Professor and Associate Chair, University of Florida, College of Veterinary Medicine
Gainesville, FL, USA
Adrenocortical insufficiency can result from the following causes: iatrogenic adrenocortical atrophy from glucocorticoid administration, o,p'-DDD-induced adrenocortical destruction, hemorrhage or infarction of the adrenal glands, mycotic or neoplastic involvement, surgical adrenalectomy, anterior pituitary gland insufficiency, and, primary hypoadrenocorticism.
The pathophysiologic consequences of primary adrenocortical insufficiency are a direct result of glucocorticoid and aldosterone deficiencies. Glucocorticoid depletion results from impaired function of the zona fasciculata. The hypocortisolemia causes impaired gluconeogenesis and glycogenolysis, decreased sensitization of blood vessels to catecholamines, impaired renal water excretion, and decreased vitality as characterized by poor appetite, lethargy and impaired cerebration.
Aldosterone is a mineralocorticoid hormone that plays an important role in sodium and potassium homeostasis. Hypoaldosteronism occurs from impaired function of the zona glomerulosa and causes renal sodium and chloride ion wasting and potassium and hydrogen ion retention. The clinical and pathophysiologic effects of hyponatremia include lethargy, mental depression, nausea, hypotension, impaired cardiac output and renal perfusion, and hypovolemic shock. Hyperkalemia causes muscle weakness, hyporeflexia, and abnormal cardiac excitation and conduction. The addisonian crisis most often occurs in the setting of moderate to marked hyponatremia (serum sodium <132 mM/L) and hyperkalemia (serum potassium > 7.0 mM/L).
The hypoaldosteronism is the chief reason for the hyperkalemia. The hyponatremia, which occurs mostly with glucocorticoid deficiency, is caused by elevated arginine vasopressin levels and the resulting increased free water retention, decreased sodium pump activity and the resulting shift of extracellular sodium into cells, and decreased delivery of filtrate to diluting segments of the nephron as a result of decreased glomerular filtration rates.
The differential diagnosis of hypoadrenocorticism includes any illness that can characterize as vomiting, depressed appetite, weight loss, muscular weakness, or acute collapse. Some of the more common differentials include gastrointestinal disorders, renal failure, various intoxicants, liver disease, and cardiac disorders.
A tentative diagnosis of acute adrenocortical insufficiency can be made on the basis of the history and physical examination findings. Historically, the dog might have had a chronic period of weight loss, vomiting and/or diarrhea, and lethargy. Polydipsia and polyuria are rarely present in some patients. The chronicity might vary from weeks to months duration and then suddenly culminate in an acute hypotensive state of collapse. On the other hand, the addisonian crisis can occur acutely without any prior signs of illness.
The physical examination findings of the acutely decompensated patient will depict a generally ill patient that is either hypo- or normothermic. Hydration varies from normal to varying degrees of dehydration. The mentation is dull, and muscle weakness is usually marked. The respiratory rate can be normal or rapid, the latter due to either shock and/or attempted compensation for a metabolic acidosis. The mucous membranes are usually pink, but the capillary refill time is prolonged. Cardiac auscultation can detect either normal sinus rhythm or arrhythmias, especially bradyarrhythmias. The pulse quality is weak, and the rate varies from normal to slow.
The electrocardiogram is a useful diagnostic tool for the detection of the various conduction and complex abnormalities that are associated with hyperkalemia. The most common abnormalities include flattened P-waves, increased positive or negative deflected T-waves, broadened QRS complexes, bradycardia, sinoventricular complexes, and atrial standstill. These electrocardiographic abnormalities do not occur until the serum potassium exceeds 7.5 mM/L, but they can occur at 7.0 mM/L when the serum sodium is < 130 mM/L.
The tentative clinical diagnosis of Addison's disease is based on clinicopathologic test results. The hallmark findings include hyperkalemia and hyponatremia (Na/K < 25:1). Some atypical addisonian patients can have hyponatremia with normokalemia or hyperkalemia with normonatremia. Other causes of hyponatremia with hyperkalemia have to be differentiated from adrenocortical insufficiency. These include renal failure, gastroenteritis, decompensated diabetes mellitus, ascites and chylothorax. Some addisonians might have normal electrolytes yet have hypocortisolemia. Additional associated clinicopathologic abnormalities include mild to moderate hypochloremia, azotemia, hyperphosphatemia, metabolic acidosis, and rarely hypothyroidism. Mild hypercalcemia is oftentimes present, but of no clinical significance. Hypoglycemia occurs rarely, but may be the only presenting abnormality in an atypical addisonian.
Although the above historical, physical, clinicopathological and electrocardiographic abnormalities are strongly suggestive of acute hypoadrenocorticism and usually constitute the basis for the clinical diagnosis and the need for immediate therapy, the absolute diagnosis depends on the demonstration of absent or minimal adrenocortical response to an injection of corticotropin (ACTH). The following procedure is recommended soon after the patient's admission in order to avoid any unnecessary delay of therapy for the sake of performing a diagnostic test.
1. Draw blood for hemogram, serum biochemistry and basal cortisol determinations.
2. Begin the intravenous fluids and give 2-5 mg/kg of dexamethasone sodium phosphate intravenously.
3. Immediately give 0.25 mg of alpha 1-24 cosyntropin (dogs) (Cortrosyn-Organon) intramuscularly or intravenously. Cats should receive 0.125 mg.
4. Withdraw a second blood sample for plasma cortisol determination 45-60 minutes later.
The patient will derive the benefit of undelayed treatment while simultaneous confirmatory diagnostic tests are performed with the above technique. The post ACTH injection cortisol blood level will barely increase above the basal value in typical hypoadrenocorticism. Blood levels of < 1.0 µg/dl are typical, while those stimulating to only 2-3 µg/dl also suggest hypoadrenocortical function.
Treatment should begin immediately whenever the index of suspicion is strong for diagnosis of an addisionian crisis. The therapeutic objectives include (1) intravascular volume resuscitation, (2) correcting the hyponatremia and hyperkalemia, (3) providing glucocorticoids, and (4) recognizing and reversing any life-threatening cardiac arrhythmias.
Sodium chloride 0.9% is the fluid of choice and should be delivered through an indwelling intravenous catheter. The saline should be infused at a rate of approximately 75 ml/kg body weight during the first 1 to 2 hours of treatment if the dog is markedly hypotensive. Care should be taken to avoid an iatrogenic intravascular fluid overload because of the addisonian patient's theoretical intolerance to acute water loading. Central venous pressure determinations should be done in order to safeguard against this complication. For the remaining 24-hour period, the isotonic saline can be evenly infused at a maintenance rate of approximately 60 ml/kg body weight so long as the serum sodium concentration does not increase by more than 8-12 mM/L (or 0.5 to 1.0 mM/L per hour) during the first 24-hours if the initial serum Na+ was < 125 mM/L. The intravenous fluids are discontinued when hydration, urine output, serum electrolytes, the BUN levels are restored to normal (usually following 48 to 72 hours of treatment), and the patient begins eating.
Although intravenous saline will help correct the hyponatremia and hyperkalemia, the patient must also receive a mineralocorticoid drug that will enhance renal distal tubular sodium reabsorption and potassium excretion. When desoxycorticosterone acetate (DOCA) was available the dose ranged from 1.0 mg for a small dog to 5.0 mg for a large dog and was given once daily intramuscularly. In many patients, the subsequent daily doses of DOCA was decreased to approximately one-half of the initial dose due to the synergistic effects of fluids, DOCA and glucocorticoid medications. Currently DOCP (0.5 mg/kg IM) can be used in its place although its rate of onset is slower than DOCA. When DOCA or DOCP are unavailable, fludrocortisone acetate (Florinef; Bristol-Meyers Squibb Company) should be given orally at an initial dosage 0.1 mg/5 kg body weight per day. Re-assessment of the serum electrolyte levels will serve as a helpful treatment guide for further dosage adjustments.
The glucocorticoid deficiency is best corrected with rapid-acting drugs such as prednisolone sodium succinate or dexamethasone phosphate. These glucocorticoid drugs should be given intravenously once initially at doses of 5-10 mg/kg and 2-5 mg/kg body weight, respectively for prednisolone sodium succinate and dexamethasone phosphate. Subsequent glucocorticoid requirements are fulfilled by administering 1 mg/kg body weight of prednisolone orally, intramuscularly, or intravenously every 12 hours through the second day and then reducing the dose to 0.25 to 0.5 mg/kg body weight every 12 hours for the remainder of hospitalization.
Hydrocortisone sodium succinate can be given for glucocorticoid replacement taking advantage of the fact that this particular glucocorticoid contains some mineralocorticoid activity. The emergency dose for shock is 20-25 mg/kg body weight IV every 6 hours. There has been no proven advantage with the use of hydrocortisone sodium succinate.
Serum potassium concentrations greater than 7.0 mM/L can cause progressive abnormalities in myocardial excitation and conduction. The degree of hyperkalemic myocardial toxicity ranges from mild to severe based on the electrocardiographic changes, and only with severe changes is special therapy warranted. In such cases treatment should consist of 10% calcium gluconate, sodium bicarbonate, and/or insulin-dextrose solutions. Ten percent calcium gluconate solution is given at a dose of 0.5 to 1.0 ml/kg body weight intravenously over a 5- to 10-minute period, accompanied by continuous electrocardiographic monitoring. It directly antagonizes the myocardial toxic effect of hyperkalemia, but it will not lower the serum potassium level. Calcium gluconate takes its affect within minutes. To accomplish this latter effect, sodium bicarbonate solution is given at a dose of 1-2 mEq/kg body weight intravenously over a 5- to 10-minute period. Bicarbonate takes its affect after approximately 15 minutes. Regular crystalline insulin at an intravenous dose of 0.25 unit/kg body weight will also lower the serum potassium level. Two to three grams of dextrose per unit of insulin administered should also be given by intravenous push in order to avoid the anticipated hypoglycemic effects of insulin. The insulin dextrose treatment will lower the serum K+ after approximately 30 minutes. The above emergency measures for the treatment of myocardial toxicity are required only once and need not be repeated.
The majority of dogs with Addison's disease have an excellent prognosis for a normal quality of life. Early complications that might alter a favorable outcome include acute renal failure resulting from renal ischemia associated with protracted hypotension and cardiac dysfunction. If the patient is oliguric or anuric following the initial period of intravascular volume expansion, mannitol should be given intravenously at a dose of 0.5 gm/kg body weight in order to promote an osmotic diuresis. Furosemide (1-2 mg/kg IV) and dopamine (2-5 µgm/kg/minute) can also be used to counteract oliguria. An indwelling urethral catheter should be inserted to quantitate the urine output until it is deemed adequate.
Central pontine myelinosis can occur as a result of too rapid correction of the serum sodium concentration. The parenchymal central nervous system tissue changes associated with this condition can cause signs of seizures, behavioral changes and paresis. The mechanism involves an osmotic dysequilibrium between the brain parenchyma and the plasma that occurs when the onset of hyponatremia is over 24 hours duration and is corrected at a rate exceeding 0.5 to 1.0 mM/L per hour. When the initial serum sodium concentration is < 125 mM/L it should not be allowed to increase by more than 8-12 mM/L over the first 24-hours in order to avoid this complication.