Early in their course, patients with uncontrolled diabetes present with nonspecific complaints. If the disease follows an indolent course over months to years (more common for type 2 than for type 1 diabetes), patients can present with profound wasting, cachexia, and prostration similar in degree to that of patients with long-standing malignancy or chronic infection. With significant physical or emotional stress, sudden metabolic decompensation can occur.10a The cases of DKA and HHNC that are missed usually occur in patients with new-onset diabetes. All patients with nonspecific complaints should be questioned about more specific symptoms of diabetes. Polyuria (or at least nocturia) and weight loss are almost always present, although often not reported by the patient. Any patient with severe illness (acute or chronic) or neurologic changes should have glucose and electrolyte levels measured.
History and Physical Examination
DKA and HHNC are easily recognized, when considered (Table 78-1). In DKA, metabolic decompensation develops over a period of hours to a few days. Patients with severe DKA classically present with lethargy and a characteristic hyperventilation pattern with deep, slow breaths (Kussmaul respiration) associated with the fruity odor of acetone. They often complain of nausea and vomiting; abdominal pain is somewhat less frequent. The abdominal pain can be quite severe and may be associated with distention, ileus, and tenderness without rebound, but it usually resolves relatively quickly with therapy unless there is underlying abdominal pathology. Most patients are normotensive, tachycardic, and tachypneic, with signs of mild to moderate volume depletion. Hypothermia has been described in DKA, and patients with underlying infection may not manifest fever. Cerebral edema does occur.
Table 78–1. Signs and Symptoms of Glucose Metabolism Disorders ||Download (.pdf)
Table 78–1. Signs and Symptoms of Glucose Metabolism Disorders
| Weight loss|
| Skin infection|
| Blurred vision|
| Hypo- and hyperthermia|
| Lethargy to coma|
| Fruity breath|
| Abdominal pain|
| Abdominal tenderness|
| Cerebral edema|
|Hyperglycemic hyperosmolar nonketotic coma|
| Hypo- and hyperthermia|
| Stupor to coma|
| Focal neurologic signs or seizures|
| Shallow respiration|
| Hypotension to shock|
Patients with HHNC are usually stuporous, with obvious profound dehydration, and may demonstrate focal neurologic deficits, such as Babinski reflexes, asymmetric reflexes, cranial nerve findings, paresis, fasciculations, and aphasia. The syndrome evolves over days to weeks with a progressive decrease in fluid intake and decline in mental status; usually there is no prior history of diabetes. These patients are hypotensive and exhibit normal to depressed ventilation. Hypothermia, again, is common, although cerebral edema is rare.
Laboratory Tests and Differential Diagnosis
Once DKA or HHNC is considered, the diagnosis can be made quickly with routine laboratory tests. DKA and HHNC need to be differentiated from each other and from the other causes of ketosis and metabolic acidosis. This is often quite difficult; in fact, these disorders often coexist. Table 78-2 and the following discussion are provided to help in making the distinction. Blood and urine glucose and ketone levels can be obtained in minutes using glucose oxidase–impregnated strips and the nitroprusside reaction, respectively.
Table 78–2. Means of Distinguishing HHNC, DKA, and Other Causes of Metabolic Acidosis ||Download (.pdf)
Table 78–2. Means of Distinguishing HHNC, DKA, and Other Causes of Metabolic Acidosis
The sine qua non of HHNC is hyperosmolarity. The osmolarity can be measured by freezing-point depression, or it can be estimated using the following formula:
where the concentrations of glucose, blood urea nitrogen (BUN), and ethanol are in milligrams per deciliter, and the concentration of sodium is in milliequivalents per liter. In HHNC, the osmolarity generally is greater than 350 mOsm/L and can exceed 400 mOsm/L. The serum sodium and potassium levels can be high, normal, or low and do not reflect total body levels, which are uniformly depleted. The glucose concentration is usually greater than 600 mg/dL (33.3 mmol/L), and levels over 1000 mg/dL (55.6 mmol/L) are quite common. In pure HHNC, there is usually no significant metabolic acidosis or anion gap. However, severe anion-gap metabolic acidosis of uncertain etiology has been reported in HHNC.11
The sine qua non of DKA is ketoacidosis. As mentioned earlier, two ketoacids are produced in DKA—β-hydroxybutyrate and acetoacetate—as well as the neutral ketone acetone. The nitroprusside reaction commonly used to detect ketone bodies detects acetoacetate much better than acetone and does not react with β-hydroxybutyrate at all. Particularly in severe DKA, β-hydroxybutyrate is the predominant ketone, and it is possible, though unusual, to have a negative serum nitroprusside reaction in the face of severe ketosis. β-Hydroxybutyrate levels can be measured at many centers and commercially, but this service usually is not readily available. Fortunately, there is a readily available index for unmeasured anions in the blood—namely, the anion gap (normally less than 14 mEq/L):
Most persons with DKA present with an anion gap greater than 20 mEq/L, and some have an anion gap greater than 40 mEq/L. However, some patients have a hyperchloremic metabolic acidosis without a significant anion gap.12 Patients with DKA almost invariably have large amounts of ketones in their urine. The serum glucose level in DKA is usually about 500 mg/dL (27.8 mmol/L). However, an entity known as euglycemic DKA has been described, particularly in the presence of decreased oral intake or pregnancy, where the serum glucose level is normal or near normal, but the patient requires insulin therapy for the clearance of ketoacidosis.13 The arterial pH is commonly less than 7.3 and can be as low as 6.5. There is partial respiratory compensation with hypocapnia. Patients are often mildly hyperosmolar, although osmolalities greater than 330 mOsm/kg are unusual without mental status changes.
Not all patients with hyperglycemia and an anion gap metabolic acidosis will have DKA. Lactic acidosis is the most common cause of metabolic acidosis in hospitalized patients and can be seen in uncomplicated diabetes, as well as in DKA and HHNC. Lactic acidosis usually occurs in the setting of decreased tissue oxygen delivery, resulting in the nonoxidative metabolism of glucose to lactic acid. Lactic acidosis complicates other primary metabolic acidoses as a consequence of dehydration or shock. Thus, assessing its relative contribution can be difficult. The presentation is identical to that seen in DKA. In pure lactic acidosis, the serum glucose and ketone levels should be normal, and the serum lactate concentration should be greater than 5 mM. The therapy of lactic acidosis is directed at the underlying cause and at optimizing tissue perfusion.14
Starvation ketosis results from inadequate carbohydrate availability, resulting in physiologically appropriate lipolysis and ketone production to provide fuel substrates for muscle. The blood glucose level usually is normal. Although the urine can have large amounts of ketones, the blood rarely does. Usually the arterial pH is normal, and the anion gap is at most mildly elevated.
Alcoholic ketoacidosis is a more severe form of starvation ketosis wherein the appropriate ketogenic response to poor carbohydrate intake is increased through as yet poorly defined effects of alcohol on the liver. Classically, these patients are long-standing alcoholics for whom ethanol has been the main caloric source for days to weeks. The ketoacidosis manifests itself when, for whatever reason, the intake of alcohol and calories decreases. In isolated alcoholic ketoacidosis, the metabolic acidosis is usually mild to moderate in severity. The anion gap is elevated. Serum and urine ketones are always present. However, alcoholic ketoacidosis produces an even higher ratio of β-hydroxybutyrate to acetoacetate than does DKA, and negative or weakly positive serum nitroprusside reactions are common. Respiratory alkalosis associated with delirium tremens, agitation, or pulmonary processes often normalizes the pH but the underlying acidosis should be evident with careful analysis of acid-base status. Usually the patient is normoglycemic or hypoglycemic; sometimes mild hyperglycemia is present. Patients who are significantly hyperglycemic should be treated as if they had DKA. The therapy of alcoholic ketoacidosis consists of administration of thiamine, carbohydrates, fluids, and electrolytes, with special attention to the more severe consequences of alcohol toxicity, alcohol withdrawal, and chronic malnutrition. In more severely ill patients in whom alcoholic ketoacidosis is considered a possibility, there is usually another underlying illness, such as pancreatitis, gastrointestinal bleeding, hepatic encephalopathy, delirium tremens, or infection complicated by coexisting lactic acidosis.15
Uremic acidosis is characterized by very large elevations in the BUN level and the creatinine level with normoglycemia. The pH and anion gap are usually only mildly abnormal. The treatment is supportive, with careful attention to fluid and electrolytes until dialysis can be performed. Rhabdomyolysis is a cause of renal failure in which the anion gap can be elevated significantly and acidosis can be severe. There should be marked elevation of creatine phosphokinase (CPK) and myoglobin levels. It should be noted that mild rhabdomyolysis is not uncommon in DKA, but the presence of hyperglycemia and ketonemia leaves no doubt as to the primary etiology of the acidosis.16
Toxic ingestions can be differentiated from DKA by history and laboratory investigation. Salicylate intoxication can produce an anion-gap metabolic acidosis, usually with a respiratory alkalosis. The plasma glucose level is normal or low and the osmolality normal, and salicylates are detected in the urine or blood. Salicylate uncouples oxidative phosphorylation; consequently, ketonemia and lactic acidosis develop. It should be noted that salicylates can cause a false-positive glucose determination when the cupric sulfate method is used and a false-negative result when the glucose oxidase reaction is used. Methanol and ethylene glycol also produce an anion gap metabolic acidosis without hyperglycemia or ketones; they need to be kept in mind primarily because they produce an increase in the measured serum osmolality but not in the calculated serum osmolality—an osmolar gap. Their serum levels also can be measured. Isopropyl alcohol does not cause a metabolic acidosis, but it needs to be borne in mind because it is metabolized to acetone, which can produce a positive result on the nitroprusside reaction commonly used for the detection of ketoacids. Therapy of these intoxications is discussed elsewhere17–19 (see Chap. 102). Rare cases of anion gap acidoses have been reported with other ingestions, including toluene, iron, hydrogen sulfide, nalidixic acid, papaverine, paraldehyde, strychnine, and isoniazid.
It should be remembered that patients often present with combinations of the preceding conditions. As already noted, DKA not uncommonly appears with hyperosmolarity and coma. HHNC can have mild to moderate ketonemia and acidosis. Alcoholic ketoacidosis can contribute to either DKA or HHNC, and lactic acidosis is common in severe DKA and HHNC. We believe that any patient with hyperglycemia above 250 mg/dL (13.9 mmol/L) and an anion gap metabolic acidosis should be treated according to the general principles outlined below, with special consideration for possible other contributing metabolic acidoses (see Chaps. 77 and 102).