Adrenal Insufficiency.ppt

ADRENAL INSUFFICIENCY IN THE CRITICALLY ILL PATIENT Physiology,Diagnosis,Management.

Fadi Seif, PGY 3Moderator: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.






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 patient’s metabolic demandsinadequate for the patient’s 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 patient’s metabolic demandsinadequate for the patient’s metabolic demands

• Rapid improvement on Hydrocortisone therapy

0%

10%

20%

30%

40%

50%

60%

70%

Septic Shock Other ICU Patients

CABG Ruptured AAA

others

CABG Ruptured AAA

others

Incidence of Relative Adrenal Insufficiency

Incidence of Relative Adrenal Insufficiency

JCEM (2006) 91: 105–114

CORTISOL

ACTH

CRH

STRESS:Physical stressEmotional stress HypoglycemiaCold exposurePain

Adrenal CortexAnterior Lobe of Pituitary Gland

Hypothalamus

Cortisol ActionCortisol 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 T1/2 = 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 T1/2 = 70-120 min

• Bound to circulating CBG, albumin, 1-acid glycoprotein

• 10% free = biologically active

• CBG ↓ rapidly in critically ill pts free cortisol

• Bound to circulating CBG, albumin, 1-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-α– 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-α– ANS

modulators of modulators of HPA functionHPA function

Anesthesiology (1993) 77: 426–431

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: 1690–1694Neuroendocrinology (1997) 66: 54–62Clin Endocrinol (Oxf) (2004) 60: 29–35

During an Inflammatory Process

JCEM (1997) 82: 2343–2349JCEM (1999) 84: 1729–1736

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 hepatocellularfunctionImpaired hepatic bloodflowImpaired renal/thyroidfunction

J Clin Invest (1958) 37: 1791–1798

• 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: 39–51

Arginine Vasopressin

Endothelin

Atrial Natriuretic Factor (ANF)

Variety of Cytokines (IL-6)

• Cortisol secretion during critical illnesses:

– Excessive (reaching levels those achieved in patients with Cushing’s syndrome)

– Less suppressible by exogenous glucocorticoid administration (dexamethasone)

• Cortisol secretion during critical illnesses:

– Excessive (reaching levels those achieved in patients with Cushing’s syndrome)

– Less suppressible by exogenous glucocorticoid administration (dexamethasone)

N Engl J Med (2004) 350: 1629–1638Crit Care Med (1993) 21: 396–401

Type & Severity of IllnessType & Severity of Illness• Acute phase of illnesscortisol levels proportionate to degree of stress

• Cortisol levels:major surgery vs sepsisSIMILAR ELEVATION

• Cortisol elevations in sepsis:

-wide range

-? don’t 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 didn’t survive

• Glucocorticoid resistant patients have higher levels

• Acute phase of illnesscortisol levels proportionate to degree of stress

• Cortisol levels:major surgery vs sepsisSIMILAR ELEVATION

• Cortisol elevations in sepsis:

-wide range

-? don’t 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 didn’t survive

• Glucocorticoid resistant patients have higher levelsJCEM (2001) 86: 2811–2816Intensive Care Med (2001)27: 1584-1591Clin Endocrinol (2004) 60:29-35.

Variations Among IndividualsVariations 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 enzymeJCEM(2004) 89: 563-564JCEM(2004) 89: 565-573

Short-Term Stresses vs. ProtractedCritical Illness

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

• 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: 1827-34J 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: 384–392

Benefits Related To Long Term Complications

Providing energy Hyperglycemia

Maintaining volume Myopathy

Minimizing inflammation Psychiatric alterations

Poor wound healing

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 Risk for Adrenal InsufficiencyPatients 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

• 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

oralparenteralInhaled GLUCOCORTICOIDdermal intraarticularRU486KETOCONAZOLEETOMIDATE

– 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 patientis often difficult in the critically ill patient

Lab Test Difficulties in Critical IllnessLab 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 250g 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

• Can be done at any time of day

• Baseline cortisol 250g 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

Random Cortisol LevelRandom Cortisol Level

Poor prognosis in septic shock patients:

– extremely HIGH (>34g/dL) total cortisol

– extremely LOW (<25g/dL) total cortisol

Poor prognosis in septic shock patients:

– extremely HIGH (>34g/dL) total cortisol

– extremely LOW (<25g/dL) total cortisol

N Engl J Med (2003) 348 (8): 727-734Chest (2002) 122 (5): 1784-1796Critical 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: 1206-1212N Engl J Med (2003) 348: 727–734

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)

Transcortin levels (not readily available in most laboratories)

Alternative ApproachesAlternative Approaches

Serum Free Cortisol Level as a Marker of Glucocorticoid Secretion

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

• 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

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) :1601–1602

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 hypoproteinemichypoproteinemic, critically ill subjects:, critically ill subjects:

Serum Free CortisolSerum Free Cortisol

• Salivary cortisol

• ACTH-dependent steroids (DHEA, DHEA-S)

another, yet untested approach

• Salivary cortisol

• ACTH-dependent steroids (DHEA, DHEA-S)

another, yet untested approach

N Engl J Med (2004) 350: 1629–1638

Alternative MeasurementsAlternative Measurements

• Studies over the past 15–20 yrs have demonstrated:

- Cortisol concentrations (saliva)

- Free/unbound plasma cortisol level

• Studies over the past 15–20 yrs have demonstrated:

- Cortisol concentrations (saliva)

- Free/unbound plasma cortisol level

JCEM(1988) 66:343–348

Salivary Cortisol as a Marker 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)



Program of the 87th Annual Meeting of The Endocrine Society, San Diego, CA, 2005 (Abstract P3-440)

Salivary CortisolSalivary 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)

Medications Modulating Serum Total Cortisol Concentrations in Critically Ill Medications Modulating Serum Total

Cortisol Concentrations in Critically Ill

DRUG MECHANISM IMPACT EXAMPLE

Estrogen Increased CBGHigher total cortisol; Normal free cortisol

Estrogen, oral contraceptives; pregnancy; hepatitis

KetoconazoleDecreased synthesis of

cortisolLower serum cortisol; low

free cortisol Patients receiving the drug

SpironolactoneInterference in the assay depending on antibody

specificity

Generally higher levels; variable influence

depending on the assay specificity

Patients on the drug

Aminoglutathemide Inhibit cortisol synthesisLower serum total and

free cortisol

Patients on the drug e.g., medical adrenalectomy for metastatic breast cancer.

EtomidateDecreased 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: 1896–1904

HPA Function During Experimental Endotoxemia

HPA Function During Experimental Endotoxemia

Acute Inflammatory Process:fever

tachycardialeukocytosis

immune cell activation

LPS injection →

↑

• ACTH

• Catecholamines

• GH

• Cortisol (11.5 → 29 g/dl within 2 hrs)

• Anti-inflammatory cytokine IL-11 (protective role during sepsis)

Immunobiology (1993) 187:403–416 Infect Immun. 1997 June; 65(6): 2378–2381

• Helpful approach in understanding the body’s response to acute inflammation

• Not considered a good model for sepsis or septic shock

• Helpful approach in understanding the body’s 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

Numerous studies documented activation of HPA axis during acute and chronic stress:

• Surgery --Ann Surg. (1995) 221: 372–380

• Sepsis -- Ann Surg. (1977) 186: 29–33

• Trauma – JCEM (2006) 10: 3725-3745

• Burns -- J Trauma (1982) 221: 263–273

• Other critical illnesses

Numerous studies documented activation of HPA axis during acute and chronic stress:

• Surgery --Ann Surg. (1995) 221: 372–380

• Sepsis -- Ann Surg. (1977) 186: 29–33

• Trauma – JCEM (2006) 10: 3725-3745

• Burns -- J Trauma (1982) 221: 263–273

• Other critical illnesses

The Concept of Relative Adrenal InsufficiencyThe 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


20 %-75 % in patients with sepsis/ septic shock


0-25 % in other critically ill patients


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 InsufficiencyThe 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

• Drawback: 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

• Drawback: 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 4–6 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 4–6 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 IllnessGlucocorticoid 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) 173:276–280

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 ReplacementOutcome 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

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.




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.




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.




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 illnessD1:100-150mg 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 illnessD1:100-150mg HC IVD(continuous)




N Engl J Med (1997) 337: 1285-1292

X capable to ↑ serum cortisol

Conclusion: Future studiesConclusion: 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.

Adrenal Insufficiency.ppt

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