Diabetic ketoacidosis in adults: Treatment

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Diabetic ketoacidosis in adults: Treatment

Authors: Irl B Hirsch, MD, Michael Emmett, MD
Section Editor: David M Nathan, MD
Deputy Editor: Katya Rubinow, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Dec 2024. | This topic last updated: Nov 25, 2024.

What's New

Consensus guidelines for the management of hyperglycemic crises in adults

with diabetes (October 2024)

New consensus guidelines for the management of diabetic ketoacidosis (DKA) and…
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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 and HHS often occur together (mixed DKA/HHS).
Ketoacidosis with mild hyperglycemia or even normal blood glucose ("normoglycemic"
DKA) has become more common with the increased use of sodium-glucose cotransporter 2
[SGLT2] inhibitors.

The treatment of DKA in adults will be reviewed here. The epidemiology, pathogenesis,
clinical features, evaluation, and diagnosis of DKA and HHS are discussed separately, as is
the treatment of HHS in adults. 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: Clinical
features, evaluation, and diagnosis".)
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Diabetic ketoacidosis in adults: Treatment
● (See "Hyperosmolar hyperglycemic state in adults: Treatment".)
● (See "Diabetic ketoacidosis in children: Clinical features and diagnosis".)
● (See "Diabetic ketoacidosis in children: Treatment and complications".)

DISTINGUISHING DKA FROM HHS

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) differ clinically
according to the presence of ketoacidosis and, usually, the degree of hyperglycemia (
table 1) [1-3]. However, approximately one-third of patients have a mixed presentation
of DKA and HHS.
● In DKA, metabolic acidosis, ketonemia, and hyperglycemia are typically the major
findings. The serum glucose concentration is generally below 800 mg/dL (44.4
mmol/L) and often in the 350 to 500 mg/dL (19.4 to 27.8 mmol/L) range [2-4].
However, serum glucose concentrations may exceed 900 mg/dL (50 mmol/L) in
patients with DKA, usually in association with coma [3,5], or may be normal or
minimally elevated (<200 mg/dL [11.1 mmol/L]) in patients with normoglycemic DKA.
Normoglycemic DKA occurs more often in patients with poor oral intake, those
treated with insulin prior to arrival in the emergency department, pregnant women,
those who use sodium-glucose cotransporter 2 [SGLT2] inhibitors, and insulin pump-
treated patients in whom insulin delivery is interrupted due to catheter or pump
failure.
● In HHS, ketoacid accumulation is mild or absent, 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) [2,4,6].

The typical total body deficits of water and electrolytes in DKA and HHS are compared in
the table ( table 2). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in
adults: Clinical features, evaluation, and diagnosis", section on 'Serum glucose' and
"Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features,
evaluation, and diagnosis", section on 'Diagnostic criteria'.)

TREATMENT
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Diabetic ketoacidosis in adults: Treatment

Overview and protocols — The treatment of diabetic ketoacidosis (DKA) ( algorithm 1)

includes correcting the fluid and electrolyte abnormalities that are typically present
(hyperosmolality, hypovolemia, metabolic acidosis, and potassium depletion) and
administering insulin [7].
● Determine the site of care – For the vast majority of patients, treatment of DKA
should occur in the emergency room or inpatient setting where volume and
electrolyte repletion and insulin therapy can be administered safely. Outpatient
management may be a reasonable option for selected patients with mild DKA (eg,
hyperglycemia and positive ketones without nausea or vomiting) who have a known
diagnosis of diabetes and a clear and readily reversible cause of DKA (eg, occlusion of
insulin pump tubing). Such patients must have adequate insulin and glucose testing
supplies; detailed instructions for insulin administration, fluid intake, and glucose
monitoring; and close telephone follow-up with clinic staff.
● Assess vital signs, cardiorespiratory status, and mental status – Initial evaluation
should include assessment of the patient's cardiovascular, respiratory, and mental
status. For patients who present with stupor or coma, a Glasgow Coma Scale score
should be determined ( table 3). In patients with a score ≤8, endotracheal
intubation is usually required for airway protection. (See "Stupor and coma in adults",
section on 'Management'.)
● Treat the volume depletion and electrolyte abnormalities – The first step in the
treatment of DKA is infusion of isotonic fluid (saline or buffered crystalloid) to expand
extracellular volume and stabilize cardiovascular status ( table 4). Volume
expansion also increases insulin responsiveness by lowering the plasma osmolality,
reducing vasoconstriction and improving perfusion, and reducing stress hormone
levels [8,9]. The next step is correction of the potassium deficit (if present). Potassium
repletion may inform the choice of fluid replacement; the osmotic effect of potassium
repletion must be considered since potassium is as osmotically active as sodium. (See
'Fluid replacement' below and 'Potassium replacement' below.)
● Administer insulin – Low-dose intravenous (IV) insulin should be administered to all
patients with moderate to severe DKA who have a serum potassium ≥3.5 mEq/L. If
the serum potassium is <3.5 mEq/L, insulin therapy should be withheld until
potassium replacement has increased the serum potassium concentration above 3.5
mEq/L. This delay in insulin initiation is necessary because insulin will drive potassium

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Diabetic ketoacidosis in adults: Treatment

into cells and worsen hypokalemia, which could trigger cardiac arrhythmias. IV
regular insulin and rapid-acting insulin analogs are equally effective in treating DKA.
Subcutaneous rather than IV insulin may be used in individuals with uncomplicated
mild to moderate DKA. (See 'Insulin' below.)

Managing DKA requires frequent clinical and laboratory monitoring and the identification
and treatment of any precipitating events, including infection. Sodium-glucose
cotransporter 2 (SGLT2) inhibitors, which can precipitate DKA, should be discontinued.
Permanent discontinuation of the SGLT2 inhibitor should be strongly considered. (See
'Monitoring' below and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in
adults: Clinical features, evaluation, and diagnosis", section on 'Precipitating factors'.)

Our approach outlined below is based upon clinical experience and is largely in agreement
with consensus guidelines from the American Diabetes Association (ADA), Joint British
Diabetes Societies for Inpatient Care (JBDS), American Association of Clinical Endocrinology
(AACE), and Diabetes Technology Society (DTS) for the management of hyperglycemic
crises ( algorithm 1) [4,10,11].

Fluid replacement — In patients with DKA, we recommend IV electrolyte and fluid

replacement to correct both hypovolemia and hyperosmolality.

Initial choice of fluid

● IV isotonic fluid – Isotonic saline (0.9 percent sodium chloride [NaCl]) or isotonic
buffered crystalloid (eg, Lactated Ringer) should be used for volume repletion.
Buffered crystalloid may reduce time to DKA resolution and reduces the degree of
hyperchloremic, non-anion gap metabolic acidosis that often results from high
volume isotone saline administration.

No trials have directly compared saline with buffered crystalloid specifically in

patients with DKA. In a subgroup analysis of two cluster-randomized trials evaluating
choice of isotonic fluid in an emergency or critical care setting, adults with DKA who
received buffered crystalloids (n = 94) had a shorter time to DKA resolution compared
with those who received saline (n = 78; median 13 versus 16.9 hours, respectively)
[12]. A subsequent cohort study and meta-analysis both reached similar conclusions
[13,14].
● Adding dextrose to IV fluids – For patients who present with an initial serum
glucose <250 mg/dL [13.9 mmol/L]), dextrose is added to IV fluids at the initiation of

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therapy. Such patients require both insulin and glucose to treat the ketoacidosis and
prevent hypoglycemia, respectively.

Initial rate of fluid administration — The optimal rate of initial isotonic saline infusion
depends on the volume status of the patient:
● In patients with hypovolemic shock, isotonic fluid should initially be infused as quickly
as possible. (See "Treatment of severe hypovolemia or hypovolemic shock in adults".)
● In hypovolemic patients without shock or heart or kidney failure, isotonic fluid is
infused at a rate of 15 to 20 mL/kg lean body weight per hour (approximately 1000
mL/hour in an average-sized person) for the first few hours, with a maximum of <50
mL/kg in the first four hours ( algorithm 1) [1].
● In patients with mild hypovolemia or euvolemia, isotonic fluid is infused at a lower
rate, guided by clinical assessment.

The goal is to correct estimated deficits within the first 24 to 48 hours. Osmolality should
not be reduced too rapidly, because this may precipitate cerebral edema. Adequacy of fluid
replacement is judged by frequent hemodynamic and laboratory monitoring. (See
'Monitoring' below and 'Cerebral edema' below.)

Subsequent fluid management

● Switching to hypotonic fluid – After the second or third hour of fluid administration,
optimal fluid replacement depends upon the volume and hydration status, serum
electrolyte levels, and urine output. The most appropriate IV fluid composition is
determined by the sodium concentration "corrected" for the degree of
hyperglycemia. The "corrected" sodium concentration can be approximated by
adding 2 mEq/L to the plasma sodium concentration for each 100 mg/dL (5.5 mmol/L)
increase above 100 mg/dL (5.5 mmol/L) (calculator 1).

If the "corrected" serum sodium concentration is [1]:

• <135 mEq/L, isotonic fluid infusion should be continued at a rate of approximately

250 to 500 mL/hour

• ≥135 mEq/L, isotonic fluid infusion is generally switched to one-half isotonic saline
at a rate of 250 to 500 mL/hour to provide electrolyte-free water
● Adding dextrose to IV fluids – For patients who present with hyperglycemic DKA, we
add dextrose (5 to 10 percent) to the saline solution when the serum glucose declines

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to <250 mg/dL (13.9 mmol/L) ( algorithm 1).

Special considerations

High-dose potassium replacement — Major potassium replacement at rates >20 to

30 mEq/hr is rarely required. If such high infusion rates are needed, the potassium chloride
(KCl) should be added to one-half isotonic (0.45 percent NaCl) rather than isotonic (0.9
percent NaCl) saline. Potassium salts have an osmotic effect equivalent to sodium salts,
and adding potassium to isotonic fluids generates a hypertonic solution. (See 'Osmotic
effect of potassium salts' below.)

Reduced kidney or cardiac function — In patients with reduced kidney or cardiac

function, more frequent monitoring must be performed to avoid iatrogenic fluid overload
[4,9,15]. Rather than continuous isotonic fluid infusion, such patients may be managed
with repeated, small-volume fluid boluses (eg, 250 mL) [4].

Potassium replacement — Potassium replacement is initiated immediately if the serum

potassium is ≤5.0 mEq/L, provided urine output is adequate (urine output approximately
≥50 mL/hour or 0.5 mL/kg/hour) ( algorithm 1). Almost all patients with DKA have a
substantial potassium deficit, usually due to urinary losses generated by the glucose-
driven osmotic diuresis and secondary hyperaldosteronism. Despite the total body
potassium deficit, the serum potassium concentration is usually normal or, in
approximately one-third of cases, elevated at presentation. This is largely due to insulin
deficiency, hyperosmolality, and acidosis, which cause potassium movement out of the
cells [16].

Initial potassium replacement

● Serum potassium <3.5 mEq/L – If the initial serum potassium is <3.5 mEq/L, insulin
should not be administered until the potassium has been raised above this threshold.
IV potassium chloride (KCl; 10 to 20 mEq/hour, which usually requires 10 to 20 mEq/L
added to each liter of IV fluid) should be given. Patients with marked hypokalemia
may require more aggressive potassium replacement (eg, 30 mEq/hour, potentially
requiring central venous access) to raise the serum potassium concentration above
3.5 mEq/L [17-19]. If needed, potassium infusion rates >20 to 30 mEq/hr are highly
irritating to peripheral veins and generally must be infused into a large central vein or
via multiple peripheral veins. Such high infusion rates also usually require cardiac
rhythm monitoring.

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Diabetic ketoacidosis in adults: Treatment
● Serum potassium 3.5 to 5.0 mEq/L – If the initial serum potassium is 3.5 to 5.0
mEq/L, IV KCl (10 to 20 mEq) is added to each liter of IV fluid. Adjust potassium
replacement to maintain the serum potassium concentration in the range of 4 to 5
mEq/L.
● Serum potassium >5.0 mEq/L – If the initial serum potassium concentration is >5.0
mEq/L, then potassium replacement should be delayed until the serum concentration
has fallen below this level. Serum potassium should be monitored every two hours.

Insulin administration rapidly reverses the altered potassium distribution and can result in
a dramatic fall in the serum potassium concentration, despite potassium replacement
[17,18]. However, potassium replacement must be done cautiously, particularly if kidney
function is decreased and/or urine output remains below 50 mL/hour. Careful monitoring
of the serum potassium is essential. (See 'Monitoring' below and "Diabetic ketoacidosis
and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis", section
on 'Potassium'.)

Osmotic effect of potassium salts — Potassium salts added to IV fluids have the same
osmotic effect as sodium salts, and this should be considered when determining the
potential impact of IV fluid infusion on osmolality. As an example, 40 mEq of KCl added to 1
L of fluid generates 80 mOsmol/L of electrolyte osmolarity. The addition of 40 mEq of
potassium to 1 L of one-half isotonic saline creates a solution with an osmolarity of 234
mOsmol/L (77 mEq NaCl and 40 mEq KCl), which is osmotically equal to three-quarters
isotonic saline. (The osmolarity of isotonic saline is 308 mOsmol/L.) If 40 mEq of KCl is
added to isotonic saline, the final osmolarity will be approximately 388 mOsmol/L.
However, KCl will not have the same extracellular fluid (ECF) expansion effect as NaCl,
because most of the potassium will shift into cells very rapidly. (See "Maintenance and
replacement fluid therapy in adults", section on 'Choice of replacement fluid'.)

Insulin

Initiating insulin treatment

● Timing of insulin initiation – We recommend initiating insulin treatment
immediately in all patients with DKA who have a serum potassium ≥3.5 mmol/L. The
only indication for delaying the initiation of insulin therapy is a serum potassium <3.5
mEq/L since insulin will worsen hypokalemia by driving potassium into cells. Patients
with an initial serum potassium <3.5 mEq/L should receive fluid and potassium
replacement prior to treatment with insulin. Insulin therapy should be withheld until
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the serum potassium is >3.5 mEq/L to avoid complications such as cardiac

arrhythmias, cardiac arrest, and respiratory muscle weakness [1,17,18]. (See 'Fluid
replacement' above and 'Potassium replacement' above.)
● Effects on glucose and ketoacidemia – Insulin therapy lowers the serum glucose
concentration (primarily by decreasing hepatic glucose production and also by
enhancing peripheral utilization [20]), diminishes ketone production (by reducing
both lipolysis and glucagon secretion), and may augment ketone utilization.
Inhibition of lipolysis and ketogenesis requires a much lower level of insulin than that
required to reduce the serum glucose concentration. Therefore, if the administered
dose of insulin is reducing the glucose concentration, it should be sufficient to stop
ketone generation [20-22]. (See "Diabetic ketoacidosis and hyperosmolar
hyperglycemic state in adults: Epidemiology and pathogenesis", section on
'Pathogenesis'.)

Moderate to severe DKA

Intravenous insulin — In moderate to severe DKA, treatment can be initiated with a

fixed-rate continuous infusion of regular insulin of 0.1 units/kg per hour (equivalent to 7
units/hour in a 70-kg patient) ( algorithm 1) [21,23-26]. Alternatively, a variable rate
insulin infusion may be administered using a nurse-driven protocol. IV regular insulin and
rapid-acting insulin analogs are equally effective in treating DKA [27]. The choice of IV
insulin is based on institutional preferences, clinician experience, and cost concerns. We
generally prefer regular insulin, rather than rapid-acting or ultra rapid-acting insulin
analogs, due to its similar availability when given intravenously and much lower cost. (See
"General principles of insulin therapy in diabetes mellitus", section on 'Human insulins'.)
● Insulin bolus if infusion is delayed – If initiating the insulin infusion is delayed (eg,
due to difficulty with venous access), an IV or intramuscular (IM) bolus of regular
insulin (0.1 units/kg body weight) should be administered to raise insulin levels
rapidly, followed by continuous infusion.
● Role of long-acting, subcutaneous insulin – For acute management of DKA, expert
approaches differ in the use of long-acting, subcutaneous basal insulin. Some experts
avoid subcutaneous basal insulin during IV insulin infusion due to possible increased
risk of hypoglycemia and/or hypokalemia. However, other experts administer long-
acting insulin during insulin infusion based on evidence that it accelerates DKA
resolution and reduces length of hospital stay [4]. All patients require subcutaneous
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basal insulin prior to the discontinuation of IV insulin. (See 'Converting to

subcutaneous insulin' below.)
● Expected glucose response – Regular insulin infusion should decrease the serum
glucose concentration by approximately 50 to 70 mg/dL (2.8 to 3.9 mmol/L) per hour
[20,24-26]. Higher doses do not generally produce a more prominent glucose-
lowering effect, probably because the insulin receptors are fully saturated by the
lower doses [23]. However, if the serum glucose does not fall by at least 50 to 70
mg/dL (2.8 to 3.9 mmol/L) from the initial value in the first hour, check the IV access
to ensure that the insulin is being delivered and that no IV line filters that may bind
insulin have been inserted into the line. After these possibilities are eliminated, the
insulin infusion rate should be doubled every hour until a steady decline in serum
glucose of this magnitude is achieved.

The fall in serum glucose is the result of both insulin activity and volume repletion.
Volume repletion alone can initially reduce the serum glucose by 35 to 70 mg/dL (1.9
to 3.9 mmol/L) per hour due to the combination of ECF expansion, reduction of
plasma osmolality, increased urinary losses resulting from improved kidney
perfusion, and a reduction in stress hormone levels [25,28].

Insulin titration and dextrose administration — When the serum glucose is <250
mg/dL (13.9 mmol/L), add 5 to 10 percent dextrose to the IV fluid, and decrease the insulin
infusion rate to 0.05 units/kg per hour (or according to the variable rate protocol) [7,9,23].
If possible, do not allow the serum glucose to fall rapidly to below 200 mg/dL (11.1
mmol/L), because this may promote the development of cerebral edema. (See 'Cerebral
edema' below and "Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)".)

Serum glucose should be maintained between 150 and 200 mg/dL (8.3 and 11.1 mmol/L)
until resolution of DKA. (See 'Resolution criteria' below.)

Uncomplicated mild to moderate DKA

Subcutaneous insulin — Patients with uncomplicated, mild to moderate DKA (

table 1) can be safely treated with subcutaneous, rapid-acting insulin analogs on a
general medical floor or in the emergency department, provided adequate staffing is
available to carefully monitor the patient and check capillary blood glucose with a reliable
glucose meter, typically every hour. We do not recommend the use of continuous glucose
monitoring (CGM) in this setting due to a lack of supporting evidence.

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Diabetic ketoacidosis in adults: Treatment
● Insulin bolus – An initial bolus of rapid-acting insulin 0.1 units/kg body weight should
be administered.
● Initial insulin regimen – Following the initial bolus, either of the following rapid-
acting insulin regimens may be used:

• 0.1 units/kg given every hour

or
• 0.2 units/kg given every two hours
In patients with uncomplicated DKA, IM, subcutaneous, and IV insulin therapy show similar
efficacy and safety [29-33]. Subcutaneous administration is less painful than IM, and trial
data support the safety of rapid-acting insulin analogs (eg, insulin lispro, aspart) given
every one or two hours ( algorithm 1) [30,31]. In patients with mild DKA, intermediate- or
long-acting insulin can be administered at the initiation of treatment, along with rapid-
acting insulin.

Insulin titration and dextrose administration — When the serum glucose is <250
mg/dL (13.9 mmol/L), do both of the following:
● Reduce the insulin dose to 0.05 units/kg every hour or 0.1 units/kg every two hours.
● Add 5 to 10 percent dextrose to the IV fluid. For patients who initially present with
serum glucose <250 mg/dL, dextrose should be added immediately to IV fluids and
initiated concurrently with insulin therapy.

Normoglycemic DKA (glucose <200 mg/dL [11.1 mmol/L]) — For patients who present
with normoglycemic DKA, initial treatment is similar to that for patients with mild to
moderate DKA. However, our approach differs as follows:
● Dextrose (5 to 10 percent) should be added immediately to IV fluids and initiated
concurrently with insulin therapy.
● We do not administer a rapid-acting insulin bolus.
● The initial insulin dose is 0.05 units/kg every hour or 0.1 units/kg every two hours.

If normoglycemic DKA is associated with SGLT2 inhibitor use, the SGLT2 inhibitor should be
stopped immediately. For people who develop DKA during SGLT2 inhibitor treatment,
restarting the agent after DKA resolution is not recommended [4].

Method of glucose measurement — Serum glucose measurements should be done with

hospital-approved bedside devices or in the chemistry laboratory and not with CGM
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devices. CGM devices measure interstitial rather than circulating glucose concentrations.
As a result, if glucose is rapidly changing, changes in CGM-derived values may have a 10-
to 15-minute delay relative to venous glucose levels. Further, CGM may be less accurate in
the setting of severe hyper- or hypoglycemia, volume depletion, large volume shifts,
and/or acidosis. (See "Glucose monitoring in the ambulatory management of nonpregnant
adults with diabetes mellitus", section on 'CGM systems'.)

Bicarbonate and metabolic acidosis

Indications for bicarbonate (rarely administered) — Although the indications for

sodium bicarbonate therapy are controversial [34], selected patients may benefit from
cautious alkali therapy. They include:
● Arterial pH <7.0 – In patients with an arterial pH <7.0, decreased cardiac contractility
and vasodilatation can impair tissue perfusion [35,36]. At an arterial pH ≥7.0, most
experts agree that bicarbonate therapy is not necessary since insulin therapy and
volume expansion will largely reverse the metabolic acidosis [37].

In patients with DKA, evidence of benefit from bicarbonate therapy is lacking [38-40],
and largely theoretical concerns persist about potential harms. In a randomized trial
of 21 DKA patients with an admission arterial pH between 6.90 and 7.14 (mean 7.01),
bicarbonate therapy did not change morbidity or mortality [38]. However, the study
was small and limited to patients with an arterial pH ≥6.90, and the rate of rise in the
arterial pH and serum bicarbonate did not differ between the bicarbonate and
placebo groups. No trials have been performed to evaluate bicarbonate
administration in DKA with pH values <6.90.
● Serum potassium >6.4 mEq/L or hyperkalemic changes on electrocardiogram
(ECG) – In patients with potentially life-threatening hyperkalemia and acidemia,
bicarbonate administration may drive potassium into cells, thereby lowering the
serum potassium concentration. The exact potassium level that should trigger this
intervention has not been defined; we generally administer sodium bicarbonate if the
potassium level is >6.4 mEq/L or if hyperkalemic changes are evident on ECG [41].
(See "Treatment and prevention of hyperkalemia in adults".)

Dose and monitoring — For patients with pH <7.0, we give 100 mmol of sodium
bicarbonate in 400 mL sterile water administered over two hours [4]. If the serum
potassium is <5.0 mEq/L, we add 20 mEq of KCl. When the bicarbonate concentration
increases, the serum potassium may fall and more aggressive KCl replacement may be
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required.

The venous pH and bicarbonate concentration should be monitored every two hours, and
bicarbonate doses can be repeated until the pH rises above 7.0. (See 'Monitoring' below.)

Potential risks of bicarbonate — Bicarbonate administration is also controversial

because of the following, potentially harmful effects:
● The administration of alkali may slow the rate of recovery of the ketosis [42,43]. In a
study of seven patients, the three patients treated with bicarbonate had a rise in
serum ketoacid anion levels and a six-hour delay in resolution of ketosis [42]. Animal
studies indicate that bicarbonate infusion can accelerate ketogenesis. This may be
due to a "braking effect" of acidemia on organic acid generation that is attenuated by
any intervention that increases systemic pH [38].
● Alkali administration can lead to post-treatment metabolic alkalosis. Insulin
accelerates the metabolism of ketoacid anions and consequently generates
bicarbonate; thus, insulin alone is usually sufficient to correct the metabolic acidosis.
(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:
Epidemiology and pathogenesis", section on 'Anion gap metabolic acidosis'.)

Phosphate repletion (rarely needed) — We do not recommend the routine use of

phosphate replacement in the treatment of DKA.

However, if severe hypophosphatemia occurs (serum phosphate concentration <1 mg/dL

or 0.32 mmol/L), phosphate replacement should be administered, especially if cardiac
dysfunction, hemolytic anemia, and/or respiratory depression develop [44-48]. When
needed, potassium or sodium phosphate 20 to 30 mEq can be added to 1 L of IV fluid.

Although whole-body phosphate depletion is common in uncontrolled diabetes mellitus,

the serum phosphate concentration may initially be normal or elevated due to movement
of phosphate out of the cells [45,49]. Like potassium, phosphate depletion and
hypophosphatemia may be rapidly unmasked following the institution of insulin therapy
and IV volume expansion. This frequently leads to asymptomatic hypophosphatemia,
which gradually resolves. (See "Hypophosphatemia: Clinical manifestations of phosphate
depletion".)

Prospective, randomized trials of patients with DKA have failed to show a beneficial effect
of phosphate replacement on the duration of ketoacidosis, dose of insulin required, or the
rate of morbidity or mortality [50-52]. In addition, phosphate replacement may have

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Diabetic ketoacidosis in adults: Treatment

adverse effects, such as hypocalcemia and hypomagnesemia [50,53-55].

MONITORING

Monitoring schedule — A flow sheet of laboratory values and clinical parameters allows
better visualization and evaluation of the clinical picture throughout treatment of diabetic
ketoacidosis (DKA) ( form 1).
● Hyperglycemia and metabolic acidosis – The serum glucose should initially be
measured every hour until stable, while serum electrolytes, blood urea nitrogen
(BUN), phosphorus, creatinine, and venous pH should be measured every two to four
hours, depending upon disease severity and the clinical response [1,7]. Serum
glucose measurement should be done with hospital-approved bedside devices or in
the chemistry laboratory and not with continuous glucose monitoring (CGM) devices,
which may not reflect rapidly changing levels and may be less accurate in the setting
of volume depletion. (See 'Method of glucose measurement' above.)

Monitoring with arterial blood gases is unnecessary during the treatment of DKA;
venous pH, which is approximately 0.03 units lower than arterial pH [56], is adequate
to assess the response to therapy and avoids the pain and potential complications
associated with repeated arterial punctures. If blood chemistry results are promptly
available, an alternative to monitoring venous pH is to monitor the serum
bicarbonate concentration (to assess correction of the metabolic acidosis).
● Ketonemia

• Blood or serum beta-hydroxybutyrate (preferred when available) – Blood or

serum beta-hydroxybutyrate should be measured every two hours. Where
available, bedside ketone meters that measure capillary blood beta-
hydroxybutyrate are an alternative to measuring serum beta-hydroxybutyrate
[4,57]. These devices are increasingly available, reliable, and convenient.

• Serum anion gap – When bedside meters and serum beta-hydroxybutyrate

measurement are not available, monitoring venous pH and/or the venous
bicarbonate with a calculated serum anion gap is sufficient. Accumulation of
ketoacid anions (the sum of beta-hydroxybutyrate and acetoacetate) increases the
anion gap above its baseline, and the increment reflects the sum of their
concentrations in serum. The anion gap is calculated by subtracting the major
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measured anions (chloride and bicarbonate) from the major measured cation
(sodium). The sodium concentration used for this calculation is the concentration
reported by the laboratory, not the "corrected" sodium concentration.

• Serum or urine ketones (not appropriate for monitoring) – Although

assessments of urinary or serum ketone levels by the nitroprusside method can
be used for the initial diagnosis of ketoacidosis, they should not be used for
monitoring resolution of DKA. Nitroprusside reacts mainly with acetoacetate, to a
much lesser degree with acetone (which is not an acid), but not with beta-
hydroxybutyrate. A positive nitroprusside test may persist for up to 36 hours after
resolution of ketoacidosis due to a positive reaction with acetone, which is slowly
eliminated, mainly via the lungs [58,59]. Since acetone is not an acid, a persistent
nitroprusside reaction due to acetone does not indicate ketoacidosis. In addition,
active treatment of ketoacidosis shifts the reaction between beta-hydroxybutyrate
and acetoacetate toward acetoacetate. This may result in an increasingly positive
nitroprusside test (due to higher acetoacetate concentrations) despite an overall
improvement of the ketoacidosis ( figure 1) [22].

Resolution criteria — The following criteria are used to define DKA resolution:
● Blood or serum beta-hydroxybutyrate <0.6 mmol/L or normalization of the serum
anion gap (≤12 mEq/L).
● Venous pH ≥7.3 or serum bicarbonate ≥18 mmol/L – In patients who received isotonic
saline, monitoring for resolution of acidosis may be complicated by the evolution a
hyperchloremic, non-anion gap acidosis. Hyperchloremic acidosis does not indicate
unresolved DKA. (See 'Hyperchloremic acidosis' below.)
● Serum glucose <200 mg/dL (11.1 mmol/L).

CONVERTING TO SUBCUTANEOUS INSULIN

We initiate a multiple-dose (basal-bolus), subcutaneous insulin schedule when the

ketoacidosis has resolved and the patient is able to eat. (See 'Resolution criteria' above.)

Designing an insulin regimen

● Prior diagnosis of diabetes – For patients with known diabetes who were previously
being treated with insulin, their pre-diabetic ketoacidosis (DKA) insulin regimen may

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Diabetic ketoacidosis in adults: Treatment

be restarted if preadmission glycemia was near or at target. For patients treated with
continuous subcutaneous insulin infusion (insulin pump), the previous basal rate can
be resumed. However, if the intravenous (IV) insulin requirements are significantly
higher than their usual insulin requirements, it is reasonable to increase the basal
rate temporarily. For those using partially automated insulin delivery (hybrid closed-
loop) systems, it is also reasonable to stay in "manual mode" for the first 24 to 48
hours while insulin requirements return to baseline. If automated insulin delivery is
immediately resumed, blood glucose levels likely will be higher for the first few days.
● New-onset diabetes

• Total daily dose – In patients with new-onset type 1 diabetes who presented with
DKA, an initial total daily dose (TDD) of 0.5 to 0.6 units/kg of insulin per day is
reasonable, until an optimal dose is established. In patients at increased risk of
hypoglycemia, an initial TDD of 0.3 units/kg may be used. (See "Management of
blood glucose in adults with type 1 diabetes mellitus" and "General principles of
insulin therapy in diabetes mellitus".)

• Basal insulin – Approximately 40 to 60 percent of the TDD should be given as

basal insulin, either as once- or twice-daily U-100 glargine or detemir (to be
discontinued in the United States in 2024), or as twice-daily intermediate-acting
insulin (neutral protamine Hagedorn [NPH]). The long-acting insulin can be given
either at bedtime or in the morning; the NPH is usually given as approximately
two-thirds of the dose in the morning and one-third at bedtime. In this setting, we
do not use degludec or ultra long-acting U-300 insulin glargine, as these require
at least three to four days to reach steady state due to their long half-life [60].

• Prandial insulin – The remainder of the TDD is given as short-acting or rapid-

acting insulin, divided before meals. If NPH is the basal insulin used, a mid-day
(pre-lunch) rapid-acting insulin may not be necessary. Frequent glucose
monitoring or preferably continuous glucose monitoring (CGM) and
comprehensive diabetes education are vital after initiating a new insulin regimen
in treatment-naïve patients. (See "General principles of insulin therapy in diabetes
mellitus" and "Management of blood glucose in adults with type 1 diabetes
mellitus", section on 'Designing an MDI insulin regimen' and "Insulin therapy in
type 2 diabetes mellitus".)

Timing of initial dose — The IV insulin infusion should be continued for one to two hours
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Diabetic ketoacidosis in adults: Treatment

after initiating subcutaneous rapid-acting insulin. The first dose of basal insulin also should
be administered before IV insulin is discontinued. If short- or long-acting insulin is initiated
without rapid-acting insulin, the IV insulin infusion should be continued for two to four
hours after subcutaneous insulin administration. Abrupt discontinuation of IV insulin
acutely reduces insulin levels and may result in recurrence of hyperglycemia and/or
ketoacidosis.

Basal insulin (eg, NPH, U-100 glargine, or detemir) can be administered either at the same
time as the first injection of rapid-acting insulin (eg, in the morning before breakfast) or at
bedtime the previous night.

COMPLICATIONS

Hypoglycemia and hypokalemia are the most common complications of diabetic

ketoacidosis (DKA) treatment. These complications have become much less common since
low-dose intravenous (IV) insulin treatment and careful monitoring of serum potassium
have been implemented [61]. Hyperglycemia may recur from interruption or
discontinuation of IV insulin without adequate overlap coverage with subcutaneous
insulin.

Cerebral edema — Cerebral edema in uncontrolled diabetes mellitus is primarily a disease

of children, and almost all affected patients are younger than 20 years old [62]. Symptoms
typically emerge within 12 to 24 hours of the initiation of treatment for DKA but may exist
prior to the onset of therapy. Issues related to cerebral edema in DKA, including
pathogenesis, are discussed in detail separately but will be briefly reviewed here. (See
"Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)".)
● Clinical features — DKA-associated cerebral edema has a mortality rate of
approximately 30 percent [4]. Thus, careful monitoring for changes in mental or
neurologic status that would permit early identification and therapy of cerebral
edema is essential. Headache is the earliest clinical manifestation, followed by
lethargy and decreased arousal. Neurologic deterioration may be rapid. Seizures,
incontinence, pupillary changes, bradycardia, and respiratory arrest can develop.
Symptoms progress if brainstem herniation occurs, and the rate of progression may
be so rapid that clinically recognizable papilledema does not develop.
● Preventive measures – The following preventive measures may reduce the risk of
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Diabetic ketoacidosis in adults: Treatment

cerebral edema in high-risk patients:

• Gradually replacing sodium and water deficits in patients with hyperosmolarity (

algorithm 1).

• Adding dextrose to the IV fluids once the serum glucose level falls to <250 mg/dL
(13.9 mmol/L). (See 'Initial choice of fluid' above.)
● Management – Data evaluating the outcome and treatment of cerebral edema in
adults are not available. Recommendations for treatment are based upon clinical
judgment in the absence of scientific evidence. Case reports and small series in
children suggest benefit from prompt administration of mannitol (0.25 to 1 g/kg) and
perhaps from hypertonic (3 percent) saline (5 to 10 mL/kg over 30 min) [62]. These
interventions raise the plasma osmolality and generate an osmotic movement of
water out of brain cells and a reduction in cerebral edema.

Hyperchloremic acidosis — In the absence of severe kidney disease, most patients

treated with isotonic saline develop a hyperchloremic, normal anion gap acidosis ("non-
gap" or "hyperchloremic acidosis") during the resolution phase of the ketoacidosis. This
occurs for two reasons. First, IV volume expansion reverses volume contraction and
improves kidney function, which accelerates the loss of ketoacid anions with sodium and
potassium [63,64]. The loss of these ketoacid anion salts into the urine represents
"potential" bicarbonate loss from the body. Second, isotonic saline has a chloride
concentration of 154 mEq/L and does not contain any bicarbonate precursors. Therefore,
volume expansion with isotonic saline generates an element of hyperchloremic metabolic
acidosis. The hyperchloremic acidosis slowly resolves as the kidneys excrete ammonium
chloride and regenerate bicarbonate. The risk of hyperchloremic acidosis is lower with
buffered crystalloid than with isotonic saline because its chloride concentration is lower,
and it contains "potential bicarbonate" (eg, acetate, lactate). There are generally no clinical
sequelae of hyperchloremic acidosis in this setting.

Noncardiogenic pulmonary edema — Hypoxemia and rarely noncardiogenic pulmonary

edema can complicate the treatment of DKA [65-68]. Hypoxemia is attributed to a
reduction in colloid osmotic pressure that results in increased lung water content and
decreased lung compliance [9]. Patients with DKA who are found to have a wide alveolar-
arterial oxygen gradient and/or rales may be at higher risk for the development of
pulmonary edema.

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Diabetic ketoacidosis in adults: Treatment

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 hyperglycemic state (The Basics)")

SUMMARY AND RECOMMENDATIONS

● General principles – The treatment of diabetic ketoacidosis (DKA) involves correcting

of the fluid and electrolyte abnormalities that are typically present, including
hyperosmolality, hypovolemia, metabolic acidosis, and potassium depletion, and
administering insulin ( algorithm 1 and table 1 and table 4). Frequent
monitoring is essential, and underlying precipitating events should be identified and
corrected. (See 'Overview and protocols' above.)
● Fluid replacement – Individuals with DKA require intravenous (IV) fluid replacement
to correct both hypovolemia and hyperosmolality. Isotonic saline and isotonic
buffered crystalloid (eg, Lactated Ringer) are both reasonable options. The optimal

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Diabetic ketoacidosis in adults: Treatment

rate is guided by clinical assessment.

For patients who present with an initial serum glucose <250 mg/dL [13.9 mmol/L]),
dextrose (5 to 10 percent) is added to IV fluids at the initiation of therapy.

• Initial rate of administration – Fluid replacement should correct estimated

volume deficits within the first 24 to 48 hours, with care to avoid an overly rapid
reduction in the serum osmolality. (See 'Fluid replacement' above.)
- Hypovolemia with shock – Isotonic fluid (0.9 percent saline or buffered
crystalloid) should be infused as quickly as possible in patients with
hypovolemic shock. (See "Treatment of severe hypovolemia or hypovolemic
shock in adults", section on 'Nonhemorrhagic shock'.)
- Hypovolemia without shock – In hypovolemic patients without shock or
heart failure, we suggest isotonic fluid infused at a rate of 15 to 20 mL/kg per
hour (approximately 1000 mL/hour in an average-sized person) for the first
few hours (Grade 2C).
- Mild hypovolemia or euvolemia – Isotonic fluid is infused at a lower rate
than in hypovolemic patients without shock, guided by clinical assessment.

• Subsequent fluid management – After the fluid deficit is corrected, one-half

isotonic (0.45 percent) saline is administered at a rate of approximately 250 to 500
mL/hour if the serum sodium (corrected for hyperglycemia) is normal or elevated;
isotonic saline is continued at a rate of approximately 250 to 500 mL/hour if the
serum sodium (corrected for hyperglycemia) is low. (See 'Subsequent fluid
management' above.)
● Potassium replacement – Most patients with DKA require IV potassium
replacement. The dose depends on the initial serum potassium level ( algorithm 1).
In patients with high potassium (>5.0 mEq/L) and/or low urine output (eg, <50
mL/hour or 0.5 mL/kg/hour), potassium replacement should be delayed until
potassium is ≤5.0 mEq/L and urine output ≥50 mL/hour.

Most patients with DKA have a substantial potassium deficit (due to urinary losses
and secondary hyperaldosteronism) that may not be reflected in serum levels. (See
'Fluid replacement' above and 'Potassium replacement' above.)
● Insulin – In patients with initial serum potassium <3.5 mEq/L, insulin therapy should
be delayed until the serum potassium is >3.5 mEq/L to avoid complications of
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Diabetic ketoacidosis in adults: Treatment

hypokalemia. Aggressive potassium replacement is needed to avoid further delay in

insulin therapy and increased risk of progressive acidosis ( algorithm 1). (See
'Insulin' above.)

Insulin dosing is titrated based on hourly glucose measurement. We add dextrose to

the IV fluids when the serum glucose is <250 mg/dL (13.9 mmol/L). In patients with
DKA who present with an initial serum glucose <250 mg/dL, we add dextrose to the IV
fluids at the initiation of therapy. (See 'Fluid replacement' above.)

• Moderate to severe DKA – Patients with moderate to severe DKA and a serum
potassium ≥3.5 mEq/L require intensive insulin therapy (intravenous insulin
infusion). We suggest IV regular insulin rather than rapid-acting insulin analogs
(eg, insulin lispro, aspart, and glulisine) (Grade 2C), due to similar efficacy and
much lower cost. Treatment can be initiated with a fixed-rate continuous infusion
of regular insulin of 0.1 units/kg per hour ( algorithm 1) [21,23-26]. The dose is
doubled if the glucose does not fall by 50 to 70 mg/dL (2.8 to 3.9 mmol/L) in the
first hour. Alternatively, a variable rate insulin infusion may be administered using
a nurse-driven protocol. Serum glucose should be maintained between 150 and
200 mg/dL (8.3 and 11.1 mmol/L) until resolution of DKA. (See 'Moderate to severe
DKA' above and 'Resolution criteria' above.)

• Mild DKA – For patients with mild DKA ( table 1), subcutaneous rapid-acting
insulin analogs may be used for initial treatment. Subcutaneous administration of
insulin is safe only when adequate staffing is available to allow for close patient
monitoring and frequent capillary blood glucose measurement with a reliable
glucose meter, typically every hour. (See 'Uncomplicated mild to moderate DKA'
above.)

• Normoglycemic DKA – For patients who present with normoglycemic DKA, initial
treatment is similar to that for patients with mild DKA. Dextrose (5 to 10 percent)
should be added immediately to IV fluids and initiated concurrently with insulin
therapy. (See 'Normoglycemic DKA (glucose <200 mg/dL [11.1 mmol/L])' above.)
● Indications for bicarbonate – For most patients with DKA, we suggest not giving
sodium bicarbonate (Grade 2C). However, in patients with severe acidosis (arterial pH
<7.0), bicarbonate administration is reasonable. (See 'Bicarbonate and metabolic
acidosis' above.)
● Indications for phosphate – For most patients, we suggest not administering
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Diabetic ketoacidosis in adults: Treatment

phosphate (Grade 2B). Whole-body phosphate depletion is usually present, but

routine phosphate administration does not appear to have clear benefit and can be
associated with hypocalcemia and hypomagnesemia.

However, patients with severe hypophosphatemia (<1 mg/dL [0.32 mmol/L]) should
receive phosphate. (See 'Phosphate repletion (rarely needed)' above.)
● Monitoring – Monitoring involves hourly glucose measurement until stable and basic
chemistry profile, phosphorus, and venous pH every two to four hours. The course of
ketoacidemia can be assessed by direct measurement of beta-hydroxybutyrate, the
major circulating ketoacid, and/or measurement of the serum anion gap. In contrast,
nitroprusside tablets or reagent sticks should not be used, because they react with
acetoacetate and acetone but not with beta-hydroxybutyrate. (See 'Monitoring'
above.)
● Potential complications – Cerebral edema is rare in adults but is associated with
high rates of morbidity and mortality. Possible preventive measures in high-risk
patients include gradual rather than rapid correction of fluid and sodium deficits and
maintenance of a slightly elevated serum glucose until the patient is stable. (See
'Cerebral edema' above.)
● Converting to subcutaneous insulin – We initiate a multiple-dose (basal-bolus),
subcutaneous insulin schedule when the ketoacidosis has resolved and the patient is
able to eat. The IV insulin infusion should be continued for one to two hours after
initiating subcutaneous rapid-acting insulin. The first dose of basal insulin also should
be administered before IV insulin is discontinued. If short- or long-acting insulin is
initiated without rapid-acting insulin, the IV insulin infusion should be continued for
two to four hours after subcutaneous insulin administration. Abrupt discontinuation
of IV insulin acutely reduces insulin levels and may result in recurrence of
hyperglycemia and/or ketoacidosis.

When converting to subcutaneous insulin, we do not use ultra-long-acting insulins

(eg, degludec, U-300 glargine) as the basal insulin; these have a long half-life and
require two to three days to reach steady state. (See 'Converting to subcutaneous
insulin' above.)

ACKNOWLEDGMENT

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Diabetic ketoacidosis in adults: Treatment

The UpToDate editorial staff acknowledges Abbas Kitabchi, PhD, MD, FACP, MACE, who
contributed to an earlier version of this topic review.

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Topic 1795 Version 57.0

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