Acute Complications of Diabetes Mellitus

Insulin deficiency and an increase in counterregulatory hormones (glucagon, catecholamines, cortisol) causes the body to metabolize triglycerides and amino acids instead of glucose for energy. Serum levels of glycerol and free fatty acids rise because of unrestrained lipolysis. Alanine levels rise because of muscle catabolism. Glycerol and alanine provide substrate for hepatic gluconeogenesis, which is stimulated by the excess of glucagon that accompanies insulin deficiency.

Glucagon also stimulates mitochondrial conversion of free fatty acids into ketones. Insulin normally blocks ketogenesis by inhibiting the transport of free fatty acid derivatives into the mitochondrial matrix, but ketogenesis proceeds in the absence of insulin. The major ketoacids produced, acetoacetic acid and beta-hydroxybutyric acid, are strong organic acids that create metabolic acidosis. Acetone derived from the metabolism of acetoacetic acid accumulates in serum and is slowly disposed of by respiration.

Hyperglycemia due to insulin deficiency causes an osmotic diuresis that leads to marked urinary losses of water and electrolytes. Urinary excretion of ketones obligates additional losses of sodium and potassium. Serum sodium may fall due to natriuresis or rise due to excretion of large volumes of free water.

Potassium is also lost in large quantities. Despite a significant total body deficit of potassium, initial serum potassium is typically normal or elevated because of the extracellular migration of potassium in response to acidosis. Potassium levels generally fall further during treatment as insulin therapy drives potassium into cells. If serum potassium is not monitored and replaced as needed, life-threatening hypokalemia may develop.

Symptoms and signs of diabetic ketoacidosis include symptoms of hyperglycemia with the addition of nausea, vomiting, and—particularly in children—abdominal pain. Lethargy and somnolence are symptoms of more severe decompensation. Patients may be hypotensive and tachycardic due to dehydration and acidosis; they may breathe rapidly and deeply to compensate for acidemia (Kussmaul respirations). They may also have fruity breath due to exhaled acetone. Fever is not a sign of DKA itself and, if present, signifies underlying infection. In the absence of timely treatment, DKA progresses to coma and death.

Acute cerebral edema, a complication in less than 1% of patients with DKA (1, 2), occurs primarily in children and less often in adolescents and young adults. Headache and fluctuating level of consciousness herald this complication in some patients, but respiratory arrest is the initial manifestation in others. The cause is not well understood but may be related to too-rapid reductions in serum osmolality or to brain ischemia. In studies primarily of children, those the highest blood urea nitrogen (BUN) levels and lowest PaCO2 at presentation appear to be at greatest risk. Delays in correction of hyponatremia, and the use of bicarbonate during DKA treatment are other possible risk factors (3).

• Arterial pH

• Serum glucose

• Serum and urine ketones

• Calculation of anion gap

• Serum electrolytes, BUN, and creatinine

In patients suspected of having diabetic ketoacidosis, serum electrolytes, blood urea nitrogen (BUN) and creatinine, glucose, ketones, and osmolarity should be measured. Urine should be tested for ketones. Patients who appear significantly ill and those with positive ketones should have arterial blood gas measurement.

Diagnostic criteria for DKA include (1, 2, 3):

• Arterial or venous pH < 7.30

• Anion gap > > 10 to 12 mEq/L (10 to 12 mmol/L)

• Serum bicarbonate < 15 to 18 mEq/L (15 to 18 mmol/L)

• Presence of serum or urine ketones

• Serum glucose > 200 to 250 mg/dL (11.1 to 13.8 mmol/L)

Some guidelines do not require a specific serum glucose level for the diagnosis of DKA and allow for the presence of known diabetes to substitute for a specific glucose cutoff due to the recognition that DKA can occur in patients with normal or mildly elevated glucose levels (euglycemic DKA) (1, 2, 3).

A presumptive diagnosis may be made when urine glucose and ketones are positive on urinalysis. Urine test strips and some assays for serum ketones may underestimate the degree of ketosis because they detect acetoacetic acid and not beta-hydroxybutyric acid, which is usually the predominant ketoacid. Blood beta-hydroxybutyrate can be measured, or treatment can be initiated based on clinical suspicion and the presence of anion gap acidosis if serum or urine ketones are low.

Symptoms and signs of a triggering illness should be pursued with appropriate studies (eg, cultures, imaging studies). Adults should have an ECG to screen for acute myocardial infarction and to help determine the significance of abnormalities in serum potassium.

Other laboratory abnormalities include:

• Hyponatremia

• Elevated serum creatinine

• Elevated plasma osmolality

• Hypokalemia, after correction of acidosis

• Elevated serum amylase and lipase

Hyperglycemia may cause dilutional hyponatremia, so measured serum sodium is corrected by adding 1.6 mEq/L (1.6 mmol/L) for each 100 mg/dL (5.6 mmol/L) elevation of serum glucose over 100 mg/dL (5.6 mmol/L).

Clinical Calculators

Sodium Correction in Hyperglycemia (Katz 1973)

As acidosis is corrected, serum potassium drops. An initial potassium level < 4.5 mEq/L (< 4.5 mmol/L) indicates marked potassium depletion and requires immediate potassium supplementation.

Serum amylase and lipase are often elevated, even in the absence of pancreatitis (which may be present in patients with alcoholic ketoacidosis and in those with coexisting hypertriglyceridemia).

Clinical Calculators

Anion Gap

• Fluid resuscitation with IV 0.9% saline

• Correction of hypokalemia

• IV insulin (as long as serum potassium is ≥ 3.3 mEq/L [3.3 mmol/L])

• Rarely IV sodium bicarbonate (if pH Rarely IV sodium bicarbonate (if pH< 7 after 1 hour of treatment)

The most urgent goals for treating diabetic ketoacidosis are rapid intravascular volume repletion, correction of hyperglycemia and acidosis, and prevention of hypokalemia (1, 2, 3). Identification of precipitating factors is also important.

Treatment of most cases of DKA should occur in intensive care settings because clinical and laboratory assessments are initially needed every hour or every other hour with appropriate adjustments in treatment. Milder cases may be able to be managed with subcutaneous insulin every 1 to 2 hours, in a step-down or emergency room.Treatment of most cases of DKA should occur in intensive care settings because clinical and laboratory assessments are initially needed every hour or every other hour with appropriate adjustments in treatment. Milder cases may be able to be managed with subcutaneous insulin every 1 to 2 hours, in a step-down or emergency room.

Overall mortality rates for diabetic ketoacidosis are < 1% (1); however, mortality is higher in older patients and in patients with other life-threatening illnesses. Type 2 (versus type 1) diabetes, sepsis, altered level of consciousness, and obesity are also associated with an increased risk of mortality (2, 3). Cerebral edema in adults with DKA is thought to be very rare.

The primary symptom of hyperosmolar hyperglycemic state is altered consciousness, varying from confusion or disorientation to coma, usually as a result of extreme dehydration with or without prerenal azotemia, hyperglycemia, and hyperosmolality. In contrast to diabetic ketoacidosis, focal or generalized seizures and transient hemiplegia may occur.

The diagnostic criteria for HHS are (1):

• Plasma glucose level ≥ 600 mg/dL (33.3 mmol/L)

• Serum osmolality > 300 mOsm/kg

• Absence of ketosis: Urine ketones < 2+ or beta-hydroxybutyrate < 3.0 mmol/L

• Absence of acidosis: pH ≥ 7.3 and serum bicarbonate ≥ 15 mEq/L (15 mmol/L)

Hyperosmolar hyperglycemic state is initially suspected when a markedly elevated glucose level is found in a fingerstick specimen obtained in the course of an evaluation of altered mental status. If measurements have not already been obtained, urine should be tested for ketones and the following should be measured in a blood sample:

• Serum electrolytes

• Blood urea nitrogen (BUN)

• Creatinine

• Glucose

• Ketones

• Plasma osmolality

Serum potassium levels are usually normal, but sodium may be low or high, depending on volume deficits.

Hyperglycemia may cause dilutional hyponatremia, so measured serum sodium is corrected by adding 1.6 mEq/L (1.6 mmol/L) for each 100 mg/dL (5.6 mmol/L) elevation of serum glucose over 100 mg/dL (5.6 mmol/L).

BUN and serum creatinine levels are markedly increased.

Arterial pH is usually > 7.3, but occasionally mild metabolic acidosis develops due to lactate accumulation.

The fluid deficit can exceed 10 L, and acute circulatory collapse is a common cause of death. Widespread thrombosis is a frequent finding on autopsy and in some cases bleeding may occur as a consequence of disseminated intravascular coagulation. Other complications include aspiration pneumonia, acute renal failure, and acute respiratory distress syndrome.

It is not uncommon for features of both DKA and HHS to be present. For example, mild ketonemia often occurs in individuals with HHS. However, if significant ketonemia and acidosis are present in a patient with HHS/ DKA overlap, insulin should be administered according to DKA protocols. It is not uncommon for features of both DKA and HHS to be present. For example, mild ketonemia often occurs in individuals with HHS. However, if significant ketonemia and acidosis are present in a patient with HHS/ DKA overlap, insulin should be administered according to DKA protocols.

Clinical Calculators

Anion Gap

• IV 0.9% saline

• Correction of any hypokalemia

• IV insulin (as long as serum potassium is ≥ 3.3 mEq/L [≥ 3.3 mmol/L])

All patients with hyperosmolar hyperglycemic state should be hospitalized and managed in the intensive care setting.

Treatment consists of IV saline, correction of hypokalemia, and IV insulin (1, 2, 3).

Treatment is 0.9% (isotonic) saline solution; 1000 mL is given in the first hour. Smaller boluses (500 mL) can be given if there is risk for exacerbation of heart failure or volume overload. Additional boluses may be needed for patients who are hypotensive.

After the first hour, intravenous fluids should be adjusted based on hemodynamic and electrolyte status but should generally be continued at a rate of 250 to 500 mL/hour.

A corrected sodium should be calculated. If the corrected sodium is < 135 mEq/L (< 135 mmol/L), then isotonic saline can be continued. If the corrected sodium is normal or elevated, then 0.45% saline (half normal) should be used.

Dextrose should be added once the glucose level reaches 250 to 300 mg/dL (13.9 to 16.7 mmol/L). Dextrose should be added once the glucose level reaches 250 to 300 mg/dL (13.9 to 16.7 mmol/L).

The rate of infusion of IV fluids should be adjusted depending on blood pressure, cardiac status, and the balance between fluid input and output.

Insulin is given as a 0.05 unit/kg/hour infusion after the first liter of saline has been infused and hypokalemia has been corrected. Hydration alone can sometimes precipitously decrease plasma glucose, so insulin dose may need to be reduced. A too-quick reduction in osmolality can lead to cerebral edema. Occasional patients with insulin-resistant type 2 diabetes with hyperosmolar hyperglycemic state require larger insulin doses. Once plasma glucose reaches 300 mg/dL (16.7 mmol/L), insulin infusion should be reduced to basal levels (1 to 2 units/hour) until rehydration is complete and the patient is able to eat.

If significant ketonemia and acidosis are present in a patient with HHS/ DKA overlap, insulin should be administered according to DKA protocols. If significant ketonemia and acidosis are present in a patient with HHS/ DKA overlap, insulin should be administered according to DKA protocols.

Target plasma glucose is between 250 and 300 mg/dL (13.9 to 16.7 mmol/L). After recovery from the acute episode, patients are usually switched to adjusted doses of subcutaneous insulin.Target plasma glucose is between 250 and 300 mg/dL (13.9 to 16.7 mmol/L). After recovery from the acute episode, patients are usually switched to adjusted doses of subcutaneous insulin.

Potassium replacement is similar to that in diabetic ketoacidosis: 40 mEq/hour for serum potassium < 3.3 mEq/L (< 3.3 mmol/L); 20 to 30 mEq/hour for serum potassium between 3.3 and 4.9 mEq/L (3.3 and 4.9 mmol/L); and none for serum potassium ≥ 5 mEq/L (≥ 5 mmol/L).

Alcohol diminishes hepatic gluconeogenesis and leads to decreased insulin secretion, increased lipolysis, impaired shunting of fatty acids to mitochondria, fatty acid oxidation, and subsequent ketogenesis, causing an elevated anion gap metabolic acidosis. Growth hormone, epinephrine, cortisol, and glucagon are all increased. Plasma glucose levels are usually low or normal, but mild hyperglycemia sometimes occurs.

Typically, an alcohol binge leads to vomiting and the cessation of alcohol or food intake for ≥ 24 hours. During this period of starvation, vomiting continues and abdominal pain develops, leading the patient to seek medical attention. Pancreatitis may occur.

• Calculation of anion gap

• Exclusion of other disorders

Diagnosis requires a high index of suspicion; similar symptoms in a patient with alcohol use disorder may result from acute pancreatitis, methanol or ethylene glycol poisoning (see table Symptoms and Treatment of Specific Poisons), or diabetic ketoacidosis (DKA). Often, blood alcohol levels are no longer elevated when patients present with alcoholic ketoacidosis.

In patients suspected of having alcoholic ketoacidosis, serum electrolytes (including magnesium), blood urea nitrogen (BUN) and creatinine, glucose, ketones, amylase, lipase, and plasma osmolality should be measured. Urine should be tested for ketones. Patients who appear significantly ill and those with positive ketones should have arterial blood gas and serum lactate measurements.

The absence of hyperglycemia makes diabetic ketoacidosis improbable. Patients with mild hyperglycemia may have underlying diabetes mellitus, which may be recognized by elevated levels of glycosylated hemoglobin (HbA1C).

Typical laboratory findings include:

• High anion gap metabolic acidosis

• Ketonemia and ketonuria

• Hypokalemia

• Hypomagnesemia

• Hypophosphatemia

Detection of acidosis may be complicated by concurrent metabolic alkalosis due to vomiting, resulting in a relatively normal pH; the main clue is the elevated anion gap. If history does not exclude toxic alcohol ingestion as a cause of the elevated anion gap, serum methanol and ethylene glycol levels should be measured.

The presence of calcium oxalate crystals in the urine also suggests ethylene glycol poisoning.

Lactic acid levels are often elevated because of hypoperfusion and the altered balance of reduction and oxidation reactions in the liver.

Clinical Calculators

Anion Gap

• IV thiamine and other vitamins plus magnesiumIV thiamine and other vitamins plus magnesium

• IV 5% dextrose in 0.9% salineIV 5% dextrose in 0.9% saline

An IV infusion of 0.9% saline solution is given, usually with 5% dextrose. In patients with hypoglycemia, higher concentrations of dextrose may be given initially. Initial IV fluids should contain added water-soluble vitamins and magnesium, with potassium and phosphate replacement as required. Patients are also given thiamine 100 to 200 mg IV (500 mg in patients at increased risk of Wernicke encephalopathy) to prevent development of may be given initially. Initial IV fluids should contain added water-soluble vitamins and magnesium, with potassium and phosphate replacement as required. Patients are also given thiamine 100 to 200 mg IV (500 mg in patients at increased risk of Wernicke encephalopathy) to prevent development ofWernicke encephalopathy or Korsakoff psychosis (1, 2).

Ketoacidosis and gastrointestinal symptoms usually respond rapidly. Serum potassium level should be monitored closely; as with diabetic ketoacidosis, total body potassium is often depleted and intracellular shift with correction of acidosis via fluid resuscitation can lower serum potassium (1). Use of insulin is appropriate only if there is any question of atypical diabetic ketoacidosis or if hyperglycemia > 300 mg/dL (> 16.7 mmol/L) develops.