Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in those with type 1 diabetes, but it can occur in those with type 2 diabetes under certain circumstances. DKA results from a shortage of insulin; in response the body switches to burning fatty acids and producing acidic ketone bodies that cause most of the symptoms and complications.^[1]

DKA may be the first symptom of previously undiagnosed diabetes, but it may also occur in known diabetics due to a variety of causes, such as intercurrent illness or poor compliance with insulin therapy. Vomiting, dehydration, deep gasping breathing, confusion and occasionally coma are typical symptoms. DKA is diagnosed with blood and urine tests; it is distinguished from other, rarer forms of ketoacidosis by the presence of high blood sugar levels. Treatment involves intravenous fluids to correct dehydration, insulin to suppress the production of ketone bodies, treatment for any underlying causes such as infections, and close observation to prevent and identify complications.^[1][2]

DKA is a medical emergency, and without treatment it can lead to death. DKA was first described in 1886; until the introduction of insulin therapy in the 1920s it was almost universally fatal.^[3] It now carries a mortality of less than 5% with adequate and timely treatment.^[4]

Signs and symptoms

he symptoms of an episode of diabetic ketoacidosis usually evolve over the period of about 24 hours. Predominant symptoms are nausea and vomiting, pronounced thirst, excessive urine production and abdominal pain that may be severe. Those who measure their glucose levels themselves may notice hyperglycemia (high blood sugar levels). In severe DKA, breathing becomes labored and of a deep, gasping character (a state referred to as "Kussmaul respiration").^[4] The abdomen may be tender to the point that an acute abdomen may be suspected, such as acute pancreatitis, appendicitis or gastrointestinal perforation.^[4] Coffee ground vomiting (vomiting of altered blood) occurs in a minority of patients; this tends to originate from erosion of the esophagus.^[3] In severe DKA, there may be confusion, lethargy, stupor or even coma (a marked decrease in the level of consciousness).^[4][5]

On physical examination there is usually clinical evidence of dehydration, such as a dry mouth and decreased skin turgor. If the dehydration is profound enough to cause a decrease in the circulating blood volume, tachycardia (a fast heart rate) and low blood pressure may be observed. Often, a "ketotic" odor is present, which is often described as "fruity", often compared to the smell of pear drops whose scent is a ketone. If Kussmaul respiration is present, this is reflected in an increased respiratory rate.^[4]

Small children with DKA are relatively prone to cerebral edema (swelling of the brain tissue), which may cause headache, coma, loss of the pupillary light reflex, and progress to death. It occurs in 0.7–1.0% of children with DKA, and has been described in young adults, but is overall very rare in adults.^[1][4][6] It carries a 20–50% mortality.^[7]

Mechanism

Diabetic ketoacidosis arises because of a lack of insulin in the body. The lack of insulin and corresponding elevation of glucagon leads to increased release of glucose by the liver (a process that is normally suppressed by insulin) from glycogen and through gluconeogenesis. High glucose levels spill over into the urine, taking water and solutes (such as sodium and potassium) along with it in a process known as osmotic diuresis. Ketones, too, participate in osmotic diuresis and lead to further electrolyte losses.^[1] This leads to polyuria, dehydration, and compensatory thirst and polydipsia. The absence of insulin also leads to the release of free fatty acids from adipose tissue, which are converted, again in the liver, into ketone bodies (acetoacetate and β-hydroxybutyrate). β-Hydroxybutyrate can serve as an energy source in absence of insulin-mediated glucose delivery, and is a protective mechanism in case of starvation. The ketone bodies, however, have a low pH and therefore turn the blood acidic (metabolic acidosis). The body initially buffers the change with the bicarbonate buffering system, but this system is quickly overwhelmed and other mechanisms must work to compensate for the acidosis. One such mechanism is hyperventilation to lower the blood carbon dioxide levels (a form of compensatory respiratory alkalosis). This hyperventilation, in its extreme form, may be observed as Kussmaul respiration.^[1][4]

In various situations such as infection, insulin demands rise but are not matched by the failing pancreas. Blood sugars rise, dehydration ensues, and resistance to the normal effects of insulin increases further by way of a vicious circle.^[1][3]

As a result of the above mechanisms, the average adult DKA patient has a total body water shortage of about 6 liters (or 100 mL/kg), in addition to substantial shortages in sodium, potassium, chloride, phosphate, magnesium and calcium. Glucose levels usually exceed 13.8 mmol/L or 250 mg/dL^[1]

β-hydroxybutyrate, despite chemically not actually being a ketone, is the principal "ketone body" in diabetic ketoacidosis.

DKA is common in type 1 diabetes as this form of diabetes is associated with an absolute lack of insulin production by the islets of Langerhans. In type 2 diabetes, insulin production is present but is insufficient to meet the body's requirements as a result of end-organ insulin resistance. Usually, these amounts of insulin are sufficient to suppress ketogenesis. If DKA occurs in type 2 diabetics, their condition is called "ketosis-prone type 2 diabetes".^[8] The exact mechanism for this phenomenon is unclear, but it appears that very high levels of glucose suppress the release of insulin from the pancreas through "glucotoxicity", leading to levels that are insufficient to suppress ketogenesis.^[1] Furthermore, insulin resistance may be so severe that ketogenesis cannot be suppressed.^[8] Once the condition has been treated, insulin production resumes and often the patient may be able to resume diet or tablet treatment like other type 2 diabetics. Nevertheless, a small proportion of this population has detectable antibodies against islets of Langerhans, and could therefore be regarded as having a form of type 1 diabetes.^[1]

The clinical state of DKA is associated, in addition to the above, with the release of various counterregulatory hormones such as glucagon and adrenaline as well as cytokines, the latter of which leads to increased markers of inflammation, even in the absence of infection.^[1][2]

Cerebral edema, which is the most dangerous DKA complication, is probably the result of a number of factors. Some authorities maintain that it is the result from overvigorous fluid replacement, but the complication may develop before treatment has been commenced.^[6][7] It is more likely in those with more severe DKA,^[2][6] Likely factors in the development of cerebral edema are dehydration, acidosis and low carbon dioxide levels; in addition, the increased level of inflammation and coagulation may, together with these factors, lead to decreased blood flow to parts of the brain, which then swells up once fluid replacement has been commenced.^[6] The swelling of brain tissue leads to raised intracranial pressure^[2][7] and in the first episode of DKA. ultimately leading to death.