The Treatment of Sepsis:

Early Goal Directed Therapy

and Beyond
Anthony J. Hericks, D.O.
South Dakota
ACP
Scientific Meeting
September 13th, 2013

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

Surviving Sepsis Campaign

Sponsoring Organizations
American Association of Critical-Care
Nurses
American College of Chest Physicians
American College of Emergency Physicians
Australian and New Zealand Intensive Care
Society
Asia Pacific Association of Critical Care
Medicine
American Thoracic Society
Brazilian Society of Critical Care(AIMB)
Canadian Critical Care Society
Emirates Intensive Care Society
European Respiratory Society
European Society of Clinical Microbiology
and Infectious Diseases
European Society of Intensive Care
Medicine
European Society of Pediatric and Neonatal
Intensive Care

Infectious Diseases Society of America

Indian Society of Critical Care Medicine
Japanese Association for Acute Medicine
Japanese Society of Intensive Care
Medicine
Latin American Sepsis Institute
Pan Arab Critical Care Medicine Society
Pediatric Acute Lung Injury and Sepsis
Investigators
Society for Academic Emergency Medicine
Society of Critical Care Medicine
Society of Hospital Medicine
Surgical Infection Society
World Federation of Critical Care Nurses
World Federation of Societies of Intensive
and Critical Care Medicine
German Sepsis Society

Surviving Sepsis Campaign (SSC)

Guidelines for Management of Severe
Sepsis and Septic Shock
Dellinger RP, et al. Surviving Sepsis Campaign guidelines for
management of severe sepsis and septic shock. Crit Care Med
2004, 32:858-873.
Dellinger RP, et al. Surviving Sepsis Campaign: International
guidelines for management of severe sepsis and septic shock:
2008 Crit Care Med 2008, 36:296-327.
Levy MM, et al. Surviving Sepsis Campaign: Results of an
international guidelines performance improvement program
targeting severe sepsis. Crit Care Med 2010,
38:367-374.
Dellinger RP, et al. Surviving Sepsis Campaign: International
Guidelines for Management of Severe Sepsis and Septic
Shock:
2012. Crit Care Med 2013, 41(2):580-637.
Angus DC, et al. Severe Sepsis and Septic Shock. NEJM 2013;
369(9): 840-851

Surviving Sepsis Campaign

Conclusions
Strong agreement among a large cohort of
international experts
Many level 1 recommendations
Significant number of recommendations
with relatively weak recommendations
Evidence-based recommendations are the
foundation of improved outcomes

Dellinger RP, CCM 2013

Grading of Recommendations
(Grading of Recommendations Assessment, Develop and Evaluation GRADE)

A 82 year old white female present to the emergency

department with complaints of dysuria, frequency and
urgency. Her temperature is 100.4 F, HR 92, RR 21 and
BP 122/86. What should she be classified as?
1.
2.
3.
4.
5.

Systemic Inflammatory
Response Syndrome
Sepsis
Severe Sepsis
Septic Shock
Multi-Organ
Dysfunction/Failure
Syndrome

A 82 year old white female present to the emergency

department with complaints of dysuria, frequency and
urgency. Her temperature is 100.4 F, HR 92, RR 21 and
BP 122/86. What should she be classified as?
1.
2.
3.
4.
5.

Systemic Inflammatory
Response Syndrome
Sepsis
Severe Sepsis
Septic Shock
Multi-Organ
Dysfunction/Failure
Syndrome

Identification of Sepsis: Definitions

Systemic Inflammatory Response (SIRS)
Sepsis
Severe Sepsis
Septic Shock
Multi-Organ Failure Syndrome (MOFS)
Death

SIRS
Heart Rate > 90
Respiratory Rate > 20
WBC > 12K or < 4K
Temp > 38 C (100.4 F) or < 36 C (96.8 F)
Any two of the above
Very nonspecific

Sepsis
SIRS + signs of a suspected or known
infection
WBCs in normally sterile fluid
Infiltrate on chest x-ray
Bacteria in normally sterile fluid

Diagnostic
Criteria
for
Sepsis

Severe Sepsis
Sepsis + sepsis-induced tissue
hypoperfusion or organ dysfunction

Sepsis Induced Hypotension

SBP < 90 mmHg
OR
MAP < 70 mmHg
OR
SBP > 40 mmHg < 2 SD below the nml for
age

Septic Shock
Severe Sepsis or sepsis-induced
hypoperfusion persistent despite:
Adequate/initial fluid challenge/resuscitation
Lactate > 4 mmol
Addition of pressors

Sepsis-induced hypoperfusion = infection-

induced hypotension, elevated lactate or

oliguria

MOFS
Altered organ function, involving two or
more organs, in an acutely ill patient
requiring medical intervention to achieve
homeostasis

Death
The permanent the cessation of all vital
functions in an individual who has
sustained either (1) irreversible cessation
of circulatory and respiratory functions, or
(2) irreversible cessation of all functions of
the entire brain, including the brain stem
Severe Sepsis/Septic Shock mortality =
~30-46%

Consideration for Limitation of

Support
We recommend that the goals of care
and prognosis be discussed with patients
and families and these be incorporated
into the patients treatment along with endof-life care planning and utilizing palliative
Grade 1B
care principles.
Re-address goals as earlier as feasible, but
no later than 72 hours of admit Grade 2C

Incidence of Severe Sepsis

Estimated to be:
2% of all patients admitted to the hospital
10% of all patients in the ICU
< 750,000 cases per year and rising
Mortality rate of 20-30%

NEJM 369(9): 840-851

Pathophysiology of Sepsis

Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular
management of septic shock. Crit Care Med 2003;31:946-955.

Based on Dr. Rivers article re: Early Goal Directed Therapy,

what is the ultimate goal in the first 6 hours?

1.

2.
3.
4.
5.

CVP of 8-12
unventilated/12-15
ventilated
MAP >65
Cardiac Output > 8 LPM
Hemoglobin > 10 gm/dL
ScvO2 > 70%

Based on Dr. Rivers article re: Early Goal Directed Therapy,

what is the ultimate goal in the first 6 hours?

1.

2.
3.
4.
5.

CVP of 8-12
unventilated/12-15
ventilated
MAP >65
Cardiac Output > 8 LPM
Hemoglobin > 10 gm/dL
ScvO2 > 70%

Initial Resuscitation:
Goals of Early Goal Directed Therapy
CVP 8-12 cmH2O
12-15 cmH2O on the ventilator
MAP > 65 mmHg
May need to be higher in patients with HTN
UOP > 0.5 mL/Kg /hour
ScvO2 > 70%

Grade 1C

SvO2 > 65%

Goal: Normalize lactate Grade 2C
Goal in the first 6 hours after diagnosis

16-17% decrease in mortality

Rivers E. N Engl J Med 2001; 345:1368-77

Central Venous Pressure

Crystalloid or Colloid?
Volume?
Goal?

Crystalloid or Colloid
SAFE Study
Crystalloid (NS) = Colloid
(4% Albumin)
Less volume, more
PRBCs, higher CVP and
Albumin

No difference in mortality
(p = 0.87)
Trend for increased risk of
death in Trauma (0.06)
Trend for decreased risk
of death in Severe Sepsis
(0.09)

Grade 1B

Finfer S. N Engl J Med 2004; 350:22472256

SSC Recommendations
Crystalloids

Albumin

Grade 1B

Grade 2C

If substantial fluid is required

Hydroxyethyl Starch (HES)

Increased risk of acute kidney injury and
death in sepsis
Variable findings depending on studies
Schortgen G. Lancet 2001; 357:911-916.
Sakr Y. Br J Anaesth 2007; 98:216-224.
Brunkhorst FM. N Engl J Med 2008; 358: 125139.
Perner A. N Engl J Med 2012; 367:124-134.

Risk and no benefit, HES should not be

used!!!
Grade 1B

Fluid Volume
30 mL/Kg crystalloid

Grade 1C

A portion may be an albumin equivalent

More rapid administration or larger amounts
may be needed

Continue fluid administration as long as

there appears to be hemodynamic
improvement Grade UG

Volume Responsiveness
CVP > 8 cmH2O

Grade 1C

> 12 cmH2O on the vent

Swan-Ganz Catheter
PCWP
Cardiac output

Non-invasive Monitors
PiCCO Catheter
FloTrac
Pulse Pressure Variation

IVC via Echo

MAP and Heart Rate
Grade 1D

CVP
Spontaneous Breathing > 8 cmH2O
Ventilatory Breathing > 12 cmH2O
Primarily based on expert opinion
Dellinger RP. Crit Care Med 2004; 32:858873
Rivers E. N Engl J Med 2001; 345:13681377
Practice parameters for hemodynamic support of
sepsis in adult patients with sepsis. Crit Care Med
1999; 27:639660

Pulmonary Capillary Wedge Pressure

PCWP < 12 mmHg predicts a fluid bolus
with increase cardiac output with a PPV of
only 54%
However the Gold Standard for volume
responsiveness may be a increase in
cardiac output of > 15% after a fluid
challenge
Osman D. Crit Care Med 2007; 35:6468

Non-invasive Monitoring

PPV
PPV
PPV
CVP
PCWP

Echocardiography

Does volume overload contribute to morbidity and

mortality?

1. True
2. False

Does volume overload contribute to

morbidity and mortality?
1. True
2. False

Avoid Volume Overload

Tolerated as long as volume responsive
Fluid challenges usually required for the initial
24-48 hours
Finfer S. N Engl J Med 2004; 350:22472256

Decrease the rate when no longer volume

responsive

Grade 1D

Volume Overload, Contd

Independent predictor of mortality
Boyd JH. Crit Care Med 2011; 39(2):259-265
Vincent JL. Crit Care Med 2006; 34:344353
Uchino S. Crit Care Med 2006; 10:R174

Prolonged mechanical ventilation

Upadya A. Intensive Care Med 2005; 31:16431647

ARDS

Humphrey H. Chest 1990; 97:11761180

Simmons RS. Am Rev Respir Dis 1987; 135:924929
Mitchell JP. Am Rev Respir Dis 1992; 145:990998
Wiedemann HP. N Engl J Med 2006; 354:25642575

Sepsis
Alsous F. Chest 2000; 117:17491754
Rivers E. N Engl J Med 2001; 345:13681377

Abdominal compartment syndrome

Malbrain ML. Crit Care Med 2005; 33:315322
McNelis J. Arch Surg 2002;137:133136

Cerebral edema and herniation

Uchino S. Crit Care 2006; 10:R174

MAP

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 g)

6.0 +1.6

5.8 +11

5.3 +0.9

.59/.55

0.42 +0.06

0.44 +016

0.42 +0.06

.74/.97

Pico2 (mm Hg)

41 +2

47 +2

46 +2

.11/.12

Pa-Pico2 (mm Hg)

13 +3

17 +3

16 +3

.27/.40

Red Cell
Velocity (au)

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

Grade 1C

What is the pressor of choice for a patient in

septic shock?
1. Dopamine
2. Norepinephrine

(Levophed)
3. Vasopressin
4. Phenylephrine
(Neosynephrine)
5. All the above

What is the pressor of choice for a patient in

septic shock?
1. Dopamine
2. Norepinephrine

(Levophed)
3. Vasopressin
4. Phenylephrine
(Neosynephrine)
5. All the above

Vasopressors
Norepinephrine
Dopamine
Vasopressin
Epinephrine
Phenylephrine

Norepinephrine vs Dopamine
No significant difference in mortality (p = 0.10)
Trend for less death in the ICU (p = 0.07)
No difference at hospital discharge or 1 yr

Increased rate of adverse events with Dopamine

Arrhythmias (p = < 0.001)
Atrial Fibrillation
Ventricular Tachycardia
Ventricular Fibrillation

Skin Ischemia (trend; p = 0.09)

DeBacker D. N Engl J Med 2010; 362:779-789

Norepinephrine vs Dopamine,
Contd
Norepinephrine should be the first line
Grade 1B
vasopressor
Dopamine is an alternative to
Norepinephrine
Only in highly selected patients with low risk
of:
Tachyarrhythmias
Absolute or relative bradycardia
Grade 2C

Vasopressin
Adding Vasopressin to Norepinephrine
showed no mortality benefit compared to
Norepinephrine alone (p = 0.26)
Did lower Norepinephrine requirements
May have other potential physiologic benefits

Should not be used as a single agent

Grade UG

Russel JA. N Engl J Med 2008; 358:877-887

Epinephrine
First line in pts poorly responsive to
Norepinephrine and Dopamine
No evidence of worse outcomes
Increased risk of:
Tachycardia
Elevated lactate
Decreased splanchnic circulation

Add to or instead of Norepinephrine

Grade 2B

Phenylephrine
Not recommended!!!
Except:
Norepinephrine induced arrhythmias
Cardiac output is high
Persistently low BP
Salvage therapy

Decreases cardiac output

Grade 1C

Hemodynamic Equations
DaO2 = CO x Hgb x SaO2
Oxygen delivery

VO2 = CO x Hgb x (SaO2 - SvO2)

Oxygen consumption

O2 ER= VO2/DaO2
Oxygen extraction ratio
~ 0.2 to 0.3

VO2 > DaO2 OR

DaO2 < VO2 = Dysoxia
Dysoxia = lactic acidosis = organ failure = death

Venous Oxygen Saturation

Physiology

Adapted from:
http://ht.edwards.com/resourcegallery/products/swanganz/pdfs/svo2edbook.pdf

ScvO2/SvO2 Goal
> 70%/65% respectively
Normal or shunt physiology

< 70%/65% respectively

Transfuse to a Hgb > 10
OR
Start Dobutamine
No specific cardiac output/index
Grade 1C

ScvO2 = subclavian vein

SvO = pulmonary artery

Ionotropic Therapy
Dobutamine:
Max dose 20 mcg/Kg/min
Titrate to NO pre-defined CO
Grade 1B

Used in states with:

Elevated cardiac filling pressures
Low cardiac output
ScvO2 < 70% OR SvO2 < 65%
Grade 1C

RBC Transfusion Therapy

Only if the Hgb < 10 with EGDT
Only if the Hgb < 7.0 g/dL in other ICU
patients
Grade 1B

Target 7 to 9 g/dL
Consider earlier for myocardial
ischemia/ischemic coronary disease, severe
hypoxemia, acute hemorrhage, cyanotic heart
disease or lactic acidosis

No EPO

Grade 1B
Napolitano LM. Crit Care Med 2009; 37(12): 3124-3157

FFP Transfusion Therapy

No FFP to reverse coagulopathy in the
absence of bleeding or invasive
procedures
Grade 2D

No high-dose Antithrombin
Studies had revealed that a subgroup with
severe sepsis and high risk of death = better
survival
Grade 1B

Platelet Transfusion Therapy

< 10,000 prophylactically in absence of
bleeding
< 20,000 - significant risk of bleeding
> 50,000 active bleeding, surgery or
invasive procedures
Grade 2D

Other Investigation Therapy

Immunoglobulins
No use
Grade 2B

Selenium
Antioxidant
No use
Grade 2C

Diagnostic Testing
Lactate level
Within 3 hours

Cultures
Prior to antibiotic administration

Grade 1D

Do not delay resuscitation for antibiotic administration

> 50% of cases of severe sepsis and septic shock will be
culture negative

Minimum 2 blood cultures

One peripheral and one from each vascular access device

Imaging
If not too unstable
Grade 1C

Diagnostic Testing, Contd

Serologies:

Strep pneumo and Legionella Urine Ag

Mycoplasma IgM
1,3 B-D-glucan Grade 2B
Mannan and anti-mannan Abs

Procalcitonin
Use low levels to assist with Abx D/C

Grade 2C

Antibiotic Therapy
IV route within the 1st hour
Septic Shock Grade 1B
Severe Sepsis Grade 1C
One or more drugs with activity against the likely
pathogens Grade 1B
Double cover if MDR pathogens Grade 2B
Combo therapy for neutropenic fever Grade 2B
Beta-lactam and macrolide for Strep pneumonia
Grade 2B

ABX, Contd
Reassess routinely

Grade 1B

De-escalate after >3-5 days

Grade 2B

Duration of treatment ~7-10 days

Grade 2C

Stop therapy if the syndrome is not

infectious Grade 1D

Source Control
Seek, diagnose or exclude potential anatomical
infections and treat expectantly
Within the first 12 hrs

Grade 1C

Delay definitive treatment of peripancreatic

necrosis until demarcation of tissue has
occurred Grade 2B
Attempt percutaneous over surgical intervention
if possible Grade UG
Remove vascular access suspected after other
access has been placed Grade UG

Corticosteroids
Hydrocortisone
200 mg/day
Only with persistent hypotension/poorly
responsive to vasopressor therapy Grade 2C
Consider a continuous infusion Grade 2D
Do not do an ACTH stimulation test Grade 2B

No Dexamethasone Grade 2B
Fludrocortisone if other steroid than HCT
Wean steroids when off pressors Grade 2D

Grade 2C

Corticosteroids, Contd
Annane D. JAMA 2002; 288:862871
Cosyntropin Stim Test delta < 9 = non-responders
10% decrease in mortality if treated with steroids
17% decrease in pressor requirements

Sprung CL. N Engl J Med 2008; 358:111-124

No significant difference in mortality
Shock was reversed more quickly
More episodes of superinfection, including new sepsis
and septic shock but not statistically significant

CIRCI
(Critical Illness Related Corticosteroid Insufficiency)

Marik PE. Crit Care Med 2008 Vol. 36 (6): 1937-1949

CIRCI, Contd

Recombinant Human Activated Protein C

(Xigris)
Withdrawn from the market 2011
No benefit

Mechanical Ventilation
Target tidal volume = 6 mL/Kg Grade 1A
Plateau pressure goal < 30 cmH2O Grade 1B
Allow permissive hypercapnia Grade 1C
Use PEEP to decrease FiO2 Grade 1B
Higher PEEP vs lower

Grade 2C

Recruitment maneuvers Grade 2C

ARDS
ARMA Trial
The Acute Respiratory Distress Syndrome
Network. N Engl J Med 2000;342:1301-08.

Alveoli Trial
Brower RG. N Engl J Med 2004;351:327-36

Mechanical Ventilation, Contd

Consider prone positioning
P:F ration <100

Grade 2C

HOB elevated

Grade 1B

Goal > 30-45

Grade 1B

NIPPV considered in mild ALI/ARDS

Low threshold for intubation

Grade 2B

Mechanical Ventilation, Contd

Weaning protocols Grade 1A
Selective Oral/Digestive Decontamination
Oral chlorhexidine gluconate
Decreases VAP

Grade 2B

Avoid pulmonary artery catheters Grade 1A

Conservative fluid management (FACTT)
Wiedemann et al. N Engl J Med 2006;
354:2564-2575. Grade 1C

Beta-Agonists
No recommended for routine use

Grade 1B

Nebulized (Ok if concern for bronchospasm)

Trend for less vent days
Slightly faster heart rates at day #2
Trend for increased mortality

Intravenous (Salbutamol)
Increased mortality

Sedation, Analgesia and NMB

Use Sedation protocol

Grade 1B

Minimize intermittent and continuous

treatments

Use Sedation scales

Avoid NMB

Grade 1B

Grade 1C

Without ARDS
With ARDS (Sepsis-induced and P:F <150)
< 48 hours

Grade 2C

Glucose Control
Use intravenous insulin to control blood
sugars Grade 2C
If 2 consecutive BSs > 180

Goal < 180

Grade 1B

Grade ? 1A

? Target range 110-180 mg/dL

Avoid hypoglycemia

Renal Replacement Therapy

CRRT and Intermittent HD are equivalents
Grade 2B

CRRT should be used if hemodynamically

unstable
Grade 2D

Bicarbonate Therapy
Avoid NaHCO3 in patients with a pH > 7.15
and lactic acidemia for the purpose of
improving hemodynamics or to reduce
vasopressor requirements
Grade 2B

Thromboembolism Prophylaxis
LMWH daily vs Low dose UFH BID
LMWH daily vs Low dose UFH TID

Grade 1B
Grade 2C

Dalteparin if creat clearance < 30 mL/min

LMWH

Grade 2C

or UFH

Grade 1A

Grade 1A

Mechanical prophylaxis if
contraindications to heparin
products
Grade 2C

Combo therapy in patients who are high risk

Severe sepsis, history of DVT, or orthopedic surgery
Grade 2C

Stress Ulcer Prophylaxis

If risk of bleeding
H2 blocker
Grade 1B

Proton Pump Inhibitor

Grade 1B

PPI over H2

Grade 2C

No risk of bleeding = no PPI

Grade 2B

Nutrition
Oral or enteral nutrition in the 1 st 48 hrs vs
complete fasting or just glucose Grade 2C
Avoid full caloric feeding for the 1 st full
week Grade 2B
Low dose feeding up to 500 Kcal/day and
advance as tolerated (60-70%)

IV glucose and EN vs TPN alone or TPN

and EN in the 1st week Grade 2B
No specific immunomodulating form Grade 2C

Surviving Sepsis Bundles

Bundles
Point/Counterpoint Editorials
Are the best patient outcomes achieved when
ICU bundles are rigorously adhered to?
Pros: Dr. Delinger
Not perfect/have flaws, but are based on the best
available evidence.

Cons: Dr. Marik

Not completely evidence based and cook book
medicine can harm the patient.

CHEST 2013; 144(2):372-380

Is there byass/conflict of interest when it comes to the

Surviving Sepsis Campaign Guidelines and Early Goal
Directed Therapy?

1. Yes
2. No

Is there byass/conflict of interest when it comes to the

Surviving Sepsis Campaign Guidelines and Early Goal
Directed Therapy?

1. Yes
2. No

Benefits of the
Surviving Sepsis Campaign
Surviving Sepsis Campaign Improvement
Program
Resuscitation Bundle - First 6 hours
Compliance increase linearly from 10.9% to 31.3% over two
years ( p = 0.0001)

Management Bundle - First 24 hours

Compliance increase linearly from 18.4% to 36.1% over two
years ( p = 0.008)

Unadjusted odds ratio for hospital mortality decreased

from 37% to 30.8% over two years (p = 0.001)

THE END
?? QUESTIONS ??