Dka & HHS - Ispad 2022

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Received: 16 August 2022 Accepted: 17 August 2022
DOI: 10.1111/pedi.13406
ISPAD GUIDELINES
ISPAD Clinical Practice Consensus Guidelines 2022: Diabetic

ketoacidosis and hyperglycemic hyperosmolar state
Nicole Glaser1 | Maria Fritsch2 | Leena Priyambada3 | Arleta Rewers4 |

Valentino Cherubini5 | Sylvia Estrada6 | Joseph I. Wolfsdorf7 | Ethel Codner8
1
Department of Pediatrics, Section of Endocrinology, University of California, Davis School of Medicine, Sacramento, California, USA
2
Department of Pediatric and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Austria Medical University of Graz, Graz, Austria
3
Division of Pediatric Endocrinology, Rainbow Children's Hospital, Hyderabad, India
4
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado, USA
5
Department of Women's and Children's Health, G. Salesi Hospital, Ancona, Italy
6
Department of Pediatrics, Division of Endocrinology and Metabolism, University of the Philippines, College of Medicine, Manila, Philippines
7
Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
8
Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile
Correspondence
Nicole Glaser, Department of Pediatrics, Section of Endocrinology, University of California, Davis School of Medicine, Sacramento, CA, USA.
Email: [email protected]
1 | S U M M A R Y O F W H A T I S N E W OR symptoms of DKA are non-specific. Therefore, fingerstick blood glu-

DIFFERENT cose measurements should be considered for all children presenting
with rapid breathing or with vomiting and abdominal pain without
Changes to previous recommendations include: diarrhea.
The following recommendations are based on currently available
• Biochemical criteria to diagnose diabetic ketoacidosis (DKA) evidence and are intended to be a general guide to DKA management.
include serum bicarbonate <18 mmol/L Because there is considerable individual variability in presentation of
• Infusion of initial fluid bolus(es) over 20–30 min DKA (ranging from mild to severe and life threatening), some children
• Promoting a rise in serum sodium concentrations during DKA may require specific treatment that, in the judgment of the treating
treatment is no longer considered necessary physician, may occasionally be outside the range of options presented
• Increased emphasis on differences in treatment recommendation here. Clinical judgment should be used to determine optimal treat-
for HHS and mixed presentation of DKA and HHS (hyperosmolar ment for the individual child, and timely adjustments to treatment
DKA) compared to standard DKA treatment should be based on ongoing clinical and biochemical monitoring of the
response to treatment.
Emergency assessment should follow the general guidelines for
2 | E X E C U T I V E SU M M A R Y Pediatric Advanced Life Support (PALS) and includes: Immediate mea-
surement of blood glucose, blood or urine ketones, serum electrolytes
The biochemical criteria for the diagnosis of DKA are: and blood gases; and assessment of level of consciousness. (E) Two
peripheral intravenous (IV) catheters should be inserted (E).
• Hyperglycemia (blood glucose >11 mmol/L [≈200 mg/dl]) Management should be conducted in a center experienced in
• Venous pH <7.3 or serum bicarbonate <18 mmol/L(C) the treatment of DKA in children and where vital signs, neurologi-
• Ketonemia (blood ß-hydroxybuyrate ≥3 mmol/L) (C) or moderate cal status, and laboratory results can be monitored frequently.
or large ketonuria. (E) Where geographic constraints require that management be initi-
ated in a center with less experience, there should be telephone or
Not all children or caregivers volunteer classic symptoms of dia- videoconference support from a physician with expertise in
betes (polyuria, polydipsia) at the time of diagnosis of DKA, and other DKA (E).
Pediatr Diabetes. 2022;23:835–856. wileyonlinelibrary.com/journal/pedi © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. 835
13995448, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pedi.13406 by Consorci De Serveis Universitaris De Catalunya, Wiley Online Library on [04/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
836 GLASER ET AL.
Meticulous monitoring of the clinical and biochemical response • Plasma glucose concentration > 33.3 mmol/L (600 mg/dl)
to treatment is necessary so that timely adjustments in treatment can • Venous pH > 7.25; arterial pH > 7.30
be made when indicated by clinical or laboratory data (E). • Serum bicarbonate >15 mmol/L
Goals of therapy are to correct dehydration, correct acidosis and • Small ketonuria, absent to mild ketonemia
reverse ketosis, gradually restore hyperosmolality and blood glucose • Effective serum osmolality >320 mOsm/kg
concentration to near normal, monitor for acute complications, and
identify and treat any precipitating event. In HHS, the goals of initial fluid therapy are to expand the intra-
Fluid replacement should begin before starting insulin therapy. and extravascular volume, restore normal renal perfusion, and pro-
Expand volume using one or more boluses of 0.9% saline infused over mote a gradual decline in corrected serum sodium concentration and
20–30 min to restore peripheral circulation (E). Calculate the subse- serum osmolality. Differences in treatment strategy between HHS
quent rate of fluid administration (0.45% to 0.9% saline), including the and DKA include the volume of fluid administered, the timing of insu-
provision of maintenance fluid requirements, aiming to replace the lin administration, and monitoring of the decline in corrected serum
estimated fluid deficit over 24 to 48 h (A). sodium concentration.
Insulin therapy: begin with 0.05–0.1 U/kg/h (0.05 U/kg/h can be In HHS, begin insulin administration at a dose of 0.025 to
considered with pH > 7.15) at least 1 h AFTER starting fluid replace- 0.05 U/kg/h once plasma glucose is decreasing less than 3 mmol/L
ment therapy (B). (50 mg/dl) per hour with fluid alone (C). Rates of fluid administration,
Potassium: If the child has hyperkalemia (potassium both as initial fluid boluses to restore circulation and as ongoing defi-
>5.5 mmol/L), defer potassium replacement therapy until urine out- cit replacement, are substantially higher than for DKA.
put is documented. Begin intravenous fluid treatment with non-
potassium containing fluids and measure potassium hourly. Begin
potassium infusion when potassium <5.5 mmol/L. In the rare child 3 | P A TH OP H Y SI O LO GY
with hypokalemia (potassium <3.0 mmol/L), defer insulin treatment
and give a bolus of potassium (not to exceed 0.5 mEq/Kg/h), along Diabetic ketoacidosis (DKA) results from deficiency of circulating insu-
with cardiac monitoring. Otherwise, begin with 40 mmol potas- lin and increased levels of the counterregulatory hormones: glucagon,
sium/L (E). catecholamines, cortisol and growth hormone.1–3 In most cases, DKA
Bicarbonate administration is not recommended except for treat- is caused by new onset of diabetes, omission of insulin injections,
ment of life-threatening hyperkalemia or for severe acidosis (venous interruption of insulin delivery in children using an insulin pump, or
pH < 6.9) with evidence of compromised cardiac contractility (C). inadequate management of an infection. Severe insulin deficiency
Warning signs and symptoms of cerebral injury include: Onset of occurs in previously undiagnosed T1D and when patients deliberately
headache or vomiting after beginning treatment or progressively or inadvertently do not inject insulin, especially the long-acting com-
worsening or severe headache, slowing of heart rate not related to ponent of a basal-bolus regimen, or markedly reduce the doses of
sleep or improved intravascular volume, change in neurological status insulin, for example, during an intercurrent illness such as gastroenter-
(irritability, lethargy, confusion, incontinence), specific neurological itis. Children who use an insulin pump can rapidly develop DKA when
signs (e.g., cranial nerve palsies), decreased oxygen saturation. insulin delivery fails for any reason.4 Relative insulin deficiency occurs
(C) Hypertension occurs commonly in children with DKA and should when the concentrations of counterregulatory hormones markedly
not be considered a warning sign for cerebral injury, in the absence of increase in conditions such as sepsis, trauma, or febrile illness, which
other findings. overwhelm homeostatic mechanisms and lead to metabolic decom-
In children with multiple risk factors for cerebral injury (elevated pensation despite the patient injecting the usual recommended dose
serum urea nitrogen concentration (>20 mg/dl), severe acidosis of insulin.
(pH < 7.1), severe hypocapnia (pCO2 < 21 mmHg), age < 5 years), The combination of absolute or relative insulin deficiency and
have mannitol or hypertonic saline at the bedside and the dose calcu- high counterregulatory hormone concentrations causes an accelerated
lated. (E) If neurologic status deteriorates acutely, hyperosmolar ther- catabolic state with increased glucose production by the liver and kid-
apy with mannitol or hypertonic saline should be given ney (via glycogenolysis and gluconeogenesis) and impaired peripheral
immediately (C). glucose utilization, which result in hyperglycemia and hyperosmolality.
Prevention: Management of DKA is not complete until an Insulin deficiency and high counterregulatory hormone concentrations
attempt has been made to identify and treat the cause. DKA without also increase lipolysis and ketogenesis and cause ketonemia and meta-
a preceding illness in a child with known diabetes is almost always the bolic acidosis. Hyperglycemia exceeding the usual renal threshold of
result of failure to appropriately administer insulin injections or inter- approximately 10 mmol/L (180 mg/dl) together with hyperketonemia
ruption of insulin delivery, most often as a result of insulin pump infu- cause osmotic diuresis and obligatory loss of electrolytes (sodium,
sion set dysfunction. In new onset diabetes, DKA is frequently the potassium, phosphate, magnesium) leading to dehydration, often
consequence of a delay in diagnosis (E). aggravated by vomiting associated with severe ketosis. These changes
The criteria for Hyperglycemic Hyperosmolar State (HHS) stimulate further stress hormone production, which induces more
include all the following: severe insulin resistance and worsening hyperglycemia and
GLASER ET AL. 837
F I G U R E 1 Pathophysiology of diabetic ketoacidosis. Copyright © 2006 American Diabetes Association. Adapted from diabetes care, Vol.
29, 2006:1150–1159. Reprinted with permission of The American Diabetes Association
hyperketonemia. Lactic acidosis from hypoperfusion may contribute high-carbohydrate content (fruit juices or sugar-containing soft drinks)
to the acidosis.5,6 Hyperglycemia also causes a hyperinflammatory may exacerbate hyperglycemia.9
state that increases insulin resistance and is involved in the patho-
physiology of several DKA complications. If this cycle is not inter-
rupted by exogenous insulin together with fluid and electrolyte
Clinical manifestations of diabetic ketoacidosis
therapy, fatal dehydration and metabolic acidosis will ensue (Figure 1).
Diabetic ketoacidosis (DKA) is characterized by severe depletion
of water and electrolytes from both the intra- and extracellular fluid • Dehydration
compartments5; the typical range of losses is shown in Table 1. • Tachypnea; deep, sighing (Kussmaul) respiration
Despite substantial dehydration, children generally continue to main- • Nausea, vomiting, and abdominal pain that may mimic an
tain normal blood pressure or even have high blood pressure,7,8 possi- acute abdominal condition
bly due to elevated plasma catecholamine concentrations, increased • Confusion, drowsiness
release of antidiuretic hormone (ADH) in response to hyperosmolality
(which increases blood pressure via vasporessin 2 receptors),
increased osmotic pressure from marked hyperglycemia, or other fac-
tors.7,8 Considerable urine output persists because of glucosuria until
extreme volume depletion leads to a critical decrease in renal blood
flow and glomerular filtration. At presentation, the specific deficits in 4 | DEFINITION OF DIABETIC
an individual child vary depending upon the duration and severity of KETOACIDOSIS
illness, the extent to which the child was able to maintain intake of
fluid and electrolytes, and the content of food and fluids consumed The diagnosis of DKA is based on the triad of hyperglycemia, ketosis
before coming to medical attention. Consumption of fluids with a and metabolic acidosis; however, specific biochemical criteria used to
838 GLASER ET AL.
T A B L E 1 Losses of fluid and electrolytes in diabetic ketoacidosis initial volume expansion. Serum bicarbonate concentration alone can
and maintenance requirements in normal children substitute for venous pH to diagnose DKA and classify severity in
Average (range) children with new onset diabetes mellitus and is an alternative to
losses per kg 24-h maintenance requirements venous pH in circumstances where pH measurement is not
Water 70 ml (30–100) * ≤ 10 kg 100 ml/kg/24 h available.24
11–20 kg 1000 ml + 50 ml/ The frequency of type 2 diabetes in the pediatric age range is
kg/24 h for each kg from 11–20
increasing worldwide.25–28 Overall, 5% to 25% of children with type
>20 kg 1500 ml + 20 ml/kg/24 h
for each kg >20 2 diabetes have DKA at the time of diagnosis.29,30 In the SEARCH for
Diabetes in Youth Study in the USA, DKA occurred in nearly 6% of
Sodium 6 mmol (5–13) 2–4 mmola
youth with type 2 diabetes.31,32
Potassium 5 mmol (3–6) 2–3 mmol
The severity of DKA is categorized by the degree of acidosis10,33
Chloride 4 mmol (3–9) 2–3 mmol
Phosphate 0.5–2.5 mmol 1–2 mmol
• Mild: venous pH < 7.3 or serum bicarbonate <18 mmol/L24
Note: Data are from measurements in only a few children and • Moderate: pH < 7.2 or serum bicarbonate <10 mmol/L
adolescents.124–128 In any individual patient, actual losses may be less or • Severe: pH < 7.1 or serum bicarbonate <5 mmol/L
more than the ranges shown.
Note: Three methods for determining maintenance water requirements in
children are commonly used: *the Holliday–Segar formula273 (Table 1), a Diabetic ketoacidosis (DKA) should be distinguished from HHS,
simplified Holliday-Segar formula (see below), and a formula based on which is characterized by severe hyperglycemia and markedly
body surface area for children who weigh more than 10 kg (1500 ml/ increased serum osmolality without substantial ketosis and acidosis.
m2/24 h).274
HHS may occur in children with type 2 diabetes,30,34–36 type
Note: Simplified method based on Holliday–Segar: <10 kg 4 ml/kg/h; 11–
20 kg 40 + 2 ml/kg/h for each kg between 11 and 20; >20 kg 1 diabetes,37 cystic fibrosis,35 and in infants, especially those with
60 + 1 ml/kg/h for each kg >20. neonatal diabetes.38,39 Medications such as corticosteroids40 and
a
Maintenance electrolyte requirements in children are per 100 ml of atypical antipsychotics41 can precipitate HHS. Although definitions
maintenance IV fluid.274,275
vary slightly,3 a committee of the Pediatric Endocrine Society pro-
posed the following criteria for HHS in the pediatric age range42:
define DKA vary in different parts of the world and among different
research studies.3 All three biochemical criteria are required to • plasma glucose concentration >33.3 mmol/L (600 mg/dl)
diagnose DKA10: • arterial pH > 7.30; venous pH > 7.25
• serum bicarbonate >15 mmol/L
• Hyperglycemia (blood glucose >11 mmol/L [200 mg/dl]) • small ketonuria, absent to small ketonemia*
• Venous pH < 7.3 or serum bicarbonate <18 mmol/L • effective serum osmolality >320 mOsm/kg
• Ketonemia* or ketonuria • obtundation, combativeness, or seizures (in approximately 50%)
*Although not universally available, blood beta-hydroxybutyrate The characteristic features of HHS and DKA may overlap and
(BOHB) concentration should be measured whenever possible. BOHB some children with HHS, especially those with severe dehydration,
≥3 mmol/L is a sensitive indicator of DKA11 but is not as specific as a may have mild or moderate acidosis that is mainly due to hypoperfu-
value of ≥5.3 mmol/L, which has optimal accuracy (91%) for predict- sion and lactic acidosis. Conversely, some children with DKA may
ing DKA in children with hyperglycemia presenting to an Emergency have features of HHS (severe hyperglycemia).9 Therapy must be
Department. 12
Urine ketones are typically ≥2+ (“moderate or large”). appropriately modified to address the pathophysiology and particular
Urine ketone testing detects acetoacetate and acetone but not biochemical disturbances of the individual child (see below).
BOHB, the main ketone in DKA.13 Therefore, reliance on urine testing
alone may underestimate the severity of ketonemia. Several
sulfhydryl-containing drugs (captopril, N-acetylcysteine, mesna, peni- 5 | FR E Q U E N C Y A N D C A U S E S O F D K A
cillamine) and valproic acid, which is partly eliminated as a ketone-
containing metabolite,14 give false positive urine tests.15,16 Expired or Children with new onset of type 1 diabetes (T1D) frequently present
improperly stored urine test strips can give false negative results.17 with DKA. Frequencies range from approximately 15% to 70% in
Partially treated children and those who have consumed little or Europe and North America.32,43–51 Several countries have reported
no carbohydrate may have only modestly elevated blood glucose con- recent increases in the frequency of DKA at diagnosis of T1D.51–53
18,19
centrations, referred to as euglycemic ketoacidosis. This can be Very young children and those of underserved ethnic groups are at
caused by starvation/fasting, a low carbohydrate-high fat diet, or the increased risk of presenting with DKA.54,55 Delayed diagnosis of dia-
20–23
off-label use of SGLT2-inhibitors. Management of euglycemic betes is an important factor increasing the risk of DKA and this associ-
ketoacidosis should follow standard DKA guidelines except that ation has been particularly evident during the SARS-CoV2
dextrose-containing fluids should be started earlier, immediately after pandemic.56–59 Prevention campaigns targeting awareness of diabetes
839
Algorithm for the management of DKA. Adapted from Pinhas-Hamiel and Sperling.272 NG, nasogastric; SC, subcutaneous.
GLASER ET AL.
FIGURE 2
840 GLASER ET AL.
TABLE 2 Glasgow coma scale (GCS)
Best verbal response (nonverbal

Best eye response Best verbal response children) Best motor response
1. No eye opening 1. No verbal response 1. No response 1. No motor response
2. Eyes open to pain 2. No words, only incomprehensible 2. Inconsolable, irritable, restless, cries 2. Extension to pain
3. Eyes open to verbal sounds; moaning 3. Inconsistently consolable and moans; (decerebrate posture)
command 3. Words, but incoherenta makes vocal sounds 3. Flexion to pain (decorticate
4. Eyes open 4. Confused, disoriented conversationb 4. Consolable when crying and interacts posture)
spontaneously 5. Oriented, normal conversation inappropriately 4. Withdrawal from pain
5. Smiles, oriented to sound, follows 5. Localizes pain
objects and interacts 6. Obeys commands
Note: The GCS consists of three parameters and is scored between 3 and 15; 3 being the worst and 15 the best.81 One of the components of the GCS is
the best verbal response, which cannot be assessed in non-verbal young children. A modification of the GCS was created for children too young to talk.
a
Inappropriate words, random or exclamatory articulated speech, but no sustained conversational exchange.
b
Attention can be held; patient responds to questions coherently, but there is some disorientation and confusion.
symptoms have been successful in reducing DKA frequency.60 In chil- examiners.76–78 The most useful clinical signs for predicting
dren with established diabetes, the risk of recurrent DKA is 1%–10% dehydration are:
per patient-year.4,61–66 Most cases of DKA in children with estab- • prolonged capillary refill time (normal capillary refill is ≤2 s),
lished diabetes are due to insulin omission or interruption of insulin abnormal skin turgor (‘tenting’ or inelastic skin), dry mucus
delivery in children using insulin pumps.63,64 A minority of DKA cases membranes, sunken eyes, absent tears, weak pulses, cool
in children are caused by infections (mainly gastroenteritis). extremities.79
Laboratory measures have been found to be better predictors
of dehydration severity than clinical signs.80 These include:
6 | MANAGEMENT OF DKA • Higher serum urea nitrogen (>20 mg/dl)
• Lower pH (<7.1)
6.1 | Emergency assessment ≥10% dehydration is suggested by the presence of weak or
impalpable peripheral pulses, hypotension or oliguria.
Acute management (Figure 2) should follow the general guidelines for • Assess level of consciousness (Glasgow coma scale [GCS]–see
PALS,67,68 with particular attention to the following: Table 2)81,82
• In the unconscious or severely obtunded child without normal air-
• Obtain vital signs and measure weight–The current weight should way protective reflexes, secure the airway by rapid sequence
be used for calculations and not a weight from a previous visit. If intubation.
body surface area is used for fluid therapy calculations, measure Insert a nasogastric tube with continuous suction to prevent
height or length to determine surface area. Note that despite severe pulmonary aspiration.
dehydration, hypertension occurs in 12% of children with DKA at Intubation should be avoided if possible; an increase of pCO2
presentation and develops during treatment in an additional 16%.7 during or following intubation above the level that the patient
• Insert peripheral intravenous line, obtain blood for laboratory eval- had been maintaining may cause cerebrospinal fluid (CSF) pH to
uation, and start intravenous fluid therapy following guidelines (see decrease and contribute to worsening of cerebral injury.83,84
Section 6.3). • Give oxygen to patients with circulatory impairment or shock.
• Immediately measure blood glucose and blood BOHB levels with • A continuous cardiac monitor should be used to assess degree of
bedside meters or urine acetoacetic acid concentrations with urine tachycardia, monitor for arrhythmias, and assess T-waves for evi-
test strips if bedside blood ketone measurements are not available. dence of hyper- or hypokalemia.85,86
Measurement of blood BOHB concentration with a point-of-care • A second peripheral intravenous (IV) catheter should be placed for
meter, if available, is very useful to confirm ketoacidosis convenient and painless repetitive blood sampling. An arterial
(≥3 mmol/L in children)11 and to monitor the response to treat- catheter may, rarely, be necessary in some critically ill children
ment.12,69–75 managed in an intensive care unit.
• Measure venous pH, pCO2, glucose, electrolytes (including serum Unless absolutely necessary, avoid placing a central venous
bicarbonate), serum urea nitrogen, and creatinine. catheter because of the high risk of thrombosis. If a central
• Perform a detailed history and physical exam with particular atten- catheter has been inserted, the catheter should be removed as
tion to mental status and any possible source of infection. soon as the child's clinical status permits.87,88 Mechanical and
• Severity of dehydration pharmacologic prophylaxis (low molecular weight heparin)
Estimation of the degree of dehydration is imprecise in DKA should be considered for those with central venous catheters,
and shows only fair to moderate agreement among especially in children >12 years.
GLASER ET AL. 841
Insulin should not be given through a central line unless it is the teams should be knowledgeable about DKA management or have
only available option because its infusion may be interrupted access to a medical control physician with appropriate expertise and
when other fluids are given through the same line. have rescue medications available during transport, including high
• Antibiotics may be required for children with evidence of infec- concentration IV dextrose solutions and mannitol or 3% hypertonic
tion after obtaining appropriate cultures such as blood, urine, spi- saline.
nal fluid, throat, or tracheal aspirate as indicated. In a child with established diabetes, whose parents have been
• Bladder catheterization usually is not necessary but should be con- trained in sick day management, hyperglycemia, and ketosis without
sidered if the child is unconscious or severely ill. vomiting or severe dehydration can be managed at home with subcu-
• Additional laboratory measurements include: taneous insulin, or in an outpatient health care facility
Hemoglobin/ hematocrit (e.g., emergency ward) with supervision from an experienced diabetes
Albumin, calcium, phosphate and magnesium concentrations team.33,89,90
Hemoglobin A1c may be useful to confirm the diagnosis of dia-
betes (e.g., in a child with hyperglycemia suspected to be due to
a stress response and metabolic acidosis caused by dehydration)
Goals of therapy
or as an indicator of duration of hyperglycemia
Complete blood counts (CBC) frequently show increased WBC
and left shift in children with DKA, even without infection. • Correct acidosis and reverse ketosis
Infection evaluation should be based on the clinical scenario • Correct dehydration
and not on the white cell count. • Restore blood glucose to near normal
• If laboratory measurement of serum potassium is delayed, perform • Monitor for complications of DKA and its treatment
an electrocardiogram (ECG) for baseline evaluation of potassium • Identify and treat any precipitating event
status.85,86
6.2 | Where should the child with DKA be

managed? 6.3 | Fluid and electrolyte replacement
After initial life support, the child should receive care in a unit 6.3.1 | Principles of fluid and electrolyte therapy
that has:
Children with DKA have a deficit in extracellular fluid (ECF) volume
• Experienced nursing and medical staff trained in pediatric DKA that is typically about 7% of body weight.76,78,80 Shock with hemody-
management who are available to perform meticulous monitoring namic compromise is rare in pediatric DKA. Clinical estimates of the
until DKA has resolved. volume deficit based on physical exam and vital signs are inaccu-
• Care policies and procedures based on clinical practice guidelines. rate76,78,80; therefore, in mild DKA assume 5%, moderate DKA 7%
Staff should have access to clinical practice guidelines in written or and severe DKA 10% dehydration. Increased serum urea nitrogen and
electronic format. anion gap at presentation are the measures most strongly correlated
• Access to a laboratory that can provide frequent and timely mea- with volume deficit.80 The serum sodium concentration is an unreli-
surements of biochemical variables. able measure of the degree of ECF contraction because glucose
largely restricted to the extracellular space, causes osmotic movement
Whenever possible, a specialist/consultant pediatrician with train- of water into the extracellular space thereby causing dilutional hypo-
ing and expertise in the management of DKA should direct inpatient natremia.91 It is useful to calculate the corrected sodium concentra-
management. If this is not possible due to geographic or resource con- tion to help assess relative deficits of sodium and water (the formula
straints, arrangements should be made to access telephone or video- for corrected sodium can be found in the Monitoring section).5,92 The
conference support from a physician with expertise in DKA “corrected” sodium represents the expected serum sodium concentra-
management. tion in the absence of hyperglycemia. As the plasma glucose concen-
Children with severe DKA (long duration of symptoms, compro- tration decreases after administering fluid and insulin, the measured
mised circulation, or depressed level of consciousness) or those who serum sodium concentration should increase and the glucose-
are at increased risk for cerebral injury (e.g., <5 years of age, pH < 7.1, corrected sodium concentration should slowly decrease or remain in
pCO2 < 21 mmHg, blood urea nitrogen > 20 mg/dl) should be consid- the normal range.
ered for immediate treatment in an intensive care unit (pediatric if The objectives of fluid and electrolyte replacement therapy are to:
available) or in a unit that has equivalent resources and supervision,
such as a children's ward specializing in diabetes care. Transport • Restore circulating volume
842 GLASER ET AL.
• Replace sodium and water deficits Adolescent Diabetes (ISPAD)10,103–105 and incorporate the recom-
• Improve glomerular filtration and enhance clearance of glucose and mendations from the PECARN FLUID Trial96 and other recent data.
ketones from the blood Note that IV fluids given in another facility before assessment should
be factored into calculations of deficit and replacement volumes.
Controversies surrounding optimal fluid treatment regimens for
children with DKA have largely focused on the role of intravenous
fluids in causing or contributing to risk of cerebral edema and cerebral 6.3.2 | Resuscitation fluids
injury.93–95 Although the pathogenesis of DKA-related cerebral injury
remains incompletely understood, recent evidence suggests that For children who are volume depleted but not in shock, volume
abnormalities in cerebral perfusion and the hyperinflammatory state expansion (resuscitation) should begin immediately with 0.9% saline,
caused by DKA play important roles, and that variations in fluid treat- 10 to 20 ml/kg infused over 20–30 min to restore the peripheral cir-
ment likely have minimal effects.95–99 A large prospective randomized culation. If tissue perfusion is poor the initial fluid bolus volume
clinical trial (the PECARN FLUID Trial) compared acute and long-term should be 20 ml/kg.
neurological outcomes in 1389 children with DKA treated with slower
versus more rapid fluid administration using either 0.45% saline or • In the rare child with DKA in shock, rapidly restore circulatory vol-
0.9% saline.96 The PECARN FLUID Trial showed no significant differ- ume with 0.9% saline in 20 ml/kg boluses infused as quickly as
ences in the frequency of either altered mental status or clinical diag- possible through a large bore cannula with reassessment of circula-
noses of cerebral injury in any of the treatment arms, and long-term tory status after each bolus.
neurocognitive outcomes were similar in all groups. Point estimates • Use crystalloid not colloid. There are no data to support the use of
suggested lower frequencies of altered mental status in children rehy- colloid in preference to crystalloid in the treatment of DKA.
drated more rapidly with 0.45% saline, but these differences did not
reach statistical significance.96 The results of this study suggest that a
range of fluid protocols can be safely used to treat DKA in children, 6.3.3 | Deficit replacement fluids
and that clinicians should not unnecessarily restrict fluid administra-
tion if clinical signs suggest the need for circulatory volume expansion. Subsequent fluid management (deficit replacement) can be accom-
As protocols outside of the range used in the PECARN FLUID Trial plished with 0.45%–0.9% saline or a balanced salt solution (Ringer's
have not been thoroughly investigated, we recommend that fluid lactate, Hartmann's solution or Plasmalyte).96,100,102,106–114
treatment remain within the variations used in the trial. These include
assumed fluid deficits between 5% and 10% of body weight, replace- • Fluid therapy should begin with deficit replacement plus mainte-
ment of deficits over 24 to 48 h,† provision of maintenance fluids, nance fluid requirements.
and use of fluids with a sodium content between 0.45% and 0.9% All children will experience a decrease in vascular volume when
NaCl. Although previous retrospective studies have found associa- plasma glucose concentrations fall during treatment; therefore,
tions between declines in serum sodium concentrations during DKA it is essential to ensure that they receive sufficient intravenous
treatment and DKA-related cerebral injury,100,101 a recent large pro- fluid to maintain adequate tissue perfusion.
spective study found no such association. 102
In that study, declines in • Deficit replacement should be with a solution that has a tonicity in
glucose-corrected sodium concentrations were not associated with the range of 0.45%–0.9% saline, with added potassium chloride,
altered mental status or clinically apparent cerebral injury. Serum potassium phosphate or potassium acetate (see below under potas-
sodium trends during DKA treatment largely reflected the balance of sium replacement).96,100,102,106–108,110,113,115,116 Decisions regarding
sodium and water losses at presentation, with those presenting with use of isotonic versus hypotonic solution for deficit replacement
higher initial sodium concentrations (greater free water losses) nor- should depend on clinician judgment based on the child's hydration
malizing sodium concentrations during treatment. The study also status, serum sodium concentration, and osmolality.
found that the sodium content of intravenous fluids significantly influ- • In addition to providing the usual daily maintenance fluid require-
enced changes in sodium concentrations during treatment, but the ment, replace the estimated fluid deficit (minus initial fluid bolus
rate of infusion of intravenous fluids had minimal effects. These find- amount) over 24–48 h.96 Although rehydration is generally
ings suggest that promoting a rise in the serum sodium concentration planned to occur over 24 h or longer, DKA typically resolves
need not be a routine focus of DKA treatment. In the event that before 24 h and remaining fluid deficits are replaced by oral intake
changes in serum sodium concentration are required, the sodium con- after transition to subcutaneous insulin.
tent of intravenous fluids should be adjusted, but not the rate of • Clinical assessment of circulatory status, fluid balance, and trends
infusion. in serum sodium levels are valuable guides to fluid and electrolyte
The principles described below are based on consensus state- therapy. The serum sodium concentration typically increases as the
ments from panels of expert physicians representing the Pediatric serum glucose concentration decreases.
Endocrine Society (PES), the European Society for Pediatric Endocri- • Avoiding declines in intravascular volume is of particular impor-
nology (ESPE), and the International Society for Pediatric and tance for children with severe dehydration or circulatory
GLASER ET AL. 843
compromise. In these situations, the sodium content of the fluid excretion. High doses administered intravenously for a prolonged
should be increased if the measured serum sodium concentration period may contribute to hypokalemia despite potassium administra-
is low and does not rise appropriately as the plasma glucose con- tion. The duration and dosage of intravenous insulin should be mini-
centration falls.102,112 mized to decrease the risk of hypokalemia. The serum potassium
• Urinary losses should not routinely be added to the calculation of concentration may decrease rapidly during treatment, predisposing to
replacement fluid, but this may be necessary in some circum- cardiac arrhythmias. Severe hypokalemia (<2.5 mmol/L) is an indepen-
stances, particularly in children with a mixed presentation of DKA dent marker of poor treatment outcome and mortality.132,133
and HHS (see below). Careful monitoring of fluid intake and output Potassium replacement is required regardless of the serum potas-
is essential to ensure positive fluid balance. sium concentration, except if renal failure is present.125,134
• Calculation of fluid infusion rates for obese children should be sim-
ilar to those of other children. Using ideal body weight for fluid cal- • If the child is hypokalemic, start potassium replacement at the time
culations for these children is not necessary. If fluid calculations for of initial volume expansion and before starting insulin therapy. For
obese children exceed those typically used in adult protocols, then rare children with initial potassium levels <3.5 mmol/L, defer insulin
adult DKA fluid protocols can be used (e.g., 1 L maximum per bolus treatment and give a bolus of potassium (not to exceed 0.5 mmol/
and 500 ml/h fluid infusion). Kg/h), along with cardiac monitoring.135 Otherwise, start-replacing
• The use of large amounts of chloride-rich fluids (combined with potassium after initial volume expansion and concurrent with start-
preferential renal excretion of ketones over chloride) is often asso- ing insulin therapy. If the child is hyperkalemic, defer potassium
ciated with development of hyperchloremic metabolic replacement therapy until urine output is documented. Begin infu-
116–121
acidosis. sion with non-potassium fluids, remeasure potassium hourly, and
When hyperchloremia develops, a persisting base deficit or low begin potassium infusion when serum potassium is below
bicarbonate concentration can be erroneously interpreted as 5.5 mmol/L.
being due to ongoing ketosis.122 • If immediate serum potassium measurements are unavailable, an
To avoid this misinterpretation, measurement of bedside BOHB ECG may help to determine whether the child has hyper- or hypo-
levels (or calculation of anion gap if bedside BOHB is not avail- kalemia.85,86 Prolongation of the PR interval, T wave flattening and
able) should be used to determine resolution of ketoacidosis. inversion, ST depression, prominent U waves, apparent long QT
Hyperchloremic acidosis is generally asymptomatic and resolves interval (due to fusion of the T and U waves) indicates hypokale-
spontaneously. mia. Tall, peaked, symmetrical, T waves and shortening of the QT
The chloride load can be reduced by using potassium salts other interval are signs of hyperkalemia.
than potassium chloride, or by using fluids such Ringer's lactate • The starting potassium concentration in the infusate should be
or Plasmalyte in which a portion of the chloride is replaced by 40 mmol/L.136 Subsequent potassium replacement therapy should
123
lactate or acetate, respectively. be based on serum potassium measurements.
• If there is hypokalemia, potassium replacement should begin con-
current with initial volume expansion, using a separate IV infusion.
6.3.4 | Potassium replacement • Potassium phosphate may be used together with potassium chlo-
ride or acetate; for example, 20 mmol/L potassium chloride and
Children with DKA have total body potassium deficits on the order of 20 mmol/L potassium phosphate or 20 mmol/L potassium phos-
3 to 6 mmol/kg.124–128 The major loss of potassium is from the intra- phate and 20 mmol/L potassium acetate. Administration of potas-
cellular pool. Intracellular potassium is depleted because of transcellu- sium entirely as potassium chloride contributes to the risk of
lar shifts caused by hypertonicity (increased plasma osmolality causes hyperchloremic metabolic acidosis, whereas administration entirely
solvent drag in which water and potassium are drawn out of cells) and as potassium phosphate can result in hypocalcemia.
acidosis, as well as glycogenolysis and proteolysis secondary to insulin • Potassium replacement should continue throughout IV fluid
deficiency.5 Potassium is lost from the body via vomiting and osmotic therapy.
diuresis. In addition, volume depletion causes secondary hyperaldos- • The maximum recommended rate of intravenous potassium
teronism, which promotes urinary potassium excretion. The incidence replacement is usually 0.5 mmol/kg/h.
and severity of hypokalemia (potassium < 3.5 mmol/L) may be higher • If hypokalemia persists despite a maximum rate of potassium
in malnourished children.129 In spite of total body depletion, serum replacement, then the rate of insulin infusion can be reduced.
potassium levels may be normal, increased, or decreased at presenta-
tion.130 Renal dysfunction caused by DKA enhances hyperglycemia
and reduces potassium excretion, thereby raising serum potassium 6.3.5 | Phosphate
concentrations at presentation.130 Administration of insulin and the
correction of acidosis drives potassium back into the cells, decreasing Phosphate depletion occurs in DKA due to osmotic diuresis and a shift
serum potassium levels during DKA treatment.131 Insulin also has an of intracellular phosphate to the extracellular compartment as a result
aldosterone-like effect leading to increased urinary potassium of metabolic acidosis.5,124–126,137,138 Plasma phosphate levels
844 GLASER ET AL.
decrease during treatment due to dilution by fluid replacement and Route of administration: Intravenous (IV)
insulin-mediated entry of phosphate into cells.137,139–141 During treat- An IV insulin bolus should not be used at the start of therapy; it
96
ment, 50%–60% of children develop hypophosphatemia. The is unnecessary,163,165 can precipitate shock by rapidly decreas-
138
degree of metabolic acidosis is a main determinant. Although ing osmotic pressure, and can exacerbate hypokalemia.
severe hypophosphatemia can occur at any time during DKA treat- • Infusion tubing should be flushed with the insulin solution before
ment, continuation of intravenous therapy without food consumption administration.
beyond 24 h is a risk factor for clinically significant If IV cannulation is not possible due to severe dehydration, insu-
hypophosphatemia.124–126 To date, studies of phosphate replacement lin can be administered IM.
in children with DKA have involved small numbers of children with Central venous catheters should not be used for insulin adminis-
limited statistical power, therefore data for evidence-based guidelines tration because the large dead space may cause erratic insulin
is lacking. delivery.
• The dose of insulin should usually remain at 0.05–0.1 unit/kg/h at
• Severe hypophosphatemia is uncommon but can have serious con- least until resolution of DKA (pH > 7.30, serum bicarbonate
sequences. Clinical manifestations are largely due to intracellular >18 mmol/L, BOHB <1 mmol/L, or closure of the anion gap), which
phosphate depletion. Decreased intracellular adenosine triphos- invariably takes longer than normalization of blood glucose con-
phate (ATP) levels impair cellular functions that depend on energy- centrations.166 Monitor venous pH (and serum BOHB concentra-
rich phosphate compounds, and a decrease in tion where possible) every 2 h to ensure steady improvement. If
2,3-diphosphoglycerate (DPG) level increases the affinity of hemo- the insulin effect is adequate, serum BOHB should decrease by
142
globin for oxygen and reduces oxygen release in tissues. Many approximately 0.5 mmol/L per hour.70 Increase the insulin dose if
organ systems can be affected. Manifestations of severe hypopho- the expected rate of biochemical improvement does not occur.
sphatemia include metabolic encephalopathy, seizures,143 impaired • If the child shows marked sensitivity to insulin (e.g., some young
myocardial contractility, ventricular arrhythmia,144 respiratory children with DKA, children with HHS, and some older children
137 145
failure, hemolytic anemia, muscle dysfunction with proximal with established diabetes), the insulin dose may be decreased, pro-
myopathy, dysphagia, ileus, and rhabdomyolysis.146–149 vided that metabolic acidosis continues to resolve.
• Severe hypophosphatemia (<1 mg/dl [0.32 mmol/L]) with or with- • For less severe DKA (pH > 7.15), 0.05 U/kg/h (0.03 U/kg/h for
out associated symptoms should be treated promptly.143,150 Insulin age < 5 years with mild DKA) is usually sufficient to resolve the
infusion may need to be reduced or temporarily halted until phos- acidosis. Uncontrolled retrospective studies and small RCTs have
phorus levels increase. reported comparable efficacy and safety using 0.05 unit/kg/h com-
• Routine phosphate replacement to prevent hypophosphatemia is pared to 0.1 unit/kg/h,113,167–169 and some pediatric centers rou-
advisable in locations where this treatment is readily available, par- tinely use this dose for treatment of DKA.
ticularly for children with severe DKA. • During initial volume expansion, the plasma glucose concentration
• Potassium phosphate can be combined with potassium chloride or falls steeply.153 Thereafter, and after commencing insulin therapy,
potassium acetate to provide phosphate replacement without sub- the plasma glucose concentration typically decreases at a rate of
stantial risk of hypocalcemia. 2–5 mmol/L per hour.157–160,163,170
• Carefully monitor serum calcium and magnesium concentrations • To prevent an unduly rapid decrease in plasma glucose concentra-
during phosphate infusion to avoid hypocalcemia.151,152 tion and hypoglycemia, 5% dextrose should be added to the IV
fluid when the plasma glucose falls to approximately 14–
17 mmol/L (250–300 mg/dl), or sooner if the rate of fall is precipi-
6.4 | Insulin therapy tous (>5 mmol/L/h after initial fluid expansion).
It may be necessary to use 10% or even 12.5% dextrose to pre-
Diabetic ketoacidosis (DKA) is caused by a decrease in the effective cir- vent hypoglycemia while continuing to infuse insulin to correct
culating insulin level associated with increases in counter-regulatory the metabolic acidosis.
hormone concentrations. Although rehydration alone frequently causes • If biochemical parameters of DKA (venous pH, anion gap, BOHB
a marked decrease in blood glucose concentration,153,154 insulin ther- concentration) do not improve, reassess the child, review insulin
apy is essential to restore normal cellular metabolism, to suppress lipol- therapy, and consider other possible causes of impaired response
ysis and ketogenesis, and to normalize blood glucose concentrations.155 to insulin; for example, infection, errors in insulin preparation or
route of administration.
• Start insulin infusion 1 h after initiation of IV fluid treatment.156 • In circumstances where continuous IV administration is not possi-
• Correction of insulin deficiency ble and in children with uncomplicated mild to moderate DKA,
Dose: 0.05–0.1 U/kg/h of regular (soluble) insulin (e.g., one hourly or 2-hourly subcutaneous (SC) rapid-acting insulin analog
method is to dilute 50 units regular [soluble] insulin in 50 ml (insulin lispro or insulin aspart) is safe and may be as effective as IV
0.9% saline, 1 unit = 1 ml).157–164 The lower dosage (0.05 U/ regular insulin infusion.170–174 This method should not be used in
kg/h) can be considered for children with pH > 7.15. children whose peripheral circulation is impaired. Dose SC:
GLASER ET AL. 845
0.15 units/kg every 2 h (initiated 1 h after the start of fluid replace- should be administered in addition to rapid- or short-acting insulin.
ment). The dose can be reduced to 0.1 unit/kg every 2 h if BG con- The most convenient time to change to SC insulin is just before a
tinues to decrease by >5 mmol/L (90 mg/dl) even after adding mealtime. Alternatively, basal insulin may be given while the child is
dextrose.175–177 still receiving intravenous insulin infusion. This method is safe and
• Subcutaneous administration of short-acting (regular) insulin every may help to facilitate transition to a subcutaneous regimen.188,189
4 h is another alternative in mild DKA when IV infusion or rapid- • To prevent rebound hyperglycemia, the first SC injection should be
178
acting insulin analogs are not available. A suggested starting given 15–30 min (with rapid-acting insulin) before stopping the
dose is 0.13–0.17 units/kg/dose of regular insulin every 4 h (0.8–1 insulin infusion to allow sufficient time for the insulin to be
unit/kg/day in divided doses). Doses are increased or decreased by absorbed. With long-acting insulin, the overlap should be longer,
10%–20% based on the blood glucose level before the next insulin and the rate of IV insulin administration gradually decreased. For
178
injection. Dosing frequency may be increased to every 2 or 3 h example, for children on a basal-bolus insulin regimen, the first
if acidosis is not improving. dose of basal insulin may be administered in the evening and the
IV insulin infusion is stopped the next morning.
• The regimen, dose, and type of SC insulin should be according to
6.5 | Acidosis local preferences and circumstances.
• After transitioning to SC insulin, frequent blood glucose monitoring
Fluid and insulin replacement reverses acidosis. Insulin stops further is required to avoid marked hyperglycemia and hypoglycemia.
ketoacid production and allows ketoacids to be metabolized, which
generates bicarbonate. Treatment of hypovolemia improves tissue
perfusion and renal function, thereby increasing the excretion of 7 | C L I N I C A L A N D BI O C H E M I C A L
organic acids. A recent large study of children with DKA showed that MONITORI NG
faster compared to slower fluid administration caused earlier normali-
zation of the anion gap; however, pH did not normalize more rapidly Successful management of DKA and HHS requires meticulous moni-
with more rapid fluid infusion, likely due to increased frequency of toring and recording of the clinical and biochemical response to treat-
hyperchloremic acidosis.117 ment so that timely adjustments in treatment can be made when
Lack of resolution of acidosis is most frequently due to develop- indicated by clinical or laboratory data. There should be documenta-
ment of hyperchloremic acidosis. This is generally a benign condition tion on a flow chart of hour-by-hour clinical observations, medica-
and should not delay transition to subcutaneous insulin. Rare causes of tions, fluids, and laboratory test results.
persistent acidosis include insufficient fluid administration, infection/ Monitoring during the initial treatment of DKA should include the
sepsis and incorrect preparation of the intravenous insulin infusion. following:
Controlled trials have shown no clinical benefit from bicarbonate
administration.179–182 Bicarbonate therapy may cause paradoxical • Hourly (or more frequently as indicated)
CNS acidosis183,184 and rapid correction of acidosis with bicarbonate Vital signs (heart rate, respiratory rate, blood pressure)
causes hypokalemia.183,185,186 Bicarbonate administration may be Neurological assessment (Glasgow coma scale score or similar
beneficial in rare children with life-threatening hyperkalemia or assessments; Table 2) for warning signs and symptoms of cere-
unusually severe acidosis (venous pH < 6.9) that have compromised bral injury (see Section 8.2)
cardiac contractility.187 Amount of administered insulin
Accurate fluid input (including all oral fluid) and output.
Capillary blood glucose concentration should be measured
6.6 | Introduction of oral fluids and transition to hourly (but must be crosschecked against laboratory venous glu-
SC insulin injections cose because capillary methods may be inaccurate when there
is poor peripheral circulation and when plasma glucose levels
• Oral fluids should be introduced only when substantial clinical are extremely high). The utility of continuous monitoring of
improvement has occurred (mild acidosis/ketosis may still be interstitial glucose during DKA management is currently being
present). evaluated.190
Measurement of urine ketones with test strips is based on the • At admission and every 2–4 h, or more frequently, as clinically
nitroprusside reaction, which measures acetoacetate and ace- indicated
tone. Persistent ketonuria characteristically occurs for several Serum electrolytes, glucose, blood urea nitrogen, calcium, mag-
hours after serum BOHB levels have returned to normal.70,71 nesium, phosphate, and blood gases
Absence of ketonuria should not be used as an endpoint for Blood BOHB concentrations, if available, are useful for tracking
determining resolution of DKA. DKA resolution.11,12,69–71,73,75 Point-of-care BOHB measure-
• When ketoacidosis has resolved, oral intake is tolerated, and the ments correlate well with a reference method up to 3 mmol/L,
change to SC insulin is planned, a dose of basal (long-acting) insulin but are not accurate above 5 mmol/L.73,191
846 GLASER ET AL.
• Laboratory observations • Hypocalcemia, hypomagnesemia151

Serum may be lipemic, which in extreme cases can interfere • Severe hypophosphatemia138,143,145,149 *
with accuracy of electrolyte measurements in some • Hyperchloremic acidosis117
laboratories.192
• Hypochloremic alkalosis206
If the laboratory cannot provide timely results, a portable bio- • Other central nervous system complications including cerebral
chemical analyzer that measures serum electrolytes and blood venous sinus thrombosis, basilar artery thrombosis, intracranial
gases on finger stick blood samples at the bedside is a useful hemorrhage, cerebral infarction207–209
adjunct to laboratory-based determinations. Blood glucose and • Deep venous thrombosis87,88,210 *
blood or urine ketone concentrations can also be measured at • Pulmonary embolism211 *
the bedside while awaiting results from the laboratory. • Rhinocerebral or pulmonary mucormycosis212,213
• Measure body weight each morning • Aspiration pneumonia*
• Calculations: • Pulmonary edema214,215 *
Anion gap = Na – (Cl + HCO3): normal is 12 ± 2 mmol/L • Adult respiratory distress syndrome (ARDS)216
• In DKA the anion gap is typically 20–30 mmol/L; an anion • Prolonged QTc217,218
gap >35 mmol/L suggests concomitant lactic acidosis 193,194
• Pneumothorax, pneumomediastinum and subcutaneous
Corrected sodium = measured Na + 1.6([plasma glu- emphysema219,220
cose – 5.6]/5.6) mmol/L or measured Na + 1.6([plasma glu- • Rhabdomyolysis221 *
cose – 100]/100) mg/dL91,92,195 • Ischemic bowel necrosis222
Effective osmolality (mOsm/kg) = 2 (plasma Na) + plasma • Renal failure*
glucose mmol/L; normal range is 275–295 mOsm/kg • Acute pancreatitis223 *
*These complications, often with fatality, have been more fre-

8 | C O M P L I CA T I O N S quent in HHS.224 The pathophysiology and management of HHS are
discussed in the other sections of this guideline.
8.1 | Morbidity and mortality
Diabetic ketoacidosis (DKA) is associated with a wide range of compli- 8.2 | Cerebral injury
cations. These include:
The incidence of clinically overt DKA-related cerebral injury is 0.5%–
• Mortality mainly due to cerebral injury. In developed countries, the 0.9% and the mortality rate is 21%–24%.101,225,226 Mental status
death rate from DKA is <1%, while in developing countries it is abnormalities (GCS scores <14) occur in approximately 4%–15% of
much higher reaching 3%–13%.196–199 The mortality rate in HHS is children treated for DKA and are often associated with mild cerebral
reported to be higher; however, reliable data are lacking in pediat- edema on neuroimaging.227,228 Neuroimaging studies have led to the
ric populations. appreciation that cerebral edema is not a rare phenomenon in children
• Permanent severe neurological sequelae resulting from DKA- with DKA but occurs frequently and with varying severity.227,229,230
related brain injuries are infrequent. However, alterations in mem- Clinically overt cerebral injury represents the most severe manifesta-
ory, attention, verbal intelligence quotient, and brain microstruc- tion of a common phenomenon.231
ture may result from apparently uncomplicated DKA episodes. The cause of DKA-related cerebral injury is a topic of ongoing
Even a single DKA episode is associated with subtle memory investigation. Rapid fluid administration resulting in changes in serum
declines soon after a T1D diagnosis.200,201 osmolality was initially thought to be the cause, however, more recent
• Renal tubular damage (RTD) and acute kidney injury (AKI)202–204 evidence suggests that cerebral hypoperfusion and the hyperinflam-
occurs in a high proportion (43% to 64%) of children hospitalized matory state caused by DKA play central roles.98,232–236 It is notewor-
for DKA and is more common among children with more severe thy that the degree of cerebral edema that develops during DKA
acidosis and volume depletion.203,204 AKI is defined by the Kidney correlates with the degree of dehydration and hyperventilation at pre-
Disease Improving Global Outcomes (KDIGO) serum creatinine cri- sentation, but not with initial osmolality or osmotic changes during
teria (AKI Stage 1, 2, or 3 defined by serum creatinine 1.5, 2, or treatment.228 Evidence of neuroinflammation has been demonstrated
205
3 times estimated baseline creatinine). RTD and AKI are man- in animal models of DKA, including elevated cytokine and chemokine
aged with the restoration of fluid, electrolyte and glycemic balance. concentrations in brain tissue, activation of brain microglia and reac-
tive astrogliosis.98,99,237–240 Disruption of the blood–brain-barrier has
Other complications include: also been found in DKA, particularly in cases of fatal cerebral
injury.236,241,242
• Hypokalemia* Cerebral injury occurs more frequently in younger children,243
• Hypoglycemia those with new onset of diabetes,198,243 and those with longer
GLASER ET AL. 847
duration of symptoms.244 These risk associations may reflect the • Adjust fluid administration rate as needed to maintain normal
greater likelihood of severe DKA in these children. Epidemiological blood pressure while avoiding excessive fluid administration that
studies have identified several biochemical risk factors at diagnosis might increase cerebral edema formation. Assiduously avoid hypo-
including: tension that might compromise cerebral perfusion pressure.
• Hyperosmolar agents should be readily available at the bedside.
• Greater hypocapnia at presentation after adjusting for degree of • Give mannitol, 0.5–1 g/kg IV over 10–15 min.254–256 The effect of
acidosis 101,228,245
mannitol should be apparent after 15 min and is expected to last
• Increased serum urea nitrogen at presentation101,228 about 120 min. If necessary, the dose can be repeated after 30 min.
• More severe acidosis at presentation156,246,247 • Hypertonic saline (3%), suggested dose 2.5–5 ml/kg over 10–
15 min, may be used as an alternative to mannitol, or in addition to
Bicarbonate treatment for correction of acidosis has also been mannitol if there has been no response to mannitol within 15–
associated with increased risk of cerebral injury. This association was 30 min.257,258
found to persist after adjusting for DKA severity. 101,248
3% Hypertonic saline 2.5 ml/kg is equimolar to mannitol 0.5 g/
Clinically significant cerebral injury usually develops within the first kg. Intubation may be necessary for the patient with impending
12 h after treatment has started but can occur before treatment has respiratory failure due to severe neurologic compromise. For
begun101,225,249–251 or, rarely, may develop as late as 24–48 h after the intubated patients, the PCO2 level should approximate that pre-
start of treatment.101,243,252 Symptoms and signs are variable. Mild to dicted for the level of metabolic acidosis. Hypocapnia beyond
moderate headache at presentation is not unusual in children with DKA, this level should be avoided except when necessary to treat
however, development of headache or substantial worsening of headache clinically overt elevated intracranial pressure.259
after commencing treatment is concerning. A method of clinical diagnosis • After hyperosmolar treatment has been started, cranial imaging
based on bedside evaluation of neurological state is shown below.253 may be considered. However, treatment of the clinically symptom-
One diagnostic criterion, two major criteria, or one major and two minor atic patient should not be delayed in order to obtain imaging.260
criteria have a sensitivity of 92% and a false positive rate of only 4%. The primary concern that would warrant neuroimaging is whether
Signs that occur before treatment should not be considered in the diag- the patient has a lesion requiring emergency neurosurgery
nosis. Neuroimaging is not required for diagnosis of cerebral injury. (e.g., intracranial hemorrhage) or a lesion that may necessitate
Diagnostic criteria anticoagulation (e.g., cerebrovascular thrombosis), as suggested by
clinical findings, particularly focal neurologic deficits.207,261,262
• Abnormal motor or verbal response to pain
• Decorticate or decerebrate posture
• Cranial nerve palsy (especially III, IV, and VI) 9 | P RE V E N T I O N O F RE C U R R EN T DK A
• Abnormal neurogenic respiratory pattern (e.g., grunting, tachypnea,
Cheyne-Stokes respiration, apneusis) Most episodes of DKA in children with previously diagnosed diabetes are
the result of insulin omission, either inadvertent or deliberate. Families of
Major criteria children with recurrent episodes of DKA should work with a diabetes pro-
fessional to ensure proper understanding of procedures for managing sick
• Altered mentation, confusion, fluctuating level of consciousness days and insulin pump failures. A social worker or clinical psychologist
• Sustained heart rate deceleration (decrease more than 20 beats should be consulted to identify the psychosocial reason(s) contributing to
per minute) not attributable to improved intravascular volume or DKA episodes when deliberate insulin omission is suspected.
sleep state
• Age-inappropriate incontinence
10 | H Y P E R G L Y C E M I C H Y P E R O S M O L A R
Minor criteria STATE
• Vomiting This syndrome is characterized by extremely elevated serum glucose

• Headache concentrations and hyperosmolality without significant ketosis. Rates
• Lethargy or not easily arousable of treatment complications and mortality are substantially higher than
• Diastolic blood pressure > 90 mmHg those of DKA.42 The incidence of HHS in children and adolescents is
• Age <5 years increasing35 with up to 2% of children presenting with HHS at onset
of type 2 diabetes.30 HHS manifests with gradually increasing polyuria
and polydipsia that may go unrecognized resulting in profound dehy-
8.2.1 | Treatment of cerebral injury dration and electrolyte losses at the time of presentation. Frequently
it is accompanied by lethargy, weakness, confusion, dizziness, and
• Initiate treatment as soon as the condition is suspected. behavioral change.35,263 Obesity and hyperosmolality can make the
848 GLASER ET AL.
FIGURE 3 Treatment of hyperglycemic hyperosmolar syndrome (HHS)224
clinical assessment of dehydration challenging. Despite severe volume • The initial bolus should be ≥20 ml/kg of isotonic saline (0.9% NaCl)
depletion and electrolyte losses, hypertonicity preserves intravascular and a fluid deficit of approximately 12% to 15% of body weight
volume and signs of dehydration may be less evident. should be assumed. Additional fluid boluses should be given rap-
During therapy, decreasing serum osmolality results in movement idly, if necessary, to restore peripheral perfusion.
of water out of the intravascular space resulting in decreased intravas- • Thereafter, 0.45% to 0.75% NaCl should be administered to
cular volume. In addition, pronounced osmotic diuresis may continue replace the deficit over 24 to 48 h.
for many hours in children with extremely increased plasma glucose • Because isotonic fluids are more effective in maintaining circulatory
concentrations. Early during treatment, urinary fluid losses may be volume, isotonic saline should be restarted if perfusion and hemody-
considerable. Because intravascular volume may decrease rapidly dur- namic status appear inadequate as serum osmolality declines.
ing treatment in children with HHS, more aggressive replacement of • Serum sodium concentrations should be measured frequently and
intravascular volume (as compared to treatment of children with DKA) the sodium concentration in fluids adjusted to promote a gradual
is required to avoid vascular collapse. decline in corrected serum sodium concentration and osmolality.
Although there are no data to indicate an optimal rate of decline
in serum sodium concentration, 0.5 mmol/L per hour has been
10.1 | Treatment of HHS recommended for hypernatremic dehydration.264 With ade-
quate rehydration alone (i.e., before commencing insulin ther-
There are no prospective data to guide treatment of children and ado- apy), serum glucose concentrations should decrease by 4.1 to
lescents with HHS. The following recommendations are based on 5.5 mmol/L (75 to 100 mg/dl) per hour.265,266
2
extensive experience in adults and an appreciation of the pathophys- Mortality has been associated with failure of the corrected
iological differences between HHS and DKA224 (Figure 3). Children serum sodium concentration to decline with treatment.35
should be admitted to an intensive care unit or comparable setting A more rapid rate of decline in serum glucose concentration is
where expert medical, nursing and laboratory services are available. typical during the first several hours of treatment due to expan-
sion of the intravascular volume leading to improved renal per-
fusion. If there is a continued rapid fall in serum glucose
10.1.1 | Fluid therapy in HHS (>5.5 mmol/L, 100 mg/dl per hour) after the first few hours,
consider adding 2.5% or 5% glucose to the rehydration fluid.
The goal of initial fluid therapy is to expand the intra- and extravascu- Failure of the expected decrease in plasma glucose concentra-
lar volume and restore normal renal perfusion. The rate of fluid tion should prompt reassessment and evaluation of renal
replacement should be more rapid than is recommended for DKA. function.
GLASER ET AL. 849
Unlike treatment of DKA, replacement of urinary losses is phosphate replacement while avoiding clinically significant
recommended.164 The typical urine sodium concentration dur- hypocalcemia.
ing an osmotic diuresis approximates 0.45% saline; however, Serum phosphorus concentrations should be measured every
when there is concern about the adequacy of circulatory vol- 3 to 4 h.
ume, urinary losses may be replaced with a fluid containing a • Replacement of magnesium should be considered in the occasional
higher sodium concentration. patient who experiences severe hypomagnesemia and hypocalce-
mia during therapy. The recommended dose is 25 to 50 mg/kg per
dose for 3 to 4 doses given every 4 to 6 h with a maximum infusion
10.1.2 | Insulin therapy in HHS rate of 150 mg/min and 2 g/h.
Early insulin administration is unnecessary in HHS as ketosis usually is

minimal and fluid administration alone causes a marked decline in 10.2 | Complications of HHS
serum glucose concentration. The osmotic pressure exerted by glu-
cose within the vascular space contributes to the maintenance of • To prevent venous thrombosis, mechanical and pharmacologic pro-
blood volume. A rapid fall in serum glucose concentration and osmo- phylaxis (low molecular weight heparin) should be considered,
lality after insulin administration may lead to circulatory compromise especially in children >12 years.224
and venous thrombosis unless fluid replacement is adequate. Children • Rhabdomyolysis may occur in children with HHS resulting in acute
with HHS also have extreme potassium deficits; a rapid insulin- kidney failure, severe hyperkalemia, hypocalcemia, and muscle
induced shift of potassium to the intracellular space can trigger an swelling causing compartment syndrome.221,263,267,268 The classic
arrhythmia. symptom triad of rhabdomyolysis includes myalgia, weakness, and
dark urine. Monitoring creatine kinase concentrations every 2 to
• Insulin administration should be initiated when serum glucose con- 3 h is recommended for early detection.
centration is no longer declining at a rate of at least 3 mmol/L • For unknown reasons, several children with HHS have had clinical
(50 mg/dl) per hour with fluid administration alone. manifestations consistent with malignant hyperthermia, which is
• In children with more severe ketosis and acidosis (mixed presenta- associated with a high mortality rate.269,270 Children who have a
tion of DKA and HHS – see later), however, insulin administration fever associated with a rise in creatine kinase concentrations may
should be initiated earlier. be treated with dantrolene, which reduces calcium release from
• Continuous administration of insulin at a rate of 0.025 to the sarcoplasmic reticulum and stabilizes calcium metabolism
0.05 units per kg per hour can be used initially, with the dosage within muscle cells; however, mortality rates are high, even with
titrated to achieve a decrease in serum glucose concentration of treatment.269,270
3–4 mmol/L (50–75 mg/dl) per hour. • Altered mental status is common in adults whose serum osmolality
Insulin boluses are not recommended. exceeds 330 mOsm/kg; however, cerebral edema is rare.35 Among
96 cases of HHS reported in the literature up to 2010, including
32 deaths, there was only one instance of cerebral edema,35 and
10.1.3 | Electrolytes in HHS there have been no further reports of cerebral edema in children
with HHS to date. A decline in mental status after hyperosmolality
In general, deficits of potassium, phosphate, and magnesium are has improved with treatment is unusual and should be promptly
greater in HHS than DKA. investigated.
• Potassium replacement (40 mmol/L of replacement fluid) should

begin as soon as the serum potassium concentration is within the 10.3 | Mixed HHS and DKA
normal range and adequate renal function has been established.
Higher rates of potassium administration may be necessary, par- Mixed presentation of HHS and DKA is frequently unrecognized
ticularly after starting an insulin infusion and managed inappropriately which may increase the risk of com-
Serum potassium concentrations should be monitored every 2– plications.271 Children with mixed presentation meet criteria for
3 h along with cardiac monitoring. diagnosis of DKA and have hyperosmolality (blood glucose concen-
Hourly potassium measurements may be necessary if the child tration > 33.3 mmol/L (600 mg/dl) and effective osmolality
has hypokalemia. >320 mOsm/Kg). Treatment must account for potential complica-
• Bicarbonate therapy is contraindicated; it increases the risk of tions of both DKA and HHS. Mental status must be closely moni-
hypokalemia and may adversely affect tissue oxygen delivery. tored and frequent reassessment of circulatory status and fluid
• In children with hypophosphatemia, an intravenous solution that balance is necessary to guide therapy. To maintain adequate circu-
contains a 50:50 mixture of potassium phosphate and either potas- latory volume, the rate of fluid and electrolyte administration usu-
sium chloride or potassium acetate generally permits adequate ally exceeds that required for the typical case of DKA. Insulin is
850 GLASER ET AL.
necessary to resolve ketosis and arrest hepatic gluconeogenesis; 7. DePiero A, Kuppermann N, Brown K, et al. Hypertension during dia-
however, insulin infusion should be deferred until the child has betic ketoacidosis in children. J Pediatr. 2020;223:156-163.
8. Deeter K, Roberts J, Bradford H, et al. Hypertension despite dehy-
received initial fluid boluses and the circulation has been stabilized.
dration during severe pediatric diabetic ketoacidosis. Pediatr Diab.
Severe hypokalemia and hypophosphatemia may occur, and potas- 2011;12:295-301.
sium and phosphate concentrations should be carefully monitored 9. McDonnell C, Pedreira C, Vadamalayan B, Cameron F, Werther G.
as described above for HHS. Diabetic ketoacidosis, hyperosmolarity and hypernatremia: are high-
carbohydrate drinks worsening initial presentation? Pediatr Diab.
2005;6:90-94.
CONF LICT OF IN TE RE ST 10. Dunger D, Sperling M, Acerini C, et al. ESPE / LWPES consensus
None of the authors has any conflicts of interest relevant to the sub- statement on diabetic ketoacidosis in children and adolescents. Arch
ject matter of the article. Dis Child. 2003;89:188-194.
11. Sheikh-Ali M, Karon BS, Basu A, et al. Can serum beta-
hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes
AUTHOR CONTRIBUTIONS Care. 2008;31(4):643-647.
All authors reviewed and summarized literature about Pediatric DKA 12. Tremblay ES, Millington K, Monuteaux MC, Bachur RG,
and drafted one or more sections of the manuscript. All authors Wolfsdorf JI. Plasma beta-Hydroxybutyrate for the diagnosis of dia-
betic ketoacidosis in the emergency department. Pediatr Emeg Care.
reviewed and edited the manuscript drafts. NG coordinated revisions
2021;37(12):e1345-e1350. doi:10.1097/pec.0000000000002035
of the manuscript based on input from ISPAD membership, the co-
13. Laffel L. Ketone bodies: a reivew of physiology, pathophysiology,
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P EE R R EV I E W 14. Lewis J. Valproic acid (Depakene). A new anticonvulsant agent.
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DATA AVAI LAB ILITY S TATEMENT sulfhydryl drugs [letter]. Diabetes Care. 1996;19(6):673-674.
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ORCID the development of euglycemic ketoacidosis during periods of insu-
lin deficiency. J Clin Endocrinol Metab. 1993;76:1192-1198.
Nicole Glaser https://orcid.org/0000-0003-1278-0801
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Valentino Cherubini https://orcid.org/0000-0002-7664-1475 hood diabetes mellitus: A prospective population-based study. Dia-
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ENDNOTES
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†
In the PECARN FLUID Trial, the rapid fluid infusion arm rates were cal- 21. Goldenberg RM, Berard LD, Cheng AYY, et al. SGLT2 inhibitor-
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remaining deficit over the subsequent 24 h. As DKA typically resolves tions for prevention and diagnosis. Clin Ther. 2016;38(12):2654-
within 12 h for most children, these rates are equivalent to those calcu- 64 e1.
lated to replace the full deficit over 24 h in the majority. Therefore, for 22. Misaghian-Xanthos N, Shariff AI, Mekala K, et al. Sodium-glucose
simplicity, we have recommended a range of 24 to 48 h for deficit cotransporter 2 inhibitors and diabetic ketoacidosis: A case series
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23. Danne T, Garg S, Peters A, et al. International consensus on risk
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diabetic ketoacidosis. N Engl J Med. 1983;309:159-169. tes Care. 2019;42(6):1147-1154. doi:10.2337/dc18-2316
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Donnino MW. Prevalence and significance of lactic acidosis in dia- tes in children and adolescents: a systematic review and evaluation of
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13995448, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pedi.13406 by Consorci De Serveis Universitaris De Catalunya, Wiley Online Library on [04/12/2022].

ISPAD Clinical Practice Consensus Guidelines 2022: Diabetic

Nicole Glaser1 | Maria Fritsch2 | Leena Priyambada3 | Arleta Rewers4 |

1 | S U M M A R Y O F W H A T I S N E W OR symptoms of DKA are non-specific. Therefore, fingerstick blood glu-

TABLE 2 Glasgow coma scale (GCS)

Best verbal response (nonverbal

6.2 | Where should the child with DKA be

• Laboratory observations • Hypocalcemia, hypomagnesemia151

*These complications, often with fatality, have been more fre-

• Vomiting This syndrome is characterized by extremely elevated serum glucose

FIGURE 3 Treatment of hyperglycemic hyperosmolar syndrome (HHS)224

Early insulin administration is unnecessary in HHS as ketosis usually is

• Potassium replacement (40 mmol/L of replacement fluid) should

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