Pediatric Diabetic Ketoacidosis (DKA)

Diabetic ketoacidosis (DKA) in children is defined as a blood glucose level over 11 mmol/L, venous pH below 7.3 or serum bicarbonate level below 15 mmol/L, and either the presence of ketonemia (blood β-hydroxybutyrate level ≥ 3 mmol/L) or moderate to high ketonuria.[1]  

This condition, together with the major complication of cerebral edema, is the most important cause of mortality and severe morbidity in pediatric cases of diabetes, particularly at the time of first diagnosis. (See Pathophysiology and Prognosis.)

Early recognition and careful management of ketoacidosis—a metabolic derangement caused by the absolute or relative deficiency of the anabolic hormone insulin—are essential if death and disability are to be avoided. (See Pathophysiology, Etiology, Presentation, Workup, Treatment, and Medication.)[4]

Patient education

For patient education information, see the Diabetes Center, as well as Diabetic Ketoacidosis.

Insulin is the pivotal hormone of blood glucose regulation, increasing peripheral glucose uptake and switching off hepatic gluconeogenesis, while stimulating glycogen synthesis and peripheral fat deposition.

Insulin deficiency exaggerates the normal response to fasting, which is to increase liver production of glucose by gluconeogenesis from fat and protein together with the breakdown of liver glycogen stores by glycogenolysis. Peripheral glucose uptake is impaired and levels of the main counterregulatory hormones (ie, glucagon, cortisol, catecholamines, growth hormone) increase. Various metabolic consequences follow.[5]

Hyperglycemia

Glucagon stimulates glycogenolysis and gluconeogenesis, doubling liver glucose production. Hyperglycemia further impairs peripheral glucose uptake and inhibits any residual insulin synthesis. Blood glucose levels rise above the renal threshold for glucose reabsorption, causing an osmotic diuresis.

Fluid and electrolytes

Although they tend to be overestimated, fluid losses can be considerable, typically reaching 3-8% of body weight.[6] Most water is lost by osmotic diuresis, with important contributions from hyperventilation and vomiting. The diuresis also leads to significant urinary losses of potassium, sodium, phosphate, and magnesium ions.

Ketoacidosis

Insulin inhibits the lipolytic action of cortisol and growth hormone; thus, insulin deficiency increases circulating levels of fatty acids. These are oxidized in the liver, producing the acidic ketone bodies beta hydroxybutyrate and acetoacetate, from which acetone spontaneously forms. The resulting acidosis primarily is due to circulating ketone bodies, with additional contributions from excess fatty acids and lactic acidosis, as a consequence of poor tissue perfusion.

Eventually, hyperventilation no longer can compensate for the metabolic acidosis, which, together with dehydration, leads to renal failure and circulatory collapse, followed by coma and death.

Cerebral edema

The cause of cerebral edema associated with diabetic ketoacidosis is unknown, but associated factors include duration and severity of diabetic ketoacidosis before treatment, overaggressive fluid replacement, the use of sodium bicarbonate to treat the acidosis, too early an introduction of insulin therapy, cerebral anoxia, and degree of hyperglycemia.[7, 8, 9, 10, 11, 12]  

Various theories have been offered to explain cerebral edema’s pathogenesis in diabetic ketoacidosis.

A widely accepted hypothesis suggests that cerebral edema results from ischemia-reperfusion injury, with inflammation and impaired cerebrovascular autoregulation playing a role in the pathogenesis.[12]  Similary, some researchers propose cerebral edema develops secondary to cerebral ischemia caused by hypocapnia, dehydration, and hyperglycemia.[13] This explains why some children present with cerebral edema before treatment and most known factors (eg, severity of hypocapnia, acidosis, dehydration, duration of ketoacidosis). Cerebral imaging studies of children with diabetic ketoacidosis and animal models make this the most compelling theory and offer an opportunity to actively prevent or better treat cerebral edema developing with ketoacidosis.[13]

Another theory postulates that brain cells produce idiogenic osmoles to prevent cell shrinkage in a hyperosmolar environment. These osmoles are slow to clear from the cells, and as plasma osmolarity falls during treatment, water is drawn into the brain cells by the resulting osmotic gradient. This accounts for the belief that overrapid correction of hyperosmolarity is associated with cerebral edema.

A third theory proposes an effect on the cell membrane sodium/hydrogen transport system. As diabetic ketoacidosis develops, acidic molecules accumulate in intracellular and extracellular fluids. With treatment, the concentration of acid falls more rapidly in the extracellular compartment, causing a net influx of sodium and water into the cells as hydrogen ions are exchanged. This may explain why cerebral edema seems to appear with biochemical correction of acidosis.

Twenty-five percent of patients with a new diagnosis of diabetes present with diabetic ketoacidosis; a missed diagnosis of diabetes is the most common cause, especially in young children.

In children with established diabetes, the causes of diabetic ketoacidosis vary with age. Infection is the most likely precipitant in the prepubertal child; missed injections or emotional upset are more usual in the older teenager.

Failure to administer prescribed insulin is the most common cause of diabetic ketoacidosis in adolescents.[14, 15] Children with high glycosylated hemoglobin (HbA1c) levels (a measure of control over an 8- to 12-wk period) may be receiving only a third or less of the prescribed insulin dose.[16] Total insulin deficiency obviously leads to diabetic ketoacidosis, but inadequate doses render the child more liable to decompensate with other stresses such as infection, emotional turmoil, or food bingeing.[17]

Children on continuous subcutaneous insulin infusion are at particular risk of diabetic ketoacidosis if the device fails or if insulin delivery is disrupted, because they have no effective depot of insulin and become insulin-deficient very quickly. Diabetic ketoacidosis is most likely to occur in the first year after commencing continuous subcutaneous insulin infusion. Children with diabetic ketoacidosis often present with vomiting and abdominal pain, symptoms that are mistaken for gastroenteritis or food poisoning.

Children using only analogue insulins are also at risk of rapid-onset diabetic ketoacidosis. Omitting an evening dose of long-acting insulin may result in insulin deficiency through the night and typically leads to the child waking up vomiting.

Some children have repeated episodes of diabetic ketoacidosis (so-called brittle diabetics). These children usually have major emotional disturbances relating to home, school, or relationships with their peer group. They may repeatedly present in a critical condition but invariably deny any failure of compliance. Helping these children is extremely difficult.

Alcohol and drug abuse, particularly with cocaine, amphetamine derivatives, and their analogues, are other precipitants of diabetic ketoacidosis.[18]

In the developing world, infection and the lack of available insulin are the most important causes of diabetic ketoacidosis.

Exact figures for the incidence of diabetic ketoacidosis are not available. The estimated incidence of diabetic ketoacidosis in pediatric type 1 diabetes mellitus in resource-rich countries appears to be 1-10% per year.{ref55-INVALID REFERENCE}

Occurrence in the United States

An estimated one third of children present with diabetic ketoacidosis at diagnosis of type 1 diabetes.[1] A multicenter, population-based study reported that around 25% of new cases of type I diabetes mellitus presented with ketoacidosis, resulting in an approximate annual incidence of 4 cases per 100,000 children.[19] The youngest children were at the greatest risk, with more than 37% presenting with diabetic ketoacidosis. The rates for children with established diabetes increase with age.[20, 21]

International occurrence

As in the United States, few data are available on the incidence of diabetic ketoacidosis. A large, multicenter European study showed widely varying rates of diabetic ketoacidosis at diagnosis (26-67%), with rates inversely related to the overall incidence of childhood diabetes.[22] Diabetic ketoacidosis rates in children with established diabetes widely vary; in a United Kingdom national prospective study, 60% of all cases occurred in patients with known diabetes.[23, 24] Diabetic ketoacidosis at the time of diagnosis is more likely in the most deprived communities.

A 2011 study analyzing 46 published reports[25] reinforced the above statements. The groups most likely to present with diabetic ketoacidosis at diagnosis were the youngest children, particularly those younger than 2 years, and children from the most deprived communities, including children from ethnic minorities or without health insurance. Factors protecting against diabetic ketoacidosis at diagnosis were having a first-degree relative with type 1 diabetes, having better-educated parents, and living in a community with a high background incidence of childhood diabetes.

A multicenter study from Germany and Austria, using a database containing information on 28,770 children aged 19 years or younger, reported that the greatest risk of diabetic ketoacidosis in established cases of type 1 diabetes was in the early teenage years. This was particularly the case in girls and in children from immigrant families.[26]

Race-, sex-, and age-related demographics

Race alone does not appear to have any influence on the likelihood of developing diabetic ketoacidosis,[27] but immigrant communities may be at a higher risk of problems in established cases.[26]

Although no difference in diabetic ketoacidosis rates between the sexes is observed at diagnosis and during early childhood, adolescent girls with diabetes are more likely to develop diabetic ketoacidosis than adolescent boys.[26, 28]

Infants and children younger than 5 years are at the greatest risk of presenting with diabetic ketoacidosis because the diagnosis of diabetes in younger children is more difficult and is more likely to be delayed.[25, 29] Adolescents are more likely to develop diabetic ketoacidosis after the diagnosis of diabetes.

Expect full recovery with appropriate management of diabetic ketoacidosis. The degree and quality of monitoring are probably the most important factors in determining outcomes. However, even if cerebral edema has not occurred, a risk of long-term intellectual deficit is noted in children who have had an episode of diabetic ketoacidosis.[30]

Morbidity and mortality

Diabetic ketoacidosis is the most common cause of diabetes-related death in childhood. Without insulin therapy, the mortality rate is 100%, but current mortality rates are around 2-5%.[31, 32, 33]

Treatment for diabetic ketoacidosis may cause life-threatening, predictable, and avoidable acute complications such as hypokalemia, hypoglycemia, hyponatremia, and fluid overload. Other complications, such as cerebral edema, are not as predictable but are very important.

Indeed, cerebral edema is the most important cause of mortality and long-term morbidity in patients with diabetic ketoacidosis.[12] The overall risk of cerebral edema is 1%,[1] with the condition occurring in 0.4% of established cases and in 1.2% of newly diagnosed cases. Mortality is high, approximately 20-25%,[1] with permanent neurologic deficits in 35% or more of survivors.[31, 9]

Other rare complications of diabetic ketoacidosis include acute respiratory distress syndrome (ARDS) with pulmonary edema,[34, 35] pneumomediastinum (secondary to hyperventilation), rhabdomyolysis, and acute renal failure. Patients with type 1 diabetes mellitus and diabetic ketoacidosis often suffer acute kidney injury, a more severe course occurring in those with a longer duration of type 1 diabetes and a higher anion gap measurement.[36]  In addition, acute kidney injury and neurocognitive outcomes are not only associated with diabetic ketoacidosis in children, but they are more likely to affect those with greater acidosis and circulatory volume depletion.[37, 38]

Diabetic ketoacidosis during pregnancy is associated with a very high risk of fetal loss. 

When diabetic ketoacidosis occurs as a first presentation of diabetes, symptoms are likely to develop over several days, with progressive dehydration and ketosis. In a small child wearing diapers and with naturally high fluid intake, polyuria and polydipsia are easily missed. When diabetes is developing, the stress and symptoms of another illness may precipitate diabetic ketoacidosis, as well as mask the underlying problem.

Diabetic ketoacidosis can develop very rapidly in a patient with established diabetes, particularly when insulin therapy has been forgotten, deliberately omitted, or disrupted, as with children on continuous subcutaneous insulin infusions or using the newer analogue insulins. Under these circumstances, diabetic ketoacidosis may present with relatively normal blood glucose levels (ie, 250 mg/dL, 15 mmol/L) or less.

Hyperglycemia

Symptoms of hyperglycemia include the following:

• Polyuria - Increased volume and frequency of urination

• Polydipsia - Thirst is often extreme, with children waking at night to consume large quantities of any available drink

• Nocturia and secondary enuresis in a previously continent child

• Weight loss - May be dramatic due to breakdown of protein and fat stores

• Muscle pains and cramps

Acidosis and dehydration

Symptoms of acidosis and dehydration include the following:

• Abdominal pain that may be severe enough to present as a surgical emergency; for children with a failure of continuous subcutaneous insulin infusion, this may be the first presenting sign, along with vomiting

• Shortness of breath that may be mistaken for primary respiratory distress

• Confusion and coma in the absence of recognized head injury[2]

Cerebral edema

Presentation of cerebral edema varies; most cases occur 4-12 hours after initiation of treatment. Typically, the child appears to be improving until a sudden deterioration occurs, with increasing coma; fixed, dilated pupils; and, finally, respiratory arrest. Other patients may have a progressively worsening coma. Children may occasionally present with signs of cerebral edema before treatment begins. Regular monitoring of neurologic status to detect early changes, together with prompt corrective treatment, is important to avoid death or damage.

Clinical signs of developing cerebral edema can be divided into 3 main categories. One diagnostic criteria, 2 major criteria, or 1 major and 2 minor criteria have a sensitivity of 92% and false-positive rate of 4%.[39]

Diagnostic criteria

• Abnormal motor or verbal response to pain

• Decorticate or decerebrate posture

• Cranial nerve palsy (especially III, IV, and VI)

• Abnormal neurogenic breathing pattern (eg, Cheyne-Stokes), apneusis

Major criteria

• Altered mentation, fluctuating level of consciousness

• Sustained and inappropriate bradycardia

• Age-inappropriate incontinence

Minor criteria

• Vomiting

• Headache

• Abnormally drowsy

• Diastolic hypertension (>90 mm Hg)

Additional symptoms

Patients with diabetic ketoacidosis may also have the following symptoms:

• Vomiting

• Signs of intercurrent infection (eg, urinary tract infection, respiratory tract infection)

• Weakness and nonspecific malaise that may precede other symptoms of hyperglycemia

Dehydration may be observed in patients with diabetic ketoacidosis. The degree of dehydration is often reported to be approximately 5-10% but easily can be overestimated (see Table 1, below). One report suggested that children with severe ketoacidosis are rarely more than 8% dehydrated.[6] Clinical signs such as dry mouth, sunken eyes, and decreased skin turgor, are present from about 3% dehydration. Little correlation with hydration status was found in diabetic ketoacidosis patients when using single biochemical or clinical markers.[40]

Table 1. Clinical Assessment of Dehydration (Open Table in a new window)

Other symptoms can include the following:

• Blood pressure - Usually normal until terminal stages of illness

• Tachycardia - May be present

• Capillary refill - Initially maintained, but a combination of increasing acidosis and dehydration cause poor tissue perfusion

• Kussmaul breathing or deep sighing respiration - A mark of acidosis; these symptoms may be mistaken for status asthmaticus, pneumonia, and even hysterical hyperventilation

• Ketone odor - Patient may have a smell of ketones on the breath, although many people cannot detect this smell

• Impaired consciousness - Occurs in approximately 20% of patients

• Coma - May be present in 10% of patients

• Abdominal tenderness - May occur; tenderness is usually nonspecific or epigastric in location; bowel sounds may be reduced or absent in severe cases

Rapid onset of diabetic ketoacidosis that presents with relatively low blood glucose levels, vomiting, and abdominal pain can occur in children using short-acting and long-acting insulin analogues or continuous subcutaneous insulin infusions.

The following lab studies are indicated in patients with diabetic ketoacidosis:

• Blood glucose

• Blood gases

• Potassium

• Sodium

• Blood urea and creatinine

• Bicarbonate - Usually available from blood gas analysis

• Capillary blood ketone

• Glycosylated hemoglobin (HbA1c)

• Serum osmolarity

Additional laboratory studies are often measured but have limited value in management without specific indication

• Full blood count

• Cultures

• Insulin

• Phosphate, calcium, and magnesium levels

• Amylase levels

• Lipids

Imaging studies

Perform head computed tomography (CT) scanning if coma is present or develops. Concurrently, initiate appropriate measures to manage cerebral edema. Perform chest radiography if clinically indicated.

Consciousness

Check the patient’s consciousness level hourly for up to 12 hours, especially in a young child with a first presentation of diabetes. The Glasgow coma scale (see the image below) is recommended for this purpose.

Pediatric Diabetic Ketoacidosis. Glasgow Coma Scale, modified for age of verbal response.

The normal maximum score on the Glasgow coma scale is 15. A score of 12 or less implies significant impairment of consciousness. A falling score may signify the development of cerebral edema.

Blood glucose

Capillary blood samples analyzed on any modern blood glucose meter are acceptable for monitoring changes in blood glucose levels as treatment progresses, but measure at least 1 whole blood glucose at presentation.

Check blood glucose at least hourly during the initial stages of treatment (more frequently if blood glucose levels fall quickly or if changes to insulin infusion rates are made).

Blood gases

Traditionally, arterial blood samples are used; however, free-flowing capillary or venous samples are as reliable as the arterial samples for monitoring acidosis, are much easier to collect, and are less traumatic for the child.[41]

The severity of diabetic ketoacidosis can be defined by blood gas results, as follows:

• Mild diabetic ketoacidosis - pH level of less than 7.3, bicarbonate level of less than 15 mmol/L

• Moderate diabetic ketoacidosis - pH level of less than 7.2, bicarbonate level of less than 10 mmol/L

• Severe diabetic ketoacidosis - pH level of less than 7.1, bicarbonate level of less than 5 mmol/L

Potassium

Initial blood potassium levels are usually normal or high, despite considerable deficits of total body potassium. This is because the acidosis encourages leakage of intracellular potassium. Insulin drives potassium back into the cells, and levels may drop very quickly with treatment.

Frequent checks of potassium levels (ie, every 1-2 h), together with electrocardiographic monitoring, may be required in the first hours of therapy.

Sodium

Measured sodium values are likely to be low because of the dilutional effect of hyperglycemia. True sodium levels can be calculated by adding 1.6 mEq/L sodium for every 100 mg/dL glucose (ie, 1 mmol/L sodium for 3 mmol/L glucose).

Sodium levels should rise with treatment. Failure of sodium levels to rise is associated with an increased risk of cerebral edema.

Blood urea and creatinine

Some creatinine assays can be affected by the presence of ketones, thus giving falsely elevated results. Under these circumstances, blood urea may give a better measure of dehydration.

Capillary blood ketone

Capillary blood ketone can be measured using a handheld meter; the level is always elevated at presentation of diabetic ketoacidosis (>2 mmol/L). Two studies have proposed using serial measurements as a way of indicating the resolution of diabetic ketoacidosis when the pH level is more than 7.3 and the sequential capillary blood ketone level is less than 1 mmol/L.[42, 43]

Insulin

Insulin levels may be indicated in children with recurrent diabetic ketoacidosis, as an absence of measurable insulin can be used to emphasize that omission is probable. Caution is needed because not all assays measure the newer analogue insulins; insulin antibody levels can also affect the result.

Additional studies

Other lab studies include the following:

• Bicarbonate (usually available from blood gas analysis) - This reflects the degree of acidosis

• Glycosylated hemoglobin (HbA1c) - High results are expected in a patient with newly diagnosed diabetes and in patients with an established diagnosis who have poor compliance with treatment. A normal result may be seen where acute failure of insulin delivery from an insulin pump results in rapid onset DKA.

• Urine - Check all urine for glucose and ketones for at least 24 hours, particularly if capillary blood ketones are not available

• Full blood count - The white blood cell (WBC) count is usually elevated, even in the absence of infection

• Culture - Perform blood culture and other cultures if clinically indicated in the presence of fever or symptoms (eg, urine, throat swab)

• Amylase - Blood amylase levels often are elevated in diabetic ketoacidosis and can be misleading in the presence of abdominal pain

• Serum osmolarity - This is usually elevated

• Phosphate, calcium, and magnesium - These levels are invariably reduced but without obvious clinical significance

• Lipids - Extremely high triglyceride levels are sometimes present; this causes an artificial lowering of other blood values, such as those for glucose, sodium, and potassium, but abnormal lipids are almost an inevitable consequence of DKA

Ideally, insert a good-sized venous cannula into each arm, the first for fluid, electrolyte, and insulin replacement and the second for regular sampling.

Arterial cannulation is appropriate for patients who require mechanical ventilation or for those who need intensive care for conditions such as coma, shock, or severe acidosis.

Insert a nasogastric tube and aspirate the gastric contents for all patients with impaired consciousness and for children with repeated vomiting.

Consider urinary catheterization for children with impaired consciousness. This allows accurate calculation of urinary losses, particularly in the early hyperosmolar phases of diabetic ketoacidosis in which osmotic diuresis can lead to massive urinary losses, even in the presence of dehydration.

Manage cerebral edema with intubation and mechanical ventilation in addition to osmotic diuresis.

Electrocardiography (ECG) is a useful adjunct to monitor potassium status. Characteristic changes appear with extremes of potassium status. Characteristic changes of hypokalemia as represented on ECG (see the image below) are as follows:

• Apparent prolongation of QT interval

• ST segment depression

• Flat or diphasic T waves

• Prominent U waves

• Prolongation of PR interval

• Sinoatrial block

  Pediatric Diabetic Ketoacidosis. A graphical representation of the electrocardiographic changes of hypokalemia.

Hyperkalemia may develop due to overcorrection of potassium loss, with electrocardiographic changes occurring as follows (see the image below):

• Broadening of the QRS

• Peaked T waves

• Prolonged PR interval

• Disappearance of P wave

• Diphasic QRS complex

• Asystole

  Pediatric Diabetic Ketoacidosis. A graphical representation of the electrocardiographic changes of hyperkalemia (due to overcorrection of potassium loss).

In patients with diabetic ketoacidosis, the first principals of resuscitation apply (ie, the ABCs [airway, breathing, circulation]).[4] Outcomes are best when children are closely monitored and a changing status is promptly addressed.[3, 44]  Give oxygen, although this has no effect on the respiratory drive of acidosis. Diagnose by clinical history, physical signs, and elevated blood glucose.

Fluid, insulin, and electrolyte (potassium and, in select cases, bicarbonate) replacement is essential in the treatment of diabetic ketoacidosis.

Early in the treatment of diabetic ketoacidosis, when blood glucose levels are very elevated, the child can continue to experience massive fluid losses and deteriorate. Strict measurement of fluid balance is essential for optimal treatment.

Continuous subcutaneous insulin infusion therapy using an insulin pump should be stopped during the treatment of diabetic ketoacidosis.

Inpatient care

Children with severe acidosis (ie, pH < 7.1) or with altered consciousness should be admitted to a pediatric intensive care unit.

In cases in which the occurrence of diabetic ketoacidosis signals a new diagnosis of diabetes, the process of education and support by the diabetes team should begin when the patient recovers.

In cases in which diabetic ketoacidosis occurs in a child with established diabetes, explore the cause of the episode and take steps to prevent a recurrence.

Following recovery from diabetic ketoacidosis, patients require subcutaneous insulin therapy.

Outpatient care

Organize outpatient care through the pediatric diabetes care team.

Consultations

Consult a neurosurgeon if cerebral edema is suspected.

Diet

Once the child has recovered, he or she can resume a normal diet.

Guidelines

The International Society for Pediatric and Adolescent Diabetes published guidelines for the management of diabetic ketoacidosis in children at http://www.ispad.org/FileCenter/10-Wolfsdorf_Ped_Diab_2007,8.28-43.pdf.

Until relatively recently no randomized trials of fluid replacement had been conducted and, over the years, various regimens have been proposed. Published series suggest that the best outcomes have been achieved by using isotonic sodium chloride solution or half-strength sodium chloride solution for first resuscitation and replacement.[3] Slowly correcting the fluid deficit over 48 hours appears to be safer than rapid rehydration and, thus, forms the basis of the following regimen:

• Calculate fluid deficit by weight loss or clinical assessment to a maximum 8% of body weight

• In a child with severe acidosis or compromised circulation, an initial resuscitation of 10-20 mL/kg of isotonic sodium chloride solution (0.9%) can be administered over 30 minutes

• Remember to subtract any initial resuscitation fluid boluses given from the total calculated deficit

• After resuscitation, slowly correct the fluid deficit over 48 hours by providing normal maintenance fluids together with the calculated deficit

• Administer isotonic sodium chloride solution until blood glucose levels have fallen to 250-300 mg/dL (ie, 12-15 mmol/L), at which time glucose-containing fluids should be introduced (either 5% glucose with 0.9% saline or 5% glucose with 0.45% saline); continue maintenance with dextrose saline until the child is eating and drinking normally.

• If cerebral edema develops, restrict fluid replacement to two thirds of normal maintenance and replace the deficit over a period of 48 hours or longer

• Although strict assessment of fluid balance is important, replacement of ongoing losses is not normally required

The fluid maintenance rates typically advised for children are probably too generous for use in children with diabetic ketoacidosis. Table 2, below, can be used to calculate more appropriate infusion rates.

Table 2. Suggested Daily Maintenance Fluid Replacement Rates (Open Table in a new window)

Continuous, low-dose, intravenous (IV) insulin infusion is generally accepted as the safest and most effective method of insulin delivery for treating diabetic ketoacidosis. Low-dose IV insulin infusion is simple, provides more physiologic serum levels of insulin, allows gradual correction of hyperglycemia, and reduces the likelihood of sudden hypoglycemia and hypokalemia.

The results of a prospective national study of diabetic ketoacidosis in the United Kingdom suggested a greater risk of cerebral edema in patients who received insulin within the first hour of treatment.[23] In light of these results, starting insulin therapy an hour after fluid resuscitation has commenced is prudent, especially in the newly diagnosed child.

The correct dose of insulin to infuse in the treatment of diabetic ketoacidosis is under debate. Traditionally, 0.1 U/kg/h is given, but a lower dose of 0.05 U/kg/h is enough to prevent gluconeogenesis and results in a slower reduction of blood glucose levels. One study showed no disadvantage to using the lower infusion rate of 0.05 U/kg/h.[45] Adolescents with secondary diabetic ketoacidosis and insulin resistance may need more than 0.1 U/kg/h.

Authorities commonly recommend that blood glucose levels not fall faster than 90 mg% (ie, 5 mmol/L) per hour. The infusion rate of insulin can be reduced as blood glucose levels fall but should not drop below 0.05 U/kg/h, to prevent any recurrence of ketosis. Do not discontinue infusion until subcutaneous insulin has been given when the child has recovered. If blood glucose falls below 120 mg% (ie, 7 mmol/L), increase the concentration of infused glucose to prevent hypoglycemia. Ketosis clears more quickly if insulin infusions are prolonged for 36 hours or more.

In cases of mild to moderate diabetic ketoacidosis in which the patient is able to tolerate oral fluids, giving repeated (hourly) subcutaneous injections of regular or fast-acting analogue insulins in a dose of 0.1 U/kg is possible. This is as effective as IV insulin.[46, 47]

Potassium

Patients with diabetic ketoacidosis always have a total-body deficit of potassium. After initial resuscitation and if serum/plasma levels are below 5 mEq/L or a good renal output has been maintained, add potassium to all replacement fluids.

Table 3, below, provides examples of infusion concentrations in milliequivalents per liter for differing degrees of potassium status. Potassium chloride most commonly is administered. This theoretically could make the acidosis worse, but no evidence indicates that administration of other potassium salts, such as phosphate or acetate, is more effective.

Table 3. Infusion Rates of Potassium Chloride (Open Table in a new window)

Bicarbonate

Although metabolic acidosis may be severe, no evidence supports the administration of IV sodium bicarbonate to improve outcomes; on the contrary, the evidence indicates that IV bicarbonate may cause harm and delay recovery.[48, 49] Failure of the acidosis to improve with treatment more likely reflects inadequate fluid and insulin replacement. The only justification for using IV bicarbonate is acidosis sufficiently severe to compromise cardiac contractility.

Other electrolytes

Although patients usually have an absolute deficit of phosphate and magnesium, no evidence indicates that either needs to be replaced in patients with diabetic ketoacidosis.

If cerebral edema is suspected and hypoglycemia is excluded, prompt treatment with an osmotic diuretic is indicated, followed by a CT scan and referral to a neurosurgeon. Intubation, hyperventilation, and intracranial pressure monitoring reportedly improve outcomes.

Although mannitol has been the most commonly used osmotic diuretic, theoretical and experimental reasons for using hypertonic saline (3%) have been noted.[50] The usual dose of mannitol to treat cerebral edema is 0.5-1 g/kg infused over 30 minutes, which can be repeated after 1 hour. The usual dose of hypertonic saline is 5-10 mL/kg, again infused over 30 minutes, which can be repeated after 1 hour.

Only half of children who develop cerebral edema have obvious signs of deterioration; children may present with respiratory arrest. Young children have a greater risk of respiratory arrest, and the outcome for these children is particularly bad. A United Kingdom study reported that every child who presented with respiratory arrest either died or was left with neurologic deficits.

Attention to detail is important to achieving a good outcome. Carefully monitor potassium status to prevent complications from hypokalemia.

Hypoglycemia should not occur with adequate monitoring and is less likely if low-dose, continuous insulin infusions are administered together with dextrose when blood glucose levels fall below 200 mg/dL (11 mmol/L).

Specifically designed recording charts (see the images below) make the process of care much easier. Ideally, these charts include all important measurements of clinical and biochemical status, fluid balance, and insulin prescription.

Pediatric Diabetic Ketoacidosis. Diabetic ketoacidosis treatment and results chart (page 1 of 4).

Pediatric Diabetic Ketoacidosis. Diabetic ketoacidosis treatment and results chart (page 2 of 4).

Pediatric Diabetic Ketoacidosis. Diabetic ketoacidosis treatment and results chart (page 3 of 4).

Pediatric Diabetic Ketoacidosis. Diabetic ketoacidosis treatment and results chart (page 4 of 4).

Frequent review of neurologic status—at least hourly (or any time a change in the level of consciousness is suspected)—is essential during the first 12 hours of diabetic ketoacidosis treatment. Promptly treat any suspected cerebral edema.

Diabetic ketoacidosis in a patient in whom diabetes is newly diagnosed can be prevented only if the general public and primary care physicians know the symptoms and if physicians are alert, particularly with regard to young children, to the possibility of diabetic ketoacidosis developing.[51] A urine test for glycosuria is easy to perform.

Adequate education and support for patients with established diabetes (and for their families) should prevent diabetic ketoacidosis occurring as a result of illness (see the videos below). Intervention is much more difficult when insulin is withheld deliberately or administered improperly. Identification of children at risk for such behaviors and intervention with social and psychological support may alleviate these problems.[52]

The cornerstones of diabetic ketoacidosis management are fluid resuscitation, insulin administration, electrolyte monitoring and administration, and close observation to minimize the effects of cerebral edema.

As previously mentioned, continuous, low-dose IV insulin infusion is generally accepted as the safest and most effective method of insulin delivery for treating diabetic ketoacidosis.

Potassium chloride is commonly administered in electrolyte replacement therapy for diabetic ketoacidosis. IV bicarbonate replacement, in contrast, is justified only if the patient’s acidosis is severe enough to compromise cardiac contractility.

Class Summary

The best outcomes have been achieved by using normal- or half-strength saline (ie, 0.9% or 0.45% sodium chloride) for first resuscitation and replacement. Slowly correcting the fluid deficit over 48 hours appears to be safer than rapid rehydration.

In a child with severe acidosis or compromised circulation, an initial resuscitation of 10-20mL/kg of isotonic sodium chloride solution (0.9%) can be administered over 30 minutes. Include this fluid as part of total replacement. After resuscitation, slowly correct the fluid deficit over 24-48 hours by providing normal maintenance fluids together with the calculated deficit. Administer isotonic sodium chloride solution until blood glucose levels have fallen to 250-300mg/dL (ie, 12-15mmol/L), at which time glucose-containing fluids should be introduced (eg, 5% glucose with 0.45% sodium chloride). Continue maintenance with dextrose saline until the child is eating and drinking normally.

Sodium chloride 0.9%

This agent is used for resuscitation and for dehydration associated with diabetic ketoacidosis. Calculate the fluid deficit by weight loss or clinical assessment.

Class Summary

Insulin is the only treatment that addresses the cause of diabetic ketoacidosis. Results from a prospective study of diabetic ketoacidosis suggested the risk of cerebral edema was higher in those who received immediate insulin treatment and starting insulin infusion one hour after fluid resuscitation has begun is suggested.

Intravenous insulin is probably the safest and most effective method for treating severe diabetic ketoacidosis. To reduce the risk of hypoglycemia, infuse the insulin through a Y-site or 3-way connector into the same intravenous line used for the maintenance fluid.

Only regular or fast-acting analogue insulins are suitable for intravenous use. Frequent, small subcutaneous doses of insulin lispro or insulin aspart have been used successfully to treat milder cases of diabetic ketoacidosis in which oral fluid replacement is possible. Once the child has recovered, administer subcutaneous insulin for further diabetes maintenance. Administer subcutaneous insulin at least 30 minutes before discontinuing the intravenous insulin.

Insulin regular human (Humulin, Novolin)

This is a short-acting form of insulin traditionally used in the management of diabetic ketoacidosis, as it may be used intravenously. It stimulates the proper use of glucose by the cells and reduces blood sugar levels.

Have the pharmacy prepare the syringe at a concentration of 1 U/mL (ie, 50 U insulin qs with 0.9% sodium chloride to 50 mL). Because of the adsorption of insulin to the tubing and syringe, the actual amount of insulin administered may be less than the apparent amount. Adjust the doses according to the effect and not to the apparent insulin dose.

Insulin lispro (Humalog)

Insulin lispro is a novel, short-acting, recombinant human insulin analogue that can be given intravenously to manage diabetic ketoacidosis. Insulin lispro is an insulin analog that has a more rapid onset and a shorter duration of action than does regular human insulin. Insulin lispro stimulates the proper use of glucose by the cells and reduces blood sugar levels.

Have the pharmacy prepare the syringe at a concentration of 1 U/mL (ie, 50 U insulin qs with 0.9% sodium chloride to 50 mL). Because of adsorption of insulin to the tubing and syringe, the actual amount of insulin administered may be less than the apparent amount. Adjust the doses according to the effect and not to the apparent insulin dose.

Insulin aspart (NovoLog)

Insulin aspart is homologous with regular human insulin, with the exception of a single substitution of the amino acid proline with aspartic acid in position B28. It is produced by recombinant deoxyribonucleic acid (DNA) technology.

Insulin lowers blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. It inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis. Insulin is the principal hormone required for proper glucose use in normal metabolic processes.

Class Summary

Patients with diabetic ketoacidosis always have a total body deficit of potassium. After initial resuscitation, and provided serum or plasma levels are below 5 mEq/L or a good renal output has been maintained, add potassium to all replacement fluids.

Potassium chloride

Potassium chloride is essential for the transmission of nerve impulses, contraction of cardiac muscle, maintenance of intracellular tonicity, skeletal and smooth muscles, and maintenance of normal renal function.

Class Summary

These agents are used for the emergency treatment of cerebral edema. Urgent treatment is required if neurologic status deteriorates and hypoglycemia is excluded; delaying beyond 10 minutes is associated with very poor outcomes.

Hypertonic saline (3% NaCl)

This is a hypertonic solution of sodium chloride that can be used as an alternative to mannitol in the treatment of cerebral edema caused by diabetic ketoacidosis.

Mannitol (Osmitrol)

Mannitol is an osmotic diuretic traditionally used to treat cerebral edema. It is presented as a 10% or 20% solution for infusion, with the latter being preferable for pediatric use.