ADRENAL INSUFFICIENCY IN THE CRITICALLY ILL PATIENT

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ADRENAL INSUFFICIENCY IN THE CRITICALLY ILL
PATIENT
Physiology,Diagnosis,Management.
Fadi Seif, PGY 3 ModeratorDr.G.Yadavalli
2
Topics to be Addressed?

• Definition physiology.
• Diagnostic challenges.
• Examples of stressful conditions.
• Relative AI and steroid therapy in the
  critically-ill patient.
• Stress doses in patients maintained on steroids.

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Topics to be Addressed?

• Definition physiology.
• Diagnostic challenges.
• Examples of stressful conditions.
• Relative AI and steroid therapy in the
  critically-ill patient.
• Stress doses in patients maintained on steroids.

4
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 inadequate for the patients metabolic
  demands
• Rapid improvement on Hydrocortisone therapy

5
Incidence of Relative Adrenal Insufficiency
CABG Ruptured AAA others
JCEM (2006) 91 105114
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Hypothalamus
STRESS Physical stress Emotional stress
Hypoglycemia Cold exposure Pain
CRH
CORTISOL
ACTH
Anterior Lobe of Pituitary Gland
Adrenal Cortex
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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

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• Bound to circulating CBG, albumin, ?1-acid
  glycoprotein
• 10 free biologically active
• CBG ? rapidly in critically ill pts ? ? free
  cortisol

• 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 T1/2 70-120 min

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HPA Alteration During Critical Illness

• 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-a
• ANS

modulators of HPA function
Anesthesiology (1993) 77 426431
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During an Inflammatory Process

• 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
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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
These cytokines act synergistically to augment
ACTH secretion BEYOND that achieved by CRH alone
JCEM (1997) 82 23432349 JCEM (1999) 84
17291736
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Increased Serum Cortisol (free cortisol level)

• Increased steroid production
• Decreased steroid clearance

Impaired hepatocellular function Impaired
hepatic blood flow Impaired renal/thyroid function
Stress
J Clin Invest (1958) 37 17911798
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• 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

Arginine Vasopressin Endothelin Atrial
Natriuretic Factor (ANF) Variety of Cytokines
(IL-6)
J Inflamm (1996) 47 3951
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• 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
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Type Severity of Illness

• Acute phase of illness?cortisol levels
  proportionate to degree of stress
• Cortisol levelsmajor surgery vs sepsis?SIMILAR
  ELEVATION
• Cortisol elevations in sepsis
• -wide range
• -? dont correlate with APACHE
• -highest levels ?highest 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)
6029-35.
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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

JCEM(2004) 89 563-564 JCEM(2004) 89 565-573
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Short-Term Stresses vs. ProtractedCritical
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

JCEM (1998)83 1827-34 J Trauma (1987)27 384-392
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• 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
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Persistent Hypercortisolism Observed in
Protracted Critical Illness

• J Trauma (1987) 27 384392

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Topics to be Addressed?

• Definition physiology.
• Diagnostic challenges.
• Examples of stressful conditions.
• Relative AI and steroid therapy in the
  critically-ill patient.
• Stress doses in patients maintained on steroids.

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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

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Patients at Risk 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

oral parenteral Inhaled
GLUCOCORTICOID dermal intraarticular RU486 KETOCO
NAZOLE ETOMIDATE
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It is important to raise similar concerns in
patients with medical illnesses that are more
likely associated with adrenal insufficiency

• 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)

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In evaluating such patients for the risk of
adrenal insufficiency, one can look for

• 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

Even though the interpretation of such clinical
data is often difficult in the critically ill
patient
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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

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High-Dose ACTH Stimulation Test

• Can be done at any time of day
• Baseline cortisol ? 250?g ACTH ? measure
  cortisol at 30 and 60 minutes
• Non-stressed pt increase to ?18 ?g /dL R/O AI
• High sensitivity specificity for primary AI
  using threshold value of 15 ?g /dL
• Less sensitive for secondary AI

Critical care clinics (2006) 22 (2) 245-53
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Random Cortisol Level

• Poor prognosis in septic shock patients
• extremely HIGH (gt34?g/dL) total cortisol
• extremely LOW (lt25?g/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
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Diagnostic Criteria

• Unstressed subjects, AI
• ACTH stimulated cortisol ? 18-20 ug/dl
• Critically illness, AI
• random cortisol lt15 or 25 ug/dl (if on pressors)
• cortisol increment after ACTH stimulation lt
  9ug/dl
• Severe hypoproteinemia, AI
• serum free cortisol lt 2 ug/dl or
• ACTH stimulated value lt 3.1 ug/dl

N Engl J Med (1996) 335 1206-1212 N Engl J Med
(2003) 348 727734
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Alternative Approaches

• Calculated free cortisol index
• Calculating free cortisol concentrations (using
  the Coolens method)

? Transcortin levels (not readily available in
most laboratories)
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Serum Free Cortisol Level as a Marker of
Glucocorticoid Secretion

• Serum free cortisol concentrations
• ? most appropriate approach for assessing
  glucocorticoid secretion in the critically ill
• Patients with low plasma proteins (albumin 2.5
  gm/dl)
• ? best 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

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Serum Free Cortisol
Measurements of serum free cortisol represent the
most ideal approach in assessing glucocorticoid
secretion, especially in hypoproteinemic,
critically ill subjects

• Assays for determining serum free cortisol
  concentrations (difficult, time consuming, and
  labor intensive).
• Rapid assays for measurements of serum free
  cortisol levels will become available in the near
  future.
• Alternative approaches should be explored in the
  assessment of glucocorticoid secretion (until
  these assays become available for routine
  clinical care).
• Such approaches include measurements of salivary
  cortisol,other ACTH dependent adrenal
  steroids(DHEA and DHEA-S).
  

NEngl J Med (350) 16011602
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Alternative Measurements

• Salivary cortisol
• ACTH-dependent steroids (DHEA, DHEA-S)
• ? another, yet untested approach

N Engl J Med (2004) 350 16291638
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Salivary Cortisol as a Marker of Glucocorticoid
Secretion

• Studies over the past 1520 yrs have
  demonstrated
• - Cortisol concentrations (saliva)
  
• - Free/unbound plasma cortisol level
  

in equilibrium, and highly correlate
JCEM(1988) 66343348
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Salivary Cortisol as a Marker of Glucocorticoid
Secretion

• ? 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)
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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)

Program of the 87th Annual Meeting of The
Endocrine Society, San Diego, CA, 2005 (Abstract
P3-440)
36
Topics to be Addressed?

• Definition physiology.
• Diagnostic challenges.
• Examples of stressful conditions.
• Relative AI and steroid therapy in the
  critically-ill patient.
• Stress doses in patients maintained on steroids.

37
Medications Modulating Serum Total Cortisol
Concentrations in Critically Ill
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HPA Function During Experimental Endotoxemia

• Well-characterized model of acute inflammation
• IV administration of Gram-negative bacterial
  lipopolysaccharide (LPS) endotoxin

Acute Inflammatory Process fever tachycardia leuk
ocytosis immune cell activation
J Clin Invest (1990) 85 18961904
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• ACTH
• Catecholamines
• GH
• Cortisol (11.5 ? 29 ?g/dl within 2 hrs)
• Anti-inflammatory cytokine IL-11 (protective
  role during sepsis)

LPS injection ? ?
Immunobiology (1993) 187403416 Infect Immun.
1997 June 65(6) 23782381
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Experimental Endotoxemia

• Helpful approach in understanding the bodys
  response to acute inflammation
• Not considered a good model for sepsis or septic
  shock

? Data obtained in patients during experimental
endotoxemia cannot be extrapolated/applied to
others with sepsis or septic shock
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Topics to be Addressed?

• Definition physiology.
• Diagnostic challenges.
• Examples of stressful conditions.
• Relative AI and steroid therapy in the
  critically-ill patient.
• Stress doses in patients maintained on steroids.

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• 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

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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

? limit total cortisol measurements
N Engl J Med (2003)348727-734
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Relative Adrenal Insufficiency in Critically Ill
Patients

• 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
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• Prevalence of relative AI
• 20 -75 in patients with sepsis/ septic
  shock

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• Prevalence of relative AI
• 0-25 in other critically ill patients

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The Concept of Relative Adrenal Insufficiency

• 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) 68435-441
Anesthesia(1999) 54861-67
48

• 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 gtgt 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
• Drawback did not indicate whether those who did
  not receive etomidate did/did not benefit from
  hydrocortisone

JAMA(2002) 288 862-871
Intensive care(2003) Med 31 1454
Intensive care Med(2005) 31325-326
49

• 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)

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• 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
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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 lt 0.035)
  
• adequate adrenal function (20 of 23)
• adrenal insufficiencyHC (32 of 35) vs
  placebo (24 of 35).
• Mechanism(s) ????
• Importantly? hydrocortisone therapy ?
• 
  

Hospital Stay Hospital Mortality
Additional studies are needed to confirm this
finding and, once confirmed, to examine
mechanisms of potential benefit from
hydrocortisone on ventilator weaning
Am J Resp Crit Care Med (2006) 173276280
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CORTICUS study

• 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

NEJM (2008) 358111-124
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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

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Topics to be Addressed?

• Definition physiology.
• Diagnostic challenges.
• Examples of stressful conditions.
• Relative AI and steroid therapy in the
  critically-ill patient.
• Stress doses in patients maintained on steroids.

55
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

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Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency

• At least 3 recent studies showed that major
  surgery in patients on glucocorticoids did not
  require more steroids than their regular daily
  dose.

Transplantation (1991) 51 385-390
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Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency

• 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.
  
  

Surgery (1997) 121 123-129
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Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency

• 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.

N Engl J Med 1997 337 1285-1292
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Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency

• The most reasonable approach to this issue is
  expressed in a consensus article and recommended
• 25 mg hydrocortisone(or equivalent) for minor
  stress surgery/ hernioplasty
• 50-75 mg for moderate stress/abdominal
  hysterectomy
• 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.
  
  

Ann Surg (1994) 219 416-425
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Stress Dosing of Steroids in Patients with
Chronic Adrenal Insufficiency

• 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 illness?D1100-150mg HC
  IVD(continuous)
  

X capable to ? serum cortisol
N Engl J Med (1997) 337 1285-1292
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CONCLUSION
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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.

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THANK YOU