Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical

features, evaluation, and diagnosis

Authors:
Irl B Hirsch, MD
Michael Emmett, MD
Section Editor:
David M Nathan, MD
Deputy Editor:
Jean E Mulder, MD

Contributor Disclosures

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.

INTRODUCTION — Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state

(HHS, also known as hyperosmotic hyperglycemic nonketotic state [HHNK]) are two of the
most serious acute complications of diabetes. DKA is characterized by ketoacidosis and
hyperglycemia, while HHS usually has more severe hyperglycemia but no ketoacidosis
(table 1). Each represents an extreme in the spectrum of hyperglycemia.

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.

●(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:

Epidemiology and pathogenesis".)
●(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:
Treatment".)
●(See "Clinical features and diagnosis of diabetic ketoacidosis in children and
adolescents".)
●(See "Treatment and complications of diabetic ketoacidosis in children and
adolescents".)

PRECIPITATING FACTORS — A precipitating event can usually be identified in patients

with diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS) (table 2) [1-
3]. The most common events are infection (often pneumonia or urinary tract infection) and
discontinuation of or inadequate insulin therapy. Compromised water intake due to
underlying medical conditions, particularly in older patients, can promote the development
of severe dehydration and HHS [3-5].

Other conditions and factors associated with DKA and HHS include:

●Acute major illnesses such as myocardial infarction, cerebrovascular accident,

sepsis, or pancreatitis.
 ●New onset type 1 diabetes, in which DKA is a common presentation.
●In established type 1 diabetes, omission of insulin in setting of gastroenteritis when
patient mistakenly stops insulin because of reduced oral intake.
●Drugs that affect carbohydrate metabolism, including glucocorticoids, higher-dose
thiazide diuretics, sympathomimetic agents (eg, dobutamine and terbutaline) [6], and
second-generation “atypical” antipsychotic agents [7].
●SGLT2 inhibitors, mostly used in type 2 diabetes but also used off-label in type 1
diabetes. There is a complex physiology that has resulted in reports of DKA in both
types of diabetes [8].
●Cocaine use, which has been associated with recurrent DKA [9,10].
●Psychological problems associated with eating disorders and purposeful insulin
omission, particularly in young patients with type 1 diabetes [11]. Factors that may
lead to insulin omission in younger patients include fear of weight gain, fear of
hypoglycemia, rebellion from authority, and the stress of chronic disease.
●Poor compliance with the insulin regimen.
●Malfunction of continuous subcutaneous insulin infusion devices (CSII), which was
initially reported in the early 1980s [12]. Pump malfunction is now uncommon, but
system failure due to blockage or leakage in the syringe or the infusion set or
connectors, causing an interruption of infusion flow infusion set, can lead to DKA. The
frequency of DKA with pump therapy, however, appears to be no different from that
with multiple daily injections of insulin [13].

CLINICAL PRESENTATION — Diabetic ketoacidosis (DKA) usually evolves rapidly, over

a 24-hour period. In contrast, symptoms of hyperosmolar hyperglycemic state (HHS)
develop more insidiously with polyuria, polydipsia, and weight loss, often persisting for
several days before hospital admission.

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.

Neurologic symptoms — Neurologic deterioration primarily occurs in patients with an

effective plasma osmolality above 320 to 330 mosmol/kg [1,14-16] (see 'Plasma
osmolality'below). Mental obtundation and coma are more frequent in HHS than DKA
because of the usually greater degree of hyperosmolality in HHS (table 1) [17]. In addition,
some patients with HHS have focal neurologic signs (hemiparesis or
hemianopsia) and/or seizures [17-21]. Mental obtundation may occur in patients with DKA,
who have lesser degrees of hyperosmolality, when severe acidosis exists [22]. However,
stupor or coma in diabetic patients with an effective plasma osmolality lower than
320 mosmol/kg demands immediate consideration of other causes of the mental status
change.
Abdominal pain in DKA — Patients with DKA may present with nausea, vomiting, and
abdominal pain; although more common in children, these symptoms can be seen in
adults [23]. Abdominal pain is unusual in HHS. In a review of 189 consecutive episodes of
DKA and 11 episodes of HHS, abdominal pain was reported in 46 percent of patients with
DKA compared with none of the patients with HHS [24]. Abdominal pain was associated
with the severity of the metabolic acidosis (occurring in 86 percent of those with a serum
bicarbonate ≤5 but only 13 percent of those with a serum bicarbonate ≥15 mEq/L) but did
not correlate with the severity of hyperglycemia or dehydration.

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).

DIAGNOSTIC EVALUATION — Both diabetic ketoacidosis (DKA) and hyperosmolar

hyperglycemic state (HHS) are medical emergencies that require prompt recognition and
management (table 3).

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:

●Airway, breathing, and circulation (ABC) status

●Mental status
●Possible precipitating events (eg, source of infection, myocardial infarction)
●Volume status

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].

Measurement of glycated hemoglobin (A1C) may be useful in determining whether the

acute episode is the culmination of an evolutionary process in previously undiagnosed or
poorly controlled diabetes or a truly acute episode in an otherwise well-controlled patient.

Laboratory findings — Hyperglycemia and hyperosmolality are the two primary

laboratory findings in patients with DKA or HHS; patients with DKA also have a high anion
gap metabolic acidosis (table 1).

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.

Serum glucose — The serum glucose concentration frequently exceeds

1000 mg/dL (56 mmol/L) in HHS [14,28], but is generally less than
800 mg/dL (44 mmol/L) and often approximately 350 to 500 mg/dL (19.4 to
27.8 mmol/L) in DKA [15,28]. Euglycemic DKA, in which the serum glucose is normal or
near normal, has been described, particularly in patients with poor oral intake, treatment
with insulin prior to arrival in the emergency department, or in pregnant women [29-31].

Euglycemic or minimally hyperglycemic diabetic ketoacidosis has also been described in

patients treated with the class of drugs that block the sodium/glucose cotransporter 2
(SGLT2 inhibitors). The glucosuria these drugs produce can minimize or block the
development of hyperglycemia when insulin levels/activity are too low to prevent the
development of ketoacidosis. SGLT2 inhibitors and their adverse effects are reviewed in
detail elsewhere. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of
type 2 diabetes mellitus", section on 'Diabetic ketoacidosis'.)

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'.)

Nitroprusside testing — This chemical develops a purple color in the presence of

acetoacetic acid (and to a much lesser degree, acetone). Urine dipstick testing
with nitroprusside tablets (Acetest) or reagent sticks (Ketostix) is widely utilized and results
are available within minutes. Serum testing is necessary to determine if serum ketone
levels can explain the high anion gap acidosis. A 4+ reaction with serum diluted 1:1 is
highly suggestive of ketoacidosis. A 4+ reaction in more diluted serum (ie, 1:4, 1:8, etc)
provides evidence of even higher concentrations of acetoacetic acid. Although one cannot
directly extrapolate from the nitroprusside result to the severity of the acidosis or the
magnitude of the anion gap, this is a useful semiquantitative test for the evaluation of
possible ketoacidosis. Although the nitroprusside reaction is still widely used to detect
ketone bodies in urine, its use for serum testing has become uncommon. Both false-
negative and false-positive results should be considered.

●False-negative nitroprusside testing – The fact that nitroprusside reacts with

acetoacetate and, to a lesser degree, acetone (which is not an acid), but not with
beta-hydroxybutyrate, can cause diagnostic confusion. This is important because
beta-hydroxybutyrate can become the predominant ketone, particularly in severe
DKA. The ratio of beta-hydroxybutyrate to acetoacetate, which is about 1:1 in normal
subjects, can increase to as high as 10:1 in DKA [32]. This ratio also increases when
lactic acidosis coexists with ketoacidosis. It is therefore possible, although unusual, to
have a negative serum nitroprusside reaction in the presence of severe ketosis.
●False-positive nitroprusside testing – False-positive nitroprusside urine ketone
results can be generated by drugs containing free sulfhydryl groups that react with
nitroprusside. Captopril, penicillamine, and mesna are several drugs with this
property.

Direct measurement of serum beta-hydroxybutyrate — For a number of reasons,

including the problems described above, the serum nitroprusside test for ketone bodies
has been largely replaced by direct assays for beta-hydroxybutyrate [33]. Several beta-
hydroxybutyrate assay instruments are commercially available [32,34-36]. Direct assays
for serum beta-hydroxybutyrate will eliminate the problems associated with nitroprusside
testing. One limitation of some of these assays is that beta-hydroxybutyrate cannot be
quantitated above a level of 6 mEq/L. An ideal assay for "ketoacids" would measure the
concentrations of both acetoacetate and beta-hydroxybutyrate.

Point-of-care bedside analyzers to measure capillary blood beta-hydroxybutyrate are

becoming increasingly available [37,38].

Anion gap metabolic acidosis — The serum anion gap is calculated as follows:

Serum anion gap = Serum sodium - (serum chloride + bicarbonate)

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.

The serum bicarbonate concentration in DKA is usually moderately-to-markedly reduced.

In contrast, the serum bicarbonate concentration is normal or only mildly reduced in HHS
(table 1). Patients with DKA usually present with a serum anion gap greater than
20 mEq/L (normal range approximately 3 to 10 mEq/L). In patients with DKA, the elevated
anion gap metabolic acidosis is caused by the accumulation of beta-hydroxybutyric and
acetoacetic acids. However, the increase in anion gap is variable, being determined by
several factors: the rate and duration of ketoacid production, the rate of metabolism of the
ketoacids and their loss in the urine, and the volume of distribution of the ketoacid anions.
(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology
and pathogenesis", section on 'Anion gap metabolic acidosis'.)

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:

Effective Posm = [2 x Na (mEq/L)] + [glucose (mg/dL) ÷ 18]

Effective Posm = [2 x Na (mmol/L)] + glucose (mmol/L)

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:

Effective Posm = Measured Posm - [BUN (mg/dL) ÷ 2.8]

Effective Posm = Measured Posm - BUN (mmol/L)

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].

The measured serum sodium concentration in uncontrolled diabetes mellitus is variable

because of the interaction of multiple factors, some lower sodium concentration and others
that raise it. The increase in plasma osmolality created by hyperglycemia pulls water out of
the cells, and this reduces the plasma sodium (Na) concentration. Physiologic calculations
suggest that, in the absence of urine losses, the serum sodium concentration should fall by
about 1.6 mEq/L for each 100 mg/100 mL (5.5 mmol/L) increase in glucose concentration.
We use a simple ΔNa/ΔGlucose concentration ratio of 2.0 mEq/L decline in Na for each
100 mg/100 mL (5.5 mmol/L) increase in glucose concentration. The "corrected" sodium
concentration can then be approximated by adding 2.0 mEq/L to the plasma sodium
concentration for each 100 mg/100 mL (5.5 mmol/L) increase above normal in glucose
concentration (calculator 1). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic
state in adults: Epidemiology and pathogenesis", section on 'Plasma osmolality and
sodium' and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:
Treatment", section on 'Fluid replacement'.)
Pseudohyponatremia/pseudohyperchloremia — Some patients with uncontrolled
diabetes develop marked hyperlipidemia and have lactescent serum. This can create
electrolyte artifacts when certain analyzers are utilized. Hyperlipidemia will displace water
and thereby reduce the plasma water phase fraction below its normal 93 percent. If any
step in the analysis requires an exact volume of plasma (or serum), then a reduced
amount of water (and electrolyte) will be analyzed. This can result in
“pseudohyponatremia.” This artifact occurs with any flame photometric analysis and most
indirect potentiometric or ion selective electrode methods. However, direct potentiometry
analytical methods are generally not susceptible to this artifact [43-45]. (See "Diagnostic
evaluation of adults with hyponatremia".)

However, hyperlipemia can have an opposite artifactual effect on the chloride

concentration when certain chloride analyzers are employed, generating marked
pseudohyperchloremia [46]. (See "Serum anion gap in conditions other than metabolic
acidosis", section on 'Negative serum anion gap'.)

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'.)

Serum phosphate — Patients with uncontrolled hyperglycemia are typically in negative

phosphate balance because of decreased phosphate intake, an acidosis-related shift of
phosphate into the extracellular fluid (ECF) when metabolic acidosis exists, and
phosphaturia caused by osmotic diuresis. Despite phosphate depletion, the serum
phosphate concentration at presentation is usually normal or even high because both
insulin deficiency and metabolic acidosis cause a shift of phosphate out of the cells and as
a result of ECF volume contraction [52,53].

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'.)

The mechanisms for non-pancreatitis associated hyperamylasemia and hyperlipasemia in

DKA are not well understood, but the following observations have been made:

●In a review of 134 consecutive episodes of DKA in patients without evidence of

acute pancreatitis on computed tomography (CT) scan, elevations of serum amylase
and lipase (threefold or higher in some patients) were seen in 17 and 24 percent,
respectively [56]. Abdominal pain was present in 19 percent of the patients in this
series.
●The source of these nonspecific amylase elevations is most often salivary, though
some may also be of pancreatic origin [57,58,60]. The source of nonspecific lipase
elevations is not known.
●The rise in amylase correlates with pH and plasma osmolality, while the rise in
lipase correlates only with plasma osmolality [56]. Values peak within 24 hours of
presentation [60].
●In 100 consecutive cases of DKA, 11 did have acute pancreatitis confirmed by CT
scan. The most common causes of pancreatitis in these patients were
hypertriglyceridemia and chronic alcohol intake [61]. Two of the 10 evaluable patients
(one was comatose) did not have abdominal pain.

Leukocytosis — The majority of patients with hyperglycemic emergencies present with

leukocytosis, which is proportional to the degree of ketonemia [6,62]. Leukocytosis
unrelated to infection may occur as a result of hypercortisolemia and increased
catecholamine secretion [63]. However, a white blood cell count greater
than 25,000/microL or more than 10 percent bands increases suspicion for infection and
should be evaluated [64].
Lipids — Patients with DKA or HHS may present with marked hyperlipidemia and
lactescent serum. In a study of 13 patients with DKA, the mean plasma triglyceride and
cholesterol levels on admission were 574 mg/dL (6.5 mmol/L) and
212 mg/dL (5.5 mmol/L), respectively [65]. Triglycerides fell below
150 mg/dL (1.7 mmol/L) in 24 hours with insulin therapy.

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.

DIAGNOSTIC CRITERIA — Diabetic ketoacidosis (DKA) and hyperosmolar

hyperglycemic state (HHS) are distinguished by the absence of ketoacidosis and usually
greater degree of hyperglycemia in HHS [25,28,66]. The diagnostic criteria proposed by
the American Diabetes Association (ADA) for mild, moderate, and severe DKA and HHS
are shown in the table (table 1).

●DKA is characterized by the triad of hyperglycemia, anion gap metabolic acidosis,

and ketonemia. Metabolic acidosis is often the major finding. The serum glucose
concentration is usually less than 800 mg/dL (44 mmol/L) and often approximately
350 to 500 mg/dL (19.4 to 27.8 mmol/L) [15,28]. However, serum glucose
concentrations may exceed 900 mg/dL (50 mmol/L) in patients with DKA who are
comatose [67]. In certain settings, such as starvation, pregnancy, treatment with
insulin prior to arrival in the emergency department, or use of SGLT2 inhibitors, the
glucose level may be only mildly elevated.
●In HHS, there is little or no ketoacid accumulation, the serum glucose concentration
frequently exceeds 1000 mg/dL (56 mmol/L), the plasma osmolality may reach
380 mosmol/kg, and neurologic abnormalities are frequently present (including coma
in 25 to 50 percent of cases) [14,25,28]. Most patients with HHS have an admission
pH >7.30, a serum bicarbonate >20 mEq/L, a serum glucose
>600 mg/dL (33.3 mmol/L), and test negative for ketones in serum and urine,
although mild ketonemia may be present.

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].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of hyperglycemic crises

includes other causes of ketosis, acidosis, hyperosmolality, and/or coma (table 5).
Alcoholic and fasting ketoacidosis — Alcoholic ketoacidosis (AKA) and starvation
ketosis are other causes of ketoacidosis. Low carbohydrate diets can also precipitate
ketoacidosis [69]. The acidosis can be relatively severe in AKA. However, ketoacid levels
with prolonged fasting ketoacidosis rarely exceed 8 to 10 mEq/L. Therefore, the serum
bicarbonate concentration is typically above 17 mEq/L with uncomplicated fasting [70].
More severe ketoacidosis may develop in fasting children and pregnant women [71,72].
(See "Fasting ketosis and alcoholic ketoacidosis".)

Ketoacidosis without hyperglycemia in a patient with chronic alcoholism is virtually

diagnostic of AKA. Modest elevations in serum glucose in patients with alcoholic
ketoacidosis may reflect underlying unrecognized diabetes or a catecholamine-mediated
stress response [73]. Measurement of glycated hemoglobin (A1C) may help confirm
chronic hyperglycemia.

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".)

Metabolic encephalopathy — Toxic metabolic encephalopathy is usually a consequence

of systemic illness, and its causes are diverse. In patients with diabetes, both severe
hypoglycemia and severe hyperglycemia can result in coma. Measurement of fingerstick
(capillary) or plasma glucose may be diagnostic (table 5). (See "Acute toxic-metabolic
encephalopathy in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines

from selected countries and regions around the world are provided separately.
(See "Society guideline links: Hyperglycemic emergencies".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Diabetic ketoacidosis (The

Basics)" and "Patient education: Hyperosmolar nonketotic coma (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Although part of a spectrum of diabetic complications, diabetic ketoacidosis (DKA)

and hyperosmolar hyperglycemic state (HHS) primarily differ according to the
presence of ketoacidosis and the degree of hyperglycemia (table 1).
(See 'Introduction' above.)
●A precipitating event can usually be identified in patients with DKA or HHS. The
most common are infection (most often pneumonia or urinary tract infection) and
discontinuation of or inadequate insulin therapy (table 2). (See 'Precipitating
factors' above.)
●Neurologic symptoms, which may include focal findings, are more often seen in
HHS and primarily occur when the effective plasma osmolality is greater than 320 to
330 mosmol/kg. The presence of stupor or coma in diabetic patients with an effective
plasma osmolality below 320 mosmol/kg demands immediate consideration of other
causes of the mental status change. Abdominal pain is common in DKA but not in
HHS, and requires evaluation if it does not resolve with treatment of the acidosis.
Infection can occur without fever. (See 'Clinical presentation' above.)
●The initial evaluation of patients with hyperglycemic crises should include
assessment of cardiorespiratory status, volume status, and mental status (table 3).
The initial laboratory evaluation of a patient with suspected DKA or HHS should
include determination of serum glucose, 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), and electrocardiogram.
(See 'Diagnostic evaluation' above.)
●Three ketone bodies are produced in DKA: one ketoacid (acetoacetic acid), one
hydroxyacid (beta-hydroxybutyric acid), and one neutral ketone (acetone). Testing for
serum ketones is generally performed if urine testing is positive. Urine ketone bodies
are detected by a dipstick 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. (See 'Serum
ketones' above.)
●Patients with DKA usually present with a serum anion gap greater than 20 mEq/L.
However, the increase in anion gap is variable, being determined by several factors:
the rate and duration of ketoacid production, the rate of metabolism of the ketoacids
 and their loss in the urine, and the volume of distribution of the ketoacid anions.
(See 'Anion gap metabolic acidosis' above and "Diabetic ketoacidosis and
hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis", section
on 'Anion gap metabolic acidosis'.)
●Most patients with DKA and HHS are mildly hyponatremic, but patients who have a
marked osmotic diuresis may have a normal or even elevated serum sodium
concentration. The serum sodium concentration in DKA and HHS reflects the balance
between the dilutional effect of water moving out of cells in response to the
hyperglycemia-induced increase in serum osmolality and the increase in water
excretion due to the glucosuria-induced osmotic diuresis (table 4). (See 'Serum
sodium' above and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in
adults: Epidemiology and pathogenesis", section on 'Plasma osmolality and sodium'.)
●Patients with DKA or HHS have a potassium deficit that averages 300 to 600 mEq.
Despite this deficit, the serum potassium concentration is often elevated at
presentation, as both insulin deficiency and hyperosmolality result in potassium
movement out of the cells into the extracellular fluid (ECF). Insulin therapy lowers the
potassium concentration and may cause severe hypokalemia, particularly in patients
with a normal or low serum potassium concentration at presentation. Thus, careful
monitoring and timely administration of potassium supplementation are essential.
(See 'Serum potassium' above.)
●Serum amylase and lipase levels are elevated in 15 to 25 percent of patients with
DKA and, in most cases, do not reflect acute pancreatitis. The diagnosis of
pancreatitis should be based upon clinical findings and confirmed by imaging.
(See 'Serum amylase and lipase' above.)
●DKA is diagnosed when the triad of hyperglycemia, anion gap metabolic acidosis,
and ketonemia is present. Metabolic acidosis is often the major finding. The serum
glucose concentration is usually less than 800 mg/dL (44 mmol/L) and often
approximately 350 to 500 mg/dL (19.4 to 27.8 mmol/L). In HHS, there is little or no
ketoacid accumulation, the serum glucose concentration frequently exceeds
1000 mg/dL (56 mmol/L), the effective plasma osmolality is >320 mosmol/kg, and
neurologic abnormalities are frequently present (including coma in 25 to 50 percent of
cases) (table 1). (See 'Diagnostic criteria' above.)
●Ketoacidosis may also be caused by alcohol abuse or fasting. Other causes of an
anion gap acidosis include lactic acidosis, ingestion of drugs such as aspirin,
methanol, and ethylene glycol, and advanced chronic kidney disease.
(See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — We are saddened by the death of Abbas Kitabchi, PhD, MD,

FACP, MACE, who passed away in July 2016. UpToDate wishes to acknowledge Dr.
Kitabchi's past work as an author for this topic.

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 REFERENCES

1. Kitabchi AE, Razavi L.Hyperglycemic Crises: Diabetic Ketoacidosis (DKA), And Hyperglyc
emic Hyperosmolar State (HHS). In: http://www.endotext.org/diabetes/diabetes24/diabetes
frame24.htm (Accessed on January 30, 2013).
2. Randall L, Begovic J, Hudson M, et al. Recurrent diabetic ketoacidosis in inner-city
minority patients: behavioral, socioeconomic, and psychosocial factors. Diabetes Care
2011; 34:1891.
3. Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, et al. Hyperosmolarity and acidosis in
diabetes mellitus: a three-year experience in Rhode Island. J Gen Intern Med 1991; 6:495.
4. Wachtel TJ. The diabetic hyperosmolar state. Clin Geriatr Med 1990; 6:797.
5. Wachtel TJ, Silliman RA, Lamberton P. Prognostic factors in the diabetic hyperosmolar
state. J Am Geriatr Soc 1987; 35:737.
6. Kitabchi AE, Murphy MB. Consequences of insulin deficiency. In: Atlas of Diabetes, 4th, S
kyler J (Ed), Springer US, New York 2012. p.39.
7. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a
comprehensive literature review. CNS Drugs 2005; 19 Suppl 1:1.
8. Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin
Endocrinol Metab 2015; 100:2849.
9. Warner EA, Greene GS, Buchsbaum MS, et al. Diabetic ketoacidosis associated with
cocaine use. Arch Intern Med 1998; 158:1799.
10. Nyenwe EA, Loganathan RS, Blum S, et al. Active use of cocaine: an independent risk
factor for recurrent diabetic ketoacidosis in a city hospital. Endocr Pract 2007; 13:22.
11. Polonsky WH, Anderson BJ, Lohrer PA, et al. Insulin omission in women with IDDM.
Diabetes Care 1994; 17:1178.
12. Peden NR, Braaten JT, McKendry JB. Diabetic ketoacidosis during long-term treatment
with continuous subcutaneous insulin infusion. Diabetes Care 1984; 7:1.
13. Pańkowska E, Błazik M, Dziechciarz P, et al. Continuous subcutaneous insulin infusion vs.
multiple daily injections in children with type 1 diabetes: a systematic review and meta-
analysis of randomized control trials. Pediatr Diabetes 2009; 10:52.
14. Daugirdas JT, Kronfol NO, Tzamaloukas AH, Ing TS. Hyperosmolar coma: cellular
dehydration and the serum sodium concentration. Ann Intern Med 1989; 110:855.
15. Fulop M, Tannenbaum H, Dreyer N. Ketotic hyperosmolar coma. Lancet 1973; 2:635.
16. Kitabchi AE, Fisher JN. Insulin therapy of diabetic ketoacidosis: Physiologic versus pharm
acologic doses of insulin and their routes of administration. In: Handbook of Diabetes Mellit
us, Brownlee M (Ed), Garland ATPM Press, New York 1981. p.95.
17. Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 1995; 79:39.
18. Maccario M. Neurological dysfunction associated with nonketotic hyperglycemia. Arch
Neurol 1968; 19:525.
19. Guisado R, Arieff AI. Neurologic manifestations of diabetic comas: correlation with
biochemical alterations in the brain. Metabolism 1975; 24:665.
20. Lavin PJ. Hyperglycemic hemianopia: a reversible complication of non-ketotic
hyperglycemia. Neurology 2005; 65:616.
21. Harden CL, Rosenbaum DH, Daras M. Hyperglycemia presenting with occipital seizures.
Epilepsia 1991; 32:215.
22. Nyenwe EA, Razavi LN, Kitabchi AE, et al. Acidosis: the prime determinant of depressed
sensorium in diabetic ketoacidosis. Diabetes Care 2010; 33:1837.
23. Malone ML, Gennis V, Goodwin JS. Characteristics of diabetic ketoacidosis in older versus
younger adults. J Am Geriatr Soc 1992; 40:1100.
24. Umpierrez G, Freire AX. Abdominal pain in patients with hyperglycemic crises. J Crit Care
2002; 17:63.
25. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients
with diabetes. Diabetes Care 2009; 32:1335.
26. Barrett EJ, DeFronzo RA. Diabetic ketoacidosis: diagnosis and treatment. Hosp Pract (Off
Ed) 1984; 19:89.
27. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in
patients with diabetes. Diabetes Care 2001; 24:131.
28. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features,
pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria
and the effects of therapy in 37 cases. Medicine (Baltimore) 1972; 51:73.
29. Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycaemic diabetic ketoacidosis. Br
Med J 1973; 2:578.
30. Burge MR, Hardy KJ, Schade DS. Short-term fasting is a mechanism for the development
of euglycemic ketoacidosis during periods of insulin deficiency. J Clin Endocrinol Metab
1993; 76:1192.
31. Eisenbarth GS, Polonsky KS, Buse JB. Type 1 diabetes mellitus: Acute diabetic emergenci
es: Diabetic ketoacidosis. In: Williams Textbook of Endocrinology, Larsen PR, Kronenberg
HM, Melmed S, Polonsky KS (Eds), Elsevier Science, Philadelphia 2003. p.1500.
32. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of
monitoring to diabetes. Diabetes Metab Res Rev 1999; 15:412.
33. Sheikh-Ali M, Karon BS, Basu A, et al. Can serum beta-hydroxybutyrate be used to
diagnose diabetic ketoacidosis? Diabetes Care 2008; 31:643.
34. Wiggam MI, O'Kane MJ, Harper R, et al. Treatment of diabetic ketoacidosis using
normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency
management. A randomized controlled study. Diabetes Care 1997; 20:1347.
35. Porter WH, Yao HH, Karounos DG. Laboratory and clinical evaluation of assays for beta-
hydroxybutyrate. Am J Clin Pathol 1997; 107:353.
36. Fulop M, Murthy V, Michilli A, et al. Serum beta-hydroxybutyrate measurement in patients
with uncontrolled diabetes mellitus. Arch Intern Med 1999; 159:381.
37. Smith SW, Manini AF, Szekely T, Hoffman RS. Bedside detection of urine beta-
hydroxybutyrate in diagnosing metabolic acidosis. Acad Emerg Med 2008; 15:751.
38. Bektas F, Eray O, Sari R, Akbas H. Point of care blood ketone testing of diabetic patients
in the emergency department. Endocr Res 2004; 30:395.
39. DeFronzo RA, Matzuda M, Barret E. Diabetic ketoacidosis: a combined metabolic-
nephrologic approach to therapy. Diabetes Rev 1994; 2:209.
40. Adrogué HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels
in diabetic ketoacidosis. Medicine (Baltimore) 1986; 65:163.
41. Khardori R, Soler NG. Hyperosmolar hyperglycemic nonketotic syndrome. Report of 22
cases and brief review. Am J Med 1984; 77:899.
42. Phillips PA, Bretherton M, Johnston CI, Gray L. Reduced osmotic thirst in healthy elderly
men. Am J Physiol 1991; 261:R166.
43. Kaminska ES, Pourmotabbed G. Spurious laboratory values in diabetic ketoacidosis and
hyperlipidemia. Am J Emerg Med 1993; 11:77.
44. Rumbak MJ, Hughes TA, Kitabchi AE. Pseudonormoglycemia in diabetic ketoacidosis with
elevated triglycerides. Am J Emerg Med 1991; 9:61.
45. Emmett M. Case 6: Diabetes and Acidosis. In: NephSAP: Nephrology Self-Assessment Pr
ogram: Fluid, Electrolyte, and Acid-Base Disturbances, Sterns RH, Emmett M (Eds), The A
merican Society of Nephrology 2013. Vol 12, No 3, p.191.
46. Graber ML, Quigg RJ, Stempsey WE, Weis S. Spurious hyperchloremia and decreased
anion gap in hyperlipidemia. Ann Intern Med 1983; 98:607.
47. Kreisberg RA. Diabetic ketoacidosis: new concepts and trends in pathogenesis and
treatment. Ann Intern Med 1978; 88:681.
48. Abramson E, Arky R. Diabetic acidosis with initial hypokalemia. Therapeutic implications.
JAMA 1966; 196:401.
49. Murthy K, Harrington JT, Siegel RD. Profound hypokalemia in diabetic ketoacidosis: a
therapeutic challenge. Endocr Pract 2005; 11:331.
50. Arora S, Cheng D, Wyler B, Menchine M. Prevalence of hypokalemia in ED patients with
diabetic ketoacidosis. Am J Emerg Med 2012; 30:481.
51. Atchley DW, Loeb RF, Richards DW, et al. ON DIABETIC ACIDOSIS: A Detailed Study of
Electrolyte Balances Following the Withdrawal and Reestablishment of Insulin Therapy. J
Clin Invest 1933; 12:297.
52. Kebler R, McDonald FD, Cadnapaphornchai P. Dynamic changes in serum phosphorus
levels in diabetic ketoacidosis. Am J Med 1985; 79:571.
53. Shen T, Braude S. Changes in serum phosphate during treatment of diabetic ketoacidosis:
predictive significance of severity of acidosis on presentation. Intern Med J 2012; 42:1347.
54. Molitch ME, Rodman E, Hirsch CA, Dubinsky E. Spurious serum creatinine elevations in
ketoacidosis. Ann Intern Med 1980; 93:280.
55. Kemperman FA, Weber JA, Gorgels J, et al. The influence of ketoacids on plasma
creatinine assays in diabetic ketoacidosis. J Intern Med 2000; 248:511.
56. Yadav D, Nair S, Norkus EP, Pitchumoni CS. Nonspecific hyperamylasemia and
hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical
abnormalities. Am J Gastroenterol 2000; 95:3123.
57. Warshaw AL, Feller ER, Lee KH. On the cause of raised serum-amylase in diabetic
ketoacidosis. Lancet 1977; 1:929.
58. Vinicor F, Lehrner LM, Karn RC, Merritt AD. Hyperamylasemia in diabetic ketoacidosis:
sources and significance. Ann Intern Med 1979; 91:200.
59. Vantyghem MC, Haye S, Balduyck M, et al. Changes in serum amylase, lipase and
leukocyte elastase during diabetic ketoacidosis and poorly controlled diabetes. Acta
Diabetol 1999; 36:39.
60. Kjaergaard JJ, Salling N, Magid E, Ditzel J. Serum amylase during recovery from diabetic
ketoacidosis. Diabete Metab 1984; 10:25.
61. Nair S, Yadav D, Pitchumoni CS. Association of diabetic ketoacidosis and acute
pancreatitis: observations in 100 consecutive episodes of DKA. Am J Gastroenterol 2000;
95:2795.
62. Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE. Proinflammatory cytokines, markers of
cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic
crises. Diabetes 2004; 53:2079.
63. Nematollahi LR, Taheri E, Larijani B, et al. Catecholamine-induced leukocytosis in acute
hypoglycemic stress. J Investig Med 2007; 55:S262.
64. Slovis CM, Mork VG, Slovis RJ, Bain RP. Diabetic ketoacidosis and infection: leukocyte
count and differential as early predictors of serious infection. Am J Emerg Med 1987; 5:1.
65. Weidman SW, Ragland JB, Fisher JN Jr, et al. Effects of insulin on plasma lipoproteins in
diabetic ketoacidosis: evidence for a change in high density lipoprotein composition during
treatment. J Lipid Res 1982; 23:171.
66. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th, McGr
aw-Hill, New York 2001. p.809-815.
67. Morris LR, Kitabchi AE. Efficacy of low-dose insulin therapy for severely obtunded patients
in diabetic ketoacidosis. Diabetes Care 1980; 3:53.
68. Szeto CC, Li KY, Ko GT, et al. Acromegaly in a woman presenting with diabetic
ketoacidosis and insulin resistance. Int J Clin Pract 1997; 51:476.
69. Shah P, Isley WL. Ketoacidosis during a low-carbohydrate diet. N Engl J Med 2006;
354:97.
70. Reichard GA Jr, Owen OE, Haff AC, et al. Ketone-body production and oxidation in fasting
obese humans. J Clin Invest 1974; 53:508.
71. Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006; 26:1.
72. Mahoney CA. Extreme gestational starvation ketoacidosis: case report and review of
pathophysiology. Am J Kidney Dis 1992; 20:276.
73. Wrenn KD, Slovis CM, Minion GE, Rutkowski R. The syndrome of alcoholic ketoacidosis.
Am J Med 1991; 91:119.

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