Surviving Sepsis Campaign

Guidelines for Management of

Severe Sepsis/Septic Shock

An Overview
 Surviving Sepsis

A global program to:

Reduce mortality rates in severe sepsis
 Surviving Sepsis
Phase 1 Barcelona
declaration
Phase 2 Evidence based
guidelines
Phase 3 Implementation
and education
Su rvivin g Se psis
Phase 1 Barcelona
declaration
Phase 2 Evidence based
guidelines
Phase 3 Implementation
and education
 Sponsoring Organizations
 American Association of Critical Care Nurses
 American College of Chest Physicians
 American College of Emergency Physicians
 American Thoracic Society
 Australian and New Zealand Intensive Care Society
 European Society of Clinical Microbiology and Infectious
Diseases
 European Society of Intensive Care Medicine
 European Respiratory Society
 International Sepsis Forum
 Society of Critical Care Medicine
 Surgical Infection Society
 Guidelines Committee*
Dellinger (RP) Ramsay Harvey Sprung
Carlet Zimmerman Hazelzet Torres
Masur Beale Hollenberg Vendor
Gerlach Bonten Jorgensen Bennet
Levy Brun-Buisson Maier Bochud
Vincent Carcillo Maki Cariou
Calandra Cordonnier Marini Murphy
Cohen Dellinger (EP) Opal Nitsun
Gea-Banacloche Dhainaut Osborn Szokol
Keh Finch Parrillo Trzeciak
Marshall Finfer Rhodes Visonneau
Parker Fourrier Sevransky

*Primary investigators from recently performed positive trials with implications for
septic patients excluded from committee selection.
 Surviving Sepsis Campaign (SSC)
Guidelines for Management of Severe
Sepsis and Septic Shock

Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T,

Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker
MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM and
the
SSC Management Guidelines Committee

Crit Care Med 2004;32:858-873

Intensive Care Med 2004;30:536-555
available online at
[Link]
[Link]
[Link]
Sackett DL. Chest 1989; 95:2S–4S
Sprung CL, Bernard GR, Dellinger RP. Intensive Care Medicine 2001; 27(Suppl):S1-S2
 Clarifications
 Recommendations grouped by category
and not by hierarchy
 Grading of recommendation implies
literature support and not priority of
importance
Initial Resuscitation
Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular
management of septic shock. Crit Care Med 2003;31:946-955.
 The Importance of Early Goal-Directed
Therapy for Sepsis Induced Hypoperfusion
NNT to prevent 1 event (death) = 6-8
60 Standard therapy
EGDT
Mortality (%)
50
40
30
20
10
0
In-hospital 28-day 60-day
mortality mortality mortality
(all
patients)
Adapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al.
Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med
2001; 345:1368-1377
 Initial Resuscitation
 In the presence of sepsis-induced
hypoperfusion
 Hypotension
 Lactic acidosis
 MAP
65 mm Hg 75 mm Hg 85 mm Hg F/LT

Urinary
output (mL) 49 +18 56 + 21 43 +13 .60/.71

Capillary blood
flow (mL/min/100 6.0 + 1.6 5.8 + 5.3 + 0.9 .59/.55
g) 11
Red Cell
Velocity (au) 0.42 + 0.44 0.42 + 0.06 .74/.97
0.06 +016
Pico2 (mm Hg) 41 + 2 47 + 46 + 2 .11/.12
2
Pa-Pico2 (mm 13 + 3 17 + 3 16 + 3 .27/.40
Hg)
Adapted from Table 4, page 2731, with permission from LeDoux, Astiz ME, Carpati CM,
Rackow ED. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care
Med 2000; 28:2729-2732
 Initial Resuscitation
Goals during first 6 hours:

 Central venous pressure: 8–12 mm Hg

 Mean arterial pressure ≥ 65 mm Hg
 Urine output ≥ 0.5 mL kg-1/hr-1
 Central venous (superior vena cava) or
mixed venous oxygen [SvO2] saturation ≥
70%
Grade B
 Initial Resuscitation
Goals during first 6 hours:

 Central venous or mixed venous O2 sat <

70% after CVP of 8–12 mm Hg
• Packed RBCs to Hct 30%
• Dobutamine to max 20 µg/kg/min

Grade B
 Diagnosis
 Appropriate cultures
 Minimum 2 blood cultures
• 1 percutaneous
• 1 from each vascular access ≥ 48
hrs

Grade D
 Antibiotic Therapy
 Begin intravenous antibiotics within
first hour of recognition of severe
sepsis.

Grade E
 Antibiotic Therapy
 One or more drugs active against likely
bacterial or fungal pathogens.
 Consider microorganism susceptibility
patterns in the community and hospital.

Grade D
 Antibiotic Therapy
Reassess antimicrobial regimen
at 48-72 hrs
• Microbiologic and clinical data
• Narrow-spectrum antibiotics
• Non-infectious cause identified
• Prevent resistance, reduce toxicity,
reduce costs

Grade E
 Source Control
 Evaluate patient for a focused infection
amendable to source control measures
including abscess drainage or tissue
debridement.
• Move rapidly
• Consider physiologic upset of measure
• Intravascular access devices

Grade E
Photograph used with permission from Janice L. Zimmerman, MD
EKG tracing reproduced with permission from Janice L. Zimmerman, MD
 Fluid Therapy

 Fluid resuscitation may consist of natural or

artificial colloids or crystalloids.

Grade C
Figure 2, page 206, reproduced with permission from Choi PT, Yip G, Quinonez L, Cook DJ.
Crystalloids vs. colloids in fluid resuscitation: A systematic review. Crit Care Med 1999; 27:200–210
 Fluid Therapy
 Fluid challenge over 30 min
• 500–1000 ml crystalloid
• 300–500 ml colloid
 Repeat based on response
and tolerance

Grade E
 Vasopressors
 Either norepinephrine or dopamine
administered through a central
catheter is the initial vasopressor of
choice.
• Failure of fluid resuscitation
• During fluid resuscitation

Grade D
 Effects of Dopamine, Norepinephrine,
and Epinephrine on the Splanchnic
Circulation in Septic Shock

Figure 2, page 1665, reproduced with permission from De Backer D, Creteur J, Silva E, Vincent
JL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in
septic shock: Which is best? Crit Care Med 2003; 31:1659-1667
 Vasopressors

 Do not use low-dose dopamine for

renal protection.

Grade B

Bellomo R, et al. Lancet 2000; 356:2139-2143

 Vasopressors
 In patients requiring vasopressors,
place an arterial catheter as soon as
possible.

Grade E
 Circulating Vasopressin Levels in Septic Shock

Figure 2, page 1755 reproduced with permission from Sharshar T, Blanchard A, Paillard
M, et al. Circulating vasopressin levels in septic shock. Crit Care Med 2003; 31:1752-1758
Vasopressin and Septic Shock
• Versus cardiogenic shock
• Decreases or eliminates
requirements of traditional
pressors
• As a pure vasopressor expected
to decrease cardiac output
 Vasopressors
Vasopressin
 Not a replacement for norepinephrine or
dopamine as a first-line agent
 Consider in refractory shock despite high-
dose conventional vasopressors
 If used, administer at 0.01-0.04 units/minute
in adults

Grade E
 During Septic Shock

Diastole Systole

10 Days Post Shock

Diastole Systole

Images used with permission from Joseph E. Parrillo, MD

 Inotropic Therapy
 Consider dobutamine in patients with
measured low cardiac output despite
fluid resuscitation.

 Continue to titrate vasopressor to mean

arterial pressure of 65 mm Hg or greater.

Grade E
 Inotropic Therapy
 Do not increase cardiac index to achieve
an arbitrarily predefined elevated level of
oxygen delivery.

Grade A

Yu, et al. CCM 1993; 21:830-838

Hayes, et al. NEJM 1994; 330-1717-1722
Gattinoni, et al. NEJM 1995; 333:1025-1032
 Steroid Therapy

Figure 2A, page 867, reproduced with permission from Annane D, Sébille V, Charpentier C, et
al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in
patients with septic shock. JAMA 2002; 288:862-871
 P = .045

P = .007

Figure 2 and Figure 3, page 648, reproduced with permission from Figure 2 and Figure 3, page 727, reproduced with permission from
Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone
shock with supraphysiologic doses of hydrocortisone. Crit Care reverse hyperdynamic septic shock: A prospective, randomized,
Med 1998; 26:645-650 double-blind, single-center study. Crit Care Med 1999; 27:723-732
 Annane, Bollaert and Briegel
 Different doses, routes of administration
and stopping/tapering rules
 Annane
 Required hypotension despite
therapeutic intervention
 Bollaert and Briegel
 Required vasopressor support only
 Steroids
 Treat patients who still require
vasopressors despite fluid
replacement with hydrocortisone
200-300 mg/day, for 7 days in
three or four divided doses or by
continuous infusion.

Grade C
Figure 2B, page 867, reproduced with permission from Annane D, Sébille V, Charpentier C, et al.
Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients
with septic shock. JAMA 2002; 288:862-871
 Identification of
Relative Adrenal Insufficiency
Recommendations vary based on
different measurements and different
cut-off levels
 Peak cortisol after stimulation
 Random cortisol
 Incremental increase after stimulation
 Lower dose ACTH stimulation test
 Combinations of these criteria
 Steroids
Optional:
 Adrenocorticotropic hormone
(ACTH) stimulation test (250-µg)

Continue treatments only in

nonresponders (rise in
cortisol ≤9 µg/dl)

Grade E
Dexamethasone and
Cortisol Assay
 Steroids

Optional:
 Decrease steroid dose if septic
shock resolves.

Grade E
 Steroids

Optional:
 Taper corticosteroid dose at
end of therapy.

Grade E
 Immunologic and Hemodynamic Effects
of “Low-Dose” Hydrocortisone in Septic Shock

Figure 3, page 515, reproduced with permission from Keh D, Boehnke T, Weber-
Cartens S, et al. Immunologic and hemodynamic effects of “low dose” hydrocortisone
in septic shock. Am J Respir Crit Care Med 2003;167:512-520
 Steroids

Optional:
 Add fludrocortisone (50 µg orally
once a day) to this regimen.

Grade E
 ADRENALS AND SURVIVAL
FROM ENDOTOXEMIA

90 DEATH %
80
70
60
50
40
30
20
10
0
INTACT SHAM ADRNX MEDX
Adapted from Figure 7, page 437, with permission from Witek-Janusek L, Yelich MR.
Role of the adrenal cortex and medulla in the young rats’ glucoregulatory response
to endotoxin. Shock 1995; 3:434-439
 Steroids
 Do not use corticosteroids >300
mg/day of hydrocortisone to treat
septic shock.
Grade A

Bone, et al. NEJM 1987; 317-658

VA Systemic Sepsis Cooperative Study Group. NEJM 1987; 317:659-665
 Human Activated Protein C
Endogenous Regulator of Coagulation

Protein Protein C Activity

C (Inactive)
Protein
S
Blood Vessel
Blood Flow ⇒
Thrombin Protein C
Receptor
Thrombomodulin
 Results: 28-Day All-Cause Mortality
Primary analysis results
2-sided p-value 0.005
Adjusted relative risk reduction 19.4%
Increase in odds of survival 38.1%
35
30.8%
30 6.1% absolute
reduction in
25
24.7%
mortality
Mortality (%)

20

15 Placebo Drotrecogin
alfa
10 (n-840)
(activated)
(n=850)
5

0
Adapted from Table 4, page 704, with permission from Bernard GR, Vincent JL, Laterre PF, et al.
Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med
2001; 344:699-709
Patient Selection for rhAPC
 Full support patient
 Infection induced organ/system
dysfunction
 High risk of death
 No absolute contraindications
 Mortality and APACHE II Quartile

118:80
50
Placebo
45
Mortality (percent)

40 Drotrecogin
35
58:48
30
57:49
25
20
15
26:33
10
5
0
1st (3-19) 2nd (20-24) 3rd (25-29) 4th (30-53)
APACHE II Quartile
*Numbers above bars indicate total deaths
Adapted from Figure 2, page S90, with permission from Bernard GR. Drotrecogin alfa (activated)
(recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003;
31[Suppl.]:S85-S90
 Mortality and Numbers of Organs Failing
60

50
Percent 40
Mortality
30

20

Placebo 10
Drotrecogin
0
1 2 3 4 5
Number of Organs Failing at Entry
Adapted from Figure 4, page S91, with permission from Bernard GR. Drotrecogin alfa (activated)
(recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003;
31[Suppl.]:S85-S90
 Recombinant Human Activated
Protein C (rhAPC)
 High risk of death
 APACHE II ≥ 25
 Sepsis-induced multiple organ failure
 Septic shock
 Sepsis induced ARDS
 No absolute contraindications
 Weigh relative contraindications

Grade B
 Transfusion Strategy
in the Critically Ill

Figure 2A, page 414, reproduced with permission from Hebert PC, Wells G, Blajchman MA, et al. A multicenter,
randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340:409-417
 Blood Product Administration
Red Blood Cells
Tissue hypoperfusion resolved
No extenuating circumstances
 Coronary artery disease
 Acute hemorrhage
 Lactic acidosis
Transfuse < 7.0 g/dl to maintain 7.0-9.0 g/dL

Grade B
 Blood Product Administration

 Do not use erythropoietin to treat sepsis-

related anemia. Erythropoietin may be
used for other accepted reasons.

Grade B
Blood Product Administration

Fresh frozen plasma

• Bleeding
• Planned invasive procedures.

Grade E
Blood Product Administration

• Do not use antithrombin therapy.

Grade B

Warren et al. JAMA 2001; 1869-1878

Blood Product Administration
 Platelet administration
 Transfuse for < 5000/mm3 -
 Transfuse for 5000/mm3 – 30,000/mm3 with
significant bleeding risk
 Transfuse < 50,000/mm3 for invasive
procedures or bleeding

Grade E
Mechanical Ventilation of
Sepsis-Induced ALI/ARDS
 ARDSnet Mechanical Ventilation Protocol
Results: Mortality
40
35
30
25
% Mortality

6 ml/kg
20
12 ml/kg
15
10
5
0

Adapted from Figure 1, page 1306, with permission from The Acute Respiratory Distress
Syndrome Network. N Engl J Med 2000;342:1301-1378
 Peak Airway
Pressure

Inspiratory Plateau
Pressure
5 PEEP (5 cm
H2O

0
 Mechanical Ventilation of
Sepsis-Induced ALI/ARDS
 Reduce tidal volume over 1–2 hrs
to 6 ml/kg predicted body weight
 Maintain inspiratory plateau
pressure < 30 cm H20

Grade B
 Mechanical Ventilation of
Sepsis-Induced ALI/ARDS
 Minimum PEEP
 Prevent end expiratory lung
collapse
 Setting PEEP
 FIO2 requirement
 Thoracopulmonary compliance

Grade E
 The Role of Prone Positioning in ARDS
 70% of prone 100
patients improved 75

Survival (%)
oxygenation Supine group
50
 70% of response
25 Prone group
within 1 hour
P=0.65
 10-day mortality rate in 0
quartile with lowest 0 3 60 90 120 150 180
PaO2:FIO2 ratio (≤88) 0 Days
 Prone — 23.1% Kaplan-Meier
 Supine – 47.2% estimates of
survival at 6 months
Gattinoni L, et al. N Engl J Med 2001;345:568-73; Slutsky AS. N Engl J Med 2001;345:610-2.
The Role of Prone Positioning in ARDS

Consider prone positioning in ARDS when:

 Potentially injurious levels of F1O2 or
plateau pressure exist
 Not at high risk from positional changes

Grade E
 Mechanical Ventilation
of Severe Sepsis
 Semirecumbent position unless
contraindicated with head of the bed
raised to 45o
Grade C

Drakulovic et al. Lancet 1999; 354:1851-1858

 Mechanical Ventilation
of Septic Patients
 Use weaning protocol and a
spontaneous breathing trial (SBT),
at least daily
Grade A

Ely, et al. NEJM 1996; 335:1864-1869

Esteban, et al. AJRCCM 1997; 156:459-465
Esteban, et al. AJRCCM 1999; 159:512-518
 Mechanical Ventilation
of Septic Patients

SBT options
• Low level of pressure support
with continuous positive airway
pressure 5 cm H2O
• T-piece
 Prior to SBT
a) Arousable
b) Hemodynamically stable (without
vasopressor agents)
c) No new potentially serious conditions
d) Low ventilatory and end-expiratory
pressure requirements
• Requiring levels of FIO2 that could be
safely delivered with a face mask or nasal
cannula
Consider extubation if SBT is unsuccessful
 Sedation and Analgesia in Sepsis
 Sedation protocol for mechanically
ventilated patients with standardized
subjective sedation scale target.
• Intermittent bolus
• Continuous infusion with daily
awakening/retitration
Grade B

Kollef, et al. Chest 1998; 114:541-548

Brook, et al. CCM 1999; 27:2609-2615
Kress, et al. NEJM 2000; 342:1471-1477
 Neuromuscular Blockers
 Avoid if possible
 Used longer than 2-3 hrs
 PRN bolus
 Continuous infusion with twitch monitor

Grade E
 The Role of Intensive
Insulin Therapy in the Critically Ill
100

In-hospital survival (%)

96
Intensive treatment
92
At 12 months, intensive insulin P=0.01
therapy reduced mortality by 88
Conventional treatment
3.4% (P<0.04)
84

80
0
0 50 100 150 200 250
Days after admission

Adapted from Figure 1B, page 1363, with permission from van den Berghe G, Wouters P,
Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67
 Glucose Control
 After initial stabilization
 Glucose < 150 mg/dL
 Continuous infusion insulin and glucose
or feeding (enteral preferred)
 Monitoring
• Initially q30–60 mins
• After stabilization q4h
Grade D
 Renal Replacement
 Absence of hemodynamic instability
 Intermittent hemodialysis and
continuous venovenous filtration equal
(CVVH)
 Hemodynamic instability
 CVVH preferred

Grade B
 Bicarbonate Therapy
 Bicarbonate therapy not recommended to
improve hemodynamics in patients with
lactate induced pH >7.15

Grade C

Cooper, et al. Ann Intern Med 1990; 112:492-498

Mathieu, et al. CCM 1991; 19:1352-1356
 Changing pH Has Limited Value
Treatment Before After
NaHCO3 (2 mEq/kg)
pH 7.22 7.36
PAOP 15 17
Cardiac output 6.7 7.5
0.9% NaCl
pH 7.24 7.23
PAOP 14 17
Cardiac output 6.6 7.3

Cooper DJ, et al. Ann Intern Med 1990; 112:492-498

 Deep Vein Thrombosis Prophylaxis

Heparin (UH or LMWH)

Contraindication for heparin
 Mechanical device (unless contraindicated)
High risk patients
 Combination pharmacologic and mechanical

Grade A
 Primary Stress Ulcer Risk Factors
Frequently Present in Severe Sepsis

 Mechanical ventilation
 Coagulopathy
 Hypotension
 Choice of Agents for
Stress Ulcer Prophylaxis

 H2 receptor blockers
 Role of proton pump inhibitors

Grade C

Cook DJ, et al. Am J Med 1991; 91:519-527

 Consideration for
Limitation of Support
 Advance care planning, including the
communication of likely outcomes and
realistic goals of treatment, should be
discussed with patients and families.
Decisions for less aggressive support
or withdrawal of support may be in the
patient’s best interest.

Grade E
 Surviving Sepsis
Phase 1 Barcelona declaration
Phase 2 Evidence based guidelines
Paediatric issues
Phase 3 Implementation and
education
 Fluid Resuscitation
 Aggressive fluid resuscitation with boluses
of 20 ml/kg over 5-10 min
 Blood pressure by itself is not a reliable
endpoint for resuscitation
 Initial resuscitation usually requires 40-60
ml/kg, but more may be required
 Hemodynamic Support
 Hemodynamic profile may be variable
 Dopamine for hypotension
 Epinephrine or norepinephrine for dopamine-
refractory shock
 Dobutamine for low cardiac output state
 Inhaled NO useful in neonates with post-partum
pulmonary hypertension and sepsis
 Therapeutic Endpoints
 Capillary refill < 2 sec
 Warm extremities
 Urine output > 1 ml/kg/hr
 Normal mental status
 Decreased lactate
 Central venous O2 saturation > 70%
 Other Therapies
 Steroids: recommended for children with
catecholamine resistance and suspected or
proven adrenal insufficiency.
 Activated protein C not studied adequately in
children yet.
 GM-CSF shown to be of benefit in neonates
with sepsis and neutropenia.
 Extracorporeal membrane oxygenation
(ECMO) may be considered in children with
refractory shock or respiratory failure.
 Surviving Sepsis
Phase 1 Barcelona
declaration
Phase 2 Evidence based
guideline
Phase 3 Implementation
and education
Sepsis Resuscitation Bundle
 Serum lactate measured
 Blood cultures obtained prior to
antibiotic administration
 From the time of presentation, broad-
spectrum antibiotics administered
within 3 hours for ED admissions and
1 hour for non-ED ICU admissions
 Sepsis Resuscitation Bundle
 In the event of hypotension and/or
lactate >4 mmol/L (36 mg/dl):
 Deliver an initial minimum of 20 ml/kg of
crystalloid (or colloid equivalent*)
 Apply vasopressors for hypotension not
responding to initial fluid resuscitation to
maintain mean arterial pressure (MAP) ≥65
mm Hg
*See the individual chart measurement tool for an equivalency
chart.
 Sepsis Management Bundle
 Low-dose steroids* administered for
septic shock in accordance with a
standardized ICU policy
 Drotrecogin alfa (activated)
administered in accordance with a
standardized ICU policy
*See the individual chart measurement tool for an equivalency chart.
Sepsis Management Bundle
 Glucose control maintained ≥ lower limit
of normal, but < 150 mg/dl (8.3 mmol/L)
 Inspiratory plateau pressures maintained
< 30 cm H2O for mechanically ventilated
patients.
 Sepsis Resuscitation Bundle
 In the event of persistent hypotension
despite fluid resuscitation (septic
shock) and/or lactate > 4 mmol/L (36
mg/dl):
 Achieve central venous pressure (CVP) of
8 mm Hg
 Achieve central venous oxygen saturation
(ScvO2) of ≥ 70%**
**Achieving a mixed venous oxygen saturation (SvO2) of 65% is an
acceptable alternative.
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
Actual title of painting is “Hercules Kills
Cerberus,” by Renato Pettinato, 2001.
Painting hangs in Zuccaro Place in Agira,
Sicily, Italy. Used with permission of artist
and the Rubolotto family.
[Link]

♦♦♦

[Link]
 Acknowledgment

The SSC is grateful to R. Phillip

Dellinger, MD, for his input into
creation of this slide kit.