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Diabetic ketoacidosis in children: Treatment and complications

Diabetic ketoacidosis in children: Treatment and complications
Literature review current through: Sep 2023.
This topic last updated: Feb 16, 2023.

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-abundant settings [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. Other aspects of DKA are discussed in separate topic reviews:

(See "Diabetic ketoacidosis in children: Clinical features and diagnosis".)

(See "Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)".)

(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis".)

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 2022 [9]:

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

Metabolic acidosis – Venous pH <7.3 or serum/plasma bicarbonate <18 mEq/L (18 mmol/L)

Ketosis – Determined by the presence of ketones in the blood (beta-hydroxybutyrate [BOHB] >3 mmol/L [31 mg/dL]) or urine ("moderate" or "large" urine ketones)

(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

Absent to mild ketosis

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 (12 to 15 percent of body weight) and requires greater fluid resuscitation than DKA. In addition, delayed initiation of insulin treatment and lower insulin doses are 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 (hyperosmolar DKA) can also occur and often requires greater fluid resuscitation and electrolyte replacement than are typical for DKA [9]. 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. Children with a new onset of diabetes typically have more severe dehydration than those with previously diagnosed diabetes. (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

BOHB

Electrolytes – Including bicarbonate

Blood urea nitrogen (BUN), creatinine

Venous or arterial pH and partial pressure of carbon dioxide (pCO2)

Complete blood count

Calcium, phosphorus, magnesium – Severe abnormalities in these measures 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. Note that the white blood cell count is frequently elevated in children with DKA and should not be considered a sign of infection in the absence of other findings.

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). Prolonged QTc has also been found to occur frequently in children with DKA and is correlated with DKA severity and anion gap [13,14]. Patients with prolonged QTc interval (>460 msec) should have continuous monitoring of heart rhythm during DKA treatment because of possible increased risk for arrhythmias.

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) [9]:

Mild – pH 7.2 to <7.3, bicarbonate 10 to <18 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 a clinically practical and accurate measure of the overall level of acidosis (with metabolic and, possibly, respiratory contributors). However, measurements of serum bicarbonate may be used alone, especially in resource-limited settings, and are closely correlated with venous pH [15].

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 mEq/L (or mmol/L)

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, administration of large amounts of chloride in intravenous (IV) fluids, and preferential renal excretion of ketones rather than chloride, often causes hyperchloremic acidosis. Therefore, the anion gap is a better measure of the effectiveness of treatment and DKA resolution than is 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 [16-18].

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)

Low pCO2 (≤20 mmHg)

High BUN

Significant hyper- or hypokalemia, or other severe electrolyte disturbances.

In some institutions, all patients receiving 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 [19]. Patients who will be managed without continuous cardiac monitoring should have an initial electrocardiogram to measure the QTc interval. (See 'Clinical assessment' above.)

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) [20-22]. 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 [20]. Increased blood urea nitrogen (BUN) concentrations and low pH have been found to be the best predictors of dehydration severity. Children with a new onset of diabetes also tend to have more severe dehydration. Children with pH <7.1, BUN >20 mg/dL, or a new onset of diabetes should be assumed to have approximately 8 percent dehydration. All other children should be assumed to have approximately 6 percent dehydration. 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 infused over 20 to 30 minutes [9,23]. 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 [23]. 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 — An IV insulin infusion should be initiated approximately one hour after the patient begins IV fluids. Insulin administration 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 [24,25]; however, larger-scale randomized trials are needed for a more comprehensive comparison of benefits and risks of various insulin infusion rates. Until more evidence is available, lower rates of insulin infusion should mainly be considered for children with mild DKA.

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) [26,27].

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 [19,28]. 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 [9,29-31].

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 [32]. 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]. Rare patients who develop severe hypokalemia or severe hypophosphatemia during DKA treatment may also require temporary reductions in insulin infusion until potassium or phosphorus levels improve.

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. It is anticipated that the measured sodium concentration will rise approximately 1.6 mEq/L for every 100 mg/dL (5.5 mmol/L) decrease in glucose concentration [33]. In older retrospective studies, failure of the serum sodium concentration to rise during treatment was found to be associated with cerebral injury [34,35]. However, a subsequent large prospective study found no such association, with similar rates of altered mental status and clinical diagnoses of cerebral injury among patients with and without declines in serum sodium concentration during treatment [36]. Although changes in sodium concentrations do not appear to contribute to risk of cerebral injury, declines in intravascular volume should be avoided, particularly in children with severe dehydration or findings suggesting circulatory compromise. In these situations, the sodium content of the fluid should be increased if the measured serum sodium concentration is low and does not rise appropriately as the plasma glucose concentration falls.

Serum sodium trends have been shown to be mainly driven by the sodium content of IV fluids, rather than the rate of infusion [36]; however, development of severe hypernatremia during DKA treatment may indicate insufficient volume replacement. (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 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, defer potassium replacement therapy until the serum potassium falls to normal and urine production/adequate renal function is documented (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 (12±2 mEq/L or mmol/L), serum BOHB is ≤1 mmol/L (10.4 mg/dL), and venous pH is ≥7.3 [9,37]. 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 [38,39], 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 [40,41].

The administration of alkali may slow the rate of resolution of ketosis [42].

Bicarbonate therapy has been associated with the development of cerebral injury [35]. (See 'Cerebral injury' below.)

The rapid correction of acidosis with bicarbonate therapy may result in hypokalemia [43,44].

In rare situations (severe acidosis resulting in impaired cardiac contractility and 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 mild and asymptomatic; however, severe hypophosphatemia resulting in rhabdomyolysis, muscle weakness/paralysis, and hemolytic anemia may also occur [45-47]. (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. Continuous cardiac monitoring is prudent for children with moderate to severe DKA and those with prolonged QTc interval on initial electrocardiogram.

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 to ensure ongoing positive fluid balance. 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 >18 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 [48].

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 [49]. Regular insulin (given every four hours) has also been used in these circumstances [50].

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 [1-3,51]. Cerebral injury accounts for the majority of deaths (60 to 90 percent) [35,52]. Mortality is substantially higher in resource-limited settings [53].

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 [2,23,35,51,54]. 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 [23]. (See 'Subsequent fluid administration' above.)

Cerebral injury generally develops during the first 12 hours of treatment but can also occur before treatment [35,55]. 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 [56-59]. 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 [56,58-61].

Venous thrombosis — Children with DKA are at increased risk for deep venous thrombosis, particularly in association with femoral central venous catheter placement [62,63]. This may in part be due to a prothrombotic state associated with DKA [64].

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 [65,66]. 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 (approximately 50 percent) [67-70]. Many of these children have stage 2 or 3 AKI, suggesting intrinsic tubular injury beyond prerenal dysfunction. Kidney failure can also occur but is rare. Renal function generally returns to normal after recovery from DKA; however, episodes of DKA-related AKI have been shown to increase the long-term risk of diabetic kidney disease [71].

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 [13,67,72-80]. Patients with DKA are also uniquely susceptible to rhinocerebral or pulmonary mucormycosis, a rare and frequently fatal fungal infection [81,82]. 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 [83] and identifying high-risk individuals through family history, genetic, and immunologic screening. (See "Prediction of type 1 diabetes mellitus" and "Type 1 diabetes mellitus: Prevention and disease-modifying therapy".)

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'.)

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: Diabetes mellitus in children" and "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 topics (see "Patient education: Diabetic ketoacidosis (The Basics)" and "Patient education: Managing blood sugar in children with diabetes (The Basics)")

Beyond the Basics topic (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Laboratory monitoring – Obtain initial laboratory studies including blood glucose, electrolytes, blood urea nitrogen (BUN) and creatinine, venous or arterial pH and partial pressure of carbon dioxide (pCO2), 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 and phosphorus, calcium, and magnesium every four to six hours, until ketoacidosis is resolved. (See 'Laboratory testing' above and 'Monitoring' above.)

Care setting – 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.)

Monitoring for cerebral injury – 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.)

Fluid and insulin therapy – Treatment of DKA involves administration of IV fluids and insulin. (See 'Dehydration' above and 'Hyperglycemia' above.)

The first step is volume expansion, 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 the initial volume expansion is complete, begin an IV insulin infusion 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 volume expansion, replace the remaining fluid deficit 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.)

Bicarbonate should not be administered to treat acidosis, except in specific rare circumstances. (See 'Metabolic acidosis' above.)

Endpoint of therapy – The insulin infusion should be continued until the anion gap is normal or BOHB ≤1 mmol/L (10.4 mg/dL), acidosis and hyperglycemia have resolved, and the patient is tolerating oral intake. (See 'Metabolic acidosis' above and 'Discontinuing the insulin infusion' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges George S Jeha, MD, and Morey Haymond, MD, who contributed to earlier versions of this topic review.

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