Hyperglycemic Crises in Adult Patients With Diabetes

Abbas E. Kitabchi, PHD, MD; Guillermo E. Umpierrez, MD; John M. Miles, MD; Joseph N. Fisher, MD


Diabetes Care. 2009;32(7):1335-1343. 

In This Article


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. Protocols for the management of patients with DKA and HHS are summarized in Fig. 2[52].

Figure 2.

Protocol for management of adult patients with DKA or HHS. DKA diagnostic criteria: blood glucose 250 mg/dl, arterial pH 7.3, bicarbonate 15 mEq/l, and moderate ketonuria or ketonemia. HHS diagnostic criteria: serum glucose >600 mg/dl, arterial pH >7.3, serum bicarbonate >15 mEq/l, and minimal ketonuria and ketonemia. 15–20 ml/kg/h; serum Na should be corrected for hyperglycemia (for each 100 mg/dl glucose 100 mg/dl, add 1.6 mEq to sodium value for corrected serum value). (Adapted from ref [13].) Bwt, body weight; IV, intravenous; SC, subcutaneous.

Fluid Therapy

Initial fluid therapy is directed toward expansion of the intravascular, interstitial, and intracellular volume, all of which are reduced in hyperglycemic crises[53] and restoration of renal perfusion. In the absence of cardiac compromise, isotonic saline (0.9% NaCl) is infused at a rate of 15–20 ml · kg body wt-1 · h-1 or 1–1.5 l during the first hour. Subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels, and urinary output. In general, 0.45% NaCl infused at 250–500 ml/h is appropriate if the corrected serum sodium is normal or elevated; 0.9% NaCl at a similar rate is appropriate if corrected serum sodium is low (Fig. 2). Successful progress with fluid replacement is judged by hemodynamic monitoring (improvement in blood pressure), measurement of fluid input/output, laboratory values, and clinical examination. Fluid replacement should correct estimated deficits within the first 24 h. In patients with renal or cardiac compromise, monitoring of serum osmolality and frequent assessment of cardiac, renal, and mental status must be performed during fluid resuscitation to avoid iatrogenic fluid overload[4,10,15,53]. Aggressive rehydration with subsequent correction of the hyperosmolar state has been shown to result in a more robust response to low-dose insulin therapy[54].

During treatment of DKA, hyperglycemia is corrected faster than ketoacidosis. The mean duration of treatment until blood glucose is <250 mg/dl and ketoacidosis (pH >7.30; bicarbonate >18 mmol/l) is corrected is 6 and 12 h, respectively[9,55]. Once the plasma glucose is ~ 200 mg/dl, 5% dextrose should be added to replacement fluids to allow continued insulin administration until ketonemia is controlled while at the same time avoiding hypoglycemia.

Insulin Therapy

The mainstay in the treatment of DKA involves the administration of regular insulin via continuous intravenous infusion or by frequent subcutaneous or intramuscular injections[4,56,57]. Randomized controlled studies in patients with DKA have shown that insulin therapy is effective regardless of the route of administration[47]. The administration of continuous intravenous infusion of regular insulin is the preferred route because of its short half-life and easy titration and the delayed onset of action and prolonged half-life of subcutaneous regular insulin[36,47,58].

Numerous prospective randomized studies have demonstrated that use of low-dose regular insulin by intravenous infusion is sufficient for successful recovery of patients with DKA. Until recently, treatment algorithms recommended the administration of an initial intravenous dose of regular insulin (0.1 units/kg) followed by the infusion of 0.1 units · kg-1 · h-1 insulin (Fig. 2). A recent prospective randomized study reported that a bolus dose of insulin is not necessary if patients receive an hourly insulin infusion of 0.14 units/kg body wt (equivalent to 10 units/h in a 70-kg patient)[59]. In the absence of an initial bolus, however, doses <0.1 units · kg-1 · h-1 resulted in a lower insulin concentration, which may not be adequate to suppress hepatic ketone body production without supplemental doses of insulin[15].

Low-dose insulin infusion protocols decrease plasma glucose concentration at a rate of 50–75 mg · dl-1 · h-1. If plasma glucose does not decrease by 50–75 mg from the initial value in the first hour, the insulin infusion should be increased every hour until a steady glucose decline is achieved (Fig. 2). When the plasma glucose reaches 200 mg/dl in DKA or 300 mg/dl in HHS, it may be possible to decrease the insulin infusion rate to 0.02– 0.05 units · kg-1 · h-1, at which time dextrose may be added to the intravenous fluids (Fig. 2). 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.

Treatment with subcutaneous rapid-acting insulin analogs (lispro and aspart) has been shown to be an effective alternative to the use of intravenous regular insulin in the treatment of DKA. Treatment of patients with mild and moderate DKA with subcutaneous rapid-acting insulin analogs every 1 or 2 h in non–intensive care unit (ICU) settings has been shown to be as safe and effective as the treatment with intravenous regular insulin in the ICU[60,61]. The rate of decline of blood glucose concentration and the mean duration of treatment until correction of ketoacidosis were similar among patients treated with subcutaneous insulin analogs every 1 or 2 h or with intravenous regular insulin. However, until these studies are confirmed outside the research arena, patients with severe DKA, hypotension, anasarca, or associated severe critical illness should be managed with intravenous regular insulin in the ICU.


Despite total-body potassium depletion, mild-to-moderate hyperkalemia is common in patients with hyperglycemic crises. Insulin therapy, correction of acidosis, 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 is to maintain serum 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 maintain a serum potassium concentration within the normal range. Rarely, DKA patients may present with significant hypokalemia. In such cases, potassium replacement should begin with fluid therapy, and insulin treatment should be delayed until potassium concentration is restored to >3.3 mEq/l to avoid life-threatening arrhythmias and respiratory muscle weakness[4,13].

Bicarbonate Therapy

The use of bicarbonate in DKA is controversial[62] because most experts believe that during the treatment, as ketone bodies decrease there will be adequate bicarbonate except in severely acidotic patients. Severe metabolic acidosis can lead to impaired myocardial contractility, cerebral vasodilatation and coma, and several gastrointestinal complications[63]. A prospective randomized study in 21 patients 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[64]. Nine small studies in a total of 434 patients with diabetic ketoacidosis (217 treated with bicarbonate and 178 patients without alkali therapy[62] 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. Moreover, several deleterious effects of bicarbonate therapy have been reported, such as increased risk of hypokalemia, decreased tissue oxygen uptake[65], cerebral edema[65], and development of paradoxical central nervous system acidosis.

No prospective randomized studies concerning the use of bicarbonate in DKA with pH values <6.9 have been reported[66]. Because severe acidosis may lead to a numerous adverse vascular effects[63], it is recommended that adult patients with a pH <6.9 should receive 100 mmol sodium bicarbonate (two ampules) in 400 ml sterile water (an isotonic solution) with 20 mEq KCI administered at a rate of 200 ml/h for 2 h until the venous pH is >7.0. If the pH is still <7.0 after this is infused, we recommend repeating infusion every 2 h until pH reaches >7.0 (Fig. 2).


Despite whole-body phosphate deficits in DKA that average 1.0 mmol/kg body wt, serum phosphate is often normal or increased at presentation. Phosphate concentration decreases with insulin therapy. Prospective randomized studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in DKA[46,67], and overzealous phosphate therapy can cause severe hypocalcemia[46,68]. However, 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, anemia, or respiratory depression and in those with serum phosphate concentration <1.0 mg/dl[4,12]. When needed, 20–30 mEq/l potassium phosphate can be added to replacement fluids. The maximal rate of phosphate replacement generally regarded as safe to treat severe hypophosphatemia is 4.5 mmol/h (1.5 ml/h of K2 PO4)[69]. No studies are available on the use of phosphate in the treatment of HHS.

Transition to Subcutaneous Insulin

Patients with DKA and HHS should be treated with continuous intravenous insulin until the hyperglycemic crisis is resolved. 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. Resolution of HHS is associated with normal osmolality and regain of normal mental status. When this occurs, subcutaneous insulin therapy can be started. To prevent recurrence of hyperglycemia or ketoacidosis during the transition period to subcutaneous insulin, it is important to allow an overlap of 1–2 h between discontinuation of intravenous insulin and the administration of subcutaneous insulin. If the patient is to remain fasting/nothing by mouth, it is preferable to continue the intravenous insulin infusion and fluid replacement. 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 [13]. Human insulin (NPH and regular) are usually given in two or three doses per day. More recently, basal-bolus regimens with basal (glargine and detemir) and rapid-acting insulin analogs (lispro, aspart, or glulisine) have been proposed as a more physiologic insulin regimen in patients with type 1 diabetes. A prospective randomized trial compared treatment with a basal-bolus regimen, including glargine once daily and glulisine before meals, with a split-mixed regimen of NPH plus regular insulin twice daily following the resolution of DKA. Transition to subcutaneous glargine and glulisine resulted in similar glycemic control compared with NPH and regular insulin; however, treatment with basal bolus was associated with a lower rate of hypoglycemic events (15%) than the rate in those treated with NPH and regular insulin (41%)[55].


Hypoglycemia and hypokalemia are two common complications with overzealous treatment of DKA with insulin and bicarbonate, respectively, but these complications have occurred less often with the low-dose insulin therapy[4,56,57]. Frequent blood glucose monitoring (every 1–2 h) is mandatory to recognize hypoglycemia because many patients with DKA who develop hypoglycemia during treatment do not experience adrenergic manifestations of sweating, nervousness, fatigue, hunger, and tachycardia. Hyperchloremic non–anion gap acidosis, which is seen during the recovery phase of DKA, is self-limited with few clinical consequences[43]. This may be caused by loss of ketoanions, which are metabolized to bicarbonate during the evolution of DKA and excess fluid infusion of chloride containing fluids during treatment[4].

Cerebral edema, which occurs in ~0.3–1.0% of DKA episodes in children, is extremely rare in adult patients during treatment of DKA. Cerebral edema is associated with a mortality rate of 20–40%[5] and accounts for 57–87% of all DKA deaths in children[70,71]. Symptoms and signs of cerebral edema are variable and include onset of headache, gradual deterioration in level of consciousness, seizures, sphincter incontinence, pupillary changes, papilledema, bradycardia, elevation in blood pressure, and respiratory arrest[71]. A number of mechanisms have been proposed, which include the role of cerebral ischemia/hypoxia, the generation of various inflammatory mediators[72], increased cerebral blood flow, disruption of cell membrane ion transport, and a rapid shift in extracellular and intracellular fluids resulting in changes in osmolality. Prevention might include avoidance of excessive hydration and rapid reduction of plasma osmolarity, a gradual decrease in serum glucose, and maintenance of serum glucose between 250–300 mg/dl until the patient's serum osmolality is normalized and mental status is improved. Manitol infusion and mechanical ventilation are suggested for treatment of cerebral edema[73].


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