms of acute lung injury: what have we learned from experimental animal models?. Clin Care Clin 1986; 2: 455-70.
Management of adult respiratory distress syndrome
The adult respiratory distress syndrome (ARDS) was first characterised in 1967.1 A wide range of both direct and indirect pulmonary insults can lead to the high-permeability pulmonary oedema that characterises this condition with mortality rates varying from 50-90%.2 ARDS is now recognised as the pulmonary component of a generalised disorder of endothelial structure and function brought on most commonly by trauma or sepsis and resulting in failure of multiple organ systems (the multiple organ failure
syndrome).
Diagnosis Clinical criteria The diagnosis of ARDS is mainly clinical and criteria vary between centres (table). The effects of pulmonary endothelial damage range from mild respiratory impairment to the overwhelming pulmonary oedema that characterises ARDS.3 Murray and colleagues have described a scoring system that categorises patients according to their underlying condition and quantifies the severity of lung injury from chest radiographic appearances, degree of hypoxaemia, requirement of positive end-expiratory pressure (PEEP), and thoracic compliance.4 This system allows ARDS to be defmed more precisely and could be a valuable method of assessing disease progression.
Haemodynamic measurements The insertion of a balloon-tipped pulmonary artery catheter allows pulmonary artery occlusion pressure and cardiac output
be monitored. These data and blood gas from arterial and mixed venous blood enable oxygen delivery (D02) and peripheral
measurements
samples
to
uptake (V02) to be calculated. Several studies have an abnormal relation between D02 and V02 in some patients with ARDS and sepsis.5,6 At rest, V02 is normally independent of DOz as long as the latter is maintained above a critical level, but oxygen consumption becomes delivery dependent above this threshold in ARDS, oxygen
identified
such that the oxygen extraction ratio (V02/D02) remains (fig 1). The mechanisms underlying this observation are poorly understood, but it has been interpreted as evidence of occult tissue hypoxia and has been associated with a high mortality. An increased plasma lactate concentration, which may reflect an imbalance between metabolic requirements and DOz, could be a useful marker of oxygen-uptake supply dependency.7 constant
ADDRESS Department of Clinical Physiology, Anaesthesia, and Intensive Care, National Heart and Lung Institute, Royal Brompton National Heart and Lung Hospital, Sydney Street, London SW3 6NP, UK (P D. Macnaughton, MRCP, T. W. Evans, MD).
Correspondence to Dr T
W Evans.
