Systemic Inflammatory

Response
Syndrome
(SIRS) &
SEPSIS
Dr.H.Asril Zahari Sp.B.KBD

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
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 (PaO 2 /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

SIRS

Sepsis

Severe
Sepsis

Septic
Shock

A clinical response arising from

a nonspecific insult, with 2 of

the following:
T >38oC or <36oC
HR >90 beats/min
RR >20/min
WBC >12,000/mm3 or
<4,000/mm3 or >10% bands

SIRS with a
presumed
or confirmed
infectious
process

Sepsis with
organ failure

Refractory
hypotension

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
Activation

Coagulation
Activation

Oxidases

Kinins
Complement

Cytokines
TNF, IL-1, IL-6

Coagulopathy/DIC
Vascular/Organ System Injury

mage
a
d
l
a
i
l
e
h
Endot

Endothelial d
amage

Multi-Organ Failure
Death

Normal Systemic Response to

Infection and Injury (1)
Leukocytosis
Tachycardia
Fever

Mobilizes neutrophils into the circulation

Increases cardiac output, blood flow to
injuried tissue
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,
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
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, 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.

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, grampositives, 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 gramnegative, 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 physic
al exam should include rectal, pelvic, and ge
nital 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.

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.

60
50
40

Early Goal-Directed Therapy

Results 28-day Mortality
49.2%

P = 0.01*
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 Piperacillintazobactam
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.