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 and uncomplicated HHS in step-down or intermediate care units, many cases will require intensive care unit (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.[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.[2]
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.
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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.[2] 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.[2]
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.[9]
Fluid therapy
Patients with severe volume depletion (100 mL/kg or approximately 7 to 9 L, orthostatic or supine hypotension, dry mucous membranes, poor skin turgor) should receive fluid resuscitation in addition to maintenance fluid therapy. Hydration status should be continuously evaluated clinically. Most clinical guidelines recommend the administration of 0.9% sodium chloride (isotonic saline) as the initial resuscitation because of its widespread availability, lower cost, and efficacy in restoring circulating volume in clinical studies.
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.[2][44] Once hypotension is corrected, fluid resuscitation should be continued with 0.9% sodium chloride at 250 to 500 mL/hour.[44]
Older adults, or patients with heart failure or end-stage kidney disease on dialysis, should be treated cautiously, with smaller boluses of isotonic solutions (e.g., 250 mL boluses) and frequent assessment of hemodynamic status.[3][54] In such patients, the use of a standard fluid replacement protocol may be associated with treatment-related complications including volume overload, mechanical ventilation, and longer length of stay.[54]
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).
In patients with HHS, the usual time to resolve hyperglycemia is between 8 and 10 hours and the decline should not exceed 90 to 120 mg/dL/hour (5.0 to 6.7 mmol/L/hour) to prevent cerebral edema. Initial fluid replacement will lower the glucose concentration and osmolality, causing a shift of water into the intracellular space, which may result in a rise in serum sodium (a reduction of 100 mg/dL [5.6 mmol/L] will result in a 1.6 mmol/L rise in sodium concentration).[2][9][44]
The initial rise in serum sodium is not an indication to give hypotonic fluids, and the administration of 0.45% sodium chloride is only indicated if osmolality is not declining despite adequate positive fluid balance and appropriate insulin administration. To prevent too rapid a fall in osmolality, some have recommended that insulin be withheld until glucose has stopped dropping with initial fluid administration alone.[44]
Hyperosmolality therapy
Plasma osmolality is usually greater than 320 mOsm/kg in HHS. Similarly, the rate of decline of serum sodium should not exceed 10 mEq/L in 24 hours and the rate of fall in osmolality should be no greater than 3.0 to 8.0 mOsm/kg/hour to minimize the risk of neurologic complications. 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.[44]
Vasopressors
If hypotension persists after forced hydration, a vasopressor agent should be started under specialist supervision.[55] Patients requiring vasoactive drugs (vasopressor and/or inotrope) need continuous monitoring in a critical care setting.
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 followed by a continuous infusion.[2]
If the serum glucose does not fall by at least 10% in the first hour, then a further bolus should be administered, while continuing the previous insulin infusion rate. Once the blood glucose reaches 300 mg/dL or less, the insulin infusion should be reduced, while maintaining the blood glucose between 200 and 300 mg/dL, until the patient is mentally alert.[2]
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.[15] Fluid replacement and low-dose insulin therapy decrease plasma glucose concentration at a rate of 50 to 75 mg/dL/hour.
Subcutaneous insulin administration by a sliding scale alone is not 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. Insulin therapy, correction of acidosis, volume expansion, and increased urinary loss of potassium decrease serum potassium. Within 48 hours of admission, potassium levels typically decline by 1 to 2 mEq/L in patients with diabetic ketoacidosis (DKA), HHS, and mixed DKA/HHS. To prevent hypokalemia, potassium replacement should be started after serum levels fall below 5.0 mEq/L with the aim of maintaining a potassium level of 4 to 5 mEq/L.
If baseline serum potassium is ≤3.3 mEq/L:
Insulin therapy should be delayed and potassium should be replaced until >3.3 mEq/L (guidelines suggest replacement with 20 to 30 mEq potassium per liter of infusion fluid, though in practice we recommend 10 to 20 mmol per liter).[2]
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.[2]
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.[2]
Phosphate therapy
Whole-body phosphate is low in HHS, but routine phosphate replacement has not resulted in clinical benefits to patients.[4]
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.[2]
Ongoing therapy
Management and monitoring should continue until resolution of HHS. Criteria for resolution of HHS are:[2]
Normal plasma glucose
Normal plasma osmolality
Normal hemodynamic and improved 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.
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