Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is an acute, major, life-threatening complication of diabetes. DKA mainly occurs in patients with type 1 diabetes, but it is not uncommon in some patients with type 2 diabetes.
DKA is a state of absolute or relative insulin deficiency aggravated by ensuing hyperglycemia, dehydration, and acidosis-producing derangements in intermediary metabolism. The most common causes are underlying infection, disruption of insulin treatment, and new onset of diabetes.
DKA is defined clinically as an acute state of severe uncontrolled diabetes associated with ketoacidosis that requires emergency treatment with insulin and intravenous fluids.
Biochemically, DKA is defined as an increase in the serum concentration of ketones greater than 5 mEq/L, a blood glucose level greater than 250 mg/dL (although it is usually much higher), and a blood (usually arterial) pH less than 7.3. Ketonemia and ketonuria are characteristic, as is a serum bicarbonate level of 18 mEq/L or less (< 5 mEq/L is indicative of severe DKA)
If you're diagnosed with diabetic ketoacidosis, you may be treated in the emergency room or admitted to the hospital. Treatment is usually a three-pronged approach:
DKA is a state of absolute or relative insulin deficiency aggravated by ensuing hyperglycemia, dehydration, and acidosis-producing derangements in intermediary metabolism. The most common causes are underlying infection, disruption of insulin treatment, and new onset of diabetes.
DKA is defined clinically as an acute state of severe uncontrolled diabetes associated with ketoacidosis that requires emergency treatment with insulin and intravenous fluids.
Biochemically, DKA is defined as an increase in the serum concentration of ketones greater than 5 mEq/L, a blood glucose level greater than 250 mg/dL (although it is usually much higher), and a blood (usually arterial) pH less than 7.3. Ketonemia and ketonuria are characteristic, as is a serum bicarbonate level of 18 mEq/L or less (< 5 mEq/L is indicative of severe DKA)
If you're diagnosed with diabetic ketoacidosis, you may be treated in the emergency room or admitted to the hospital. Treatment is usually a three-pronged approach:
- Fluid replacement. You'll receive fluids — either orally or through a vein (intravenously) — until you're rehydrated. The fluids will replace those you've lost through excessive urination, as well as help dilute the excess sugar in your blood.
- Electrolyte replacement. Electrolytes are minerals in your blood that carry an electric charge, such as sodium, potassium and chloride. The absence of insulin can lower the level of several electrolytes in your blood. You'll receive electrolytes through your veins to help keep your heart, muscles and nerve cells functioning normally.
- Insulin therapy. Insulin reverses the processes that cause diabetic ketoacidosis. Along with fluids and electrolytes, you'll receive insulin therapy — usually through a vein. When your blood sugar level falls below 240 mg/dL (13.3 mmol/L) and your blood is no longer acidic, you may be able to stop intravenous insulin therapy and resume your normal insulin therapy.
Pathophysiology
Diabetic ketoacidosis (DKA) is a complex disordered metabolic state characterized by hyperglycemia, ketoacidosis, and ketonuria. DKA usually occurs as a consequence of absolute or relative insulin deficiency that is accompanied by an increase in counter-regulatory hormones (ie, glucagon, cortisol, growth hormone, epinephrine). This type of hormonal imbalance enhances hepatic gluconeogenesis, glycogenolysis, and lipolysis.
Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia, while lipolysis increases serum free fatty acids. Hepatic metabolism of free fatty acids as an alternative energy source (ie, ketogenesis) results in accumulation of acidic intermediate and end metabolites (ie, ketones, ketoacids). Ketones include acetone, beta-hydroxybutyrate, and acetoacetate.
Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia, while lipolysis increases serum free fatty acids. Ketone bodies are produced from acetyl coenzyme A mainly in the mitochondria within hepatocytes when carbohydrate utilization is impaired because of relative or absolute insulin deficiency, such that energy must be obtained from fatty acid metabolism. High levels of acetyl coenzyme A present in the cell inhibit the pyruvate dehydrogenase complex, but pyruvate carboxylase is activated.
Thus, the oxaloacetate generated enters gluconeogenesis rather than the citric acid cycle, as the latter is also inhibited by the elevated level of nicotinamide adenine dinucleotide (NADH) resulting from excessive beta-oxidation of fatty acids, another consequence of insulin resistance/insulin deficiency. The excess acetyl coenzyme A is therefore rerouted to ketogenesis. Ketones include acetone, beta-hydroxybutyrate, and acetoacetate.
Progressive rise of blood concentration of these acidic organic substances initially leads to a state of ketonemia, although extracellular and intracellular body buffers can limit ketonemia in its early stages, as reflected by a normal arterial pH associated with a base deficit and a mild anion gap.
When the accumulated ketones exceed the body's capacity to extract them, they overflow into urine (ie, ketonuria). If the situation is not treated promptly, a greater accumulation of organic acids leads to frank clinical metabolic acidosis (ie, ketoacidosis), with a drop in pH and bicarbonate[1] serum levels. Respiratory compensation for this acidotic condition results in rapid shallow breathing (Kussmaul respirations).
Ketones─in particular, beta-hydroxybutyrate─induce nausea and vomiting that consequently aggravate fluid and electrolyte loss already existing in DKA. Moreover, acetone produces the fruity breath odor that is characteristic of ketotic patients.
Hyperglycemia, osmotic diuresis, serum hyperosmolarity, and metabolic acidosis result in severe electrolyte disturbances. The most characteristic disturbance is total body potassium loss. This loss is not mirrored in serum potassium levels, which may be low, within the reference range, or even high.
Potassium loss is caused by a shift of potassium from the intracellular to the extracellular space in an exchange with hydrogen ions that accumulate extracellularly in acidosis. Much of the shifted extracellular potassium is lost in urine because of osmotic diuresis.
Patients with initial hypokalemia are considered to have severe and serious total body potassium depletion. High serum osmolarity also drives water from intracellular to extracellular space, causing dilutional hyponatremia. Sodium also is lost in the urine during the osmotic diuresis.
Typical overall electrolyte loss includes 200-500 mEq/L of potassium, 300-700 mEq/L of sodium, and 350-500 mEq/L of chloride. The combined effects of serum hyperosmolarity, dehydration, and acidosis result in increased osmolarity in brain cells that clinically manifests as an alteration in the level of consciousness.
Many of the underlying pathophysiologic disturbances in DKA are directly measurable by the clinician and need to be monitored throughout the course of treatment. Close attention to clinical laboratory data allows for tracking of the underlying acidosis and hyperglycemia, as well as prevention of common potentially lethal complications such as hypoglycemia, hyponatremia, and hypokalemia.
Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia, while lipolysis increases serum free fatty acids. Hepatic metabolism of free fatty acids as an alternative energy source (ie, ketogenesis) results in accumulation of acidic intermediate and end metabolites (ie, ketones, ketoacids). Ketones include acetone, beta-hydroxybutyrate, and acetoacetate.
Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia, while lipolysis increases serum free fatty acids. Ketone bodies are produced from acetyl coenzyme A mainly in the mitochondria within hepatocytes when carbohydrate utilization is impaired because of relative or absolute insulin deficiency, such that energy must be obtained from fatty acid metabolism. High levels of acetyl coenzyme A present in the cell inhibit the pyruvate dehydrogenase complex, but pyruvate carboxylase is activated.
Thus, the oxaloacetate generated enters gluconeogenesis rather than the citric acid cycle, as the latter is also inhibited by the elevated level of nicotinamide adenine dinucleotide (NADH) resulting from excessive beta-oxidation of fatty acids, another consequence of insulin resistance/insulin deficiency. The excess acetyl coenzyme A is therefore rerouted to ketogenesis. Ketones include acetone, beta-hydroxybutyrate, and acetoacetate.
Progressive rise of blood concentration of these acidic organic substances initially leads to a state of ketonemia, although extracellular and intracellular body buffers can limit ketonemia in its early stages, as reflected by a normal arterial pH associated with a base deficit and a mild anion gap.
When the accumulated ketones exceed the body's capacity to extract them, they overflow into urine (ie, ketonuria). If the situation is not treated promptly, a greater accumulation of organic acids leads to frank clinical metabolic acidosis (ie, ketoacidosis), with a drop in pH and bicarbonate[1] serum levels. Respiratory compensation for this acidotic condition results in rapid shallow breathing (Kussmaul respirations).
Ketones─in particular, beta-hydroxybutyrate─induce nausea and vomiting that consequently aggravate fluid and electrolyte loss already existing in DKA. Moreover, acetone produces the fruity breath odor that is characteristic of ketotic patients.
Hyperglycemia, osmotic diuresis, serum hyperosmolarity, and metabolic acidosis result in severe electrolyte disturbances. The most characteristic disturbance is total body potassium loss. This loss is not mirrored in serum potassium levels, which may be low, within the reference range, or even high.
Potassium loss is caused by a shift of potassium from the intracellular to the extracellular space in an exchange with hydrogen ions that accumulate extracellularly in acidosis. Much of the shifted extracellular potassium is lost in urine because of osmotic diuresis.
Patients with initial hypokalemia are considered to have severe and serious total body potassium depletion. High serum osmolarity also drives water from intracellular to extracellular space, causing dilutional hyponatremia. Sodium also is lost in the urine during the osmotic diuresis.
Typical overall electrolyte loss includes 200-500 mEq/L of potassium, 300-700 mEq/L of sodium, and 350-500 mEq/L of chloride. The combined effects of serum hyperosmolarity, dehydration, and acidosis result in increased osmolarity in brain cells that clinically manifests as an alteration in the level of consciousness.
Many of the underlying pathophysiologic disturbances in DKA are directly measurable by the clinician and need to be monitored throughout the course of treatment. Close attention to clinical laboratory data allows for tracking of the underlying acidosis and hyperglycemia, as well as prevention of common potentially lethal complications such as hypoglycemia, hyponatremia, and hypokalemia.
Hypoglycemia
The absence of insulin, the primary anabolic hormone, means that tissues such as muscle, fat, and liver do not take up glucose. Counterregulatory hormones, such as glucagon, growth hormone, and catecholamines, enhance triglyceride breakdown into free fatty acids and gluconeogenesis, which is the main cause for the elevation in serum glucose level in DKA. Beta-oxidation of these free fatty acids leads to increased formation of ketone bodies.
Overall, metabolism in DKA shifts from the normal fed state characterized by carbohydrate metabolism to a fasting state characterized by fat metabolism.
Secondary consequences of the primary metabolic derangements in DKA include an ensuing metabolic acidosis as the ketone bodies produced by beta-oxidation of free fatty acids deplete extracellular and cellular acid buffers. The hyperglycemia-induced osmotic diuresis depletes sodium, potassium, phosphates, and water, as well as ketones and glucose.
Hyperglycemia usually exceeds the renal threshold of glucose absorption and results in significant glycosuria. Consequently, water loss in the urine is increased due to osmotic diuresis induced by glycosuria. This incidence of increased water loss results in severe dehydration, thirst, tissue hypoperfusion, and, possibly, lactic acidosis.
Patients often are profoundly dehydrated and have a significantly depleted potassium level (as high as 5 mEq/kg body weight). A normal or even elevated serum potassium concentration may be seen due to the extracellular shift of potassium in acidotic conditions, and this very poorly reflects the patient's total potassium stores. The serum potassium concentration can drop precipitously once insulin treatment is started, so great care must be taken to repeatedly monitor serum levels. Urinary loss of ketoanions with brisk diuresis and intact renal function also may lead to a component of hyperchloremic metabolic acidosis.
Overall, metabolism in DKA shifts from the normal fed state characterized by carbohydrate metabolism to a fasting state characterized by fat metabolism.
Secondary consequences of the primary metabolic derangements in DKA include an ensuing metabolic acidosis as the ketone bodies produced by beta-oxidation of free fatty acids deplete extracellular and cellular acid buffers. The hyperglycemia-induced osmotic diuresis depletes sodium, potassium, phosphates, and water, as well as ketones and glucose.
Hyperglycemia usually exceeds the renal threshold of glucose absorption and results in significant glycosuria. Consequently, water loss in the urine is increased due to osmotic diuresis induced by glycosuria. This incidence of increased water loss results in severe dehydration, thirst, tissue hypoperfusion, and, possibly, lactic acidosis.
Dehydration and electrolyte loss
Typical free water loss in DKA is approximately 6 liters or nearly 100 mL/kg of body weight. The initial half of this amount is derived from intracellular fluid and precedes signs of dehydration, while the other half is from extracellular fluid and is responsible for signs of dehydration.Patients often are profoundly dehydrated and have a significantly depleted potassium level (as high as 5 mEq/kg body weight). A normal or even elevated serum potassium concentration may be seen due to the extracellular shift of potassium in acidotic conditions, and this very poorly reflects the patient's total potassium stores. The serum potassium concentration can drop precipitously once insulin treatment is started, so great care must be taken to repeatedly monitor serum levels. Urinary loss of ketoanions with brisk diuresis and intact renal function also may lead to a component of hyperchloremic metabolic acidosis.
Etiology
The most common scenarios for diabetic ketoacidosis (DKA) are underlying or concomitant infection (40%), missed insulin treatments (25%), and newly diagnosed, previously unknown diabetes (15%). Other associated causes make up roughly 20% in the various scenarios.
Causes of DKA in type 1 diabetes mellitus include the following:
Causes of DKA in type 1 diabetes mellitus include the following:
- In 25% of patients, DKA is present at diagnosis of type 1 diabetes due to acute insulin deficiency (occurs in 25% of patients)
- Poor compliance with insulin through the omission of insulin injections, due to lack of patient/guardian education or as a result of psychological stress, particularly in adolescents
- Bacterial infection and intercurrent illness (eg, urinary tract infection [UTI], vomiting)
- Klebsiella pneumoniae (the leading cause of bacterial infections precipitating DKA)
- Medical, surgical, or emotional stress
- Brittle diabetes
- Idiopathic (no identifiable cause)
- Insulin infusion catheter blockage
- Mechanical failure of the insulin infusion pump
- Intercurrent illness (eg, myocardial infarction, pneumonia, prostatitis, UTI)
- Medication (eg, corticosteroids, pentamidine, clozapine)
Epidemiology
Despite advancements in self-care of patients with diabetes, DKA accounts for 50% of diabetes-related admissions in young persons and 1-2% of all primary diabetes-related admissions. DKA frequently is observed during the diagnosis of type 1 diabetes and often indicates this diagnosis. While the exact incidence is not known, it is estimated to be 1 out of 2000.
DKA occurs primarily in patients with type 1 diabetes. The incidence is roughly 2 episodes per 100 patient years of diabetes, with about 3% of patients with type 1 diabetes initially presenting with DKA. It can occur in patients with type 1 diabetes as well; this is less common, however.
The incidence of diabetic ketoacidosis in developing countries is not known, but it may be higher than in industrialized nations.
The incidence of DKA is higher in whites because of the higher incidence of type 1 diabetes in this racial group. The incidence of diabetic ketoacidosis (DKA) is slightly greater in females than in males for reasons that are unclear. Recurrent DKA frequently is seen in young women with type 1 diabetes and is caused mostly by the omission of insulin treatment.
Among persons with type 1 diabetes, DKA is much more common in young children and adolescents than it is in adults. DKA tends to occur in individuals younger than 19 years, but it may occur in patients with diabetes at any age.
DKA occurs primarily in patients with type 1 diabetes. The incidence is roughly 2 episodes per 100 patient years of diabetes, with about 3% of patients with type 1 diabetes initially presenting with DKA. It can occur in patients with type 1 diabetes as well; this is less common, however.
The incidence of diabetic ketoacidosis in developing countries is not known, but it may be higher than in industrialized nations.
The incidence of DKA is higher in whites because of the higher incidence of type 1 diabetes in this racial group. The incidence of diabetic ketoacidosis (DKA) is slightly greater in females than in males for reasons that are unclear. Recurrent DKA frequently is seen in young women with type 1 diabetes and is caused mostly by the omission of insulin treatment.
Among persons with type 1 diabetes, DKA is much more common in young children and adolescents than it is in adults. DKA tends to occur in individuals younger than 19 years, but it may occur in patients with diabetes at any age.
Prognosis
The overall mortality rate for DKA is 2% or less. The presence of deep coma at the time of diagnosis, hypothermia, and oliguria are signs of poor prognosis.
The prognosis of properly treated patients with diabetic ketoacidosis is excellent, especially in younger patients if intercurrent infections are absent. The worst prognosis usually is observed in older patients with severe intercurrent illnesses (eg, myocardial infarction, sepsis, or pneumonia), especially when these patients are treated outside an intensive care unit.
When DKA is treated properly, it rarely produces residual effects. With modern fluid management, the mortality rate of DKA is about 2% per episode. Before the discovery of insulin in 1922, the mortality rate was 100%. In the last 20 years, mortality rates from DKA have markedly decreased, from 7.96% to 0.67%.[5]
DKA accounts for 14% of all hospital admissions of patients with diabetes and 16% of all diabetes-related fatalities. A fetal mortality rate as high as 30% is associated with DKA. The rate is as high as 60% in diabetic ketoacidosis with coma. Fetal death typically occurs in women with overt diabetes, but it may occur with gestational diabetes. In children younger than 10 years, diabetic ketoacidosis causes 70% of diabetes-related fatalities.
The best results are observed in patients treated in intensive care units during the first 1-2 days of hospitalization. The overall mortality rate from DKA ranges from 1-10% of all DKA admissions. A high mortality rate among non-hospitalized patients illustrates the necessity of early diagnosis and implementation of effective prevention programs.
Cerebral edema remains the most common cause of mortality, particularly in young children and adolescents. Cerebral edema frequently results from rapid intracellular fluid shifts. Other causes of mortality include severe hypokalemia, adult respiratory distress syndrome, and co-morbid states (e.g. pneumonia, acute myocardial infarction).
A heightened understanding of the pathophysiology of DKA along with proper monitoring and correction of electrolytes has resulted in a significant reduction in the overall mortality rate from this life-threatening condition in most developed countries.
For the long term, it is imperative to implement a wholefoods-based nutritional program such as the Death to Diabetes Super Meal Diet.
The prognosis of properly treated patients with diabetic ketoacidosis is excellent, especially in younger patients if intercurrent infections are absent. The worst prognosis usually is observed in older patients with severe intercurrent illnesses (eg, myocardial infarction, sepsis, or pneumonia), especially when these patients are treated outside an intensive care unit.
When DKA is treated properly, it rarely produces residual effects. With modern fluid management, the mortality rate of DKA is about 2% per episode. Before the discovery of insulin in 1922, the mortality rate was 100%. In the last 20 years, mortality rates from DKA have markedly decreased, from 7.96% to 0.67%.[5]
DKA accounts for 14% of all hospital admissions of patients with diabetes and 16% of all diabetes-related fatalities. A fetal mortality rate as high as 30% is associated with DKA. The rate is as high as 60% in diabetic ketoacidosis with coma. Fetal death typically occurs in women with overt diabetes, but it may occur with gestational diabetes. In children younger than 10 years, diabetic ketoacidosis causes 70% of diabetes-related fatalities.
The best results are observed in patients treated in intensive care units during the first 1-2 days of hospitalization. The overall mortality rate from DKA ranges from 1-10% of all DKA admissions. A high mortality rate among non-hospitalized patients illustrates the necessity of early diagnosis and implementation of effective prevention programs.
Cerebral edema remains the most common cause of mortality, particularly in young children and adolescents. Cerebral edema frequently results from rapid intracellular fluid shifts. Other causes of mortality include severe hypokalemia, adult respiratory distress syndrome, and co-morbid states (e.g. pneumonia, acute myocardial infarction).
A heightened understanding of the pathophysiology of DKA along with proper monitoring and correction of electrolytes has resulted in a significant reduction in the overall mortality rate from this life-threatening condition in most developed countries.
For the long term, it is imperative to implement a wholefoods-based nutritional program such as the Death to Diabetes Super Meal Diet.
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