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

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

3. Pathophysiology of Sepsis
Insert ugly pathophys diagram of sepsis

4. Pathophysiology of Sepsis
Insert ugly pathophys diagram of sepsis

5. 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

6. 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

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

8. 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

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

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

11. 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

12. 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

13. 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

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

15. 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 / 35 / 158 / 18
Na Cl K TCO Glucose 2.8
Diagnosis?

16. 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

17. 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

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

19. 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%

20. 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

21. 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?
% mortality / hour delay
5 % mortality / hour delay
8 % mortality / hour delay
12 % mortality / hour delay
% mortality / hour delay

22. 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 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:

23. 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 [ ] 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

24. 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

25. 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)

26. Antibiotics

27. 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

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

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

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

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

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

33. 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)

36. How much Fluid?

37. How much Fluid?
LOTS!!!

38. 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

39. 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

40. 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

41. Steroids?

42. 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

43. 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.

44. 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:

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

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

47. 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