Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment

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Diabetic ketoacidosis and hyperosmolar

hyperglycemic state 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: Apr 2023. | This topic last updated: Aug 24, 2022.

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. They are part of the spectrum of hyperglycemia, and each
represents an extreme in the spectrum.

The treatment of DKA and HHS in adults will be reviewed here. The epidemiology,
pathogenesis, clinical features, evaluation, and diagnosis 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: Clinical
features, evaluation, and diagnosis".)
● (See "Diabetic ketoacidosis in children: Clinical features and diagnosis".)
● (See "Diabetic ketoacidosis in children: Treatment and complications".)

DEFINITIONS

DKA and HHS differ clinically according to the presence of ketoacidosis and, usually, the

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degree of hyperglycemia [1-3]. The definitions proposed by the American Diabetes

Association (ADA) for DKA and HHS are shown in the table ( table 1) [1].

● In DKA, metabolic acidosis is often the major finding, while 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 [1-3]. However, serum glucose concentrations may
exceed 900 mg/dL (50 mmol/L) in patients with DKA, most of whom are comatose
[3,4], or may be normal or minimally elevated (<250 mg/dL [13.9 mmol/L]) in patients
with euglycemic DKA (which occurs more often in patients with poor oral intake,
those treated with insulin prior to arrival in the emergency department, pregnant
women, and those who use sodium-glucose co-transporter 2 [SGLT2] inhibitors).

● In HHS, there is little or no ketoacid accumulation, the serum glucose concentration

frequently exceeds 1000 mg/dL (56 mmol/L), the plasma osmolality (Posm) may reach
380 mOsmol/kg, and neurologic abnormalities are frequently present (including
coma in 25 to 50 percent of cases) [1,2,5,6].

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

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

( algorithm 2) is similar, including correction of the fluid and electrolyte abnormalities
that are typically present (hyperosmolality, hypovolemia, metabolic acidosis [in DKA], and
potassium depletion) and the administration of insulin [1,7-9].

● Correction of fluid and electrolyte abnormalities – The first step in the treatment
of DKA or HHS is infusion of isotonic saline to expand extracellular volume and
stabilize cardiovascular status ( table 3). This also increases insulin responsiveness
by lowering the plasma osmolality (Posm), reducing vasoconstriction and improving
perfusion, and reducing stress hormone levels [10,11]. The next step is correction of
the potassium deficit (if present). The choice of fluid replacement should be
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influenced by the potassium deficit. 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.)

● Administration of insulin – Low-dose intravenous (IV) insulin should be

administered to all patients with moderate to severe DKA who have a serum
potassium ≥3.3 mEq/L. If the serum potassium is less than 3.3 mEq/L, insulin therapy
should be delayed until potassium replacement has begun and the serum potassium
concentration has increased. The delay is necessary because insulin will worsen the
hypokalemia by driving potassium into the cells, and this could trigger cardiac
arrhythmias. IV regular insulin and rapid-acting insulin analogs are equally effective
in treating DKA. (See 'Insulin' below.)

Therapy requires frequent clinical and laboratory monitoring and the identification and
treatment of any precipitating events, including infection. Sodium-glucose co-transporter 2
(SGLT2) inhibitors, which can precipitate DKA, should be discontinued. (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 the American Diabetes Association (ADA) consensus algorithms for the treatment of
DKA ( algorithm 1) and HHS ( algorithm 2) and the Joint British Diabetes Societies
guideline for the management of DKA [1,12,13].

Fluid replacement — In patients with DKA or HHS, we recommend IV electrolyte and fluid
replacement to correct both hypovolemia and hyperosmolality. Fluid repletion is usually
initiated with isotonic saline (0.9 percent sodium chloride [NaCl]). Patients with euglycemic
DKA generally require both insulin and glucose to treat the ketoacidosis and prevent
hypoglycemia, respectively, and in such patients, dextrose is added to IV fluids at the
initiation of therapy. For patients with a more classic presentation of hyperglycemic DKA,
we add dextrose to the saline solution when the serum glucose declines to 200 mg/dL
(11.1 mmol/L) in DKA ( algorithm 1) or 250 to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS
( algorithm 2).

The optimal rate of initial isotonic saline infusion is dependent upon the clinical state
of the patient:

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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment
● In patients with hypovolemic shock, isotonic saline should be infused as quickly as
possible. (See "Treatment of severe hypovolemia or hypovolemic shock in adults".)

● In hypovolemic patients without shock (and without heart failure), isotonic saline 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 couple of hours, with a maximum of
<50 mL/kg in the first four hours ( algorithm 1 and algorithm 2) [1].

● In euvolemic patients, isotonic saline is infused at a lower rate, guided by clinical

assessment.

After the second or third hour, optimal fluid replacement depends upon the state of
hydration, serum electrolyte levels, and the 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/100 mL (5.5 mmol/L) increase
above normal in glucose concentration (calculator 1).

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

● Less than 135 mEq/L, isotonic saline should be continued at a rate of approximately
250 to 500 mL/hour

● Normal or elevated, the IV fluid is generally switched to one-half isotonic saline at a

rate of 250 to 500 mL/hour in order to provide electrolyte-free water

The timing of one-half isotonic saline therapy may also be influenced by potassium
balance. Potassium repletion affects the saline solution that is given since potassium is as
osmotically active as sodium. Thus, concurrent potassium replacement may be another
indication for the use of one-half isotonic saline. (See 'Potassium replacement' below.)

Adequate rehydration with correction of the hyperosmolar state may enhance the
response to low-dose insulin therapy [10,11]. Adequacy of fluid replacement is judged by
frequent hemodynamic and laboratory monitoring (see 'Monitoring' below). In patients
with abnormal renal or cardiac function, more frequent monitoring must be performed to
avoid iatrogenic fluid overload [8,9,11,14-17]. The goal is to correct estimated deficits
( table 2) within the first 24 hours. However, osmolality should not be reduced too
rapidly, because this may generate cerebral edema. (See 'Cerebral edema' below and
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"Diabetic ketoacidosis in children: Treatment and complications", section on 'Cerebral

injury'.)

Potassium replacement — Potassium replacement is initiated immediately if the serum

potassium is <5.3 mEq/L as long as there is adequate urine output (approximately >50
mL/hour) ( algorithm 1). Almost all patients with DKA or HHS have a substantial
potassium deficit, usually due to urinary losses generated by the glucose 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 and hyperosmolality, each of which
cause potassium movement out of the cells [18].

● If the initial serum potassium is below 3.3 mEq/L, IV potassium chloride (KCl; 20 to 40
mEq/hour, which usually requires 20 to 40 mEq/L added to saline) should be given.
The choice of replacement fluid (isotonic or one-half isotonic saline) depends upon
the state of hydration, corrected sodium concentration, dose of KCl, blood pressure,
and a clinical assessment of overall volume status. Patients with marked hypokalemia
require aggressive potassium replacement (40 mEq/hour, with additional
supplementation based upon hourly serum potassium measurements) to raise the
serum potassium concentration above 3.3 mEq/L [19-21].

● If the initial serum potassium is between 3.3 and 5.3 mEq/L, IV KCl (20 to 30 mEq) is
added to each liter of IV replacement fluid. Adjust potassium replacement to maintain
the serum potassium concentration in the range of 4 to 5 mEq/L.

● If the initial serum potassium concentration is greater than 5.3 mEq/L, then
potassium replacement should be delayed until its concentration has fallen below
this level.

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
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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'.)

The altered potassium distribution is rapidly reversed with the administration of insulin
and can result in an often dramatic fall in the serum potassium concentration, despite
potassium replacement [19,20]. However, potassium replacement must be done cautiously
if renal function remains depressed and/or urine output does not increase to a level >50
mL/hour. Careful monitoring of the serum potassium is essential for the management of
both DKA and HHS. (See 'Monitoring' below and "Diabetic ketoacidosis and hyperosmolar
hyperglycemic state in adults: Epidemiology and pathogenesis", section on 'Potassium'.)

Insulin — We recommend initiating treatment with low-dose IV insulin in all patients with
moderate to severe DKA or HHS who have a serum potassium ≥3.3 mEq/L. The only
indication for delaying the initiation of insulin therapy is if the serum potassium is below
3.3 mEq/L since insulin will worsen the hypokalemia by driving potassium into the cells.
Patients with an initial serum potassium below 3.3 mEq/L should receive fluid and
potassium replacement prior to treatment with insulin. Insulin therapy should be delayed
until the serum potassium is above 3.3 mEq/L to avoid complications such as cardiac
arrhythmias, cardiac arrest, and respiratory muscle weakness [1,19,20]. (See 'Fluid
replacement' above and 'Potassium replacement' above.)

IV regular insulin and rapid-acting insulin analogs are equally effective in treating DKA [22].
The choice of IV insulin is based upon institutional preferences, clinician experience, and
cost concerns. We generally prefer regular insulin, rather than rapid-acting insulin analogs,
due to its much lower cost. For acute management of DKA or HHS, there is no role for
long- or intermediate-acting insulin; however, long-acting (glargine, detemir) or
intermediate-acting (NPH) insulin is administered after recovery from ketoacidosis, prior to
discontinuation of IV insulin, to ensure adequate insulin is available when IV insulin is
discontinued. In this setting, we do not use degludec or ultra-long-acting U-300 insulin
glargine (given their long half-life) as it will take at least three to four days to reach steady
state [23]. In patients with mild DKA (particularly in patients with mild DKA due to rationed
or missed doses of basal insulin), intermediate- or long-acting insulin can be administered
at the initiation of treatment, along with rapid-acting insulin. (See 'Intravenous regular
insulin' below and 'Converting to subcutaneous insulin' below and 'Intravenous insulin
analogs' below and 'Subcutaneous insulin regimens' below.)
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Insulin therapy lowers the serum glucose concentration (by decreasing hepatic glucose
production, the major effect, and enhancing peripheral utilization, a less important effect
[24]), diminishes ketone production (by reducing both lipolysis and glucagon secretion),
and may augment ketone utilization. Inhibition of lipolysis 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 more than
enough to stop ketone generation [8,24,25]. (See "Diabetic ketoacidosis and hyperosmolar
hyperglycemic state in adults: Epidemiology and pathogenesis", section on 'Pathogenesis'.)

Intravenous regular insulin — In HHS or moderate to severe DKA, treatment can be

initiated with an IV bolus of regular insulin (0.1 units/kg body weight) followed within five
minutes by a continuous infusion of regular insulin of 0.1 units/kg per hour (equivalent to
7 units/hour in a 70-kg patient) [8,26-29]. Alternatively, the bolus dose can be omitted if a
higher dose of continuous IV regular insulin (0.14 units/kg per hour, equivalent to 10
units/hour in a 70-kg patient) is initiated [30]. The insulin dosing is the same in DKA and
HHS ( algorithm 1 and algorithm 2). The possible role of other insulin preparations is
discussed below. (See 'Intravenous insulin analogs' below and 'Subcutaneous insulin
regimens' below.)

These doses of IV regular insulin usually decrease the serum glucose concentration by
approximately 50 to 70 mg/dL (2.8 to 3.9 mmol/L) per hour [24,27-29]. Higher doses do not
generally produce a more prominent glucose-lowering effect, probably because the insulin
receptors are fully saturated and activated by the lower doses [26]. 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 be certain 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 the beneficial effects of
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 renal perfusion and
glomerular filtration; and a reduction in the levels of "stress hormones," which oppose the
effects of insulin [15,28]. The serum glucose levels often fall more rapidly in patients with
HHS who are typically more volume depleted.
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When the serum glucose approaches 200 mg/dL (11.1 mmol/L) in DKA or 250 to 300 mg/dL
(13.9 to 16.7 mmol/L) in HHS, switch the IV saline solution to dextrose in saline and attempt
to decrease the insulin infusion rate to 0.02 to 0.05 units/kg per hour [9,11,26]. If possible,
do not allow the serum glucose at this time to fall below 200 mg/dL (11.1 mmol/L) in DKA
or 250 to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS, because this may promote the
development of cerebral edema. (See 'Cerebral edema' below and "Diabetic ketoacidosis in
children: Cerebral injury (cerebral edema)".)

Intravenous insulin analogs — There is no advantage of rapid-acting or ultra-rapid-

acting insulin analogs over regular insulin. Intravenous regular insulin and glulisine insulin
are equally effective and equipotent for the treatment of DKA [22]. (See "General principles
of insulin therapy in diabetes mellitus", section on 'Human insulins'.)

Subcutaneous insulin regimens — Patients with mild DKA ( table 1) can be safely

treated with subcutaneous, rapid-acting insulin analogs on a general medical floor or in
the emergency department but only when 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 situation, as it has not been studied.

Subcutaneous insulin protocols are being used with increasing frequency to treat selected
patients with mild to moderate DKA during the COVID-19 pandemic, when intravenous
insulin may not be practical owing to the need to limit frequency of contact of staff with
patients. In this setting, dosing and monitoring is being performed every two to four
hours. (See "COVID-19: Issues related to diabetes mellitus in adults", section on 'DKA/HHS'.)

Treatment of DKA with subcutaneous insulin has not been evaluated in severely ill patients.
In mild DKA, direct comparison of intramuscular, subcutaneous, and IV insulin therapy for
hemodynamically stable DKA patients shows similar efficacy and safety [31-34]. In addition,
subcutaneous administration of rapid-acting insulin analogs (eg, insulin lispro, aspart)
given every one or two hours has been demonstrated to be safe in two randomized trials
in adults with uncomplicated DKA ( algorithm 1) [32,33]. In one trial, for example, 40
patients with DKA were assigned to one of two regimens [32]:

● Subcutaneous, rapid-acting insulin lispro as an initial injection of 0.3 units/kg,

followed by 0.1 units/kg every hour until the serum glucose was less than 250 mg/dL
(13.9 mmol/L). The insulin lispro dose was then decreased to 0.05 to 0.1 units/kg and
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administered every one or two hours until resolution of the ketoacidosis. These
patients were treated on a regular internal medicine floor or in an intermediate care
unit.

● IV regular insulin as an initial bolus of 0.1 units/kg, followed by an infusion of 0.1

units/kg per hour until the serum glucose was less than 250 mg/dL (13.9 mmol/L).
The insulin dose was then decreased to 0.05 to 0.1 units/kg per hour until resolution
of the ketoacidosis. These patients were treated in the intensive care unit.

The duration of therapy until correction of hyperglycemia and resolution of ketoacidosis

was the same with both regimens (7 and 10 to 11 hours, respectively), but there was a 39
percent reduction in cost with insulin lispro, mainly related to the higher cost of treatment
in the intensive care unit.

Bicarbonate and metabolic acidosis — Although the indications for sodium bicarbonate

therapy to help correct metabolic acidosis are controversial, there are selected patients
who may benefit from cautious alkali therapy [35]. They include:

● Patients with an arterial pH ≤6.9 in whom decreased cardiac contractility and

vasodilatation can impair tissue perfusion [36,37]. At an arterial pH above 7.0, most
experts agree that bicarbonate therapy is not necessary since therapy with insulin
and volume expansion will largely reverse the metabolic acidosis [38].

For patients with pH ≤6.9, we give 100 mEq of sodium bicarbonate in 400 mL sterile
water administered over two hours. If the serum potassium is less than 5.3 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 required.

● Patients with potentially life-threatening hyperkalemia, since bicarbonate

administration in acidemic patients 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 administer sodium bicarbonate if the
potassium level is >6.4 mEq/L [39]. (See "Treatment and prevention of hyperkalemia
in adults".)

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.)

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The indications for bicarbonate therapy in DKA are controversial [40], and evidence of
benefit is lacking [41-43]. 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 [41]. However, the study was small, limited to patients with an
arterial pH 6.90 and above, and there was no difference in the rate of rise in the arterial pH
and serum bicarbonate between the bicarbonate and placebo groups. No prospective
randomized trials have been performed concerning the use of bicarbonate in DKA with pH
values less than 6.90.

Bicarbonate administration is also controversial because, in addition to lack of evidence for

benefit, there are several potential harmful effects:

● If bicarbonate infusion successfully increases the blood bicarbonate concentration,

this can reduce the hyperventilatory drive, which will raise the blood partial pressure
of carbon dioxide (pCO2). Increased blood carbon dioxide (CO2) tension is more
quickly reflected across the blood brain barrier than the increased arterial
bicarbonate. This may cause a paradoxical fall in cerebral pH. Although neurologic
deterioration has been attributed to this mechanism, it remains a very controversial
effect and, if it occurs, is rare [35].

● The administration of alkali may slow the rate of recovery of the ketosis [44,45]. 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 [44]. Animal
studies indicate that bicarbonate infusion can accelerate ketogenesis. This is thought
to be related to the fact that acidemia has a "braking effect" on organic acid
generation. This brake is lessened by any maneuver that increases systemic pH [41].

● Alkali administration can lead to a post-treatment metabolic alkalosis since

metabolism of ketoacid anions with insulin results in the generation of bicarbonate
and spontaneous correction of most of the metabolic acidosis. (See "Diabetic
ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and
pathogenesis", section on 'Anion gap metabolic acidosis'.)

Phosphate depletion — Based upon the observations described below, we do not

recommend the routine use of phosphate replacement in the treatment of DKA or HHS.
However, phosphate replacement should be strongly considered if severe
hypophosphatemia occurs (serum phosphate concentration below 1 mg/dL or 0.32
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mmol/L), especially if cardiac dysfunction, hemolytic anemia, and/or respiratory depression

develop [46-50]. 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 [7,47]. Similar to 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 fall of serum glucose, morbidity, or mortality [51-53]. In addition, phosphate
replacement may have adverse effects, such as hypocalcemia and hypomagnesemia
[51,54-56]. Consequently, routine replacement is not indicated. When the patient stabilizes,
phosphate-rich food such as dairy products and almonds may be recommended.

MONITORING

General — The serum glucose should initially be measured every hour until stable, while
serum electrolytes, blood urea nitrogen (BUN), creatinine, and venous pH (for DKA) should
be measured every two to four hours, depending upon disease severity and the clinical
response [1,9]. In-patient serum glucose measurement should be done with hospital-
approved bedside devices or in the chemistry laboratory and not with continuous glucose
monitoring (CGM) devices.

The effective plasma osmolality (effective Posm) or tonicity can be estimated from the
sodium and glucose concentrations using 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 in these equations is the actual measured plasma sodium concentration and not
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the "corrected" sodium concentration.

It is strongly suggested that a flow sheet of laboratory values and clinical parameters be
utilized because it allows better visualization and evaluation of the clinical picture
throughout treatment of DKA ( form 1).

Monitoring with arterial blood gases is unnecessary during the treatment of DKA; venous
pH, which is approximately 0.03 units lower than arterial pH [57], 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) and the serum anion gap (to assess correction
of the ketoacidemia).

Where available, bedside ketone meters that measure capillary blood beta-
hydroxybutyrate are an alternative to the measurement of electrolytes and anion gap for
monitoring the response to treatment. These devices are increasingly available, reliable,
and convenient [13]. Beta-hydroxybutyrate can then be measured every two hours
depending on the clinical response [58]. When bedside meters are not available,
monitoring venous pH and/or the venous bicarbonate and anion gap is sufficient.

Resolution of DKA/HHS — The hyperglycemic crisis is considered to be resolved when the

following goals are reached:

● The ketoacidosis has resolved, as evidenced by normalization of the serum anion gap
(less than 12 mEq/L) and, when available, blood beta-hydroxybutyrate levels

● Patients with HHS are mentally alert and the effective plasma osmolality has fallen
below 315 mOsmol/kg

● The patient is able to eat

The disappearance of ketoacid anions in the serum and correction of the ketoacidosis can
be monitored by measuring venous pH, beta-hydroxybutyrate directly, and/or serum
electrolytes and bicarbonate concentrations with calculation of the serum anion gap. The
serum anion gap provides an estimate of the quantity of unmeasured anions in the
plasma. It is calculated by subtracting the major measured anions (chloride and
bicarbonate) from the major measured cation (sodium). The sodium concentration used
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for this calculation is the concentration reported by the laboratory not the "corrected"
sodium concentration.

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. Monitoring the anion gap will provide a reasonable estimate of
changes in these serum ketoacid anion concentrations. The anion gap returns to the
normal range when ketoacid anions have disappeared from the serum.

Correction of the ketoacidosis can also be monitored by direct measurement of serum or

capillary beta-hydroxybutyrate. Although assessments of urinary or serum ketone levels by
the nitroprusside method can be used for the initial diagnosis of ketoacidosis, it 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), and not with
beta-hydroxybutyrate. These characteristics of this test can generate clinical confusion. For
example, a positive nitroprusside test may persist for up to 36 hours after resolution of the
ketoacidosis due to a positive reaction with acetone, which is slowly eliminated, mainly via
the lungs [59,60]. 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) [25].

In the absence of severe kidney disease, almost all patients develop a normal anion gap
acidosis ("non-gap" or "hyperchloremic acidosis") during the resolution phase of the
ketoacidosis. This occurs because aggressive intravenous (IV) volume expansion reverses
volume contraction and improves renal function, which accelerates the loss of ketoacid
anions with sodium and potassium [61,62]. The loss of these ketoacid anion salts into the
urine represent "potential" bicarbonate loss from the body. Insulin therapy will have no
further effect on the acidosis when this stage evolves. The hyperchloremic acidosis will
slowly resolve as the kidneys excrete ammonium chloride (NH4Cl) and regenerate
bicarbonate.

Converting to subcutaneous insulin — For patients with DKA, we initiate a multiple-dose

(basal-bolus), subcutaneous insulin schedule when the ketoacidosis has resolved and the
patient is able to eat (see 'Resolution of DKA/HHS' above). If the patient is unable to eat, it

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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment

is preferable to continue the IV insulin infusion. For patients with HHS, IV insulin infusion
can be tapered and a multiple-dose (basal-bolus), subcutaneous insulin schedule started
when the serum glucose falls below 250 to 300 mg/dL (13.9 to 16.7 mmol/L).

The most convenient time to transition to subcutaneous insulin is before a meal. The IV
insulin infusion should be continued for two to four hours after initiating the short- or
rapid-acting subcutaneous insulin because abrupt discontinuation of IV insulin acutely
reduces insulin levels and may result in recurrence of hyperglycemia and/or ketoacidosis.
Basal insulin (NPH, U-100 glargine, or detemir) can be administered either (a) at the same
time as the first injection of rapid-acting insulin, or (b) earlier (for example, the previous
evening), along with a decrease in the rate of IV insulin infusion. We typically do not
administer degludec or U-300 glargine as the basal insulin when transitioning from IV
insulin due to its very long half-life, and subsequently, the time it takes to reach steady
state (two to three days).

For patients with known diabetes who were previously being treated with insulin, their pre-
DKA or pre-HHS insulin regimen may be restarted. For patients who are treated with
continuous subcutaneous insulin infusion (insulin pump), the previous basal rate can be
resumed. However, if the IV insulin requirements are significantly higher than their usual
insulin requirements, it is reasonable to increase the basal rate temporarily.

In patients with new-onset type 1 diabetes who have presented with DKA, an initial total
daily dose (TDD) of 0.5 to 0.8 units/kg units of insulin per day is reasonable, until an
optimal dose is established. Approximately 40 to 50 percent of the TDD should be given as
a basal insulin, either as once- or twice-daily U-100 glargine or detemir, or as twice-daily
intermediate-acting insulin (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. The remainder of the TDD is given as short-acting or
rapid-acting insulin, divided before meals. The pre-meal dosing is determined by the pre-
meal glucose level, meal size, and content, glucose trends (when available from CGM), as
well as activity and exercise pattern. If NPH is the basal insulin used, a mid-day (pre-lunch)
rapid-acting insulin may not be necessary. Good clinical judgment and frequent glucose
assessment are vital in initiating a new insulin regimen in insulin-naive patients. Most
importantly, the regimen needs to be adjusted based on empiric results provided by
glucose monitoring and responsive to individual lifestyle patterns including eating and
activity and exercise patterns. (See "General principles of insulin therapy in diabetes
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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment

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".)

COMPLICATIONS

Hypoglycemia and hypokalemia are the most common complications of the treatment of
DKA and HHS. These complications have become much less common since low-dose
intravenous (IV) insulin treatment and careful monitoring of serum potassium have been
implemented [63]. Hyperglycemia may recur from interruption or discontinuation of IV
insulin without adequate coverage with subcutaneous insulin.

Cerebral edema — Cerebral edema in uncontrolled diabetes mellitus (usually DKA, with

only occasional reports in HHS) is primarily a disease of children, and almost all affected
patients are younger than 20 years old [64]. 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 in the pediatric section but will be briefly reviewed here. (See "Diabetic
ketoacidosis in children: Cerebral injury (cerebral edema)".)

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.

DKA-associated cerebral edema has a mortality rate of 20 to 40 percent [1]. Thus, careful
monitoring for changes in mental or neurologic status that would permit early
identification and therapy of cerebral edema is essential.

The 2009 American Diabetes Association (ADA) guidelines on hyperglycemic crises in

diabetes in adults suggested that the following preventive measures may reduce the risk
of cerebral edema in high-risk patients [1]:

● Gradual replacement of sodium and water deficits in patients who are hyperosmolar.
The usual IV fluid regimen during the first few hours of treatment is isotonic saline at

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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment

a rate of 15 to 20 mL/kg lean body weight per hour (approximately 1000 mL/hour in
an average-sized person) with a maximum of <50 mL/kg in the first two to three
hours ( algorithm 1 and algorithm 2).

● Dextrose should be added to the saline solution once the serum glucose levels have
fallen to 200 mg/dL (11.1 mmol/L) in DKA or 250 to 300 mg/dL (13.9 to 16.7 mmol/L)
in HHS. In patients with HHS, the serum glucose should be maintained at 250 to 300
mg/dL (13.9 to 16.7 mmol/L) until the hyperosmolality and mental status improve and
the patient is clinically stable.

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) [64]. These interventions raise the plasma osmolality (Posm)
and generate an osmotic movement of water out of brain cells and a reduction in cerebral
edema.

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 [11]. 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.

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
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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment

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) and hyperosmolar

hyperglycemic state (HHS) are similar and involves correction of the fluid and
electrolyte abnormalities that are typically present, including hyperosmolality,
hypovolemia, metabolic acidosis (in DKA), and potassium depletion, and the
administration of insulin ( table 3 and algorithm 1 and algorithm 2). Frequent
monitoring is essential, and underlying precipitating events should be identified and
corrected. (See 'Overview and protocols' above.)

● Fluid replacement – We recommend intravenous (IV) fluid replacement to correct

both hypovolemia and hyperosmolality (Grade 1A). Fluid replacement should correct
estimated deficits within the first 24 hours, with care to avoid an overly rapid
reduction in the serum osmolality. The optimal rate of initial isotonic saline infusion is
dependent upon the clinical state of the patient. (See 'Fluid replacement' above.)

• Hypovolemia with shock – Isotonic saline should be infused as quickly as

possible in patients with hypovolemic shock.

• Hypovolemia without shock – In hypovolemic patients without shock (and

without heart failure), we begin with isotonic (0.9 percent) saline infused at a rate
of 15 to 20 mL/kg per hour (approximately 1000 mL/hour in an average-sized

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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment

person) for the first couple of hours. This is followed by one-half isotonic (0.45
percent) saline 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. We add dextrose to the saline solution when the serum
glucose reaches 200 mg/dL (11.1 mmol/L) in DKA or 250 to 300 mg/dL (13.9 to 16.7
mmol/L) in HHS. (See 'Fluid replacement' above.)

The need for potassium repletion may influence the timing of one-half isotonic
saline therapy since the addition of potassium to isotonic saline creates a
hypertonic solution that can worsen the underlying hyperosmolality. (See
'Potassium replacement' above.)

• Euvolemia – Isotonic saline is infused at a lower rate than in hypovolemic patients

without shock, guided by clinical assessment.

● Potassium replacement – We recommend that replacement with IV potassium

chloride (KCl) (Grade 1A) be initiated when the serum potassium concentration is ≤5.3
mEq/L. Patients with an initial serum potassium below 3.3 mEq/L should receive fluid
and potassium replacement prior to treatment with insulin to prevent initial
worsening of the hypokalemia. (See 'Fluid replacement' above and 'Potassium
replacement' above.)

Patients with DKA or HHS typically have a marked degree of potassium depletion due
to both renal and, in some patients, gastrointestinal losses. However, because of
potassium redistribution from the cells into the extracellular fluid (ECF), the initial
serum potassium concentration is often normal or elevated, an effect that will be
reversed by insulin therapy.

● Insulin

• Moderate to severe DKA – We recommend initial treatment with low-dose IV

insulin in all patients with moderate to severe DKA or HHS who have a serum
potassium ≥3.3 mEq/L (Grade 1B). Patients with an initial serum potassium below
3.3 mEq/L should receive aggressive fluid and potassium replacement prior to
treatment with insulin. (See 'Potassium replacement' above.)

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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment

The insulin regimen is the same in DKA and HHS ( algorithm 1 and
algorithm 2). If the serum potassium is ≥3.3 mEq/L, we give a continuous IV
infusion of regular insulin at 0.14 units/kg per hour; at this dose, an initial IV bolus
is not necessary. An alternative option is to administer an IV bolus (0.1 units/kg
body weight) of regular insulin, followed by a continuous infusion at a dose of 0.1
units/kg per hour. 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. (See 'Insulin' above.)

• Mild DKA – A cost-effective alternative to IV insulin in the initial treatment of mild

DKA ( table 1) is the use of subcutaneous, rapid-acting insulin analogs (insulin
lispro, aspart, and glulisine) in selected patients in settings in which adequate
monitoring can be assured. (See 'Subcutaneous insulin regimens' above.)

● Indications for bicarbonate – Indications for sodium bicarbonate therapy to help

correct the metabolic acidosis are controversial. We suggest treatment with IV
sodium bicarbonate in patients with an arterial pH less than 6.9 (Grade 2B). (See
'Bicarbonate and metabolic acidosis' above.)

● Indications for phosphate – Although whole-body phosphate depletion is usually

present, we recommend not administering phosphate routinely (Grade 1A). We
suggest phosphate replacement for patients with severe hypophosphatemia (<1
mg/dL [0.32 mmol/L]), respiratory or cardiac failure, or hemolytic anemia (Grade 2C).
(See 'Phosphate depletion' above.)

● Monitoring – Monitoring involves hourly glucose measurement until stable and basic
chemistry profile and venous pH (for DKA) 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. Acetone is not an acid
and does not generate metabolic acidosis. (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
(maximum reduction in plasma osmolality [Posm] of 3 mOsmol/kg per hour), and
maintenance of a slightly elevated serum glucose until the patient is stable. (See
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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment

'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. For patients with HHS, IV insulin infusion can be tapered and a multiple-
dose, subcutaneous insulin schedule started when the serum glucose falls below 250
to 300 mg/dL (13.9 to 16.7 mmol/L). The IV insulin infusion should be continued for
two to four hours after initiating the subcutaneous insulin to avoid recurrence of
hyperglycemia. When converting to subcutaneous insulin, we do not use ultra-long-
acting insulins (eg, degludec, U-300 glargine) as the basal insulin, given their long
half-life and the time it takes to reach steady state (two to three days). (See
'Converting to subcutaneous insulin' above.)

ACKNOWLEDGMENT

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 50.0

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