1. Oh How Pendulums Swing! Revisiting Severe Sepsis and Septic Shock
Chris Droege, PharmD
Clinical Pharmacy Specialist, Critical Care
UC Health – University of Cincinnati Medical Center
NYSHP Critical Care Symposium
September 19, 2015
Authors of this presentation have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation.

2. Disclosures
The author of this presentation has nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter

3. Objectives
Describe differences between sepsis, severe sepsis, and septic shock
Outline the rationale for use of intravenous fluids, catecholamines and vasopressin for the hemodynamic reversal of septic shock
Design appropriate antimicrobial treatment strategies
Develop a treatment pathway for that incorporates the 2012 Surviving Sepsis Campaign guideline recommendations and care bundle

4. Assessing the Burden International audit of worldwide ICU patients
10069 patients from 730 participating centers in 84 countries for up to 28 days of data
Pharmacist available 24/7?
Hospital Mortality
ICU Mortality
Whole Population
24.2 (21.6 – 23.2)
16.2 (15.5 – 16.9)
Sepsis Population
35.3 (33.5 – 37.1)
25.8 (24.2 – 27.4)
Data represented as % (95% confidence interval)
276 (37.8%)
Vincent JL, et al. Lancet Respir Med 2014;2:380-6.

5. Population-Adjusted Incidence of Sepsis (#/100,000)
Martin GS, et al. N Engl J Med 2003 Apr 17;348(16):

6. Systemic Inflammatory Response Syndrome
Defined as a response to a physiologic insult manifested by two of the following four criteria:
Temperature > 38°C (101.4°F) or < 36°C (96.8°F)
HR > 90 beats/min
RR > 20 breaths/min or PaCO2 < 32 mmHg
WBC > 12,000 cells/mm3, < 4,000 cells/mm3, or a bandemia > 10%
Dellinger RP, et al. Crit Care Med 2013 Feb;41(2):

7. Definitions Sepsis Severe sepsis Septic shock
SIRS with an infection present or suspected
Severe sepsis
Sepsis associated with organ dysfunction or hypoperfusion
Septic shock
Severe sepsis along with hypotension refractory to fluid resuscitation
Acute circulatory failure leading to ineffective tissue perfusion
Dellinger RP, et al. Crit Care Med 2013 Feb;41(2):

8. Challenge of Definitions
Difficulty between individuals with specific disorder versus epidemiological purpose
Individual: easy to apply; direct therapeutic and prognostic implications
Epidemiologic: robust, rigorous; used in clinical trials
Definitions deemed imprecise and inadequate
Call for further update and revision of criteria
Step away from non-infectious inflammatory disorders
Vincent JL, et al. Lancet 2013; 381:774-5.
Cohen J, et al. Lancet Infect Dis 2015;15:

9. Severe Sepsis Mortality – 10 Years
Kaukonen KM, et al. JAMA 2014 Apr 2;311(13):

10. Sepsis Shock Pathophysiology
Features of each shock type
Vasodilation
Inappropriate activation of vasodilatory mechanisms
Failure of vasoconstrictive pathways
Decreased preload
Loss of intravascular contents
Increased venous pool
Impaired cardiac output
Stroke volume decreased
Myocardial dysfunction secondary to cytokines
Landry DW, Oliver JA. N Engl J Med 2001;345:

11. Inflammatory Response
Proinflammatory
Cytokines
Tone
(SVR)
TOTAL
VOLUME
SHOCK
TOTAL
VOLUME

12. Septic Shock: Therapeutic Goals
Restore effective tissue perfusion
Therapy selection dependent on source of dysfunction
Fluids increase preload
Vasopressors increase vascular tone
Inotropes increase cardiac output
Hollenberg SM. Am J Respir Crit Care Med 2011;183:

13. Sepsis Research: Success? Frustration?
1975 – 1985: 6,500 papers published
1996 – 2006: 20,000 papers published
No novel drug has passed the “test of time”
Hundreds of clinical trials involving tens of thousands of patients and costing hundreds of millions of dollars
Acknowledgement should not undervalue observed management improvements
Cohen J, et al. Lancet Infect Dis 2015;15:

14. Initial Resuscitation Goals
Begin resuscitation immediately in patients with hypotension or elevated serum lactate >4 mmol/L
Resuscitation goals (within six hours):
CVP 8–12 mm Hg (12-15 if mechanically ventilated)
Mean arterial pressure ≥65 mmHg
Urine output ≥0.5 mL/kg/hr
ScVO2 ≥70%, or mixed venous ≥65%
Target resuscitation to normalize lactate levels as a marker of tissue hypoperfusion
Dellinger RP, et al. Crit Care Med 2013 Feb;41(2):

15. Fluid Therapy Crystalloids initial fluids of choice
No hydroxyethyl starch (HES) use
Albumin use when patients require substantial amounts of crystalloids
Initial fluid challenge of 30 mL/kg of crystalloids
Fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement
Dellinger RP, et al. Crit Care Med 2013 Feb;41(2):

16. Fluid Challenge Approach
Attempt to evaluate type, volume, and rate of fluid given in challenge
Determine triggers to compare further fluid administration based on original response
Observational study of 2213 ICU patients
Median amount: 500 mL
Median time and rate: 24 minutes; 1000 mL/h
Cecconi M, et al. Intensive Care Med 2015;41:

17. Fluid Challenge Characteristics
Type of Fluid n
% of Category
% All Fluids
Crystalloids
1713
74.3
NaCl 0.9%
786
45.9
34.1
Balanced
916
53.5
39.8
D5W 4
0.2
D5 NaCl 0.45% 7
0.4
0.3
Colloids
591
25.6
HES
249
42.1
10.8
Albumin 4-5%
101
17.1
4.3
Gelatin
203
34.3
8.8
Dextran 13
2.2
0.5
Albumin 20% 25
4.2
1.1
NaCl, saline; balanced crystalloids with chloride concentration lower than saline; D5W, dextrose 5% in water; HES, hydroxylethyl starch
Cecconi M, et al. Intensive Care Med 2015;41:

18. Indications for Fluid Challenge
Hypotension
1211 (58.7)
Weaning vasopressor
146 (7.1)
Cardiac output
62 (3.0)
Oliguria
372 (18.0)
Skin mottling
36 (1.7)
Lactate
128 (6.2)
SvO2/ScvO2
10 (0.5)
SVV/PPV
37 (1.8)
CVP/PAOP
60 (2.9)
SvO2, mixed venous saturation; ScvO2, central venous oxygen saturation; SVV, stroke volume variation; PPV, pulse pressure variation; CVP, central venous pressure; PAOP, pulmonary artery occlusion pressure
Cecconi M, et al. Intensive Care Med 2015;41:

19. Road to the “Right” Fluid
Saline versus Albumin Fluid Evaluation study
ICU patients randomly assigned to 4% albumin or normal saline for resuscitation
Primary outcome: death from any cause during 28-day period after randomization
6997 patients enrolled
APACHE II scores ~19 in both groups
Finfer S, et al. N Engl J Med 2004;350:

20. Locking the SAFE? Patients Albumin Saline Relative Risk (95%CI)
No. of deaths/total no.
Overall
726/3473
729/3460
0.99 (0.91 – 1.09)
Trauma
Yes
81/596
59/590
1.36 (0.99 – 1.86) No
641/2831
666/2830
0.96 (0.88 – 1.06)
Severe sepsis
185/603
217/615
0.87 (0.74 – 1.02)
518/2734
492/2720
1.05 (0.94 – 1.17)
ARDS
24/61
28/66
0.93 (0.61 – 1.41)
697/3365
697/3354
1.00 ( )
0.5
Albumin better
1.0
2.0
Saline
better
Finfer S, et al. N Engl J Med 2004;350:

21. More-Concentrated Albumin
Albumin Italian Outcome Sepsis study
ICU patients randomly assigned to 20% albumin and crystalloid or crystalloid alone
Target serum albumin concentration: 3 g/dL or more
Primary outcome: death from any cause during 28-day period after randomization
1818 patients enrolled
Caironi P, et al. N Engl J Med 2014;370:

22. Breaking Down ALBIOS First seven days, albumin vs. crystalloid:
Higher MAP (p=0.03); lower HR (p=0.02)
Lower net fluid balance (p<0.001)
Time to hemodynamic instability, 3 v 4d; p=0.007 10 20 30 40 50 28 90
p=0.94
Albumin
Crystalloid
p=0.29
32%
41%
44%
Mortality
Percent
Outcome Day
Caironi P, et al. N Engl J Med 2014;370:

23. Septic Shock Conundrum
Subgroup
No. of Patients
Albumin
Crystalloids
Relative Risk (95% CI)
No. of deaths (%)
All patients
1781
365 (41.1)
389 (43.6)
0.94 (0.85 – 1.05)
Enrollment time
< 6 hours
569
115 (40.6)
116 (40.6)
1.00 (0.82 – 1.22)
6 – 24 hours
1212
250 (41.3)
273 (45.0)
0.92 (0.81 – 1.05)
Septic shock
Yes
660
122 (37.0)
108 (32.7)
1.13 (0.92 – 1.39) No
1121
243 (43.6)
281 (49.9)
0.87 (0.77 – 0.99)
0.25
0.50
1.0
2.0
4.0
Albumin better
Saline better
Caironi P, et al. N Engl J Med 2014;370: Supplementary Appendix.

24. Determining Transfusion Requirements
Benefits and/or harms of hemoglobin thresholds in septic shock not well-established
Multicenter, parallel-group trial with two groups
Lower hemoglobin threshold: 7 g/dL
Higher hemoglobin threshold: 9 g/dL
Primary outcome: death by 90 days
Analyzed data from 998 patients
Transfusion Requirements in Septic Shock
Holst LB, et al. N Engl J Med 2014;371:

25. Relative Risk of Primary Outcome
Subgroup
Lower Group
Higher Group
Relative Risk (95% CI)
No. events/No. Pts in Subgroup
Age
>70 yr
93/173
98/185
0.98 (0.79 – 1.18)
≤70 yr
123/329
125/311
0.94 (0.75 – 1.14)
Chronic CV disease
Yes
42/75
33/66
1.08 (0.75 – 1.40) No
174/427
190/430
0.90 (0.75 – 1.06)
Baseline SAPS II
>53
112/207
139/226
0.83 (0.64 – 1.04)
≤53
104/295
84/270
1.10 (0.91 – 1.30)
All patients
216/502
223/496
0.94 (0.78 – 1.09)
CV, cardiovascular; SAPS, simplified acute physiology score
Lower hemoglobin threshold better
1.0
1.5
2.0
0.7
0.5
Higher hemoglobin threshold better
Holst LB, et al. N Engl J Med 2014;371:

26. Summary of Major Advances: Fluids
Source
Setting
(Study Duration)
No. of Pts
(% in Septic Shock)
Intervention
Control
Primary Outcome
RR (95% CI), Primary Outcome
Conclusions
Caironi et al, 20141
100 Mixed ICUs
( )
1810 (63)
20% Albumin + crystalloids
Crystalloids alone
28-d mortality
1.00 ( )
No difference in 28-d or 90-d mortality
Perner et al, 20122
26 Mixed ICUs
( )
798 (84)
HES
Ringer acetate
6-mo mortality
1.12 ( )
No difference in 6-mo or 1-yr mortality
Annane et al, 20133
57 Mixed ICUs
( )
2857 (54)
Gelatins, dextrans, HES, 4 or 20% albumin
Isotonic, hypertonic saline, Ringer lactate
0.96 ( )
No difference in 28-d morality
Myburgh et al, 20124
23 Mixed ICUs
( )
7000 (13)
6% HES in 0.9% sodium chloride
0.9% sodium chloride
90-d mortality
1.06 ( )
No difference in 90-d morality
1.17 ( )
Greater 90-d mortality and RRT with HES
RR, relative risk; CI, confidence interval; HES, hydroxyethyl starch; RRT, renal replacement therapy
1Caironi P, et al. N Engl J Med 2014;370:
2Perner A, et al. N Engl J Med 2012;367(2):
3Annane D, et al. JAMA 2013;310(17):
4Myburgh JA, et al. N Engl J Med 2012;367(20):

27. Early Goal-Directed Therapy
Sedation, paralysis
(if intubated), or both
CVP
MAP
ScvO2
Goals
achieved
Hospital admission
Yes
≥ 70%
≥ 65 and ≤ 90 mmHg
8 – 12 mmHg
Crystalloid
Colloid
Vasopressors
Transfusion of pRBCs
until hematocrit ≥ 30%
Inotropes
< 8 mmHg
< 65 mmHg
> 90 mmHg
< 70%
Rivers E, et al. N Engl J Med 2001 Nov 8;345(19):

28. Early Goal-Directed Therapy
Mortality
n = 263
EGDT
Usual Care
p=0.03 60
p=0.01
p=0.009
56.9
49.2
46.5
44.3 40
Percent
33.3
30.5 20
Hospital
28-Day
60-Day
Rivers E, et al. N Engl J Med 2001 Nov 8;345(19):

29. Focus on “Goal-Directed”
Three-center randomized, noninferiority trial in patients with severe sepsis or septic shock
ScvO2 of at least 70% versus lactate clearance of at least 10%
Normalized CVP and MAP
Primary outcome: absolute in-hospital mortality rate; noninferiority margin of 10%
ScvO2, central venous oxygen saturation; CVP, central venous pressure; MAP, mean arterial pressure
Jones AE, et al. JAMA 2010 Feb 24;303(8):

30. Focus on “Goal-Directed”
300 patients enrolled; no differences in treatment during initial 72 hours
No difference in adverse effects 23 22 17 30
Per protocol
ITT
In Hospital Mortality (%)
Lactate Clearance
ScvO2
Proportion difference: 6% (-3% to 15%)
Proportion difference: 5% (-3% to 14%)
Jones AE, et al. JAMA 2010 Feb 24;303(8):

31. EGDT Controversies Internal validity External validity
No blinding process
Unclear which intervention lead to positive outcomes
Goal-directed protocol? ScvO2 use?
External validity
Control arm mortality higher than expected
Baseline ScvO2 remarkably low
Translation to ICU care never clear
Russel JA, et al. Intensive Care Med 2015;41:

32. ProCESS Study Design Early detection and fluid administration
Protocol-based EGDT
Protocol-based Standard
Usual Care
Venous Access
Bedside providers
directed all care
Oximetric CVC
2 large bore IVs
Protocol Goals
CVP 8-12 mm Hg
SBP ≥ 100 mm Hg
MAP mm Hg
Shock index < 0.8
ScvO2 ≥ 70% (pRBC if Hct <30%)
Adequate perfusion (pRBC if Hgb <7.5 g/dL)
Protocol implemented by dedicated team
CVC, central venous catheter; CVP, central venous pressure; MAP, mean arterial pressure; SBP, systolic blood pressure; ScvO2, central venous oxygen saturation; pRBC, packed red blood cell; Hct, hematocrit; Hgb, hemoglobin
Yealey DM, et al. N Engl J Med 2014;370:

33. ProCESS Study Results EGDT Standard Usual Care p=0.83 p=0.66 p=0.0421 6 20 40
Hospital Mortality
90-Day Mortality
New Renal Failure
EGDT
Standard
Usual Care
p=0.83
p=0.66
n = 1341
p=0.04 18 19 32 31 34 3
Outcome
Percent
Yealey DM, et al. N Engl J Med 2014;370:

34. ARISE Study
ANZICS group; conducted in 51 academic and non-academic centers
Antibiotics initiated prior to enrollment
Patients assigned to EGDT or usual care
Primary outcome: all-cause mortality at 90 days
Peake SL, et al. N Engl J Med 2014;371:

35. ARISE Study Results p<0.001 p=0.90 p=0.53 Outcome 76.3 65.8 18.6
EGDT Usual Care
p<0.001 80
n = 1600
76.3
65.8 60 40
Percent
p=0.90
p=0.53 20
18.6
18.8
14.8
15.9
90-day Mortality
28-day Mortality
Vasopressor Support
Outcome
Peake SL, et al. N Engl J Med 2014;371:

36. ProMISe Trial
England; pragmatic randomized trial conducted in 56 hospitals
Integrated cost-effectiveness analysis
Assigned to EGDT (6-hour resuscitation) or usual care
Primary outcome: all-cause mortality at 90 days
Mouncey PR, et al. N Engl J Med 2015;372:

37. Dollars (expressed in thousands)
ProMISe Trial Results
EGDT Usual Care
29.2 30
90-day Costs
n = 1251 20 10
29.5
17.6
16.2
90-day Mortality
28-day Mortality
24.8
Outcome
Percent
p=0.90
p=0.26
24.5
Dollars (expressed in thousands)
Mouncey PR, et al. N Engl J Med 2015;372:

38. Clear as Mud?
Systematic review showed no difference in mortality; increased vasopressor and ICU admit
Estimated versus actual mortality differences
EGDT†
ProCESS‡
ARISE‡
ProMISe‡
Mortality, PA
? 15% RRR
30-46%
28%
40%
Mortality, APACHE II
38.9
23.5
29.1
Actual mortality
49.2
18.9
18.8
29.2
†, based on 28-day mortality; ‡, based on 90-day mortality; all values represented as a %
PA, power analysis; APACHE II, Acute Physiology and Chronic Health Evaluation; RRR, relative risk reduction
Systematic “contamination” of principles
Caironi P, et al. N Engl J Med 2014;370:
Angus DC, et al. Intensive Care Med 2015;41:

39. Vasoactive Agents 2012 SCCM Recommendations
Only norepinephrine (NE) recognized as first line
Epinephrine (EPI) considered first alternative
Vasopressin (VP) as adjunctive therapy to increase MAP and decrease NE requirements
Dopamine (DA) and phenylephrine (PE) for use in select populations
VP not recommended as initial vasopressor
Dellinger RP, et al. Crit Care Med 2013 Feb;41(2):

40. SOAP II Trial Multicenter, randomized trial
1,679 patients randomly assigned to either dopamine or NE as first line vasopressor
If MAP not maintained with 20 mcg/kg/min of dopamine or 0.19 mcg/kg/min of NE, open-label NE, epinephrine,or vasopressin could be added
Primary outcome
Rate of death at 28 days after randomization
De Backer D, et al. N Engl J Med 2010 Mar 4;362(9):

41. SOAP II Trial Results p=0.10 53 49 p<0.001 26 24 20 12 7 4 Dopamine
Norepinephrine 53 75 50 25
n=1679
p<0.001
p=0.10 49 26 20 24 12 7 4
28-d Mortality
Open Label NE
Arrhythmias
Skin Ischemia
Percent
De Backer D, et al. N Engl J Med 2010 Mar 4;362(9):

42. CATS Study – NE vs. EPI Enrolled only patients with septic shock
Dobutamine (DBT) added to NE if CI ≤ 2.5 L/min/m2
Outcomes at Day 28
Epinephrine
(n=161)
NE ± DBT
(n=169)
p-value
All-cause mortality
64 (40%)
58 (34%)
0.31
Vasopressor-free days
20 (0-24)
22 (6-25)
0.05
At day 14
56 (35%)
44 (26%)
0.08
At day 28 *
Lactate (mmol/L)
Day 2 3 4 9 7 5 1 *
Arterial pH 2 3 4
7.5
7.4
7.3
7.2
7.1
7.0
Day
*p<0.01
NE ± DBT
EPI
Annane D, et al. Lancet 2007;370:

43. CATS Study – NE vs. EPI 18 40 19 30 60 20 10 Arrhythmias p=0.72
Arrhythmias
p=0.72
n = 330
p=0.31 50
28-d Mortality
EPI
NE ± DBT 34
Percent
Annane D, et al. Lancet 2007;370:

44. Vasopressin in Septic Shock Trial
In septic shock, requiring norepinephrine (NE) at a dose of > 5 mcg/min for at least 6 hours and at least one other organ failure
Received open-label NE in addition to blinded administration of:
Vasopressin (0.01 – 0.03 units/min) OR
Norepinephrine ( mcg/min)
Russell JA, et al. N Engl J Med 2008 Feb 28;358(9):

45. Vasopressin in Septic Shock Trial
Percent
28-d Mortality
90-d Mortality 39 35 36 27 43 44 50 46 53 52
p=0.26
p=0.05
p=0.11
p=0.04
* Defined as a NE requirement of at least 15 mcg/min or equivalent
Russell JA, et al. N Engl J Med 2008 Feb 28;358(9):

46. Antimicrobial Therapy
Prompt initiation of appropriate therapy is crucial
Within one hour of severe sepsis or septic shock diagnosis
Empiric regimen broad enough to cover all likely pathogens
Local epidemiology; medical history; recent therapies
Pharmacokinetic-pharmacodynamic optimization
Cohen J, et al. Lancet Infect Dis 2015;15:

47. Early Effective Antimicrobial Treatment
Each hour of delay from hypotension onset was associated with an average decrease in hospital survival of 7.6%
Percent
Duration of Hypotension (Hours)
Kumar A, et al. Crit Care Med 2006 Jun;34(6):

48. Mortality and Time to Antibiotics
Study
No. of Patients
Odds Ratio (95% CI)
Ferrar et al, 2014
5062
1.07 ( )
Puskarich et al, 2011
172
0.77 ( )
Gaieski et al, 2010
261
1.65 ( )
Ferrar et al, 2009
1737
1.43 ( )
Kumar et al, 2006
2174
7.33 ( )
Yokota et al, 2014
358
1.13 ( )
Ryoo et al, 2015
426
1.09 ( )
Bloos et al, 2014
827
1.06 ( )
Pooled OR
1.46 ( )
0.2
0.5 1 2 5 10
Sterling SA, et al. Crit Care Med 2015;43:

49. Antibiotic Therapy
Regimen could rely on mono- or combination therapy with two or more agents
Monotherapy: extended-spectrum penicillin with or without β-lactamase inhibitor
Therapy Approach
Potential Agents
Monotherapy
Extended-spectrum penicillin with or without β-lactamase inhibitor
3rd or 4th generation cephalosporin
Carbapenem
Combination Therapy
β-lactam
Aminoglycoside OR fluoroquinolone
Anti-Gram positive agent (e.g., vancomyin; linezolid; daptomycin)
Cohen J, et al. Lancet Infect Dis 2015;15:
Dellinger RP, et al. Crit Care Med 2013 Feb;41(2):

50. Mono- vs. Combination Therapy
Combination therapy found superior to monotherapy for Gram negative sepsis
Primarily retrospective and observational
Meta-analyses suggest monotherapy as efficacious and less toxic than combination therapy in immunocompetent patients
Cohen J, et al. Lancet Infect Dis 2015;15:
Paul M, et al. Cochrane Database Syst Rev 2014 Jan 7;1:CD

51. Monotherapy Versus Combination Therapy
Outcome or subgroup
No. of Studies
No. of Patients
Risk Ratio (95% CI)
All-cause mortality
Same beta lactam
Different beta lactam 13 31
1431
4146
0.97 ( )
0.85 ( )
All-cause mortality, group
Same sepsis
Different sepsis 7 21
839
3298
1.08 ( )
0.83 ( )
Clinical failure 20 46
1870
4933
1.11 ( )
0.75 ( )
Bacterial superinfection 28
3135
0.75 ( )
Any nephrotoxicity
Once-daily aminoglycoside
Twice-daily aminoglycoside
Thrice-daily aminoglycoside 5 24
5269
865
1127
2138
0.30 ( )
0.17 ( )
0.43 ( )
0.28 ( )
Cohen J, et al. Lancet Infect Dis 2015;15:
Paul M, et al. Cochrane Database Syst Rev 2014 Jan 7;1:CD

52. Guidance for Therapy Duration
Empiric combination therapy should be continued no longer than three to five days
De-escalate to appropriate targeted therapy as soon as possible
Therapy duration typically seven to ten days
Consider use of biomarkers to guide discontinuation of empiric therapy
7-10 days: grade 2C rec
Dellinger RP, et al. Crit Care Med 2013 Feb;41(2):

53. Rapid Diagnostics
Matrix-associated laser desorption ionization-time of flight (MALDI-TOF)
Peptide nucleic acid fluorescence in situ hybridization (PNA FISH)
Mass spectroscopy
Polymerase chain reaction (PCR)
Singleplex; multiplex real-time; broad range; digital
Reduced time to pathogen identification
Earlier, appropriate tailoring of therapy
Improved mortality and morbidity
Cohen J, et al. Lancet Infect Dis 2015;15:

54. Antimicrobial Stewardship Programs
Core responsibilities
Provider education; guideline development; dose optimization; therapy de-escalation; parenteral to enteral conversions
Goals
Improving outcomes; decrease “inappropriate” antimicrobial use; prevent adverse drug reactions; minimize resistance development
DeWaele JJ, et al. Intensive Care Med 2015 Aug 20. [Epub ahead of print]

55. Surviving Sepsis Campaign Bundles
To be accomplished as soon as possible and scored over first three hours:
To be accomplished as soon as possible and scored over the first six hours:
Serum lactate measured
Blood cultures obtained prior to antibiotics administered
Administer broad-spectrum antibiotics
For hypotension and/or lactate > 4 mmol/L:
Deliver an initial minimum of 30 mL/kg of crystalloid
Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain MAP ≥ 65 mmHg
In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥ 4 mmol/L:
Measure CVP
Measure ScvO2
Re-measure lactate if initial lactate is elevated
Dellinger RP, et al. Crit Care Med 2013 Feb;41(2):

56. IMPreSSed with Compliance?
Detail
Compliance, n (%)
3-h bundle compliance (all patients, n = 1794)
Full bundle
Lactate measurement
Obtain blood cultures before antibiotic administration
Administration of broad-spectrum intravenous antibiotics
Administration of 30 mL/kg crystalloid fluid challenge
Hospital mortality, compliance
Hospital mortality, non-compliance
340 (19.0)
1002 (55.9)
883 (49.2)
1155 (64.4)
1017 (56.7)
67/340 (19.7)
443/1454 (30.5)*
6-h bundle compliance (all patients)
Repeat lactate measurement
Application of vasopressors for hypotension
637 (35.5)
1077 (60.0)
1479 (82.4)
143/637 (22.4)
367/1157 (31.7)*
6-h bundle compliance, hypotension (n = 824)
90 (10.9)
530 (63.4)
544 (66.0)
* Represents p≤ by Fishers exact test
Global, prospective, observational, quality improvement study of SSC bundle compliance
DeWaele JJ, et al. Intensive Care Med 2015;41:

57. National Quality Forum #0500
A. Measure lactate level
B. Obtain blood cultures prior to antibiotics
C. Administer broad spectrum antibiotics
D. Administer 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L
E. Apply vasopressors (for hypotension that does not respond to maintain a MAP ≥ 65 mmHg
F. In the event persistent hypotension after initial fluid challenge or if lactate ≥ 4 mmol/L‡, reassess intravascular volume status and tissue perfusion and document findings.
*To meet requirements, a focused exam including vital signs, cardiopulmonary, capillary refill, pulse and skin findings, or any 2 other items below are required:
Measure CVP
Measure ScvO2
Bedside cardiovascular ultrasound
Dynamic reassessment of fluid
G. Re-measure lactate if initial lactate is elevated
‡ Would also require another fluid challenge
Revised after ProCESS and ARISE to remove CVP and ScvO2 mandates
Dellinger RP, et al. Crit Care Med 2015 Sep;43(9):

58. Rapid clinical reassessment within 15-30 min
Patient with clinical criteria for septic shock
Suspected or documented infection
Arterial hypotension (SBP ≤ 90; MAP ≤ 65)
Evidence of tissue hypoperfusion
Address suspected infection
Immediately obtain body fluid cultures
Begin appropriate broad-spectrum antibiotics
Consider diagnostic imaging
Institute prompt infectious source control
Begin fluid bolus therapy
IVF, mL/kg over min;
hold if fluid replete or overload
Assess clinical severity
Measure lactate immediately
Obtain additional laboratory tests
(e.g., arterial blood gas; troponin)
Initial management No
Rapid clinical reassessment within min A
Yes
Is shock still present?
Consider focused cardiac ultrasound
Consider arterial catheter for blood pressure monitoring and obtaining blood samples
Consider central venous catheter for reliable vascular access No
LV or RV dysfunction?
Yes
Advanced diagnostics
Consider formal ECHO,
repeat EKG, troponin levels
Consider PCA and ScvO2 measurement
Seymour CW, et al. JAMA 2015 Aug 18;314(7):

59. Is there arterial hypotension? Fluid replete or overload?
Yes
Fluid replete or overload? No
Yes
Start vasopressors
Norepinephrine as first-line agent
Consider IVF to replace ongoing losses
Prompt clinical reassess within hours
Repeat lactate level
Perform clinical examination at bedside (mental status; peripheral perfusion; urine output)
Reassess if fluid replete or overload
Persistent shock?
Yes
Address treatment of persistent shock
Reassess etiology of shock and control of infectious source
Consider vasopressin, 0.04 u/min, if high NE requirements
Consider hydrocortisone if multiple pressors
If steroids started, consider removing when vasopressors are discontinued No
Yes No
De-escalate therapy for septic shock and consider fluid volume removal when safe A
Persistent shock?
Seymour CW, et al. JAMA 2015 Aug 18;314(7):

60. Swing Away!
First six hours after diagnosis will continue to be time period of greatest interest, but…
What is the right amount of intravascular volume in septic shock?
Is one crystalloid preferred to achieve that volume?
What is the optimal balance between fluid administration and vasopressor use to maintain MAP?
Do evidence-based monitoring variables exist to facilitate achieving these targets?
Dellinger RP, et al. Crit Care Med 2015 Sep;43(9):

61. Oh How Pendulums Swing! Revisiting Severe Sepsis and Septic Shock
Chris Droege, PharmD
Clinical Pharmacy Specialist, Critical Care
UC Health – University of Cincinnati Medical Center
NYSHP Critical Care Symposium
September 19, 2015
Authors of this presentation have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation.