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Adult Respiratory Distress SyndromeUNDERSTANDING of the adult respiratory distress

syndrome (ARDS) grows apace but therapeuticadvance remains tantalisingly just upon the horizon-and no nearer. It is a good time to make an inventory ofour knowledge and to look to the future.Some twenty years ago, it was recognised that

respiratory failure could develop in patients who hadno obvious involvement of the lung.’ I This

complication arose in varying conditions includingsepticaemia, severe trauma, massive blood transfusion,and pancreatitis, after a delay of 24-72 h. Histologicalexamination suggested superficial similarity to theneonatal respiratory distress syndrome and the termadult respiratory distress syndrome was coined.The syndrome is common-in Britain there may be

10 000-15 000 cases each year 2-and has a case-

fatality rate of 60% in many series, and even 90% wheresepsis is predominant.3,4 In the initial stages it ischaracterised by a reduced lung compliance with a highventilation/perfusion imbalance leading to severe

hypoxia. Later, pulmonary hypertension is added, butunless there are additional cardiac complications thewedge pressure remains norma1.5-7 Radiologically,there are widespread bilateral infiltrates which

progressively become confluent-though often sparingthe costophrenic angles and apices.An important advance in understanding of the syndrome

came with the realisation that intravenous injection of gram-negative bacteria or endotoxin provided an excellent model inanimals. Transient pulmonary hypertension was followed byprogressive lung damage starting with interstitial pulmonaryoedema-itself caused by increased capillary permeability.8no1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults.

Lancet 1967; ii: 319-23.2. Wardle EN. Shock lungs; the post traumatic respiratory syndrome. Quart J Med 1984;

211: 317-19.

3. Kaplan RL, Sahn SA, Petty TL. Incidence and outcome of the respiratory distresssyndrome in gram-negative spesis. Arch Intern Med 1979; 139: 867-69.

4. Fine AM, Lippman N, Holdzman H, Eliarz A, Goldberg SK. The risk factors,incidences and prognosis of the adult respiratory distress syndrome followingsepticemia. Chest 1983; 83: 40-42.

5. Petty TL, Ashbaugh DG. The adult respiratory distress syndrome-clinical features,factors influencing prognosis and principles of management. Chest 1971; 70:233-39.

6. Pontoppidan H, Geffin B, Lowenstein E. Acute respiratory failure in the adult. N EnglJ Med 1972; 287: 690, 743, 799.

7 Bredenberg CE. Acute respiratory distress. Surg Clin N Am 1974; 54: 1043-66.

So the concept grew up that low-pressure (permeability)oedema was the central, initiating event and the other

pathological changes seen in the fully developed syndromewere secondary. These include alveolar flooding and

haemorrhage (caused when interstitial oedema damages thealveolar walls), atelectasis (probably from decreased

surfactant), vascular microthrombi, and pneumonia. Thismodel may be an oversimplification for, as we shall see,prevention of the oedema may not always stop the

development of other features of the syndrome. Nonetheless,success in unravelling fluid dynamics and attributing theonset ofARDS to a "permeability oedema" promptly led to asearch for the mechanism of capillary damage and forcedconsideration of whether there was a single mechanism ormany.Complement-induced neutrophil aggregation in the lung

capillaries is an important mechanism of damage. It is readilytriggered by gram-negative endotoxaemia (which is

frequently present even when, as in severe trauma, it is notthe primary event), by teichoic acid in gram-positive disease,and by other factors such as thermal injury and the foreignsurfaces of dialysis membranes. 11,12 Its importance isindicated by neutrophil clustering in lung capillaries in thehuman syndrome and animal models, by correlation betweensyndrome onset, severity, and complement C5a levels, and byexperimental demonstration that the syndrome was limitedby neutropenia. 13-15 After the initial aggregation the capillarydamage is thought to result from free radicals of oxygengenerated by the activated white cells.12,15-17

Lately, intense interest has been aroused by the possiblerole of eicosanoids. Various metabolites of arachidonic acid

(by both the cyclo-oxygenase and lipo-oxygenase pathways)can mimic virtually the whole range of primary andsecondary pathophysiology seen in ARDS includingpulmonary hypertension (prostaglandins A2,, B2, D2, , F2a’H2, thromboxane B2),18 changes in lung mechanics

(leukotrienes B4 and D4),"° hypoxaemia (prostaglandinEl ),21 increased permeability (leukotrienes C4 and D4),22,23

8. Bachofen M, Bachofen H, Weibel E. Lung edema in the adult respiratory distresssyndrome. In: Fishman AP, Renkm EW, eds. Pulmonary edema. Baltimore:Williams and Wilkins, 1979.

9. Gorin AB, Weidner WJ, Demling RM, Staub NC. Non-invasive measurements ofpulmonary transvascular protein flux in sheep. J Appl Physio! 1978; 45: 225-33.

10. Prichard JS, Rajagopalan B, Lee G de J. Transvascular albumin flux and the interstitialwater volume in experimental pulmonary oedema in dogs. Clin Sci 1980; 59:105-13.

11. Jacob HS, Craddock PR, Hammerschmidt DE, Muldow CF. Complement inducedgranulocyte aggregation. N Engl J Med 1980; 302: 789-93.

12. Till GO, Beauchamp C, Menapace D, et al. Oxygen radical dependent lung damagefollowing thermal injury of rat skin. J Trauma 1983; 23: 269-77.

13. Hammerschmidt DE, Weaver LJ, Hudson LD, et al. Association of complementactivation and elevated plasma C5a with adult respiratory distress syndrome. Lancet1980; i: 947-49.

14. Heflm AC, Brigham KL. Prevention by granulocyte depletion of increased vascularpermeability of sheep lung following endotoxemia. J Clin Invest 1981; 68: 1253-60.

15. Flick MR, Peel A, Staub NC. Leucocytes are required for increased lung microvascularpermeability after microembolisation in sheep. Circulation Res 1981; 48: 344-51.

16. Tate RM, Repine JE. Neutrophils and the adult respiratory distress syndrome. Am RevResp Dis 1983; 128: 552-59.

17. Baldwin SR, Simon RH, Grum CM, Ketai LH, Boxer LA, Devall LJ. Oxidant activityin expired breath of patients with adult respiratory distress syndrome Lancet 1986;i: 11-14.

18. Brigham KL, Dukes SS. Prostaglandms in lung disease. Semin Resp Med 1985; 7:11-16.

19. Sheller JR, Brigham KL. Effect of leukotrienes on sheep airway smooth muscle.Am Rev Resp Dis 1984; 4: A232 (abstr).

20. Ogletree ML, Snapper JR, Brigham KL. Immediate pulmonary vascular and airwaysresponses after intravenous LTD4 injections in awake sheep. Physiologist 1982; 25:275 (abstr).

21. Ogletree ML, Brigham KL. Pulmonary vascular and hemo-dynamic effects of

prostaglandin E in unanesthetised sheep Microcirculation Endothelium Lymphatics1984; 1: 307-27.

22. Williams T, Piper P. The action of chemically pure SRS-A on the microcirculation invivo. Prostaglandins 1980; 19: 779-89.

23. Albert R, Henderson W. Leukotriene C4 increases pulmonary vascular permeabilty inexcised rat, lungs. Fed Proc 1982; 41: 1503 (abstr).

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and enhanced neutrophil adherence (leukotriene B4).Furthermore, release of eicosanoids, often in a specificsequence, has been observed both in the human syndromeand in animal models.1S,25,26 Finally, drugs that inhibit

various phases of arachidonic acid metabolism can block theexperimental syndrome and this suggests that at least some ofthe eicosanoids play an integral rather than an incidental role(see below). Despite the extent of the new knowledge a clearview of this role has not yet emerged, but a sensible

suggestion is that, in granulocyte aggregation, they act asmodulators and mediators27 and the production of the sameeicosanoids by different mechanisms under othercircumstances links these forms ofARDS with those in which

septicaemia predominates.In this explosion of knowledge, lung recovery has received

little attention, despite its importance if mortality andmorbidity are to be reduced. In brief, the syndrome is largelyirreversible once initiated-for the flooding of the interstitialspace (and alveoli) with plasma proteins limits subsequentosmotic resorption of fluid, overwhelms the plasminogensystem (thereby allowing deposition of a fibrin network forsubsequent fibrosis), and occludes essential lymphatics withfibrin clots. Finally, epithelial healing occurs by proliferationof type II pneumocytes; and, although some partialtransdifferentiation to type I occurs, this is incomplete.z8The very irreversibility of the syndrome forces

attention upon the timing of the events that lead to it.Although in the human syndrome onset of respiratoryfailure may be delayed, the animal model emphasisesthe speed with which events follow one another.Granulocyte aggregation occurs rapidly," whilst mosteicosanoids are rapidly produced and rapidlydestroyed. Of those identified in lymph, thromboxaneB2, 6-keto-PGFl, 5-hydroxyeicosatetraenoic acid, and12-HETE show their maximum concentrations at

I - 0, 1 - 5, 2-5, and 3 ° 0 h respectively.’8 Of thephysiological events, the initial phase of pulmonaryhypertension is at its height 1 h after endotoxininjection and permeability changes changes are fullyestablished within 2 h.9,1O,IS

Unfortunately, this proliferation of knowledge hasnot yet led to effective treatment and, since the

syndrome is both irreversible and of rapid onset,current therapy consists only of support.2,2S,29 Thisincludes control of sepsis, prevention of intensificationof oedema by control of fluid balance and pulmonaryvascular pressures, treatment of respiratory failure bysupplemental oxygen, and artificial ventilation (withpositive end expiratory pressure if necessary). Anyadvance must depend either on development of

preventive measures or on discovery of some method ofreversing the secondary changes. Prevention of ARDSis in its infancy and counter measures are little differentfrom those used in supportive treatment. However,24. Dahlen S, Bjork J, Hedqvist P, et al. Leukotrienes promote plasma leakage and

leukocyte adhesion in post-capillary venules. Proc Natl Acad Sci 1981; 78: 3887-9125. Brigham KL. Mechanisms of lung injury. Clin Chest Med 1982; 3: 9-24.26 Frolich J, Ogletree M, Brigham KL. Gram-negative endotoxemia in sheep: pulmonary

hypertension correlated to pulmonary thromboxane synthesis. Adv ProstaglandinThromboxane Res 1980; 7: 745-49.

27. Weksler BB, Goldstein IM. Prostaglandin interactions with platelets and

polymorphonuclear leukocytes in hemostasis and inflammation. Am J Med 1980;68: 419-28.

28. Prichard JS. Edema of the lung. Springfield, Illinois Charles C. Thomas, 1982.29. Transbaugh RF, Lewis RF. Respiratory insufficiency. Surg Clin N Am 1982; 139:

867-69.

agents may already be available that can opposedevelopment of the syndrome. These includeantibodies to the lipid-A component of endotoxin,corticosteroids, prostanoids, leukotrienes, prostanoidand leukotriene inhibitors, inhibitors of cyclo-oxygenase and lipo-oxygenase, and free radical

scavengers. Superficially, corticosteroids seem themost promising drugs immediately available and thereis theoretical support for their use. They inhibit

complement-induced granulocyte aggregation.","Furthermore, they inhibit phospholipase A2, the

enzyme responsible for liberation of free arachidonicacid from membrane phospholipids. Thus, ifeicosanoids do play the important roles currentlyenvisaged, steroids should inhibit these. Finally, underexperimental conditions, the increase in capillarypermeability is prevented if steroids are given beforeadministration of endotoxin.32-34 Unfortunately,despite this evidence of potential usefulness, no

adequate trial has ever shown that steroids are beneficialin the established syndrome. This may be because,almost inevitably, they are used too late to preventpermeability change35-39 or subsequent secondarychanges,4° but in the experimental model steroids donot block all the effects of endotoxin, for the early,transient pulmonary hypertension is only reduced andlater hypoxia is not prevented.34 So, a further step hasbeen to combine steroids with the cyclo-oxygenaseinhibitor meclofenamate. Under. experimental condi-tions, abolition of the response is then virtuallycomplete.41Among other approaches based upon knowledge of

eicosanoids, prostacyclin (PGI2) has some protectiveeffect-perhaps dependent upon its properties as avasodilator and inhibitor of granulocyteaggregation.42,43 The benefit is nonetheless puzzlingsince the appearance of PGI2 in pulmonary lymphcorrelates with the severity of lung damage.’8

30. Sheagren JN. Septic shock and corticosteroids. N Engl J Med 1981; 305: 465-67.31. Hammerschmidt DE, White JG, Craddock PR, Jacobs HS. Corticosteroids inhibit

complement induced granulocyte aggregation. J Clin Invest 1979; 63: 798-803.32. Pringleton WW, Coalson JJ, Hinshaw LB, Guenter, CA. The effect of steroid pre-

treatment on development of shock lung. Lab Invest 1972; 27: 445-56.33. Hinshaw LB, Beller-Todd BK, Archer LT, et al. Effectiveness of steroid/antibiotics

treatment in primates administered LD100 Escherichia coli. Ann Surg 1981; 194:51-56.

34. Brigham KL, Bowers RE, McKeen CR. Methyl-prednisolone prevents increased lungvascular permeability following endotoxemia in sheep. J Clin Invest 1981; 67:1103-10.

35. Bone RC. Adult respiratory distress syndrome: a need for comparative studies. ArchIntern Med 1978; 138: 908

36. Sprung CL, Panagista VC, Marcial EH, et al. The effects of high dose corticosteroids inpatients with septic shock. N Engl J Med 1984; 311: 1137-43.

37 Wynn JW, Modell JH. Respiratory aspiration ofthe stomach contents. Ann Intern Med1980; 87: 466-74.

38. Moylan JA. Diagnostic techniques and steroids. J Trauma 1979; 19 (suppl): 91739. Schonfeld SA, Ploysongsant Y, Dilisio R, et al. Fat embolism prophylaxis with

corticosteroids. Ann Intern Med 1983; 99: 438-43.40. Sibbald WJ, Anderson RR, Reid B, Holliday RL, Driedger AA. Alveolar-capillary

permeability in human septic ARDS: Effect of high dose corticosteroid therapyChest 1981; 79: 133-42.

41. Begley CJ, Ogletree ML, Meyerick BO, Brigham KL. Modification of pulmonaryresponses to endotoxemia in awake sheep by steroidal and non-steroidal anti-inflammatory agents. Am Rev Resp Dis 1984; 130: 1140-64.

42. Kraus MM, Utsonomiya T, Feuerstein G, Wolf JHN, Sheparo D, Hechtman HBProstacyclin reversal of lethal endotoxemia in dogs. J Clin Invest 1981; 67:1118-25

43. Stemberg SM, Dehring DJ, Gower WR, Vento JM, Lowry BD, Cloutier CTProstacyclin therapy in experimental septic acute respiratory failure. J Surg Res1983; 34: 298-302

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Imidazole, 13-azo-prostanoic acid, and deficiency ofessential fatty acids have similarly been assessed inrats.44 Vasoactive intestinal peptide, which counteractscertain leukotriene effects, is also potentially useful intherapy.45 A different approach has been to use the freeradical scavengers N-acetyl cysteine, catalase, andsuperoxide dismutase in an attempt to prevent damageby free radicals from aggregated neutrophils. Again, inthe experimental model, these drugs do limit damagewhen given early.19,46,47 Finally, since lipid A is thetoxin common to all gram-negative endotoxins, thepossibility of its neutralisation by appropriate IgGantibodies is intriguing. 48,49Thus, after these experimental studies, we are surely

at the stage where further clinical trials are essential.Whatever drugs are to be evaluated, it is obvious thatthey must be used at the earliest possible moment.Furthermore, since the syndrome develops in onlyabout 7% of all those at risk,28 any assessment will take aconsiderable time unless the actual cases can beidentified much earlier. There are two possibilities. Inthe one, basic physiological, biochemical, and

immunological knowledge is applied. In the other,indices of risk are derived from clinical observations.The experimental identification of ARDS as a

"permeability oedema" led to measurement of

capillary permeability in man, but the technique iscumbersome and the time taken could delay therapy.49Biochemical and immunological markers have beensought in blood50 and in bronchoalveolar-lavage fluidbut the difficulty is to find one that appears early in thesequence of damage. Gram-negative endotoxin couldmark a phase even before damage develops but may nothave universal applicability. C5a complement is

suitable,’3 but more attention has lately beenconcentrated on leukotrienes (particularly LTB4) andother neutrophil chemotactic substances in the lungsthemselves. 51,52PÇJI2 concentrations relate to

endothelial damage, 18 as does extraction of labelledpropranolol and serotonin, 53 but these may signal aphase too late for worthwhile therapeutic intervention.Oxidant activity in exhaled breath marks a mechanismof endothelial damage, but oral contamination mayrestrict the technique to intubated patients.17 As to44. Cook JA, Wise WC, Halushka PV. Elevated thromboxane levels in the rat during

endotoxin shock: protective effects of imidazole; 13-azo-prostanoic acid or essentialfatty acid deficiency. J Clin Invest 1980; 65: 227-30.

45. Said SS. Mechanisms of acute lung injury. Prog Crit Care Med 1985; 2: 36-43.46 Turrens JF, Crapo JD, Freeman BA. Protection against oxygen toxicity by

intravenous injection of liposome entrapped catalase and superoxide dismutase.J Clin Invest 1984; 73: 87-92.

47. McMillan DD, Boyd GN. The role of anti-oxidants and diet in the prevention ofoxygen induced lung microvascular injury Ann NY Acad Sci 1982; 384: 535-43.

48. Wardle EN. Importance of anti-lipid A in prevention of shock lung and acute renalfailure World J Surg 1982; 6: 616-23.

49. Ziegler EJ, McCutchan JA, Fieren J, et al. Treatment of gram-negative bacteremia andshock with human anti-serum to a mutant E coli. N Engl J Med 1982; 307: 1225-30.

50 Gorin AB, Kohler J, Denardo G. Non-invasive measurement of pulmonarytransvascular protein flux in normal man. J Clin Invest 1980; 66: 869-77.

51. Hussein A, Lloyd J, Tagan H, et al. Granulocytes and slow-reacting substances ofanaphylaxis in high permeability lung oedema of adult respiratory distress

syndrome. Clin Sci 1984, 67: 52P.52 Parsons PE, Fowler AA, Hyers TM, Henson PM. Chemotactic activity in

bronchoalveolar lavage fluid from patients with adult respiratory distress syndrome.Am Rev Resp Dis 1985; 132: 490-93

53 Morell DR, Dargent F, Bachmann M, Suter PM, Junod AF. Pulmonary extraction ofserotonin and propranolol in patients with adult respiratory distress syndrome.Am Rev Resp Dis 1985; 132: 479-84.

clinical prediction of the syndrome, we know that themain pointers are sepsis, aspiration, multiple bodytrauma, major blood transfusion, overwhelmingpneumonia, and disseminated intravascular coagu-lation. 14, 11 This list is too extensive to be of more than

marginal practical help, but more detailed analysis hasidentified three variables of particular significance-namely, less than 10% band forms on the initial

peripheral blood smear, persistent acidaemia, andreduced (calculated) serum HC03. 55,56In twenty years, knowledge of ARDS has come from

mere recognition to considerable understanding. Wenow have many drugs that experimentally can modifyor prevent the syndrome. But in the coming clinicalassessments at least two conceptual difficulties remain.Firstly, can therapy be applied sufficiently early, orwill the explosive nature of the syndrome’s onsetalways be victorious? Here, the delay in onset of thehuman syndrome gives hope. Secondly, might bettercontrol of ARDS reveal that it is not even the pivotalpoint of a much broader syndrome of capillary damageand vasomotor instability?57,58

Haemostatic Abnormalities and

Malignant DiseaseTHE syndrome of recurrent venous thrombosis in a

patient with visceral carcinoma, often occult, is linkedwith the name of Trousseau. Bell and co-workers1 havedescribed two cases that illustrate the difficulties posedby the coagulation changes in such patients. They triedheparin and warfarin treatment, but only heparinseemed to control the thrombotic process.Abnormalities of clotting- and fibrinolysis are

common in patients with malignant disease. Theincidence varies according to the type and extent of thetumour, but some abnormality is present in about 50%of patients with tumours and over 90% of patients withmetastatic disease.2,3 Often these abnormalities causeno fresh symptoms, but up to 15% of patients haveclinically evident bleeding or thrombosis, theincidence again varying according to the load and typeoftumour.4 These complexities, coupled with a lack ofgood controlled clinical trial data, exclude a universaltreatment approach. At the acute end of the spectrum isthe patient who presents with severe recurrent

54. Pepe E, Potkin PJ, Reus DH, et al. Clinical predictors of adult respiratory distresssyndrome. Am J Surg 1982; 144: 124-30.

55. Fowler AM, Hamman RF, Good JT, et al. Adult respiratory distress syndrome: riskwith predispositions. Ann Intern Med 1983; 98: 593-97.

56. Fowler AM, Hamman RF, Zerbe GO, Benson KN, Hyers TM. Adult respiratorydistress syndrome: prognosis after onset. Am Rev Resp Dis 1985; 132: 472-78.

57. Montgomery AB, Steager MA, Carrico CJ, Hudson LD. Causes of mortality in patientswith the adult respiratory distress syndrome. Am Rev Resp Dis 1985; 132: 485-89.

58. Faden AI, Holaday JW. Experimental endotoxic shock: the pathophysiologicalfunction of endorphins and treatment with opiate antagonists. J Infect Dis 1980;142: 229-38.

1. Bell WR, Starksen NF, Tong S, et al. Trousseau’s Syndrome. Devastatingcoagulopathy m the absence of heparin. Am J Med 1985; 79: 423-30.

2. Miller SP, Sanchez-Avalos J, Stefanski T, et al Coagulation disorders in cancer.Clinical and laboratory studies. Cancer 1967; 20: 1452-65.

3. Slichter SJ, Harker LA. Hemostasis in malignancy. Ann NY Acad Sci 1974; 230:252-61.

4. Sun NCJ, McAfee WM, Hum GJ, et al Hemostatic abnormalities in malignancy, aprospective study of one hundred patients. Am J Clin Pathol 1979; 71: 10-16.