Pediatric Drugs

https://doi.org/10.1007/s40272-020-00397-0

REVIEW ARTICLE

Management of Diabetic Ketoacidosis in Children and Adolescents

with Type 1 Diabetes Mellitus
Luz Castellanos1 · Marwa Tuffaha1 · Dorit Koren1   · Lynne L. Levitsky1 

© Springer Nature Switzerland AG 2020

Abstract
Diabetic ketoacidosis (DKA) is the end result of insulin deficiency in type 1 diabetes mellitus (T1D). Loss of insulin pro-
duction leads to profound catabolism with increased gluconeogenesis, glycogenolysis, lipolysis, and muscle proteolysis
causing hyperglycemia and osmotic diuresis. High levels of counter-regulatory hormones lead to enhanced ketogenesis and
the release of ‘ketone bodies’ into the circulation, which dissociate to release hydrogen ions and cause an overwhelming
acidosis. Dehydration, hyperglycemia, and ketoacidosis are the hallmarks of this condition. Treatment is effective repletion
of insulin, fluids and electrolytes. Newer approaches to early diagnosis, treatment, and prevention may diminish the risk of
DKA and its childhood complications including cerebral edema. However, the potential for some technical and pharmaco-
logic advances in the management of T1D to increase DKA events must be recognized.

Key Points  1 Background

Incidence of diabetic ketoacidosis (DKA) in newly
diagnosed and known type 1 diabetes mellitus (T1D)
can be reduced by public health measures and improved
technology and drug therapies.
Successful treatment of DKA includes fluid and electro-
lyte replacement derived from retrospective reviews and
clinical trial outcomes.
A menu of options now exists for outcome-driven insulin
therapy in DKA.
Newer drugs and technologies for the treatment of T1D
may enhance the risk of ketoacidosis.
Luz Castellanos and Marwa Tuffaha Co-first-authors.
* Lynne L. Levitsky
Lynne.Levitsky@mgh.harvard.edu
1 minority status, younger age, male sex, lower income, lower
Division of Pediatric Endocrinology and Pediatric Diabetes
Center, Massachusetts General Hospital, 175 Cambridge
Street, 5th Floor, Boston, MA 02114, USA
Type 1 diabetes mellitus (T1D) is likely the result of envi-
ronmentally triggered, autoimmune-mediated pancreatic
β-cell destruction in a genetically susceptible host. The end
result of the autoimmune process is insulinopenia, leading
to hyperglycemia and the breakdown of insulin-dependent
processes of cellular energy storage and synthesis [1–3].
Insulin deficiency induces glycogenolysis, gluconeogenesis,
proteolysis, and lipolysis. In addition, increases in counter-
regulatory hormones enhance lipolysis and ketogenesis.
Ketone bodies produced in uncontrolled T1D can reach cir-
culating levels of up to 25 mmol/L, far above levels seen in
normal fasting (< 0.5 mmol/L) or even prolonged fasting
(6–7.5 mmol/L) [4–6]. The accumulation of hydrogen ions
because of dissociation of these relatively strong metabolic
acids soon exceeds the buffering capacity of the kidney. The
result is diabetic ketoacidosis (DKA), a condition of high
ketone body levels in the blood, dehydration, and acidosis,
associated with significant morbidity and mortality. DKA
may be the presentation of T1D, may occur occasionally
during the course of T1D, or more rarely may be a recurrent
problem. This review focuses on aspects of DKA in T1D and
its management and prevention.
Risk factors for DKA at diagnosis include racial/ethnic
parental education level, and lack of health insurance [7–9].
Rates of DKA at diagnosis vary from 11 to 80% depending

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upon region, even in developed countries [10–14]. Children
who present with ketoacidosis at the time of diagnosis are
at greater long-term risk of poor glycemic control independ-
ent of concurrent socioeconomic and demographic risk fac-
tors. Therefore, interventions aimed at improved recognition
of early T1D before development of DKA and at reducing
rates of recurrent DKA are crucial [15]. These rates can be
improved with earlier recognition and educational public
health interventions [12, 16].
The risk of DKA in children after diagnosis of T1D is
1–10/100 person-years [14]. DKA is usually induced by
intentional or inadvertent insulin omission, sometimes
associated with intercurrent illness and increased insulin
requirement. Lower socioeconomic status is associated with
a higher risk of DKA and a higher rate of diabetes-related
complications in children and adults, both in countries with
and without universal access to health care [17–22]. The
price of diabetes supplies and insulin may contribute to risk
of DKA [23–25], as may belonging to a racial or ethnic
group with decreased access to care [1, 26]. Paradoxically,
advances in care using insulin pump therapy (continuous
subcutaneous insulin infusion or CSII) have been associated
with an increase in DKA in many but not all studies [27–30].
If there is an interruption in insulin delivery because of
Fig. 1  Pathophysiology of diabetic ketoacidosis
L. Castellanos et al.
pump or infusion-site problems, and the regimen, as is
common, does not include subcutaneous long-acting basal
insulin, ketoacidosis can develop within 4–6 h. The provid-
ers of pediatric pump therapy should recognize the impor-
tance of a multidisciplinary diabetes team, including nursing
and education, to ensure good outcomes of CSII therapy.
Recurrent DKA is variably defined as three to five or more
episodes within a period of 3–4 years [31–33]. Omission of
insulin is the leading cause of recurrent DKA, accounting for
67–84% of cases. Intercurrent illness is typically seen in only
15–30% of cases in adults and children [31, 34, 35]. When a
responsible adult administers insulin, there may be as much
as a tenfold reduction in frequency of recurrent DKA [31].
2 Pathophysiology of Diabetic Ketoacidosis
(DKA)
A summary of the pathophysiology of DKA is outlined in
Fig. 1. With loss of β-cell mass, circulating plasma insulin
drops to low levels, which are insufficient to meet metabolic
needs. Skeletal muscle and adipose tissue glucose uptake
by insulin-dependent glucose transporters (predominantly
GLUT4) is impaired [36]. A profoundly catabolic state
Diabetic Ketoacidosis in Children and Adolescents
ensues, in which glycogenolysis is accelerated and skeletal
muscle wasting leads to increased urinary nitrogen excretion
and increased circulating plasma amino acids as substrate
for gluconeogenesis and ketogenesis [3, 37]. Breakdown of
triacylglycerol from fat provides substrate for gluconeogen-
esis via glycerol and an increase in serum free fatty acids,
substrates for fatty acid oxidation and ketogenesis [38].
Loss of the paracrine suppressive effect exerted by β-cells
and mediated by insulin as well as co-secreted amylin and
zinc enhances α-cell glucagon production [39, 40]. High
circulating levels of glucagon promote glycogenolysis,
gluconeogenesis, and hyperglycemia. Cortisol levels are
also frequently elevated in people with new-onset diabetes,
increasing gluconeogenesis and lipolysis; elevated cortisol
levels and consequent insulin resistance may predispose to
developing DKA [41, 42]. Epinephrine over-production and
elevation of growth hormone levels have been reported in
people with T1D and stress in the context of acute illness,
also predisposing to DKA [41, 43]. These changes have also
been reported in adults during experimental insulin with-
drawal [44–46].
Insulinopenia promotes lipolysis, leading to accumulation
of free fatty acids (FFA) in the plasma [47]. Hydrolysis of
the released triacyclglycerols is accelerated by the actions
of the counterregulatory hormones, with hepatic oxidation
of the FFA and subsequent ketogenesis. Although insulin
deficiency alone in pancreatectomized patients can lead to
DKA, glucagon is very important in the development of
ketoacidosis because it shifts hepatic intracellular metab-
olism towards production of ketones [48, 49]. The three
‘ketone bodies’ found in largest amounts are acetone, which
is a true ketone chemically, BHB (beta-hydroxybutyrate),
which is a reduced ketoacid, and ACAC (acetoacetate), a
true ketoacid. Insulin deficiency decreases ketone uptake and
utilization in peripheral tissues and renal ketone clearance is
reduced with dehydration [3]. BHB and ACAC are relatively
strong acids that dissociate freely to produce large amounts
of hydrogen ion. This overwhelms the buffering capacity of
both serum and body tissues including, importantly, the kid-
ney, resulting in the development of metabolic acidosis [50].
The initial bicarbonate level may not be at all representative
of the anion gap, as the acidosis can range from anion gap
acidosis to hyperchloremic metabolic acidosis [51]. Acidosis
stimulates central and peripheral chemoreceptors that con-
trol respiration. This leads to alveolar hyperventilation in an
attempt to raise extracellular pH by lowering p­ CO2 levels;
clinically, this deep, sighing breathing pattern is known as
Kussmaul respiration [52].
Uncontrolled diabetes is a pro-inflammatory, highly oxi-
dative state. People with T1D have elevations in inflamma-
tory cytokines, including C-reactive protein, tumor necro-
sis factor (TNF)-α, interleukin (IL)-6, IL-1B, and IL-8
[38, 53, 54]. This elevation is seen in DKA, but also in
hyperglycemia without ketosis or acidemia, suggesting that
hyperglycemia itself and not acidosis is the source of the
inflammatory response; supporting this is the finding that
infusion of insulin leads to normalization of inflammatory
markers [55, 56].
3 Clinical Presentation of DKA
Progressive hyperglycemia, ketonemia, and acidosis over-
whelm the glucose resorptive and buffering capacity of
the kidney leading to glycosuria and consequent osmotic
diuresis, ketoacidosis, and electrolyte abnormalities. The
biochemical criteria for diagnosis of DKA include hyper-
glycemia (plasma glucose above 200 mg/dL or 11 mmol/L),
venous pH < 7.3 or bicarbonate level < 15 mmol/L, with ele-
vated serum or urine ketones. Clinical signs and symptoms
of DKA include dehydration, abdominal pain accompanied
by nausea and emesis (which may be mistaken for gastroen-
teritis), the odor of acetone and other ketones on the breath,
tachycardia, tachypnea, and deep, sighing Kussmaul respi-
rations. Finally, if untreated, confusion, drowsiness, altered
mental status, and loss of consciousness develops [14]. Eug-
lycemic ketoacidosis (blood glucose < 200 mg/dL) can be
seen in starvation, young children, pregnancy and lactation,
and other circumstances when circulating glucose supply
is diminished, as in people treated with drugs designed to
increase glucose excretion [57–61].
Electrolyte imbalances and hyperosmolar dehydration
associated with DKA carry a risk of arrhythmia, acute renal
disease, and cardiopulmonary arrest [62]. These have been
well described in the adult literature but are somewhat less
common in children. In one prospective study, 43% of the
children with DKA had severe dehydration (> 6% in chil-
dren, > 10% in infants) and mean dehydration was 6.8% of
body weight, greater than previous reported rates of severe
dehydration of 12–24% [63]. These data underly the current
International Society for Pediatric and Adolescent Diabetes
(ISPAD) recommendations to assume a 10% magnitude of
dehydration in pediatric DKA [64]. One study found a simi-
lar median pH (7.12–7.15) in a large group of retrospectively
reviewed children with DKA [65]. Despite similar acidosis,
another study found that duration of insulin infusion was
greater in newly diagnosed rather than established diabe-
tes, suggesting that duration of preceding symptoms may
be most predictive of duration of time it takes for resolution
[66].
Osmotic diuresis leads to renal potassium wasting and
subsequent total body potassium depletion. Initial serum
potassium during diagnosis of DKA may underestimate
total body potassium depletion. Buffering of elevated hydro-
gen ions by proton/potassium exchange leads to extracel-
lular shifts of potassium. Osmotic shrinkage of cells due

to increased plasma osmolality increases the intracellu-
lar–extracellular potassium concentration gradient, and
shifts potassium ions from the intracellular to the extracel-
lular space. In addition, insulin deficiency leads to a lack
of the usual insulin-mediated stimulation of Na,K-ATPase
that normally drives potassium intracellularly. Even if serum
potassium is initially elevated, treatment with insulin and
fluids leads to re-entry of potassium from the extracellular to
the intracellular compartment, necessitating close monitor-
ing and potassium replacement [67].
Ongoing osmotic diuresis also results in phosphaturia
and total body phosphate depletion. Because of extracel-
lular shifts, this may become obvious only after treatment
initiation [68]. Insulin and fluid treatment leads to a rapid
entry of glucose and phosphate into intracellular tissues for
cellular phosphorylation [69]. Plasma phosphate levels may
fall precipitously and hypophosphatemia may last for some
days [70].
The most serious clinical complication of DKA in child-
hood is cerebral edema, although other acute and chronic
complications are not rare. DKA/hyperglycemia was
implicated in 83% of pediatric diabetes-related deaths in a
national database review in the United Kingdom. The most
common cause of death was cerebral edema (62–82%) [71].
A follow-up to this study reported a mortality rate of 24%
among 34 children who presented with cerebral edema and
DKA [33]. Similarly, in a study of DKA-associated deaths
in the US, 21% of children with clinical cerebral edema
died [72]. Subclinical cerebral edema is thought to occur
in most pediatric DKA, but clinically significant cerebral
edema complicates approximately 0.5% of episodes of DKA
[73]. Risk factors for symptomatic cerebral edema include
young age, new diagnosis of diabetes, severe DKA, lower
­PaCO2 (partial pressure of carbon dioxide), higher blood
urea nitrogen, lack of rise of sodium during rehydration, and
bicarbonate administration [73, 74]. Initially, it was thought
the overall rate of fluid administration inversely correlated
with time to brain injury [75]. A case–control study sup-
ported this by identifying early insulin administration and
high volumes of fluid as risk factors for cerebral edema [76].
This has led to a series of studies exploring the best fluid and
insulin administration techniques for the resolution of DKA
in young people. It was initially thought that brain cells
accumulated intracellular osmolytes (‘idiogenic osmoles’)
during hyperosmolality, and that DKA treatment decreased
intravascular osmolality resulting in osmosis of water into
brain cells leading to cerebral edema [75]. More recently,
good data support that cerebral hypoperfusion and neuro-
inflammation leads to hypoperfusion/reperfusion injury
and vasogenic cerebral edema [77–81]. The first large rand-
omized, prospective trial of fluid infusion rates and cerebral
outcomes in pediatric patients with DKA was published in
2018 (PECARN study). The study concluded that within
L. Castellanos et al.
a range of bolus infusions of 0.9% sodium chloride, fluid
repletion rates assuming 10% dehydration over 24–48 h, and
replacement fluids of 0.45% or 0.9% sodium chloride, there
was no significant difference in neurologic outcome [62].
Clinically important pulmonary edema is a rare compli-
cation of pediatric DKA, although interstitial pulmonary
edema that worsened during treatment and self-resolved by
discharge has been identified by CT scan in studied patients.
The mechanism may be similar to that for cerebral edema.
Rare children are at risk of developing hypoxemia requiring
oxygen. Treatment includes fluid restriction, although this
may be challenging during the treatment of dehydration that
accompanies DKA [82, 83].
DKA is a pro-thrombotic inflammatory state with an
increased risk of thrombosis and stroke. Transient abnor-
malities in the coagulation cascade including Protein C, Pro-
tein S, plasma homocysteine, and von Willebrand Factor are
not uncommon [84]. Venous thrombosis is increased with
central venous catheter (CVC) use. Fifty per cent of children
with DKA who required CVC placement developed deep
venous thrombosis (DVT) [85, 86]. It has been suggested
that any child with DKA who developed CVC-associated
venous thromboembolism be treated with low molecular
weight heparin until DVT resolution, and that CVC should
be removed as quickly as feasible to reduce DVT risk in
these children [86].
Children with DKA often present with abdominal pain
that may be difficult to distinguish from pancreatitis. One
study found that 40% of children with ketoacidosis had
elevated amylase or lipase; however, only 2% developed
pancreatitis [87]. The cause of the non-specific enzyme
elevation is unclear; however, in cases of true acute pan-
creatitis, transient hypertriglyceridemia is thought to lead
to pancreatic injury [88]. Management includes fluids and
diet restriction.
Rhabdomyolysis is a frequent complication of DKA. In
one study, 10% of children with new-onset T1D presented
with myoglobinuria. Fluid administration is recommended to
prevent further kidney injury [89]. Elevated serum osmolal-
ity, severe hyperglycemia and hypophosphatemia appear to
be risk factors; one proposed mechanism is that the meta-
bolic disturbances associated with DKA disrupt the Na/K
ATPase pump, thereby leading to myocyte destruction
[90–92]. Nephrolithiasis may complicate DKA [93]. Acute
kidney injury has been reported in 64% of children with
DKA—there is a known relationship with the development
of chronic kidney disease [94]. In addition, children with
DKA are at increased risk of developing cognitive deficits
[95–97]. Retrospective and prospective studies of children
with T1D with and without DKA have found differences
in memory performance and morphologic and functional
brain changes. The Diabetes Research in Children Net-
work (DirecNet) study group recently reported that a single
Diabetic Ketoacidosis in Children and Adolescents
episode of ketoacidosis at the time of T1D diagnosis was
associated with lower IQ scores and cognitive performance
on testing 18 months later [98]. Long-term, recurrent epi-
sodes of DKA also increase the risk of chronic complica-
tions of diabetes, including retinopathy [99].
4 Treatment Strategies in DKA
Interventions to treat insulin deficiency, repair electrolyte
abnormalities, and prevent or ameliorate the acute and
chronic complications of DKA in childhood differ some-
what from regimens in adults. In adult DKA, concerns about
cerebral edema are minimal, but underlying cardiac or renal
disease may alter management. These recommendations are
based upon expert review of retrospective and prospective
controlled studies [43, 100, 101]. Proper management of
DKA involves volume resuscitation, electrolyte replace-
ment, insulin administration, and close monitoring of clini-
cal state and laboratory values. In most settings, standard
of care treatment for DKA involves an intravenous infusion
of regular insulin, with hourly fingerstick glucose monitor-
ing and regular monitoring of mental status and electrolytes
[64]. However, in the setting of either limited resources or a
need to limit glucose monitoring, uncomplicated and milder
DKA may be treated with subcutaneous short-acting insulin
injections administered every 2 h as was done successfully
for many years before the use of continuous intravenous
insulin infusion [102].
Treatment needs to be individualized because response
to therapy may vary. Vital signs should be monitored every
hour or more frequently if needed. Initial blood glucose,
ketones, blood gas, and electrolytes (including sodium,
potassium, bicarbonate, calcium and phosphate) should be
obtained. Blood glucose should be repeated every hour and
ketones and electrolytes every 2–4 h so that fluid adjust-
ments can be made [14, 64]. Presently accepted guidelines
from ISPAD are summarized critically in the following sec-
tions [64], along with the logic and data underpinning these
guidelines.
4.1 Replete Water and Salt
Most DKA patients have moderate to severe dehydration
(6–10% dehydration) and children younger than 2 years of
age are more likely to have more severe dehydration, relat-
ing to osmotic diuresis [64]. Intravenous fluid replacement
should be started as soon as DKA diagnosis is confirmed and
should begin with a bolus of isotonic fluids (10 mL/kg) over
30 min to 1 h. After the initial fluid bolus, a second bolus
can be administered in those who are more critically dehy-
drated and then transition to replacing fluid deficit evenly
over 24–48 h with a rough estimate of 1.5–2 times the main-
tenance rate of fluid replacement.
DKA increases risk of electrolyte disturbances. In addi-
tion, pseudohyponatremia can occur because of fluid shifts
to extracellular space related to elevated osmolality from
hyperglycemia. Corrected sodium should be calculated
by the following formula: corrected sodium = measured
sodium + 2 (plasma glucose mg/dL–100/100). Sodium-con-
taining fluids are infused as part of the treatment; however,
the goal is sodium repletion and not sodium excess, which
may also concomitantly lead to chloride excess and enhance
hyperchloremia. Usually the rehydration fluid will at least
initially consist of 0.45–0.9% sodium chloride [64].
Patients with DKA may present with hyperchloremic aci-
dosis [103]. Iatrogenic hyperchloremic metabolic acidosis is
a frequent complication of DKA treatment. Isotonic saline
infusion results in an infusion of high volumes of sodium
and chloride, resulting in a relative excess of chloride and its
obligate excretion as ammonium chloride, thereby generat-
ing a metabolic acidosis [37]. This hyperchloremic meta-
bolic acidosis may prolong the course of the acidemia and
delay recovery. With use of more hypotonic fluids, such as
0.45% saline or even 0.68% saline, chloride delivery is less.
For this reason, some have advocated for administration of
more hypotonic saline after the initial corrective fluid bolus.
The PECARN study showed no differences in neurologic
outcome or time to DKA resolution, but hyperchloremic
acidosis was more frequent in those receiving 0.9% NaCl
and more rapid fluid delivery [62]. The recent ISPAD guide-
lines recommend that “the initial bolus should be ≥ 20 mL/
kg of isotonic saline (0.9% NaCl) and a fluid deficit should
be calculated so that correction also includes ongoing fluid
requirement. Additional fluid boluses should be given rap-
idly, if necessary, to restore peripheral perfusion. Thereafter,
0.45–0.75% NaCl should be administered to replace the defi-
cit over 24–48 h.” However, the ISPAD guidelines do leave
room for clinical judgement, including use of 0.9% saline
depending on the child’s initial sodium, and also offer the
option of use of Lactated Ringer’s solution (LR) [64]. Use of
Plasma-Lyte, another crystalloid solution of lower chloride
content than 0.9% saline, has also been examined in DKA,
with equipoise between Plasma-Lyte and DKA regarding
time to DKA resolution [104, 105].
It has been suggested that LR represents a more balanced
crystalloid solution [106]. A randomized control trial of var-
ious crystalloid solutions in adults found similar times to
resolution of acidosis, but a recent review of a large United
States national database in children with DKA found that
the use of LR as opposed to isotonic saline was associated
with lower rates of reported cerebral edema [107]. The rates
of reported cerebral edema were less than the 0.5% usually
quoted in national studies, so the quality of the data may be
open to review. Regardless of the choice of fluid, care must

be taken to avoid an overly rapid drop in serum osmolality,
while striving to minimize excessive chloride load.
4.2 Decrease Acidosis and Ketosis and Control
Hyperglycemia
Insulin treatment should start only after initial fluid resus-
citation, in order to decrease risk of cerebral edema and
hypokalemia [108]. At the second hour of therapy, insulin
can be administered intravenously continuously until acido-
sis resolves (pH > 7.3 and bicarbonate > 15). Once plasma
glucose decreases to < 300 mg/dL, infusion fluid should
contain dextrose (D5 0.45 or 0.9% saline with added potas-
sium) with a goal to decrease blood glucose by 50–75 mg/
dL per hour in order to prevent an inappropriately rapid drop
in osmolality [14, 64]. The rate of insulin infusion can be
decreased if hypoglycemia occurs despite infusion of maxi-
mal dextrose concentrations in IV fluids, to as low as 0.2
units insulin/kg body weight per hour. Because insulin sup-
presses ketone body formation, ketosis subsequently resolves
but may resolve more slowly than hyperglycemia [50].
For over 40 years, intravenous administration of regular
insulin at 0.1 units/kg of body weight per hour has been
considered standard of care. However other approaches
have been equally efficacious. For example, in recent years,
randomized controlled trials in childhood DKA have dem-
onstrated that a lower dose of insulin (0.05 units/kg body
weight per hour) [109] or subcutaneous injections of rapid-
acting insulin analogs at doses of 0.15 unit/kg administered
every 2 h [110] were also effective treatments for DKA.
Serum ketones (primarily BHB during acidosis) will
decrease with treatment; however, urine ketone levels will
initially appear to increase because BHB is metabolized
to ACAC during recovery—and this ketoacid is measured
in urine ketone strips or tablets. Circulating BHB is more
reflective of the true state of ketosis [111]. The use of bicar-
bonate in treatment of severe DKA is still controversial. The
rationale is that severe metabolic acidosis is associated with
impaired myocardial contractility and lower cardiac output,
reduced tissue oxygen delivery as a consequence of altered
oxyhemoglobin dissociation, altered cellular metabolism,
and cerebral and hepatic dysfunction, and that bicarbonate
will correct the metabolic acidosis and improve these issues
[112, 113]. However, while there may be transient improve-
ment in metabolic acidosis with bicarbonate therapy, use of
bicarbonate does not lead to more rapid resolution of DKA,
may increase the risk of cerebral edema, and causes a para-
doxical intracellular acidosis as H ­ CO3 and ­CO2 cross the
cellular membrane at different rates. A worsening of ketosis
and need for potassium supplementation due to more rapid
intracellular potassium shifts has also been reported [113].
For this reason, the ISPAD guidelines generally recommend
against administration of bicarbonate, with the following
L. Castellanos et al.
caveats: “Bicarbonate administration is not recommended
except for treatment of life‐threatening hyperkalemia or unu-
sually severe acidosis (venous pH < 6.9) with evidence of
compromised cardiac contractility” [64]. Thus, routine use
of bicarbonate is not recommended, and any contemplated
use should be reserved for children with very severe acidosis
(pH < 6.9) that fails to respond to standard treatment.
4.3 Avoid Hypokalemia and Hypophosphatemia
Potassium should be replaced after initial saline bolus (if
serum potassium is below 5.5–6 mmol/L) to avoid hypoka-
lemia during insulin treatment. Recommended concen-
trations are 20–40 mEq/L of KCl or a mixture of Kphos-
phate and KCl or Kacetate. However, to avoid a small risk
of cardiac arrhythmia, potassium levels should normalize
and voiding should occur before initiating intravenous
potassium replacement if there is anuria or hyperkalemia.
Because DKA leads to total body depletion of phosphorus,
replacing half of the K as a Kphosphate solution should
safely replace some phosphate without causing hypocalce-
mia [64]. Hypophosphatemia can cause cardiac arrhythmia
as well as muscle weakness and malaise and, if it persists
after recovery from DKA, supplementation with exogenous
phosphate, intravenously or orally, is occasionally necessary.
EKG monitoring should be continued, and serum calcium
levels should be monitored carefully. Evaluation for vitamin
D deficiency or underlying phosphate wasting is important
in a patient with severe hypophosphatemia [114].
4.4 Avoid Complications Including Severe Cerebral
Edema
Clinical vigilance should decrease complications associ-
ated with DKA, such as severe cerebral edema, arrhyth-
mias, infection, or deep venous thrombosis. Fluid and insulin
administration should be closely monitored. To decrease the
risk of cerebral edema, a normal saline bolus should precede
administration of insulin drip by 1–2 h. Based upon several
retrospective studies, insulin should never be administered as
an IV bolus in pediatric patients during DKA treatment [77,
115]. If cerebral edema is suspected before or during ther-
apy, treatment should immediately be initiated with man-
nitol or hypertonic saline [64, 116]. Mannitol 0.5–1 g/kg IV
should be administered over 10–15 min and can be repeated
in 30 min. Hypertonic saline is dosed as 2.5–5 mL/kg over
10–15 min; however, caution is encouraged if is used, as
one retrospective review found increased risk of mortality
with hypertonic saline versus mannitol use in treatment of
DKA-associated cerebral edema [116].
Continuous cardiac monitoring to assess for potential
arrhythmias should be used to monitor for T-wave changes
associated with hypokalemia or hyperkalemia [117]. Central
Diabetic Ketoacidosis in Children and Adolescents
venous catheter placement should be avoided because of
associated risk of thrombosis [86].
Concurrent illness should be assessed and treated appro-
priately. Patients presenting with symptoms of pancreatitis
should have pancreatic enzymes tested [87]. Administration
of antibiotics should be guided by results of specimen cul-
tures; however, starting empiric antibiotics on suspicion of
febrile infection until culture results return has been rec-
ommended [64]. This recommendation is not based upon
prospective outcome data.
4.5 Transition to Subcutaneous Insulin
The transition from intravenous insulin infusion to a subcu-
taneous insulin regimen is recommended after the acidemia
resolves (pH > 7.3 and bicarbonate > 15). Insulin and fluid
infusions may be stopped 15–30 min after administration of
short-acting subcutaneous insulin, preferably coordinated
with a meal. Long-acting insulin should have a longer dura-
tion of overlap (for example, the first dose could be adminis-
tered in the evening during treatment and the insulin infusion
stopped in the morning) [64]. Supplementing with insulin
glargine before resolution of DKA led to faster resolution
of acidosis in one controlled study and this could potentially
translate to shorter ICU length of stay [118].
5 Newer Issues in Management
and Treatment
5.1 Drugs that May Increase the Risk of DKA
in Known Type 1 Diabetes (T1D)
Sodium-glucose transporter (SGLT)-2 inhibitors, oral
agents that block glucose uptake by the kidney, can
decrease insulin needs and lead to weight loss by induc-
tion of glycosuria. Large prospective controlled trials
have shown that this class of drugs may decrease hyper-
tension, adverse cardiovascular events, and death from
T2D in some high-risk populations [119]. They have also
been shown to be effective in improving glycemic control
in adults with T1D [120], although none have yet been
approved for this use in the United States. Known side
effects include increased urination, potential for dehydra-
tion, urinary tract infection, and genital mycotic infec-
tions, as might be expected. However, a less common but
potentially lethal side effect is the risk of DKA. Because
insulin needs will decrease when this drug is used, some
individuals have developed euglycemic ketoacidosis as a
result of insulin deficiency because, although glycemia
is controlled, the catabolic effects of insulin deficiency
have not been detected early enough. A recent interna-
tional consensus conference has suggested that although
these drugs hold great promise, prevention of DKA may
require determining the appropriate anticatabolic insulin
dose for each patient, as well as careful ketone monitor-
ing in blood and/or urine. The literature is filling with
case series of euglycemic ketoacidosis associated with use
of these drugs in adults [121, 122]. None of these drugs
have been approved for use in children. Sotagliflozin, an
SGLT inhibitor with the capacity to block both glucose
re-uptake by the kidney (SGLT2) and glucose uptake by
the gut (SGLT1), has also been evaluated in prospective
trials in T1D adults. It leads to improved glycemic control,
less hypoglycemia and decreased insulin requirement [123,
124]. However, the risk of DKA is significant enough that
the Food and Drug Administration (FDA) declined to
approve its use in T1D (March 2019) [125]. These drugs
have been approved for use in Europe and in Japan.
Glucagon-like peptide-1 (GLP-1) receptor agonists
and dipeptidyl peptidase-4 (DPP-4) inhibitors are another
group of medications that are very useful in the treatment
of T2D in adults [126, 127]. One GLP-1 agonist has been
approved in pediatric T2D [128]. GLP-1 agonists have
been employed in small studies of adults with both T1D
and obesity with the aim of using these agents to help con-
trol weight and glycemia [129]. Use has been associated
with an increased risk of both hypoglycemia and hyper-
glycemia with ketosis, although weight loss and decreased
insulin requirements are reported [130]. Agents that
reduce peripheral insulin levels and control the metabolic
effects of obesity would logically be excellent additions to
pharmacologic treatment of T1D, but presently available
medications are relatively high risk and are not approved
for use in children and adolescents with T1D [130].
5.2 Drugs That May Induce T1D and DKA
PEG-asparaginase, a drug used frequently in the treat-
ment of acute lymphoblastic leukemia, is well known to be
associated with hyperglycemia and transient or sometimes
permanent T1D. In rare instances, use of this drug can
result in DKA—glycemia and ketosis must be monitored
carefully during its use [131].
A newer class of anticancer drugs, immune checkpoint
inhibitors (antibodies directed against T-cells to maintain
their ability to kill malignant cells) are known to be associ-
ated with an increased risk of autoimmune endocrinopa-
thy, including diabetes [132, 133]. These drugs are just
beginning to be introduced into pediatric oncology for
solid tumors, and to date, although DKA has been reported
in treated adults, there have been no such reports in chil-
dren [134, 135].

5.3 Pharmacologic Approaches to Secondary
Prevention of DKA
As discussed in Sect. 1, DKA after diagnosis can be traced
to lack of sufficient education, lack of adult attention to man-
agement, or inability or failure to access continuing subspe-
cialty medical care. However, drug- and technology-driven
approaches may also be useful. A recent study suggested
that even a 1-week course of real-time continuous glucose
monitoring (CGM) could reduce the risk of recurrent DKA
over the 4 months following such intervention [136]. Some
endocrinologists treating children with pumps choose to give
a portion (a third to a half) of the basal insulin requirement
as a daily injection of long-acting insulin. This then pro-
tects against development of ketoacidosis because of pump
or catheter failure during the night. However, no long-term
studies validate this logical approach. Insulin degludec, a
long-acting insulin approved for use in children when given
daily, has a particularly long half-life of several days and
has been associated with a decreased prevalence of ketosis
compared with another long-acting insulin [137]. Use of this
insulin in one study somewhat decreased risk of DKA [138].
6 Conclusion
DKA is the end result of insulin deficiency leading to an
acidotic catabolic state, dehydration, and hyperglycemia.
Newer treatment regimens have somewhat decreased the risk
of cerebral edema, the major serious complication of treat-
ment of DKA in children, but DKA is still associated with
many acute and chronic complications, including diminished
school and intellectual function. Prevention of DKA at the
time of diagnosis requires heightened awareness by health-
care providers and family. Later prevention of recurrent
DKA requires an educated, involved family with access to
medical treatment and to appropriate and regular health care.
Pharmacologic and technologic approaches to DKA preven-
tion include use of continuous glucose monitoring, monitor-
ing of blood ketone levels, and use of longer-acting insulin
preparations. New drugs approved in Europe and Japan for
the treatment of T1D in adults have been associated with an
increased risk for euglycemic DKA.
Compliance with Ethical Standards  Pediatrics. 2009;124(6):e1134–e1141141.
Funding  No outside funding was used in the preparation of this review
article.
Conflict of interest  Dr. Levitsky is a consultant to Eli Lilly on a study
of a diabetes drug and has been a consultant to Novo Nordisk on a
diabetes drug trial. The remaining authors have no potential conflicts
of interest to declare.
L. Castellanos et al.
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