The major acute complications of diabetes are the hyperglycemic and hypoglycemic emergencies. Hyperglycemic emergencies include diabetic ketoacidosis, mainly in patients with type 1 disease, and hyperglycemic hyperosmolar syndrome (HHS), primarily in patients with type 2 disease. If untreated, these conditions can result in severe sequelae and require urgent medical attention.
Diabetic ketoacidosis (DKA) is the most life-threatening acute complication of diabetes, and is often the presenting manifestation of type 1 diabetes. In patients with established type 1 disease, DKA may occur during superimposed acute infections, such as influenza, pneumonia or gastroenteritis, especially in patients who do not follow “sick day” rules; in patients on insulin pumps when insulin infusion is technically interrupted; or in patients who are noncompliant. Noncompliance is generally a problem in teenagers and in substance abusers. In almost all cases, DKA is preventable by a well-educated patient who is compliant with glucose monitoring and understands the need for increased insulin doses during stress. DKA may occur in patients with type 2 disease during severe medical stress, such as with overwhelming infection or myocardial infarction.
The syndrome of DKA indicates profound insulin deficiency, in combination with excess circulating concentrations of counter-regulatory factors, especially glucagon. The major manifestations of DKA—hyperglycemia, ketosis and dehydration—are directly or indirectly related to insulin deficiency. The lack of insulin prevents glucose uptake by muscle and allows unrestrained hepatic glucose production. Lack of suppression of lipolysis also leads to excess free fatty acids, which are converted into ketoacids (beta hydroxybutyrate and acetoacetate) by the liver. These unmeasured anions lead to acidosis, and eventually acidemia, which may impair cardiac function. Because of the effects of renal clearance, the marked hyperglycemia and ketonemia result in an osmotic diuresis with loss of water and electrolytes. As a result, the patient with DKA is frequently severely volume contracted, with total body water losses in the 6- to 10-liter range. DKA is clinically defined by a plasma glucose value of 250 mg/dL or greater, positive serum and/or urine ketones, an anion gap of more than 10 to 12, a serum bicarbonate level of 18 mEq/L or less and an arterial pH of 7.3 or less. Cautiously aggressive treatment of DKA is critical to avoid adverse outcomes.
Patients with DKA usually present with a several-day history of polyuria, polydipsia and blurred vision, culminating in nausea, vomiting, abdominal pain, dyspnea and altered mental status. Physical examination findings include deep, labored breathing (Kussmaul's respirations), a fruity odor to the breath (from acetone), poor skin turgor, tachycardia and hypotension. Bowel sounds are commonly absent, and the abdomen may be diffusely tender. Laboratory findings include marked hyperglycemia; an anion gap metabolic acidosis; increased urinary and plasma ketones; and elevated creatinine and blood, urea and nitrogen levels. The arterial blood gas shows acidemia with respiratory compensation. The serum sodium concentration is often low, a normal response to the osmotic shifts of severe hyperglycemia. The “corrected” sodium concentration should be considered (by adding 1.6 mEq of sodium for each 100 mg/dL of glucose above normal) when assessing the patient's osmolar status. Serum potassium concentration is often high because of the acidosis, yet total body potassium stores are usually low. Of importance, serum potassium levels fall precipitously on correction of the acidosis, and supplemental potassium is almost invariably required. The differential diagnosis includes other causes of metabolic acidosis, such as lactic acidosis, acute renal failure and alcoholic ketoacidosis. In the setting of marked hyperglycemia, however, the diagnosis is unmistakable, particularly in a patient with known diabetes.
Patients with DKA should generally be managed in the intensive care unit. If the DKA is mild, the patient can be managed on general hospital wards if intravenous insulin can be administered and if close nursing supervision and frequent phlebotomy are available. In uncomplicated cases, a patient's DKA should be resolved within 12 hours of hospital presentation, and transition to subcutaneous insulin and transfer to a general medical ward should be accomplished by 24 hours. The major efforts in the management of the patient with DKA are to correct the acidosis, volume deficits and hyperglycemia; to ensure stability of electrolytes; and to identify the precipitating cause. Rapid normalization of the plasma glucose concentration is not necessary and actually may be harmful because of the effects of rapid osmotic shifts, especially as related to cerebral edema. Instead, glucose levels should be lowered gradually. The mainstays of therapy include intravenous insulin and crystalloid solutions. The former suppresses lipolysis, ketogenesis and hepatic glucose production and augments glucose disposal into skeletal muscle. The result is cessation of urinary fluid and electrolyte losses and improvement in the acid–base status. Just as important as insulin, however, is intravenous volume repletion, which improves hyperglycemia and acidosis primarily by improving circulatory volume and renal blood flow and reducing counter-regulatory hormones, particularly catecholamines. Initially, efforts should focus on expanding the intravascular space, optimally with 0.9% sodium chloride. Because patients with DKA are usually young and otherwise healthy, aggressive fluid repletion is safe. Inadequate replenishment of fluid deficits delays recovery. Given the typically severe volume deficits, initially intravenous fluid should be administered as quickly as possible until the clinical signs of intravascular volume contraction improve. Subsequently rates may be reduced. Once plasma volume is restored, based on clinical and laboratory findings, a more hypotonic solution is advisable (for example, 0.45% sodium chloride) so that free water losses, predominantly from the intracellular space, can also be replenished.
Ideally, insulin should be administered intravenously to ensure adequate systemic delivery and so that the dose may be altered from hour to hour, based on an individual patient's needs. Initially, a bolus of 0.15 unit/kg is recommended, followed immediately by an infusion at a rate of 0.1 unit/h. The goal should be reduced glucose by 50 to 100 mg/dL per hour. Once the glucose is in the 200 mg/dL range, continued insulin is required until ketones are cleared and the anion gap has closed. However, as this process may take several more hours, the glucose level may fall into the hypoglycemic range. As a result, fluids should at this point be changed to dextrose-containing solutions. The insulin infusion rate can be decreased to that required to suppress lipolysis, which in most adults is 1 to 2 units/h. An adequate amount of dextrose (typically 5 to 10 g/h) maintains circulating glucose concentrations between 150 to 200 mg/dL. Once the anion gap has closed and the patient is ready to eat, the transition to subcutaneous insulin injections should be undertaken. A mixture of long- and short-acting insulin is provided at this time, overlapped with the drip for at least one hour to ensure adequate insulin levels. Occasional patients with type 2 diabetes and DKA may ultimately be able to be managed with oral agents alone. This management is generally not advisable during the hospitalization, however, and instead should be deferred to the outpatient setting.
Correction of acidosis necessarily follows insulin repletion. Because cardiac dysfunction may occur as the pH falls below 7.0, intravenous bicarbonate may be used judiciously in patients with a pH less than 7.0, although randomized trials have generally failed to show any benefit on outcomes. Theoretically, too much bicarbonate may lead to cerebral alkalosis, which can impair the respiratory compensation for systemic acidosis. In addition, as the ketone body production is halted, a correction alkalosis may occur. More important, large infusions of bicarbonate tend to lower serum potassium concentrations, which can aggravate the potential for severe hypokalemia.
Management of potassium is more challenging during therapy for DKA. Although potassium depletion may be in excess of 100 mEq, the admission potassium concentration is elevated because of the systemic acidosis, with resultant movement of potassium from the intracellular to the extracellular space. Frequent monitoring of the potassium concentration is therefore mandatory, and aggressive repletion is an important part of care of patients with DKA. As the glucose level falls and the pH normalizes, the potassium concentration decreases rapidly and must be corrected to avoid cardiac dysrhythmias. All intravenous fluid should contain at least 20 mEq/L of potassium unless the serum potassium is already in excess of 5.0 mEq/L. Additional potassium is necessary either orally or intravenously once the concentration falls below 4.0 mEq/L. Phosphate levels may also be labile during the management of the patient with DKA. Initially elevated, particularly in patients with renal insufficiency, phosphate levels also drop significantly once metabolic correction has been established. Although complications related to hypophosphatemia are rare and it has been difficult to demonstrate a clear benefit from routine phosphate repletion, maintenance of normal phosphate levels during therapy is advisable. Concurrent replacement of both potassium and phosphate with intravenous potassium phosphate should be considered to maintain the serum phosphate level above 1 mg/dL.
Cerebral edema is a rare but life-threatening complication of DKA and its treatment, occurring primarily in children and adolescents. Clues include headache and altered level of consciousness with subsequent neurologic deterioration several hours after therapy is initiated. The diagnosis must be suspected early and treated with mannitol and mechanical ventilation with lowering of the Paco2 to decrease intracranial pressure. Other complications of DKA include myocardial infarction, stroke, acute respiratory distress syndrome, deep venous thrombosis/pulmonary embolism and cardiac dysrhythmias, including ventricular tachycardia. Evaluation and management of patients with DKA must also include a detailed search for the precipitating cause, such as infection or myocardial infarction.
Hyperglycemic hyperosmolar syndrome
The hyperglycemic hyperosmolar syndrome (HHS), which occurs in patients with type 2 diabetes, is defined by a plasma osmolarity greater than 320 mOsm/L and a plasma glucose level greater than 600 mg/dL but a normal bicarbonate level, normal pH and no significant evidence of ketosis. The diagnosis is considered in any elderly patient with altered mental status and dehydration, particularly if a diagnosis of diabetes is already established. Rarely, HHS may be the presenting feature in the newly diagnosed patient. Many patients have overlap hyperglycemic syndromes with features of both HHS and DKA, such as severe hyperosmolarity but also mild acidosis. The absence of significant acidosis makes the management of HHS somewhat simpler than that for DKA. However, the more profound volume depletion and the older age of the patients typically affected, who are more likely to have underlying vascular disease, make potential complications more serious. Moreover, patients with HHS usually have identifiable precipitating factors, such as severe infection, myocardial infarction or new renal insufficiency, which can complicate therapy. HHS is common in debilitated patients from chronic care facilities who initially become ill and, because of insensible losses and perhaps an abnormal thirst mechanism, develop worsening hyperosmolarity and volume contraction. The counter-regulatory factors in response lead to hyperglycemia, which in turn results in more fluid losses. Eventually glucose clearance by the kidney declines, resulting in extreme hyperglycemia and hyperosmolarity. Coma may ensue as a result of the deleterious effects of hyperosmolarity on cerebral function.
Treatment of HHS is directed mainly at identifying the underlying illness that predisposed to hyperglycemia and at restoring a markedly contracted plasma volume. Subsequently and more slowly, the intracellular fluid deficits, which are substantial, require correction. The type of intravenous solution and the infusion rate depend on the degree of hyperosmolality and the extent of intravascular volume depletion. Normal saline, which is already typically hypotonic in these patients, is usually chosen first to quickly replenish the extracellular space. If the patient is hypotensive, fluids should be administered as quickly as possible and tolerated to restore plasma volume. Once blood pressure is restored and urine output is established, rates should be slowed and truly hypotonic solutions such as 0.45% sodium chloride should be used. The total body water deficits can be calculated using standard formulas, with the goal to replace one-half of the deficit during the first 24 hours and the remainder over the next two to three days. Ongoing insensible losses should be incorporated into these calculations. Because patients with HHS are usually older and prone to cardiovascular impairments, pulmonary and oxygenation status should be closely monitored. Occasionally, central venous pressure monitoring may be necessary.
Insulin reduces glucose levels, but should be administered only after plasma expansion has been initiated. If insulin is given before plasma expansion, theoretically, movement of glucose into cells may reduce circulating volume further, threatening cerebral and coronary perfusion. Intravenous insulin is preferred, with an initial bolus of 0.1 unit/kg and a rate of 0.1 unit/h. Electrolytes should be monitored, especially potassium because the concentration may fall as urine output is restored and renal function improves. Correction of hypokalemia should be aggressive, with maintenance of serum potassium at 4 mEq/L or more. Any mild metabolic acidosis present does not require bicarbonate therapy because normalization of circulating volume quickly corrects this defect. Once the plasma glucose level falls to less than 200 mg/dL, and if the patient is eating, subcutaneous insulin injections should replace intravenous insulin. Mental status in patients with HHS may lag behind correction of osmolarity, but usually full recovery occurs unless a cerebral ischemic insult has also occurred.
Hypoglycemia in diabetic patients (plasma glucose concentration less than 60 mg/dL) occurs because of excessive insulin supply for the needs of the patient at that particular time. Most commonly, hypoglycemia occurs in patients treated with insulin injections, but it can also occur in patients treated with insulin secretagogues, such as sulfonylureas. Initially, hyperadrenergic signs, such as diaphoresis, tachycardia, anxiety and tremor, develop. When the blood glucose level falls to less than 40 to 50 mg/dL, neuroglycopenic signs and symptoms develop, such as personality change, cognitive impairment, loss of consciousness and seizures. In severe cases, coma and irreversible brain injury may occur. Hypoglycemia usually occurs in the setting of missed meals, excess exercise, alcohol use or overenthusiastic insulin dosing. If the patient maintains consciousness, the symptoms can quickly be reversed with the ingestion of rapidly absorbed carbohydrates, such as glucose- or sucrose-containing foods. If the patient is unconscious or otherwise unable to swallow, intravenous dextrose infusion or intramuscular injection of glucagon is necessary. Identification of the precipitating factors is important to prevent future episodes. The antidiabetic regimen should be accordingly adjusted. Hypoglycemia remains the most important impediment to achieving tight glycemic control in insulin-treated patients.