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Sepsisandseveresepsis

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  • Figure 2. Protocol for Early Goal-Directed Therapy. CVP denotes central venous pressure, MAP mean arterial pressure, and ScvO2 central venous oxygen saturation.
  • Figure 2. Kaplan-Meier Curves for Overall Survival. Panel A shows the comparison of overall survival between patients receiving intensive insulin therapy and those receiving conventional insulin therapy (P=0.36 by the log-rank test). Panel B shows the comparison between patients receiving pentastarch (HES) for volume resuscitation and those receiving Ringer's lactate (P=0.14 by the log-rank test). Panel C shows the comparison between patients in the low-dose HES subgroup (<=22 ml per kilogram of body weight per day), who received a median cumulative dose of 48.3 ml per kilogram (interquartile range, 21.9 to 96.2), and those in the high-dose subgroup (>22 ml per kilogram for at least 1 day during the study period), who received a median cumulative dose of 136.0 ml per kilogram (interquartile range, 79.0 to 180.0) (P<0.001 by the log-rank test).
  • Figure 2. Protocol for Early Goal-Directed Therapy. CVP denotes central venous pressure, MAP mean arterial pressure, and ScvO2 central venous oxygen saturation.
  • Figure 1. Kaplan-Meier Curves Showing Cumulative Survival of Patients Who Received Intensive Insulin Treatment or Conventional Treatment in the Intensive Care Unit (ICU). Patients discharged alive from the ICU (Panel A) and from the hospital (Panel B) were considered to have survived. In both cases, the differences between the treatment groups were significant (survival in ICU, nominal P=0.005 and adjusted P<0.04; in-hospital survival, nominal P=0.01). P values were determined with the use of the Mantel-Cox log-rank test.
  • Figure 2. Kaplan-Meier Curves for Overall Survival. Panel A shows the comparison of overall survival between patients receiving intensive insulin therapy and those receiving conventional insulin therapy (P=0.36 by the log-rank test). Panel B shows the comparison between patients receiving pentastarch (HES) for volume resuscitation and those receiving Ringer's lactate (P=0.14 by the log-rank test). Panel C shows the comparison between patients in the low-dose HES subgroup (<=22 ml per kilogram of body weight per day), who received a median cumulative dose of 48.3 ml per kilogram (interquartile range, 21.9 to 96.2), and those in the high-dose subgroup (>22 ml per kilogram for at least 1 day during the study period), who received a median cumulative dose of 136.0 ml per kilogram (interquartile range, 79.0 to 180.0) (P<0.001 by the log-rank test).
  • Figure 1. Enrollment and Outcomes.
  • Figure 1. Proposed Actions of Activated Protein C in Modulating the Systemic Inflammatory, Procoagulant, and Fibrinolytic Host Responses to Infection. The inflammatory and procoagulant host responses to infection are intricately linked. Infectious agents and inflammatory cytokines such as tumor necrosis factor {alpha} (TNF-{alpha}) and interleukin-1 activate coagulation by stimulating the release of tissue factor from monocytes and the endothelium. The presentation of tissue factor leads to the formation of thrombin and a fibrin clot. Inflammatory cytokines and thrombin can both impair the endogenous fibrinolytic potential by stimulating the release of plasminogen-activator inhibitor 1 (PAI-1) from platelets and the endothelium. PAI-1 is a potent inhibitor of tissue plasminogen activator, the endogenous pathway for lysing a fibrin clot. In addition, the procoagulant thrombin is capable of stimulating multiple inflammatory pathways and further suppressing the endogenous fibrinolytic system by activating thrombin-activatable fibrinolysis inhibitor (TAFI). The conversion of protein C, by thrombin bound to thrombomodulin, to the serine protease activated protein C is impaired by the inflammatory response. Endothelial injury results in decreased thrombomodulin levels. The end result of the host response to infection may be the development of diffuse endovascular injury, microvascular thrombosis, organ ischemia, multiorgan dysfunction, and death. Activated protein C can intervene at multiple points during the systemic response to infection. It exerts an antithrombotic effect by inactivating factors Va and VIIIa, limiting the generation of thrombin. As a result of decreased thrombin levels, the inflammatory, procoagulant, and antifibrinolytic response induced by thrombin is reduced. In vitro data indicate that activated protein C exerts an antiinflammatory effect by inhibiting the production of inflammatory cytokines (TNF-{alpha}, interleukin-1, and interleukin-6) by monocytes and limiting the rolling of monocytes and neutrophils on injured endothelium by binding selectins. Activated protein C indirectly increases the fibrinolytic response by inhibiting PAI-1.12,13,14,15,16,17
  • Figure 2. Kaplan-Meier Estimates of Survival among 850 Patients with Severe Sepsis in the Drotrecogin Alfa Activated Group and 840 Patients with Severe Sepsis in the Placebo Group. Treatment with drotrecogin alfa activated was associated with a significantly higher rate of survival (P=0.006 by the stratified log-rank test).
  • Table 5. Incidence of Serious Adverse Events.
  • Transcript

    • 1. SEPSIS ,SEVERE SEPSIS AND SEPTIC SHOCK 2008 UPDATE J.TAVARES,MD,FCCP,FAASM
    • 2. Rivers E et al. N Engl J Med 2001;345:1368-1377 Protocol for Early Goal-Directed Therapy
    • 3.
      • SEPSIS RESUSCITATION BUNDLE:
      • 1-Serum Lactate
      • 2-Blood Cultures
      • 3-Antibiotics within 3 hours/1 hr
      • 4-IVF
      • 5-CVP 8-12 or 12-15mmHg
      • 6-Scv02>70%
    • 4. LACTIC ACID
      • High Lactate levels due to liver failure.
      • Cutoff value still 4mmol/L .
      • Rapid turnaround time (ABG analyzer).
    • 5.
      • SEPSIS RESUSCITATION BUNDLE:
      • 1-Serum Lactate
      • 2-Blood Cultures
      • 3-Antibiotics within 3 hours/1 hr
      • 4-IVF
      • 5-CVP 8-12 or 12-15mmHg
      • 6-Scv02>70%
    • 6. FLUID MANAGEMENT
      • 1-Crystalloids comparable to Colloids(SAFE Trial:NEJM,2004)
      • 2-May use Albumin in individuals with Albumin less than 4.
      • 3- ?Hydroxyethyl starch(HES )
    • 7. PENTASTARCH
      • NEJM(358;2; jan 10/08)
      • Ringer’s Lactate vs Pentastarch
      • Mortality: no diference at 28 days(24.1% vs 26.7%) ; higher in the Pentastarch group at 90 days(33.9% vs 41.0%; P=0.09)
    • 8. PENTASTARCH
      • MORBIDITY:
      • Higher rate of acute renal failure(22.8% vs 34.9%)
      • Lower platelets count
      • More PRBC transfusions
    • 9. Brunkhorst F et al. N Engl J Med 2008;358:125-139 Kaplan-Meier Curves for Overall Survival
    • 10.
      • SEPSIS RESUSCITATION BUNDLE:
      • 1-Serum Lactate
      • 2-Blood Cultures
      • 3-Antibiotics within 3 hours/1 hr
      • 4-IVF
      • 5-CVP 8-12 or 12-15mmHg
      • 6-Scv02>70%
    • 11. CVP 8-12:?for how long
      • Comparison of 2 fluid mngt strategies in ALI(nejm;354,2006
      • 1000 Pts(500 conservative fluid mangt;497 liberal)
      • No difference in 60 day mortality,but less lung injury, faster weaning and fewer days in ICU for conservative.
    • 12.  
    • 13.  
    • 14.  
    • 15.  
    • 16.  
    • 17. Rivers E et al. N Engl J Med 2001;345:1368-1377 Protocol for Early Goal-Directed Therapy
    • 18. RBC Transfusion
      • Controversies in RBC transfusion in the critically ill(chest/131/5/may,2007)
      • TRICC trial(NEJM 1999;340)
      • Lack of benefit of RBC transfusions:1-immune suppression(leukocytes);2-prolonged RBC storage
    • 19. RBC TransfusionClinical Recommendations)
      • 1-general critically ill:Hb=7g/dl
      • 2-critically ill with septic shock(<6h):8-10
      • 3-critically ill with septic shock(>6h):7g/dl
      • 4-critically ill with chronic cardiac disease:7g/dl
      • 5-critically ill with acute cardiac disease:8-10g/dl
    • 20. Sepsis management bundle
      • 1-Tight blood sugar control
      • 2-Low dose steroids
      • 3-Drotrecogin alfa
      • 4-Plateau pressures<30cm H2O
      • 5-Extubation readiness.
    • 21. Intensive insulin therapy in the ICU
      • Leuven study(nejm;nov2001)
      • 1-BG<110
      • 2-mortality reduced from 8% to 4.6%
      • 3-Severe hypoglycemia(<40): 0.8% in the conventional group and 5.1% in the intensive treatment group.
      • 4-Surgical ICU patients.
    • 22. Van den Berghe G et al. N Engl J Med 2001;345:1359-1367 Kaplan-Meier Curves Showing Cumulative Survival of Patients Who Received Intensive Insulin Treatment or Conventional Treatment in the Intensive Care Unit (ICU)
    • 23. IIT in the ICU
      • Leuven 2(nejm 2006;354)
      • 1-Blood glucose 80-110
      • 2- patients staying in ICU for 3 or more days: mortality decreased from 52.3% to 43%
      • 3-Severe hypoglycemia(<40): 3.1% in the conventional group and 18.7% in the treatment group.
      • 4-medical IICU patients.
    • 24. IIT in the ICU
      • VISEP studies and Glucocontrol studies both in Europe(stopped because of increased risk of hypoglycemia).
      • Both criticized for not having enough number of patients.
      • Ongoing clinical trial by NIH(NICE-SUGAR) trial may have sufficient statistical power to address the above issues.
    • 25. Brunkhorst F et al. N Engl J Med 2008;358:125-139 Kaplan-Meier Curves for Overall Survival
    • 26. ITT in the ICU
      • Glycemic control needs to be done safely.
      • Use of computerized systems:
      • Glucommander(can be loaded in a bedside computer,hanheld computer or nursing station computer
    • 27. Glucommander
      • 5 parameters:
      • 1-low end of target range for blood glucose
      • 2-high end of target range for glucose
      • 3-the initial multiplier(adjusted for insulin sensitivity)
      • 4-the maximum time interval between measurements
      • 5-the insulin concentration
    • 28. Sepsis management bundle
      • 1-Tight blood sugar control
      • 2-Low dose steroids
      • 3-Drotrecogin alfa
      • 4-Plateau pressures<30cm H2O
      • 5-Extubation readiness.
    • 29. Adrenal Insufficiency
      • 2002:Annane et al(JAMA;288):299 patients-76% of nonresponders to cosyntropin stimulation test,on ventilator were randomized to hydrocortisone plus fludrocortisone for 7 days:13% reduction in mortality for those treated
    • 30. Adrenal Insufficiency
      • The CORTICUS trial(double-blinded,randomized,placebo-controlled multicenter European trial)( Goal:800 patients):
      • Comparing hydrocortisone(50mg IV q6h for 5 days,taper to 50mg IV q12h for 3 days,then 50mg daily for 3 days)with placebo in septic shock.
    • 31. Adrenal Insufficiency
      • The retrospective Corticus cohort study(Critical Care Medicine:Volume 35(4) April 2007pp 1012-1018)
      • Total of 562 patients(after exclusion:477pts were left)
    • 32. Sprung C et al. N Engl J Med 2008;358:111-124 Enrollment and Outcomes
    • 33. CORTICUS
      • 1-Hydrocortisone did not improve survival or reversal of shock even in patients who did not respond to Cosyntropin test
      • 2- Hydrocortisone hastened reversal of shock.
    • 34. Sepsis management bundle
      • 1-Tight blood sugar control
      • 2-Low dose steroids
      • 3-Drotrecogin alpha
      • 4-Plateau pressures<30cm H2O
      • 5-Extubation readiness.
    • 35. Bernard G et al. N Engl J Med 2001;344:699-709 Proposed Actions of Activated Protein C in Modulating the Systemic Inflammatory, Procoagulant, and Fibrinolytic Host Responses to Infection
    • 36. Drotrecogin Alfa
      • 1-PROWESS trial:NEJM 2001;344:699-709.
      • 2-ADDRESS trial:(APACHE<25 or only one organ dysfunction at baseline)-NEJM 2005;353:1332-1341.:no significant reduction in 28-day mortality.
      • 3-ADDRESS one year follow-up(critical care medicine 2007;35:1457-1463):no increased risk of death or evidence of harm at 1 year.
    • 37. Bernard G et al. N Engl J Med 2001;344:699-709 Kaplan-Meier Estimates of Survival among 850 Patients with Severe Sepsis in the Drotrecogin Alfa Activated Group and 840 Patients with Severe Sepsis in the Placebo Group
    • 38. Bernard G et al. N Engl J Med 2001;344:699-709 Incidence of Serious Adverse Events
    • 39. How do I do it(Resuscitation Phase)
      • Septic shock:
      • 1-IVF (up to 20cc/kg bolus to keep MAP>=65
      • 2-if unable to achieve above,place central line for CVP monitoring:keep CVP 8-12mmHg(12-15 if PPV).
      • 3-If CVP goal achieved but MAP<65,start vasopressors
    • 40. How do I do it(Resuscitation Phase)
      • 4-NE,DA,PE,Vasopressin
      • 5-follow serial lactate levels
      • 6-If MAP>65,check ScVo2(goal is ScVo2>70%).
      • 7-If ScVo2<70% and Ht<30%,transfuse PRBC
    • 41. How do I do it(Resuscitation Phase)
      • 9-If Ht>30% and ScVo2 still <70%,start Dobutamine.
      • If ScVo2>70%,goal achieved
    • 42. FLUIDS
      • Normal Saline:500 cc boluses
      • Albumin:25g iv x 3 doses
      • Avoid Hespan
    • 43. Vasopressin
      • 0.01-0.04 units/mn IV
      • Do not titrate.
    • 44. How do I do it(Management Phase)
      • STEROIDS
      • 1-No need for baseline cortisol level or Cosyntropin test: If BP is not responding to IVF and Vasopressors after 1 to 2 hours,start HYDROCORTISONE at 50mg IV every 6 hours for 5 days(do not taper)
    • 45. How do I do it(Management)
      • ACTIVATED PROTEIN C
      • 2-APACHE>25 or at least two organs failure,start drotrecogin alpha.
      • 3-If APACHE<25 or only one organ failure,may consider drotrecogin.
    • 46. How do I do it(management)
      • BLOOD GLUCOSE
      • 4-Tight Blood Sugar control: use hospital protocol). Acceptable to keep blood sugar less than 150.
    • 47. How do I do it(Management)
      • Mechanical ventilation
      • 5-keep plateau pressure below 30 cmH20
      • 6-Spontaneous Awakening Trials
      • 7-Spontaneous Breathing Trials
    • 48. Antibiotics
      • USE HOSPITAL PROTOCOL
    • 49. Goal for 2009
      • DECREASE SEPSIS MORTALITY BY 25%
    • 50. Material for Research
      • 1-Procalcitonin
      • 2-C Reactive Protein
      • 3-Statins

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