Hypoadrenocorticism in the emergency setting

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Hypoadrenocorticism, also known as Addison disease, can result in serious systemic derangements and potentially life-threatening crises. It is a disease process that results in deficits in both mineralocorticoids and glucocorticoids. There is also atypical Addison disease, which is a deficiency only in glucocorticoids. Hypoadrenocorticism is an uncommon disease in dogs with an estimate of occurrence between 0.36% and 0.5%.¹ Although it is an uncommon disease, it is one that can present in many different fashions and should be on the list of differentials for many presentations. While emergency doctors do not commonly manage Addison disease long term, they need to know what to look for when diagnosing and managing an acute crisis. Most small animals that have hypoadrenocorticism are dogs, but this is a disease that can also affect an even smaller percentage of cats.²

Adrenal glands are composed of three layers, with each layer producing different hormones that serve different purposes. The outer layer is the zona glomerulosa, which makes and secretes mineralocorticoid hormones, the most significant of these being aldosterone. Aldosterone plays a crucial role in the body’s regulation of sodium and potassium. This hormone regulates renal potassium excretion,¹ mainly through action on the principal cells in the kidney.

The middle layer of the adrenal glands is the zona fasciculata, which, through a series of different feedback loops, secretes glucocorticoid hormones. The most significant glucocorticoid is cortisol, which affects almost every tissue in the body.¹ Some of the important actions of cortisol in the body include maintaining blood pressure, water balance, and vascular volume, and particularly in canines, it increases vascular sensitivity to catecholamines.¹

The innermost layer is the zona reticularis, which secretes sex hormones. These are not clinically important in hypoadrenocorticism. Hypoadrenocorticism occurs when one or more of the layers of the adrenal glands become dysfunctional.

Hypoadrenocorticism is usually secondary to atrophy or destruction of the adrenal gland layers.¹ Primary immune-mediated destruction is the most common cause of Addison disease in humans and dogs. Other reasons that have been documented for adrenal cortex destruction include neoplasia, fungal disease, trauma, and coagulopathies.¹

Atypical hypoadrenocorticism, when there is only a glucocorticoid deficiency, is less commonly diagnosed than primary hypoadrenocorticism. These patients will have normal serum electrolytes at diagnosis but will have abnormal adrenocorticotropic hormone (ACTH) testing. These patients may advance to glucocorticoid and mineralocorticoid deficiency at some point in their lives.

Dogs with primary hypoadrenocorticism commonly have other endocrinopathies. Any dog diagnosed with primary hypoadrenocorticism should undergo further investigation for other confounding underlying endocrine diseases,² such as diabetes mellitus, hypoparathyroidism, and azoospermia.³ Iatrogenic hypoadrenocorticism can be seen secondary to destruction of the adrenal cortices due to drug administration. Mitotane (Lysodren, o,p’-DDD) is used to treat pituitary-dependent hyperadrenocorticism and can have cytotoxic effects on the adrenal cortex.¹ Some dogs will develop permanent hypoadrenocorticism after being on mitotane and require lifelong medications. Another medication used to treat hyperadrenocorticism is trilostane (Vetoryl), which reversibly and competitively inhibits the enzyme 3B-hydroxysteroid dehydrogenase. In most cases this will suppress glucocorticoid secretion without necrosis/destruction.¹ In some patients, this will also affect mineralocorticoid secretion. If iatrogenic hypoadrenocorticism is noted, the drug can be discontinued, with most animals returning to typical cortisol and mineralocorticoid secretion, but some patients will have persistent/permanent iatrogenic hypoadrenocorticism.

Iatrogenic secondary hypoadrenocorticism can also be seen secondary to prolonged glucocorticoid administration. If rapid discontinuation of glucocorticoids occurs, a hypoadrenocorticism crisis could manifest. Any pets on glucocorticoids should have a controlled taper to allow the body to adjust.

This disease most commonly affects young adult patients but can happen at any age. There are certain breeds that are overrepresented, including poodles, poodle mixes, Nova Scotia duck tolling retrievers, Portuguese water dogs, bearded collies, and West Highland white terriers.¹ In cats, there is no sex or breed predisposition.²

Clinical signs

Addison disease features highly variable clinical signs. They can be as mild as a patient who has a poor appetite with lethargy or a young patient with chronic gastrointestinal signs, or they can be as significant as a patient who presents laterally recumbent in a critical state.

The most common clinical signs seen in patients that are in an acute crisis include gastrointestinal signs (vomiting, diarrhea, inappetence), lethargy, and/or collapse/weakness. Some pets will have had vague signs before presenting in a crisis and upon history gathering, waxing/ waning signs of illness will become evident. Some pets will present in an acute crisis with minimal previous medical history prior to their current signs.

A patient’s clinical signs can be mild with minimal disturbances to their vitals. In these cases, the initial diagnosis may be missed and treated with outpatient supportive care and re-present later when more severe signs are noted. Some pets will present in severe profound cardiovascular shock. In these cases, the patient is commonly recumbent (sternal or lateral), hypotensive, hypothermic, tachycardic, or bradycardic, with poor/snappy femoral pulses and varying levels of dehydration and hypovolemia.

Diagnosis

While diagnosis of hypoadrenocorticism can be straightforward in some cases, its milder forms may need extensive diagnostics. A definitive diagnosis of Addison disease is made through an ACTH stimulation test. Diagnostic findings that may be supportive of hypoadrenocorticism and lead to ACTH stimulation testing include:

• Complete blood cell count:
  • Lack of a stress leukogram
  • Mild, normochromic nonregenerative anemia, suspected to be secondary to bone marrow suppression from lack of glucocorticoids¹
• Chemistry panel:
  • Azotemia: This can be multifactorial, most commonly prerenal secondary to GI losses (vomiting/diarrhea) and dehydration, but can also be from decreased renal perfusion and decreased glomerular filtration rate.
  • Glucose: Patients with hypoadrenocorticism are commonly noted to be hypoglycemic secondary to lack of glucocorticoids and their role in glucose regulation.¹ They can also have concurrent infections, so sepsis should be on the list of other possibilities.
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are elevated.
  • Albumin: Hypoalbuminemia is noted in 17% to 39% of Addisonian dogs, secondary to impaired albumin synthesis, anorexia, GI loss, and impaired nutrient absorption.¹
• Electrolytes: These are the most classic findings in a patient in an Addisonian crisis (but can be normal in an atypical crisis).
  • Sodium: Hyponatremia results from aldosterone deficiency
  • Potassium: Hyperkalemia results from aldosterone deficiency
• Abdominal ultrasound: Slender adrenal glands are commonly seen when Addisonian patients are ultrasounded. In small dogs and cats, they may not be able to be visualized. Normal adrenal glands on ultrasound do not rule out Addison disease.

If any of these abnormalities are noted and the clinical picture could fit, then further definitive testing should be performed. Minimally, a baseline cortisol level should be completed. If baseline cortisol is greater than 2 ug/dL, hypoadrenocorticism is successfully ruled out.⁴ If baseline cortisol is less than 2 ug/dL, then a full ACTH stimulation test should be performed. Dogs with hypoadrenocorticism do not possess adequate reserves to respond properly during an ACTH stimulation test.⁵ Definitive diagnosis of hypoadrenocorticism would be an ACTH stimulation test pre and post sample of less than 2 ug/dL. A point to remember is that patients that have atypical Addison disease will only be glucocorticoid deficient; their electrolytes may be normal, but they will still have an abnormal ACTH stimulation test.

If a patient is suspected to have hypoadrenocorticism and is clinically affected, treatment should be started once the preliminary testing is completed and the ACTH stimulation test has been submitted. With the presence of bedside baseline cortisol testing now, the delay in waiting for outside labs for the initial testing has been decreased.

Treatment

A patient’s clinical signs may vary based on the level of severity, and treatment needs to be adjusted based on the animal’s needs. These patients tend to have significant fluid requirements, as they are commonly both dehydrated and hypovolemic. Fluid therapy should be based on using a balanced isotonic crystalloid (eg, Normosol-R, lactated Ringer solution, Plasma-Lyte); this not only can be used as bolus therapy to help with hypovolemia and hypo- tension, but also to rehydrate. This fluid type is recommended due to the presence of bicarbonate precursors, which can further help to normalize pH imbalances that can present.

Another fluid option is 0.9% NaCl; this is chosen by some clinicians due to lack of potassium in fluids and a higher sodium concentration to help normalize the hyponatremia faster.⁵ This fluid lacks a bicarbonate precursor, prolonging pH normalization. The choice between the 2 is clinician dependent. Fluid therapy in these patients involves being aggressive and reassessing to adjust to their needs. If the patient is in hypovolemic shock and/ or hypotensive, a fluid bolus would be recommended, with a starting dose of 10 mL/kg for up to 30 minutes in dogs and 5 mL/kg over 30 to 45 minutes in cats. Patients that have cardiac disease (heart murmur, cardiac enlargement on radiographs, or echocardiogram-diagnosed disease), may still have fluid deficits but need more conservative doses or longer duration of administration. It is often surprising how large of a fluid deficit is present in patients in an Addisonian crisis.

The next step to stabilization on an emergency basis is to evaluate the electrolytes. Patients in an Addisonian crisis are commonly hyperkalemic and hyponatremic. The most concerning of these findings is hyperkalemia, as it can lead to cardiac disturbances. Intravenous (IV) fluid therapy will improve metabolic acidosis by encouraging extracellular potassium to move intracellularly.⁵ In cases where hyperkalemia is significant and bradycardia is noted, more direct therapy should be provided. Options for treatment of hyperkalemia include:

• Regular insulin IV bolus given at 0.2 u/kg followed immediately by a dextrose bolus (50% solution at 0.5-1 mL/kg) and then started on 5% dextrose supplementation in IV fluids.⁵ This helps to draw extracellular potassium intracellularly. Monitoring a patient’s blood glucose is important as they can become hypoglycemic, and sometimes are already hypoglycemic, and higher supplementation may be needed. Monitoring should be at a minimum hourly until blood glucose normalizes with supplementation.
• Calcium gluconate can be given as a cardioprotectant medication. Calcium gluconate of 10% given at a dose of 0.5-1 mL/kg slowly over 15 to 30 minutes, while monitoring the patient’s ECG, is recommended. Bolusing calcium gluconate can cause worsening bradycardia. Therefore, monitor for worsening bradycardia; infusion should be slowed down or stopped if this is noted. This does not directly decrease potassium levels but instead antagonizes the effect of hyperkalemia on the membrane potential of cardiomyocytes.⁵ Calcium gluconate helps in the immediate crisis but needs to be used in addition to IV fluids and insulin/dextrose to help decrease potassium levels.
• Sodium bicarbonate can be used to treat hyperkalemia by pushing potassium intracellularly while pushing hydrogen ions extracellularly.⁵ The dose should be 1-2 meq/kg IV as a slow infusion (15 to 30 minutes), but it can take at least an hour to see an effect.⁵
• Mineralocorticoid supplementation can be administered once a confirmatory diagnostic has been drawn and is in the process of being completed. In the US, the available drug is desoxycorticosterone pivalate (Percorten-V or Zycortal). This medication is long-acting and can stay in their system up to 25 days after intramuscular administration. No short-acting mineralocorticoid medication is currently available in the US. This medication is used long term every 25 to 28 days in hypoadrenocorticism patients for lifelong maintenance.

If the patient is hypoglycemic, a bolus of dextrose should be administered at 0.5-1 mL/kg of 50% dextrose diluted 1:1 with sterile saline over 5 to 10 minutes.⁵ The patient should then be started on a dextrose constant rate infusion in IV fluids to maintain them at euglycemia during stabilization. They will commonly stabilize to normoglycemia after initial stabilization and glucocorticoid supplementation is started.

If gastrointestinal signs are present, appropriate medications should be provided. Nausea and antiemetics should be given to inappetent patients or patients with vomiting/regurgitation. Multimodal therapy is helpful in these patients, and if ileus is present, promotility agents should be provided.

Evidence of sepsis can include persistent hypoglycemia despite support, neutropenia, nonfluid responsive hypotension, or direct evidence such as intracellular bacteria on cytological evaluation of bodily fluids. In these cases, broad-spectrum antibiotics should be administered.

Glucocorticoid therapy is also needed in hypoadrenocorticism patients. Initial diagnostics should be collected and processing before starting glucocorticoid therapy, as it can artificially affect ACTH stimulation tests. One dose of dexamethasone SP can be given prior to ACTH testing, but ideally, glucocorticoids should be administered after testing is complete. Prednisone and hydrocortisone use before ACTH testing is not recommended and can impair getting accurate ACTH stimulation results. Patients that are in a crisis should be given IV dexamethasone SP at 3 to 10 times the physiological dose during initial stabilization.⁵ Physiological dose is generally considered to be 0.025 mg/kg dexamethasone or 0.25 mg/kg prednisone. They may need additional doses every few hours until stabilization is complete. Once eating and drinking, consider switching to oral glucocorticoids. They should be on a greater than physiological dose for a few days after a crisis, then tapered to a physiological dose that would become their lifetime supplementation dose. Atypical Addisonian patients do not need mineralocorticoid supplementation, just glucocorticoid.

While in the hospital, from the initial stages of triage until discharge, it is important to frequently assess them and make changes to the treatment plan that reflect their individual needs. Commonly needed basic monitoring includes ECG/telemetry in patients who are bradycardic or suffering from arrhythmias. Blood pressure should be checked regularly until it normalizes, then the frequency can be decreased. Weight checks can help to monitor hydration status. Electrolytes should be monitored multiple times a day until the potassium is closer to normal levels. It may take longer for the sodium to normalize; therefore, the normalization of potassium is of more importance.

Discharging the patient is based on normalization of vitals, blood glucose, and electrolytes in addition to eating/drinking with no vomiting and diarrhea. They will need a greater than physiological dose of corticosteroids for a few days during recovery and then a transition to physiological dose (0.25 mg/kg prednisone once daily. The patient should be watched closely at home and rechecked at any point if not continuing to recover. They minimally need to be rechecked at 23 to 25 days after mineralocorticoid injection to recheck electrolytes and receive the next dose. In the long term, the patient’s daily prednisone dose should be increased to 2 to 3 times normal dose during times of stress.

Carey Hemmelgarn, DVM, DACVECC, received her bachelor of science degree from Utah State University and her doctor of veterinary medicine degree from Washington State University. Following veterinary school, Hemmelgarn went on to pursue a one-year small animal rotating internship at Garden State Veterinary Specialists and a three-year emergency critical care residency at Oradell Animal Hospital in Paramus, New Jersey. She has been practicing as a board-certified emergency and critical care specialist at BluePearl Specialty and Emergency Pet Hospital in its Brooklyn, New York, and Paramus, New Jersey, hospitals for the past 5 years.

References

1. Klein SC, Peterson ME. Canine hypoadrenocorticism: part I. Can Vet J. 2010;51(1):63-69.
2. Bruyette, D. Feline hypoadrenocorticism: Yes, cats get Addison too. dvm360. February 22, 2017. Accessed October 21, 2022. https://www.dvm360.com/ view/feline-hypoadrenocorticism-yes-cats-get-addison-s-disease-too
3. Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction. 3rd ed. WB Saunders; 2004:394–439.
4. Bovens C, Tennant K, Reeve J, Murphy KF. Basal serum cortisol concentra- tion as a screening test for hypoadrenocorticism in dogs. J Vet Intern Med. 2014;28(5):1541-1545. doi:10.1111/jvim.12415
5. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. Can Vet J. 2010;51(2):179-184.