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  1. 1. Hydrocortisone Therapy for Patients with Septic Shock (CORTICUS) PRENTED BY M.A.MONEIM NGHA - DAMMAM ICU January 10, 2008
  2. 2. Previous studies <ul><li>Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone </li></ul><ul><li>on </li></ul><ul><li>Mortality in Patients With SepticShock </li></ul><ul><li>Djillali Annane; Véronique Sébille; Claire Charpentier; et al </li></ul><ul><li>JAMA. 2002;288(7):862-871 (doi:10.1001/jama.288.7.862) </li></ul><ul><li>Objective  To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency </li></ul><ul><li>Conclusion  a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events </li></ul>
  3. 3. This study <ul><li>Purpose </li></ul><ul><ul><li>is to determine whether steroids decrease 28-day mortality in patients with septic shock </li></ul></ul><ul><li>Study Type :  Interventional </li></ul><ul><li>Study Design :   </li></ul><ul><ul><li>Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study </li></ul></ul><ul><li>52 participating intensive care units (ICUs) in 9 countries </li></ul><ul><li>Eligibility: 18 years old or more </li></ul><ul><li>Study Start Date:  March 2002 </li></ul><ul><li>Study Completion Date:  November 2005 </li></ul>
  4. 4. Inclusion Criteria <ul><li>1.Clinical evidence of infection within the previous 72 hours (may be present longer than 72 hours) (a, b, c, or d - only 1 required) </li></ul><ul><ul><li>Presence of polymorphonuclear cells in a normally sterile body fluid (excluding blood) </li></ul></ul><ul><ul><li>Culture or Gram stain of blood, sputum, urine or normally sterile body fluid positive for a pathogenic micro-organism </li></ul></ul><ul><ul><li>Focus of infection identified by visual inspection (e.g. ruptured bowel with the presence of free air or bowel contents in the abdomen found at the time of surgery, wound with purulent drainage) </li></ul></ul><ul><ul><li>Other clinical evidence of infection - treated community acquired pneumonia, purpura fulminans, necrotising fascitis, etc. </li></ul></ul><ul><li>2.Evidence of a systemic response to infection as defined by the presence of two or more of the following signs within the previous 24 hours. These signs may be present longer than 72 hours. </li></ul><ul><ul><li>Fever (temperature >38.3°C) or hypothermia (rectal temperature < 35.6°C) </li></ul></ul><ul><ul><li>Tachycardia (heart rate of >90 beat/min) </li></ul></ul><ul><ul><li>Tachypnea (respiratory rate > 20 breaths/min, PaC02<32 mmHg) or patient requires invasive mechanical ventilation </li></ul></ul><ul><ul><li>Alteration of the WBC count >12,000 cells/mm3, <4,000 cells/mm3 or >10% immature neutrophils (bands). </li></ul></ul><ul><li>3.Evidence of shock defined by (A + B- both required within the previous 72 hours (may NOT be present longer than 72 hours). </li></ul><ul><li>A. A systolic blood pressure < 90 mmHg or a decrease in SBP of more than 50 mmHg from baseline in previous hypertensive patients (for at least one hour) despite adequate fluid replacement OR need for vasopressors for at least one hour (infusion of dopamine ≥ 5 mcg/kg/min or any dose of adrenaline, noradrenaline, phenylephrine or vasopressin) to maintain a SBP ≥ 90 mmHg </li></ul><ul><li>B. Hypoperfusion or organ dysfunction which is not the result of underlying diseases or drugs, but is attributable to sepsis, including one of the following: </li></ul><ul><ul><ul><li>Sustained oliguria (urine output < 0.5 ml/kg/hr for a minimum of 1 hour) </li></ul></ul></ul><ul><ul><ul><li>Metabolic acidosis [pH of < 7.3, or a base deficit of > or = 5.0 mmol/L, or an increased lactic acid concentration (> 2 mmol/L)]. </li></ul></ul></ul><ul><ul><ul><li>Arterial hypoxemia (Pa02/FI02<280 in the absence of pneumonia)(Pa02/FI02<200 in the presence of pneumonia) </li></ul></ul></ul><ul><ul><ul><li>Thrombocytopenia - platelet count ≤ 100,000 cells/mm3 </li></ul></ul></ul><ul><ul><ul><li>Acute altered mental status (Glasgow Coma Scale < 14 or acute change from baseline) </li></ul></ul></ul><ul><li>4. Informed Consent </li></ul><ul><li>5. Cortisol level at baseline and 60 minutes after 0.25 mg cosyntropin </li></ul>
  5. 5. Exclusion Criteria <ul><ul><li>Pregnancy </li></ul></ul><ul><ul><li>Age less than 18 </li></ul></ul><ul><ul><li>Underlying disease with a prognosis for survival of less than 3 months </li></ul></ul><ul><ul><li>Cardiopulmonary resuscitation within 72 hours before study. </li></ul></ul><ul><ul><li>Drug-induced immunosuppression, including chemotherapy or radiation therapy within 4 weeks before the study </li></ul></ul><ul><ul><li>Administration of chronic corticosteroids in the last 6 months or acute steroid therapy (any dose) within 4 weeks (including inhaled steroids) Topical steroids are not exclusions </li></ul></ul><ul><ul><li>HIV positivity </li></ul></ul><ul><ul><li>Presence of an advanced directive to withhold or withdraw life sustaining treatment (i.e. DNR) </li></ul></ul><ul><ul><li>Advanced cancer with a life expectancy less than 3 months </li></ul></ul><ul><ul><li>Acute myocardial infarction or pulmonary embolus </li></ul></ul><ul><ul><li>Another experimental drug study within the last 30 days </li></ul></ul><ul><ul><li>Moribund patients likely to die within 24 hours </li></ul></ul><ul><ul><li>Patients in the ICU for more than 2 months at the time of the start of septic shock </li></ul></ul>
  6. 6. End Points <ul><li>Primary Outcome Measures: </li></ul><ul><ul><li>28 day mortality in all the non-responders to ACTH </li></ul></ul><ul><li>Secondary Outcome Measures: </li></ul><ul><ul><li>28 day all cause mortality in the total group </li></ul></ul><ul><ul><li>28 day all cause mortality in responders </li></ul></ul><ul><ul><li>One year mortality in nonresponders, total and responders </li></ul></ul><ul><ul><li>ICU and hospital mortality </li></ul></ul><ul><ul><li>Organ system failure reversal, especially shock </li></ul></ul><ul><ul><li>Duration of ICU and total hospitalisation </li></ul></ul>
  7. 7. Definitions <ul><li>Organ-system failure was defined for each of the six major organ systems as a Sequential Organ Failure Assessment (SOFA) score of 3 or 4 points (on a scale ranging from 0 to 4 for each organ system, for an aggregate score of 0 to 24, with higher scores indicating more severe organ dysfunction) </li></ul><ul><li>Reversal of shock was defined as the maintenance of a systolic blood pressure of at least 90 mm Hg without vasopressor support for at least 24 hours </li></ul><ul><li>The absence of a response to a corticotropin test was defined as an increase in the cortisol level of no more than 9 μg per deciliter (248 nmol per liter) </li></ul>
  8. 8. Arms Experimental Placebo Comparator Intervention Intervention Placebo Placebo Drug hydrocortisone sodium succinate hydrocortisone sodium succinate 50 mg intravenous bolus every six hours for 5 days, then tapered to 50 mg intravenously every 12 hours for days 6-8, 50 mg every 24 hours for days 9-11 and then stopped Drug
  9. 9. Patients 500 -1(consent was withdrawn) 499 Hydrocortisone 252 Placebo 248 No response to corticotropin 125/108 233 ( % 46.7) Response To corticotropin 136 unknown4(2.4%) Response To corticotropin 118 Unknown 8 Projected 800 P Slow recruitment Termination of funding Time expiry of the trial drug
  10. 10. Results <ul><li>At baseline, the two study groups were well balanced with regard to </li></ul><ul><li>Demographic characteristics </li></ul><ul><li>Clinical characteristics </li></ul><ul><li>Type and site of infection </li></ul><ul><li>Infecting organisms </li></ul>
  11. 11. Demographic Characteristics of the Patients, According to Subgroup
  12. 12. Clinical Characteristics of the Patients at Baseline, According to Subgroup Results
  13. 13. Results <ul><li>Mortality </li></ul><ul><ul><li>There was no significant difference between the two study groups in the primary outcome, the rate of death at 28 days among patients who did not have a response to corticotropin </li></ul></ul>Primary End Points <ul><ul><li>No differences in mortality were seen between the study groups or between the corticotropin subgroups at any other time point </li></ul></ul>
  14. 14. Mortality <ul><li>there was no significant difference among </li></ul><ul><li>Those who did not have a response to a corticotropin test </li></ul><ul><li>(Panel A) </li></ul><ul><li>Those who had a response to corticotropin (Panel B ) </li></ul><ul><li>All patients who underwent evaluation (Panel C) </li></ul>Results Kaplan–Meier Curves for Survival at 28 Days For the comparison between patients with septic shock who received hydrocortisone and those who received placebo
  15. 15. <ul><li>Reversal of Shock </li></ul>Secondary outcome The proportions of patients who underwent a reversal of shock were similar Among patients who did not have a response to corticotropin and in the placebo group (76.0%; 95% CI, 68.5 to 83.5) (70.4%; 95% CI, 61.8 to 79.0; P = 0.41) Among patients who had a response to corticotropin hydrocortisone group and in the placebo group (84.7%; 95% CI, 78.3 to 91.2) (76.5%; 95% CI, 69.3 to 83.6;P = 0.13) And among all patients
  16. 16. <ul><li>Reversal of Shock </li></ul>(Panel A) patients who did not have a response to a corticotropin test P = 0.06 (Panel B) patients who had a response to corticotropin P<0.001 (Panel C) all patients Kaplan–Meier Curves for the Time to Reversal of Shock For the comparison between patients with septic shock who received hydrocortisone and those who received placebo The duration of time until the reversal of shock was significantly shorter among patients receiving hydrocortisone for all patients (P<0.001), for those who had a response to corticotropin (P<0.001), and for those who did not have a response to corticotropin (P = 0.06)
  17. 17. MV The number of extubated patients on day 28 was similar in the two study groups Antibiotics There was no significant difference in outcome between study groups among patients receiving appropriate antibiotic therapy and those receiving inappropriate therapy Etomidate Among the 96 patients who had received Etomidate, 58(60.4%) did not have a response to corticotropin, as compared with 175 of 403 who did not receive etomidate (43.4%, P = 0.004) Results
  18. 18. Adverse Events <ul><li>In the hydrocortisone group, there was an increased incidence of superinfections </li></ul>including new episodes of sepsis or septic shock, with a combined odds ratio of 1.37 (95% CI, 1.05 to 1.79)
  19. 19. Adverse Events <ul><li>there was also an increased incidence of hyperglycemia and hypernatremia </li></ul>Neuromuscular weakness was rarely reported
  20. 20. Discussion <ul><li>In this study, the use of low-dose hydrocortisone had no significant effect on the rate of death in patients with septic shock at 28 days, regardless of the patients’ adrenal responsiveness to corticotropin </li></ul><ul><li>The proportion of patients in whom reversal of shock was achieved was similar in the two groups, though this goal was achieved earlier in patients who received hydrocortisone </li></ul><ul><li>This study showed an increased incidence of superinfection, including new episodes of sepsis or septic shock, in the hydrocortisone group </li></ul><ul><li>These results are in marked contrast to those of the study by Annane et al., in which both improved survival and reversal of shock were reported in patients with no response to corticotropin who received hydrocortisone plus fludrocortisone </li></ul><ul><li>The increased glucose levels in the hydrocortisone group may have contributed to increased mortality </li></ul>
  21. 21. In summary <ul><li>the use of hydrocortisone did not decrease mortality in a general population of patients with septic shock, even though the drug hastened reversal of shock </li></ul><ul><li>This lack of improvement may be related to an increased incidence of superinfection and new septic episodes </li></ul><ul><li>No benefit was seen in a subgroup of patients who had had no response to corticotropin, as was shown previously for patients with severe septic shock </li></ul>
  22. 22. Study recommendations <ul><li>Hydrocortisone cannot be recommended as general adjuvant therapy for septic shock (vasopressor responsive) </li></ul><ul><li>Corticotropin testing cannot be recommended to determine which patients should receive hydrocortisone therapy </li></ul><ul><li>Hydrocortisone may have a role among patients who are treated early after the onset of septic shock who remain hypotensive despite the administration of high-dose vasopressors (vasopressor unresponsive) </li></ul>
  23. 23. Editorials <ul><li>Encouraging results in small trials and then in a larger trial (Annane et al) led to previous recommendations to treat patients with septic shock with physiologic doses of hydrocortisone </li></ul><ul><li>The recommendations are based on five trials involving a total of 464 patients, of whom 265 (57.1%) died </li></ul><ul><li>A meta-analysis of these trials suggested that the use of corticosteroids reduced mortality </li></ul><ul><li>A metaanalysis that includes data from the CORTICUS trial is not likely to support the use of corticosteroids </li></ul><ul><li>And it seems clear that the corticotropin stimulation test does not identify patients who would benefit from corticosteroids </li></ul>
  24. 24. Editorials <ul><li>Clinicians who treat their patients with corticosteroids because they have observed a rapid reduction in the need for vasopressors should be aware that more rapid weaning from vasopressors is an unreliable surrogate outcome since it does not predict improved survival </li></ul><ul><li>To researchers it should be clear that substantial uncertainty over the role of corticosteroids persists. Reliable treatment recommendations will be possible only if a much larger trial is conducted. To avoid generating further uncertainty, the minimum sample size should substantially exceed the total number of patients who have been studied so far. The detection of a 15% reduction in relative risk from a rate of death of 35% will require a study of at least 2600 patients </li></ul>
  25. 25. International guidelines for management of severe sepsis and septic shock: 2008 <ul><li>Corticosteroids </li></ul>1. We suggest that intravenous hydrocortisone be given only to adult septic shock patients after it has been confirmed that their blood pressure is poorly responsive to fluid resuscitation and vasopressor therapy (grade 2C) 2.We suggest that the ACTH stimulation test not be used to identify the subset of adults with septic shock who should receive hydrocortisone (grade 2B) 3.We suggest that patients with septic shock should not receive dexamethasone if hydrocortisone is available (grade 2B) 4. We suggest the daily addition of oral fludrocortisone (50 mcg) if hydrocortisone is not available and the steroid that is substituted has no significant mineralocorticoid activity. Fludrocortisone is considered optional if hydrocortisone is used (grade 2C). 5. We suggest that clinicians wean the patient from steroid therapy when vasopressors are no longer required (grade 2D) . 6. We recommend that doses of corticosteroids comparable to 300 mg of hydrocortisone daily not be used in severe sepsis or septic shock for the purpose of treating septic shock (grade 1A) 7. We recommend that corticosteroids not to be administered for the treatment of sepsis in the absence of shock. There is, however, no contraindication to continuing maintenance steroid therapy or to using stress-dose steroids if the patient’s endocrine or corticosteroid administration history warrants (grade 1D)
  26. 27. Outcomes According to Subgroup