Rachel Hinerman, MD FCCP
Definitions
 Sepsis = suspected or proven infection and some of the
following:
 General Variables
 Inflammatory Variables
 Hemodynamic Variables
 Organ Dysfunction Variables
 Tissue Perfusion Variables
Sepsis Variables
General
Inflammatory
 Fever
 Leukocytosis
 Hypothermia
 Leukopenia
 Tachycardia
 Normal WBC with > 10 %
 Altered Mental Status
immature forms
 C-reactive protein > 2 SD
 Procalcitonin > 2 SD
 Edema
 Hyperglycemia
Sepsis Variables
Hemodynamic
Organ Dysfunction
 SBP <90
 P/F < 300
 MAP < 70
 UO < .5 ml/kg for 2 hours
 SBP decrease > 40
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Tissue Perfusion
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 Lactate > 1
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 Mottling
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 Decreased Capillary Refill
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despite volume resuscitation
Cr increase > .5
INR > 1.5
Ileus
Plt < 100 K
Bili > 4
Severe Sepsis Definition
 Sepsis induced organ dysfunction, hypoperfusion, or
hypotension
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Hypotension
Elevated Lactic Acid
Oliguria
ALI with P/F < 250 without pneumonia
ALI with P/F < 200 with pneumonia
Cr > 2
Bili > 2
Plt < 100K
INR > 1.5
Septic Shock
 Sepsis-induced hypotension that persists despite
adequate fluid resuscitation
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*All definitions cited from “Surviving Sepsis Campaign”
published in Critical Care Medicine Feb 2013
Spectrum Of Severity
Infection
Sepsis
Severe Sepsis Septic Shock
Dellinger, RP. et al. Crit Care Med 2004;32
A National Health Concern?
 Myocardial Infarction
 Incidence 900,000
 Deaths 225,000
 Mortality 25%
 Cerebrovascular Accident
 Incidence 700,000
 Deaths 163,5000
 Mortality 23%
 Trauma
 Incidence 2,900,000
 Deaths 42,643
 Mortality 1.5%
 Severe Sepsis
 Incidence 751,000
 Deaths 215,000
 Mortality 40-60%
Angus, DC. et al Crit Care Med 2000;29
National Highway Traffic Safety Commission, 2003
AHA- Heart Disease and Stroke Statistics, 2005 update
Deaths/Year
Relative Mortality
Angus DC et al. Crit Care Med 2001; 29. American Cancer Society
Karon et al. Am J Public Health 2001; 91. American Heart Assoc., 2001
Determinants of Mortality
 Source control is most vital factor
 Adequate resuscitation or re-established perfusion in 6
hours
 Appropriate antibiotic therapy within 1 hr of
hypotension
Interventions
 Early Goal Directed Therapy (EGDT)
 Anti-microbials
 Steroids
 Glucose Control
 Lung Protective Ventilation
Absolute Risk Reduction
%
Bernard et al. NEJM 2001; 344. Van den Berghe et al. NEJM 2001; 345. Rivers et al. NEJM 2001; 345
Annane et al. JAMA 2002; 288. ARDS-Net Investigators, NEJM; 2000
EGDT Resuscitation
 Begin at onset of hypotension or lactate >4
 Do not delay while awaiting ICU admission
 Initial bolus is 30 ml/kg crystalloid
Rivers E et al. N Engl J Med 2001; 345:1368–1377
EGDT
 Initial Resuscitation targets
 CVP 8-12 (12-15 if mechanically ventilated)
 Mean arterial pressure ≥65
 Urine output ≥ 0.5 ml/kg/hour
 Central venous oxygen saturation ≥ 65%
 If venous oxygen target still not achieved:

trial of fluid or transfuse PRBCs to HCT ≥30% and/or start
dobutamine infusion
Rivers, NEJM 2001;
345:1368
EGDT Outcomes
Rivers, E et al. N Engl J Med 2001; 345
EGDT Cost
 23% reduction in hospital cost
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Most cost effective if patient volume > 16 cases/year
 Mean reduction of 4 days per hospital admission
 Cost per life saved of approximately $32,336
 Reduction in hospital charges from $135,000 to $82,000
Treciak S et al. Chest 2006;129:225-232
Huang DT, et al Crit Care 2003;7:S116
Shapiro N, et al. Crit Care Med 2006;34:1025-1032
What to Use?
 SAFE study: 28 day outcomes
 RCT n=6997, 4% albumin or normal saline
 Albumin group, 726 deaths - Saline group, 729 deaths
 New organ failure was similar in the two groups
 No difference: ICU or hospital LOS, mechanical
ventilation days, or days of renal-replacement therapy
 Guideline: colloid or crystalloid may be used
Schierhout G et al. BMJ 1998; 316:961–964
Finfer S et al. N Engl J Med 2004; 350:2247–2256
EGDT
(and we mean EARLY)
 Retrospective analysis of 212 patients
 Diagnosis: septic shock and ALI within 72 hours
 Adequate initial fluid resuscitation (AIFR) group
 Administration of an initial fluid bolus of ≥ 20 mL/kg
prior to and achievement of a central venous pressure of
≥ 8 mm Hg within 6 h after the onset of therapy with a
vasopressor
 Conservative late fluid management (CLFM)
 Even-to-negative fluid balance measured on at least 2
consecutive days during the first 7 days after septic
shock onset
Murphy C V et al. Chest 2009;136:102-109
Mean daily fluid balance days 1 through 7
NONSURVIVORS
SURVIVORS
Murphy C V et al. Chest 2009;136:102-109
Hospital mortality for AIFR, CLFM, both, or neither
77%
57%
42%
18%
Murphy CV et al. Chest 2009; 136:102-109
EGDT & Intubation
 No difference: P/F ratio at 6h;
EGDT with higher P/F at 72h
 No difference in intubation rates at 6 hours
 7-72 hour intubation rate: EGDT 2% vs. standard 16.8%
Rivers, E et al. N Engl J Med 2001; 345
Otero R, et al. Chest 2006;130:1579-1595
Vasopressors
 Mean arterial pressure (MAP) maintained ≥ 65
 First choice: norepinephrine or epinephrine
 Vasopressin 0.03 units/min may be added
Vasopressin
 VASST Trial
 Hypothesis: VP will increase survival compared to NE at
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28d
779 patients in septic shock requiring vasopressors for
≥6 hours
Randomization to vasopressin or norepinephrine
No difference in 28-day survival (35.4% v 39.3%, P =.27).
When groups were stratified by severity of hypotension
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Low-dose NE improved survival with VP 26% v 35%, P .05
Result persisted at 90 days: mortality of 36% vs. 46 %, P =.04
Russell J et al. NEJM2008;358,9.
Inotropes
 Dobutamine infusion for suspected myocardial
dysfunction suggested by elevated cardiac filling
pressures and low cardiac output
 Recommend against a strategy to increase cardiac
index to supranormal levels
Gattinoni L, et al. New Engl J Med 1995; 333:1025-32
Hayes MA, et al. New Engl J Med 1994; 330:1717-22
Interventions
 Early Goal Directed Therapy (EGDT)
 Anti-microbials
 Steroids
 Glucose Control
Antimicrobials
 Begin therapy within the first hour of recognizing
severe sepsis or septic shock
 Broad spectrum: one or more agents against likely
bacterial or fungal pathogens
 Consider combination therapy for potentially resistant
gram negative pathogens
 Consider combination therapy in neutropenic patients
 Narrow coverage when culture data available
Garnacho-Montero J et al. CCM2007;25:1888-1895
Antimicrobials
 Study objective: to determine the impact of initial
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antimicrobial therapy on survival in patients with
septic shock
Data: 5,715 cases between 1996 and 2005
Community-acquired = 55%; nosocomial origin = 45%
Appropriate empiric antimicrobial therapy = 80%
Overall rate of survival to hospital discharge = 43%
The survival rates:
 Appropriate initial therapy 52%
 Inappropriate initial therapy 10%
Kumar A et al. Chest 2009;136:1237-1248
Interventions
 Early Goal Directed Therapy (EGDT)
 Anti-microbials
 Steroids
 Glucose Control
2012 Steroid Guidelines
 The ACTH stimulation test should not be used to
identify the subset of adults with septic shock who
should receive hydrocortisone.
 Do not use corticosteroids in the treatment of sepsis in
the absence of shock.
 Corticosteroid therapy may be weaned when
vasopressors are no longer required.
 Recommended: hydrocortisone 50 mg iv q 6 hours
Dellinger RP, et al Crit Care Med 2008;36:296-327
Interventions
 Early Goal Directed Therapy (EGDT)
 Anti-microbials
 Steroids
 Glucose Control
Glucose Controversy
 Leuven protocol: 80-110
 Cardiac-surgical ICU
 Reduced ICU LOS
 Less organ dysfunction
 Hypoglycemia 6.2%
 Decreased Mortality
 3.4% ARR all patients
 9.4% ARR LOS >5 days
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Leuven protocol: 80-110
Medical ICU
Reduced ICU LOS
Less ventilator days
Less acute renal injury
Hypoglycemia 18%
Mortality difference
 Overall: no difference
 LOS > 3 days: ↓ mortality
Van den Berghe G, et al. NEJM 2006; 354:449-461
Van den Berghe G, et al. NEJM 2001;345:1359-1367
NICE-SUGAR
 RCT open-label comparing intensive BS 80-110 vs..
conventional BS <180
 6,104 ICU heterogeneous patients
 Primary end point: 90-day mortality
 Secondary end points:
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Hypoglycemia
Infection
Need for organ support
Intensive care unit and hospital length of stay
The NICE-SUGAR Study Investigators NEJM 2008; Volume 360:1283-1297
2012 Glucose Control
Guidelines
 Patients with severe sepsis and hyperglycemia in the
ICU should receive intravenous insulin.
 Use validated protocol for insulin dose adjustment
with a target glucose <180.
 All patients on intravenous insulin receive a glucose
calorie source.
Dellinger RP, et al Crit Care Med 2008;36:296-327
Resuscitation “Bundles”
 Severe Sepsis 3 Hour Bundle
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Recognition
Fluid Resuscitation
Antimicrobial Therapy
Oxygen Delivery
 Severe Sepsis 6 Hour Bundle
 Low-dose Steroids
 Glucose Control
 Lung Protective Ventilation
NYS Sepsis Initiative
 Hospitals shall have in place evidence-based protocols
for the early recognition and treatment of severe sepsis
and septic shock.
 Hospitals shall have a process for screening all adult
and pediatric patients for sepsis, severe sepsis, and
septic shock in the ED and hospital.
 Quality measures will be collected and reported.