Adrenal Disorders and Critical Illness-Related Corticosteroid Insufficiency (CIRCI)

Pheochromocytoma

Adrenal Insufficiency

Gland composed from outer to inner:

Zona Glomerulosa producing aldosterone in response to Angio II, ACTH, and serum Na/K levels

Zona Fasiculata producing glucocorticoids in response to corticotropin-releasing hormone (CRH)

Zona Reticularis producing androgens in response to ACTH

GFR=salt, sugar, sex

Inner medulla produces catecholamines

circulating cortisol is usually increased in the morning hours.

The stress response is characterized by continuous ACTH release despite levels of cortisol and increases cortisol production regardless of time of day

Primary adrenal insufficiency can be caused by autoimmune disease, infections such as TB or histoplasma, AIDS, neoplasms, medications such as ketoconazole, etomidate, dilantin, and rifampin, adrenal hemorrhage,

Secondary from pituitary disorders or exogenous steroids

Weakness, fatigue, n/v, weight loss, anorexia, nausea, diarrhea, vomiting, abdominal pain. If primary, hyperpigmentation may be seen, especially in skin creases.

Labs show hyponatremia, acidosis, prerenal azotemia, hyperkalemia, hypoglycemia,

Waterhouse-Friedrichson Syndrome-after overwhelming septicemia

Dexamethasone will not affect cortisol stimulation test/levels (2 mg=100 mg of hydrocortisone)

IV Fluids and dextrose replacement

Hydrocortisone 100 mg IVP x1 and add 2nd 100 mg to first liter of fluids then 100-200 IVPB Q6-8 hours (Parrillo recommends 100 Q8) Has both gluco- and mineralocorticoid activity.

Random cortisol at any time of day (critically ill patients lose diurnal variation) <25 indicates insufficiency and these patients should receive supplemental steroids

· Give hydrocortisone 100 mg IV Q8 or Dex 4 mg then 2 mg IV Q8 (allows ACTH stim, but has no mineralocorticoid activity) If hydrocortisone is tapered to less than 100 mg/day, can add Fludrocortisone 0.05-0.20 mg/day

(Chest 122:5, 2002)

Other algorithm:

ACTH Stim test

can be performed at any time of day in the critically ill as the diurnal variation is lost

draw a cortisol level and then give Cosyntropin 250 mcg IV. Draw cortisol at 30 and 60 minutes. A normal response is an increase of 9 and a total poststim cortisol of >20

At STC, they use cosyn 1 mcg

Previous Volume 350:1629-1638 April 15, 2004 Number 16 Next Measurements of Serum Free Cortisol in Critically Ill Patients Amir H. Hamrahian, M.D., Tawakalitu S. Oseni, M.D., and Baha M. Arafah, M.D.

etomidate may cause relative adrenal insuffic. even after one dose (Inten Care Med 2005;31:388) and (Chest 2005;127:1031) Endocrinology Critical Care Related Chapters at Harrison’s Online ABSTRACT Background Because more than 90 percent of circulating cortisol in human serum is protein-bound, changes in the binding proteins can alter measured serum total cortisol concentrations without influencing free concentrations of this hormone. We investigated the effect of decreased amounts of cortisol-binding proteins on serum total and free cortisol concentrations during critical illness, when glucocorticoid secretion is maximally stimulated. Methods Base-line serum total cortisol, cosyntropin-stimulated serum total cortisol, aldosterone, and free cortisol concentrations were measured in 66 critically ill patients and 33 healthy volunteers in groups that were similar with regard to sex and age. Of the 66 patients, 36 had hypoproteinemia (albumin concentration, 2.5 g per deciliter or less), and 30 had near-normal serum albumin concentrations (above 2.5 g per deciliter). Results Base-line and cosyntropin-stimulated serum total cortisol concentrations were lower in the patients with hypoproteinemia than in those with near-normal serum albumin concentrations (P<0.001). However, the mean (±SD) base-line serum free cortisol concentrations were similar in the two groups of patients (5.1±4.1 and 5.2±3.5 µg per deciliter [140.7±113.1 and 143.5±96.6 nmol per liter]) and were several times higher than the values in controls (0.6±0.3 µg per deciliter [16.6±8.3 nmol per liter], P<0.001 for both comparisons). Cosyntropin-stimulated serum total cortisol concentrations were subnormal (18.5 µg per deciliter [510.4 nmol per liter] or less) in 14 of the patients, all of whom had hypoproteinemia. In all 66 patients, including these 14 who had hypoproteinemia, the base-line and cosyntropin-stimulated serum free cortisol concentrations were high-normal or elevated. Volume 350:1629-1638 April 15, 2004 Number 16 Conclusions During critical illness, glucocorticoid secretion markedly increases, but the increase is not discernible when only the serum total cortisol concentration is measured. In this study, nearly 40 percent of critically ill patients with hypoproteinemia had subnormal serum total cortisol concentrations, even though their adrenal function was normal. Measuring serum free cortisol concentrations in critically ill patients with hypoproteinemia may help prevent the unnecessary use of glucocorticoid therapy. NEJM Volume 350:1629-1638 April 15, 2004 Number 16

Non-responders to cosynotropin stim benefited from steroids (JAMA Aug 21, 2002 288:7)

50 mg Hydrocortisone Q6 and 50 mcg of fludrocortisone QD

Low dose hydrocortisone

Crit Care Med 2005;33(11):2457

Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock Conclusions: Treatment with low-dose hydrocortisone accelerates shock reversal in early hyperdynamic septic shock. This was accompanied by reduced production of proinflammatory cytokines, suggesting both hemodynamic and immunomodulatory effects of steroid treatment. Hemodynamic improvement seemed to be related to endogenous cortisol levels, whereas immune effects appeared to be independent of adrenal reserve.

Annane study

showed mortality benefit if steroids are given to non-responders (<9) regardless of cortisol levels. (JAMA 2002;288(7):862)

Corticus

N Engl J Med 2008;358:111-24.

Editorial N Engl J Med 2008;358:188

The rate of death in the control group was lower than expected, and this factor, combined with early stopping of the study, meant that the study had a power of less than 35% to detect a 20% reduction in the relative risk of death. With this caveat, the primary conclusion of the study was that treatment with corticosteroids had no effect on the rate of death at 28 days, a finding that was consistent in the overall population (relative risk, 1.09; 95% confidence interval [CI], 0.84 to 1.41), in patients who had a response to corticotropin (relative risk, 1.00; 95% CI, 0.68 to 1.49), and in those who did not have a response to corticotropin (relative risk, 1.09; 95% CI, 0.77 to 1.52). The lack of treatment effect was also consistent regardless of the duration of septic shock before recruitment. Also notable is that shock was reversed more rapidly in patients receiving hydrocortisone but that this factor did not result in reduced mortality.

Hepatoadrenal Syndrome

Liver failure pts have an exceedingly high incidence of adrenal failure (Crit Care Med 2005;33:1254)

Special Note [GC = glucocorticoid] index drug: hydrocortisone 20 mg [MC = mineralocorticoid] index drug: fludrocortisone 0.1 mg betamethasone [GC 0.6 mg; MC n/a] cortisone [GC 25 mg; MC 20 mg] dexamethasone [GC 0.75 mg; MC n/a] fludrocortisone [GC 1.3 mg; MC 0.1 mg] hydrocortisone [GC 20 mg; MC 20 mg] methylprednisolone [GC 4 mg; MC n/a] prednisolone [GC 5 mg; MC 50 mg] prednisone [GC 5 mg; MC 50 mg] triamcinolone [GC 4 mg; MC n/a]

Adrenal Insufficiency

Gland composed from outer to inner:

Zona Glomerulosa producing aldosterone in response to Angio II, ACTH, and serum Na/K levels

Zona Fasiculata producing glucocorticoids in response to corticotropin-releasing hormone (CRH)

Zona Reticularis producing androgens in response to ACTH

GFR=salt, sugar, sex

Inner medulla produces catecholamines

circulating cortisol is usually increased in the morning hours.

The stress response is characterized by continuous ACTH release despite levels of cortisol and increases cortisol production regardless of time of day

Secondary from pituitary disorders or exogenous steroids

Weakness, fatigue, n/v, weight loss, anorexia, nausea, diarrhea, vomiting, abdominal pain. If primary, hyperpigmentation may be seen, especially in skin creases.

Labs show hyponatremia, acidosis, prerenal azotemia, hyperkalemia, hypoglycemia,

Waterhouse-Friedrichson Syndrome-after overwhelming septicemia

Dexamethasone will not affect cortisol stimulation test/levels (2 mg=100 mg of hydrocortisone)

IV Fluids and dextrose replacement

Hydrocortisone 100 mg IVP x1 and add 2nd 100 mg to first liter of fluids then 100-200 IVPB Q6-8 hours (Parrillo recommends 100 Q8) Has both gluco- and mineralocorticoid activity.

Random cortisol at any time of day (critically ill patients lose diurnal variation) <25 indicates insufficiency and these patients should receive supplemental steroids

Review Article

(Chest 2002;122(5):1784)

Other algorithm:

ACTH Stim test

can be performed at any time of day in the critically ill as the diurnal variation is lost

draw a cortisol level and then give Cosyntropin 250 mcg IV. Draw cortisol at 30 and 60 minutes. A normal response is an increase of 9 and a total poststim cortisol of >20

At STC, they use cosyn 1 mcg

Previous Volume 350:1629-1638 April 15, 2004 Number 16 Next Measurements of Serum Free Cortisol in Critically Ill Patients Amir H. Hamrahian, M.D., Tawakalitu S. Oseni, M.D., and Baha M. Arafah, M.D.

Meta-analysis of etomidate shows increased mortality (Crit Care Med 2012;40:2945)

Non-responders to cosynotropin stim benefited from steroids (JAMA Aug 21, 2002 288:7)

50 mg Hydrocortisone Q6 and 50 mcg of fludrocortisone QD

Annane study showed mortality benefit if steroids are given to non-responders (<9) regardless of cortisol levels. (JAMA 2002;288(7):862)

Study looks at all possible ways of diagnosing

b/c of the variability of serum levels based on varying albumin concentration, absolute cortisol is no good

free is better,

but the best is the response to 250mcg stim at 30 and 60 minutes. >9=no deficiency

higher cortisol was associated with increased need for norepi in non-treated group

Crit Care 2006;10:R149

Hepatoadrenal Syndrome

Liver failure pts have an exceedingly high incidence of adrenal failure (Crit Care Med 2005;33:1254)

Adrenal function in sepsis: the retrospective Corticus cohort study. Lipiner-Friedman D, Sprung CL, Laterre PF, Weiss Y, Goodman SV, Vogeser M, Briegel J, Keh D, Singer M, Moreno R, Bellissant E, Annane D; Corticus Study Group. Service de Réanimation, Hôpital Raymond Poincaré (APHP), Faculté de Médecine Paris Ile de France Ouest (UVSQ), Garches, France. OBJECTIVE: To refine the value of baseline and adrenocorticotropin hormone (ACTH)-stimulated cortisol levels in relation to mortality from severe sepsis or septic shock. DESIGN: Retrospective multicenter cohort study. SETTING: Twenty European intensive care units. PATIENTS: Patients included 477 patients with severe sepsis and septic shock who had undergone an ACTH stimulation test on the day of the onset of severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Compared with survivors, nonsurvivors had higher baseline cortisol levels (29.5 +/- 33.5 vs. 24.3 +/- 16.5 microg/dL, p = .03) but similar peak cortisol values (37.6 +/- 40.2 vs. 35.2 +/- 22.9 microg/dL, p = .42). Thus, nonsurvivors had lower Deltamax (i.e., peak cortisol minus baseline cortisol) (6.4 +/- 22.6 vs. 10.9 +/- 12.9 microg/dL, p = .006). Patients with either baseline cortisol levels <15 microg/dL or a Deltamax <or=9 microg/dL had a likelihood ratio of dying of 1.26 (95% confidence interval, 1.11-1.44), a longer duration of shock, and a shorter survival time. Patients with a Deltamax <or=9 microg/dL but any baseline cortisol value had a likelihood ratio of dying of 1.38 (95% confidence interval, 1.18-1.61). CONCLUSIONS: Although delta cortisol and not basal cortisol level was associated with clinical outcome, further studies are still needed to optimize the diagnosis of adrenal insufficiency in critical illness. Etomidate influenced ACTH test results and was associated with a worse outcome. Go to source>>

The real corticus (NEJM 2008;358:111)

the editorial (NEJM 2008;358(2):188)

Increased Risk of Adrenal Insufficiency Following Etomidate Exposure in Critically Injured Patients Bryan A. Cotton, MD; Oscar D. Guillamondegui, MD; Sloan B. Fleming, PharmD; Robert O. Carpenter, MD; Shivani H. Patel, PharmD; John A. Morris Jr, MD; Patrick G. Arbogast, PhD Arch Surg. 2008;143(1):62-67. Background Timely diagnosis and treatment of adrenal insufficiency (AI) dramatically reduces mortality in trauma patients. We sought to identify risk factors and populations with a high risk of developing AI. Design Retrospective registry study. Setting Academic level I trauma center. Patients All trauma patients in the intensive care unit who underwent cosyntropin stimulation testing (CST) for presumed AI from January 1, 2002, through December 31, 2004. Interventions Cosyntropin stimulation testing, in which response was defined as an increase of 9 µg/dL (248 nmol/L) or more in cortisol level. Main Outcome Measures Risk factors for developing AI in critically ill trauma patients. Results In 137 patients, CST was performed; 83 (60.6%) were nonresponders and 54 (39.4%) were responders. Age, sex, race, trauma mechanism, Injury Severity Score, and Revised Trauma Score were not statistically different between the groups. Rates of sepsis/septic shock, mechanical ventilation, and mortality were also similar between the 2 groups. However, rates of hemorrhagic shock on admission (45 [54%] vs 16 [30%]), requirement of vasopressor support (65 [78%] vs 28 [52%]), and etomidate exposure (59 [71%] vs 28 [52%]) were all significantly higher in the nonresponder group (P < .01). The increased risk of AI remained after controlling for potential confounding covariates (age, mechanism, Injury Severity Score, and Revised Trauma Score). Conclusions Exposure to etomidate is a modifiable risk factor for the development of AI in this sample of critically injured patients. The use of etomidate for procedural sedation and rapid-sequence intubation in this patient population should be reevaluated. Author Affiliations: Division of Trauma and Surgical Critical Care, Department of Surgery (Drs Cotton, Guillamondegui, Carpenter, and Morris), and Departments of Clinical Pharmacology (Drs Fleming and Patel) and Biostatistics (Dr Arbogast), Vanderbilt University Medical Center, Nashville, Tennessee.

etomidate causes adrenal suppression for 48 hours (Inten Care Med 2008;34:714)

Sub-analysis of CORTICUS shows etomidate increases mortality (Inten Care Med 2009;35:1868)

(Ann Emerg Med 2010;56(5):481) Non-sig on LOS, but also non-sig mortality increase

Bellissant E, Annane D. Effect of hydrocortisone on phenylephrine — mean arterial pressure dose-response relationship in septic shock. Clin Pharmacol Ther 2000;68:293-303. [CrossRef][ISI][Medline]

Most recent meta-analysis shows etomidate causes increased mortality in the critically ill (Intens Care Med 2011;:37:901)

Dave Seder’s retrospective review showed no increased mortality. Retrospective review of ICU intubations (Critical Care Medicine Issue: Volume 41(3), March 2013, p 774–783)

In this study 2616 patients receiving etomidate for induction and a volatile agent for maintenance are included. This showed an increased OR for 30-days mortality with a factor of 2.5 and 1.5 times greater chance for a major cardiovascular event in hospital. (Anesth Analg. 2013 Dec;117(6):1329-37)

Recs from ACCM

(Crit Care Med 2008;36:1937)

MA in JAMA still worth giving for pressor dependent patients ( JAMA. 2009;301(22):2362-2375)

Aldosterone

The differential diagnosis of syndromes involving hypokalemia, metabolic alkalosis, and hypertension

from Renal Fellow Network by aqlam While there are a number of conditions which can cause the combination of hypokalemia and metabolic alkalosis there are a limited number of disease processes which lead to hypokalemia, metabolic alkalosis, AND hypertension. In order to have hypertension in this setting, the pathological disease process must involve increased sodium (and water) reabsorption which leads to volume expansion and elevated blood pressure. The list of these diseases includes:1. Liddle’s syndrome. Autosomal dominant condition caused by a gain-of-function mutation in the epithelial sodium channel (ENaC) which results in increased Na+ reabsorption.2. Licorice ingestion and the Syndrome of Apparent Mineralocorticoid Excess (SAME). Ingestion of large amounts of licorice (or licorice-containing tobacco or gun) can lead to inhibition of the enzyme 11-beta-hydroxysteroid dehydrogenase, which converts cortisol into the cortisone in aldosterone target tissues (e.g. collecting ducts). Since cortisol has an equal affinity for the mineralocorticoid receptor compared to aldosterone, it would act as the primary mineralocorticoid if it were not converted into the inactive cortisone. The compound in licorice that is responsible for this enzyme inhibitory activity is glycyrrhetinic acid, which also has some mild mineralocorticoid activity. The mechanism is similar in SAME, in which one has mutations in the 11-beta-hydroxysteroid dehydrogenase enzyme that prevent proper conversion of cortisol into cortisone. 3. Renal artery stenosis and renin secreting tumors. Both of these etiologies are the result of elevated production and secretion of renin leading to hyperaldosteronism.4. Adrenal hyperfunction. This category includes causes of primary hyperaldosteronism, including adrenal adenoma, adrenal hyperplasis, and adrenal carcinoma.All of these conditions essentially result in or mimic hyperaldosteronism and can be partly differentiated on the basis of the response of the renin-angiotensin-aldosterone system to the disease processes:Liddle’s — high renin, high aldoLicorice and SAME — low renin, low aldoRenal artery stenosis and renin-secreting tumors — high renin, low aldoAdrenal hyperfunction — low renin, high aldo