Closing the Gap: DKA

Management Pearls
Brit Long, MD and Alex Koyfman, MD
September 30, 2019

Diagnosis is not always straightforward, here’s what you need to

consider.

Case: A 27-year-old female with a history of insulin-dependent

diabetes and recurrent episodes of diabetic ketoacidosis presents
with polyurea, polydipsia, blurry vision, and “high” blood glucose
readings. You diagnosed her with diabetic ketoacidosis (DKA) due
to a pH of 7.18, positive serum ketones, and low bicarbonate. You
remember something about using basal insulin early in
management. Should you start basal insulin, and what other
components of management should you consider?

The diagnosis and management of DKA seem simple… Metabolic

acidosis, low bicarbonate, high glucose for the diagnosis, and
ketones… Replenish intravascular volume, replace potassium, and
start insulin. Unfortunately, this is not always the case.

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Diagnosis is easy, right?

Recent literature has questioned our approach to DKA. Many

patients will have obvious DKA with known diabetes, large anion gap
and ketones, and a history and exam suggesting DKA. While DKA is
associated with hyperglycemia, acidosis, and low bicarbonate,
patients can have normal glucose (euglycemic DKA) and normal pH
and normal bicarbonate (ketoacidosis with metabolic alkalosis from
fluid depletion and vomiting).[1-6]

Interestingly, the Canadian DKA guidelines state that “there are no

definitive criteria for diagnosis of DKA.”[7] The American Diabetes
Association (ADA) defines DKA as glucose > 250 mg/dL, pH < 7.3,
serum bicarbonate < 18 mmol/L, and anion gap > [10,8] while the UK
guidelines use glucose > 200 mg/dL (or known diabetes), positive
ketones, pH < 7.3, and bicarbonate < 15 mmol/L, but no anion gap.
[9]

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An easier way to diagnose DKA is to use a venous blood gas

(chemistry, anion gap), and serum ketones, preferably beta-
hydroxybutyrate. Utilizing urine ketones can be challenging, as this
test mainly assesses the presence of acetoacetate, which may not
be necessarily present.[5,6,10] Beta-hydroxybutyrate is the
predominant ketone in DKA, which is converted to acetoacetate.
Urine ketone assays measure acetoacetate, and thus patients
presenting early in the disease may have negative urine ketone
levels.[1,5,6]

Interestingly, you can use end tidal CO2 (ETCO2) to assist. An

ETCO2 > 35 mm Hg can rule out DKA with 100% sensitivity, while a
level < 21 mm Hg is 100% specific for diagnosis.[11,12] Along with
diagnosis, determining the etiology is vital. The most common
triggers include infection and medication/insulin noncompliance, but
other stressors include pregnancy, alcohol/other substance use,
surgery, trauma, pancreatitis, infarction/ischemia, and many others.
[1,8,13-17]
Case: You have completed a focused physical exam and cannot
find a source of infection, the EKG is normal other than tachycardia,
and the patient has no other complaints or signs/symptoms other
than the polydipsia and dry mouth. The chest x-ray is negative, and
the abdominal exam and lipase are normal. Serum potassium is 4.4
mEq/L.

What should you use for your initial resuscitation?

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Our patient appears dehydrated on exam. The more IV peripheral

access you can obtain, the better. Most patients with DKA can be
adequately treated with peripheral access only. Unfortunately, these
patients may be prone to difficult access, and an external jugular IV
line, internal jugular peripheral IV placement, or central access using
the femoral vein may be required.[6,18]

Patients with DKA are often severely intravascularly depleted due to

the osmotic diuresis, vomiting, and reduced oral intake, on average
3-6L.[8,19] Start with 10-20 cc/kg based on actual body weight of
lactated ringers (LR) or plasmalyte.[13] We recommend a balanced
crystalloid, rather than normal saline, which can potentially worsen
non-anion gap metabolic acidosis.[20-24] While there are little data
directly comparing LR and NS in DKA resuscitation, one study found
a trend towards faster improvement in serum pH with LR, as well as
serum bicarbonate increase with LR.21 NS reduced serum
bicarbonate.[21] Plasmalyte possesses more data, with improved
serum bicarbonate and less hyperchloremia compared with NS.
[22,23] Repeat 500 cc to 1L boluses until the patient’s fluid status
has improved.[5] Be careful using urine output as a measure of
resuscitation, as patients will have increased urine output due to the
osmotic diuresis.

What should you consider with potassium?

Before we start insulin, you should ensure serum potassium is

normal or high (up to 5% of patients will have low serum potassium
in DKA).[24] If hypokalemia is present (< 3.5 mEq/L), hold insulin and
replace potassium. You can administer up to 20 mEq/L bilaterally
through separate IVs, or through central access. Infusions up to 40
mEq/L can be utilized as long as careful monitoring of the IV site is
possible, based on the current literature.[20,25] Most patients suffer
from severe nausea with DKA, and repleting with oral potassium
may not be possible.[5,6,20]

If serum potassium is 3.5-5.5 mEq/L, start potassium replacement

with insulin.[5,6,8] Keep in mind that resuscitation of the patient with
DKA will result in rapid potassium decrease, and aim for the higher
level of normal for serum potassium (4.5-5 mEq/L).20 If the patient
is hyperkalemic with ECG changes such as PR or QRS widening or
hemodynamic instability, you should provide an IV fluid bolus and IV
calcium gluconate, but insulin and fluid resuscitation are also vital
therapies in this setting.

What are the finer points of insulin administration?

Once the potassium is normal or high, insulin is necessary. Just

remember…your goal is to correct the ketoacidosis, not necessarily
the serum glucose.[5,20] There are two schools of thought: 1)
administering 10 units insulin bolus followed by an infusion of 0.1
units/kilogram/hour (U/kg/hr), or 2) administering an insulin infusion
at 0.14 U/kg/hr without the bolus.[6,8,20,26,27]

Insulin infusion without bolus may be associated with reduced rates

of hypoglycemia and hypokalemia, as well as improved resolution of
hyperglycemia and acidosis, but if the infusion will take some time
to obtain,[26,27] consider 10 units IV as a bolus. For patients with
severe acidosis, you may need to set the infusion at 0.2 U/kg/hr.
Titrate the infusion to reduce glucose by 50-70 mg/dL per hour.
[8,28] If you are unable to reduce glucose levels by this every hour,
increase the insulin by 1-2 units per hour. Also, ensure you are
basing your infusion on true body weight, not ideal body weight.
[5,6,8,20] For example, if the patient’s glucose drops by 200 mg/dL in
an hour, remember that we are treating the ketoacidosis with the
insulin.[5] If the pH and serum bicarbonate are not improving
despite this decrease in glucose, leave the insulin infusion rate alone
and instead provide glucose.[5,20]

Now that you have resuscitated the patient and have insulin
infusing, what should you follow? Your target is to close the anion
gap, normalize pH, and normalize bicarbonate safely while avoiding
hypoglycemia and hypokalemia.[5,6,8] Measure glucose every hour,
and watch urine output. If the patient is not producing urine,
consider renal failure and/or shock.

Long-acting insulin was often avoided in the past in the ED. Instead,
we typically administer an intermediate form with a two-hour
overlap with the infusion.[6,8] However, long-acting insulins like
glargine or detemir can assist if provided correctly. Literature
suggests long-acting insulin used early in the patient’s course can
reduce rebound hyperglycemia (after discontinuation of insulin
infusion), assist with moving from insulin infusion, and decrease
length of stay.[5,8,28-32]

The UK DKA guidelines incorporate using a patient’s home-dose

basal insulin in DKA management.[9] If using long-acting insulin, use
the patients home regimen (usually a single daily dose).[20] If the
patient does not use insulin, start 0.25 U/kg of glargine per day.[5,20]
Do not reduce the patient’s home dose, and if the patient takes
glargine twice daily, do not stop the insulin infusion until after the
second inhospital dose of glargine.[20] Importantly, in patients with
an underlying etiology for their DKA that results in physiologic stress
and catecholamine release, an increased insulin requirement may be
present. You can also consider combining the two doses into a
single once daily dose.[7,20] Glargine has a delayed onset of action
compared to other forms such as intermediate insulins (NPH). Thus,
if you elect to use glargine, you should start it earlier than the
normal two hours.[7,20] If the insulin infusion is discontinued within
this two-hour window, ketoacidosis can potentially worsen.[5,8]

What if I am treating a patient with relatively mild DKA who

appears otherwise well?

A major issue with initiating an insulin IV infusion is that this often

requires an ICU for admission. However, this may not be always
needed. Patients with mild DKA typically only need some IV fluids
and insulin; they may even be appropriate for discharge directly
from the ED with follow up. Mild DKA is defined by a serum
bicarbonate just below 18 or pH slightly less than 7.[3] and patients
may be appropriate for discharge home.[5,8,20,33,34] One treatment
option is subcutaneous (SC) rapid-acting insulin. Literature
suggests that SC rapid-acting insulin is safe and effective for mild
or moderate DKA.[35-41] Studies also show that SC insulin does not
increase risk of hypoglycemia or recurrent DKA. Patients can be
given 0.3 U/kg SC bolus, followed by 0.1 U/kg SC every hour or 0.2
U/kg every two hours.[35-41]

Monitoring of serum glucose every hour is recommended. If the

patient is on a long-acting insulin, this can be utilized. Ensure the
patient has adequate insulin for home. After several hours of
monitoring with insulin and fluids, recheck labs, including
bicarbonate and anion gap. If the gap has closed, the bicarbonate
has normalized, and glucose is < 250 mg/dL, the patient can be
discharged home with follow up.[5,6,8,20]

What about the patient with a pH < 6.9 or bicarbonate < 5?

Should we administer sodium bicarbonate?

The ADA recommends bicarbonate for DKA with pH < 6.9,8 but data
does not support this approach.[20] This degree of acidosis can be
frightening, but patients typically do not require sodium bicarbonate
infusion.[20] To increase the pH, the patient must get rid of CO2,
and in severe states the patient is maximizing respiratory
compensation.[5,6,20] One study found that serum bicarbonate
administered to patients with serum pH > 6.85 can worsen
hypokalemia, delay resolution of ketosis, and increase risk of
cerebral edema.[42]

Bicarbonate administration can instead worsen intracellular

acidosis, and it can further drop serum potassium levels.[20,42] The
best means of addressing low serum bicarbonate is to increase the
insulin infusion, or bolus 10 units IV. This may require additional
potassium and glucose to match the increased insulin. Administer
bicarbonate in the following: cardiac arrest and DKA, hyperkalemia
with DKA and life-threatening dysrhythmia, and hemodynamic
compromise despite fluid resuscitation.[5,6,20]

My patient is tiring and looks like he will require intubation…

Avoid intubation if you can, especially for altered mental status

alone (which should improve with IV fluid resuscitation and insulin).
[5,6] If possible, delay intubation to optimize volume status and
correct ketoacidosis. These patients are at severe risk of
hemodynamic compromise, worsening acidosis, and vomiting with
aspiration during intubation.[43]
Patients who are unable to control secretions or those in respiratory
arrest should be intubated.[20] Just be sure to mitigate the
previously mentioned risks with IV fluid resuscitation, starting a
vasopressor if needed, use hemodynamic dosing of the sedative,
avoid regurgitation by placing an nasogastric tube prior to intubation
if the patient has a full stomach, consider sodium bicarbonate 2-3
ampules over 10-15 minutes, use rocuronium and a larger
endotracheal tube (8.0), and consider mechanically controlled
apneic ventilation.[20,43]

If the patient has increased work of breathing, or for severe

metabolic acidosis, attempt high-flow nasal cannula (HFNC). This
supports the work of breathing and improves compensation for
metabolic acidosis. Set the FiO2 to over 90%, and increase the flow
rate to 60 L/min, which blows off more CO2 by reducing dead
space.[20,43] While we often rely on noninvasive positive pressure
ventilation with a full face mask, this can be dangerous in patients
with severe nausea/vomiting, resulting in aspiration.[7]

What do I do with IV fluids once the patient has been

resuscitated and the ketoacidosis has improved?

The patient will require a maintenance fluid infusion, dependent on

the serum glucose. If glucose is > 250-300 mg/dL, start LR at
approximately 200 mL/hr.[8,13] However, once the glucose
decreases to < 250-300 mg/dL, a glucose infusion is needed.[8,13]
You have a couple options. You can use D5 ½ NS at 200 mL/hr, or
you can reduce the LR infusion to 100 mL/hr and add a D10W
infusion at 100 mL/hr.20 This essentially creates a D5 ½ LR solution.
[20] These two fluids are compatible, but a premade fluid is typically
not available in the ED. You can administer these fluids through
separate IV lines, which allows you to titrate the D10W infusion to
the patient’s glucose requirements.
Other items to consider include phosphate and magnesium.
Phosphate may drop in patients with severe DKA, and this will need
to be replaced if the phosphate is < 1 mg/dL.[8,13] Also pay attention
to the serum magnesium. Magnesium on the higher level of normal
may assist in prevention of arrhythmias (> 2.2 mg/dL).[20]

When should you stop the insulin infusion?

Ensure the anion gap is < 10-12 mEq/L (except for patients with end
stage renal disease and uremia, in which patients will have an
elevated anion gap due to uremia) and/or use a serum beta-
hydroxybutyrate level < 0.6.[5-8,20] Also make sure the patient has a
serum bicarbonate > 18 mEq/L, the patient has received the long
acting insulin at least two hours earlier (preferably sooner), the
glucose has improved to < 250 mg/dL, and the patient is PO
tolerant (and hopefully hungry, which is an indirect way of assessing
for the absence of ketoacidosis).[5,6,8] If the patient has
gastroenteritis as the etiology for their DKA or gastroparesis, use an
infusion of D5W at 75 mL/hr.20 Encourage the patient to eat, and
use sliding-scale insulin (0.08 U/kg rapid acting per meal).[5,8] Keep
watching for the recurrence of DKA by following glucose levels and
repeat electrolytes.

The anion gap is not closing… what could be wrong?

There can be a variety of problems. Ensure the patient has been

adequately resuscitated with fluids, the insulin dose is appropriate,
and that the underlying cause has been addressed. For example, if
the patient presented with severe abdominal pain and you thought
ketones were the sole cause of the pain, is the patient better after
fluids and insulin? [5,20] If not, consider imaging. An underlying
etiology that has not been addressed can result in failure to close
the anion gap.[5,20]
What about a non-anion gap metabolic acidosis (NAGMA)?

NAGMA often develops later in the management of DKA due to use

of NS in resuscitation and/or excretion of ketoacid in the urine.[20] If
the patient’s bicarbonate remains low but the anion gap has closed,
consider NAGMA. This is often found with a low serum bicarbonate
despite closed anion gap. Treatment of NAGMA includes isotonic
sodium bicarbonate infusion.[20]

I’ve heard about euglycemic DKA. What does this entail?

Euglycemic DKA is DKA with glucose < 250 mg/dL, which occurs in
up to 10% of patients with DKA.[2,3,44] Causes include SGLT2
inhibitors, decreased hepatic glucose production (starvation,
pregnancy), and partial treatment with insulin before the patient
presents to the ED. If the anion gap is elevated or ketones are
present, consider euglycemic DKA.[2,5,6,20] Treatment is similar to
DKA with fluid and insulin, but IV glucose will need to be started
with insulin.[20]

Key Points:

DKA diagnosis is not always straightforward: be wary in the

patient with history of diabetes who has positive ketones, low
serum bicarbonate or low pH, or anion gap.
Begin therapy with fluid resuscitation, preferably balanced
crystalloids. Ensure serum potassium is normal or high before
initiating insulin.
Insulin infusion at 0.14 U/kg/hr IV is efficacious with no bolus.
Long acting insulin can assist with transitioning to SC insulin
therapy when provided early in management. Subcutaneous
insulin can be used in those with mild to moderate DKA.
Intubating a patient with DKA is fraught with danger. Attempt
high flow nasal cannula first.
 While bicarbonate is not necessary for all patients with DKA, it
may help with resolving NAGMA.
Euglycemic DKA exists. Ask about SGLT2 inhibitors.

References:

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Hyperglycemic Crises: Diabetic Ketoacidosis and
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