Skip to main content

Advertisement

SpringerLink
Log in

The difficulties of clinical trials evaluating therapeutic agents in patients with severe sepsis

  • Review Article
  • Published:
Irish Journal of Medical Science Aims and scope Submit manuscript

Abstract

Introduction

Although the pathophysiology of sepsis has been extensively studied, the disease remains a common cause of death in the critically ill patient. It thus remains one of the most pressing clinical and economic problems of modern medicine. A vast amount of inflammatory mediators have been identified as key factors in driving sepsis. Therapeutic agents designed to target these mediators have so far failed to demonstrate significant clinical benefit.

Methods

Clinical trials are the standard for assessing safety and efficacy of novel agents but are made difficult by the heterogeneous nature of septic patients. This review aims to highlight the complex nature of sepsis and the inherent difficulties encountered in designing clinical trials in these patients. The major factors contributing to the difficulties in improving internal and external validity will be discussed with the aim of guiding future study design.

Conclusions

The design of clinical trials on the septic patient remains a challenge. Methodology must be rigorous if seemingly positive clinical trials which are widely implemented are later discredited as a result of poor study design. Many lessons can be learnt from the study design of the PROWESS trial, however there remains room for improvement. This review serves as a stimulus and guide in motivating much needed high quality clinical trials in sepsis.

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

Similar content being viewed by others

References

  1. Vincent JL, Sakr Y, Sprung CL et al (2006) Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34(2):344–353

    Article  PubMed  Google Scholar 

  2. Harrison DA, Welch CA, Eddleston JM (2006) The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care 10(2):R42

    Article  PubMed  Google Scholar 

  3. Dellinger RP, Levy MM, Carlet JM et al (2008) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock. Intensive Care Med 34:17–60

    Article  PubMed  Google Scholar 

  4. Levy MM, Dellinger RP, Townsend SR et al (2010) Surviving sepsis campaign: the Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 38:367–374

    Article  PubMed  Google Scholar 

  5. Opal SM (1995) Lessons learned from clinical trials of sepsis. J Endotoxin Res 2:221–226

    Google Scholar 

  6. Vincent JL (2004) Evidence-based medicine in the ICU: important advances and limitations. Chest 12(2):592–600

    Article  Google Scholar 

  7. Vincent JL, Sun Q, Dubois MJ (2002) Clinical trials of immunomodulatory therapies in severe sepsis and septic shock. Clin Infect Dis 34:1084–1093

    Article  PubMed  CAS  Google Scholar 

  8. Fisher CJ, Agosti JM Jr, Opal SM et al (1996) Treatment of septic shock by tumour necrosis factor receptor: Fc fusion protein. N Engl JMed 334:1697–1702

    Article  CAS  Google Scholar 

  9. Annane D (2000) Effects of the combination of hydrocortisone (HC)-fludrocortisone (FC) on mortality in septic shock. Crit Care Med 28:A63

    Article  Google Scholar 

  10. van den Berghe G, Wouters P, Weekers F et al (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345:1359–1367

    Article  PubMed  Google Scholar 

  11. Bernard GR, Vincent JL, Laterre PF et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709

    Article  PubMed  CAS  Google Scholar 

  12. Sprung CL, Annane D, Keh D et al (2008) Corticus study group: hydrocortisone therapy for patients with septic shock. N Engl J Med 358:111–124

    Article  PubMed  CAS  Google Scholar 

  13. Brunkhorst FM, Engel C, Bloos F et al (2008) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125–139

    Article  PubMed  CAS  Google Scholar 

  14. Rowan KM, Kerr JH, Major E, Mc Pherson K, Short A, Vessey MP (1993) Intensive care society APACHE II study in Britain and Ireland II: outcome comparisons of intensive care units after adjustment for case mix by the American APACHE II method. BMJ 307:977–981

    Article  PubMed  CAS  Google Scholar 

  15. Sprung CL, Eidelman LA, Pizov R et al (1997) Influence of alterations in foregoing life-sustaining treatment practices on a clinical sepsis trial. Crit Care Med 25:383–387

    Article  PubMed  CAS  Google Scholar 

  16. Opal SM (2003) Clinical trial design and outcomes in patients with severe sepsis. Shock 20(4):295–302

    Article  PubMed  CAS  Google Scholar 

  17. Opal SM, Cohen J (1999) Clinical Gram-positive sepsis: Does it fundamentally differ from Gram-negative bacterial sepsis. Crit Care Med 27:1608–1616

    Article  PubMed  CAS  Google Scholar 

  18. Bone RC (1993) Gram-negative sepsis: a dilemma of modern medicine. Clin Microbiol Rev 6:57–68

    PubMed  CAS  Google Scholar 

  19. Pournaras S, Iosifidis E, Roilides E (2009) Advances in antibacterial therapy against emerging bacterial pathogens. Semin Hematol 46(3):198–211

    Article  PubMed  CAS  Google Scholar 

  20. Bates DW, Pruess KE, Lee TH (1995) How bad are bacteremia and sepsis? Outcomes in a cohort with suspected bacteremia. Arch Intern Med 155:593–598

    Article  PubMed  CAS  Google Scholar 

  21. Bone RC (1994) Gram-positive organisms and sepsis. Arch Intern Med 154(1):26–34

    Article  PubMed  CAS  Google Scholar 

  22. Valles J, Leon C, Alvarez-Ledrma F (1997) Nosocomial bacteremia in critically ill patients: a multicentre study evaluating epidemiology and prognosis. Clin Infect Dis 24:403–408

    Article  Google Scholar 

  23. Gao H, Evans TW, Finney SJ (2008) Bench-to-bedside review: sepsis, severe sepsis and septic shock-does the nature of the infecting organism matter? Crit Care 12(3):213 Epub 2008 May 6

    Article  PubMed  Google Scholar 

  24. Fisher CJ, Agosti J, Opal SM et al (1996) A phase II, double-blind, randomized, clinical trial of soluble TNF receptor:Fc fusion protein in the treatment of severe sepsis. N Engl J Med 334:1697–1702

    Article  PubMed  CAS  Google Scholar 

  25. Cross AS, Opal SM, Sadoff JD, Gemski P (1993) Choice of bacteria in animal models of sepsis. Infect Immun 61:2741–2744

    PubMed  CAS  Google Scholar 

  26. Andersson J, Nagy S, Bjork L, Abrams J, Holm S, Andersson U (1992) Bacterial toxin-induced cytokine production studied at the single-cell level. Immunol Rev 127:69–96

    Article  PubMed  CAS  Google Scholar 

  27. Westendorp RGJ, Langermans JAM, Huizinga TWJ et al (1997) Genetic influence on cytokine production and fatal meningococcal disease. Lancet 349:170–173

    Article  PubMed  CAS  Google Scholar 

  28. Sørensen TI, Nielsen GG, Andersen PK, Teasdale TW (1988) Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 318(12):727–732

    Article  PubMed  Google Scholar 

  29. Holmes CL, Russell JA, Walley KR (2003) Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for Therapy. Chest 124:1103–1115

    Article  PubMed  CAS  Google Scholar 

  30. Burt RA (1999) Genetics of host response to malaria. Int J Parasitol 29:973–979

    Article  PubMed  CAS  Google Scholar 

  31. Newport MJ, Huxley CM (1996) Huston S et al.: A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med 335:1941–1949

    Article  PubMed  CAS  Google Scholar 

  32. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV (1998) Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 338:640–644

    Article  PubMed  CAS  Google Scholar 

  33. Bernard GR, Vincent JL, Laterre PF et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709

    Article  PubMed  CAS  Google Scholar 

  34. Abraham E, Laterre PF, Garg R et al (2005) Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death: administration of drotrecogin alfa (activated) in early stage severe sepsis (ADDRESS) study group. N Engl J Med 353(13):1332–1341

    Article  PubMed  CAS  Google Scholar 

  35. Smedira NG, Evans BH, Grais LS et al (1990) Withholding and withdrawl of life support from the critically ill. New Eng J Med. 322:309–315

    Article  PubMed  CAS  Google Scholar 

  36. Opal SM (1998) New strategies in the management of sepsis. Biomed Prog 11:52–56

    Google Scholar 

  37. Levy MM, Fink MP, Marshall JC et al (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 29:530–538

    PubMed  Google Scholar 

  38. Pierrakos C, Vincent JL (2010) Sepsis biomarkers: a review. Critical Care 14:R15

    Article  PubMed  Google Scholar 

  39. Vincent JL (1997) Dear SIRS, Im sorry to say that I don’t like you. Crit Care Med 25(2):372–374

    Article  PubMed  CAS  Google Scholar 

  40. Bossink AW, Groeneveld J, Hack CE, Thijs LG (1998) Prediction of mortality in febrile medical patients: How useful are systemic inflammatory response syndrome and sepsis criteria? Chest 113(6):1533–1541

    Article  PubMed  CAS  Google Scholar 

  41. 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

    Article  PubMed  CAS  Google Scholar 

  42. Bone RC, Grodzin CJ, Balk RA (1997) Sepsis: a new hypothesis for the pathogenesis of the disease process. Chest 112:235–243

    Article  PubMed  CAS  Google Scholar 

  43. Rubulotta F, Marshall JC, Ramsay G, Nelson D, Levy M, Williams M (2009) Predisposition, insult/infection, response, and organ dysfunction: a new model for staging severe sepsis. Crit Care Med 37(4):1329–1335

    Article  PubMed  Google Scholar 

  44. Predicting outcome in ICU patients. 2nd European consensus conference in intensive care medicine. Intensive Care Med. (1994) 20:390–397

  45. Vincent J, De Mendonca A, Cantraine F et al (1998) Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicentre, prospective study. Working group on “sepsis related problems”. Crit Care Med 26:1793–1800

    Article  PubMed  CAS  Google Scholar 

  46. Opal SM, Cross AS (1999) Clinical trials for severe sepsis. Past failures, and future hopes. Infect Dis Clin North Am 13(2):285–297

    Article  PubMed  CAS  Google Scholar 

  47. Brandtzaeg P, Kerrulf P, Gaustad P et al (1989) Plasma endotoxin as a predictor of multiple organ failure and death in systemic meningococcal disease. J Infect Dis 159:195–204

    Article  PubMed  CAS  Google Scholar 

  48. Warren HS, Suffredini AF, Eichacker PQ, Munford RS (2002) Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med 347:1027–1030

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK

    T. C. Hall, D. K. Bilku, D. Al-Leswas & A. R. Dennison

  2. Department of Anaesthesia, University Hospitals of Leicester NHS Trust, Leicester, UK

    C. Horst

Authors
  1. T. C. Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. K. Bilku
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Al-Leswas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Horst
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. R. Dennison
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. C. Hall.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hall, T.C., Bilku, D.K., Al-Leswas, D. et al. The difficulties of clinical trials evaluating therapeutic agents in patients with severe sepsis. Ir J Med Sci 181, 1–6 (2012). https://doi.org/10.1007/s11845-011-0778-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11845-011-0778-1

Keywords

Search

Navigation