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1. Sepsis and Septic Shock
Kassahun B.
1

2. Introduction
• Sepsis is a clinical syndrome that has
physiologic, biologic, and biochemical
abnormalities caused by a dysregulated host
response to infection.
• Sepsis and the inflammatory response that
ensues can lead to multiple organ dysfunction
syndrome and death.
2

3. Definition
• The term SIRS: Systemic inflammatory response
Syndrome (identifiable infection)
• Severe sepsis:
– an acute organ dysfunction such as acute renal failure or
respiratory failure.
– Mortality rate of approximately 40%.
• Septic shock:
– sepsis patients with arterial hypotension that is refractory
to adequate fluid resuscitation, thus requiring vasopressor
administration
– Mortality rate: 50% to 80%
• multiple-organ dysfunction syndrome (MODS)
3

4. Definitions Related to Sepsis
Condition Definition
Bacteremia
(fungemia)
Presence of viable bacteria (fungi)
in the bloodstream
Infection Inflammatory response to invasion
of normally sterile host tissue by
the microorganisms
4

5. Systemic inflammatory response syndrome (SIRS):
• Systemic inflammatory response to a variety of clinical insults that can
be infectious or noninfectious etiology.
• The response is manifested by two or more of the following
conditions:
• T >38°C (100.4°F) or <36°C (96.8°F);
• HR >90 beats/min;
• RR >20 breaths/min or PaCO2 <32
• WBC >12,000 cells/mm3, <4,000 cells/mm3, or >10% immature (band)
forms;
• Positive fluid balance (>20 mL/kg over 24 h);
• hyperglycemia;
• plasma C-reactive protein/procalcitonin >2 SD above normal value;
• arterial hypotension; cardiac index >3.5 L/min; arterial hypoxemia;
• acute oliguria; creatinine increase >0.5 mg/dL;
• coagulation abnormalities; ileus, platelets <100,000 mcL; bilirubin >4
mg/dL; hyperlactatemia; decreased capillary refill
5

6. Definitions Related to Sepsis
Condition Definition
Sepsis • The SIRS secondary to infection
Severe
sepsis
• Sepsis associated with organ
dysfunction, Hypoperfusion, or
hypotension.
• Hypoperfusion and perfusion
abnormalities can include lactic
acidosis, oliguria, or acute
alteration in mental status.
6

7. Definitions Related to Sepsis
Condition Definition
Septic shock • Sepsis with persistent
hypotension despite fluid
resuscitation
• Patients who are on inotropic
or vasopressor agents may not
be hypotensive at the time
perfusion abnormalities are
measured.
Multiple-organ
dysfunction
syndrome (MODS)
• Presence of altered organ
function requiring intervention
to maintain homeostasis 7

8. 8

9. Infection Sites And Pathogens
 The leading primary sites:
1. Respiratory tract (40-42%)
2. Intra-abdominal space (31%–34%),
3. Urinary tract (11%–15%).
 Etiologic pathogens:
 Gram-negative bacteria (44-59%)
 Gram-positive bacteria (37-52% of patients),
 Anaerobes (5%)
 Fungi (4-10%)
9

10. Gram-Negative Bacterial Sepsis
 Progression to Septic Shock: 25(gram +ve) vs
50%(gram –ve)
 Pseudomonas aeruginosa has the higher
mortality rate
 Predominant agents:
 Escherichia coli(55-60%), Klebsiella species(8-23%)
and Pseudomonas aeruginosa (7-18%)
 Anaerobes (low-risk)
 Exist with others
 Polymicrobial: 5% to 39%
10

11. Gram-Positive Bacterial Sepsis
• Causative organisms:
– S. aureus, Strp. pneumoniae, coagulase-negative
staphylococci, and Enterococcus species
• S.aureus bacteremia: is associated with 10-30%
mortality rate
• S. pneumoniae sepsis: mortality rate >25%
• Staphylococcus epidermidis is mostly
– related to infected intravascular devices & catheters
• Enterococcal bacteremia: is associated with
– Prolonged hospitalization and treatment with broad-
spectrum cephalosporins. 11

12. Fungal Sepsis
 Incidence: >200% (from 1979 to 2000)
 Candida species:
 Candida albicans (38-61%), non-albicans Candida
species collectively(54.4%) which includes Candida
glabrata, Candida parapsilosis, Candida tropicalis,
and Candida krusei
 Overall Mortality: 35.5%
12

13. Pathogenesis
• Sepsis is the result of complex interaction among
the invading pathogen, the host immune system
and the inflammatory responses.
• The inflammatory response leads to damage to
the host tissue and the anti-inflammatory
response causes leukocytes to activate.
• Once the balance to control the local
inflammatory process to eradicate the invading
pathogen is lost, systemic inflammatory response
occurs, converting the infection to sepsis or
severe septic shock.
13

14. Cellular Components for Initiating the
Inflammatory Process for Gram-Negatives
 Endotoxin:
 lipopolysaccharide component of the bacterial cell
wall
 unique to the outer membrane of the gram-negative
cell wall,
 released with bacterial lysis
 Lipid A, the innermost region of the
lipopolysaccharide
 highly immunoreactive and is considered responsible
for most of the toxic effects observed with gram-
negative sepsis.
 activate macrophages and trigger inflammatory
cascades
 Endotoxin leads to the activation and the release
of cytokine mediators
15

15. Cellular Components for Initiating the
Inflammatory Process for Gram-Positives
• The Exotoxin peptidoglycan
– appears to exhibit proinflammatory activity.
• Peptidoglycan comprises up to 40% of gram-
positive cell mass, and is exposed on the cell wall
surface.
• Although it competes with lipid A for similar
binding sites on CD14, the potency of
peptidoglycan is less than that of endotoxin
• However, an important feature of gram-positive
bacteria is the production of potent exotoxins
16

16. Pro- and Antiinflammatory
Mediators
 Steps in pathophysiology of Sepsis:
 Activation of inflammatory pathways, and a complex
interaction between proinflammatory and
antiinflammatory mediators
 The key proinflammatory mediators:
tumor necrosis factor- α (TNF- α ),
interleukin-1 (IL-1), and
interleukin-6 (IL-6) which are secreted by activated
macrophages
• Other mediators that may be important for the
pathogenesis of sepsis are interleukin-8(IL-
8),platelet activating factor (PAF),leukotrines
and thromboxane A2
17

17. Pro- and Antiinflammatory
Mediators
 Anti-inflammatory mediators:
 inhibit the production of the proinflammatory
cytokines and down regulate some inflammatory
cells. includes
 interleukin-1 receptor antagonist (IL-1RA),
 interleukin-4 (IL-4), and
 interleukin-10 (IL-10)
 IL-10 and IL-1RA are produced in large amounts
in septic shock than in sepsis.
19

18. Pro- and Antiinflammatory
Mediators
 Excessive proinflammatory mediators leads to
SIRS and possibly MODS
 After this initial phase, counter regulatory pathways
become activated, excessive antiinflammatory
mediators, representing a compensatory
antiinflammatory response syndrome (CARS).
 The balance between pro- and
antiinflammatory mechanisms determines
 the degree of inflammation, ranging from local
antibacterial activity to systemic tissue toxicity or organ
failure 20

19. 21

20. Complications
 The three most frequent organ
dysfunctions:
 Respiratory, circulatory, and renal
 Shock is the most ominous complication
associated with sepsis
 Mortality occurs in approximately one-half of
the patients with septic shock.
22

21. Complications
 Severe hypotension appears to be caused
 By the release of vasoactive peptides, such as
bradykinin and serotonin, and by endothelial cell
damage
 lead to the extravasation of fluids into interstitial
spaces
 Complications of Septic shock:
 Disseminated intravascular coagulation
 Acute respiratory distress syndrome, and
 Multiple organ failure
23

22. Signs and Symptoms Associated with Sepsis
EARLY SEPSIS LATE SEPSIS
 Fever or hypothermia  Lactic acidosis
 Rigors, chills  Oliguria
 Tachycardia  Leukopenia
 Tachypnea  DIC
 Nausea, vomiting  Myocardial depression
 Hyperglycemia  Pulmonary edema
 Myalgias  Hypotension (shock)
 Lethargy, malaise  Hypoglycemia
 Proteinuria  Azotemia
 Hypoxia  Thrombocytopenia
 Leukocytosis  ARDS
 Hyperbilirubinemia  Gastrointestinal hemorrhage
 Coma 29

23. Prognosis
• Mortality rate:
– SIRS  sepsis  severe sepsis  septic shock
• Mortality with age
– 10% in children
– 38.4% over 85 years
• ICU admission
– 51.1% of the patients with severe sepsis require
ICU admission and of those patients,
– Mortality: 34.1%.
30

24. Prognosis
• Elevated lactate
–>4 mmol/L in the presence of the SIRS
–Mortality rate: 89%.
• Mortality vs. # of dysfunctioning organs
–From two to five: mortality increased from
54% to 100%
–Duration of organ dysfunction also affect the
overall mortality rate.
31

25. 32

26. Diagnosis and Identification of
Pathogen
• Bacteremia:
– Two sets of blood samples from a peripheral vein
– Aerobic and anaerobic culture
• Suspected catheter-related infection
– a pair of blood cultures obtained simultaneously
through the catheter hub and a peripheral site
• Suspected soft tissue infection
– a gram stain and bacterial culture of any obvious
wound exudates
– A needle aspiration of a closed infection such as
cellulitis or abscess
33

27. Diagnosis and Identification of
Pathogen
• Pneumonia
– blood cultures and respiratory secretions
• Lumbar puncture
– mental alteration, severe headache, or a seizure,
assuming there are no focal cranial lesions identified
by computed tomography scan.
• The laboratory tests
– hemoglobin, white blood cell count with differential,
– platelet count
– complete chemistry profile, coagulation parameters,
serum lactate, and arterial blood gases.
34

28. Treatment Approach
• The primary goals of therapy for patients with
sepsis include:
a. timely diagnosis and identification of pathogen;
b. rapid elimination of the source of infection
medically and/or surgically;
c. early initiation of aggressive antimicrobial
therapy;
d. interruption of pathogenic sequence leading to
septic shock;
e. Avoidance of organ failure.
35

29. Empiric Antimicrobial Regimens in Sepsis
INFECTION
(SITE OR TYPE)
ANTIMICROBIAL REGIMEN
Community-acquired Hospital-acquired
Urinary tract Ceftriaxone or
Ciprofloxacin/
Levofloxacin
Ciprofloxacin/ Levofloxacin
or Ceftazidime/ Ceftriaxone
Respiratory
tract
Newer Fluoroquinolone
or
Ceftriaxone + Azithromy
cin
Piperacillin, Ceftazidime, or
Cefepime +
Gentamicin or
Ciprofloxacin/levofloxacin±
Vancomycin
Intraabdomi
nal
Beta-lactamase Inhibitor
Combo or
Ciprofloxacin + Metroni
dazole
Piperacillin/Tazobactam or
Carbapenem
Ceftazidime/cefipime +
Metronidazole 39

30. Empiric Antimicrobial Regimens in Sepsis
INFECTION
(SITE OR TYPE)
ANTIMICROBIAL REGIMEN
COMMUNITY-
ACQUIRED
HOSPITAL-ACQUIRED
Skin/soft
tissue
Vancomycin or
linezolid or
daptomycin
Vancomycin + Piperacillin
Catheter-related Vancomycin
Unknown Piperacillin or
ceftazidime/cefepime or
imipenem/meropenem
40

31. Antifungal Therapy in Sepsis
• Candida species:
– Associated with high mortality rate
• Treatment options:
– Amphotericin B–based preparations, the azole antifungal
agents, the echinocandin antifungal agents, or combination
therapy with fluconazole plus amphotericin B.
• The new lipid formulations of amphotericin:
– Amphotericin B lipid complex, amphotericin B cholesteryl
sulfate, and liposomal amphotericin B
– Less nephrotoxic, allow increased daily dose, have high tissue
concentrations in the reticuloendothelial organs such as lungs,
liver, and spleen, and have decreased infusion-associated side
effects.
– But reserved for patients who are intolerant: Superior clinical
efficacy, and higher cost
41

32. Duration of therapy
–7 to 10 days and fungal infections can require 10
to 14 days.
–Recommend a "step-down” from IV to oral:
• In hemodynamically stable, afebrile for 48 to 72 hours,
• a normalizing white blood cell (WBC) count, and
• ability to take oral medications,
42

33. Hemodynamic Support
• Hemodynamic support is divided in to three
– fluid therapy, vasopressor therapy, and inotropic therapy.
• Rationale:
– A high cardiac output and a low systemic vascular
resistance characterize septic shock.
• Hypotension:
– low systemic vascular resistance and abnormal
distribution of blood flow in the microcirculation, resulting
in compromised tissue perfusion
• Because approximately half of patients with septic
shock die of multiple organ system failure
– Use of noninvasive evaluation is not accurate hence
invasive (right-sided heart catheter in an intensive care
unit are recommended. 43

34. Fluid Therapy
• Rationale:
– Peripheral vasodilation and capillary leakage
– Initial symptom of sepsis is hypotension (50%)
• Goal:
– maximize cardiac output (left ventricular preload)
– restore tissue perfusion
• Titrate fluid administration: based on
– heart rate, urine output, blood pressure, and mental
status.
• Isotonic crystalloids:
– 30 mL/kg of IV crystalloid fluid within the first 3 hours
– target MAP of 65 mg Hg
44

35. Vasopressor and Inotropic Therapy
 Used when the patient is unresponsive to fluid
resuscitation alone.
 Inotropic agents:
dopamine and dobutamine, increase COP by
increasing cardiac contractility
 Vasopressors: such as norepinephrine,
phenylephrine, and epinephrine are used when
SBP <90 mm Hg or MAP<60 to 65 mm Hg after
adequate preload and inotrope therapy
 Complications:
tachycardia and myocardial ischemia and
infarction in pts with coexisting coronary disease
45

36. Vasopressor and Inotropic Therapy
• Norepinephrine: First line of choice for septic
shock
– a potent alpha-adrenergic agent with less
pronounced beta-adrenergic activity
• Dose: 0.01 to 3 mcg/kg/min
• More potent agent than dopamine in
refractory septic shock
46

37. Dopamine
• Mechanism
– An alpha- and beta-adrenergic agent
– combined vasopressor and inotropic effects
– Dose dependent pharmacologic effect
• Increase MAP and cardiac output
– stroke volume and heart rate
• Dose
– Low-dose dopamine: 1 to 5 mcg/kg/min increases renal
perfusion through dopamine receptor activation
– Higher dose: >5 mcg/kg/min exhibit alpha and beta
activity; support blood pressure and cardiac index (CI)
– At high dose alpha adrenergic activity predominates
• Causes Tachycardia and can be more arrhythmogenic
47

38. Inotropes and Vasopressers
• Dobutamine:
– Beta-adrenergic inotropic agent for
improvement of cardiac output and oxygen
delivery
– Doses: 2 to 20 mcg/kg/min increases CI and HR
– Used in pts with adequate filling pressures and
blood pressure but low CI
• Phenylephrine
– A selective alpha1-agonist, rapid onset, short
duration, and primary vascular effects,
– Effect on tachycardia: Use when tachycardia
limits the usage of other vasopressors 48

39. Epinephrine
• Nonspecific apha-and beta-adrenergic
agonist
• Doses:
–0.1 to 0.5 mcg/kg/min.
• Reserved for unresponsives:
–propensity to increase lactate level;
impair blood flow to the splanchnic
system
49

40. Receptor Activity of Cardiovascular Agents
Commonly Used in Septic Shock
Agent alpha1 alpha2 beta1 beta2
Dopamin
ergic
Dopamine ++/+++ ? ++++ ++ ++++
Dobutamine + + ++++ ++ 0
Norepinephrine +++ +++ +++ +/++ 0
Phenylephrine ++/+++ + ? 0 0
Epinephrine ++++ ++++ ++++ +++ 0
50

41. Adjunctive Therapies
 ARDS and hypoxia (Oxygen
 O2 saturation >90%
 Hyperglycemia:
 Refractory to exogenous insulin
 BS level: 180 or less is recommended
 Hypoglycemia: highest mortality rate was
documented when BG level is less than 40%
51

42. Adjunctive Therapies
• IV hydrocortisone is recommended for
adult patients with septic shock who are
hemodynamically unstable after initial
resuscitation with IV fluids and
vasopressors. (hydrocortisone 100 mg BID-
TID)
 Deep vein thrombosis prophylaxis
 Low-dose unfractionated heparin or low-
molecular weight heparin
 Stress ulcer prophylaxis:
 Proton pump inhibitors
 H2 receptor antagonists
52

43. Evidence-based Treatment Recommendations
For Sepsis And Septic Shock
Antibiotic therapy
• Use a broad initial empirical antibiotic regimen against all likely
pathogens
• There is no evidence of higher efficacy with combination therapy
Fluid therapy
• Immediate initial resuscitation to reverse hypoperfusion should
be instituted to achieve central venous pressure 8–12 mm Hg,
mean arterial pressure 65 mm Hg, urine output 0.5 mL/kg/h,
central venous or mixed venous oxygen saturation 70%
• There is no clinical outcome difference between colloids and
crystalloids
53

44. Evidence-based Treatment Recommendations
For Sepsis And Septic Shock
Vasopressors
• The advantages of norepinephrine and dopamine over
epinephrine (potential tachycardia, possibly disadvantageous
effects on splanchnic circulation) and phenylephrine (decrease
in stroke volume) are not supported by the literature.
• There is no support of low doses of dopamine to maintain or
improve renal function
Inotropic therapy
• Dobutamine as the first-choice inotrope to increase cardiac
output combined with norepinephrine in the presence of low
blood pressure is not supported in the literature.
54

45. EVIDENCE-BASED TREATMENT RECOMMENDATIONS FOR
SEPSIS AND SEPTIC SHOCK
Glucose control
• There is minimal support to have blood
glucose <150 mg/dL to improve survival
Steroids
• The value of IV hydrocortisone 200–300 mg/day for
7 days in 3-4 divided doses in patients with septic
shock is not clear.
• The use of fludrocortisone 50 mcg orally per day is
not supported
55

46. EVIDENCE-BASED TREATMENT RECOMMENDATIONS FOR
SEPSIS AND SEPTIC SHOCK
Deep vein thrombosis prophylaxis
• Either low-dose unfractionated heparin or low-molecular
weight heparin are effective in preventing deep vein
thrombosis
Stress ulcer prophylaxis
• H2 receptor inhibitors are more efficacious than sucralfate
56

47. Neonatal sepsis
• Neonatal sepsis is a clinical syndrome in an infant 28
days of life or younger, manifested by systemic signs
of infection and isolation of a bacterial pathogen
from the bloodstream.
• Bacterial sepsis and meningitis often are linked
closely in neonates; meningitis is present with Early-
onset sepsis (in 30% of cases), late onset sepsis (in
75% of cases).
• GBS and E-coli are the most common causes of both
early- and late-onset sepsis, accounting for
approximately two-thirds of early-onset infections 57

48. 58
• Early-onset sepsis
– Birth to 7 days (usually less than 72 hrs)
– Is multiorgan system disease frequently manifested as
respiratory failure, shock, meningitis (in 30% of cases), DIC, acute
tubular necrosis, and symmetrical peripheral gangrene.
– Usually is a result of infection caused by the bacteria in the
mother’s genitourinary tract.
– Organisms related to this sepsis include group B streptococci, E.
coli, Klebsiella, L. monocytogenes, and H. influenzae.
– Most infected infants are premature and show nonspecific
cardiorespiratory signs, such as grunting, tachypnea, and
cyanosis at birth.

49. 59
• Early-onset sepsis
– Risk factors for early-onset sepsis include
• vaginal colonization with group B streptococci,
• prolonged rupture of the membranes (>24 hours),
• amnionitis,
• maternal fever or leukocytosis,
• fetal tachycardia, and
• preterm birth
• African American race and
• male sex
Neonatal sepsis

50. 60
• Early-onset sepsis
– Early manifestations—grunting, poor feeding, pallor, apnea,
lethargy, hypothermia, or and abnormal cry—may be
nonspecific.
– Profound neutropenia, hypoxia, and hypotension may be
refractory to treatment with broad-spectrum antibiotics,
mechanical ventilation, and vasopressors such as dopamine and
dobutamine.
– In the initial stages of early-onset septicemia in a preterm infant,
it is often difficult to differentiate sepsis from respiratory
distress syndrome.
– Early-onset sepsis should be evaluated by blood and CSF
cultures, CSF Gram stain, cell count, and protein and glucose
levels.
Neonatal sepsis

51. 61
• Early-onset sepsis
– Normal newborns generally have an elevated CSF protein
content (100 to 150 mg/dL) and may have 25 to 30/mm3 white
blood cells, which are 75% lymphocytes in the absence of
infection.
– Some infants with neonatal meningitis caused by group B
streptococci do not have an elevated CSF leukocyte count but
are seen to have microorganisms in the CSF on Gram stain.
Neonatal sepsis

52. 62
• Early-onset sepsis
– Empiric management
• Ampicillin + gentamicin; 10 days for bacteremia; 14 days for
GBS and uncomplicated meningitis; extend to 21-28 days for
complicated infections.
• Consider adding a third-generation cephalosporin (cefotaxime
preferred) or carbapenem for infants suspected of meningitis.
• Tailor therapy to pathogen.
• Consider discontinuation of therapy if pathogen not isolated.
• For term and late preterm neonates ≤7 days old, the dose of
ampicillin is 100 mg/kg/dose given IV every eight hours.
Gentamicin dosing is 4 mg/kg/dose IV every 24 hours
Neonatal sepsis

53. 63
• Late-onset sepsis (8 to 28 days)
– Usually occurs in a healthy full-term infant who was discharged
in good health
– Clinical manifestations may include lethargy, poor feeding,
hypotonia, apathy, seizures, bulging fontanelle, fever, and direct-
reacting hyperbilirubinemia.
– Late-onset sepsis may be caused by the same pathogens as
early-onset sepsis,
– Late in the neonatal period also may have infections caused by
the pathogens usually found in older infants (H. influenzae, S.
pneumoniae, and N. meningitidis).
– In addition, viral agents (HSV, cytomegalovirus, or enteroviruses)
may manifest with a late-onset, sepsis-like picture.
Neonatal sepsis

54. • Late-onset sepsis
• Empiric management
– The choice of empiric therapy depends upon whether
the infant is admitted from the community and thus is
at lower risk for infection caused by a MDR pathogen or
is hospitalized since birth and thus at a higher risk
• Admitted from the community
– The preferred regimen is ampicillin plus gentamicin
– For term and late preterm neonates >7 days old, the
dose of ampicillin is 75 mg/kg/dose IV every six hours.
Gentamicin dosing is 5 mg/kg/dose IV every 24 hours
– Consider adding cephalosporin if meningitis suspected
64

55. • Hospitalized since birth
– Are at high risk of MDR organisms
– Vancomycin + aminoglycoside is the drug of choice
– The initial IV loading dose of vancomycin is 20 mg/kg;
subsequent dosing depends on serum creatinine (Scr)
Scr <0.7 mg/dL – 15 mg/kg/dose IV every 12 hours
Scr 0.7 to 0.9 mg/dL – 20 mg/kg/dose IV every 24 hrs
Scr 1 to 1.2 mg/dL – 15 mg/kg/dose IV every 24 hours
Scr 1.3 to 1.6 mg/dL – 10 mg/kg/dose IV every 24 hrs
Scr >1.6 mg/dL – 15 mg/kg/dose IV every 48 hours
65

56. The End!
66