SYSTEMIC RESPONSE TO INJURY Pathways which these hormones generates:
Dr. De los Reyes 1. Receptor kinases (such as insulin or insulin-like growth
June 26, 2013
Group 10
OBJECTIVES:
o 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 pro-inflammatory
to occur
o Restore the homeostasis of the individual
*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 pro-inflammatory release of tissue
macrophages.
HORMONAL R ESPONSE – CLASSIFICATION OF HORMONES
 Polypeptides
o Cytokines, glucagon and insulin
 Amino Acids
o Epinephrine, serotonin and histamine
 Fatty Acids
o Glucocorticoids, prostaglandins and leukotrienes
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
 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
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  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-α
 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 ≥ 38°C or ≤ 36°C
 Heart Rate ≥ 90 beats/minute
 Respiratory rate ≥ 20 breaths/min or PaCO2 ≤
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
 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
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  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 cardio-
pulmonary 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
o 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
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
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 o Suppression of bone marrow function
Resuscitation
Disseminated Intravascular Coagulation (DIC) – is the most  Early goal-directed resuscitation – is to support organ
fulminate expression of hematologic dysfunction. Deranged platelet, function rather that to restore physiologic or biochemical
coagulation disorders and the presence of fibrin degradation normalcy
products. o Hemodynamic homeostasis
 Preload delivered to the atrium (Frank-
GIT dysfunction Starling Law)
 Ileus  Intrinsic contractility of the
 GI bleeding myocardium
 Bacterial translocation  After load
o Gut barrier theory is based on the principle that (Adequate urine output, reduction of
the gut microorganisms which are normally lactic acidosis)
present in the gut lumen translocate outside
causing infection and eventually sepsis Prophylaxis
o The reason why prophylactic antibiotics are given  Antibiotic both systemic and locally acting in the gut
(SDD or selective decontamination of the  Have been proven to reduce nosocomial infection
digestive tract)
o Reason why early enteral feeding is necessary for
patients with risks to develop MODS to reverse Mediator targeted therapy
bacterial translocation  Activated protein
o Enteral feeding thru a tube placed in the jejunum  Corticosteroids
during the first operation  Antibody to TNF

Neurologic dysfunction
 Altered levels of consciousness usually evaluated by the Outcome or Prognosis
Glasgow coma scale  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

ICU INTERVENTIONS TO REDUCE MORTALITY AND

ATTENUATE ORGAN DYSFUNCTION

OBJECTIVE INTERVENTION
RESUSCITATION Early goal-directed resuscitation
Prophylaxis Selective digestive tract
decontamination
ICU Support Restrictive transfusion strategy
Low tidal volume ventilation
Daily wakening
Tight glucose control
Enteral feeding
Mediator targeted therapy Activated Proteins
Corticosteriods
Antibody for TNF
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