Systemic Inflammatory

Response Syndrome
(SIRS)



PRANEE SITAPOSA, MD.
www.anaesthesia.co.in anaesthesia.co.in@gmail.com
SEPSIS and Its 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 >38C (100.4) or <36C (96.8F).
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.
Severe Sepsis
Sepsis with organ hypoperfusion
one of the followings :
SBP < 90 mmHg
Acute mental status change
PaO
2
< 60 mmHg on RA (PaO
2
/FiO2 < 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.
MODS
(Multiple Organ Dysfunction Syndrome)
Sepsis with 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.

Relationship between SIRS
and Sepsis
Bone RC et al, Chest1992;101:164-55.
The Sepsis Continuum
A clinical response
arising from a
nonspecific insult, with
2 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.
Sepsis SIRS
Severe
Sepsis
Septic
Shock
Sepsis with
organ failure
Refractory
hypotension
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
Oxidases
Platelet
Activation
Kinins
Complement
Coagulopathy/DIC
Vascular/Organ System Injury
Multi-Organ Failure
Death
Coagulation
Activation
Cytokines
TNF, IL-1, IL-6
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, -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-)
Protease inhibitors (e.g.,1-antiprotease)
Antioxidants (haptoglobin)
Reprograms circulating leukocytes (epinephrine,
cortisol, PGE
2
, ?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
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.
Patients at increased risks of
developing sepsis
Underlying diseases: neutropenia, solid tumors,
leukemia, dysproteinemias, cirrhosis of the liver,
diabetes, 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
ulceration.
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,
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.
Diagnosis
History
community or nosocomially acquired infection
immunocompromised patient
exposure to animals, travel, tick bites, occupational
hazards, alcohol use, seizures, loss of
consciousness, medications
underlying diseases ; specific infectious agents
Some clues to a septic event include
Fever or unexplained signs with malignancy or
instrumentation
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
with as suspected pelvic infection the
physical exam should include rectal, pelvic,
and genital examinations
perirectal, and/or perineal abscesses
pelvic inflammatory disease and/or
abscesses, 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.
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.
Diagnosis
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.
CVP : central
venous
pressure

MAP : mean
arterial
pressure

ScvO
2
: central
venous
oxygen
saturation


Early Goal-Directed
Therapy
NEJM 2001;345:1368-77.
49.2%
33.3%
0
10
20
30
40
50
60
Standard Therapy
n=133
EGDT
n=130
P = 0.01*
*Key difference was in sudden CV collapse, not MODS
28-day Mortality

Early Goal-Directed Therapy
Results
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.
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