SYSTEMIC RESPONSE

TO INJURY

Dr. De los Reyes

June 26, 2013
Group 10
OBJECTIVES:
Inflammation the basic response of
the body injury

system inflammatory response

syndrome (SIRS)

multi-organ
dysfunction
syndrome (MODS)

multi-organ failure (MOF)

o Basic response to the inflammatory or
injury

Hormonal

Cytokines
and
other
substances

Cellular response

Tissue response
INFLAMMATORY RESPONSE

The primary goal of inflammatory response

following trauma (injury) or infection is to
restore tissue function and to eradicate
the invading microorganism

The response of the body to injury depends

upon the degree of the insult (directly
proportional)

Pro-inflammatory Phase (SIRS)

o Activation of the various processes to
restore tissue function and to eradicate
invading microorganism

Anti-inflammatory Phase (CARS)

o Regulate to prevent excessive proinflammatory to occur
o Restore the homeostasis of the
individual

o Cytokines, glucagon and insulin

Amino Acids
o Epinephrine, serotonin and histamine
Fatty Acids
o Glucocorticoids, prostaglandins and
leukotrienes

*SIRS-system inflammatory response syndrome

*CARS-counterregulatory anti-inflammatory response
syndrome

ROLE OF THE CNS

Operating via the autonomic pathways it

regulates inflammatory response involuntarily
(reflex manner)
o Directs proportion to degree of pain
and responses of the body
Afferent signals from the site of injury via the
circulation (TNF-a) and the neural pathways
(cytokines
and
interleukins)
to
the
hypothalamus
o Afferent signals can trigger neural
pathways to the hypothalamus
The CARS is mediated via the parasympathetic
pathway with acetylcholine as the primary
neurotransmitter causing reduction of proinflammatory release of tissue macrophages.

HORMONAL R ESPONSE CLASSIFICATION OF

HORMONES

Pathways which these hormones generates reaction:

1. Receptor kinases (such as insulin or insulinlike growth factors)
2. Guanine nucleotide binding or G-protein
receptors (such as neurotransmitter and
prostaglandin receptors)
3. Ligand-gated
ion
channels
transmembrane receptors that allow the rapid
influx of ions (e.g., sodium, calcium, potassium,
chloride) and are central to the signal
transduction of neurotransmitters

HORMONES

WITH
SIGNIFICANT
CLINICAL
IMPACT
Adrenocorticotropic hormone (ACTH)

binds with receptors in the zona fasciculata of

the adrenal gland, which mediate intracellular
signaling and subsequent cortisol release

Its elevation is proportional to the severity of

the injury

Pain, anxiety, vasopressin intestinal peptides

and cholecystokinins are mediators of ACTH
release of the injured patient

Following ACTH stimulation the following are

also released:

Glucocoticoids (Cortisol)

Mineralcorticoids

Cortisol and Glucocoticoids

Basically for survival of px e.g. for burn

patients its level can be elevated for as long as
4 weeks

Metabolic effects:
o Potentiates the action of glucagon and
epinephrine causing hyperglycemia
o In the liver it favors gluconeogenesis

acts on liver enzymes by

decreasing glycogenesis, while
increasing gluconeogenesis
o Release of FFA, TAG and glycerol from
adipose tissues for energy sources

have immunosuppressive properties that have

been used when needed, as in organ
transplantation
Aldosterone and Mineralcorticoids

Basically for survival

Maintain intravascular volume

o Conserving sodium
o Eliminating potassium and hydrogen
ions
Catecholamines

Polypeptides

are hormones secreted by the chromaffin cells

of the adrenal medulla and function as
neurotransmitters in the CNS
In the liver it promotes glycogenolysis,
gluconeogenesis, lipolysis and ketogenesis
All
these
results
to
stress
induced
hyperglycemia basically similar to the effects
of cortisol
Unlike cortisol its contribution to metabolic
effects are short-lived (24-48 hours)
exert several hemodynamic effects, including
increased
cardiac
oxygen
demand,
vasoconstriction, and increased cardiac output.

Insulin

hallmarks of critical illness due to the catabolic

effects of circulating mediators, including
catecholamines, cortisol, glucagon, and growth
hormone
Hormones
and
inflammatory
mediators
responding to a stress or injury inhibit insulin
release
The net effect of this is stress-induced
hyperglycemia
Unlike in a healthy individual insulin promotes:
o Hepatic glycogenesis and glycolysis
o Glucose transport into the cells
o Adipose tissue lipogenesis
o Protein synthesis

MEDIATORS OF INFLAMMATION

Cytokines
Heat shock proteins
Reactive oxygen metabolites
Eicosanoids
Fatty acid metabolites
Kallikrein-kinin system
Serotonin
Histamines

Cytokines

The most potent of the inflammatory response

They have the capability of eradicating

microorganisms and promote wound healing

It is considered a double edged sword since

while it is beneficial if controlled but once it is
uncontrolled it may contribute to MODS anfd
MOF

mediate a broad sequence of cellular

responses, including cell migration, DNA

replication, cell turnover, and immunocyte

proliferation
Tumor necrosis factor-a
Interleukin
Interferon
Granulocyte-macrophage colony stimulating
factor

Tumor Necrosis Factor-

cytokine that is rapidly mobilized in response

to stressors such as injury and infection, and is

a potent mediator of the subsequent

inflammatory response
Is the earliest and most potent mediator of
inflammatory response with a half-life less than
20 minutes but with profound effects
o Coagulation, muscle catabolism and
stress-induced cachexia plus its ability
to activate other mediators
primary sources are form the monocytes,
macrophages and T cells
Areas where these are abundant are in the
peritoneum and splanchnic tissues
The Kupffer cells contain a very high
concentration of the macrophages in the
human body
composed of two subtypes: TNFR-1 and TNFR-2

Reactive Oxygen Metabolites

main areas of ROS production include

o
mitochondrial electron transport
o
peroxisomal fatty acid metabolism
o
cytochrome P-450 reactions
o
respiratory burst of phagocytic cells

Short-lived, highly reactive molecular oxygen

species with an unpaired outer orbit resulting
from a complex coupled with reduction of
oxygen to superoxide anion

can cause cellular injury to both host cells and

invading pathogens through the oxidation of
unsaturated fatty acids within cell membranes.

Superoxide anion is further metabolized to

other species such as hydrogen peroxide and
hydroxyl radicals

Cause tissue injury by oxidation of unsaturated

fatty acids within the cell membrane

Protective mechanisms by the cells against

these oxygen metabolites

Gluthathione and catalases are scavengers for

these metabolites

In tissue ischemia the lack of oxygen supply

causes the mechanism for oxygen metabolite
production to remain nonfunctional but

Upon restoration of blood flow and oxygen

supply large quantities of O2 oxygen
metabolites are released reperfusion injury
SIRS
Two or more of the following

Temperature 38C or

Heart Rate 90 beats/minute

Respiratory rate 20 breaths/min or PaCO2

36C

32mmHg or mechanical ventilation

WBC 12,000/mm3 or

4,000mm3 or

10% band forms

(All of these denote a clinical response of the individual
independent of its cause. It can be infection, trauma or
immune
reaction,
immunogenic
factors
and
intoxications)

TERMS
2

Sepsis when there is an identifiable source

of infection + SIRS
Severe sepsis - sepsis + organ dysfunction
Septic shock sepsis + cardiovascular
collapse (requiring vasopressor support)
MODS multi-organ dysfunction syndrome
MOF multi-organ failure

MODS Multiple Organ Dysfunction Syndrome

Replaces previous terminologies which denote

the variety of clinical response following sepsis

A clinical syndrome of altered physiologic irgan

system function that arises in the wake of an
acute severe insult to normal homeostasis such
that it cannot be maintained without
intervention

Unlike sepsis and SIRS, it is not clear that

MODS is a distinct clinical syndrome with a
unique pathophysiological basis

It is a graded degree of organ dysfunction

rather than irreversible failure

Graded degree of organ dysfunction rather

than irreversible failure

Provides a convenient framework for describing

morbidity in critical illness so that a validated
scoring system can be established

No consensus on the criteria to define MODS

Respiratory, renal, hepatic

Implications of SIRS and MODS

Both are evoked by the same clinical triggers

Both appear to be mediated through the

elaboration of host-derived inflammatory
mediators

SIRS is a risk factor for MODS

SIRS
describes
a
process
whereas
SEPSIS/MODS/MOF describes the outcome of
that process

SIRS can help prognosticate outcomes such as

mortality
o 2 SIRS criteria 5%
o 3 SIRS 10%
o 4 SIRS 15-20%
Clinical response of patients

Ebb phase
o Elevated blood glucose level
o Normal glucose production
o Elevated FFA level
o Low insulin concentration
o Elevated levels of catecholamines and
glucagon
o Elevated blood lactate levels
o Depressed O2 consumption
o Below normal cardiac output
o Below normal core temperature
o Dominated by cardiovascular instability
o Alterations in circulating blood volume
o Impairment of O2 transport
o Heightened autonomic activity

Emergency support of cardiopulmonary

performance
is
paramount
Shock is a prototypical clinical
manifestation
of
the Ebb
phase.

Flow phase
o Normal or slightly elevated blood
glucose level
o Increased glucose production
o Normal or slightly elevated free fatty
acid levels
o Normal
or
elevated
insulin
concentration
o High normal or elevated levels of
catecholamines and glucagon levels
o Normal blood lactate level
o Elevated O2 consumption
o Increased cardiac output
o Elevated core temperature

Anabolic phase
o Repletion of lean tissue and fat stores
o Restoration of strength and stamina
begins

MODS/MOF

Risk factor categories

Infection

peritonitis,
intraabdominal
infections, pneumonia, necrotinizing soft tissue
infections

Inflammation pancreatitis

Injury polytrauma, burn injury

Ischemia hypovolemic shock, mesenteric

ischemia

Immune reaction autoimmune, transplant

rejection

Iatrogenic factors delayed or missed injury,

blood transfusion, mechanical ventilator injury

Intoxication
drug reactions, arsenic
intoxication, drug overdose

Idiopathic
factors

thrombonic
thrombocytopenic purpura, hypoadrenalism,
pheochromocytoma
Organ system involved and the indicator of
dysfunction

Respiratory PaO2/FiO2 ratio

Renal serum creatinine level

Hepatic - serum bilirubin levels

Cardiovascular pressure adjusted heart rate

(HR x CVP/MAP)

Hematologic platelet count

GIT bleeding

Neurologic Glasgow Coma Scale

Respiratory dysfunction

Acute Respiratory Distress Syndrome

(ARDS) is the prototypical expression of
respiratory dysfunction in MODS

In its mildest form, will present as

tachypnea, hypocapnia and hypoxia
which will need mechanical ventilator
support
Pathophysiology results from increased
capillary permeability and neutrophil influx
(wet lung syndrome)
PaO2/F1O2 lower than 200
Earliest insult to the kidneys result from
hypotension and decreased renal blood flow
resulting
to
decreased
urine
output,
progressively rising serum creatinine
Pathophysiology decreased blood flow will
result to intrarenal vasoconstriction and
reduction of GFR, injury to the tubules and
eventually to renal ischemia
o

o
o

The reason why prophylactic antibiotics

are
given
(SDD
or
selective
decontamination of the digestive tract)
Reason why early enteral feeding is
necessary for patients with risks to
develop MODS to reverse bacterial
translocation
Enteral feeding thru a tube placed in
the jejunum during the first operation

Neurologic dysfunction

Altered levels of consciousness

evaluated by the Glasgow coma scale

usually

Hepatic dysfunction

Ischemic hepatitis or shock liver

o Splanchnic hypoperfusion
o Elevated serum aminotransferases

ICU jaundice
o Increased serum bilirubin levels
(These conditions are not life threatening)
Cardiovascular dysfunction

Involves the peripheral vascular bed and the

myocardium
o Reduced vascular resistance and
increased microvascular permeability =
hyperdynamic
circulation
and
peripheral edema
o Resulting
deprivation
of
oxygen
delivery because of increased distance
between cells and capillaries
o Shunting occurs due t thrombi and
other products of inflammation causing
further tissue hypoxia
o Loss of normal heart rate signifies
advanced CV dysfunction
Hematologic dysfunction

Thrombocytopenia is the most common

hematologic abnormality
o Increased consumption of platelets
o Intravascular sequestration
o Suppression of bone marrow function
Disseminated Intravascular Coagulation (DIC) is
the most fulminate expression of hematologic
dysfunction. Deranged platelet, coagulation disorders
and the presence of fibrin degradation products.
GIT dysfunction

Ileus

GI bleeding

Bacterial translocation
o Gut barrier theory is based on the
principle that the gut microorganisms
which are normally present in the gut
lumen translocate outside causing
infection and eventually sepsis

ICU
INTERVENTIONS
TO
REDUCE
MORTALITY AND ATTENUATE ORGAN
DYSFUNCTION
OBJECTIVE
RESUSCITATION
Prophylaxis
ICU Support

Mediator targeted therapy

INTERVENTION
Early
goal-directed
resuscitation
Selective
digestive
tract decontamination
Restrictive transfusion
strategy
Low
tidal
volume
ventilation
Daily wakening
Tight glucose control
Enteral feeding
Activated Proteins
Corticosteriods
Antibody for TNF

Resuscitation

Early goal-directed resuscitation is to

support organ function rather that to restore
physiologic or biochemical normalcy
o Hemodynamic homeostasis

Preload delivered to the atrium

(Frank-Starling Law)

Intrinsic contractility of the

myocardium

After load
(Adequate
urine
output,
reduction of lactic acidosis)

Prophylaxis

Antibiotic both systemic and locally acting in

the gut

Have been proven to reduce nosocomial

infection
Mediator targeted therapy

Activated protein

Corticosteroids

Antibody to TNF

Outcome or Prognosis

APACHE (Acute Physiology and Chronic Health

Evaluation) II scoring

Two hit hypothesis

o Acute insult initial action which
primes the host such as trauma,
infection or SIRS
o Subsequent insult overwhelm the
host such as nosocomial infection,
missed injury, iatrogenic injury
\