Skip to main content
Log in

Influence of pentoxifylline on cytokine levels and inflammatory parameters in septic shock

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

Abstract

Objective

To evaluate the influence of pentoxifylline (PTX), a phosphodiesterase inhibitor, on cytokines and inflammatory proteins in patients suffering from septic shock.

Design

Prospective study comparing a therapy group to a matched control group.

Setting

Medical intensive care unit at a university hospital.

Patients

Twenty four patients fulfilling the criteria of septic shock were included in this study. Twelve patients received PTX (therapy group) and 12 patients matched for diagnosis, age and gender served as the control group.

Interventions

Pentoxifylline at 1 mg/kg per hour over 24 h in the therapy group.

Measurements ad results

Cytokine levels [tumor necrosis factor-α (TNF)], soluble TNF receptor [TNF-R], and interleukin-6 [IL-6] and inflammatory proteins [C-reactive protein, α-1-antitrypsin (AAT), fibronectin, and haptoglobin], as well as hemodynamic parameters and the APACHE III score were evaluated before initiation of therapy and 24 h later. After 24 h, TNF levels were significantly lower in the therapy group (p=0.013), while IL-6 levels were significantly higher in the therapy group (p=0.030). Within the 24 h TNF declined significantly in the therapy group (p=0.006), while IL-6 showed a significant increase (p=0.043). AAT and the APACHE III score tended to differ significantly after 24 h between the groups [AAT levels higher in the therapy group (p=0.05), APACHE III score lower (p=0.05)]. In the therapy group, the systemic vascular resistance index was significantly higher after 24 h (p=0.0026) whereas the cardiac index declined (p=0.035).

Conclusions

PTX does influence TNF levels in septic shock patients. Nevertheless, inhibiting a single mediator in severe septic shock cannot stop the inflammatory overreaction.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Moldawer LL (1994) Biology of proinflammatory cytokines and their antagonists. Crit Care Med 22:S 3-S 7

    Google Scholar 

  2. Bone RC (1994) Sepsis and its complications: the clinical problem. Crit Care Med 22:S 8-S 11

    Google Scholar 

  3. Bellomo R (1992) The cytokine network in the critically ill. Anaesth Intensive Care 20:288–302

    PubMed  Google Scholar 

  4. Parrillo JE (1993) Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471–1477

    Article  PubMed  Google Scholar 

  5. Suffredini AF (1994) Current prospects for the treatment of clinical sepsis. Crit Care Med 22:S 12-S 18

    Google Scholar 

  6. Doherty GM, Jensen JC, Alexander HR, Buresh CM, Norton JA (1991) Pentoxifylline suppression of tumor necrosis factor gene transcription. Surgery 110:192–198

    PubMed  Google Scholar 

  7. Beutler B, Grau GE (1993) Tumor necrosis factor in the pathogenesis of infectious disease. Crit Care Med 21:S423-S435

    PubMed  Google Scholar 

  8. Mackay J, Boyd OF, Henderson S, Bennett ED (1992) Pentoxifylline causes a dose dependent reduction in mortality in patients with sepsis syndrome (abstract). Clin Sci 82:33P

    Google Scholar 

  9. Mayer N, Steltzer H, Klimscha W, Oismueller C, Hammerle AF (1991) Cardiorespiratory effects of pentoxifylline in septic and non-septic states (abstract). Anesthesiology 75:A232

    Google Scholar 

  10. Harada H, Ishizaka A, Yonemaru M, Mallick AA, Hatherill JR, Zheng H (1989) The effects of aminophylline and pentoxifylline on multiple organ damage afterEscherichia coli sepsis. Am Rev Respir Dis 140:974–980

    PubMed  Google Scholar 

  11. Noel P, Nelson S, Bokulic R, Bagby G, Lippton H, Lipscomb G (1990) Pentoxifylline inhibits lipopolysaccharide-induced serum tumor necrosis factor and positively influences mortality. Life Sci 47:1023–1029

    Article  PubMed  Google Scholar 

  12. Schade UF (1990) Pentoxifylline increases survival in murine endotoxin shock and decreases formation of tumor necrosis factor. Circ Shock 31: 171–181

    PubMed  Google Scholar 

  13. Barraso-Aranda J, Schmit-Schoenbein GW (1990) Pentoxifylline pretreatment decreases neutrophil activation during endotoxin shock and improves survival. In: Hakim J, Mandell GL, Novick WJ (ed) Pentoxifylline and analogues: effects on leukocyte function. Karger, Basel, pp 86–90

    Google Scholar 

  14. Law WR, Nadkarni VM, Fletcher MA, Nevola JJ, Eckstein JM, Quance J (1992) Pentoxifylline treatment of sepsis in conscious Yucatan minipigs. Circ Shock 37:291–300

    PubMed  Google Scholar 

  15. Sarma PSA (1990) Pentoxifylline in septic shock. Postgrad Med J 66: 980–981

    PubMed  Google Scholar 

  16. Bone RC, Fisher CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA (1989) Sepsis syndrome: a valid clinical entity. Crit Care Med 17:389–393

    PubMed  Google Scholar 

  17. Sullivan GW, Carper HT, Novick WJ, Mandell GL (1988) Pentoxifylline inhibits the inflammatory effects of endotoxin and endotoxin-induced cytokines on neutrophil function. In: Mandell GL, Novick WJ (eds) Pentoxifylline and leukocyte function. Hoechst-Roussel, Sommerville, pp 37–48

    Google Scholar 

  18. Rao KMK, Padmanabhan J, Cohen HJ, Curris MS (1990) Effect of pentoxifylline and analogs on actin state and cell surface receptor expression in human leukocytes. In: Hakim J, Mandell GL, Novick WJ (eds) Pentoxifylline and analogues: effects on leukocyte function. Karger, Basel, pp 64–70

    Google Scholar 

  19. Barroso-Aranda J, Schmid-Schoenbein GW (1990) Pentoxifylline pretreatment decrease the pool of activated neutrophils, in-vivo adhesion to endothelium, and improves survival from hemorrhagic shock. Biorheology 27:401–418

    PubMed  Google Scholar 

  20. Sourbier P, Perianin A, Hakim J (1988) In vitro effects of pentoxifylline on human neutrophil function. In: Mandell GL, Novick WJ (eds) Pentoxifylline and leukocyte function. Hoechst-Roussel-Sommerville, pp 56–67

    Google Scholar 

  21. Slater K, Wiseman MS, Shale DJ, Fletcher J (1988) The effect of pentoxifylline on neutrophil function in vitro and ex vivo in human volunteers. In: Mandell GL, Novick WJ (eds) Pentoxifylline and leukocyte function. Hochest-Roussel, Sommerville, pp 115–123

    Google Scholar 

  22. Kumar KV, Das UN, Kumar GS, Das NP, Tan BK (1992) Effect of pentoxifylline on freed radical generation in human peripheral leukocytes. Asia Pac J Pharmacol 7:89–93

    Google Scholar 

  23. Beutler B (1990) Cachectin/tumor necrosis factor and lymphotoxin. In: Sporn MB, Roberts AB (eds) Handbook of experimental pharmacology: peptide growth factors and their receptors II. Springer, Berlin Heidelberg New York, pp 39–70

    Google Scholar 

  24. Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey TJ, Zentella A, Albert JD (1986) Shock and tissue injury induced by recombinant human cachectin. Science 234:470–474

    PubMed  Google Scholar 

  25. Tracey KJ, Lowry SF, Fahey TJ, Albert JD, Fong Y, Hesse D, Beutler B, Manogue KR, Calvano S, Wei H (1987) Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gynecol Obstet 164:415–442

    PubMed  Google Scholar 

  26. Tighe D, Moss R, Heath MF, Hynd J, Bennet ED (1989) Pentoxifylline reduces pulmonary leucostasis and improves capillary patency in a rabbit peritonitis model. Circ Shock 28:159–164

    PubMed  Google Scholar 

  27. Tighe D, Moss R, Hynd J, Boghossian S, Al Saady N, Heath MF (1990) Pretreatment with pentoxifylline improves the hemodynamic and histologic changes and decreases neutrophil adhesiveness in a pig fecal peritonitis model. Crit Care Med 18:184–189

    PubMed  Google Scholar 

  28. Zabel P, Wolter DT, Schoenharting MM, Schade UF (1989) Oxpentifylline in endotoxaemia. Lancet 334: 1474–1477

    Article  Google Scholar 

  29. Beutler BA, Milsark IW, Cerami A (1985) Cachectin/tumor necrosis factor: production, distribution, and metabolic fate in vivo. J Immunol 135: 3972–3977

    PubMed  Google Scholar 

  30. Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ, Dupont E (1993) Serum cytokine levels in human septic shock. Chest 103:565–575

    PubMed  Google Scholar 

  31. Pfizenmaier K, Himmler A, Schutze S (1993) TNF receptors and TNF signal transduction. In: Beutler B (ed) Tumor necrosis factors: the molecules and their emerging roles in medicine. Raven, New York, pp 439–472

    Google Scholar 

  32. Higuch M, Aggarwal BB (1992) Inhibition of ligand binding and antiproliferative effects of tumor necrosis factor and lymphotoxin by soluble forms of recombinant P 60 and P 80 receptors. Biochem Biophys Res Commun 182: 638–643

    Article  PubMed  Google Scholar 

  33. Spinas GA, Keller U, Brockhaus M (1992) Release of soluble receptors for tumor necrosis factor (TNF) in relation to circulating TNF during experimental endotoxinemia. J Clin Invest 90: 533–536

    PubMed  Google Scholar 

  34. Porteu F, Nathan C (1990) Shedding of tumor necrosis factor receptors by activated human neutrophils. J Exp Med 172:599–607

    Article  PubMed  Google Scholar 

  35. Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D (1992) Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med 175:323–329

    Article  PubMed  Google Scholar 

  36. 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 therapeutics agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 151: 1548–1561

    PubMed  Google Scholar 

  37. De Boer JP, Wolbink GJ, Thijs LG, Baars JW, Wagstaff J, Hack CE (1992) Interplay of complement and cytokines in the pathogenesis of septic shock. Immunopharmacology 24:135–148

    Article  PubMed  Google Scholar 

  38. Waage A, Sorensen M, Fladvad Stordal B (1990) Effects of pentoxifylline and HWA 138 on production of tumor necrosis factor and interleukin 6 from monocytes. In: Hakim J, Mandell GL, Novick WJ (eds) Pentoxifylline and analogues: effects on leukocyte function. Karger, Basel, pp 86–90

    Google Scholar 

  39. Zabel P, Schoenharting MM, Schade UF, Schlaak M (1991) Effects of pentoxifylline in endotoxinemia in human volunteers. Prog Clin Biol Res 367: 207–213

    PubMed  Google Scholar 

  40. Schade UF (1989) The role of prostacyclin in the protective effects of pentoxifylline and other xanthine derivatives in endotoxin action in mice. Eicosanoids 2:183–188

    PubMed  Google Scholar 

  41. Sinzinger H (1983) Pentoxifylline enhances formation of prostacyclin from rat vascular and renal tissue. Prostaglandin Leukocyte Med 12:217–226

    Article  Google Scholar 

  42. Lefer AM, Lefer DJ (1993) Pharmacology of the endothelium in ischemia-reperfusion and circulatory shock. Annu Rev Pharmacol Toxicol 33:71–90

    Article  PubMed  Google Scholar 

  43. Kainoh M, Imai R, Umetsu T, Hattori M, Nishio S (1990) Prostacyclin and beraprost sodium as suppressors of activated rat polymorphonuclear leukocytes. Biochem Pharmacol 39:477–484

    Article  PubMed  Google Scholar 

  44. Simpson PJ, Mitsos SE, Ventura A, Gallagher KP, Fantone JC, Abrams GD, Schork MA, Lucchesi BR (1987) Prostacyclin protects ischemic reperfused myocardium in the dog by inhibition of neutrophil activation. Am Heart J 113:129–137

    Article  PubMed  Google Scholar 

  45. Zabel P, Schade U (1993) Therapiestrategien gegen Mediatoren beim septischen Schock. Immun Infekt 21: 45–50

    PubMed  Google Scholar 

  46. Roberts PJ, Yong KL, Khawa A, Johnson BV, Pizzey AR, Carver JE, Addison IE, Linch DC (1993) Pentoxyifylline at clinically achievable levels inhibits FMLP-induced neutrophil responses, but not priming, uregulation of cell-adhesion molecules, or migration induced by GM-CSF. Eur J Hematol 50:1–10

    Google Scholar 

  47. Endres S, Fülle HJ, Sinha B, Stoll D, Dinarello CA, Gerzer R, Weber PC (1991) Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-α and interleukin-1β by human mononuclear cells Immunology 72:56–60

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Staudinger, T., Presterl, E., Graninger, W. et al. Influence of pentoxifylline on cytokine levels and inflammatory parameters in septic shock. Intensive Care Med 22, 888–893 (1996). https://doi.org/10.1007/BF02044112

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02044112

Key words

Navigation