The Management of Septic Shock Anthony J. Courey, MD Assistant Professor of Medicine Associate Director, CCMU Pulmonary & Critical Care Medicine Conflicts & Disclosures • No conflicts • No disclosures Overview and Objectives • Definitions and clinical criteria for diagnosis • Epidemiology • Recognition • Early Goal Directed Therapy • Recent sepsis resuscitation trials • Surviving Sepsis Guidelines Overview of Surviving Sepsis Guidelines • Initial Resuscitation • Fluid Therapy • Vasopressor Therapy • Inotropic Therapy • Antibiotics & Other Therapies • Source Control Definitions & Clinical Criteria Definitions of Sepsis • A clinical syndrome – not a specific disease with a single specific cause – e.g. Flu-like syndrome vs actual influenza virus infection – We use syndromes to more easily recognize and prevent morbidity and mortality with common illness, e.g. asthma, hypertension,“flu” and sepsis • Infection-induced systemic inflammatory response • Recognition of sepsis syndrome severity is also important Bone RC et al, Chest 1992;101:1644 Systemic Inflammatory Response Syndrome (SIRS) Criteria • Temperature > 38 C or < 36 C • Heart rate > 90 • Respiratory rate > 20 • PaCO2 < 32 mm Hg • WBC > 12 or < 4 • > 10% Bands/Immature Segs • “THeRe aRe CO2WBoyS” mnemonic Definitions of Sepsis Severity Possible 2 or more Sepsis SIRS criteria Confirmed OR suspected Sepsis infection Severe ANY organ Sepsis dysfunction Septic After initial Shock fluid bolus Refractory High-dose Septic Shock vasopressors Annane et al, Lancet 2005;365:63 Sepsis = SIRS + Infection BACTEREMIA TRAUMA FUNGEMIA INFECTION SEPSIS SIRS BURNS PARASITEMIA VIREMIA OTHER OTHER PANCREATITIS Bone RC et al, Chest 1992;101:1644 SIRS vs Sepsis Severity-Mortality Sepsis severity is more than just numbers! Martin et al, NEJM 2003; 348: 1546-1554 SIRS vs Sepsis Severity-Mortality NEJM 2015: ANZICS group: You don’t have to meet 2 SIRS criteria to die of sepsis! Kaukonen et al, NEJM 2015; 327: 1629-1638 Epidemiology Epidemiology of Sepsis-Incidence It’s Not Just the Years, but the Miles • Age • Co-morbidities – Diabetes • Male sex – Malignancy • African American – Alcoholism • Acute organ failure – HIV infection – Renal – Immunosuppression – Cardiovascular • Chronic organ failure – Neurological – CHF – Respiratory – Chronic liver disease Martin et al, NEJM 2003; 348: 1546-1554 Recognition …Always begins with the ABCs …And a high index of suspicion … Sepsis-Induced Organ Dysfunction Always start at the beginning • A: Airway: Independent life is impossible without it • B: Breathing: 53% of both arms of the Early Goal- Directed Therapy landmark RCT were intubated within 6 hours • Circulation: Assess organ perfusion & IV access: – BP, skin, mental status, elevated lactate levels (>2 mmol/L) Early NMB in Severe Sepsis with MV Cohort In 3,518 patients matched on the propensity for treatment, receipt of a neuromuscular blocking agent was associated with a reduced risk of in- hospital mortality (risk ratio, 0.88; 95% CI, 0.80, 0.96). Steingrub et al Crit Care Med 2014 Steingrub et al Crit Care Med 2014 Sepsis Induced Organ Dysfunction • Vascular: Relative IVVD Hypotension • Cardiac: Sepsis cardiomyopathy • Pulmonary: Noncardiogenic pulmonary edema ARDS • Renal: Intravascular volume depletion Hypoperfusion Acute Kidney Injury (AKI) Acute tubular necrosis (ATN) • GI: Stress ulceration, hypoalbuminemia, gut bacterial translocation Sepsis Induced Organ Dysfunction • Blood: Decreased RBC deformability Hemolysis and microthrombi Impaired microcirculation Global tissue hypoxia • Platelets: Nonspecific tissue activation Microthrombi; platelet consumption DIC with bleeding and clotting risks • Leukocyte & Compliment : Activation Indiscriminate organ injury • Brain: Encephalopathy, confusion, agitation are NOT benign (e.g. CURB-65 mortality indicator in pneumonia) Sepsis Induced Organ Dysfunction • Skin: – EARLY: Vasodilated, high cardiac output WARM – LATE: Intravascular hypovolemia, poor cardiac output, shunting to vital organs, microthrombi COLD • Mottling • Petechiae and purpura with DIC Skin Mottling Predicts Sepsis Mortality Disseminated Intravascular Coagulation (DIC) In meningococcemia called purpura fulminans Early Goal-Directed Therapy … A revolution in the care of septic shock Early Goal-Directed Therapy • Randomized, prospective , single center trial treatment • 260 patients randomized • 2/4 SIRS criteria and SBP < 90 mmHg or lactate > 4 mmol/L • Patients randomized to 6 hours of goal-directed therapy vs standard therapy Rivers et al, NEJM 2001 Randomization 6 hours EGDT- Protocol In Depth Prior to EGDT all pts received a 20-30 cc/kg IF good bolus of 0.9% saline findings 53% move 500 cc down; every 12-15 mm 30 min IF bad if MV turn NE/Epi/Dopa/PE right! RBCs Dobutamine EGDT: Results ARR Death = 46.5 – 30.5 = 16% NNT = 7 EGDT: Results EGDT At 72 hrs the Treatment total IVF Group <100 cc difference Differences in between the first 6 hrs: groups? 1. More IVF 2. More PRBC 3. More ionotrope ARISE the PROMISE of a new PROCESS Surviving Sepsis Guidelines for the Management of Severe Sepsis & Septic Shock … And some of the supporting evidence Formed in 2002 The Surviving Sepsis Guidelines Recommendation #1: Initial Resuscitation • We recommend the protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (defined as hypotension persisting after initial fluid challenge or lactate ≥4 mmol/L). This protocol should be initiated as soon as hypoperfusion is recognized and should not be delayed pending ICU admission. • We suggest, in patients with elevated lactate levels as a marker of tissue hypoperfusion, targeting resuscitation to normalize lactate as rapidly as possible. (Grade 2C) Recommendation #1: Initial Resuscitation GOALS The Surviving Sepsis Guidelines The Evidence: Lactate Clearance Mortality (%) Jones A. JAMA. 2010;303:739–746 The Evidence: Lactate Clearance Adjusted HR= 0.61; adjusted95% CI, 0.43 -HR=0.87; P =0.61; 0.006 95% CI, 0.43-0.87; Lactate P= 0.006 vs Control 348 patients: decrease in lactate levels of 20% or more in the first 8 hours, in addition to ScvO2 target achievement, and was associated with a 9.6% absolute reduction in mortality Jansen TC. Am J Respir Crit Care Med. 2010;182:752–761. Recommendation #2: Fluid Therapy • We recommend crystalloids be used as the initial fluid of choice in the resuscitation of severe sepsis and septic shock. (Grade 1B) • We recommend against the use of hydroxy- ethyl starches for fluid resuscitation of severe sepsis and septic shock. (Grade 1B) • We recommend an initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients. (Grade 1C) Recommendation #2: Fluid Therapy • We recommend that a fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables (Ungraded). • My favorite quote “ A fluid bolus is a liter or more in thirty minutes or less… and more may need to be given” • R. Phillip Dellinger, Surviving Sepsis Guidelines The Evidence: Albumin vs. Crystalloid ALBIOS Study Caironi et al, N Engl J Med 2014; 370:1412-1421 The Evidence: Albumin vs. Crystalloid Albumin recommended in severe sepsis and septic shock when significant crystalloid has been given Christian J. Wiedermann, et al, Meta-analysis of pooled data from the three large trials. Recommendation #3: Vasopressors • We recommend that vasopressor therapy initially target a mean arterial pressure (MAP) of 65 mm Hg. (Grade 1C) • We recommend norepinephrine as the first- choice vasopressor. (Grade 1B) • We suggest epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure. (Grade 2B) Recommendation #3: Vasopressors • Vasopressin up to 0.03 units/minute can be added to norepinephrine with the intent of raising MAP to target or decreasing norepinephrine dosage. • Low-dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension, and vasopressin doses higher than 0.03-0.04 units/minute should be reserved for salvage therapy (failure to achieve adequate MAP with other vasopressor agents). • We suggest dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg, patients with low risk of arrhythmias and/or low heart rate). (Grade 2C) The Evidence: NE vs Dopamine Meta-Analysis Information from 4 randomized trials (n=540) comparing norepinephrine to epinephrine found no evidence for differences in the risk of dying (RR=0.96; 0.77 to 1.21; fixed effect; I2=0%). Meta-analysis performed by Djillali Annane for Surviving Sepsis Campaign, using following publications: • Annane D et al. Lancet. 2007;370:676-684 The Evidence: NE vs. Epinephrine Information from 4 randomized trials (n=540) comparing norepinephrine to epinephrine found no evidence for differences in the risk of dying (RR=0.96; 0.77 to 1.21; fixed effect; I2=0%). Meta-analysis performed by Djillali Annane for Surviving Sepsis Campaign, using Annane D et al. Lancet. 2007;370:676- 684 Recommendation #5: Ionotropes • We recommend that a trial of dobutamine infusion up to 20 μg/kg/min be administered or