Amjad Bani Hani

S IR S , S EP S IS , A N D
M ODS

O bjectives
To know definitions of SIRS, sepsis,

septic shock, MODS

To become familiar with the
epidemiology of sepsis
To learn basic pathophysiology
(inflammation, cardiovascular
physiology) of SIRS and sepsis
But first, a real case:

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

Case Presentation -4
Early gram stain on blood revealed

gram negative rods

Patient started on:
Hydrocortisone 100 mg iv q8h
Recombinant activated protein C

24g/kg/hour for 96 hours

Enteral nutrition via nasojejunal feeding
tube
Prophylaxis for stress ulcers, deep
venous thromboses

Case Presentation -Resolution

Patient gradually stabilized and improved with

complete resolution of organ dysfunction over 5 days

Final cultures confirmed diagnosis as
meningococcemia

Infection:Part ofa bigger

picture

Infection:

Presence of organisms in a
closed space or location
where not normally found

Infection

Adapted from: Bone RC et al. Chest. 1992;101:1644-55.

Opal SM et al. Crit Care Med. 2000;28:S81-2.

SIRS:System ic Infl
am m atory Response
Syndrom e
SIRS: A clinical

response arising from a

nonspecific insult
manifested by
2 of the following:
Temperature
38C or 36C
HR 90 beats/min
Respirations 20/min
WBC count
12,000/mL or
4,000/mL or >10%
immature neutrophils
Adapted from: Bone RC et al. Chest. 1992;101:1644-55.
Opal SM et al. Crit Care Med. 2000;28:S81-2.

Sepsis:M ore Than Just Infl

am m ation
Sepsis:
Known or suspected
infection
SIRS criteria

Adapted from: Bone RC et al. Chest. 1992;101:1644-55.

Severe Sepsis:Acute O rgan

D ysfunction
Severe Sepsis =

Sepsis with signs of

acute organ
dysfunction in any of
the following systems:
Cardiovascular (septic
shock)
Renal
Respiratory
Hepatic
Hemostasis
CNS
Unexplained
metabolic
Adapted from:
Bone RC et al.acidosis
Chest. 1992;101:1644-55.

Sepsis:A Com plex D isease

Adapted from: Bone RC et al. Chest. 1992;101:1644-55.

Opal SM et al. Crit Care Med. 2000;28:S81-2.

Jargon 2002: PIRO

Predisposition
Insult

Response

Infection
Inflammation

Physiologic
Biochemical

Severe
Sepsis

Specific Organ
Severity

Organ Dysfunction

Predisposition
Pre-existing disease
Cardiac, Pulmonary, Renal
HIV

Age (extremes of age)

Gender (males)
Genetics
TNF polymorphisms (TNF promoter high

secretor genotype)

Response
Physiology
Heart rate
Respiration
Fever
Blood pressure
Cardiac output
WBC
Hyperglycemia

Markers of

Inflammation
TNF
IL-1
IL-6
Procalcitonin
PAF

O rgan D ysfunction
Lungs
Kidneys
CVS
CNS
PNS
Coagulation
GI
Liver

Adult Respiratory Distress Syndrome

Acute Tubular Necrosis
Shock
Metabolic encephalopathy
Critical Illness Polyneuropathy
Disseminated Intravascular

Coagulopathy
Gastroparesis and ileus
Cholestasis

Endocrine
Skeletal Muscle
Adrenal insufficiency
Rhabdomyolysis Specific therapy
exists

M agnitude ofthe Problem

Estimated 215,000 deaths from US

1995 data
High cost for management (ICU care,
diagnostic testing, drugs)
Estimated 20 day LOS; $22,000 cost

Represents 9.3% of all deaths

Equals deaths after acute myocardial

infarction

The Incidence ofSepsis in the

U nited States
The incidence of sepsis has

increased 91.3 percent over the

last ten years.

This year, severe sepsis will likely

take 215,000 lives.

Sepsis is the leading cause of

death in the non-coronary ICU.

 Severe sepsis takes more lives

than breast, colon/rectal,

pancreatic, and prostate cancer
combined.

One of every three patients who

develop severe sepsis

will die within a month.
Source: Society of Critical Care

Severe Sepsis is deadly

Severe Sepsis is C om m on

Severe Sepsis is increasing

in incidence

Sepsis:D efi
ning a D isease Continuum
Infection/
Trauma

SIRS

A clinical response
arising
from a nonspecific
insult, including 2 of
the following:

Sepsis

Severe
Sepsis

SIRS with a presumed or

confirmed infectious
process

Temperature 38oC or

36oC
HR 90 beats/min
Respirations 20/min
WBC count
12,000/mm3 or
4,000/mm3 or
>10% immature
neutrophils

SIRS = systemic inflammatory response

syndrome.
Bone et al. Chest. 1992;101:1644.

Sepsis:D efi
ning a D isease Continuum
Infection/
Trauma

SIRS

Sepsis

Shock

Severe
Sepsis
Sepsis with 1 sign of organ
failure
Cardiovascular (refractory
hypotension)
Renal
Respiratory
Hepatic
Hematologic
CNS
Unexplained metabolic
acidosis

Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207.

Epidem iology ofSepsis

The InternationalCohort Study

Infectio
n

Sepsis

Severe
Sepsis

Septic
Shock

Percent of cases within each category

18

28

24

30

35% mortality

8353 patients with LOS > 24h

4277 infections (2696 on admission)
Alberti, Int Care Med 2002

Causes ofSepsis
Bacterial infections are

the most common cause

of sepsis, but sepsis can
also be caused by fungal,
parasitic, or viral
infections.
The infection can
originate from anywhere
in the body.
www.clevelandclinic.org : Source

Sources ofSepsis
The InternationalCohort Study

Severe
Sepsis
Respiratory

Septic
Shock

66

53

20

Bacteremia

14

16

Urinary

11

11

Multiple

Abdomen

M icrobiology ofSepsis
The InternationalCohort Study

Severe
Sepsis

Septic
Shock

Gram-positive

44

40

Gram-negative

47

47

Fungal

13

Polymicrobial

Pathogenesis ofSIRS/M O D S
Preoperative Illness

Trauma or
Operation

Tissue Injury

optimal oxygen
delivery and
support

Recovery

Excessive
Inflammatory
Response

Inadequate
Resuscitation

SIRS/MODS

Initiation ofInfl
am m atory Response

From Wheeler & Bernard, NEJM 1999

M ediators of Septic
R esponse

P ro-inf a
lm m atory
M ediators
Bacterial Endotoxin
TNF-
Interleukin-1
Interleukin-6
Interleukin-8
Platelet Activating Factor (PAF)
Interferon-Gamma
Prostaglandins
Leukotrienes
Nitric Oxide

A nti-inf a
lm m atory
M ediators
Interleukin-10
PGE2
Protein C
Interleukin-6
Interleukin-4
Interleukin-12
Lipoxins
GM-CSF
TGF
IL-1RA

Pathophysiology ofSepsis
Sepsis can lead to widespread

inflammation and blood clotting.

Blood clotting during sepsis causes

reduced blood flow to limbs and

vital organs, and can lead to organ
failure or tissue damage.
Source: Critical Care Nurse Supplement, 2004

Pathophysiology ofSepsis
In simple terms
sepsis can be viewed
as an imbalance of
inflammation,
coagulation, and
.fibrinolysis
In normal patients
homeostasis is
maintained when
.these are balanced

Pathophysiology ofSepsis
During a normal response to bacteria in
the blood the immune system releases
inflammatory mediators to promote
recovery of the tissue.
These mediators are known as:

Tumor Necrosis Factor (TNF)

Interleukins (IL)
Cytokines
Prostaglandins
Platelet Activating Factor

Source: New England Journal of Medicine, 2003

Pathophysiology ofSepsis
The release of the inflammatory

mediators starts the Coagulation Cascade

leading to the development of a clot.

To maintain this clot, inhibitors are

released
to suppress fibrinolysis or breakdown.
This is necessary to have time for the
body to destroy the bacteria before the
clot is gone.

Source: Critical Care Nurse Supplement, 2004

Pathophysiology ofSepsis
Once the bacteria or
antigen is isolated,
the pro-inflammatory
mediators attract
neutrophils or WBCs
which attack the
antigen and try to
. engulf it
Graphics: Delores Zittel, 2006

Pathophysiology ofSepsis
To prevent the response from
damaging normal tissue, antiinflammatory mediators are released
including transforming growth factors
and interleukins (IL-4). This balance of
inflammatory and anti-inflammatory
mediators restricts the inflammation
.response to the local site of infection
Source: Critical Care Nurse Supplement, 2004

Pathophysiology ofSepsis
When the body is unable to maintain
the appropriate balance, the immune
response is no longer local but
becomes systemic.
Inflammation and altered clotting
quickly spread through the body.

Source: Critical Care Nurse Supplement, 2004

Pathophysiology ofSepsis
The person with
the infection
which was once
localized could
become critically
ill if this process is
.not corrected

H om eostasis 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.

Coagulation and Fibrinolysis

Bernard, GR. NEJM 2001;344;10:699-709

Lets Look a Little D eeper

There are 3 integrated responses to sepsis
Activation of Inflammation

Activation of Coagulation

Impairment of Fibrinolysis

Activation ofInfl
am m ation
Inflammation is the bodys response to
.infection
When this occurs white blood cells (WBCs)
generate and release cytokines or
. mediators of inflammation
Inflammatory mediators include: Tumor
necrosis factor-a, Interleukin-1(IL-1),
Interleukin-6 (IL-6) and Platelet activating
.factor

Activation ofInfl
am m ation
Although these cytokines (TNF, IL-1,IL-6)
play a critical role to fight off infection the
body tries to reestablish balance by
releasing anti-inflammatory cytokines as
well.
Anti-inflammatory cytokines include
interleukin -4 (IL-4) and interleukin-10 (IL10)

Activation ofInfl
am m ation
There is basically a tugPro-inflammatory (IL-1,IL-6,TNF)
of war going on between
the pro-inflammatory
and anti- inflammatory
components of the body.
In sepsis, continued
release of proinflammatory cytokines
overwhelms the antiinflammatory cytokines.

Anti-inflammatory (IL-4, IL10)

Activation ofCoagulation
Inflammation and coagulation are
closely linked. The cytokines from
inflammation stimulate coagulation
pathways. This results in the forming of
the enzyme thrombin.
This produces clotting in the body.

Activation ofCoagulation
The enhanced
clotting continues
making tiny clots or
microthrombi in
the vascular system
which impairs blood
flow and organ
.perfusion

Activation ofFibrinolysis
Fibrinolysis, or the breakdown of clots, is
the bodys response to the increased
clotting and inflammation.
In sepsis this breakdown is inhibited or
slowed because of mediators. These
mediators are called:
Plasminogen Activator Inhibitor-1 (PAI-

1)
Thrombin Activatable Fibrinolysis
Inhibitor (TAFI)

Activation ofFibrinolysis
The increase levels of these two
inhibitors,
Plasminogen Activator Inhibitor1(PAI-1) and Thrombin Activatable
Fibrinolysis Inhibitor (TAFI), suppress
fibrinolysis even more creating a
state of coagulopathy.

The Inflammatory, Coagulation,

and Fibrolytic Response to
Infection

Graphics: Delores Zittel, 2006

M aking M atters W orse

The Role ofEndothelium in
Sepsis

Graphic: Delores Zittel, 2006

M aking M atters W orse

The Role ofEndothelium in
Sepsis
Normal endothelium has anticoagulant abilities
and plays a role in the bodys homeostasis
abilities including:
Vasomotor tone
Movement of cells and nutrients
Maintaining blood fluidity

When activated, endothelium also plays a role in

the inflammatory, coagulation, and fibrinolytic
.components of sepsis

M aking M atters W orse

In sepsis the endothelium becomes

damaged which makes the

inflammatory process worse by
releasing more cytokines (TNF-a and IL1) causing neutrophils to stick to its
lining.
The activation of the capillary
endothelium leads to increased
permeability causing fluid to leak out
of the capillaries and into the
extracellular spaces.

D am aged Endothelium

Graphics: Delores Zittel,

2006

Putting it allTogether
The imbalance
of Inflammation,
Coagulation, and
Fibrinolysis and the
effects on endothelium
can lead to organ
failure even death if
left undetected or
untreated.

Pathogenesis ofSIRS/M O D S
Preoperative Illness

Trauma or
Operation

Tissue Injury

optimal oxygen
delivery and
support

Recovery

Excessive
Inflammatory
Response

Inadequate
Resuscitation

SIRS/MODS

Regulation ofoxygen delivery

Normal
Cardiac
output

Abnormal

BP=CO * SVR

Cardiac
Output

regional distribution

regional distribution

Intra Organ Distribution

Intra Organ Distribution

Microcirculation

Microcirculation

QO2 = Flow * O2
content

O xygen D elivery

Delivery:Demand mismatch
Diffusion limitation (edema)

O xygen Consum ption

H+

H+

NADH + H+

H+

NAD+

Cytc

III

H+

IV

1/2 O2 + H+ H2O
ADP + Pi

Pyruvate Dehydrogenase (PDH) activity decreased

Decreased delivery of Acetyl CoA to TCA cycle
Mitochondrial dysfunction

H+

ATP

Q uestion: W hy do Septic
?Patients D ie

Answer: Organ

Failure

O rgan Failure and

M ortality
Knaus, et al. (1986):
Direct correlation between number of organ
systems failed and mortality.
Mortality Data:

#OSF

1
2
3

D1

D2

D3

D4

D5

D6

D7

22% 31% 34% 35% 40% 42% 41%

52% 67% 66% 62% 56% 64% 68%
80% 95% 93% 96% 100 100 100
%
%
%

Evidence-B ased Sepsis

G uidelines
Components:
Early Recognition
Early Goal-Directed Therapy
Monitoring
Resuscitation
Pressor / Inotropic Support

Steroid Replacement
Recombinant Activated Protein C
Source Control
Glycemic Control
Nutritional Support
Adjuncts: Stress Ulcer Prophylaxis, DVT
Prophylaxis, Transfusion, Sedation,
Analgesia, Organ Replacement

Evidence-B ased Sepsis

G uidelines

Severe Sepsis:
The FinalCom m on Pathw ay
Endothelial Dysfunction and
Microvascular Thrombosis

Hypoperfusion/Ischemia

Acute Organ Dysfunction

(Severe Sepsis)

Death

Severe Sepsis:
M anagem ent ofO ur Case
Endothelial Dysfunction and
Microvascular Thrombosis

rhAPC
Corticosteroids

Hypoperfusion/Ischemia

Fluids
Vasopressors

Acute Organ Dysfunction

(Severe Sepsis)

Death

CVVHF
Enteral
nutrition
Survival