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The Treatment of Sepsis: Early Goal Directed Therapy and Beyond
Anthony J. Hericks, D.O. South Dakota ACP Scientific Meeting September 13th, 2013
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A clinician, armed with the sepsis bundles, attacks the three heads of severe sepsis: hypotension, hypoperfusion and organ dysfunction. Crit Care Med 2004; 320(Suppl):S595-S597
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Surviving Sepsis Campaign Sponsoring Organizations
American Association of Critical-Care Nurses American College of Chest Physicians American College of Emergency Physicians Australian and New Zealand Intensive Care Society Asia Pacific Association of Critical Care Medicine American Thoracic Society Brazilian Society of Critical Care(AIMB) Canadian Critical Care Society Emirates Intensive Care Society European Respiratory Society European Society of Clinical Microbiology and Infectious Diseases European Society of Intensive Care Medicine European Society of Pediatric and Neonatal Intensive Care Infectious Diseases Society of America Indian Society of Critical Care Medicine Japanese Association for Acute Medicine Japanese Society of Intensive Care Medicine Latin American Sepsis Institute Pan Arab Critical Care Medicine Society Pediatric Acute Lung Injury and Sepsis Investigators Society for Academic Emergency Medicine Society of Critical Care Medicine Society of Hospital Medicine Surgical Infection Society World Federation of Critical Care Nurses World Federation of Societies of Intensive and Critical Care Medicine German Sepsis Society
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Surviving Sepsis Campaign (SSC) Guidelines for Management of Severe Sepsis and Septic Shock
Dellinger RP, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004, 32: Dellinger RP, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 Crit Care Med 2008, 36: Levy MM, et al. Surviving Sepsis Campaign: Results of an international guidelines performance improvement program targeting severe sepsis. Crit Care Med 2010, 38: Dellinger RP, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: Crit Care Med 2013, 41(2): Angus DC, et al. Severe Sepsis and Septic Shock. NEJM 2013; 369(9):
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Surviving Sepsis Campaign Conclusions
Strong agreement among a large cohort of international experts Many level 1 recommendations Significant number of recommendations with relatively weak recommendations Evidence-based recommendations are the foundation of improved outcomes Dellinger RP, CCM 2013
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Grading of Recommendations (Grading of Recommendations Assessment, Develop and Evaluation – GRADE)
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A 82 year old white female present to the emergency department with complaints of dysuria, frequency and urgency. Her temperature is F, HR 92, RR 21 and BP 122/86. What should she be classified as? Systemic Inflammatory Response Syndrome Sepsis Severe Sepsis Septic Shock Multi-Organ Dysfunction/Failure Syndrome
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A 82 year old white female present to the emergency department with complaints of dysuria, frequency and urgency. Her temperature is F, HR 92, RR 21 and BP 122/86. What should she be classified as? Systemic Inflammatory Response Syndrome Sepsis Severe Sepsis Septic Shock Multi-Organ Dysfunction/Failure Syndrome
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Identification of Sepsis: Definitions
Systemic Inflammatory Response (SIRS) Sepsis Severe Sepsis Septic Shock Multi-Organ Failure Syndrome (MOFS) Death
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SIRS Heart Rate > 90 Respiratory Rate > 20
WBC > 12K or < 4K Temp > 38 C (100.4 F) or < 36 C (96.8 F) Any two of the above Very nonspecific
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Sepsis SIRS + signs of a suspected or known infection
WBC’s in normally sterile fluid Infiltrate on chest x-ray Bacteria in normally sterile fluid
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Diagnostic Criteria for Sepsis
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Severe Sepsis Sepsis + sepsis-induced tissue hypoperfusion or organ dysfunction
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Sepsis Induced Hypotension
SBP < 90 mmHg OR MAP < 70 mmHg SBP > 40 mmHg < 2 SD below the nml for age
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Septic Shock Severe Sepsis or sepsis-induced hypoperfusion persistent despite: Adequate/initial fluid challenge/resuscitation Lactate > 4 mmol Addition of pressors Sepsis-induced hypoperfusion = infection-induced hypotension, elevated lactate or oliguria
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MOFS Altered organ function, involving two or more organs, in an acutely ill patient requiring medical intervention to achieve homeostasis
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Death The permanent the cessation of all vital functions in an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem Severe Sepsis/Septic Shock mortality = ~30-46%
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Consideration for Limitation of Support
“We recommend that the goals of care and prognosis be discussed with patients and families and these be incorporated into the patients treatment along with end-of-life care planning and utilizing palliative care principles.” Re-address goals as earlier as feasible, but no later than 72 hours of admit Grade 1B Grade 2C
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Incidence of Severe Sepsis
Estimated to be: 2% of all patients admitted to the hospital 10% of all patients in the ICU < 750,000 cases per year and rising Mortality rate of 20-30% NEJM 369(9):
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Pathophysiology of Sepsis
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Based on Dr. Rivers article re: Early Goal Directed Therapy, what is the ultimate goal in the first 6 hours? CVP of 8-12 unventilated/12-15 ventilated MAP >65 Cardiac Output > 8 LPM Hemoglobin > 10 gm/dL ScvO2 > 70%
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Based on Dr. Rivers article re: Early Goal Directed Therapy, what is the ultimate goal in the first 6 hours? CVP of 8-12 unventilated/12-15 ventilated MAP >65 Cardiac Output > 8 LPM Hemoglobin > 10 gm/dL ScvO2 > 70%
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Initial Resuscitation: Goals of Early Goal Directed Therapy
CVP 8-12 cmH2O 12-15 cmH2O on the ventilator MAP > 65 mmHg May need to be higher in patients with HTN UOP > 0.5 mL/Kg /hour ScvO2 > 70% SvO2 > 65% Goal: Normalize lactate Goal in the first 6 hours after diagnosis 16-17% decrease in mortality Grade 1C Grade 2C Rivers E. N Engl J Med 2001; 345:
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Central Venous Pressure
Crystalloid or Colloid? Volume? Goal?
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Crystalloid or Colloid
SAFE Study Crystalloid (NS) = Colloid (4% Albumin) Less volume, more PRBC’s, higher CVP and Albumin No difference in mortality (p = 0.87) Trend for increased risk of death in Trauma (0.06) Trend for decreased risk of death in Severe Sepsis (0.09) Grade 1B Finfer S. N Engl J Med 2004; 350:2247–2256
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SSC Recommendations Crystalloids Albumin
If substantial fluid is required Grade 1B Grade 2C
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Hydroxyethyl Starch (HES)
Increased risk of acute kidney injury and death in sepsis Variable findings depending on studies Schortgen G. Lancet 2001; 357: Sakr Y. Br J Anaesth 2007; 98: Brunkhorst FM. N Engl J Med 2008; 358: Perner A. N Engl J Med 2012; 367: Risk and no benefit, HES should not be used!!! Grade 1B
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Fluid Volume 30 mL/Kg crystalloid
A portion may be an albumin equivalent More rapid administration or larger amounts may be needed Continue fluid administration as long as there appears to be hemodynamic improvement Grade 1C Grade UG
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Volume Responsiveness
Grade 1C CVP > 8 cmH2O > 12 cmH2O on the vent Swan-Ganz Catheter PCWP Cardiac output Non-invasive Monitors PiCCO Catheter FloTrac Pulse Pressure Variation IVC via Echo MAP and Heart Rate Grade 1D
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CVP Spontaneous Breathing > 8 cmH2O
Ventilatory Breathing > 12 cmH2O Primarily based on expert opinion Dellinger RP. Crit Care Med 2004; 32:858–873 Rivers E. N Engl J Med 2001; 345:1368–1377 Practice parameters for hemodynamic support of sepsis in adult patients with sepsis. Crit Care Med 1999; 27:639–660
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Pulmonary Capillary Wedge Pressure
PCWP < 12 mmHg predicts a fluid bolus with increase cardiac output with a PPV of only 54% However the “Gold Standard” for “volume responsiveness” may be a increase in cardiac output of > 15% after a fluid challenge Osman D. Crit Care Med 2007; 35:64–68
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Non-invasive Monitoring
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PPV PPV PPV CVP PCWP
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Echocardiography
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Does volume overload contribute to morbidity and mortality?
True False
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Does volume overload contribute to morbidity and mortality?
True False
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Avoid Volume Overload Tolerated as long as volume responsive
Fluid challenges usually required for the initial hours Finfer S. N Engl J Med 2004; 350:2247–2256 Decrease the rate when no longer volume responsive Grade 1D
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Volume Overload, Cont’d
Independent predictor of mortality Boyd JH. Crit Care Med 2011; 39(2): Vincent JL. Crit Care Med 2006; 34:344–353 Uchino S. Crit Care Med 2006; 10:R174 Prolonged mechanical ventilation Upadya A. Intensive Care Med 2005; 31:1643–1647 ARDS Humphrey H. Chest 1990; 97:1176–1180 Simmons RS. Am Rev Respir Dis 1987; 135:924–929 Mitchell JP. Am Rev Respir Dis 1992; 145:990–998 Wiedemann HP. N Engl J Med 2006; 354:2564–2575 Sepsis Alsous F. Chest 2000; 117:1749–1754 Rivers E. N Engl J Med 2001; 345:1368–1377 Abdominal compartment syndrome Malbrain ML. Crit Care Med 2005; 33:315–322 McNelis J. Arch Surg 2002;137:133–136 Cerebral edema and herniation Uchino S. Crit Care 2006; 10:R174
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MAP Grade 1C
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What is the pressor of choice for a patient in septic shock?
Dopamine Norepinephrine (Levophed) Vasopressin Phenylephrine (Neosynephrine) All the above
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What is the pressor of choice for a patient in septic shock?
Dopamine Norepinephrine (Levophed) Vasopressin Phenylephrine (Neosynephrine) All the above
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Vasopressors Norepinephrine Dopamine Vasopressin Epinephrine
Phenylephrine
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Norepinephrine vs Dopamine
No significant difference in mortality (p = 0.10) Trend for less death in the ICU (p = 0.07) No difference at hospital discharge or 1 yr Increased rate of adverse events with Dopamine Arrhythmias (p = < 0.001) Atrial Fibrillation Ventricular Tachycardia Ventricular Fibrillation Skin Ischemia (trend; p = 0.09) DeBacker D. N Engl J Med 2010; 362:
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Norepinephrine vs Dopamine, Cont’d
Norepinephrine should be the first line vasopressor Dopamine is an alternative to Norepinephrine Only in highly selected patients with low risk of: Tachyarrhythmias Absolute or relative bradycardia Grade 1B Grade 2C
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Vasopressin Adding Vasopressin to Norepinephrine showed no mortality benefit compared to Norepinephrine alone (p = 0.26) Did lower Norepinephrine requirements May have other potential physiologic benefits Should not be used as a single agent Russel JA. N Engl J Med 2008; 358: Grade UG
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Epinephrine First line in pts poorly responsive to Norepinephrine and Dopamine No evidence of worse outcomes Increased risk of: Tachycardia Elevated lactate Decreased splanchnic circulation Add to or instead of Norepinephrine Grade 2B
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Phenylephrine Not recommended!!! Decreases cardiac output Except:
Norepinephrine induced arrhythmias Cardiac output is high Persistently low BP Salvage therapy Decreases cardiac output Grade 1C
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Hemodynamic Equations
DaO2 = CO x Hgb x SaO2 Oxygen delivery VO2 = CO x Hgb x (SaO2 - SvO2) Oxygen consumption O2 ER= VO2/DaO2 Oxygen extraction ratio ~ 0.2 to 0.3 VO2 > DaO2 OR DaO2 < VO2 = Dysoxia Dysoxia = lactic acidosis = organ failure = death
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Venous Oxygen Saturation
Physiology Adapted from:
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ScvO2/SvO2 Goal > 70%/65% respectively < 70%/65% respectively
Normal or shunt physiology < 70%/65% respectively Transfuse to a Hgb > 10 OR Start Dobutamine No specific cardiac output/index ScvO2 = subclavian vein SvO2 = pulmonary artery Grade 1C
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Ionotropic Therapy Dobutamine: Max dose 20 mcg/Kg/min
Titrate to NO pre-defined CO Used in states with: Elevated cardiac filling pressures Low cardiac output ScvO2 < 70% OR SvO2 < 65% Grade 1B Grade 1C
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RBC Transfusion Therapy
Only if the Hgb < 10 with EGDT Only if the Hgb < 7.0 g/dL in other ICU patients Target 7 to 9 g/dL Consider earlier for myocardial ischemia/ischemic coronary disease, severe hypoxemia, acute hemorrhage, cyanotic heart disease or lactic acidosis No EPO Grade 1B Grade 1B Napolitano LM. Crit Care Med 2009; 37(12):
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FFP Transfusion Therapy
No FFP to reverse coagulopathy in the absence of bleeding or invasive procedures No high-dose Antithrombin Studies had revealed that a subgroup with severe sepsis and high risk of death = better survival Grade 2D Grade 1B
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Platelet Transfusion Therapy
< 10,000 – prophylactically in absence of bleeding < 20,000 - significant risk of bleeding > 50,000 – active bleeding, surgery or invasive procedures Grade 2D
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Other Investigation Therapy
Immunoglobulins No use Selenium Antioxidant Grade 2B Grade 2C
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Diagnostic Testing Lactate level Cultures Imaging Within 3 hours
Prior to antibiotic administration Do not delay resuscitation for antibiotic administration > 50% of cases of severe sepsis and septic shock will be culture negative Minimum 2 blood cultures One peripheral and one from each vascular access device Imaging If not too unstable Grade 1D Grade 1C
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Diagnostic Testing, Cont’d
Serologies: Strep pneumo and Legionella Urine Ag Mycoplasma IgM 1,3 B-D-glucan Mannan and anti-mannan Ab’s Procalcitonin Use low levels to assist with Abx D/C Grade 2B Grade 2C
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Antibiotic Therapy IV route within the 1st hour Septic Shock
Severe Sepsis One or more drugs with activity against the likely pathogens Double cover if MDR pathogens Combo therapy for neutropenic fever Beta-lactam and macrolide for Strep pneumonia Grade 1B Grade 1C Grade 1B Grade 2B Grade 2B Grade 2B
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ABX, Cont’d Reassess routinely De-escalate after >3-5 days
Duration of treatment ~7-10 days Stop therapy if the syndrome is not infectious Grade 1B Grade 2B Grade 2C Grade 1D
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Source Control Seek, diagnose or exclude potential anatomical infections and treat expectantly Within the first 12 hrs Delay definitive treatment of peripancreatic necrosis until demarcation of tissue has occurred Attempt percutaneous over surgical intervention if possible Remove vascular access suspected after other access has been placed Grade 1C Grade 2B Grade UG Grade UG
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Corticosteroids Hydrocortisone No Dexamethasone
200 mg/day Only with persistent hypotension/poorly responsive to vasopressor therapy Consider a continuous infusion Do not do an ACTH stimulation test No Dexamethasone Fludrocortisone if other steroid than HCT Wean steroids when off pressors Grade 2C Grade 2D Grade 2B Grade 2B Grade 2C Grade 2D
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Corticosteroids, Cont’d
Annane D. JAMA 2002; 288:862–871 Cosyntropin Stim Test delta < 9 = non-responders 10% decrease in mortality if treated with steroids 17% decrease in pressor requirements Sprung CL. N Engl J Med 2008; 358: No significant difference in mortality Shock was reversed more quickly More episodes of superinfection, including new sepsis and septic shock but not statistically significant
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CIRCI (Critical Illness Related Corticosteroid Insufficiency)
Marik PE. Crit Care Med 2008 Vol. 36 (6):
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CIRCI, Cont’d
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Recombinant Human Activated Protein C (Xigris)
Withdrawn from the market 2011 No benefit
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Mechanical Ventilation
Target tidal volume = 6 mL/Kg Plateau pressure goal < 30 cmH2O Allow permissive hypercapnia Use PEEP to decrease FiO2 Higher PEEP vs lower Recruitment maneuvers Grade 1A Grade 1B Grade 1C Grade 1B Grade 2C Grade 2C
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ARDS ARMA Trial Alveoli Trial
The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342: Alveoli Trial Brower RG. N Engl J Med 2004;351:327-36
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Mechanical Ventilation, Cont’d
Consider prone positioning P:F ration <100 HOB elevated Goal > 30-45 NIPPV considered in mild ALI/ARDS Low threshold for intubation Grade 2C Grade 1B Grade 1B Grade 2B
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Mechanical Ventilation, Cont’d
Weaning protocols Selective Oral/Digestive Decontamination Oral chlorhexidine gluconate Decreases VAP Avoid pulmonary artery catheters Conservative fluid management (FACTT) Wiedemann et al. N Engl J Med 2006; 354: Grade 1A Grade 2B Grade 1A Grade 1C
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Beta-Agonists No recommended for routine use
Nebulized (Ok if concern for bronchospasm) Trend for less vent days Slightly faster heart rates at day #2 Trend for increased mortality Intravenous (Salbutamol) Increased mortality Grade 1B
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Sedation, Analgesia and NMB
Use Sedation protocol Minimize intermittent and continuous treatments Use Sedation scales Avoid NMB Without ARDS With ARDS (Sepsis-induced and P:F <150) < 48 hours Grade 1B Grade 1B Grade 1C Grade 2C
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Glucose Control Use intravenous insulin to control blood sugars
If 2 consecutive BS’s > 180 Goal < 180 ? Target range mg/dL Avoid hypoglycemia Grade 2C Grade 1B Grade ? 1A
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Renal Replacement Therapy
CRRT and Intermittent HD are equivalents CRRT should be used if hemodynamically unstable Grade 2B Grade 2D
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Bicarbonate Therapy Avoid NaHCO3 in patients with a pH > 7.15 and lactic acidemia for the purpose of improving hemodynamics or to reduce vasopressor requirements Grade 2B
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Thromboembolism Prophylaxis
LMWH daily vs Low dose UFH BID LMWH daily vs Low dose UFH TID Dalteparin if creat clearance < 30 mL/min LMWH or UFH Mechanical prophylaxis if contraindications to heparin products Combo therapy in patients who are high risk Severe sepsis, history of DVT, or orthopedic surgery Grade 1B Grade 2C Grade 1A Grade 2C Grade 1A Grade 2C Grade 2C
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Stress Ulcer Prophylaxis
If risk of bleeding H2 blocker Proton Pump Inhibitor PPI over H2 No risk of bleeding = no PPI Grade 1B Grade 1B Grade 2C Grade 2B
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Nutrition Oral or enteral nutrition in the 1st 48 hrs vs complete fasting or just glucose Avoid full caloric feeding for the 1st full week Low dose feeding up to 500 Kcal/day and advance as tolerated (60-70%) IV glucose and EN vs TPN alone or TPN and EN in the 1st week No specific immunomodulating form Grade 2C Grade 2B Grade 2B Grade 2C
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Surviving Sepsis Bundles
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Bundles Point/Counterpoint Editorials
Are the best patient outcomes achieved when ICU bundles are rigorously adhered to? Pros: Dr. Delinger Not perfect/have flaws, but are based on the best available evidence. Cons: Dr. Marik Not completely “evidence based” and “cook book” medicine can harm the patient. CHEST 2013; 144(2):
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Is there byass/conflict of interest when it comes to the Surviving Sepsis Campaign Guidelines and Early Goal Directed Therapy? Yes No
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Is there byass/conflict of interest when it comes to the Surviving Sepsis Campaign Guidelines and Early Goal Directed Therapy? Yes No
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Benefits of the Surviving Sepsis Campaign
Surviving Sepsis Campaign Improvement Program Resuscitation Bundle - First 6 hours Compliance increase linearly from 10.9% to 31.3% over two years ( p = ) Management Bundle - First 24 hours Compliance increase linearly from 18.4% to 36.1% over two years ( p = 0.008) Unadjusted odds ratio for hospital mortality decreased from 37% to 30.8% over two years (p = 0.001)
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THE END ?? QUESTIONS ??
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