Review
Diabetic Ketoacidosis Management: Updates and Challenges
for Specific Patient Population
Azza B. El-Remessy 1,2
Citation: El-Remessy, A.B. Diabetic
Ketoacidosis Management: Updates
and Challenges for Specific Patient
Population. Endocrines 2022, 3,
801–812. https://doi.org/10.3390/
endocrines3040066
Academic Editors: Maria Mirabelli,
Eusebio Chiefari and Antonio
Brunetti
Received: 15 August 2022
Accepted: 5 December 2022
Published: 8 December 2022
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Copyright: © 2022 by the author.
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Endocrines 2022, 3, 801–812. https://doi.org/10.3390/endocrines3040066
1 Department of Pharmacy, Doctors Hospital of Augusta, Augusta, GA 30909, USA; aelremessy@outlook.com
2 Nour Therapeutics LLC, Augusta, GA 30907, USA
Abstract: Diabetic ketoacidosis (DKA) is the most common hyperglycemic emergency and causes the
greatest risk for death that could be prevented in patients with diabetes mellitus. DKA occurs more
commonly among patients with type-1 diabetes with a thirty percent of the cases take place in patients
with type 2 diabetes. DKA is characterized by sever hyperglycemia, metabolic acidosis and ketosis.
Proper management of DKA requires hospitalization for aggressive replacement and monitoring
of fluids, electrolytes and insulin therapy. Management of DKA has been updated with guidelines,
to help standardize care, and reduce mortality and morbidity. The major precipitating factors for
DKA include new diagnosis of diabetes, non-adherence to insulin therapy as well as infection in
patients with diabetes. Discharge plans should include appropriate selection of insulin dosing
and regimens as well as patient education to prevent recurrence of DKA. Further, definition and
management of euglycemic DKA in patients prescribed sodium-glucose co-transporter 2 inhibitors
are discussed. Special consideration is reviewed for specific patient population including pregnancy,
renal replacement, acute pancreatitis, and insulin pump users as well as patients with COVID-19.
Keywords: diabetes mellitus; DKA; fluid management; ketoacidosis; euglycemic DKA; special
population; SGLT2 inhibitors; insulin pump; pregnancy; COVID-19
1. Introduction
1.1. Diabetic Ketoacidosis (DKA)
DKA is characterized by uncontrolled hyperglycemia (>250 mg/dL), metabolic aci-
dosis, and increased ketone concentration [1]. DKA incidence increased at annual rate of
6.3% most notably in persons aged <45 years with significant increase in hospitalization
rate between 2008 and 2018 [2]. Nevertheless, overall in-hospital mortality rates declined
during the study period from 1.1% to 0.4% [3]. DKA is a life-threatening, but preventable
complication of type-1 diabetes with a thirty percent of the cases that could be attributed
to type-2 diabetes. The major clinical difference between these two types of diabetes is a
lesser degree of acidosis and absence of hyperkalemia in type 2 diabetes [4].
1.2. Pathophysiology of DKA
The pathophysiology of DKA is a multifactorial and driven by hyperglycemia, de-
hydration, ketosis, and electrolyte imbalance. As depicted in Figure 1, insulin deficiency
triggers a cascade of maladaptive physiologic responses involving hormone-sensitive li-
pase which is activated such as lipoprotein lipase resulting in increased triglycerides and
free fatty acids (FFA). In return, FFA triggers excessive ketone bodies formation in the
liver leading to metabolic acidosis. Activation of counter regulatory hormones (cortisol,
glucagon, growth hormone, and catecholamines) drive hyperglycemia via various mecha-
nisms including increased glycogenolysis, gluconeogenesis resulting in progressive volume
depletion and electrolyte loss (reviewed in [5]). Production of prostaglandins can contribute
also to nausea, vomiting and abdominal pain [6]. Additional risk factors include infection,
https://www.mdpi.com/journal/endocrines
OR PEER REVIEW 2

Endocrines 2022, 3 802

also to nausea, vomiting and abdominal pain [6]. Additional risk factors include infection,
pancreatitis, myocardial infarction, stroke as well as secondary causes due to drugs such
pancreatitis, myocardial infarction, stroke as well as secondary causes due to drugs such as
as steroid, thiazides, sympathomimetics.
steroid, thiazides, sympathomimetics.

Figure 1. Schematic framework of theframework

Figure 1. Schematic pathophysiology of diabetic of
of the pathophysiology ketoacidosis. In DKA,
diabetic ketoacidosis. In insulin
DKA, insulin
insufficiency sets off insufficiency
a cascade of maladaptive
sets off a cascade ofphysiologic responsesresponses
maladaptive physiologic involving activation
involving of lipase,
activation of lipase, in-
increased free fatty acids
creasedthat
freetriggers
fatty acidsexcessive ketone
that triggers bodies
excessive ketoneleading to metabolic
bodies leading acidosis.
to metabolic acidosis.Acti-
Activation
vation of counter regulatory hormones drive hyperglycemia via various mechanisms includingincreased
of counter regulatory hormones drive hyperglycemia via various mechanisms including in-
creased glycogenolysis,glycogenolysis, gluconeogenesis
gluconeogenesis resultingresulting in progressive
in progressive volumedepletion
volume depletion and
andelectrolyte
electrolyteloss.
loss. 1.3. DKA Presentation and Diagnosis
As a result of increased lipolysis and decreased lipogenesis, surplus free fatty acids
1.3. DKA Presentation
are and Diagnosis
converted to ketone bodies: β-hydroxybutyrate (β-OHB) and acetoacetate. Majority
As a result of of patients with
increased DKA present
lipolysis with symptoms
and decreased such as polyuria,
lipogenesis, surpluspolydipsia,
free fattyweight
acids loss,
vomiting, dehydration, weakness, and mental status changes. Physical findings include
are converted to ketone bodies: β-hydroxybutyrate (β-OHB) and acetoacetate. Majority of
poor skin turgor, Kussmaul (deep/labored) respirations, tachycardia and/or hypotension.
patients with DKAGastrointestinal
present withsymptoms
symptoms such as
can include polyuria,
nausea, vomitingpolydipsia,
and diffuse weight
abdominal loss,
pain [1].
vomiting, dehydration, weakness,
The American and Association
Diabetes mental status changes.
diagnostic Physical
criteria for DKAfindings include
include elevated serum
glucose level
poor skin turgor, Kussmaul above 250 mg/dL,
(deep/labored) respirations, ≤7.30, bicarbonate
arterial pH oftachycardia and/or level of ≤18 mEq/L an
hypotension.
elevated serum ketone level, a pH less than 7.3 and, a serum bicarbonate level less than
Gastrointestinal symptoms can include nausea, vomiting and diffuse abdominal pain [1].
18 mEq per L (18 mmol per L) and adjusted for albumin anion gap of >10–12.3. Table 1,
The American Diabetes
adoptedAssociation
from Kitabchidiagnostic criteria
et al., 2009 [1] for DKA
shows detailed includecriteria
diagnostic elevated serumstages
for various
glucose level aboveof 250
DKAmg/dL,
based onarterial
the degreepH of of ≤7.30,The
acidosis. bicarbonate
detection of level ofurine
positive ≤18 or
mEq/L
serum an
ketones
elevated serum ketone level, a pH less than 7.3 and, a serum bicarbonate level less than can
further confirm the diagnosis of DKA, however obtaining serum level of ketone bodies
be moreper
18 mEq per L (18 mmol laborious.
L) andOfadjusted
note, the diagnosis of DKA
for albumin could gap
anion be challenging
of >10–12.3.in patients
Tablewith
1, end
stage renal disease, due to existing chronic metabolic acidosis or mixed acid-base disorders.
adopted from Kitabchi et al., 2009 [1] shows detailed diagnostic criteria for various stages
Therefore, detection of anion gap of >20 usually is used to support the diagnosis of DKA in
of DKA based on the degree
these patientsof[7].
acidosis. The detection of positive urine or serum ketones
further confirm the diagnosis of DKA, however obtaining serum level of ketone bodies
can be more laborious. Of note, the diagnosis of DKA could be challenging in patients
with end stage renal disease, due to existing chronic metabolic acidosis or mixed acid-
base disorders. Therefore, detection of anion gap of >20 usually is used to support the
diagnosis of DKA in these patients [7].
Endocrines 2022,3 3, FOR PEER REVIEW
Endocrines2022, 803
3

Table1.1. Diagnostic
Table Diagnostic criteria
criteria and deficits of electrolytes
electrolytes in
in different
different stages
stagesof
ofdiabetic
diabeticketoacidosis
ketoacidosis
(DKA).
(DKA).Reprinted/adapted
Reprinted/adapted with with permission
permission from
fromKitabchi
Kitabchietetal.,
al.,2009
2009“hyperglycemic
“hyperglycemiccrises
crisesininadult
adult
patientswith
patients with diabetes”
diabetes” [1].
[1]. Copyright © 2009 by the American
American Diabetes
DiabetesAssociation
Association.
Mild DKA (glu > 250)
Mild DKA (glu > 250) Moderate
Moderate DKA (gluDKA (glu >250) Severe
>250) Severe DKA
DKA (glu
(glu > 250)
> 250)
Arterial pH 7.25–7.30 7.00 to <7.24 <7.00
Arterial pH 7.25–7.30 7.00 to <7.24 <7.00
Serum bicarbonate 15–18 10 to <15 <10
Serum bicarbonate 15–18 10 to <15 <10
Urine ketone Positive Positive Positive
Urine ketone Positive Positive Positive
Serum ketone Positive
Serum ketone Positive PositivePositive Positive
Positive
Serum osmolality
Serum osmolality Variable Variable Variable Variable Variable
Variable
Anion gap gap
Anion >10 >10 >12 >12 >12
>12
Mental status
Mental status Alert Alert Alert/drowsy
Alert/drowsy Stupor/coma
Stupor/coma

2. Management
2. Management of of DKA
DKA
2.1. Standard
2.1. Standard Treatment
Treatment of of DKA
DKA
Most patients
Most patients with
withDKA DKApresent
presenttoto thethe
emergency
emergency roomroomfor the
for management
the managementof hy-of
hyperglycemic crisis. Successful treatment of DKA requires correction of dehydration,hy-
perglycemic crisis. Successful treatment of DKA requires correction of dehydration, hy-
perglycemiaand
perglycemia andelectrolyte
electrolyteimbalances
imbalanceswith withfrequent
frequent monitoring
monitoring of of clinical
clinical andand meta-
metabolic
bolic parameters
parameters that support
that support resolution
resolution of DKA of DKA [1]. Specific
[1]. Specific therapeutic
therapeutic goalsgoals of DKA
of DKA man-
management
agement include
include optimization
optimization of volume
of (1) (1) volume status;
status; (2)(2) hyperglycemiaand
hyperglycemia andketoacidosis;
ketoacido-
sis;electrolyte
(3) (3) electrolyte abnormalities;
abnormalities; andand (4) potential
(4) potential precipitating
precipitating factors.
factors.
As depicted in Figure 2, early steps of DKA management include:
As depicted in Figure 2, early steps of DKA management include: 1—collection
1—collectionofof
blood for metabolic profile before initiation of intravenous fluids;
blood for metabolic profile before initiation of intravenous fluids; 2—infusion of 1-L 2—infusion of 1-L of
of 0.9%
0.9% sodium chloride over 1 h after drawing initial blood samples; 3—ensuring
sodium chloride over 1 h after drawing initial blood samples; 3—ensuring potassium level potassium
level
of >3.3ofmEq/L
>3.3 mEq/L
beforebefore initiation
initiation of insulin
of insulin therapytherapy and 4—initiating
and 4—initiating insulin
insulin therapy
therapy only
only execution
after after execution
of theofinitial
the initial
stepssteps
[1–3].[1–3].

Figure 2.
Figure 2. Schematic
Schematic representation
representation of
ofaasimplified
simplifiedprotocol/workflow
protocol/workflowfor formanagement
managementofofadult
adult
patients with DKA. Abbreviations: NS, normal saline, H, hour, Bl. blood, K potassium, IV IV
patients with DKA. Abbreviations: NS, normal saline, H, hour, Bl. blood, K potassium, intrave-
intravenous.
nous.
2.2. Treatment–Fluid Therapy
2.2. Treatment–Fluid Therapy
Since DKA patients experience fluid loss of approximately 6–9 L, the goal of fluid
Since DKA
resuscitation aimspatients experience
to replete fluid within
that volume loss of 24–36
approximately
h with 50% 6–9ofL,resuscitation
the goal of fluidfluid
resuscitation aims
administered to first
within replete
8–12that volume
h of within 24–36
presentation. h with
Current DKA 50%guidelines
of resuscitation fluid
recommend
administered
initiating within
volume first 8–12
repletion withh of presentation.
isotonic Current
saline (0.9% DKAatguidelines
NaCl) recommend
15–20 mL/kg/h in-
followed
itiating
by volume
hypotonic repletion
saline solutionwith(0.45%
isotonic salineat(0.9%
saline) NaCl)
a rate at 15–20
of 4–14 mL/kg/hmL/kg/hthenfollowed by
re-evaluate.
hypotonic
Fluid saline solution
resuscitation continue (0.45% saline)
as long as at a rate
the of 4–14
patient mL/kg/h then re-evaluate.
is hemodynamically stable andFluidthe
resuscitation continue as long as the patient is hemodynamically stable
corrected serum sodium is normal to high. If not, corrected sodium level can dictate and the corrected
serum sodium
further volumeisrepletion
normal towithhigh.aIfdifferent
not, corrected
type ofsodium level[8].
IV fluid canFluid
dictateresuscitation
further volume will
Endocrines 2022, 3 804

decrease hyperglycemia by stimulating osmotic diuresis if renal function is not severely

compromised and restore peripheral action of insulin. Traditionally, hyperglycemia is
corrected faster than ketoacidosis (6 and 12 h, respectively) [9]. Hence, when glucose levels
fall below 200–250 mg/dL, intravenous fluids should be switched to dextrose-containing
0.45% NaCl solution to allow continued insulin administration until ketonemia and avoid
hypoglycemia [9].
Due to hyperglycemia in DKA causing osmotic diuresis and severe dehydration,
the mainstay of treatment is rehydration. Traditional treatment as mentioned above is
“one bag protocol (1 L/bag)” with normal saline and supplemental electrolytes vs. “two
bag protocol (1 L/bag)”. The two bags of fluids include one containing 1N saline (0.9%
NaCl) and supplemental electrolytes and the other bag contains 0.45% NaCl solution with
additional 10% dextrose. By changing the individual rates of Bag 1 and Bag 2 and hence, by
changing the relative amounts of the two fluids will functionally change the final dextrose
concentration to cope with glucose level. The change in percentages of fluids changes
the sodium concentration as well. For instance, when the glucose level >300 mg/dL, the
rate of Bag 1 will be 100% and Bag 2 will be zero and when glucose level <300 mg/dL
and >200 mg, then the rate of Bag1 will be 50% and Bag 2 will be 50% and when the
glucose level <150 mg then the rate of Bag 1 will be zero and Bag 2 will be 100%. Of note,
each institution will modify and adopt the exact rate and type of fluids with the goal of
maintaining glucose of 150–300. Published studies showed significant improvement of
earlier closure of anion gap with “two bag protocol” (~10-h) compared to “one bag protocol”
(~14-h) [10,11]. Hyperglycemia was also noted to improve faster in “two bag protocol”
(7 h) compared to “one bag protocol” (9 h). On the other hand, there was no difference in
the time to improve serum HCO3 level >18 mg/dL or the hospital length of stay differed
between the two groups [11].

2.3. Treatment–Insulin Therapy

Randomized controlled studies in patients with DKA have shown that insulin ther-
apy is effective regardless of the route of administration whether insulin is delivered
via continuous intravenous infusion or by frequent subcutaneous or intramuscular injec-
tions [12,13]. Recently, inhaled insulin was used for management of DKA in a patient
with subcutaneous insulin resistance syndrome [14]. However, IV continuous infusion
with regular insulin remains the mainstay of treatment due to its short half-life and easy
titration in comparison to other modes of administration [12,15]. Treatment algorithms rec-
ommended the administration of an initial intravenous dose of regular insulin (0.1 unit/kg)
followed by infusion of (0.1 unit/kg/h). Other studies showed that an hourly insulin
infusion of (0.14 units/kg body wt) would be sufficient without a bolus dose [16]. Monitor
glucose (every 1 to 2 h) and expect decrease of 50 to 75 mg/dL/h. If the level did not
drop, then infusion rate should be increased or bolus another dose of 0.14 unit/kg. When
the plasma glucose reaches 200 mg/dL, the rate of insulin infusion should be decreased
to 0.02–0.05 unit/kg/h. Continue close monitoring glucose to maintain glucose level at
150–200 mg/dL.
Other delivery methods of insulin delivery include subcutaneous rapid-acting insulin
analogs in in non–intensive care unit (ICU) settings. Safety and efficacy of subcutaneous
treatment with rapid-acting such as lispro and aspart every 1 or 2 h has been shown to be
similar to the standard I.V regular insulin in the ICU settings [17]. The clinical parameters
including the decline rate of blood glucose level and the correction of ketosis duration
were similar among the two groups [17]. Additionally, review of literature of 5 randomized
clinical trials in patients with DKA showed no significant difference between the use
of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin [18].
Incidence of hypoglycemic episodes was the main adverse effect for both regimens.
Endocrines 2022, 3 805

2.4. Treatment-Potassium
Despite total-body potassium depletion, patients with hyperglycemic crises can
present with mild hyperkalemia that could be attributed to reduced glomerular filtra-
tion rate and/or extracellular shift of potassium. The later could be triggered by insulin
deficiency, hypertonicity, or acidemia [19]. Occasionally, patients with DKA may present
with significant hypokalemia as a result of correction of volume or metabolic acidosis
and/or insulin therapy [1]. Hypokalemia can cause life-threatening arrhythmias and res-
piratory muscle weakness [20]. In such cases, potassium replacement should begin with
fluid therapy, and insulin treatment should be delayed until potassium concentration is
restored to >3.3 mEq/L. Generally, administration of 20–30 mEq potassium in each liter of
infusion fluid is sufficient to maintain a serum potassium concentration within the normal
range of 4–5 mEq/L.

3. DKA in Special Population

3.1. DKA in Pregnancy
DKA in pregnancy is poorly understood condition due to limited published evidence
of risk factors and outcomes. DKA in pregnancy is an obstetric and medical emergency
for both the pregnant woman and the fetus and therefore requires prompt and aggressive
treatment [21]. Fetal and neonatal morbidity can be the direct consequence of the extremely
poor tolerance of the fetus to acidosis, resulting in intrauterine death or preterm delivery.
DKA in pregnancy can occur at near normal levels of blood glucose (euglycemic DKA)
and often progresses more rapidly as compared with nonpregnancy [22]. Prior studies
identified number of risk factors that can lead to precipitating episodes of diabetic ketoaci-
dosis in pregnant patients. The major risk factors are intractable vomiting and starvation
(53%), inadequate insulin management (18%), and infection (27%) including pyelonephritis,
respiratory, chorioamnionitis, ear infection, cellulitis, or tooth abscess. Additional common
causes include the use of β-sympathomimetic drugs, steroid administration for fetal lung
maturation) and diabetic gastroparesis [21]. Management of DKA during pregnancy is
similar to DKA in non-pregnant patients. Initial fluid replacement starts with 0.9% sodium
chloride (normal saline) at a rate of 15 to 20 mL/kg (−1–1.5 L) over the first hour then the
rate and type of fluids are determined accordingly. The clinical assessment of the mother
involves blood pressure, pulse, hydration, mental status, fluid input and urine output.
Additionally, fetal heart rate monitoring is recommended for a gestational age of 24 weeks
or more [23].

3.2. DKA in Renal Replacement

Diabetes is one of the major precipitating factors of end-stage renal disease (ESRD) in
the US [24]. A normal renal function is integral to maintain insulin homeostasis including
its secretion, clearance and level of sensitivity. Hence, impairment or loss of renal function
presents multiple challenges in glycemic control for ESRD-patients. Driven mainly by
accumulated uremic toxins, ESRD can increase hepatic gluconeogenesis reduce utilization
of insulin peripherally and drive insulin resistance [25]. Interestingly, DKA is uncommon in
ESRD-patients possibly because of the absence of glycosuria and osmotic diuresis. Clinical
and biochemical lab presentation of DKA in ESRD-dialysis patients is different when
compared to non-dialysis patients [26]. For instance, patients with ESRD present with
higher admission blood glucose, volume overload and need for mechanical ventilation [27].
Interestingly, ESRD-patients have lower A1c, similar mortality, but longer length of stay
and higher hospital costs [27].
Overall, ESRD dialysis patients maintain normal intracellular and extracellular volume.
Therefore, they present with minimal volume depletion, and instead they might experience
edema of lungs and lower extremities as well as elevated blood pressure; collectively
signs of volume expansion. Traditionally, dialysis patients do not require intravenous
fluids unless patients exhibit clinical signs of extracellular fluid loss such as vomiting
or diarrhea. If needed, small boluses of normal saline (250 mL) would be administered
Endocrines 2022, 3 806

under tight monitoring to maintain stable hemodynamic parameters. Hemodialysis is

reserved for severe hyperkalemia and pulmonary edema and continues to be controversial
in general. Hyperkalemia in ESRD can be life threatening and could be attributed to reduced
glomerular filtration rate, lack of insulin, and hypertonicity [28]. Severe hyperkalemia
requires close monitoring for signs of cardiac toxicity and detection of potassium level
post hemodialysis.

3.3. DKA in Acute Pancreatitis and Islets Transplants

Acute pancreatitis (AP) is one of the common causes of acute abdominal pain related
hospital admission with high morbidity and mortality [29]. AP is associated mostly with
hyperlipidemia, uncontrolled diabetes, alcoholism and is seen more with patients with
familial hyperlipidemia [30]. Several reports showed the incidence of severe DKA in
patients with AP that was associated with hypertriglyceridemia [29,31–34]. It is difficult
to establish a causal relationship whether DKA is the cause or the result of AP, DKA was
managed using standard fluid resuscitation and insulin infusion in these patients.
With the success of organ transplants, wide use of immunosuppressants including
tacrolimus can cause drug-induced pancreatic islet cell damage and subsequent decrease
in insulin secretion [35]. This can lead to post-transplant diabetes mellitus and diabetic
ketoacidosis [36]. Recent report documented a case of tacrolimus-induced acute pancreatitis
in association with hypertriglyceridemia and DKA post-kidney transplant [37]. Pancreatic
islet transplantation is becoming a potential approach to β-cell replacement therapy and
the treatment of insulin-deficient diabetes in the setting of recurrent AP or chronic pan-
creatitis [38]. Additionally, recurrent episodes of DKA in patients with type-1 diabetes is
one of the considerations for islet transplantation [39]. Islet auto-transplantation involves
infusion of islets isolated from the diseased pancreas via the portal vein and intrahepatic
engraftment. Tacrolimus remains one of the maintenance immunosuppression for islet
transplant recipients with close monitoring for glucose levels and insulin secretions in these
patients [40]. Despite the success of islet transplantation in improving insulin-requirements
in type-1 diabetes, it comes with a list of limitations mainly associated with sustained use
of immunosuppressants [38]. As such, it should be saved for patients with type-1 diabetes
in whom other, less invasive current treatments have been repeatedly ineffective.

3.4. DKA and Sodium–Glucose Cotransporter (SGLT) Inhibitors

SGLT2 inhibitors including Canagliflozin, Dapagliflozin, Empagliflozin and Ertugliflozin
are popular in the US and Europe as their use is approved in patients with type-2 diabetes
as a first line therapy. Further, they have been studied and used off-label in combination
with insulin therapy in patients with type 1 diabetes [41]. The use of SGLT2 inhibitors
has been increasingly associated with an increased risk of DKA primarily in patients with
type-1 diabetes and to a lesser extent in type-2 diabetes. Blocking SGLT2 transporter in
the proximal tubule of the kidney results in glycosuria and natriuresis. SGLT-2 inhibition
results in excretion of 50–60% of the filtered glucose, but also exerts a mild natriuretic effect
that provide additional benefits including weight loss and reduction in systolic/diastolic
blood pressure [42]. SGLT-2 inhibitors are potent cardioprotective and nephroprotective
agents, offering reductions of up to 38% in cardiovascular mortality, 35% in heart failure
hospitalization, 45% in progression of renal disease, and 30% in all-cause mortality (re-
viewed in [43]). The ability of SGLT2 inhibitors to induce osmotic diuresis allows the body
to get rid of extra free water and supported potential use of SGLT2 inhibitors in cases of
euvolemic hyponatremia [44,45]. While this particular use warrant further studies, a recent
case review showed that SGLT2 inhibitors can cause hyponatremia as a potential, rare
side effect and that the use of SGLT2 inhibitor should be evaluated or stopped in case of
persistent hyponatremia [46].
Development of euglycemic DKA and ketonemia remain the most dangerous side
effects for patients who develop DKA while on SGLT inhibitor therapy [47]. SGLT2 in-
hibitors can induce a state of ketosis by increasing both urinary glucose excretion and
Endocrines 2022, 3, FOR PEER REVIEW 7

Endocrines 2022, 3 Development of euglycemic DKA and ketonemia remain the most dangerous side 807
effects for patients who develop DKA while on SGLT inhibitor therapy [47]. SGLT2 inhib-
itors can induce a state of ketosis by increasing both urinary glucose excretion and reab-
sorption of ketone
reabsorption bodies.
of ketone Precipitating
bodies. factors
Precipitating include
factors prolonged
include periods
prolonged of fasting,
periods re-
of fasting,
duced carbohydrate intake, excessive physical activity, infection, pregnancy or
reduced carbohydrate intake, excessive physical activity, infection, pregnancy or alcohol alcohol
consumption[48].
consumption [48].These
Thesefactors
factorscan
can accelerate
acceleratelipolysis
lipolysisand
andincreased
increasedfree
freefatty
fattyacid
acidlevels
levels
that eventually trigger hepatic formation of ketone bodies (see Figure
that eventually trigger hepatic formation of ketone bodies (see Figure 3). 3).

Figure 3.
Figure 3. Schematic
Schematicrepresentation
representationofofpossible
possiblemechanisms
mechanismsinvolved
involvedin the development
in the developmentof euglyce-
of eug-
mic diabetic ketoacidosis (DKA) associated with sodium glucose transporter (SGLT) inhibitors.
lycemic diabetic ketoacidosis (DKA) associated with sodium glucose transporter (SGLT) inhibitors. Pre-
cipitating factors are also included. Abbreviations—FFA: free fatty acids, Bl.: blood.
Precipitating factors are also included. Abbreviations—FFA: free fatty acids, Bl.: blood.

SGLT2inhibitors
SGLT2 inhibitorsare areapproved
approved forfor type
type 1 diabetes
1 diabetes in Europe
in Europe and and
Japan,Japan,
with with off-
off-label
label use in type-1 diabetes in the US [49]. Due to mild hyperglycemia
use in type-1 diabetes in the US [49]. Due to mild hyperglycemia associated with SGLT associated with
SGLT
use, DKAuse,diagnosis
DKA diagnosiscan be can be missed
missed or delayed.
or delayed. Therefore,
Therefore, there isthere is afor
a need need for patients
patients to be
to be educated
educated regardingregarding
how tohow to recognize
recognize and reduceand reduce
elevated elevated ketone Development
ketone levels. levels. Develop- of
ment of symptoms
unusual unusual symptoms
of physicalofsickness
physical sickness
such suchvomiting,
as nausea, as nausea, vomiting,
abdominal abdominal
pain, fatigue
pain,
or fatigue
malaise in or malaise
these in these
patients shouldpatients should beRecognizing
be recognized. recognized. Recognizing
these symptoms theseshould
symp-
prompt measuring ketones in the blood (preferred) or urine to evaluate for DKA [50].for
toms should prompt measuring ketones in the blood (preferred) or urine to evaluate A
DKA [50].
number of A numberhave
protocols of protocols have beentodeveloped
been developed treat DKAtofor treat DKA for who
individuals individuals who
are treated
are treated
with SGLT2 with SGLT2One
inhibitors. inhibitors.
of them Oneis theofSTOP
themDKA is theprotocol
STOP DKA protocol (Symptomatic
(Symptomatic to stop SGLT
to stop SGLT
inhibitor, inhibitor,
Test ketones andTest ketones
glucose, andingestion
Oral glucose, of Oral ingestion
fluids of fluids and Protocol
and carbohydrates, carbohy-
drates, Protocol
instructions instructions
for insulin for insulin and [50].
and carbohydrates) carbohydrates)
STOP DKA [50]. STOPmild
defines DKAketonemia
defines mild as
ketonemia
<1.0 mmol/L as vs.
<1.00.6mmol/L
mmol/L vs. in
0.6most
mmol/L in other
of the most of the otherSGLT2
protocols. protocols. SGLT2should
inhibitors inhibitorsbe
should be
stopped as stopped
soon as any as soon as anyofsymptoms
symptoms of physical
physical illness illness (e.g.,
(e.g., lethargy, losslethargy, loss
of appetite, of ap-
nausea,
or abdominal
petite, nausea,pain) or elevatedpain)
or abdominal ketoneor levels
elevatedare ketone
detected and resumed
levels are detectedonlyandafterresumed
ketone
levels return
only after to normal.
ketone levelsGenerally,
return topatients
normal.should consume
Generally, carbohydrates
patients and givecarbohy-
should consume insulin
in an attempt
drates and giveto lower
insulinketone
in anlevels.
attempt If levels
to lowerof ketones
ketone are elevated
levels. thenofthe
If levels STICHare
ketones (STop
ele-
SGLT
vatedinhibitor, Insulin (STop
then the STICH administration, Carbohydrate
SGLT inhibitor, Insulin consumption,
administration,Hydration)
Carbohydrate protocol
con-
should
sumption,be initiated
Hydration) [51].protocol
After stopping
should SGLT2 inhibitor
be initiated [51].therapy, patientsSGLT2
After stopping shouldinhibitor
receive
rapid-
therapy, patients should receive rapid- or short-acting insulin and consume 15–30such
or short-acting insulin and consume 15–30 g of rapidly absorbed carbohydrate g of
as juice, absorbed
rapidly soda, or milk along with
carbohydrate such300–500
as juice,mLsoda,of or
fluid.
milkThe alonglevel
withof300–500
ketonesmL should be
of fluid.
monitored
The level of every
ketones3–4 h until resolution
should be monitored backevery
to normal. Comparatively,
3–4 h until resolution backthe STOP DKA
to normal.
protocol provides
Comparatively, thespecific
STOP DKA insulin recommendations
protocol provides specific based on blood
insulin glucose and ketone
recommendations based
levels,
on bloodwhile the STICH
glucose protocol
and ketone recommends
levels, while thethat STICHpatients take recommends
protocol 1.5 times theirthatusual dose
patients
of insulin.
take 1.5 times their usual dose of insulin.
If symptoms of physical sickness or high ketone levels (>3.0 mmol/L) persist, patients
should pursue medical help and hospitalization. Standard DKA treatment protocols are
followed as described earlier (Section 2.1), with careful monitoring of ketone levels and
Endocrines 2022, 3 808

allowing patients to consume carbohydrates. Of note, DKA related to SGLT2 inhibitors

may result in glycosuria for at least 3 additional days after hospital admission in patients
with either type 1 or type 2 diabetes [52], suggesting that the SGLT2 inhibitors require more
time to clear after stopping the medication. Future studies are warranted to provide further
information for DKA management in patients with SGLT2 inhibitors.

3.5. DKA in Patients with Congestive Heart Failure (CHF)

Similar to patients with chronic kidney disease, specific population considerations
should be given to patients with CHF [10]. These patients tend to retain fluids; therefore,
volume resuscitation should be carefully titrated in patient with CHF. A conservative fluid
resuscitation is crucial in the management of the DKA patient with CHF. Minimal fluid
bolus, such as (250–500 mL) is recommended in hypovolemic patients with subsequent
monitoring for signs/symptoms of volume overload. Intravenous insulin is the main stay
to improve acidosis by preventing ketone production [25]. Further, urine output monitoring
is an important step in patients with hyperglycemic crises.
Recently, the SGLT2 inhibitors demonstrated significant cardiorenal benefits and they
are now approved to reduce CV events/death, heart failure hospitalization [53], even in pa-
tients with no diabetes history. There is a higher possibility to exhibit euglycemia DKA [54].
Hence, similar consideration for these patients with CHF to be educated regarding how to
recognize and treat euglycemic DKA and manage ketone levels as described earlier.

3.6. DKA and Insulin Pump Users

Early studies showed that insulin pump users commonly known as continuous subcu-
taneous insulin infusion are more prone to development of DKA [55]. Insulin pump users
rely on rapid or short acting insulin, but not the long acting insulin. Hence, if the pump
fails or the canula blocked or dislodged, the insulin delivery will be stopped and blood
glucose levels rise triggering ketoacidosis to develop rapidly. The prevalence of DKA in
users of insulin pump therapy is decreasing most likely due to significant improvements
of technology [56]. Of note, impact of patient training and education is most evident by
improved glycemic control, and fewer of episodes of hypoglycemia and DKA after 1-year
of pump use [56].
For the management of possible DKA associated with insulin pump therapy, first the
pump-related problem should be identified and rectified. For example, re-calibrating the
pump, re-siting the cannula, and changing the tubing should be part of patient education.
Switching insulin pump to alternative insulin such as an intravenous infusion can be useful
because of altered insulin absorption and tissue perfusion [57]. If a pump user develops
DKA, insulin pump should be immediately discontinued and standard DKA treatment
started. Once DKA has resolved, insulin pump therapy can be restarted at the patient’s
usual basal rate along with transitional dose of intravenous insulin infusion until a bolus is
given via pump [58].

3.7. DKA in Patients with COVID-19

During the SARS-CoV-2 commonly referred to as COVID-19 pandemic, it has been
established that diabetes is a frequent comorbidity and DKA has been documented in
patients with COVID-19 in both patients with T1D and patients with T2D [59]. There is
evidence that support a possible bidirectional relationship between SARS-CoV2 infection
and diabetes, with infection being associated with worsening of hyperglycemia in preexist-
ing diabetes and new-onset hyperglycemia [60]. Nevertheless, there are insufficient data to
determine if DKA is more prevalent in COVID-19 and if the SARS-CoV-2 virus poses an
increased risk over other severe infectious diseases. To date, only 1 study has described
the prevalence of acidosis and ketoacidosis in 658 hospitalized patients with confirmed
COVID-19 [61]. In the same study, patients with ketosis were about twice as likely to
have diabetes at baseline, and the 3 individuals who developed DKA had underlying
diabetes (1 with T1D, 2 with T2D). Ketosis was also associated with higher mortality. A
Endocrines 2022, 3 809

more recent metanalysis showed that DKA is not uncommon in COVID-19 patients with
diabetes mellitus and results in a mortality rate of 25.9% [62]. The major determinants of
mortality in DKA patients with COVID-19 infection are pre-existing diabetes mellitus type
2, older age [≥60 years old], male gender, BMI ≥ 30, blood glucose level > 1000 mg/dL,
and anion gap ≥ 30 mEq/L [62].
One of the important and common finding among COVID-19 patients is that severe
disease is accompanied by high levels of inflammatory markers, which are also elevated
in the setting of DKA independent of accompanying illness. IL-6 has been highlighted as
likely playing a role in a maladaptive immune response to the SARS-CoV-2 virus and has
been proposed as a possible treatment target [63]. Interestingly, IL-6 has also been also
found to be elevated in patients with DKA and is thought to be mostly a driver of ketosis
rather than a result [64]. Future studies are warranted to explore the role of inflammation
in DKA and COVID-19 in relation to clinical outcomes.

4. Summary and Conclusions

DKA is the most common hyperglycemic emergency and causes the greatest risk
for mortality in patients with diabetes mellitus. Epidemiological studies showed more
prevalence of DKA among patients with type-1 diabetes, yet almost a third of the cases
occur among those with type 2 diabetes. DKA is characterized by hyperglycemia, metabolic
acidosis and ketosis. Patients with diabetes in general, and those with type-1 diabetes
would benefit from being educated to recognize and reduce early signs of DKA. Standard
management of DKA requires hospitalization and involves aggressive intravenous fluids,
insulin therapy, electrolyte replacement. It is also clear that special patient population
requires additional tweaking of DKA management as detailed above. With the wide use
of SGLT2 inhibitors due to cardio- and reno-protective effects, incidence of euglycemic
DKA has been increasing. Euglycemic DKA patients present with milder hyperglycemia,
which makes early detection and intervention harder. Detection of ketonemia is the key for
DKA risk mitigation along with consumption of oral carbohydrates and fluid and insulin
for successful management. Future studies are warranted to continue to streamline and
provide exact tweaks on the management of DKA in special patient population.

Funding: Self-funded.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: Figures were created by BioRender.com, the online software.
Conflicts of Interest: ABE is listed as an inventor on patents relating to targeting p75NTR , which are
assigned to the VA Medical Center. ABE is the Founder of Nour Therapeutics LLC with interest to
develop therapeutics for diabetic complications.

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