Systemic Inflammatory

Response
Syndrome (SIRS)

PRANEE SITAPOSA, MD.

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

 Infection
 Presence of microorganisms in a normally
sterile site.
 Bacteremia
 Cultivatable bacteria in the blood stream.
 Sepsis
 The systemic response to infection.
If associated with proven or clinically
suspected infection, SIRS is called “sepsis”.

American College of Chest Physicians/Society of Critical Care Medicine Consensus

Conference Committee. Crit Care Med. 1992;20:864-874.
 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.
 Severe Sepsis
 Sepsis with organ hypoperfusion
one of the followings :
 SBP < 90 mmHg
 Acute mental status change
 PaO2 < 60 mmHg on RA (PaO2 /FiO2 < 250)
 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.
 MODS
(Multiple Organ Dysfunction Syndrome)
 Sepsis with multiorgan hypoperfusion
Two or more of the followings:
 SBP < 90 mmHg

 Acute mental status change

 PaO2 < 60 mmHg on RA (PaO2 /FiO2 < 250)

 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.
Relationship between SIRS
and Sepsis

Bone RC et al, Chest1992;101:164-55.

 The Sepsis Continuum
Severe Septic
SIRS Sepsis Sepsis Shock

A clinical response arising from

a nonspecific insult, with 2 of Refractory
the following: SIRS with a Sepsis with
 T >38oC or <36oC presumed organ failure hypotension
 HR >90 beats/min or confirmed
 RR >20/min
infectious
 WBC >12,000/mm3 or
<4,000/mm3 or >10% bands
process

SIRS = systemic inflammatory

response syndrome
Chest 1992;101:1644.
Mortality rate in SIRS

Rangel-Frausto, et al. JAMA 273:117-123, 1995.

The Response to Pathogens “
Cross-Talk”

NEJM 2003;348:138-150.
Inflammatory Response to
Sepsis

NEJM 2006;355:1699-1713.
Procoagulant Response in
Sepsis

NEJM 2006;355:1699-1713.
Pathogenesis of sepsis and
septic shock

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

 Pathogenesis of Severe Sepsis
Infection

Microbial Products
(exotoxin/endotoxin)

Cellular Responses
Platelet Coagulation Kinins Cytokines
Activation Activation Oxidases Complement TNF, IL-1, IL-6

Coagulopathy/DIC
Vascular/Organ System Injury

Endothelial d lia l da m age

amage Endothe
Multi-Organ Failure

Death
 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.

 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)
 Sequesters iron (lactoferrin) and zinc (metallothionein)

Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

 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.

 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.

 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 granuloc
yopenia.
 Neonates are more likely to develop sepsis (ex. group B
Streptococcal infections).
 increased use of invasive devices such as surgical protheses, inhal
ation 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.

Patients at increased risks of
developing sepsis
 Underlying diseases: neutropenia, solid tumors, l
eukemia, dysproteinemias, cirrhosis of the liver, dia
betes, AIDS, serious chronic conditions.
 Surgery or instrumentation: catheters.
 Prior drug therapy: Immuno-suppressive drugs, e
specially with broad-spectrum antibiotics.
 Age: males, above 40 y; females, 20-45 y.
 Miscellaneous conditions: childbirth, septic aborti
on, trauma and widespread burns, intestinal ulcerat
ion.
Angus DC, et al. Crit Care Med 2001, 29:1303-1310.
Source (
usually an endogenous source of infection)

 intestinal tract
 oropharynx
 instrumentation sites
 contaminated inhalation therapy equipment
 IV fluids.
 Most frequent sites of infection: Lungs, abdo
men, and urinary tract.
 Other sources include the skin/soft tissue and t
he CNS.

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

Diagnosis
 History
 community or nosocomially acquired infection
 immunocompromised patient
 exposure to animals, travel, tick bites, occupational ha
zards, alcohol use, seizures, loss of consciousness, m
edications
 underlying diseases ; specific infectious agents
 Some clues to a septic event include
 Fever or unexplained signs with malignancy or inst
rumentation
 Hypotension
 Oliguria or anuria
 Tachypnea or hyperpnea
 Hypothermia without obvious cause
 Bleeding

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

 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.
 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.
Diagnosis
 Physical Examination
 essential
 In all neutropenic patients and in patients wit
h as suspected pelvic infection the physical e
xam should include rectal, pelvic, and genital
examinations
 perirectal, and/or perineal abscesses

 pelvic inflammatory disease and/or absce

sses, or prostatitis

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

 Signs and Symptoms
 Nonspecific symptoms of sepsis : not pathognomonic
 fever
 chills
 constitutional symptoms of fatigue, malaise
 anxiety or confusion
 absent symptoms in serious infections, especially in
elderly individuals

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

Complications

 Adult respiratory distress syndrome (ARDS)

 Disseminated Intravascular Coagulation (DIC)
 Acute Renal failure (ARF)
 Intestinal bleeding
 Liver failure
 Central Nervous System dysfunction
 Heart failure
 Death

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

 Surviving Sepsis Campaign

Guidelines for Management of

Severe Sepsis and Septic Shock

Dellinger RP, et al. Crit Care Med 2004; 32:858-873.

 Diagnosis
 Before the initiation of antimicrobial therapy, at least two blood cultures
should be obtained
 At least one drawn percutaneously

 At least one drawn through each vascular access device if inserted

longer than 48 hours
 Other cultures such as urine, cerebrospinal fluid, wounds, respiratory
secretions or other body fluids should be obtained as the clinical
situation dictates
 Other diagnostic studies such as imaging and sampling should be
performed promptly to determine the source and causative organism of
the infection
 may be limited by patient stability

Weinstein MP. Rev Infect Dis 1983;5:35-53

Blot F. J Clin Microbiol 1999; 36: 105-109.

Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

 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.

 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.
 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.
 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.
 Early Goal-Directed
Therapy

CVP : central
venous
pressure

MAP : mean
arterial
pressure

ScvO2: central

venous
oxygen

saturation

NEJM 2001;345:1368-77.
 Early Goal-Directed Therapy
Results 28-day Mortality
60
49.2%
50 P = 0.01*

40
33.3%
30

20

10

0
Standard Therapy EGDT
n=133 n=130
*Key difference was in sudden CV collapse, not MODS
NEJM 2001;345:1368-77.
 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.

 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.

 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.

 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.

NEJM;355:1699-1723.
Sepsis Cascade
Activated Protein C (Xigris)

NEJM;355:1640, October 19, 2006.