Approach

The main goals of treatment in hyperosmolar hyperglycemic state (HHS) are:

  • Restoration of volume deficit. Fluid therapy should be started immediately after initial laboratory evaluations. Infusion of 0.9% sodium chloride should begin at a rate of 1 to 2 L/hour for the first hour

  • Resolution of hyperglycemia

  • Correction of electrolyte abnormalities (the potassium level should be >3.3 mEq/L before initiation of insulin therapy). Use of insulin in a patient with hypokalemia may further decrease serum potassium owing to potassium shifting to the intracellular space, which may result in respiratory paralysis, cardiac arrhythmias, and death

  • Treatment of the precipitating events and prevention of complications.

Although it is possible to manage mild HHS without admission to the intensive care unit (ICU), many cases will require ICU care. Successful treatment requires frequent monitoring of clinical and laboratory parameters to achieve resolution criteria. A treatment protocol and a flow sheet for recording the treatment stages and laboratory data should be maintained.[1][9]

Diagnosis of precipitating factors, such as urinary tract infection, pneumonia, or causative medications, and appropriate treatment with antibiotics, and removal of the offending medication should be sought.[15]

Patients with hemodynamic, cardiovascular, or respiratory instability or altered mental status

The diagnosis of hemodynamic instability is made by observing hypotension and clinical signs of poor tissue perfusion, including oliguria, cyanosis, cool extremities, and altered mental state. These patients require urgent admission to the ICU.

After admission to the ICU, frequent blood pressure and hemodynamic monitoring is needed. A central venous catheter and/or a Swan-Ganz catheterization and continuous percutaneous oximetry are also required. Oxygenation and airway protection are crucial. Intubation and mechanical ventilation are commonly required, with constant monitoring of respiratory parameters.


Tracheal intubation: animated demonstrationTracheal intubation: animated demonstration

Bag-valve-mask ventilation: animated demonstrationBag-valve-mask ventilation: animated demonstration

Supportive care

Diagnosis of precipitating factors, such as infections or causative medications, and appropriate treatment (e.g., antibiotics for infection or removal of an offending medication) should be performed in all patients, as appropriate.[15] Monitoring of hemodynamic status, respiratory parameters, and urine output are essential, particularly in hemodynamically unstable patients. Frequent glucose monitoring at the bedside should be performed every 1 to 2 hours until hyperglycemia is corrected.[3]

Subsequent to initial laboratory evaluation, serum electrolytes should be checked every 2 to 4 hours, and calcium, magnesium phosphate, BUN, and creatinine checked every 2 to 6 hours, depending on the patient's clinical condition and response to therapy. Repeated measurement of serum/urine ketone levels is not indicated. A flow sheet classifying these findings as well as mental status, vital signs, insulin dose, fluid, electrolyte therapies, and urine output enables easy analysis of response to therapy and resolution of crises.[1][9]

Fluid therapy

Patients with severe volume depletion (100 mL/kg or approximately 7 to 9 L, orthostatic or supine hypotension, dry mucus membranes, poor skin turgor) should receive fluid resuscitation in addition to maintenance fluid therapy. Hydration status should be continuously evaluated clinically.

In the setting of severe volume deficit and shock, and in the absence of cardiac compromise, patients should receive 0.9% sodium chloride at a rate of 15 to 20 mL/kg/hour or 1 to 2 L during the first hour.[1][46] Once hypotension is corrected, fluid resuscitation should be continued with 0.9% sodium chloride at 500 mL/hour for 4 hours, then 250 mL/hour for another 4 hours.[46]

Potassium should be added to maintenance fluid therapy for patients who are normokalemic or hypokalemic.[40]

Maintenance fluid therapy is based on the corrected serum sodium level. Corrected sodium (mEq/L) = measured sodium (mEq/L) + 0.016 (glucose (mg/dL)-100).

Hyponatremic patients

Subsequent fluid therapy may be continued with 0.9% sodium chloride at 250 to 500 mL/hour; when plasma glucose reaches 250 to 300 mg/dL, fluid therapy should be changed to 5% dextrose with 0.9% sodium chloride at 150 to 250 mL/hour.[1][40][9][46]

Hypernatremic or eunatremic patients

Subsequent fluid therapy should be changed to 0.45% sodium chloride at 250 to 500 mL/hour; when plasma glucose reaches 250 to 300 mg/dL, it should be changed to 5% dextrose with 0.45% sodium chloride at 150 to 250 mL/hour.[1][40][9][46]

If plasma osmolality is falling more rapidly than 3 mOsm/kg/hour, continuing 0.9% sodium chloride may be more appropriate.[40]

Hyperosmolality therapy

Plasma osmolality is usually greater than 320 mOsm/kg in HHS. A rapid reduction of plasma osmolality can lead to cerebral edema, and it is therefore recommended that plasma osmolality not be lowered by more than 3 mOsm/kg/hour. This can be achieved by monitoring plasma osmolality, adding dextrose to intravenous fluids once plasma glucose falls below 250 to 300 mg/dL, and selecting the correct concentration of intravenous saline depending on serum sodium concentration.[14][46]

Vasopressors

If hypotension persists after forced hydration, a vasopressor agent should be started. Norepinephrine or dopamine are considered first-line drugs. Dopamine increases stroke volume and heart rate and norepinephrine increases mean arterial pressure.

Insulin therapy

The goal is the steady, gradual reduction of serum glucose and plasma osmolality (to reduce the risk of treatment complications, e.g., hypoglycemia and hypokalemia) by low-dose insulin therapy.

A continuous intravenous infusion of regular insulin is usually recommended if the serum potassium is >3.3 mEq/L. The insulin can be started with a bolus of 0.1 units/kg followed by 0.1 units/kg/hour continuous infusion. Alternatively, a continuous insulin infusion of 0.14 units/kg/hour can be commenced without the initial insulin bolus.[1]

If the serum glucose does not fall by at least 10% in the first hour, then a bolus of 0.14 units/kg of intravenous insulin should be administered, while continuing the previous insulin infusion rate (i.e., either 0.1 units/kg/hour or 0.14 units/kg/hour). Once the blood glucose reaches 300 mg/dL or less, the insulin infusion should be reduced to 0.02 to 0.05 units/kg/hour, while maintaining the blood glucose between 200 and 300 mg/dL, until the patient is mentally alert.[1]

Rapid reductions in blood glucose concentrations must be avoided to prevent sudden osmolar changes and cerebral edema. One series reported that the mean duration of treatment until correction of hyperglycemia is 9 ± 1 hours.[10] Fluid replacement and low-dose insulin therapy decrease plasma glucose concentration at a rate of 50 to 75 mg/dL/hour.

Insulin injection by a sliding scale is no longer recommended in the treatment of HHS.

Potassium therapy

Insulin therapy and correction of hyperosmolality drive potassium into cells, which may cause serious hypokalemia. The goal is to maintain potassium levels within the normal range in order to prevent complications of hypokalemia, including respiratory paralysis and cardiac dysrhythmia. An adequate urine output of >50 mL/hour should be ensured while the patient is on potassium therapy and the hydration status should be continuously evaluated clinically.

If baseline serum potassium is ≤3.3 mEq/L:

  • insulin therapy should be delayed and 20 to 30 mEq potassium should be given per hour until potassium is >3.3 mEq/L.[1]

If baseline serum potassium level is between 3.4 to 5.2 mEq/L:

  • potassium replacement should be started at 20 to 30 mEq/L in each liter of intravenous fluid.[1]

If the baseline serum potassium level is ≥5.3 mEq/L (or above the upper limit of normal in the laboratory):

  • potassium replacement is not needed but levels should be checked every 2 hours.[1]

Phosphate therapy

Whole-body phosphate is low in HHS, but routine phosphate replacement has not resulted in clinical benefits to patients.[2]

In the presence of severe hypophosphatemia (<1 mg/dL) in patients with cardiac dysfunction (e.g., with signs of left ventricular dysfunction), symptomatic anemia, or respiratory depression (e.g., decreased oxygen saturation), careful phosphate therapy may be indicated to avoid cardiac, respiratory, and skeletal muscle dysfunction.[1]

Ongoing therapy

Management and monitoring should continue until resolution of HHS. Criteria for resolution of HHS are:[1]

  • Normal plasma glucose (<250 to 300 mg/dL)

  • Normal plasma effective osmolality (<315 mOsm/kg)

  • Normal hemodynamic and mental status.

Once HHS is resolved and the patient is able to tolerate oral intake, transition to subcutaneous insulin needs to be initiated. Patients should be given subcutaneous insulin 1 to 2 hours before the termination of insulin infusion to enable sufficient time for subcutaneous insulin to begin to work.

Intermediate or long-acting insulin is recommended for basal requirements and short-acting insulin for prandial glycemic control.


Central venous catheter insertion: animated demonstrationCentral venous catheter insertion: animated demonstration

Peripheral venous cannulation: animated demonstrationPeripheral venous cannulation: animated demonstration

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