Pathophysiology

Diabetic ketoacidosis (DKA) is a complicated form of diabetes mellitus characterized by hyperglycemia, production of ketone bodies and resultant acidosis. This complicated metabolic syndrome occurs commonly at the time of initial diagnosis of DM, but may also occur in currently diagnosed and treated diabetics that have insulin antagonism from counter regulatory hormone production secondary to co-morbid disease. Diabetic ketoacidosis occurs in patients who may have an absolute or relative insulin deficiency. Insulin antagonism may occur due to another systemic disease that increases the circulation of counter-regulatory hormones or associated with an altered metabolic milieu. Recent research suggests specific cytokines may be involved in the pathogenesis of DKA.

Hypoinsulinemia and elevated counter-regulatory hormones result in hyperglycemia and ketone body production. Both glucose and ketones act as osmotic diuretics once their respective renal thresholds are exceeded. Ketones are negatively charged, requiring concurrent renal elimination of a positively charged cation concurrently; thus loss of electrolytes is common. Increased solute excretion yields impaired ability of the proximal tubule and Loop of Henle to reabsorb water. An excessive amount of sodium, chloride, potassium, phosphorous, and water is lost, leading to volume contraction and tissue hypoperfusion. Insulin deficiency further exacerbates water and electrolyte losses due to inherent effects on water and salt absorption in the proximal and distal portions of the nephron.

Acidosis results when the body consumes its buffer bases and ketone bodies accumulate. Anorexia, vomiting, and diarrhea lead to hypovolemia, hypoperfusion, and lactic acidosis that further exacerbate the acidemia. Hypovolemia leads to decreased glomerular filtration rate that prevents elimination of accumulated acids and glucose. Hyperglycemia contributes to increased plasma osmolality that may induce cellular dehydration; when this process involves the central nervous system, a patient may develop obtundation/coma.

Clinical Presentation/Diagnosis

Patients with diabetic ketoacidosis typically present with a history of polyuria/polydipsia, hyporexia/anorexia, vomiting, lethargy; some may have recently experienced weight loss. Physical examination commonly reveals evidence of hypovolemia, dehydration and weakness. Cervical ventroflexion may also be present with marked hypokalemia, and a bilateral plantigrade stance may be observed. The diagnosis of diabetic ketosis with or without acidosis is based on a fasting hyperglycemia, glycosuria, ketonuria/ketonemia.

A urinalysis and urine culture should be performed in every patient with diabetic ketoacidosis. Diabetes mellitus predisposes patients to urinary tract infection. Urine specific gravity should be determined prior to fluid therapy to determine the kidneys' ability to concentrate urine. However, glucosuria will falsely increase USG when measured by the refractometer. Serum osmolality is expected to be elevated in patients with DKA. Ketonemia results in a high anion gap acidosis. Severe hyperglycemia contributes to a reduced GFR due to dehydration, poor renal perfusion, hypovolemia, and hypotension. Renal azotemia may occur with diabetes-induced glomerular microangiopathy, hemodynamic alterations associated with ketoacidosis, concurrent necrotizing pancreatitis, prolonged dehydration or even pyelonephritis.

Electrolyte abnormalities are common in patients with diabetic ketoacidosis. Excessive natriuresis, hyperglucagonemia, vomiting, and/or diarrhea may cause hyponatremia. Hypoinsulinemia may also cause sodium wasting due to insulin's ability to enhance sodium reabsorption by nephrons. A pseudohyponatremia also occurs secondary to hyperglycemia.

Patients with DKA may also have hypokalemia, normokalemia, or even hyperkalemia with the former being most common; hypokalemia is exacerbated by fluid therapy, insulin administration, gastrointestinal losses from vomiting/diarrhea, and improvement of acidemia. Calcium is usually normal unless another disease process is present such as pancreatitis (can result in hypocalcemia) or chronic kidney disease (CKD). In patients with normal kidney function, hypophosphatemia is common. Those with serum phosphorous concentrations less than 0.32–0.48 mmol/L (1–1.5 mg/dl) often manifest hematologic abnormalities and/or neuromuscular clinical signs. Hypomagnesemia often results from osmotic diuresis and the movement of magnesium into the intracellular space secondary to insulin therapy (similar to potassium). Clinical signs of hypomagnesemia include lethargy, anorexia, muscle weakness, muscle fasciculations, seizures, ataxia and even coma.

Other laboratory abnormalities common in patients with diabetic ketoacidosis include a predominantly neutrophilic leukocytosis that can occur with inflammation and/or infection. In cats, anemia may be present due to Heinz bodies that form from oxidative damage and lowered red blood cell deformability that occurs secondary to membrane protein glycosylation. A biochemical profile may show hypertriglyceridemia that occurs due to hypoinsulinemia. Insulin deficiency causes a decrease in lipoprotein lipase activity that aids in the metabolism of triglyceride-rich VLDL and chylomicrons. It is also common to see elevations in hepatocellular and/or cholestatic enzymes due to concurrent primary hepatopathy (lipidosis, cholangiohepatitis, lymphoma), pancreatitis, sepsis, and/or hepatic hypoperfusion.

Treatment

After successfully addressing hypovolemia and reaching desired endpoints of resuscitation, an intravenous balanced isotonic solution should be administered based on the patient's hydration, acid/base balance, and electrolyte status. Insulin therapy should generally be delayed for 4–6 hours after fluid therapy has been initiated.

There are several techniques for insulin administration. A constant rate infusion (CRI) or intermittent intramuscular (IM) administration of short-acting insulin is most commonly employed as initial insulin treatment for DKA in dogs and cats. Subcutaneous administration of short- acting insulin is inappropriate in dehydrated patients, as the insulin will not be reliably absorbed. In general insulin administration rate should be increased or decreased to achieve a rate of decline of blood glucose of 2.8–3.9 mmol/L/hr (50–70 mg/dl/hr). Osmolality should be changed slowly, which may be accomplished by changing sodium no faster than 1 mmol/L per hour and glucose by no more than 2.78–5.5 mmol/L/hr (50–100 mg/dl/hr) in patients that are hyperosmolar.

Patients with hypokalemia require potassium supplementation, and use of potassium CRI is commonly employed with values less than 3.2 mmol/L. Rate of administration generally should not exceed 0.5 mEq/ kg/hr, and appropriate cardiovascular monitoring (e.g.: electrocardiography/telemetry) is recommended. A lack of improvement in serum potassium levels despite apparently adequate supplementation should raise concern for concurrent hypomagnesemia. Clinical signs of hypomagnesemia are usually not seen unless ionized magnesium is less than 0.41 mmol/L. Supplementation is indicated in cases of refractory hypokalemia, certain ventricular dysrhythmias, and/or patients with persistent lethargy, hyporexia/anorexia, and/or weakness. Phosphorous may rapidly decrease due to translocation into the cell associated with insulin administration, and dilution, as well as renal and/or gastrointestinal loss. Replacement of phosphorous should occur if levels are less than 0.48 mmol/L (1.5 mg/dl).

The use of sodium bicarbonate is controversial, as correction of acidosis is usually accomplished with intravenous fluids and insulin. Detrimental effects include hypocalcemia, hypokalemia, decreased DO2, paradoxical central nervous system acidosis, and prolongation of ketone metabolism. Supplementation should be considered with serum bicarbonate levels lower than 8 mmol/L, pH less than 7.1, and clinical signs of metabolic acidosis.

Prognosis

Hume et al. found 70% of dogs with DKA were discharged from the hospital. The median duration of hospitalization was 6 days. Of those diagnosed with DKA, 65% were newly diagnosed diabetics and 69% had a concurrent disorder. 41% of the population had pancreatitis, 20% had a bacterial urinary tract infection, 15% had hyperadrenocorticism, 10% were receiving glucocorticoids, and 6% had pneumonia. More than 33% had more than one disorder. Survival in dogs was correlated with the degree of anemia, hypocalcemia, and acidosis.

Bruskiewicz et al. previously documented a mortality rate of 26% for feline DK or DKA patients. Azotemia, metabolic acidosis, and hyperosmolality were more severe in those patients than died compared to those that survived. Recurrence of DK or DKA was documented in 42% of these cats. However, remission of DM in cats with DKA is possible. Cooper et al recently retrospectively evaluated 93 cats with DKA. Poorer outcomes were associated with increased initial creatinine, BUN, total magnesium, and total bilirubin concentrations. Good outcome was associated with a higher concentration of IV insulin CRI.

References

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2.  Sears KW, Drobatz KJ, Hess RS. Use of lispro insulin for treatment of diabetic ketoacidosis in dogs. J Vet Emerg Crit Care. 2012;22(2):211–218.

3.  Marshall RD, Rand JS, Gunew MN, et al. Intramuscular glargine with or without concurrent subcutaneous administration for treatment of feline diabetic ketoacidosis. J Vet Emerg Crit Care. 2013;23(3):296–300.

4.  Claus MA, Silverstein DC, Shofer FS, et al. Comparison of regular insulin infusion doses in critically ill diabetic cats: 29 cases (1999–2007). J Vet Emerg Crit Care. 2010;20(5):509–517.

5.  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.

6.  Cooper RL, Drobatz KJ, Lennon EM, et al. Retrospective evaluation of risk factors and outcome predictors in cats with diabetic ketoacidosis (1997–2007): 93 cases. J Vet Emerg Crit Care. 2015;25(2):263–272.

7.  Bruskiewicz KA, Nelson RW, Feldman EC, et al. Diabetic ketosis and ketoacidosis in cats: 42 cases (1980–1995). J Am Vet Med Assoc. 1997;211(2):188–192.

8.  Sieber-Ruckstuhl NS, Kley S, Tschuor F, et al. Remission of diabetes mellitus in cats with diabetic ketoacidosis. J Vet Intern Med. 2008;22(6):1326–1332.

9.  Hume DZ, Drobatz KJ, Hess RS. Outcome of dogs with diabetic ketoacidosis: 127 dogs (1993–2003). J Vet Intern Med. 2006;20(3):547–555.