Death from sepsis is still the most common cause of death in the intensive care unit
and the 13th most common cause of mortality overall [
1
]. While treatment of the primary etiology has improved the outcome, mortality rates
remain up to 50% [
2
]. This is likely due to the increase of circulating pro-inflammatory mediators that
result in multiple organ dysfunction, initially described by Hack et al. in 1989 [
3
]. It is clear from experimental and clinical studies that patients with sepsis have
elevated cytokine levels [
4
]. Due to the impact on critically ill patients, much work has been done in the laboratory
and in clinical trials to attempt to treat septic shock by modulating the inflammatory
response. Early trials starting in 1963 using corticosteroids to treat sepsis, while
initially encouraging, did not prove to be of benefit after more careful study [
5
,
6
,
7
,
8
]. Nitric oxide synthase inhibitors were purported to restore the responsiveness of
the septic vasculature to catecholamines in animals [
9
,
10
]. Tumor necrosis factor (TNF) is a strong pro-inflammatory cytokine found in septic
patients in higher levels and correlates with clinical outcome. When given systemically,
TNF mimics several pathophysiologic changes similar to those observed in human sepsis
[
11
]. Passive immunization against TNF protected mice from lethal endotoxic shock but
did not result in improved survival in humans [
12
,
13
,
14
]. Targeting specific cytokines such with recombinant IL-1 receptor antagonist also
resulted in reduced mortality in animal models of endotoxic shock however human clinical
trials again did not show protective effects [
15
,
16
]. Studies evaluating platelet activating factor receptor antagonists and platelet-activating
factor acetylhydrolases were also promising in animal studies but these agents did
not demonstrate significant beneficial effects on survival in clinical trials [
17
]. The pharmacologic treatment with the greatest promise is recombinant human activated
protein C (APC - drotrecogin α), which has shown benefit in clinical trials [
18
] and may act by exerting anti-inflammatory effect via inhibiting cytokine production in monocytes (TNF-, IL-1 and IL-6) and by reducing
adhesive interactions between neutrophils and endothelial cells [
19
]. APC significantly decreased mortality from 30.8% in controls to 24.7% in treated
patients in a single phase III trial (P < 0.005) [
20
].To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Surgical ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Understanding pathophysiology.4th edition. Mosby Publishing, Matyland Heights, MO2008 (pp. 423–436)
- Robbins basic pathology.8th edition. Saunders Elsevier, Philadelphia, PA2007 (pp. 102–103)
- Increased plasma levels of interleukin-6 in sepsis.Blood. 1989; 74: 1704
- Regulatory effects of hydrogen sulfide on IL-6, IL-8 and IL-10 levels in the plasma and pulmonary tissue of rats with acute lung injury.Exp Biol Med. 2008; 233: 1081
- The effectiveness of hydrocortisone in the management of severe infection.JAMA. 1963; 183: 462
- A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock.N Engl J Med. 1987; 317: 653
- Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock.Crit Care Med. 2005; 33: 2457
- Corticosteroids for severe sepsis and septic shock: A systematic review and meta-analysis.BMJ. 2004; 329: 480
- Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis.Ann Intern Med. 1994; 120: 771
- Nitric oxide and septic vascular dysfunction.Anesth Analg. 2000; 90: 89
- Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings.Surgery. 1988; 104: 280
- Shock and tissue injury induced by recombinant human cachectin.Science. 1986; 234: 470
- Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia.Nature. 1987; 330: 662
- Anti-tumor necrosis factor therapy in sepsis: Update on clinical trials and lessons learned.Crit Care Med. 2001; 29: S121
- Interleukin-1 receptor antagonist reduces mortality from endotoxin shock.Nature. 1990; 348: 550
- Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group.Crit Care Med. 1997; 25: 1115
- Should we continue to target the platelet-activating factor pathway in septic patients?.Crit Care Med. 2004; 32: 585
- Efficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med. 2001; 344: 699
- Recombinant human activated protein C in sepsis: Inconsistent trial results, an unclear mechanism of action, and safety concerns resulted in labeling restrictions and the need for phase IV trials.Crit Care Med. 2003; 31: S94
- Efficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med. 2001; 344: 699
- Removal of 17 cytokines, HMGB1, and albumin by continuous hemofiltration using a cellulose triacetate membrane: An ex vivo study.J Surg Res. 2011; (in press)
- Studies on the ability of hemodialysis membranes to induce, bind, and clear human interleukin-1.J Lab Clin Med. 1988; 112: 76
- The potential role of hemofiltration in the treatment of patients with septic shock and multiple organ dysfunction syndrome.Adv Renal Replace Ther. 1994; 1: 176
- Proinflammatory cytokines and hemofiltration membranes.J Am Soc Nephrol. 1994; 5: 228
- Early isovolemic hemofiltration in oliguric patients with septic shock.Intensive Care Med. 2006; 32: 80
- Intensity of continuous renal replacement therapies in patients with severe sepsis and septic shock: A systematic review and meta-analysis.Anaesth Intensive Care. 2011; 39: 373
Article info
Publication history
Published online: September 14, 2011
Accepted:
August 19,
2011
Received:
August 15,
2011
Identification
Copyright
© 2011 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
