Objectives. Management of Septic Shock. Definitions Progression of sepsis. Epidemiology of severe sepsis. Major goals of therapy

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1 Objectives Management of Septic Shock Review of the Evidence and Implementation of Pediatric Guidelines at Christus Santa Rosa Manish Desai, M.D. PL 5 2 nd year Pediatric Critical Care Fellow Review of current evidence and practice recommendations in septic shock Implement a set of pediatric guidelines to improve the quality of care in our patients with septic shock Establish quality indicators for monitoring adherence to the guidelines Definitions Progression of sepsis Sepsis Systemic inflammatory response to an infection Severe sepsis Sepsis and associated inflammatory response with organ dysfunction, hypotension, or hypoperfusion Septic shock Sepsis induced hypotension and inadequate organ perfusion despite adequate fluid resuscitation Epidemiology of severe sepsis Incidence of 3 cases per 1000 people annually Overall hospital mortality rate 28.6% Pediatric 10% Adults 38.4% (higher in many studies) Average cost of $2200 per case and an annual cost 16.7 billion dollars nationally Major goals of therapy Resuscitation to correct hypoxia, hypotension, and impaired tissue oxygenation Identify source of infection and treat to include antimicrobials and/or surgery Maintain organ system function and halt the development of multiorgan dysfunction Early goal directed therapy 263 adult patients with severe sepsis or septic shock Goal directed therapy or standard therapy upon presentation and for initial 6 hours Resuscitation goals Central venous pressure (CVP) 8 Mean arterial pressure (MAP) 65 Urine output 0.5 cc/kg/hr Central venous oxygen saturation (ScvO 2 ) 70% Rivers E, et al, N Engl J Med

2 Early goal directed therapy Interventions used to achieve goals Aggressive fluid resuscitation to reach CVP 8 Vasopressors to reach MAP 65 Transfusion of PRBCs until Hct 30 followed by use of inotropic agents to reach ScvO 2 70% Early goal directed therapy improved mortality (30.5% versus 46.5%, p=0.009) Early reversal of shock Retrospective review of 91 children presenting to community physicians with septic shock Reversal of shock by community physicians within first 75 minutes improved survival by >9 fold Each hour of persistent shock beyond this point was associated with a >2 fold increased mortality Adherence to ACCM PALS resuscitation guidelines led to improved survival: 8% vs 38% mortality Han YY, Carcillo JA, et al, Pediatrics 2003 Rivers E, et al, N Engl J Med 2001 Surviving Sepsis Campaign Evidence based guidelines Areas of management addressed include: Aggressive fluid resuscitation Antibiotic therapy and source control Vasopressors and inotropes Stress dose and low dose corticosteroids Glycemic control Mechanical ventilation Pediatric considerations Fluid resuscitation Fluid resuscitation to CVP 8 Give fluid as long as hemodynamic improvement is seen Decrease rate of fluid administration when increases in filling pressures are not associated with improved hemodynamics Antibiotic Therapy and Source Control Give Broad spectrum antibiotic therapy within the first hour Obtain cultures before starting antibiotics, but do not delay antibiotics for cultures Start at least one antibiotic for all likely pathogens which penetrate to all likely sources Antibiotic Therapy and Source Control Reassess antibiotics daily Combination therapy for pseudomonas Combination therapy for neutropenia Recommend duration of therapy be 7 to 10 days, longer for select cases Remember: blood cultures may be negative in up to 50% bacterial or fungal infections 2

3 Antibiotic Therapy and Source Control Identify sources requiring control as early as possible, ideally within 6 hours Identify abscesses that need drainage and devices (including lines) that may be infected When source control is required, recommend least invasive effective intervention be done If intravascular device is a possible source of septic shock, recommend prompt removal Antibiotics: Every hour counts Retrospective study of 2,154 adults Giving antibiotics within the first hour of hypotension led to a 79.9% survival rate Each hour delay over the next 6 hours was associated with a 7.6% decrease in survival Only 50% of septic shock patients received antibiotics within the first 6 hours Kumar, et al, Crit Care Med 2006 Antibiotics: Err on the side of caution Retrospective study of 5,715 adults Examined appropriateness of antibiotic therapy based on infection site and relevant pathogens Appropriate antibiotics started in 80% of cases Survival rates after appropriate vs inappropriate antibiotics were 52% vs 10.3% (p<0.0001) Kumar, et al, Chest 2009 Antibiotics and acute kidney injury Retrospective study of 4,532 adults 64.4% developed some degree of AKI Patients who developed AKI had longer delays in antibiotics (4.3 hrs vs 6 hrs, p<0.0001) Increased odds of AKI per hour of delay (OR 1.14) AKI increased mortality (OR 1.73, p<0.0001) Bagshaw, et al, Intensive Care Med 2009 Vasopressors Recommend that MAP be kept 65 Recommend either norepinephrine or dopamine as first choice Suggest epinephrine, phenylephrine, and vasopressin should not be administered as first line Vasopressors Suggest epinephrine be the first chosen alternative to dopamine or norepinephrine Vasopressin 0.03 units/min may be added later Recommend that all patients requiring vasopressors have arterial line as soon as practical if resources are available 3

4 Norepinephrine vs. Dopamine Trial of 1679 adults with shock (all types) who received norepinephrine or dopamine first line No significant difference in overall mortality More arrhythmias with dopamine (24 vs 12%, p<0.001) Dopamine showed higher mortality only in cardiogenic shock patients (p=0.03) De Backer, et al, NEJM 2010 Vasopressors Epinephrine considered second line due to potential for ischemia and effects on gastric blood flow Epinephrine vs Norepinephrine Randomized trial of 280 adults with shock No difference in mortality 13% of patients epinephrine group patients withdrawn for lactic acidosis or tachycardia Myburgh, et al, Intensive Care Med 2008 Vasopressors Vasopressin depleted after initial hours of septic shock, giving rationale for low dose vasopressin VASST trial 778 adults with pressor dependent septic shock receiving low dose vasopressin or norepinephrine No significant difference in mortality or adverse effects overall, but vasopressin was more beneficial in less severe septic shock group Inotropic therapy Recommend dobutamine be used as first line therapy in the presence of myocardial dysfunction evidenced by elevated filling pressures and low cardiac output Recommend against strategy of increasing cardiac index to some predetermined elevated value in an effort to improve oxygen delivery Corticosteroids Multiple large RCTs in the 1980s showed that high doses of steroids were not beneficial and caused an increase in the rate of secondary infections More recently, lower doses have been used for relative insufficient stress responses Large randomized placebo controlled adult study 7 days of low dose steroids improved survival in nonresponders to corticoptopin stimulation 53% vs 63% mortality (p=0.02) Annane, et al, NEJM 2002 CORTICUS study Corticosteroids Multicenter, randomized, placebo controlled trial of 499 adults (largest trial of steroids in shock) No difference in mortality for patients receiving hydrocortisone in all patients regardless of their response to corticotropin stimulation Faster shock reversal in those receiving hydrocortisone, but increased superinfections 4

5 Corticosteroids Surviving Sepsis Campaign Suggest IV hydrocortisone only be used in septic shock that is poorly responsive to fluid resuscitation and vasopressor therapy Steroid therapy should not be guided by corticotropin stimulation test results Cortisol levels or response to stimulation test do not predict who will respond clinically to steroids with hemodynamic improvement Recombinant activated protein C Mixed results in adults, but showed benefit in severe sepsis and septic shock (APACHE II >25) RESOLVE trial Large clinical trial in pediatric patients with sepsis Stopped early due to lack of benefit Increased risk of intracranial hemorrhage, especially in infants 60 days Etomidate and septic shock Substudy of CORTICUS: corticotropin response and mortality in 96 adults receiving etomidate Higher portion of non responders in those receiving etomidate (61 vs 44.6%, p=0.004) Hydrocortisone administration did not change mortality in these non responders (45 vs 40%) Etomidate was associated with a higher mortality in patients with septic shock (p=0.02) Cuthbertson et al, Intensive Care Med 2009 Glycemic control Treat hyperglycemia with insulin after stabilization Suggest protocol with target glucose < 150 Large randomized adult trial showed a reduction in ICU mortality with intensive insulin targeting glucoses of (Leuven protocol, NEJM 2001) More recent trials for aggressive control showed no benefit and had higher rates of hypoglycemia Glycemic control NICE SUGAR study, NEJM 2009 Trial of 6100 adult ICU patients randomized to intensive therapy (glucose ) or conventional therapy (glucose <180) Mortality of 27.5% in the intensive therapy group vs 24.9% in the conventional therapy group Severe hypoglycemia of 6.8% in the intensive group vs 0.5% in the conventional group Glycemic control COIITSS study, JAMA 2010 Randomized trial of intensive vs conventional insulin therapy in 509 adults with septic shock who received hydrocortisone Compared with conventional therapy, intensive insulin therapy did not improve mortality Patients treated with intensive insulin had significantly more episodes of hypoglycemia 5

6 Mechanical ventilation Tidal volumes of 6 8 ml/kg and peak pressures 30 cm H 2 0 Elevated head of bed to to limit risk of aspiration and ventilator associated pneumonia Recommend ventilator weaning protocol and spontaneous breathing trials Recommend sedation protocols Pediatric considerations Mortality much lower (10%) than in adults Boluses of 20ml/kg titrated to hemodynamics Use dopamine as initial pressor Pediatric patients may have variable CI and SVR Suggest tailoring pressor/inotropes to the patient Use epinephrine or norepinephrine if fails dopamine Hemodynamic support of pediatric and neonatal septic shock Practice parameters from the American College of Critical Care Medicine (Crit Care Med 2009) Address the following: Resuscitation goals for children Fluid resuscitation (proportionally more than adults) Inotropic, vasopressor, and vasodilator therapies Hydrocortisone for adrenal insufficiency ECMO for refractory shock Pediatric practice parameters Recommend that diagnosis of septic shock rely on clinical examination, but lactate may be useful Hemodynamic parameters and mortality Tachycardia/bradycardia (3%) Hypotension with cap refill <3 sec (5%) Normotension with cap refill >3 sec (7%) Hypotension with cap refill >3 sec (33%) Pediatric practice parameters Use cardiac output and perfusion pressure Urine output estimates adequacy of perfusion pressure in absence of invasive monitoring Multiple methods to measure cardiac output, but not routinely available and can be unreliable SvO 2 can estimate whether cardiac output meets tissue metabolic demands Validating SvO 2 use in pediatrics 102 children with septic shock treated by ACCM/PALS guidelines Half randomized to SvO 2 monitoring for first 6 hrs Volume, PRBCs, +/ inotropes to reach SvO 2 70 Lower 28 day mortality: 11.8 vs 39.2%, p=0.002 Lower incidence of new organ dysfunction as well Oliveira, et al, Intensive Care Med

7 Pediatric practice parameters No advantage to colloids over crystalloids Blood transfusions Goal hemoglobin >10 in septic shock Vasopressors Typically recommend use of dopamine first line Agree with using norepinephrine alone with low SVR and wide pulse pressure, DBP < ½SBP Pediatric practice parameters 2002 guidelines discouraged use of vasoactive agents until central access was in place Newer guidelines recommend use of peripheral inotropes (not vasopressors) until central access is attained Low dose dopamine or epinephrine Obtain arterial access when able, but this should not delay use of vasopressors Bundled care for septic shock Prospective 2 year interventional study The second year added an early goal directed therapy protocol to ED management 79 patients pre intervention, 77 postintervention Patients in the post intervention year: Received significantly greater fluid volumes Had increased use of early vasopressors Had reduction in mortality (18% vs 27%) Jones A, et al, Chest 2007 Bundled care for septic shock Septic shock bundle used over 2 year period Initiate CVP/SvO 2 monitoring within 2 hrs Broad spectrum antibiotics within 4 hrs Complete early goal directed therapy within 6 hrs Give corticosteroids if indicated Monitor lactate clearance 330 total patients; mortality 20.8% if bundle completed vs 39.5% if not completed (p<0.01) Nguyen, et al, Crit Care Med 2007 Bundled care for septic shock Surviving Sepsis Campaign, Crit Care Med hr resuscitation and 24 hr management bundles Data collected from for hospitals enrolled Data from 165 sites and over 15,000 patients analyzed Full bundle compliance increased from 10.9% initially to 31.3% by the end of two years Overall mortality decreased from 37% to 30.8% over two years (p=0.001), and survival improved the longer a center was in the campaign Bundled care for septic shock Meta analysis of 8 trials of bundled care for septic shock Sepsis bundles associated with a consistent increase in survival (odds ratio 1.91, p < ) All studies reported decreases in time to antibiotics and increased appropriateness of antibiotics All other elements were inconsistently reported Barochia, et al, Crit Care Med

8 Pediatric Guidelines for Initial Management of Septic Shock Obtain cultures and start broad spectrum antibiotics within 1 hour (do not delay antibiotics for cultures) Recognize decreased mental status and perfusion Maintain or establish airway and IV access per PALS Fluid refractory shock: Start dopamine at 10 15mcg/kg/min; Arterial/central access as able Warm shock: Begin norepinephrine at mcg/kg/min and titrate to BP Aggressive fluid resuscitation with 20ml/kg boluses up to and over 60ml/kg Notify PICU if requiring >40ml/kg fluid resuscitation If at risk for adrenal insufficiency, consider baseline cortisol level and hydrocortisone with 100mg/m 2 loading dose Titrate pressors and give additional volume as needed Monitor CVP, arterial blood pressure, lactates, SvO2 Assess for and treat: Hxpoxia Hypoglycemia Hypocalcemia Consider elective intubation if persistent shock with respiratory distress Dopamine resistant shock: Assess pulses, capillary refill, and pulse pressure and add epinephrine or norepinephrine as indicated below OR Cold shock: Begin epinephrine at mcg/kg/min and titrate to BP Pediatric guidelines for initial management of septic shock Recognize decreased mental status and perfusion Maintain or establish airway and IV access per PALS Fluid challenges: 20cc/kg boluses up to and over 60cc/kg unless clinically worse due to fluids Obtain cultures and start broad spectrum antibiotics within 1 hour (do not delay for cultures) Assess for and treat hypoxia, hypoglycemia, and hypocalcemia Pediatric guidelines for initial management of septic shock Notify PICU if requiring > 40ml/kg in boluses Consider intubation for persistent shock and/or respiratory distress Fluid refractory shock: Start dopamine and obtain central and arterial access as able Consider norepinephrine alone for warm shock if central access is in place Pediatric guidelines for initial management of septic shock Dopamine resistant shock: Add epinephrine for cold shock or norepinephrine for warm shock If at risk for adrenal insufficiency, consider baseline cortisol level and give hydrocortisone 100mg/m 2 loading dose Titrate pressors; give additional volume as needed Monitor CVP, arterial blood pressure, lactates, and SvO 2 as able Quality Indicators Time to antibiotics Time to achieve CVP 8 Time to achieve adequate age adjusted BP Questions??? Time to achieve SvO2 70 8

9 References 1) Angus DC, Linde Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. Jul 2001;29(7): ) Rivers E, et al. Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med. 2001; 345: ) Han YY, Carcillo JA, et al. Early reversal of pediatric neonatal septic shock by community physicians is associated with improved outcome. Pediatrics 2003; 112: ) Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines fir management of severe sepsis and septic shock: Crit Care Med 2008, 36: ) Kumar A, Roberts D, Wood K, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34: ) Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009; 136: ) Bagshaw S, Lapinsky S, Dial S, et al. Acute kidney injury in septic shock: clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy, Intensive Care Med 2009; 35: ) De Backer D, et al. Comparison of dopamine and norepinephrine in the treatment of shock. NEJM 2010; 362: ) Myburgh J, et al. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008; 34: ) Russell J et al. Vasopressin versus norepinephrine infusion in patients with septic shock. NEJM 2008; 358: ) Annane D et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. NEJM 2002; 288: ) Sprung C et al, Hydrocortisone therapy for patients with septic shock. NEJM 2008; 358: References 13) Cuthbertson B et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med 2009; 35: ) Van Den Berghe G, et al. Intensive insulin therapy in critically ill patients. NEJM 2001; 345: ) NICE SUGAR study investigators. Intensive versus conventional glucose control in critically ill patients. NEJM 2009; 360: ) COIITSS study investigators. Corticosteroid treatment and intensive insulin therapy for septic shock in adults. JAMA 2010; 303: ) Brierley J, Carcillo JA, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009; 37: ) Oliveira CF et al. ACCM/PALS hemodynamic support guidelines for pediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 2008; 34: ) Jones A, et al. Prospective external validation of the clinical effectiveness of an emergency department based early goal directed therapy protocol for severe sepsis and septic shock. Chest 2007; 132: ) Nguyen HB et al. Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med 2007; 35: ) Levy M, Dellinger P, et al. The Surviving Sepsis Campaign: results of an international guidelinebased performance improvement program targeting severe sepsis. Crit Care Med 2010; 38: ) Barochia A, et al. Bundled care for septic shock: an analysis of clinical trials. Crit Care Med 2010; 38: