Diabetic Ketoacidosis: Causes, Recognition, and Treatment

To understand how diabetic ketoacidosis (DKA) develops, it is important to know how the body normally uses glucose for energy and its compensatory mechanisms if energy needs are not being met.

Normal Glucose Metabolism

In a healthy patient, insulin and glucagon work together to maintain a stable glucose level that allows cells to perform functions essential for life (BOX 1).¹ When blood glucose levels are high, the β-cells of the islets of Langerhans in the pancreas secrete insulin,² which binds to insulin receptors on cell membranes. This binding allows glucose to enter the cell, where it is converted into adenosine triphosphate (ATP) through cellular respiration. ATP is the main energy source for cells. Once cells’ energy needs are met, insulin stimulates conversion of excess glucose into glycogen that can be stored in the liver. Insulin also causes amino acids to be stored as protein and fatty acids to be stored in adipose tissue.³

If cells’ energy needs are not being met (e.g., during fasting), the α-cells of the islets of Langerhans secrete glucagon. Glucagon is insulin’s opposite: It stimulates glycogenolysis (breakdown of glycogen into glucose), proteolysis (breakdown of protein into amino acids), and lipolysis (breakdown of adipose tissue into fatty acids). The body then uses the released glucose and other components to maintain consistent energy production.

Not all glucose can be immediately transported into cells or converted into glycogen. Some remains in the bloodstream and travels to the kidneys, where, in a normal, healthy patient, the proximal convoluted tubule of the nephron reabsorbs it so it can reenter circulation.² However, there is a limit to how much glucose the tubules can reabsorb; this is referred to as the renal threshold and is normally 180 to 220 mg/dL.⁴ As long as blood glucose is below this threshold, glucose should never be excreted into the urine. It is all used for energy or stored as glycogen.

Pathophysiology of Diabetes Mellitus

When there is a deficiency in insulin, diabetes mellitus develops. Without adequate insulin, glucose in the bloodstream cannot enter cells at sufficient levels to meet energy needs, leading to cell starvation. In response, glucagon is secreted to increase the breakdown of glycogen, protein, and fat. The result is a huge increase in glucose, but still little to none of it can enter the cells. Blood glucose rises to surpass the renal threshold and excess glucose is secreted into the urine.¹ Due to glucose’s high osmolality, more water is pulled into the urine, leading to polyuria. The resulting free water loss, along with the lack of cellular energy, stimulates the hunger and thirst control centers of the hypothalamus, causing polydipsia and polyphagia.² However, despite the patient eating more and appearing hungry more often, weight loss occurs as muscle and fat continue to be broken down in the ongoing absence of insulin. Polyuria, polydipsia, polyphagia, and weight loss are the typical presenting concerns of clients with diabetic pets. Dogs may also experience cataract formation caused by accumulation of fluid in the lens and subsequent lens fiber rupture.⁴

Why is there suddenly an inadequate amount of insulin? In dogs and cats, there are 2 general reasons: insulin deficiency and insulin resistance (BOX 2). Insulin deficiency is the result of loss of functioning β-cells,⁴ leading to a decrease in the overall amount of insulin in the body. Insulin resistance occurs when cells have reduced sensitivity to insulin and therefore do not use it in appropriate amounts. In addition, β-cells fail to compensate for this reduced sensitivity and do not increase insulin secretion; this failure is not fully understood.⁵ The clinical difference between insulin deficiency and insulin resistance may not be entirely important; however, it is estimated that 80% to 90% of cats with diabetes mellitus are insulin resistant, which is why cats can go into remission (i.e., there is no loss of functioning β-cells).⁵ β-Cell loss cannot be reversed, and patients with β-cell loss cannot go into remission.

Progression to Diabetic Ketoacidosis

Patients can compensate for undiagnosed diabetes mellitus for weeks to months without severe consequences, as long as there is some circulating insulin.⁶ However, if another disease develops (BOX 3), metabolic homeostasis becomes more difficult to achieve and compensatory mechanisms are quickly overwhelmed and begin to fail. A retrospective study found that of 127 dogs diagnosed with DKA, 70% had concurrent diseases, with 20% having a urinary tract infection, 15% having hyperadrenocorticism, and 6% having pneumonia.⁷

Stress, such as concurrent illness, stimulates the release of catecholamines (epinephrine and norepinephrine), cortisol, growth hormone, and glucagon.^6,8 Referred to as diabetogenic, or glucose counter-regulatory, hormones, these hormones increase blood glucose concentration through glycogenolysis, gluconeogenesis, lipolysis, and/or proteolysis (FIGURE 1). In a normal patient, these hormones help support the body during a stressful event by increasing the amount of glucose available to be converted into energy. In diabetic patients, the resulting level of hyperglycemia—added to the demands of an activated immune system and the effects of ongoing total body cell starvation, water loss, and breakdown of muscle and fat—leads to increasingly detrimental attempts to compensate.

Figure 1. Diabetogenic hormones and their effects.9 Extreme stress, including illness, causes the adrenal medulla to secrete catecholamines. Cortisol, a glucocorticoid that suppresses immune response, is secreted by the cortex of the adrenal gland during times of fasting. Growth hormone is secreted by the anterior lobe of the pituitary gland in response to stress. Glucagon is secreted by the pancreas in response to inadequate cellular energy production. In diabetic patients, the combined effect of these hormones exacerbates existing hyperglycemia and muscle and fat breakdown.

Ketone Formation and Acidemia

Lipolysis increases the level of free fatty acids, which are converted by the liver into acetyl coenzyme A (acetyl-CoA). Normally, acetyl-CoA enters the citric acid (Kreb’s) cycle to form ATP, but in diabetic patients, due to depletion of other enzymes during gluconeogenesis, it is instead converted into β-hydroxybutyrate, which is further broken down into acetoacetate and acetone.^2,8 β-Hydroxybutyrate, acetoacetate, and acetone are all ketones, which are acidic.

In DKA, the rising ketone concentration eventually leads to acidemia (lowering of pH in the blood).⁸ As ketone levels increase, the pH continues to decrease. Because cells only function within a very narrow pH range (7.35 to 7.45), the increasing acidemia can cause multiple metabolic disruptions.⁶

Hypovolemic Shock and Electrolyte Imbalances

Excretion of ketones into the urine further exacerbates osmotic diuresis. At this point, water loss dehydrates the patient to the point of hypovolemia. Hypovolemia leads to low cardiac output because stroke volume is decreased, and hypotension occurs, compromising oxygen delivery to the tissues and resulting in poor perfusion to all vital organs. The renin-angiotensin-aldosterone system is activated in an attempt to increase cardiac output by decreasing water loss and increasing systemic vascular resistance. However, the degree of continued diuresis in DKA patients overwhelms this compensatory system, resulting in hypovolemic shock.

Osmotic diuresis also causes severe electrolyte disturbances resulting from excess excretion of sodium, potassium, magnesium, and phosphorus by the kidneys into the urine. The body compensates by shifting intracellular stores into the extracellular fluid (plasma), but a total body deficit of each electrolyte remains. Sodium is particularly affected, as most sodium is stored in the extracellular fluid and has already been depleted due to water loss; therefore, hyponatremia cannot be compensated for in this way.

Presentation of Diabetic Ketoacidosis

As in normal diabetic patients, presenting complaints for patients with DKA usually include polyuria, polydipsia, polyphagia, and weight loss. Other clinical signs depend on concurrent disease(s) and may include vomiting and/or regurgitation, diarrhea, anorexia, abnormal breathing or dyspnea, stranguria, or outward signs of infection (e.g., skin, upper respiratory tract).

On physical examination, the patient may be tachycardic or bradycardic; have weak pulses, a low body temperature due to hypotension, a fever due to infection, a dull mentation, or abdominal distention secondary to concurrent diseases (e.g., hepatomegaly, pancreatitis)⁸; display Kussmaul respiration⁸; or be dyspneic, in cases of pneumonia.

Kussmaul respiration is characterized by rapid, deep breaths and is an attempt to blow off extra carbon dioxide, which is acidic, to compensate for acidemia. Mucous membranes may be pale due to peripheral vasoconstriction from hypotension or appear icteric from hepatopathy.

Most patients appear cachexic, have a poor body condition score, and have sunken eyes from muscle and fat breakdown and dehydration. Some may have the smell of acetone detectable on their breath.

Stabilization of Diabetic Ketoacidosis

Even before diagnosis, any patient presenting with severe lethargy in addition to many of the above clinical signs should have an intravenous catheter immediately placed and flow-by oxygen administered, if applicable.

After the degree of dehydration is assessed and cardiopulmonary auscultation is performed, fluid resuscitation is critical. If the degree of hypotension warrants it, sequential, small-volume boluses (5 to 10 mL/kg for cats, 10 to 20 mL/kg for dogs) should be given until the patient is normotensive; however, fluid therapy should continue. Heat support may be indicated for hypothermic patients.

Diagnostic Testing

To diagnose DKA, hyperglycemia, ketonemia or ketonuria, and acidemia must be present. Measuring ketonemia has proven to be more accurate and effective in diagnosing DKA than is assessing ketonuria.¹⁰ Obtaining a small blood sample may also be easier than collecting urine from a severely dehydrated patient.

Blood Glucose, Ketones, and pH Measurement

To measure blood glucose and ketones, cage-side glucometers and ketometers provide fairly rapid results, and each requires only a drop of blood. In patients with DKA, the blood glucose often exceeds 500 mg/dL; in many cases, it is too high to read. For the commonly used AlphaTRAK glucometer (Zoetis; zoetispetcare.com), this means the blood glucose is over 750 mg/dL.

Cutoff values for DKA on ketometers seem to vary slightly. One study found that a value > 2.4 mmol/L in cats was sufficient to diagnose DKA,¹¹ while another concluded that > 3.8 mmol/L was the best cutoff value for monitoring ketosis and ketoacidosis in dogs.¹² If a ketometer is not available, urine strips can be used to measure ketonuria; however, they are less sensitive and accurate in showing the degree of ketosis because they do not detect β-hydroxybutyrate.

Blood gas must be measured to obtain the pH status of the patient. Metabolic acidosis is a hallmark of DKA.

Complete Blood Count, Serum Biochemistry, and Electrolyte Testing

A complete blood count (CBC) and full serum biochemistry and electrolyte profile should be performed as soon as possible. The CBC may reveal hemoconcentration from dehydration; however, anemia is present in approximately 20% of patients.⁸ A blood smear may show Heinz body formation in cats, which has been correlated with the presence of β-hydroxybutyrate.³ Leukocytosis, if present, indicates inflammation or infection.

Potassium, magnesium, and phosphorus levels may initially be normal or low; however, sodium will always be low due to free water loss. Increased alanine aminotransferase, alkaline phosphatase, and total bilirubin levels may be seen due to diabetic hepatopathy, decreased hepatic perfusion, hepatic lipidosis, pancreatitis, or any combination of these.⁸ Diabetic hepatopathy and hepatic lipidosis occur due to the greatly increased mobilization of free fatty acids to the liver to be metabolized into acetyl-CoA. Decreased hepatic perfusion occurs due to hypovolemia.

Elevated kidney values (blood urea nitrogen and creatinine) may also be seen due to hypovolemia causing decreased renal perfusion (prerenal azotemia). Kidney values may be increased due to acute or chronic concurrent kidney disease. Hyperlipidemia may be seen in serum or plasma because of the increased concentration of free fatty acids in the blood and because insulin deficiency prevents activation of lipoprotein lipase, which would decrease the number of circulating triglycerides.⁸

Urine Testing

A sterile urine sample should be obtained prior to any antibiotic therapy and submitted for culture and sensitivity testing. The urine will appear very dilute, but the specific gravity may be higher than expected (1.025 to 1.035) due to the amount of glucose¹ and ketones present. A urine strip will confirm glucosuria and show ketonuria.

Imaging

Thoracic and/or abdominal radiographs should be obtained to rule out neoplasia and metastatic disease, which may alter prognosis and the owner’s desire to proceed with treatment. Pneumonia may also be confirmed. Once the patient is stable, a full abdominal ultrasound examination should be considered to assess for intra-abdominal diseases such as pancreatitis, chronic kidney disease, hepatic lipidosis, and neoplasia.

Insulin Therapy

After fluid therapy, the most important intervention in treating a patient with DKA is starting insulin treatment. Fluid therapy helps correct hypovolemia, rehydrate the patient, and dilute the concentrations of glucose and diabetogenic hormones. Insulin is necessary to metabolize ketone bodies, thereby correcting acidemia.⁸

A recent retrospective study found that starting insulin within 6 hours of presentation was associated with more rapid resolution of ketonemia and acidemia.¹³ Several methods of providing insulin have been successfully used to treat DKA, but a consensus on which is superior has yet to be established by the veterinary community; therefore, the method chosen will be the veterinarian’s preference.

Constant-Rate Infusion of Regular Insulin

Constant-rate infusion (CRI) is currently the most common method of insulin administration in patients with DKA. The benefits of using an insulin CRI are less discomfort to the patient (compared with intramuscular injections) and ease of adjustment. CRI offers the most control in stabilizing blood glucose. However, the blood glucose should ideally be monitored hourly, and adjustments might be needed every hour, which can be tedious and expensive. In addition, if the CRI is running at a high rate and there is a delay in checking blood glucose, iatrogenic hypoglycemia can result.

To set up an insulin CRI:

• Add 2.2 U/kg (dogs) or 1.1 U/kg (cats) of regular insulin into a 250-mL bag of 0.9% saline.
• “Bleed” the drip set and all connected extension lines with 50 mL of the solution because insulin binds to plastic.

The CRI is run in conjunction with crystalloid fluids, and the rate of crystalloid fluids should be adjusted depending on the insulin CRI rate, which is determined by the patient’s blood glucose (TABLE 1). For example, if a patient needs to receive 150 mL/h of fluid and the patient’s blood glucose is 570 mg/dL, the crystalloid rate should be 140 mL/h because the insulin CRI rate will be 10 mL/h. This adjustment is to avoid fluid overload, especially in cats and smaller dogs, which require much lower fluid rates.

Intermittent Injections of Glargine

One study effectively treated 15 cats with DKA by using a combination of intramuscular and subcutaneous glargine injections.¹⁴ In this study, 1 to 2 units of glargine were given intramuscularly up to every 2 hours in addition to 1 to 3 units of glargine given subcutaneously every 12 hours. There has been some apprehension in recommending this protocol because 2 of the 15 cats in the study required blood transfusions due to hypophosphatemia, but it is unknown if this was due to the protocol or to the disease process itself.¹ Additional research using this protocol is required to better evaluate its efficacy and safety.

Intermittent Injections of Regular Insulin and Glargine

Another study investigating cats with DKA found that combining intramuscular regular insulin with subcutaneous glargine resulted in more rapid resolution of ketonemia than using a regular insulin CRI.¹⁵ Regular insulin was administered at 1 unit up to every 6 hours and glargine was given at 0.25 U/kg every 12 hours. Additional research is needed, especially in dogs, to confirm this protocol’s superiority to using only regular insulin CRI.

Monitoring and Electrolyte Supplementation

Regardless of the type of insulin protocol used, the blood glucose will need to be frequently checked. Placing a central venous catheter or a sampling catheter not only allows veterinary nurses to obtain samples easily but also helps decrease patient discomfort by limiting the number of venipunctures performed. Ideally, blood glucose is checked every hour, especially if an insulin CRI is being used, so that the insulin dose can be adjusted accordingly.

Fluid therapy alone lowers blood glucose and causes some electrolytes (e.g., potassium, magnesium, phosphorus) to shift back into the intracellular space, revealing the true total body electrolyte deficit. Insulin also causes potassium and phosphorus to shift intracellularly; therefore, insulin therapy further exacerbates hypokalemia and hypophosphatemia.¹⁶ Hypokalemia can cause generalized skeletal muscle weakness, potentially leading to impaired ventilation; hypophosphatemia can cause muscle weakness, altered mental status, and hemolysis of red blood cells.¹⁶ Hypomagnesemia can cause twitching and arrhythmias. Electrolyte supplementation may therefore be needed.

Scott’s sliding scale (TABLE 2) can be used to calculate an appropriate amount of potassium supplementation, but the potassium administration rate should not exceed 0.5 mEq/kg/h (Box 4). Doses of potassium supplementation that exceed this rate can lead to iatrogenic hyperkalemia, which can cause bradycardia that can progress to death. Recommended dosing for phosphorus supplementation is variable, but most sources indicate to supplement phosphorus with potassium phosphate and base the dose on the patient’s potassium level.¹⁶ Magnesium can be supplemented at a dose of 0.7 to 1 mEq/kg/day.¹⁶

Treating Concurrent Diseases

Each patient with DKA is treated differently depending on its concurrent disease(s). Although details of individual treatment protocols are beyond the scope of this article, they may include antibiotics, antinausea medications and prokinetics, hepatic support medications, nasogastric tube placement, oxygen therapy, and nebulization treatment. Pain medications and/or anxiolytics should be considered and advocated for, as pain and anxiety induce a stress response, increasing the release of diabetogenic hormones.

Prognosis and Client Education

The goals of treatment of patients with DKA are to correct ketonemia and acidemia, restore and maintain fluid balance, and treat concurrent diseases.⁸ One study found that the degree of acidemia was associated with survival—the worse the acidemia, the poorer the outcome.⁷

Once these goals are achieved and the patient is eating, long-acting insulin can be administered. Ideally the blood glucose should be monitored for the next 12 to 24 hours to ensure correct dosage before discharge. Up to 70% of patients diagnosed with DKA survive to discharge.⁷ However, upon diagnosis of DKA, the patient’s owner needs to be informed about the financial undertaking of an extended hospitalization and that certain concurrent diseases, such as pancreatitis, can prolong the time it takes to reach recovery⁷ and increase cost. DKA is not a disease that can be treated halfway, and owners must understand the financial commitment before initiating treatment. Diabetes is also a new diagnosis for many patients with DKA³; therefore, client education about diabetes mellitus and compliance with at-home treatment are paramount for the health of the patient once discharged. Upon discharge, owners should also be advised of warning signs of general illness, as all diabetic patients are at risk of going into DKA with any additional stress. Early recognition of sickness is therefore crucial to limiting future hospitalization.

Summary

DKA is a medical emergency characterized by hyperglycemia, ketonemia, and acidemia. Concurrent illnesses make treating each patient unique, but fluid resuscitation and insulin therapy are essential to resolving hypovolemic shock and life-threatening acidemia in all patients with DKA. These patients require frequent reevaluation of hydration status and vital parameters and diligent monitoring of electrolytes and blood glucose. Because DKA is one of the most common endocrine emergencies in veterinary medicine, it is important for veterinary nurses to understand how and why this condition occurs to be better able to give excellent care to these critical patients.