Dilemmas in Septic Shock

Dilemmas in Septic Shock William Janssen, M.D. Assistant Professor of Medicine National Jewish Health University of Colorado Denver Health Sciences Center A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes and CHF. T 102, HR 130, RR 24, BP 100/50, SaO 2 = 94% on 6L. Breath sounds are decreased with egophony in the left base. CXR shows LLL consolidation. Wbc 18, Na 128, Creatinine 2.2, Lactate 1.1 What is the next best step? A. Insert a central line and initiate early goal directed therapy B. Give antibiotics to cover community acquired pneumonia C. Start norepinephrine to improve tissue perfusion D. Start dobutamine to improve tissue perfusion Prompt Administration of Antibiotics Saves Lives % Surviving N = 2731 patients 10 hospitals, 14 ICUs Time to Antibiotic Administration (hrs) Kumar. Crit Care Med 2006 1

Prompt Administration of Antibiotics Saves Lives 82.7% 77.2% % Surviving 42% Time to Antibiotic Administration (hrs) Kumar. Crit Care Med 2006 Prompt Administration of Antibiotics Saves Lives % Surviving Each hour of delay is associated with an 8% decrease in survival Time to Antibiotic Administration (hrs) Kumar. Crit Care Med 2006 More Studies Demonstrating The Importance of Prompt Treatment With Antibiotics 261 ED Patients Septic Shock 241 Patients with VAP % Surviving _ % Receiving Antibiotics Time to Antibiotics (hrs) Gaieski. Crit Care Med 2010 Time to Antibiotics Clech. Intensive Care Med 2004 2

Delay in Administration of Antibiotics is Common % Surviving 261 ED Patients Septic Shock % Receiving Antibiotics _ Time to Antibiotics Time to Antibiotics (hr) _ Gaieski. Critc Care Med 2010 Antibiotic Administration is Often Delayed % Receiving Antibiotics Kumar. Crit Care Med 2006 Time from Onset of Hypotension A 62 year-old female presents to the ED with fever, cough, dyspnea. She has type 2 DM and CHF. T 102, HR 130, RR 24, BP 100/50, SaO 2 = 94% on 6L. Breath sounds are decreased with egophony in the left base. CXR shows LLL consolidation. Wbc 18, Na 128, Creatinine 2.2, Lactate 1.1 What is the next best step? A. Insert a central line and initiate early goal directed therapy B. Give antibiotics to cover community acquired pneumonia C. Start norepinephrine to improve tissue perfusion D. Start dobutamine to improve tissue perfusion 3

A 62 year-old female presents to the ED with fever, cough, dyspnea. She has type 2 DM and CHF. T 102, HR 130, RR 24, BP 100/50, SaO 2 = 94% on 6L. Breath sounds are decreased with egophony in the left base. CXR shows LLL consolidation. Wbc 18, Na 128, Creatinine 2.2, Lactate 1.1 What is the next best step? A. Insert a central line and initiate early goal directed therapy B. Give antibiotics to cover community acquired pneumonia C. Start norepinephrine to improve tissue perfusion D. Start dobutamine to improve tissue perfusion Summary: Antibiotics for Sepsis Sepsis is an emergency! Early identification and treatment is crucial Get cultures and give antibiotics ASAP Make sure that all care providers understand the sense of urgency Give the most potent antibiotic first You are called to admit a 49 year old male alcoholic that was found down at the bus stop T 96, HR 130, RR 24, BP 80/50, SaO 2 = 94% on 6L. Arousable but confused. CXR shows RLL consolidation. Wbc 18, Na 128, Creatinine 2.2, Lactate 5.1, BAL negative. Antibiotics are given. What is the next best step? A. Insert a central line and initiate early goal directed therapy B. Give 1 Liter normal saline wide open C. Start norepinephrine to improve tissue perfusion D. Start dobutamine to improve tissue perfusion 4

Physiologic response in sepsis Vasodilation Venous capacitance beds Arterial beds Intravascular volume depletion Increased microvascular permeability Insensible losses Myocardial Suppression Decreased ejection fraction Increased cardiac output (early) Inadequate cardiac output (late) Maldistribution of Flow Decreased blood flow to myocardium, skeletal muscles, gut, pancreas Preserved flow to kidneys, brain Increased Cellular Metabolism Increased oxygen demand Physiologic response in sepsis Vasodilation Venous capacitance beds Arterial beds Intravascular volume depletion Increased microvascular permeability Insensible losses Myocardial Suppression Decreased ejection fraction Decreased cardiac output (early) Inadequate cardiac output (late) Maldistribution of Flow Decreased blood flow to myocardium, skeletal muscles, gut, pancreas Preserved flow to kidneys, brain Increased Cellular Metabolism Increased oxygen demand Imbalance between systemic oxygen delivery and oxygen demand. Global Tissue Hypoxia and Shock Assessment of tissue hypoxia Vital signs, central venous pressure are not sensitive Urine output can be misleading Resuscitation endpoints are more sensitive Mixed venous oxygen saturation Arterial lactate ph or base deficit 5

Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock Design Single-center prospective randomized trial 263 consecutive patients with at least 2 SIRS criteria and SBP < 90 despite 1L fluid challenge or lactate > 4 mmol / L Randomized within 4 hours of arrival in ED Treatment Standard therapy MAP > 65 mm Hg CVP > 8-12 mm Hg Urine output > 0.5 ml/kg/hr Goal directed therapy Rivers, E. NEJM 2001;345:1368-1377 Severe Sepsis or Septic Shock Early Goal Directed Therapy 8-12 mm Hg CVP < 8 mm Hg IV Fluids MAP < 65 mm Hg Vasopressors > 65 mm Hg SvO 2 < 70% Transfuse blood until Hct > 30% > 70% < 70% No > 70% Goals Met? Dobutamine Yes ICU Admission Rivers. NEJM 345:1368-1377,2001 Fluid Therapy - Liters Liters of Fluid = p < 0.01 Rivers. NEJM 345:1368-1377,2001 6

RBC Transfusion Patients Transfused (%) = p < 0.01 Rivers. NEJM 345:1368-1377,2001 Use of Vasopressors % Patients Requiring Pressors = p < 0.01 Rivers. NEJM 345:1368-1377,2001 Health Care Resource Use = p < 0.01 Days Rivers. NEJM 345:1368-1377,2001 7

Survival Mortality p<0.05 p<0.01 Rivers. NEJM 345:1368-1377,2001 Summary: Early Goal-directed Therapy Sepsis is an emergency! Early identification and treatment is crucial Place a central venous catheter Volume resuscitate to achieve CVP 8-12 mm Hg 5-8 L in the first 6 hrs Add a vasopressor if MAP < 65 mm Hg Norepinephrine, dopamine, or vasopressin Transfuse blood or start dobutamine if SvO 2 < 70 % You are called to admit a 49 year old male alcoholic that was found down at the bus stop T 96, HR 130, RR 24, BP 80/50, SaO 2 = 94% on 6L. Arousable but confused. CXR shows RLL consolidation. Wbc 18, Na 128, Creatinine 2.2, Lactate 5.1, BAL negative. Antibiotics are given. What is the next best step? A. Insert a central line and initiate early goal directed therapy B. Give 1 Liter normal saline wide open C. Start norepinephrine to improve tissue perfusion D. Start dobutamine to improve tissue perfusion 8

You are called to admit a 49 year old male alcoholic that was found down at the bus stop T 96, HR 130, RR 24, BP 80/50, SaO 2 = 94% on 6L. Arousable but confused. CXR shows RLL consolidation. Wbc 18, Na 128, Creatinine 2.2, Lactate 5.1, BAL negative. Antibiotics are given. What is the next best step? A. Insert a central line and initiate early goal directed therapy B. Give 1 Liter normal saline wide open C. Start norepinephrine to improve tissue perfusion D. Start dobutamine to improve tissue perfusion A 49 year old male alcoholic was found down at the bus stop. In the ED he was diagnosed with pneumonia. He s received empiric antibiotics and 2L saline. A central line is placed. T 102, HR 150s, RR 24, BP 88/42, SaO 2 = 94% on 6L. EKG shows atrial fibrillation. Wbc 18, Na 128, Creatinine 2.2, Lactate 5.1 What is the best choice of vasopressors? A. Dopamine B. Dobutamine C. Norepinephrine D. Phenylephrine Vasopressors - Mechanisms of Action Dopamine Low dose - 2 to 5 μg/kg/min ("renal dose )# Binds D 1 receptors# Dilates blood vessels, increasing blood flow to renal, mesenteric and coronary arteries# Intermediate dose- 5 to 10 μg/kg/min# Activates β 1 receptors# Has positive inotropic and chronotropic effects (increase HR, CO)# High dose - 10 to 20 μg/kg/min ("pressor dose )# Activates α 1 receptors# Causes vasoconstriction, increases systemic vascular resistance, increases blood pressure# 9

Vasopressors - Mechanisms of Action Dobutamine Beta adrenergic receptor agonist# Activates β 1 > β 2 receptors# β 1 effects - increased heart rate and myocardial contractility# β 2 effects - peripheral vasodilation# Great for treatment of diastolic heart failure# Used in sepsis in conjunction with an vasoconstrictor# Vasopressors - Mechanisms of Action Norepinephrine Potent α 1 and β 1 receptor agonist# α 1 effects # peripheral arterial and venous vasoconstriction# β 1 effects# increased heart rate and myocardial contractility# Increased afterload (from vasoconstriction) often blunts chronotropic effects# Vasopressor of choice in septic shock# Vasopressors - Mechanisms of Action Phenylephrine Pure α 1 receptor agonist# α 1 effects # peripheral arterial and venous vasoconstriction# Can reduce cardiac output by increasing afterload# Used in patients with distributive shock and preserved myocardial function# 10

Vasopressors in Septic Shock Key Points Norepinephrine is the agent of choice# Dopamine is a good vasoconstrictor at high doses but causes tachycardia# Dobutamine can improve cardiac output but also causes vasodilation# Phenylephrine is a potent vasoconstrictor but can reduce cardiac output# A 49 year old male alcoholic was found down at the bus stop. In the ED he was diagnosed with pneumonia. He s received empiric antibiotics and 2L saline. A central line is placed. T 102, HR 150s, RR 24, BP 88/42, SaO 2 = 94% on 6L. EKG shows atrial fibrillation. Wbc 18, Na 128, Creatinine 2.2, Lactate 5.1 What is the best choice of vasopressors? A. Dopamine B. Dobutamine C. Norepinephrine D. Phenylephrine A 49 year old male alcoholic was found down at the bus stop. In the ED he was diagnosed with pneumonia. He s received empiric antibiotics and 2L saline. A central line is placed. T 102, HR 150s, RR 24, BP 88/42, SaO 2 = 94% on 6L. EKG shows atrial fibrillation. Wbc 18, Na 128, Creatinine 2.2, Lactate 5.1 What is the best choice of vasopressors? A. Dopamine B. Dobutamine C. Norepinephrine D. Phenylephrine 11

A 49 year old male alcoholic was found down at the bus stop. In the ED he was diagnosed with pneumonia. He s received empiric antibiotics and 3L saline. A central line was placed and norepinephrine has been started HR 110, RR 32, BP 105/65, SaO 2 = 88% on 100% O 2 Lactate 5.5, S c VO 2 55%, Hgb 7.2, poor capillary refill What is the best way to improve oxygen delivery? A. Start dobutamine B. Transfuse packed red blood cells C. Intubate and initiate mechanical ventilation D. All of the above E. A and B Oxygen Delivery Fundamental Equations Arterial oxygen content = C a O 2 Oxygen Delivery Fundamental Equations Arterial oxygen content = C a O 2 = 1.34 x Hgb x S a O 2 +.003 x P a O 2 12

Oxygen Delivery Fundamental Equations Arterial oxygen content = C a O 2 = 1.34 x Hgb x S a O 2 +.003 x P a O 2 Oxygen Delivery = DO 2 Oxygen Delivery Fundamental Equations Arterial oxygen content = C a O 2 = 1.34 x Hgb x S a O 2 +.003 x P a O 2 Oxygen Delivery = DO 2 = C a O 2 x Q where Q = C.O. Oxygen Delivery Fundamental Equations Arterial oxygen content = C a O 2 = 1.34 x Hgb x S a O 2 +.003 x P a O 2 Oxygen Delivery = DO 2 = C a O 2 x Q where Q = C.O. What factors determine Q? 13

Oxygen Delivery Fundamental Equations Arterial oxygen content = C a O 2 = 1.34 x Hgb x S a O 2 +.003 x P a O 2 Oxygen Delivery = DO 2 = C a O 2 x Q where Q = C.O. What factors determine Q? CO = SV x HR Ohm s Law Oxygen Delivery Equations (Continued) Ohm s law V = IR Oxygen Delivery Equations (Continued) Ohm s law V = IR P = Q x R Q = P = MAP - CVP R R 14

Oxygen Delivery Equations (Continued) Arterial oxygen content = C a O 2 = 1.34 x Hgb x S a O 2 +.003 x P a O 2 Oxygen Delivery = DO 2 = C a O 2 x Q where Q = C.O. What factors determine Q? CO = SV x HR Ohm s Law => Q = (MAP - CVP) / R Oxygen Delivery Key Points Improving oxygen delivery to starved tissues is essential Critical contributors to oxygen delivery include: 1. Blood pressure 2. Cardiac output (dobutamine) 3. Oxygen carrying capacity red cells oxygen saturation Severe Sepsis or Septic Shock Early Goal Directed Therapy 8-12 mm Hg CVP < 8 mm Hg IV Fluids MAP < 65 mm Hg Vasopressors > 65 mm Hg SvO 2 < 70% Transfuse blood until Hct > 30% > 70% < 70% No > 70% Goals Met? Dobutamine Yes ICU Admission Rivers. NEJM 345:1368-1377,2001 15

A 49 year old male alcoholic was found down at the bus stop. In the ED he was diagnosed with pneumonia. He s received empiric antibiotics and 3L saline. A central line was placed and norepinephrine has been started HR 110, RR 32, BP 105/65, SaO 2 = 88% on 100% O 2 Lactate 5.5, S c VO 2 55%, Hgb 7.2, poor capillary refill What is the best way to improve oxygen delivery? A. Start dobutamine B. Transfuse packed red blood cells C. Intubate and initiate mechanical ventilation D. All of the above E. A and B A 49 year old male alcoholic was found down at the bus stop. In the ED he was diagnosed with pneumonia. He s received empiric antibiotics and 3L saline. A central line was placed and norepinephrine has been started HR 110, RR 32, BP 105/65, SaO 2 = 88% on 100% O 2 Lactate 5.5, S c VO 2 55%, Hgb 7.2, poor capillary refill What is the best way to improve oxygen delivery? A. Start dobutamine B. Transfuse packed red blood cells C. Intubate and initiate mechanical ventilation D. All of the above E. A and B 75 year old male with COPD and CHF. Required hospitalization 1 month ago for MRSA foot infection. Now with fever and purulent sputum. CXR shows RLL pneumonia. Wbc 18.2. Cultures are pending What is the best regimen? A. Vancomycin, ertapenem B. Vancomycin, pipercillin/tazobactam, levofloxacin C. Linezolid, ertapenem D. Azithromycin and ceftriaxone E. Daptomycin, pipercillin/tazobactam, azithromycin 16

Health-Care Associated Pneumonia (HCAP) Pneumonia that develops in a patient that: 1. Was hospitalized in last 90 days (greater than 2 day stay) 2. Resides in a nursing home or long-term care facility 3. Received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days 4. Attended a hemodialysis clinic in last 30 days Prompt administration of the appropriate antibiotic improves survival. Making the diagnosis is essential. Treatment: Empiric Antibiotics Start immediately! Prompt administration of appropriate antibiotics reduces mortality by up to 50% Choice of initial antibiotics should be driven by local resistance patterns and risk factors for multi-drug resistant pathogens (MDR) Multidrug Resistance (MDR): Risk Factors Receipt of antibiotics within the preceding 90 days Recent hospitalization (last 30 days) Current hospitalization of 5 days High frequency of antibiotic resistance in the community Immunocompromised host Age > 70 Chronic pulmonary disease 17

Multidrug Resistance (MDR): Pathogens Methicillin-resistant Staph aureus (MRSA) Pseudomonas aeruginosa Antibiotic-resistant gram-negative bacilli Acinetobacter Klebsiella Legionella Empiric Antibiotics: MRSA Vancomycin (15-20mg/kg IV q8-12) Penetrates the lungs poorly Goal trough = 15-20 mcg / ml Linezolid (600 mg IV q12) Good tissue penetration May limit staph toxin production No data to suggest superiority of linezolid over vanco Daptomycin doesn t penetrate the lungs Empiric Antibiotics: Gram Negative Coverage Chose one of these: A. Beta lactam Piperacillin-tazobactam B. Cephalosporins Cefipime Ceftazidime C. Carbipenems Imipenem Meropenem Doripenem Consider adding: A. Fluoroquinolone Levofloxacin Ciprofloxacin B. Aminoglycside Tobramycin Gentamycin Amikacin 18

Empiric Antibiotics: Gram Negative Coverage Chose one of these: Consider adding: A. Beta lactam A. Fluoroquinolone Piperacillin-tazobactam Levofloxacin B. Cephalosporins Ciprofloxacin Cefipime B. Aminoglycside Ceftazidime Tobramycin C. Carbipenems Gentamycin Imipenem Amikacin Meropenem Doripenem Ertapenem is not active against pseudomonas, acinetobacter# 75 year old male with COPD and CHF. Required hospitalization 1 month ago for MRSA foot infection. Now with fever and purulent sputum. CXR shows RLL pneumonia. Wbc 18.2. Cultures are pending What is the best regimen? A. Vancomycin, ertapenem B. Vancomycin, pipercillin/tazobactam, levofloxacin C. Linezolid, ertapenem D. Azithromycin and ceftriaxone E. Daptomycin, pipercillin/tazobactam, azithromycin 75 year old male with COPD and CHF. Required hospitalization 1 month ago for MRSA foot infection. Now with fever and purulent sputum. CXR shows RLL pneumonia. Wbc 18.2. Cultures are pending What is the best regimen? A. Vancomycin, ertapenem B. Vancomycin, pipercillin/tazobactam, levofloxacin C. Linezolid, ertapenem D. Azithromycin and ceftriaxone E. Daptomycin, pipercillin/tazobactam, azithromycin 19

Health Care Associated Pneumonia Key Concepts Initial therapy should include antibiotics that cover pseudomonas (and in most cases MRSA) Use culture data to guide subsequent therapy Lung penetration Linezolid > vancomycin > daptomycin Ertapenem does not cover pseudomonas Treat for 7-10 days 20