Diabetic Ketoacidosis Uptodate

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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in

adults: Epidemiology and pathogenesis
Authors: Irl B Hirsch, MD, Michael Emmett, MD
Section Editors: David M Nathan, MD, Joseph I Wolfsdorf, MD, BCh
Deputy Editor: Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2020. | This topic last updated: Mar 29, 2020.
INTRODUCTION
Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also called hyperosmotic
hyperglycemic nonketotic state [HHNK]) are two of the most serious acute complications of diabetes. They
each represent an extreme in the hyperglycemic spectrum.
The epidemiology and the factors responsible for the metabolic abnormalities of DKA and HHS in adults
will be discussed here. The clinical features, evaluation, diagnosis, and treatment of these disorders are
discussed separately. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical
features, evaluation, and diagnosis" and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in
adults: Treatment".)
EPIDEMIOLOGY
Diabetic ketoacidosis (DKA) is characteristically associated with type 1 diabetes. It also occurs in type 2
diabetes under conditions of extreme stress such as serious infection, trauma, cardiovascular or other
emergencies, and, less often, as a presenting manifestation of type 2 diabetes, a disorder called ketosis-
prone diabetes mellitus. (See "Syndromes of ketosis-prone diabetes mellitus".)
DKA is more common in young (<65 years) patients, whereas hyperosmolar hyperglycemic state (HHS)
most commonly develops in individuals older than 65 years [1,2]. According to the Diabetes Surveillance
System of the Centers for Disease Control and Prevention (CDC), overall, age-adjusted DKA hospitalization
rates decreased slightly from 2000 to 2009, then reversed direction, steadily increasing from 2009 to 2014
at an average annual rate of 6.3 percent. In-hospital case-fatality rates declined consistently during the
study period from 1.1 to 0.4 percent ( figure 1) [3].
Population-based data are not available for HHS. The rate of hospital admissions for HHS is lower than the
rate for DKA and accounts for less than 1 percent of all primary diabetic admissions [1,4-6]. The mortality
rate for patients with HHS is between 10 and 20 percent, which is approximately 10 times higher than that
for DKA [7]. The mortality rate for hyperglycemic crisis declined between 1980 and 2009 [8]. Mortality in
hyperglycemic crisis is primarily due to the underlying precipitating illness and only rarely to the
metabolic complications of hyperglycemia or ketoacidosis [1,9]. The prognosis of hyperglycemic crisis is
substantially worse at the extremes of age and in the presence of coma and hypotension [9-12].
PATHOGENESIS
Normal response to hyperglycemia — The hormonal regulation of glucose homeostasis is discussed in

detail elsewhere. (See "Pancreatic beta cell function" and "Insulin action" and "Physiologic response to
hypoglycemia in normal subjects and patients with diabetes mellitus".)
Summarized briefly, the extracellular concentration of glucose is primarily regulated by two hormones:
insulin and glucagon. As the serum glucose concentration rises after a glucose meal, glucose enters the
pancreatic beta cells, initiating a sequence of events leading to insulin release.
Insulin restores normoglycemia by diminishing hepatic glucose production via reductions in both
glycogenolysis and gluconeogenesis and by increasing glucose uptake by skeletal muscle and adipose
tissue. Insulin-induced inhibition of glucagon secretion contributes to the decline in hepatic glucose
production; this effect is mediated by direct inhibition of glucagon secretion and of the glucagon gene in
the pancreatic alpha cells [13-15].
Spectrum of metabolic abnormalities — Two hormonal abnormalities are largely responsible for the
development of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) in patients with
uncontrolled diabetes [13,14,16]:
● Insulin deficiency and/or resistance.
● Glucagon excess, which may result from removal of the normal suppressive effect of insulin.
Although glucagon excess contributes to the development of DKA, it is not essential. As an example,
patients with complete pancreatectomies and who have no pancreatic glucagon will develop DKA if
insulin is withheld; however, it takes longer for DKA to develop compared with patients with type 1
diabetes [17].
In addition to these primary factors, increased secretion of catecholamines, cortisol, and growth
hormone, which oppose the actions of insulin, also contribute to the increases in glucose and ketoacid
production ( algorithm 1) [1].
The deficiency in insulin (either absolute deficiency, or a relative deficiency caused by excess
counterregulatory hormones) is more severe in DKA compared with HHS. Since suppression of lipolysis
and ketogenesis is more sensitive to insulin than the inhibition of gluconeogenesis, the residual insulin
secretion and its systemic activity in HHS is sufficient to minimize the development of ketoacidosis but not
adequate to control hyperglycemia [1]. The increase in glucagon levels and activity is also less in HHS
generating a smaller decrease in the insulin/glucagon ratio, which generates a lesser stimulus to
ketogenesis [7].
In patients with absolute or relative insulin deficiency, DKA and HHS are usually precipitated by stresses
that act in part by increasing the secretion of glucagon, catecholamines, and cortisol ( table 1). (See
"Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and
diagnosis", section on 'Precipitating factors'.)
DKA and HHS are two extremes in the spectrum of hyperglycemic crisis, and patients can present
anywhere along the continuum of diabetic metabolic derangement ( table 2). (See "Diabetic
ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and
diagnosis", section on 'Diagnostic criteria'.)
Hyperglycemia — The serum glucose concentration in HHS frequently exceeds 1000 mg/dL (56
mmol/L), but in DKA, it is generally below 800 mg/dL (44 mmol/L) and often in the 350 to 450 mg/dL (19.4
to 27.8 mmol/L) range [18]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:
Clinical features, evaluation, and diagnosis", section on 'Laboratory findings'.)
At least two factors contribute to less severe hyperglycemia in DKA:
● Patients with DKA often present earlier in the course of their acute disease with symptoms of
ketoacidosis (such as shortness of breath, abdominal pain, and nausea and vomiting), rather than
late with symptoms due to hyperosmolality.
● Patients with DKA tend to be younger and to have a higher glomerular filtration rate. During the first
several years of diabetes, patients may have a supranormal glomerular filtration rate, with levels as
great as 50 percent above predicted. As a result, patients with DKA generally have a much greater
capacity to excrete glucose than the usually older patients with HHS. This severe degree of glucosuria
limits the severity of the hyperglycemia. (See "Diabetic kidney disease: Pathogenesis and
epidemiology".)
Although the glucosuria associated with DKA (and HHS) initially minimizes the rise in serum glucose,
the osmotic diuresis caused by glucosuria usually leads to volume depletion and a reduction in
glomerular filtration rate that limits further glucose excretion [18-21]. This effect is more pronounced
in HHS, which results in a higher serum glucose than seen in DKA.
Hormonal alterations in DKA and HHS generate hyperglycemia by their impact on three fundamental
processes in glucose metabolism ( algorithm 1) [1,22,23]:
● Impaired glucose utilization in peripheral tissues

● Increased hepatic and renal gluconeogenesis
● Increased glycogenolysis
Insulin deficiency and/or resistance in diabetic patients impair peripheral glucose utilization in skeletal
muscle. However, decreased glucose utilization alone will produce only postprandial hyperglycemia;
glycogenolysis and increased gluconeogenesis are also required for development of the often severe
fasting hyperglycemia which occurs in DKA and HHS.
Insulin deficiency and/or resistance promote and accelerate hepatic gluconeogenesis for several reasons
[13-15].
Insulin deficiency and/or resistance:
● Increase the delivery of gluconeogenic precursors (glycerol from fat and alanine and other amino
acids from muscle) to the liver
● Activate multiple enzymes in the gluconeogenic metabolic pathway
● Increase glucagon levels by removing the inhibitory effect of insulin on both glucagon synthesis and
secretion
Oxidation of fatty acids, which are delivered in large amounts to the liver due to lipolysis of fat stores,
provides the metabolic energy required to drive gluconeogenesis [16,24,25].
The importance of glucagon in the development of hyperglycemia and ketoacidosis in uncontrolled

diabetes has been demonstrated by the following observations:
● After discontinuing insulin in a patient with type 1 diabetes, the rate of rise in serum glucose can be
markedly attenuated if glucagon release is prevented by infusing somatostatin [13].
● The magnitude of this effect is illustrated by studies in patients who have undergone total
pancreatectomy who make neither insulin nor glucagon. In one report, four such patients and six
with type 1 diabetes were fasted after having been maintained on intravenous insulin for 24 hours
[17]. After withdrawal of insulin, there was a sharp increase in serum glucagon in the patients with
type 1 diabetes. Compared with the pancreatectomized patients, these patients had significantly
greater increases in blood glucose (225 versus 139 mg/dL [12.5 versus 7.7 mmol/L]) and blood ketone
concentration (4.1 versus 1.8 mmol/L) at 12 hours. (See 'Ketone production' below.)
Ketone production — Both insulin deficiency and glucagon excess contribute to the genesis of DKA
[17,24,26]. As noted above, however, glucagon is contributory, but not essential, for DKA to occur. Insulin
deficiency and resistance (eg, due to high catecholamine levels) will cause enhanced lipolysis from
peripheral fat stores, largely related to increased activity of hormone sensitive lipase, which releases free
fatty acids and glycerol. The fatty acids are transported, mainly bound to albumin, to the splanchnic bed
and are taken up by hepatocytes. Within the hepatocyte cytoplasm, they are "activated" by linkage of the
fatty acid to coenzyme A (CoA), forming acyl-CoA (ie, fatty acid-CoA). The combination of low insulin and
increased glucagon activity in the liver cells creates conditions that accelerate the entry of the acyl-CoA
into the mitochondria. This transport is mediated by a pair of carnitine palmityl transferase reactions
[16,24,26-30].
Within the mitochondria, beta-oxidation splits the fatty acids into multiple two-carbon units of acetyl-CoA.
This molecule can have one of three fates:
● Enter the Krebs cycle to be oxidized to carbon dioxide (CO2) and water (H2O), thereby creating
adenosine triphosphate (ATP)
● Be indirectly exported into the cytoplasm where the acetyl-CoA is used to synthesize fatty acids
● Enter the ketogenic metabolic path to form acetoacetic acid
When fatty acid delivery to the mitochondria is high, then beta-oxidation of the fatty acid usually occurs in
a hormonal milieu characterized by low insulin and high glucagon activity. Under these conditions, entry
of acetyl-CoA into the Krebs cycle becomes rate limiting, and acetyl-CoA instead is converted to
acetoacetic acid. This true ketoacid is the first "ketone body" which forms. The acetoacetic acid may then
be reduced to beta-hydroxybutyric acid, which is also an organic acid, or nonenzymatically decarboxylated
to acetone, which is not an acid [31]. Ketones provide an alternate water-soluble source of energy when
glucose availability is reduced.
The factors responsible for the general absence of ketogenesis in HHS are incompletely understood.
However, one important issue is the differential sensitivity of fat metabolism and glucose metabolism to
the effects of insulin. Studies in humans have demonstrated that the concentration of insulin required to
suppress lipolysis is only one-tenth that required to promote glucose utilization [32]. Thus, less severe
insulin deficiency, as occurs in HHS compared with DKA, might be associated with sufficient insulin activity
to minimize lipolysis (and therefore ketoacid formation) but not enough to block gluconeogenesis,
promote glucose utilization, and thereby prevent the development of hyperglycemia [33]. Less marked
elevation of glucagon levels and therefore a higher insulin/glucagon ratio also minimizes ketogenesis [7].
There are several observations compatible with this general hypothesis. DKA tends to occur in patients
with type 1 diabetes, who produce little or no insulin. HHS, in comparison, is found primarily in older
patients with type 2 diabetes, who have decreased, but not absent, insulin effect [16,23,34]. However, this
distinction is not absolute, since DKA can occur in patients with type 2 diabetes (see "Syndromes of
ketosis-prone diabetes mellitus"). This most often occurs in obese African Americans but has also been
described in other populations in the setting of extreme stress, such as sepsis or an acute myocardial
infarction, with very elevated counterregulatory hormones [35].
Anion gap metabolic acidosis — DKA typically presents as an elevated anion gap metabolic acidosis.
This is caused by the production and accumulation of beta-hydroxybutyric and acetoacetic acids. The
anion gap is calculated by subtracting the serum concentrations of chloride and bicarbonate from the
concentration of sodium [36]:
Serum anion gap = serum sodium - (serum chloride + bicarbonate)

By convention, the measured (reported) sodium concentration (not the sodium concentration corrected
for hyperglycemia) should be used for the calculation of the anion gap.
The severity of the metabolic acidosis and the increase of the anion gap are dependent upon a number of
factors:
● The rate and duration of ketoacid production

● The rate of metabolism of the ketoacids
● The rate of loss of ketoacid anions in the urine
● The volume of distribution of the ketoacid anions
● The rate of renal net acid excretion
The rate of ketoacid anion excretion depends upon the patient's volume status, renal function, and the
degree to which glomerular filtration is maintained. Patients with relatively preserved extracellular fluid
(ECF) volume and higher renal function can excrete large quantities of ketoacids (as much as 30 percent of
the ketoacid load), and thereby minimize the elevation in anion gap [37]. The magnitude of this effect was
illustrated in a study of patients with DKA; ketone production averaged 51 mEq/hour, while net acid
excretion with the ketoacid anions averaged 15 mEq/hour or 30 percent of the ketoacid load [38]. The
conversion of acetoacetic acid to acetone can neutralize another 15 to 25 percent of the acid load [38,39].
Rarely, patients excrete ketoacids so efficiently that they present with only a small, or no, elevation in
serum anion gap (they have a pure non-gap, or hyperchloremic, metabolic acidosis) [37,40-42].
Renal excretion of ketoacid anions increases when patients are treated with intravenous isotonic fluids to
correct the hypovolemia. Excretion of ketoacid anions reduces the anion gap, but to the extent that they
are excreted as sodium and potassium salts, the severity of the systemic acidemia is unchanged
[37,40,43,44]. Sodium or potassium ketoanion salts represent both "decomposed" bicarbonate and also
"potential bicarbonate." When the ketoacids are generated, the protons mainly combine with bicarbonate
to form CO2. Thus, in essence, bicarbonate anions in the serum are replaced with ketoacid anions
("decomposed bicarbonate"). If the ketoacids are metabolized, then a bicarbonate anion is regenerated
("potential bicarbonate"). Therefore, the urinary loss of ketoacid anions as sodium or potassium salts
represents the loss of "potential bicarbonate." Furthermore, excretion of beta-hydroxybutyrate and
acetoacetate as sodium and potassium salts will reduce the anion gap and convert the anion gap acidosis
to a hyperchloremic, or non-gap, acidosis. Thus, almost all patients with DKA who have relatively intact
renal function will develop some degree of hyperchloremic (normal anion gap) metabolic acidosis when
they are treated with isotonic saline and insulin, due to the urinary loss of potential bicarbonate. These
principles are discussed in detail elsewhere. (See "The delta anion gap/delta HCO3 ratio in patients with a
high anion gap metabolic acidosis", section on 'The delta AG/delta HCO3 in ketoacidosis'.)
Studies have demonstrated that a portion of the anion gap acidosis in most patients with DKA is due to
yet another organic acid: D-lactic acid. A small, but clinically significant, fraction of ketoacids, acetone, and
dihydroxyacetone phosphate (a product of glycolysis) can each be converted to D-lactic acid [45]. D-lactic
acid can account for as much as 8 to 10 mEq/L of the anion gap elevation and bicarbonate reduction in
patients with severe DKA [45]. (See "The delta anion gap/delta HCO3 ratio in patients with a high anion
gap metabolic acidosis", section on 'D-lactic acidosis and toluene inhalation'.)
Plasma osmolality and sodium — Plasma osmolality is always elevated in patients with HHS but less
so with DKA ( table 2). The increase in plasma osmolality created by hyperglycemia pulls water out of
the cells, expands the ECF, and thereby reduces the plasma sodium (Na) concentration. If a patient with
normal serum electrolytes (Na = 140 mEq/L) rapidly developed a glucose concentration of 1000 mg/100
mL and no urine was made, then that patient's serum sodium concentration would fall to value between
119 and 126 mEq/L and the osmolality would increase to a level between 294 and 308 mosmol/L.
However, the osmolality usually increases to a greater degree because a large volume of relatively
electrolyte-deficient urine is excreted during the evolution of the hyperglycemic state. The loss of this
electrolyte-free water further raises the osmolality [18]. In patients with ketoacidosis, high plasma
acetone levels also contribute to the elevated osmolality.
The measured serum sodium concentration in uncontrolled diabetes mellitus is affected by the
interaction of multiple factors, some that lower and others that raise it:
● Hyperglycemia raises the ECF osmolality (and tonicity) and shifts water from the intracellular fluid
(ICF) space to the ECF space. Expansion of the ECF dilutes serum sodium and reduces its
concentration.
● Glucosuria generates an osmotic diuresis which causes the excretion of sodium and potassium salts,
and water. The sum of the concentrations of sodium and potassium salts in the urine is generally
much lower than the sodium concentration in blood. This indicates that electrolyte-free water is being
excreted in the urine. Loss of electrolyte-free water will raise the serum sodium concentration and
plasma osmolality.
● The variable intake of water and the loss of free water in vomitus or nasogastric suction will also
impact the serum sodium concentration and plasma osmolality.
Physiologic calculations suggest that, in the absence of urine losses, the serum sodium concentration
should fall by approximately 1.6 mEq/L for each 100 mg/100 mL (5.5 mmol/L) increase in glucose
concentration [46]. However, when hyperglycemia was induced in six healthy subjects by the
administration of somatostatin (to block endogenous insulin secretion) and the infusion of hypertonic
dextrose solution, the relationship between the fall in sodium concentration and the increase in glucose
concentration was not linear and the reduction in sodium was greater than had been previously reported
[47]. These authors suggested that the sodium should fall by approximately 2.4 mEq/L for each 100
mg/100 mL (5.5 mmol/L) increase in glucose concentration. A number of prior and subsequent studies
reported a fall in sodium between 1.6 and 2.4 mEq/L for each 100 mg/100 mL increase in glucose [48]. It
must be emphasized that these ratios are only very approximate estimates of potential water deficits (or
less commonly, excess). However, they do provide a rough estimate of how much the serum sodium
concentration will rise as the hyperglycemia is corrected. Because there is so much variation in the
literature and so many variables affect this relationship, we recommend the use of a simple ratio of a 2
mEq/L decline in sodium for each 100 mg/100 mL (5.5 mmol/L) increase in glucose concentration above
the normal range.
Potassium — Patients presenting with DKA or HHS have a potassium deficit that averages 300 to 600
mEq ( table 3) [49-51]. A number of factors contribute to this deficit, particularly increased urinary
losses due both to the glucose osmotic diuresis and the excretion of potassium ketoacid anion salts (the
ketoacid anions are filtered primarily as sodium salts, but some of the sodium is reabsorbed in the distal
renal tubule in exchange for potassium as a result of volume contraction-related secondary
hyperaldosteronism). Gastrointestinal losses and the loss of potassium from the cells due to
glycogenolysis and proteolysis also may play a contributory role.
Despite these large total body potassium deficits, the serum potassium concentration is usually normal
or, in one-third of patients, elevated on admission [18,49,52]. This is mainly due to hyperosmolality and
insulin deficiency [22,49,53]. (See "Causes and evaluation of hyperkalemia in adults".)
● The rise in plasma osmolality causes osmotic water movement out of the cells. Potassium also moves
into the ECF as a result of at least two mechanisms [46]:
• The contraction of the ICF space increases intracellular potassium concentration and favors
passive potassium exit through potassium channels in the cell membrane
• The frictional forces between solvent (water) and solute result in potassium being carried across
the cell membrane with water (this process is called solvent drag)
● Insulin normally promotes potassium uptake by the cells. Therefore, insulin deficiency contributes to
elevated serum potassium levels.
Acidemia per se plays a small role in the shift of potassium from the ICF to the ECF in patients with DKA.
Although a transcellular exchange of potassium with hydrogen ions does increase serum potassium in
some forms of "inorganic" metabolic acidosis [54], it is less important in organic metabolic acidoses such
as ketoacidosis or lactic acidosis [49,54-56]. The important role of hyperosmolality and insulin deficiency is
illustrated by the observation that hyperkalemia also often occurs in HHS, despite the absence of acidosis
[18]. (See "Potassium balance in acid-base disorders", section on 'Metabolic acidosis'.)
Inflammation — Hyperglycemic crises are proinflammatory states that lead to generation of reactive

oxygen species and oxidative stress. Studies have shown elevated proinflammatory cytokines including
tumor necrosis factor-alpha and interleukin (IL)-1B, IL-6, and IL-8. Lipid peroxidation markers, as well as
plasminogen activator inhibitor-1 and C-reactive protein (CRP), are also increased [57]. Proinflammatory
factors returned to near-normal levels within 24 hours of insulin therapy and resolution of hyperglycemia.
The proinflammatory state in DKA results in in vivo activation of T-lymphocytes with de novo emergence
of growth factor receptors [58].
A variety of eicosanoids, including prostaglandins, are involved in the pathogenesis of diabetes mellitus
and its complications [59]. Some are protective and others accelerate organ dysfunction, including
pancreatic beta-cell destruction. Prostaglandins accumulate during DKA, increase in the circulation before
elevation of epinephrine, and return promptly to normal levels with insulin therapy [60,61].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the
world are provided separately. (See "Society guideline links: Hyperglycemic emergencies".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These articles are
best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Hyperosmolar nonketotic coma (The Basics)")
SUMMARY
● Diabetic ketoacidosis (DKA) is more common in younger patients with type 1 diabetes, though it can
occur in type 2 diabetes. HHS occurs less frequently and is associated with higher mortality, at least in
part due to underlying comorbidity. (See 'Epidemiology' above.)
● DKA and hyperosmolar hyperglycemic state (HHS) are part of a spectrum, representing the metabolic
consequences of insulin deficiency, glucagon excess, and counterregulatory hormonal responses to
stressful triggers in patients with diabetes ( table 2). (See 'Spectrum of metabolic abnormalities'
above.)
● Glucose concentrations are typically lower (usually <800 mg/dL [44 mmol/L]) in DKA compared with
HHS (usually >1000 mg/dL [56 mmol/L]). Patients with DKA present earlier because of symptoms and
generally can excrete glucose more effectively than older patients with HHS. (See 'Hyperglycemia'
above.)
● Hyperglycemia results from impaired glucose utilization, increased gluconeogenesis, and increased
glycogenolysis ( algorithm 1). Gluconeogenesis results from delivery of precursors to the liver from
breakdown of fat and muscle and is promoted by insulin deficiency and glucagon excess.
Glycogenolysis is stimulated by catecholamines and a high glucagon-to-insulin ratio. Osmotic diuresis
further contributes to elevated blood glucose. (See 'Hyperglycemia' above.)
● Ketoacidosis results from lipolysis, with synthesis of ketones from free fatty acids in the liver
mitochondria. Insulin levels in HHS are insufficient to allow appropriate glucose utilization but are
adequate to prevent lipolysis and subsequent ketogenesis. (See 'Ketone production' above.)
● The elevated anion gap metabolic acidosis characteristic of DKA is caused by the production and
accumulation of beta-hydroxybutyric and acetoacetic acids. The severity of the metabolic acidosis is
dependent upon a number of factors, including the rate and duration of ketoacid production, the rate
of metabolism of the ketoacids, and the rate of acid excretion in the urine. (See 'Anion gap metabolic
acidosis' above.)
● Plasma osmolality is always elevated in patients with HHS but less so with DKA ( table 2). The
marked hyperosmolality seen in HHS is only in part due to the rise in serum glucose. It is also due to
the glucose osmotic diuresis that causes urine electrolyte-free water loss. These factors also influence
the measured serum sodium concentration, which is variable because of the interaction of multiple
factors, some that lower and others that raise it. (See 'Plasma osmolality and sodium' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge Abbas Kitabchi, PhD, MD, FACP, MACE, now
deceased, who contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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32. ZIERLER KL, RABINOWITZ D. EFFECT OF VERY SMALL CONCENTRATIONS OF INSULIN ON FOREARM
METABOLISM. PERSISTENCE OF ITS ACTION ON POTASSIUM AND FREE FATTY ACIDS WITHOUT ITS
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33. Kitabchi AE, Fisher JN. Insulin therapy of diabetic ketoacidosis: Physiologic versus pharmacologic dos
es of insulin and their routes of administration. In: Handbook of Diabetes Mellitus, Brownlee M (Ed),
Garland ATPM, New York 1981. p.95.
34. Khardori R, Soler NG. Hyperosmolar hyperglycemic nonketotic syndrome. Report of 22 cases and
brief review. Am J Med 1984; 77:899.
35. Umpierrez GE, Smiley D, Kitabchi AE. Narrative review: ketosis-prone type 2 diabetes mellitus. Ann
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36. Emmett M, Narins RG. Clinical use of the anion gap. Medicine (Baltimore) 1977; 56:38.
37. Adrogué HJ, Eknoyan G, Suki WK. Diabetic ketoacidosis: role of the kidney in the acid-base
homeostasis re-evaluated. Kidney Int 1984; 25:591.
38. Owen OE, Licht JH, Sapir DG. Renal function and effects of partial rehydration during diabetic
ketoacidosis. Diabetes 1981; 30:510.
39. Fulop M. The treatment of severely uncontrolled diabetes mellitus. Adv Intern Med 1984; 29:327.
40. Adrogué HJ, Wilson H, Boyd AE 3rd, et al. Plasma acid-base patterns in diabetic ketoacidosis. N Engl J
Med 1982; 307:1603.
41. Oh MS, Carroll HJ, Goldstein DA, Fein IA. Hyperchloremic acidosis during the recovery phase of
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44. Latif KA, Freire AX, Kitabchi AE, et al. The use of alkali therapy in severe diabetic ketoacidosis.
45. Lu J, Zello GA, Randell E, et al. Closing the anion gap: contribution of D-lactate to diabetic
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46. Katz MA. Hyperglycemia-induced hyponatremia--calculation of expected serum sodium depression.

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Electrolyte, and Acid-Base Disturbances, Sterns RH, Emmett M (Eds), The American Society of Nephro
logy 2013. Vol 12, No 3, p.191.
49. Adrogué HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels in diabetic
ketoacidosis. Medicine (Baltimore) 1986; 65:163.
50. Kreisberg RA. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment. Ann
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Topic 1794 Version 15.0

GRAPHICS
Age-adjusted diabetic ketoacidosis hospitalization rate per 1000 persons with

diabetes and in-hospital case-fatality rate: United States, 2000-2014
Symbols indicate observed points; lines indicate modeled trends. All modeled trends were significant at a p-
value of <0.05.
DKA: diabetic ketoacidosis.
Reproduced from: Benoit SR, Zhang Y, Geiss LS, et al. Trends in diabetic ketoacidosis hospitalizations and in-hospital mortality
— United States, 2000–2014. MMWR Morb Mortal Wkly Rep 2018; 67:362.
Graphic 117707 Version 1.0

Pathogenesis of diabetic ketoacidosis and hyperosmolar hyperglycemic state
DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.

++: Accelerated pathway.
Copyright © 2006 American Diabetes Association From Diabetes Care Vol 29, Issue 12, 2006. Reprinted with
permission from The American Diabetes Association.

Predisposing or precipitating factors for diabetic ketoacidosis and hyperosmolar hyperglycemic state
DKA HHS
Inadequate insulin treatment or noncompliance Inadequate insulin treatment or noncompliance (21 to 41 percent)
New-onset diabetes (20 to 25 percent) Acute illness
Acute illness Infection (32 to 60 percent)
Infection (30 to 40 percent) Pneumonia

Urinary tract infection
Cerebral vascular accident
Sepsis
Myocardial infarction
Cerebral vascular accident
Acute pancreatitis
Myocardial infarction
Drugs
Acute pancreatitis
Clozapine or olanzapine
Acute pulmonary embolus
Cocaine
Intestinal obstruction
Lithium
Dialysis, peritoneal
SGLT2 inhibitors
Mesenteric thrombosis
Terbutaline
Renal failure
Heat stroke
Hypothermia
Subdural hematoma
Severe burns
Endocrine
Acromegaly
Thyrotoxicosis
Cushing's syndrome
Drugs/therapy
Beta-adrenergic blockers
Calcium-channel blockers
Chlorpromazine
Chlorthalidone
Cimetidine
Clozepine
Diazoxide
Ethacrynic acid
Immunosuppressive agents
L-asparaginase
Loxapine
Olanzapine
Phenytoin
Propranolol
Steroids
Thiazide diuretics
Total parenteral nutrition
Previously undiagnosed diabetes
DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state; SGLT2: sodium-glucose co-transporter 2.
Data from: Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes mellitus (Technical Review). Diabetes
Care 2001; 24:131.

Typical laboratory characteristics of DKA and HHS*
DKA
HHS
Mild Moderate Severe
Plasma glucose (mg/dL) >250 >250 >250 >600
Plasma glucose (mmol/L) >13.9 >13.9 >13.9 >33.3
Arterial pH 7.25 to 7.30 7.00 to 7.24 <7.00 >7.30
Serum bicarbonate (mEq/L) 15 to 18 10 to <15 <10 >18
Urine ketones ¶ Positive Positive Positive Small
Serum ketones - Nitroprusside reaction Positive Positive Positive ≤ Small
Serum ketones - Enzymatic assay of beta hydroxybutyrate 3 to 4 mmol/L 4 to 8 mmol/L >8 mmol/L <0.6 mmol/L
(normal range <0.6 mmol/L) Δ
Effective serum osmolality (mOsm/kg) ◊ Variable Variable Variable >320
Anion gap § >10 >12 >12 Variable
Alteration in sensoria or mental obtundation Alert Alert/drowsy Stupor/coma Stupor/coma
DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.

* There may be considerable diagnostic overlap between DKA and HHS.
¶ Nitroprusside reaction method.
Δ Many assays for beta hydroxybutyrate can only report markedly elevated values as >6.0 mmol/L.
◊ Calculation: 2[measured Na (mEq/L)] + glucose (mg/dL)/18.
§ Calculation: (Na+) – (Cl– + HCO3–) (mEq/L).
Copyright © 2006 American Diabetes Association. From Diabetes Care Vol 29, Issue 12, 2006. Information updated from Kitabchi AE, Umpierrez GE, Miles JM,
Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009; 32:1335. Reprinted with permission from the American Diabetes Association.

Typical total body deficits of water and electrolytes in diabetic ketoacidosis and hyperosmolar
hyperglycemic state*
DKA HHS
Total water (L) 6 9
Water (mL/kg ¶) 100 100 to 200
Na + (mEq/kg) 7 to 10 5 to 13
Cl - (mEq/kg) 3 to 5 5 to 15
K + (mEq/kg) 3 to 5 4 to 6
PO 4 (mmol/kg) 5 to 7 3 to 7
Mg ++ (mEq/kg) 1 to 2 1 to 2
Ca ++ (mEq/kg) 1 to 2 1 to 2
DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state; Na +: sodium; Cl -: chloride; K +: potassium; PO 4 : phosphate; Mg ++: magnesium;
Ca ++: calcium.
* Data are from Ennis et al (1994) and Kreisberg (1978).
¶ Per kilogram of body weight.
Copyright © 2006 American Diabetes Association From Diabetes Care Vol 29, Issue 12, 2006. Reprinted with permission from the American Diabetes Association.

Contributor Disclosures
Irl B Hirsch, MD Grant/Research/Clinical Trial Support: Medtronic [Diabetes], Insulet Corporation [Diabetes].
Consultant/Advisory Boards: Abbott [Diabetes]; Roche [Diabetes]; Bigfoot Biomedical [Diabetes]. Michael Emmett,
MD Consultant/Advisory Boards: AstraZeneca [Hyperkalemia]. David M Nathan, MD Nothing to disclose Joseph I
Wolfsdorf, MD, BCh Consultant/Advisory Boards: Ultragenyx DSMB [Glycogen storage disease type 1a]. Jean E
Mulder, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support
the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy

Diabetic ketoacidosis in children: Clinical features and

diagnosis
Author: Nicole Glaser, MD
Section Editor: Joseph I Wolfsdorf, MD, BCh
Deputy Editor: Alison G Hoppin, MD
Literature review current through: Dec 2020. | This topic last updated: Oct 30, 2020.
INTRODUCTION
Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1
diabetes mellitus. It occurs at the time of diagnosis of type 1 diabetes in approximately one-third of
children in the United States [1-5]. In children with established diabetes, DKA occurs at rates of 6 to 8
percent per year [6,7]. DKA can also occur in children with type 2 diabetes (and particularly in African
American adolescents with obesity), although at lower rates than those observed in type 1 diabetes [8-15].
The clinical features and diagnosis of DKA in children will be reviewed here. Topic reviews with related
content include:
● (See "Overview of the management of type 1 diabetes mellitus in children and adolescents".)
● (See "Diabetic ketoacidosis in children: Treatment and complications".)
● (See "Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)".)
● (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features,
evaluation, and diagnosis".)
DEFINITIONS
● Diabetic ketoacidosis (DKA) – DKA is defined by the presence of all of the following in a patient with
diabetes, as outlined in a consensus statement from the International Society for Pediatric and
Adolescent Diabetes in 2018:
• Hyperglycemia – Blood glucose >200 mg/dL (11 mmol/L)

• Metabolic acidosis – Venous pH <7.3 or serum bicarbonate <15 mEq/L (15 mmol/L)
• Ketosis – Presence of ketones in the blood (>3 mmol/L beta-hydroxybutyrate) or urine ("moderate
or large" urine ketones)
The severity of DKA can be categorized according to the degree of acidosis as mild, moderate, or
severe ( table 1). (See 'Diagnosis' below and 'Assessment of severity' below.)
● Hyperglycemic hyperosmolar state (HHS) – HHS is a hyperglycemic emergency, which is

distinguished from classic DKA by:
• Marked hyperglycemia (blood glucose >600 mg/dL [>33.3 mmol/L])

• Minimal acidosis (venous pH >7.25 or arterial pH >7.3 and serum bicarbonate >15 mmol/L)
• Absent to mild ketosis
• Marked elevation in serum osmolality (effective osmolality >320 mOsm/kg)
Altered consciousness occurs frequently in HHS [16,17]. HHS occurs most commonly in adults with
poorly controlled type 2 diabetes but has also been reported in children, most often in African
American adolescents with type 2 diabetes [18-20]. (See 'Hyperglycemic hyperosmolar state' below.)
EPIDEMIOLOGY
DKA and its complications are the most common cause of hospitalization, mortality, and morbidity in
children with type 1 diabetes mellitus and is frequently present at diagnosis [21]. It can also occur in
children with type 2 diabetes, although at lower rates than those observed in type 1 diabetes [8-15]. (See
"Classification of diabetes mellitus and genetic diabetic syndromes", section on 'DKA in type 2 diabetes'.)
DKA at initial presentation of type 1 diabetes mellitus — DKA occurs at the time of diagnosis of type 1
diabetes in approximately 30 percent of children in the United States and Canada [1-5,22]. Factors that
increase the risk that a child will have DKA at the initial presentation of type 1 diabetes include [17,22-26]:
● Young age (<5 years of age and especially <2 years)

● Low socioeconomic status or lack of health insurance
● Ethnic minority
● Delayed diagnosis of diabetes, including reduced access to medical care
● Children living in countries with low prevalence of type 1 diabetes
The importance of socioeconomic status was illustrated in a review of 139 patients with newly diagnosed
type 1 diabetes mellitus seen at a single center in the United States [27]. Children without private health
insurance (a proxy for low socioeconomic status) had a 62 percent frequency of DKA at presentation
compared with 34 percent among those with private insurance. The frequency of DKA at presentation of
type 1 diabetes has been shown to vary inversely with the frequency of type 1 diabetes in the population,
presumably reflecting a greater frequency of missed diagnoses of type 1 diabetes when clinicians are less
familiar with the disorder [4].
DKA in established type 1 diabetes mellitus — In children with established diabetes, DKA occurs at
rates of 6 to 8 percent per year [6,7,22]. Groups with increased risk for DKA include [6,17]:
● Children with poor metabolic control (higher hemoglobin A1c [HbA1c] values and higher reported
insulin requirements)
● Gastroenteritis with vomiting and dehydration
● Peripubertal and pubertal adolescent girls
● Children with a history of psychiatric disorders (including eating disorders) or unstable family
circumstances
● Children with limited access to medical care (underinsured)
● Inadvertent or intentional omission of insulin, including failure of an insulin pump
In a large prospective study in the United States, almost 60 percent of DKA episodes in children with
established diabetes occurred in only 5 percent of children [6]. Similar findings were noted in the United
Kingdom [21]. Patients who had four or more episodes of DKA (4.8 percent of patients) accounted for 35
percent of all episodes. Thus, a small group of patients consume a disproportionate amount of health
care resources and costs [6].
DKA in type 2 diabetes mellitus — Although less common, ketosis and DKA can occur in children with
type 2 diabetes, particularly in African American adolescents with obesity [8-15]. In a retrospective review
of 69 patients (9 to 18 years of age) who presented with DKA, 13 percent had type 2 diabetes [12]. At
presentation, there was no difference in pH levels, but patients with type 2 diabetes had higher blood
glucose levels at presentation than those with type 1 diabetes. Mixed presentations of DKA and
hyperglycemic hyperosmolar state (HHS) may also occur [16]. (See "Classification of diabetes mellitus and
genetic diabetic syndromes", section on 'DKA in type 2 diabetes'.)
PRECIPITATING FACTORS
Common precipitating factors for DKA include the following; in many cases, multiple precipitating factors
coexist:
● Poor metabolic control or missed insulin doses – Insulin omission and other diabetes
mismanagement accounts for the majority of DKA episodes in children with established diabetes
[6,28]. Omission of insulin injections (both intentional and unintentional) is particularly frequent
among adolescents. (See "Complications and screening in children and adolescents with type 1
diabetes mellitus", section on 'Eating disorders'.)
● Illness – Intercurrent illnesses, particularly when associated with vomiting and dehydration, can
precipitate DKA by increasing stress hormone levels (catecholamines, cortisol, and glucagon) that
increase hepatic glucose output, cause peripheral insulin resistance, and promote ketogenesis.
Illnesses involving vomiting are particularly problematic because they interrupt food intake, often
requiring a reduction in the amount of insulin administered. Patients may completely omit insulin in
an effort to avoid causing hypoglycemia. Anticipatory guidance for families on management of
intercurrent illness can be helpful to avoid the need for hospitalization. (See "Special situations in
children and adolescents with type 1 diabetes mellitus", section on 'Sick-day management'.)
● Medications – Certain medications, such as corticosteroids, atypical antipsychotics, tacrolimus, L-

asparaginase, and diazoxide, have precipitated DKA in individuals not previously diagnosed with type
1 diabetes mellitus [29-32]. In children with established diabetes, use of corticosteroids can also lead
to substantial insulin resistance with hyperglycemia and occasionally ketosis. Use of sodium-glucose
cotransporter 2 (SGLT2) medications, which increase renal glucose excretion, have also been
associated with increased risk of DKA in adults [33,34]. Patients using these medications may present
with euglycemic DKA. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of
hyperglycemia in type 2 diabetes mellitus", section on 'Diabetic ketoacidosis'.)
● Drugs and alcohol – In adolescents with type 1 diabetes, use of illicit drugs and alcohol may interfere
with adherence to good medical management recommendations, resulting in poor metabolic control,
which increases the risk for DKA. Acute ingestion of alcohol can cause hypoglycemia (rather than
DKA) by decreasing hepatic gluconeogenesis. Case reports have described recurrent DKA in
individuals with hyperemesis due to cannabis use [35]. (See "Cannabis (marijuana): Acute
intoxication", section on 'Cannabis hyperemesis syndrome'.)
CLINICAL FEATURES
The clinical diagnosis of diabetes in a previously healthy child requires a high index of suspicion. Signs
and symptoms of DKA are the result of acidosis, hyperglycemia, volume depletion, and electrolyte losses.
Signs and symptoms — The earliest symptoms of diabetes are related to hyperglycemia and are most
apparent in older children and adolescents. Symptoms include polyuria (due to glucose-induced osmotic
diuresis), polydipsia (due to increased urinary water losses), and fatigue. Other findings include weight
loss, nocturia, and enuresis. Occasionally, vaginal or cutaneous moniliasis may occur.
In infants, the diagnosis is more difficult because of lack of toilet training and difficulty expressing thirst.
As a result, polyuria may not be appreciated and polydipsia is not apparent. However, decreased energy
and activity, irritability, weight loss, and physical signs of dehydration are common findings. In addition,
severe Candida diaper rash should raise suspicion for diabetes. (See "Diaper dermatitis".)
A number of other clinical findings may be seen in children with DKA:
● Children with DKA typically present with anorexia, nausea, vomiting, and abdominal pain. Focal pain
may occur and can mimic appendicitis or other intraabdominal pathology. Polyphagia may be present
early in the course of the illness. However, once insulin deficiency becomes more severe and
ketoacidosis develops, appetite is suppressed. (See "Acute appendicitis in children: Clinical
manifestations and diagnosis".)
● Hyperventilation and deep (Kussmaul) respirations represent the respiratory compensation for
metabolic acidosis. Hyperpnea results from an increase in minute volume (rate × tidal volume) and
can be increased by tidal volume alone without an increase in respiratory rate. In infants, hyperpnea
may be manifested only by tachypnea. Patients may also have fruity breath odor secondary to
exhaled acetone.
● Clinical signs of intravascular volume depletion such as tachycardia, poor peripheral perfusion, and
decreased skin turgor occur in children with DKA but tend to be less prominent than in patients with
the same degree of fluid loss from other conditions. This is because the intravascular volume is
relatively preserved due to increased intravascular osmolality resulting from hyperglycemia. In
addition, free water losses frequently exceed sodium losses. Finally, hyperglycemia-induced osmotic
diuresis preserves urine output. Clinical estimates of the degree of dehydration are inaccurate [36]
and unlikely to be helpful. Instead, patients should be rehydrated based upon a presumed fluid
deficit and clinical response. (See "Diabetic ketoacidosis in children: Treatment and complications",
section on 'Dehydration'.)
● Neurologic findings ranging from drowsiness, lethargy, and obtundation to coma are mainly related
to the degree of acidosis [37]. Cerebral injury occurs in 0.3 to 0.9 percent of cases of DKA in children
and is the leading cause of mortality. (See "Diabetic ketoacidosis in children: Cerebral injury (cerebral
edema)".)
Fluid and electrolyte deficits — Children with DKA generally present with a 5 to 10 percent fluid deficit
[1,38]. Measured weight loss provides the best estimate of volume depletion if an accurate recent
measured weight is available for comparison. Otherwise, average fluid deficits of approximately 7 percent
should be assumed [36,39,40] and fluid administration rates adjusted according to clinical response. (See
"Diabetic ketoacidosis in children: Treatment and complications", section on 'Dehydration'.)
Total body sodium deficits in children with DKA range from 5 to 13 mmol/kg. Potassium deficits range
from 3 to 6 mmol/kg [17].
Laboratory abnormalities
Blood glucose — A blood glucose level greater than 200 mg/dL (11 mmol/L) is generally required for
the diagnosis of DKA [38,41]. This degree of hyperglycemia exceeds the renal tubular threshold for
glucose reabsorption, resulting in osmotic diuresis with polyuria; volume depletion occurs when fluid
losses are not sufficiently compensated by increased fluid intake.
In specific circumstances (pregnancy, use of sodium-glucose cotransporter 2 [SGLT2] inhibitor

medications), DKA with normal or near-normal glucose levels can occur [33,34,42]. Also, children with
established diabetes who have administered insulin prior to arrival in the emergency department may
present with normal or near-normal glucose levels.
Acidosis — One of the diagnostic criteria for DKA is metabolic acidosis, defined as a venous pH <7.3 or
serum bicarbonate concentrations <15 mEq/L. Venous pH is the most accurate measure of acidosis;
however, measurements of serum bicarbonate may be used alone, especially in resource-limited settings,
and are closely correlated with venous pH [43]. For particularly vulnerable patients such as young children
or in resource-limited settings, higher thresholds for bicarbonate may be used to increase sensitivity for
the diagnosis of DKA (eg, bicarbonate <18 mEq/L for mild DKA).
Insulin deficiency and increased plasma concentrations of glucagon, cortisol, and epinephrine increase
glucose production, lipolysis, and ketogenesis, which collectively contribute to the development of both
hyperglycemia and ketoacidosis. Acetoacetate is the initial ketone formed and is reduced to beta-
hydroxybutyrate (BOHB) or decarboxylated to acetone. The latter will be detected as a ketone but does
not contribute to the acidosis. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in
adults: Epidemiology and pathogenesis".)
The severity of metabolic acidosis depends upon the rate and duration of increased ketoacid production,
the rate of acid excretion in the urine, and adequacy of respiratory compensation [44,45]. Therefore, the
acidosis will be more severe in a patient with delayed presentation or renal insufficiency.
Ketosis — The degree of ketosis can be estimated in several ways:
● Blood or serum BOHB – Measurement of serum BOHB is the most accurate clinically available index
of ketosis and should be used whenever possible. Most patients with DKA will have BOHB
concentrations ≥3 mmol/L (31 mg/dL). BOHB in blood is available as a point-of-care test and is
reasonably accurate in children and adults up to a blood BOHB concentration of 5 mmol/L (52 mg/dL)
[46]. Measurement of BOHB in serum can also be performed in a clinical laboratory and is
significantly more accurate than point-of-care testing at levels of BOHB >5 mmol/L.
● Urine ketones – Clinical testing with nitroprusside strips can be used to determine the presence of
ketosis but is inaccurate for assessment of the degree of ketosis. In addition, this test may give a false
impression of persistent ketoacidosis during recovery from DKA. This is because the nitroprusside
test strip reacts with acetoacetate and acetone but not BOHB, which makes up 75 percent of
circulating ketones. During recovery from DKA, BOHB is converted to acetoacetate and acetone,
which are excreted in urine for several hours after the serum BOHB concentration has returned to
normal.
● Anion gap – The anion gap is also useful in estimating the severity of ketosis, and the normalization
of the anion gap is a helpful measure of the resolution of ketoacidemia. The normal anion gap in
children is 12±2 mmol/L. The mean anion gap at presentation of DKA in children is 30±3 mmol/L [47].
When insulin is given to patients with DKA, metabolism of the ketoacid anions results in the
regeneration of HCO3– and correction of the metabolic acidosis. For this reason, ketoacid anions have
been called "potential bicarbonate," and their loss in the urine represents the loss of HCO3–. As a
result of this precursor loss, as well as the high chloride content of intravenous fluids, a normal anion
gap acidosis (hyperchloremic acidosis) is often seen during the treatment phase of DKA.
The anion gap is calculated in units of mEq/L or mmol/L, using a calculator (calculator 1) or the
following formula:
Anion gap = Serum sodium – (Serum chloride + bicarbonate)
Serum sodium — Patients with DKA have a total body sodium deficit ranging from 5 to 13 mmol/kg.
Despite this deficit, their initial serum sodium concentrations can vary widely, ranging from mild
hyponatremia (most patients) to mild hypernatremia. This is because the serum sodium concentration is
influenced by two opposing effects of hyperglycemia:
● Hyperglycemia tends to lower the serum sodium concentration because it increases the plasma
osmolality, resulting in movement of water from the intracellular to the extracellular space as a result
of osmotic forces, thus lowering the serum sodium by dilution. In this setting, the patient's sodium
status can be estimated by calculating a "corrected" plasma sodium concentration, which reflects the
expected serum sodium concentration if the patient's glucose concentration were normal. The
measured serum sodium is reduced by 1.6 mmol/L for every 100 mg/dL (5.5 mmol/L) increase in the
blood glucose concentration above 100 mg/dL [48,49]. (See "Diabetic ketoacidosis in children:
Treatment and complications", section on 'Serum sodium'.)
● Glucosuria-induced osmotic diuresis tends to raise the serum sodium concentration because of water
loss in excess of sodium. This effect may partially correct the hyponatremia caused by hyperglycemia.
If water intake is inadequate (which may be a particular problem in hot weather and in infants and
young children who cannot independently access water), hypernatremia may occasionally occur.
If hyperlipidemia is present, the measured serum sodium concentration may be reduced due to a
laboratory artifact. Hyperlipidemia can cause pseudohyponatremia by reducing the fraction of plasma
that is water. As a result, the amount of sodium in the specimen is reduced and the measured plasma
sodium concentration will be lower, even though the physiologically important plasma water sodium
concentration and plasma osmolality are not affected [50]. With modern laboratory techniques, however,
these erroneous sodium concentration measurements are uncommon. (See "Diagnostic evaluation of
adults with hyponatremia".)
Serum potassium — Estimated potassium deficits in children with DKA are 3 to 6 mmol/kg. In spite of
this total body deficit, serum potassium levels are usually normal or slightly elevated at presentation,
reflecting the redistribution of potassium ions from the intracellular to the extracellular space. Regardless
of the initial potassium level, therapy with insulin and fluids will lower the serum potassium
concentration. As a result, potassium replacement, with careful monitoring of potassium levels, is
essential. (See "Diabetic ketoacidosis in children: Treatment and complications".)
Some of the potassium deficit is due to urinary potassium loss from osmotic diuresis and ketoacid
excretion. Elevated aldosterone concentrations in response to intravascular volume depletion also cause
increased renal potassium loss. Additional potassium may be lost through vomiting (and through
diarrhea in the case of DKA triggered by gastroenteritis). In addition, during DKA, potassium ions
redistribute from the intracellular to the extracellular space as a result of the direct effects of low insulin
concentrations (impairing potassium entry into cells), hypertonicity causing solvent drag, intracellular
protein and phosphate depletion, and buffering of hydrogen ions in the intracellular fluid compartment.
(See "Potassium balance in acid-base disorders".)
Serum phosphate — Children with DKA are typically in negative phosphate balance because of
decreased phosphate intake and phosphaturia caused by glucosuria-induced osmotic diuresis. Despite
the presence of phosphate depletion, at presentation, the serum phosphate concentration is usually
normal or even slightly elevated because both insulin deficiency and metabolic acidosis cause a shift of
phosphate out of the cells [51]. This transcellular shift is reversed and phosphate levels typically decline
during DKA treatment. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:
Treatment", section on 'Phosphate depletion'.)
Blood urea nitrogen and creatinine — Patients with DKA often have elevated blood urea nitrogen
(BUN) concentrations, which correlate with the degree of hypovolemia [52]. This finding at presentation
may have predictive value since it is an important risk factor for cerebral injury during therapy [53]. (See
"Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)", section on 'Risk factors'.)
Many children with DKA have acute increases in serum creatinine compared with baseline, reflecting
acute kidney injury (AKI). In one study, some degree of AKI was observed in 42 to 65 percent (depending
on the criteria used) of children with DKA [54]. Within the group of children who had AKI, 65 percent had
stage 2 or 3 AKI, suggesting renal tubular injury rather than prerenal dysfunction that is volume
responsive. Whether DKA-related AKI fully resolves over time or may persist and contribute to chronic
kidney disease in patients with diabetes is unclear.
EVALUATION
Initial laboratory testing should include the following [17,38,41]:
Immediate (point-of-care) tests — If DKA is suspected, the following tests should be performed to
confirm the diagnosis:
● Blood glucose
● Blood beta-hydroxybutyrate (BOHB) or urine ketones (acetoacetate)
BOHB is the most direct and reliable measure of the degree of ketoacidemia. Measurement of urine
ketones is less reliable but can be used to document the presence of ketosis and make a provisional
diagnosis of DKA. (See 'Ketosis' above.)
Laboratory tests — At the same time, the following tests should be sent to the laboratory for more
accurate measurements and to further characterize acid-base and electrolyte abnormalities:
● Blood glucose
● Electrolytes, including serum bicarbonate concentration
● Blood urea nitrogen (BUN) and creatinine
● Venous pH and partial pressure of carbon dioxide (pCO2)
● Calcium, phosphorus, and magnesium – Abnormalities in these measures are unusual but
occasionally require treatment
A complete blood count (CBC) is not essential for evaluation of a child with suspected DKA. If a CBC is
performed in a child with DKA, typical findings include elevated white blood cell count with increased
neutrophils. These findings are characteristic of DKA and do not help to identify children with infection.
Laboratory testing for specific clinical circumstances might also include:
● Serum BOHB concentration – This is useful when point-of-care testing for blood BOHB is not available
or when urine ketone testing cannot be done or yields unclear results.
● Blood lactate concentration – This is useful in situations where the diagnosis of DKA is unclear and
increased anion gap metabolic acidosis could be caused by lactic acidosis (eg, patients with very
severe dehydration, shock, or suspected sepsis).
● Hemoglobin A1c (HbA1c) – This is useful in patients with known diabetes to evaluate the degree of
metabolic control. HbA1c levels within the target range suggest that DKA was precipitated by an
acute event. Elevated HbA1c levels suggest that chronic poor adherence to insulin treatment is a
contributing factor. For patients with new onset of diabetes, HbA1c measurements are unnecessary
for management of DKA.
● Diabetes-associated antibodies – Diabetes-associated antibodies (glutamic acid decarboxylase

antibodies, insulin auto-antibodies, islet cell antibodies, and zinc transporter 8 antibodies) are not
useful for management of DKA. However, they are useful in children with new onset of diabetes
because positive results confirm the diagnosis of type 1 diabetes (diabetes of autoimmune origin). It
should be noted, however, that approximately 10 to 15 percent of children with type 1 diabetes do
not have detectable autoantibodies. (See "Epidemiology, presentation, and diagnosis of type 1
diabetes mellitus in children and adolescents", section on 'Type 1 versus type 2 diabetes'.)
● C-peptide levels – C-peptide levels may be helpful as an assessment of endogenous insulin

production and insulin resistance in children suspected to have type 2 diabetes. (See "Epidemiology,
presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents", section on
'Diagnosis'.)
DIAGNOSIS
Diabetic ketoacidosis — DKA is diagnosed when patients with diabetes mellitus exhibit all of the
following:
● Hyperglycemia (blood glucose >200 mg/dL [11 mmol/L])
● Metabolic acidosis (venous pH <7.3 or serum bicarbonate <15 mEq/L [15 mmol/L])
● Ketosis (presence of ketones in the blood or urine)
Beta-hydroxybutyrate (BOHB) in blood or serum is the most accurate measure of ketosis and should be
used whenever available. Serum BOHB concentrations ≥3 mmol/L (31 mg/dL) are present in most children
with DKA [46]. Standard measurements of urine ketones should not be used to determine the severity of
ketonemia, because this test only measures acetoacetate (see 'Ketosis' above). Venous pH is the most
accurate measure of metabolic acidosis in patients with DKA. For particularly vulnerable patients such as
young children or in resource-limited settings, higher thresholds for bicarbonate may be used to
diagnose DKA (eg, bicarbonate <18 mEq/L). (See 'Acidosis' above.)
Hyperglycemic hyperosmolar state — DKA must be distinguished from hyperglycemic hyperosmolar

state (HHS), which is characterized by:
● Marked hyperglycemia (plasma glucose >600 mg/dL [>33.3 mmol/L])

● Minimal acidosis (venous pH >7.25 or arterial pH >7.3 and serum bicarbonate >15 mmol/L)
● Absent to mild ketosis
● Marked elevation in serum osmolality (effective osmolality >320 mOsm/kg)
HHS occurs most commonly in adults with poorly controlled type 2 diabetes but has also been reported in
children, most often in African American adolescents with type 2 diabetes [18-20]. Recognition of HHS is
important because it is associated with more severe dehydration and a higher frequency of complications
than is typical of DKA. Management of HHS is discussed in a separate topic review, as well as in published
pediatric guidelines [16,17]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:
Treatment", section on 'Fluid replacement'.)
ASSESSMENT OF SEVERITY
At presentation, the following clinical and laboratory findings may be used to estimate the severity of DKA
and risks for complications:
● Acid-base status – The venous pH and serum bicarbonate concentration directly reflect the severity
of the acidosis ( table 1). The respiratory rate and partial pressure of carbon dioxide (pCO2) also
may be helpful since the magnitude of the respiratory compensation is directly related to the severity
of the acidosis.
● Ketosis – Measurement of blood or serum beta-hydroxybutyrate (BOHB), rather than urine ketone
concentration, is the optimal method for monitoring the degree of ketoacidemia. The magnitude of
the anion gap is another measure of the severity of the ketosis and can be a helpful estimate of
acidosis. A very large anion gap may also reflect decreased renal perfusion, which limits ketoacid
excretion. (See 'Ketosis' above.)
● Neurologic state – Severe alterations in mental status at presentation or during DKA treatment may
be indicative of DKA-related cerebral injury, a complication with high rates of morbidity and mortality.
The pathophysiology, treatment, and prognosis of cerebral injury in children with DKA are discussed
in detail separately. (See "Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)".)
● Volume status – Measured weight loss provides the best estimate of volume depletion if an accurate
recent measured weight is available for comparison. Other signs concerning for severe volume
depletion include decreased urine output during hyperglycemia and the presence of hypotension. Of
note, some patients with DKA present with paradoxical hypertension, although they are hypovolemic,
or hypertension may develop during treatment [55]. This finding is associated with more severe DKA
and/or alterations in mental status.
Markedly elevated blood urea nitrogen (BUN) or creatinine (or hemoglobin and hematocrit) also
suggests significant dehydration, although elevated creatinine concentrations can also indicate DKA-
related acute kidney injury (AKI). (See 'Blood urea nitrogen and creatinine' above.)
Together, these clinical features help to determine the appropriate clinical setting in which to treat the
child. For example, mild DKA without vomiting in a child with established diabetes can often be safely
managed in the outpatient setting, under close supervision and monitoring by an experienced diabetes
team. On the other hand, a patient with severe DKA should be managed in a pediatric intensive care unit
[38,41]. (See "Diabetic ketoacidosis in children: Treatment and complications".)
world are provided separately. (See "Society guideline links: Diabetes mellitus in children" and "Society
guideline links: Hyperglycemic emergencies".)
searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Diabetic ketoacidosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1
diabetes mellitus. DKA also can occur in children with type 2 diabetes mellitus.
● DKA is diagnosed when patients with diabetes mellitus exhibit all of the following (see 'Diagnosis'
above):
• Hyperglycemia (blood glucose of >200 mg/dL [11 mmol/L])

• Metabolic acidosis (venous pH <7.3 or serum bicarbonate <15 mEq/L [15 mmol/L])
• Ketosis (presence of ketones in the blood or urine)
● DKA must be distinguished from hyperglycemic hyperosmolar state (HHS), which is a hyperglycemic
emergency characterized by:
• Marked hyperglycemia (blood glucose >600 mg/dL [>33.3 mmol/L])

• Minimal acidosis (venous pH >7.25 or arterial pH >7.3 and serum bicarbonate >15 mmol/L)
• Marked elevation in serum osmolality (effective osmolality >320 mOsm/kg)
HHS occasionally occurs in pediatric patients, most often adolescents with type 2 diabetes.
Recognition of HHS is important because it is associated with more severe dehydration than DKA and
requires a different management approach. (See 'Hyperglycemic hyperosmolar state' above and
"Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation,
and diagnosis".)
● DKA is the presenting feature of new-onset type 1 diabetes in approximately 30 percent of cases in
the United States. Very young children and those of lower socioeconomic status are more likely to
have DKA when they present with type 1 diabetes. (See 'DKA at initial presentation of type 1 diabetes
mellitus' above.)
● Presenting symptoms of diabetes in older children and adolescents include polyuria, polydipsia, and
fatigue. Other findings include weight loss, nocturia (with or without secondary enuresis), daytime
enuresis, and vaginal or cutaneous moniliasis. Infants tend to present with decreased energy and
activity, irritability, weight loss, and physical signs of dehydration; a severe Candida diaper rash is
common. (See 'Signs and symptoms' above.)
● Initial laboratory testing should include blood glucose, blood or serum beta-hydroxybutyrate (BOHB),
serum electrolytes, creatinine, blood urea nitrogen (BUN), and venous blood gases. The diagnosis of
DKA is confirmed by the findings of hyperglycemia, a high anion gap acidosis, and significant
ketonemia. (See 'Evaluation' above and 'Diagnosis' above.)
● The venous pH and serum bicarbonate concentration directly reflect the severity of the acidosis (
table 1). Neurologic status should also be formally assessed at presentation and periodically
during treatment because cerebral injury is an important cause of morbidity and mortality in patients
with DKA. (See 'Assessment of severity' above and "Diabetic ketoacidosis in children: Cerebral injury
(cerebral edema)".)
ACKNOWLEDGMENTS
The editorial staff at UpToDate would like to acknowledge Morey W Haymond, MD, and George S Jeha,
MD, who contributed to earlier versions of this topic review.
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Pediatr 2020; 223:156.

GRAPHICS
Assessment of severity of diabetic ketoacidosis in children
Defining features Severe Moderate Mild
Venous pH <7.1 7.1 to <7.2 7.2 to <7.3
Serum bicarbonate (mEq/L) <5* 5 to 9 10 to <15*
Venous pH is the most accurate measure of acidosis in patients with DKA. However, measurements of serum bicarbonate may be used alone,
especially in resource-limited settings, and are closely correlated with venous pH.

* For particularly vulnerable patients such as young children or in resource-limited settings, higher thresholds for bicarbonate may be used for
increased sensitivity, eg, bicarbonate <7 mEq/L for severe DKA and <18 mEq/L for mild DKA.
Data from: von Oettingen J, Wolfsdorf J, Feldman HA, Rhodes ET. Use of serum bicarbonate to substitute for venous pH in new-onset diabetes. Pediatrics 2015;
136:e371.

Nicole Glaser, MD Nothing to disclose Joseph I Wolfsdorf, MD, BCh Consultant/Advisory Boards: Ultragenyx DSMB
[Glycogen storage disease type 1a]. Alison G Hoppin, MD Nothing to disclose
evidence.

Diabetic ketoacidosis in children: Treatment and complications

Section Editors: Joseph I Wolfsdorf, MD, BCh, Adrienne G Randolph, MD, MSc
Literature review current through: Dec 2020. | This topic last updated: Dec 16, 2020.
INTRODUCTION
Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1
diabetes, with a case fatality rate ranging from 0.15 to 0.31 percent in the United States and other
resource-rich countries [1-3]. DKA also can occur in children with type 2 diabetes; this presentation is most
common among adolescents of African American descent [4-8]. (See "Classification of diabetes mellitus
and genetic diabetic syndromes".)
The management of DKA in children is summarized in the table ( table 1) and is reviewed in detail
below. The clinical manifestations and diagnosis of DKA in children as well as the pathogenesis of DKA are
discussed elsewhere. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis" and "Diabetic
ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis".)
DEFINITION
● Diabetic ketoacidosis (DKA) – DKA is defined by the presence of all of the following in a patient with
diabetes, as outlined in a consensus statement from the International Society for Pediatric and
Adolescent Diabetes in 2018 [9]:
• Hyperglycemia – Blood glucose of >200 mg/dL (11 mmol/L)

• Metabolic acidosis – Venous pH <7.3 or a plasma bicarbonate <15 mEq/L (15 mmol/L)
• Ketosis – Determined by the presence of ketones in the blood or urine
Ketosis is ideally determined by measuring serum beta-hydroxybutyrate (BOHB) in the laboratory

or by a point-of-care device. BOHB concentrations ≥3 mmol/L (31 mg/dL) are consistent with DKA
[9]. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis".)
Disturbances in fluid and electrolyte balance result in volume depletion and mild to moderate serum
hyperosmolality. The clinical manifestations of DKA are related to volume depletion, electrolyte
imbalances, and acidosis [10]. Some children present with severe hyperglycemia and may have mixed
features of DKA and hyperglycemic hyperosmolar state (HHS), as described below. (See "Diabetic
ketoacidosis in children: Clinical features and diagnosis".)
● HHS – HHS is a hyperglycemic emergency that is distinguished from DKA by:
• Marked hyperglycemia – Blood glucose >600 mg/dL (>33.3 mmol/L)

• Minimal acidosis – Venous pH >7.25, arterial pH >7.3, or serum bicarbonate >15 mmol/L
• Marked elevation in serum osmolality – Effective osmolality >320 mOsm/kg
Patients with HHS frequently have altered consciousness (in approximately 50 percent) and moderate
lactic acidosis. HHS requires prompt recognition and management that is distinct from that of DKA. In
particular, dehydration in HHS is typically severe and requires greater fluid resuscitation than DKA. In
addition, delayed initiation of insulin treatment is recommended for HHS. HHS is more common
among adolescents at the onset of type 2 diabetes compared with type 1 diabetes [9,11]. A mixed
presentation with features of both HHS and DKA can also occur. Further details about how to identify
and treat HHS are discussed in separate topic reviews. (See "Diabetic ketoacidosis in children: Clinical
features and diagnosis", section on 'Hyperglycemic hyperosmolar state' and "Diabetic ketoacidosis
and hyperosmolar hyperglycemic state in adults: Treatment".)
INITIAL RAPID ASSESSMENT
All patients with suspected DKA should be rapidly evaluated as follows.
Clinical assessment
● Measure vital signs and assess for signs of shock caused by volume depletion (eg, decreased blood
pressure, reduced peripheral pulses, tachycardia, and significant postural changes in blood pressure).
Of note, hypertension is present in more than 10 percent of children when they present with DKA
(despite hypovolemia) or may develop during treatment [12]. This finding is associated with more
severe DKA, stage 2 to 3 acute kidney injury (AKI), and alterations in mental status. Such patients
require volume replacement despite the hypertension and should be monitored particularly carefully
for signs and symptoms of impending cerebral injury.
● Measure weight for use in calculating fluid replacement and insulin infusion rates. If recent
measurements of weight are available (within the previous one to two weeks), these should be
compared with the current weight to estimate the fluid deficit.
● Estimate the degree of dehydration. Note that clinical symptoms and signs of dehydration, such as
skin turgor and dryness of mucus membranes, tend to underestimate the degree of dehydration in a
child with DKA, and urine specific gravity is not valid, because of both glycosuria and ketonuria.
Therefore, targets for fluid repletion generally rely on assumptions of a 5 to 10 percent fluid deficit,
rather than on clinical estimates of dehydration. (See 'Dehydration' below.)
● Assess the neurologic state using the Glasgow Coma Scale (GCS) or similar assessment ( table 2).
GCS and/or other neurologic assessments should be repeated hourly throughout treatment or until
the patient is clinically recovered from ketoacidosis and mental status has returned to normal. (See
'Cerebral injury' below.)
Severe neurologic compromise at presentation is concerning because such patients may have DKA-
related cerebral injury or be at increased risk for developing cerebral injury during therapy. (See
"Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)", section on 'Treatment'.)
Laboratory testing
● Immediate (point-of-care) testing – Measure using a point-of-care meter (if available) to confirm the
diagnosis of DKA:
• Blood glucose – Blood glucose >200 mg/dL (11 mmol/L) confirms hyperglycemia.
• Blood beta-hydroxybutyrate (BOHB) – Concentrations ≥3 mmol/L (31 mg/dL) are consistent with
DKA [9]. Once the initial degree of ketonemia has been established, either BOHB or the anion gap
may be used to monitor the response to treatment, as described below. (See 'Monitoring' below.)
• Urine ketones – Measurement of urine ketones confirms ketosis but should not be used to judge
the severity of ketonemia or acidosis, because this test measures acetoacetate rather than BOHB,
which is the predominant ketone body at presentation of DKA. Urine acetoacetate (ketonuria)
may persist for some time after resolution of DKA and should not be considered an indication of
persistent ketoacidosis.
● Additional testing – Send to the laboratory for more accurate measurements and to further
characterize the patient's acid-base status, electrolyte balance, and dehydration:
• Blood glucose
• Electrolytes – Including bicarbonate
• Blood urea nitrogen (BUN), creatinine
• Venous pH and partial pressure of carbon dioxide (pCO2)
• Complete blood count
• Calcium, phosphorus, magnesium – Severe abnormalities in these values are uncommon but can
have serious consequences if undetected, particularly in the case of hypophosphatemia
● Additional evaluation for specific circumstances:
• Blood lactate – In a patient with very severe dehydration or shock, sepsis, or hyperglycemic
hyperosmolar state (HHS). In such patients, the blood lactate level will help determine the
contribution of lactic acid to the metabolic acidosis.
• Cultures of blood, urine, and/or throat or other evaluation for infection – If fever or localizing
signs of infection are present.
• Electrocardiogram – If laboratory measurement of potassium status is delayed. In this case, the

electrocardiogram will help to assess for evidence of hyperkalemia (indicated by the finding of a
peaked T wave).
Assessment of severity — Categorizing the severity of DKA at presentation helps to determine the

appropriate level of care (eg, need for intensive care unit admission).
● Venous pH and serum bicarbonate – The severity of DKA at presentation is categorized by acid-base
status ( table 3):
• Mild – pH 7.2 to <7.3; bicarbonate 10 to <15 mEq/L

• Moderate – pH 7.1 to <7.2; bicarbonate 5 to 9 mEq/L
• Severe – pH <7.1; bicarbonate <5 mEq/L
Venous pH is the most accurate measure of acidosis. However, measurements of serum bicarbonate
may be used alone, especially in resource-limited settings, and are closely correlated with venous pH
[13]. For particularly vulnerable patients such as young children or in resource-limited settings, higher
thresholds for bicarbonate may be used for increased sensitivity (eg, bicarbonate <7 mEq/L for severe
DKA and <18 mEq/L for mild DKA).
● Anion gap – The anion gap can be used as an index of the severity of the metabolic acidosis and is
calculated from the following equation:
Anion gap = sodium – (chloride + bicarbonate); a normal anion gap is 12±2
At presentation, the presence of a large anion gap in the absence of significant ketosis (BOHB <3
mmol) strongly suggests significant lactic acidosis and the possibility of HHS or sepsis [9]. (See
'Definition' above.)
During treatment, the anion gap tends to normalize before resolution of the acidosis, frequently
resulting in a mild "non-gap" acidosis as treatment progresses. This is usually associated with
hyperchloremic metabolic acidosis, resulting from the large amount of chloride administered during
rehydration. Therefore, the anion gap is a better measure of effective treatment than the serum
bicarbonate concentration. (See 'Metabolic acidosis' below.)
Other clinical features associated with more severe ketoacidosis include longer duration of symptoms,
depressed level of consciousness, or compromised circulation [14-16].
Disposition — All patients with DKA should be managed in a unit with personnel and facilities capable of
frequent monitoring of clinical symptoms, fluid status, and laboratory results. The experienced clinician is
in the best position to determine the safest place for therapy within a particular institution. In most
tertiary care institutions, patients should be triaged as follows [9]:
● A pediatric intensive care unit (PICU) or specialized inpatient diabetes care unit is appropriate for
patients with severe DKA or signs of or risk factors for cerebral injury, which include altered
consciousness, age younger than five years, severe acidosis (venous pH <7.1 or low pCO2), high BUN,
significant hyper- or hypokalemia, or other severe electrolyte disturbances. In some institutions, all
patients receiving intravenous (IV) insulin or needing frequent monitoring are hospitalized in the
PICU.
● The regular inpatient care area is appropriate for patients with mild to moderate uncomplicated DKA,
if this unit is capable of providing close monitoring and IV insulin infusions [17].
● Emergency department care with outpatient follow-up may be appropriate for patients with
established diabetes and very mild DKA. In some cases, initial IV fluid and insulin therapy in the
emergency department can significantly improve the clinical picture and allow the medical team to
discharge the patient to home, provided that the patient has access to point-of-care testing of both
glucose and ketones, the caretakers are proficient in diabetes sick-day management, and the patient
has access to ongoing advice from an experienced diabetes care team via telephone. (See 'Treatment
of mild diabetic ketoacidosis' below.)
TREATMENT OF MODERATE AND SEVERE DIABETIC KETOACIDOSIS
The general approach and principles of management are the same for all children with DKA, regardless of
the severity. The clinician must individualize the treatment plan based on the child's physical and
laboratory findings, and treatment will need to be adjusted over time for each child. Protocols for
management of fluids and insulin dosing are helpful but should be used in conjunction with clinical
reassessments and judgment. Flow charts can be used to track hourly vital signs and neurologic
symptoms, fluid status (input and output), and insulin dosing, as well as laboratory results ( table 4).
During therapy, the patient should be carefully monitored for signs of cerebral injury. (See 'Monitoring'
below and 'Cerebral injury' below.)
For patients with moderate and severe DKA, the main principles of management are to administer insulin
to resolve ketosis and reduce hyperglycemia, correct dehydration with intravenous (IV) fluids, and correct
electrolyte abnormalities with electrolyte replacement.
Dehydration — Average water losses in children with DKA are approximately 70 mL/Kg (range 30 to 100
mL/Kg) [18-20]. Volume depletion is caused by urinary losses from osmotic diuresis, as well as
gastrointestinal losses from vomiting and insensible losses from hyperventilation.
Clinical signs of dehydration tend to be inaccurate for assessing dehydration severity in DKA [18].
Increased blood urea nitrogen (BUN) concentrations or elevated hematocrit can be helpful markers of
hydration status. Fluid calculations usually should be based upon the assumption of 5 to 7 percent
dehydration for mild to moderate DKA and 7 to 10 percent for severe DKA. Hypovolemic shock is rare in
DKA but, if present, should be promptly treated. Patients in shock should be evaluated for other causes of
shock, such as sepsis. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis", section on
'Signs and symptoms'.)
Initial volume expansion — The goals of initial volume expansion are to restore the effective
circulating volume by acutely replacing some of the sodium and water loss and to improve the glomerular
filtration rate to enhance clearance of ketones and glucose from the blood [9].
Initial volume expansion of 10 to 20 mL/kg should be administered as an IV bolus, using isotonic saline
(0.9% sodium chloride [NaCl]) or Ringer's lactate [9,21]. If circulating volume is still compromised after the
initial bolus is complete, additional IV bolus infusions of 10 to 20 mL/kg can be given (see "Diabetic
ketoacidosis in children: Clinical features and diagnosis", section on 'Signs and symptoms'). Patients with
mild DKA who may not require hospital admission also often benefit from an IV fluid bolus and/or fluid
infusion during management in the emergency department to hasten recovery. (See 'Treatment of mild
diabetic ketoacidosis' below.)
Subsequent fluid administration — Once the child is hemodynamically stable, additional IV fluids

should be administered, calculated to replace the remaining fluid deficit over 24 to 48 hours, using IV
fluids with 0.45 to 0.9% NaCl.
A range of IV fluid protocols can be safely used to rehydrate children with DKA. This was shown in a large
randomized clinical trial (the Pediatric Emergency Care Applied Research Network FLUID Study), which
found no differences in acute or post-recovery neurologic outcomes of children with DKA treated with
more rapid versus slower rehydration [21]. Similarly, there were no differences in neurologic outcomes of
children treated with 0.9 versus 0.45% NaCl fluids. Children presenting with very low Glasgow coma scale
(GCS) scores (suggesting cerebral injury prior to treatment) were not enrolled in this study. Fluid therapy
in cerebral injury is discussed separately. (See "Diabetic ketoacidosis in children: Cerebral injury (cerebral
edema)", section on 'Pathophysiology'.)
Clinical findings and laboratory values should be carefully monitored during DKA treatment and the IV
fluid volume and composition adjusted as necessary based on the patient's fluid balance and
hemodynamic state. Administration of IV fluids should not be unnecessarily restricted (due to concerns
about causing cerebral edema), if clinical and laboratory findings suggest the need for increased fluid
volume. Potassium replacement is also a necessary component of IV fluid therapy. (See 'Serum potassium'
below.)
Hyperglycemia — Following the initial IV fluid bolus [22], an IV insulin infusion should be administered.
Insulin administration offsets insulin resistance, suppresses hepatic glucose output and ketogenesis, and
stimulates peripheral glucose uptake and metabolism to lower serum glucose concentrations and resolve
ketosis. In addition, volume expansion will lower the serum glucose concentration by dilution and via
improvements in renal perfusion. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in
adults: Epidemiology and pathogenesis".)
Insulin infusion — Insulin should be administered as an IV infusion at a rate of 0.1 unit/kg/hour [9].

Small studies comparing lower insulin infusion rates (0.05 unit/kg/hour) with this standard rate found no
differences in the rate of blood glucose decline and time to achieve the blood glucose target of 250 mg/dL
[23,24]; however, larger-scale randomized trials are needed for a more comprehensive comparison of
benefits and risks of various insulin infusion rates.
Insulin can be mixed in saline (0.45 or 0.9% NaCl) and administered in a syringe infusion pump to control
the rate of administration. The solution should be concentrated as much as possible and should be
flushed through the tubing before starting the infusion to minimize binding of insulin to the tubing and
syringe. As an example, 50 units of regular insulin are added to 50 mL of 0.45% NaCl, providing 1 unit per
mL of infusate. The syringe is then "piggybacked" into the patient's IV catheter as close as possible to the
venous site.
An initial insulin "bolus" or loading dose is unnecessary because the continuous IV insulin infusion rapidly
achieves steady-state serum insulin levels (100 to 200 microU/mL) [25,26].
For mild DKA treated in the emergency department (see 'Treatment of mild diabetic ketoacidosis' below)
or in unusual circumstances where facilities to administer IV insulin are not readily available,
subcutaneous insulin can be used. A protocol for this approach has been suggested by the International
Society for Pediatric and Adolescent Diabetes [17,27]. However, when insulin is administered
subcutaneously, absorption may be inconsistent, particularly in the setting of volume depletion and
secondary sympathetic activation, which can decrease peripheral perfusion [9,28-30].
Adding dextrose to intravenous fluids — In most patients, insulin and IV fluid treatment correct the
hyperglycemia before resolving the ketoacidosis. When the serum glucose concentration decreases to
250 to 300 mg/dL (13.9 to 16.7 mmol/L), dextrose should be added to the IV fluid infusion. This allows
continued administration of insulin, which is necessary to correct the residual ketoacidosis [9]. If the
blood glucose level falls below 150 mg/dL (8.0 mmol/L) before complete resolution of ketoacidosis, the
concentration of dextrose in the IV solution should be increased (eg, to 10 or 12.5%) to permit continued
insulin infusion. To avoid hypoglycemia or hyperglycemia, it is advisable to keep blood glucose
concentrations around 100 to 150 mg/dL in older children (5.5 to 8.3 mmol/L), or 150 to 180 mg/dL (8.3 to
11.1 mmol/L) in younger children, throughout the insulin infusion.
The "two-bag system" is an efficient method to maintain the patient's blood glucose in an acceptable
range [31]. In this technique, two bags of the selected IV fluid solution are infused concurrently, one
containing 10% dextrose and the other containing no dextrose. By adjusting the relative rates of fluid
administration from each bag, the rate of fluid and electrolyte administration can be kept constant, while
variable rates of dextrose infusion can be achieved to respond to changes in the patient's blood glucose
concentrations.
For most patients, the insulin infusion rate should be reduced only after the ketoacidosis is corrected or
nearly corrected. However, if the patient shows marked sensitivity to insulin, as in some younger or
malnourished children, it may be necessary to decrease the insulin infusion rate to avoid hypoglycemia
(eg, to 0.05 units/kg/hour), provided that the ketoacidosis continues to improve [9].
If ketoacidosis does not improve as anticipated with insulin and IV fluid infusion, the patient should be
assessed for causes of persistent acidosis, such as infection/sepsis or incorrect preparation or
administration of the insulin solution.
Electrolyte and acid-base disturbances
Serum sodium — The serum sodium concentration at the time of diagnosis of DKA can vary widely,
but many patients have mild hyponatremia due to osmotic effects of hyperglycemia. During treatment,
the serum sodium concentration should gradually rise because water moves out of the vasculature as the
blood glucose declines. To determine if the hyponatremia is appropriate for the degree of hyperglycemia,
some clinicians calculate a "corrected" sodium concentration, as described in the related topic review on
evaluation. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis", section on 'Serum
sodium'.)
The serum sodium concentration should be measured every two to four hours during treatment to
ensure that it is rising as expected, at a rate of approximately 1.6 mEq/L for every 100 mg/dL (5.5 mmol/L)
decrease in glucose concentration [32]. Failure of the serum sodium concentration to rise as the glucose
concentration declines has been associated with cerebral injury [33,34]. Therefore, lack of the expected
rise in the serum sodium concentration should prompt careful and frequent assessment of the patient's
neurologic status. (See "Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)".)
Serum potassium — Patients with DKA have a total body deficit of potassium, although potassium
levels at presentation may be normal or even increased. Potassium levels routinely decline during DKA
treatment due to insulin-stimulated transport to the intracellular space and exchange for intracellular
hydrogen ions with correction of acidosis. Therefore, potassium replacement is necessary for nearly all
DKA patients. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis".)
Potassium replacement should generally begin after initial volume expansion, concurrent with initiation
of insulin therapy. In rare cases of hyperkalemia or renal failure, potassium replacement should be
delayed. It is uncommon for patients to have hypokalemia before volume expansion; however, should this
be the case, earlier and more aggressive potassium replacement is indicated [9].
Specific recommendations based on the initial serum potassium concentration are as follows:
● If the patient is hyperkalemic, potassium replacement should not be given initially but should be
initiated when the serum potassium falls to normal and after verifying urine production/adequate
renal function (to rule out acute renal failure caused by acute tubular necrosis or renal vein
thrombosis).
● If the patient is normokalemic and voiding, potassium replacement should be given with the start
of insulin therapy. The usual starting concentration is 40 mEq/L (40 mmol/L) of potassium added to
the IV fluid solution (but not in the initial fluid bolus).
● If the patient is hypokalemic, potassium replacement should be started immediately and the insulin
infusion should be delayed until serum potassium has been restored to a near-normal concentration.
The serum potassium concentrations should be monitored hourly and the replacement adjusted as
needed.
Potassium replacement should be given as a mixture of potassium phosphate and either potassium
chloride or potassium acetate (see 'Phosphate' below). Administration of potassium chloride alone should
be avoided to reduce the risk of hyperchloremic metabolic acidosis.
Potassium replacement therapy should continue throughout IV insulin and fluid therapy. The serum
potassium should typically be monitored every two to four hours and the potassium concentration in IV
fluids adjusted as necessary to maintain normal serum potassium levels. Electrocardiographic monitoring
is recommended for most DKA patients but particularly for those with either hyperkalemia or
hypokalemia.
Metabolic acidosis — Either the calculated anion gap or measured beta-hydroxybutyrate (BOHB)

concentrations can be used to monitor resolution of ketosis. Ketoacidosis can be considered resolved
when the anion gap is normal, serum BOHB ≤1 mmol/L (10.4 mg/dL), and venous pH ≥7.3 [9,35].
Ketonuria (urine acetoacetate) may persist for some time after resolution of DKA and should not be
considered an indication of persistent ketoacidosis.
Treatment resolves acidosis through several mechanisms: Insulin promotes the metabolism of ketoacid
anions (BOHB and acetoacetic acid), which also generates bicarbonate. Insulin also halts hepatic
production of ketoacids and the release of free fatty acids from fat to fuel ketogenesis. Meanwhile,
rehydration improves renal perfusion and promotes excretion of ketone bodies. Improved tissue
perfusion also corrects lactic acidosis that may contribute to the metabolic acid load.
Hyperchloremic acidosis often develops during DKA treatment as a result of urinary ketoacid loss (which
reduces bicarbonate generation from ketoacid oxidation) and the high chloride load administered in IV
fluids. For this reason, the anion gap or serum BOHB concentrations are better indicators of resolution of
ketosis than the serum bicarbonate concentration.
Bicarbonate therapy generally should not be used in children with DKA. In addition to lack of clinical
benefit [36,37], there are potential risks from bicarbonate therapy:
● Bicarbonate therapy can decrease the acidemic stimulus for hyperventilation, leading to a rise in
partial pressure of carbon dioxide (pCO2) and causing a paradoxical fall in cerebral pH as the lipid-
soluble CO2 rapidly crosses the blood-brain barrier [38,39].
● The administration of alkali may slow the rate of resolution of ketosis [40].
● Bicarbonate therapy has been associated with the development of cerebral injury [34]. (See 'Cerebral
injury' below.)
● The rapid correction of acidosis with bicarbonate therapy may result in hypokalemia [41,42].
In rare situations (severe acidosis resulting in hemodynamic instability, life-threatening hyperkalemia),

cautious administration of bicarbonate therapy can be considered [9].
Phosphate — Cellular phosphate depletion is common in uncontrolled diabetes. Similar to the serum

potassium concentration, the serum phosphate concentration may initially be normal or elevated due to
movement of phosphate out of cells. Serum phosphate concentrations typically decline during DKA
treatment, and hypophosphatemia can occur.
Therefore, phosphate should be replaced during DKA treatment (typically by including potassium
phosphate in IV fluids), guided by intermittent monitoring of serum phosphate concentrations. Most
hypophosphatemia during DKA is asymptomatic; however, case reports describe rhabdomyolysis, muscle
weakness/paralysis, and hemolytic anemia resulting from severe hypophosphatemia during DKA
treatment [43-45]. In addition, hypophosphatemia could theoretically have adverse effects on tissue
oxygenation because it decreases erythrocyte 2,3-diphosphoglycerate concentrations, which could shift
the oxyhemoglobin dissociation curve, although the clinical relevance of this effect is debated [46]. (See
'Serum potassium' above.)
Calcium and magnesium — Mild hypocalcemia and hypomagnesemia may occur during DKA
treatment. Severe or symptomatic abnormalities are rare. Periodic monitoring of calcium and magnesium
(approximately every four to six hours during DKA treatment) is recommended.
Monitoring — Treatment of DKA requires close monitoring of the patient's clinical condition, including
changes in vital signs, neurologic status, fluid status, and metabolic state [9]. Flowcharts or electronic
spreadsheets are useful for the tracking of trends in clinical and laboratory measures.
Routine monitoring should generally include the following, as detailed in the table ( table 4):
● Blood glucose concentrations should be monitored hourly while the patient is receiving IV insulin
infusion. Venous measurements may be necessary early in treatment when blood glucose
concentrations are frequently above the detectable range of point-of-care meters.
● Electrolytes (sodium, potassium, chloride, bicarbonate, BUN, and creatinine), venous pH, and pCO2
should be measured every two to four hours. More frequent measurements may be necessary for
patients with severe electrolyte derangements or rapidly changing electrolyte levels. Serum
phosphate, calcium, and magnesium can generally be measured less frequently (every four to six
hours) unless significant derangements in these electrolytes are present.
● Clinical parameters including heart rate, respiratory rate, blood pressure, and oxygen saturation
should be monitored continuously. Inappropriate declines in heart rate or development of severe
hypertension are concerning findings suggesting possible cerebral injury.
● Neurologic examinations (GCS or other similar measures) should be done hourly to detect possible
cerebral injury. More frequent neurologic assessments may be necessary in patients with altered
mental status or severe DKA. (See 'Cerebral injury' below.)
● Fluid intake and output should be accurately measured and recorded. If the patient is neurologically
impaired or it is difficult to ascertain urine output, a urine catheter should be placed.
The initial evaluation of children with DKA is discussed separately. (See "Diabetic ketoacidosis in children:
Clinical features and diagnosis".)
Discontinuing the insulin infusion — The insulin infusion should continue at 0.05 to 0.1 units/kg/hour
until all of the following conditions are met:
● Serum anion gap reduced to normal (12±2 mEq/L) or serum BOHB ≤1 mmol/L (10.4 mg/dL)
● Venous pH >7.3 or serum bicarbonate >15 mEq/L
● Blood glucose <200 mg/dL (11.1 mmol/L)
● Patient is tolerating oral intake
Patients may continue to have mild hyperchloremic acidosis and/or ketonuria for some time after the
above conditions are met. Hyperchloremic acidosis with a normal anion gap is not a contraindication for
switching the patient to subcutaneous insulin.
The most convenient time to transition to subcutaneous insulin is before a meal. For patients using basal-
bolus insulin, the IV insulin infusion should be discontinued 15 to 30 minutes after the first injection of
rapid-acting insulin. Basal insulin can be administered either (A) at the same time as the first injection of
rapid-acting insulin, or (B) earlier (for example, the previous evening), along with a decrease in the rate of
IV insulin infusion [47].
TREATMENT OF MILD DIABETIC KETOACIDOSIS
Older children and adolescents with established diabetes and mild DKA ( table 3) can frequently be
managed in the emergency department. These patients often improve substantially after intravenous (IV)
fluid therapy and subcutaneous insulin administration. Rapid-acting insulin can be given at an initial dose
of 0.1 units/kg every one to two hours, with close monitoring of blood glucose and adjustment of insulin
dose based on the clinical response [48]. Regular insulin (given every four hours) has also been used in
these circumstances [49].
Subsequent management can be done at home, provided that acidosis has resolved after emergency
department treatment and the patient is tolerating oral fluids. The patient must have access to point-of-
care testing of both blood glucose and urine or blood ketone levels, and the caretakers must be proficient
in diabetes sick-day management (see 'Disposition' above). Ongoing home management will include
administration of rapid-acting insulin subcutaneously every three hours (with the dose adjusted
depending upon the response), rehydration with oral fluids, and frequent monitoring of both glucose and
ketone levels.
COMPLICATIONS AND MORTALITY
Reported mortality rates for DKA are consistent in developed countries, ranging from 0.15 to 0.31 percent
in national population studies in Canada, the United Kingdom, and the United States [1-3,50]. Cerebral
injury accounts for the majority of deaths (60 to 90 percent) [34,51]. Mortality is likely substantially higher
in resource-limited settings.
Cerebral injury — Cerebral injury occurs in 0.3 to 0.9 percent of children with DKA and has a high
mortality rate of 21 to 24 percent [2,21,34,50,52]. Children who have severe acidosis and/or severe
dehydration are at the greatest risk. A range of intravenous (IV) fluid protocols can be used for treatment
of DKA without apparent effect on risk for cerebral injury [21]. (See 'Subsequent fluid administration'
above.)
Cerebral injury generally develops during the first 12 hours of treatment but can also occur before
treatment [34]. Throughout the course of treatment for DKA, all children should be carefully monitored
for signs and symptoms that suggest cerebral injury, which include changes in mental status, urinary
incontinence, and new headache or recurrence of vomiting [9]. The decision to treat should be based on
clinical changes in mental status or the neurologic examination; abnormalities detectable by head
computed tomography may not be present at the time of neurologic deterioration. If DKA-related cerebral
injury is suspected, treatment should be initiated promptly using mannitol (0.5 to 1 gm/kg) and/or
hypertonic saline (3% saline, 2.5 to 5 mL/kg over 30 minutes). An approach to monitoring and intervention
is outlined in the table ( table 5) and discussed in detail separately. (See "Diabetic ketoacidosis in
children: Cerebral injury (cerebral edema)".)
Cognitive impairment — DKA may be associated with subtle neurocognitive dysfunction after recovery,
even in patients who did not have clinical evidence of cerebral injury during DKA treatment [53-56]. Subtle
alterations in memory, attention, and intelligence quotient (IQ) and changes in cerebral microstructure
have been detected in children with a history of DKA, compared with children with diabetes but no history
of DKA [53,55,57,58].
Venous thrombosis — Children with DKA are at increased risk for deep venous thrombosis, particularly
in association with femoral central venous catheter placement [59,60]. This may in part be due to a
prothrombotic state associated with DKA [61].
Pancreatic enzyme elevations — Mild elevations in serum amylase and lipase are seen in approximately
40 percent of children with DKA and are also common in adults with DKA [62,63]. In most cases, this does
not reflect acute pancreatitis. The diagnosis of acute pancreatitis should be based on clinical findings and
confirmed by a computed tomography scan. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic
state in adults: Clinical features, evaluation, and diagnosis", section on 'Serum amylase and lipase'.)
Acute kidney injury — Studies have documented a high frequency of acute kidney injury (AKI) in children
with DKA (43 to 64 percent) [64,65]. Many of these children have stage 2 or 3 AKI, suggesting intrinsic
tubular injury beyond prerenal dysfunction. Renal failure can also occur but is rare. AKI generally resolves
after recovery from DKA.
Other complications — Rare complications of pediatric DKA include cardiac arrhythmias resulting from
electrolyte derangements, pulmonary edema, multiple organ dysfunction syndrome, intestinal necrosis,
and acute pancreatitis [64,66-74]. Patients with DKA are also uniquely susceptible to rhinocerebral or
pulmonary mucormycosis, a rare and frequently fatal fungal infection [75,76]. Cases of mucormycosis
occur most commonly in patients with chronic poor glycemic control who likely have ongoing intermittent
ketosis. (See "Mucormycosis (zygomycosis)".)
PREVENTION
Attempts should be made to prevent DKA both before and after the diagnosis of diabetes has been
established. Methods that may promote earlier diagnosis of diabetes include increasing awareness
among health care providers and the general public [77] and identifying high-risk individuals through
family history, genetic, and immunologic screening. (See "Prediction of type 1 diabetes mellitus" and
"Prevention of type 1 diabetes mellitus".)
In children with established diabetes, insulin omission or other diabetes mismanagement is the most
common cause of recurrent DKA (see "Diabetic ketoacidosis in children: Clinical features and diagnosis",
section on 'Precipitating factors'). Diabetes care providers can address frequent DKA recurrences by
increasing the intensity of parental involvement in diabetes care, reinforcing diabetes self-management
education, and intensifying the involvement of the diabetes care team with the family via frequent phone
calls or clinic visits. Psychologic counseling may also be helpful. (See "Overview of the management of
type 1 diabetes mellitus in children and adolescents", section on 'Other management issues'.)
searching on "patient info" and the keyword[s] of interest.)
● Basics topics (see "Patient education: Diabetic ketoacidosis (The Basics)" and "Patient education:
Controlling blood sugar in children with diabetes (The Basics)")
● Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)")
The following is a summary of the above discussion regarding the treatment of diabetic ketoacidosis
(DKA) and is consistent with guidelines from the International Society for Pediatric and Adolescent
Diabetes [9]:
● Obtain initial laboratory studies including blood glucose, electrolytes, blood urea nitrogen (BUN) and
creatinine, venous pH and partial pressure of carbon dioxide (pCO2), hematocrit, phosphorus,
calcium, magnesium, and a urine analysis (and blood beta-hydroxybutyrate [BOHB], if available) (
table 4). Monitor blood glucose hourly while receiving intravenous (IV) insulin treatment. Measure
electrolytes, venous pH, and pCO2 every two to four hours until ketoacidosis is resolved. (See
'Laboratory testing' above and 'Monitoring' above.)
● Admission to a pediatric intensive care unit (PICU) for management of DKA is appropriate for children
with increased risk for cerebral injury, including altered consciousness, age younger than five years,
severe acidosis or hypocapnia, or high BUN. Some hospitals require PICU admission for all children
treated with IV insulin infusions. (See 'Disposition' above.)
● All children with DKA should have serial monitoring for signs and symptoms of cerebral injury until
the DKA has resolved. Signs and symptoms that suggest cerebral injury include changes in mental
status, urinary incontinence, and new headache or recurrence of vomiting ( table 5). (See 'Cerebral
injury' above.)
● Treatment of DKA involves administration of IV fluids and insulin. (See 'Dehydration' above and
'Hyperglycemia' above.)
• Initial volume expansion should be given using isotonic crystalloid solution (eg, normal saline)
administered as an IV bolus of 10 to 20 mL/kg. This initial volume expansion can be repeated if
there is continued hemodynamic instability or circulatory compromise. (See 'Initial volume
expansion' above.)
• After initial volume expansion, an IV insulin infusion should be administered at a rate of 0.1
unit/kg/hour. An insulin bolus is unnecessary and is not recommended. (See 'Insulin infusion'
above.)
• After the initial fluid bolus(es), replacement of the remaining fluid deficit should be accomplished
over 24 to 48 hours using 0.45 to 0.9% sodium chloride (NaCl). (See 'Subsequent fluid
administration' above.)
• Dextrose should be added to the IV fluids when the blood glucose concentration decreases to
250 to 300 mg/dL (13.9 to 16.7 mmol/L). Use of a "two-bag system" can facilitate adjustments of
dextrose infusion while maintaining a constant rate of fluid administration. (See 'Adding dextrose
to intravenous fluids' above.)
• All patients with DKA require potassium replacement, and serum potassium should be carefully
monitored during therapy. The timing of initiating potassium replacement should be based on
the serum potassium level at presentation. (See 'Serum potassium' above.)
● The serum anion gap or BOHB level can be used to monitor DKA resolution. (See 'Assessment of
severity' above and 'Metabolic acidosis' above.)
● Bicarbonate should not be administered to treat acidosis, except in specific rare circumstances. (See
'Metabolic acidosis' above.)
ACKNOWLEDGMENTS
The editorial staff at UpToDate would like to acknowledge George S Jeha, MD, and Morey Haymond, MD,
who contributed to an earlier version of this topic review.
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GRAPHICS
Rapid overview of the initial evaluation and treatment of moderate to severe diabetic ketoacidosis (DKA)
in children and adolescents
Clinical suspicion
DKA is the first presentation of diabetes in approximately one-third of children. Presenting symptoms:
Initial – Polyuria, polydipsia, fatigue, weight loss, nocturia, enuresis (due to hyperglycemia).
Subsequent – Nausea/vomiting, abdominal pain, fruity breath, Kussmaul breathing, sometimes altered consciousness.
Definition of DKA
DKA is defined by the presence of all of the following in a patient with diabetes:
Hyperglycemia – Blood glucose ≥200 mg/dL (11 mmol/L).
Metabolic acidosis – Venous pH <7.30 and/or serum bicarbonate <15 mEq/L.
Ketosis – Elevated levels of ketones in urine or blood*.
NOTE: Patients with marked hyperglycemia but with mild or minimal ketosis and acidosis may have HHS, which is a metabolic emergency
(refer to UpToDate content on HHS).
Laboratory assessment
Immediate (point-of-care) testing:
Blood glucose.
Urine ketones and/or blood BOHB (if available).
Laboratory tests:
Serum glucose
Serum electrolytes, creatinine, urea nitrogen
Venous pH and pCO 2
Calcium, phosphorus, magnesium
Hemoglobin A1c ¶
Urinalysis
Severity of DKA:
Mild – pH 7.2 to 7.3; bicarbonate 10 to 15 mEq/L.
Moderate – pH 7.1 to 7.2; bicarbonate 5 to 10 mEq/L.
Severe – pH <7.1; bicarbonate <5 mEq/L.
Degree of dehydration: Patients with DKA are usually more dehydrated than suggested by the clinical examination. Initial fluid management
should be based on:
Mild DKA – Assume 5 to 7% fluid deficit.
Moderate to severe DKA – Assume 7 to 10% fluid deficit.
Neurologic status: Patients with abnormal mental status may have cerebral injury (refer to complications below). Monitor mental status
closely, and treat promptly if it fails to improve or worsens during initial treatment.
Management
Fluids:
Give 10 to 20 mL/kg of 0.9% NaCl (normal saline), or other isotonic solution, administered as an IV bolus:
Mild DKA – 10 mL/kg bolus.
Moderate or severe DKA – 20 mL/kg bolus.
Additional boluses may be given if necessary, based on cardiovascular status. Larger fluid volumes may be needed for patients presenting
with mixed features of DKA and HHS, regardless of the level of acidosis.
Hypovolemic shock is a rare occurrence in DKA, and should prompt evaluation for other causes, such as sepsis.
Following initial fluid resuscitation, replace the estimated fluid deficit over 24 to 48 hours, in addition to maintenance fluids. IV fluids with
sodium content between 0.45 and 0.9% NaCl should be used as the replacement fluid.
Electrolytes:
Sodium: Serum sodium levels are generally low (due to dilutional effect of hyperglycemia), but may be normal or even high (due to water
loss). If serum sodium is low, it should rise as hyperglycemia is corrected.
Potassium: The timing of potassium replacement depends on the initial serum potassium concentration: Δ
Low potassium (<3.5 mEq/L) – Add 40 mEq/L of potassium to IV fluids as soon as possible, and delay insulin therapy until serum
potassium is in the normal range.
Normal potassium (3.5 to 4.5 mEq/L) – Add 40 mEq/L of potassium to IV fluids when insulin therapy is started.
High potassium (>4.5 mEq/L) – Monitor every hour and begin potassium replacement when serum potassium decreases to the
normal range.
Provide potassium as potassium phosphate plus either potassium chloride or potassium acetate.
Insulin: After the initial fluid bolus, begin a continuous insulin infusion at 0.1 units/kg per hour. ◊ Mix 50 units of regular insulin in 50 mL of
saline (0.45% or 0.9% NaCl), such that 1 mL of the infusion provides 1 unit of insulin.
Glucose: Add dextrose to the IV fluids when the blood glucose falls below approximately 300 mg/dL (17 mmol/L), to prevent hypoglycemia
during treatment. §
Monitoring
Record vital signs and check neurologic status hourly, as well as fluid intake (IV and oral) and losses.
Measure blood glucose hourly. Measure electrolytes, venous pH and pCO 2 every two to four hours. Measure calcium, phosphorus, and
magnesium every four to six hours. More frequent monitoring may be necessary for patients with severe electrolyte derangements or rapid
changes in these laboratory values.
Complications
Cerebral injury:
Risk factors – Greater degrees of acidosis, hypocapnia, dehydration and younger age.
Symptoms and signs – Monitor neurologic status carefully during the first 12 to 24 hours of DKA treatment. Suspicious symptoms
include changes in mental status, new or worsening headache, recurrence of vomiting, and age-inappropriate incontinence. ¥
Initiate treatment promptly with 0.5 to 1 g/kg of mannitol if cerebral injury is suspected based on signs and symptoms. Do not rely on
cerebral imaging to make or exclude the diagnosis.
Venous thrombosis: Avoid central venous catheters, if possible, because of increased risk for venous thrombosis in these patients.
Mild pancreatic enzyme elevations are common in patients with DKA; no specific therapy is needed other than correction of DKA unless other
symptoms of pancreatitis are present.
This table outlines a typical protocol for management of DKA in an urgent care setting. Somewhat different approaches to fluid
volumes and composition may be used, according to patient characteristics and clinician preference.
DKA: diabetic ketoacidosis; HHS: hyperglycemic hyperosmolar state; BOHB: beta-hydroxybutyrate; pCO 2 : partial pressure of carbon dioxide; NaCl:
sodium chloride; IV: intravenous.
* Ketosis is ideally determined by measuring serum BOHB in the laboratory or by a point-of-care device. BOHB concentrations ≥3 mmol/L (31 mg/dL)
are consistent with DKA.
¶ A1c is useful in patients with known diabetes, to evaluate the degree of metabolic control, or in rare cases in which the diagnosis of diabetes/DKA is
uncertain.
Δ Regardless of the initial measured serum potassium concentration, patients with DKA have a total body potassium deficit, and therapy with insulin
and fluids will lower serum potassium concentration. Use of a mixture of potassium salts (potassium phosphate, plus either potassium chloride or
potassium acetate) is recommended, to decrease chloride administration and replace phosphorus losses.
◊ For mild DKA treated in the emergency department or in unusual circumstances where facilities to administer IV insulin are not readily available,
subcutaneous insulin can be used.
§ A "two bag system" is a method to maintain the patient's blood glucose in an acceptable range. In this technique, two bags of the selected IV fluid
solution are infused concurrently, one containing 10% dextrose and the other containing no dextrose. By adjusting the relative rates of fluid
administration from each bag, the rate of fluid and electrolyte administration can be maintained constant, while varying the rate of dextrose infusion to
respond to changes in the patient's blood glucose concentrations.
¥ Altered mental status in DKA can be caused by a variety of factors other than cerebral injury, including acidosis, other metabolic derangements, and
sleep deprivation. Nonetheless, clinicians should maintain a high level of suspicion for evidence of cerebral injury and intervene promptly if the
diagnosis is suspected. Refer to UpToDate content on signs and symptoms cerebral injury in DKA.

Glasgow Coma Scale and Pediatric Glasgow Coma Scale
Glasgow Coma
Sign Pediatric Glasgow Coma Scale [2] Score
Scale [1]
Eye opening Spontaneous Spontaneous 4
To command To sound 3
To pain To pain 2
None None 1
Verbal Oriented Age-appropriate vocalization, smile, or orientation to sound; interacts (coos, babbles); 5
response follows objects
Confused, disoriented Cries, irritable 4
Inappropriate words Cries to pain 3
Incomprehensible sounds Moans to pain 2
None None 1
Motor Obeys commands Spontaneous movements (obeys verbal command) 6

response
Localizes pain Withdraws to touch (localizes pain) 5
Withdraws Withdraws to pain 4
Abnormal flexion to pain Abnormal flexion to pain (decorticate posture) 3
Abnormal extension to Abnormal extension to pain (decerebrate posture) 2

pain
None None 1
Best total score 15
The Glasgow Coma Scale (GCS) is scored between 3 and 15, with 3 being the worst and 15 the best. It is composed of 3 parameters: best eye
response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example,
E2V3M4 results in a GCS of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a
score of 8 or less represents severe brain injury. The Pediatric Glasgow Coma Scale (PGCS) was validated in children 2 years of age or younger.
Data from:
1. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2:81.
2. Holmes JF, Palchak MJ, MacFarlane T, Kuppermann N. Performance of the pediatric Glasgow coma scale in children with blunt head trauma. Acad Emerg
Med 2005; 12:814.

Assessment of severity of diabetic ketoacidosis in children
Defining features Severe Moderate Mild
Venous pH <7.1 7.1 to <7.2 7.2 to <7.3
Serum bicarbonate (mEq/L) <5* 5 to 9 10 to <15*
Venous pH is the most accurate measure of acidosis in patients with DKA. However, measurements of serum bicarbonate may be used alone,
especially in resource-limited settings, and are closely correlated with venous pH.

* For particularly vulnerable patients such as young children or in resource-limited settings, higher thresholds for bicarbonate may be used for
increased sensitivity, eg, bicarbonate <7 mEq/L for severe DKA and <18 mEq/L for mild DKA.
Data from: von Oettingen J, Wolfsdorf J, Feldman HA, Rhodes ET. Use of serum bicarbonate to substitute for venous pH in new-onset diabetes. Pediatrics 2015;
136:e371.

Monitoring of children during treatment for diabetic ketoacidosis
Parameter Frequency Comments
Vital signs Hourly Decreased resting heart rate or increased blood pressure suggest
possible cerebral injury.
Fluid intake and output Hourly
Neurologic status At least hourly Use GCS or similar assessment (refer to UpToDate content on cerebral
injury in children with DKA).
Blood glucose Hourly Use a point-of-care meter, but cross-check with laboratory tests to
ensure correlation.
Blood BOHB Every 2 to 4 hours, if available Perform if test is available.

Resolution of DKA is indicated by BOHB ≤1 mmol/L (10.4 mg/dL) on 2
successive occasions.
Electrolytes, BUN, creatinine, Every 2 to 4 hours Timing of initiating potassium replacement depends on initial serum
venous blood gas potassium level (refer to UpToDate topic text).
Calculate the anion gap:
Anion gap = Sodium – (Chloride + bicarbonate)
Normal anion gap = 12±2; indicates resolution of DKA
Calculate the corrected sodium concentration:
Corrected sodium = Measured sodium + 1.6 (Glucose – 100
mg/dL)/100
Note: For glucose measured in mmol, use: (Glucose – 5.56)/5.56
Calcium, magnesium, phosphorus Every 4 to 6 hours More frequent measurements may be required for patients with
significant derangements in these laboratory values.
ECG monitoring Continuous, if available Required for patients with severe DKA or significant electrolyte
abnormalities (particularly potassium), but recommended for all
patients.
GCS: Glasgow Coma Scale; DKA: diabetic ketoacidosis; BOHB: beta-hydroxybutyrate; BUN: blood urea nitrogen; ECG: electrocardiogram.

Cerebral injury (cerebral edema) in children with diabetic ketoacidosis: Rapid overview
Risk factors
Severe acidosis at presentation
Substantially elevated BUN at presentation
Severe hypocapnia
Young child (<5 years) and/or new onset of diabetes – These are not independent risk factors but are markers for more severe DKA because
they are associated with delayed diagnosis of DKA
Diagnosis of cerebral injury*

Minor criteria (moderately suspicious findings)
Headache – Although headache is frequently present at diagnosis, worsening or recurrence of headache during treatment is suspicious for
cerebral injury
Vomiting – Vomiting is suspicious if it develops or recurs during treatment
Irritability, lethargy, or not easily aroused from sleep – These features are suspicious particularly if they occur or worsen after initiation of
therapy
Elevated BP (eg, diastolic BP >90 mmHg).
Major criteria (very suspicious findings)
Abnormal or deteriorating mental status after initiation of therapy, agitated behavior, or fluctuating level of consciousness
Incontinence inappropriate for age
Inappropriate slowing of heart rate – eg, decline more than 20 beats per minute that is not attributable to improved intravascular volume
or sleep state
Diagnostic criteria (signs of significant brain injury, increased intracranial pressure, or brain herniation)
Abnormal motor or verbal response to pain
Decorticate or decerebrate posture
Abnormal pupillary response or other CN palsy ¶
Abnormal neurogenic respiratory pattern – eg, grunting, tachypnea, Cheyne-Stokes respiration, apnea
Treatment
Indications*
Child with DKA and:

1 diagnostic criterion, or
2 major criteria, or
1 major and 2 minor criteria, or
1 major and 1 minor criterion (if child under 5 years of age)
The decision to treat should be based on signs and symptoms; do not rely on neuroimaging to make or exclude the diagnosis
Interventions
Give mannitol, 0.5 to 1 g/kg intravenously over 15 minutes; the mannitol dose may be repeated in 30 minutes, if there is no initial
response Δ
Adjust fluid administration as indicated to maintain normal BP and optimize cerebral perfusion
Avoid hypotension that might compromise cerebral perfusion pressure
Neurosurgery consultation regarding further management, including possible invasive monitoring of intracranial pressure in selected
cases
BUN: blood urea nitrogen; DKA: diabetic ketoacidosis; BP: blood pressure; CN: cranial nerve.
* These clinical criteria and indications are based upon an evidence-based protocol, as outlined in the source below.
¶ Key steps are to evaluate extraocular movements (CN III, IV, and VI) and pupillary dilation and reactivity (CN II and III).
Δ Hypertonic (3%) saline (2.5 to 5 ml/Kg over 10 to 15 minutes) can be used as an alternative to mannitol or if initial treatment with mannitol does not
result in improved mental status.
Adapted from: Muir AB, Quisling RG, Yang MCK, Rosenbloom AL. Cerebral edema in childhood diabetic ketoacidosis. Diabetes Care 2004; 27:1541.

[Glycogen storage disease type 1a]. Adrienne G Randolph, MD, MSc Equity Ownership/Stock Options: Abbvie.
Grant/Research/Clinical Trial Support: Genentech [Influenza critical illness]. Consultant/Advisory Boards: La Jolla
Pharmaceuticals [Pediatric refractory shock]. Alison G Hoppin, MD Nothing to disclose
evidence.

Diabetic ketoacidosis in children: Cerebral injury (cerebral

edema)
Section Editors: Joseph I Wolfsdorf, MD, BCh, Adrienne G Randolph, MD, MSc
Literature review current through: Dec 2020. | This topic last updated: Nov 12, 2020.
INTRODUCTION
Cerebral injury (cerebral edema) is an uncommon but potentially devastating consequence of diabetic
ketoacidosis (DKA). This complication is far more common among children with DKA than among adults.
Children presenting with more severe DKA (higher blood urea nitrogen levels and more severe acidosis and
hypocapnia) are at greatest risk [1-4]. These children are often younger and newly diagnosed with diabetes
due to the greater difficulty detecting symptoms in these children, which leads to delayed diagnoses and
more severe presentations. Symptoms of cerebral injury typically emerge during treatment for DKA but may
be present prior to initiation of therapy. In most cases, symptoms become apparent between 3 and 12 hours
after the initiation of therapy and, rarely, later than 24 hours [2,5-7].
The pathophysiology, diagnosis, and treatment of cerebral injury in children with DKA will be discussed here.
The diagnosis and treatment of DKA in children are discussed separately. (See "Diabetic ketoacidosis in
children: Clinical features and diagnosis" and "Diabetic ketoacidosis in children: Treatment and
complications".)
INCIDENCE
Clinically significant cerebral injury occurs in 0.3 to 0.9 percent of episodes of DKA in children and has a
mortality rate of 20 to 25 percent [1-3,8,9]. Overall mortality rates for DKA in children and adolescents range
from 0.15 to 0.51 percent in national population studies in Canada, the United Kingdom, and the United
States [1,5,10-13]; 50 to 80 percent of diabetes-related deaths in children are caused by cerebral injury [2,14].
Subclinical cerebral edema, as detected by ventricular narrowing on imaging studies or alterations in brain
water distribution on magnetic resonance imaging (MRI), has been reported in the majority of children with
DKA, even in the absence of neurologic signs or symptoms ( image 1) [6,15,16]. In a study of 41 children
with DKA, the width of the lateral ventricles (measured by MRI) was significantly smaller in patients during
treatment for DKA than after recovery (mean width 9.3±0.3 versus 10.2±0.3 mm, respectively) [16]. Fifty-six
percent of the children had ventricular narrowing during treatment. In this study, ventricular narrowing was
more common in children who had subtle mental status abnormalities during DKA (abnormal Glasgow
Coma Scale scores). In addition, subclinical cerebral edema detected by diffusion-weighted MRI is more
severe in children who present with risk factors for clinically apparent cerebral injury (greater
hyperventilation, higher blood urea nitrogen levels) [17].
Multiple lines of evidence suggest that subtle cerebral injury occurs commonly during DKA, and it is possible
that clinically apparent cerebral injury may represent the most severe presentation of an otherwise common
phenomenon. As an example, studies demonstrate subtle alterations in cognitive functioning, including
deficits in memory, attention, and verbal intelligence quotient (IQ), in children with type 1 diabetes who have
had one or more DKA episodes compared with children with diabetes without DKA history [18-20]. In a large
study involving 1134 children with diabetes, a single episode of DKA was associated with subtle deficits in
memory shortly after diagnosis of diabetes [21]. Repeated DKA episodes over time were associated with
sizable declines in IQ. In addition, studies using MRI document cerebral microstructural alterations in
children after recovery from DKA [19,22], while other studies have found elevated levels of neuron-specific
enolase, a marker of neuronal injury, in children with uncomplicated DKA, as well as cerebral metabolic
alterations suggestive of hypoxia/ischemia [23-26].
PATHOPHYSIOLOGY
Initial theories based on osmotic change — The cause of DKA-related cerebral injury is not fully
understood. In the 1980s, retrospective studies documented an increased frequency of cerebral injury in
children who received intravenous fluids at higher rates [27,28]. It was therefore proposed that cerebral
injury results from osmotic changes and fluid shifts during DKA. According to this theory, the hyperosmolar
state during DKA causes brain cells to accumulate intracellular osmolytes. During DKA treatment, a decline
in intravascular osmolality results in osmotically mediated movement of water into brain cells, causing
cerebral edema and increased intracranial pressure and resulting in cerebral injury [27,29,30]. This theory
was widely adopted, leading many pediatric DKA guidelines to recommend conservative rehydration
strategies with slow intravenous infusions of isotonic fluids.
Over time, however, multiple lines of evidence have challenged the theory that cerebral injury is caused
primarily by osmotic changes and fluid shifts:
● PECARN FLUID trial (2018) – The most definitive investigation of the relationship of intravenous fluid
treatment to cerebral injury in children with DKA comes from the "PECARN FLUID" (Pediatric Emergency
Care Applied Research Network, Fluid Therapies Under Investigation in DKA) trial [31]. This trial
examined neurologic outcomes of DKA in 1389 children randomized to one of four intravenous fluid
treatment regimens to compare rapid versus slow rehydration and use of 0.45 versus 0.9% sodium
chloride (NaCl) fluids, using a 2 × 2 factorial design. There were no significant differences between arms
in mental status during DKA treatment (rates of decline in Glasgow Coma Scale scores or alterations in
tests of working memory), nor in rates of clinically apparent cerebral injury. Contrary to previous
hypotheses, analyses of the subgroup with more severe DKA (pH or partial pressure of carbon dioxide
[pCO2] in the lowest quartiles of the study population) suggested that more rapid fluid infusion was
associated with more rapid improvement in scores on working memory tests during DKA treatment.
Tests of memory and intelligence quotient (IQ) two to six months after recovery from DKA showed no
differences between the four fluid treatment arms. These data underscore the lack of causal association
between intravenous fluid therapies and DKA-related cerebral injury, at least within the range used in
this trial.
● Additional evidence against osmolar change as a cause of DKA-related cerebral injury – Early
studies comparing children with DKA-related cerebral injury with those with uncomplicated DKA were
limited because they were not adjusted for factors related to DKA severity. By contrast, subsequent
larger studies adjusting for DKA severity (including degree of acidosis and dehydration) did not find
associations between fluid infusion rates and cerebral injury [2]. In addition, properly controlled studies
of risk factors for DKA-related cerebral injury have not found associations between higher initial glucose
levels or higher osmolality and risk for cerebral injury [2,3]. Although a lesser rise in the serum sodium
level during DKA treatment has been found to be associated with risk for cerebral injury, changes in
glucose and osmolality have not been similarly associated [2]. Furthermore, case reports and case series
document the occurrence of severe and even fatal cerebral injury or cerebral edema occurring before
treatment of DKA, including reports of deaths at home in children with diabetes found to have cerebral
injury or cerebral edema at autopsy ( image 1) [5,7,32]. Studies demonstrate that 5 to 19 percent of
clinically apparent DKA-related cerebral injuries occur before initiation of DKA treatment in the
emergency department [1,2], suggesting that intravenous fluid therapy cannot be solely responsible for
causing cerebral injury.
Studies documenting imaging findings in children with severe DKA-related brain injuries also provide
important information regarding causation. One large case series examined radiographic findings in
children with profound neurologic alterations during DKA who were diagnosed with "cerebral edema" [33].
In this series, 39 percent had no evidence of edema on radiographic studies done at the time of neurologic
decline but developed edema hours to days later. These findings suggest that edema may be a consequence
of injury rather than the main cause, similar to edema that results from cellular energy failure during
hypoxic-ischemic brain injuries. Studies using magnetic resonance imaging (MRI) to evaluate changes in
brain water distribution during DKA also provide evidence to inform theories on causation. Diffusion-
weighted MRI studies demonstrate that subclinical cerebral edema occurring during DKA in children is
vasogenic, with increased accumulation of water in the extracellular space [34-36]. This finding is counter to
what would be expected from edema caused by osmotic fluid shifts, where increased intracellular water
content (cell swelling) would be anticipated, and suggests that abnormalities in blood-brain barrier function
may occur during DKA [37,38].
Current theories of cerebral hypoperfusion and neuroinflammation — Several lines of evidence suggest

that cerebral hypoperfusion may occur during DKA and that hypoperfusion/reperfusion may play a role in
causing DKA-related cerebral injury.
● Fluctuation in cerebral blood flow – In a rat model, studies using MR spectroscopy to measure cerebral
metabolism during DKA demonstrate elevated levels of lactate in the brain, as well as decreased high-
energy phosphate levels and low N-acetylaspartate:creatine ratio, a marker of neuronal integrity (
figure 1) [37]. In humans who died from DKA-related cerebral injury, autopsy results also show
findings similar to hypoxic-ischemic injury [39-41]. In addition, clinical studies demonstrate that factors
affecting cerebral blood flow during DKA (dehydration and hypocapnia) are most strongly associated
with risks of both life-threatening and more subtle cerebral injury in children [2,17]. In a rat DKA model,
cerebral blood flow is reduced and gradually rises during treatment with insulin and intravenous fluids
[42].
Although there are no data documenting cerebral blood flow during untreated DKA (ie, before
treatment commences) in humans, several studies have assessed cerebral blood flow during DKA
treatment. These studies show elevated cerebral blood flow, along with increased extracellular water
content, consistent with hyperemia and associated vasogenic cerebral edema [34-36]. Studies using
near-infrared spectroscopy during DKA treatment show elevated regional cerebral oxygen saturation,
suggesting that cerebral blood flow is elevated in excess of metabolic demand [35]. This abnormal
elevation in cerebral blood flow may persist for hours after DKA resolution. Studies using transcranial
Doppler ultrasound also document abnormalities in cerebral autoregulation during DKA [43,44].
● Inflammatory responses – Although alterations in cerebral blood flow appear to play a role in DKA-
related cerebral injury, the severity of cerebral blood flow reduction caused by dehydration and
hypocapnia alone is unlikely to be sufficient to cause substantial ischemic injury. Studies suggest that
inflammatory factors present during DKA may act synergistically with hypoperfusion/reperfusion to
cause injury or may increase the vulnerability of the brain to ischemic injury. DKA elicits a marked
systemic inflammatory response, and several inflammatory factors may play a role in causing
neuroinflammation or affecting the function of the blood-brain barrier [45-48]:
• As an example, children with DKA have altered matrix metalloproteinases (MMP) levels and these
are correlated with levels of various inflammatory mediators (CXCL8, IL1-beta), some of which also
increase leukocyte adhesion to blood-brain barrier endothelia [49,50]. MMPs are endopeptidases
that degrade tight junction proteins and endothelial basement membranes, allowing fluid and
blood-borne proinflammatory/neurotoxic proteins to invade the central nervous system. MMPs
have been implicated as mediators of blood-brain barrier dysfunction in many disease states
characterized by systemic inflammation with associated cerebral injury. The observed patterns of
change in MMPs during DKA are similar to those documented during cerebral ischemia/reperfusion
in studies of stroke [49].
• Furthermore, studies using immunohistochemistry in a rat DKA model demonstrate a

neuroinflammatory response involving reactive astrogliosis in the hippocampus and activation of
microglia in most brain regions ( picture 1) [51]. Microglia are inflammatory cells that respond to
alterations in levels of cytokines becoming activated during various types of cerebral injury,
including the secondary injury that occurs during reperfusion after ischemia [52,53]. These studies
therefore suggest that various inflammatory pathways may participate in DKA-related cerebral
injury.
The precise roles of these inflammatory responses and their relationships to alterations in cerebral
perfusion are yet to be delineated.
CLINICAL PRESENTATION AND EVALUATION
Risk factors — Studies documenting risk factors for clinically apparent cerebral injury in children with DKA
are useful in identifying children requiring more intensive monitoring [1-4]. Important risk factors for
cerebral injury are:
● Severe acidosis at presentation of DKA [1,3,29].
● Increased blood urea nitrogen at presentation (which may represent a greater degree of hypovolemia)
[1,2].
● A lower initial partial pressure of carbon dioxide (pCO2) [2,4].
● Failure of the measured serum sodium to rise during DKA treatment [2,27]. Serum sodium should rise
by approximately 1.6 mEq/L for every 100 mg/dL (5.5 mmol/L) decrease in glucose concentration. (See
"Diabetic ketoacidosis in children: Treatment and complications", section on 'Serum sodium'.)
● Young age (<5 years) and new onset of diabetes – These are not independent risk factors, but they are
markers for more severe DKA because they are associated with delayed diagnosis of DKA.
Use of bicarbonate therapy for correction of acidosis in DKA is also associated with increased risk of cerebral
injury [2,54] and is no longer recommended for pediatric DKA treatment, except under specific rare
circumstances. (See "Diabetic ketoacidosis in children: Treatment and complications".)
Monitoring protocol
● Initial evaluation – All children presenting with DKA should have a rapid assessment of level of
consciousness using the Glasgow Coma Scale ( table 1B) or a similar neurologic evaluation, with
particular attention to findings associated with cerebral injury (see 'Clinical criteria' below). Assessment
of risk factors for cerebral injury is also helpful in determining the level of monitoring that is necessary.
(See 'Risk factors' above.)
● Care setting – Patients with risk factors for cerebral injury (see 'Risk factors' above), abnormalities in
mental status, or other findings concerning for cerebral injury (see 'Clinical criteria' below) should be
managed in a specialized unit in which careful clinical and biochemical monitoring can occur (most
commonly in a pediatric intensive care unit) because abrupt deterioration in neurologic status can occur
and should be treated immediately.
● Monitoring – Neurologic monitoring using the Glasgow Coma Scale or other similar assessments should
be repeated at least hourly during the first 12 to 24 hours of treatment ( table 1B). More frequent
assessments may be necessary for children with altered mental status.
DIAGNOSIS
The presence of any of the symptoms listed below should raise suspicion for the possibility of cerebral injury
[33]. Altered mental status in children with DKA can be caused by a variety of factors other than cerebral
injury, including acidosis, other metabolic derangements, and sleep deprivation. Nonetheless, clinicians
should maintain a high level of suspicion for evidence of cerebral injury and intervene promptly if the
diagnosis is suspected.
Clinical criteria — The following criteria have been proposed for clinical diagnosis of DKA-related cerebral
injury ( table 1A) (modified from [33]):
● Minor criteria (moderately suspicious findings):
• Headache – Although headache is frequently present at diagnosis, worsening or recurrence of

headache during treatment is concerning
• Vomiting – Vomiting is suspicious if it develops or recurs during treatment
• Irritability, lethargy, or not easily aroused from sleep – These features are particularly suspicious if
they occur or worsen after initiation of therapy
• Elevated blood pressure – Eg, diastolic blood pressure >90 mmHg
● Major criteria (very suspicious findings):
• Abnormal or deteriorating mental status after initiation of therapy, agitated behavior, or fluctuating
level of consciousness
• Inappropriate slowing of heart rate – Eg, decline more than 20 beats per minute that is not
attributable to improved intravascular volume or sleep state
• Incontinence inappropriate for age
● Diagnostic criteria (signs of significant brain injury, increased intracranial pressure, or brain
herniation):
• Abnormal motor or verbal response to pain
• Decorticate or decerebrate posture
• Abnormal pupillary response or other cranial nerve (CN) palsy – Key steps are to evaluate
extraocular movements (CN III, IV, and VI) and pupillary dilation and reactivity (CN II and III) (see
"Detailed neurologic assessment of infants and children", section on 'Cranial nerves')
• Abnormal neurogenic respiratory pattern – Eg, grunting, abnormal tachypnea, Cheyne-Stokes

respiration, apnea
In some cases, DKA-related cerebral injury may have other manifestations. Seizures have been described in
some patients, as has a rapidly rising serum sodium level caused by diabetes insipidus that may occur in
association with cerebral injury.
Provisional diagnosis and indications for treatment — We suggest immediate treatment for patients with
any of the following, using the criteria above [33]:
● One diagnostic criterion

● Two major criteria
● One major and two minor criteria
● One major and one minor criterion (for children under five years of age)
(See 'Treatment' below.)
TREATMENT
Treatment for cerebral injury should be initiated as soon as the disorder is diagnosed, based on the clinical
criteria outlined above. It is appropriate to treat promptly based on clinical suspicion because untreated
cerebral injury has a high rate of mortality and morbidity, and treatment with a hyperosmolar agent
(mannitol or hypertonic saline) may be beneficial. Evidence supporting the use of hyperosmolar treatments
for cerebral injury consists of case reports and case series documenting rapid clinical improvement after
administration of these agents in DKA-associated cerebral injury [55-58] and successful use in patients with
cerebral edema due to other causes.
Although cerebral edema may be detectable on imaging studies in some children, edema is not uniformly
present and may develop hours to days after neurologic decline [33]. For this reason, initial treatment
decisions should not rely on findings from imaging studies [59]. Imaging studies should be considered after
initiating treatment, depending on the clinical response, to detect cerebral herniation or impending
herniation, cerebral infarction, hemorrhage, or thrombosis. All patients with suspected cerebral injury
should be managed in an intensive care unit.
Treatment for cerebral injury consists of the following [60]:
● Immediately give mannitol 0.5 to 1 g/kg intravenously over 10 to 15 minutes. Mannitol administration
can be repeated after 30 minutes. Effects of mannitol generally are rapidly apparent (within 15 minutes).
● Adjust fluid administration as indicated to maintain normal blood pressure and optimize cerebral
perfusion. Avoid hypotension that might compromise cerebral perfusion pressure.
● Administer oxygen as needed to maintain normal oxygen saturation.
● Intubation may be necessary for patients with apnea or abnormal respirations or to protect the airway.
Hyperventilation below the partial pressure of carbon dioxide (pCO2) level appropriate to the patient's
level of acidosis has been associated with poor outcomes of DKA-related cerebral injury and should be
avoided unless absolutely necessary to treat elevated intracranial pressure [8].
● Monitoring of intracranial pressure may be necessary in selected patients.
The mechanism of action of mannitol in DKA-related cerebral injury is unclear. Improvements in mental
status are often more rapidly evident than would be anticipated based on reductions in edema. These effects
may result from improvements in blood viscosity and red blood cell deformability that have been described
with mannitol treatment, with beneficial effects on cerebral blood flow [61,62].
Hypertonic (3%) saline (2.5 to 5 mL/kg over 10 to 15 minutes) can be used if initial treatment with mannitol
does not result in improved mental status. For most patients, we suggest using hypertonic saline as a
secondary intervention in patients with progressive symptoms and no response to mannitol. Some experts
use hypertonic saline as a first-line treatment, especially for children who present with signs and symptoms
of cerebral injury in the early phases of treatment, while they are still severely dehydrated and acidotic. One
retrospective study found higher mortality rates in patients treated with hypertonic saline alone than in
those treated with mannitol; however, these results may not reflect a causal association and should be
interpreted with caution [12]. (See "Elevated intracranial pressure (ICP) in children: Management", section on
'Hyperosmolar therapy'.)
OUTCOME
The mortality rate among children with DKA who develop definite cerebral injury is approximately 20 to 25
percent. Among survivors, approximately 21 to 26 percent have permanent neurologic sequelae [8,14,63].
Risk factors for death or survival in a vegetative state were identified in a retrospective multicenter study of
61 children [8]:
● Elevated blood urea nitrogen at the time of initial presentation

● Intubation with aggressive hyperventilation (targeting a partial pressure of carbon dioxide [pCO2] of less
than 22 mmHg)
● Severe neurologic compromise at diagnosis of cerebral injury (all patients who either died or survived in
a persistent vegetative state had Glasgow Coma Scale scores ≤7 when cerebral injury was diagnosed)
● Cerebral injury (cerebral edema) occurs in 0.3 to 0.9 percent of cases of diabetic ketoacidosis (DKA) in
children and is responsible for most DKA-related deaths. Among children with DKA who develop cerebral
injury, the mortality rate is 20 to 25 percent and 21 to 26 percent of survivors have permanent
neurologic sequelae. (See 'Incidence' above and 'Outcome' above.)
● More subtle forms of cerebral injury occur commonly during DKA. A single episode of DKA may be
associated with subtle deficits in memory, and multiple episodes of DKA are associated with cognitive
declines. (See 'Incidence' above.)
● Children who present with elevated blood urea nitrogen or more profound acidosis and hypocapnia are
at greatest risk for cerebral injury. Younger children and those with new onset of diabetes are more
likely to present with these risk factors because recognition of DKA is often delayed in these patients.
(See 'Risk factors' above.)
● Children undergoing DKA treatment should be monitored for signs and symptoms of cerebral injury (
table 1A-B). (See 'Monitoring protocol' above and 'Clinical criteria' above.)
● Changes detectable on cerebral imaging studies may occur late in the development of cerebral injury.
Therefore, the decision to treat should be based on clinical evaluation ( table 1A). Imaging may be
useful to exclude other causes of neurologic deterioration but should not delay treatment. (See
'Treatment' above.)
● Cerebral injury is associated with high mortality and morbidity and must be treated promptly with
osmotic therapy when strongly suspected based on clinical criteria, even before imaging is obtained (
table 1A) (see 'Treatment' above):
• We suggest treatment with mannitol (0.5 to 1 g/kg) rather than hypertonic saline (Grade 2C). Very
limited evidence suggests that hypertonic saline may be associated with a higher mortality rate than
mannitol.
If there is no clinical improvement in mental status, the same dose should be repeated after 30
minutes. It is also reasonable to use hypertonic saline (2.5 to 5 mL/kg over 10 to 15 minutes) if initial
treatment with mannitol does not result in improved mental status.
• Intubation and mechanical ventilation may be required; however, aggressive hyperventilation

(beyond the level appropriate to the patient's degree of acidosis) should be avoided.
ACKNOWLEDGMENTS
The editorial staff at UpToDate would like to acknowledge George Jeha, MD, and Morey W Haymond, MD,
who contributed to an earlier version of this topic review.
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GRAPHICS
Computed tomography scan showing cerebral edema in diabetic ketoacidosis
A 12-year-old boy in DKA (left) and following recovery from the DKA episode (right). Axial FLAIR images (1.5 T) demonstrate that the
intercaudate distance (A) is smaller during DKA than after recovery, suggesting mild diffuse brain swelling. No parenchymal signal
abnormality is seen. Although slight changes in position, hydration state, or serum osmolality can affect this measurement in a single
patient, narrowing of the cerebral ventricles in children in DKA has been found to be statistically significant across a number of patients,
suggesting that some degree of brain swelling occurs during DKA.
Reprinted by permission from: Springer: Pediatric Radiology. Wootton-Gorges SL, Glaser NS. Imaging of the brain in children with type I diabetes mellitus.
Pediatr Radiol 2007; 37:863. Copyright © 2007. https://link.springer.com/journal/247.

Cerebral metabolic abnormalities suggesting cerebral injury in a child with diabetic ketoacidosis
Proton magnetic resonance spectroscopy in a 13-year-old girl with DKA. Spectra from the right basal ganglia reveal a lower NAA/Cr ratio during the
DKA episode (A), compared with recovery (B). The lower NAA/Cr ratio during the DKA episode suggests cerebral hypoperfusion.
DKA: diabetic ketoacidosis; NAA: N-acetylaspartate; Cr: creatinine.
Republished with permission of the American Society of Neuroradiology, from Wootton-Gorges SL, Buonocore MH, Kuppermann N, et al. Cerebral proton magnetic
resonance spectroscopy in children with diabetic ketoacidosis. Am J Neuroradiol 2007; 28(5):895. Permission conveyed through Copyright Clearance Center, Inc.

Neuroinflammation (reactive astrogliosis) in a rat model of juvenile diabetic ketoacidosis
Representative brain sections stained for GFAP (red) and NeuN (green) in the dentate gyrus region of the hippocampus. GFAP expression
was signiﬁcantly increased in the hippocampus during DKA, with peak values observed after 4 hours of treatment with insulin and saline.
DKA: diabetic ketoacidosis; DKA 4: DKA treated for 4 hours with insulin/saline; DKA 24: 24 hours after treatment; DKA 72: 72 hours after treatment;
GFAP: glial ﬁbrillary acidic protein.
From: Lo W, O'Donnell M, Tancredi D, et al. Diabetic ketoacidosis in juvenile rats is associated with reactive gliosis and activation of microglia in the
hippocampus. Pediatr Diabetes 2016; 17(2):127-39. https://onlinelibrary.wiley.com/doi/abs/10.1111/pedi.12251. Copyright © 2016 International Society for
Pediatric and Adolescent Diabetes. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further
permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email:
permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library
(http://onlinelibrary.wiley.com).

Glasgow Coma Scale and Pediatric Glasgow Coma Scale
Glasgow Coma
Sign Pediatric Glasgow Coma Scale [2] Score
Scale [1]
Eye opening Spontaneous Spontaneous 4
To command To sound 3
To pain To pain 2
None None 1
Verbal Oriented Age-appropriate vocalization, smile, or orientation to sound; interacts (coos, babbles); 5
response follows objects
Confused, disoriented Cries, irritable 4
Inappropriate words Cries to pain 3
Incomprehensible sounds Moans to pain 2
None None 1
Motor Obeys commands Spontaneous movements (obeys verbal command) 6

response
Localizes pain Withdraws to touch (localizes pain) 5
Withdraws Withdraws to pain 4
Abnormal flexion to pain Abnormal flexion to pain (decorticate posture) 3
Abnormal extension to Abnormal extension to pain (decerebrate posture) 2

pain
None None 1
Best total score 15
The Glasgow Coma Scale (GCS) is scored between 3 and 15, with 3 being the worst and 15 the best. It is composed of 3 parameters: best eye
response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example,
E2V3M4 results in a GCS of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a
score of 8 or less represents severe brain injury. The Pediatric Glasgow Coma Scale (PGCS) was validated in children 2 years of age or younger.
Data from:
1. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2:81.
2. Holmes JF, Palchak MJ, MacFarlane T, Kuppermann N. Performance of the pediatric Glasgow coma scale in children with blunt head trauma. Acad Emerg Med
2005; 12:814.

Cerebral injury (cerebral edema) in children with diabetic ketoacidosis: Rapid overview
Risk factors
Severe acidosis at presentation
Substantially elevated BUN at presentation
Severe hypocapnia
Young child (<5 years) and/or new onset of diabetes – These are not independent risk factors but are markers for more severe DKA because they
are associated with delayed diagnosis of DKA
Diagnosis of cerebral injury*

Minor criteria (moderately suspicious findings)
Headache – Although headache is frequently present at diagnosis, worsening or recurrence of headache during treatment is suspicious for
cerebral injury
Vomiting – Vomiting is suspicious if it develops or recurs during treatment
Irritability, lethargy, or not easily aroused from sleep – These features are suspicious particularly if they occur or worsen after initiation of
therapy
Elevated BP (eg, diastolic BP >90 mmHg).
Major criteria (very suspicious findings)
Abnormal or deteriorating mental status after initiation of therapy, agitated behavior, or fluctuating level of consciousness
Incontinence inappropriate for age
Inappropriate slowing of heart rate – eg, decline more than 20 beats per minute that is not attributable to improved intravascular volume or
sleep state
Diagnostic criteria (signs of significant brain injury, increased intracranial pressure, or brain herniation)
Abnormal motor or verbal response to pain
Decorticate or decerebrate posture
Abnormal pupillary response or other CN palsy ¶
Abnormal neurogenic respiratory pattern – eg, grunting, tachypnea, Cheyne-Stokes respiration, apnea
Treatment
Indications*
Child with DKA and:

1 diagnostic criterion, or
2 major criteria, or
1 major and 2 minor criteria, or
1 major and 1 minor criterion (if child under 5 years of age)
The decision to treat should be based on signs and symptoms; do not rely on neuroimaging to make or exclude the diagnosis
Interventions
Give mannitol, 0.5 to 1 g/kg intravenously over 15 minutes; the mannitol dose may be repeated in 30 minutes, if there is no initial response Δ
Adjust fluid administration as indicated to maintain normal BP and optimize cerebral perfusion
Avoid hypotension that might compromise cerebral perfusion pressure
Neurosurgery consultation regarding further management, including possible invasive monitoring of intracranial pressure in selected cases
BUN: blood urea nitrogen; DKA: diabetic ketoacidosis; BP: blood pressure; CN: cranial nerve.
* These clinical criteria and indications are based upon an evidence-based protocol, as outlined in the source below.
¶ Key steps are to evaluate extraocular movements (CN III, IV, and VI) and pupillary dilation and reactivity (CN II and III).
Δ Hypertonic (3%) saline (2.5 to 5 ml/Kg over 10 to 15 minutes) can be used as an alternative to mannitol or if initial treatment with mannitol does not result
in improved mental status.
Adapted from: Muir AB, Quisling RG, Yang MCK, Rosenbloom AL. Cerebral edema in childhood diabetic ketoacidosis. Diabetes Care 2004; 27:1541.

[Glycogen storage disease type 1a]. Adrienne G Randolph, MD, MSc Equity Ownership/Stock Options: Abbvie.
Grant/Research/Clinical Trial Support: Genentech [Influenza critical illness]. Consultant/Advisory Boards: La Jolla
Pharmaceuticals [Pediatric refractory shock]. Alison G Hoppin, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by
vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.

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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in

Normal response to hyperglycemia — The hormonal regulation of glucose homeostasis is discussed in

● Insulin deficiency and/or resistance.

At least two factors contribute to less severe hyperglycemia in DKA:

● Impaired glucose utilization in peripheral tissues

Insulin deficiency and/or resistance:

The importance of glucagon in the development of hyperglycemia and ketoacidosis in uncontrolled

● Enter the ketogenic metabolic path to form acetoacetic acid

Serum anion gap = serum sodium - (serum chloride + bicarbonate)

● The rate and duration of ketoacid production

Inflammation — Hyperglycemic crises are proinflammatory states that lead to generation of reactive

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14. Diamond MP, Hallarman L, Starick-Zych K, et al. Suppression of counterregulatory hormone

22. DeFronzo RA, Matzuda M, Barret E. Diabetic ketoacidosis: a combined metabolic-nephrologic

46. Katz MA. Hyperglycemia-induced hyponatremia--calculation of expected serum sodium depression.

Topic 1794 Version 15.0

Age-adjusted diabetic ketoacidosis hospitalization rate per 1000 persons with

DKA: diabetic ketoacidosis.

Graphic 117707 Version 1.0

DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.

Graphic 78145 Version 4.0

New-onset diabetes (20 to 25 percent) Acute illness

Acute illness Infection (32 to 60 percent)

Infection (30 to 40 percent) Pneumonia

Total parenteral nutrition

Previously undiagnosed diabetes

Graphic 64374 Version 5.0

Plasma glucose (mg/dL) >250 >250 >250 >600

Plasma glucose (mmol/L) >13.9 >13.9 >13.9 >33.3

Arterial pH 7.25 to 7.30 7.00 to 7.24 <7.00 >7.30

Serum bicarbonate (mEq/L) 15 to 18 10 to <15 <10 >18

Urine ketones ¶ Positive Positive Positive Small

Serum ketones - Nitroprusside reaction Positive Positive Positive ≤ Small

Effective serum osmolality (mOsm/kg) ◊ Variable Variable Variable >320

Anion gap § >10 >12 >12 Variable

Alteration in sensoria or mental obtundation Alert Alert/drowsy Stupor/coma Stupor/coma

DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.

Graphic 72111 Version 8.0

Total water (L) 6 9

Water (mL/kg ¶) 100 100 to 200

Graphic 76060 Version 6.0

Conflict of interest policy

Diabetic ketoacidosis in children: Clinical features and

• Hyperglycemia – Blood glucose >200 mg/dL (11 mmol/L)

● Hyperglycemic hyperosmolar state (HHS) – HHS is a hyperglycemic emergency, which is

• Marked hyperglycemia (blood glucose >600 mg/dL [>33.3 mmol/L])

● Young age (<5 years of age and especially <2 years)

● Medications – Certain medications, such as corticosteroids, atypical antipsychotics, tacrolimus, L-

A number of other clinical findings may be seen in children with DKA:

In specific circumstances (pregnancy, use of sodium-glucose cotransporter 2 [SGLT2] inhibitor

Ketosis — The degree of ketosis can be estimated in several ways:

Anion gap = Serum sodium – (Serum chloride + bicarbonate)

Initial laboratory testing should include the following [17,38,41]:

Laboratory testing for specific clinical circumstances might also include:

● Diabetes-associated antibodies – Diabetes-associated antibodies (glutamic acid decarboxylase

● C-peptide levels – C-peptide levels may be helpful as an assessment of endogenous insulin

Hyperglycemic hyperosmolar state — DKA must be distinguished from hyperglycemic hyperosmolar

● Marked hyperglycemia (plasma glucose >600 mg/dL [>33.3 mmol/L])

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