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Recognizing and Managing Adrenal Disorders in the Emergency Department

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Table of Contents
 
About This Issue

Adrenal disorders can be life-threatening if they are unrecognized. In this issue, you will learn to:

Distinguish primary and secondary adrenal insufficiency from many similar presentations

Order laboratory tests in the ED that will assist emergent management

Look for the electrolyte disorder that is present in 90% of new diagnoses

Administer the optimal corticosteroid in the correct dose to quickly manage the cortisol deficit

Recognize and treat adrenal insufficiency in patients with critical illnesses

Table of Contents
  1. Abstract
  2. Case Presentations
  3. Introduction
  4. Selected Abbreviations
  5. Critical Appraisal of the Literature
  6. Etiology and Pathophysiology
    1. Primary Adrenal Insufficiency (Addison Disease)
      1. Congenital Adrenal Hyperplasia
    2. Secondary Adrenal Insufficiency
    3. Adrenal Crisis
    4. Critical-Illness-Related Corticosteroid Insufficiency
  7. Differential Diagnosis
    1. Sepsis
    2. Diabetic Ketoacidosis
    3. Ingestions
  8. Prehospital Care
  9. Emergency Department Evaluation
    1. History
    2. Physical Examination
  10. Diagnostic Studies
    1. Laboratory Testing
      1. Adrenal Function Testing
      2. Testing for Cortisol or ACTH
        • Cortisol Testing
        • ACTH Stimulation Testing
    2. Imaging Studies
  11. Treatment
  12. Special Circumstances
    1. Pregnancy
    2. Congenital Screening
  13. Controversies and Cutting Edge
    1. Etomidate Use in Patients With Sepsis
    2. Adrenal Insufficiency in Sepsis
    3. Adrenal Insufficiency After Cardiac Arrest
  14. Disposition
  15. Summary
  16. Key Points
  17. Risk Management Pitfalls for Adrenal Insufficiency and Adrenal Crisis
  18. Time- and Cost-Effective Strategies
  19. Case Conclusions
  20. Clinical Pathway for Emergency Department Treatment of Suspected Adrenal Crisis
  21. Tables and Figures
    1. Table 1. Causes of Primary Adrenal Insufficiency
    2. Table 2. Causes of Secondary Adrenal Insufficiency
    3. Table 3. Differential Diagnosis for Common Presenting Complaints of Adrenal Crisis
    4. Table 4. History and Physical Examination Elements to Aid Diagnosis of Adrenal Emergencies
    5. Table 5. Recommended Testing for Adrenal Disease in the Emergency Department
    6. Table 6. Glucocorticoid and Mineralocorticoid Comparison
    7. Table 7. Hydrocortisone Stress-Dosing by Age for Adrenal Crisis
    8. Table 8. Hydrocortisone for Adrenal Crisis Prophylaxis During Illness
    9. Table 9. Hydrocortisone Prophylaxis Dosing for Surgery and Procedures
    10. Figure 1. Hypothalamic-Pituitary-Adrenal Axis and Feedback Loops
    11. Figure 2. Hyperpigmented Skin
    12. Figure 3. Hyperpigmentation in Addison Disease
  22. References

Abstract

Primary and secondary adrenal insufficiency are underrecognized conditions among emergency department patients, affecting an estimated 10% to 20% of critically ill patients. The signs and symptoms of cortisol deficit can be nonspecific and wide-ranging, and identification and swift treatment with stress-dosing of hydrocortisone is vital to avoid life-threatening adrenal crisis. Laboratory evaluation focuses on identification of electrolyte abnormalities typical of adrenal insufficiency, and while additional testing may depend on the type and severity of symptoms, it should not delay corticosteroid replacement. This issue provides recommendations on effective management of patients presenting with adrenal insufficiency, with particular attention to the management of critically ill and septic patients, pregnant patients, and children.

Case Presentation

A 56-year-old man presents complaining of a productive cough, fatigue, and shortness of breath. A chest x-ray demonstrates a left lower lobe infiltrate, and he is diagnosed with community-acquired pneumonia. His blood pressure, which was 119/67 mm Hg upon arrival, has decreased to 83/52 mm Hg on reassessment after the chest x-ray. You order antibiotics, and he is given a 30 mL/kg bolus of IV fluids. His blood pressure remains low, at 82/40 mm Hg. You arrange admission to the ICU, and initiate a norepinephrine infusion titrated to a mean arterial pressure of 65 mm Hg, as well as an additional IV fluid bolus. Despite the 30 mcg/min norepinephrine infusion, the patient’s MAP is still < 60 mm Hg. You perform a focused bedside ultrasound and note that his inferior vena cava measures 2.2 cm, with minimal respiratory variation. You wonder if you should just add on an additional vasopressor, or if there is something else you should consider…

A 24-year-old woman presents with complaint of nausea with vomiting and diarrhea for 3 days. She has not been able to keep anything down, including any of her medications, for the last 36 hours. A review of her chart reveals that she has primary adrenal insufficiency. Her triage vital signs include mild hypotension of 81/48 mm Hg and tachycardia, at 120 beats/min. Two liters of IV normal saline (0.9% sodium chloride) are ordered, and antiemetics are administered. Her tachycardia begins to improve, but her blood pressure remains low, with systolic blood pressure in the low 80s. You wonder: What is the best way to replace steroids, and is there any indication for obtaining cortisol levels or ACTH stimulation testing?

A 15-day-old full-term infant girl with no prenatal care presents to the ED for poor feeding and lethargy. Her vital signs include a heart rate of 185 beats/min; respiratory rate, 35 breaths/min; blood pressure, 62/40 mm Hg; temperature, 37°C; and oxygen saturation, 98% on room air. Examination reveals a lethargic infant with poor tone and weak cry. Her head is normocephalic and atraumatic, she has a sunken fontanelle, no meningismus, dry mucous membranes, and there is no rash. The lungs are clear and the heart has a regular rate with no murmurs. The abdomen is soft and nontender, and her labia are enlarged and hyperpigmented. You know something is wrong, but you're not quite sure what…

Introduction

First described over 150 years ago, adrenal insufficiency remains a rare, but important, endocrine disorder that is underrecognized among emergency department (ED) patients. Adrenal emergencies occur for a number of reasons and can affect patients of any age and gender. Primary adrenal insufficiency (PAI), historically associated with tuberculosis, is now more commonly caused by autoimmune disorders1 and is more often seen in women between the ages of 30 and 50 years.2 Secondary adrenal insufficiency (SAI) is more common than PAI, and is classically seen in an older patient population that uses chronic steroids. Congenital adrenal hyperplasia (CAH) can be diagnosed at birth, but it can also present in older children. Due to its many confounders, adrenal disease can be challenging to diagnose, and once diagnosed, can be challenging to treat efficiently.

Adrenal crisis is the most dramatic and life-threatening manifestation of adrenal disease. Diagnosing adrenal crisis in a patient without known adrenal insufficiency can be difficult because it is nonspecific and often mimics other common diseases. Even in patients with known adrenal insufficiency, adrenal crisis can be difficult to prevent3 and treat in a timely manner.4 In a 2015 prospective study, Hahner et al described 364 patients with known PAI or SAI who were followed for 2 years. There were 64 episodes of adrenal crisis, with 4 deaths attributed to adrenal crisis.5 The same author found in a patient-survey-based study that 42% of patients with known adrenal insufficiency reported at least 1 crisis.4 Hahner et al examined the time to treatment in patients with known adrenal insufficiency and found that the gravity of the condition and need for timely treatment was underappreciated by clinicians, considering the delay observed in time to glucocorticoid administration in healthcare facilities.4

The adrenal system plays an integral role in the body’s response to critical illnesses, such as in severe sepsis and post–cardiac arrest syndrome. For patients with underlying adrenal disease, the diagnosis of adrenal crisis can be easy to miss, but it remains a high-stakes diagnosis to make. Once suspected, the treatment pathway is clear and potentially life-saving if administered in a timely manner. When treating critically ill patients, knowledge of the controversies and supporting evidence for use of corticosteroids can help optimize management. For all emergency clinicians, a basic understanding of the pathophysiology of the adrenal axis and treatment can have a substantial impact on patients suffering from acute adrenal diseases. This issue of Emergency Medicine Practice reviews the subtle and often-missed signs of adrenal disease, the evidence-based pharmacologic treatments, and the management of adrenal insufficiency in critically ill patients.

Selected Abbreviations

ACTH  Adrenocorticotropic hormone
CAH  Congenital adrenal hyperplasia
CI  Confidence interval
CIRCI  Critical-illness-related corticosteroid insufficiency
ECG  Electrocardiogram
ED  Emergency department
HPA  Hypothalamic-pituitary-adrenal
OR  Odds ratio
PAI  Primary adrenal insufficiency
RR  Relative risk
SAI  Secondary adrenal insufficiency

Critical Appraisal of the Literature

A broad search for literature published over the past 10 years was performed, using the key words: adrenal crisis, primary adrenal insufficiency, secondary adrenal insufficiency, and adrenal hyperplasia. These yielded a pool of 2679 articles that were surveyed. Several key topics were identified, which resulted in additional searches for the following topics with no date restriction: etomidate + adrenal, cardiac arrest + steroids. Investigation into relevant cited literature was also performed. This resulted in a total of 132 articles with relevance to emergency medicine practice, 50 of which have been cited here.

Review of the available literature demonstrates an overall consensus in the diagnosis and treatment of adrenal crisis that has changed very little over the past 50 years. Several clinical practice guidelines and consensus statements exist that address the basic tenets of diagnosis and treatment.6-11 A few high-quality randomized controlled trials and cohort studies exist; however, these primarily address the controversial aspects and special populations that are encountered in adrenal emergencies.

Risk Management Pitfalls for Adrenal Insufficiency and Adrenal Crisis

1. “She had a history of chronic corticosteroid use with pneumonia, but I thought she was hypotensive from sepsis, so I didn’t give her corticosteroids.”

Hypotension may be related to septic shock, cardiac dysfunction, medication side effects, or a host of other causes. However, in the patient on chronic corticosteroids or who has a history of adrenal insufficiency, a single dose of IV hydrocortisone should be administered early in the resuscitation, as adrenal insufficiency/ adrenal crisis are of great concern in this population.

2. “He had a history of chronic corticosteroid use with pneumonia, but I thought he was hypotensive from adrenal crisis, so I didn’t give him antibiotics.”

While administering corticosteroids is key, it should never be done instead of conventional treatments. Antibiotics, IV fluids, vasopressors, or antidotal care should be administered as if the patient was not adrenally insufficient, but it should be done in addition to the IV hydrocortisone.

3. “I presumed the neonate’s poor feeding was the reason for his hyponatremia. He had a normal newborn screen.”

Newborn screens miss a significant number of children with congenital salt wasting, and relying on that alone to exclude the diagnosis of adrenal crisis with CAH can lead to an incorrect diagnosis. Poor feeding and salt wasting can be presenting complaints of CAH in the neonate.

4. “I thought he was in adrenal crisis, but I wanted to get his cortisol result back to be sure before giving him steroids.”

Cortisol or ACTH testing may have a role to assist inpatient workup, but in the acute setting, it should never delay the administration of stress-dose corticosteroids in the patient with adrenal crisis.

5. “I gave the patient with adrenal insufficiency oral prednisone as his stress-dose, since he could tolerate oral medication.”

The medication of choice in adrenal crisis or adrenal insufficiency is IV hydrocortisone. It has the proper mix of mineralocorticoid and glucocorticoid function and is preferred over dexamethasone, prednisolone, methylprednisolone, or prednisone.

6. “The patient told me she took ‘herbals,’ but I didn’t ask which ones.”

Any history of taking dietary supplements, “natural” remedies, compounded medication, or medications from a foreign country should prompt further questioning. Steroid contamination of these products, purposely or accidentally, may lead to an increased risk of adrenal crisis. As such, a detailed medication history should be obtained, including doses, schedules, compliance, and type of drugs.

7. “The patient has a history of stopping his corticosteroids. He was altered, but did not improve after we gave him IV hydrocortisone and IV fluids. We are waiting for the chemistry to come back from the lab.”

Hypoglycemia is a common problem in the adrenal crisis patient. Bedside glucose measurement should be a regular part of evaluating any altered patient, but in the patient with potential adrenal suppression, this is vital.

8. “The patient gave a good history for adrenal crisis, but he was only hyponatremic, and not hyperkalemic or hypoglycemic, which is why I didn’t give him corticosteroids.”

While the classic laboratory abnormalities are the triad of hyponatremia, hyperkalemia, and hypoglycemia, by no means are they required to make the diagnosis. Hyponatremia is the most common, but approximately 10% of patients do not manifest an abnormal sodium level during periods of acute adrenal crisis.

9. “The patient was being admitted to the floor for sepsis, so we gave her a dose of hydrocortisone.”

Corticosteroids for the stable septic patient are not indicated.

10. “The patient has a history of adrenal insufficiency and has a gastrointestinal illness. As long as he can take his medications by mouth after fluids and antiemetics in the ED, he can take his regular dosing at home.”

Gastrointestinal illness is the most common reason for adrenal crisis, and as such, stress-dose corticosteroids should be administered promptly after arrival to the ED.

Tables and Figures

Table 1. Causes of Primary Adrenal Insufficiency

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study is included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.

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  5. * Hahner S, Spinnler C, Fassnacht M, et al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab. 2015;100(2):407-416. (Prospective survey; 423 patients)
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  22. Khalaf MW, Khader R, Cobetto G, et al. Risk of adrenal crisis in dental patients: results of a systematic search of the literature. J Am Dent Assoc. 2013;144(2):152-160. (Review)
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Publication Information
Authors

Amy Cutright, MD, Stephen Ducey, MD, Claudia L. Barthold, MD

Publication Date

September 1, 2017

CME Expiration Date

October 1, 2020

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