Canine diabetic ketoacidosis

Introduction

Diabetes mellitus (DM) is characterized by the body’s inability to utilize glucose, leading to cellular starvation and clinicopathological abnormalities. This may be secondary to lack of insulin secretion (DM type 1) or insulin resistance (DM type 2). DM type 1 is the more common scenario in dogs; its pathogenesis seems multifactorial, involving genetic predisposition, autoimmune mechanisms, environmental factors and concomitant insulin-resistant diseases 1.

When these mechanisms are exacerbated, severe hyperglycemia, ketonemia, electrolyte and acid-base balance abnormalities develop, causing a condition known as diabetic ketoacidosis (DKA). This, and hyperglycemic hyperosmolar syndrome (HHS), are complicated forms of DM, and are both diabetic emergencies, but they have different characteristics, underlying comorbidities and management. This article will focus on DKA in dogs, discussing its diagnosis, treatment and complications.

From diabetes to DKA

When glucose is unable to enter body tissues, cellular starvation and extra-cellular hyperglycemia develop; this is worsened by increased gluconeogenesis and glycogenolysis. In time, blood glucose (BG) can reach the renal threshold (180-220 mg/dL, 10.0-12.2 mmol/L), leading to glycosuria with subsequent fluid and electrolyte losses due to osmotic diuresis. As a consequence of the inefficient glucose utilization, cells use alternative energy pathways, mainly lipolysis (Figure 1). The hormone-sensitive lipase stimulates hydrolysis of triglycerides into free fatty acids (FFA); these in turn undergo beta-oxidation in hepatocyte mitochondria into acetyl coenzyme A (Acetyl-CoA). In the presence of oxaloacetate, Acetyl-CoA can enter the Krebs cycle and produce energy, but during DKA oxaloacetate is preferentially directed toward gluconeogenesis; therefore, especially when Acetyl-CoA production is excessive, it accumulates and combines to form ketone bodies (KBs): acetoacetate (AcAc), beta-hydroxybutyrate (BHB), and acetone 2,3.

In small amounts, KBs are an important energy source, but an excess can be detrimental; as strong acids, their dissociation leads to metabolic acidosis. In order to maintain serum electrical neutrality, negatively charged KBs are excreted in the kidneys along with positive ions, causing osmotic diuresis and electrolyte deficiencies. Excessive KB production and severe hyperglycemia are further promoted by the insulin-resistance action of so-called counter-regulatory hormones (glucagon, cortisol, growth hormone, adrenaline), which increase with stressful conditions and comorbidities. They further stimulate gluconeogenesis, lipolysis and glycogenolysis 2,3. Moreover, hyperglycemia itself is recognized as a pro-inflammatory state that promotes cytokine release and development of reactive oxygen species, further promoting insulin resistance 4.

DKA diagnosis

The DKA acronym acts as a reminder that the condition is characterized by hyperglycemia (D) (as in diabetes mellitus), ketonemia/ketonuria (K), and metabolic acidosis (A) 2,5. DKA patients may present with a previous DM diagnosis, or a history consistent with DM (polyuria, polydipsia, polyphagia, weight loss) as well as signs indicative of an underlying pathology or DM decompensation (vomiting, anorexia, lethargy, hematuria). DKA is more common in middle-aged and older dogs, and some breed predisposition is reported 1,6.

Clinical findings may include dehydration, hypovolemic shock, abnormal respiratory rate or effort (from acidosis or lung pathology), abdominal pain, acetone breath, lethargy (or more severe neurologic deficits), or signs of other comorbidities (e.g., dermatitis, alopecia, otitis) 6. If history and physical examination are indicative of decompensated DM, a minimum database evaluating BG, electrolytes, acid-base balance and ketonemia/ketonuria is essential (Figure 2).

D. Persistent fasting hyperglycemia is characteristic of DM (normal BG: 80-120 mg/dL, 4.4-6.6 mmol/L). This can be rapidly measured via a validated point-of-care (POC) glucometer. If the glucose value is above the instrumental threshold, blood gas analysis or sample dilution should be considered. When whole blood is used for analysis, the patient’s packed cell volume needs to be taken in consideration, as POC glucometers are inaccurate in hemodiluted and hemoconcentrated samples 7.

K. Ketonemia and ketonuria are indicative of an excessive KB production and therefore negative energy balance. KBs can be measured via a POC ketonometer or nitroprusside-reactive urine dipsticks (using either plasma or urine, plasma being considered more sensitive). The dipstick is a semi-quantitative test based on visual interpretation, and with a high risk of both false positive and negative results. Dipsticks primarily measure AcAc, so this may result in an underestimate of ketosis, as AcAc is less abundant than BHB in DKA. Furthermore, detection of DKA resolution is delayed using a urine dipstick because insulin promotes BHB conversion back to AcAc, such that a dipstick reading may still suggest high levels of KBs 3,8,9. Ketosis (BHB concentration > 0.1 mmol/L) may also develop with acute pancreatitis, starvation, low-carbohydrate diets, fever and pregnancy, but a BHB concentration above 3.5 mmol/L is suggestive of DKA, whereas with a value below 2.8 mmol/L DKA is considered unlikely 9.

A. Metabolic acidosis (pH < 7.3, bicarbonate < 15 mmol/L) in DKA is mainly secondary to KB accumulation, hypovolemia (lactic acidosis, volume-responsive azotemia), hyperchloremia and uremia. KB (unmeasured anions) accumulation causes a high anion gap (AG) acidosis (normal AG: 12-24 mEq/L).

This last letter of the DKA acronym can also be an aide memoire for the other two main “abnormalities” of these patients: electrolyte and osmolarity imbalances, as discussed below.

Up to 70% of DKA patients are in a state of decompensated DM because of concomitant pathologies responsible for increased insulin resistance – common comorbidities are acute pancreatitis, bacterial urinary tract infection and hyperadrenocorticism. Glucocorticoid use, bacterial pneumonia, uterine pathology, dermatitis, chronic kidney disease, pyelonephritis, diestrus and neoplasia have also been reported 6,8,9. Therefore, once the patient is stable, further investigations (e.g., hematology, biochemistry, urine analysis with culture, pancreatic lipase serology, endocrine tests, imaging) are necessary in order to identify possible triggers. Impaired neutrophil adhesion, chemotaxis, phagocytosis and bactericidal activity may explain the higher predisposition of DM patients to secondary infection 10.

Electrolytes and DKA

The main electrolyte imbalances in DKA involve potassium, sodium, phosphate and magnesium 6,9.

Potassium

Total body potassium is generally depleted in DKA, but levels can vary between patients, and although not as frequent as in human medicine, hyperkalemia can be present. This can be a consequence of dehydration and/or hypovolemia, hyperosmolarity, hypoinsulinemia (potassium, like glucose, relies on insulin-dependent transporters to move intracellularly) or acidemia (as hydrogen ions move into the cells, potassium moves out to maintain cellular electronegativity). After insulin treatment (potassium shift) and fluid therapy (dilutional effect, acidosis correction) true hypokalemia becomes evident. When potassium accumulates extracellularly, it can be easily lost as a consequence of osmotic diuresis. Hypokalemia may also be exacerbated by reduced food intake, vomiting and diarrhea. Muscular weakness, arrhythmias, gastrointestinal stasis, poor renal water retention, and respiratory failure may all develop secondary to hypokalemia 2,11.

Phosphate

Total body phosphate is also reduced by previously discussed mechanisms, with insulin and fluid therapy further exacerbating the situation. Hypophosphatemia can cause hemolysis, neurological signs, muscle weakness and rhabdomyolysis 2,11.

Magnesium

Hypomagnesemia is a common finding in human DKA patients, and whilst a high prevalence of hypomagnesemia has been reported in critically ill dogs, it was not a common finding in the subpopulation of dogs with DKA 6,12. Magnesium is an essential cofactor in energy production pathways; hypomagnesemia is linked to cardiovascular, immunological, neurological and platelet dysfunction, refractory hypokalemia and hypocalcemia. Moreover, hypomagnesemia is associated with insulin resistance and poor glycemic control, while magnesium supplementation improves insulin sensitivity 11.

Sodium and osmolality

In DKA, hyperglycemia is the main contributor for dysnatremia. In biological fluids, glucose and sodium are defined as effective osmoles, as they have the ability to move water in relation to their concentration through a semi-permeable barrier (effective osmolality). Their importance is highlighted by the effective osmolality formula (Table 1). In dogs, hyperosmolality is defined as an effective osmolality above 330 mOsm/kg (normal: 290-310 mOsm/Kg) 2,13. In DKA, glucose accumulates in the extracellular space and, as an effective osmole, is able to pull water from cells into the extracellular space, resulting in cellular dehydration and dilutional hyponatremia, with the main effects occurring in the brain. It is the sodium concentration (total body sodium content relative to extracellular water) rather than the total sodium content that decreases. In addition, osmotic diuresis, ketonuria and gastrointestinal losses may also contribute to dysnatremia, making the real sodium content difficult to estimate.

Blood gas analyzers yield the sodium concentration, which is misleading in DKA patients. Mathematical formulae have therefore been extrapolated in order to estimate the patient-corrected sodium in a normoglycemic state, adjusting for the effect of fluid shift caused by hyperglycemia. These formulae establish that for every 100 mg/dL (5.5 mmol/L) increase in BG, there is an average decrease in serum sodium (by dilution) of 2.4 mmol/L; this correlation is not linear, so alternatively, a correction factor of 1.6 can be used for BG up to 400 mg/dL (22 mmol/L) and a factor of 4 for BG above 400 mg/dL 14.

Dysnatremia and hyperosmolarity can produce neurologic signs, which can occur at presentation or after treatment. Cerebral edema is a rare complication in veterinary medicine and its pathogenesis is unclear; although BG, sodium and osmolality may play a role, ischemic-reperfusion injury, inflammation and increase vascular permeability seem to be the main contributing factors 13,15.

Table 1. Useful formulae 2,11.

Treatment: from DKA to DM

Insulin is obviously an essential treatment in diabetic patients, but correct management of electrolyte and acid-base imbalances is equally important, and treatment must be tailored to the individual patient (Box 1).

Fluid therapy

DKA patients normally require fluid therapy due to fluid losses secondary to osmotic diuresis, hypoinsulinemia, vomiting, diarrhea, reduced fluid intake and co-morbidities. The severity of fluid loss is variable; if the patient is volume-depleted and hemodynamically unstable, fluid resuscitation is required. If pathologies that predispose to fluid intolerance can be excluded, one or more boluses of 10-20 mL/kg over 15-20 minutes of an isotonic crystalloid are advised, guided by resuscitation endpoints. Once effective circulating volume is restored, the aim is to correct dehydration (over 6-24 hours) and to provide fluids for maintenance (increased because of osmotic diuresis) and ongoing losses. Frequent reassessment (every 4-6 hours) of losses, and any evidence of fluid deficit or overload, such as changes in bodyweight, is important in order to modify the fluid plan 11.

Fluid therapy improves acidemia, hyperglycemia and ketonemia through dilution, improved glomerular filtration rate, increased blood flow and reduction of counter-regulatory hormones. Due to their ability to rehydrate interstitial and intracellular space, isotonic crystalloids are considered a good choice for DKA patients, however no clinical trials have yet indicated whether balanced isotonic crystalloids (such as Lactated Ringers) are superior to 0.9% saline 2. Chloride-rich fluids can cause hyperchloremic metabolic acidosis, which may worsen or delay acidemia resolution; in addition, some studies report an association between hyperchloremia and renal vasoconstriction that may translate into acute kidney injury 16. Correcting hyperglycemia along with natremia without significant changes in osmolarity is another important aim of the fluid therapy plan, and reduces the risk of cerebral edema and neurological deficits 13,15. Human studies lack good quality evidence to suggest a superiority amongst crystalloids in DKA treatment. However, due to the beneficial effects of buffered crystalloid vs. 0.9% saline in critically ill patients, alongside some evidence of a more rapid resolution of ketoacidosis in DKA, buffered solutions are now increasingly recommended as a first-line DKA replacement fluid 16,17.

Bicarbonate

Bicarbonate supplementation is controversial. Although it can transiently improve acidosis in DKA, most studies do not report improvements in outcome. As there is a lack of studies evaluating bicarbonate supplementation in human patients with pH < 6.9, several human guidelines consider its supplementation (over 2 hours, alongside potassium supplementation) in this subpopulation with a pH of 7 as the end-goal. However, other sources advise bicarbonate use only in case of persistent acidosis requiring inotropes 5,18.

A study of dogs with DKA found an association between bicarbonate supplementation and worse outcome, although an association between acidosis and worse outcome was also present 6. Bicarbonate replacement, especially in hypoventilating patients, is related to several complications: worsening hypokalemia and hypocalcemia, risk of volume overload, cerebral paradoxical acidosis, hyperosmolarity, right shift of oxyhemoglobin curve, cerebral edema and worsening of ketonemia (mainly via increased AcAc levels for augmented hepatic ketogenesis) 17.

In summary, because of the risks associated with its supplementation and the lack of benefits in this population, bicarbonate is rarely given.

Electrolyte supplementation

Total body electrolyte depletion, worsened by insulin treatment, is common in DKA. Therefore prior to starting insulin, these deficiencies should be corrected (Table 2). Initially, electrolytes are monitored every 4-6 hours, however when values improve, intervals can be increased.

If hypokalemia is present, potassium supplementation via constant rate infusion (CRI) should be started with a maximum rate of 0.5 mEq/kg/h. Higher rates (with electrocardiography monitoring) may be indicated for severe hypokalemia, however evidence for this is scarce and it is rarely advised due to possible serious adverse effects. If hyperkalemia is present, potassium supplementation should be withheld until reassessment. A minimal supplementation is recommended if the patient is normokalemic 2,5,11,18.

Routine phosphate supplementation has not been shown to improve outcome in human DKA patients, and guidelines advise it should only be done with severe hypophosphatemia 11,17. This requires CRI of sodium or potassium phosphate; the amount of potassium present in the latter needs to be considered alongside potassium supplementation. Note phosphate is incompatible with Lactated Ringer’s solution. Magnesium supplementation, as magnesium sulphate or chloride, should be considered in cases of refractory hypokalemia.

Table 2. Electrolyte supplementation based on 11.

Insulin therapy

Insulin is essential to decrease gluconeogenesis, improve glucose utilization and to both reduce KB production and increase KB metabolism. In reducing hyperglycemia (and therefore osmolality), insulin promotes fluid shift from the extra to intracellular space, worsening hypovolemia. It also causes electrolyte shifts, unmasking deficiencies, therefore insulin is started once these electrolyte deficiencies (particularly hypokalemia) and hypovolemia are corrected. Fluid therapy itself improves hyperglycemia, therefore starting insulin too soon may cause a rapid decline in BG. Human guidelines advise initiation of insulin therapy after at least an hour of fluid therapy, and with a potassium value of at least 3.3-3.5 mEq/L 5,18. A veterinary study showed that starting insulin within 6 hours of hospital admission reduces time for DKA resolution (based on ketonuria) and does not increase the complication rate 19. Although this study did not analyze outcome and complications in the 1-6-hour timeframe, it may be acceptable to start insulin sooner than previously believed, but certainly only when the patient is fluid-resuscitated and the main electrolyte abnormalities are improved, as per human guidelines.

A CRI of regular (short-acting) insulin is advised because of its rapid onset, short half-life and easy titration. Low doses are preferred, with an initial rate of 0.1 IU/kg/h 5,11. However, intermittent intramuscular (IM) protocols may be considered, especially for uncomplicated cases with financial restrictions 20 (Table 3). As an alternative to regular insulin, other type of short-acting insulins (lispro, insulin aspart) have been evaluated with promising results 21,22. Some human studies advise co-administration of long-acting subcutaneous insulin alongside regular insulin CRI in order to reduce insulin requirements and accelerate ketoacidosis resolution; it will also help avoid rebound hyperglycemia once regular insulin is stopped 23.

BG should be monitored every 1-2 hours during the IV protocol and initially hourly for the IM protocol. BG should drop by 50-75 mg/dL/h (3-4 mmol/L/h); human guidelines suggest to increase the insulin rate hourly by 1U if this goal is not achieved. Once BG reaches 200 mg/dL (11.1 mmol/L) insulin should be reduced and dextrose supplementation added (Table 3). The goal is to maintain BG between 150-200 mg/dL (8-25 mmol/L), avoiding hypoglycemia but continuing insulin until ketosis resolution 5,11. If the measured sodium does not increase concomitant with BG decline, fluid therapy needs to be modulated in order to reduce the risk for cerebral edema 15.

Once ketoacidosis is resolved (AG < 10-12 mEq/L, BHB < 0.6 mmol/L, pH > 7.3), glucose levels are well controlled, and patient is eating (or would eat at home) and drinking, long-acting insulin is started. This has a delayed onset, therefore an overlap between the two protocols is necessary to avoid rebound hyperglycemia. Porcine lente (intermediate-acting) insulin, at a starting dose of 0.25 IU/kg every 12 hours, is the gold standard for dogs; it has an onset of action of about 3 hours, with a nadir at 4-8 hours 24.

Table 3. Insulin protocols. 

Monitoring and supportive care

Monitoring and treatment are intrinsically linked in managing DKA cases; frequent blood samples to assess BG, electrolytes and acid-base balance are necessary, so once the patient is hemodynamically stable, a central venous catheter is advisable. This reduces patient stress, allows for longer dwell time and safer administration of high osmolarity fluids.

Another useful tool, especially if a central line is contraindicated, is to use one of the continuous (flash) glucose monitoring devices which are now widely available (Figure 3). These are small sensors that allow continuous monitoring via a subcutaneous filament that measures glucose levels in the interstitial fluid. They reduce patient stress, nurse workload and provide continuous glucose reading, although they seem less accurate in dehydrated patients 25.

The presence of ketosis, free fatty acids (FFA), abdominal pain, nausea or vomiting may cause reduced oral intake in DKA. After 3 days of anorexia, if the patient is hydrated, hemodynamically stable, with corrected electrolyte and acid-base imbalances, enteral or parenteral nutrition (the first being considered more physiological and safer) is advised. Early enteral nutrition is associated with a better outcome in critically ill patients, and a human study showed shorter hospitalization in DKA patients in which enteral nutrition was started within 24 hours from hospital admission 26. If short-term nutritional support is expected, naso-esophageal or naso-gastric feeding tubes are chosen (Figure 4). Although diabetic diets have high levels of fiber and complex carbohydrates, during DKA the main goal is to provide a good quality diet, and concomitant pathology requirements should be considered. As long as anorexia has not been prolonged, nutrition should start at 25-33% of resting energy requirements, with a gradual increase every 12-24h, taking into account the patient’s tolerance to nutrition 11.

Conclusion

70% of dogs treated for DKA are successfully discharged, with a median of 6 days of hospitalization. Complications include hypoglycemia, hypokalemia, hyperglycemia and (rarely) cerebral edema, and in addition, severe acidosis, pancreatitis or hyperadrenocorticism are associated with a worse outcome. It is therefore essential for the successful management of DKA patients to include strict monitoring of blood glucose, electrolyte and acid-base imbalances, together with diagnosis of comorbidities and a personalized treatment plan.