This Article Full Text Full Text (PDF) Online Data Supplement All Versions of this Article: 200204-302OCv1 166/9/1197    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eichacker, P. Q. Articles by Natanson, C. Search for Related Content PubMed PubMed Citation Articles by Eichacker, P. Q. Articles by Natanson, C.

Risk and the Efficacy of Antiinflammatory Agents

Retrospective and Confirmatory Studies of Sepsis

Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland

Correspondence and requests for reprints should be addressed to Peter Q. Eichacker, M.D., Critical Care Medicine Department, National Institutes of Health, Building 10, Room 7D43, 10 Center Drive, MSC 1662, Bethesda, MD 20892–1662. E-mail: peichacker{at}nih.gov

We investigated whether a relationship between risk of death and treatment effect could explain the disparate results between the preclinical and clinical sepsis trials of antiinflammatory agents over the last decade. A metaregression analysis of cited preclinical studies showed that the treatment effects of these agents were highly dependent on risk of death (p = 0.0001) and that animals were studied at significantly higher control mortality rates than humans (median [25th–75th quartile], 88% [79–96%] versus 39% [32–42%], p = 0.0001). An analysis of the clinical trials showed that antiinflammatory agents were also significantly more efficacious in septic patients with higher risk of death (p = 0.002) and were harmful in those with low risk. To test this relationship prospectively, we studied antiinflammatory agents in models employing differing doses of bacterial challenge to produce the full range of risk of death. We found that the efficacy of these agents, although very beneficial at high control mortality rates, was much reduced (p = 0.0001) and similar to those in human trials at moderate control mortality rates (i.e., 30 to 40%). The efficacy of antiinflammatory agents during sepsis is dependent on the risk of death, an observation that explains the apparent contradiction between preclinical and clinical trial results. Accounting for this relationship may be necessary for the safe and effective development of antiinflammatory therapies for sepsis.

Key Words: septic shock • preclinical and clinical trials • metaregression analysis • antiinflammatory therapies

This article has been cited by other articles:

				M. R. Daley, N. Seam, R. Luboshitzky, G. Qupti, P.-E. Bollaert, P. E. Marik, S. M. Pastores, B. P. Kavanagh, S. Manoach, C. L. Sprung, et al. Corticosteroids for Septic Shock N. Engl. J. Med., May 8, 2008; 358(19): 2068 - 2071. [Full Text] [PDF]

				A. O. Etogo, J. Nunez, C. Y. Lin, T. E. Toliver-Kinsky, and E. R. Sherwood NK but Not CD1-Restricted NKT Cells Facilitate Systemic Inflammation during Polymicrobial Intra-Abdominal Sepsis J. Immunol., May 1, 2008; 180(9): 6334 - 6345. [Abstract] [Full Text] [PDF]

				S. F. Lowry and S. E. Calvano Challenges for modeling and interpreting the complex biology of severe injury and inflammation J. Leukoc. Biol., March 1, 2008; 83(3): 553 - 557. [Abstract] [Full Text] [PDF]

				H. V. Groesdonk, F. Wagner, B. Hoffarth, M. Georgieff, and U. Senftleben Enhancement of NF-{kappa}B Activation in Lymphocytes Prevents T Cell Apoptosis and Improves Survival in Murine Sepsis J. Immunol., December 15, 2007; 179(12): 8083 - 8089. [Abstract] [Full Text] [PDF]

				R. Wu, W. Dong, M. Zhou, F. Zhang, C. P. Marini, T. S. Ravikumar, and P. Wang Ghrelin Attenuates Sepsis-induced Acute Lung Injury and Mortality in Rats Am. J. Respir. Crit. Care Med., October 15, 2007; 176(8): 805 - 813. [Abstract] [Full Text] [PDF]

				M. F. Osuchowski, K. Welch, H. Yang, J. Siddiqui, and D. G. Remick Chronic Sepsis Mortality Characterized by an Individualized Inflammatory Response J. Immunol., July 1, 2007; 179(1): 623 - 630. [Abstract] [Full Text] [PDF]

				D. Rittirsch, L. M. Hoesel, and P. A. Ward The disconnect between animal models of sepsis and human sepsis J. Leukoc. Biol., January 1, 2007; 81(1): 137 - 143. [Abstract] [Full Text] [PDF]

				J. A. Russell Management of Sepsis N. Engl. J. Med., October 19, 2006; 355(16): 1699 - 1713. [Full Text] [PDF]

				J. F. P. Berbee, C. C. van der Hoogt, R. Kleemann, E. F. Schippers, R. L. Kitchens, J. T. van Dissel, I. A. J. M. Bakker-Woudenberg, L. M. Havekes, and P. C. N. Rensen Apolipoprotein CI stimulates the response to lipopolysaccharide and reduces mortality in Gram-negative sepsis FASEB J, October 1, 2006; 20(12): 2162 - 2164. [Abstract] [Full Text] [PDF]

				M. F. Osuchowski, K. Welch, J. Siddiqui, and D. G. Remick Circulating Cytokine/Inhibitor Profiles Reshape the Understanding of the SIRS/CARS Continuum in Sepsis and Predict Mortality J. Immunol., August 1, 2006; 177(3): 1967 - 1974. [Abstract] [Full Text] [PDF]

				S. Talwar, P. J. Munson, J. Barb, C. Fiuza, A. P. Cintron, C. Logun, M. Tropea, S. Khan, D. Reda, J. H. Shelhamer, et al. Gene expression profiles of peripheral blood leukocytes after endotoxin challenge in humans Physiol Genomics, April 13, 2006; 25(2): 203 - 215. [Abstract] [Full Text] [PDF]

				R. S. Jawa, M. N. Kulaylat, H. Baumann, and M. T. Dayton What Is New in Cytokine Research Related to Trauma/Critical Care J Intensive Care Med, March 1, 2006; 21(2): 63 - 85. [Abstract] [PDF]

				F. Dal-Pizzol, L. P. Di Leone, C. Ritter, M. R. Martins, A. Reinke, D. Pens Gelain, A. Zanotto-Filho, L. F. de Souza, M. Andrades, D. F. Barbeiro, et al. Gastrin-releasing Peptide Receptor Antagonist Effects on an Animal Model of Sepsis Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 84 - 90. [Abstract] [Full Text] [PDF]

				R. G. Wunderink Nosocomial Pneumonia, Including Ventilator-associatedPneumonia Proceedings of the ATS, December 1, 2005; 2(5): 440 - 444. [Abstract] [Full Text] [PDF]

				S. Zeerleder, C. E. Hack, and W. A. Wuillemin Disseminated Intravascular Coagulation in Sepsis Chest, October 1, 2005; 128(4): 2864 - 2875. [Abstract] [Full Text] [PDF]

				M. Haley, C. Parent, X. Cui, A. Kalil, Y. Fitz, R. Correa-Araujo, C. Natanson, R. L. Danner, S. M. Banks, and P. Q. Eichacker Neutrophil inhibition with L-selectin-directed MAb improves or worsens survival dependent on the route but not severity of infection in a rat sepsis model J Appl Physiol, June 1, 2005; 98(6): 2155 - 2162. [Abstract] [Full Text] [PDF]

				A. S. Damazo, S. Yona, F. D'Acquisto, R. J. Flower, S. M. Oliani, and M. Perretti Critical Protective Role for Annexin 1 Gene Expression in the Endotoxemic Murine Microcirculation Am. J. Pathol., June 1, 2005; 166(6): 1607 - 1617. [Abstract] [Full Text] [PDF]

				B. Witzenbichler, D. Westermann, S. Knueppel, H.-P. Schultheiss, and C. Tschope Protective Role of Angiopoietin-1 in Endotoxic Shock Circulation, January 4, 2005; 111(1): 97 - 105. [Abstract] [Full Text] [PDF]

				X. Cui, C. Parent, H. Macarthur, S. D. Ochs, E. Gerstenberg, S. Solomon, Y. Fitz, R. L. Danner, S. M. Banks, C. Natanson, et al. Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model J Appl Physiol, October 1, 2004; 97(4): 1349 - 1357. [Abstract] [Full Text] [PDF]

				P. C. Minneci, K. J. Deans, S. M. Banks, P. Q. Eichacker, and C. Natanson Meta-Analysis: The Effect of Steroids on Survival and Shock during Sepsis Depends on the Dose Ann Intern Med, July 6, 2004; 141(1): 47 - 56. [Abstract] [Full Text] [PDF]

				I. A. Clark, L. M. Alleva, A. C. Mills, and W. B. Cowden Pathogenesis of Malaria and Clinically Similar Conditions Clin. Microbiol. Rev., July 1, 2004; 17(3): 509 - 539. [Abstract] [Full Text] [PDF]

				G. Mancuso, A. Midiri, C. Beninati, C. Biondo, R. Galbo, S. Akira, P. Henneke, D. Golenbock, and G. Teti Dual Role of TLR2 and Myeloid Differentiation Factor 88 in a Mouse Model of Invasive Group B Streptococcal Disease J. Immunol., May 15, 2004; 172(10): 6324 - 6329. [Abstract] [Full Text] [PDF]

				X. Cui, M. Moayeri, Y. Li, X. Li, M. Haley, Y. Fitz, R. Correa-Araujo, S. M. Banks, S. H. Leppla, and P. Q. Eichacker Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R699 - R709. [Abstract] [Full Text] [PDF]

				W. Y. W. Lew Endotoxin attacks the cardiovascular system: Black death at the tollgate J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1663 - 1665. [Full Text] [PDF]

				W. C. Aird The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome Blood, May 15, 2003; 101(10): 3765 - 3777. [Abstract] [Full Text] [PDF]

				C. Ronco, R. Bellomo, G. Lonneman, P. K. Agarwal, R. Kumari, M. G. Netea, J. W. Van der Meer, B. J. Kullberg, R. S. Hotchkiss, and I. E. Karl Sepsis -- Theory and Therapies N. Engl. J. Med., April 17, 2003; 348(16): 1600 - 1602. [Full Text] [PDF]

				M. J. Tobin Critical Care Medicine in AJRCCM 2002 Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 294 - 305. [Full Text] [PDF]

				C. A. Dinarello and E. Abraham Does Blocking Cytokines in Sepsis Work? Am. J. Respir. Crit. Care Med., November 1, 2002; 166(9): 1156 - 1157. [Full Text] [PDF]