ADRENAL INSUFFICIENCY IN

THE CRITICALLY ILL PATIENT

Physiology,Diagnosis,Management.
Fadi Seif, PGY 3
Moderator:Dr.G.Yadavalli
Topics to be Addressed? Topics to be Addressed?
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
Topics to be Addressed? Topics to be Addressed?
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
Relative (Functional) Adrenal
Insufficiency
Relative (Functional) Adrenal
Insufficiency
Reported in critically ill patients
Subnormal adrenal corticosteroid production
Hypoadrenal state without clearly defined defects
in HPA axis
Difficult to define based on serum cortisol
concentrations:
Although cortisol level may be normal, it may remain Although cortisol level may be normal, it may remain
inadequate for the patients metabolic demands inadequate for the patients metabolic demands
Rapid improvement on Hydrocortisone therapy
Reported in critically ill patients
Subnormal adrenal corticosteroid production
Hypoadrenal state without clearly defined defects
in HPA axis
Difficult to define based on serum cortisol
concentrations:
Although cortisol level may be normal, it may remain Although cortisol level may be normal, it may remain
inadequate for the patients metabolic demands inadequate for the patients metabolic demands
Rapid improvement on Hydrocortisone therapy
0%
10%
20%
30%
40%
50%
60%
70%
Sep Sho k O her ICU Patients
CABG
Ruptured AAA
others
CABG
Ruptured AAA
others
Incidence of Relative Adrenal
Insufficiency
Incidence of Relative Adrenal
Insufficiency
JCEM (2006) 91: 105114
CORTISOL
ACTH
CRH
STRESS:
Physical stress
Emotional stress
Hypoglycemia
Cold exposure
Pain
Adrenal Cortex
Anterior Lobe of
Pituitary Gland
Hypothalamus
Cortisol Action Cortisol Action
Increased sensitivity to pressors
Anti-inflammatory effect on immune
system
Maintenance of vascular tone &
endothelial integrity
Modulation of angiotensinogen
synthesis
Reduction of NO-mediated
vasodilation
Increased sensitivity to pressors
Anti-inflammatory effect on immune
system
Maintenance of vascular tone &
endothelial integrity
Modulation of angiotensinogen
synthesis
Reduction of NO-mediated
vasodilation
Basal Cortisol Production
= 8-25 mg/24hrs
Cortisol Production can
be 6-fold in stress
Diurnal pattern of cortisol
production lost in stress
situations
Cortisol T
1/2
= 70-120 min
Basal Cortisol Production
= 8-25 mg/24hrs
Cortisol Production can
be 6-fold in stress
Diurnal pattern of cortisol
production lost in stress
situations
Cortisol T
1/2
= 70-120 min
Bound to circulating
CBG, albumin, E1-
acid glycoprotein
10% free =
biologically active
CBG rapidly in
critically ill pts free
cortisol
Bound to circulating
CBG, albumin, E1-
acid glycoprotein
10% free =
biologically active
CBG rapidly in
critically ill pts free
cortisol
Classical regulators of the axis continue to
be operable in critically ill patients but with
significant alterations:
Hypothalamic hormones
CRH
Vasopressin
Inflammatory cytokines: IL-1, IL-
6,TNF-
ANS
Classical regulators of the axis continue to
be operable in critically ill patients but with
significant alterations:
Hypothalamic hormones
CRH
Vasopressin
Inflammatory cytokines: IL-1, IL-
6,TNF-
ANS
modulators of modulators of
HPA function HPA function
Anesthesiology (1993) 77: 426431
HPA Alteration During Critical Illness
Cytokines stimulate/maintain glucocorticoid
production to high levels
IL-6 is one of the most important cytokines
IL-6 receptors: pituitary corticotrophs &
adrenal cortical cells
Cytokines stimulate/maintain glucocorticoid
production to high levels
IL-6 is one of the most important cytokines
IL-6 receptors: pituitary corticotrophs &
adrenal cortical cells
JCEM (1993) 77: 16901694
Neuroendocrinology (1997) 66: 5462
Clin Endocrinol (Oxf) (2004) 60: 2935
During an Inflammatory Process
JCEM (1997) 82: 23432349
JCEM (1999) 84: 17291736
These cytokines act synergistically to
augment ACTH secretion BEYOND
that achieved by CRH alone
Cytokines released from the site of
injury or after exposure to endotoxin
activate the HPA by stimulating the
classical pathway of CRH and ACTH
secretion
Impaired hepatocellular
function
Impaired hepatic blood
flow
Impaired renal/thyroid
function
J Clin Invest (1958) 37: 17911798
Increased steroid
production
Decreased steroid
clearance
Increased Serum Cortisol
(free cortisol level)
Stress
ACTH and cortisol
responsiveness to exogenous
CRH is enhanced during
critical illnesses
ACTH = dominant factor
stimulating cortisol secretion
throughout the critical illness
other factors play a
significant modulating
influence on the axis
ACTH and cortisol
responsiveness to exogenous
CRH is enhanced during
critical illnesses
ACTH = dominant factor
stimulating cortisol secretion
throughout the critical illness
other factors play a
significant modulating
influence on the axis
J Inflamm (1996) 47: 3951
Arginine Vasopressin
Endothelin
Atrial Natriuretic Factor
(ANF)
Variety of Cyto ines
(IL-6)
Cortisol secretion during critical illnesses:
Excessive (reaching levels " those achieved
in patients with Cushings syndrome)
Less suppressible by exogenous
glucocorticoid administration
(dexamethasone)
Cortisol secretion during critical illnesses:
Excessive (reaching levels " those achieved
in patients with Cushings syndrome)
Less suppressible by exogenous
glucocorticoid administration
(dexamethasone)
N Engl J Med (2004) 350: 16291638
Crit Care Med (1993) 21: 396401
Type & Severity of Illness Type & Severity of Illness
Acute phase of illnesspcortisol levels proportionate to degree of stress
Cortisol levels:major surgery vs sepsisSIMILAR ELEVATION
Cortisol elevations in sepsis:
-wide range
-? dont correlate with APACHE
-highest levels phighest mortality
Sepsis vs Trauma patients:
-similar cortisol elevation
-M-MIF markedly higher in:
Sepsis,
Progression to ARDS,
Patients who didnt survive
Glucocorticoid resistant patients have higher levels
Acute phase of illnesspcortisol levels proportionate to degree of stress
Cortisol levels:major surgery vs sepsisSIMILAR ELEVATION
Cortisol elevations in sepsis:
-wide range
-? dont correlate with APACHE
-highest levels phighest mortality
Sepsis vs Trauma patients:
-similar cortisol elevation
-M-MIF markedly higher in:
Sepsis,
Progression to ARDS,
Patients who didnt survive
Glucocorticoid resistant patients have higher levels
JCEM (2001) 86: 28112816
Intensive Care Med (2001)27: 1584-1591
Clin Endocrinol (2004) 60:29-35.
Variations Among Individuals Variations Among Individuals
Wide range in measured random or baseline serum cortisol
concentrations
The latter variability represents:
- different illnesses
- perhaps differences in assay methods
- mutations in the TL receptors
- polymorphism in glucocorticoid receptors
- variation in ACTH or CRH receptor activities
- variability of the 11beta hydroxysteroid dehydrogenase enzyme
Wide range in measured random or baseline serum cortisol
concentrations
The latter variability represents:
- different illnesses
- perhaps differences in assay methods
- mutations in the TL receptors
- polymorphism in glucocorticoid receptors
- variation in ACTH or CRH receptor activities
- variability of the 11beta hydroxysteroid dehydrogenase enzyme
JCEM(2004) 89: 563-564
JCEM(2004) 89: 565-573
Short-Term Stresses vs. Protracted
Critical Illness
Short-Term Stresses vs. Protracted
Critical Illness
Initial phase is characterized by:
ACTH
Cortisol
Protracted critical illness:
ACTH
Cortisol
cortisol secretion is being regulated and stimulated by alternative
pathways other than the classical hypothalamic CRH
Initial phase is characterized by:
ACTH
Cortisol
Protracted critical illness:
ACTH
Cortisol
cortisol secretion is being regulated and stimulated by alternative
pathways other than the classical hypothalamic CRH
JCEM (1998)83: 1827-34
J Trauma (1987)27: 384-392
Plasma ACTH levels and serum total
cortisol concentrations
Measured before and during the first
48 hours after pituitary surgery in
patients with adenoma
Normal HPA function before and
after adenomectomy.
Patients with ACTH secreting
adenomas were excluded
Plasma ACTH levels and serum total
cortisol concentrations
Measured before and during the first
48 hours after pituitary surgery in
patients with adenoma
Normal HPA function before and
after adenomectomy.
Patients with ACTH secreting
adenomas were excluded
J Clin Endocrinol Metab (2003)80(4):1238-1242
Persistent Hypercortisolism Observed in
Protracted Critical Illness
Persistent Hypercortisolism Observed in
Protracted Critical Illness
J Trauma (1987) 27: 384392
Benefits Related To Long Term Complications
Providing energy Hyperglycemia
Maintaining volume Myopathy
Minimizing inflammation Psychiatric alterations
Poor wound healing
Topics to be Addressed? Topics to be Addressed?
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
Diagnostic Clues in Critically Ill
Patients
Diagnostic Clues in Critically Ill
Patients
Persistent hypotension despite adequate
volume resuscitation
Hyperdynamic circulation and low SVR
Ongoing inflammation w/o obvious source
that does not respond to empiric treatment
Persistent hypotension despite adequate
volume resuscitation
Hyperdynamic circulation and low SVR
Ongoing inflammation w/o obvious source
that does not respond to empiric treatment
Patients at Ris for Adrenal Insufficiency Patients at Ris for Adrenal Insufficiency
Adrenal insufficiency can be difficult to diagnose
in critically ill patients unless clues from patients
prior clinical history are considered in that
context:
prior history of unexplained fatigue
arthralgias
intake of medications known to suppress the HPA
axis
Adrenal insufficiency can be difficult to diagnose
in critically ill patients unless clues from patients
prior clinical history are considered in that
context:
prior history of unexplained fatigue
arthralgias
intake of medications known to suppress the HPA
axis
oral
parenteral
Inhaled GLUCOCORTICOID
dermal
intraarticular
RU486
KETOCONAZOLE
ETOMIDATE
Hypothalamic- pituitary disease (tumors, central
nervous system irradiation, sarcoidosis)
HIV
Multiple autoimmune illnesses (primary hypothyroidism,
Graves disease, type 1 diabetes mellitus, vitiligo,
autoimmune arthritis, premature gray hair, pernicious
anemia)
Hypothalamic- pituitary disease (tumors, central
nervous system irradiation, sarcoidosis)
HIV
Multiple autoimmune illnesses (primary hypothyroidism,
Graves disease, type 1 diabetes mellitus, vitiligo,
autoimmune arthritis, premature gray hair, pernicious
anemia)
It is important to raise similar concerns in patients It is important to raise similar concerns in patients
with medical illnesses that are more likely with medical illnesses that are more likely
associated with adrenal insufficiency: associated with adrenal insufficiency:
hyperpigmentation
clinical features of combined pituitary hormone deficiencies (hypothyroidism,
hypogonadism)
features suggesting loss of adrenal androgen production (loss of axillary and
pubic body hair in women)
biochemical features to consider include:
eosinophilia
hypoglycemia
Hyponatremia
hyperpigmentation
clinical features of combined pituitary hormone deficiencies (hypothyroidism,
hypogonadism)
features suggesting loss of adrenal androgen production (loss of axillary and
pubic body hair in women)
biochemical features to consider include:
eosinophilia
hypoglycemia
Hyponatremia
In evaluating such patients for the risk of adrenal In evaluating such patients for the risk of adrenal
insufficiency, one can look for: insufficiency, one can look for:
Even though the interpretation of such clinical data Even though the interpretation of such clinical data
is often difficult in the critically ill patient is often difficult in the critically ill patient
Lab Test Difficulties in Critical Illness Lab Test Difficulties in Critical Illness
Cortisol level interpretation complicated by:
Difficulty in defining normal ranges
Reduced CBG
Changes in tissue resistance to cortisol
Local release of free cortisol
Etomidate use for intubation
Cortisol level interpretation complicated by:
Difficulty in defining normal ranges
Reduced CBG
Changes in tissue resistance to cortisol
Local release of free cortisol
Etomidate use for intubation
High-Dose ACTH Stimulation Test: High-Dose ACTH Stimulation Test:
Can be done at any time of day
Baseline cortisol 250Qg ACTH measure
cortisol at 30 and 60 minutes
Non-stressed pt: increase to u18 Qg /dL R/O AI
High sensitivity & specificity for primary AI using
threshold value of 15 Qg /dL
Less sensitive for secondary AI
Can be done at any time of day
Baseline cortisol 250Qg ACTH measure
cortisol at 30 and 60 minutes
Non-stressed pt: increase to u18 Qg /dL R/O AI
High sensitivity & specificity for primary AI using
threshold value of 15 Qg /dL
Less sensitive for secondary AI
Critical care clinics (2006) 22 (2): 245-53
Random Cortisol Level Random Cortisol Level
Poor prognosis in septic shock patients:
extremely HIGH (>34Qg/dL) total cortisol
extremely LOW (<25Qg/dL) total cortisol
Poor prognosis in septic shock patients:
extremely HIGH (>34Qg/dL) total cortisol
extremely LOW (<25Qg/dL) total cortisol
N Engl J Med (2003) 348 (8): 727-734
Chest (2002) 122 (5): 1784-1796
Critical care medicine (2003) 31 (1): 141-145
Unstressed subjects, AI:
ACTH stimulated cortisol 18-20 ug/dl
Critically illness, AI:
random cortisol <15 or 25 ug/dl (if on pressors)
cortisol increment after ACTH stimulation < 9ug/dl
Severe hypoproteinemia, AI:
serum free cortisol < 2 ug/dl or
ACTH stimulated value < 3.1 ug/dl
Unstressed subjects, AI:
ACTH stimulated cortisol 18-20 ug/dl
Critically illness, AI:
random cortisol <15 or 25 ug/dl (if on pressors)
cortisol increment after ACTH stimulation < 9ug/dl
Severe hypoproteinemia, AI:
serum free cortisol < 2 ug/dl or
ACTH stimulated value < 3.1 ug/dl
N Engl J Med (1996) 335: 1206-1212
N Engl J Med (2003) 348: 727734
Diagnostic Criteria
Calculated free cortisol index
Calculating free cortisol
concentrations (using the Coolens
method)
Calculated free cortisol index
Calculating free cortisol
concentrations (using the Coolens
method)
p Transcortin levels
(not readily available
in most laboratories)
Alternative Approaches Alternative Approaches
Serum Free Cortisol Level as a Mar er of
Glucocorticoid Secretion
Serum Free Cortisol Level as a Mar er of
Glucocorticoid Secretion
Serum free cortisol concentrations:
pmost appropriate approach for assessing glucocorticoid
secretion in the critically ill
Patients with low plasma proteins (albumin 2.5 gm/dl):
pbest demonstrated the discordance between the total
and free hormone concentrations
Nearly 40% of critically ill patients with low serum albumin
had low serum total cortisol levels
interpreted to be consistent with adrenal insufficiency
even though they had normally stimulated adrenal function
Serum free cortisol concentrations:
pmost appropriate approach for assessing glucocorticoid
secretion in the critically ill
Patients with low plasma proteins (albumin 2.5 gm/dl):
pbest demonstrated the discordance between the total
and free hormone concentrations
Nearly 40% of critically ill patients with low serum albumin
had low serum total cortisol levels
interpreted to be consistent with adrenal insufficiency
even though they had normally stimulated adrenal function
1. Assays for determining serum free cortisol concentrations (difficult,
time consuming, and labor intensive).
2. Rapid assays for measurements of serum free cortisol levels will
become available in the near future.
3. Alternative approaches should be explored in the assessment of
glucocorticoid secretion (until these assays become available for routine
clinical care).
4. Such approaches include: measurements of salivary cortisol,other
ACTH dependent adrenal steroids(DHEA and DHEA-S).
1. Assays for determining serum free cortisol concentrations (difficult,
time consuming, and labor intensive).
2. Rapid assays for measurements of serum free cortisol levels will
become available in the near future.
3. Alternative approaches should be explored in the assessment of
glucocorticoid secretion (until these assays become available for routine
clinical care).
4. Such approaches include: measurements of salivary cortisol,other
ACTH dependent adrenal steroids(DHEA and DHEA-S).
NEngl J Med (350) :16011602
Measurements of serum free cortisol represent the most Measurements of serum free cortisol represent the most
ideal approach in assessing glucocorticoid secretion, ideal approach in assessing glucocorticoid secretion,
especially in especially in hypoproteinemic hypoproteinemic, critically ill subjects: , critically ill subjects:
Serum Free Cortisol Serum Free Cortisol
Salivary cortisol
ACTH-dependent steroids (DHEA, DHEA-S)
Salivary cortisol
ACTH-dependent steroids (DHEA, DHEA-S)
N Engl J Med (2004) 350: 16291638
Alternative Measurements Alternative Measurements
Studies over the past 1520 yrs have
demonstrated:
- Cortisol concentrations (saliva)
- Free/unbound plasma cortisol level
Studies over the past 1520 yrs have
demonstrated:
- Cortisol concentrations (saliva)
- Free/unbound plasma cortisol level
JCEM(1988) 66:343348
Salivary Cortisol as a Mar er of
Glucocorticoid Secretion
Salivary Cortisol as a Mar er of
Glucocorticoid Secretion
in equilibrium, and highly
correlate
Plasma free cortisol : reflected by a change in
salivary cortisol concentration within a few minutes
Superior to simple measurements of serum total
cortisol levels, particularly in hypoalbuminic patients
Plasma free cortisol : reflected by a change in
salivary cortisol concentration within a few minutes
Superior to simple measurements of serum total
cortisol levels, particularly in hypoalbuminic patients
Program of the 87th Annual Meeting of The Endocrine
Society, San Diego, CA, 2005 (Abstract P3-440)
Salivary Cortisol as a Mar er of
Glucocorticoid Secretion
Salivary Cortisol as a Mar er of
Glucocorticoid Secretion
Program of the 87th Annual Meeting of The Endocrine
Society, San Diego, CA, 2005 (Abstract P3-440)
Salivary Cortisol Salivary Cortisol
Simple to obtain
Easy to measure in most laboratories
Provide a reliable/practical measure of the
serum free cortisol in a timely manner
Limiting factor: ability to obtain saliva from
some patients (intubated)
Simple to obtain
Easy to measure in most laboratories
Provide a reliable/practical measure of the
serum free cortisol in a timely manner
Limiting factor: ability to obtain saliva from
some patients (intubated)
Topics to be Addressed? Topics to be Addressed?
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
Medications Modulating Serum Total
Cortisol Concentrations in Critically Ill
Medications Modulating Serum Total
Cortisol Concentrations in Critically Ill
DRUG MECHANISM IMPACT EXAMPLE
Estrogen Increased CBG
Higher total cortisol;
Normal free cortisol
Estrogen, oral contraceptives;
pregnancy; hepatitis
Ketoconazole
Decreased synthesis of
cortisol
Lower serum cortisol; low
free cortisol
Patients receiving the drug
Spironolactone
Interference in the assay
depending on antibody
specificity
Generally higher levels;
variable influence
depending on the assay
specificity
Patients on the drug
Aminoglutathemide Inhibit cortisol synthesis
Lower serum total and
free cortisol
Patients on the drug e.g.,
medical adrenalectomy for
metastatic breast cancer.
Etomidate
Decreased synthesis due
to 11-Beta hydroxylase
inhibition
Lower serum cortisol
levels; decreased
responsiveness to
Cosyntropin
Use of the drug
Well-characterized model of acute
inflammation
IV administration of Gram-negative
bacterial lipopolysaccharide (LPS)
endotoxin
Well-characterized model of acute
inflammation
IV administration of Gram-negative
bacterial lipopolysaccharide (LPS)
endotoxin
J Clin Invest (1990) 85: 18961904
HPA Function During Experimental
Endotoxemia
HPA Function During Experimental
Endotoxemia
Acute Inflammatory Process:
fever
tachycardia
leukocytosis
immune cell activation
LPS injection
ACTH
Catecholamines
GH
Cortisol (11.5 29
Q Qg/dl within 2 hrs)
Anti-inflammatory
cytokine IL-11 (protective
role during sepsis)
Immunobiology (1993) 187:403416
Infect Immun. 1997 June; 65(6): 23782381
Helpful approach in understanding the bodys
response to acute inflammation
Not considered a good model for sepsis or septic
shock
Helpful approach in understanding the bodys
response to acute inflammation
Not considered a good model for sepsis or septic
shock
Experimental Endotoxemia Experimental Endotoxemia
Data obtained in patients during experimental
endotoxemia cannot be extrapolated/applied to others
with sepsis or septic shock
Topics to be Addressed? Topics to be Addressed?
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
Numerous studies documented activation of HPA
axis during acute and chronic stress:
Surgery --Ann Surg. (1995) 221: 372380
Sepsis -- Ann Surg. (1977) 186: 2933
Trauma JCEM (2006) 10: 3725-3745
Burns -- J Trauma (1982) 221: 263273
Other critical illnesses
Numerous studies documented activation of HPA
axis during acute and chronic stress:
Surgery --Ann Surg. (1995) 221: 372380
Sepsis -- Ann Surg. (1977) 186: 2933
Trauma JCEM (2006) 10: 3725-3745
Burns -- J Trauma (1982) 221: 263273
Other critical illnesses
The Concept of Relative Adrenal Insufficiency The Concept of Relative Adrenal Insufficiency
Introduced to describe:
-group of patients who had no risk factors or prior evidence for adrenal dysfunction
-patients who, during a critical illness, had serum total cortisol levels that were
judged to be inadequate for the severity of their illness
Most of these patients were likely to have:
- albumin
- transcortin
Introduced to describe:
-group of patients who had no risk factors or prior evidence for adrenal dysfunction
-patients who, during a critical illness, had serum total cortisol levels that were
judged to be inadequate for the severity of their illness
Most of these patients were likely to have:
- albumin
- transcortin
N Engl J Med (2003)348:727-734
limit total cortisol measurements
Multiple factors may contribute to hypoadrenalism in critically ill patients:
Anatomic damage
Acute destruction of the adrenal gland (hemorrhage or
infection)
Hypoperfusion or cytokine-induced inhibition of the
adrenal or the HP area
functional impairment of different components of the axis
(more common)
Usage of some drugs
Multiple factors may contribute to hypoadrenalism in critically ill patients:
Anatomic damage
Acute destruction of the adrenal gland (hemorrhage or
infection)
Hypoperfusion or cytokine-induced inhibition of the
adrenal or the HP area
functional impairment of different components of the axis
(more common)
Usage of some drugs
J Clin Anesth (1999) 11: 425-430
Arch Surg (1998) 133: 199-204
Relative Adrenal Insufficiency in Critically
Ill Patients
Relative Adrenal Insufficiency in Critically
Ill Patients
Prevalence of
relative AI:
20 %-75 % in
patients with
sepsis/ septic
shock
Prevalence of
relative AI:
20 %-75 % in
patients with
sepsis/ septic
shock
Prevalence of
relative AI:
0-25 % in other
critically ill
patients
Prevalence of
relative AI:
0-25 % in other
critically ill
patients
Initial reports:
2 critically ill, hypotensive subjects on vasopressor therapy
subnormal responses to ACTH
both responded to glucocorticoid therapy and recovered
documented to have normal pituitary adrenal function
Close review of the clinical data in those two subjects showed that
both had received etomidate
Following that publication, several reports described the entity of
Relative Adrenal Insufficiency in patients with septic shock and the
influence of hydrocortisone therapy was investigated
Initial reports:
2 critically ill, hypotensive subjects on vasopressor therapy
subnormal responses to ACTH
both responded to glucocorticoid therapy and recovered
documented to have normal pituitary adrenal function
Close review of the clinical data in those two subjects showed that
both had received etomidate
Following that publication, several reports described the entity of
Relative Adrenal Insufficiency in patients with septic shock and the
influence of hydrocortisone therapy was investigated
Mayo Clin Proc.(1993) 68:435-441
Anesthesia(1999) 54:861-67
The Concept of Relative Adrenal Insufficiency The Concept of Relative Adrenal Insufficiency
Annane et. al:
299 patients with septic shock (largest)
200 mg IV hydrocortisone (50 mg every 6 h) + 0.1 mg PO
fludrocortisone vs. placebo for 7 days
Non-responders >> responders (229 to 70)
72 patients received etomidate
68/72 = non-responders group to ACTH-stimulation
hydrocortisone showed benefit (TRUE AI)
Conclusion 1-Patients benefited from hydrocortisone
2-Etomidate treated patients benefited from
hydrocortisone
Drawbac : did not indicate whether those who did not
receive etomidate did/did not benefit from hydrocortisone
Annane et. al:
299 patients with septic shock (largest)
200 mg IV hydrocortisone (50 mg every 6 h) + 0.1 mg PO
fludrocortisone vs. placebo for 7 days
Non-responders >> responders (229 to 70)
72 patients received etomidate
68/72 = non-responders group to ACTH-stimulation
hydrocortisone showed benefit (TRUE AI)
Conclusion 1-Patients benefited from hydrocortisone
2-Etomidate treated patients benefited from
hydrocortisone
Drawbac : did not indicate whether those who did not
receive etomidate did/did not benefit from hydrocortisone
Intensive care Med(2005) 31:325-326
JAMA(2002) 288: 862-871
Intensive care(2003) Med 31: 1454
If glucocorticoid therapy is to be used:
physiologically meaningful fashion
continuous IV infusion (preferable)
frequent (every 46 h) IV boluses
dose 200mg qd
not a permanent therapy
tapered quickly as clinically indicated
Hydrocortisone with its potent glucocorticoid and
mineralocorticoid activities is the preferred agent
(no definitive data on the use of fludrocortisone)
If glucocorticoid therapy is to be used:
physiologically meaningful fashion
continuous IV infusion (preferable)
frequent (every 46 h) IV boluses
dose 200mg qd
not a permanent therapy
tapered quickly as clinically indicated
Hydrocortisone with its potent glucocorticoid and
mineralocorticoid activities is the preferred agent
(no definitive data on the use of fludrocortisone)
Patients with central
adrenal insufficiency
IV hydrocortisone 50 mg
q6hrs
Measurements after the IV
dose
Degree of elevation
achieved
Levels much higher than
those noted in any group of
critically ill patients
This should call into
question the practice of
using such high doses that
are incorrectly referred to
as low-dose.
Patients with central
adrenal insufficiency
IV hydrocortisone 50 mg
q6hrs
Measurements after the IV
dose
Degree of elevation
achieved
Levels much higher than
those noted in any group of
critically ill patients
This should call into
question the practice of
using such high doses that
are incorrectly referred to
as low-dose.
Am J Respir Crit Care Med(2003) 167: 512-520
Glucocorticoid Therapy During Critical Illness Glucocorticoid Therapy During Critical Illness
Prospective, placebo-controlled study
? hydrocortisone therapy (50 mg iv every 6 h) on ventilator weaning
70 critically ill, intubated patients with relative adrenal insufficiency
Rate of successful ventilator weaning (P < 0.035)
adequate adrenal function (20 of 23)
adrenal insufficiency+HC (32 of 35) vs placebo (24 of 35).
Mechanism(s) ????
Importantly hydrocortisone therapy
Prospective, placebo-controlled study
? hydrocortisone therapy (50 mg iv every 6 h) on ventilator weaning
70 critically ill, intubated patients with relative adrenal insufficiency
Rate of successful ventilator weaning (P < 0.035)
adequate adrenal function (20 of 23)
adrenal insufficiency+HC (32 of 35) vs placebo (24 of 35).
Mechanism(s) ????
Importantly hydrocortisone therapy
Am J Resp Crit Care Med (2006) 173:276280
Additional studies are needed to confirm this finding and, once confirmed, to examine
mechanisms of potential benefit from hydrocortisone on ventilator weaning
Hospital Stay
Hospital Mortality
The CORTICUS study involves:
-800 patients
-Septic shock (non-refractory)
-Objective: ? glucocorticoids have beneficial or adverse effects in either
the responders or the nonresponders to ACTH(as was described in
the study of Annane et al,2002).
-Analyzing such an important study is necessary to determine whether
glucocorticoids have any advantage and in which patients with septic
shock they should be administered.
-Results:
No benefit in mortality
No benefit in non-responders
Earlier reversal of shock with steroids
The CORTICUS study involves:
-800 patients
-Septic shock (non-refractory)
-Objective: ? glucocorticoids have beneficial or adverse effects in either
the responders or the nonresponders to ACTH(as was described in
the study of Annane et al,2002).
-Analyzing such an important study is necessary to determine whether
glucocorticoids have any advantage and in which patients with septic
shock they should be administered.
-Results:
No benefit in mortality
No benefit in non-responders
Earlier reversal of shock with steroids
CORTICUS study
NEJM (2008) 358:111-124
Outcome of Steroid Replacement Outcome of Steroid Replacement
Cochrane Database Meta-analysis :
15 trials no significant reduction in all-cause mortality at
28 days with steroid replacement in septic shock
4 trials reduced mortality & increased shock reversal
with long courses of low dose steroids
Cochrane Database Meta-analysis :
15 trials no significant reduction in all-cause mortality at
28 days with steroid replacement in septic shock
4 trials reduced mortality & increased shock reversal
with long courses of low dose steroids
Topics to be Addressed? Topics to be Addressed?
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
1. Definition & physiology.
2. Diagnostic challenges.
3. Examples of stressful conditions.
4. Relative AI and steroid therapy in the
critically-ill patient.
5. Stress doses in patients maintained on
steroids.
Case Scenarios
WHAT DOSE TO BE PLACED ON?
WHAT IS THE STRESS DOSE?
Case Scenarios
WHAT DOSE TO BE PLACED ON?
WHAT IS THE STRESS DOSE?
50 male RA on prednisone 10mg qd
presenting for laminectomy
50 female Asthmatic on prednisone 10mg
qd presenting for TAHBSO
50 male chronic 2ry AI on prednisone
10mg qd admitted for CABG
50 male RA on prednisone 10mg qd
presenting for laminectomy
50 female Asthmatic on prednisone 10mg
qd presenting for TAHBSO
50 male chronic 2ry AI on prednisone
10mg qd admitted for CABG
At least 3 recent studies showed that major surgery in
patients on glucocorticoids did not require more steroids
than their regular daily dose.
At least 3 recent studies showed that major surgery in
patients on glucocorticoids did not require more steroids
than their regular daily dose.
Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency
Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency
Transplantation (1991) 51: 385-390
12 patients underwent MAJOR surgery without any additional
supplementation other than their regular dose of prednisone:
-Only 1/12 had a hypotensive episode (bleeding during splenectomy)
Based on these data, it is quite reasonable to postulate that for
most elective surgery, a continuation of the current dose of
corticosteroids is enough to maintain cardiovascular function.
12 patients underwent MAJOR surgery without any additional
supplementation other than their regular dose of prednisone:
-Only 1/12 had a hypotensive episode (bleeding during splenectomy)
Based on these data, it is quite reasonable to postulate that for
most elective surgery, a continuation of the current dose of
corticosteroids is enough to maintain cardiovascular function.
Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency
Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency
Surgery (1997) 121: 123-129
If the operation or the illness is complicated or
prolonged:
-need higher doses of corticosteroids,
-overtreatment for several days is unlikely to cause
any harm.
If the operation or the illness is complicated or
prolonged:
-need higher doses of corticosteroids,
-overtreatment for several days is unlikely to cause
any harm.
Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency
Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency
N Engl J Med 1997; 337: 1285-1292
The most reasonable approach to this issue is expressed in a
consensus article and recommended:
1. 25 mg hydrocortisone(or equivalent) for minor stress surgery/
hernioplasty
2. 50-75 mg for moderate stress/abdominal hysterectomy
3. 100-150 mg for major stress/CABG
for a period of 1 to 3 d.
Similar guidelines could be extrapolated to patients with critical medical
illness in the intensive care unit.
The most reasonable approach to this issue is expressed in a
consensus article and recommended:
1. 25 mg hydrocortisone(or equivalent) for minor stress surgery/
hernioplasty
2. 50-75 mg for moderate stress/abdominal hysterectomy
3. 100-150 mg for major stress/CABG
for a period of 1 to 3 d.
Similar guidelines could be extrapolated to patients with critical medical
illness in the intensive care unit.
Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency
Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency
Ann Surg (1994) 219: 416-425
In contrast to patients on glucocorticoids for
nonendocrine disease, patients with established disease
of :
-adrenal cortex
- HP area
Such patients should routinely receive supplemental
glucocorticoid therapy:
-Major surgery/severe illnesspD1:100-150mg HC
IVD(continuous)
In contrast to patients on glucocorticoids for
nonendocrine disease, patients with established disease
of :
-adrenal cortex
- HP area
Such patients should routinely receive supplemental
glucocorticoid therapy:
-Major surgery/severe illnesspD1:100-150mg HC
IVD(continuous)
Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency
Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency
N Engl J Med (1997) 337: 1285-1292
X capable to serum
cortisol
Conclusion: Future studies Conclusion: Future studies
It is evident from that there are more questions than answers in this
important field. It is likely that studies will be conducted to address some of
these questions.
Efforts to improve biochemical measures of adrenal function will
undoubtedly continue. It is likely that newer techniques for determining
serum free cortisol will become widely available over time.
Investigating polymorphism in the glucocorticoid receptor would be another
interesting approach in attempts to understand this complex system.
Another area of future investigation would be to examine the optimal doses
of glucocorticoids to patients who might benefit from such therapy.
This is particularly important in view of the extreme elevation in serum
cortisol concentrations using current doses mistakenly labeled as low-dose
therapy.
It is evident from that there are more questions than answers in this
important field. It is likely that studies will be conducted to address some of
these questions.
Efforts to improve biochemical measures of adrenal function will
undoubtedly continue. It is likely that newer techniques for determining
serum free cortisol will become widely available over time.
Investigating polymorphism in the glucocorticoid receptor would be another
interesting approach in attempts to understand this complex system.
Another area of future investigation would be to examine the optimal doses
of glucocorticoids to patients who might benefit from such therapy.
This is particularly important in view of the extreme elevation in serum
cortisol concentrations using current doses mistakenly labeled as low-dose
therapy.