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 Moderator:Dr.G.Yadavalli

Topics to be Addressed? : 

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.

Topics to be Addressed? : 

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.

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 inadequate for the patient’s metabolic demands Rapid improvement on Hydrocortisone therapy

Incidence of Relative Adrenal Insufficiency : 

CABG Ruptured AAA others Incidence of Relative Adrenal Insufficiency JCEM (2006) 91: 105–114

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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

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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

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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 HPA function Anesthesiology (1993) 77: 426–431 HPA Alteration During Critical Illness

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

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JCEM (1997) 82: 2343–2349 JCEM (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

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Impaired hepatocellular function Impaired hepatic blood flow Impaired renal/thyroid function J Clin Invest (1958) 37: 1791–1798 Increased steroid production Decreased steroid clearance Increased Serum Cortisol (free cortisol level) Stress

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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 J Inflamm (1996) 47: 39–51 Arginine Vasopressin Endothelin Atrial Natriuretic Factor (ANF) Variety of Cytokines (IL-6)

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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: 1629–1638 Crit Care Med (1993) 21: 396–401

Type & Severity of Illness : 

Type & Severity of Illness Acute phase of illnesscortisol levels proportionate to degree of stress Cortisol levels:major surgery vs sepsisSIMILAR 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 JCEM (2001) 86: 2811–2816 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 JCEM(2004) 89: 563-564 JCEM(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 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

Persistent Hypercortisolism Observed in Protracted Critical Illness : 

Persistent Hypercortisolism Observed in Protracted Critical Illness J Trauma (1987) 27: 384–392

Topics to be Addressed? : 

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.

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

Patients at Risk for Adrenal Insufficiency : 

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 KETOCONAZOLE ETOMIDATE

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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 with medical illnesses that are more likely 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 In evaluating such patients for the risk of adrenal insufficiency, one can look for: Even though the interpretation of such clinical data 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

High-Dose ACTH Stimulation Test: : 

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

Random Cortisol Level : 

Random Cortisol Level Poor prognosis in septic shock patients: extremely HIGH (>34g/dL) total cortisol extremely LOW (<25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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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: 727–734 Diagnostic Criteria

Alternative Approaches : 

Calculated free cortisol index Calculating free cortisol concentrations (using the Coolens method)  Transcortin levels (not readily available in most laboratories) Alternative 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 : 

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) :1601–1602 Measurements of serum free cortisol represent the most ideal approach in assessing glucocorticoid secretion, especially in hypoproteinemic, critically ill subjects: Serum Free Cortisol

Alternative Measurements : 

Salivary cortisol ACTH-dependent steroids (DHEA, DHEA-S)  another, yet untested approach N Engl J Med (2004) 350: 1629–1638 Alternative Measurements

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

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↑ 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 Marker of Glucocorticoid Secretion

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

Topics to be Addressed? : 

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.

Medications Modulating Serum Total Cortisol Concentrations in Critically Ill : 

Medications Modulating Serum Total Cortisol Concentrations in Critically Ill

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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 Acute Inflammatory Process: fever tachycardia leukocytosis immune cell activation

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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

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Helpful approach in understanding the body’s response to acute inflammation Not considered a good model for sepsis or septic shock 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? 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: 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 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 N Engl J Med (2003)348:727-734  limit total cortisol measurements

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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

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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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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

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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

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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)

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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

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 → 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

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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

Topics to be Addressed? : 

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.

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

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

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

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

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

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D1:100-150mg HC IVD(continuous) Stress Dosing of Steroids in Patients with Chronic Adrenal Insufficiency N Engl J Med (1997) 337: 1285-1292 X capable to ↑ serum cortisol

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CONCLUSION

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.

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THANK YOU

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