WVC—Chasing the ketones when diabetes runs amok

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“DKA is a manifestation of insulin deficiency in a diabetic animal that has a concurrent disease on top of that,” said Patty Lathan, VMD, MS, DACVIM, associate professor of small animal internal medicine at Mississippi State University, in a lecture at the Western Veterinary Conference in February.

Picture a pond full of fish and a fisherman who can’t catch any of them because his arthritis prevented him from weaving a net. So he scrounges for snails at the water’s edge. But when he eats the snails, they make him very sick. This is DKA.

The pathogenesis of DKA is nothing short of a metabolic tsunami, according to Dr. Lathan: It begins with insulin deficiency (or resistance) that deprives the tissues of energy-giving glucose they are trying to extract from glucose-rich blood. So the starved body breaks down fat in a desperate attempt to grab nutrients.

Stress or concurrent illness increases insulin resistance and peripheral lipolysis, resulting in a flood of circulating free fatty acids, which are converted into ketones in the liver. Ketosis results in metabolic acidosis, osmotic diuresis, renal water and electrolyte loss, increased serum osmolality… and a very sick patient.

The arthritis in our fishing analogy could be one of many underlying conditions that inflame the situation. Some 70% of dogs with DKA have a concomitant condition, most commonly acute pancreatitis, bacterial urinary tract infection or Cushing’s disease; Cushing’s bodes particularly poorly for the DKA patient. Nine out of 10 DKA cats have an underlying disease, most commonly hepatic lipidosis. Other attendant maladies are acute pancreatitis, chronic kidney disease, bacterial/viral infection or neoplasia.

Diagnosing DKA

For over half of cats and 65% of dogs in DKA, diabetes is undiagnosed prior to their hospitalization. While the clinical signs of diabetes—polyuria/polydipsia, polyphagia, weight loss, blindness and plantigrade stance—might be missed, DKA’s calling card is much more jarring: extreme inappetence, vomiting, weight loss, weakness and lethargy, sometimes accompanied by abdominal pain due to pyelonephritis or gastrointestinal problems.

On physical exam, the animal in DKA is bound to be dehydrated, underweight and weak. Other observations include mental dullness, an unkempt haircoat, cataracts and ketone breath. In people, the criteria for diagnosis of DKA are a blood glucose exceeding 250 mg/dl, increased serum ketones, an arterial pH less than 7.3 and serum bicarbonate less than 18 mEq/L;¹ the findings in animals with DKA run parallel to this.

Three types of ketones may be present in the blood and urine: acetoacetate, β-hydroxybutyrate and acetone. Acetoacetate is converted to β-hydroxybutyrate, which is sometimes present at high levels in DKA but does not register on most test strips.² So false-negative results can occur in very sick dogs and cats. As acidosis is corrected, ketone levels appear to rise because the measurable ketones no longer convert into the immeasurable form.

Dr. Lathan cautioned that the mere presence of ketonuria or ketonemia does not constitute a DKA diagnosis, Rather, she explained, an animal must also appear sick.

Other diagnostics include a complete blood cell count, serum chemistry, urinalysis, urine culture and, depending on the suspected underlying disease, chest/abdominal radiography and abdominal ultrasonography. The typical clinicopathologic profile in a DKA patient includes hemoconcentration or anemia, neutrophilia, azotemia, elevated liver enzymes, hypercholesterolemia/hypertriglyceridemia, hyponatremia, hypokalemia, hypophosphatemia, hypomagnesemia and hyperosmolality/hyperglycemia.

Treating DKA

Treatment of DKA is aimed at restoring electrolytes, rehydrating, correcting acidosis, providing insulin (plus carbohydrate substrate) and addressing any underlying illness.

The primary treatment is fluid therapy, and the goal is to correct dehydration over 12 to 24 hours. This also helps resolve acidosis and hyperglycemia, and restores normal electrolyte levels. Dr. Lathan recommended Plasma-Lyte or lactated Ringer’s solution over 0.9% NaCl because of their higher alkalinity.

DKA patients are hyperosmolar because of hyperglycemia and fluid losses, but correcting it too fast can result in neurologic depression, so moderation is key. As hyperglycemia normalizes, hyponatremia also resolves, so this isn’t usually a problem unless the patient started out with a high or normal sodium concentration.³

Potassium and phosphorus decrease with fluid therapy, which is bad because they are already low in the DKA patient. Hypokalemia causes weakness and, in cats, possible ventroflexion. If low, potassium should be supplemented—before insulin is initiated—but not at a higher rate than 0.5 mEq/kg/hr. Phosphorus, if low, should also be boosted prior to insulin therapy at a rate of 0.01 to 0.03 mmol/kg/hr. Both potassium and phosphorus should be rechecked 12 to 24 hours later.

Antibiotics are also important, Dr. Lathan explained, because infection often triggers DKA onset. “Because infection is such a common cause or precipitating factor in DKA, I go ahead and start them all on antibiotics,” she said.

Once intravenous fluids have been on board for several hours, insulin should be added as a constant-rate infusion (CRI). The primary purpose of insulin is to inhibit ketone production, and the goal is to drop the glucose gradually (50-100 mg/dl/hr). If administering regular insulin intravenously, dogs and cats should be started at an insulin rate of 2.2 mg/kg/hr; insulin should be decreased in conjunction with drops in blood glucose, which should be checked every two hours. Once blood glucose drops below 250 mg/dl, dextrose should be added to avoid hypoglycemia.

As soon as the patient is hydrated, ketonemia/ketonuria has resolved and the patient is eating, it’s time to switch to injectable insulin. Dr. Lathan typically begins with NPH or porcine zinc insulin suspension (Vetsulin) in dogs at a dose of 0.25 to 0.5 U/kg twice daily; in cats glargine or PZI is administered at a dose of 1 to 2 U twice daily.

A recent study compared low-dose regular insulin CRI with a protocol that combined regular insulin given intramuscularly and long-acting insulin (glargine) given subcutaneously. The latter group experienced significantly hastier resolution of ketonemia, acidosis and hyperglycemia, resulting in shorter hospitalization times.⁴

Dr. Lathan’s review of several studies in animals with DKA shows average times for resolution of ketosis to be three days in dogs and two to three days in cats; hospitalization time averaged six days for dogs versus five days for cats.

Owners can monitor their pet’s interstitial glucose at home using a continuous “flash” monitoring sensor. With the FreeStyle Libre brand (Abbott), a subcutaneous sensor reads the interstitial glucose every 15 minutes and results are displayed on a reader device or an iPhone. A recent study showed that the results correlate well with glucometer readings,⁵ although in some cases the flash monitors overcalled hyperglycemia.

Prognosis for DKA patients

Dr. Lathan pointed to multiple studies showing a 70% overall survival rate for dogs and cats experiencing a DKA episode. The outlook is dimmer for cushingoid dogs and for azotemic or hyperbilirubinemic cats, but it’s better for cats with a history of steroid treatment that pushed them into DKA.

“The prognosis of the patient with DKA,” Dr. Lathan said, “is largely dependent on their concurrent disease and (its severity).”

References

1. Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009;32(7): 335-1343.

2. Stojanovic V, Ihle S. Role of beta-hydroxybutyric acid in diabetic ketoacidosis: A review. Can Vet J 2011;52(4):426-430.

3. Schermerhorn T, Barr S. Relationships between glucose, sodium and effective osmolality in diabetic dogs and cats. J Vet Emerg Crit Care 2006;16(1):19-24.

4. Gallagher BR, Mahony OM, Rozanski EA, et al. A pilot study comparing a protocol using intermittent administration of glargine and regular insulin to a continuous rate infusion of regular insulin in cats with naturally occurring diabetic ketoacidosis. J Vet Emerg Crit Care 2015;25(2):234-239.

5. Malerba E, et al. Accuracy of a flash glucose monitoring system in dogs with diabetic ketoacidosis. J Vet Int Med 2020;34(1)83.