Dalal Abdelgadir R2 pediatics Objectives To review normal physiology of adrenal gland and glucocorticoids Normal adrenal response to stress Adrenal insufficiency in critical illness pathophysiology ID: 195929
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Slide1
Adrenal insufficiency in critically ill patients
Dalal
Abdelgadir
R2
pediaticsSlide2
Objectives
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 patientsSlide3
Physiology of the adrenal gland
CRH produced by hypothalamus
CRH stimulates pituitary gland to produce ACTH
ACTH stimulates adrenals to produce cortisol
Cortisol exerts a negative feedback on production of CRH and CortisolSlide4
Zona
fasiculata
75%
Zona
Glomerulosa
15%
Zona
reticularis
10%
mineralocorticoids
Stress cortisol, androgens
Basal cortisol, androgensSlide5
Production of steroid hormonesSlide6
Physiology of glucocorticoids
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 genesSlide7
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 pressureIncreases sensitivity of vasculature to catecholamines
& angiotensin IISlide8
Physiology of glucocorticoids
Anti-inflammatory effects:
Reduces circulating T, B lymphocytes,
esinophils
,
monocytes
and neutrophils at sites of inflammationDecreases production of cytokines &
chemokines Increased production of microphage migration inhibitory factor
Increases red cell productionSlide9
Adrenal insufficiencySlide10
Adrenal insufficiency
Primary adrenal insufficiency
Secondary adrenal insufficiency
Critical illness related corticosteroid insufficiencySlide11
Primary adrenal insufficiency
Congenital:
CAH
Adrenal hypoplasia
congenita
Familial glucocorticoid deficiency
Adrenoleukodystrophy
Aldosterone deficiency
Acquired:AutoimmuneInfectious diseasesInfiltrative processes
Drugs Slide12
Secondary adrenal insufficiency
Congenital ACTH, CRH deficiency:
Isolated
Panhypopituitarism
Associated with structural defects e.g. supra optic
dyplasia
Acquired:
Lymphocytic hypophysitis
NeoplasmsExogenous steroidsSlide13
Critical illness related GC insufficiency
Is inadequate cellular corticosteroid activity for the severity of the patients illnessSlide14
Normal HPA response to stress
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 cortisolSlide15
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 functionSlide16
Adrenal insufficiency -
pathophysiology
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 AISlide17
AI – pathophysiology
Most critically ill develop reversible HPA axis dysfunction
Decreased production of CRH, ACTH or cortisol
Decrease and alterations of glucocorticoid receptors
Decrease nuclear translocation of glucocorticoid-receptor complexes due to
endotoxins
and proinflammatory cytokines
Failure of activated GRs to down regulate production of inflammatory mediators (systemic inflammation-associated GC resistance)Slide18
Translocation inhibited by
endotoxins
and cytokines
Decreased or abnormal receptors
Failure of GR to down regulate
proinflammatory
factors
CRH
ACTH
cortisolSlide19
AI – pathophysiology
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
testOthers 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 outcomeSlide20
When to suspect AI in critically ill pts
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 Slide21
Incidence of AI
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 mortalitySlide22
Incidence of AI
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 Slide23
Diagnosis of AI
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)Slide24
Diagnosis of AI
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)Metyrapone stimulation test: inhibits conversion of 11
deoxycortisol to cortisol, leading to increase in 11 deoxycortisol and drop of cortisolLow cortisol increases ACTH leading to further increase in 11
deoxycortisolSlide25
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 Slide26
Should
stress dose glucocorticoids
be included in management of septic shock? Slide27
Rational behind treatment with GC
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 processesSlide28
Rational behind treatment with GC
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
factorsSlide29
Should we treat with glucocorticoids
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 Slide30
Should we treat with glucocorticoids
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
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 groupsSlide31
Should we treat with GC
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
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 observedSlide32
Should we treat with GC
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 groupLimitation: no data on severity of illnessSlide33
PALS algorithm for septic shockSlide34
Can we make conclusions?
Comparison of those studies difficult
Small sample size
Different definitions of adrenal insufficiency
Different indications for treatment
Different steroid regimens Slide35
Downside of treating with GC
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 BPDSlide36
Downside of treating with GC
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 weaknessSlide37
Case presentationSlide38
Case presentation
14 yr old boy with
Trisomy
21
Admitted to the PICU after cervical fusion for
atlantoaxial
instabilityPresented with gradual decline of motor function over 1.5 yrsNo past
hx of hypothyroidism, other endocrinological disorders or exposure to exogenous steroidsSlide39
Case presentation
Initial plan was to keep him
intubated
for 48 hrs post op
On POD 3 developed fever and increased
ventilatory
requirementsLater developed hypotension requiring fluid resuscitation and eventually vasopressors
Subsequently diagnosed with pneumonia and sepsisContinued to be vasopressor dependant for 6 days
Adrenal insufficiency suspectedSlide40
Case presentation
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) Slide41
Case presentation
Received hydrocortisone: 80 mg/m2/day x 1 day then weaned gradually over 1week
Dramatic improvement, weaned off
vasopressors
within 24 hrs
Hydrocortisone gradually weanedSlide42
Case presentation
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 fedTransferred to
Bloorview hospital for rehabilitationSlide43
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 MedicineSlide44
Recommendations for diagnosis and management in adults
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 timeSlide45
Recommendations for diagnosis and management in adults
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)Slide46
Recommendations for diagnosis and management in adults
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)Slide47
Recommendations for diagnosis and management in adults
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)Slide48
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 1daySlide49
CORTICUS - results
Results:
More rapid resolution of shock in treatment group
No difference in 28 d mortality
Higher incidence of new infections and septic shockSlide50
Landmark studies in adults
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 non-responder groupSlide51
In summary
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 unknownSlide52
References
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. 3Slide53
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