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01-03-2008 | Experimental

Risk of death does not alter the efficacy of hydrocortisone therapy in a mouse E. coli pneumonia model

Risk and corticosteroids in sepsis

Authors: Yan Li, Xizhong Cui, Xuemei Li, Steven B. Solomon, Robert L. Danner, Steven M. Banks, Yvonne Fitz, Djillali Annane, Charles Natanson, Peter Q. Eichacker

Published in: Intensive Care Medicine | Issue 3/2008

Abstract

Background

Risk of death may influence the efficacy of anti-inflammatory agents in sepsis. “Physiologic” dose corticosteroids, while improving survival in earlier trials with higher control mortality rates (> 50%), were not beneficial in the recent CORTICUS trial with lower control mortality (31%). We investigated whether risk of death altered the effects of hydrocortisone in a mouse pneumonia model.

Methods

Mice (n = 637) challenged with high, medium or low intratracheal E. coli doses were randomized to receive one of three hydrocortisone doses (5, 25 or 125 mg/kg) or normal saline (NS) only (control) for 4 days. All animals were treated with similar volumes of ceftriaxone and NS support following E. coli and were observed for 168 h.

Results

Decreasing E. coli doses reduced control mortality rates (from 94 to 12%). In similar patterns (not significant) each hydrocortisone dose increased the odds ratio (OR) of survival (95% confidence interval) with each E. coli dose (ORs ranging from 1.2 [0.4, 3.7] to 6.1 [0.6, 61.0]). The effect of hydrocortisone on the OR was not related to control mortality rate (r = –0.13, p = 0.29) and overall was highly significant (2.04 [1.37, 3.03], p = 0.0004). In randomly selected animals 48 h after the highest E. coli dose, compared with the control, hydrocortisone (125 mg/kg) significantly decreased IL-6, INFγ, and nitric oxide levels.

Conclusions

In this mouse model the beneficial effects of hydrocortisone were independent of risk of death. These findings suggest that factors other than risk of death may underlie the differing effects of corticosteroids in recent sepsis trials.

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Knaus WA, Harrell FE, LaBrecque JF, Wagner DP, Pribble JP, Draper EA, Fisher CJ, Soll L (1996) Use of predicted mortality to evaluate the efficacy of anti-cytokine therapy in sepsis: the IL-1ra Phase III Sepsis Syndrome Study Group. Crit Care Med 24:46–56PubMedCrossRef

Panacek EA, Marshall JC, Albertson TE, Johnson DH, Johnson S, MacArthur RD, Miller M, Barchuk WT, Fischkoff S, Kaul M, Teoh L, Van Meter L, Daum L, Lemeshow S, Hicklin G, Doig C, Monoclonal Anti-TNF: a Randomized Controlled Sepsis Study Investigators (2004) Efficacy and safety of the monoclonal anti-tumor necrosis factor F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med 32:2173–2182PubMed

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

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 97:1349–1357PubMedCrossRef

Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant Human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group (2001) Efficacy and safety of recombinant activated protein C for severe sepsis. N Engl J Med 344:699–709PubMedCrossRef

Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C (2004) Meta-analysis: the effect of steroids on survival and shock during sepsis depended on dose. Ann Intern Med 141:47–56PubMed

Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A (1998) Reversal of late septic shock with supraphysiologic dose hydrocortisone. Crit Care Med 26:645–650PubMedCrossRef

Yildiz O, Doganay M, Aygen B, Guven M, Keletimur F, Tutus A (2002) Physiological-dose steroid therapy in sepsis [ISRCTN36253388]. Crit Care 6:251–259PubMedCrossRef

Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E (2002) Effect of treatment with low doses of corticosteroid and fludrocortisone on mortality in patients with septic shock. JAMA 288:862–871PubMedCrossRef

10.

Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della Porta R, Giorgio C, Blasi F, Umberger R, Meduri GU (2005) Hydrocortisone infusion for severe community-acquired pneumonia. A preliminary randomized study. Am J Respir Crit Care Med 171:242–248PubMedCrossRef

11.

Sprung CL, Annane D, Briegel J, Keh D, Moreno R, Singer M, Weiss Y, Sorenson F (2007) Corticosteroid therapy of septic shock (CORTICUS). Am J Respir Crit Care Med 175:A507

12.

Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310PubMedCrossRef

13.

Marrie TJ, Fine MJ, Obrosky DS, Coley C, Singer DE, Kapoor WN (1998) Community-acquired pneumonia due to Escherichia coli. Clin Microbiol Infect 4:717–723PubMedCrossRef

14.

Babcock HM, Zack JE, Garrison T, Trovillion E, Kollef MH, Fraser VJ (2003) Ventilator-associated pneumonia in a multi-hospital system: differences in microbiology by location. Infect Control Hosp Epidemiol 24:853–858PubMedCrossRef

15.

http://www.globalrph.com/corticocalc.htm

16.

Greisman SE, DuBuy JB, Woodward CL (1979) Experimental gram-negative bacterial sepsis: prevention of mortality not preventable by antibiotics alone. Infect Immun 25:538–557PubMed

17.

Johnston CA, Greisman SE (1984) Endotoxemia induced by antibiotic therapy: a mechanism for adrenal corticosteroid protection in gram-negative sepsis. Trans Assoc Am Physicians 97:172–181PubMed

18.

Greisman SE (1982) Experimental Gram-negative bacterial sepsis: optimal methylprednisolone requirements for prevention of mortality not preventable by antibiotics alone. Proc Soc Exp Biol Med 170:436–442PubMed

19.

Freeman BD, Correa R, Karzai W, Natanson C, Patterson M, Banks S, Fitz Y, Danner RL, Wilson L, Eichacker PQ (1996) Controlled trials of rG-CSF and CD11b-directed MAb during hyperoxia and E. coli pneumonia in rats. J Appl Physiol 80:2066–2076PubMed

20.

Cui X, Moayeri M, Li Y, Li X, Haley M, Fitz Y, Correa-Araujo R, Banks SM, Leppla SH, Eichacker PQ (2004) 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 Regul Integr Comp Physiol 286:R699–R709PubMed

21.

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 32:1263–1270PubMedCrossRef

22.

Cui X, Li Y, Li X, Laird MW, Subramanian M, Moayeri M, Leppla SH, Fitz Y, Su J, Sherer K, Eichacker PQ (2007) Bacillus anthracis edema and lethal toxin have different hemodynamic effects but function together to worsen shock and outcome in a rat model. J Infect Dis 195:572–580PubMedCrossRef

23.

Chawla K, Kupfer Y, Goldman I (1999) Hydrocortisone reverses refractory septic shock [abstract]. Crit Care Med [Suppl] 27(1):A33CrossRef

24.

Oppert M, Schindler R, Husung C, Offermann K, Graf KJ, Boenisch O, Barckow D, Frei U, Eckardt KU (2005) Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med 33:2457–2464PubMedCrossRef

25.

Briegel J, Jochum M, Gippner-Steppert C, Thiel M (2001) Immunomodulation in septic shock: hydrocortisone differentially regulates cytokine responses. J Am Soc Nephrol 12:S70–S74PubMed

26.

Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H (2003) Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock. A double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med 167:512–520PubMedCrossRef

27.

Briegel J, Forst H, Haller M, Schelling G, Kliger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, Stoll C, Peter K (1999) Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 27:723–731PubMedCrossRef

28.

Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM, Surviving Sepsis Campaign Management Guidelines Committee (2004) Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 32:858–873PubMedCrossRef

29.

Mansart A, Bollaert PE, Seguin C, Levy B, Longrois D, Mallie JP (2003) Hemodynamic effects of early versus late glucocorticosteroid administration in experimental septic shock. Shock 19:38–44PubMedCrossRef

30.

Annane D, Bellissant E, Sebille V, Lesieur O, Mathieu B, Raphael JC, Gajdos P (1998) Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve. Br J Clin Pharmacol 46:589–597PubMedCrossRef

31.

Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y (2004) Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 329:480PubMedCrossRef

32.

Hsu FH, Prueksaritanont T, Lee MG, Chiou WL (1987) The phenomenon and cause of the dose-dependent oral absorption of chlorothiazide in rats: extrapolation to human data based on the body surface area concept. J Pharmacokinet Biopharm 15:369–386PubMedCrossRef

33.

Samtani MN, Jusko WJ (2005) Stability of dexamethasone sodium phosphate in rat plasma. Int J Pharm 301:262–266PubMedCrossRef

34.

Van Dijk H, Bloksma N, Rademaker PM, Schouten WJ, Willers JM (1979) Differential potencies of corticosterone and hydrocortisone in immune and immune-related processes in the mouse. Int J Immmunopharmacol 1:285–292CrossRef

35.

Van Ogtrop ML, Mattie H, Sekh BR, Van Strijen E, Van Furth R (1992) Comparison of antibacterial efficacies of ampicillin and ciprofloxacin against experimental infections with Listeria monocytogenes in hydrocortisone-treated mice. Antimicrob Agents Chemother 36:2375–2380PubMed

Title: Risk of death does not alter the efficacy of hydrocortisone therapy in a mouse E. coli pneumonia model
Risk and corticosteroids in sepsis
Authors: Yan Li
Xizhong Cui
Xuemei Li
Steven B. Solomon
Robert L. Danner
Steven M. Banks
Yvonne Fitz
Djillali Annane
Charles Natanson
Peter Q. Eichacker
Publication date: 01-03-2008
Publisher: Springer-Verlag
Published in: Intensive Care Medicine / Issue 3/2008
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-007-0921-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Risk of death does not alter the efficacy of hydrocortisone therapy in a mouse E. coli pneumonia model

Risk and corticosteroids in sepsis

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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