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 factors)
Group 10 2. Guanine nucleotide binding or G-protein receptors (such
as neurotransmitter and prostaglandin receptors)
3. Ligand-gated ion channels - transmembrane receptors that
OBJECTIVES: allow the rapid influx of ions (e.g., sodium, calcium,
o Inflammation – the basic response of the body potassium, chloride) and are central to the signal
injury transduction of neurotransmitters
 system inflammatory response
syndrome (SIRS) HORMONES WITH SIGNIFICANT CLINICAL IMPACT
 multi-organ dysfunction syndrome Adrenocorticotropic hormone (ACTH)
(MODS)  binds with receptors in the zona fasciculata of the adrenal
 multi-organ failure (MOF) gland, which mediate intracellular signaling and
o Basic response to the inflammatory or injury subsequent cortisol release
 Hormonal  Its elevation is proportional to the severity of the injury
 Cytokines and other substances  Pain, anxiety, vasopressin intestinal peptides and
 Cellular response cholecystokinins are mediators of ACTH release of the
 Tissue response injured patient
INFLAMMATORY RESPONSE  Following ACTH stimulation the following are also
 The primary goal of inflammatory response following released:
trauma (injury) or infection is to restore tissue function  Glucocoticoids (Cortisol)
and to eradicate the invading microorganism  Mineralcorticoids
 The response of the body to injury depends upon the
degree of the insult (directly proportional) Cortisol and Glucocoticoids
 Pro-inflammatory Phase (SIRS)  Basically for survival of px e.g. for burn patients its level
o Activation of the various processes to restore can be elevated for as long as 4 weeks
tissue function and to eradicate invading  Metabolic effects:
microorganism o Potentiates the action of glucagon and
 Anti-inflammatory Phase (CARS) epinephrine causing hyperglycemia
o Regulate to prevent excessive pro-inflammatory o In the liver it favors gluconeogenesis
to occur  acts on liver enzymes by decreasing
o Restore the homeostasis of the individual glycogenesis, while increasing
gluconeogenesis
*SIRS-system inflammatory response syndrome o Release of FFA, TAG and glycerol from adipose
*CARS-counterregulatory anti-inflammatory response syndrome tissues for energy sources
 have immunosuppressive properties that have been used
ROLE OF THE CNS when needed, as in organ transplantation
 Operating via the autonomic pathways it regulates
Aldosterone and Mineralcorticoids
inflammatory response involuntarily (reflex manner)
o Directs proportion to degree of pain and  Basically for survival
responses of the body  Maintain intravascular volume
o Conserving sodium
 Afferent signals from the site of injury via the circulation
(TNF-a) and the neural pathways (cytokines and o Eliminating potassium and hydrogen ions
interleukins) to the hypothalamus
o Afferent signals can trigger neural pathways to Catecholamines
the hypothalamus  are hormones secreted by the chromaffin cells of the
adrenal medulla and function as neurotransmitters in the
 The CARS is mediated via the parasympathetic pathway
CNS
with acetylcholine as the primary neurotransmitter causing
reduction of pro-inflammatory release of tissue  In the liver it promotes glycogenolysis, gluconeogenesis,
macrophages. lipolysis and ketogenesis
 All these results to stress induced hyperglycemia basically
similar to the effects of cortisol
HORMONAL R ESPONSE – CLASSIFICATION OF HORMONES  Unlike cortisol its contribution to metabolic effects are
 Polypeptides
short-lived (24-48 hours)
o Cytokines, glucagon and insulin
 exert several hemodynamic effects, including increased
 Amino Acids cardiac oxygen demand, vasoconstriction, and increased
o Epinephrine, serotonin and histamine cardiac output.
 Fatty Acids
o Glucocorticoids, prostaglandins and leukotrienes Insulin

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  hallmarks of critical illness due to the catabolic effects of o respiratory burst of phagocytic cells
circulating mediators, including catecholamines, cortisol,  Short-lived, highly reactive molecular oxygen species with
glucagon, and growth hormone an unpaired outer orbit resulting from a complex coupled
 Hormones and inflammatory mediators responding to a with reduction of oxygen to superoxide anion
stress or injury inhibit insulin release  can cause cellular injury to both host cells and invading
 The net effect of this is stress-induced hyperglycemia pathogens through the oxidation of unsaturated fatty acids
 Unlike in a healthy individual insulin promotes: within cell membranes.
o Hepatic glycogenesis and glycolysis  Superoxide anion is further metabolized to other species
o Glucose transport into the cells such as hydrogen peroxide and hydroxyl radicals
o Adipose tissue lipogenesis  Cause tissue injury by oxidation of unsaturated fatty acids
o Protein synthesis within the cell membrane
 Protective mechanisms by the cells against these oxygen
metabolites
MEDIATORS OF INFLAMMATION  Gluthathione and catalases are scavengers for these
 Cytokines metabolites
 Heat shock proteins  In tissue ischemia the lack of oxygen supply causes the
 Reactive oxygen metabolites mechanism for oxygen metabolite production to remain
nonfunctional but
 Eicosanoids
 Upon restoration of blood flow and oxygen supply large
 Fatty acid metabolites
quantities of O2 oxygen metabolites are released –
 Kallikrein-kinin system
reperfusion injury
 Serotonin
 Histamines
SIRS
Two or more of the following
Cytokines
 Temperature ≥ 38°C or ≤ 36°C
 The most potent of the inflammatory response
 They have the capability of eradicating microorganisms  Heart Rate ≥ 90 beats/minute
and promote wound healing  Respiratory rate ≥ 20 breaths/min or PaCO2 ≤
 It is considered a double edged sword since while it is 32mmHg or mechanical ventilation
beneficial if controlled but once it is uncontrolled it may  WBC ≥ 12,000/mm3 or ≤ 4,000mm3 or ≥ 10% band
contribute to MODS anfd MOF forms
 mediate a broad sequence of cellular responses, (All of these denote a clinical response of the individual independent
including cell migration, DNA replication, cell turnover, and of its cause. It can be infection, trauma or immune reaction,
immunocyte proliferation immunogenic factors and intoxications)
 Tumor necrosis factor-a
 Interleukin TERMS
 Interferon  Sepsis – when there is an identifiable source of infection +
 Granulocyte-macrophage colony stimulating factor SIRS
 Severe sepsis - sepsis + organ dysfunction
Tumor Necrosis Factor-α  Septic shock – sepsis + cardiovascular collapse (requiring
 cytokine that is rapidly mobilized in response to stressors vasopressor support)
such as injury and infection, and is a potent mediator of  MODS – multi-organ dysfunction syndrome
the subsequent inflammatory response  MOF – multi-organ failure
 Is the earliest and most potent mediator of inflammatory
response with a half-life less than 20 minutes but with MODS Multiple Organ Dysfunction Syndrome
profound effects  Replaces previous terminologies which denote the variety
o Coagulation, muscle catabolism and stress- of clinical response following sepsis
induced cachexia plus its ability to activate other  A clinical syndrome of altered physiologic irgan system
mediators function that arises in the wake of an acute severe insult to
 primary sources are form the monocytes, macrophages normal homeostasis such that it cannot be maintained
and T cells without intervention
 Areas where these are abundant are in the peritoneum  Unlike sepsis and SIRS, it is not clear that MODS is a
and splanchnic tissues distinct clinical syndrome with a unique pathophysiological
 The Kupffer cells contain a very high concentration of the basis
macrophages in the human body  It is a graded degree of organ dysfunction rather than
 composed of two subtypes: TNFR-1 and TNFR-2 irreversible failure
 Graded degree of organ dysfunction rather than
Reactive Oxygen Metabolites irreversible failure
 main areas of ROS production include  Provides a convenient framework for describing morbidity
o mitochondrial electron transport in critical illness so that a validated scoring system can be
o peroxisomal fatty acid metabolism established
o cytochrome P-450 reactions  No consensus on the criteria to define MODS

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  Respiratory, renal, hepatic  Iatrogenic factors – delayed or missed injury, blood
transfusion, mechanical ventilator injury
Implications of SIRS and MODS  Intoxication – drug reactions, arsenic intoxication, drug
 Both are evoked by the same clinical triggers overdose
 Both appear to be mediated through the elaboration of  Idiopathic factors – thrombonic thrombocytopenic
host-derived inflammatory mediators purpura, hypoadrenalism, pheochromocytoma
 SIRS is a risk factor for MODS
 SIRS describes a process whereas SEPSIS/MODS/MOF Organ system involved and the indicator of dysfunction
describes the outcome of that process  Respiratory – PaO2/FiO2 ratio
 SIRS can help prognosticate outcomes such as mortality  Renal – serum creatinine level
o 2 SIRS criteria – 5%  Hepatic - serum bilirubin levels
o 3 SIRS – 10%  Cardiovascular – pressure adjusted heart rate (HR x
o 4 SIRS – 15-20% CVP/MAP)
 Hematologic – platelet count
 GIT – bleeding
Clinical response of patients  Neurologic – Glasgow Coma Scale
 Ebb phase
o Elevated blood glucose level
o Normal glucose production Respiratory dysfunction
o Elevated FFA level  Acute Respiratory Distress Syndrome (ARDS) – is the
o Low insulin concentration prototypical expression of respiratory dysfunction in MODS
o Elevated levels of catecholamines and glucagon o In its mildest form, will present as tachypnea,
o Elevated blood lactate levels hypocapnia and hypoxia which will need
o Depressed O2 consumption mechanical ventilator support
o Below normal cardiac output  Pathophysiology results from increased capillary
o Below normal core temperature permeability and neutrophil influx (wet lung syndrome)
o Dominated by cardiovascular instability  PaO2/F1O2 lower than 200
o Alterations in circulating blood volume  Earliest insult to the kidneys result from hypotension and
o Impairment of O2 transport decreased renal blood flow resulting to decreased urine
o Heightened autonomic activity output, progressively rising serum creatinine
 Pathophysiology – decreased blood flow will result to
 Emergency support of cardio- intrarenal vasoconstriction and reduction of GFR, injury to
pulmonary performance is paramount the tubules and eventually to renal ischemia
 Shock is a prototypical clinical
manifestation of the Ebb phase. Hepatic dysfunction
 Ischemic hepatitis or shock liver
 Flow phase o Splanchnic hypoperfusion
o Normal or slightly elevated blood glucose level o Elevated serum aminotransferases
o Increased glucose production  ICU jaundice
o Normal or slightly elevated free fatty acid levels o Increased serum bilirubin levels
o Normal or elevated insulin concentration
(These conditions are not life threatening)
o High normal or elevated levels of catecholamines
and glucagon levels
Cardiovascular dysfunction
o Normal blood lactate level
 Involves the peripheral vascular bed and the myocardium
o Elevated O2 consumption
o Reduced vascular resistance and increased
o Increased cardiac output
microvascular permeability = hyperdynamic
o Elevated core temperature
circulation and peripheral edema
o Resulting deprivation of oxygen delivery because
 Anabolic phase
of increased distance between cells and
o Repletion of lean tissue and fat stores
capillaries
o Restoration of strength and stamina begins
o Shunting occurs due t thrombi and other
products of inflammation causing further tissue
MODS/MOF hypoxia
Risk factor categories o Loss of normal heart rate signifies advanced CV
 Infection – peritonitis, intraabdominal infections, dysfunction
pneumonia, necrotinizing soft tissue infections
 Inflammation – pancreatitis Hematologic dysfunction
 Injury – polytrauma, burn injury  Thrombocytopenia is the most common hematologic
 Ischemia – hypovolemic shock, mesenteric ischemia abnormality
 Immune reaction – autoimmune, transplant rejection 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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