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?
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.
A 76-year-old man with COPD, and prior head and neck radiation for a pituitary tumor, and worsening dementia presents with hypotension after running out of his medications last week. He is admitted to the ICU for management of hypotension.
Which of the following electrolyte values are most likely present?
Correct Answer: B
This patient likely has secondary adrenal insufficiency from radiation affecting the pituitary gland, resulting in a deficit in ACTH production. Other potential causes of secondary insufficiency include pituitary tumors or craniopharyngiomas, postpartum hypopituitarism (“Sheehan’s syndrome”), and pituitary infiltrative diseased (hemochromatosis, sarcoidosis). There may be clinical manifestations of a pituitary or hypothalamic tumor, such as symptoms and signs of deficiency of other anterior pituitary hormones, headache, or visual field defects. This patient has developed adrenal crisis because he has been unable to take his daily replacement steroids. When differentiating primary from secondary adrenal insufficiency, it is important to remember that mineralocorticoid production is affected in primary but unchanged in secondary adrenal insufficiency (ACTH does not play a major role in regulation of aldosterone). Thus, hyperkalemia is usually present in primary insufficiency but absent in secondary. Hyponatremia is a feature of both, but in primary insufficiency it is associated with volume contraction resulting in an elevated blood urea nitrogen (BUN) and creatinine; whereas in secondary adrenal insufficiency, hyponatremia is dilutional because of decreased ability to excrete water and increased vasopressin levels. Hypoglycemia is present in both primary and secondary because of cortisol deficiency. Hyperaldosteronism is characterized by a normal sodium, hypokalemia, alkalemia, and hyperglycemia.
A 56-year-old woman with hypertension, rheumatoid arthritis, and gastroesophageal reflux disease presents with perforated diverticulitis. Her home medications include lisinopril 10 mg, prednisone 15 mg, and omeprazole 40 mg. After emergent small bowel resection she was admitted to the ICU with low-dose norepinephrine. She is initially treated with piperacillin-tazobactam, and her home prednisone is continued. She remains vasopressordependent despite 30 mL/kg of normal saline and the addition of vasopressin.
Which of the following treatment regimens is most appropriate at this time?
This patient likely has a suppressed hypothalamic-pituitary-adrenal axis due to long-term exogenous glucocorticoid intake. These patients do well with normal activities but may be unable to mount an adequate steroid response to the stress of surgery or critical illness. Typical patients are those with chronic autoimmune or inflammatory diseases (asthma, ulcerative colitis, rheumatoid arthritis), or those with underlying primary or secondary adrenal insufficiency who take chronic steroid supplementation. Although past recommendations have indicated that all patients on chronic steroids require “stress dose,” it is now generally accepted to be necessary only for patients taking 5 mg or greater of prednisone, per day, for more than 3 weeks. In addition to their typical daily maintenance dose, patients should receive additional steroids commensurate with the anticipated stress. A reasonable approach is to use 50 mg of hydrocortisone followed by 25 mg every 8 hours for surgeries with minor (eg hernioplasty, colonoscopy) or moderate surgical stress (eg total joint replacement, cholecystectomy). A higher initial dose of 100 mg followed by 50 mg every 8 hours is recommended for surgeries with major surgical stress such as cardiac surgery. A higher dose may be needed for critical illness–related corticosteroid insufficiency. In contrast to nonendocrine diseases, patients with organic primary or secondary adrenal insufficiency are not capable of augmenting their serum cortisol levels at all, and these patients should always receive supplemental glucocorticoids
There is no indication that the current antibiotic regimen is insufficient as it adequately covers for abdominal sepsis, and cultures have not shown any resistant organisms. She has received adequate fluid resuscitation for septic shock, and there is no clinical reason to bolus further. Although epinephrine may be added to support her blood pressure, it will not treat the underlying cause of adrenal insufficiency.
A 26-year-old woman with a history of seizures controlled on phenytoin has been undergoing chemotherapy for treatment of acute myelogenous leukemia. She is admitted to the ICU with fungal pneumonia. She is intubated with etomidate and rocuronium, started on ketoconazole, and given 30 mL/kg of normal saline. Thirty-six hours later she becomes increasingly hypotensive despite escalating vasopressor doses. She is subsequently treated with hydrocortisone with good response.
Which of the following medications likely contributed to her clinical decompensation?
Correct Answer: D
Critical illness-related corticosteroid insufficiency (CIRCI), formerly known as relative adrenal insufficiency, results from inadequate cellular corticosteroid activity for the severity of a patient’s illness. Most individuals will mount a strong corticosteroid response to critical illness, but a certain subset fail to do so. Although relative adrenal insufficiency relies on measurement of deficiency cortisol concentrations, CIRCI is a clinical diagnosis. The clinical presentation of this patient, like other adrenal insufficiency, is catecholamine-dependent vasoplegic shock that responds to steroids. Morphologic and structural changes in the adrenal gland in these cases are generally minor, with some adrenal cortical hyperplasia. There is also peripheral glucocorticoid resistance mediated by systemic inflammation, although absolute cortisol levels might be normal. In septic shock specifically, insufficiency may be due to impaired pituitary corticotropin release, attenuated adrenal response to corticotropin, and reduced cortisol synthesis. Various medications used in critical care may interfere with the hypothalamic-pituitary-adrenal axis: either by increased metabolism of cortisol (phenytoin, rifampin) or impairing steroid synthesis (etomidate, ketoconazole).
A 56-year-old woman is admitted to the ICU with septic shock from community-acquired pneumonia. She is intubated with etomidate and rocuronium, fluid resuscitated with 30 mL/kg of normal saline and treated with cefepime and levofloxacin. Despite treatment she becomes increasingly hypotensive requiring escalating vasopressor doses. A random cortisol level is sent to test for adrenal insufficiency.
Which of the following levels would be the lowest indicating an ADEQUATE adrenal response?
Correct Answer: C
Cortisol secretion normally exhibits a diurnal variation, with peak concentrations in the morning (around 8:00 am) correlating with waking and accelerating activity after sleeping. For outpatient testing, early morning “peak” measurements are typically used for diagnosing adrenal insufficiency. However, the timing of such testing is not always appropriate in the critical care setting. Providers can measure “random” cortisol levels as a gross test of hypothalamic-pituitary-adrenal axis integrity. Values below an established threshold indicate adrenal insufficiency that would respond to steroid administration. For critically ill patients, a lower bound of 20 to 25 µg/dL (depending on desired diagnostic sensitivity) is considered an adequate random cortisol. A level less than 5 µg/dL constitutes adrenal insufficiency with 100% specificity. In unstressed individuals (ie outpatients) a random cortisol >15 µg/dL is sufficient to rule out adrenal insufficiency. A level of 50 µg/dL would be considered adequate response in a critically ill patient.
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