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Program Information. Critical Care Update 2008: implications of recent trials. Richard H. Savel, MD, FCCM Co-Director, Surgical ICU Maimonides Medical Center New York, NY. Slide Sub-Title. Important trials in early 2008. Corticus Trial VISEP study VASST trial

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  1. Program Information

  2. Critical Care Update 2008:implications of recent trials Richard H. Savel, MD, FCCM Co-Director, Surgical ICU Maimonides Medical Center New York, NY Slide Sub-Title

  3. Important trials in early 2008 • Corticus Trial • VISEP study • VASST trial • And 2 trials looking at low/high PEEP in ALI/ARDS: • Express trial • LOVS trial

  4. Corticus

  5. Corticus Trial • Still trying to answer the question: • Is there a value to corticosteroids as part of therapy for severe sepsis syndrome? NEJM 2008; 358: 111-24.

  6. Corticus: the patients • Age ≥ 18 yrs • clinical evidence of infection • evidence of a systemic response to infection • the onset of shock within the previous 72 hours • as defined by a systolic blood pressure of <90 mm Hg despite adequate fluid replacement or a need for vasopressors for at least 1 hour • hypoperfusion or organ dysfunction attributable to sepsis

  7. Corticus: the intervention • Hydrocortisone was administered as: • a 50-mg intravenous bolus every 6 hours for 5 days • then tapered to 50 mg intravenously every 12 hours for days 6 to 8 • 50 mg every 24 hours for days 9 to 11 • then stopped

  8. Enrollment and Outcomes

  9. Corticus: endpoints • Primary endpoint: • the rate of death at 28 days in patients who did not have a response to corticotropin • Secondary end-points were: • the rates of death at 28 days in patients who had a response to corticotropin and in all patients • the rates of death in the ICU and in the hospital • the rates of death at 1 year after randomization • a reversal of organ system failure (including shock) • and the duration of the stay in the ICU and the hospital

  10. 39.2 % N=125 36.1 % N=108 Corticus: primary outcome Rate of death at 28 days in patients who did not have a response to corticotropin (p=0.69)

  11. 28.7 % N=136 28.8% N=118 Corticus: secondary outcome Rate of death at 28 days in patients who did have a response to corticotropin (p= 1.00)

  12. 34.3% N=251 31.5 % N=248 Corticus: secondary outcome Rate of death at 28 days in all patients (p= 0.51)

  13. Corticus: other secondary outcomes • No other secondary outcomes were improved with steroids • rates of death in ICU, hospital, or at one year, as well as duration of stay in ICU or hospital • Reversal of organ system failure was improved with steroids

  14. Subgroup Outcomes

  15. P=0.06 P<0.001 P<0.001

  16. Corticus: adverse events • In the hydrocortisone group, there was an increased incidence of superinfections, including new episodes of sepsis or septic shock • There was also an increased incidence of hyperglycemia and hypernatremia

  17. Corticus: note on etomidate • Post hoc analyses also revealed an increased rate of death at 28 days among patients who received etomidate before randomization in both groups: • Etomidate/steroids:45.1% • No etomidate/steroids:31.5% • Etomidate/no steroids: 40.0% • No etomidate/no steroids: 29.6% • P=0.03 Overall mortality: etomidate: 43% no etomidate: 30.5%

  18. Corticus: Conclusions • In summary, 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. • This lack of improvement may be related to an increased incidence of superinfection and new septic episodes.

  19. Corticus: Conclusions • No benefit was seen in a subgroup of patients who had had no response to corticotropin, as had been demonstrated previously for patients with severe septic shock.

  20. Corticus: Conclusions • On the basis of these findings, hydrocortisone cannot be recommended as general adjuvant therapy for septic shock (vasopressor responsive), nor can corticotropin testing be recommended to determine which patients should receive hydrocortisone therapy.

  21. Corticus: Conclusions • 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).

  22. VISEP

  23. VISEP Study Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) NEJM 2008; 358: 125-39.

  24. VISEP study • Two-by-two factorial design: • Evaluate safety and efficacy of intensive insulin therapy compared with conventional insulin therapy • Evaluate safety and efficacy of hydroxyethyl starch (HES) compared with Ringer’s lactate (RL) in patients with severe sepsis syndrome or septic shock

  25. VISEP study • Randomized patients with severe sepsis to either : • intensive insulin therapy, or conventional insulin therapy AND • 10% pentastarch, a low-molecular weight hydroxyethyl starch, or modified Ringer’s lactate for fluid resuscitation

  26. VISEP study • The trial was stopped for safety reasons. • 537 patients evaluated: • Intensive insulin: 112 mg/dL • Conventional therapy: 151 mg/dL • P<0.001

  27. VISEP study • At 28 days, no difference between the 2 groups in rate of death, or organ failure score • Rate of severe hypoglycemia (≤40 mg/dL) was higher in intensive insulin group (17.0% vs. 4.1%, p< 0.001)

  28. VISEP study • Rate of serious adverse reactions were also higher in intensive insulin therapy group (10.9% vs. 5.2%, p=0.01)

  29. VISEP study • HES therapy was associated with higher rates of acute renal failure (34.9% vs. 22.8%, p=0.002) and renal-replacement therapy (RRT) (31% vs. 18.8%, P=0.001)

  30. VISEP study • Direct correlation between cumulative dose of HES and both need for RRT and rate of death at 90 days…not true for cumulative dose of RL. • Cox regression analysis identified the occurrence of hypoglycemia as an independent risk factor for death from any cause.

  31. VISEP study • Overall conclusions from this study: • “Taken together, our study and the medical ICU study by Van den Berghe et al. establish that intensive insulin therapy has no measurable, consistent benefit in critically ill patients in a medical ICU, regardless of whether the patients have severe sepsis, and that such therapy increases the risk of hypoglycemic episodes.”

  32. VISEP study • Overall conclusions from this study: • “Fluid resuscitation with 10% HES 200/0.5 is harmful in patients with severe sepsis. At recommended doses, it causes renal impairment, and at high doses, it impairs long-term survival. Since adverse effects have been attributed to various HES solutions… HES solutions should be avoided.”

  33. VASST

  34. Vasopressin and Septic Shock Trial:VASST NEJM 2008; 358: 877-87.

  35. VASST trial • 778 patients with septic shock (receiving at least 5mcg/min of norepinephrine) underwent randomization to either • Low-dose vasopressin (0.01-0.03 U/min) • Or • Norepinephrine (5-15 mcg/min)

  36. Enrollment and Outcomes

  37. VASST trial • Primary endpoint: • Death from any cause at 28 days • Secondary endpoints: • 90-day mortality • ICU and hosp length-of-stay • Days alive and free of : • organ dysfunction, vasopressor use, mechanical ventilation, renal replacement therapy, SIRS, corticosteroid use

  38. VASST trial • No significant differences in any of the primary or secondary endpoints when comparing the vasopressin with the “placebo” (i.e., norepinephrine) group

  39. Anaylsis of Death Rates & Risks

  40. VASST trial: Conclusions • “We did not find a significant reduction in mortality rates with vasopressin.”

  41. PEEP in ALI / ARDS • Recent randomized trials on high vs. low Positive End-Expiratory Pressure (PEEP) for Acute Lung Injury/ARDS

  42. JAMA 2008 • LOVEs trial • Meade et al. JAMA. 2008;299(6):637-645 • Express trial • Mercat et al. JAMA. 2008;299(6):646-655 • Looking at high vs. low PEEP • Not better…not worse…

  43. LOVs Trial JAMA. 2008;299(6):637-645 Meade et al.

  44. LOVs Trial

  45. LOVs Trial

  46. LOVs Trial LOVs Trial

  47. Outcomes

  48. Express Trial JAMA. 2008;299(6):646-655 Mercat et al.

  49. EXPRESS trial

  50. Express Trial

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