Endocrine Emergencies.part1.endocrine Pancreatic Disorders

Vol. 19, No. 1 January 1997

V

HEINZ SYMPOSIUM 1996

Continuing Education Article

FOCAL POINT ★Diabetic ketoacidosis is a common emergency in small animal practice.

KEY FACTS ■ In diabetic ketoacidosis, serum potassium is usually elevated but the body stores of potassium are typically depleted. ■ Hemolysis in diabetic cats may be caused by Heinz-body formation. ■ Hyperosmolar nonketotic syndrome is usually preceded by the classic signs of diabetes mellitus. ■ Attempts to restore euglycemia in a patient with insulinoma may result in rebound hypoglycemia.

Endocrine Emergencies. Part I. Endocrine Pancreatic Disorders Colorado State University

Deborah S. Greco, DVM, PhD

P

ancreatic disorders often cause emergencies in small animal practice. This article reviews the signs and immediate medical management of emergencies related to high or low blood glucose.

DIABETIC KETOACIDOSIS Pathophysiology Diabetic ketoacidosis is probably the most common endocrine emergency in small animal practice. Diabetes mellitus results from impaired glucose utilization, increased gluconeogenesis, and increased hepatic glycogenolysis. Decreased peripheral utilization of glucose leads to accumulation of glucose in serum, followed by osmotic diuresis. Osmotic diuresis drives polydipsia, and inadequate intake of fluid results in dehydration. Insulin is anabolic; therefore, insulin deficiency leads to protein catabolism and contributes to the clinical signs of weight loss and muscle atrophy. As a consequence of protein catabolism, amino acids are utilized by the liver to promote gluconeogenesis. Stress hormones, such as cortisol and epinephrine, stimulate protein catabolism and glycogenolysis, respectively.1 Some of the most profound changes associated with the ketoacidotic diabetic state occur in lipid metabolism. Because of increased lipase activity, adipose tissue is broken down at an accelerated rate into nonesterified fatty acids. Hepatic assimilation of these fatty acids, which depends on the rate of lipolysis, is also accelerated.2 Nonesterified fatty acids are released into the bloodstream and delivered to the liver for repackaging as triglycerides or are used extrahepatically as oxidative fuels.1 With insulin deficiency, lipid metabolism in the liver becomes deranged and nonesterified fatty acids are converted to acetyl coenzyme A rather than being incorporated into triglycerides. Acetyl coenzyme A accumulates in the liver and is converted into acetoacetyl coenzyme A and then ultimately to acetoacetic acid. Finally, the liver starts to generate large amounts of acetoacetic acid, βhydroxybutyrate, and acetone.1,2

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As insulin deficiency culminates in diabetic ketoacidosis, accumulation of ketones and lactic acid in the blood and loss of electrolytes and water via urine result in profound dehydration, hypovolemia, metabolic acidosis, and shock. Nausea, anorexia, and vomiting result when ketonemia and hyperglycemia stimulate the chemoreceptor trigger; they contribute to the dehydration caused by osmotic diuresis. Ketonuria and osmotic diuresis result in sodium and potassium loss via urine, thus exacerbating hypovolemia and dehydration. Eventually, severe dehydration may result in hyperviscosity, thromboembolism, severe metabolic acidosis, renal failure, and finally death.

Diagnosis The clinical signs and physical examination findings in animals with acute diabetic ketoacidosis are dramatic. These dogs and cats typically have a history of anorexia, weakness, depression, and vomiting that was preceded by polydipsia, polyuria, and weight loss.3,4 Animals suffering from diabetic ketoacidosis are often presented in shock. Physical examination findings may include depression, tachypnea, dehydration, weakness, and vomiting.3,4 Diabetic cats may exhibit clinical icterus as a result of hemolysis, hepatic lipidosis, biliary obstruction due to pancreatitis, or acute pancreatitis. The gastrointestinal signs (e.g., vomiting, abdominal distention, and abdominal pain) are similar to those of pancreatitis (which can occur concurrently with diabetic ketoacidosis) and peritonitis.1 Diagnosis of diabetic ketoacidosis is based on hyperglycemia, glycosuria, and ketonuria or ketonemia. Treatment Treatment, as outlined in Treatment of Diabetic Ketoacidosis, includes the following steps (in order of importance):

lar catheter to avoid overhydration. Fluid rates depend on the severity of dehydration, maintenance requirements, continuing losses (vomiting and diarrhea), and the presence of concurrent disease (e.g., congestive heart failure). Use of hypotonic solutions is controversial because serum hyperosmolality often causes idiogenic osmoles in the brain, which are trapped when serum osmolality decreases and rapidly produce cerebral edema.5

Insulin Insulin therapy should be initiated as soon as possible. Either intravenous insulin or low intramuscular doses are given.5 The protocol outlines the intravenous insulin fluid rate, which should preferably be administered via a separate peripheral catheter. Approximately 50 ml of fluid and insulin is allowed to run through the intravenous drip set and then discarded because insulin binds to the plastic tubing.5 The species of regular insulin (beef, pork, or human) does not affect response; however, the type of insulin given is critical. Regular insulin must be used; insulin zinc suspension, extended insulin zinc suspension, and isophane insulin suspension should never be given intravenously. Intravenous insulin reduces blood glucose to below 250 mg/dl within approximately 10 hours in dogs and after about 16 hours in cats.5 Once euglycemia has been achieved, the animal is maintained on subcutaneous regular insulin (0.1 to 0.4 U/kg subcutaneously every 4 to 6 hours) until it starts to eat and/or the ketosis has resolved. An alternative, as shown in the protocol, is to use low-dose intramuscular insulin. However, blood glucose levels may drop precipitously as depots of intramuscular insulin are absorbed from muscle tissue that had been poorly perfused.

intravenous)5 ■ Electrolyte supplementation (potassium chloride and/or potassium phosphate, magnesium) ■ Reversal of metabolic acidosis

Electrolytes Electrolyte (specifically potassium) balance may be difficult to manage during a ketoacidotic crisis. Potassium should be supplemented as soon as insulin therapy is initiated. Although serum potassium may be normal or elevated in animals with diabetic ketoacidosis, the animal’s total body stores of potassium are actually depleted.

Fluid Therapy Fluid therapy should consist of 0.9% saline supplemented with potassium when insulin therapy is initiated. A large central venous catheter should be used to administer the fluid because the animals are severely dehydrated and require rapid fluid administration; central venous pressure may also be monitored via a jugu-

Metabolic Acidosis Correction of the metabolic acidosis tends to drive potassium intracellularly in exchange for hydrogen ions. Insulin facilitates this exchange. The net effect is a dramatic decrease in serum potassium, which must be attenuated with appropriate potassium supplementation in fluids. Refractory hypokalemia may be compli-

■ Fluid therapy with 0.9% saline ■ Insulin therapy (low-dose intramuscular or

CENTRAL VENOUS CATHETER ■ REGULAR INSULIN ■ POTASSIUM

The Compendium January 1997

Small Animal

Treatment of Diabetic Ketoacidosis Step One: Fluid Therapy ■

Place intravenous catheter, preferably central venous.

Administration rate: ■

■

Estimate dehydration deficit (ml): Deficit (ml) = Dehydration (%) × body weight (kg) × 1000 ml

Estimate maintenance needs: 2 ml/kg/hr × hours required to rehydrate (24 hours)

■

Estimate losses (vomiting, diarrhea)

Fluid dose = Dehydration deficit + maintenance needs + losses Hourly fluid administration rate (ml/hr) = Fluid dose (ml) ÷ 24 hours

Fluid composition: Blood Glucose (mg/dl)

Fluids

Rate

Route

Monitor

Frequency

> 250

0.9% saline

Up to 90 ml/kg/hr to rehydrate

Intravenous

Packed cell volume, total solids, sodium, potassium, osmolality

Every 4 hr

200–250

0.45% saline plus 2.5% dextrose

Up to 90 ml/kg/hr to rehydrate

Intravenous

Packed cell volume, total solids, sodium, potassium, osmolality

Every 4 hr

150–200

0.45% saline plus 2.5% dextrose

Up to 90 ml/kg/hr to rehydrate

Intravenous

Central venous pressure, urine output

Every 2 hr

100–150

0.45% saline plus 2.5% dextrose

Up to 90 ml/kg/hr to rehydrate

Intravenous

Central venous pressure, urine output

Every 2 hr

<100

0.45% saline plus 5% dextrose

Up to 90 ml/kg/hr to rehydrate

Intravenous

Central venous pressure, urine output

Every 2 hr

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Step Two: Insulin Intravenous insulin (regular only) is mixed in 250 ml of 0.9% saline; 50 ml is allowed to run through the administration set and discarded. See the text for treatment recommendations for hyperosmolar coma. Blood Glucose (mg/dl)

Rate

Route

Dose (U/kg)

Intravenous (regular only) >250 10 ml/hr

Intravenous

Cats: 1.1 Dogs: 2.2

Blood glucose

Every 1–2 hr

200–250

7 ml/hr

Intravenous

Cats: 1.1 Dogs: 2.2

Blood glucose

Every 1–2 hr

150–200

5 ml/hr

Intravenous

Cats: 1.1 Dogs: 2.2

Blood glucose

Every 4 hr

100–150

5 ml/hr

Intravenous

Cats: 1.1 Dogs: 2.2

Blood glucose

Every 4 hr

<100

Stop intravenous insulin; begin subcutaneous insulin every 4 hours

Subcutaneous 0.1–0.4

Blood glucose

Every 2 hr

Intramuscular Intramuscular Intramuscular Subcutaneous

Blood glucose Blood glucose Blood glucose Blood glucose

Hourly Hourly Every 4–6 hr Every 6–8 hr

Intramuscular (regular only) >250 mg/dl Initial dose Every hour <250 mg/dl Every 4–6 hr Every 6–8 hr

0.2 0.1 0.1 0.1–0.4

Monitor

Frequency

Step Three: Electrolytes Electrolyte Concentration Potassium 3.6–5.0 mEq/L 2.6–3.5 mEq/L 2.1–2.5 mEq/L <2.0 mEq/L

Amount Added to Fluid (mEq/L)

Maximum Fluid Administration Rate (ml/kg/hr)

20 40 60 80

26 12 9 7

Phosphorus 1–2 mg/dl

0.03 mmol/kg/hr

Monitor serum phosphorus every 6 hr

<1.0 mg/dl

0.1 mmol/kg/hr

Monitor serum phosphorus every 6 hr

0.75–1 mEq/kg/day (magnesium chloride or sulfate) in a constantrate infusion

Use 5% dextrose; magnesium is incompatible with calcium and sodium bicarbonate solutions

Magnesium <1.2 mg/dl

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Step Four: Acid–Base Balance pH

Bicarbonate Concentration

Dose of Bicarbonate (ml)

Rate

< 7.1

<12 mEq/L

0.1 × body weight (kg) × (4 – bicarbonate [mEq/L])

Over 2 hr

cated by hypomagnesemia. The article by Dr. Macintire on disorders of potassium, phosphorus, and magnesium in this issue of Compendium provides guidelines for the supplementation of serum potassium and other electrolytes in patients with diabetic ketoacidosis. Serum and tissue phosphorus may also be depleted during a ketoacidotic crisis, and some of the potassium supplementation (one third of the potassium dose) may consist of potassium phosphate—particularly for small dogs and cats, which are most susceptible to hemolysis caused by hypophosphatemia.5,6 Oversupplementation of phosphorus can result in metastatic calcification and hypocalcemia. Cats with diabetic ketoacidosis may also have a mild increase in mean cell volume because hypophosphatemia causes erythrocytes to swell.6 Another cause of hemolysis in cats with diabetic ketoacidosis is Heinz-body anemia.7 Although Heinzbody anemia usually does not result in overt hemolysis by itself, it probably shortens the erythrocyte life span. When coupled with low phosphorus levels, it may precipitate a hemolytic crisis.6 The first three steps in the treatment of diabetic ketoacidosis usually correct serum acid–base status. However, some patients with blood pH under 7.1 or serum bicarbonate below 12 mEq/L need bicarbonate therapy (see the protocol).5 Caution is recommended because metabolic alkalosis may be difficult to reverse.

HYPEROSMOLAR COMA In humans, nonketotic hyperosmolar diabetes is defined as extreme hyperglycemia (serum glucose >600 mg/dl), hyperosmolality (>350 mOsm/L), severe dehydration, central nervous system depression, and a paucity of ketones or metabolic acidosis.5 Hyperosmolar nonketotic syndrome in dogs and cats is an unusual syndrome characterized by neurologic and gastrointestinal abnormalities (e.g., progressive weakness, anorexia, vomiting, and lethargy). These signs are usually preceded by the classic signs of uncomplicated diabetes mellitus: polydipsia, polyuria, weight loss, and polyphagia. Physical examination reveals severe dehydration, hypothermia, extreme depression, lethargy, and coma.5

Approximately one third of ketoacidotic diabetic cats are presented in recumbency and with a serum osmolality in the range of 388 mOsm/L; this may be a manifestation of mixed hyperosmolar syndrome.5 Treatment of hyperosmolar coma is difficult. Several guidelines, which differ from the treatment of diabetic ketoacidosis, should be followed. First, fluid therapy should be approached cautiously by estimating the fluid needs (dehydration deficit) and replacing 80% of the deficit over a 12- to 24-hour period.5 Isotonic, rather than hypotonic, solutions should be used. Hyperglycemia should also be reversed very slowly. A lower dosage of insulin (1.1 U/kg over 24 hours) is recommended for hyperosmolar animals, and insulin therapy should be delayed until 2 to 4 hours after fluid therapy begins.5

HYPOGLYCEMIC SEIZURES Causes of hypoglycemia include iatrogenic insulin overdose, insulinoma, sepsis, large tumors, hunting dog and puppy hypoglycemia, hypoadrenocorticism, portosystemic shunts, hypothyroidism, growth hormone deficiency, and (rarely) starvation.8–14 Insulin overdose, hypoadrenocorticism, and insulinoma are the most common endocrine disorders that result in hypoglycemia. Treatment should consist of administration of a slow intravenous bolus of 50% dextrose (0.5 g/kg diluted 1:4). If no vein is readily accessible, corn syrup or pancake syrup may be applied to the oral mucous membranes with a large syringe. Thereafter, animals with hypoglycemia of any cause should be given a continuous infusion of 5% dextrose until they can be fed. Veterinarians should avoid the temptation to restore blood glucose concentrations to the normal range in dogs with insulinoma. Administration of higher and higher doses of 50% dextrose in an attempt to restore euglycemia may result in a cycle of rebound hypoglycemia by provoking insulin secretion. The goal of intravenous glucose therapy is to stop the seizure rather than to normalize blood glucose.

HEINZ-BODY ANEMIA ■ HEMOLYSIS ■ REBOUND HYPOGLYCEMIA

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Long-term management of hypoglycemia depends on the cause. The veterinarian must therefore use appropriate diagnostics to identify the cause of the hypoglycemia. The immediate therapy for hypoglycemia resulting from insulin overdose is the same as for other causes of hypoglycemia. However, endogenous glucose stores may have been depleted by the insulin overdose; it may take several days for hyperglycemia to recur.5 In these cases, insulin therapy should be discontinued until hyperglycemia recurs. Insulin overdose in animals may lead to cerebral edema and temporary blindness or behavior changes. These signs are often temporary and resolve after several weeks or months.

About the Author Dr. Greco is affiliated with the Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, and is a Diplomate of the American College of Veterinary Internal Medicine.

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REFERENCES 1. Nelson RW: Diabetes mellitus, in Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, ed 4. Philadelphia, WB Saunders Co, 1995, pp 1510–1537. 2. Feldman EC: Diabetic ketoacidosis in dogs. Compend Contin Educ Pract Vet 2(6):456-463, 1980. 3. Schaer M: Insulin treatment for the diabetic dog and cat. Compend Contin Educ Pract Vet 5(7):579–590, 1983. 4. Ling TV, Lowenstine LJ, Pulley LT, Kaneko JJ: Diabetes mellitus in dogs: A review of initial evaluation, immediate and long-term management and outcome. JAVMA 170:521–530, 1977. 5. Macintire DK: Emergency therapy of diabetic crises: Insulin overdose, diabetic ketoacidosis and hyperosmolar coma. Vet Clin North Am Small Anim Pract 25(3):639–650, 1995. 6. Nichols R, Crenshaw KL: Complications and concurrent disease associated with diabetic ketoacidosis and other severe forms of diabetes mellitus. Vet Clin North Am Small Anim Pract 25(3):617–624, 1995. 7. Christopher MM: Hematologic complications of diabetes mellitus. Vet Clin North Am Small Anim Pract 25(3): 625–638, 1995. 8. Rogers KS: Hyperinsulinism. Compend Contin Educ Pract Vet 7(10):829–841, 1985. 9. Atkins CE: Disorders of glucose homeostasis in neonatal and juvenile dogs: Hypoglycemia—Part I. Compend Contin Educ Pract Vet 6(3):197–208, 1984. 10. Atkins CE: Disorders of glucose homeostasis in neonatal and juvenile dogs: Hypoglycemia—Part II. Compend Contin Educ Pract Vet 6(4):353–366, 1984. 11. Breitschwerdt EB, Loar AS, Hribernik TN, McGrath RK: Hypoglycemia in four dogs with sepsis. JAVMA 178: 1072–1076, 1981. 12. Leifer CE, Peterson ME, Matus RE, Patnaik AK: Hypoglycemia associated with nonislet cell tumor in 13 dogs. JAVMA 186:53–55, 1985.

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13. Turnwald GH, Troy GC: Hypoglycemia. Part I. Carbohydrate metabolism and laboratory evaluation. Compend Contin Educ Pract Vet 5(11):932–938, 1983.

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14. Turnwald GH, Troy GC: Hypoglycemia. Part II. Clinical aspects. Compend Contin Educ Pract Vet 6(2):115–125, 1984.