Hyperglycemia

In these patients, a thorough history and physical examination should be performed with a focus on trying to identify a precipitating cause of hyperglycemia, such as infection. In patients with an incidental finding of mild to moderate hyperglycemia or those with minor symptoms little else may be necessary beyond anticipatory guidance and proper follow up. In those with blood glucose levels greater than 250 mg/dL, further laboratory assessments will be needed to distinguish presence of DKA and/or HHS. In more severe manifestations of DKA and HHS, these children are often severely ill with CNS depression to a point of coma and hemodynamic instability and the following measures should be instituted:

• Close attention should be paid to the ABC's (airway, breathing, circulation).
• Obtain IV access.
• IV bolus of 10-20 mL/kg of isotonic crystalloid fluid (0.9% normal saline).
• Place the patient on a cardiac monitor.

Careful assessment of neurologic function should be done, including a Glasgow Coma Scale (GCS) to assess for signs of cerebral edema. A key feature of both DKA and HHS is severe dehydration; following the initial crystalloid bolus, further volume replacement should be guided by the underlying etiology of DKA vs HHS, as their management strategies differ.

For patients with hyperglycemia, it is important to have the following differential diagnosis:

• Dietary indiscretion
• DKA
• HHS
• New onset or uncontrolled diabetes
• Medication non-adherence

A number of other conditions can affect patients with diabetes resulting in an increase in counter-regulatory hormones and hyperglycemia, some of which can precipitate DKA or HHS. These include:

• Infection
• Surgery
• Trauma
• Stress

In addition, some medications may induce hyperglycemia and even precipitate DKA in susceptible patients, which include:

• Corticosteroids
• Immunosuppressants
• Diazoxide
• Atypical antipsychotic agents

Classic Presentation

Patients with mild hyperglycemia may, in fact, be asymptomatic. In early DKA and HHS, impaired glucose uptake from inadequate circulating insulin results in ever increasing hyperglycemia. Once the blood glucose level rises above approximately 180 mg/dL (renal threshold), patients will start to develop an osmotic diuresis. At this time, patients may present with a variety of symptoms, including polyuria, polydipsia, polyphagia, or weight loss. These symptoms will be highly variable from patient to patient. Some will also develop tachycardia, dizziness, lightheadedness, and weakness as a result of dehydration and electrolyte imbalance. In DKA, increasing ketones created by lipolysis leads to acidemia which further impairs kidney function and exacerbates volume depletion and electrolyte disturbances, resulting in a cascade of additional symptoms including:

• Abdominal pain.
• Nausea and vomiting.
• Hyperpneic respirations (fast and deep Kussmaul respirations from acidemia).
• Hypotension.
• Ketotic breath (fruity odor in DKA).
• Marked tachycardia.
• Neurologic symptoms (seizures, focal weakness, lethargy, coma, etc.).

With HHS, the hyperglycemia is more severe, leading to a greater degree of osmotic diuresis. The increasing blood glucose concentration results in further dehydration by drawing water from bodily tissue. As a result, HHS is associated with a higher degree of volume loss and often presents with more severe CNS depression.

The extent of diagnostic testing will depend on the patient’s presenting symptoms, the physician’s differential diagnosis, and suspicion for complications related to their diabetes/hyperglycemia. Some patients may need no more than bedside glucose testing +/- urinalysis, while others may need more in-depth diagnostic testing, such as patients with concern for complications such as DKA or HHS. For patients presenting with hyperglycemia with FSBS > 200, the following diagnostic tests should be performed:

• Complete metabolic profile (remember to correct serum sodium based on the serum glucose).
• Complete blood count (often obtained when suspicious for an infectious etiology, sensitive but not specific).
• Blood gas determination (venous blood gas sample provides accurate information regarding blood pH and closely approximates that of arterial pH).
• Additional electrolytes (phosphorus, magnesium) may be important in patients profoundly dehydrated.
• Electrocardiogram (ECG). In patients with marked acidemia or severe hyperglycemia, extracellular potassium shifts may result in ECG manifestations of hyperkalemia despite total body losses.
• Serum ketones and beta-hydroxybutyrate are more sensitive than urine ketones.
• Hemoglobin A1c.
• Urinalysis for evaluation of ketones.
• Additional testing based on patient presentation (lipase, chest radiograph, blood cultures, etc.).

Diagnosing DKA or HHS is done at the bedside with a high clinical suspicion based on the patient's history, physical exam, and initial laboratory findings. The following table presents the diagnostic criteria for DKA and HHS. It should be remembered that HHS can present with both an anion gap and ketosis (approximately 50% of patients) but usually will not have a significant acidosis.

Diabetic Ketoacidosis vs Hyperglycemic Hyperosmolar State

In patients with an uncomplicated presentation associated with mild-moderate hyperglycemia without signs of DKA or HHS and known history of diabetes, often no urgent treatment is required outside of development of management plan for blood glucose control based on the patient’s treatment regimen or in consultation with the patient’s endocrinologist or pediatrician. Patients presenting with hyperglycemia and diagnostic work-up consistent with a new diagnosis of diabetes should be discussed with a pediatric endocrinologist for management planning and consideration for admission. For patients with isolated hyperglycemia and blood glucose measurements <200 mg/dL, evaluation for causes of elevated glucose should be considered, such as reasons for stress induced or medication induced hyperglycemia.

DKA Treatment

Treatment for DKA is centered around gradual correction of intravascular volume depletion, management of electrolyte abnormalities, insulin replacement therapy to safely reduce the serum glucose concentration, and identification of and treatment of any underlying precipitants.

Fluid Replacement

• Start with isotonic saline (0.9%) with an initial fluid bolus of 10-20 cc/kg run over the first hour. If the patient appears to be in shock, additional fluid boluses can be considered.
• After initial fluid resuscitation, the remainder of fluid deficit is corrected over the next 24-48 hours through the use of a two-bag system if the patient has a normal potassium level and no signs of cerebral edema. A two-bag system of intravenous fluids consists of one bag of 0.45% or 0.9% sodium chloride with potassium (typically a combination of 10-20 mEq/L potassium acetate and 10-20 mEq/L potassium phosphate) and one bag of D10 + the same sodium chloride and potassium supplementation as the other bag of IV fluid. The total IV fluid rate combined from the two-bag system is at the 1.5 times maintenance fluid rate for the child's weight in kilograms. Adjustment of each individual bag fluid rate is based on the patient's hourly glucose check while on the two-bag system and IV insulin infusion. An example of a two-bag system based on glucose levels is shown below, but will vary based on local institutional treatment pathways.

Insulin Replacement

• Insulin therapy after fluid resuscitation has been initiated. It should be used in conjunction with the two-bag system.
• Start with an infusion of regular insulin at 0.1 U/kg/hr. If a patient is sensitive to insulin infusion, the rate can be decreased to 0.05 U/kg/hr. Insulin boluses are not used in the pediatric population.

Potassium Replacement

• If the initial potassium is < 3.3 mEq/L then DELAY insulin therapy until potassium is replaced, no more than 0.5 mEq/kg/hr.
• Administer potassium with initial fluid replacement if potassium levels are normal or low and maintained between 3.5-5.4 mEq/L.
• If the patient's initial potassium is > 5.4 mEq/L, then starting the two-bag system without potassium supplementation is recommended.

Bicarbonate

Use of bicarbonate is not recommended due to the association of cerebral edema and hypokalemia. Treatment with bicarbonate is reserved only for patients with associated cardiac dysfunction based on hyperkalemia or severe acidosis.

Monitoring of Electrolytes

Patients with both DKA will require serial monitoring of:

• Blood glucose every hour until stable, then every two-four hours.
• Basic metabolic profile and blood pH every two-four hours during therapy until patient stabilizes.
• Magnesium and phosphorous levels should be monitored with the same frequency of the basic metabolic profile.
• Serum sodium concentration will need correction based on the glucose level and should be corrected.

HHS Treatment

Treatment for HHS in children is based on an approach that focuses more on fluid resuscitation than pathways for diabetic ketoacidosis as fluid deficits are 1.5-2 times greater in HHS than in DKA. In HHS, the fluid deficit should be assumed to be 12-15%. The goal for fluid replacement in HHS is within 24 hours for DKA, as opposed to the more gradual approach in DKA.

Fluid Replacement

• Initial fluid boluses should consist of isotonic (0.9%) saline at 20cc/kg until intravascular volume is sufficient to support perfusion, with a minimum of 40cc/kg in the first six hours for restoration of peripheral perfusion.
• After restoration of perfusion, transitioning to 0.45% or 0.75% saline is recommended to gradually reduce sodium concentrations. The total fluid deficit should be replaced over 24-48 hours.
• With rehydration, serum glucose will have a more rapid decline in the first several hours of treatment. Serum sodium concentrations will need to be monitored to ensure a rapid reduction does not occur. Suggested rate of decline is 0.5 mEq/L/hr.

Insulin Replacement

• Early insulin replacement is not indicated in HHS due to the lack of ketosis and the improvement in glucose with IV fluids.
• If a plateau is reached in glucose reduction less than 50mg/dL/hr, then administration of insulin should be considered at a lower rate than in DKA. Insulin infusion should occur at the rate of 0.025-0.05 U/kg/hr if initiated to reach a goal of an hourly reduction in glucose of 50-75 mg/dL/hr.

Bicarbonate and Electrolytes in HHS

• Bicarbonate administration is contraindicated in HHS as it may exacerbate hypokalemia.
• Potassium replacement should be initiated once potassium concentrations are within normal ranges.
• Hypokalemia can be replaced by adding potassium phosphate and potassium chloride or acetate to IV fluids in 50:50 ratio.
• Electrolyte levels, magnesium, and phosphorous levels should be checked every two-three hours with treatment.

Complications

One very serious complication of DKA/HHS is cerebral edema. It is mainly seen in children and young adults suffering from DKA, occurring 4-12 hours into treatment with a high degree of morbidity and mortality. Clinically, it is often preceded by headache, lethargy, and then neurologic deterioration (seizures, coma) with bradycardia and respiratory arrest. Although not completely understood, development of cerebral edema is correlated with bicarbonate administration and massive fluid resuscitation. Treatment includes administration of mannitol (0.5-1g/kg IV over 10-15 minutes) with signs of improvement typically occurring after 15–20 mins. If the patient is not responsive to treatment, a second dose of mannitol can be given or hypertonic saline 3% can be used (2.5-5 cc/kg over 10-15 minutes). Cerebral edema is rare in HHS, even though patients will present with altered mental status. A more common complication seen in HHS is rhabdomyolysis. Patients with myalgias, weakness, dark urine or not improving renal function should have rhabdomyolysis in the differential with HHS.

Patients with uncomplicated hyperglycemia with established cause can typically be managed as an outpatient based on the etiology of the hyperglycemia and determination of associated conditions. Patients with a new diagnosis of diabetes, or patients suffering from DKA and HHS, require hospital admission with the level of care depending on the patient's mental status, laboratory parameters, and institutional care pathways.

• Physicians should consider other coexisting illnesses as a precipitant of DKA and HHS.
• Insulin therapy should be started after administering an initial amount of normal saline and checking the potassium level.
• Electrolyte levels should be routinely monitored during treatment of DKA and HHS.
• In children, continue to monitor for and promptly treat signs/symptoms of cerebral edema.

The patient has a fingerstick glucose performed, which reveals a serum glucose of 450 mg/dL. The patient has further diagnostic studies to evaluate the hyperglycemia, while also starting a 0.9% NaCl infusion at 10cc/kg over 30 minutes. Diagnostic studies reveal a pH of 7.1, with a serum bicarbonate of 12 mEq/L and an anion gap of 18. Urinalysis is positive for large ketones. The patient is started on a two-bag IV fluid system, along with an insulin drip at 0.1U/kg/hr. The patient is admitted to the hospital for further management of her DKA.

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