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
PaCO2 <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 < 60 mmHg on RA (PaO /FiO < 250)
2 2 2
 Increased lactic acid/acidosis
 Oliguria
 DIC or Platelet < 80,000 /mm3
 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
Severe Septic
SIRS Sepsis Sepsis Shock
A clinical response
arising from a SIRS with a Sepsis with Refractory
nonspecific insult, with presumed organ failure hypotension
≥2 of the following: or confirmed
 T >38oC or <36oC infectious
 HR >90 beats/min process
 RR >20/min
 WBC >12,000/mm3 or SIRS = systemic inflammatory
<4,000/mm3 or >10% response syndrome
bands Chest 1992;101:1644.

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

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

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

11. Normal Systemic Response to
Infection and Injury (1)
 Leukocytosis Mobilizes 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, PGE2, ?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. Regulation of oxygen delivery
Normal Abnormal
Cardiac
output BP=CO * SVR Cardiac
Output
regional distribution regional distribution
Intra Organ Distribution Intra Organ Distribution
Microcirculation Microcirculation
QO2 = Flow * O2 content

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

19. Oxygen Consumption
H+ H+ Cytc H+ H+
I Q III IV
NADH + H+ H+ 1/2 O2 + H+ H2O
NAD+
ADP + Pi ATP
•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
24µg/kg/hour for 96 hours
 Enrolled in RCT (double-blind) of
vasopressin vs norepinephrine for BP
support
 Enteral nutrition via nasojejunal feeding
tube

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 rhAPC
Microvascular Thrombosis Corticosteroids
Fluids
Hypoperfusion/Ischemia Vasopressors
Acute Organ Dysfunction CVVHF
(Severe Sepsis) Enteral nutrition
Death 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.