Sirs

1. Systemic Inflammatory
Response
Syndrome (SIRS)
Dr. Madhu Aryal

2. SEPSIS and It’s Disease
spectrum
Various stages of disease
Bacteremia
SIRS
Sepsis syndrome
Sepsis shock : early and refractory

3. Definition
Infection
Presence of microorganisms in a normally
sterile site.
Bacteremia
Cultivatable bacteria in the blood stream.
Sepsis
SIRS criteria + suspected or proven infection
American College of Chest Physicians/Society of Critical Care Medicine Consensus
Conference Committee. Crit Care Med. 1992;20:864-874.

4. SIRS
(Systemic Inflammatory Response Syndrome)
The systemic response to a wide range of stresses.
Temperature >38°C (100.4°) or <36°C (96.8°F).
Heart rate >90 beats/min.
Respiratory rate >20 breaths/min or
PaCO
2
<32 mmHg.
White blood cells > 12,000

cells/ml or < 4,000 cells/ml or
>10% immature (band) forms.
Note
Two or more of the following must be present.
These changes should be represent acute alterations from
baseline in the absence of other known cause for the
abnormalities.
American College of Chest Physicians/Society of Critical Care Medicine Consensus
Conference Committee. Crit Care Med. 1992;20:864-874.

5. MODS
(Multiple Organ Dysfunction Syndrome)
 multiorgan hypoperfusion
Two or more of the followings:
SBP < 90 mmHg
Acute mental status change
PaO
2
< 60 mmHg on RA (PaO
2
/FiO
2
< 250)
Increased lactic acid/acidosis
Oliguria
DIC or Platelet < 80,000 /mm
3
Liver enzymes > 2 x normal





American College of Chest Physicians/Society of Critical Care Medicine Consensus
Conference Committee. Crit Care Med. 1992;20:864-874.

6. Severe Sepsis
Sepsis with organ hypoperfusion
one of the criteria of MODS
Septic Shock- Severe sepsis + Hypotension
Refractory septic Shock- shock not controlled by IV fluids
and pressor agents
American College of Chest Physicians/Society of Critical Care Medicine Consensus
Conference Committee. Crit Care Med. 1992;20:864-874.

7. The Sepsis Continuum
A clinical response
arising from a
nonspecific insult, with
³2 of the following:
T >38
o
C or <36
o
C
HR >90 beats/min
RR >20/min
WBC >12,000/mm
3
or
<4,000/mm
3
or >10%
bands
SIRS = systemic inflammatory
response syndrome
SIRS with a
presumed
or confirmed
infectious
process
Chest 1992;101:1644.
SepsisSIRS
Severe
Sepsis
Septic
Shock
Sepsis with
organ failure
Refractory
hypotension

8. Mortality rate in SIRS
Rangel-Frausto, et al. JAMA 273:117-123, 1995.

9. Organ Dysfunction
Lungs
Kidneys
CVS
CNS
PNS
Coagulation
GI
Liver
Endocrine
Skeletal Muscle
Adult Respiratory Distress Syndrome
Acute Tubular Necrosis
Shock
Metabolic encephalopathy
Critical Illness Polyneuropathy
Disseminated Intravascular Coagulopathy
Gastroparesis and ileus
Cholestasis
Adrenal insufficiency
Rhabdomyolysis
Specific therapy exists

10. Response of body to
inflamation
Physiology
Heart rate
Respiration
Fever
Blood pressure
Cardiac output
WBC
Hyperglycemia
Markers of
Inflammation
TNF
IL-1
IL-6
Procalcitonin
PAF

11. Normal Systemic Response to
Infection and Injury (1)
LeukocytosisMobilizes neutrophils into the circulation
Tachycardia Increases cardiac output, blood flow to
injuried tissue
Fever Raises core temperature; peripheral
vasoconstriction shunts blood flow to
injuried tissue. Occurs much more often
when infection is the trigger for systemic
responses
Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

12. Normal Systemic Response to
Infection and Injury (2)
Acute-Phase Responses
Anti-infective
Increases synthesis of complement factors, microbe
pattern-recognition molecules(mannose-binding lectin,
LBP, CRP, CD14, Others)
Haptoglobins, C-Reactive proteins, ESR
Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

13. Normal Systemic Response to
Infection and Injury (3)
Anti-inflammatory
Releases anti-inflammatory neuroendocrine hormones
(cortisol, ACTH, epinephrine, α-MSH)
Increases synthesis of proteins that help prevent
inflammation within the systemic compartment
Cytokine antagonists (IL-1Ra, sTNF-Rs)
Anti-inflammatory mediators (e.g.,IL-4, IL-6, IL-6R,
IL-10, IL-13, TGF-β)
Protease inhibitors (e.g.,α1-antiprotease)
Antioxidants (haptoglobin)
Reprograms circulating leukocytes (epinephrine,
cortisol, PGE
2
, ?other)
Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

14. Normal Systemic Response to
Infection and Injury (4)
Procoagulant
Walls off infection, prevents systemic spread
Increases synthesis or release of fibrinogen, PAI-1, C4b
Decreases synthesis of protein C, anti-thrombin III
Metabolic
Preserves euglycemia, mobilizes fatty acids, amino acids
Epinephrine, cortisol, glucagon, cytokines
Thermoregulatory
Inhibits microbial growth
Fever
Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

15. Pathogenesis of sepsis and
septic shock
Angus DC, et al. Crit Care Med 2001, 29:1303-1310.

16. Homeostasis Is Unbalanced in
Severe Sepsis
Carvalho AC, Freeman NJ. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock.
1996;5:223-8; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44.

17. QO2 = Flow * O2 content
BP=CO * SVR
Intra Organ Distribution
regional distribution
Microcirculation
Cardiac
Output
Intra Organ Distribution
regional distribution
Microcirculation
Regulation of oxygen delivery
Cardiac
output
Normal Abnormal

18. Oxygen Delivery
Delivery:Demand mismatch
Diffusion limitation (edema)

19. Oxygen Consumption
III
NADH + H
+
NAD+
ADP + P
i
1/2 O
2
+ H
+
ATP
I
H
+
Cytc
H
2
O
H
+
H
+
H
+
H
+
Q IV
•Pyruvate Dehydrogenase (PDH) activity decreased
•Decreased delivery of Acetyl CoA to TCA cycle
•Mitochondrial dysfunction

20. Inflammatory Response to
Sepsis
NEJM 2006;355:1699-1713.

21. Risk factors of sepsis
aggressive oncological chemotherapy and radiation therapy
use of corticosteroid and immunosuppressive therapies for organ
transplants and inflammatory diseases
longer lives of patients predisposed to sepsis, the elderly, diabetics,
cancer patients, patients with major organ failure, and with
granulocyopenia.
Neonates are more likely to develop sepsis (ex. group B
Streptococcal infections).
increased use of invasive devices such as surgical protheses,
inhalation equipment, and intravenous and urinary catheters.
indiscriminate use of antimicrobial drugs that create conditions of
overgrowth, colonization, and subsequent infection by aggressive,
antimicrobial-resistant organisms.

Angus DC, et al. Crit Care Med 2001, 29:1303-1310.

22. Patients at increased risks of
developing sepsis
Underlying diseases: neutropenia, solid tumors,
leukemia, dysproteinemias, cirrhosis of the liver, di
abetes, AIDS, serious chronic conditions.
Surgery or instrumentation: catheters.
Prior drug therapy: Immuno-suppressive drugs,
especially with broad-spectrum antibiotics.
Age: males, above 40 y; females, 20-45 y.
Miscellaneous conditions: childbirth, septic
abortion, trauma and widespread burns, intestinal u
lceration.
Angus DC, et al. Crit Care Med 2001, 29:1303-1310.

23. Source
(usually an endogenous source of infection)
intestinal tract
oropharynx
instrumentation sites
contaminated inhalation therapy equipment
IV fluids.
Most frequent sites of infection: Lungs,
abdomen, and urinary tract.
Other sources include the skin/soft tissue and
the CNS.
Angus DC, et al. Crit Care Med 2001, 29:1303-1310.

24. Specific Infectious agents
Splenectomy (traumatic or functional)
S pneumoniae, H influenzae, N meningitidis
Neutropenia (<500 neutrophil/ml)
Gram-negative, including P aeruginosa, gram-
positives, including S aureus
Fungi, especially Candida species
Hypogammaglobulinemia (e.g.,CLL)
S pneumoniae, E coli
Burns
MRSA, P aeruginosa, resistant gram-negatives
MacArthur RD, et al. Mosby, 2001:3-10.
Wheeler AP, et al. NEJM 1999;340:207-214.
Chaowagul W, et al. J Infect Dis 1989;159:890-899.

25. Specific Infectious agents
Aids
P aeuginosa (if neutropenic), S aureus, PCP
pneumonia
Intravascular devices
S aureus, S epidermidis
Nosocomial infections
MRSA, Enterococcus species, resistant gram-
negative, Candida species
Septic patients in NE of Thailand
Burkholderia pseudomallei
MacArthur RD, et al. Mosby, 2001:3-10.
Wheeler AP, et al. NEJM 1999;340:207-214.
Chaowagul W, et al. J Infect Dis 1989;159:890-899.

26. Surviving Sepsis Campaign
Guidelines for Management of
Severe Sepsis and Septic Shock
Dellinger RP, et al. Crit Care Med 2004; 32:858-873.

27. Case presentation
43-year-old male
Flu-like symptoms for 1
day
In ER
Temp 39.5
Pulse 130
Blood pressure 70/30
Respirations 32
Petechial rash
Chest, CV, Abdominal
exam normal

28. Case presentation - 2
Laboratory
pH 7.29, PaO2 82,
PaCO2 29
Investigations pending
Blood, urine cultures
Orally intubated and
placed on mechanical
ventilation
Central venous catheter
inserted
Cefotaxime 2 g iv
Normal saline 2 litres
initially, repeated
Admitted to ICU

29. Case presentation - 3
In ICU:
Noradrenaline started to
support blood pressure
Additional fluid (saline
and pentastarch) given
based on low CVP
Pulmonary artery
catheter inserted to aid
further hemodynamic
management
Despite therapy patient
remained anuric
Continuous venovenous
hemofiltration initiated

30. Case presentation - 4
Early gram stain on blood revealed gram
negative rods
Patient started on:
Hydrocortisone 100 mg iv q8h
Recombinant activated protein C
24mg/kg/hour for 96 hours
Enrolled in RCT (double-blind) of
vasopressin vs norepinephrine for BP
support
Enteral nutrition via nasojejunal feeding
tube
Prophylaxis for stress ulcers, deep venous
thromboses

31. Case Presentation -
Resolution
Patient gradually stabilized and improved with
complete resolution of organ dysfunction over 5
days
Final cultures confirmed diagnosis as
meningococcemia

32. Severe Sepsis:
Management of Our Case
Endothelial Dysfunction and
Microvascular Thrombosis
Hypoperfusion/Ischemia
Acute Organ Dysfunction
(Severe Sepsis)
Death
rhAPC
Corticosteroids
Fluids
Vasopressors
CVVHF
Enteral nutrition
Survival

33. Sepsis resuscitation bundle
Serum lactate measured
Blood cultures obtained before antibiotics administered
Improve time to broad-spectrum antibiotics
In the event of hypotension or lactate > 4 mmol/L (36 mg/dL)
a. Deliver an initial minimum of 20 mL/kg of crystaloid
(or colloid equivalent)
b. apply vasopressors for ongoing hypotension
In the event of persistent hypotension despite fluid
resuscitation or lactate > 4 mmol/L (36 mg/dL)
a. achieve central venous pressure of > 8 mmHg
b. achieve central venous oxygen saturation of > 70%
Hurtado FJ. et al. Crit Care Clin;2006; 22:521-9.

34. Sepsis management bundle
Fluid resuscitation
Appropriate cultures prior to antibiotic
administration
Early targeted antibiotics and source control
Use of vasopressors/inotropes when fluid
resuscitation optimized
Surviving Sepsis Campaign Management Guidelines Committee. Crit Care Med 2004; 32:858-873.

35. Sepsis management bundle
Evaluation for adrenal insufficiency
Stress dose corticosteroid administration
Recombinant human activated protein C (xigris)
for severe sepsis
Low tidal volume mechanical ventilation for
ARDS
Tight glucose control
Surviving Sepsis Campaign Management Guidelines Committee. Crit Care Med 2004; 32:858-873.

36. Infection Control
Appropriate cultures prior to antibiotic
administration
Early targeted antibiotics and source control
Surviving Sepsis Campaign Management Guidelines Committee. Crit Care Med 2004; 32:858-873.

37. Antibiotic use in Sepsis (1)
The drugs used depends on the source of the sepsis
Community acquired pneumonia
third (ceftriaxone) or fourth (cefepime) generation
cephalosporin is given with an aminoglycoside (usually
gentamicin)
Nosocomial pneumonia
Cefipime or Imipenem-cilastatin and an aminoglycoside
Abdominal infection
Imipenem-cilastatin or Pipercillin-tazobactam and
aminoglycoside
Angus DC, et al. Crit Care Med 2001, 29:1303-1310.

38. Antibiotic use in Sepsis (2)
Nosocomial abdominal infection
Imipenem-cilastatin and aminoglycoside or
Pipercillin-tazobactam and Amphotericin B
Skin/soft tissue
Vancomycin and Imipenem-cilastatin or Piperacillin-
tazobactam
Nosocomial skin/soft tissue
Vancomycin and Cefipime
Urinary tract infection
Ciprofloxacin and aminoglycoside
Angus DC, et al. Crit Care Med 2001, 29:1303-1310.

39. Antibiotic use in Sepsis (3)
Nosocomial urinary tract infection:
Vancomycin and Cefipime
CNS infection:
Vancomycin and third generation cephalosporin or
Meropenem
Nosocomial CNS infection:
Meropenem and Vancomycin
Drugs will change depending on the most likely cause of the
patient's sepsis
Single drug regimens are usually only indicated when the organism
causing sepsis has been identified and antibiotic sensitivity testing
Angus DC, et al. Crit Care Med 2001, 29:1303-1310.

40. New Drug in Treating Severe
Sepsis
It is the first agent approved by the FDA effective
in the treatment of severe sepsis proven to reduce
mortality. Activated Protein C (Xigris) mediates
many actions of body homeostasis. It is a potent
agent for the:
suppression of inflammation
prevention of microvascular coagulation
reversal of impaired fibrinolysis
Angus DC, et al. Crit Care Med 2001, 29:1303-1310.