Adrenal Dysfunction following Cardiac Surgery JM Co, MD, FPCP, FPSEM Endocrinology, diabetes and metabolism UERMMMCI St luke’s medical center QC Cardinal santos medical center May 24, 2012

Should I be concerned re adrenal dysfunction? Hypotension post-cardiac surgery? Probably cardiac. Why is my patient still hypotensive several days after cardiac surgery? Am I missing something?! I’m just here for the sugars! Does he have adrenal dysfunction?

Why? Is this condition a common occurrence? Consider adrenal dysfunction in your post-cardiac surgery patient whom you have difficulty weaning off vasopressors. Why? Is this condition a common occurrence?

Incidence in surgical ICU Incidence of adrenal insufficiency among surgical ICU patients > 55 years of age with postoperative hypotension requiring vasopressors was as high as 32.7% Rivers EP, Gaspari M, Saad GA et al. Chest 2001; 119:889-896

120 elective CABG patients 93 had relative adrenal insufficiency (77.5%) Of the 78 patients who received etomidate, 69 had developed relative adrenal insufficiency (88%) Of the 42 patients who did not receive etomidate, 24 developed relative Adrenal insufficiency (57.1%) Iribarren et al. Journal of Cardiothoracic Surgery 2010, 5:26

Diagnostic criteria still needs work ACTH-stimulation tests in CABG patients 38.5% of the clinically euadrenal and maximally stressed surgical patients with an uneventful clinical course showed an inadequate rise of cortisol levels after the 250 ug ACTH-stimulation, when using the 9 ug/dL criterion. J Clin Endocrinol Metab 90: 4579–4586, 2005

The adrenal gland Mineralocorticoids (eg Aldosterone) Glucocorticoids (eg Cortisol) Androgens Catecholamines (eg Epinephrine)

Cortisol 90% bound; 10% free Circulating half-life 70-120 mins Not stored in the adrenal gland Binds to intracellular glucocorticoid receptors Affect the transcription of thousands of genes in every cell of the body. Marik PE et al. Crit Care Med 2008 Vol. 36, No. 6

Cortisol affects the transcription of thousands of genes in every cell of the body. Effects Increases glucose Activation of lipolysis Increases sensitivity to vasopressor agents such as catecholamines and angiotensin II Anti-inflammatory actions Reduction in the number and function of various immune cells at sites of inflammation Decreases the production of cytokines, chemokines, and eicosanoids Marik PE et al. Crit Care Med 2008 Vol. 36, No. 6

Adrenal response to stress With severe infection, trauma, burns, illness, or surgery, there is an increase in cortisol production by as much as a factor of six that is roughly proportional to the severity of the illness. Diurnal variation in cortisol secretion is also lost. These effects are due to increased production of CRH and ACTH and a reduction in negative feedback from cortisol. Cooper M, Stewart P. N Engl J Med 2003. 348;8

Adrenal response to surgery Surgery is one of the most potent activators of the hypothalamic-pituitary-adrenal axis Maximum cortisol levels are reached in the early postoperative period, especially following anaesthesia reversal and endotracheal extubation In CABG Peak cortisol levels achieved 30 minutes after extubation Cortisol levels have high normal values about 48-72 hours after surgical procedure Marik PE et al. Crit Care Med 2008 Vol. 36, No. 6

Why would the adrenal fail? Strong inflammatory signals, such as cytokines (TNF-α) or other peptides, known as corticostatins, compete with ACTH for binding on its receptor, thus resulting in decreased cortisol production and secretion Other neuropeptides, signaling molecules, components of oxidative stress and the impaired adrenal blood flow contribute to adrenal insufficiency. Some inflammatory factors may cause glucocorticoid resistance at the level of target cell, affecting vital steps of the glucocorticoid receptor signaling. http://www.endotext.org accessed 23 May 2012

Now that you are considering adrenal dysfunction.. What should I do?

Was adrenal dysfunction present before surgery? Ask for symptoms Weakness and fatigue Anorexia, nausea, vomiting Abdominal pain Myalgia or arthralgia History of steroid use? Prednisone, Medrol, Decilone Celestamine, Claricort Nasal sprays (?) History of pituitary dysfunction? History of low TSH and FT4? Brain surgery / trauma / irradiation / Sheehan’s? Look for: Decreased body hair Vitiligo Increased pigmentation Cooper M, Stewart P. N Engl J Med 2003. 348;8

Features suggesting corticosteroid insufficiency Clinical problems Hemodynamic instability Ongoing inflammation with no obvious source Multiple-organ dysfunction Laboratory findings Hyponatremia Hyperkalemia Hypoglycemia Eosinophilia Rarely seen in ICU patients Cooper M, Stewart P. N Engl J Med 2003. 348;8

Before you test for cortisol.. Septic shock and ARDS should be treated with glucocorticoids Septic shock SIRS Infection End-organ damage Refractory hypotension ARDS Hypoxia Chest X-Ray: Bilateral diffuse infiltrates of the lungs No cardiovascular lesion PaO2/FiO2 ratio less than 200 Marik PE et al. Crit Care Med 2008 Vol. 36, No. 6

Cooper M, Stewart P. N Engl J Med 2003. 348;8

Cooper M, Stewart P. N Engl J Med 2003. 348;8

Corticotropin test / ACTH stimulation test Baseline cortisol Administer synthetic ACTH (synacthen) 250g IV over 2 minutes (do not use 1 g) Get cortisol at 30 and 60 mins Adequate response:  Cortisol ≥ 9g/dl Where can I get ACTH (synacthen)? Makati Medical Center (clinic of Dra. Crisostomo or Dra. Isidro): Php500 St. Luke’s Medical Center QC DTEC (7230101 local 5210): Php4,350 The Medical City and UST: in-hospital use only

American College of Critical Care Medicine At this time, adrenal insufficiency in critical illness is best diagnosed by:  cortisol (after 250 µg cosyntropin) of <9 µg/dL Random total cortisol of <10 µg/dL Marik PE et al. Crit Care Med 2008 Vol. 36, No. 6

ACTH is not available in my area, can’t I just do a random cortisol assay? Yes but if your result is between 15-34 µg/dL, still better to do corticotropin test. My patient is hypotensive! Isn’t that stress enough to stimulated the adrenals? It may sound plausible, but I can’t give you any evidence to recommend such at this time.

Can I do an insulin tolerance test instead of giving ACTH? No, this is contraindicated in patients with ischemic heart disease. My lab doesn’t do cortisol. Can I just go clinical and treat? No evidence that treatment may be harmful, so maybe could be acceptable.

Corticosteroid-replacement doses Cooper M, Stewart P. N Engl J Med 2003. 348;8

Glucocorticoid supplementation For severe surgical stress, including cardiothoracic surgery: IV hydrocortisone 150mg/day (eg 50mg q8h) Taper over next 2-3 days post-surgery For myocardial infarction: Same dose as above Taper once clinical condition stabilizes Septic shock / major trauma / life-threatening complication Maximum 200mg/day IV hydrocortisone (eg 50mg q6h) Jung C et al. Med J Aust 2008 188:409-413

Are glucocorticoids beneficial? 69% of patients with functional hypoadrenalism (Cortisol < 30 g/dL or  cortisol ≤ 9 g/dL) could be weaned from treatment with vasopressors within 24 h (p<0.031) This benefit was not seen in patients with normal adrenal response Mortality was also lower in the hydrocortisone-treated Adrenal Insufficiency patients: 21% vs 45% (p < 0.01) Rivers EP, Gaspari M, Saad GA et al. Chest 2001; 119:889-896

More data is needed re the benefits of treatment The role of glucocorticoids in the management of patients with community-acquired pneumonia, liver failure, pancreatitis, those undergoing cardiac surgery, and other groups of critically ill patients requires further investigation. Please contribute to our knowledge through research Marik PE et al. Crit Care Med 2008 Vol. 36, No. 6

Wow, this cardiologist really takes everything into consideration! Let’s work this patient up for adrenal dysfunction and give steroids if warranted Hey I should have thought of that earlier!

Adrenal Dysfunction following Cardiac Surgery JM Co, MD, FPCP, FPSEM Endocrinology, diabetes and metabolism FOR SLIDE REQUESTS: JMCOMD@YAHOO.COM