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All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2017. | This topic last updated: Dec 07, 2016.
The precipitating factors, clinical features, evaluation, and diagnosis of DKA and HHS in
adults will be reviewed here. The epidemiology, pathogenesis, and treatment of these
disorders are discussed separately. DKA in children is also reviewed separately.
Other conditions and factors associated with DKA and HHS include:
The earliest symptoms of marked hyperglycemia are polyuria, polydipsia, and weight loss.
As the degree or duration of hyperglycemia progresses, neurologic symptoms, including
lethargy, focal signs, and obtundation, can develop. This can progress to coma in later
stages. Neurologic symptoms are most common in HHS, while hyperventilation and
abdominal pain are primarily limited to patients with DKA.
Possible causes of abdominal pain include delayed gastric emptying and ileus induced by
the metabolic acidosis and associated electrolyte abnormalities [1]. Other causes for
abdominal pain, such as pancreatitis, should be sought when they occur in the absence of
severe metabolic acidosis and when they persist after the resolution of ketoacidosis.
Physical examination — Signs of volume depletion are common in both DKA and HHS
and include decreased skin turgor, dry axillae and oral mucosa, low jugular venous
pressure, tachycardia, and, if severe, hypotension. Neurologic findings, noted above, also
may be seen, particularly in patients with HHS. (See 'Neurologic symptoms' above
and "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".)
Patients with DKA may have a fruity odor (due to exhaled acetone; this is similar to the
scent of nail polish remover) and deep respirations reflecting the compensatory
hyperventilation (called Kussmaul respirations).
Initial evaluation — The initial evaluation of patients with hyperglycemic crises should
include assessment of cardiorespiratory status, volume status, and mental status. The
initial history and rapid but careful physical examination should focus on:
The initial laboratory evaluation of a patient with suspected DKA or HHS should include
determination of:
●Serum glucose
●Serum electrolytes (with calculation of the anion gap), blood urea nitrogen (BUN),
and plasma creatinine
●Complete blood count (CBC) with differential
●Urinalysis and urine ketones by dipstick
●Plasma osmolality
●Serum ketones (if urine ketones are present)
●Arterial blood gas if the serum bicarbonate is substantially reduced or hypoxia is
suspected
●Electrocardiogram
Additional testing, such as cultures of urine, sputum, and blood, serum lipase and
amylase, and chest radiograph should be performed on a case-by-case basis. Infection
(most commonly pneumonia and urinary tract infection) is a common precipitating event.
Thus, cultures should be obtained if there are suggestive clinical findings. Recognize that
infection may exist in the absence of fever in these patients [25-27].
A variety of other laboratory tests may be affected. The impact of hyperglycemia, insulin
deficiency, osmotic diuresis, and fluid intake in each individual patient leads to variable
laboratory findings, depending upon the relative importance of these factors.
Patients with euglycemic diabetic ketoacidosis generally require both insulin and glucose
to reverse the ketoacidosis. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic
state in adults: Treatment", section on 'Fluid replacement' and "Diabetic ketoacidosis and
hyperosmolar hyperglycemic state in adults: Treatment", section on 'Insulin'.)
The mechanism underlying the hyperglycemia in DKA and HHS is reviewed in detail
separately. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:
Epidemiology and pathogenesis", section on 'Hyperglycemia'.)
Serum ketones — Three ketone bodies are produced and accumulate in DKA:
acetoacetic acid, which is the only one that is a true ketoacid; beta-hydroxybutyric acid (a
hydroxyacid formed by the reduction of acetoacetic acid); and acetone, which is derived
from the decarboxylation of acetoacetic acid. Acetone is a true ketone, not an acid. Testing
for serum ketones is generally performed if urine testing is positive. Urine ketone bodies
are detected with nitroprusside tests, while serum ketones can be detected with either a
nitroprusside test or by direct assay of beta-hydroxybutyrate levels. Direct assay of beta-
hydroxybutyrate levels is preferred, particularly for monitoring response to therapy.
(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment",
section on 'Monitoring'.)
Anion gap metabolic acidosis — The serum anion gap is calculated as follows:
By convention, it is the actual measured plasma sodium concentration and not the sodium
concentration corrected for the simultaneous glucose concentration that is used for this
calculation.
Compensatory hyperventilation reduces the partial pressure of carbon dioxide (CO2) and
mitigates the fall in arterial pH. However, severe ketoacidosis can reduce the pH below
7.0, especially if hyperventilation is compromised.
Plasma osmolality — Plasma osmolality is always elevated in patients with HHS but less
so with DKA (table 1). The typical total body deficits of water and electrolytes in DKA and
HHS are compared in a table (table 4). In patients with HHS, the effective plasma
osmolality is typically >320 mosm/kg.
Effective plasma osmolality (Posm, in mosmol/kg) is the portion of total osmolality which is
generated by sodium salts and glucose (and if present, mannitol or sucrose). Effective
osmoles do not penetrate most cell membranes and can cause movement of water across
membranes to achieve osmolal equilibrium. Effective plasma osmolality does not include
"ineffective" osmoles, such as urea, because urea is rapidly permeable across most cell
membranes and its accumulation does not induce major water shifts between the
intracellular spaces (including the brain) and the extracellular water space [39].
Effective osmolality can be estimated with either of the following equations, depending
upon the units for sodium (Na) and glucose:
The Na is the actual measured plasma sodium concentration and not the corrected sodium
concentration. The Na is multiplied by two to account for the osmotic contribution of
sodium’s accompanying anions (primarily chloride and bicarbonate). Eighteen is a factor to
convert glucose units from mg/dL into mmol/L.
If the plasma osmolality is measured, using a freezing point reduction osmometer, the
result is the total osmolality. Because effective osmolality excludes urea osmoles (BUN), it
can be estimated as:
2.8 is a factor to convert urea concentration from units of mg/dL into mmol/L.
Serum sodium — Most patients with DKA and HHS are mildly hyponatremic [40].
However, patients with HHS who have a marked osmotic diuresis may present with a
normal or even elevated serum sodium concentration, despite a markedly elevated serum
glucose concentration that can exceed 1000 mg/dL (56 mmol/L) [41]. These patients have
a markedly elevated effective plasma osmolality and often have neurologic symptoms that
can include seizures and coma (see 'Neurologic symptoms' above). Inadequate water
intake contributes to the hyperosmolality and is a particular problem in hot weather and in
older individuals who may have an impaired thirst mechanism [42].
Serum potassium — Patients presenting with DKA or HHS have a potassium deficit that
averages 300 to 600 mEq (table 4) [40,47,48]. A number of factors contribute to this
deficit, particularly increased urinary losses due both to the glucose osmotic diuresis and
to the excretion of potassium ketoacid anion salts. Despite these total body potassium
deficits, hypokalemia is observed in only approximately 5 percent of cases [49,50]. The
serum potassium concentration is usually normal or, in one-third of patients, elevated on
admission [28,40,51]. This is mainly due to a shift of potassium from intracellular fluid to
extracellular fluid caused by hyperosmolality and insulin deficiency [6,39,40].
(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology
and pathogenesis", section on 'Potassium'.)
Insulin therapy shifts potassium into cells and lowers the potassium concentration. This
may cause severe hypokalemia, particularly in patients who present with a normal or low
serum potassium concentration [48]. Careful monitoring and timely administration of
potassium supplementation are essential. (See "Diabetic ketoacidosis and hyperosmolar
hyperglycemic state in adults: Treatment", section on 'Potassium replacement'.)
This transcellular shift is reversed and the true state of phosphate balance is unmasked
after treatment with insulin and volume expansion. In a review of 69 episodes of DKA, the
mean serum phosphate concentration fell from 9.2 mg/dL (3 mmol/L) at presentation to
2.8 mg/dL (0.9 mmol/L) at 12 hours, and in some patients to levels as low as
1.0 mg/dL (0.32 mmol/L) [52]. (See "Diabetic ketoacidosis and hyperosmolar
hyperglycemic state in adults: Treatment", section on 'Phosphate depletion'.)
Serum creatinine — Most patients with uncontrolled hyperglycemia have acute elevations
in the BUN and serum creatinine concentration, which reflect the reduction in glomerular
filtration rate induced by hypovolemia. High acetoacetate levels can also artifactually
increase serum creatinine levels when certain colorimetric assays are utilized [54].
However, most laboratories now utilize enzymatic assays which are not affected by this
artifact [55].
Serum amylase and lipase — Acute pancreatitis may precipitate or complicate DKA.
Serum amylase and lipase are generally used to diagnose acute pancreatitis, but each of
these enzymes is often elevated in patients with DKA who do not have any other clinical or
radiological evidence of pancreatitis [56-60]. Therefore, the diagnosis of pancreatitis in
patients with DKA should be primarily based upon clinical findings and imaging.
(See "Clinical manifestations and diagnosis of acute pancreatitis", section on 'Imaging'.)
Lipolysis in DKA, and to a lesser extent in HHS, is due to insulin deficiency, combined with
elevated levels of lipolytic hormones (catecholamines, growth hormone, corticotropin
[ACTH], and glucagon). Lipolysis releases glycerol and free fatty acids into the circulation.
High levels of serum fatty acids inhibit glycolysis, and in the hepatocyte mitochondria is the
substrate for ketoacid generation. Insulin is the most potent anti-lipolytic hormone.
Factors that contribute to the lesser degree of hyperglycemia in DKA, compared with HHS,
are discussed elsewhere. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic
state in adults: Epidemiology and pathogenesis", section on 'Hyperglycemia'.)
Significant overlap between DKA and HHS has been reported in more than one-third of
patients [1,4,16,68].
Anion gap acidosis — Diabetic ketoacidosis (DKA) must be distinguished from other
causes of high anion gap metabolic acidosis including lactic acidosis (which can rarely be
induced by metformin, particularly in patients with impaired renal
function); aspirin or acetaminophen toxicity, and poisoning with methanol, ethylene glycol,
and propylene glycol; D-lactic acidosis; and advanced chronic kidney disease (table 6).
Although none of these disorders cause ketoacidosis (table 5), several causes of acidosis
may coexist, especially lactic acid and ketoacidosis. (See "Approach to the adult with
metabolic acidosis".)
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