Systemic Inflammatory

Response
Syndrome (SIRS)

Dr. Madhu Aryal

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
 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.
 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.
 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.
 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.
 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.
Mortality rate in SIRS

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

 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

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
 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)

Haptoglobins, C-Reactive proteins, ESR

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.

Pathogenesis of sepsis and
septic shock

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

 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.
 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

Oxygen Delivery

 Delivery:Demand mismatch
 Diffusion limitation (edema)
 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
Inflammatory Response to
Sepsis

NEJM 2006;355:1699-1713.
 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.

 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.
 Surviving Sepsis Campaign

Guidelines for Management of

Severe Sepsis and Septic Shock

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

 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
 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
 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
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
 Case Presentation -
Resolution
 Patient gradually stabilized and improved with
complete resolution of organ dysfunction over 5
days
 Final cultures confirmed diagnosis as
meningococcemia
 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
 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.
 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.