Priorities in Septic Shock / Severe Sepsis Dr. Shelly Zubert, FRCPC Emergency Medicine Physician Health Sciences Centre Critical Care Fellow sazpeto@shaw.ca

Disclosures No Funding No Sponsorship No Grant No Invested Interests Not a representative of any Pharmaceuticals

Pathophysiology of Sepsis Insert ugly pathophys diagram of sepsis

Pathophysiology of Sepsis Insert ugly pathophys diagram of sepsis

Objectives Severe Sepsis / Septic Shock Just kidding ….. We will…. NOT review complicated pathophysiology!!!!! Early Recognition Hypotension = Septic Shock Hypoperfusion = Severe Sepsis Antibiotics within 30 minutes of Recognition! Antibiotics FAST Broad Spectrum Antibiotics The right antibiotics FIRST

Objectives Severe Sepsis / Septic Shock We will…. Emergency Department Disease Definitions Priorities in Sepsis FAST Early Antibiotics FIRST The RIGHT Broad spectrum antibiotics FIND Get the CULTURES!!!! Adjunctive Therapies in Sepsis Early Recognition Hypotension = Septic Shock Hypoperfusion = Severe Sepsis Antibiotics within 30 minutes of Recognition! Antibiotics FAST Broad Spectrum Antibiotics The right antibiotics FIRST

Spectrum of Infection Transient Local Systemic SIRS Septic Severe Bacteremia Infection Infection Shock Sepsis

Definitions SIRS Systemic Inflammatory Response Syndrome 2 + of the following: WBC < 4 OR > 12 OR > 10% Bands Temp < 36 (96.8) OR > 38(100.4) C HR > 90 RR > 20 OR Pa CO2 < 32 Dellinger Crit Care Med 2008; 36:296-7

Definitions Bacteremia Presence of viable bateria in the blood 50% of septic shock patents Dellinger Crit Care Med 2008; 36:296-7

Definitions Sepsis Presence or Presumed Minimum 2+ SIRS criteria Infection Minimum 2+ SIRS criteria Dellinger Crit Care Med 2008; 36:296-7

Definitions Severe Sepsis Sepsis Minimum 1 organ failure ALI / ARDS Coagulopathy Thrombocytopenia < 100 Altered Mentation Renal Failure Liver Failure Heart Failure Hypoperfusion Dellinger Crit Care Med 2008; 36:296-7

Definitions Septic Shock Sepsis Persistent Hypotension Hypotension SBP < 90 MAP < 70 Drop in SBP > 40 from well established baseline >2 SD less than Normal for age Despite fluid challenge (20 – 40 mL/kg) Dellinger Crit Care Med 2008; 36:296-7

Definitions Sepsis Induced Hypoperfusion: Sepsis induced Hypotension Lactate elevation Oliguria < 0.5 mL/kg/hour for at least 2 hours Dellinger RP et al. Surviving Sepsis Campaign Critical Care Medicine 2008; 36:296-7

Case Diagnosis? 30 YO C3/C4 Quadriplegic Male Recurrent UTIs Self Catheterizes Presents with 3 days Sweating Vomiting Anorexia Fever Diagnosis?

Case Diagnosis? WBC 13.9 BP 86 / 35 after 500 mL RL HR 120 Temp 38.3 RR 35 O2 Sats - 90% 15 L Face Mask ABG 7.27 / 35 / 158 / 18 Na 135 Cl 95 K 4.5 TCO2 20 Glucose 2.8 Diagnosis?

Diagnosis? Severe Sepsis Bacteremia Sepsis Sepsis induced hypotension Severe Sepsis Septic Shock WBC 13.9 BP 86 / 35 after 500 mL RL HR 120 Temp 38.3 O2 Sats – 90% 15 L Face Mask RR 35 ABG 7.27 / 35 / 158 / 18 Na 135 Cl 95 K 4.5 TCO2 20 Glucose 2.8

Diagnosis? infection SIRS+ Hypotension Response to Fluid Organ Failure Yes +/- No Anion Gap = Na+ - Cl- - TCO2 AG = 135 – 95 – 20 = 20 Normal AG 8-12 Bacteremia Sepsis Sepsis induced hypotension Severe Sepsis Septic Shock WBC 13.9 BP 86 / 35 after 500 mL RL HR 120 Temp 38.3 O2 Sats – 90% 15 L Face Mask RR 16 ABG 7.27 / 35 / 158 / 18 Na 135 Cl 95 K 4.5 TCO2 20 Glucose 2.8

Questions Antibiotics? Fluids? Pressors? Biomarkers? Steroids? Activated Protein C? Other?

Relative Mortality Reduction aPC EGDT Corticosteroids IgG Insulin Ventilator Strategy Optimal Hematocrit Optimal Antibiotics 20% 35% 15% ??? 40% 25% 15% 30% You’ll actually end up with spontaneous new life generated if you can manage to accomplish all these with resuscitating you septic shock patients 200%

Absolute Mortality Reduction aPC EGDT Corticosteroids 6% 17% Never Replicated ----- ??? ----- You’ll actually end up with spontaneous new life generated if you can manage to accomplish all these with resuscitating you septic shock patients

1. 0.5 % mortality / hour delay 5 % mortality / hour delay What is the absolute reduction of survival for every hour delay in effective antibiotics administered in Severe Sepsis / Septic Shock? 1. 0.5 % mortality / hour delay 5 % mortality / hour delay 8 % mortality / hour delay 12 % mortality / hour delay 5. 21% mortality / hour delay

Cumulative Initiation of Effective Antimicrobial Therapy and Survival in Septic Shock time from hypotension onset (hrs) 0-0.5 0.5-1 1-2 2-3 3-4 4-5 5-6 6-9 9-12 12-24 24-36 36+ fraction of total patients 0.0 0.2 0.4 0.6 0.8 1.0 survival fraction cumulative antibiotic initiation This graph has become famous in the world of sepsis. It was created by Dr. Kumar and published in CCM in 2006. The Red bars are the fraction of patients that survive. Time zero is the point of recognized hypotension. This is actually quite easy to identify because if you are looking back at the charts the nursing team always documents the vitals at the same time as notifying the physician. So time 0 is easily identified. Again the nursing record and now our online records as they evolve also document time antibiotics given. As you can see as time passes ….. 30 minutes, 1 hour, 2 hours, etc … survival plummets. The yellow bars represent the initiation of effective antibiotic coverage. So at time 30 minutes only a small fraction of patients have received the appropriate antibiotics (< 10%) however this subset of the septic shock population has 90% chance of surviving !!!! At 6 hours 50% have received appropriate antibiotics and look at survival already 40% !!! Let’s say BID antibiotics are ordered and the patient just missed the 10 AM dose. It will be 12 hours until he receives his dose – his chances of survival are 20%. Finding How long do you think it takes on average to receive antibiotics from the time of hypotension at HSC? We actually have data on this. 6 Hours…… St B 6 hours …. Toronto ….. 6 hours. Note survival 40% At 1 hour antibiotics received the ptx has 85% survival. For every 1 hour delay in receiving antibiotics survival decreases 7% Kumar et al. CCM. 2006:34:1589-96.

Golden Hour: Thrombolysis in AMI The concept of the golden hour for treatment is not new. We apply the golden hour to MI with thrombolytics and PCI, with trauma for resuscitation, and it’s also been recently advocated for in massive pulmonary embolism. So why not apply this to sepsis as well…. These graphs clearly demonstrate benefit with limited treatment delay in AMI. Early thrombolytic treatment in acute myocardial infarction: Reappraisal of the golden hour. Source: The lancet [0099-5355] Boersma yr:1996 vol:348 iss:9030 pg:771 Figure 3. Proportional effect of fibrinolytic therapy on 35-day mortality according to treatment delay Odds ratios, plotted with 95% CI on a log scale, are significantly different over the six groups (Breslow-Day test, p=0001). Areas of black squares proportional to amount of statistical information Figure 4. Absolute 35-day mortality reduction versus treatment delay Small closed dots: information from trials included in FTT analysis; open dots: information from additional trials; small squares: data beyond scale of x/y cross. The linear (34·7-1·6x) and non-linear (19·4−0·6x+29·3x−1) regression lines are fitted within these data, weighted by inverse of the variance of the absolute benefit in each datapoint.4 Black squares: average effects in six time-to-treatment groups (areas of squares inversely proportional to variance of absolute benefit described). Boersma et al. The Lancet 1996;348:771

Timing of Antibiotics Surviving Sepsis Campaign: “IV antibiotics should be started within the first hour of recognition of severe sepsis” OUR GOAL: 30 minutes “Establishing a supply of pre-mixed antibiotics in the ED is an appropriate strategy” Dellinger RP. CCM 2004; 32:858

Causes for Delays Failure to recognize: Hypotension == septic shock Effect of inappropriate antibiotic initiation Failure to recognize risk of resistant organisms ALL ANTIBIOTIC ORDERS IN SEPTIC SHOCK ARE STAT Non specified order of multiple antibiotic administration Waiting for blood cultures Avoid delays to cultures Cultures don’t delay antibiotics! Get the cultures! Transfer from ER before antibiotics given Transfer of care in ER before antibiotics given Non-uniform approach to septic shock Adoption of syndrome based guidelines Administrative/logistic delays Physician autonomy Failure to recognize: Hypotension == septic shock Effect of inappropriate antibiotic initiation Failure to appreciate risk of resistant organisms in certain scenarios (e.g. immunocompromised vs immunosuppressed; antecedent antimicrobial use) Wait for blood cultures from IV techs Transfer from ER before antibiotics given Failure to use “stat” orders No specified order with multiple drug regimens Administrative/logistic delays (nursing/pharmacy/ ward clerk)

Antibiotics

EMPIRIC ANTIBIOTICS Community-Acquired Pneumonia Septic Shock / Severe Sepsis S. pneumoniae E. coli S. aureus Legionella Gram Negatives Ceftriaxone + Gentamicin or Quinolone Vancomycin (CA-MRSA) Quinolone

EMPIRIC ANTIBIOTICS Septic Shock Source Unclear Piperacillin/tazobactam or Imipenem or Meropenem + Vancomycin Aminoglycoside

EMPIRIC ANTIBIOTICS Nosocomial Septic Shock Resistant E. Coli Pseudomonas Enterococcus S. pneumoniae S. aureus Pip-Tazo + Aminoglycoside Vancomycin Alternate: Ceftriaxone + Levofloxacin + Vancomycin

EMPIRIC ANTIBIOTICS Nosocomial Septic Shock Catheter Related Bloodstream Infection Central Line TPN Femoral catheter or Immunocompromised Vancomycin Caspofungin Aminoglycoside

EMPIRIC ANTIBIOTICS Urosepsis E. Coli (Nitrite +) Enterococcus S. aureus Pseudomonas Gentamicin or Quinolone + Ampicillin OR Pip/Tazo

EMPIRIC ANTIBIOTICS Meningitis S. pneumoniae N. meningitidis Lysteria monocytogenes (Elderly, Immunocompromised) Don’t forget Steroids!!! Ceftriaxone + Vancomycin Ampicillin

EMPIRIC ANTIBIOTICS Severe Skin + Soft Tissue Necrotizing Fasciitis Group A B - Hemolytic Streptoccus / Staph aureus Clostridium / Anaerobes E. coli MRSA Penicillin and Clindamycin + B-lactamase inhibitor (polymicrobial) +/- Vancomycin (MRSA)

How much Fluid?

How much Fluid? LOTS!!!

Early Goal-Directed Therapy: The First 6 Hours EGDT Standard Total Fluids (mL) 4981 +/- 2984 3499 +/- 2438 RBC Transfusion (%) 64 18 Any Pressor (%) 27 30 Inotrope-dobutamine (%) 14 1 Mech. Ventilation (%) 53 54 We know that the thrust of the Rivers paper was the principle of EGDT. (Measuring and treating CVP, SCVO2, HCT, etc…) However if you look at the amount of fluid the EGDT group received relative to the Standard Therapy, they were on average resuscitated with 1.5 to 3 L more crystalloid than the standard therapy group. So is the difference due to the fluid resuscitation or the achievement of the EGDT goals Rivers E. NEJM 2001; 345:1368

Lactate VBG Jones AE et al. JAMA 2010; 303:739-46 94% Sensitive 57% Specific Negative is helpful Measure of cell anaerobic metabolism May ID occult sepsis early Jones AE et al. JAMA 2010; 303:739-46

Lactate Clearance 300 Patients Severe Sepsis Multicenter Randomized Trial EGDT CVP, MAP, SCVO2 versus Lactate clearance> 10% Time 0 to 6 hours Goal: Test noninferiority of lactate clearance to SCVO2 as a goal of early sepsis resuscitation Group 1 resuscitated to normalize CVP, MAP, SCVO2 of at least 70% Versus Group 2 resuscitated to normalize CVP, MAP and Lactate clearance of at least 10% Primary outcome: absolute in-hospital mortality rate The noninferiority threshold was set at -10% - allowed 71% power in detection of inferiority. 10% chosen based on demonstrated in hospital mortality using SCVO2 and some literature surrounding lactate clearance in addition to the knowledge that mortality in Severe sepsis varies 10% based on location and resource availability. Jones AE et al. JAMA 2010; 303:739-46

Steroids?

Steroids? HIGH Dose Steroids HAVE NOT BEEN shown to improve Mortality in sepsis Lefering R. Critical Care Med 1995; 23;1294 Cronin L Critical Care Med 1995; 23: 1430

LOW Dose Steroids in Septic Shock 299 Patients with Septic Shock – Mean Age 60 Fluid Non Responsive on Mechanical Ventilation Hydrocortisone 50 mg q6h + Flucortisone 50 mcg q24h 28 DAY Mortality(n,%) Steroid Placebo Cort. Stim Test Non-Responders 60 / 114 (53) 73 / 115 (63) Responders 22 / 36 (61) 18 / 34 (53) All Patients 82 / 150 (55) 91 / 149 (61) Annane et al.

CORTICUS TRIAL RESULTS 499 Patients with Sepsis Placebo vs Hydrocortisone 50 mg q6h X 5 days RESULTS No Difference Mortality (31% versus 34%) No difference by responder status Trend toward higher superinfection in steroid group 26% versus 33% Sprung CL et al. NEJM 2008; 358: 111-24

Steroids RECOMMENDATION Suspected adrenal insufficiency ONLY! IE: Patient remains vasopressor AND Dependant despite 6-8 L IV Fluid AND Supportive History

Source Control Cholecystitis / Pancreatitis / Appendicitis / Ascending cholangitis OR, ERCP, MRCP Abscess Drainage Urinary outflow tract obstruction Debridement SSTI

Objectives Severe Sepsis / Septic Shock Hopefully I did…. Emergency Department Disease Definitions Priorities in Sepsis FAST Early Antibiotics FIRST The RIGHT Broad spectrum antibiotics FIND Get the CULTURES!!!! Adjunctive Therapies in Sepsis Hopefully I’ve convinced you that Septic shock and severe sepsis is an emergency department disease. In our medical system we own the outcomes of this disease and as you can see in the data I showed you we aren’t yet creating our best outcomes. We can champion this disease as we do have the tools and the ability to dramatically affect outcomes in septic shock. In order to do that we reviewed….. The definitions – not only so we speak the same language but rather so we recognize this disease when it’s subtle, when we don’t have the chart, when we have no history and you have to take that leap to treat…… Early recognition is the key. Early Recognition Hypotension = Septic Shock Hypoperfusion = Severe Sepsis Antibiotics within 30 minutes of Recognition! Antibiotics FAST Broad Spectrum Antibiotics The right antibiotics FIRST