European Journal of Internal Medicine xxx (xxxx) xxx

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review Article

Management of diabetic ketoacidosis

Leonid Barski a, *, Evgeny Golbets a, Alan Jotkowitz b, Dan Schwarzfuchs c
a
Department of Internal Medicine F, Soroka Univerity Medical Center, P.O.Box 151, Beer–Sheva 84101, Israel
b
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel
c
Department of Emergency Medicine, Soroka University Medical Center, Beer–Sheva, Israel

A R T I C L E I N F O A B S T R A C T

Keywords: Diabetic ketoacidosis (DKA) is an acute life-threatening emergency in patients with diabetes, it can result in
Diabetic ketoacidosis serious morbidity and mortality. Management of DKA requires reversing metabolic derangements, correcting
Management of DKA volume depletion, electrolyte imbalances and acidosis while concurrently treating the precipitating illness.
DKA treatment
There are still controversies regarding certain aspects of DKA management. Different society guidelines have
inconsistencies in their recommendations, while some aspects of treatment are not precise enough or have not
been thoroughly studied. These controversies may include issues such as optimal fluid resuscitation, rate and
type of Insulin therapy, potassium and bicarbonate replacement. Many institutions follow common society
guidelines, however, other institutions either develop their own protocols for internal use or do not routinely use
any protocols, resulting in inconsistencies in treatment and increased risk of complications and suboptimal
outcomes. The objectives of this article are to review knowledge gaps and controversies in the treatment of DKA
and provide our perspective on these issues.
Moreover, we believe that special patient factors and comorbidities should receive more careful attention and
consideration. Factors like pregnancy, renal disease, congestive heart failure, acute coronary syndrome, older
age, use of sodium-glucose cotransporter-2 (SGLT2) inhibitors and site of care all impact the treatment approach
and require tailored management strategies.
However, guidelines often lack sufficient recommendations regarding specific conditions and comorbidities,
we aim to address unique circumstances and provide an approach to managing complex patients with specific
conditions and co-morbidities. We also sought to examine changes and trends in the treatment of DKA, illuminate
on aspects of latest research with a perspective towards future developments and modifications.

1. Introduction life-threatening iatrogenic complications such as hyper/hypokalemia,

Diabetic ketoacidosis (DKA) is an acute life-threatening emergency
in patients with diabetes, characterized by hyperglycemia, metabolic
acidosis and ketonemia, it can result in serious morbidity and mortality
[1]. Management of DKA requires reversing metabolic derangements by
correcting volume depletion and electrolyte imbalances and adminis­
tering insulin to correct acidosis while concurrently treating the
precipitating illness [1]. Suboptimal management may lead to
hypoglycemia, cerebral edema, and cardiac arrhythmias.
DKA occurs most often in patients with type 1 diabetes; however
patients with type 2 diabetes are also susceptible to DKA under stressful
conditions. Severity of presentation and DKA duration are similar in
both type 1 and type 2 diabetes, suggesting that the same clinical
management protocol is equally effective, however patients with type 2
diabetes have longer hospital stays [2,3].
Although mortality rates for diabetic ketoacidosis (DKA) have been

Abbreviations: DKA, diabetic ketoacidosis; ADA, The American Diabetes Association; EASD, European Association for the Study of Diabetes; BES, balanced
electrolyte solutions; normal saline, 0.9% sodium chloride; RL, ringer lactate; CII, continuous insulin infusion; RII, regular insulin infusion; ICU, intensive care unit;
GM, Glucommander™; EMR, electronic medical record; BG, blood glucose; FAIAs, fast-acting insulin analogues; LAI, long-acting insulins; LOS, length of stay; ED,
Emergency Departments; HDU, high dependency unit; HF, heart failure; ACS, acute coronary syndrome; SGLT2, sodium-glucose cotransporter-2; ACE, angiotensin-
converting enzyme; ARB, angiotensin receptor blocker; GLP-1, glucagon-like peptide-1; AKI, acute kidney injury; ESKD, end-stage renal disease; HbA1C, hemoglobin
A1C (glycated hemoglobin).
* Corresponding author.
E-mail address: lbarski@bgu.ac.il (L. Barski).

https://doi.org/10.1016/j.ejim.2023.07.005
Received 27 April 2023; Received in revised form 27 June 2023; Accepted 3 July 2023
0953-6205/© 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Leonid Barski et al., European Journal of Internal Medicine, https://doi.org/10.1016/j.ejim.2023.07.005
L. Barski et al.
steadily declining in the USA with a current in-hospital fatality rate of
0.4%, trends have shown that DKA hospitalization rates have dramati­
cally increased by 54.9% which reflects a significant healthcare burden
[4].
There are still controversies regarding several aspects of DKA man­
agement [4–6]. Many institutions follow common guidelines such as The
American Diabetes Association (ADA), the European Association for the
Study of Diabetes (EASD), updated guidelines from the Joint British
Diabetes Society for Inpatient Care. However, other institutions either
develop their own protocols for internal use or do not routinely use any
protocols, resulting in inconsistencies in treatment, risk for suboptimal
treatment and thus an increased risk of complications and mortality
[5–11].
The objectives of this article are to review knowledge gaps and
controversies in the treatment of DKA and provide our perspective on
these issues. We also sought to examine changes and trends in the
treatment of DKA with a perspective on future developments.
With the extension of life expectancy and improvements in diagnosis
and treatment many patients present with unique conditions and
comorbidities, which necessitate special attention to specific clinical
factors and treatment modification. However, guidelines often lack
sufficient recommendations regarding specific conditions and comor­
bidities. Factors like pregnancy, renal disease, congestive heart failure,
acute coronary syndrome, older age, use of sodium-glucose cotrans­
porter-2 (SGLT2) inhibitors and site of care all impact treatment and
require tailored management strategies. We aim to address these unique
circumstances and provide an approach to managing complex patients
with specific conditions and co-morbidities.
2. Fluid resuscitation
Along with insulin therapy, intravenous fluid administration to
expand intravascular, interstitial, and intracellular volume is a key
component of the acute management of DKA [7–10].
Current guidelines suggest the use of 0.9% sodium chloride solution
(normal saline) as the preferred resuscitation fluid in the management of
DKA [5–7,9,10]. However, balanced electrolyte solutions (BES) have
been proposed as an alternative due to a lower propensity to cause
hyperchloremic metabolic acidosis [4,12]. The American Diabetes As­
sociation (ADA) guidelines recommends initial treatment with 1.0–1.5 L
of normal saline over one hour, followed by continuous infusion with
either normal saline or 0.45% saline depending on serum sodium con­
centration [7]. Similarly, Diabetes Canada recommends initial volume
resuscitation with NS and suggests varying rates of infusion tailored to
the volume deficit [10]. The guidelines created by the Joint British
Diabetes Societies Inpatient Care Group acknowledge the paucity of
evidence for the use of one type of fluid over another and include a
statement that balanced electrolyte solutions (BES) can be used. None­
theless, they recommend the use of normal saline in the acute man­
agement of DKA, given the degree of historical experience with its
administration [5,6,13].
In recent years, much attention has focused on selecting the appro­
priate crystalloid fluid for acute resuscitation purposes [14]. Normal
saline, composed of equal concentrations of sodium and chloride, is an
inexpensive and commonly used fluid in the acute setting. However, the
chloride concentration in normal saline (154 mmol/L) is higher than
that in human plasma (94–111 mmol/L), which can cause a non-anion
gap hyperchloremic metabolic acidosis, especially when administered
in large volumes [15–19]. Moreover, accumulating evidence suggests
that normal saline may increase the risk of acute kidney injury thus
impairing patient recovery [14,15,20].
BES, including Ringer lactate (RL) and Plasma-Lyte A (Baxter Inc),
are isotonic crystalloids that have more similar composition to human
plasma. In addition to sodium chloride, BES contains potassium, cal­
cium, and lactate. Although normal saline and BES are both considered
isotonic, the former has a higher osmolality (308 mOsm/L vs LR 273
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European Journal of Internal Medicine xxx (xxxx) xxx
mOsm/L), lower pH (5.5 vs RL 6.6), and a higher chloride concentration
(154 mEq/L vs RL 109 mEq/L), which often associates with the devel­
opment of hyperchloremic metabolic acidosis [4–6,12,16–19].
Several small studies of adults with DKA revealed that fluid admin­
istration of BES was associated with faster resolution of DKA compared
to normal saline. The authors concluded that these results suggest that
BES may be preferred for acute management of DKA [4,20].
Balanced electrolyte solutions are more expensive than normal saline
and have several potential adverse effects. For example, the buffers
present in these solutions are converted to bicarbonate upon infusion,
which can lead to metabolic alkalosis [14,20,21]. The infusion of
Ringer’s lactate may also cause elevations in potassium and lactate
serum levels, with a greater concern for the latter in patients with liver
failure [14,22–24]. The lactate may be converted to glucose which may
exacerbate hyperglycemia [14,24], while acetate has been associated
with altered myocardial activity and impaired hemodynamics [14,25].
Finally, administration of large volume crystalloid fluids that are more
hypotonic in comparison to normal saline may increase the risk of ce­
rebral edema, especially relevant in pediatric and elderly patients [14,
26].
Thus, the question of crystalloid fluid choice in patients with DKA
remains open. The clinician ought to weigh the association between
normal saline and the development of hyperchloremic metabolic
acidosis, as well as the possibility of kidney injury, with the potential
side effects of BES and the limited data and experience supporting their
use a should also to be considered.
We believe that the selection of crystalloids for fluid resuscitation
should be personalized based on the patient’s individual characteristics,
such as clinical and laboratory data and comorbidities. Future ran­
domized controlled trials are needed to make better evidence-based
recommendations, but in our opinion, the more favorable physiolog­
ical characteristics of BES are likely to lead to its wider acceptance and
use.
3. Insulin therapy
Insulin therapy is a crucial component of DKA management as it
reduces hepatic gluconeogenesis and suppresses ketogenesis [27].
Continuous insulin infusion (CII) is historically recommended and
widely accepted as standard of care for the treatment of DKA [7,9,10].
Intravenous regular insulin infusion (RII) has a rapid (15 min) onset of
action and allows for titratable drug administration to match changing
glucose levels [10]. Insulin rates approximating 0.1 unit/kg/h, are
recommended during this initial stage of management by various in­
ternational guidelines [5–7,9,10]. Treatment usually resolves hyper­
glycemia before acidosis; however, continued ketoacid suppression
requires a careful balance of insulin and dextrose infusions to prevent
hypoglycemia. However relatively little attention has been given by
international guidelines who offer conflicting recommendations [5,6].
The insulin rate reduction to 0.05 unit/kg/h when initiating dextrose
was the ‘most important’ protective factor against hypoglycemia,
though no data were provided to support it [5,6,28]. This rate reduction
is not associated with a delay in resolution of anion gap acidosis, an
excess of rebound hyperglycemia or a prolongation of intensive care unit
(ICU) stay [28]. The incidence of hypoglycemia due to intravenous in­
sulin in DKA treatment has not been well studied, but 35% incidence of
hypoglycemia was described with standard care of intravenous RII [28].
Insulin use causing hypoglycemia or spontaneous hypoglycemia are
associated with increased mortality among hospitalized patients [29,
30].
Several options are available for improving the use intravenous in­
sulin therapy for patients with DKA. One of these is computer-based
algorithms of CII. It is not known, however, if computer-based algo­
rithms are superior to standard protocols. Furthermore, there are no
intravenous protocols that have been specifically validated for the
treatment of DKA and guidelines do not allude to using a specific
L. Barski et al.
protocol over another. In a one retrospective study, authors compare a
computer decision support system (Glucommander™ (GM)) for insulin
dosing, versus conventional protocol. Glucommander™ (GM) is a soft­
ware that uses algorithms to provide dosing recommendations for
intravenous and subcutaneous insulin. It takes into account clinical
variables and integrates with electronic medical record (EMR) systems.
The GM therapy group was associated with a lower hypoglycemia
rate with a faster normalization of bicarbonate levels. The initial blood
glucose (BG) was significantly higher in the GM group but the time for
resolution of DKA was faster with GM [31]. We expect to see more de­
cision support systems used in the future; their efficaciousness will need
to be demonstrated through prospective trials. In our opinion, such
systems have the potential to reduce complications, help medical teams,
and minimize healthcare costs.
In the past two decades, fast-acting insulin analogues (FAIAs): in­
sulin lispro, insulin aspart, insulin glulisine and fast-acting insulin aspart
(faster aspart), have been developed. Subcutaneous administration of
these FAIAs has an onset of action of ≈5–15 min, a peak action of 1–3 h
and duration of action of 3–5 h [32]. These pharmacological properties
suggest that subcutaneous FAIAs may produce clinical benefits compa­
rable with intravenous RII in DKA and may be useful to manage some
DKA cases outside the ICU [6,33,35]. Previous investigations comparing
the effects of subcutaneous FAIAs versus intravenous RII for treating
mild-to-moderate DKA are inconclusive [33,35]. Subcutaneous
long-acting insulins (LAI): insulin glargine, insulin detemir and insulin
degludec, provides a basal insulin component, and its concomitant
administration with intravenous RII in DKA accelerates ketoacidosis
resolution and prevents rebound hyperglycaemia, especially during
transition from intravenous RII to subcutaneous insulin. Early insulin
glargine use in DKA was safe and associated with a trend towards faster
DKA resolution and a shorter length of stay (LOS) [6,33,34,36,37]. In a
recent large retrospective pre- and post- cohort study (n = 7989),
combination therapy with subcutaneous insulin lispro and subcutaneous
insulin glargine reduced rates of ICU admission and 30-day hospital
readmission with no increase in hypoglycemia or 30-day mortality rates
when compared with intravenous RII [38]. The use of subcutaneous
FAIAs in the treatment of DKA can be safe, provided that there is
appropriate patient selection. Potential candidates include those who
are alert, have few or no comorbidities and are diagnosed with mild to
moderate DKA. Factors that affect absorption into the bloodstream,
including obesity, the use of vasoconstricting drugs, and blood pressure,
are important to consider in identifying the right patients. Currently,
there is an underutilization of this option that could potentially reduce
complications and healthcare costs.
4. Potassium replacement
Patients with DKA usually present with significant potassium defi­
ciency. It is caused by osmotic diuresis, excretion of potassium ketoacid
anion salts, secondary hyperaldosteronism, and gastrointestinal loss.
However, patients often present with normal or even elevated potassium
concentrations due to intracellular shift [39]. The current recommen­
dations of all guidelines determine the amount of potassium that should
be supplemented depending on blood potassium levels [5–7,9,10].
The administration of insulin stimulates the activity of Na+/K+-
ATPase, which results in active uptake of potassium by cells, leading to
intracellular shift of potassium and hypokalemia. During DKA treat­
ment, the serum potassium level decreases rapidly and can result in life
threatening complications, such as bradycardia, ventricular fibrillation,
or acute respiratory failure [39,40]. Therefore, continuous monitoring
of blood potassium levels and adherence to potassium replacement
protocols is crucial [5–7,9,10,39].
5. Bicarbonate replacement
Severe cases of DKA (pH ≤ 7.00, bicarbonate level ≤ 10.0 (mEq/L),
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European Journal of Internal Medicine xxx (xxxx) xxx
anion gap > 12, and altered mental status) carry an ominous prognosis
[41]. The acid-base status has received great attention, due to the po­
tential of bicarbonate-based therapy, however it’s use remains
controversial.
Severe acidemia has been associated with impaired hemodynamics,
including vasodilation, and decreased cardiac output in animal studies
[41]. Studies involving large case series of patients with severe DKA,
showed little differences were found in clinical outcomes when
considering the degree of acidosis as an isolated variable [41,42]. In one
study that included 18 patients with severe DKA, the rapid recovery that
characterized these patients, regardless of whether they received bi­
carbonate therapy, provides additional support for the idea that the
degree of acidosis does not determine the outcome of DKA. The authors
suggest that the severity of acidemia may influence mortality in children
with type 1 diabetes, but this does not appear to be the case in adults
with type 2 diabetes and concluded that hydration state or sepsis are
more important to hemodynamics than the severity of acidemia [41].
Although, use of intravenous bicarbonate may be considered for
patients with a pH less than 6.9 according to the ADA, the impact of this
therapy is unclear [7,27]. In one study adult patients with severe DKA
and initial pH less than 7.0, were stratified into two groups based on
receipt of intravenous bicarbonate. The authors observed no significant
difference in time to resolution of acidosis or time to hospital discharge
between patients who received intravenous bicarbonate compared with
those who did not. There was no significant difference in hours of
continuous insulin infusion or potassium requirements [43].
Owing to the possible harm and lack of evidence for clinical benefit,
the use of bicarbonate should be discouraged and limited to rare and
critical cases when the pH is below 6.9.
6. Special considerations
6.1. Site of treatment and hospitalization. Management of patients with
DKA outside of the intensive care (ICU) unit
DKA is a life-threatening state; hence, it is essential that patients are
managed in the most appropriate setting. To meet this goal, scientific
societies worldwide have developed recommendations and step-by-step
algorithms for DKA treatment. Emergency Departments (EDs) are typi­
cally the initial site of diagnosis, treatment initiation and stabilization.
When possible, intubation should be avoided in the DKA patients.
However, the comatose DKA patient, especially if vomiting, requires
intubation. In intubated DKA patients, maintenance of hyperventilation
is important for prevention of worsening of acidosis.
In general, it is recommended that DKA will be treated with intra­
venous RII in the ICU or high dependency unit (HDU). The treatment
requires intensive monitoring of vital signs, frequent blood tests, use of
intravenous insulin with increased risk of life-threatening complications
(e.g., severe electrolyte disturbances, pulmonary edema, cerebral coma)
[7,9,10,44,45]. The ICU and HDU are scarce and expensive resources
that are often critically strained [46]. Thus, incorporating new man­
agement strategies can enable emergency situations that were tradi­
tionally treated in the ICU/HDU to be managed outside of these settings
[33,47]. DKA has been identified as suitable for treatment in a
non-ICU/HDU setting if the right patient selection, appropriate treat­
ment, and monitoring can be put in place [48,49].
It has been demonstrated that DKA patients can be safely treated in a
non-ICU environment, such as a general ward or an emergency
department [47,50]. In several trials, treatment of selected DKA patients
in a non-ICU setting was not associated with increased mortality or
longer time to DKA resolution and was found to be more cost effective
when compared to patients treated in the ICU [47,50]. In low ICU
resource environments, an ICU physician prioritizes ICU bed allocation
based on the cases present in the medical center at any given time.
Previous studies conducted in ICU restricted environments have
demonstrated that both short and long-term survival rates were
L. Barski et al.
associated with ICU admission [47,50,51].
Some medical centers have resources for intravenous RII and the
ability for monitoring patients with DKA in medical ward departments,
but other medical centers may successfully use subcutaneous FAIAs.
Furthermore, subcutaneous LAI provides a basal insulin component, and
its concomitant administration with intravenous RII accelerates ketoa­
cidosis resolution and prevents rebound hyperglycemia, thus may
facilitate treatment in non-ICU setting [33,34,47–49].
Therefore, in our opinion, in a setting of limited ICU capacity, DKA
treatment does not necessarily require admission to the ICU. Our pre­
vious results highlight the importance of including step-down units
when devising local protocols for care of these patients [47]. We believe
that in the future, more patients will be able to receive treatment in
general wards, in an ED setting or even through home care services with
remote monitoring. More prospective research is needed in this area,
with an emphasis on appropriate patient selection, with attention given
not only to the severity of DKA but also to the triggers and underlying
comorbidities.
6.2. Management of DKA in patients with CHF and ACS
The impact of heart failure (HF) on management of patients with
DKA has limited data and no clear recommendations exist in current
guidelines. Moreover, the dramatic nature of hospitalizations for DKA
can sometimes lead clinicians to overlook the potential influence of a
patient’s history of HF on the outcomes of their DKA episode [52]. It has
been shown that a history of HF is associated with increased risks for
in-hospital mortality among patients admitted for DKA. Additionally,
such patients are more prone to experiencing extended LOS and have a
higher likelihood of being transferred to a nursing home or similar
short-term healthcare facilities [52]. Current guidelines for DKA provide
no specific recommendations on the management of patients with a
history of HF [7,9,10]. The standard approach to the management of
DKA includes vigorous hydration, insulin therapy and electrolyte
repletion. Carefully designed studies are needed to identify the risk
factors and mechanisms that contribute to poor outcomes of HF related
hospitalizations of DKA. Knowledge of such factors could guide appro­
priate strategies for optimization of care and improve outcomes. The
management of patients with medical history of HF that develop DKA
must be very careful, particularly with cautious and closely monitored
fluid infusion. Excessive fluid load may cause decompensation of HF. In
managing patients with HF who develop DKA one should consider
stopping or decreasing the dose of all medications that could harm the
patient’s status. For example, SGLT2 inhibitors, GLP-1 agonists, ACE
inhibitors, ARBs, and diuretics.
The deleterious impact of a history of HF on clinical outcomes of DKA
might extend to patients with subclinical HF as well. In future studies, it
is important to explore this notion by analyzing biomarkers such as BNP
along with echocardiographic data including bed side echocardiography
as predictors of clinical outcomes. Such data could assist in the risk
stratification and development of management strategies for patients
with subclinical HF who are hospitalized for DKA. Until then, the
development of expert guidelines would be helpful to guide clinicians in
the management of DKA in these patients. [52].
DKA is associated with an increased risk of subsequent major adverse
cardiovascular events [53]. Myocardial infarction is a rare but
well-known cause of diabetic decompensation. ACS and DKA are two
conditions that can trigger each other, and it is often difficult to know
which condition appears first. The mortality rate is significantly greater
for the DKA patients with elevated troponin compared with the patients
with normal troponin levels [54]. In addition, the elevated troponin
level is a predictor of poor outcome in patients admitted to intensive
care for clinical conditions other than ACS [54]. Notwithstanding that
DKA is a known cause of troponin increase without ACS, it stands to
reason that a troponin elevation in a DKA patient should always be
considered as an ACS until proven otherwise [53,55]. Therefore, all
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European Journal of Internal Medicine xxx (xxxx) xxx
patients with elevated troponin and suspected ACS must undergo
comprehensive investigation with echocardiography and coronary
stratification.
6.3. Management of DKA in patients with type 2 diabetes treated with
sodium-glucose cotransporter-2 (SGLT2) inhibitors
Sodium-glucose cotransporter-2 (SGLT2) inhibitors were approved
in 2013 for the treatment of adults with type 2 diabetes mellitus. They
have been shown to reduce the risk of myocardial infarction, cardio­
vascular mortality, heart and renal failure [56].
In adults with type 2 diabetes, SGLT2 inhibitors were found to in­
crease the risk of DKA (and euglycemic DKA), in observational studies
and randomized clinical trials [56]. In addition, patients with DKA and
SGLT2 inhibitors treatment had longer time to resolution than type 1
diabetes patients. The mechanisms by which SGLT2 inhibitors are
associated with ketoacidosis are not fully understood. It may be related
to the insulin-independent reduction of blood glucose through increased
urine glucose excretion, which allows for glycemic control with
concomitant reduction in insulin requirement. Moreover, the potential
increase in glucagon secretion leads to a decrease in the
insulin-to-glucagon ratio and promotes ketogenesis [57,58].
Placebo-controlled trials in type 1 diabetes have consistently shown
an increased risk of DKA associated with the use of SGLT2 inhibitors. As
a result, the FDA has not approved their use for the treatment of type 1
diabetes [57,58].
Patients with a longstanding history of type 2 diabetes mellitus and
poor glucose control appear to have a higher susceptibility to develop­
ment of DKA, other risk factors include pancreatic insufficiency, alcohol
dependence and ketogenic diets [56,57,59]. It is therefore advisable to
avoid these medications until risk factors are appropriately addressed.
To further minimize the risk of euglycemic DKA with SGLT2 inhibitors,
it is advised to discontinue these drugs for at least three to five days
before planned surgical procedures, during periods of acute illness, or
prolonged fasting [59].The absence of excessive hyperglycemia can
delay recognition of the problem by both the patients and the clinician.
Blood gasses and ketones should be obtained in any patient with nausea,
vomiting, or malaise while taking SGLT2 inhibitors. Once diagnosed,
management of euglycemic DKA is straightforward and similar to the
management of DKA [60]. The mainstay of treatment involves rapid
correction of dehydration using intravenous fluids and correction elec­
trolyte abnormalities [60,61]. The second most important step in the
management is the use of an insulin drip along with a dextrose con­
taining solution until the anion gap, and bicarbonate levels normalize
[62]. Increased glucose administration using higher percentages of
dextrose (10% or 20%) are required to facilitate the concomitant
administration of the relatively large amounts of insulin that are needed
to correct the severe acidosis in these patients [7,60,63].
6.4. Management of DKA in pregnancy
The pathophysiology of DKA in pregnancy has its own characteris­
tics. Pregnancy is characterized by insulin resistance, accelerated star­
vation and respiratory alkalosis especially in the second and third
trimesters [64]. The most important endocrine changes affecting insulin
resistance in pregnancy are increased levels of estrogen, progesterone,
cortisol and TNFα [64–66]. On the other hand, the gradual decline in
insulin sensitivity is considered to be a physiological mechanism helping
to provide glucose to the fetus. Increased alveolar ventilation in preg­
nant women gives rise to a state of respiratory alkalosis that is overcome
by means of an increased renal excretion of bicarbonate. These changes
can trigger the onset of ketoacidosis at lower glycemic levels compared
to non-pregnant patient [60,64,66–68].
DKA during pregnancy can be fatal for the fetus, with fetal demise
incidence ranging from 15% to 60%. Maternal ICU admission and higher
serum osmolality during the DKA event were associated with increased
L. Barski et al.
risk of fetal demise [64,67]. It is important to emphasize that some
patients had recurrent vomiting and therefore a co-existing starvation
state. The low blood glucose levels are associated with an increase in
glucose uptake by the fetus, as well as a decrease in hepatic glucose
production [64].
Early diagnosis and treatment including correction of all existing
disturbances are crucial for the successful management of the pregnant
patient. Treatment must be started immediately, maternal metabolic
and electrolyte disturbances if not corrected rapidly may be life
threatening for the fetus. Prevention, early recognition, immediate
hospitalization, and aggressive management remain the cornerstones of
DKA management in pregnancy [66].
6.5. Management of DKA in elderly patients
Elderly DKA patients have higher risk for hospital mortality in
addition to increased risk for prolonged hospitalization, long term
mortality and higher chances of DKA recurrences [69,70].
Elderly patients present with unique problems with multiple clinical
conditions, that may mask the diagnosis of DKA and delay treatment
[69,70].Both comorbidities and severe precipitants such as sepsis,
myocardial infarction and stroke are more prevalent among the elderly
[70]. A Mixed state of ketoacidosis and hyperosmolar state is observed
in 30% of presentations for diabetic hyperglycemic emergencies [71]. In
addition, acute kidney injury (AKI) is a frequent accompaniment of DKA
in elderly patients. Glucosuria caused by osmotic diuresis aggravates
dehydration and ultimate decline in renal function. This can lead to
impaired metabolism of many drugs, all drug therapy, including insulin,
should be reassessed [69].
Not only treatment of metabolic abnormalities of DKA, but also
careful attention to comorbidities and precipitation factors are necessary
in this population. The alertness of physicians to DKA in the elderly
population, timely diagnosis, proper treatment, and prevention are
cornerstones of care.
6.6. Management of DKA in patients with end-stage renal disease and
patients on hemodialysis
There is limited evidence to guide management in patients with end-
stage renal disease (ESRD) on chronic hemodialysis admitted with dia­
betes ketoacidosis [72]. Nevertheless, in the USA up to 7.5% of patients
admitted with DKA had ESRD listed as a comorbidity [73]. The diagnosis
and management of DKA in patients with ESRD is challenging due to
alterations in glucose metabolism, insulin sensitivity and altered renal
clearance of anti-diabetic medications [72,74,75]. There is scarce evi­
dence to guide appropriate volume replacement, insulin and potassium
therapy in patients with DKA and ESRD [72]. In one study, it was re­
ported that ESRD in patients with DKA was associated with higher
adjusted risk for all-cause readmissions, with most readmissions occur­
ring within 2 weeks after discharge [73].
Galindo et al. reported significant metabolic and clinical outcome
differences in patients with DKA and ESRD compared with patients with
preserved renal function [72]. The ESRD group had two-fold higher
glucose levels and higher potassium concentration. Compared with pa­
tients with preserved renal function, a two-fold higher rate of hypo­
glycemia and a 10-fold higher rate of volume overload was observed. In
addition, patients with ESRD had higher healthcare resource utilization,
including longer LOS and hospitalization costs [72].
The higher rates of complications observed suggest that common
treatment guidelines may not be applicable to patients with ESRD [6,72,
75]. The higher rates of volume overload suggest that current recom­
mendations for intravenous fluids resuscitation should be examined. The
main mechanism for the profound fluid and electrolyte depletion in DKA
is osmotic diuresis, which is not present in dialysis patients [72,76]. One
study reported that the degree of intracellular volume contraction is less
profound in patients with ESRD [77].
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European Journal of Internal Medicine xxx (xxxx) xxx
Several studies recommend a modified approach for fluid resuscita­
tion in patients with DKA and ESRD, preferring a small bolus of 250 mL
with reassessment after each infusion [72,76]. It has been proposed that
adequate insulin administration alone, with limited or without intra­
venous fluid resuscitation, may resolve the metabolic disturbances
without complications [72,76]. Two studies described a lower mean
glucose level by 36 to 190 mg/dL during dialysis days, suggesting that
total daily insulin can be decrease by ~25% on hemodialysis days [78,
79]. Considering the glucose-lowering effect of dialysis, a slower rate of
hyperglycemia correction may be considered, potentially avoiding a
starting intravenous insulin bolus to decrease hypoglycemia [72].
Patients with DKA and ESRD presented with higher potassium con­
centration compared with patients with preserved renal function [72].
Studies reported that insulin administration is the only treatment
required for correction of hyperkalemia [77,80]. This data suggests that
a revised approach to administering potassium is necessary when
managing DKA in patients with ESRD [72].
In summary, managing DKA in patients with end-stage renal disease
can be challenging due to alterations in glucose and insulin metabolism,
potassium homeostasis, alternation in renal clearance, and volume sta­
tus. Further research is important, however, based on the limited data
available, the treatment of these patients should focus on insulin
administration with a specifically tailored approach to fluid and potas­
sium resuscitation.
6.7. Recurrent episodes of DKA and elements of prophylaxis
Recurrent DKA is a serious and not uncommon problem. Several risk
factors for recurrence have been identified: younger age at DKA onset,
poor baseline glycemic control and elevated HbA1C, patient comor­
bidities, depression, alcohol or substance abuse, and socioeconomic
factors (such as ethnic minority, underinsurance, homelessness) [81,
82].
Awareness of the known risk factors for DKA may assist physicians to
prevent readmissions. Identifying high-risk patients during the first DKA
admission and performing relevant interventions (such as repeated in­
structions of insulin use, social help, involvement of family members,
collaboration with the primary care physician) may help prevent future
admissions [81–83].
7. Conclusions
DKA is a serious metabolic emergency that has potential for adverse
outcomes when not promptly recognized and treated. In recent decades,
there has been a concerning rise in the number of admissions for diabetic
ketoacidosis [4]. Despite well written and readily available guidelines,
these guidelines are not always consistent or followed. Rapid accumu­
lation of new data makes it challenging for guidelines to stay constantly
updated. The present article discusses knowledge gaps and controversies
in the treatment of DKA and we highlighted the need for personalized
approaches based on unique patient conditions and comorbidities.
There is an increasing interest in selecting the appropriate fluid
resuscitation for management of DKA [14]. The clinician should care­
fully consider the association between normal saline infusion and the
development of hyperchloremic metabolic acidosis, as well as the pos­
sibility of kidney injury. On the other hand, it is important to take into
account the potential side effects of BES and the limited data and
experience supporting their use [12,14,16–19,25]. In our opinion, the
more favorable physiological characteristics of BES are likely to lead to
its wider future utilization.
Hypoglycemia is a life-threatening complication in DKA treatment,
demanding a careful balance between insulin and dextrose infusion
rates. In one study, the use of a computer decision support system for
insulin dosing demonstrated promising results, including a reduced rate
of hypoglycemia and faster normalization of bicarbonate levels. The
available data remains limited, but we believe that such systems have
L. Barski et al.
the potential to reduce complications and minimize healthcare costs
[31].
DKA is a critical condition that demands close monitoring of clinical
and biochemical data. Conventionally, patients are admitted to an ICU
or HDU, however, these are scarce and expensive resources that are
often critically strained. Several trials have shown that treating selected
DKA patients outside of the ICU setting does not lead to increased
mortality or longer time to DKA resolution [47,50]. The utilization of
subcutaneous FAIAs may also facilitate treatment in non-ICU setting
[38]. Therefore, in our opinion, in situations where ICU capacity is
limited, DKA treatment does not necessarily require admission to the
ICU.
The introduction of the SGLT2 inhibitors has increased awareness of
euglycemic DKA. Risk factors include a longstanding history of type 2
diabetes mellitus, poor glycemic control, along with conditions such as
pancreatic insufficiency, alcohol dependence, and ketogenic diets [56,
57]. We believe it is advisable to avoid these medications until risk
factors are appropriately addressed.
The management of DKA in individuals with end-stage renal disease
poses challenges due to changes in glucose and insulin metabolism,
potassium homeostasis, alterations in renal clearance, and volume sta­
tus. Based on the currently available data, our perspective is that
treatment for these patients should prioritize insulin administration
while adopting a modified approach to fluid and potassium
resuscitation.
In summary, we aimed to raise awareness about these and other
important issues and encourage further research, standardization, and
personalized approaches to optimize care for DKA patients.
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