Endocrine emergencies (Proceedings)

Diabetic Ketoacidosis (DKA)

DKA is one of the more common endocrine emergencies seen in veterinary emergency centers throughout the US. It is mostly seen in newly diagnosed diabetics, or ones that have a reason for insulin resistance, such as Pyelonephritis, pancreatitis, or underlying disease.

Pathophysiology

Because glucose can not enter into cells from a lack of insulin (relative or absolute), ketones are synthesized from fatty acids as a substitute for energy. This results in severe acidosis and severe electrolyte abnormalities. The ketone bodies that are formed are beta hydroxybutyrate, acetoacetic acid, or, acetone. The diagnosis is based on evidence of metabolic acidosis (usually pH < 7.3), hyperglycemia, glucosuria, and ketonuria. The ketone strips that recognize ketone bodies in the urine are manufactured to recognize acetoacetic acid, rather then the more commonly formed ketone acid in DKA, beta hydroxybutyrate. This can be overcome by adding hydrogen peroxide to the urine, and then testing with the strip, which will convert the beta hydroxybutyrate to acetoacetic acid.

The synthesis of ketone bodies occurs from 2 units of acetyl-CoA, which condense to from acetoacetyl-CoA in multiple organs. This is then converted to acetoacetate by deacylase in the liver. The liver then converts acetoacetate to beta hydroxybutyrate and acetone. Ketone bodies are metabolized with difficulty in the liver and then enter the blood stream. The initiation of ketone bodies comes from acetyl-CoA, which is the result of B-oxidation of fatty acids. The lack of insulin and increased counter regulatory hormones (mainly glucagon, also catecholamines, glucocorticoids, and growth hormone) results in increased fatty acid oxidation, and hence excess production of acetyl-CoA.

The acidosis results mainly from the formation the of the ketone acids, but also the vomiting, dehydration, and volume contraction contribute. The electrolyte abnormalities most commonly noted in DKA patients are hypokalemia, hypophosphatemia, hyper- or hyponatremia, and hypomagnesemia. No matter what the values on the chemistry panel reveal, patients presenting with DKA are whole body potassium and phosphorous depleted. Hypokalemia results from acidosis, osmotic diuresis, ketonuria, vomiting, and extracellular fluid volume expansion from hyperglycemia. Depending on the severity of hypokalemia, clinical signs can range from muscle weakness, paralysis, respiratory and cardiac depression. Hypophosphatemia can result from metabolic acidosis and renal losses, and during initial therapy with insulin (drives into cells). Clinical signs of deficiency include weakness, respiratory and cardiac dysfunction, hemolytic anemia, decreased tissue oxygenation (loss of 2,3-DPG). Sodium alterations are due to losses through vomiting, diuresis, and the acidosis. Clinical signs of deficit or excess result in altered mental status.

Tests

As with any sick animal a minimum database and diagnostic imaging should be performed. We would recommend a CBC, chemistry with lytes (Na, K, Cl, Mg, Ca, Phos), urinalysis, urine culture (many have urinary tract infections), 3 view chest radiographs, and abdominal ultrasound.

Treatment

Fluids are the most important part of therapy for DKA. Patients suffering from this disease are volume depleted, and fluids alone will dilute out the glucose concentration and help to re-establish renal perfusion to excrete glucose, and correct acid base disturbances. Any replacement crystalloid fluid will help to accomplish these goals, although 0.9%NaCl is the fluid of choice (helps with sodium and chloride losses). Potassium supplementation is also required to replace the hypokalemia that is present, and this can be worsened when insulin therapy is commenced. It is vital to calculate the maximum rate of potassium infusion (0.5 mEq/kg/hr) for the patient to avoid over-supplementing during the treatment process. See chart below for starting recommendations, although the maximum infusion rate is sometimes required. If the patient also has significant hypomagnesemia, the this must be addressed before the hypokalemia will resolve. If the phosphorous is also low then an easy way to supplement, is to give ½ the potassium supplemented as potassium phosphate. The rate of phosphorous supplementation can be 0.01-0.03 mmol/kg/hr.

Insulin therapy should be started after the animal has been on IV fluids a short time (4-6 hrs). This will not only decease the blood glucose, but also improve perfusion for better insulin absorption. Animals that present as sick DKAs (vomiting, depressed, significant acidosis) should not be treated initially with insulin via the subcutaneous route. The intramuscular or an intravenous continuous infusion routs are the more preferred. Regular insulin is used because it has a rapid onset and a brief duration of effect, allowing the clinician to titrate the dose to desired effect. Insulin is started, not only to decrease the blood glucose, but to help resolve the ketonemia. An initial dose of 0.2 U/kg IM every 6 hours is a good starting dose. The blood glucose should not be dropped faster than 50 mg/dl/hr or significant osmotic shifts could occur. A CRI of regular insulin can also be done. A starting dose is 2.2 U/kg/day. This regime of using the CRI requires strict supervision and a very informed support staff. The goal is to keep the BG in the 100-200 mg/dl range. Below is an example of a sliding insulin scale for a sick DKA dog.

Monitor the body weight, PCV/TS, electrolytes (including phos, Mg++), blood gas and urine output to ensure fluid balance at least twice daily. A central line (ideally jugular) is ideal for monitoring CVP and serial sampling of blood glucose (every 6 hrs), electrolytes and acid base status. The use of broad spectrum antibiotics should be used due to high incidence of infection in these patients (get urine culture first). The urine should be dipped daily for glucose and ketones.

Hyperosmolar Nonketotic DM (HONKDM)

This is a less common complication of diabetes than DKA in frequency. Although, a less frequent complication it is clinically more severe. Unlike DKA, there is a relative insulin deficiency and some insulin is still present. This is why there is little or no ketones present with HONKDM. The diagnosis is made by the presence of severe hyperglycemia (> 600 mg/dl), hyperosmolarity (> 330 mOsm/kg), and lack of ketones. The extreme volume contraction and hyperglycemia cause significant hyperosmolarity, leading to dehydration and mental dullness. The effective osmolarity is defined by 2[Na] + Glu/18, and BUN and potassium are left out of the equation since they are not effective osmoles.

The treatment is similar as for DKA, but due to the severity of the hyperosmolarity and significant hyperglycemia treatment should be performed slowly and imbalances corrected gradually. If the osmolarity is corrected to fast, then there is significant risk of the patient developing cerebral edema. The goal is to correct the imbalances over 36-48 hours to prevent this complication. Decrease the osmolarity by 0.5/hour.

Addisonian crisis

The initial diagnosis of Addison's disease is usually made when a patient presents for a crisis. These dogs are typically bradycardic, hypotensive, weak, dehydrated, hypoglycemic, low cholesterol, hyponatremic, hyperkalemic, hypercalcemic, low albumin, lack of stress leukogram and varying azotemia. The weakness or collapse often results from hypovolemia and an inability to deal with stress. The bradycardia is due to the increased potassium, and the hypotension is due to the lack or cortisol required for adequate adrenergic receptor function. Please see reference of review for complete explanation of abnormalities.

Diagnosis

The diagnosis is made from performing an ACTH stimulation tests. Often treatment is started pending the results, although a Na:K ratio of ≤ 24 is 79% sensitive and 100% specific for the diagnosis of Addison's.

Treatment

Fluids are the most important part of therapy, and sometimes all that is required to stabilize these patients pending results of the ACTH stimulation test. The patients that present in crisis, often require shock doses (90 mls/kg) of IV replacement crystalloids (0.9% NaCl or LRS are good first choice). I typically do not give the entire shock dose of fluids and then re-check, but instead give 20-30 ml/kg boluses over 30 minutes until desired effect. If the patient is hypoglycemic, they may need dextrose their maintenance fluids after a bolus of 0.5 g/kg of dextrose has been given. Now that the patient is stabilized, the ACTH stimulation test can be done. If steroids are deemed to be needed, then use 0.5 mg/kg DexSp (does not interfere with ACTH stimulation test) IV.

Hyperkalemia will often resolve with fluid therapy alone, but if life threatening cardiac abnormalities occur then treatment should be indicated. The three most common treatment options are: insulin (0.1-0.2 U/kg IV) to drive K+ into the cell (will need to give 0.25-0.5 g/unit of dextrose concurrently to prevent hypoglycemia), bicarbonate (¼ - ½ of the calculated dose =[0.3 x BW(kg) x base deficit]), calcium gluconate 10% (0.5 ml/kg IV, slowly over 15 minutes) does not alter the hyperkalemia but is cardioprotective for about 30 minutes. This should allow for enough time to get them out of danger. The patient will need to be started on longer acting glucocorticoids and mineralocorticoids when stable.

Most will be able to go home once they are eating, drinking, rehydrated, and electrolyte abnormalities have corrected. Make sure the patient is making urine and hydration status has normalized. Due to electrolyte abnormalities it is always a good idea to place them on continuous EKG. Monitor electrolytes (q4-8hr until normal), renal values daily, blood gas (q8hr), and PCV/TS (daily). There has been reports of Pontine demyelination in people and dogs, when the hyponatremia is correct too rapidly. These animals present in lateral recumbency, dull, rigid, and may have seizures.

Myxedema Coma

Myxedema coma is a rare presentation of severe hypothyroidism. The presenting complaint may include mental dullness (even stupor leading to coma), depression, dry hair coat, alopecia, and unresponsiveness. Physical examination may reveal non-pitting edema of the skin, face, and jowls (tragic facial expression), hypothermia, bradycardia, hypotension and hypoventilation. The myxedema is the result of the accumulation of mucopolysaccharides and hyaluronic acid in the dermis which bind water resulting in increased thickness of skin. Myxedematous accumulations in the brain, along with hyponatremia, account for the neurologic changes. Hyponatremia is due to an increase in total body water resulting from decreased renal excretion and tissue retention.

Biochemical testing may reveal low thyroid hormone concentrations, hypercholesterolemia, hyperlipidemia, hypoglycemia, hypoxia/hypercarbia and hyponatremia. The mortality rate of myxedema coma is high due to lack of recognition of the syndrome. Treatment consists of thyroid hormone supplementation and supportive care. The intravenous administration of thyroid hormone is recommended (Sodium Levothyroxine 5 µg/kg q 12 hr). Appropriate supportive care may include fluid therapy (saline with dextrose), passive, slow rewarming and potentially assisted ventilation. Improvement is usually noted within 8 hours. Once the patient is stable and clinical signs improve, oral administration of thyroid hormone can be started.

References

Feldman EC, Nelson RW. Diabetic Ketoacidosis. In: Canine and Feline Endocrinology and Reproduction. WB Saunders, Philadelphia, PA, pp 393-421, 1996.

Feldman EC, Nelson RW. Hypoadrenocorticism. In: Canine and Feline Endocrinology and Reproduction. WB Saunders, Philadelphia, PA, pp 266-305, 1996.

Feldman EC, Nelson RW. Hypothyroidism. In: Canine and Feline Endocrinology and Reproduction. WB Saunders, Philadelphia, PA, pp 68-117, 1996.

Hess R. Modern Concepts in Endocrinology. In: Multidisciplinary Systems Review, IVECCS 2006. pp 24-31.

Mazzaferro EM. Endocrine Situations That Make Our Job Challenging And Fun. In: Multidisciplinary Systems Review, IVECCS 2004. pp 9-18.