DIABETIC KETOACIDOSIS

Introduction
Background

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 defined clinically as an acute state of severe uncontrolled diabetes 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 of greater than 250 mg/dL (although it is usually much higher), blood pH of less than 7.2, and a bicarbonate level of 18 mEq/L or less.
Pathophysiology

Diabetic ketoacidosis (DKA) is a complex disordered metabolic state characterized by hyperglycemia, acidosis, 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.

Progressive rise of blood concentration of these acidic organic substances initially leads to a state of ketonemia. Natural body buffers can buffer ketonemia in its early stages. When the accumulated ketones exceed the body's capacity of extracting them, they overflow into urine (ie, ketonuria). If the situation is not treated promptly, more accumulation of organic acids leads to frank clinical metabolic acidosis (ie, ketoacidosis), with a drop in pH and bicarbonate1 serum levels. Respiratory compensation of 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 characteristic fruity breath odor of ketotic patients.

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.

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.

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. A large part 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.
Frequency
United States

Currently, diabetic ketoacidosis (DKA) occurs less frequently in patients with known diabetes because of the introduction of diabetes educational programs in most diabetes clinics. These programs teach patients with diabetes how to test for urinary ketones and how to adjust their insulin regimen on sick days in order to avoid DKA.

In spite of the advancement in self-care of patients with diabetes, DKA still 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 frequently indicates this diagnosis. Exact incidence is not known, but it is estimated to be 1 out of 2000.

In a study of 127 patients with DKA who were admitted to a pediatric intensive care unit, Bradley and Tobias concluded that multiple weaknesses existed in the prehospital care of these patients.2 These included "lack of appropriate laboratory evaluation, excessive insulin dosing (both bolus doses and infusion rates), lack of fluid resuscitation, use of inappropriate fluids for resuscitation, and the use of sodium bicarbonate."

Although DKA was a common problem in patients with diabetes who were treated with continuous subcutaneous insulin infusion (SCII) through insulin infusion pumps, incidence of DKA became less frequent with the introduction of new pumps equipped with sensitive electronic alarm systems that alert users when the infusion catheter is blocked. Frequent blood glucose monitoring at home makes DKA less likely to occur in such patients because they always can search, in a timely manner, for possible reasons for unexpectedly high blood glucose values before the condition progresses to DKA.

DKA also occurs in pregnant women, either with preexisting diabetes or with diabetes diagnosed during pregnancy. Physiologic changes unique to pregnancy provide a background for the development of DKA. DKA in pregnancy is a medical emergency, because the mother and fetus are at risk for morbidity and mortality.
International

The incidence of diabetic ketoacidosis in developing countries is not known, but it may be higher than in industrialized nations.3
Mortality/Morbidity

When diabetic ketoacidosis (DKA) is treated properly, it rarely causes any residual effects. The overall mortality rate from DKA ranges from 1-10% of all DKA admissions, according to hospital facilities and the experiences of people who have dealt with this acute metabolic condition. Better understanding of the pathophysiology of DKA and proper monitoring and correction of electrolytes has resulted in significant reduction in the overall mortality rate from this life-threatening condition in most developed countries. Mortality rates from DKA have markedly decreased from 7.96% 20 years ago to 0.67%.4

* Best results are always observed in patients treated in ICUs during the first 1-2 days of hospitalization.
* In contrast, the mortality rate still is high in developing countries and among nonhospitalized patients. This high mortality rate illustrates the necessity of early diagnosis and the implementation of effective prevention programs.
* Cerebral edema remains the most common cause of mortality, particularly in young children and adolescents.5 Cerebral edema frequently results from rapid intracellular fluid shifts. Other causes of mortality include severe hypokalemia, adult respiratory distress syndrome, and comorbid states (eg, pneumonia, acute myocardial infarction).

Race

The incidence of diabetic ketoacidosis is higher in whites because of the higher incidence of type 1 diabetes in this racial group.
Sex

The incidence of diabetic ketoacidosis (DKA) is slightly greater in females than in males for reasons that are unclear. Recurrent DKA is frequently seen in young women with type 1 diabetes mellitus (DM) and is mostly caused by the omission of insulin treatment.
Age

Among persons with type 1 diabetes, diabetic ketoacidosis is much more common in young children and adolescents than it is in adults.
Clinical
History

* Insidious increased thirst (ie, polydipsia) and urination (ie, polyuria) are the most common early symptoms of diabetic ketoacidosis (DKA).
* Nausea and vomiting usually occur and may be associated with diffuse abdominal pain.
* Generalized weakness and fatigability may occur.
* Altered consciousness in the form of mild disorientation or confusion is a possible symptom. Although frank coma is uncommon, it may occasionally occur when the condition is neglected or if dehydration or acidosis is severe.
* Symptoms of possible associated intercurrent infection may include fever, dysuria, coughing, malaise, and arthralgia, among others.
* Acute chest pain or palpitation may occur in association with myocardial infarction. Painless infarction is not uncommon in patients with diabetes and should always be suspected in elderly patients.
* Patients may present with a history of failure to comply with insulin therapy or missed insulin injections due to vomiting or psychological reasons.
* History of rapid weight loss is a symptom in patients who are newly diagnosed with type 1 diabetes.

Physical

* Signs of dehydration - Weak and rapid pulse, dry tongue and skin, hypotension, and increased capillary refill time
* Patient odor - Characteristic acetone odor
* Signs of acidosis - Shallow rapid breathing or air hunger (Kussmaul or sighing respiration), abdominal tenderness, and disturbance of consciousness
o Although these signs are not usual in all cases of diabetic ketoacidosis (DKA), their presence signifies a severe form of DKA.
o Emphasizing that no direct correlation exists between the degree of acidosis, hyperglycemia, and the disturbances in the level of consciousness is important.
* Signs of intercurrent illness - Myocardial infarction, urinary tract infection (UTI), pneumonia, and perinephric abscess, among others
o Noticing that the body temperature may be within the reference range or low, even in the presence of intercurrent infection, is particularly important.
o Search for signs of infection is mandatory in all cases.

Causes

* Patients with type 1 diabetes6
o Diabetic ketoacidosis (DKA) present at diagnosis of type 1 diabetes due to acute insulin deficiency (occurs in 25% of patients)
o Poor compliance with insulin through the omission of insulin injections either due to lack of patient or guardian education or as a result of psychological stress, particularly in adolescents
o Bacterial infection and intercurrent illness (eg, UTI, vomiting)
o Klebsiella pneumoniae (the leading cause of bacterial infections precipitating DKA)
o Medical, surgical, or emotional stress
o Brittle diabetes
o Idiopathic (no identifiable cause)
o Insulin infusion catheter blockage
o Mechanical failure of insulin infusion pump
* Patients with type 2 diabetes7
o Intercurrent illness (eg, myocardial infarction, pneumonia, prostatitis, UTI)
o Medication (eg, corticosteroids, pentamidine, clozapine)Differential Diagnoses
Alcoholic Ketoacidosis
Sepsis, Bacterial
Hyperosmolar Coma
Toxicity, Salicylate
Lactic Acidosis

Metabolic Acidosis

Pancreatitis, Acute

Other Problems to Be Considered

Bacteremia and sepsis
Dehydration due to gastroenteritis
Workup
Laboratory Studies

* Urine
o This test is highly positive for glucose and ketones by dipstick testing. Rarely, urine is negative for ketones because most of the available laboratory tests can detect only acetoacetate, while the predominant ketone in severe untreated diabetic ketoacidosis (DKA) is beta hydroxybutyrate. When the clinical condition improves with treatment, the urine test result becomes positive due to the returning predominance of acetoacetate.
o Urine culture helps to identify any possible infecting organisms.
* Blood and plasma
o The blood glucose level usually is higher than 250 mg/dL.
o Serum ketones are present. Blood beta-hydroxybutyrate (beta-OHB) levels measured by a reagent strip (Ketostix, N-Multistix, and Labstix) and serum ketone levels assessed by the nitroprusside reaction are equally effective in diagnosing DKA among uncomplicated cases.
o Arterial blood gases (ABG) frequently show typical manifestations of metabolic acidosis, low bicarbonate, and low pH (<7.2). o Serum potassium levels initially are high or within the reference range due to the extracellular shift of potassium in exchange of hydrogen, which is accumulated in acidosis, in spite of severely depleted total body potassium. o The serum sodium level usually is low. o The serum chloride levels and phosphorus levels always are low. o The anion gap is elevated ([Na + K] - [Cl + HCO3] >13 mEq/L).
o Plasma osmolarity usually is increased (>290 mOsm/L). If plasma osmolarity cannot be directly measured, it may be calculated with this formula: plasma osmolarity = 2 (Na + K) + BUN/3 + glucose/18. Urine osmolarity also is increased.
o Even in the absence of infection, CBC shows increased WBC count.
o BUN frequently is increased.
o Blood culture findings may help to identify any possible infecting organisms.
* Frequency of laboratory studies
o Blood tests for glucose should be performed hourly (until patient is stable, then every 6 h).
o Serum electrolyte determinations should be obtained hourly (until patient is stable, then every 6 h).
o BUN should be performed initially.
o ABG should be performed initially, followed with bicarbonate as necessary.

Imaging Studies

* Plain chest radiograph may reveal signs of pneumonia.
* If it occurs during therapy, magnetic resonance imaging (MRI) is helpful in detecting early cerebral edema and should only be ordered if altered consciousness is present.5

Other Tests

* Electrocardiogram (ECG)
o This test may reveal signs of acute myocardial infarction that could be painless in patients with diabetes, particularly in those with autonomic neuropathy.
o T-wave changes may produce the first warning sign of disturbed serum potassium levels.
o Low T wave and apparent U wave always signify hypokalemia, while peaked T wave is observed in hyperkalemia.
* ECG should be performed every 6 hours during the first day, unless the patient is monitoreTreatment
Medical Care

Managing diabetic ketoacidosis (DKA) in an ICU during the first 24-48 hours is always advisable. When treating DKA, the points that must be considered and closely monitored include correction of fluid loss with IV fluids; correction of hyperglycemia with insulin; correction of electrolyte disturbances, particularly potassium loss; correction of acid-base balance; and treatment of concurrent infection if present.

Paying great attention to the correction of fluid and electrolyte loss during the first hour of treatment, followed by gradual correction of hyperglycemia and acidosis, always is advisable. Correction of fluid loss makes the clinical picture clearer and may be sufficient to correct acidosis. The presence of even mild signs of dehydration means that at least 3 liters of fluid already have been lost.

* Fluids: Initial correction of fluid loss is either by isotonic sodium chloride solution or by lactated Ringer solution.
o Administer 1 liter over the first 30 minutes.
o Administer 1 liter over the second hour.
o Administer 1 liter over the following 2 hours.
o Administer 1 liter every 4 hours, depending on the degree of dehydration and central venous pressure (CVP) readings.
o When the patient becomes euvolemic, the physician may switch to half the isotonic sodium chloride solution, particularly if hypernatremia exists.
o When blood sugar decreases to less than 180 mg/dL, isotonic sodium chloride solution is replaced with 5-10% dextrose with half isotonic sodium chloride solution.
* Insulin8
o When insulin treatment is started, several points must be considered.
+ A low-dose insulin regimen has the advantage of not inducing severe hypoglycemia or hypokalemia, as may be observed with a high-dose insulin regimen.
+ Only short-acting insulin is used for correction of hyperglycemia.
+ Subcutaneous absorption of insulin is reduced in DKA because of dehydration; therefore, using IV or IM routes is traditionally preferable. Subcutaneous use of the fast-acting insulin analog (lispro) has been tried in pediatric DKA (0.15 U/kg q2h). The results were shown to be comparable to IV insulin, but ketosis took 6 more hours to resolve. Such technically simplified methods may be cost-effective and may preclude ICU admissions in mild cases.
o The initial insulin dose is a continuous IV insulin infusion using an infusion pump, if available, at a rate of 0.1 U/kg/h. A mix of 24 units of regular insulin in 60 mL of isotonic sodium chloride solution usually is infused at a rate of 15 mL/h (6 U/h) until the blood sugar drops to less than 180 mg/dL, then the rate of infusion decreases to 5-7.5 mL/h (2-3 U/h) until the ketoacidotic state abates. Larger volumes of an insulin and isotonic sodium chloride solution mixture can be used, providing that the infusion dose of insulin is similar. Larger volumes may be easier in the absence of an intravenous infusion pump (eg, 60 U of insulin in 500 mL of isotonic sodium chloride solution at a rate of 50 mL/h).
o The optimal rate of glucose decline is 100 mg/dL/h.
o Do not allow the blood glucose level to fall below 200 mg/dL during the first 4-5 hours of treatment.
o Hypoglycemia may develop rapidly with correction of ketoacidosis.
o A common mistake is to allow blood glucose to drop to hypoglycemic levels. This mistake usually results in a rebound ketosis derived by counter-regulatory hormones. Rebound ketosis requires a longer duration of treatment. The other hazard is that rapid correction of hyperglycemia and hyperosmolarity may shift water rapidly to the hyperosmolar intracellular space and may induce cerebral edema.
* Electrolyte correction
o Potassium
+ If the potassium level is greater than 6 mEq/L, do not administer potassium supplement.
+ If the potassium level is 4.5-6 mEq/L, administer 10 mEq/h of potassium chloride.
+ If the potassium level is 3-4.5 mEq/L, administer 20 mEq/h of potassium chloride.
+ Monitor serum potassium levels hourly, and the infusion must stop if the potassium level is greater than 5 mEq/L.
+ Monitoring of serum potassium must continue even after potassium infusion is stopped in the case of (expected) recurrence of hypokalemia.
+ In severe hypokalemia, not to starting insulin therapy is advisable unless potassium replacement is underway in order to avoid potentially serious cardiac dysrhythmia that may result from hypokalemia.
* Correction of acid-base balance
o Sodium bicarbonate only is infused if decompensated acidosis starts to threaten the patient's life, especially when associated with either sepsis or lactic acidosis.
o If sodium bicarbonate is indicated, 100-150 mL of 1.4% concentration is infused initially. This may be repeated every half hour if necessary.
o Rapid and early correction of acidosis with sodium bicarbonate may worsen hypokalemia and cause paradoxical cellular acidosis.
* Treatment of concurrent infection
o In the presence of infection, administer proper antibiotics guided by the results of culture and sensitivity studies.
o Starting empiric antibiotics on suspicion of infection until culture results are available may be advisable.

Medication

Regular and analog human insulins8 are used for correction of hyperglycemia, unless bovine or pork insulin is the only available insulin. Clinical considerations in treating diabetic ketoacidosis (DKA) include the following: (1) only short-acting insulin is used for correction of hyperglycemia in DKA, (2) the optimal rate of glucose decline is 100 mg/dL/h, (3) the blood glucose level should not be allowed to fall lower than 200 mg/dL during the first 4-5 hours of treatment, and (4) avoid induction of hypoglycemia because it may develop rapidly during correction of ketoacidosis and may not provide sufficient warning time.
Hypoglycemic agents

These agents reduce plasma glucose levels.

Regular insulin (Humulin, Novolin), Ultra–short-acting insulin analog (Humalog, NovoLog, Apidra)

Insulin suppresses hepatic glucose output and enhances glucose uptake by peripheral tissues. Insulin also suppresses ketogenesis and lipolysis, stimulates proper use of glucose by the cells, and reduces blood sugar levels.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

0.1 U/kg/h IV infusion; lower to 0.05 U/kg/h when blood glucose level drops to <180 mg/dL
Pediatric

Administer as in adultsFollow-up
Further Inpatient Care

* Patients are not usually discharged from the hospital unless they have switched back to their daily insulin regimen without recurrence of ketosis. When the condition is stable, pH is greater than 7.3, and bicarbonate is greater than 18 mEq/L, the patient is allowed to eat a meal preceded by an SC dose of regular insulin. Insulin infusion can be discontinued 30 minutes later. If the patient is still nauseated and cannot eat, continue dextrose infusion and administer regular or ultra–short-acting insulin SC every 4 hours according to blood glucose level, while trying to maintain blood glucose values at 100-180 mg/dL.
* In established patients with diabetes, SC long-acting insulin (eg, insulin glargine, Detemir, Ultralente) should be initiated back at the same dose that was used prior to diabetic ketoacidosis. However, if neutral protamine Hagedorn (NPH) insulin was previously used, start back at the usual dose only when the patient eats well and is able to retain meals without vomiting; otherwise, the dose should be reduced to avoid hypoglycemia during its peak efficacy period.
* In newly diagnosed patients with type 1 DM, a careful estimate of the long-acting insulin dose should be considered. Starting with smaller doses generally is recommended to avoid unneeded hypoglycemia.

Further Outpatient Care

* Psychological counseling of young children and adolescents usually is helpful.

Complications

* Cerebral edema is a serious, major complication that may evolve during treatment of diabetic ketoacidosis (DKA). Be extremely cautious to avoid cerebral edema during initiation of therapy. Deterioration of the level of consciousness in spite of improved metabolic state usually indicates the occurrence of cerebral edema. MRI usually is used to confirm the diagnosis. If cerebral edema occurs at initiation of therapy, it usually worsens during the course of treatment. Clinical cerebral edema is rare and carries the highest mortality rate. Although mannitol (0.25-1 g/kg IV) and dexamethasone (2-4 mg q6-12h) frequently are used in this situation, no specific medication has proven to be useful in such instances.
* Cardiac dysrhythmia may occur secondary to severe hypokalemia and/or acidosis either initially or as a result of therapy. Usually, correction of the cause is sufficient to treat cardiac dysrhythmia, but, if it persists, consultation with a cardiologist is mandatory. Performing cardiac monitoring on patients with DKA during correction of electrolytes always is advisable.
* Pulmonary edema may occur for the same reasons as cerebral edema. Although it is rare, be cautious of possible overcorrection of fluid loss. Diuretics and oxygen therapy are often sufficient for the management of pulmonary edema.
* Nonspecific myocardial injury may occur in severe DKA, which is associated with minute elevations of myocardial biomarkers (troponin T and CK-MB) and initial ECG changes compatible with myocardial infarction (MI). Acidosis and very high levels of free fatty acids could cause membrane instability and biomarker leakage. Coronary arteriography usually is normal, and patients usually recover fully without further evidence of ischemic heart disease. Regardless of the pathogenesis, the presence of minute biomarker elevations and ECG changes do not necessarily signify MI in DKA.
* Microvascular changes consistent with diabetic retinopathy have been reported prior to and after treatment of DKA; however, the blood-retinal barrier does not experience the same degree of perturbation as the blood-brain barrier does.

Prognosis

* The prognosis of properly treated patients with diabetic ketoacidosis is excellent, especially in younger patients if intercurrent infections are absent. The worst prognosis is usually observed in patients who are older with severe intercurrent illnesses, eg, myocardial infarction, sepsis, or pneumonia, especially when they are treated outside an ICU.
* The presence of deep coma at the time of diagnosis, hypothermia, and oliguria are signs of poor prognosis.

Patient Education

* Educate patients in the prevention of diabetic ketoacidosis so that a recurrent episode can be avoided.
* Promotion of self-management and dealing with the stress of intercurrent illness always is part of the education process for adult patients with diabetes.9,10
* For excellent patient education resources, visit eMedicine's Diabetes Center. Also, see eMedicine's patient education article, Diabetic Ketoacidosis.

Miscellaneous
Medicolegal Pitfalls

* Failure to diagnose diabetic ketoacidosis (DKA) in the absence of a urinary test result that is positive for ketones
* False belief that DKA is worsening based on positive results of a urine test for ketones, while, in fact, DKA is improving with return of predominate ketones from beta hydroxybutyrate to acetoacetate
* Failure to recognize associated conditions, eg, myocardial infarction, UTI, pneumonia, perinephric abscess, or hidden sepsis
* Failure to recognize signs and symptoms of cerebral edema
* Rapid correction of hyperglycemia in the first 4-5 hours
* Rapid correction of metabolic acidosis with sodium bicarbonate before correction of fluid loss
* Stopping monitoring of serum potassium after it returns to the reference range
* Infusing potassium chloride without continuous monitoring of serum potassium or ECG