Diabetic ketoacidosis (DKA) and the hyperosmolar hyperglycemic state (HHS) are the two most serious acute metabolic complications of diabetes. The triad of uncontrolled hyperglycemia, metabolic acidosis (SAG elevated metabolic acidosis), and increased total body ketone concentration characterizes DKA. HHS is characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of significant ketoacidosis.

Pathogenesis

DKA

In DKA, hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and imaired glucose utilization by peripheral tissues.

The mechanisms of these three processes include: reduced effective insulin concentrations and increased concentrations of counterregulatory hormones (catecholamines, cortisol, glucagon, and growth hormone) lead to hyperglycemia and ketosis.

The combination of insulin deficiency and increased counterregulatory hormones in DKA lead to the release of free fatty acids into the circulation from adipose tissue (lipolysis) and to unrestrained hepatic fatty acid oxidation in the liver to ketone bodies (β-hydroxybutyrate and acetoacetate), with resulting ketonemia and metabolic acidosis.

HHS

The pathogenesis of HHS is not as well understood as that of DKA, but a greater degree of dehydration (due to osmotic diuresis) and differences in insulin availability distinguish it from DKA. Although relative insulin deficiency is clearly present in HHS, endogenous insulin secretion (reflected by C-peptide levels) appears to be greater than in DKA, where it is negligible. Insulin levels in HHS are inadequate to facilitate glucose utilization by insulin-sensitive tissues but adequate to prevent lipolysis and subsequent ketogenesis.

Figure 1. Pathogenesis of DKA and HHS

Precipitating Factors

The most common precipitating factor in the developmemt of DKA and HHS is infection. Other precipitating factors include discontinuation of or inadequate insulin therapy, pancreatitis, myocardial infarction, cerebrovascular accident, and drugs.

However, an increasing number of DKA cases without precipitating cause have been reported in patients with diabetes.

On admission, leukocytosis with cell counts in the 10,000-15,000 mm3 range is the rule in DKA and may not be indicative of an infectious process. However, leukocytosis with cell counts >25,000 mm3 may designate infection and require further evaluation.

Diagnosis

The key diagnostic feature in DKA is the elevation in circulating total blood ketone concentration and hyperglycemia. If available, measurement of β-hydroxybutyrate may be useful for diagnosis. For hyperglycemia, however, a wide range of plasma glucose can be present on admission.

While HHS is characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of significant ketoacidosis. Studies on serum osmolality and mental alteration have established a positive linear relationship between osmolality and mental obtundation. The occurrence of stupor or coma in a diabetic patient in the absence of definitive elevation of effective osmolality (≥320 mOsm/kg) demands immediate consideration of other causes of mental status change.

PS: The effective osmolality can be calculated as: [sodium ion (mEq/L) × 2 + glucose (mg/dL)/18]. For example, a given serum sodium ion concentration of 100 mEq/L, with a serum glucose concentration of 750 mg/dL, the effective osmolality should be [100 × 2 + 750/18] = 241.67 mOsm/kg. Note that the BUN/urea concentration is not taken into account becaue it is freely permeable and its accumulation dose not induce major changes in intracellular volume or osmotic gradient across the cell membrane.

Diagnostic Criteria for DKA and HHS

Treatment

Fluid and Electrolyte Correction

Successful treatment of DKA and HHS requires correction of dehydration, hyperglycemia, and electrolyte imbalances; identification of comorbid precipitating events; and above all, frequent patient monitoring. Generally, the treatment strategies include fluid therapy (necessary), insulin therapy (necessary), potassium correction (necessary), pH correction (if necessary), and phosphate correction (if necessary).

Initial fluid therapy for both DKA and HHS is fluid replacement with 0.9% NaCl infused at a rate of 15-20 ml · kg body wt-1 · h-1 or  1-1.5 l during the first hour. Thereafter if the corrected serum sodium is low, 0.9% NaCl should be administered at a rate of 250-500 ml/h. Conversely, if the corrected serum after the fluid replacement of the initial first hour is normal or elevated, 0.45% NaCl infused at a rate of 250-500 ml/h is the strategy. Subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels, and urinary output.

Once the plasma glucose is ~ 200 mg/dL (DKA) or ~ 300 mg/dL (HHS), the fluid replacement should be changed to 5% dextrose with 0.45% NaCl at the drip rate of 150-250 ml/hr.

Despite total-body potassium depletion, mild-to-moderate hyperkalemia is common in patients with hyperglycemic crises. Insuilin therapy, correction of acidosis (alkali replacement enhance the risk of increased potassium waste), and volume expansion decrease serum potassium concentration. To prevent hypokalemia, potassium replacement is initiated after serum levels fall below the upper level of normal for the particular laboratory (5.0-5.2 mEq/L). The treatment goal of potassium replacement is to maintain srum potassium levels within the normal range of 4-5 mEq/L. Generally, 20-30 mEq potassium in each liter of infusion fluid is sufficient to get this goal. Rarely, DKA patients may present with significant hypokalemia. In such cases, potassium replacement should begin with fluid therapy (note that in such cases insulin therapy should be delayed until serum potassium restores to >3.3 mEq/Ll).

Despite whole-body phosphate deficits in DKA, serum phosphate is often normal or increased at presentation. Phosphate concentration decreases with inslulin therapy. However, prospective randomized studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in DKA, and overzealous phosphate therapy can cause severe hypocalcemia. But, to avoid potential cardiac and skeletal muscle weakness and respiratory depression due to hypophosphatemia, careful phosphate replacement may sometimes be indicated in patients with cardiac dysfunction and in those with serum phosphate concentration <1.0 mg/dL. When needed, 20-30 mEq/L potassium phosphate can be added to replacement fluids. For HHS, no studies are available on the use of phosphate.

The maximal rate of phosphate replacement generally regarded as safe to treat severe hypophosphatemia is 4.5 mmol/h.

Insulin Therapy

Low-dose regular insulin by intravenous infusion have demonstrated it effectiveness and benefit in the treatment of both DKA and HHS. Regular insulin should be given to patients with DKA or HHS on admission, but, for patients with significant hypokalemia on admission, insulin treatment should be delayed until patassium concentration is restored to >3.3 mEq/L. Regular insulin should be administered intravenously at a continuous dose of 0.1 U/kg/hr, with a prior IV bolus dose of 0.1 U/kg. If serum glucose dose not fall by at leaset 10% in the first hour, we should give 0.14 U/kg as IV bolus, then continue previous Rx.

Once the plasma glucose is ~ 200 mg/dL (DKA) or ~ 300 mg/dL (HHS), the rate of intravenously continuous regular insulin should be decreased to 0.02-0.05 U/kg/hr. Thereafter, the rate of insulin administration or the concentration of dextrose may need to be adjusted to maintain glucose values between 150 and 200 mg/dL in DKA or 250 and 300 mg/dL in HHS until they are resolved.

Transition to subcutaneous insulin. Once DKA or HHS is resolved, subcutaneous insulin theray can be started and continuous intravenous insulin should be allow a overlap of 1-2 h before discontinuation due to prevention recurrence of hyperglycemia or ketoacidosis during the transition period from IV insulin to SC insulin. Patients with known diabetes may be given insulin at the dosage they were receiving before the onset of DKA so long as it was controlling glucose properly. In insulin-naïve patients, a multidose insulin regimen should be started at a dose of 0.5-0.8 units · kg-1 · day-1.

Acid-Base Disorders

Prospective randomized study failed to show either beneficial or deleterious changes in morbidity or mortality with bicarbonate therapy in DKA patients with an admission arterial pH between 6.9 and 7.1. Nine small studies in a total of 434 patients with diabetic ketoacidosis (217 treated with bicarbonate and 178 without alkali therapy) support the notion that bicarbonate therapy for DKA offers no advantage in improving cardiac or neurologic functions or in the rate of recovery of hyperglycemia and ketoacidosis. However, due to the reason that severe acidosis may lead to a numerous adverse vascular effects, it is recommended that adult patients with a pH <6.9 should receive 100 mmol sodium bicarbonate in 400mml sterile water (an isotonic solution) with 20 mEq KCl (due to that alkali therapy enhance the risk of increased potassium wasting) administered at a rate of 200 ml/h for 2 hours until the venous pH is >7.0. If the pH is still <7.0 after this is infused, it is recommended repeating infusion every 2 h unitl pH reaches >7.0.

Recovery criteria

Criteria for resolution of ketoacidosis include a blood glucose <200 mg/dL and two of the following criteria: a serum bicarbonate level ≥15 mEq/L, a venous pH >7.3, and a calculated anion gap ≤12 mEq/L (DKA belongs to elevated anion gap metabolic acidosis).

Criteria for resolution of HHS is associated with normal osmolality and regain of normal mental status.