Critical Care Medicine-Endocrine Disorders>>>>>Hypothalamic-Pituitary-Adrenal Axis
Question 1#

A 35-year-old man presents to the emergency department with fever, nausea, vomiting, and diarrhea for the last 2 days. His vital signs are:

His abdominal examination is soft and nontender. His only past medical history is unexplained orthostasis. Despite administration of 6 L of normal saline over 3 hours, he remains hypotensive and is started on a norepinephrine infusion. Point of care ultrasound reveals normal cardiac function.

Which of the following laboratory tests would be most immediately helpful to establishing a diagnosis and to guide treatment?

A. Cortisol
B. ACTH stimulation
C. Insulin
D. Aldosterone

Correct Answer is A


Correct Answer: A

This patient’s presentation is consistent with adrenal insufficiency, and he is suffering from adrenal crisis. Primary adrenal insufficiency is the inability of the adrenal gland to produce steroid hormones even when the stimulus by the pituitary gland via corticotropin is adequate or increased. Chronic primary adrenal insufficiency (Addison disease) results from the destruction of the adrenal cortex. The most common causes are autoimmune destruction (70%-80%), tuberculosis (∼20%), and adrenal metastases. In primary disorders, both glucocorticoid (cortisol) and mineralocorticoid (aldosterone) secretion are affected. Typical features of primary adrenal insufficiency fatigue, orthostasis, hyperpigmentation, and scant axillary and pubic hair. About 25% of patients with adrenal insufficiency present with adrenocortical crisis. The symptoms are nonspecific and include sudden dizziness, weakness, dehydration, hypotension, and shock. In many cases, the clinical picture may be indistinguishable from shock because of loss of intravascular fluid volume. Glucocorticoid (cortisol) deficiency decreases vascular responsiveness to angiotensin II, and norepinephrine reduces the synthesis of renin and increases the production and effects of prostacyclin and other vasodilatory hormones. In acute cases, mineralocorticoid deficiency leads to hypotension. 

The diagnosis of adrenal crisis in this patient would be best supported by a low serum cortisol level. Serum cortisol and aldosterone levels would be low in patients with primary adrenal insufficiency. However, patients with secondary adrenal insufficiency have normal aldosterone levels and can also present in the refractory shock due to adrenal crisis. Thus, measurement of just the aldosterone level is not sufficient. Though serum ACTH level is expected to be high in primary insufficiency, it could be elevated in other conditions too. Lastly although the cortisol response to ACTH stimulation is the standard way to interrogate the function of the hypothalamic-pituitary-adrenal axis, the results may be impacted by critical illness and might lead to misdiagnosis. It also takes two repeated measurement to generate results. Thus, for patients in the ICU it remains extremely difficult to recognize acute, absolute adrenal insufficiency based on clinical symptoms. Because a missed diagnosis is often fatal, patients with sudden deterioration and unexplained catecholamine resistant should be initially screened with a cortisol level for adrenal insufficiency. The insulin-induced hypoglycemia test is used to evaluate integrity of the full hypothalamic-pituitary-adrenal axis as hypoglycemia acts centrally to stimulate hypothalamic corticotropin-releasing hormone release and, therefore, ACTH release. In this test, blood is drawn to measure the blood glucose and cortisol levels, followed by an injection of fast-acting insulin. Blood glucose and cortisol levels are measured again at 30, 45, and 90 minutes after the insulin injection. The normal response is for blood glucose levels to fall and cortisol levels to rise. In most settings the ACTH stimulation test provides nearly the same information, is less difficult to perform, and is without risk to the patient.


  1. Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med. 2001;163:1520-1523.
  2. Vincent JL, Abraham E, Moore FA, et al, eds. Textbook of Critical Care. 7th ed. Philadelphia, PA: Elsevier; 2017.