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ARDS: The Therapeutic Dilemma
CHEST editorials VOLUME 97 I NUMBER 5 I MAY, 1990
ARDS: The Therapeutic Dilemma The adult respiratory distress syndrome (ARDS) has numerous clinical predispositions, but the most common is infection with aerobic, Gram-negative rods. The syndrome can result after direct bacterial infection of the lungs or more frequently after abdominal or other distant infection, presumably due to intravascular spread of bacteria or toxic bacterial products. Manifesting itself as overwhelming acute respiratory failure with an exudative pulmonary edema, ARDS usually occurs in the absence of significant cardiac dysfunction. However, other organs frequently fail, most notably the kidneys, liver, and gastrointestinal, hematologic, and central nervous systems. Despite improvements in respiratory support, approximately two of three patients with ARDS die within three weeks of the syndrome's onset, usually of multiple organ failure caused by sepsis. Since the lesion of ARDS is primarily inflammatory, much effort has focused on anti-inflammatory agents in treatment and prevention. Unfortunately, glucocorticoids and prostaglandin E 1 have not proven efficacious in treatment trials of ARDS. 1-3 As a prophylaxis, moderate levels of positive end-expiratory pressure did not prevent the syndromes onset. Currently, much interest centers on the possible therapeutic benefits of antibodies to endotoxin and blockers of tumor necrosis factor and of other putative peptide or lipid mediators. In contrast to this direction of research Humphrey et al present retrospective information i~ this issue (see page 1176) to support the hypothesis that early lowering of the pulmonary artery occlusion pressure results in significantly improved survival in patients with ARDS. The explanation for this felicitous relationship is not immediately apparent. Since the pathologic abnormality in ARDS is exudative rather than transudative, lowering pulmonary microvascular hydrostatic pressure would not seem to be particularly helpful. However, the lungs serve as an important reservoir of bacterial infection as the syndrome progresses, 4 and early improvement in pulmonary function that results in a shorter stay in the ICU might lessen this incidence of nosocomial pneumonia. s In this regard, other interventions aimed at improving pulmonary function such as supplementation with
exogenous surfactant might improve outcome by decreasing the rate of nosocomial pneumonia. Caution must be exercised in the interpretation of the findings of Humphrey et al. Since patients were not randomly assigned to therapy, it is likely that significant baseline differences existed between the two groups. The group of survivors, after all, were an average of 18 years younger than the nonsurvivors. Furthermore, therapeutic interventions other than lowering of pulmonary artery occlusion pressure may have explained the subsequent difference in outcome. However, the intriguing findings reported by these authors, coupled with results from animal studies, argue strongly for the conduct of a controlled clinical trial. The trial should be randomized, double blind, and placebo controlled. Since diuresis or phlebotomy could worsen organ function in marginally perfused, septic patients, an adverse outcome with treatment groups should be anticipated and actively looked for. The practical implications of these statements are that the statistical design should be two tailed, and individuals assessing outcome variables should be blinded to therapy. Lacking a positive result from this type of prospective study, aggressive lowering of pulmonary artery occlusion pressure cannot be currently advocated as a treatment for ARDS. Thomas M. Hyers, M.D., F.C.C.P. St. Louis Division of Pulmonology, Department of Internal Medicine St Louis University School of MeC:licine. ' ·
REFERENCES 1 LuceJM, Montgomery 8, MarksJD, Turner J, MetzCA, Murray JF. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis 1988; 138:62-8 2 Bernard GR, Luce JM, Spring 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, Silverman H, Hyers TM, Kerstein M, et al. Randomized, double-blind multi-center study of prostaglandin E, in patients with the adult respiratory distress syndrome. Chest 1989; 96:114-19 4 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 5 Fagon J, Chastre J, Domart Y, Trouillet J, Pierre J, Darne C, et al. Nosocomial pneumonia in patients receiving continuous mechanical ventilation. Am Rev Respir Dis 1989; 139:877-84 CHEST I 97 I 5 I MAY. 1990
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ARDS: The Therapeutic Dilemma The adult respiratory distress syndrome (ARDS) has numerous clinical predispositions, but the most common is infection with aerobic, Gram-negative rods. The syndrome can result after direct bacterial infection of the lungs or more frequently after abdominal or other distant infection, presumably due to intravascular spread of bacteria or toxic bacterial products. Manifesting itself as overwhelming acute respiratory failure with an exudative pulmonary edema, ARDS usually occurs in the absence of significant cardiac dysfunction. However, other organs frequently fail, most notably the kidneys, liver, and gastrointestinal, hematologic, and central nervous systems. Despite improvements in respiratory support, approximately two of three patients with ARDS die within three weeks of the syndrome's onset, usually of multiple organ failure caused by sepsis. Since the lesion of ARDS is primarily inflammatory, much effort has focused on anti-inflammatory agents in treatment and prevention. Unfortunately, glucocorticoids and prostaglandin E 1 have not proven efficacious in treatment trials of ARDS. 1-3 As a prophylaxis, moderate levels of positive end-expiratory pressure did not prevent the syndromes onset. Currently, much interest centers on the possible therapeutic benefits of antibodies to endotoxin and blockers of tumor necrosis factor and of other putative peptide or lipid mediators. In contrast to this direction of research Humphrey et al present retrospective information i~ this issue (see page 1176) to support the hypothesis that early lowering of the pulmonary artery occlusion pressure results in significantly improved survival in patients with ARDS. The explanation for this felicitous relationship is not immediately apparent. Since the pathologic abnormality in ARDS is exudative rather than transudative, lowering pulmonary microvascular hydrostatic pressure would not seem to be particularly helpful. However, the lungs serve as an important reservoir of bacterial infection as the syndrome progresses, 4 and early improvement in pulmonary function that results in a shorter stay in the ICU might lessen this incidence of nosocomial pneumonia. s In this regard, other interventions aimed at improving pulmonary function such as supplementation with
exogenous surfactant might improve outcome by decreasing the rate of nosocomial pneumonia. Caution must be exercised in the interpretation of the findings of Humphrey et al. Since patients were not randomly assigned to therapy, it is likely that significant baseline differences existed between the two groups. The group of survivors, after all, were an average of 18 years younger than the nonsurvivors. Furthermore, therapeutic interventions other than lowering of pulmonary artery occlusion pressure may have explained the subsequent difference in outcome. However, the intriguing findings reported by these authors, coupled with results from animal studies, argue strongly for the conduct of a controlled clinical trial. The trial should be randomized, double blind, and placebo controlled. Since diuresis or phlebotomy could worsen organ function in marginally perfused, septic patients, an adverse outcome with treatment groups should be anticipated and actively looked for. The practical implications of these statements are that the statistical design should be two tailed, and individuals assessing outcome variables should be blinded to therapy. Lacking a positive result from this type of prospective study, aggressive lowering of pulmonary artery occlusion pressure cannot be currently advocated as a treatment for ARDS. Thomas M. Hyers, M.D., F.C.C.P. St. Louis Division of Pulmonology, Department of Internal Medicine St Louis University School of MeC:licine. ' ·
REFERENCES 1 LuceJM, Montgomery 8, MarksJD, Turner J, MetzCA, Murray JF. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis 1988; 138:62-8 2 Bernard GR, Luce JM, Spring 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, Silverman H, Hyers TM, Kerstein M, et al. Randomized, double-blind multi-center study of prostaglandin E, in patients with the adult respiratory distress syndrome. Chest 1989; 96:114-19 4 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 5 Fagon J, Chastre J, Domart Y, Trouillet J, Pierre J, Darne C, et al. Nosocomial pneumonia in patients receiving continuous mechanical ventilation. Am Rev Respir Dis 1989; 139:877-84 CHEST I 97 I 5 I MAY. 1990
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