Pseudosepsis Syndrome, Multiple-System Organ Failure, and Chronic Salicylate Intoxication
1991; Elsevier BV; Volume: 100; Issue: 5 Linguagem: Inglês
10.1378/chest.100.5.1188
ISSN1931-3543
Autores Tópico(s)Respiratory Support and Mechanisms
ResumoIn the quest to ameliorate the cardinal effects of inflammation, Americans consume up to 16,000 tons of aspirin per year in transactions involving 80 million tablets and $2 billion.1Weissmann G. Aspirin..Sci Am. 1991; 264: 187-193Crossref Scopus (228) Google Scholar Acetylsalicylic acid (ASA) is the gold standard against which nonsteroidal anti-inflammatory drugs (NSAIDs) are compared. Although highly effective in modulating inflammation, the exact mechanisms of action of ASA remain unclear. However, such an understanding is central in determining how ASA intoxication paradoxically induces inflammatory processes that escape host regulatory control to enhance tissue injury.2Templar AR. Acute and chronic effects of aspirin toxicity and their treatment..Arch Intern Med. 1981; 141: 364-369Crossref PubMed Scopus (134) Google Scholar3Heffner JE Sahn SA. Salicylate-induced pulmonary edema: clinical features and prognosis..Ann Intern Med. 1981; 95: 405-409Crossref PubMed Scopus (99) Google Scholar Many forms of tissue damage are due to production of cyclooxygenase pathway metabolites.4Vane JR Botting RM. Prostaglandins, prostacyclin, thromboxane, and leukotrienes: the arachidonic acid cascade..in: Shoemaker RC Fuhrnan BT Critical care: state of the art. Society of Critical Care Medicine, Fullerton, Calif1989: 1-24Google Scholar Most mammalian cells possess the requisite microsomal enzymes for prostaglandin (PG) biosynthesis. By acetylating a serine residue, ASA inhibits cyclooxyenase-mediated transformation of arachidonic acid to PGG2.1Weissmann G. Aspirin..Sci Am. 1991; 264: 187-193Crossref Scopus (228) Google Scholar The causal role of PGs in inducing inflammation supports the hypothesis that suppression of excessive PG production by ASA or NSAIDs is beneficial during pathologic conditions ranging from rheumatic disorders to septic shock.1Weissmann G. Aspirin..Sci Am. 1991; 264: 187-193Crossref Scopus (228) Google Scholar5Mozes T Ziijlstra FJ Heiligers PC Saxena PR Bonta IL. Sequential release of eicosanoids during endotoxin-induced shock in aneshetized pigs..Prostaglandins Leukot Essent Fatty Acids. 1991; 42: 209-216Abstract Full Text PDF PubMed Scopus (11) Google Scholar Both ASA and NSAIDs may have anti-inflammatory effects by additional mechanisms, including binding to cell membranes1Weissmann G. Aspirin..Sci Am. 1991; 264: 187-193Crossref Scopus (228) Google Scholar and receptor-linked G proteins.6Abramson S Korchak H Ludewig R Edelson H Haines K Levin RI et al.Modes of action of aspirin-like drugs..Proc Natl Acad Sci U S A. 1985; 82: 7227-7231Crossref PubMed Scopus (203) Google Scholar Why, then, is salicylate intoxication associated with proinflammatory effects? In contrast to the reversible toxicity associated with acute ASA overdose, chronic salicylism is characterized by protean clinical manifestations, frequent delayed diagnoses, and significant morbidity and mortality.2Templar AR. Acute and chronic effects of aspirin toxicity and their treatment..Arch Intern Med. 1981; 141: 364-369Crossref PubMed Scopus (134) Google Scholar3Heffner JE Sahn SA. Salicylate-induced pulmonary edema: clinical features and prognosis..Ann Intern Med. 1981; 95: 405-409Crossref PubMed Scopus (99) Google Scholar In this issue, Leatherman and Schmitz (see page 1391) retrospectively document the clinical course of five patients in whom chronic salicylate intoxication strongly simulated a sepsis syndrome. As acknowledged, certain features of this symptom complex (eg, fever, ARDS, and acute renal failure) have been characterized previously.2Templar AR. Acute and chronic effects of aspirin toxicity and their treatment..Arch Intern Med. 1981; 141: 364-369Crossref PubMed Scopus (134) Google Scholar3Heffner JE Sahn SA. Salicylate-induced pulmonary edema: clinical features and prognosis..Ann Intern Med. 1981; 95: 405-409Crossref PubMed Scopus (99) Google Scholar However, attention is drawn to the leukocytosis, shock, and multiple organ failure. By what mechanisms can these observations be explained? Exclusion of sepsis is problematic, since sepsis syndromes can arise and resolve with antimicrobial treatment in the absence of microbiologic proof of infection.7Goris RJA te Boekhorst PAT Nuytinck JKS Gimbrere JSF. Multiple organ failure: generalized autodestructive inflammation?.Arch Surg. 1985; 120: 1109-1115Crossref PubMed Scopus (1004) Google Scholar Furthermore, high levels of salicylates increase endothelial permeability, as typified by salicylate-induced pulmonary edema.3Heffner JE Sahn SA. Salicylate-induced pulmonary edema: clinical features and prognosis..Ann Intern Med. 1981; 95: 405-409Crossref PubMed Scopus (99) Google Scholar Therefore, one cannot exclude ASA-induced increases in gastrointestinal mucosal permeability generating an endogenous endotoxemia. Assuming that salicylate did not interfere with cytokine measurements, the increased serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in two patients deserve comment. First, while recognized as mediators of Gram-negative sepsis,8Offner F Philippe J Vogelaers D Colardyn F Baele G Baudrihaye M et al.Serum tumor necrosis factor levels in patients with infectious disease and septic shock..J Lab Clin Med. 1990; 116: 100-105PubMed Google Scholar, 9Alexander HR Doherty GM Buresh CM Venzon DJ Norton JA. A recombinant human antagonist to interleukin 1 improves survival after lethal endotoxemia in mice..J Exp Med. 1991; 173: 1029-1032Crossref PubMed Scopus (254) Google Scholar, 10Hack CE De Groot ER Felt-Bersma JF Nuijens JH Strack Van Schijndel RJM Eerenberg-Belmer AJM et al.Increase plasma levels of interleukin-6 in sepsis..Blood. 1989; 74: 1704-1710PubMed Google Scholar these cytokines can be released in response to tissue injury.11Maury CPJ Teppo AM. Circulating tumour necrosis factor-alpha (cachectin) in myocardial infarction..J Intern Med. 1989; 225: 333-336Crossref PubMed Scopus (153) Google Scholar Second, eicosanoids act as second messengers for several tissue-specific effects of TNF-α, IL-1β, and IL-6. Pharmacologic inhibition of the cyclooxygenase pathway blocks cytokine-eicosanoid interactions and blunts several pathophysiologic effects of cytokines.12Michie HR Manogue KR Spriggs DR Revhaug A O'Dwyer S Dinarello CA et al.Detection of circulating tumor necrosis factor after endotoxin administration..N Engl J Med. 1988; 318: 1481-1486Crossref PubMed Scopus (1415) Google Scholar However, such inhibition augments circulating cytokine levels.13Ertel W Morrison MH Ayala A Perrin MM Chaudry IH. Blockade of prostaglandin production increases cachectin synthesis and prevents depression of macrophage functions after hemorrhagic shock..Ann Surg. 1991; 213: 265-271Crossref PubMed Scopus (67) Google Scholar Spinas et al14Spinas GA Bloesch D Keller U Zimmerli W Cammisuli S. Pretreatment with ibuprofen augments circulating tumor necrosis factor-α, interleukin-6, and elastase during acute endotoxemia..J Infect Dis. 1991; 163: 89-95Crossref PubMed Scopus (117) Google Scholar found increased TNF-α and IL-6 concentrations after endotoxin challenge in ibuprofen-pretreated humans despite amelioration of clinical responses. Similarly, a 4.2-fold increase in TNF-α occurred in other ibuprofen-pretreated subjects following endotoxemia.15Martich GD Danner RL Ceska M Suffredini AF. Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents..J Exp Med. 1991; 173: 1021-1024Crossref PubMed Scopus (381) Google Scholar This appears secondary to interruption of dose-dependent inhibitory feedback of PGE2 on cytokine gene expression.16Kunkel SL Spengler M May MA Spengler R Larrick J Remick D. Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression..J Biol Chem. 1988; 263: 5380-5384PubMed Google Scholar, 17Lehmann V Benninghoff B Droge W. Tumor necrosis factor-induced activation of peritoneal macrophages is regulated by prostaglandin E2 and cAMP..J Immunol. 1988; 141: 587-591PubMed Google Scholar, 18Spatafora M Chiappara G D'Amico D Volpes D Melis M Pace E et al.Effect of indomethacin on the kinetics of tumour necrosis factor alpha release and tumour necrosis factor gene expression by human blood monocytes..Pharmacol Res. 1991; 23: 247-257Crossref PubMed Scopus (29) Google Scholar The clinical consequences of altered cytokine responses by anti-inflammatory agents are incompletely understood. Conceivably, sustained suppression of regulatory eicosanoids, such as PGE2, by chronically elevated ASA levels partially accounts for the clinical manifestations of salicylate toxicity described in the current report. For example, elevated plasma cytokine concentrations are found in Reye's syndrome.19Larrick JW Kunkel SL. Is Reye's syndrome caused by augmented release of tumor necrosis factor?.Lancet. 1986; 2: 132-133Abstract PubMed Scopus (34) Google Scholar Sustained alterations in cytokine responses during chronic salicylate intoxication and transient changes during therapeutic inhibition of the cyclooxygenase pathway may thus represent two different points along an immunophysiologic continuum. Both phenomena clearly require more investigation.
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