1 / 56

Surviving Sepsis

javan
Download Presentation

Surviving Sepsis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

    1. Surviving Sepsis Eloise Harman

    3. The Sepsis Continuum A clinical response arising from a nonspecific insult, with ?2 of the following: T >38oC or <36oC HR >90 beats/min RR >20/min WBC >12,000/mm3 or <4,000/mm3 or >10% bands

    4. Sepsis: A Major Cause of ICU Death More than 750,000 cases of severe sepsis in the US each year Mortality about 20% (recent decline) Economic cost of $17 billion each year Incidence is projected to increase by 1.5% yearly Although prognosis has improved, because of increased incidence, actual deaths will increase

    5. Surviving Sepsis Campaign Launched in Fall 2002 as a collaborative effort of European Society of Intensive Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine Goal: reduce sepsis mortality by 25% in the next 5 years Guidelines revealed at SCCM in Feb 2004 Critical Care Medicine March 2004 32(3):858-87. Website: survivingsepsis . org

    6. Key Components Fluid resuscitation Appropriate cultures prior to antibiotic administration Early targeted antibiotics and source control Use of vasopressors/inotropes when fluid resuscitation optimized

    7. Key Components Evaluation for adrenal insufficiency Stress dose corticosteroid administration Recombinant human activated protein C (xigris) for severe sepsis Low tidal volume mechanical ventilation for ARDS Tight glucose control

    8. Key Components: Prevent Complications of Critical Illness Prophylaxis for DVT Stress ulcer prophylaxis Prevention of nosocomial pneumonia by elevation of head to 45 degrees Facilitate extubation by daily interruption of sedation and early SBT Narrowing of antibiotic spectrum when appropriate

    9. Key Components: Infection Control Appropriate cultures prior to antibiotic administration Early targeted antibiotics and source control

    10. Early Appropriate Antibiotics and Source Control Gram positive organisms have surpassed gram negatives as the most common source of sepsis Therapy targeted to the suspected site (eg, CAP, intra-abdominal source) Drainage, debridement and device removal as indicated

    11. Therapy Across the Sepsis Continuum

    12. Therapy Across the Sepsis Continuum

    13. Goal Directed Therapy Administration of fluids, pressors and transfusion based upon targets for CVP, blood pressure, urine output, mixed venous oxygen saturation and hematocrit

    14. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock Study purpose: to evaluate the efficacy of early goal-directed therapy in patients presenting to an emergency department with severe sepsis or septic shock (prior to ICU admission) Study design: prospective, randomized controlled, partially blinded, single center trial

    15. “The protocol was as follows: A 500-ml bolus of crystalloid was given every 30 minutes to achieve a central venous pressure of 8 to 12 mm Hg. If the mean arterial pressure was less than 65 mm Hg, vasopressors were given to maintain a mean arterial pressure of at least 65 mm Hg. If the mean arterial pressure was greater than 90 mm Hg, vasodilators were given until it was 90 mm Hg or below. If the central venous oxygen saturation was less than 70 percent, red cells were transfused to achieve a hematocrit of at least 30 percent. After the central venous pressure, mean arterial pressure, and hematocrit were thus optimized, if the central venous oxygen saturation was less than 70 percent, dobutamine administration was started at a dose of 2.5 ľg per kilogram of body weight per minute, a dose that was increased by 2.5 ľg per kilogram per minute every 30 minutes until the central venous oxygen saturation was 70 percent or higher or until a maximal dose of 20 ľg per kilogram per minute was given. Dobutamine was decreased in dose or discontinued if the mean arterial pressure was less than 65 mm Hg or if the heart rate was above 120 beats per minute. To decrease oxygen consumption, patients in whom hemodynamic optimization could not be achieved received mechanical ventilation and sedatives.” (p. 1370) CVP - central venous pressure MAP - mean arterial pressure ScvO2 – central venous oxygen saturation SaO2 - arterial oxygen saturation VO2 - systemic oxygen consumption. Per communication with Emmanual Rivers: Standard therapy patients were transferred to the ICU as soon as possible; however, most of the standard therapy patients ended up spending about 6 hours in the ED ( 6.5 hours standard therapy vs. 8-9 hours EGDT patients).“The protocol was as follows: A 500-ml bolus of crystalloid was given every 30 minutes to achieve a central venous pressure of 8 to 12 mm Hg. If the mean arterial pressure was less than 65 mm Hg, vasopressors were given to maintain a mean arterial pressure of at least 65 mm Hg. If the mean arterial pressure was greater than 90 mm Hg, vasodilators were given until it was 90 mm Hg or below. If the central venous oxygen saturation was less than 70 percent, red cells were transfused to achieve a hematocrit of at least 30 percent. After the central venous pressure, mean arterial pressure, and hematocrit were thus optimized, if the central venous oxygen saturation was less than 70 percent, dobutamine administration was started at a dose of 2.5 ľg per kilogram of body weight per minute, a dose that was increased by 2.5 ľg per kilogram per minute every 30 minutes until the central venous oxygen saturation was 70 percent or higher or until a maximal dose of 20 ľg per kilogram per minute was given. Dobutamine was decreased in dose or discontinued if the mean arterial pressure was less than 65 mm Hg or if the heart rate was above 120 beats per minute. To decrease oxygen consumption, patients in whom hemodynamic optimization could not be achieved received mechanical ventilation and sedatives.” (p. 1370) CVP - central venous pressureMAP - mean arterial pressureScvO2 – central venous oxygen saturationSaO2 - arterial oxygen saturation VO2 - systemic oxygen consumption. Per communication with Emmanual Rivers: Standard therapy patients were transferred to the ICU as soon as possible; however, most of the standard therapy patients ended up spending about 6 hours in the ED ( 6.5 hours standard therapy vs. 8-9 hours EGDT patients).

    16. Early Goal-Directed Therapy BACK-UP SLIDE: This slide shows specifically how the monitored parameters in EGDT were maintained. “The protocol was as follows: A 500-ml bolus of crystalloid was given every 30 minutes to achieve a central venous pressure of 8 to 12 mm Hg. If the mean arterial pressure was less than 65 mm Hg, vasopressors were given to maintain a mean arterial pressure of at least 65 mm Hg. If the mean arterial pressure was greater than 90 mm Hg, vasodilators were given until it was 90 mm Hg or below. If the central venous oxygen saturation was less than 70 percent, red cells were transfused to achieve a hematocrit of at least 30 percent. After the central venous pressure, mean arterial pressure, and hematocrit were thus optimized, if the central venous oxygen saturation was less than 70 percent, dobutamine administration was started at a dose of 2.5 ľg per kilogram of body weight per minute, a dose that was increased by 2.5 ľg per kilogram per minute every 30 minutes until the central venous oxygen saturation was 70 percent or higher or until a maximal dose of 20 ľg per kilogram per minute was given. Dobutamine was decreased in dose or discontinued if the mean arterial pressure was less than 65 mm Hg or if the heart rate was above 120 beats per minute. To decrease oxygen consumption, patients in whom hemodynamic optimization could not be achieved received mechanical ventilation and sedatives.” (p. 1370) BACK-UP SLIDE: This slide shows specifically how the monitored parameters in EGDT were maintained. “The protocol was as follows: A 500-ml bolus of crystalloid was given every 30 minutes to achieve a central venous pressure of 8 to 12 mm Hg. If the mean arterial pressure was less than 65 mm Hg, vasopressors were given to maintain a mean arterial pressure of at least 65 mm Hg. If the mean arterial pressure was greater than 90 mm Hg, vasodilators were given until it was 90 mm Hg or below. If the central venous oxygen saturation was less than 70 percent, red cells were transfused to achieve a hematocrit of at least 30 percent. After the central venous pressure, mean arterial pressure, and hematocrit were thus optimized, if the central venous oxygen saturation was less than 70 percent, dobutamine administration was started at a dose of 2.5 ľg per kilogram of body weight per minute, a dose that was increased by 2.5 ľg per kilogram per minute every 30 minutes until the central venous oxygen saturation was 70 percent or higher or until a maximal dose of 20 ľg per kilogram per minute was given. Dobutamine was decreased in dose or discontinued if the mean arterial pressure was less than 65 mm Hg or if the heart rate was above 120 beats per minute. To decrease oxygen consumption, patients in whom hemodynamic optimization could not be achieved received mechanical ventilation and sedatives.” (p. 1370)

    17. Early Goal-Directed Therapy Results: 28 Day Mortality Cause of in-hospital death: --Sudden Cardiovascular collapse Standard Tx= 25/119 (21%) EGDT 12/117 (10.3%) --MODS Standard Tx 26/119(21.8%) EGDT 19/117 (16.2%) P. 1374Cause of in-hospital death: --Sudden Cardiovascular collapse Standard Tx= 25/119 (21%) EGDT 12/117 (10.3%) --MODS Standard Tx 26/119(21.8%) EGDT 19/117 (16.2%) P. 1374

    18. Fluid Resuscitation Crystalloids and colloids are equally effective in restoring intravascular volume

    19. SAFE Study In a randomized, controlled trial conducted in 16 ICUs in Australia and New Zealand 6997 patients were randomized to receive either saline or 4% albumin for fluid resuscitation The albumin group received less fluid volume, but required more transfusion in the first 48h NEJM 2004; 350:2247

    20. Figure 1. Kaplan-Meier Estimates of the Probability of Survival. P=0.96 for the comparison between patients assigned to receive albumin and those assigned to receive saline.Figure 1. Kaplan-Meier Estimates of the Probability of Survival. P=0.96 for the comparison between patients assigned to receive albumin and those assigned to receive saline.

    21. SAFE STUDY There were also no differences in duration of mechanical ventilation or ICU stay, development of single or multiple organ failure or duration of hospitalization.

    22. Figure 2. Relative Risk of Death from Any Cause among All the Patients and among the Patients in the Six Predefined Subgroups. The size of each symbol indicates the relative number of events in the given group. The horizontal bars represent the confidence intervals (CI). ARDS denotes the acute respiratory distress syndrome.Figure 2. Relative Risk of Death from Any Cause among All the Patients and among the Patients in the Six Predefined Subgroups. The size of each symbol indicates the relative number of events in the given group. The horizontal bars represent the confidence intervals (CI). ARDS denotes the acute respiratory distress syndrome.

    23. What Pressors for Septic Shock ? Several non-randomized studies and one small prospective randomized study of dopamine vs norepinephrine for septic shock suggest that survival may be improved with the use of norepinephrine

    25. If cardiac output is inadequate with norepinephrine, as indicated by a reduced mixed venous oxygen saturation, dobutamine may be added Vasopressin is emerging as a valuable addition to therapy for septic shock in patients with catecholamine refractory hypotension

    26. Why Vasopressin ? There is vasopressin deficiency in vasodiltory shock

    29. Why Vasopressin ? Patients with septic shock have increased sensitivity to its pressor effects Vasopressin restores vascular tone in catecholamine resistant shock by several mechanisms including potentiation of adrenergic agents Low dose vasopressin increases urine output in septic patients, and increases creatinine clearance

    30. Therapy Across the Sepsis Continuum

    31. Glucose Control: Mechanisms Stress hyperglycemia is common in sepsis Glucose has pro-inflammatory effects Insulin resistance is common in sepsis Insulin has an anti-inflammatory effect, possibly via NOS. Benefit is likely related to both insulin itself and lowering of blood glucose

    32. Tight Glucose Control In a Belgian study, 1548 SICU patients on mechanical ventilation were prospectively randomized to tight glucose control (80-110) vs standard control (180-200) Tight glucose control had a dramatic effect on morbidity in mortality, especially for patients in the ICU for>5 days

    33. Intensive Insulin Therapy in Critically Ill Patients The maximal dose of insulin was arbitrarily set at 50 IU/hr When the patient left the ICU,a conventional approach was adopted (maintenance of blood glucose at a level between 180-200 mg per deciliter). Patients were randomized on admission to the ICU. The maximal dose of insulin was arbitrarily set at 50 IU/hr When the patient left the ICU,a conventional approach was adopted (maintenance of blood glucose at a level between 180-200 mg per deciliter). Patients were randomized on admission to the ICU.

    34. Tight Glucose Control Improved Survival

    35. Intensive Insulin Therapy in Critically Ill Patients: Mortality “ P values were determined with the use of the chi-square test. For the primary outcome variable (death during intensive care), the P value has been corrected for the repeated interim analyses, according to the method of Lan and DeMets; the unadjusted P value is 0.005. Sequential interim analyses were not performed for the other variables, and nominal (unadjusted) P values are given for these comparisons.” p. 1362“ P values were determined with the use of the chi-square test. For the primary outcome variable (death during intensive care), the P value has been corrected for the repeated interim analyses, according to the method of Lan and DeMets; the unadjusted P value is 0.005. Sequential interim analyses were not performed for the other variables, and nominal (unadjusted) P values are given for these comparisons.” p. 1362

    36. Tight Glucose Control Other dramatic effects: 46% decrease in bacteremias, 41% in acute renal failure requiring dialysis, 50% reduction in blood transfusion and a 44% decrease in critical illness polyneuropathy Patients with bacteremia had a mortality of 12.5% vs 29.5% and a decreased risk of MSOF

    37. Figure 3. Effect of Intensive Insulin Therapy on Morbidity. The effect of intensive insulin therapy on time to weaning from mechanical ventilation, time to discharge from the intensive care unit (ICU), and time to discharge from the hospital is shown for all patients (intention-to-treat analysis, Panel A) and for the subgroup of 767 patients staying in the ICU for three or more days (Panel B). P values for the comparison between the two groups were calculated by proportional-hazards regression analysis with censoring for early deaths. Circles represent patients.Figure 3. Effect of Intensive Insulin Therapy on Morbidity. The effect of intensive insulin therapy on time to weaning from mechanical ventilation, time to discharge from the intensive care unit (ICU), and time to discharge from the hospital is shown for all patients (intention-to-treat analysis, Panel A) and for the subgroup of 767 patients staying in the ICU for three or more days (Panel B). P values for the comparison between the two groups were calculated by proportional-hazards regression analysis with censoring for early deaths. Circles represent patients.

    38. Figure 4. Kaplan-Meier Curves for In-Hospital Survival. The effect of intensive insulin treatment on the time from admission to the intensive care unit (ICU) until death is shown for the intention-to-treat group (Panel A) and the subgroup of patients staying in the ICU for three or more days (Panel B). Patients discharged alive from the hospital were considered survivors. P values calculated by the log-rank test were 0.40 for the intention-to-treat group and 0.02 for the subgroup staying in the ICU for three or more days. P values calculated by proportional-hazards regression analysis were 0.30 and 0.02, respectively.Figure 4. Kaplan-Meier Curves for In-Hospital Survival. The effect of intensive insulin treatment on the time from admission to the intensive care unit (ICU) until death is shown for the intention-to-treat group (Panel A) and the subgroup of patients staying in the ICU for three or more days (Panel B). Patients discharged alive from the hospital were considered survivors. P values calculated by the log-rank test were 0.40 for the intention-to-treat group and 0.02 for the subgroup staying in the ICU for three or more days. P values calculated by proportional-hazards regression analysis were 0.30 and 0.02, respectively.

    39. Therapy Across the Sepsis Continuum

    40. Activated Protein C in Sepsis

    41. PROWESS Study Design

    42. PROWESS Results In the ESSENCE trial, the primary endpoint was the composite of death, myocardial infarction, or recurrent angina at 14 days of follow-up. At 14 days, the risk of death, myocardial infarction, or recurrent angina was significantly lower in the patients assigned to enoxaparin vs. those assigned to unfractionated heparin (16.6 % vs. 19.8%, p=0.019). This benefits of enoxaparin were sustained at 30 days and as shown here were sustained at one year (32% vs. 35.7%, p=0.019) The ESSENCE trial demonstrated that antithrombotic therapy with subcutaneous enoxaparin plus aspirin was more effective than UFH plus aspirin in reducing the incidence of ischemic events in patients with unstable angina or non-ST? myocardial infarction in the acute phase. In the ESSENCE trial, the primary endpoint was the composite of death, myocardial infarction, or recurrent angina at 14 days of follow-up. At 14 days, the risk of death, myocardial infarction, or recurrent angina was significantly lower in the patients assigned to enoxaparin vs. those assigned to unfractionated heparin (16.6 % vs. 19.8%, p=0.019). This benefits of enoxaparin were sustained at 30 days and as shown here were sustained at one year (32% vs. 35.7%, p=0.019) The ESSENCE trial demonstrated that antithrombotic therapy with subcutaneous enoxaparin plus aspirin was more effective than UFH plus aspirin in reducing the incidence of ischemic events in patients with unstable angina or non-ST? myocardial infarction in the acute phase.

    43. Adverse Events with Drotrecogin alfa

    45. Xigris (Drotrecogin) Mortality increased in patients with one organ failure who underwent surgery within the previous 30 days, and is contraindicated in this group

    46. Therapy Across the Sepsis Continuum

    47. Adrenal Insufficiency in Septic Shock There is significant disagreement about how to best evaluate adrenal function in critical illness General agreement that a random cortisol of less than 25 is abnormal in this population Some screen with random cortisol and reserve ACTH stim test for those with low levels Use of total rather than free cortisol in those with hypoalbuminemia may overestimate the incidence of adrenal insufficiency

    48. Stress Dose Corticosteroids in Sepsis In a double-blind, placebo controlled study in France, 300 patients were randomized to receive stress dose steroids (hydrocortisone 50 mg q6h) and fludrocortisone (50 mcg daily) or placebo for 7 days Patients first underwent a cortrosyn stimulation test to determine relative adrenal insufficiency

    49. Low Dose Steroid Treatment in Septic Shock: Study Design This slide illustrates the study design of the combination or hydrocortisone and fludrocortisone on mortality in septic shock study. In original study design, randomization had to occur within 3 hours of the onset of shock. Later this was amended to allow for randomization within 8 hours after the onset of shock. A short corticotropin stimulation test was performed in all patients by intravenously injecting 250-mcg IV bolus of tetracosactrin; blood samples were taken immediately before the test (time 0) and 30 (T30) and 60 (T60) minutes after the test. Then the patients were randomized to steroids or placebo. Samples were measured at a central laboratory. “Cortisol response was defined as the difference between the highest of the concentrations taken after the test and those taken before the test. Relative adrenal insufficiency (ie., nonresponders) was defined by a response of 9 mcg/dL or less.”( p. 864.) Three-level prognostic classifications are defined (p. 865): Good: cortisol concentrations before corticotropin test < 34 mcg/dL and response to corticotropin test > 9 mcg/dL Intermediate: cortisol concentrations before corticotropin test < 34 mcg/dL and response to corticotropin test < 9 mcg/dL, or cortisol concentrations before corticotropin test > 34 mcg/dL and response to corticotropin test > 9 mcg/dL Poor: cortisol concentrations before corticotropin test > 34 mcg/dL and response to corticotropin test < 9 mcg/dL Treatment had to be initiated in the 8 hours following the onset of shock and given for 7 days.This slide illustrates the study design of the combination or hydrocortisone and fludrocortisone on mortality in septic shock study. In original study design, randomization had to occur within 3 hours of the onset of shock. Later this was amended to allow for randomization within 8 hours after the onset of shock. A short corticotropin stimulation test was performed in all patients by intravenously injecting 250-mcg IV bolus of tetracosactrin; blood samples were taken immediately before the test (time 0) and 30 (T30) and 60 (T60) minutes after the test. Then the patients were randomized to steroids or placebo. Samples were measured at a central laboratory. “Cortisol response was defined as the difference between the highest of the concentrations taken after the test and those taken before the test. Relative adrenal insufficiency (ie., nonresponders) was defined by a response of 9 mcg/dL or less.”( p. 864.) Three-level prognostic classifications are defined (p. 865): Good: cortisol concentrations before corticotropin test < 34 mcg/dL and response to corticotropin test > 9 mcg/dL Intermediate: cortisol concentrations before corticotropin test < 34 mcg/dL and response to corticotropin test < 9 mcg/dL, or cortisol concentrations before corticotropin test > 34 mcg/dL and response to corticotropin test > 9 mcg/dL Poor: cortisol concentrations before corticotropin test > 34 mcg/dL and response to corticotropin test < 9 mcg/dL Treatment had to be initiated in the 8 hours following the onset of shock and given for 7 days.

    50. Relative adrenal insufficiency was defined as a failure to increase serum cortisol by greater than 9mcg/dl after a 250 mcg ACTH stimulation test. Using this criteria, 77% of patients in this study were adrenally insufficient

    51. Low Dose Steroid Treatment in Septic Shock: 28 Day Mortality (Non-responders vs. Responders) ACTH Test Responders contained a total N of 70, this is 23% of the total study population (N=299). Responder placebo patients = 34 ( 18 deaths at 28 days, 53% mortality) and intervention patients = 36 ( 22 deaths at 28 days, 61% mortality). ACTH Test Non-responders contained a total N of 229 which is 77% of the total study population (N=299). Non-responder placebo patients = 115 (73 deaths at 28 days, 63% mortality), intervention patients = 114 (60 deaths at 28 days, 53% mortality) Placebo = 149 patients Intervention = 150 patients P value for entire study population = 0.09 Notes information from p. 868. ACTH Test Responders contained a total N of 70, this is 23% of the total study population (N=299). Responder placebo patients = 34 ( 18 deaths at 28 days, 53% mortality) and intervention patients = 36 ( 22 deaths at 28 days, 61% mortality). ACTH Test Non-responders contained a total N of 229 which is 77% of the total study population (N=299). Non-responder placebo patients = 115 (73 deaths at 28 days, 63% mortality), intervention patients = 114 (60 deaths at 28 days, 53% mortality) Placebo = 149 patients Intervention = 150 patients P value for entire study population = 0.09 Notes information from p. 868.

    52. Corticosteroids in Sepsis Obtain a baseline cortisol or ACTH stimulation Start stress dose steroids (hydrocortisone 200-300mg +/- fludrocortisone 50 mcg) Discontinue if levels are adequate

    53. SURVIVING SEPSIS Fluid resuscitation, goal-directed Appropriate cultures prior to antibiotic administration Early targeted antibiotics and source control Use of vasopressors/inotropes when fluid resuscitation optimized

    54. SURVIVING SEPSIS Evaluation for adrenal insufficiency Stress dose corticosteroid administration Recombinant human activated protein C (xigris) for severe sepsis Insulin drip for tight glucose control Low tidal volumes (6cc/kg) for mechanical ventilation in ARDS

    55. PREVENT COMPLICATIONS Stress ulcer and DVT prophylaxis Narrow antibiotic spectrum Prevent VAP: 45 degree elevation Facilitate early discontinuation of mechanical ventilation: sedation interruption, early SBT

    56. Acknowledgement Michelle Allen Pharm D Henry J. Mann, U of Minnesota

More Related