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
– WBC’s 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 end-of-life
care planning and utilizing palliative care
principles.” Grade 1B
– 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%
– SvO2 > 65%
Grade 1C
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
PRBC’s, 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; 350:2247–2256
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: 125-139.
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; 32:858–873
– Rivers E. N Engl J Med 2001; 345:1368–1377
– Practice parameters for hemodynamic support of
sepsis in adult patients with sepsis. Crit Care Med
1999; 27:639–660
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; 35:64–68
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; 350:2247–2256
Decrease the rate when no longer volume
responsive
Grade 1D
Volume Overload, Cont’d
Independent predictor of mortality
– Boyd JH. Crit Care Med 2011; 39(2):259-265
– Vincent JL. Crit Care Med 2006; 34:344–353
– Uchino S. Crit Care Med 2006; 10:R174
Prolonged mechanical ventilation
– Upadya A. Intensive Care Med 2005; 31:1643–1647
ARDS
–
–
–
–
Humphrey H. Chest 1990; 97:1176–1180
Simmons RS. Am Rev Respir Dis 1987; 135:924–929
Mitchell JP. Am Rev Respir Dis 1992; 145:990–998
Wiedemann HP. N Engl J Med 2006; 354:2564–2575
Sepsis
– Alsous F. Chest 2000; 117:1749–1754
– Rivers E. N Engl J Med 2001; 345:1368–1377
Abdominal compartment syndrome
– Malbrain ML. Crit Care Med 2005; 33:315–322
– McNelis J. Arch Surg 2002;137:133–136
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,
Cont’d
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
SvO2 = 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, Cont’d
Serologies:
–
–
–
–
Strep pneumo and Legionella Urine Ag
Mycoplasma IgM
1,3 B-D-glucan Grade 2B
Mannan and anti-mannan Ab’s
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, Cont’d
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, Cont’d
Annane D. JAMA 2002; 288:862–871
– 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, Cont’d
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, Cont’d
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, Cont’d
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 BS’s > 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 1st 48 hrs vs
complete fasting or just glucose Grade 2C
Avoid full caloric feeding for the 1st 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 ??