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


History and Physical Examination

The process of HHS usually evolves over several days to weeks, whereas the evolution of the acute DKA episode in type 1 diabetes or even in type 2 diabetes tends to be much shorter. Although the symptoms of poorly controlled diabetes may be present for several days, the metabolic alterations typical of ketoacidosis usually evolve within a short time frame (typically <24 h). Occasionally, the entire symptomatic presentation may evolve or develop more acutely, and the patient may present with DKA with no prior clues or symptoms. For both DKA and HHS, the classical clinical picture includes a history of polyuria, polydipsia, weight loss, vomiting, dehydration, weakness, and mental status change. Physical findings may include poor skin turgor, Kussmaul respirations (in DKA), tachycardia, and hypotension. Mental status can vary from full alertness to profound lethargy or coma, with the latter more frequent in HHS. Focal neurologic signs (hemianopia and hemiparesis) and seizures (focal or generalized) may also be features of HHS[4,10]. Although infection is a common precipitating factor for both DKA and HHS, patients can be normothermic or even hypothermic primarily because of peripheral vasodilation. Severe hypothermia, if present, is a poor prognostic sign[33]. Nausea, vomiting, diffuse abdominal pain are frequent in patients with DKA (>50%) but are uncommon in HHS[33]. Caution needs to be taken with patients who complain of abdominal pain on presentation because the symptoms could be either a result of the DKA or an indication of a precipitating cause of DKA, particularly in younger patients or in the absence of severe metabolic acidosis[34,35]. Further evaluation is necessary if this complaint does not resolve with resolution of dehydration and metabolic acidosis.

Laboratory Findings

The diagnostic criteria for DKA and HHS are shown in Table 1 . The initial laboratory evaluation of patients include determination of plasma glucose, blood urea nitrogen, creatinine, electrolytes (with calculated anion gap), osmolality, serum and urinary ketones, and urinalysis, as well as initial arterial blood gases and a complete blood count with a differential. An electrocardiogram, chest X-ray, and urine, sputum, or blood cultures should also be obtained.

The severity of DKA is classified as mild, moderate, or severe based on the severity of metabolic acidosis (blood pH, bicarbonate, and ketones) and the presence of altered mental status[4]. Significant overlap between DKA and HHS has been reported in more than one-third of patients[36]. Although most patients with HHS have an admission pH >7.30 and a bicarbonate level >18 mEq/l, mild ketonemia may be present[4,10].

Severe hyperglycemia and dehydration with altered mental status in the absence of significant acidosis characterize HHS, which clinically presents with less ketosis and greater hyperglycemia than DKA. This may result from a plasma insulin concentration (as determined by baseline and stimulated C-peptide ( Table 2 ) adequate to prevent excessive lipolysis and subsequent ketogenesis but not hyperglycemia[4].

The key diagnostic feature in DKA is the elevation in circulating total blood ketone concentration. Assessment of augmented ketonemia is usually performed by the nitroprusside reaction, which provides a semiquantitative estimation of acetoacetate and acetone levels. Although the nitroprusside test (both in urine and in serum) is highly sensitive, it can underestimate the severity of ketoacidosis because this assay does not recognize the presence of ß-hydroxybutyrate, the main metabolic product in ketoacidosis[4,12]. If available, measurement of serum ß-hydroxybutyrate may be useful for diagnosis[37]. Accumulation of ketoacids results in an increased anion gap metabolic acidosis. The anion gap is calculated by subtracting the sum of chloride and bicarbonate concentration from the sodium concentration: [Na - (Cl + HCO3)]. A normal anion gap is between 7 and 9 mEq/l and an anion gap >10–12 mEq/l indicate the presence of increased anion gap metabolic acidosis[4].

Hyperglycemia is a key diagnostic criterion of DKA; however, a wide range of plasma glucose can be present on admission. Elegant studies on hepatic glucose production rates have reported rates ranging from normal or near normal[38] to elevated[12,15], possibly contributing to the wide range of plasma glucose levels in DKA that are independent of the severity of ketoacidosis[37]. Approximately 10% of the DKA population presents with so-called “euglycemic DKA”—glucose levels ≤250 mg/dl[38]. This could be due to a combination of factors, including exogenous insulin injection en route to the hospital, antecedent food restriction[39,40], and inhibition of gluconeogenesis.

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[41]. In ketoacidosis, leukocytosis is attributed to stress and maybe correlated to elevated levels of cortisol and norepinephrine[42]. The admission serum sodium is usually low because of the osmotic flux of water from the intracellular to the extracellular space in the presence of hyperglycemia. An increased or even normal serum sodium concentration in the presence of hyperglycemia indicates a rather profound degree of free water loss. To assess the severity of sodium and water deficit, serum sodium may be corrected by adding 1.6 mg/dl to the measured serum sodium for each 100 mg/dl of glucose above 100 mg/dl[4,12].

Studies on serum osmolality and mental alteration have established a positive linear relationship between osmolality and mental obtundation[9,36]. 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. In the calculation of effective osmolality, [sodium ion (mEq/l) × 2 + glucose (mg/dl)/18], the urea concentration is not taken into account because it is freely permeable and its accumulation does not induce major changes in intracellular volume or osmotic gradient across the cell membrane[4].

Serum potassium concentration may be elevated because of an extracellular shift of potassium caused by insulin deficiency, hypertonicity, and acidemia[43]. Patients with low normal or low serum potassium concentration on admission have severe total-body potassium deficiency and require careful cardiac monitoring and more vigorous potassium replacement because treatment lowers potassium further and can provoke cardiac dysrhythmia. Pseudonormoglycemia[44] and pseudohyponatremia[45] may occur in DKA in the presence of severe chylomicronemia.

The admission serum phosphate level in patients with DKA, like serum potassium, is usually elevated and does not reflect an actual body deficit that uniformly exists due to shifts of intracellular phosphate to the extracellular space[12,46,47]. Insulin deficiency, hypertonicity, and increased catabolism all contribute to the movement of phosphate out of cells.

Hyperamylasemia has been reported in 21–79% of patients with DKA[48] ; however, there is little correlation between the presence, degree, or isoenzyme type of hyperamylasemia and the presence of gastrointestinal symptoms (nausea, vomiting, and abdominal pain) or pancreatic imaging studies[48]. A serum lipase determination may be beneficial in the differential diagnosis of pancreatitis; however, lipase could also be elevated in DKA in the absence of pancreatitis[48].

Differential Diagnosis

Not all patients with ketoacidosis have DKA. Starvation ketosis and alcoholic ketoacidosis are distinguished by clinical history and by plasma glucose concentrations that range from mildly elevated (rarely >200 mg/dl) to hypoglycemia[49]. In addition, although alcoholic ketoacidosis can result in profound acidosis, the serum bicarbonate concentration in starvation ketosis is usually not <18 mEq/l. DKA must also be distinguished from other causes of high–anion gap metabolic acidosis, including lactic acidosis; ingestion of drugs such as salicylate, methanol, ethylene glycol, and paraldehyde; and acute chronic renal failure[4]. Because lactic acidosis is more common in patients with diabetes than in nondiabetic persons and because elevated lactic acid levels may occur in severely volume-contracted patients, plasma lactate should be measured on admission.

A clinical history of previous drug abuse should be sought. Measurement of serum salicylate and blood methanol level may be helpful. Ethylene glycol (antifreeze) is suggested by the presence of calcium oxalate and hippurate crystals in the urine. Paraldehyde ingestion is indicated by its characteristic strong odor on the breath. Because these intoxicants are low–molecular weight organic compounds, they can produce an osmolar gap in addition to the anion gap acidosis[14]. A recent report states that active cocaine use is an independent risk factor for recurrent DKA[50].

Recently, one case report has shown that a patient with diagnosed acromegaly may present with DKA as the primary manifestation of the disease[51]. In addition, an earlier report of pituitary gigantism was presented with two episodes of DKA with complete resolution of diabetes after pituitary apoplexy[52].


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