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A New Paradigm for the Treatment of Sepsis: Is It Time To Consider Combination Therapy?

Alan S. Cross, MD; and Steven M. Opal, MD
[+] Article, Author, and Disclosure Information

From University of Maryland School of Medicine, Baltimore, Maryland; and Memorial Hospital of Rhode Island, Pawtucket, Rhode Island.

Grant Support: By National Institutes of Health grant RO1 AI42181-01.

Potential Financial Conflicts of Interest:Honoraria: S.M. Opal (Wyeth Research, Lilly Research Laboratories, Aventis Behring, ICOS Corp., Merck & Co.); Grants received: S.M. Opal (Wyeth Research, Chiron Corp.).

Requests for Single Reprints: Alan S. Cross, MD, Department of Medicine, Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF 480, Baltimore, MD 21201; e-mail, across@umm.edu.

Current Author Addresses: Dr. Cross: Department of Medicine, Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF 480, Baltimore, MD 21201.

Dr. Opal: Division of Infectious Diseases, Memorial Hospital of Rhode Island, 111 Brewster Street, Pawtucket, RI 02860.

Ann Intern Med. 2003;138(6):502-505. doi:10.7326/0003-4819-138-6-200303180-00016
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Despite the advances in supportive care and the availability of potent antimicrobial agents, mortality from sepsis, a leading cause of death in intensive care units, has not improved. Over the last decade, clinical trials with numerous adjunctive therapies, including antiendotoxin antibodies and inhibitors of the inflammatory response, have yielded disappointing results. Recently, treatment with recombinant human activated protein C reduced mortality 6% compared with controls. Given the likelihood that many processes in the complex pathophysiology of sepsis are simultaneously activated, it is unlikely that therapy directed at any one of them, as has been done in the past, will dramatically improve survival. Rather, a combination of therapies directed at many arms of the septic process, much like the strategy used for cancer and HIV infection, is required. Given the likelihood that sepsis represents an excessive innate immune response to microbial products, vigorous attempts must be made to develop rapid assays that reflect the level of innate immune activation. Such assays could be used to identify patients who would benefit from therapy and to monitor their response so that overtreatment does not completely abrogate host defense mechanisms and render these patients susceptible to fatal infection. It is now time to test a new therapeutic paradigm based on an improved understanding of the pathophysiology of the septic process and the recognition that we may have reached the limits of adjunctive monotherapy.


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Novel interventions for the treatment of severe sepsis.22

The five potential intervention points are directed toward 1) microbial mediators, 2) pathogen-associated molecular patterns, 3) signal transduction mechanisms of immune effector cells; 4) host response mediator networks, and 5) antiapoptotic pathways. The solid arrows are activation sites, and the open arrows are inhibitory sites. Interventions that have gone through phase III tests are listed, along with experimental agents that are under investigation (in parentheses). AT III = antithrombin III; BPI = bactericidal/permeability-increasing protein; HMG-1 = high mobility group 1 protein; IL-1ra = interleukin-1 receptor antagonist; LPS = lipopolysaccharide; Mab = monoclonal antibody; MAPK = mitogen-activated protein kinase; MIF = migration inhibitory factor; NO = nitric oxide; NOS = nitric oxide synthase; PAF-AH = platelet-activating factor acetyl-hydrolase; PAFra = platelet-activating factor receptor antagonist; PMX B = polymixin B; rhAPC = recombinant human activated protein C; sPLA = soluble phospholipase A ; TFPI = tissue factor pathway inhibitor; TK = tyrosine kinase; TLR = Toll-like receptor; TNF = tumor necrosis factor.

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