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24 Diabetic Ketoacidosis
Most hospital laboratories now have a direct, enzymatic assay for βHB that is
reliable and quantitative. This is the preferred assay.
• Patients with DKA often have profound total body potassium decits.
Acidosis causes intracellular potassium to shift into the extracellular space.
The osmotic diuresis causes the potassium to then be excreted in the urine.
However, measured potassium is often normal or even elevated prior to treatment. This is due to the extracellular shift of potassium with acidosis, and the
hemoconcentration/increased serum osmolarity associated with hyperglycemia. During the rst several hours of treatment, the serum potassium can drop
precipitously.
• Osmotic diuresis also leads to renal losses of sodium chloride. Hyperglycemia
causes an increase in the measured serum sodium that is factitious. The serum
sodium should be corrected for the level of hyperglycemia. The classic correction factor for serum sodium in the presence of hyperglycemia is 1.6. For
every elevation of 100mg of glucose above 100 mg/dL, you add 1.6 to the
measured serum sodium for the true sodium concentration. Some authorities
believe that the correction factor should be 2.4 when the serum glucose
exceeds 400 mg/dL.
• The osmotic diuresis causes increased urinary losses and total body depletion
of all electrolytes (including phosphorus, calcium, and magnesium). However,
just like potassium, hemoconcentration may cause the initial levels to be elevated. And as with potassium, treatment can cause precipitous drops in these
electrolytes.
• Serum creatinine is often elevated due to intravascular volume depletion from
the osmotic diuresis.
• Liver functions and lipase are often elevated in DKA even the absence of
signicant liver or pancreas pathology. These values often improve with treatment. However, they can be associated with an underlying condition that may
have precipitated the episode of DKA.
• DKA is often associated with leukocytosis, due to physiologic stress and
hemoconcentration. However, signicant bandemia (above 10 %) often
accompanies an infectious process that may have precipitated DKA.
363
Electrocardiography
• An ECG should be performed on all patients with suspected or conrmed
DKA.
• It can help in the identication of electrolyte abnormalities such as hypo- or
hyperkalemia.
• Also, as DKA can be precipitated by an acute myocardial infarction, an ECG
should be reviewed for any signs of ischemia or infarction.
364
C. J. Rees et al.
Imaging
• Imaging is not helpful in the diagnosis of DKA.
• However, imaging is often necessary in the work-up, evaluation, and treatment of DKA to search for the cause of DKA.
• Most of these patients should have chest x-ray to assess for pneumonia, congestive heart failure, or other issues that can help explain the occurrence of
DKA, or help in the safe and appropriate management of DKA.
• Abdominal pain is a difcult complaint to evaluate in DKA.It may be due to
the DKA itself, but an abdominal issue may also be the precipitant of
DKA.Many patients presenting in DKA with predominant abdominal complaints or with marked abdominal tenderness will require abdominal imaging
to evaluate for an intra-abdominal process precipitating DKA. The usual
study would be an abdominal/pelvic CT scan. Many of these patients will not
tolerate oral contrast due to profound nausea and vomiting, and IV contrast
will often be contraindicated due to an elevated creatinine from intravascular
volume depletion. A completely non-contrast-enhanced CT scan can be useful in these patients to help exclude an intra-abdominal catastrophe.
Special Populations
Age
Children
• 30–40% of cases of new-onset diabetes in children will present with DKA.
• DKA as a presenting manifestation is more common in younger children
(<5), and in those from socioeconomically disadvantaged backgrounds.
• Children are more likely to present initially with diffuse abdominal pain associated with nausea and vomiting.
• DKA in children is dened by the following biochemical abnormalities:
• Blood glucose greater than 200 mg/dL; AND
• A venous pH less than 7.3 or plasma bicarbonate less than 15 mEg/L; AND
• Ketosis (presence of ketones in the urine).
• Measurements of serum beta-hydroxybutyrate are more sensitive are more
accurate indicators of ketosis (levels greater than 3 mmol/L)
• Other clues to the presence of new-onset diabetes in children include polyuria, polydipsia, increased nocturia, and especially daytime enuresis.
• Decreased urine output from dehydration is often not appreciated in children,
due to the profound osmotic diuresis associated with DKA.
• DKA is the leading cause of morbidity and mortality in children with type 1
diabetes.
24 Diabetic Ketoacidosis
The Elderly
• The elderly are more likely to present with HHS/HHNK than DKA.
• The elderly are also more likely to present with mental status changes.
• Morbidity and mortality are also higher among the elderly.
During Pregnancy
• DKA occurring during pregnancy is associated with a fetal mortality rate
approaching 30%.
• DKA can be precipitated by lower sugar levels during pregnancy.
• Several “normal” physiologic changes of pregnancy make pregnant women
more likely to develop DKA.
• Pregnant women have lower fasting plasma glucose levels. This leads to
lower baseline insulin levels (a relative insulin deciency) and increased
baseline free fatty acid levels.
• This is also an associated increase in counter-regulatory hormone levels.
• There is a decrease in bicarbonate levels from the chronic respiratory alka-
losis in pregnancy. This leads to a decreased buffering capacity.
365
• All the uid and electrolyte changes that occur in the mother occur in the
fetus. Maternal hyperglycemia causes fetal hyperglycemia with resultant
osmotic diuresis. Maternal acidosis leads to fetal acidosis. Maternal hyperglycemia, diuresis, volume contraction, and acidosis cause decreased uterine
blood ow and decreased fetal oxygenation. Fetal hypokalemia can cause
fetal arrhythmias. All these changes lead to the increase in fetal mortality.
• Treatment priorities remain the same: uids, correction of acidosis and hyperglycemia, and electrolyte repletion.
Co-morbidities
• Any signicant medical co-morbidity can increase the morbidity and mortality associated with DKA.
• Signicant cardiac, pulmonary, renal, and liver disease can complicate both
the diagnosis and treatment of DKA.Any signicant disorder of these systems can make uid therapy challenging.
• Patients with history of severe CHF or end-stage renal disease may need central venous pressure monitoring for appropriate uid management.
366
C. J. Rees et al.
Pitfalls inDiagnosis
Critical Steps Not toMiss
• It is important to consider the diagnosis in acutely ill patient with a history of
diabetes.
• It is also important to consider the diagnosis in patients presenting acutely ill
who are found to be academic and hyperglycemic even in the absence of a
history of diabetes, as DKA can be the presenting issue with diabetes.
• It is critical to measure the all electrolytes, pH (a venous blood gas is often
sufcient), and evaluate for ketosis.
• Appropriate resuscitative measures (especially uid replacement) may need
to be started prior to adequate conrmation of the diagnosis.
• A thorough search for a precipitating cause needs to be performed.
Mimics
• Many processes can mimic the presentation of DKA, as it is a multi-system
disorder in which patients are critically ill.
• HHNK (hyperglycemic, hyperosmolar, non-ketosis) is an important mimic of
DKA.Patients have ketosis, but usually little or no elevation in the anion gap.
The glucose tends to be much higher (usually above 600) than those seen with
DKA.These patients are usually older and have more profound mental status
changes.
• Other causes of ketosis (such as alcoholic and starvation ketosis) can present
similarly, but the glucose is usually normal or low at presentation.
• Patients with SIRS (systemic inammatory response syndrome) can also
present acutely ill with hypotension, acidosis (usually from lactate), and the
two processes can co-exist. An acute infection can precipitate DKA.
Time-Dependent Interventions
• It is critically important to initiate uid resuscitation early in the course of
evaluation and treatment. Fluids should usually be started at the time of consideration of the diagnosis rather than after waiting for full laboratory
conrmation.
• Immediate interventions on consideration of the diagnosis include aggressive
uid replacement, full monitoring including cardiac monitoring, continuous
pulse ox, and frequent vital sign monitoring (blood pressure every 5 minutes
24 Diabetic Ketoacidosis
or more frequently). There should be a bedside, nger stick blood glucose
check, a urine dipstick for ketones, at least two large-bore IV’s, and a 12-lead
ECG should be performed.
Overall Principles ofTreatment
• Treatment should initially address three issues in the following order:
• Fluid repletion
• Potassium repletion
• Insulin administration
• Fluid.
• Adult patients with DKA usually have anywhere from a 5–10 liter free
water decit at presentation.
• The rst 2 liters of replacement should be given over the rst 30–120 min-
utes of treatment. Continuing uids can then be slowed with about 50 % of
the total water decit replaced over the rst 12 hours and then subsequent
50 % over the next 12 hours.
• Normal saline (NS) is the preferred uid for initial resuscitation. NS helps
increase intravascular volume and helps to prevent too rapid a fall in extracellular osmolarity. Too rapid a fall in extracellular osmolarity can lead to
rapid transfer of free water into brain cells and cerebral edema.
• After the initial resuscitation with 2 liters NS, most authorities recommend
changing to 0.45 % (half normal) saline, if the corrected serum sodium is
normal or elevated.
• When the blood glucose falls below 250 mg/dl, the uid should be changed
to 5 % dextrose in 0.45 % NS to allow the continuation of insulin therapy.
367
• Potassium.
• Patients with DKA almost universally have severe total body potassium
decits. Usually on the order of 3–5 mEq/kg.
• The development of profound hypokalemia can be a life-threatening com-
plication during the resuscitation and treatment of a patient with DKA.
• However, the initial measured serum potassium is usually normal or high,
due to the shift of intracellular potassium into the extracellular space in the
presence of acidosis. Hypokalemia on presentation is urgently life-threatening and requires rapid and careful correction.
• The primary goals of potassium replacement are to maintain normal extra-
cellular potassium concentration during the acute phases of therapy when
the most signicant shifts are expected to occur. The intracellular decit
may be corrected over days instead of hours.
• During initial resuscitation of DKA, the serum potassium may fall quickly
due to the resolution of acidosis and insulin therapy, which both cause an
368
C. J. Rees et al.
intracellular shift of potassium. This can lead to the precipitous development of profound extracellular hypokalemia with resulting cardiac arrhythmias, rhabdomyolysis, respiratory muscle paralysis, and paralytic ileus.
• The most rapid changes in potassium concentration occurs during the rst
several hours of therapy, so the potassium concentration needs to be measured frequently during this period (at least every 2 hours.)
• It is recommended that if the initial potassium concentration (prior to any
uids/insulin) is between 3.0 mEq/L and 5.5 mEq/L, then potassium
replacement should be initiated at about 10 mEq/hour.
• If the initial potassium is below 3.0 mEq/L, the initial rate of replacement
should be about 15 mEq/hour.
• If the initial serum potassium concentration is below 3.3–3.5 mEq/L, it is
recommended that potassium replacement occur prior to initiation of insulin therapy, as insulin administration will cause the potassium to shift intracellularly and can precipitate profound, life-threatening extracellular
hypokalemia.
• Potassium is usually given as potassium chloride in IV uid. Potassium
phosphate use is discouraged, as it can lead to profound hypocalcemia and
the precipitation of calcium phosphate salt in tissues.
• Insulin.
• There is nearly universal agreement that the administration of low dose
(0.1 unit/kg/hour) intravenous short-acting insulin is the safest method for
administering insulin in patients with DKA.
• This method of insulin administration allows for a gradual reduction in
plasma glucose of about 50 mg/dL/hour.
• Multiple studies document that this method of insulin administration is
associated with fewer complications (such as profound hypokalemia,
• In adults, it is acceptable to give a loading dose of insulin at a dose of 1
unit/kg.
• Children should not have a bolus dose of insulin. An IV-push loading dose
has been shown to lead to more complications in children.
• In general, insulin infusions should not be started until after an initial uid
bolus of 1–2 liters has been given.
• Insulin therapy should be withheld in the setting of profound hypokalemia
(initial serum potassium concentration less than 3.3–3.5 mEq/L) until
potassium repletion has commenced. In this setting, insulin can cause profound hypokalemia by causing an intracellular shift of extracellular
potassium.
• In the rst hours of treatment, the serum glucose should be measured at
least every 2 hours.
• The insulin infusion should be continued until the anion gap returns to
normal and ketonemia resolves.
24 Diabetic Ketoacidosis
• Hyperglycemia often resolves before the anion gap normalizes and ketone-
mia resolves. It is recommended that the IV uid be switched to uid containing 5% dextrose when the serum glucose concentration falls below 250
mg/dL.
• Therapy with subcutaneous insulin should be initiated prior to stopping the
insulin infusion. Subcutaneous insulin should be administered at least one
hour prior to stopping the insulin infusion.
• Other electrolytes.
• Phosphorus. Phosphorus (like potassium) is primarily intracellular, but
shifts to the extracellular compartment in the setting of acidosis. As such,
initial phosphorus concentrations are usually elevated in DKA but are not
reective of total body phosphorus. In DKA, total body phosphorus is usually depleted due to increased renal losses from the osmotic diuresis.
However, phosphorus levels usually fall more gradually than potassium,
and the levels often don’t decrease until 24–48 hours into therapy.
Intravenous replacement is not recommended unless the serum phosphorus
falls below 1.0 mg/dL.
• Magnesium. Magnesium concentrations may fall from the osmotic diure-
sis of DKA.Magnesium concentration doesn’t usually fall until 24 hours
into therapy. Magnesium repletion is recommended when the serum concentration falls below 2.0 mg/dL.Magnesium may be given intravenously
as magnesium sulfate 2.0 grams over one hour. If the patient is tolerating
orals, it can be given orally as magnesium oxide.
• Calcium. Calcium homeostasis usually remains intact during DKA, but
severe hypomagnesemia can lead to hypocalcemia (due to decreased parathyroid secretion). Patients with severe hypomagnesemia should have calcium levels followed and restored as necessary.
369
dicated in the vast majority of cases of DKA.The acidosis will resolve
spontaneously with resolution of ketogenesis. Bicarbonate therapy can be
associated with and cause severe hypokalemia, worsen intracellular acidosis, worsen central nervous system acidosis, shift the oxyhemoglobin dissociation curve to the left, prolong ketogenesis, and precipitate cerebral
edema.
370
Laboratory evaluation
After a brief history and physical examination, initial laboratory evaluation should include determination of
complete blood count, blood glucose, serum electrolytes, blood urea nitrogen, creatinine, serum ketones,
osmolality, arterial blood gases, and urinalysis. Admission ECG, chest radiograph, and cultures of blood,
urine, and sputum may be ordered if clinically indicated. During therapy, capillary blood glucose should be
determined every 1–2 hours at the bedside using a glucose oxidase reagent strip; an d blood should be
drawn every 4 hours for determination of serum electrolytes, glucose, blood urea nitrogen, creatinine,
phosphorus, and venous pH
Fluids
1000 mL normal saline (0.9% sodium chloride) first hour, then normal or 0.45% saline at 250–500 mL per
hour depending on serum sodium concentration and hydration status. When plasma glucose < 250
mg/dL, change to D5%1/2NS saline to allow continued insulin administration until ketonemia is controlled,
while avoiding hypoglycemia
Insulin
0.1 U/kg body weight as intravenous bolus followed by 0.1 U/kg/h as a continuous infusion. The goal is to
achieve a rate of decline of glucose between 50–100 mg per hour. When plasma glucose is < 250 mg/dL,
reduce insulin rate to 0.05 U/kg per hour. Thereafter, adjust insulin rate to maintain glucose levels
between 150–200 mg/dL until ketoacidosis is resolved. In patients with mild to moderate diabetic
ketoacidosis, subcutaneous regular insulin or rapid-acting insulin analogs may be an alternative to
intravenous insulin [037], [038]
Potassium
Serum K+> 5.0 mEq/L; no supplementation is required.
Serum K+= 4–5 mEq/L; add 20 mEq/L to each L of replacement fluid
Serum K+= 3–4 mEq/L; add 40 mEq/L to each L of replacement fluid
Serum K+< 3 mEq/L; hold insulin and give 10–20 mEq per hour until K+> 3.3, then add 40 mEq/L to each
L of replacement fluid
Bicarbonate
Arterial pH < 7.0 or bicarbonate < 5 mEq; 50 mEq/L in 200 ml of H2O over 1 hour until pH increases to >
7.0. Do not give bicarbonate if pH > 7.0
Phosphate
If indicated (serum levels < 1 mg/dL), 20–30 mmol potassium phosphate over 24 hours. Monitor serum
calcium level
Transition to subcutaneous insulin
Insulin infusion should be continued until resolution of ketoacidosis (glucose < 200 mg/dL, bicarbonate >
18 mEq/L, pH > 7.30). When this occurs, start subcutaneous insulin regimen.
To prevent recurrence of diabetic ketoacidosis during the transition period to subcutaneous insulin,
intravenous insulin should be continued for 1–2 hours after subcutaneous insulin is given [028]
C. J. Rees et al.
Summary of management of patients with diabetic ketoacidosis, (028). Fisher JN,
Shahshahani MN, Kitabchi AE.Diabetic ketoacidosis: low-dose insulin therapy by
various routes. N Engl J Med. 1977; 297:238 -247. (037). Umpierrez GE, Cuervo R,
Karabell A, etal. Treatment of diabetic ketoacidosis with subcutaneous insulin
aspart. Am J Med. 2004; 117:291 -296. (038). Umpierrez GE, Latif K, Stoever J,
etal. Efcacy of subcutaneous insulin lispro versus continuous intravenous regular
insulin for treatment of diabetic ketoacidosis. Diabetes Care. 2004; 27:1873 -1878.
[Kitabchi AE, Murphy MB.Consequences of Insulin Deciency. In: Skyler J, editor. Atlas of Diabetes. 3rd edition. Philadelphia: Current Medicine Group; 2006.
ISBN 1-57340-222-2] Caption from original
24 Diabetic Ketoacidosis
CO2—carbon dioxide; IV—intravenous; K+—potassium ion; NaCl —sodium chloride; NaHCO3—sodium
bicarbonate; SQ—subcutaneous.
Insulin Fluid Administration Potassium repletion Alkali
371
1. Give initial IV bolus of 0.2
U/kg actual body weight.
2. Add 100 U of regular
insulin to 1 L of normal
saline (0.1 U/mL), and
follow with continuous IV
drip of 0.1 U/kg actual body
weight per h until correction
of ketosis.
3. Give double rate of
infusion if the blood glucose
level does not decrease in a
2-h interval (expected
decrease is 40–80 mg/dL/h
or 10% of the initial value.)
4. Give SQ dose (10–30 U)
of regular insulin when
ketosis is corrected and the
blood glucose level
decreases to 300 mg/dL,
and continue with SQ insulin
injection every 4 h on a
sliding scale (ie, 5 U if below
150, 10 U if 150–200, 15 U
if 200–250, and 20 U if 250–
300 mg/dL).
Shock absent: Normal
saline (0.9% NaCl) at
7 mL/kg/h for 4 h, and
half this rate thereafter
Shock present: Normal
saline and plasma
expanders (ie,
albumin, low molecular
weight dextran) at
maximal possible rate
Start a glucosecontaining solution
(eg, 5% dextrose in
water) when blood
glucose level
decreases to 250
mg/dL.
Potassium chloride
should be added to
the third liter of IV
infusion and
subsequently if
urinary output is at
least 30–60 mL/h and
plasma [K
mEq/L.
Add K
L of IV fluids if initial
plasma [K
and adequate diuresis
is secured.
+
] < 5
+
to the initial 2
+
] < 4 mEq/L
Half-normal saline (0.45%
NaCl) plus 1–2 ampules (44–
88 mEq) NaHCO
when blood pH < 7.0 or total
< 5 mmol/L; in
CO
2
hyperchloremic acidosis, add
NaHCO
discontinue NaHCO
infusion when total CO
mmol/L.
per liter
3
when pH < 7.20;
3
in IV
3
>8–10
2
Diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) management.
Administration of insulin is the cornerstone of management for both DKA and
NKH.Replacement of the prevailing water, sodium, and potassium decits is also
required. Alkali are administered only under certain circumstances in DKA and
virtually never in NKH, in which ketoacidosis is generally absent. Because the uid
decit is generally severe in patients with NKH, many of whom have preexisting
heart disease and are relatively old, safe uid replacement may require monitoring
of central venous pressure, pulmonary capillary wedge pressure, or both (001),
Adrogué HJ, Madias NE. Management of life‐threatening acid‐base disorders.
N Engl J Med. 1998; 338:26 -34, 107–111. (017), AdroguÈ HJ.Diabetic ketoacidosis and hyperosmolar nonketotic syndrome. In: Suki WN, Massry SG, eds. Therapy
of Renal Diseases and Related Disorders. Boston: Kluwer Academic Publishers;
1997; 233 -251. (018). Adrogué HJ, Barrero J, Eknoyan G.Salutary effects of modest uid replacement in the treatment of adults with diabetic ketoacidosis. JAMA.
1989; 262:2108 -2113. [Adrogué HJ, Madias NE, Disorders of Acid-Base Balance.
372
C. J. Rees et al.
In: Berl T.Bonventre JV, editors. Volume 1: Disorders of Water, Electrolytes, and
Acid- Base; Acute Renal Failure. 1 edition. Philadelphia: Current Medicine Group;
1999. (Schrier RW, editor. Atlas of Diseases of the Kidney). ISBN: 0-632-04385-7]
Caption from original
Disease Course
• With appropriate and aggressive treatment, most cases of DKA resolve over
24–72 hours.
• Advances in knowledge leading to improved and more aggressive treatment
has reduced the mortality of DKA to less than 5 %.
• Currently, most mortality is seen in the very young and the very old.
• Overwhelming infection and acute myocardial infarction precipitating DKA
are associated with increased mortality.
• In general, the sicker a patient is at presentation, the higher the mortality.
• Some complications related to therapy for DKA have previously been discussed (hypokalemia, hypophosphatemia, and hypoglycemia). Other complications of therapy include the adult respiratory distress syndrome, and cerebral
edema.
• Adult respiratory distress syndrome (ARDS): This is a rare complication,
generally felt to result in over-aggressive uid repletion especially in patients
with underlying pulmonary or cardiac disease.
• Cerebral edema. Cerebral edema is a feared complication of DKA in children.
It tends to occur 4–24 hours after the initiation of therapy, and patients usually
appear to be improving prior to its onset. Cerebral edema is associated with
high morbidity and mortality. It is thought to result from free water diffusing
into brain cells at a fast rate, causing cells to swell. The only known risk factors are young age and DKA being the presenting manifestation of diabetes.
There are currently no identied presenting or treatment issues that reliably
predict the onset of cerebral edema. Symptoms may include headache, incontinence, change in mental status, seizures, or other changes in autonomic or
neurologic function. If the diagnosis of cerebral edema is being considered,
therapy with intravenous mannitol (1–2 grams/kg IV) should be started immediately, without awaiting conrmatory studies.