Evidence-Based. Management of Severe Sepsis. What is the BP Target?

Transcription

1 Evidence-Based Management of Severe Sepsis Michael A. Gropper, MD, PhD Professor and Vice Chair of Anesthesia Director, Critical Care Medicine Chair, Quality Improvment University of California San Francisco USA Management of Severe Sepsis Resuscitation Endpoints Early Goal Directed Therapy Use of Activated Protein C Replacement Dose Steroids Putting it all together What is the BP Target? BP targets are arbitrary Autoregulation is lost below MAP mmhg What is the data that we should target a MAP of 65 mmhg? 1

2 What is the BP Target? BP targets are arbitrary Autoregulation is lost below MAP mmhg What is the data that we should target a MAP of 65 mmhg? Crit Care Med 2005; 33: How Much BP is Enough? Blood Lactate (meq/l) Oxygen Consumption (ml/min/m 2 ) Oxygen Delivery (ml/min/m 2 ) Oxygen Extraction Ratio (%) 2

3 How Much BP is Enough? Urine Output (ml/h) Creatinine Clearance (ml/min) Crit Care Med 2005; 33: DOPAMINE Best Pressor: Dopamine? No evidence of increased renal perfusion at low doses Tachycardia more common than with norepinephrine May impair splanchnic blood flow Stimulates vasopressin secretion Does not confer clinically significant protection against renal dysfunction 3

4 Multicenter European observational study 198 European ICU s All patients admitted over 2 week period in 2002 Sakr et al, CCM 2006 Sakr et al, CCM 2006 Dopamine Dobutamine Epinephrine Norepinephrine Sakr et al, CCM

5 Best Pressor: Norepinephrine? No evidence of worsening renal function Less tachycardia than dopamine More rapid and effective BP control May increase splanchnic perfusion Best Pressor: Norepinephrine? Effect of norepinephrine compared with high dose dopamine and/or epinephrine on the outcome of septic shock Prospective, observational cohort N=97 Norepinephrine mortality 62% vs 82% P<0.001 RR= % CI, Martin et al, CCM 2000 Best Pressor: Epinephrine? 30 adult patients with septic shock MAP 60 mm Hg Norepinephrine and dobutamine vs epinephrine to MAP >80 mm Hg Results Similar effect on hemodynamics Epinephrine Lactate Lactate/pyruvate ratio Gastric phi Levy et al, Intens Care Med,

6 Best Pressor: Phenylephrine? 13 patients with septic shock Treated with fluids and either low-dose dopamine or dobutamine, but remained hypotensive Phenylephrine added 0.5 to 9 μg/kg/min MAP >70 mm Hg Results Increased MAP, SVR, CI, stroke index, DO 2, VO 2 and urine output No change in HR Dose 3.7 ( ) μg/kg/min Mean duration 65 hours Gregory et al, CCM, 1991 Vasopressin mechanism of action 6

7 Vasopressin in Shock Luckner et al, CCM Prospective trial in 316 patients Vasopressin infusion at 4 units/hour Measured hemodynamics, lab parameters Adverse Effects of Vasopressin Luckner et al, CCM Pressor Dose vs Mortality Luckner et al, CCM

8 Watch for side effects! VASST Trial 779 patients in septic shock requiring vasopressors for at least 6 hours and having at least 1 additional dysfunctional organ system randomized to receive AVP or norepinephrine No difference in 28-day survival between groups (35.4% vs 39.3%, P =.27). Stratified according to severity of hypotension (requiring > 15 mcg/min or < 15 mcg/min of NE at enrollment), and the patients taking lower-dose NE had improved survival with AVP (26.5% vs 35.7%, P =.05). Digital ischemia was somewhat more common in the AVP group (P =.06), while cardiac arrest was slightly more common in the NE group (P =.11). Oxygen Delivery and Consumption 8

9 Shah et al, JAMA Shah et al, JAMA

10 PAC-Man Results Venous Oximetry Measurement of the balance between systemic oxygen delivery and consumption Proven in one study (Rivers) to improve outcome 10

11 Venous oxygen saturation varies in different vascular beds Sampling needs to be well mixed: PA Oximetry Slow sampling SvO 2 vs ScvO 2 Studies are in disagreement about accuracy of ScvO 2 Most agree that the trend is accurate Early Goal Directed Therapy Hypothesis: Early in sepsis, there is inadequate oxygen delivery, manifested by low mixed-venous oxygen saturation. Early resuscitation can save these cells and prevent multi-system organ failure. 11

12 Randomized, prospective trial of early, goal-directed resuscitation of patients with severe sepsis Patients randomized to 6 hours of goal-directed therapy vs standard therapy 260 patients randomized In-hospital mortality was 30.5% with goal-directed therapy vs 46.5% with standard therapy Rivers et al, NEJM, 2001;345: Supplemental oxygen + endotracheal intubation and mechanical ventilation CVP < 8 mmhg Crystalloid Central venous and arterial catheterization 8-12 mmhg Colloid MAP < 65 mmhg >90 mmhg Vasoactive agents Sedation, paralysis (if intubated), or both >65 and <90 mmhg ScvO 2 <70% Transfusion of red cells Until hematocrit > 30% >70% Hospital admission Yes No >70% Goals Achieved Inotropic agents <70% Rivers et al, NEJM, 2001;345: Evidence: The Importance of Early Goal Directed Therapy Early goal-directed therapy in patients with severe sepsis produced: 42% in relative risk of in-hospital and 28-day mortality (P=0.009, =0.01) 33% in relative risk of death at 60 days (P=0.03) NNT to prevent 1 event (death) = 6 to Standard Therapy Early goal-directed therapy In-hospital mortality (all patients) 28-day mortality 60-day mortality Rivers E, et al. N Engl J Med 2001;345:

13 Maybe it was the volume Orthogonal Polarization Spectral Imaging Sakr et al, CCM,

14 Pathophysiology of Sepsis Coagulation fibrinolysis Endothelial injury inflammation Organ failure Phase III Trial of Drotrecogin Alfa (Activated): PROWESS PROWESS study group Randomized, double blind, placebo controlled trial 1690 Patients with sepsis were given infusion of activated PC or placebo for 96 hours Primary end point was death by 28 days Also monitored complications and coagulation activation PROWESS: Bleeding Events 14

15 Mortality Reduction in PROWESS Hospital Mortality by Subgroup 15

16 ADDRESS Trial Parameter ADDRESS: Serious Adverse Events Serious adverse event rate: Days days Serious bleeding event rate: Days days Serious non-bleeding event rate: Days days CNS bleeding events: Days days DrotAA (N=1317) n (%) 75 (5.7) 182 (13.8) 31 (2.4) 51 (3.9) 46 (3.5) 143 (10.9) 4 (0.3) 6 (0.5) Treatment Group Placebo (N=1293) n (%) 78 (6.0) 183 (14.2) 15 (1.2) 28 (2.2) 66 (5.1) 168 (13.0) 3 (0.2) 5 (0.4) P-value Observational cohort study of 312 pts with estimated ICU LOS>48hrs Measured plasma protein C and measures of organ dysfunction Brunkhorst et al, Anesthesiology,

17 Protein C and Outcomes Brunkhorst et al, Anesthesiology, Protein C and Outcomes Brunkhorst et al, Anesthesiology, Protein C and Outcomes Brunkhorst et al, Anesthesiology,

18 Hypothesis: Patients with septic shock have functional adrenal insufficiency, which contributes to their hypotension and subsequent multi-organ failure. Low dose steroids in septic shock Onset of shock Time 0 Eligibility and ACTH test Randomization At 8 hours Hydrocortisone IV 50 mg QID + Fludrocortisone 50 mcg/d for 7 d Placebo for 7 days 18

19 Low Dose Steroid Treatment in Septic Shock: 28 Day Mortality All Patients 28-day Mortality 100% 80% 60% 40% 20% 0% P= % 55% N=150 N=149 Low-dose Steroids Placebo Annane, D. JAMA, 2002; 288 (7): 868. Low Dose Steroid Treatment in Septic Shock: 28 Day Mortality (Non-responders vs. Responders) 100% Patients with Relative Adrenal Insuffiency (ACTH Test Nonresponders) (77%) 100% Patients Without Relative Adrenal Insufficiency (ACTH Test Responders) (23%) 28-day Mortality 80% 60% 40% P=0.04 P= % 63% 61% 60% 53% 53% 40% N=114 N=115 N=36 N=34 20% 20% 0% 0% Low-dose Steroids Placebo Annane, D. JAMA, 2002; 288 (7): 868. CORTICUS STUDY 19

20 Low Dose Steroid Treatment in Septic Shock : CORTICUS Study Design Objective: To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency. Primary Objective: 28-day mortality in non-responders to ACTH stimulation test Design: Placebo-controlled, randomized, double-blind, multinational European study. Setting: 52 intensive care units in multiple European countries from March 2002 to November Entry criteria similar (less sick) to Annane. Low Dose Steroid Treatment in Septic Shock : Study Design Onset of shock Randomization Eligibility and ACTH test Hydrocortisone IV 50-mg every 6 hours x 5 days Hydrocortisone IV 50-mg every 12 hours x 3 days Hydrocortisone IV 50-mg every 24 hours x 3 days Placebo X 11 days Main Outcome: 28-day survival Low Dose Steroid Treatment in Septic Shock: 28 Day Mortality All Patients 100% P= day Mortality 80% 60% 40% 20% 34% N=251 31% N=248 0% Low-dose Steroids Placebo Sprung, ESICM September

21 Low Dose Steroid Treatment in Septic Shock: 28 Day Mortality (Non-responders vs. Responders) 28-day Mortality 100% 80% 60% 40% 20% Patients with Relative Adrenal Insuffiency (ACTH Test Nonresponders) (~51%) 38% P=0.8 35% 100% 80% 60% 40% 20% Patients Without Relative Adrenal Insufficiency (ACTH Test Responders) (~47%) P=1.0 29% 29% 0% Low-dose Steroids 0% Placebo Sprung, ESICM September 2006 Retrospective multicenter study 477 patients with severe sepsis, shock All had ACTH stimulation testing Corticus Cohort Study CCM

22 Corticus Cohort Study CCM 2007 Predictors of Mortality Sepsis Bundle Implementation Kortgen et al, CCM Retrospective cohort study 30 consecutive patients meeting criteria for severe sepsis after implementation of a standard operating procedure Historical control 22

23 Interventions Early goal directed therapy Intensive insulin therapy Hydrocortisone supplementation If shock progressed Administration of rhapc Kortgen et al, CCM Results Kortgen et al, CCM

24 Survival: 30 Pts each group 24

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26 Conclusions Develop standard guidelines for sepsis treatment If pressors necessary, use norepinephrine EGDT is likely effective in reducing mortality Future resuscitation monitoring may use technology such as OPS Consider APC for patients with refractory septic shock Low dose steroids do not improve outcome in patients with septic shock 26