Endocrine dysfunction in the ICU

Physiology in trauma
Endocrine dysfunction in trauma/sepsis

Adreno-cortical
Stress hyperglycaemia
Thyroid dysfunction
Growth hormone
Calcium metabolism

Metabolic response to trauma

Any stressor will initiate the metabolic
response to trauma

injury
surgery
sepsis
burns
starvation
dehydration
vascular occlusion

Body responds
Locally with inflammation
cellular
humoral

Generally with a protective response

conservation of fluid
provision of energy for repair

Characterized by
Acute catabolic reaction
preceded by

Metabolic process of recovery

Cuthbertson described an
Ebb and Flow phase
Ebb phase

period of severe shock

depression of enzymatic activity
increased oxygen consumption
depressed cardiac output
lactic acidosis
temperature may be subnormal

 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

 In that time the body is

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)

uncontrolled activation may play a role in the

pathology of organ dysfunction

 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

generates Anaphylatoxins: C3a and C5a

are Chemotactic factors

C3a and C5a

Responsible for
activation of Basophils, Mastcells, Platelets to
secrete Histamine and Serotonin
aggregation of neutrophils
alter vascular permeability
are vasoactive

stimulate MO to secrete
IL-1 + Proteolyis inducing factor (PIF)
these stimulate production of acute phase proteins

Hormonal response of trauma to

the body
Release of various hormones, cytokines...

catecholamines
adrenaline, noradrenaline
endorphins
corticotropin and glucocorticoids
glucagon

Resulting in

vascular instability
hyperglycaemia
hypermetabolic state
hyperdynamic circulation

Hormones involved in endocrine

dysfunction

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

Summary of stress response

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

Hypothalamic response to trauma

and resultant Adreno-cortical
insufficiency
Hypothalamus is the highest level of integration
of the Stress response
H-P-A axis
Hypothalamus
Pituitary
Adrenal cortex

(CRH)
(ACTH)
(Cortisol, Aldosterone)

Adrenocortical insufficiency
The adrenal cortex synthesizes, and secretes 3
major types of hormones
Glucocorticoid

Cortisol

Mineralocorticoid

Aldosterone

Adrenal androgens

Cortisol and Aldosterone

Secretion by the adrenal cortex is controlled by
Adreno-cortico-trophic hormone

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

circulating levels of cortisol

stress
ADH, oxytocin, Angiotensin II
sleep-wake cycle,
diurnal secretory cycle

circulating levels of IL-1

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

Renin-angiotensin system via Angiotensin II

Hypovolaemia
Hypotension
Decreased Na+
Increased K+
Increased osmolarity

Aldosterone
Increases
Na+ conservation
K+ loss
by the kidneys, sweat glands, GIT

thereby increases water conservtion

major regulator of Extra-cellular fluid volume

Adrenal insufficiency in Sepsis

Difficulty defining

Relative adrenal insufficiency

as opposed to

Absolute adrenal insufficiency

Aim:
to identify those patients at risk who might benefit
from supportive cortisol replacement therapy

Who might benefit...

Main concern in ICU setting
refractory septic shock
shock that is unresponsive to catecholamine
adminstration

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

Defining Adrenal insufficiency

Absolute adrenal insufficiency
when basal cortisol levels < 100 nmol/l
stimulated values < 500-550 nmol/l
(ACTH stimulation)

cortisol increase does not occur during stress

cause
malfunction in the H-P-A axis

Defining Adrenal insuff...

Relative adrenal insufficiency
impaired stress response of the H-P-A axis
seen during
severe illness
co-morbidities
head injury
adrenal haemorrhage
pharmacological agents (etomidate, opiates)
inflammatory mediators (TNF, Interleukins)

 The term relative or functional adrenal insuff. has

been proposed for
hypotensive
septic, critically ill patients
who are resistant to catecholamine administration
who show haemodynamic improvement to cortisol
in the absence of factors known to impair the H-P-A axis

Relative adrenal insufficiency

The cortisol levels may be > 550nmol/l or within the
normal range
but are still considered to be inadequate for the given
stress
and will be unable to respond to any further stressor
this syndrome is transient, and reverses with recovery
from the illness

Relative adrenal insufficiency

NB to recognise as
it is associated with a worsened outcome

Tests for adrenal dysfunction

No strict biochemical criteria defining normal serum
cortisol or ACTH levels
or an adequate response to ACTH exists
Best consensus reference standard for diagnosis of
integral failure of H-P-A axis is the
Insulin induced hypoglycaemia test

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

Signs and symptoms

Clinician must be vigilant for subtle sings and
symptoms

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

demonstrates the obligatory metabolic

responses required to cope with the stress
degree of hyperglycaemia seems to be a
harbinger of severity of injury and outcome

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

 Severity and outcome

SH was previously considered a compensatory response
causes a range of adverse effects

abnormal immune function

increased infection rate
haemodynamic disturbances
electro-myocardial disturbances

a number of studies have shown a direct relationship

between the extent of SH and the severity and outcome

 Insulin resistance also correlates to the severity

of stress
Various studies showed that SH increases
morbidity and mortality as confounding factors
in MI, Strokes, head injury
increased non-fatal re-infarction
increased heart failure and major cardiovascular
event admissions
increased 1 year mortality post MI

 Eg. Burned children with hyperglycaemia

(>7,7mmol/l)
had an increased incidence of (+) BC
lower percent graft take
higher mortality

Cause of SH
Multitude of factors

lack of muscular activity

ageing
use of dextrose solutions
certain drugs
catecholamines
glucocorticoids
thiazides

 underlying conditions
obesity
pancreatitis
cirrhosis

Diabetes itself

Stress metabolism
Cytokines
Oxidative stress
Stress signalling pathways

Stress metabolism
Initiates a neuro-hormonal response
eg. Hypothalamus

involving counter-regulatory hormones

eg Glucagon, cortisol...

sympathetic activity raises glucose by increased

glycogenolysis
Catecholamines

this is correlated to the degree of trauma and

the circulating epinephrine

Stress metabolism
an influx of cortisol, glucagon, epinephrine, results
in

hypermetabolism (causing catabolism of proteins and fat),

a negative nitrogen balance,
hyperglycaemia,
hyperinsulinaemia
insulin resistance

hepatocytes respond with counter-regulatory stress

hormones, by...

Stress metabolism
Increased synthesis of
Acute phase proteins

CH-metabolism is altered such that the overall

whole-body production of CH is increased and
channeled toward
immune related activities of inflammation
immune cell function
wound healing

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

Summary of stress metabolism

The stressed pt characteristically
fasting and post-prandial hyperglycaemia
insulin resistance
increased hepatic glucose production
Insulin levels, although elevated are relatively low
studies suggest insulin signalling is defective

Cause of SH...
Cytokines
many of the metabolic changes arise from inter-related effects
of pro-inflammatory cytokines
eg.

Tumour necrosis factor

Interleukin-1
Interleukin-6
counter-regulatory hormones

effects
induce insulin resistance
hyperglycaemia by activation of the H-P-A axis

 Insulin has anti-inflammatory properties

induction of euglycaemic hyperinsulinaemia by
IL-6
GH
Cortisol

hyperglycaemia also causes expression of cytokines

raising S-glucose in healthy individuals, and suppressing
insulin causes an increase in
IL-6
TNF-a
IL-8

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

 acute hyperglycaemia also alters the ability of

beta cells to couple insulin secretion to glucose
changes

 The deleterious effects of hyperglycaemia may

be caused by the production of
free radicals and the associated
oxidative stress

Oxidative stress leads to

damage to DNA, proteins and lipids
dysfunctional glucose metabolism

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)

in stress situations these factors upregulate a host of

pro-inflammatory cytokines

 Cause
defective insulin signalling
insulin resistance

In summary
Cause of stress hyperglycaemia
Combination of

high levels of cytokines

beta-cell dysfunction
(pancreas)
severity of oxidative stress
glucose generating drugs
stress signalling pathways
insulin resistance
underlying genetic diabetic predisposition

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)

In severe systemic non-thyroidal illness (NTI)

profound changes occur in the H-P-A axis
called the Euthyroid sick syndrome

 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

Thyroid changes in NTI

Fall in circulating total T3 and free T3
increase in the inactive rT3
the greater the severity of the disease, the lower the
S-T3 level becomes
T4 may be decreased
in chronic illness the T4 is low and is associated
with an increased mortality

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

Is the pt with NTI euthyroid

First exclude pre-existing thyroid disease

clinically displays the classic symptoms

hypothyroidism

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

and suggests that the patient is euthyroid and does

not require L-thyroxine therapy

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

Difficult diagnosis of NTI...

Diagnosis is very difficult if not impossible

look for signs of hypothyroidism
look for other signs of pituitary failure
CTB may be of value

Thyroid crisis
Is the life-threatening clinical extreme of
hyperthyroidism

more common in woman

mortality rate 10-20% in treated
onset is usually abrupt
precipitating factor identified in 50%

most pts have have unrecognised or poorly

controlled Graves disease

 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)

diagnosis should be made with care

 Hypotension

accompanied by sinus bradycardia

baroreceptor dysfunction
tissue hypoxia compounded by shock and anaemia
myocardial myxoedematous infiltrates
pericardial effusions
cardiac tamponade

 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

cardiac, skeletal and smooth muscle excitation

cardiac action potentials and pacemaking
release of neurotransmitters
coagulation of blood
bone formation and metabolism
hormone release
ciliary motility

Hormonal regulation
Parathyroid hormone
in response to hypocalcaemia
PTH secretion is stimulated
stimulates

increases osteo-clastic activity in bone (resorption)

renal re-absorption of calcium
renal synthesis of calcitriol (active Vit. D)
promotes urinary excretion of phosphates

Vit. D
increases gut, and to a lesser extent renal reabsorpion of calcium

Metabolic factors influencing Ca

homeostasis
Changes in

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 in critically ill pts

Frequency is not well established
but less common than hypo-Ca
common causes
malignancy related to hyper-Ca
renal failure
post-hypo-Ca hypercalcaemia

Hyper-Ca
may be due to an increase in PTH
homeostatic feedback is preserved
called equilibrium hyper-Ca

may be non-parathyroid mediated

breakdown of homeostatic feedback
called dysequlibrium 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

post hypo-Ca hyper-Ca

transient phenomenen
after hypo-Ca
due to parathyroid hyperplasia

Mechanisms of hyper-Ca
Immobilisation hyper-Ca

imbalance between bone deposition and resorption

leads to loss of bone minerals
and hyper-Ca
seen in states of rapid bone turnover

Intra-vascular volume depletion

reduces renal calcium excretion
reduced GFR
increased tubular reabsorption

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

Anorexia , nausea, vomiting

constipation
peptic ulcer
pancreatitis

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

Alkalosis -increased binding of Ca by albumin

Citrate toxicity
Hyperphosphataemia
Pancreatitis
Tumour lysis syndrome
Rhabdomyolysis

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

Reduced bone turnover

osteoporosis
elderly
cachexia

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

circumoral and peripheral paraesthesia

muscle cramps
tetany
seizures
extrapyrmidal
tremor, ataxia, dystonia
proximal myopathy
depression, anxiety, psychosis

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?