Skip to main content
SpringerLink
Log in

The individual survival benefits of tumor necrosis factor soluble receptor and fluid administration are not additive in a rat sepsis model

  • Experimental
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Background

Tumor necrosis factor (TNF) antagonists [e.g., TNF soluble receptor (TNFsr)] improved survival in preclinical but not clinical sepsis trials. However fluid support—itself beneficial—is standard clinically but rarely employed in preclinical sepsis models. We hypothesized that these therapies may not have additive benefit.

Methods and results

Antibiotic-treated rats (n = 156) were randomized to intratracheal or intravenous Escherichia coli challenges (>LD50) and either placebo or TNFsr and 24 h fluid treatments alone or together. The survival effects of these therapies did not differ significantly comparing challenge routes. When averaged across route, while TNFsr or fluid alone decreased the hazard ratio of death significantly [ln ± standard error (SE): −0.65 ± 0.30 and −0.62 ± 0.30, respectively, p ≤ 0.05], together they did not (p = 0.16). Furthermore, the observed effect of TNFsr and fluid together on reducing the hazard ratio was significantly less than estimated (−0.37 ± 0.29 versus −1.27 ± 0.43, respectively, p = 0.027) based on TNFsr and fluid alone. While each treatment increased central venous pressure at 6 and 24 h, the observed effects of the combination were also less than estimated ones (p ≤ 0.0005).

Conclusions

The individual survival benefits of TNFsr and fluids were not additive in this rat sepsis model. Investigating new sepsis therapies together with conventional ones during preclinical testing may be informative.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Vicaut E, Hou X, Payen D, Bousseau A, Tedgui A (1991) Acute effects of tumor necrosis factor on the microcirculation in rat cremaster muscle. J Clin Invest 87:1537–1540

    Article  PubMed  CAS  Google Scholar 

  2. Natanson C, Eichenholz PW, Danner RL, Eichacker PQ, Hoffman WD, Kuo GC, Banks SM, MacVittie TJ, Parrillo JE (1989) Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med 169:823–832

    Article  PubMed  CAS  Google Scholar 

  3. Eichacker PQ, Hoffman WD, Farese A, Banks SM, Kuo GC, MacVittie TJ, Natanson C (1991) TNF but not IL-1 in dogs causes lethal lung injury and multiple organ dysfunction similar to human sepsis. J Appl Physiol 71:1979–1989

    PubMed  CAS  Google Scholar 

  4. Naziri W, Joshua IG (1998) Role of tumor necrosis factor-alpha in small intestinal microcirculation. Am Surg 64:203–209 discussion 209–210

    PubMed  CAS  Google Scholar 

  5. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A (1987) Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330:662–664

    Article  PubMed  CAS  Google Scholar 

  6. Eichacker PQ, Parent C, Kalil A, Esposito C, Cui X, Banks SM, Gerstenberger EP, Fitz Y, Danner RL, Natanson C (2002) Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 166:1197–1205

    Article  PubMed  Google Scholar 

  7. Bagby GJ, Plessala KJ, Wilson LA, Thompson JJ, Nelson S (1991) Divergent efficacy of antibody to tumor necrosis factor-alpha in intravascular and peritonitis models of sepsis. J Infect Dis 163:83–88

    Article  PubMed  CAS  Google Scholar 

  8. Karzai W, Cui X, Mehlhorn B, Straube E, Hartung T, Gerstenberger E, Banks SM, Natanson C, Reinhart K, Eichacker PQ (2003) Protection with antibody to tumor necrosis factor differs with similarly lethal Escherichia coli versus Staphylococcus aureus pneumonia in rats. Anesthesiology 99:81–89

    Article  PubMed  CAS  Google Scholar 

  9. Piper RD, Cook DJ, Bone RC, Sibbald WJ (1996) Introducing critical appraisal to studies of animal models investigating novel therapies in sepsis. Crit Care Med 24:2059–2070

    Article  PubMed  CAS  Google Scholar 

  10. Dorresteijn MJ, van Eijk LT, Netea MG, Smits P, van der Hoeven JG, Pickkers P (2005) Iso-osmolar prehydration shifts the cytokine response towards a more anti-inflammatory balance in human endotoxemia. J Endotoxin Res 11:287–293

    PubMed  CAS  Google Scholar 

  11. Wilson MA, Chou MC, Spain DA, Downard PJ, Qian Q, Cheadle WG, Garrison RN (1996) Fluid resuscitation attenuates early cytokine mRNA expression after peritonitis. J Trauma 41:622–627

    Article  PubMed  CAS  Google Scholar 

  12. Sherer K, Li Y, Cui X, Li X, Subramanian M, Laird MW, Moayeri M, Leppla SH, Fitz Y, Su J, Eichacker PQ (2007) Fluid support worsens outcome and negates the benefit of protective antigen-directed monoclonal antibody in a lethal toxin-infused rat Bacillus anthracis shock model. Crit Care Med 35:1560–1567

    Article  PubMed  Google Scholar 

  13. Li Y, Li X, Haley M, Fitz Y, Gerstenberger E, Banks SM, Eichacker PQ, Cui X (2006) DTPA Fe(III) decreases cytokines and hypotension but worsens survival with Escherichia coli sepsis in rats. Intensive Care Med 32:1263–1270

    Article  PubMed  CAS  Google Scholar 

  14. Haley M, Parent C, Cui X, Kalil A, Fitz Y, Correa-Araujo R, Natanson C, Danner RL, Banks SM, Eichacker PQ (2005) 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 98:2155–2162

    Article  PubMed  CAS  Google Scholar 

  15. Cui X, Zeni F, Vodovitz Y, Correa-de-Araujo R, Quezado M, Roberts A, Wahl S, Danner RL, Banks SM, Gerstenberger E, Fitz Y, Natanson C, Eichacker PQ (2003) TGF-beta1 increases microbial clearance but worsens lung injury during Escherichia coli pneumonia in rats. Cytokine 24:115–127

    Article  PubMed  CAS  Google Scholar 

  16. Cui X, Li Y, Li X, Haley M, Moayeri M, Fitz Y, Leppla SH, Eichacker PQ (2006) Sublethal doses of Bacillus anthracis lethal toxin inhibit inflammation with lipopolysaccharide and Escherichia coli challenge but have opposite effects on survival. J Infect Dis 193:829–840

    Article  PubMed  CAS  Google Scholar 

  17. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644–1655

    Article  PubMed  CAS  Google Scholar 

  18. Stack AM, Saladino RA, Thompson C, Sattler F, Weiner DL, Parsonnet J, Nariuchi H, Siber GR, Fleisher GR (1995) Failure of prophylactic and therapeutic use of a murine anti-tumor necrosis factor monoclonal antibody in Escherichia coli sepsis in the rabbit. Crit Care Med 23:1512–1518

    Article  PubMed  CAS  Google Scholar 

  19. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL (2008) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 36:296–327

    Article  PubMed  Google Scholar 

  20. Murphy CV, Schramm GE, Doherty JA, Reichley RM, Gajic O, Afessa B, Micek ST, Kollef MH (2009) The importance of fluid management in acute lung injury secondary to septic shock. Chest 136:102–109

    Article  PubMed  Google Scholar 

  21. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377

    Article  PubMed  CAS  Google Scholar 

  22. Cui X, Solomon S, Natanson C, Fitz Y, Danner RL, Gerstenberger E, Banks S, Eichacker PQ (2002) Oligonuleotide microarrays identify genes, including one for TNFsr, with changes in expression dependent on infection dose of E. coli in rats. Am J Crit Care Med 165:A521

    Google Scholar 

  23. Cui X, Parent C, Macarthur H, Ochs SD, Gerstenberg E, Solomon S, Fitz Y, Danner RL, Banks SM, Natanson C, Salvemini D, Eichacker PQ (2004) Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model. J Appl Physiol 97:1349–1357

    Article  PubMed  CAS  Google Scholar 

  24. Natanson C, Danner RL, Reilly JM, Doerfler ML, Hoffman WD, Akin GL, Hosseini JM, Banks SM, Elin RJ, MacVittie TJ et al (1990) Antibiotics versus cardiovascular support in a canine model of human septic shock. Am J Physiol 259:H1440–H1447

    PubMed  CAS  Google Scholar 

  25. Evans DA, Jacobs DO, Revhaug A, Wilmore DW (1989) The effects of tumor necrosis factor and their selective inhibition by ibuprofen. Ann Surg 209:312–321

    Article  PubMed  CAS  Google Scholar 

  26. Poon KS, Pang CC (2002) Venodilator action of an organotransition-metal nitrosyl complex. Eur J Pharmacol 436:107–110

    Article  PubMed  CAS  Google Scholar 

  27. Bemelmans MH, Gouma DJ, Buurman WA (1993) Influence of nephrectomy on tumor necrosis factor clearance in a murine model. J Immunol 150:2007–2017

    PubMed  CAS  Google Scholar 

  28. Knotek M, Rogachev B, Wang W, Ecder T, Melnikov V, Gengaro PE, Esson M, Edelstein CL, Dinarello CA, Schrier RW (2001) Endotoxemic renal failure in mice: role of tumor necrosis factor independent of inducible nitric oxide synthase. Kidney Int 59:2243–2249

    PubMed  CAS  Google Scholar 

  29. Wang W, Zolty E, Falk S, Basava V, Reznikov L, Schrier R (2006) Pentoxifylline protects against endotoxin-induced acute renal failure in mice. Am J Physiol Renal Physiol 291:F1090–F1095

    Article  PubMed  CAS  Google Scholar 

  30. Mohler KM, Torrance DS, Smith CA, Goodwin RG, Stremler KE, Fung VP, Madani H, Widmer MB (1993) Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 151:1548–1561

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH intramural fund.

Conflict of interest

None of the authors have a commercial or other association that might pose a conflict of interest.

Author information

Authors and Affiliations

  1. Critical Care Medicine Department, Clinical Center, National Institutes of Health, Building 10, Room 2C145, Bethesda, MD, 20892, USA

    Ping Qiu, Yan Li, Yi Ding, Jia Weng, Steven M. Banks, Steven Kern, Yvonne Fitz, Anthony F. Suffredini, Peter Q. Eichacker & Xizhong Cui

Authors
  1. Ping Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jia Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven M. Banks
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Steven Kern
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yvonne Fitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anthony F. Suffredini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peter Q. Eichacker
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xizhong Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Q. Eichacker.

Additional information

Steven M. Banks died unexpectedly during the preparation of this manuscript.

Part of the present paper was presented at the American Thoracic Society International Conference, May 2001, San Francisco, CA.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qiu, P., Li, Y., Ding, Y. et al. The individual survival benefits of tumor necrosis factor soluble receptor and fluid administration are not additive in a rat sepsis model. Intensive Care Med 37, 1688–1695 (2011). https://doi.org/10.1007/s00134-011-2324-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-011-2324-z

Keywords

Search

Navigation