This lecture details the science of sepsis care in 2015 with compliments to the multiple online sources used, some of which are other lectures on SlideShare.

1. Brian Wells, MD, MS, MPH

2. Inflammatory states resulting from a systemic
response to bacterial infection
In severe sepsis and septic shock, there is
critical reduction in tissue perfusion leading to
acute failure of one or more organs
Common causes in immunocompetent patients
are a variety of gram-positive and gram-
negative bacteria
Immunocompromised patients may have
uncommon bacterial or fungal species

3. Continuum of severity
Established criteria for each

4. SIRS is a constellation of symptoms of system
inflammation that may or may not be the result
of infection (ex: acute pancreatitis or trauma)
Temperature >38 or <36
Heart rate >90 beats/minute
Respiratory rate >20 breaths/minute or PaCO2 <32
mmHg
WBC >12,000 cells/uL or <4,000 cells/uL or >10%
immature forms (bands)
>= 2 of the above meets SIRS criteria

5. Bottom Line
≥2 SIRS Criteria
Lacks Sensitivity
& Specificity for
Sepsis

6. SIRS + Source of Infection

7. Sepsis + organ dysfunction, hypotension, or
hypoperfusion
Evidenced by
Lactic acidosis
SBP <90 or DBP drop >= 40 mmHg of normal
Cardiovascular failure is typically manifested by
hypotension
Respiratory failure by hypoxemia
Renal failure by oliguria and/or azotemia
Hematolotic failure by coagulopathy

8. Sepsis with refractory hypotension and
impaired organ function despite adequate fluid
resuscitation

9. Systemic Inflammatory Response
Syndrome
• Temp < 36 ° C or > 38.3 ° C
• HR > 90
• RR > 20 or PCO2 < 32
• WBC < 4K or > 12K or bands > 10%
SepsisSepsisSIRSSIRS Severe SepsisSevere Sepsis Septic ShockSeptic Shock
SIRS with
Infection
Sepsis plus Organ Dysfunction
• Elevated Creatinine (>2)
• Elevated INR (DIC)
• Altered Mental Status (GCS <12)
• Elevated Lactate (>4)
• Hypotension that responds to fluid
Severe Sepsis and Hypotension
• Hypotension that does NOT
respond to fluid (500 cc bolus)
Bone et al. Chest 1992;101:1644

10. A 70-year-old man presents to the emergency department with a 2-day
history of fever, chills, cough, and right-sided pleuritic chest pain. On the day
of admission, the patient’s family noted that he was more lethargic and dizzy
and was falling frequently. The patient’s vital signs are:
Temperature, 101.5°F; heart rate 120 bpm; respiratory rate, 30 breaths/min;
blood pressure 70/35 mm Hg; and oxygen saturation as measured by pulse
oximetry, 80% without oxygen supplementation.
A chest radiograph shows a right lower lobe infiltrate.
This patient’s condition can best be defined as
which of the following?
(A) Multi-organ dysfunction syndrome (MODS)
(B) Sepsis
(C) Septic shock
(D) Severe sepsis
(E) Systemic inflammatory response syndrome
(SIRS)

11. (D) Severe sepsis. The patient fulfills criteria for severe sepsis,
defined as sepsis with evidence of organ dysfunction,
hypoperfusion, or hypotension.
SIRS is defined as an inflammatory response to insult manifested
by 2 of the following: temperature greater than 38°C (100.4°F)
or less than 36°C (96.8°F), heart rate greater than 90 bpm,
respiratory rate greater than 20 breaths/min, and white blood
cell count greater that 12 × 103/μL, less than 4 × 103/μL, or 10%
bands.
A diagnosis of sepsis is given if infection is present in addition to
meeting criteria for SIRS. Septic shock includes sepsis-induced
hypotension (despite fluid resuscitation) along with evidence of
hypoperfusion. MODS is the presence of altered organ function
such that hemostasis cannot be maintained without
intervention.
This patient’s lack of fluid resuscitation classifies him as having
severe sepsis rather than septic shock.

12. At any given moment, approximately 50 percent
of ICU patients have a nosocomial infection and,
therefore, are at high risk for sepsis
Bacteremia –In a study of 270 blood cultures, 95
percent of positive blood cultures were
associated with sepsis, severe sepsis, or septic
shock
Advanced age (≥65 years) – Increased in older
adult patients and age is an independent
predictor of mortality due to sepsis

13. Immunosuppression – Comorbidities that depress host-defense
(eg, neoplasms, renal failure, hepatic failure, AIDS, asplenism)
and immunosuppressant medications are common among
patients with sepsis, severe sepsis, or septic shock
Diabetes and cancer – Diabetes and some cancers may alter the
immune system, result in an elevated risk for developing sepsis,
and increase the risk of nosocomial sepsis.
Community acquired pneumonia – Severe sepsis and septic
shock develop in approximately 48 and 5 percent, respectively,
of patients with community-acquired pneumonia
Genetic factors – Both experimental and clinical studies have
confirmed that genetic factors can increase the risk of infection

14. The contribution of various infectious organisms
to the burden of sepsis has changed over time
Gram positive bacteria are most frequently
identified in patients with sepsis in the United
States, although the number of cases of Gram
negative sepsis remains substantial.
The incidence of fungal sepsis has increased
over the past decade, but remains lower than
bacterial sepsis

15. The incidence and severity of sepsis appear to be
increasing, with Gram positive bacteria being the
pathogens that are most commonly isolated from
patients with sepsis.
Mortality due to sepsis is high, but appears to have
decreased.
Poor prognostic factors include the inability to mount a
fever, leukopenia, age >40 years, certain comorbidities
(eg, AIDS, hepatic failure, cirrhosis, cancer, alcohol
dependence, immunosuppression), a non-urinary
source of infection, a nosocomial source of infection,
and inappropriate antibiotic coverage.

16. An inflammatory stimulus triggers production of
pro-inflammatory mediators such as TNF and IL-
1
Leads to neutrophil-endothelial cell adhesion,
activates clotting mechanism, generates
microthrombi
Release of more mediators like leukotrienes,
histamine, serotonin, lipoxygenase

17. Arteries and arterioles dilate decreasing
peripheral arterial resistance
Cardiac output increases to compensate (warm
shock)
Later, cardiac output may decrease causing
blood pressure to fall and typical features of
shock begin to manifest

18. Vasoactive mediators cause blood flow to bypass
capillary exchange (distributive defect)
Poor capillary flow from this shunting along with
capillary obstruction by microthrombi decreases
delivery of O 2 and impairs removal of CO 2 and waste
products.
Decreased perfusion causes dysfunction and
sometimes failure of one or more organs, including the
kidneys, lungs, liver, brain, and heart.
Coagulopathy may develop because of intravascular
coagulation with consumption of major clotting
factors, excessive fibrinolysis in reaction thereto, and
more often a combination of both.

21. Management of Severe Sepsis
Initial
Resuscitation Diagnosis Antibiotic
Therapy
Source Control Fluid Therapy Vasopressors
Corticosteroids Blood Product
Administration Glucose Control

22. Objectives
BP
Target
Hb
Transfusion
Threshold
SIRS
Screening
Antibiotic
Therapy

23. Infection Control / Antibiotics
Obtain blood cultures before Antibiotics
Grade 1C
Start broad spectrum antibiotics within
1 hour Grade 1B/1C
Perform Imaging studies to confirm
Ungraded

24. M
CVP
MAP
ScvO2
<8 mmHg
<65mmHg
<70%
IVF until
CVP >=8
Pressors until
MAP >= 65
PRBCs until
Hct >= 30%

25. GuidetoRecommendations’
StrengthsandSupporting Evidence
1 = strong recommendation
2 = weak recommendation or suggestion
A = good evidence from randomized trials
B = moderate strength evidence from small
randomized trial(s) or multiple good observational
trials
C = weak or absent evidence, mostly driven by
consensus opinion

26. Surviving Sepsis Campaign
MAP ≥65 mmHg
Level 1C Rec
So… is higher MAP beneficial?

27. LeDoux D et al.
Crit Care Med 2000
Bourgoin A et al.
Crit Care Med 2005
10 Patients
MAP 65 -> 85
28 Patients
MAP 65 -> 85
MAP
65mmHg
75mmHg
85mmHg
Lactate
Renal Fxn
UOP
Had no effect on:

28. Dunser MW et al.
Crit Care Med 2009
274 Patients
MAP
<75mmHg
Increased
Renal
Replacement
Therapy
MAP
<60mmHg
Increased
Mortality 3x

29. Does a Higher MAP Decrease
Renal Failure in Sepsis?

30. SEPSISPAM - 29 Centers with 776 Patients
Primary Outcome: 28 day mortality
Also looked if higher MAP beneficial in
patients with chronic HTN

31. Low Target
Group
MAP
65 – 70 mmHg
High Target
Group
MAP
80 – 85 mmHg

32. Difference
NO
Difference
28 or 90 Day
Mortality
28 Day Survival
w/o Organ Support
More
Atrial
Fibrillation
Longer
Pressor
Duration &
Dose
Subgroup Analysis did show that patients with chronic HTN did have more doubling of Cr &
Renal Replacement therapy in 1st week of care, but no difference at 28 days

33. Don’t Chase
MAP ≥65mmHg
Bottom Line
Give Fluids
Early
Vasopressor
When Needed

34. Much debated and took over a decade to conclude
The major agents:
Norepinephrine alpha-adrenergic and beta adrenergic agent
longstanding been used
Alpha- increase vascular tone, but may decrease cardiac output
Beta maintain blood flow and increase splanchnic perfusion
Vasopressin thought to adjunct for patients with severe septic shock
(restore vascular tone)
Vasopressin thought to elevate blood pressure through smooth
muscle V1peripheral vasoconstriction
Vasoconstriction may cause decreased organ perfusion to heart,
kidneys, and intestine
Dopamine (like Norepi) alpha/beta adrenergic but also dopaminergic
receptors resulting in increase in splanchnic and renal perfusion
Unclear clinical implications

35. VAAST trial in 2008 looked at 779 patients over
28 days and divided groups into Norepinephrine
vs. Vasopressin
Hypothesized that low-dose vasopressin as
compared with norepinephrine would decrease
mortality among patients with septic shock who
were being treated with conventional
(catecholamine) vasopressors.
No mortality reduction – adjunctive therapy

36. SOAP II trial in 2010 randomized 1679 patients
and examined them at 28 days when divided
into Norepinephrine or dopamine
Showed Dopamine and Norepinephrine have
similar efficacy but dopamine associated with
increased risk of arrhythmias

37. Add a vasopressor to keep MAP > 65 Grade 1C
Norepinephrine first choice for MAPS >65 Grade 1B
If additional vasopressor needed, then utilize Epinephrine
Grade 2B
Add Vasopressin in aiding to wean off Norepinephrine
Ungraded
Low Dose Vasopressin not recommended as single initial
vasopressor Ungraded
Avoid Dopamine except in select patients (low EF, low HR,
no tachyarrythmias) Grade 2C
Infuse Dobutamine when myocardial dysfunction Grade
1C
Phenylephrine only when norepi causes arrhythmia, CO is
high and BP is low, or salvage therapy. Grade 1C

39. • The ANNANE Trial in 2002 evaluated 300 patients with placebo vs
corticosteroids; suggested a survival benefit in patients with septic
shock and relative adrenal insufficiency
• Became common practice—suggestions of no benefit; suggestions
higher incidence of infections
• The CORTICUS trial in 2008 showed hydrocortisone did not show
benefit regardless of degree of adrenal insufficiency
• Only to be used if not responsive to vasopressors and adequate
fluid replacement.
• It is suggested to use intravenous hydrocortisone alone at a dose
of 200 mg per day for 7 days (grade 2C). Do not use > 300 mg/day
(grade A)
• When hydrocortisone is given, use continuous flow (grade 2D)
• Wean from steroids when vasopressors no longer needed

40. GuidetoRecommendations’
StrengthsandSupporting Evidence
1 = strong recommendation
2 = weak recommendation or suggestion
A = good evidence from randomized trials
B = moderate strength evidence from small
randomized trial(s) or multiple good observational
trials
C = weak or absent evidence, mostly driven by
consensus opinion

41. Surviving Sepsis Campaign
Maintain Hct ≥30%
Transfuse for Hb ≤7g/dL
Level 1B Rec

42. Liberal Transfusion Harms
Hebert PC et al.
NEJM 1999
838 Patients
Mortality rate during hospitalization was lower in restrictive group 22.3% vs liberal
group 28.1% (p = 0.05), but 30 day mortality had no difference 18.7% vs 23.3% (p = 0.11).

43. Liberal Transfusion Benefits
Vincent JL et al.
Anesthesiology 2008
1,040 Patients
Park DW et al.
Crit Care Med 2012
407 Patients
multicenter, observational study (198 European ICUs)  Higher 30 day survival rate in the
transfusion group
multicenter, observational study (22 ICUs in Korea)  transfused patients
had a lower mortality at….
7 Days (9.2 vs 27.0%)
28 Days (24.3% vs 38.8%)
In-Hospital (31.6% vs 41.8%)

44. Does a Liberal Transfusion Strategy
Improve Mortality in Sepsis?

45. 32 Centers in Europe
with 998 Patients

46. Transfusion
Requirements
In
Septic Shock
(TRISS)
Multicenter, parallel group trial of patients in the ICU with septic shock and Hb ≤9g/dL
 32 ICUs in denmark, sweden, norway, and finland (998 patients)

47. Liberal
Transfusion
Hb ≤9g/dL
Restrictive
Transfusion
Hb ≤7g/dL

48. 50% Less
Transfusions
36% No
Transfusions
No 90 Day Mortality Difference
90 day Mortality: 43% vs 45% (p = 0.44)
1545 units vs 3088 units PRBCs Transfused
36.1% vs 1.2% did not require Transfusion

49. Acute
Myocardial
Infarction
Excluded

50. +
Chatterjee S et al. JAMA Intern Med 2013  Meta-
Analysis of Blood transfusion strategy in patients with
myocardial infarction
Increased All-Cause Mortality With Transfusion
18.2% vs 10.2%

51. Bottom Line
Use A
Restrictive
Transfusion
Strategy

52. EGDT Usual
IVF
Pressors
CVC
PRBC
4.9L 3.5L
27.4% 30.3%
Mandatory Mandatory
64.1% 18.5%
Rivers Study 1999

53. The saga of Early Goal Directed Therapy (EGDT) versus “usual” care
ProCESS
ARISE
ProMISe
Protocolized Care for Early Septic Shock
Australian Resuscitation in Sepsis Evaluation
Protocolized Management in Sepsis

54. Trust the ProCESS
21% 18.2% 18.9%
No statistical difference in 60 day mortality
3 Arms
31 ERs; 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446
to protocol-based standard therapy, and 456 to usual care

55. Flexibility in Management

56. 18.6% 18.8%
ARISE – 51 centers, 1600 Patients
To check or not to check ScvO2?
No statistical difference in 90 day mortality
i.e. What physicians thought best;
Not checking ScvO2
*ScvO2 = surrogate measure of oxygen flux, reflecting the balance between
oxygen delivery (DO2) and consumption (VO2); Normal >75%

57. Community/Rural
Settings = more
generalizable then
ProCESS

58. Intravenous Fluids
3 – 4.5 L
in
1st 6 Hours
based off
ProCESS and
ARISE

59. 2001 Rivers Study  Mortality
47  31% (NNT = 6)
We have lower mortality rates now compared to the 2001 Rivers et al study
now….why?
Sepsis Trilogy  Mortality
18.2 – 29.5%

60. 29.5% 29.2%
ProMISe -
The Protocolized Management in
Sepsis
No statistical difference in 90 day mortality
Open, multicentre, randomised controlled trial (RCT)

61. EGDT Usual
IVF
Pressors
CVC
PRBC
2.23L 2.02L
53.3% 46.6%
92.1% 50.9%
8.8% 3.8%
ProMISE
A-Lines 74.2% 62.2%

62. The 2001 Rivers et al study has changed how we manage sepsis (i.e.
We are more aggressive in identifying these patients, and our
“usual care” has changed to early identification, early IVFs and early
antibiotics), which may explain why we have lower mortality rates
now compared to the 2001 Rivers et al study

63. EGDT Usual Care
The Gap
Sepsis Care 2015
Sick patients need fluids, antibiotics,
and supportive therapies (i.e.
Early critical care and resuscitation),
but they don’t need CVP and SCVO2
monitoring to dictate their care

64. CVP
ScvO2
Lactate clearance in sepsis is non-inferior to continuous ScVO2
monitoring; titration of end of resuscitation to ScvO2 may not be
required monitoring (Jones, JAMA, 2010)

65. 2001;345:1368-77.

66. Surviving Sepsis Campaign
Updates 6 Hour Bundle

67. Surviving Sepsis Campaign
1. Check Lactic Acid
2. Send Blood Cultures
3. Give Antibiotics
4. 30mL/kg IVF (if low BP/High Lactate)
Within 3 Hours…..

68. Surviving Sepsis Campaign
1. Vasopressors if MAP <65mmHg
2. Re-assess Volume Status & Tissue Perfusion
3. Re-Check Lactic Acid (Unless Initially Normal)
Within 6 Hours…..
Two of these: CVP | ScvO2 | Cardiac US | Passive Leg Raise

69. MAP ≥65 mmHg
Give Fluids
Early
Restrictive
Transfusion
Hb ≤7g/dL
SIRS Criteria
Poor Sensitivity
And
Finally…
Miss 1 in 8

70. EARLY
Recognition IVF Antibiotics

71. Sepsis increases risk of DVT; use PPX Grade
1B
At risk for stress ulcer  GI hemorrhage
Grade 1B
Early oral feedings Grade 2C
Glucose control
Target an upper blood glucose <180
mg/dl rather than an upper target
blood glucose ≤ 110 mg/dL (grade 1A).

72. Management of Severe Sepsis
Initial
Resuscitation Diagnosis Antibiotic
Therapy
Source Control Fluid Therapy Vasopressors
Corticosteroids Blood Product
Administration Glucose Control

73. A 42-year-old man is evaluated in the surgical
intensive care unit after surgery for a bowel
obstruction. He presented yesterday to the
emergency department for a 2-day history of
fever, confusion, and abdominal pain. On
examination, the patient's temperature was
38.4°C (101.1°F). Cardiac examination was normal;
examination of the lungs revealed diffuse bilateral
crackles. The abdomen was diffusely and markedly
tender, with rebound and guarding. Leukocyte
count was 18,400/µL (18.4 × 109/L) with 80%
segmented neutrophils and 6% band forms.

74. In the emergency department, his plasma
glucose concentration was 205 mg/dL (11.4
mmol/L); the patient has no history of diabetes
mellitus. Chest radiograph showed pulmonary
edema, and the patient was hospitalized;
imipenem/cilastatin was started, and he was
taken to surgery. The patient was found to have
a bowel obstruction with perforation and
contamination of the peritoneal cavity. After
surgery, the plasma glucose concentration is
300 mg/dL (16.7 mmol/L).

75. Q: Which of the following is the most
appropriate management of the patient's
hyperglycemia?
A. Any insulin regimen that follows a
sliding scale
B. Intravenous insulin drip
C. Subcutaneous intermediate-acting basal
insulin
D. Subcutaneous long-acting basal insulin

76. Correct answer: B. Intravenous insulin drip.
Glucose control in critically ill patients is now practiced
widely. Hyperglycemia is believed to contribute to various
physiologic derangements, such as inflammation and
coagulopathy, that should be controlled in the septic
patient. The NICE-SUGAR study showed intensive glucose
control increased mortality among adults in the intensive
care unit; a conventional blood glucose target of less than
or equal to 180 mg/dL (10.0 mmol/L) resulted in lower
mortality than did a target of 81 to 108 mg/dL (4.5 to 6.0
mmol/L).
Continuous intravenous insulin is the most effective
method for adequate glycemic control in these patients.
Subcutaneous regular insulin based on a sliding scale and
intermediate-acting or long-acting basal insulin do not
offer the best acute titration of glucose in intensive care
unit patients who may have volatile glucose levels. An
active physiologic insulin regimen is advisable.

77. A 71-year-old woman is brought to the emergency
department from a nursing home because of
confusion, fever, and flank pain. Her temperature is
38.5°C (101.3°F), blood pressure is 82/48 mm Hg, pulse
rate is 123 beats/minute, and respiration rate is 27
breaths/minute. Physical examination reveals dry
mucous membranes, costovertebral tenderness, poor
skin turgor and no edema. Leukocyte count is 15,600
cells/µL (15.6 × 109 cells/L); urinalysis shows 50 to 100
leukocytes and many bacteria per high-powered field.
The patient has a metabolic acidosis and high lactate
levels believed due to septic shock. Antibiotic therapy
is started.

78. Which of the following is most likely to
improve survival for this patient?
A. 25% albumin infusion
B. Aggressive fluid resuscitation
C. Maintaining hemoglobin above 12
g/dL
D. Maintaining a Paco2 below 50 mm
Hg
E. Hemodynamic monitoring with a
pulmonary artery catheter

79. Correct answer: B. Aggressive fluid resuscitation.
Aggressive fluid resuscitation within 6 hours would have a
beneficial effect on this patient’s survival. The patient has
severe sepsis presumptively from pyelonephritis. The
point here is that “timing” of resuscitation matters to
survival.
Crystalloid is given much more frequently than colloid,
and there are no data to support routinely using colloid in
lieu of crystalloid, especially in patients who are so
obviously volume depleted as this patient.
Giving blood may be part of resuscitation for anemic
patients in shock, but going to hemoglobin levels above 12
g/dL (120 g/L) is not supported by evidence. In stable ICU
patients who are not in shock, a transfusion threshold of 7
g/dL is an acceptable conservative approach.
There are no data to show that either maintaining a lower
Paco2 or using a pulmonary artery catheter would help to
increase survival in this patient.