A 65 year-old female with a history of hypertension, hyperlipidemia and rheumatoid arthritis presents with generalized weakness and nausea/vomiting for 3 days. She denies fever, focal weakness, numbness or speech difficulty.

HPA Axis

Vital signs were notable for hypotension (72/48mmHg), her examination revealed diffuse weakness but no focal deficits and her abdominal examination was unremarkable. Laboratory tests were notable for hyponatremia (117 mEq/L) and new renal dysfunction. She received 2L of intravenous fluids but remained hypotensive.

Additional history revealed that the patient had been out of her home medications (including prednisone) for the past 1 week. Samples for laboratory tests (cortisol, ACTH) were drawn and she was treated with hydrocortisone 100mg IV with subsequent improvement in blood pressure – she was admitted to the ICU for adrenal crisis.

An Algorithm for the Evaluation and Management of Adrenal Insufficiency and Crisis

References:

1. Idrose, A., Tintinalli, J., Ma, O., Yealy, D., Meckler, G., Stapczynski, J., Cline, D., Thomas, S. (2020). Adrenal Insufficiency Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9e
2. Carroll, T., Aron, D., Findling, J., Tyrrell, J., Gardner, D., Shoback, D. (2017). Glucocorticoids and Adrenal Androgens Greenspan’s Basic & Clinical Endocrinology, 10e
3. Dineen, R., Thompson, C., Sherlock, M. (2019). Adrenal crisis: prevention and management in adult patients Therapeutic Advances in Endocrinology and Metabolism 10(), 2042018819848218. https://dx.doi.org/10.1177/2042018819848218
4. Rushworth, R., Torpy, D., Falhammar, H. (2019). Adrenal Crisis New England Journal of Medicine 381(9), 852-861. https://dx.doi.org/10.1056/nejmra1807486
5. Amrein, K., Martucci, G., Hahner, S. (2018). Understanding adrenal crisis Intensive Care Medicine 44(5), 652-655. https://dx.doi.org/10.1007/s00134-017-4954-2
6. Oelkers, W. (1996). Adrenal Insufficiency The New England Journal of Medicine 335(16), 1206-1212. https://dx.doi.org/10.1056/nejm199610173351607
7. Tucci, V., Sokari, T. (2014). The Clinical Manifestations, Diagnosis, and Treatment of Adrenal Emergencies Emergency Medicine Clinics of North America 32(2), 465-484. https://dx.doi.org/10.1016/j.emc.2014.01.006
8. Bleicken, B., Hahner, S., Ventz, M., Quinkler, M. (2010). Delayed Diagnosis of Adrenal Insufficiency Is Common: A Cross-Sectional Study in 216 Patients The American Journal of the Medical Sciences 339(6), 525-531. https://dx.doi.org/10.1097/maj.0b013e3181db6b7a
9. Broersen, L., Pereira, A., Jørgensen, J., Dekkers, O. (2015). Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis The Journal of Clinical Endocrinology & Metabolism 100(6), 2171-2180. https://dx.doi.org/10.1210/jc.2015-1218
10. Joseph, R., Hunter, A., Ray, D., Dixon, W. (2016). Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review Seminars in Arthritis and Rheumatism 46(1), 133-141. https://dx.doi.org/10.1016/j.semarthrit.2016.03.001

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• Hormones: aldosterone, cortisol, androgens, catecholamines
• Adrenal insufficiency
  • Primary
    • Causes
      • Autoimmune (associated with other endocrinopathies, PTH, DM)
      • Infection (TB, viral, meningococcemia)
      • Infiltration (sarcoidosis, amyloidosis)
      • Hemorrhage (trauma, anti-coagulation)
      • Malignancy (primary, metastatic)
    • Signs/Symptoms
      • AMS
      • Hypotension (refractory)
      • GI: anorexia, nausea/vomiting, diarrhea
      • Hyperpigmentation
    • Labs
      • Hyponatremia
      • Hyperkalemia
      • Hypercalcemia
      • Mild metabolic acidosis
      • Hypoglycemia
  • Secondary
    • Causes
      • Iatrogenic (>5mg prednisone/day for > 2 weeks)
      • Pituitary/sellar tumors
      • Hemorrhage (Sheehan)
      • Cranial radiation
    • Signs/Symptoms
      • RAAS function maintained, hypotension rare
      • Features of pituitary/hypothalamic dysfunction: menstrual disturbances, headache, vision changes, galactorrhea, acromegaly
  • Adrenal Crisis
    • Precipitated by physiologic stressor: sepsis, MI, trauma, surgery
    • Diagnosis
      • AM cortisol <3
      • ACTH stimulation peak cortisol <15
      • ACTH level
    • Management
      • Glucose management
      • Fluid resuscitation
      • Dexamethasone 10mg IV
      • Identify and treat precipitant

Cushing syndrome

• Causes
  • Pituitary adenoma (Cushing disease)
  • Malignancy (ACTH-producing): SCLC, pancreatic, carcinoid
  • Adrenal neoplasm
• Signs/Symptoms
  • Obesity, fat deposition in face, neck
  • Skin atrophy with striae
  • Proximal myopathy
  • Hypertension

Pheochromocytoma

• Familial: MEN 2A/2B, NF, Von Hippel-Lindau
• Signs/Symptoms
  • Refractory hypertension (paroxysmal)
  • Heat intolerance, sweating, weight loss
• Diagnosis
  • 24h urine metanephrine, catecholamine
  • CT/MRI

Hypopituitarism

• Adenoma
  • Symtoms/Signs
    • Headache
    • Vision changes (bitemporal hemianopsia)
    • Cavernous sinus involvement (CN III, IV, V1, V2, VI)
• Ischemic necrosis
  • Sickle cell disease, vasculitis, cavernous sinus thrombosis, infection, TBI, post-partum (Sheehan)
• Pituitary apoplexy
  • Acute loss of pituitary function from infection/hemorrhage, rarely tumor
  • Symptoms/Signs
    • Abrupt onset headache
    • Vision changes
    • Meningismus
    • ALOC

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30 year-old female with a history of autoimmune polyglandular syndrome (adrenal, thyroid and endocrine pancreatic insufficiency), polysubstance use, brought to the emergency department by ambulance with reported chief complaint of fever. On presentation, the patient reported fever for one day, associated with cough. She was lethargic and confused, answering yes/no questions but unable to provide detailed history. She states that she has been taking her home medications as prescribed, which include hydrocortisone, fludrocortisone, synthroid and insulin. No collateral information was immediately available.

Additional history was obtained from chart review upon discharge. The patient was hospitalized two weeks prior with pneumonia and discharged after two days. For 2-3 days prior to presentation, she reported the following symptoms to family members: nausea/vomiting, cough, decreased oral intake, fevers, and palpitations – she did not take her home medications during this time.

Physical Exam

Labs

• VBG: alkalemia, primary respiratory
• CBC: no leukocytosis, normal differential, normocytic anemia
• BMP: 131, 2.5 , 94, 28, 11, 1.6, 115
• Mg: 1.3
• Lactate: 1.0
• TSH: 17 , T4: 1.03
• Troponin: 0.129

ECG

Imaging

• CXR: Negative acute.
• CT Head: Negative acute.
• CT Cardiac: NICM, EF 35%.

Hospital Course

The patient’s evaluation in the emergency department was concerning for severe sepsis secondary to suspected pulmonary source (given association of fever with cough, hypoxia and abnormal chest imaging findings). The patient had persistent alteration in mental status concerning for CNS infection. While preparing for lumbar puncture, cardiac monitoring revealed sustained polymorphic ventricular tachycardia without appreciable pulse. CPR was initiated, amiodarone 150mg IV push administered and at first pulse check a perfusing sinus rhythm was noted with immediate recovery of prior baseline mental status. Amiodarone load was continued and additional potassium sulfate (PO and IV) was administered. Review of telemetry monitoring revealed preceding 30-45 minutes of non-sustained ventricular tachycardia. The patient had two more episodes of sustained ventricular tachycardia requiring defibrillation. The patient was admitted to the medical intensive care unit for continued management.

#Sustained Ventricular Tachycardia
Initially attributed to critical hypokalemia and hypomagnesemia. However, after appropriate repletion serial ECG’s continued to demonstrate prolonged QT interval (possibly acquired secondary to medications, later review revealed multiple promotility agents for treatment of gastroparesis which could contribute to QT-prolongation including erythromycin and metoclopramide, also associated with endocrinopathies). Early echocardiography demonstrated global hypokinesis with estimated EF 30-35%. This was initially attributed to severe sepsis, as well as recurrent defibrillation. However, cardiac CT after resolution of acute illness showed persistent depressed ejection fraction, no evidence of coronary atherosclerosis. The presence of non-ischemic cardiomyopathy (may be attributable to chronic endocrine dysfunction or prior history of methamphetamine abuse) associated with malignant dysrhythmias warranted ICD placement for secondary prevention which the patient was scheduled to receive.

#Severe Sepsis
Attributed to pulmonary source given CT findings, healthcare associated and covered broadly. Mental status gradually improved and returned to baseline. CT head was negative, lumbar puncture deferred.

#Hypokalemia
Unclear etiology. Adrenal insufficiency commonly associated with hyperkalemia and no history of surreptitious fludrocortisone use. Possibly secondary to GI losses. Improved with repletion.

#Autoimmune Polyglandular Syndrome
Started on stress-dose steroids in emergency department. Transiently developed DKA which was reversed appropriately and hydrocortisone was tapered to home regimen. Home levothyroxine was resumed.

Endocrine Emergencies: Hyperthyroidism

Symptoms

Signs

Thyroid Storm

Essentially an exaggeration of thyrotoxicosis featuring marked hyperthermia (104-106°F), tachycardia (HR > 140bpm), and altered mental status (agitation, delirium, coma).

Precipitants

Medical: Sepsis, MI, CVA, CHF, PE, visceral ischemia

Trauma: Surgery, blunt, penetrating

Endocrine: DKA, HHS, hypoglycemia

Drugs: Iodine, amiodarone, inhaled anesthetics

Pregnancy: post-partum, hyperemesis gravidarum

Scoring (Burch, Wartofsky)

• >45: thyroid storm
• 25-44: impending thyroid storm
• <25: unlikely thyroid storm

Management

Supportive measures

Volume resuscitation and cooling

Benzodiazepines for agitation

Beta-blockade

Propranolol 60-80mg PO q4h

Propranolol 0.5-1.0mg IV, repeat q15min then 1-2mg q3h

Esmolol continuous infusion

Endocrinology consultation

PTU, SSKI

Endocrine Emergencies: Hypothyroidism

Symptoms

Constitutional	Weight gain, cold intolerance, fatigue
Cardiopulmonary	Dyspnea, decreased exercise capacity
Neuropsychiatric	Impaired concentration and attention
Musculoskeletal	Extremity swelling
Gastrointestinal	Constipation
Reproductive	Irregular menses, erectile dysfunction, decreased libido
Integumentary	Coarse hair, dry skin, alopecia, thin nails

Signs

Vital signs	Bradycardia, hypothermia
Cardiovascular	Prolonged QT, increased ventricular arrhythmia, accelerated CAD, diastolic heart failure, peripheral edema
Neurologic	Lethargy, slowed speech, agitation, seizures, ataxia/dysmetria, mononeuropathy, delayed relaxation of reflexes
Musculoskeletal	Proximal myopathy, pseudohypertrophy, polyarthralgia
Gastrointestinal	Ileus

Myxedema Coma

Precipitants

Critical illness: sepsis (especially PNA), CVA, MI, CHF, trauma, burns

Endocrine: DKA, hypoglycemia

Drugs: amiodarone, lithium, phenytoin, rifampin, medication non-adherence

Environmental: cold exposure

Recognition

History: hypothyroidism, thyroidectomy scar and acute precipitating illness

Hypothermia: temp <95.9°F (or normal in presence of infection)

AMS: lethargy, confusion, coma, agitation, psychosis, seizures

Hypotension: refractory to volume resuscitation and pressors

Bradypnea: with hypercapnia and hypoxia

Hyponatremia

Management

• Airway protection
• Fluid resuscitation
• Thyroid hormone replacement
  • Young, otherwise healthy patients: T3 10ug IV q4h
  • Elderly, cardiac compromise: 300ug IV x1
• Hydrocortisone: 50-100mg IV q6-8h
• Treat precipitating illness

Interpretation of Thyroid Function Tests

Condition	TSH	T4
None	Normal	Normal
Hyperthyroidism	Low	High
Hypothyroidism	High	Low
Subclinical hyperthyroidism	Low	Normal
Subclinical hypothyroidism	High	Normal
Sick euthyroid	Low	Low

Endocrine Emergencies: Adrenal Insufficiency

Either primary due to adrenal gland failure (often secondary to autoimmune destruction), or secondary most often due to exogenous glucocorticoid administration (usually requiring more than 30mg/day for > 3wks).

Symptoms

Constitutional	Weakness, fatigue
Gastrointestinal	Anorexia, nausea, cramping
Neuropsychiatric	Depression, apathy
Reproductive	Amenorrhea, decreased libido
Musculoskeletal	Myalgia, arthralgia

Signs

General	Hyponatremia, orthostatic hypotension, low-grade fever
Primary	Hyperpigmentation, hyperkalemia, hyperchloremia, acidosis
Secondary	Hypoglycemia

Management

Maintenance

Hydrocortisone 20mg qAM, 10mg qPM

Fludrocortisone 50-100ug daily

Minor illness (x2)

Hydrocortisone 40mg qAM, 20mg qPM

Fludrocortisone 50-200ug daily

Adrenal Crisis

Dexamethasone 4mg IV or hydrocortisone 100mg IV

2-3L 0.9% NaCl

Treat precipitating illness

Life-Threatening Electrolyte Abnormalities³

Critical Hypokalemia

Causes

GI losses (diarrhea, laxative use)

Renal losses (hyperaldosteronism, diuretics)

Cellular shifts (alkalosis)

ECG changes

U-waves ⁴

T-wave flattening

Ventricular arrhythmias (exacerbated with digoxin use)

Treatment

Maximum rate 10-20mEq/h with ECG monitoring

If malignant ventricular arrhythmias or arrest imminent, consider more rapid administration (10mEq over 5 minutes)

 

Critical Hypomagnesemia

Causes

GI, renal losses

Thyroid dysfunction

Treatment

1-2g IV over 5-60 minutes or IVP for Torsades

Conclusion

Unfortunately, this patient’s comprehensive clinical picture does not fit neatly into a particular category of endocrinologic pathology. Her underlying autoimmune disorder manifests both primary adrenal and thyroid dysfunction. Components of the patient’s presentation are suggestive of critical hypothyroidism (myxedema coma) including alteration in mental status, QT-prolongation and hyponatremia as well as possible precipitant of pneumonia. However, despite elevated TSH, the patient’s free T4 level was within normal range. Also absent was hypoventilation (the patient was appropriately tachypneic for degree of hypoxia and with resultant respiratory alkalosis) or bradycardia/hypothermia.
Similarly, adrenal insufficiency is typically associated with hyperkalemia, whereas our patient had critical hypokalemia that was determined to be at least a contributory factor to her ventricular dysrhythmia. The etiology of the patient’s hypokalemia remained unexplained.

References:

1. Sharma, A., & Levy, D. (2009). Thyroid and Adrenal Disorders. In Rosen’s Emergency Medicine (8th ed., Vol. 2, pp. 1676-1692). Elsevier Health Sciences.
2. Savage MW, Mah PM, Weetman AP, Newell-Price J. Endocrine emergencies. Postgrad Med J. 2004;80(947):506–515. doi:10.1136/pgmj.2003.013474.
3. ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2005;112(24 Suppl):IV1–203. doi:10.1161/CIRCULATIONAHA.105.166550.
4. Levis JT. ECG diagnosis: hypokalemia. Perm J. 2012;16(2):57.

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