Diabetic ketoacidosis (DKA) is an acute metabolic complication of

diabetes characterized by hyperglycemia, hyperketonemia, and

metabolic acidosis. DKA occurs mostly in type 1 diabetes mellitus
(DM). It causes nausea, vomiting, and abdominal pain and can
progress to cerebral edema, coma, and death. DKA is diagnosed
by detection of hyperketonemia and anion gap metabolic acidosis
in the presence of hyperglycemia. Treatment involves volume
expansion, insulin replacement, and prevention of hypokalemia.

DKA is most common among patients with type 1 DM and

develops when insulin levels are insufficient to meet the body's
basic metabolic requirements. DKA is the first manifestation of
type 1 DM in a minority of patients. Insulin deficiency can be
absolute (eg, during lapses in the administration of exogenous
insulin) or relative (eg, when usual insulin doses do not meet
metabolic needs during physiologic stress).

Common physiologic stresses that can trigger DKA include: Acute

infection (particularly pneumonia and UTI), MI, Stroke,
Pancreatitis, Trauma.

Drugs implicated in causing DKA include: Corticosteroids, Thiazide

diuretics, Sympathomimetics

Pathophysiology
DKA is associated with a relative or absolute insulin deficiency
and a severely elevated blood glucose level, typically greater than
300 mg/dL. Due to the lack of insulin, peripheral cells are unable
to take up glucose. Even though the blood has an extremely
elevated amount of circulating glucose, the cells are basically
starving.

Ketoacidosis is an extension of normal physiological mechanisms

that compensate for starvation. Normally, in the fasting state, the
body changes from metabolism based on carbohydrate, to fat
oxidation. Free fatty acids are produced in adipocytes, and
transported to the liver bound to albumin. There they are broken
down into acetate, and then turned into ketoacids (acetoacetate
and beta-hydroxybutyrate). The ketoacids are then exported from
the liver to peripheral tissues where they can be oxidised. Note
that during ketosis, a relatively small amount of acetone is
produced, this giving ketotic patients their typical smell, often
described as 'fruity'.

DKA represents a derangement of the above mechanism. Despite

vast amounts of circulating glucose, this carbohydrate cannot be
used owing to lack of insulin. Ketogenic pathways are maximally
"turned on", supply of ketones exceeds peripheral utilisation, and
ketosis results.

As acetoacetic acid is metabolized it produces acetone, which

begins to accumulate in the blood. Small amounts of acetone are
released in respiration and produce the characteristic fruity
breath odor. In normal metabolism, ketones would be used as
fuel in the peripheral tissue; however, due to the starvation state
of the cells, the ketones are not used.

An increase in ketone production and a decrease in peripheral cell

use lead to metabolic acidosis also called ketoacidosis. This is
reflected in a decreasing pH value typically less than 7.40. The
patient will also begin to eliminate large amounts of ketones
through excretion in the urine, causing ketonuria.

Typically, when the blood glucose level reaches approximately

225 mg/dL a significant amount of glucose spills over into the
urine. A glucose molecule produces an osmotic effect by drawing
water across a semipermeable membrane. As an excessive
amount of glucose enters the renal tubules, it draws a large
amount of water that ends up producing a significant amount of
urine. This is known as osmotic diuresis and leads to volume
depletion and dehydration in the patient.

Large amounts of ketones also collect in the urine. Because

ketones are strong organic acids, they must be buffered in order
to be excreted. Sodium is typically used as the buffer. As we have
been instructed, where sodium goes, water follows. Thus, the
sodium used to buffer the ketones also draws a large amount of
water into the renal tubules, which produces excessive urine and
leads to further volume depletion and dehydration. The loss of
large amounts of fluid also leads to the excretion of other
electrolytes, such as potassium, leading to hypokalemia. This
produces electrolyte imbalance and disturbances.

Hyperglycemia due to insulin deficiency causes an osmotic

diuresis that leads to marked urinary losses of water and
electrolytes. Urinary excretion of ketones obligates additional
losses of Na and K. Serum Na may fall from natriuresis or rise due
to excretion of large volumes of free water. K is also lost in large
quantities, sometimes > 300 mEq/24 h. Despite a significant total
body deficit of K, initial serum K is typically normal or elevated
because of the extracellular migration of K in response to
acidosis. K levels generally fall further during treatment as insulin
therapy drives K into cells. If serum K is not monitored and
replaced as needed, life-threatening hypokalemia may develop.

Symptoms and Signs

Symptoms and signs of DKA include those of hyperglycemia with
the addition of nausea, vomiting, andparticularly in children
abdominal pain. Lethargy and somnolence are symptoms of more
severe decompensation. Patients may be hypotensive and
tachycardic from dehydration and acidosis; they may breathe
rapidly and deeply to compensate for acidemia (Kussmaul
respirations). They may also have fruity breath due to exhaled
acetone. Fever is not a sign of DKA itself and, if present, signifies
underlying infection. In the absence of timely treatment, DKA
progresses to coma and death.

Diagnosis
Arterial pH
Serum ketones
Calculation of anion gap

The Anion Gap

The anion gap is defined as serum Na concentration minus the
sum of Cl and HCO3 concentrations; Na (Cl + HCO3). For
example: Na, 137; K, 3.8; Cl, 90; HCO3, 22. Calculations show
elevation of the anion gap: 137 (90 + 22) = 25 (normal 10).
In patients suspected of having DKA, serum electrolytes, BUN and
creatinine, glucose, ketones, and osmolarity should be measured.
Urine should be tested for ketones. Patients who appear
significantly ill and those with positive ketones should have ABG
measurement. DKA is diagnosed by an arterial pH < 7.30 with an
anion gap > 12 and serum ketones in the presence of
hyperglycemia. A presumptive diagnosis can be made when urine
glucose and ketones are strongly positive.

Adults should have an ECG to screen for acute MI and to help

determine the significance of abnormalities in serum K.

Other laboratory abnormalities include hyponatremia, elevated

serum creatinine, and elevated plasma osmolality. Hyperglycemia
may cause dilutional hyponatremia, so measured serum Na is
corrected by adding 1.6 mEq/L for each 100 mg/dL elevation of
serum glucose over 100 mg/dL. To illustrate, for a patient with
serum Na of 124 mEq/L and glucose of 600 mg/dL, add 1.6 ([600
100]/100) = 8 mEq/L to 124 for a corrected serum Na of 132
mEq/L. As acidosis is corrected, serum K drops. An initial K level <
4.5 mEq/L indicates marked K depletion and requires immediate K
supplementation. Serum amylase and lipase are often elevated,
even in the absence of pancreatitis (which may be present in
alcoholic DKA patients and in those with coexisting
hypertriglyceridemia).

Prognosis
Mortality rates for DKA are between 1 and 10%. Shock or coma on
admission indicates a worse prognosis. Main causes of death are
circulatory collapse, hypokalemia, and infection. Among children
with cerebral edema, 57% recover completely, 21% survive with
neurologic sequelae, and 21% die.

Treatment
IV 0.9% saline
IV insulin
Correction of any hypokalemia
The most urgent goals are i) rapid intravascular volume repletion,
ii) correction of hyperglycemia and acidosis, and iii) prevention of
hypokalemia. Identification of precipitating factors is also
important. Treatment should occur in intensive care settings
because clinical and laboratory assessments are initially needed
every hour or every other hour with appropriate adjustments in
treatment.

i) Intravascular volume should be restored rapidly to raise BP and

ensure glomerular perfusion; once intravascular volume is
restored, remaining total body water deficits are corrected more
slowly, typically over about 24 h. Initial volume repletion in adults
is typically achieved with rapid IV infusion of 1 to 3 L of 0.9%
saline solution, followed by saline infusions at 1 L/h or faster as
needed to raise BP, correct hyperglycemia, and keep urine flow
adequate. Adults with DKA typically need a minimum of 3 L of
saline over the first 5 h. When BP is stable and urine flow
adequate, normal saline is replaced by 0.45% saline. When
plasma glucose falls to < 200 mg/dL (11.1 mmol/L), IV fluid
should be changed to 5% dextrose in 0.45% saline.

ii) Hyperglycemia is corrected by giving regular insulin 0.1 unit/kg

IV bolus initially, followed by continuous IV infusion of 0.1
unit/kg/h in 0.9% saline solution. Ketones should begin to clear
within hours if insulin is given in sufficient doses.

When plasma glucose becomes < 200 mg/dL (< 11.1 mmol/L) in
adults, 5% dextrose should be added to IV fluids to reduce the risk
of hypoglycemia. Insulin dosage can then be reduced to 0.02 to
0.05 unit/kg/h, but the continuous IV infusion of regular insulin
should be maintained until the anion gap has narrowed and blood
and urine are consistently negative for ketones. Insulin
replacement may then be switched to regular insulin 5 to 10 units
sc q 4 to 6 h.

iii) Hypokalemia prevention requires replacement of 20 to 30 mEq

K in each liter of IV fluid to keep serum K between 4 and 5 mEq/L.
If serum K is < 3.3 mEq/L, insulin should be withheld and K given
at 40 mEq/h until serum K is 3.3 mEq/L; if serum K is > 5
mEq/L, K supplementation can be withheld. Insulin replacement
rapidly shifts K into cells, so levels should be checked hourly or
every other hour in the initial stages of treatment.

Key Points
Acute physiologic stressors (eg, infections, MI) can trigger
acidosis, moderate glucose elevation, dehydration, and severe K
loss in patients with type 1 diabetes.
Acute cerebral edema is a rare (about 1%) but lethal
complication, primarily in children and less often in adolescents
and young adults.
Diagnose by an arterial pH < 7.30, with an anion gap > 12 and
serum ketones in the presence of hyperglycemia.
Acidosis typically corrects with IV fluid and insulin; consider
HCO3 only if marked acidosis (pH < 7) persists after 1 hr of
therapy.
Withhold insulin until serum K is 3.3 mEq/L

CLINICAL VIGNETTES

A 52-year-old male with diabetes mellitus reports that he ran out

of insulin a week ago. He is drowsy but responds to your verbal
commands, and the remainder of his examination is
unremarkable. Laboratory Findings:

Blood glucose: 625mg/dL

Serum sodium: 128 mEq/L (N 135145)
Serum potassium: 5.9 mEq/L (N 3.55.0)
Serum bicarbonate: 12 mEq/L (N 2226)
BUN: 52mg/dL(N825)

Which one of the laboratory abnormalities is an indication that he

has severe diabetic ketoacidosis?

A. Glucose | B. Sodium | C. Potassium | D. Bicarbonate | E. BUN

ANSWER: D. The diagnosis of diabetic ketoacidosis (DKA) is based
on an elevated serum glucose level (>250 mg/dL), an elevated
serum ketone level, a pH <7.3, and a serum bicarbonate level
<18 mEq/L. The severity of DKA is determined by the arterial pH,
bicarbonate level, anion gap, and mental status of the patient.
Elevation of BUN and serum creatinine levels reflects
intravascular volume loss. The measured serum sodium is
reduced as a result of the hyperglycemia, as serum sodium is
reduced by 1.6 mEq/L for each 100 mg/dL rise in serum glucose.
The degree of hyperglycemia does not necessarily correlate
closely with the degree of DKA since a variety of factors
determine the level of hyperglycemia, such as oral intake and
urinary glucose loss (SOR C).

A 19-year-old woman is brought to the emergency department by

her parents because of confusion. Her parents tell you that over
the last 2 weeks the patient has had an 11-pound weight loss and
fatigue. She had been constantly using the bathroom but they
assumed it was only because she seemed to be drinking huge
amount of liquids. Her parents reported no previous medical
problems in her history. Her last normal menstrual period ended 3
days ago. You notice a stuporous white female who appears thin
and in moderate distress. Her temperature is 38.0 C (100.4 F),
blood pressure is 90/40 mm Hg, pulse is 115/min, and respirations
are 30/min. Physical examination shows dry mucous membranes,
sunken eyes, and pale appearance. Her breath has a noticeably
fruity odor. Her heart is tachycardic and regular without any
murmurs. Her abdomen is soft, non-distended, with decreased
bowel sounds and some mild diffuse tenderness. Her extremities
are cool with weak pulses. The most likely diagnosis will be
established with

A. a CT scan of the abdomen and pelvis

B. an electrocardiogram
C. serum glucose and electrolytes
D. a urine drug screen
E. a urine pregnancy test
The correct answer is C. All of the answer choices would be
important in the initial evaluation of this patient but only serum
glucose and electrolytes would yield the diagnosis. This patient
likely has diabetic ketoacidosis. Clues to this diagnosis included
the "fruity" odor on her breath, history of polyuria and polydipsia,
recent weight loss, and dehydration. These laboratory studies will
most likely reveal an anion gap acidosis with an elevated glucose.

A CT scan of the abdomen and pelvis (choice A) would help

determine if there are and intraabdominal infections (i.e.,
appendicitis, abscess, etc.) but this is unlikely to be the cause of
this patient's illness. This patient has a benign abdominal exam,
which would further support the suspicion that there is not a
severe abdominal infection.

Finally, an electrocardiogram (choice B) would be important to

evaluate any changes consistent with ischemia, arrhythmia, or
electrolyte imbalances but would not give us a diagnosis in this
patient. The serum glucose and electrolytes should be ordered
immediately because of the physical findings. The EKG can be
performed as soon as these are drawn.

A urine drug screen (choice D) is also important in the initial

workup of the stuporous patient since drug overdose would
certainly be in the differential diagnosis.

A urine pregnancy test (choice E) is an important test to perform

in all women of childbearing age with abdominal pain. Her last
normal menstrual period ended 3 days ago, so it is unlikely that
she is pregnant. Although it would not give us the diagnosis in this
case, it should be included in initial screening to rule out an
ectopic pregnancy.

An 18-year-old man with type I diabetes mellitus is brought to the

emergency department by a friend after being found comatose.
There is a known history of noncompliance with medications,
however, there is no known history of drug use. Vital signs are:
temperature 37 C (98.6 F), blood pressure 80/65 mm Hg, pulse
110/min, and respirations 17/min. Oxygen saturation obtained
while the patient is receiving supplemental oxygen of 2 L/min via
nasal cannula is 98%. The patient is comatose and is taking rapid,
shallow breaths. Deep tendon reflexes are hypoactive. An
intravenous line has been placed in the field. A fingerstick glucose
is 430 mg/dL. An arterial blood gas, basic chemistry panel, and
toxicology screen has been sent to the laboratory. The next step
in the management of this patient is

A. a chest x-ray
B. an endotracheal intubation
C. an intravenous fluid replacement with insulin
D. methadone
E. a pulmonary artery catheter insertion

The correct answer is C. This patient is suffering from diabetic

ketoacidosis (DKA) caused by a severe deficiency of insulin.
Clinical symptoms include coma, rapid and shallow breathing,
high serum glucose levels, and metabolic acidosis. The immediate
management of this patient includes intravenous fluid
replacement and insulin infusion. When laboratory results return,
electrolyte imbalances must also be corrected.

A chest x-ray (choice A) would be complementary to a complete

the evaluation of any comatose patient. In this patient with a
picture of diabetic ketoacidosis, a chest x-ray would be a
secondary concern. The first priority is intravenous fluid
replacement and insulin therapy.

Endotracheal intubation (choice B) is not necessary at this point

as the patient has a normal oxygen saturation. Adequacy of
respiration will need to be reassessed when the arterial blood gas
results are available. The first priority is intravenous fluid
replacement and insulin therapy.

Methadone (choice D) is used to treat heroin dependency.

A pulmonary artery catheter (choice E) is not yet necessary as the

patient is at the present time hemodynamically stable. The first
priority is intravenous fluid replacement and insulin therapy.