GR2011-08 Sepsis Management 2011 - Dr Subramanian

Sepsis: 

Sepsis Indhu Subramanian, MD August 26th, 2011

Outline: 

Outline Definition Epidemiology Pathophysiology Management Protocols Future Directions Management Early Goal Directed Therapy Antimicrobial Therapy Glucocorticoids Glycemic Control Activated Protein C Ventilation Strategies Prophylaxis

Definition: ACCP/SCCM Consensus: 

Definition: ACCP/SCCM Consensus Infection - Inflammatory response to microorganism - Invasion of normally sterile tissues SIRS (>=2) (physical, chemical, or infectious insult ) - Temp >38 or <36 degrees - HR > 90/min - RR > 20/min or paCO2 <32 mmHg - WBC >12K or <4K or >10% bands Sepsis - Infection + - >= 2 SIRS Severe Sepsis - Sepsis - Organ dysfunction - Hypoperfusion - lactic acidosis - oliguria - AMS Septic Shock - Severe sepsis - Hypotension despite fluid bolus (MAP<65, SBP<90 or <40mmHg baseline) - Vasopressors MODS

Acute Organ Dysfunction: 

Acute Organ Dysfunction AMS Confusion Psychosis Tachycardia Hypotension Tachypnea PaO2 <60 mmHg PaO2/FiO2 <300 SaO2 <90% Jaundice Incr. LFTs Incr. PT Low albumin Oliguria Anuria Incr. Creatinine Low platelets Low Prot C Incr. PT/PTT Incr. DDimer

Organ Dysfunction : 

Organ Dysfunction Early Phase vs. Late Phase

Organ Dysfunction Correlates With Mortality: 

Organ Dysfunction Correlates With Mortality Marino, Paul; ICU book 2007 edition

Epidemiology: 

Epidemiology $17 billion spent in the US each year Increased incidence in the last 10yrs Incidence predicted to rise further with growth and age of population 10 th leading cause of death Martin, GS et al, NEJM 2003; 348:1546 CDC 2006

Epidemiology: 

Epidemiology Martin, GS et al, NEJM 2003; 348:1546 Mortality

Severe Sepsis Kills: 

Severe Sepsis Kills CDC 2009

Epidemiology: 

Epidemiology More gram positives in US Fungal sepsis on the rise Incidence highest in the winter months Martin, GS et al, NEJM 2003; 348:1546 Danai, PA et al, CritCareMed, 2007; 35:410 Etiology

Epidemiology Racial and Gender Differences: 

Epidemiology Racial and Gender Differences African American men at highest risk Martin, GS et al, NEJM 2003; 348:1546

Pathophysiology: 

Pathophysiology Hotchkiss, R. et al, NEJM 2003; 348;2:138 Germs, NEJM 1972; 287:553-555 Virulence Toxins Resistance Site of invasion Immune System Early vs. Late Inflamm vs. Anti-inflamm Coagulation vs. Fibrinolysis Host Bug

Pathophysiology: 

Pathophysiology Characteristics that influence outcome Host response Underlying comorbidities Age >=65 Site of infection Microorganism characteristics Kreger, BE et al, AJMed 1980; 68:344; Shorr, AF et al, CCM, 2006;34:2588 Knaus, WA et al, Chest 1992; 101:1656; Angus, DC et al, CCM 2001; 29:1303 Peres, BD et al, Intensive Care Med 2004; 30:811

Pathophysiology: 

Pathophysiology E.Rivers, Sepsis Symposium May 2010

Pathophysiology Cascade of Events: 

PNA, abscess Pyelo, cellulitis, Peritonitis Pathophysiology Cascade of Events Infection Organism Invades Blood Exotoxin TSST ToxinA Leukotoxin Structural Components Teichoic Acid Ag Peptidoglycan LPS Endotoxin ) Plasma Complement Coagulation Macrophages Cytokines PAF, NO Endothelial cell Cytokines glandins Neutrophils Lysosomes free rads,GCSF Cellular Dysfunction!!! Vessels, organs, myocardium SHOCK Hypoxic Hypoxia, Cytotoxic Hypoxia, Apoptosis

Pathophysiology Hemodynamics of Septic Shock: 

Pathophysiology Hemodynamics of Septic Shock Vascular dysfunction Peripheral vasodilatation Decreased systemic vascular resistance Myocardial dysfunction Decreased contractility LV dilation to preserve stroke volume Tachycardia to preserve cardiac output

Pathophysiology Vasodilatory Shock: 

Pathophysiology Vasodilatory Shock Landry et al, NEJM 2001 ;345;8:588

Management Failed Attempts: 

Management Failed Attempts Russell et al, NEJM 2006, 355;16:1699

Management: 

Management Russell et al, NEJM 2006,355;16:1699 Positive Studies

Slide 21: 

Revised 1/2008 CCM

Management: 

Management Early Goal Directed Therapy Antimicrobial Therapy Glucocorticoids Glycemic Control Activated Protein C Ventilation Strategies Prophylaxis

Severe Sepsis is an Emergency: 

Severe Sepsis is an Emergency Trauma Sepsis

EGDT - The Six Hour Clock: 

EGDT - The Six Hour Clock

Early Goal Directed Therapy: 

Early Goal Directed Therapy Early resuscitation limits destruction RCT blinded study targeted vs. standard resuscitation first 6 hrs of presentation for severe sepsis (lactate >4) or septic shock Both groups received “standard” resuscitation goals: CVP 8-12 mmHg MAP >=65 mmHg Urine output >=0.5cc/kg/hr EGDT group added ScvO2 of >=70% as an additional goal Rivers, E at al, NEJM 2001; 345:1368

Early Goal Directed Therapy: 

Early Goal Directed Therapy Lactate in Sepsis E.Rivers, Sepsis Symposium May 2010 Accumulation due to hypoperfusion and tissue dysoxia Shift to anaerobic metabolism

Early Goal Directed Therapy: 

Early Goal Directed Therapy Directly correlates with outcome as lactate increases > 2mmol/L Weil et al, Circulation 1970; Mikkelsen et al;CCM May 2009 Lactate in Sepsis

Early Goal Directed Therapy: 

Early Goal Directed Therapy ScvO2 Indication of O2 delivery and O2 extraction O2delivery = CO * 13.4 * Hb * SaO2 So if low, Rivers et al. enhanced O2 delivery by: Correcting anemia (HCT >= 30%) Enhancing CO with inotropes (Dobutamine) Improve oxygenation (Mechanical ventilation, sedation) Rivers, E at al, NEJM 2001; 345:1368

Early Goal Directed Therapy: 

Early Goal Directed Therapy Rivers, E at al, NEJM 2001; 345:1368

Early Goal Directed Therapy: 

Early Goal Directed Therapy Rivers, E at al, NEJM 2001; 345:1368 16% mortality reduction in EGDT group (46.5% vs. 30.5%) Better physiologic parameters Number needed to treat is 6 Grade 2C SSC

Early Goal Directed Therapy: 

Early Goal Directed Therapy Rivers, E at al, NEJM 2001; 345:1368

Early Goal Directed Therapy ScvO2 Has Limitations: 

Early Goal Directed Therapy ScvO2 Has Limitations

Slide 33: 

Jones et al; March 2010 JAMA Prospective, Randomized, NonBlinded, Noninferiority Study Both targets are equivalent Low mortality group than quoted (not as sick patients?) 10% 2 hr lactate clearance is another good target

Early Goal Directed Therapy Resuscitation Targets: 

Early Goal Directed Therapy Resuscitation Targets Fluids should be administered as well defined, rapidly infused boluses (20-40cc/kg) CVP 8-12 and Higher CVP of 12-15 mmHg in vented pts Maintain MAP >= 65 - Grade 1C Crystalloid vs. colloid makes no difference – Grade 1C Urine output > 0.5cc/kg/hr – Grade 1C Dellinger RP - Crit Care Med - 2006 Mar; 34(3); 935-936; Surviving Sepsis Campaign Guidelines, CCM, 2004 NEJM, VASST trial 2007; Russell et al CCM 2009; Journal of Critical Care 2010; JInnate Immunity 2010; NEJM 3/2010

Early Goal Directed Therapy ScvO2 target: 

Early Goal Directed Therapy ScvO2 target Controversy still exists Blood carries risk in the ICU Infection, lung injury, VAP, death Recent study shows PRBC group to have increased LOS and MV days Appropriate Hb goal unknown Scvo2 independently has not shown benefit – only as part of a bundle SCCM – Grade 2C Schmidt et al CHEST 2010; Fuller BM et al; IJCCM December 2010

Early Goal Directed Therapy Fluids and Vasopressors: 

Early Goal Directed Therapy Fluids and Vasopressors Vasopressors in Sepsis – to keep MAP>=65 Norepinephrine or dopamine - Grade 1C Multicenter RCT = Norepinephrine has less arrthymias Meta-analysis of 6 RCT suggest superiority of norepinephrine in 28 day mortality and arrhythmia risk Dellinger RP - Crit Care Med - 2006 Mar; 34(3); 935-936; Surviving Sepsis Campaign Guidelines, CCM, 2004 NEJM, NEJM 3/2010; Journal of Intensive Care Medicine March 2011

Early Goal Directed Therapy Fluids and Vasopressors: 

Early Goal Directed Therapy Fluids and Vasopressors Epinephrine is an alternative agent– Grade 2B Phenylephrine (if tachyarrthymia) Vasopressin (pH independent adjunct) VASST trial 2007; Russell et al CCM 2009; Journal of Critical Care 2010; JInnate Immunity 2010;

Apply EGDT to the Wards: 

Apply EGDT to the Wards Floor to ICU = 3x higher mortality than ED to ICU Lundberg, Critical Care Med, 1998

Antimicrobial Therapy: 

Antimicrobial Therapy Inappropriate abx use is common and kills (up to 34%) Risk factors for inappropriate abx Fungal Staph aureus, pseudomonas Significant reduction in mortality with appropriate antibiotic use Longer the delay = increased mortality Garnacho-Montero, J et al,CCM 2003;31(12):2742-51; Kumar et al; CHEST 2009 Garnacho-Montero, J et al, CritCare 2006;10(4):R111, Harbrath, S et al, AMJM 2003; 115:529-535, Kolleff et al, CHEST 1999; Kumar et al, CCM 2006.; CCM 2010 Gaieski et al,

Antimicrobial Therapy – The Golden Hour: 

Antimicrobial Therapy – The Golden Hour Kumar et al, CCM 2006

Antimicrobial Therapy: 

Antimicrobial Therapy Proper selection/ Broad spectrum – Grade 1B Use hospital antibiogram & IDSA guidelines Prompt administration within 1 hr - Grade 1B for shock Cultures prior to ABX – should not delay abx! Prompt de-escalation – Grade 1D Diagnostic studies for source control - Grade 1C Niederman, M et al, CCM 2003; 31:2:608, Bochud, P-Y et al, CCM 2004;32,11:s495 Surviving Sepsis Campaign Guidelines, CCM, 2004 ; AJRCCM, Aug 2009

The 6 Hour Bundle: 

The 6 Hour Bundle Identify severe sepsis Fluids to CVP and UOP goals Antibiotics in 1 hour Blood cultures prior to antibiotics if possible Vasopressors to get MAP >=65 Use 10% lactate clearance or Scvo2 sat goal >=70% as additional targets Consider dobutamine or blood Source control Better late than never – EGDT up to 18 hrs still confers benefit Coba et al; CCM 2009

What's next?: 

What's next?

Glucocorticoids: 

Glucocorticoids Normal response to critical illness is to increase cortisol Some patients are unable to increase cortisol in stress This is “functional” adrenal insufficiency No clear diagnostic criteria for this group Cooper, M et al, NEJM; 2003; 348:727-34, Annane et al JAMA 2002;288:862, Lipiner-Friedman, D et al, CCM 2007;35:4:1012; Marik et al CCM 2008

Glucocorticoids: 

Glucocorticoids A large multicenter DBRCT study in septic shock Placebo vs. hydrocortisone and fludricortisone for 7 days Steroid group had decreased mortality (61 vs. 72%) Multiple criticisms of study Annane et al JAMA 2002;288:862, Lipiner-Friedman, D et al, CCM 2007;35:4:1012

Glucocorticoids: 

Glucocorticoids CORTICUS STUDY Shock within prior 72 hrs Hydrocortisone vs placebo No significant changes in mortality COIITSS Study Sicker patients Fludricortisone plus Hydrocortisone vs Placebo No Mortality difference Sprung et al;NEJM, CORTICUS Jan 2008J;anuary JAMA 2010

Glucocorticoids: 

Glucocorticoids A recent meta-analysis of 20 randomized trials identified no significant beneficial effect overall A subgroup of 12 studies using longer courses >5 days of steroids did show a significant short term survival benefit. Annane et al; June 10, 2009 , JAMA

Glucocorticoids: 

Glucocorticoids Surviving Sepsis Guidelines say: Use IV hydrocortisone in refractory shock – Grade 2C Do not use ACTH stim test – Grade 2B Don’t use dexamethasone– Grade 2B Wean steroids once off pressors – Grade 2D Addition of fludricortisone 50 ug po/day is optional - Grade 2C Annane et al JAMA 2002;288:862, Lipiner-Friedman, D et al, CCM 2007;35:4:1012 Surviving Sepsis Guidelines, CCM 2008; NEJM, CORTICUS 2008

Glucocorticoids: 

Glucocorticoids American College of Critical Care Medicine Guidelines Agree Recommend steroids at least 7 days prior to tapering Recommend to not stop abruptly. Marik et al; CCM 2008; Vol 36, No.6

Glycemic Control: 

Glycemic Control Important adjunct to care in ICU patients Several potential mechanisms for benefit Enhance immune system Reduce inflammation Protect endothelium Protect mitochondrial structure/function Decreased axonal dysfunction and degeneration Improved erythropoiesis Good for coagulation Van den Berghe, G et al, NEJM 2001; 345:1359, Van den Berghe, G et al, NEJM 2006; 354:449; Hermans, G et al, AJRCCM 2007; 175:480, Finney, SJ et al, JAMA 2003; 290:2041; Brunkhorst, FM et al, Infection 2005; 33:19

Glycemic Control: 

Glycemic Control SICU patients - RCT Glucose 80-110 mg/dl vs. 180-200 mg/dl Intensive insulin group w/ decreased hospital mortality MICU patients - RCT Glucose 80-110 mg/dl vs. 180-200 mg/dl Mortality benefit seen only after 5 days in intense group <3 days increased mortality w/ intense group Van den Berghe, G et al, NEJM 2001; 345:1359; Hermans, G et al, AJRCCM 2007; 175:480 Van den Berghe, G et al, NEJM 2006; 354:449

Glycemic Control: 

Glycemic Control NICE-SUGAR Study – Glucose 80-108 mg/dl vs. target <180 Increased mortality in the intense glucose vs. control group COIITSS Study No difference in mortality Higher incidence hypoglycemia NEJM March 2009; January JAMA 2010

Glycemic Control: 

Glycemic Control Surviving Sepsis Campaign Statement 2009 changed glucose goal to < 180 (prior goal <150) – Grade 2C Krinsley et al, CCM 2007; Treggiari et al, Critical Care 2008; Brunkhorst et al (VISEP), NEJM 2008; Critchell et al,ICM 3/2007; Lacara et al, AJCC 2007

Activated Protein C: 

Activated Protein C Mathay, M et al, NEJM, 2003; 10, 761 Antithrombotic, Antiinflammatory, & Profibrinolytic

Activated Protein C: 

Activated Protein C PROWESS (Multicenter RDBPCT)– 2001 Decreased 28 day mortality Increased risk of serious bleeding FDA supported for >=25 APACHE II and >=2 organ dysfunction Study supported by Eli-Lilly -> Lots of controversy Bernard et al, NEJM 2001

Activated Protein C: 

Activated Protein C ADDRESS study Less sick patients No change in mortality Not indicated for APACHE <25 or <2 organs failure ENHANCE Mortality rates similar to PROWESS study Increased bleeding rates compared to PROWESS Patients treated within the first 24 hours fared better Vincent et al, CritCareMed, 2005; 33;:10:2266 Abraham et al, NEJM 2005

Activated Protein C Summary: 

Activated Protein C Summary Use it when the benefits outweigh the risks R/O contraindications APACHE >=25 and >= 2 organs dysfunctional – Grade 2B (Grade 2C if recent surgery) Use it within the first 24 hrs $6000/ per use Watch for bleeding! Surviving Sepsis Guidelines, CCM 2004

Ventilation Strategies: 

Ventilation Strategies Low tidal volume (6cc/kg) and lung protective strategy (plateau pressure <30) - Grade 1B After initial resuscitation, conservative fluids lead to a better outcome – Grade 1C Elevate HOB >45 - Grade 1B Weaning and sedation protocols – Grade 1A Annane, D. Intensive Care Med, 2005;31:325; Jackson, WL et al; Chest 2005;127:1031 ARDS NET, NEJM 2000;342:1301; ARDS NET, NEJM 2006, Surviving Sepsis Campaign CCM, 2004

Prophylaxis and Other Supportive Measures: 

Prophylaxis and Other Supportive Measures Stress Ulcer prophylaxis – Grade 1A H2 blocker or proton pump inhibitors Early enteral feeding – no data that this alone is adequate DVT prophylaxis – Grade 1A UFH or LMWH Mechanical compression Trzeciak, S et al, Crit Care Med, 2004; 32:S571 Cook, D et al, NEJM, 1998;338:791 Samama, M et al NEJM, 1999;341:793

Prophylaxis and Other Supportive Measures: 

Prophylaxis and Other Supportive Measures Nutritional Support Early enteral nutrition (24-48hrs) Meta-analysis of several RCTs Decreased mortality Decreased infectious complications Non-statistically significant Drakulovic, MB et al Lancet, 1999: 354 Heyland, DK et al, JPEN 2003;27:355

Protocols/Bundles Work: 

Protocols/Bundles Work Bundled together is better than individual elements Results of the Surviving Sepsis Campaign – 2010 - 165 centers implemented sepsis bundle - Mortality reduction by 7% over 2 yrs Compliance increased 20% over 2 yrs Micek ,ST et al CCM 2006; 34:2707; CCM; 2010

Standardized Order Sets Save Lives: 

Standardized Order Sets Save Lives Thiel SW et al; CCM 2009 Vol. 37

Perception vs. Practice : 

Perception vs. Practice Perception 80% of surveyed intensivists stated adherence to ARDS strategy ventilation Practice 2.6% ARDS patients had TV </=6 cc/kg 80.3% patients had TV >8 cc/kg Less than 0.1% of 2500 surveyed MDs report compliance with all elements of EGDT Crit Care Med 2008 Vol. 36, No. 10; ARISE; EMJ 2010;

Any Factors Associated with Not Using Sepsis Bundle?: 

Any Factors Associated with Not Using Sepsis Bundle? Single center ED study at UPenn Female patient Female physician Younger patient Lactate vs Hypotension as trigger for EGDT Non-consultation to sepsis team No mortality difference in the two groups Mikkelsen et al, CHEST February 2010

At ACMC: 

At ACMC Betty Moore Foundation Sepsis Grant Goal to reduce sepsis mortality in the Bay Area ACMC is a part of this ACMC Harm Reduction Team 32% to 26% mortality drop since July 2009

ACMC Bundle Compliance: 

ACMC Bundle Compliance

Future Directions: 

Future Directions 3 large EGDT studies ARISE, PROCESS, PROMISE Ongoing studies for rAPC – PROWESS Shock

Future Directions: 

Future Directions Target innate immunity Target endotoxin Target or remove cytokines Remove bugs (magnetic cleanser) Heparin Antioxidants Statins

Future Directions: 

Future Directions Cruz et al, JAMA; June 17, 2009 Targeting Endotoxin

Magnetic Blood Cleanser: 

Magnetic Blood Cleanser Children’s Hospital Boston April 2009 Ingber et al; Future Directions

Conclusion: 

Conclusion “The great secret of doctors…is that most things get better by themselves; most things, in fact, are better in the morning.” - Lewis Thomas (Scientist and Writer) Not Sepsis!

Summary: 

Summary Sepsis incidence will likely rise Mortality is high Sepsis is complex and involves an imbalance between host response and microbial invasion Treatment needs to be instituted promptly to halt the devastating cascade (6 hr timeclock) Treatment requires a multipronged approach of evidence based strategies – some are controversial Use bundles/protocols to streamline care New and exciting prospects are in the pipeline