Endocrine Emergencies

Diabetic ketoacidosis (DKA) is a syndrome of hyperglycemia, acidosis, dehydration, and electrolyte depletion caused by a relative or absolute deficiency of insulin in the setting of increased “stress”/counter-regulatory hormones. It usually occurs in type I diabetics but may also occur in type II diabetics associated with major concurrent illness, which alters the balance between insulin and counter-regulatory hormones. In either case the end result is uncontrolled catabolism.

Pathophysiology

• DKA can be precipitated by any disorder that severely alters the balance between insulin and its counter-regulatory hormones in the diabetic patient. The counter-regulatory hormones include glucagon, epinephrine, growth hormone and cortisol. Of these, glucagon is the most influential, and its levels are elevated four- to five-fold in DKA. These hormones promote gluconeogenesis and lipolysis while inhibiting peripheral glucose utilization. Insulin blocks gluconeogenesis and lipolysis while promoting peripheral glucose utilization. The hormonal imbalance between insulin and its counter-regulatory hormones promotes hyperglycemia, thyroid storm and leads to acidosis through ketogenesis.
• DKA precipitants include: insulin deficiency, infection, ischemia/infarction (cardiac and CNS), infant (pregnancy), and injury (trauma). Therefore, inadequate insulin availability, increased physiologic stress, or a combination of the two may result in DKA.
• Inadequate insulin usage in the type I diabetic is the most common cause of DKA. Infections are the second most common cause.
• Acidosis occurs secondary to increased lipolysis, which leads to an elevation of free fatty acids, the substrate of ketone formation. Elevations in ketones lead to anion gap acidosis.
• Dehydration and electrolyte depletion are the result of an osmotic diuresis caused by hyperglycemia. As the kidney’s capacity to reabsorb glucose is surpassed, the excess glucose in the renal tubule is excreted drawing out water and with it sodium, potassium, magnesium, calcium and phosphorous.

Diagnosis and Evaluation

The diagnosis of DKA is often obvious on the basis of clinical signs and symptoms alone. In the setting of hyperglycemia, metabolic acidosis, and ketonemia/ ketonuria, the diagnosis of DKA is easily made.

• The typical history is that of a type I diabetic with several days of polydipsia, polyuria, polyphagia, nausea, vomiting and malaise. A history of recent discontinuation of insulin or intercurrent illness is usually obtained.

Clinical Signs and Symptoms

• Indicators of dehydration are present including polyuria, polydipsia, weight loss, dry mucous membranes, skin tenting, sunken eyes, depressed fontanels (pediatric patient), tachycardia and, in late stages, hypotension and lack of urine production.
• Indicators of metabolic acidosis include tachypnea, Kussmaul breathing (hyperpnea), sensation of shortness of breath and a fruity odor of the breath.
• Nausea and vomiting is often severe and contributes to dehydration and hypokalemia.
• Abdominal pain is present in approximately 30% of patients, especially children. The etiology is unclear but is likely due to gastric distention or stretching of liver capsule and resolves with treatment. In adults with DKA, abdominal pain is more likely an indicator of true abdominal disease, (i.e., the precipitant of DKA as opposed to the result of it).

Laboratory/Studies

• Potassium is the most important laboratory value to determine in DKA. There is total body potassium depletion due to urinary losses and vomiting. The average deficit is 3-5 meq/kg. However, initial potassium levels obtained may be normal or high secondary to extracellular shifts in the setting of metabolic acidosis. For every 0.1. in pH, K+ will . by 0.6.
• There is a total sodium deficit secondary to urinary losses. Also hyponatremia, pseudohyponatremia results from glucose drawing water into the intravascular space, thereby diluting the serum sodium concentration. To correct add 1.6 to the sodium value for every 100 mg/dl glucose above normal.
• Corrected Na = serum Na + 1.6 (serum glu – 100)/100
• There is total body depletion as serum phosphorous follows potassium into the urine. As a component of ATP and 2,3-DPG, a severe phosphorous deficiency affects respiration, myocardial contractility and tissue oxygenation. Treat levels < 1.0. There is no evidence that routine supplementation is useful.
• There is depletion secondary to urinary losses and supplementation may be necessary.
• Perennial azotemia secondary to dehydration is present in most cases. Underlying renal insufficiency is common secondary to diabetic nephropathy. Serum creatinine determinations may be spuriously elevated in the setting of DKA, as ketones interfere with laboratory analysis.
• An initial blood gas is recommended in moderate to severe DKA to determine the degree of metabolic acidosis and respiratory compensation. In some facilities, the blood gas has the added advantage of providing a rapid set of electrolyte results (i.e., potassium). Venous blood pH is not significantly different from arterial blood pH among patients with DKA and is a reasonable alternative, especially if multiple measurements are to be taken.
• CBC is standard. Leukocytosis is common, often >15,000-20,000 without infection, making bandemia the best clue to infection. The hematocrit may be elevated due to hemoconcentration from prolonged dehydration.
• Urinalysis is mandatory. Glucose and ketones are elevated. Look for signs of urinary tract infection, a common precipitant of DKA.
• Urine pregnancy test is essential in any female of reproductive age.
• EKG should be examined for signs of a precipitant (i.e., ischemia/infarction). Look for EKG evidence of hypo/hyperkalemia (peaked T-waves of hyperkalemia of flattened T-waves or U-waves of hypokalemia)
• CXR should be examined for signs of pneumonia or CHF.

ED Management

The treatment of DKA can be divided into four basic components: rehydration, potassium replacement, insulin administration, and a careful search for and treatment of acute precipitants or underlying disease.

Rehydration

• Fluid replacement is the most critical and effective therapy for DKA. Fluids simultaneously correct dehydration, acidosis and hyperglycemia.
• The average fluid deficit is 5-10 L.
• To restore intravascular volume use normal saline. The first 1-2 L of normal saline (NS) should run in over 30-60 min/L. More normal saline may be needed depending on the level of dehydration and hemodynamic stability.
• Once intravascular volume has been restored, switch to 0.45% NS for maintenance fluids (usually 150-250 ml/h). It is important to avoid too rapid or over hydration. Complications include a precipitous drop in K+ if not supplemented early, fluid overload among patients with significant preexisting cardiac or renal disease, and cerebral edema (particularly in pediatric patient).
• Among pediatric patients, the average fluid deficit is 100-150 ml/kg. In the presence of hemodynamic instability an initial normal saline bolus of 20 ml/kg is given over 1 h. In the dehydrated, but hemodynamically stable pediatric patient an initial fluid bolus is not necessary and may increase the risks of cerebral edema. Instead, judicious administration of 1.5x maintenance fluids may be all that is needed during the emergency department course.

Potassium Repletion

• Beware of life-threatening hypokalemia once fluids and insulin are begun. K+ shifts back into cells and urinary losses are temporarily increased as renal excretion returns to normal. Monitor the potassium hourly over the first few hours.
• An initial EKG is a quick, helpful window to the K+ level before lab results are available.
• Potassium supplementation should be started when the potassium level is in the upper half of the normal range and the patient is making urine. Oral replacement, if the patient can tolerate it, is as effective and safer than intravenous routes. It may be given IV in concentrations of 20-40 meq/L at a rate of 10 meq/h (may approach 15-20 meq/h in severe hypokalemia).

Insulin Administration

• Insulin is not the first thing a person in DKA needs and can be lethal in the presence of hypokalemia. It is prudent to wait for a potassium level prior to insulin administration.
• Low dose insulin therapy is equally effective as high dose insulin therapy with fewer complications (i.e., hypokalemia, hypoglycemia).
• The frequent practice of administering a bolus of insulin is no longer recommended, as it increases risk without adding benefit.
• The half-life of insulin is 3-10 min; therefore continuous infusion provides a steady, reliable and easily titratable amount. The therapy of choice is 5-10 u/h continuous infusion or 0.1 u/kg/h drip. Before starting a drip, it is important to prime the tubing with 50 ml of the insulin infusion, as insulin will bind to the tubing.
• Once the serum glucose is = 300 switch to a glucose containing solution. The optimal rate of glucose decline is 100 mg/dl/h keeping the glucose above 250 mg/dl during the first 5 h of treatment.
• The insulin infusion should be continued until the anion gap acidosis is corrected. It is important to remember that the goal is not euglycemia but normalization of the anion gap acidosis. Also, the anion gap may correct while the serum bicarbonate level remains low. This is usually secondary to nonunion gap hyperchloremic metabolic acidosis, which may persist after over hydration with normal saline. Once the anion gap closes, and the patient has clinically improved and is able to tolerate POs, the insulin drip may be discontinued. It is important to give a dose of subcutaneous regular insulin 30 min prior to discontinuing the insulin drip to prevent a rebound of hyperglycemia and acidosis.
• A flow sheet provides an organized method of tracking a patient’s progress (Table 9A.1).

Search/Treatment for Acute Precipitant

• Infections are more common in diabetics and their presentations are often masked in DKA. The typical indicators of infection, fever and leukocytosis, are not reliable in DKA. For reasons not well understood, patients in DKA generally do not have fever, in fact, mild hypothermia is frequent. Leukocytosis is also common in DKA secondary to “stress” demargination. Bandemia is more specific for infection. It is important to rule out diabetic infectious emergencies: necrotizing fasciitis, osteomyelitis, Fournier’s gangrene, malignant otitis externa, rhino cerebral mucormycosis, emphysematous pyelonephritis and emphysematous cholecystitis.
• Diabetics are at risk for early cardiac events, which may precipitate DKA. Myocardial infarction or ischemia is often masked in adults with DKA. Pain may be atypical or absent in the setting of diabetes secondary to diabetes-related neuropathy (“silent MI”).
• All female patients of reproductive age must be screened for pregnancy. Fetal mortality may be 50-90% after a single episode of DKA.

Other Interventions

• Phosphorus: Give 20 meq of potassium phosphate for a phosphorus level < 1.
• Magnesium: If magnesium is low, give 0.35 meq/kg in fluids over first 3-5 h or 2.5-3 g for a seventy kg patient.
• Sodium Bicarbonate: The role of sodium bicarbonate is controversial. May be considered for a pH < 6.9. However, there is no evidence that patients given sodium

Special Considerations

Euglycemic DKA

• A subset of patients with DKA will have normal or only slightly elevated blood glucose. Euglycemic DKA is defined as a blood glucose level < 300 mg/dl. This may occur if insulin levels are sufficient to maintain a normal blood glucose but not sufficient to block lipolysis and ketogenesis. For example: a diabetic in early DKA precipitated by infection who has decreased carbohydrate intake secondary to nausea/vomiting and has increased their insulin dose in response to DKA.

Ketoalkalosis

• In the setting of severe vomiting (metabolic alkalosis), dehydration (contraction alkalosis), and hyperventilation (respiratory alkalosis), acidemia may not always be present.

Negative Ketone Assays

• Initially, patients in DKA may have negative tests for ketones in the serum and urine in the presence of significant ketoacidosis. The laboratory detects only acetoacetate, while the predominant ketone of early and untreated DKA is betahydroxybutyrate. As treatment is begun the levels of detectable ketones (acetoacetate) increase.

Pediatric DKA Considerations

• DKA is responsible for approximately 70% of diabetes-related deaths in children. It must be taken seriously with prompt diagnosis and treatment and early consultation of a pediatric critical care specialist and or pediatric endocrinologist. If hemodynamically unstable, give 20 ml/kg bolus of 0.9% NS. Otherwise, 0.45% NS run at 1.5x maintenance is generally sufficient and minimizes risks of rapid over hydration. During treatment the glucose level should decrease no faster than 50-100 mg/dl/h, and should be checked hourly. The insulin dosage is 0.05-0.1 u/kg/h IV infusion. When under the age of 5 yr, only mildly ill, or within 6 h of a subcutaneous dose use 0.05-0.08 u/kg/h. It is important to add 5% dextrose to IV fluids when glucose level is 250-300, or to slow the rate of glucose fall. Consider adding 10% dextrose when glucose falls below 200. The goal is to keep glucose approximately between 180-200 throughout the first 24 h of therapy.

Cerebral Edema

• Most commonly seen in children, but may be seen in adults. It involves an acute alteration in mental status usually 6-10 h after initiation of therapy. The mortality is approximately 90%. The exact etiology is unclear but may be due to “idiogenic osmoles” developed in brain cells in response to a hypertonic environment. This leads to intracellular swelling once fluids are administered. Overzealous hydration and rapid declines in serum glucose play a role. However, some evidence suggests that subclinical cerebral edema exists in most children with DKA. Treatment is mannitol 0.25-2 g/kg IV, which should be kept readily available and given at the first sign of neurologic deterioration.

Insulin Pump

• The use of insulin pumps is becoming more common, particularly in the pediatric population, secondary to the convenience and steady glucose control it provides. However, the insulin pump is associated with an increased incidence of DKA, usually secondary to mechanical problems with the tubing.

Admission Criteria

• Most patients with DKA should be admitted to the hospital. An ICU admission is recommended in the following situations:
  1. extremes of age
  2. severe concurrent illness
  3. altered mental status
  4. persistent severe acidosis
  5. severe hypokalemia
• Patients with mild to moderate DKA can generally be sent to the regular ward. In some settings a 24 h “observation” unit is available. A small subgroup of patients may be discharged from the emergency department: those with only mild DKA and complete resolution of anion gap acidosis, no precipitating illness, not the first episode, able to tolerate oral fluids and self-administer insulin, and close follow available.