Addisonian Crisis (Proceedings)

Hypoadrenocorticism, or Addison's disease, results from deficient production of glucocorticoids and/or mineralocorticoids by the adrenal glands. Primary hypoadrenocorticism, the most common type, results from impaired secretion of adrenal gland hormones. The most frequent cause is idiopathic necrosis of the adrenal glands which is generally thought to be the result of immune-mediated destruction. Other causes of adrenal gland dysfunction include o-p-DDD toxicity, infectious disease (canine distemper, systemic mycoses, tuberculosis), hemorrhagic infarct, amyloidosis, neoplasia, and surgical adrenalectomy. Secondary hypoadrenocorticism results from dysfunction of the anterior pituitary with subsequent reduction in ACTH release. Decreased ACTH levels result in bilateral atrophy of the adrenal glands and a dramatic decrease in cortisol secretion. Pituitary dysfunction can be caused by neoplasia, trauma, inflammation, or negative feedback from prolonged exogenous corticosteroid administration. In primary hypoadrenocorticism, both mineralocorticoid and glucocorticoid secretion are diminished. Secondary hypoadrenocorticism results in a selective glucocorticoid deficiency, and mineralocorticoid function is spared.

Pathophysiology

The clinical signs of hypoadrenocorticism are secondary to glucocorticoid and aldosterone deficiency. Lack of glucocorticoids causes lethargy, anorexia, decreased tolerance for stress and impaired water excretion from the kidneys. Decreased gluconeogenesis and glycogenolysis lead to hypoglycemia. Aldosterone is the primary mineralocorticoid responsible for homeostasis of sodium, potassium, plasma volume and excretion of acid in the urine. Aldosterone deficiency is associated with sodium and chloride wasting. Hyponatremia leads to hypovolemia. Volume contraction stimulates ADH release which causes free water retention, further worsening existing hyponatremia. The volume contraction can become quite severe, resulting in hypotension, poor perfusion, reduced cardiac output, pre-renal azotemia, shock and collapse.

Aldosterone deficiency also results in retention of H+ and K+ because of reduced excretion of these ions in the distal nephron. Metabolic acidosis exacerbates hyperkalemia, as H+ ions move intracellularly and are exchanged for K+ ions in the extracellular fluid. The effect of hyperkalemia on the myocardium can be life-threatening, as myocardial excitability is reduced and conduction is slowed. Electrocardiographic abnormalities include atrial standstill, bradycardia, widened QRS complexes, reduced R wave, peaked T wave, heartblock, and ventricular arrhythmias.

History and Clinical Signs

Addison's disease has been called "the Great Pretender" because clinical signs are non-specific and often mimic signs associated with other diseases. Animals may have a chronic history of weight loss, lethargy, anorexia, intermittent vomiting and diarrhea, polyuria and polydypsia, and episodic weakness. On the other hand, they may be presented in a state of acute circulatory collapse and shock with no prior history of disease.

Because of the extreme variability of clinical signs and the relative infrequency of hypoadrenocorticism compared to other disease syndromes, the correct diagnosis is often missed. Common mis-diagnoses involve the gastrointestinal, renal, and neurologic systems. Animals with signs of vomiting and diarrhea may be mis-diagnosed as parvoviral enteritis, hemorrhagic gastroenteritis, dietary indiscretion, pancreatitis, or intestinal foreign body. Animals will generally improve with symptomatic fluid therapy and correction of electrolyte and acid-base balance, but will quickly relapse when fluid therapy is discontinued. Results of abdominal ultrasound, abdominal radiographs, endoscopy, barium studies, and exploratory laparotomy are not helpful in establishing the diagnosis and generally waste the client's money and the veterinarian's time.

Animals with historical polyuria/polydypsia, non-regenerative anemia, weight loss, depression, and azotemia can be mis-diagnosed as acute or chronic renal failure. Because of renal sodium wasting and decreased renal medullary concentration gradient, animals with hypoadrenocorticism may be unable to concentrate their urine even in the face of marked dehydration and renal azotemia. It is important that the veterinarian realize that most cases of azotemia associated with Addison's disease are pre-renal, and completely reversible with appropriate therapy. The worst potential consequence of mis-diagnosis as renal failure is euthanasia of an animal that has a treatable disease.

Rarely, animals with Addison's disease can present with primary neurologic signs. Shaking and shivering are common owner complaints, and could be mistaken for muscle tremors. In addition, nausea, weakness, ataxia, and dementia may lead the veterinarian to suspect toxicosis. Obviously, inducing emesis and administering activated charcoal in these animals would be contraindicated. Rarely, animals with Addison's disease present with profound hypoglycemia causing seizures and/or coma. This condition is also totally reversible with appropriate therapy.

Diagnosis and Initial Approach

With a standard approach to the emergency patient and a high index of suspicion, the diagnosis of hypoadrenocorticism should not be missed.

The emergency clinician should begin with a standard history and physical examination. Because history and clinical signs are vague, they provide supportive but not confirmatory evidence of hypoadrenocorticism. The most common signalment is a young to middle aged female dog. Breeds identified to be at risk for hypoadrenocorticism include Standard Poodles, Great Danes, Rottweilers, Portuguese Water Dogs, and West Highland White and Wheaton Terriers.

On physical examination, a classic sign that should alert the clinician to suspect Addison's disease is inappropriate cardiovascular response for the degree of hypovolemia and shock. The animals exhibit signs of hypotension and poor perfusion (weak pulses, slow capillary refill time, low blood pressure) but often have a normal or reduced heart rate instead of the expected compensatory tachycardia which is usually seen in shock states.

The initial approach to an animal exhibiting these clinical signs is to immediately obtain a minimum emergency data base which should include PCV, total solids, reagent sticks for blood urea nitrogen and glucose, serum electrolytes (Na+, K+, Ca+ +), urinalysis, blood gases, and electrocardiogram. Classic findings for an animal with Addison's disease include hemoconcentration or anemia (PCV elevated or decreased), elevated total solids (may be decreased with severe gastrointestinal signs), azotemia, hypoglycemia, hyponatremia, hyperkalemia, hypercalcemia, and metabolic acidosis. Electrocardiographic findings parallel the degree of hyperkalemia. Urinalysis may reveal evidence of acute renal insult (casts, tubular epithelial cells) secondary to ischemic damage or hypercalcemia, indicating the need for aggressive restoration of perfusion.

With the results of the above tests, a tentative diagnosis of Addison's disease can be made within minutes. The diagnosis can be confirmed with an ACTH stimulation test. This test can be performed immediately or delayed until after treatment has been implemented. If intramuscular ACTH gel is used (2.2 mg/kg; Cortigel-40, Savage Lab, Melville, NY), testing should be delayed until perfusion is restored to promote adequate uptake from the injection site. Blood samples should be obtained at 0 and 120 minutes in dogs and 0, 60, and 120 minutes in cats. Samples should be collected in EDTA tubes and the plasma separated and frozen within 15 minutes. It can be shipped on dry ice. If synthetic ACTH is used (Cortrosyn, Organon Inc, West Orange, NJ; 0.25 mg IV - dog or 0.125 mg IV - cat), the samples are drawn at 0 and 60 min (dog) and 0, 30, and 60 min (cat). If ACTH stimulation testing is delayed, the only glucocorticoid which does not cross react with serum cortisol assays is dexamethasone. If other glucocorticoids have been administered (prednisolone, cortisone, or hydrocortisone), testing must be delayed at least 24 hours. Endogenous ACTH levels can help differentiate primary and secondary hypoadrenocorticism, as they will be very high in primary adrenal disease due to lack of negative feedback, and low or undetectable in cases of pituitary dysfunction. Plasma samples for this test must be collected before any glucocorticoids, including dexamethasone, are administered.

Management of Life Threatenina Problems

The following problems must be corrected in the patient with Addisonian crisis.

1. Shock/Poor perfusion - The fluid of choice for treating hypoadrenocorticism is 0.9% sodium chloride. The animal should be rehydrated over 2-4 hours. Caution must be used in administering very high fluid rates (i.e. 90 ml/kg/hr) to animals with severe volume contraction and bradycardia, as pulmonary edema could result from rapid replacement. Rates of 20-40 ml/kg/hr and CVP monitoring can help avoid this potential problem. Once volume replacement has occurred, the fluid rate can be decreased to 3-5 ml/kg/hr and should be continued for 24-72 hours until all laboratory parameters are normal. Urine output should be monitored closely and should be at least 1-2 ml/kg/h once the animal is rehydrated.

2. Cardiac arrhythmias/hyperkalemia - Life threatening arrhythmias (generally associated with serum potassium values > 7.5 mEq/L) should be controlled immediately with one of the following treatments:

i. Sodium bicarbonate, 1-2 mEq/kg slowly IV will shift potassium intracellularly.

ii. Calcium gluconate 10% - 1.0-1.5 ml/kg slowly IV over 10-20 minutes will protect the myocardium against the effects of hyperkalemia, but should be avoided in patients with hypercalcemia.

iii. Regular crystalline insulin 0.25 U/kg with 203 g dextrose per unit of insulin administered IV will also shift potassium intracellularly. If this treatment is used, 50-100 ml of 50% dextrose should be added to each liter of maintenance fluids to prevent hypoglycemia.

3. Metabolic acidosis can be severe in patients with hypoadrenocorticism. The bicarbonate deficit can be calculated from the following formula:

i. #mEq NaHCO3 needed = BW (kg) x 0.3 x (normal HCO3 actual HCO3)

ii. One third to one fourth of the deficit can be replaced by slow IV bolus and the remainder placed in the fluids to be given over 6-8 hours. Serial blood gasses and electrolytes should be monitored q 4-6 h.

4. Hypoglycemia can be severe. Animals with neurologic signs or blood glucose values ≤ 50 mg/dl should be treated with 1 ml/kg 50% dextrose diluted to a 10% solution as an IV bolus. 50-100 ml of 50% dextrose can be added to each liter of saline to maintain safe levels.

5. Hemorrhagic gastroenteritis can be severe in some patients with Addisonian crisis and has been associated with gastrointestinal ulceration, hemorrhage, anemia, enterotoxemia, and disseminated intravascular coagulation. Treatment is symptomatic and involves H2 blockers (cimetidine 5-10 mg/kg IV q 8 h), sucralfate (1 g PO q 8 h), and restoration of perfusion. Plasma, blood transfusions, and heparin can be given if indicated.

6. Hypercalcemia is generally not severe in animals with hypoadrenocorticism, but serum levels ≥14 mEq/L should be aggressively treated with intravenous fluids (0.9% NaCl) and glucocorticoids to prevent renal damage.

7. Glucocorticoid deficiency results in depression, lethargy and inability to handle stress. The glucocorticoid of choice is dexamethasone (2-5 mg/kg IV) because it does not interfere with testing. An alternate choice is hydrocortisone semisuccinate (1.25 mg/kg IV, then 0.5 - 1.0 mg/kg IV q 6 h) to provide both mineralocorticoid and glucocorticoid effects. After initial stabilization, animals are generally maintained on 1 mg/kg prednisolone q 12 h for 48 hours and reduced to .25 mg/kg daily.

8. Mineralocorticoid deficiency is initially treated with fludrocortisone acetate (0.1 mg per 5 kg divided q 12 h) as soon as vomiting has ceased. The animal can be continued on this drug as daily maintenance treatment or can receive desoxycorticosterone pivalate by intramuscular injection every 25-30 days (DOCA pivalate, Percorten, 25 mg/ml, CIBA-Geigy, Edison, NJ).