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Physiology in trauma
Endocrine dysfunction in trauma/sepsis
Adreno-cortical
Stress hyperglycaemia
Thyroid dysfunction
Growth hormone
Calcium metabolism
injury
surgery
sepsis
burns
starvation
dehydration
vascular occlusion
Body responds
Locally with inflammation
cellular
humoral
Characterized by
Acute catabolic reaction
preceded by
Cuthbertson described an
Ebb and Flow phase
Ebb phase
Flow Phase
divided into
Catabolic phase
Anabolic phase
Catabolic phase
fat and protein mobilisation
associated weight loss
increased secretion of urinary excretion
Anabolic phase
weight gain
restoration of fat and protein stores
Hypermetabolic
Increased Cardiac output
Increased Oxygen consumption
Increased Glucose production
Influencing factors
The magnitude of the response depends on the
degree of trauma
and concomitant contributing factors
drugs
sepsis
systemic illness
age, gender, nutritional status
less aggressive in kids and the elderly
more aggressive in burns
Initiating Factors
Hypovolaemia
hypoprefusion is the most potent precipitator of
the metabolic response to trauma
Afferent impulses
hormonal response
pain
anxiety
Initiating factors
Wound factors
tissue injury along 2 pathways
Inflammatory
Cellular
(humoral)
Immune response
Humoral
Cellular
via
via
Eicosanoids
Phagocytic cells
Eicosanoids
synthesized from Arachidonic acid from phospholipids from
damaged cells, WBCs and platelets
implicated in induction of membrane dysfunction
Prostanoids
Prostaglandin
Prostacyclin
Thromboxane
cause vasoconstriction, vasodilation, platelet aggregation, and
platelet inhibition
Leucotriens
cause vasoconstriction, increased capillary
permeability, bronchoconstriction
Cellular pathway
Activation of phagocytic cells
most NB
Polymorphs, MO
Phagocytosis starts with the activation of
Complement
2 pathways
Classical pathway
Alternative pathay
stimulate MO to secrete
IL-1 + Proteolyis inducing factor (PIF)
these stimulate production of acute phase proteins
catecholamines
adrenaline, noradrenaline
endorphins
corticotropin and glucocorticoids
glucagon
Resulting in
vascular instability
hyperglycaemia
hypermetabolic state
hyperdynamic circulation
Catecholamines
Glucocorticoids and
Mineralocorticoids
Insulin
Glucagon
Thyroid hormone
Growth hormone
Parathyroid hormone
Release of Catecholamines
Stimulate
CH metabolism
glycogenolysis in liver and muscle fibres
stimulate gluconeogenesis in the liver
inhibit glucose induced insulin secretion
nett result is hyperglycaemia
Fat metabolism
lipolysis of fatty acids
supply of energy
Catecholamines...
CH and fat metabolism is increased
metabolic rate is increased
resulting in
increased oxygen consumption/requirements
heat production
CVS
(+)inotrope
(+) chronotrope
(+)dromotrope
Insulin
CH
Causes movement of glucose across insulin dependent cell
membranes
catabolism of glucose by insulin dependent cells
glycogenolysis by
muscle fibres
hepatocytes
adipocytes
Fat
promotes lipogenesis
storage of fat
Insulin
Protein
promotes protein synthesis
Glucagon
CH
Glycogenolysis as well as gluconeogenesis
lipolysis
Proteolysis
thus
increasing glucose concentration
increasing energy
Cortisol
Increased protein catabolism
increases the amino acids in blood for
gluconeogenesis in the liver
Increased lipolysis
decreased glucose utilisation
nett result
hyperglycaemia
increased energy
(CRH)
(ACTH)
(Cortisol, Aldosterone)
Adrenocortical insufficiency
The adrenal cortex synthesizes, and secretes 3
major types of hormones
Glucocorticoid
Cortisol
Mineralocorticoid
Aldosterone
Adrenal androgens
ACTH
which is regulated by
Corticotrophin releasing hormone CRH
Pain receptors
Osmo-receptors
Baro-receptors
Chemoreceptors
stimulate ganglia in the Hypothalamus
Cortisol
is stimulated by
Cortisol
Stimulates
Gluconeogenesis
Catabolism
protein
carbohydrate
lipid n
nucleic acid metabolism
Anti-inflammatory
inhibits neutrophil and macrophage migration
microvascular stabilising effect
Aldosterone
secretion is stimulated by
Aldosterone
Increases
Na+ conservation
K+ loss
by the kidneys, sweat glands, GIT
Cortisol levels
It is impossible to define an absolute serum cortisol
threshold that would identify a patient with
functional failure of the H-P-A axis
due to
diurnal pattern of cortisol secretion
inter-individual range of circulating cortisol levels during
severe illness and stress
other test
measurement of basal ACTH (elevated)
ACTH determination is cumbersome
ACTH has a short half life
Dilemma of diagnosis
only way is to rely on a clinical assessment of the
severity of the stress
and to estimate the adequacy of the measured
cortisol level
vitiligo
depression, fatigue
nausea, abdominal pain
haemodynamic instability
unexplained fever
hyponatraemia
hypoglycaemia
unexplained eosinophilia
Glycaemic control
Hypoglycaemia
Hyperglycaemia
Stress hyperglycaemia
Acute hyperglycaemia in response to stress
diabetes of in jury or Stress hyperglycaemia
Stress Hyperglycaemia
Definition
hyperglycaemia in the previously euglycaemic patient
that resolves after the acute process
Prevalence
estimated range
3-70%
highly variable due to
an inconsistently applied definition
previously un-recognized Diabetes mellitus
Cause of SH
Multitude of factors
underlying conditions
obesity
pancreatitis
cirrhosis
Diabetes itself
Stress metabolism
Cytokines
Oxidative stress
Stress signalling pathways
Stress metabolism
Initiates a neuro-hormonal response
eg. Hypothalamus
Stress metabolism
an influx of cortisol, glucagon, epinephrine, results
in
Stress metabolism
Increased synthesis of
Acute phase proteins
Stress metabolism
The liver becomes insensitive to auto-regulation by
glucose itself and glucagon
glucose production and lactate extraction are typically
increased x 2
glycerol contribution increases by 20%
glucose uptake is near maximal at non-insulin
sensitve, immune-related sites
Cause of SH...
Cytokines
many of the metabolic changes arise from inter-related effects
of pro-inflammatory cytokines
eg.
effects
induce insulin resistance
hyperglycaemia by activation of the H-P-A axis
Cause of SH...
Oxidative stress
definition
imbalance between
the production of highly reactive oxygen and/or nitrogen
species
and endogenous anti-oxidants
this causes
an exacerbated oxidative stress on ICU pts with
systemic inflammation
Oxidative stress
hyperglycaemic exposure to endothelial cells and
smooth muscle cells stimulate oxygen radicals
formation
hyperglycaemic exposure to pancreatic beta cells
results in oxygen radical formation and decreased first
phase of insulin secretion
Pancreatic beta cells seem to express low levels of
anti-oxidants
Causes of SH
Stress signaling pathways
hyperglycaemia induced free oxygen radicals
function as an acute signaling factor for stress-sensitive
pathways
Nuclear factor Kappa B (NF KB)
c-Jun N-terminal kinase/stress activated kinase
mitogen activated protein kinase (MAPK)
Cause
defective insulin signalling
insulin resistance
In summary
Cause of stress hyperglycaemia
Combination of
Non-thyroidal illness
Definition
clinically euthyroid pts, with non-thyroidal illness
who have low T3,and N or low T4
N or low TSH
(inappropriately)
typically
normal TSH and T4
low T3
suggests a change in the H-P-A axis setpoint
NTI
thought to be a homeostatic correction by which the
body diminishes the effects of biologically active
T3
decreased de-iodination of T4 to T3 (active)
NTI occurs in most patients with systemic illness
important to recognise because
morbidity and morality rate of NTI is high
Cause of NTI
Decrease in peripheral production of T3
due to decreased extra-thyroidal conversion of T4 to
T3 (by enzyme type 1 iodo-thyronine -5-deiodinase)
circulating TSH levels are low-N despite decreased
T3
there is a blunted response of TSH to TRH and low
TSH levels are associated with a poor prognosis
H-P-A axis
critically ill pts show diminished TSH
pulsatility
a major change in thyroid hormone setpoint
regulation seems to occur in NTI
in the hypothalamus
unrelated hypotension
dry skin
bradycardia
hypothermia
Diagnosis
In primary hypothyroidism the TSH levels
sharply increase
In NTI
TSH typically stays low or in the normal range
the TSH level probably relatively accurately
reflects the amount of T3 available at the pituitary
and indirectly tissue thyroid hormone
concentrations
Diagnosis
a normal TSH most likely excludes
primary thyrotoxicosis
and hypothyroidism
Primary hypothyroidism
Pts with overt 1 hypothyroidism almost always
have raised levels of TSH
with decreased T4
and in severe cases also T3
TSH measurement is good for early detection of
1HT
but poor measure of clinical and metabolic severity
Thyroid crisis
Is the life-threatening clinical extreme of
hyperthyroidism
Provoking factors
infection
trauma
surgery
uncontrolled DM
labour
eclampsia
Sx + Tx
hyper-pyrexia
tachycardia
AF
delirium or coma
agitation
vomiting, diarrhoea
muscle weakness
May have sx of
profound exhaustion
hyporeflexia
severe myopathy
marked weight loss
hypotension
DDX
Sepsis
hyper-thermic syndromes
delirium tremens
opioid withdrawal
adrenergic or cholinergic overdose
Myxoedema coma
Hypothyroid crisis
at any age,
occurs typically during winter in the elderly females
represents the terminal stage of decompensated
hypothyroidism
has a high mortality
Sx and Tx
Cardinal symptom
deterioration of the pts mental status
those presenting in coma, have long standing
unrecognised thyroid hypofunction
(usually auto-immune, thyroidectomy, radioiodine
therapy)
Hypotension
Hypoglycaemia
common and needs early recognition
Other symptoms
Cold intolerance
decreased energy
muscular weakness
bradykinesia
dementia
delayed reflexes
dry skin
constipation
weight gain
IHD
anaemia
Coma
due to combination of
hypothermia
hypercarbia
hypoxia
cerebral oedema
other metabolic derangements
Growth Hormone
Secreted from anterior pituitary
under hypothalamic control
secreted in characteristic diurnal and pulsatile
pattern
GH...
Metabolic activities
lipolysis
enhanced amino acid transport into muscle cells
anti-insulin properties
most prominently
mitogenic and anabolic activity
via increased Insulin growth factor production
(IGF-1)
GH in critical illness
Mean concentration is acutely increased
sustained increase in interpulse GH levels
studies show
that pro-inflammatory cytokines induce a GH
resistance state
pulsatile secretion of anterior pituitary hormone is
reduced during the chronic phase of illness
non-survivors generally have higher levels of GH
than survivors
Para-thyroids
Regulation of Calcium homeostasis
Function of calcium
Hormonal regulation
Parathyroid hormone
in response to hypocalcaemia
PTH secretion is stimulated
stimulates
Vit. D
increases gut, and to a lesser extent renal reabsorpion of calcium
S-protein
(protein binding)
S-phosphate
pH
magnesium
Ca and phosphate
HPO4 (2-)
Ca(2+)
-->
CaHPO4(-)
Magnesium
is required for PTH secretion
and end organ responsiveness
Hyper-Ca
may be due to an increase in PTH
homeostatic feedback is preserved
called equilibrium hyper-Ca
Mechanisms of hyper-Ca
Malignancy related
from bony metastasis
humoral hyper-Ca of malignancy
PTH like substances, calcitriol,osteoclast activating factor and
prostaglandins are released
causing tumour osteolysis of bone
seen with bronchogenic CA and hypernephroma
Mechanisms of hyper-Ca
Immobilisation hyper-Ca
Manifestations of hyper-Ca
CVS
hypertension
arrhythmias
digitalis sensitivity
catecholamine resistance
Urinary system
nephrocalcinosis
nephrolithiasis
tubular dysfunction
renal failure
Manifestations of hyper-Ca
Gastro-intestinal
Neuro-muscular
weakness
Neuro-psychiatric
depression, psychosis
coma, seizures
disorientation
Investigations
S-Ca + S-phosphate
ALP
PTH
renal functions
skeletal survey
Hypo-Ca
Estimated incidence
70-90%
common
higher mortality
increased ICU stay
Aetiology
Various causes
Ca chelation
Aetiology
Hypoparathyroidism
Hypo- and hyper-magnesaemia
Sepsis
decreased PTH secretion
calcitriol resistance
intracellular shift of Ca
Burns
decreased PTH secretion
Neck surgery
removal of parathyroid glands
calcitonin release during surgery
hungry bone syndrome post parathyroidectomy
Aetiology
Hypovitaminosis D
inadequate intake
malabsorption
liver disease
renal failure
Aetiology
Drug induced
Phenytoin
Diphosphonates
Cis-platinum
protamine
gentamycin
Diagnosis
Patterns of recognition
eg.
Renal failure
elevated blood urea nitrogen
elevated phosphate
hypomagnesaemia
reduced ionized Ca
hypokalaemia
Sx and Tx of Hypocalcaemia
Mild degrees usually asymptomatic
CNS
Sx and Tx of Hypocalcaemia
CVS
arrhythmias
hypotension
inotrpoe unresponsiveness
prolonged QT intervals, T wave inversion
loss of digitalis effect
Respiratory
apnoea
laryngospasm
bronchospasm
Confused?