Authors:Irl B Hirsch, MDMichael Emmett, MDSection Editor:David M Nathan, MDDeputy

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: Jan 2018. | 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.

REFERENCES
Kitabchi AE, Razavi L.Hyperglycemic Crises: Diabetic Ketoacidosis (DKA), And Hyperglycemic
Hyperosmolar State (HHS). In:
http://www.endotext.org/diabetes/diabetes24/diabetesframe24.htm (Accessed on January 30,
2013).
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.
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.
Wachtel TJ. The diabetic hyperosmolar state. Clin Geriatr Med 1990; 6:797.
Wachtel TJ, Silliman RA, Lamberton P. Prognostic factors in the diabetic hyperosmolar state. J
Am Geriatr Soc 1987; 35:737.
Kitabchi AE, Murphy MB. Consequences of insulin deficiency. In: Atlas of Diabetes, 4th, Skyler
J (Ed), Springer US, New York 2012. p.39.
Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a
comprehensive literature review. CNS Drugs 2005; 19 Suppl 1:1.
Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin
Endocrinol Metab 2015; 100:2849.
Warner EA, Greene GS, Buchsbaum MS, et al. Diabetic ketoacidosis associated with cocaine
use. Arch Intern Med 1998; 158:1799.
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.
Polonsky WH, Anderson BJ, Lohrer PA, et al. Insulin omission in women with IDDM. Diabetes
Care 1994; 17:1178.
Peden NR, Braaten JT, McKendry JB. Diabetic ketoacidosis during long-term treatment with
continuous subcutaneous insulin infusion. Diabetes Care 1984; 7:1.
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.
Daugirdas JT, Kronfol NO, Tzamaloukas AH, Ing TS. Hyperosmolar coma: cellular dehydration
and the serum sodium concentration. Ann Intern Med 1989; 110:855.
Fulop M, Tannenbaum H, Dreyer N. Ketotic hyperosmolar coma. Lancet 1973; 2:635.
Kitabchi AE, Fisher JN. Insulin therapy of diabetic ketoacidosis: Physiologic versus
pharmacologic doses of insulin and their routes of administration. In: Handbook of Diabetes
Mellitus, Brownlee M (Ed), Garland ATPM Press, New York 1981. p.95.
Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 1995; 79:39.
Maccario M. Neurological dysfunction associated with nonketotic hyperglycemia. Arch Neurol
1968; 19:525.
Guisado R, Arieff AI. Neurologic manifestations of diabetic comas: correlation with biochemical
alterations in the brain. Metabolism 1975; 24:665.
Lavin PJ. Hyperglycemic hemianopia: a reversible complication of non-ketotic hyperglycemia.
Neurology 2005; 65:616.
Harden CL, Rosenbaum DH, Daras M. Hyperglycemia presenting with occipital seizures.
Epilepsia 1991; 32:215.
Nyenwe EA, Razavi LN, Kitabchi AE, et al. Acidosis: the prime determinant of depressed
sensorium in diabetic ketoacidosis. Diabetes Care 2010; 33:1837.
Malone ML, Gennis V, Goodwin JS. Characteristics of diabetic ketoacidosis in older versus
younger adults. J Am Geriatr Soc 1992; 40:1100.
Umpierrez G, Freire AX. Abdominal pain in patients with hyperglycemic crises. J Crit Care
2002; 17:63.
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with
diabetes. Diabetes Care 2009; 32:1335.
Barrett EJ, DeFronzo RA. Diabetic ketoacidosis: diagnosis and treatment. Hosp Pract (Off Ed)
1984; 19:89.
Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients
with diabetes. Diabetes Care 2001; 24:131.
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.
Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycaemic diabetic ketoacidosis. Br Med J
1973; 2:578.
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.
Eisenbarth GS, Polonsky KS, Buse JB. Type 1 diabetes mellitus: Acute diabetic emergencies:
Diabetic ketoacidosis. In: Williams Textbook of Endocrinology, Larsen PR, Kronenberg HM,
Melmed S, Polonsky KS (Eds), Elsevier Science, Philadelphia 2003. p.1500.
Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring
to diabetes. Diabetes Metab Res Rev 1999; 15:412.
Sheikh-Ali M, Karon BS, Basu A, et al. Can serum beta-hydroxybutyrate be used to diagnose
diabetic ketoacidosis? Diabetes Care 2008; 31:643.
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.
Porter WH, Yao HH, Karounos DG. Laboratory and clinical evaluation of assays for beta-
hydroxybutyrate. Am J Clin Pathol 1997; 107:353.
Fulop M, Murthy V, Michilli A, et al. Serum beta-hydroxybutyrate measurement in patients with
uncontrolled diabetes mellitus. Arch Intern Med 1999; 159:381.
Smith SW, Manini AF, Szekely T, Hoffman RS. Bedside detection of urine beta-hydroxybutyrate
in diagnosing metabolic acidosis. Acad Emerg Med 2008; 15:751.
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.
DeFronzo RA, Matzuda M, Barret E. Diabetic ketoacidosis: a combined metabolic-nephrologic
approach to therapy. Diabetes Rev 1994; 2:209.
Adrogué HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels in
diabetic ketoacidosis. Medicine (Baltimore) 1986; 65:163.
Khardori R, Soler NG. Hyperosmolar hyperglycemic nonketotic syndrome. Report of 22 cases
and brief review. Am J Med 1984; 77:899.
Phillips PA, Bretherton M, Johnston CI, Gray L. Reduced osmotic thirst in healthy elderly men.
Am J Physiol 1991; 261:R166.
Kaminska ES, Pourmotabbed G. Spurious laboratory values in diabetic ketoacidosis and
hyperlipidemia. Am J Emerg Med 1993; 11:77.
Rumbak MJ, Hughes TA, Kitabchi AE. Pseudonormoglycemia in diabetic ketoacidosis with
elevated triglycerides. Am J Emerg Med 1991; 9:61.
Emmett M. Case 6: Diabetes and Acidosis. In: NephSAP: Nephrology Self-Assessment
Program: Fluid, Electrolyte, and Acid-Base Disturbances, Sterns RH, Emmett M (Eds), The
American Society of Nephrology 2013. Vol 12, No 3, p.191.
Graber ML, Quigg RJ, Stempsey WE, Weis S. Spurious hyperchloremia and decreased anion
gap in hyperlipidemia. Ann Intern Med 1983; 98:607.
Kreisberg RA. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment.
Ann Intern Med 1978; 88:681.
Abramson E, Arky R. Diabetic acidosis with initial hypokalemia. Therapeutic implications. JAMA
1966; 196:401.
Murthy K, Harrington JT, Siegel RD. Profound hypokalemia in diabetic ketoacidosis: a
therapeutic challenge. Endocr Pract 2005; 11:331.
Arora S, Cheng D, Wyler B, Menchine M. Prevalence of hypokalemia in ED patients with
diabetic ketoacidosis. Am J Emerg Med 2012; 30:481.
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.
Kebler R, McDonald FD, Cadnapaphornchai P. Dynamic changes in serum phosphorus levels
in diabetic ketoacidosis. Am J Med 1985; 79:571.
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.
Molitch ME, Rodman E, Hirsch CA, Dubinsky E. Spurious serum creatinine elevations in
ketoacidosis. Ann Intern Med 1980; 93:280.
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.
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.
Warshaw AL, Feller ER, Lee KH. On the cause of raised serum-amylase in diabetic
ketoacidosis. Lancet 1977; 1:929.
Vinicor F, Lehrner LM, Karn RC, Merritt AD. Hyperamylasemia in diabetic ketoacidosis: sources
and significance. Ann Intern Med 1979; 91:200.
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.
Kjaergaard JJ, Salling N, Magid E, Ditzel J. Serum amylase during recovery from diabetic
ketoacidosis. Diabete Metab 1984; 10:25.
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.
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.
Nematollahi LR, Taheri E, Larijani B, et al. Catecholamine-induced leukocytosis in acute
hypoglycemic stress. J Investig Med 2007; 55:S262.
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.
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.
Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th, McGraw-
Hill, New York 2001. p.809-815.
Morris LR, Kitabchi AE. Efficacy of low-dose insulin therapy for severely obtunded patients in
diabetic ketoacidosis. Diabetes Care 1980; 3:53.
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.
Shah P, Isley WL. Ketoacidosis during a low-carbohydrate diet. N Engl J Med 2006; 354:97.
Reichard GA Jr, Owen OE, Haff AC, et al. Ketone-body production and oxidation in fasting
obese humans. J Clin Invest 1974; 53:508.
Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006; 26:1.
Mahoney CA. Extreme gestational starvation ketoacidosis: case report and review of
pathophysiology. Am J Kidney Dis 1992; 20:276.
Wrenn KD, Slovis CM, Minion GE, Rutkowski R. The syndrome of alcoholic ketoacidosis. Am J
Med 1991; 91:119.
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