Transcript Adrenal insufficiency in critically ill patients

ADRENAL INSUFFICIENCY
IN CRITICALLY ILL PATIENTS
Dalal Abdelgadir R2 pediatics
Objectives
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To review normal physiology of adrenal gland and
glucocorticoids
Normal adrenal response to stress
Adrenal insufficiency in critical illness:
pathophysiology and incidence
Evidence of treatment with glucocorticoids
Case presentation
Recommendation for diagnosis and management in
adult patients
Physiology of the adrenal gland
CRH produced by hypothalamus
Cortisol exerts a
negative feedback
on production of
CRH and Cortisol
CRH stimulates pituitary gland to produce
ACTH
ACTH stimulates adrenals to produce
cortisol
Zona
Glomerulosa
15%
mineralocorticoids
Zona
fasiculata
75%
Stress cortisol,
androgens
Zona
reticularis
10%
Basal cortisol,
androgens
Production of steroid hormones
Physiology of glucocorticoids
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90% bound to corticosteroid binding globulin and
albumin to a lesser extent
10% free cortisol is physiologically active, half life
is 70 -120 mins
Cortisol is not stored in adrenal gland
Glucocorticoids bind to intracelullar receptors then
moves into the nucleus affecting transcription of
various genes
Physiology of glucocorticoids
Metabolic:
 Stimulates gluconeogenesis, decrease glucose utilization
 Decreases protein synthesis and increases catabolism
 Increases lypolysis and oxidation of fatty acids
Cardiovascular:
 Increases blood pressure
 Increases sensitivity of vasculature to catecholamines &
angiotensin II
Physiology of glucocorticoids
Anti-inflammatory effects:
 Reduces circulating T, B lymphocytes, esinophils,
monocytes and neutrophils at sites of inflammation
 Decreases production of cytokines & chemokines
 Increased production of microphage migration
inhibitory factor
Increases red cell production
Adrenal insufficiency
Adrenal insufficiency
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Primary adrenal insufficiency
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Secondary adrenal insufficiency
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Critical illness related corticosteroid insufficiency
Primary adrenal insufficiency
Congenital:
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CAH
Adrenal hypoplasia
congenita
Familial glucocorticoid
deficiency
Adrenoleukodystrophy
Aldosterone deficiency
Acquired:
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Autoimmune
Infectious diseases
Infiltrative processes
Drugs
Secondary adrenal insufficiency
Congenital ACTH, CRH
deficiency:
Acquired:
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Isolated
Panhypopituitarism
Associated with
structural defects e.g.
supra optic dyplasia
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Lymphocytic
hypophysitis
Neoplasms
Exogenous steroids
Critical illness related GC insufficiency
Is inadequate cellular corticosteroid activity
for the severity of the patients illness
Normal HPA response to stress
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Multiple changes occur to maintain homeostasis during
stress
Activation of sympathoadrenal system leading to
secretion of epinephrine and norepinephrine
Activation of HPA axis lead to release of CRH, ACTH
and eventually cortisol
Normal HPA response to stress
Corticosteroid binding protein levels fall as low
as 50% leading to increase in free cortisol
 Increased translocation of GR complexes into
the nucleus
 Results in alteration of systemic inflammatory
response and cardiovascular function
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Adrenal insufficiency - pathophysiology
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Is inadequate cellular corticosteroid activity for the
severity of patients illness
Dynamic process, patient may not have it on
admission but develop it later
Poorly understood
Structural damage to adrenal gland due to
hemorrhage or infarction may lead to long term AI
AI – pathophysiology
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Most critically ill develop reversible HPA axis
dysfunction
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Decreased production of CRH, ACTH or cortisol
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Decrease and alterations of glucocorticoid receptors
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Decrease nuclear translocation of glucocorticoidreceptor complexes due to endotoxins and
proinflammatory cytokines
Failure of activated GRs to down regulate production
of inflammatory mediators (systemic inflammationassociated GC resistance)
CRH
Decreased or
abnormal
receptors
ACTH
cortisol
Failure of GR to
down regulate
proinflammatory
factors
Translocation
inhibited by
endotoxins
and cytokines
AI – pathophysiology
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Some studies showed non survivors of severe sepsis
have random cortisol level > 20 mcg/dl (552
nmol/l) but incremental increase < 9 (248) after
ACTH stim test
Others found that non survivors had lower random
cortisol level compared to survivors
Lower levels of cortisol and high ACTH associated
with severe disease and poor outcome
When to suspect AI in critically ill pts
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Shock poorly responding to fluids and vasopressors
especially septic shock
Catecholamine-dependant shock
Prolonged mechanical ventilation
Sudden deterioration of seriously ill patients with
DIC, traumatic shock, severe burns or sepsis may be
due to adrenal hemorrhage or infarction
Incidence of AI
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Incidence variable within studies ranging 15 – 60%
Probably due to different definitions used, different
study populations
Sarthi et al. assessed children with fluid refractory
shock
 30%
of patients with septic shock identified with AI (
increase < 9 (248) after low dose ACTH stim test)
 Patients with AI had higher incidence of catecholamine
refractory shock, but no difference in mortality
Incidence of AI
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Hatherill et al. reported incidence of 52% in
children with septic shock
Menon and Clarson reported 31% of critically ill
Menon conducted a study to determine beliefs and
practices regarding AI revealed that 41% of
endocrinologist thought it rarely or never happen in
PICU setting, 81% of intensivists thought it
sometimes or often happens
Diagnosis of AI
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Different criteria in literature include:
 Delta
cortisol after high dose ACTH stim test < 9 (248)
 Baseline cortisol < 5 (138)
 Baseline cortisol < 7 (193)
 Basal cortisol< 20 (552), Delta cortisol < 9 (248)
 Delta cortisol < 9 (193)
 Peak < (baseline x 2)
Diagnosis of AI
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Annane et al used metyrapone stim test to assess high
dose ACTH stim test:
Baseline < 10 (276) or delta cortisol < 9 (248) were best
predictors of adrenal insufficiency
 Best predictor of normal adrenal response is baseline > 44
(1214) or increase > 17 (464)
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Metyrapone stimulation test: inhibits conversion of 11
deoxycortisol to cortisol, leading to increase in 11
deoxycortisol and drop of cortisol
Low cortisol increases ACTH leading to further increase
in 11 deoxycortisol
Diagnosis of AI
Currently based on random cortisol levels and delta cortisol
after high dose ACTH stimulation test
Issues:
 Free cortisol is of more physiological importance but normal
levels in acute illness not established, test not widely
available
 Low dose ACTH stimulation test thought to be more
physiologic and sensitive but limited data
 Delta cortisol assess ability of adrenal cortex to produce
cortisol but does not confirm integrity of HPA axis
 Above tests do not evaluate resistance at end organ level
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Should stress dose glucocorticoids be
included in management of septic
shock?
Rational behind treatment with GC
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Studies showing association between AI and
refractory shock
Some studies showing favorable outcome with
administration of glucocorticoids
In severe sepsis there is compromised endothelial
integrity, systemic vasoplegia and impaired cardiac
contractility
Cortisol is thought to modulate biochemical
pathways associated with those processes
Rational behind treatment with GC
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Adults with sepsis have different dose response to
norepinephrine compared to adults without sepsis
Marked improvement of dose response is seen after
administration of GC
Down regulation of proinflammatory factors
Should we treat with glucocorticoids
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Menon survey based study revealed:
 50%
of Canadian intensivists would sometimes or often
empirically treat hypotensive patients with
glucocorticoids
 81% of endocrinologist would never or occasionally
recommend glucocorticoids
Should we treat with glucocorticoids
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Min et al. RCT of cortisol Vs placebo in Dengue
shock syndrome (1975)
 48/98
received cortisol
 Fatality was 19% in cortisol group, 44% in placebo
group
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Sumarmo et al. studied treating with cortisol (50
mg/kg single dose) in Dengue shock syndrome
(1982)
 Mortality,
length of shock, volume of fluid resuscitation
similar in both groups
Should we treat with GC
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Tassinyom et al. RCT studied single dose
methlprednisone Vs placebo in Dengue shock
syndrome (1993)
 Similar
rates of mortality and organ dysfunction in both
treatment and placebo groups
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Slusher et al. studies administering dexamethasone
0.05 mg/kg/dose q 8hrs for 2 days (1996)
 No
improved survival or time to hemodynamic stability
observed
Should we treat with GC
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Markovitz et al. Retrospective cohort study using
Pediatric Health information system database 2005
 6693
children with severe sepsis
 Mortality 30% in those treated with steroids
 Mortality 18% in those not treated with steroids
 Longer duration of inotropic support and mechanical
ventilation in steroid treated group
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Limitation: no data on severity of illness
PALS algorithm for septic shock
Can we make conclusions?
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Comparison of those studies difficult
Small sample size
Different definitions of adrenal insufficiency
Different indications for treatment
Different steroid regimens
Downside of treating with GC
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Attenuating immunity and delaying wound healing
Hyperglycemia
Adult data raised concerns of increase risk of
nosocomial infections, multiple organ dysfunctions
Possibly alteration of brain development e.g.
neurodevelopmental outcome in neonates treated
with dexamethasone for BPD
Downside of treating with GC
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Increased mortality and morbidity associated with
methylprednisone administration in traumatic brain
injury
Increased mortality in ARDS patients started on
steroids after 14 days of illness
Higher rates of neuromuscular weakness
Case presentation
Case presentation
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14 yr old boy with Trisomy 21
Admitted to the PICU after cervical fusion for
atlantoaxial instability
Presented with gradual decline of motor function
over 1.5 yrs
No past hx of hypothyroidism, other
endocrinological disorders or exposure to
exogenous steroids
Case presentation
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Initial plan was to keep him intubated for 48 hrs
post op
On POD 3 developed fever and increased
ventilatory requirements
Later developed hypotension requiring fluid
resuscitation and eventually vasopressors
Subsequently diagnosed with pneumonia and sepsis
Continued to be vasopressor dependant for 6 days
Adrenal insufficiency suspected
Case presentation
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Random cortisol was 83 nmol/L (3)
ACTH stimulation test:
 Baseline
cortisol: 95 nmol/L (3.4)
 At 30 min: 483 (17.5)
Delta: 388 (14)
 At 60 min: 472 (17.1)
Delta: 374 (13.5)
Case presentation
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Received hydrocortisone: 80 mg/m2/day x 1 day
then weaned gradually over 1week
Dramatic improvement, weaned off vasopressors
within 24 hrs
Hydrocortisone gradually weaned
Case presentation
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Course complicated by chylothorax and recurrent
pneumonia leading to prolonged ventilation
Subsequently was difficult to wean off ventilator,
failed extubation due to deconditioning of
respiratory muscles
Tracheostomy preformed
4 months later still ventilator dependant & G-tube
fed
Transferred to Bloorview hospital for rehabilitation
More in the adult world
Recommendations for the diagnosis and management
of corticosteroid insufficiency in critically ill adult
patients: Consensus statements from and
international task force by the American College of
Critical Care Medicine
Recommendations for diagnosis and management in
adults
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Dysfunction if the HPA axis in critical illness is best
described by the term critical illness related
corticosteroid insufficiency
The terms absolute or relative adrenal insufficiency
are best avoided in context of critical care
Diagnosed by delta cortisol < 9 mcg/dl after 250
mcg cosyntropin or random total cortisol of < 10
mcg/dl
Use of free cortisol can not be recommended at this
time
Recommendations for diagnosis and management
in adults
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The ACTH stimulation test should not be used to
identify those patients with septic shock or ARDS
who should receive GC
Hydrocortisone should be considered in the
management strategy of patients with septic shock,
particularly those who have responded poorly to
fluids and vasopressor agents (2B)
Recommendations for diagnosis and management
in adults
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Moderate dose GC should be considered in the
management strategy of patients with early severe
ARDS and before day 14 in patients with
unresolved ARDS. The role of GC treatment in less
severe ARDS and ALI is less clear (2B)
In patients with septic shock IV hydrocortisone should
be given in a dose of 200 mg/day in 4 different
doses or as bolus of 100 mg followed by a
continuous infusion of 10 mg/hr (1B)
Recommendations for diagnosis and management in
adults
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The optimal duration of GC treatment in patients with
septic shock and early ARDS is unclear. Patients with
septic shock should be treated > 7days before
tapering and those with ARDS > 14 days before
tapering (2B)
GC treatment should be tapered slowly and not
stopped abruptly (2B)
Treatment with fludrocortisone ( 50mcg PO OD) is
considered optional
Dexamethasone is not recommended for treatment of
septic shock or ARDS (1B)
Landmark studies in adults:
CORTICUS
 Double blinded, randomized, placebo controlled
multicentre study
 500 patients with shock and evidence of organ
dysfunction attributable to shock were enrolled
 Randomized to hydrocortisone or placebo
 50
mg q6hrs IV x 5days
 50 mg q12hrs x 3days
 50mg q24hrsx 1day
CORTICUS - results
Results:
 More rapid resolution of shock in treatment group
 No difference in 28 d mortality
 Higher incidence of new infections and septic shock
Landmark studies in adults
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Annane et al. Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality in
patients with septic shock
300 patients with refractory shock randomized to
treatment with hydrocortisone 50mg IV q6hrs x
7days + oral fludracortisone 50 mg PO OD or
placebo
30% decrease in mortality confined to the nonresponder group
In summary
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HPA activation necessary to help with adaptation to
stress
There is evidence to support existence of adrenal
insufficiency in critically ill patients
The clinical relevance of adrenal insufficiency in
critically ill pediatric patients not clear
Safety and efficacy of steroid use in critically ill
children is not proven
Wide practice variability exists
Risks of adverse effects such as hyperglycemia,
nosocomial infections and myopathy/neuropathy are
unknown
References
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Recommendations for the diagnosis and management of corticosteroid insufficiency
in critically ill adult patients: Consensus statements from an international task force
by the American College of Critical Care Medicine, Crit Care Med 2008 Vol. 36,
No. 6
Adrenal function in sepsis: The retrospective Corticus cohort study, Crit Care Med
2007 Vol. 35, No.
Endocrine Problems in Critically Ill Children, AACN Clinical Issues Volume 17,
Number 1, pp. 66–78
A history of adjunctive glucocorticoid treatment for pediatric sepsis: Moving beyond
steroid pulp fiction toward evidence-based medicine, Jerry J. Zimmerman, MD, PhD,
FCCM, Pediatr Crit Care Med 2007 Vol. 8, No. 6
Adrenal status in children with septic shock using low-dose stimulation test,
Manjunatha Sarthi, MD, Pediatr Crit Care Med 2007 Vol. 8, No. 1
Identification of adrenal insufficiency in pediatric critical illness, Kusum Menon, MD,
MSc, FRCPC; Margaret Lawson, MD, MSc, FRCPC, Pediatr Crit Care Med 2007 Vol.
8, No. 3
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