Diabetic ketoacidosis

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Diabetic ketoacidosis
Classification and external resources
Dehydration may be profound in diabetic ketoacidosis, and intravenous fluids are usually needed as part of its treatment
ICD-10	E10.1-E14.1
ICD-9	250.1
DiseasesDB	3709
MedlinePlus	000320
eMedicine	med/548
MeSH	D016883

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 an absolute shortage of insulin; in response the body switches to burning fatty acids and producing acidy 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. 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]

DKA was first described in 1886; until the introduction of insulin therapy in the 1920s it was almost universally fatal.^[2] It still carries a significant mortality of up to 5%.^[1]

[edit] Signs and symptoms

The 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").^[3] The abdomen may be tender to the point that an acute abdomen may be suspected, such as acute pancreatitis, appendicitis or gastrointestinal perforation.^[3] Coffee ground vomiting (vomiting of altered blood) occurs in a minority of patients; this tends to originate from erosions of the esophagus.^[1][2] In severe DKA, there may be confusion, lethargy, stupor or even coma (a marked decrease in the level of consciousness).^[3] 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][3]

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". If Kussmaul respiration is present, this is reflected in an increased respiratory rate.^[3]

DKA most frequently occurs in those who already have diabetes. It may also be the first presentation in someone who had not previously been known to be diabetic. There is often a particular underlying problem that has led to the DKA episode. This may be intercurrent illness (pneumonia, influenza, gastroenteritis, a urinary tract infection), pregnancy, inadequate insulin administration (e.g. defective insulin pen device), myocardial infarction (heart attack), stroke or the use of cocaine. Young patients with recurrent episodes of DKA may have an underlying eating disorder, or may be using insufficient insulin for fear that it will cause weight gain.^[1][3] In 5% of cases, no cause for the DKA episode is found.^[1]

Diabetic ketoacidosis may occur in those previously known to have diabetes mellitus type 2 or in those who on further investigations turn out to have features of type 2 diabetes (e.g. obesity, strong family history); this is more common in African, African-American and Hispanic people. Their condition is then labeled "ketosis-prone type 2 diabetes".^[1][4]

[edit] Mechanism

Diabetic ketoacidosis arises because of absolute lack of insulin in the body. The lack of insulin 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) along with it in a process known as osmotic diuresis. This leads to dehydration. The absence of insulin also leads to the release of free fatty acids from adipose tissue; these are converted, again in the liver, into ketone bodies (acetoacetate and β-hydroxybutyrate). β-Hydroxybutyrate can serve as an energy source for the brain in absence of insulin-mediated glucose delivery, and is likely 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 this with the bicarbonate buffering system, but this is quickly overwhelmed and other mechanisms to compensate for the acidosis, such as hyperventilation to lower the blood carbon dioxide levels. This hyperventilation, in its extreme form, may be observed as Kussmaul respiration.^[1][3] Ketones, too, participate in osmotic diuresis and lead to further electrolyte losses.^[1]

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][2]

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 250 mg/dl or 13.8 mmol/l.^[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".^[4] 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.^[4] 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 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]

[edit] Diagnosis

Diabetic ketoacidosis may be diagnosed when the combination of hyperglycemia (high blood sugars), ketones on urinalysis and acidosis are demonstrated. Arterial blood gas measurement is usually performed to demonstrate the acidosis; this requires taking a blood sample from an artery. Subsequent measurements (to ensure treatment is effective), may be taken from a normal blood test taken from a vein, as there is little difference between the arterial and the venous pH.^[1]

In addition to the above, blood samples are usually taken to measure urea and creatinine (measures of kidney function, which may be impaired in DKA as a result of dehydration) and electrolytes. Furthermore, markers of infection (complete blood count, C-reactive protein) and acute pancreatitis (amylase and lipase) may be measured. Given the need to exclude infection, chest radiography and urinalysis are usually performed.^[1]

[edit] Criteria

Diabetic ketoacidosis is distinguished from other diabetic emergencies by the presence of large amounts of ketones in blood and urine and metabolic acidosis. Hyperosmolar hyperglycemic state (HHS, sometimes labeled hyperosmolar non-ketotic state or HONK) is much more common in type 2 diabetes and features increased plasma osmolarity (above 320 mosm/kg) due to profound dehydration and concentration of the blood; mild acidosis and ketonemia may occur in this state, but not to the extent observed in DKA. There is a degree of overlap between DKA and HHS, as in DKA the osmolarity may also be increased, but in most situations it is possible to classify a case into either DKA or HHS.^[1]

Ketoacidosis is not always the result of diabetes. It may also result from alcohol excess and from starvation; in both states the glucose level is normal or low. Metabolic acidosis may occur in diabetics for other reasons, such as poisoning with ethylene glycol or paraldehyde. Type 2 diabetics taking metformin may develop lactic acidosis as a rare side-effect of their medication.^[1]

A 2006 American Diabetes Association statement categorizes DKA into one of three stages of severity:^[1]

• Mild: blood pH mildly decreased to between 7.25 and 7.30 (normal 7.35–7.45); serum bicarbonate decreased to 15–18 mmol/l (normal above 20); the patient is alert
• Moderate: pH 7.00–7.25, bicarbonate 10–15, mild drowsiness may be present
• Severe: pH below 7.00, bicarbonate below 10, stupor or coma may occur

[edit] Treatment

The main aims in the treatment of diabetic ketoacidosis are replacing the lost fluids and electrolytes while suppressing the high blood sugars and ketone production with insulin. Admission to an intensive care unit or similar high-dependency area or ward may be necessary.^[1]

Treatment consists of hydration to lower the osmolarity of the blood, replacement of lost electrolytes, insulin to force glucose and potassium into cells, and eventually glucose simultaneously with insulin in order to correct other metabolic abnormalities, such as elevated ketone levels. Many patients require admission to a step-down unit or an intensive care unit (ICU) due to IV administration of fluids, glucose, and insulin so that vital signs, urine output, and blood tests can be monitored frequently. Brain edema is not rare during the treatment phase, it is quite dangerous, and so this may suggest intensive monitoring as well. In patients with severe alteration of mental status, intubation and mechanical ventilation may be required. Survival is largely dependent on how badly deranged the metabolism is at presentation to a hospital, but today properly treated DKA is only occasionally fatal.^{[citation needed]}

At this point the patient is urgently in need of intravenous fluids. The basic principles of DKA treatment are:

• Rapid restoration of adequate circulation and perfusion with isotonic intravenous fluids
• Gradual rehydration and restoration of depleted electrolytes (especially sodium and potassium), even if serum levels appear adequate
• Insulin to reverse ketosis and lower glucose levels
• Careful monitoring to detect and treat complications

Treatment usually results in full recovery, though death can result from inadequate treatment or a variety of complications, such as cerebral edema (occurs mainly in children).^{[citation needed]}

[edit] Epidemiology and prevention

Diabetic ketoacidosis occurs in 4.6–8.0 per 1000 type 1 diabetics annually. In the United States, 100,000 hospital admissions occur annually as a result of DKA, at an estimated cost of $1 billion or half the total cost of caring for type 1 diabetics. Since the 1980s there has been a documented increasing trend to hospital admissions. The risk is increased in those with an ongoing risk factor, such as an eating disorder, and those who cannot afford insulin.^[1]

Attacks of DKA can be prevented in known diabetics to an extent by adherence to "sick day rules"; these are clear-cut instructions to patients how to treat themselves when unwell. Instructions include advice how much extra insulin to take when sugar levels appear uncontrolled, an easily digestible diet rich in salt and carbohydrates, means to suppress fever and treat infection, and recommendations when to call for medical help (such as a diabetes specialist nurse).^[1]

[edit] History

The first full description of diabetic ketoacidosis is attributed to Julius Dreschfeld, a German pathologist working in Manchester, United Kingdom. In his description, which he gave in an 1886 lecture at the Royal College of Physicians in London, he drew on reports by Adolph Kussmaul as well as describing the main ketones, acetoacetate and β-hydroxybutyrate, and their chemical determination.^[5] The condition remained almost universally fatal until the discovery of insulin in the 1920s; by the 1930s, mortality had fallen to 29%,^[2] and by the 1950s it had become less than 10%.^[6]

Numerous research studies since the 1950s have focused on the ideal treatment for diabetic ketoacidosis. A significant proportion of these studies have been conducted at the University of Tennessee Health Science Center and Emory University School of Medicine.^[6] Treatment options studied have included high- or low-dose intravenous, subcutaneous or intramuscular (e.g. the "Alberti regime") insulin, phosphate supplementation, need for a loading dose of insulin, and appropriateness of using bicarbonate therapy in moderate DKA.^[6] Various questions remain unanswered, such as whether bicarbonate administration in severe DKA makes any real difference to the clinical course, and whether an insulin loading dose is needed in adults.^[6]

The entity of ketosis-prone type 2 diabetes was first fully described in 1987 after several preceding case reports. It was initially thought to be a form of maturity onset diabetes of the young,^[7] and went through several other descriptive names (such as "idiopathic type 1 diabetes", "Flatbush diabetes", "atypical diabetes" and "type 1.5 diabetes") before the current terminology of "ketosis-prone type 2 diabetes" was adopted.^[1][4]

[edit] References