Diabetic ketoacidosis (DKA) is a severe alteration of metabolism caused by an insulin deficiency and is a sequela of uncontrolled diabetes mellitus. The insulin deficiency causes a lack of cellular uptake of glucose, which leads to cellular starvation in the face of hyperglycemia. Negative energy balance results in hepatic production of ketones as an alternate energy source. Ketones are organic acids, and a severe metabolic acidosis ensues. Hyperglycemia overwhelms the renal threshold for glucose reabsorption and glucosuria follows. Glucosuria and ketonuria promote an osmotic diuresis with water and electrolyte losses that exceed intake in the ill patient. Severe dehydration and electrolyte disturbances follow.

Ketone bodies include acetone, acetoacetate, and ß-hydroxybutyrate.¹ During treatment of ketoacidosis, ß-hydroxybutyrate is converted to acetoacetate.

Fluid Therapy

The first priority in treating DKA patients involves rehydration. An intravenous isotonic crystalloid solution is recommended (PLA, Normosol R, LRS) or 0.9% NaCl (if Na+ is below the reference range). Hypotonic fluids e.g., 0.45% NaCl, are reserved for rehydrated patients. Fluid deficits should be corrected within the initial 24-hour period. Prompt rehydration is vital to restore circulating volume and tissue perfusion, clear ketones, and correct electrolyte imbalances.² Early re-assessment to establish appropriate response to fluid therapy is critical as ongoing losses (e.g., polyuria, vomiting) can be profound.

Blood Glucose Reduction

Frequent blood sampling for glucose monitoring is necessary; a sampling catheter is strongly advised. Blood glucose (BG) will initially decrease with rehydration, and subsequently with insulin administration. Insulin drives glucose into the cells eliminating the stimulus for ketone production. Insulin also promotes ketone metabolism. The goal of DKA therapy is to maximize insulin administration until resolution of ketonemia/ketonuria.

Regular insulin is the most widely used and recommended insulin for the treatment of DKA. Protocols for intravenous (IV) sliding-scale infusion, or intramuscular/subcutaneous regular insulin administration have proven successful to resolve ketosis.

Veterinarians are urged to use whatever regular insulin protocol they are most comfortable with.¹ The goal of insulin therapy is to reduce and maintain serum glucose concentration between 5.5–14 mmol/L (100 to 250 g/dL), while maximizing insulin administration. When the animal’s BG falls below 14 mmol/L, dextrose (2.5–5%) is added to the crystalloid fluids so as to continue to allow administration of insulin without causing hypoglycemia.³ Regular (Toronto) insulin, when delivered intravenously via constant rate infusion (CRI), has an almost immediate onset of action; its effects cease rapidly upon its discontinuation.⁴

Intravenous insulin CRI sliding scale (example)

*Prepare a dedicated insulin infusion line—regular insulin 0.1 U/kg/hr diluted in 10 mls of 0.9% NaCl. Prepare several hours in a syringe or buretrol for patient delivery.
**Dextrose is supplemented in the patient’s intravenous fluids

When regular insulin is administered intramuscularly (IM) or subcutaneously (SC), its duration of action ranges from 2–4 hours to 4–6 hours, respectively.

Emerging considerations regarding insulin administration:

• Early initiation of insulin therapy is associated with a more rapid resolution of DKA in cats and dogs without significant differences in complication rate.⁵ In human medicine insulin is initiated after the first hour of intravenous volume resuscitation, pending a serum potassium concentration ≥3.3 mmol/L.²
• Omitting an initial intravenous regular insulin bolus prior to starting a CRI, as this practice had no added benefit, and may precipitate or aggravate the development of hypokalemia.⁶
• Transitioning to subcutaneous long-acting insulin prior to regular insulin discontinuation. IV insulin should be continued for 1–2 hours after the first administration of SC basal insulin.⁴
• Continuation of the patient’s SC long-acting (basal) insulin during the management of DKA is currently a very hot topic in human medicine. Concomitant administration of long-acting, basal insulin with regular insulin infusion accelerates ketoacidosis resolution and prevents re-bound hyperglycemia.⁷

A pilot study compared intermittent administration of glargine (0.25 U/kg SC every 12 hours) and regular insulin (1 unit/CAT, IM up to every 6 hours) to a CRI of regular insulin in cats with naturally occurring DKA. The investigation identified that intermittent short- and long-acting insulin injection was useful for the treatment of cats with DKA.⁸

A second study explored glargine IM ± concurrent SC glargine for the treatment of feline DKA. This protocol was effective in the management of feline DKA and may provide an alternative to regular insulin CRI.⁹

A recommended protocol for cats ensues: 1

• 2 U glargine/CAT SC on initiation of fluid and electrolyte replacement.
• Begin 1 U/CAT glargine IM, 1–2 h later (up to 4 h if persistent hypokalemia).
• Repeat IM glargine 4 or more hours later if glucose is >14 mmol/L (252 mg/dL).
• Continue SQ glargine every 12 h.
• Provide IV dextrose as described in the sliding scale table to maintain blood glucose levels 12–14 mmol/L (216–255 mg/dL) in the first 24 h.

Management of Electrolyte Disturbances

Hypokalemia is anticipated within 2–4 hours of initiating insulin therapy and must be closely monitored and proactively supplemented. A guide to potassium supplementation in the patient’s total fluid rate follows:

Patient’s potassium (mEq/L)

• 3.7–5.0
• 3.2–3.7
• <3.2

Hypophosphatemia is also expected and anticipated within 12–24 hours of initiating insulin therapy. Severe hypophosphatemia (phosphorus<0.3 mmol/L, 0.93 mg/dL) can precipitate a hemolytic crisis and should be actively avoided and treated. Phosphorus is supplemented with NaPO₄ or KPO₄. Consider using KPO₄ to address the hypokalemia and hypophosphatemia concurrently; decrease KCl administration accordingly.³ Recommended doses for KPO₄ supplementation range from 0.03–0.12 mmol/kg/hr; typically 0.04–0.06 mmol/kg/hr of phosphorus for 12 hours achieves normalization of phosphorus during insulin administration. Once the patient is rehydrated and no longer receiving variable fluid rates, KCl and KPO₄ can be combined with 20 mEq KCl/L and 20 mEq KPO4/L (each delivering 20 mEq of potassium) added to a 1L bag of IV fluids and delivered safely at regular hourly fluid rates. Sodium bicarbonate is discouraged. Only if a metabolic acidosis with a pH<6.9 is noted, do human guidelines recommend supplementing bicarbonate until pH>7.0.2 Conservative doses are selected. Administer 1/3 to of a calculated bicarbonate deficit.

Bicarb deficit = 0.3 x BW (kg) x (24 – patient bicarbonate)

Other Therapies

If urinalysis is suggestive of urinary tract infection, a first line antibiotic such as ampicillin is recommended pending results of urine culture and sensitivity.

Antiemetics are frequently warranted in patients with DKA. Patients can receive metoclopramide, maropitant, ondansetron or a combination for the management of severe nausea.

Nasoesophageal or nasogastric enteral nutrition should be initiated as soon as emesis is under control.

Other treatments are directed at the underlying causes that may be precipitating the DKA crisis.

Patient Monitoring

Patients diagnosed with DKA require 24-hour care and close monitoring. Vital parameters should be monitored continuously until the patient is stable, and then at least once every 12 hours. Blood glucose monitoring should be performed initially every 2 hours and subsequently extended to every 2-6 hours once a stable glucose is achieved. Electrolyte and blood gas assessment should initially be performed every 4 hours and once stable q12–24 hours. With resolution of acidosis, and ketonuria (~2–3 days),⁵ nausea and vomiting abate, and appetite resumption is expected. Once patients are eating voluntarily, regular insulin is discontinued.

REFERENCES

1.  Rand J. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in cats. Vet Clin N Amer. 2013; 43:367–379.

2.  Tran T, Pease Wood A, et al. Review of evidence for adult diabetic ketoacidosis management protocols. Front Endocrinol. 2017; 8: doi: 10.3389/fendo.2017.00106.

3.  Thomovsky E. Fluid and electrolyte therapy in diabetic ketoacidosis. Vet Clin N Amer. 2017; 47:491–503.

4.  Kelly JL. Continuous insulin infusion: when, where, and how? Diabetes Spectr. 2014; 27:218–223.

5.  DiFazio J, Fletcher D. Retrospective comparison of early versus late-insulin therapy cats: 60 cases (2003–2013). J Vet Emerg Crit Care. 2016; 26:108–115.

6.  Brown HD, Tran RH, Patka JH. Effect of bolus insulin administration followed by a continuous insulin infusion on diabetic ketoacidosis management. Pharmacy (Basel). 2018; 6(4).

7.  Barski L, Brandstaetter E, Sagy I, Jotkowitz A. Basal insulin for the management of diabetic ketoacidosis. Eur J Int Med. 2018; 47:1416.

8.  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; 25:234–9.

9.  Marshall RD, Rand JS, Gunew MN, Menrath VH. Intramuscular glargine with or without concurrent subcutaneous administration for treatment of feline diabetic ketoacidosis. J Vet Emerg Crit Care. 2013; 23: 286–290.