The document discusses systemic inflammatory response syndrome (SIRS) and defines it as a systemic response to various stresses that includes symptoms like fever, increased heart rate, respiratory rate and white blood cell count. It outlines the progression from infection to bacteremia to sepsis, which involves SIRS criteria and a suspected or proven infection. The stages of sepsis like severe sepsis, septic shock and refractory septic shock are defined based on the presence of organ dysfunction or hypotension.

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.