Surviving Sepsis: Is corticosteroid therapy beneficial … Sepsis Pat...Aka CORTICUS study Enrollment window 72 hours\爀㔀 䤀䌀唀匀 昀爀漀洀 洀愀爀挀栀 㔀 䔀砀挀氀甀猀椀漀渀
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Surviving Sepsis: Is corticosteroid therapy beneficial in patients with severe sepsis and septic shock? Patricia Leung July 11, 2013 SUNY Downstate Medical Center
Surviving Sepsis: Is corticosteroid therapy beneficial
in patients with severe sepsis and septic shock?
Patricia Leung July 11, 2013
SUNY Downstate Medical Center
Why worry? • >750,000 cases of sepsis annually in US • Leading cause of death in general ICUs • Healthcare cost $16.7 billion annually • Mortality rate for severe sepsis 10-30%; septic
shock 30-50%
Presenter
Presentation Notes
Sepsis and septic shock are common conditions that are associated with significant morbidity, mortality and health care expense Despite antimicrobial use, current resuscitation
SIRS criteria (2 or more): Temp >38 C or < 36 C HR> 90 RR> 20 or PaCO2 < 32 mm Hg WBC> 12,000/mm>3, < 4,000/mm>3, or > 10% bands?
Presenter
Presentation Notes
Lactic acidosis, oliguria, change in mental status
• Established in 2002 • Society of Critical Care Medicine,
European Society of Intensive Care Medicine, International Sepsis Forum
achieved at 6 and 24 hours • Goal: mortality reduction of 25%
in five years
Presenter
Presentation Notes
Launched in 2002 In an effort to improve care of patients with severe sepsis and septic shock Tasked with producing evidence – based guidelines Based on 5 seminal papers demonstrating mortality benefit in sepsis CVP: 8-12 mm Hg MAP > 65 mm Hg Urine output > 0.5 ml/kg / hr. Central venous (SVC) or mixed venous oxygen (SvO2) saturation > 70% Grade 1C strong recommendation, weak evidence
Criticism
• Based on results of a small, single-center studies not reproduced by multi-center studies
• Industry funding • Majority of recommendations based on Grade
E evidence
Presenter
Presentation Notes
Grade E – uncontrolled studies, case series, and expert opinion History of steroid use: Prior to 1989 – short courses of high-dose steroids increased mortality and worsened secondary infections After 1997 – longer courses of lower-dose steroids improving shock reversal and survival
24 hour goals
Grade 2 C
Presenter
Presentation Notes
Algorithm for managing sepsis, but a lot of controversy lies here SSC rec: “Consider IV hydrocortisone for adult septic shock when hypotension responds poorly to adequate fluid resuscitation and vasopressors” Grade 2C: Weak recommendation, low quality or very low quality of evidence Grading of Evidence 1A: Strong recommendation, high quality evidence 1B: Strong recommendation, moderate quality of evidence 1C: Strong recommendation, low quality or very low quality evidence 2A: Weak recommendation, high quality evidence 2B: Weak recommendation, moderate quality evidence 2001 Intensive Insulin therapy in critically ill patients – Reduced mortality benefit and increased complications 2001 Efficacy and safety of recombinant human activated protein C for severe sepsis – Xigris withdrawn due to safety concerns! 2000 Ventilation with lower tidal volumes as compared with traditional volumes for acute lung injury – litigation being brought by families of controls! Effect of steroids? (no mortality benefit)
HPA axis
- -
Presenter
Presentation Notes
The paraventricular nucleus of the hypothalamus, which contains neuroendocrine neurons that synthesize and secrete vasopressin and corticotropin-releasing hormone (CRH). These two peptides regulateThe anterior lobe of the pituitary gland. In particular, CRH and vasopressin stimulate the secretion of adrenocorticotropic hormone (ACTH), once known as corticotropin. ACTH in turn acts on: the adrenal cortex, which produces glucocorticoid hormones (mainly cortisol in humans) in response to stimulation by ACTH. Glucocorticoids in turn act back on the hypothalamus and pituitary (to suppress CRH and ACTH production) in a negative feedback cycle. Steroids increase vascular smooth muslce sensitivity to vasopressors
Adrenal dysfunction
• The incidence of adrenal dysfunction during severe sepsis and septic shock has been estimated to be as high as 50%.
• Caused by inappropriately low production of glucocorticoids or an impaired response to cortisol in the systemic circulation
• Medications - Fluconazole, Etomidate, Estrogens
• Systemic disease – HIV, liver failure, cancer
Presenter
Presentation Notes
Medications can affect the HPA axis by interacting with corticotropin receptor–binding proteins, disturbing cortisol synthesis, and through direct effects on corticotropin-releasing hormone/ACTH activity �estrogens – increase transcortin which results in higher total cortisol Fluconazole – decreased synthesis of cortisol Etomidate – carboxylated imidazole in ET decreased cortisol synthesis by reversible inhibtion of enzyme 11beta hydroxylase which is necessary for final step in cortisol synthesis – can persist for 24-36 hours after drug HIV, liver failure (hepato-adrenal dysfunction secondary to decreased HDL synthesis needed for cortisol), and cancer can all contribute to the presentation of adrenal dysfunction���
Definition
Adrenal insufficiency • Random cortisol level <10 μg/dl or • Less than a 9 μg/dl increase in cortisol 60
minutes after an ACTH stimulation test
Presenter
Presentation Notes
1 or 250 micrograms of cosyntropin is administered For this trial, the investigators defined adrenal insufficiency as a random cortisol level of less than 10 μg/dl or less than a 9 μg/dl increase in cortisol after an ACTH stimulation test. ���Read More: http://www.atsjournals.org/doi/full/10.1164/rccm.201011-1897CI
• Prospective, randomized, double-blind study • 300 patients with septic shock • Dates: 1995 to 1999 • Randomized within 8 hours of presentation • Either given 50 mg hydrocortisone IV q6H x7
days vs. placebo • Primary endpoint – 28 day survival • Days on vasopressor therapy, adverse events,
overall mortality
Presenter
Presentation Notes
Carried out in 19 french ICUS over 4 yr period 1995-1999 Criticism – late amendment to protocol was to exclude patients who received etomidate within 6 hours others: generalizability limited; Exclusion Criteria Pregnancy, MI, PE, Advanced cancer, AIDS, Contraindication for corticosteroids SSC campaign review in 2012 on effect of steroids did not identify difference in mortality rate depending on whether steroids given within 8 hours or outside 24 hr window like annane suggested
Results
• 76.5% met criteria for non-responders
• 28 day mortality rate for steroid treatment vs. placebo was significantly different at 53% vs. 63%
• Median time to withdrawal of vasopressors 7 vs. 10 days
• No significant difference in adverse events
Presenter
Presentation Notes
Secondary outcomes : ICU mortality 58 v 70 Hospital mortality 61 v 72 Mortality at 1 yr 68 v 77 Median time to withdrawl of vasopressors 7 v 10 days Adverse events :superinfection (PNA, UTI, surgical site infection), GI bleeding, psychiatric disorders
• Multicenter, prospective, randomized, double-blind, placebo-controlled study
• Dates: 2002 to 2005 • 499 patients with septic shock • 50 mg hydrocortisone q6H x5 days vs. placebo • Primary endpoint – 28 day mortality rate in
non-responders
Aka CORTICUS study
Presenter
Presentation Notes
Enrollment window 72 hours 52 ICUS from march 2002 - 2005�Exclusion criteria: underlying disease with poor prognosis, life expectancy less than 24 hours, immunosuppresion, treatment with long-term steroids within past 6 months or short-term steroids within past 4 weeks Etomidate not excluded – can decrease cortisol synthesis
Results
• 76.5% met criteria for non-responders
• 28 day mortality rate for steroid treatment vs. placebo was significantly different at 53% vs. 63%
• Median time to withdrawal of vasopressors 7 vs. 10 days
• No significant difference in adverse events
• NO difference in 28 day mortality 39% v 36% in non-responders
• Increased frequency of hyperglycemia, superinfections
• Shock reversal in 3.3 days vs. 5.8 days
Presenter
Presentation Notes
Shock reversal defined as SBP 90 without vasopressor support over 24 hours Superinfection – new infection occurring within 48 hours or more 28 v 28 in responders Differences in studies: Higher rate of death in placebo group 61 vs 32 Annane enrollment within 8 hours, Corticus 72 hours Fludrocortisone not given (200 mg hydrocortisone should provide enough mineralocorticoid activity) Annane didn’t taper, corticus tapered day 5-11 Why reversal of shock? Due to direct interaction with mechanisms producing vascular hyporeactivity
Conclusions • Despite decades of experimental animal and human trials,
the role of corticosteroid therapy remains uncertain and controversial
• Early high-dose steroids not helpful, potentially harmful • Low-dose steroids associated with improved blood pressure
and shorter duration of vasopressor support in patients with septic shock
• No evidence to support survival benefit • Possible increased infection risk • Questions: What dose to use, when to initiate treatment,
intermittent or continuous infusion therapy, duration of treatment, in what subgroup of patients are steroids beneficial
References • The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis P. C.
Minneci1,2, K. J. Deans1, P. Q. Eichacker3, C. Natanson, Clinical Microbiology and Infection Volume 15 (308-318) April 2009.
• Corticosteroids for severe sepsis and septic shock: a systematicreview and meta-analysis Djillali Annane, Eric Bellissant, Pierre Edouard Bollaert, Josef Briegel, Didier Keh, Yizhak Kupfer BMJ Aug 2004
• Low-dose steroids in adult septic shock: results of the Surviving Sepsis Campaign; Casserly B, Herwig G, Phillips G, Lemeshow S, Marshall J, Osborn T, Levy M; Intensive Care Med (2012) 38:1946-1954
• Hydrocortisone Therapy for Patients with Septic Shock Charles L. Sprung, M.D., Djillali Annane, M.D., Ph.D., Didier Keh, M.D., Rui Moreno, M.D., Ph.D.,Mervyn Singer, M.D., F.R.C.P., Klaus Freivogel, Ph.D., Yoram G. Weiss, M.D., Julie Benbenishty, R.N.,Armin Kalenka, M.D., Helmuth Forst, M.D., Ph.D., Pierre-Francois Laterre, M.D., Konrad Reinhart, M.D., Brian H. Cuthbertson, M.D., Didier Payen, M.D., Ph.D., and Josef Briegel, M.D., Ph.D., for the CORTICUS Study Group* NEJM Jan 10, 2009 Vol 358
• Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock, Annane, D, Sebille V, Charpentier, C, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E, JAMA August 21, 2002, Vol 288, No.7
• EARLY GOAL-DIRECTED THERAPY IN THE TREATMENT OF SEVERE SEPSIS AND SEPTIC SHOCK, EMANUEL RIVERS, M.D., M.P.H., BRYANT NGUYEN, M.D., SUZANNE HAVSTAD, M.A., JULIE RESSLER, B.S., ALEXANDRIA MUZZIN, B.S., BERNHARD KNOBLICH, M.D., EDWARD PETERSON, PH.D., AND MICHAEL TOMLANOVICH, M.D.,NEJM 2001 Vol 345 No. 19
• Steroids in sepsis: another swing of the pendulum in our clinical trials, Vincent, Jean-Louis; Critical Care 2008 12: 131
