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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.

470

Fig 1-Theoretical oxygen delivery (D02) and uptake (V02) normal subjects and in patients with ARDS.

in

Vascular permeability

Despite the diverse range of conditions that can cause ARDS, the ensuing pulmonary damage is uniform and characterised by increased permeability of the alveolar-

capillary membrane. This can be assessed by measuring the accumulation of intravenously injected radiolabelled transferrin in the pulmonary interstitium (the protein accumulation index).8 The clinical value of such measurements remains unclear, since patients with minor degrees of lung injury may have abnormalities of endothelial permeability of the same order as those with ARDS.3

Lung function ARDS is characterised by a reduction in functional residual capacity. Many ventilatory strategies used in ARDS are aimed at increasing this variable, and its measurement may allow both more precise monitoring of treatment and better assessment of the course of the disease process.9 Thoracic compliance is decreased, usually to less than 30 ml/cm H2O. Measurements of compliance can indicate the severity of lung injury and help selection of the

optimum method of ventilatory support. 10

Management Treatment of patients with ARDS remains supportive and aims to maintain D02 to all organ systems, as most patients with ARDS usually die from multiple organ failure rather than respiratory impairment.11 The underlying cause should be treated and any suspected sites of sepsis should be managed aggressively with broad-spectrum antibiotics and

surgical drainage. Respiratory support The spontaneously breathing patient-In patients whose lung injury is not severe, satisfactory oxygenation can be achieved by continuous positive-airways pressure

(CPAP) of between 5 and 10 cm H2O. The patient breathes spontaneously through an endotracheal tube or tightly fitting face mask an oxygen-air mixture delivered at a high flow (> 70 1/min). CPAP re-expands collapsed alveoli, functional residual capacity and compliance, such increasing that the work of breathing is reduced and gas exchange is improved. Mechanical ventilation-Most patients with ARDS require positive-pressure ventilation. Conventional techniques employ either controlled mandatory ventilation or synchronised intermittent mandatory ventilation. The synchronised technique allows the patient to initiate preset ventilator breaths whilst permitting spontaneous ventilation inbetween; the resulting lower mean intrathoracic pressure diminishes circulatory impairment and improves D02. However, ARDS frequently leads to a high respiratory drive and an increased respiratory muscle oxygen consumption. Controlled mandatory ventilation with sedation and neuromuscular blockade may then be preferable. Conventional techniques provide large tidal volumes (10-15 ml/kg) that promote the recruitment of collapsed alveoli and so overcome the adverse effects of increased alveolar dead space. Reduction in lung compliance may lead to high peak airway pressures and increase the risk of pneumothorax. Although barotrauma is probably influenced more by the severity of the underlying disease than by absolute airway pressures, it is advisable to manipulate tidal volume, inspiratory flow rate, and inspiratory time to keep peak inspiratory pressures as low as possible. The pressure-volume relation of the lung is non-linear (fig 2) and selection of an appropriate tidal volume and level of PEEP should move the lung to the steepest, most compliant part of the curve. PEEP prevents alveolar collapse at the end of expiration and will thus increase functional residual capacity, improve lung compliance, and reduce intrapulmonary shunt. However, since PEEP also increases mean intrathoracic pressure, so reducing venous return and cardiac output, oxygen delivery must be measured concurrently. The hypoxaemia of ARDS is difficult to correct even with high inspired oxygen concentrations, which may carry the risk of oxygen toxicity. Although there is no good evidence that an inspired oxygen above 60% exacerbates lung injury, most clinicians attempt to stay below this value.

New approaches to ventilation Conventional methods of ventilation, which expose the lung to high peak airway pressures, may exacerbate lung injury.12 New approaches to ventilation therefore aim to maintain a mean airway pressure high enough to recruit unstable alveoli and improve gas exchange whilst avoiding high peak inflation pressures. Inverse-ratio ventilation (IRV)-In this technique, a longer inspiratory phase increases the inspiratory to expiratory ratio to between 1:and 4:1. Volume-controlled IRV (VC- IRV) delivers a preset tidal volume irrespective of peak-inspiratory pressure and therefore allows a predictable clearance of CO2. Although mean airway pressure is increased and oxygenation is improved, substantial air trapping may occur with a rise in lung volume, high peak airway pressure, and a profound reduction in cardiac output. Pressure-controlled IRV (PC-IRV) delivers a constant preset inspiratory pressure for the desired inspiratory time and so avoids these risks. An early trial of PC-IRV showed improved oxygenation when conventional ventilation failed, whilst reducing peak airway pressure and

471

of uncontrolled trials are encouraging" and a controlled trial comparing extracorporeal CO2 removal combined with PC-IRV and conventional ventilation is in progress. One new development is an intravascular oxygenation device which, when placed in the inferior vena cava, allows gas exchange through microbore tubes coated with heparin. Animal work suggests that it can supply up to 90% of basal O2 requirements although early clinical experience with the technique has been limited. 18 Though theoretically attractive as a means of resting the injured lung and avoiding the damaging effects of mechanical ventilation, these highly invasive techniques are costly, have their own complications, and have not been shown to improve outcome in controlled trials. Their future is clearly linked to the effectiveness of other new modes of

ventilatory support. Fluid balance and renal support

Fig 2-Pressure-volume relation of the lung.

Appropriate PEEP

and tidal volume

can

limit changes

in

airway

pressure

without impairing cardiac function.13 Although a reduction in mortality has not been shown, PC-IRV is probably the best existing method of maintaining gas exchange. Airwaypressure-release ventilation allows the patient to breathe spontaneously while mean airway pressure is maintained with CPAP. COclearance is augmented by transient reductions in airway pressure, and lung volumes are allowed to fall.’4 The technique has been used successfully in patients with ARDS, although its effects on outcome remain uncertain. High-frequency jet ventilation-A high-pressure pulse (driving pressure) of oxygen/air mixture is delivered at 60-600 times per minute for a preset inspiratory time. Tidal volumes are smaller than the dead-space volume; gas exchange probably depends on convective forces. Peak airway pressures are less than those seen in conventional ventilation and the risk of barotrauma may be reduced. A prospective controlled trial showed that high-frequency jet ventilation can be used safely in acute respiratory failure although outcome was no better than that with standard techniques. The jet method was associated with improved alveolar ventilation but poorer arterial oxygenation. Jet ventilation at frequencies close to the natural resonant frequency of the lung (5-7 Hz) with high mean airway pressures has been shown recently to promote alveolar recruitment, thus improving gas exchange when conventional ventilation has failed. 16 Permissive hypercapnia-Tidal volume can be reduced to prevent high peak airway pressures although arterial CO2 will rise. Tidal volumes as low as 5 ml/kg have been used in patients with ARDS to keep peak airway pressures below 35 cm H20. Satisfactory oxygenation can be maintained and hypercapnia seems to be well tolerated.12 Extracorporeal membrane oxygenation-A catheter is inserted into the inferior vena cava via a femoral vein and blood is passed across a gas-exchanging membrane and back to the aorta via a femoral arterial catheter. Extracorporeal membrane oxygenation has not been associated with an improved outcome in ARDS.16 Extracorporeal CO2 removal is a similar venovenous technique that, when combined with low-frequency positive-pressure ventilation, reduces the minute-volume requirement, whilst gas exchange is maintained. The combination of normal pulmonary perfusion and minimum ventilation may provide the optimum conditions for lung repair. The results

inserted into the

The Starling relation predicts that a reduction in pulmonary vascular pressure decreases fluid flux in the presence of increased capillary permeability; and retrospective studies have suggested an improved outcome in patients with ARD S in whom a negative fluid balance and a reduced pulmonary artery occlusion pressure were obtained.19 Optimum management may include diuretics and fluid restriction provided that cardiac output and oxygen delivery are maintained. Renal failure is a frequent complication of the underlying conditions associated with ARDS and haemofiltration has proved valuable. 20

Circulatory support Cardiac output may be compromised in ARD S by several mechanisms including low filling pressures secondary to fluid restriction, high levels of CPAP or PEEP, and increased pulmonary vascular resistance. Myocardial function may be further compromised by circulating inflammatory mediators, especially in sepsis. Inotropes, such as dobutamine, are often required to maintain D02. Since delivery dependence ofV02 has been associated with a high mortality, therapy should probably be guided by target levels of oyxgen delivery and uptake.21 However, there are no prospective controlled trials of such therapy in patients with ARDS. D02 can be increased by fluid loading, blood transfusion, inotropes, and vasodilators. Prostacyclin raises D02 and VO2, reduces pulmonary vascular resistance, and improves right ventricular function in patients with increased pulmonary artery pressures secondary to ARDS,22 but has not been shown to influence mortality. Treatment of sepsis ARDS is almost invariably associated with sepsis, either the initiating factor or as a secondary complication. Chronic sepsis probably stimulates the inflammatory process and contributes substantially to multiple organ failure. Bacteriological evidence of sepsis should be sought and treated. Enteral feeding seems to carry a lower risk of pulmonary sepsis than parenteral nutrition.23 Enteral feeds may supply essential nutrients to the gut mucosa so helping to maintain its protective integrity and prevent absorption of bacterial products into the portal circulation.24 Enteral feeding should be given whenever possible, with parenteral as

supplementation if necessary. Prophylaxis against stress ulceration with agents that protect the gastric mucosa (eg, sucralfate) may be more appropriate than histamine (H2) receptor blockers, which can increase the risk of nosocomial pulmonary infection.25 Prophylactic antibiotic regimens

472

digestive tract) decrease the incidence of nosocomial pneumonia, but there is no clear effect on mortality. 26 (selective decontamination

of the

Drug therapy in acute lung injury Several anti-inflammatory agents have been tried in patients with ARDS. Corticosteroids have not been shown to be beneficial in reducing mortality in the acute stages,27 although longer term treatment may improve outcome in patients who have fibroproliferative disease after longlasting ARI7 S 28 Other strategies to combat immune activation are also attractive. A human monoclonal endotoxin antibody reduced mortality significantly when given to patients with gram-negative bacteraemia,z9 but its role in clinical practice be defined. No beneficial effect was found in patients who did not have confirmed gram-negative bacteraemia. ARDS is associated with abnormalities of surfactant function and early reports suggest a potential role for surfactant therapy.30

has yet

to

Conclusion

Improvements in ventilatory techniques and a greater understanding of oxygen supply and uptake relations in patients with ARDS have led to better techniques of organ support, but have failed to influence mortality significantly. However, as our understanding of the factors leading to ARDS increases, specific therapies should be forthcoming, which, when combined with the advances in supportive care described above, may result in an improved prognosis. REFERENCES

Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; ii: 319-23. 2. Fowler AA, Hamman RF, Good JT, et al. Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 1983;

extracorporeal CO2 removal in severe respiratory failure. JAMA 1986; 256: 881-86. 18. Kallis P, Al-Saady NM, Bennett D, Treasure T. Clinical use of intravascular oxygenation. Lancet 1991; 337: 549. 19. Schuller D, Mitchell JP, Calandrino FS, Schuster DP. Fluid balance during pulmonary oedema: is fluid gain a marker or cause of poor pressure ventilation with

outcome? Chest 1991; 100: 1068-75. 20.

Morgan JM, Morgan CJ, Evans TW. Clinical experience of pump assisted arteriovenous haemofiltration in the management of patients in oliguric renal failure following cardiothoracic surgery. Int J Cardiol 1988; 21: 259-67.

WC, Appel PL, Kram HB, et al. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988; 94: 1176-86. 22. Radermacker P, Santak B, Wist HJ. Prostacyclin and right ventricular function in patients with pulmonary hypertension associated with 21. Shoemaker

ARDS. Int Care Med 1990; 16: 227-32. 23. Moore FA, Moore EE, Jones TN, et al. TEN

versus

TPN

following

major abdominal trauma: reduced septic mortality. J Trauma 1989; 29: 916-23. 24. Alexander JW. Nutrition and translocation. J Parent Ent Nutr 1990; 14: 170s-74s. 25. Driks MR, Craven DE, Celli BR, et al. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. N Engl J Med 1987; 317: 1376-82. 26. Vandenbroucke-Grauls CMJE, Vandenbroucke JP. Effect of selective decontamination of the digestive tract on respiratory tract infections and mortality in the intensive care unit. Lancet 1991; 338: 859-62. 27. 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. 28. Meduri GU, Belenchia JM, Estes RJ, et al. Fibroproliferative phase of ARDS: clinical findings and effects of corticosteroids. Chest 1991; 100: 943-52. 29. Zeigler EJ, Fisher Sprung CL, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. N Engl J Med 1991; 324: 429-36. 30. Macnaughton PD, Morgan CJ, Keogh BF, Denison DM, Evans TW. Initial experience of artificial surfactant therapy in adult acute lung injury. Thorax (in press).

1.

98: 593-97. 3. Rocker GM, Pearson D, Wiseman MS, et al. Diagnostic criteria for ARDS: time for reappraisal. Lancet 1989; i: 120-23. 4. Murray VF, Mathay MA, Luce JM, et al. Pulmonary perspectives: an expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138: 720-23. 5. Mohsenifar Z, Goldbach P, Tashkin DP, Campisi DJ. Relationship between O2 delivery and O2 consumption in the adult respiratory distress syndrome. Chest 1983; 84: 267-71. 6. Dantzker DR, Foresman B, Gutierrez G. Pulmonary perspective: oxygen supply and utilisation relationships, a reevaluation. Am Rev Respir Dis 1991; 143: 675-79. 7. Vincent JL, Rowan A, De Backer D, et al. Oxygen uptake/supply dependency: effects of short term dobutamine infusion. Am Rev Respir Dis 1990; 142: 2-7. 8. Hunter DN, Morgan CJ, Evans TW. The use of radionuclide techniques in the assessment of the alveolar-capillary membrane permeability on the intensive care unit. Intensive Care Med 1990; 16: 363-71. 9. Macnaughton PD, Morgan CJ, Denison DM, Evans TW. Pulmonary function testing in the intensive care unit. Resp Med 1990; 84: 437-43. 10. Gattinoni L, Pesenti A, Caspani ML, et al. The role of total static lung compliance in the management of severe ARDS unresponsive to conventional treatment. Int Care Med 1984; 10: 121-26. 11. Montgomery AB, Stager MA, Carrico CJ, et al. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132: 485-89. 12. Hickling KG. Ventilatory management of ARDS: can if affect outcome? Intensive Care Med 1990; 16: 219-26. 13. Tharratt RS, Allen RP, Albertson TE. Pressure controlled inverse ratio ventilation in severe adult respiratory failure. Chest 1988; 94: 755-62. 14. Downs JB, Stock MG. Airway pressure release ventilation: a new concept in ventilatory support. Crit Care Med 1987; 15: 459-61. 15. Carlon GC, Howland WS, Ray C, et al. High frequency jet ventilation: a prospective randomised evaluation. Chest 1983; 84: 551-59. 16. Keogh BF, Evans TW, Morgan CJ. Improved oxygenation with ultra high frequency jet ventilation in adult respiratory distress syndrome. Eur Respir J 1990; 3 (suppl 10): 62s. 17. Gattinoni L, Pesenti A, Mascheroni D, et al. Low frequency positive

From The Lancet Less

beer, more bread

No-one can quarrel with the conclusion that today bread should claim greater respect than beer. The conservation of cereals for food purposes is of the utmost importance and it is absurd to contend seriously that beer forms, or has ever formed, an essential constituent of our food. Bread is a food and beer is a beverage, and these are quite different categories. Few people drink beer because it happens to contain a certain proportion of nutritives in the form of malt sugar, dextrin, and some proteins; it is appreciated as a pleasant, and, in the majority of cases, wholesome drink, and these qualities have made it the national beverage. But although beer does not contain a large amount of nutrient material, there is good reason for saying that in the healthy individual it favours the assimilation of food in a manner akin to such condimental substances as pepper, salt, and vinegar. Beer certainly contains, amongst other things, the vitamins in a remarkable amount, as might be expected having regard to the method of its production. There is, therefore, little question that beer increases assimilative power, thus adding to the nutrient value of the foods partaken with it. Bread and water in reasonable quantities will sustain life; the equivalent in beer would be an inconvenient bulk of material and, besides, would introduce more alcohol than would be good for the consumer... for assuming, at a low estimate, that the daily consumption of bread is half a pound only, the equivalent of this, as regards nutritive value, would be 8 pints of ordinary beer, and a larger measure of light beer. The good sense of a similar restriction in regard to the output of spirits made from farinaceous products is obvious, though exception can be made in the case of wines which are made from the grape. The grape, unlike grain or the potato, is a perishable article, and its conversion into wine would not cause any interference with the supply of food.

(Feb 3,1917)

Management of adult respiratory distress syndrome.

469 8. Baird BR, Cheronis JC, Sandhaus RA, Berger EM, White CW, Repine JE. O2 metabolites and neutrophil elastase synergistically cause edematous inj...
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