Chapter 145: Diabetes In Children

Diabetes is subclassified into several different forms. Type 1 diabetes, previously referred to as insulin-dependent diabetes mellitus or juvenile-onset diabetes because of its earlier onset, is characterized by an abrupt and frequently complete decline in insulin production. Type 2 diabetes, formerly referred to as non–insulin-dependent diabetes mellitus or adult-onset diabetes, is marked by increasing insulin resistance and most commonly occurs in the overweight adult or adolescent; there is a strong genetic tendency toward the disease. The third main form of diabetes affecting children is gestational diabetes, which can affect pregnant teens as well as the infants of diabetic mothers. There has been an increase in the prevalence of type 1 diabetes of 21% between 2001 and 2009, and an increase of 31% in type 2 diabetes in the same time period.¹ While the cause of the increase in type 1 diabetes is unknown, some experts suggest that the increasing prevalence of type 2 diabetes may be a result of minority population growth, obesity, exposure to diabetes in utero, and perhaps endocrine-disrupting chemicals.¹ Diabetes is the most common pediatric endocrine disorder, with an estimated prevalence of 1 in 400. As many as 34% of children with new-onset type 1 diabetes present in diabetic ketoacidosis (DKA).² In children with known diabetes, DKA is much less common and tends to be clustered in a small subset of patients, with 5% of children with diabetes accounting for nearly 60% of DKA episodes.³ DKA is the leading cause of mortality in patients with diabetes <24 years of age, and cerebral edema is the leading cause of mortality in DKA.⁴

The fundamental cause of DKA is an absolute or relative insulin deficiency that results in the inability of cells to take up and use glucose. Levels of counterregulatory hormones (catecholamines, cortisol, growth hormone, and glucagon) are elevated, which drives many of the physiologic disturbances observed in DKA. These hormones increase glucose production by promoting glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis, and further decrease glucose utilization by antagonizing insulin.

As the serum glucose level exceeds the renal absorption threshold, an obligatory osmotic diuresis ensues, which results in the classic symptoms of polyuria and polydipsia. If not recognized early, this can lead to profound dehydration and electrolyte disturbances. Acidosis stems from the complex metabolic derangements induced by insulin deficiency and unopposed glucagon. The cellular milieu of the body is essentially in a state of functional starvation, unable to use the excess serum glucose. Decreased lipid uptake by adipose tissue and increased lipolysis result in an overabundance of circulating free fatty acids, which are converted by the liver into the ketoacids acetoacetate and β-hydroxybutyrate.

Despite this profound shift in substrate production, ketoacid utilization and renal elimination are both impaired, which results in a wide anion gap metabolic acidosis. In certain patients, the acid-base status may be more complex. Persistent vomiting and severe volume depletion may result in a superimposed metabolic alkalosis that may mask the severity of the acidosis by producing a relatively normal pH. Severe dehydration and poor perfusion further lead to lactic acidosis, which results in a superimposed anion gap acidosis. Alternatively, a patient who remains relatively well hydrated will lose sodium with keto anions in the urine while retaining chloride and demonstrate a significant non–anion gap acidosis.

See the chapters 223 and 224, "Type 1 Diabetes Mellitus" and "Type 2 Diabetes Mellitus," respectively, for more discussion of the pathophysiology of diabetes.

Polyuria, polydipsia, and polyphagia are the classic symptom triad of type 1 diabetes. Other common symptoms include weight loss, secondary enuresis, anorexia, vague abdominal discomfort, visual changes, and genital candidiasis in a toilet-trained child. The diagnosis is established by demonstrating hyperglycemia and glucosuria in the absence of other causes such as steroid therapy, Cushing's syndrome, pheochromocytoma, hyperthyroidism, or other rare disorders. Signs of uncontrolled diabetes span the entire spectrum from simple hyperglycemia without ketonuria to diabetic ketosis (hyperglycemia with ketonuria) to full-blown DKA.

DKA is generally defined as a metabolic acidosis (pH <7.30 or serum bicarbonate level of <15 mEq/L) with hyperglycemia (serum glucose level of >200 milligrams/dL or 11 mmol/L) and ketonemia or ketonuria.^5,6 DKA is much more common in patients with type 1 diabetes than in those with type 2, but it is not uncommon for patients with type 2 to develop acidosis under moderately severe physiologic stress. This acidosis has been referred to as the hyperglycemic hyperosmolar state, which can result in severe total body water, potassium, and phosphorus deficits. Hyperglycemic hyperosmolar state, which is estimated to account for 1% of all diabetic admissions, has a case fatality rate of 5% to 20%.^5,7

In the patient with known diabetes, the diagnosis of DKA is relatively straightforward. The most common cause of DKA in children and adolescents with known diabetes is poor adherence to the prescribed insulin regimen. Other precipitants include intercurrent viral illness and focal infections such as urinary tract infection or gastroenteritis. Patients complain of polydipsia and polyuria (if not dehydrated), diffuse nonfocal abdominal pain often associated with vomiting, difficulty breathing, and generalized malaise, in addition to any localizing complaints related to a precipitating trigger. Kussmaul breathing may be mistaken for pulmonary pathology or even anxiety with hyperventilation.

Physical findings in DKA are due to dehydration and metabolic acidosis. Children appear dehydrated, are tachycardic, and may be hypotensive. Respiratory compensation for acidosis is noted in the deep Kussmaul respirations, which may be accompanied by paresthesias. Acetoacetate is converted to acetone and is responsible for the classic breath odor of nail polish. The level of consciousness may range from alert to somnolent to comatose. In a child with DKA and a depressed level of consciousness, consider the development of cerebral edema.

Abdominal pain and vomiting often accompany DKA. Distinguish nonspecific abdominal pain or gastroenteritis from more serious intra-abdominal disorders such as acute appendicitis. Focal abdominal tenderness, failure of pain to resolve with fluid therapy, and associated fever suggest an underlying intra-abdominal process.

An elevated glucose level in the presence of ketonemia/ketonuria and acidosis almost always indicates DKA. However, other rare conditions possess similar clinical characteristics. Any condition resulting in prolonged vomiting or excessive fasting can result in ketoacidosis, but the glucose level is not elevated. In adolescent patients without known diabetes, consider toxic ingestions of ethylene glycol, isopropyl alcohol, or salicylates.

PATHOPHYSIOLOGY

Cerebral edema, which occurs in approximately 0.5% to 1% of all children presenting with DKA, is the most dreaded complication, accounting for 60% to 90% of all pediatric DKA-associated deaths.⁴ Mortality rates range from 21% to 24%, and only 14% to 57% of children who develop the disorder recover neurologically normal.⁸ Cerebral edema more commonly develops in children <5 years old and is rare in persons >20 years old (see Table 145–1).⁸ It is likely that all patients with severe DKA have some degree of subclinical cerebral edema,⁹ but the specific risk factors associated with overt, life-threatening cerebral edema are young age, severe hyperosmolality, persistent hyponatremia, and severe acidosis.^5,8 Failure of serum sodium level to rise commensurately with the fall in glucose level during therapy may be an important predictor.⁸ Newer studies refute the belief that overaggressive fluid resuscitation per se is a significant risk factor.^2,10 The incidence of cerebral edema has not changed over the past 15 to 20 years, despite the introduction of gradual rehydration protocols over the same interval.¹⁰ Furthermore, a randomized study of two rehydration protocols in DKA was assessed for the risk of associated MRI-documented subclinical cerebral edema and showed no difference in the rate of cerebral edema between an aggressive and a more judicious rehydration protocol.¹¹ A vasogenic process has been postulated as the predominant mechanism of cerebral edema formation in DKA rather than osmotic cellular swelling.^9,12 A study using perfusion MRI during DKA treatment in children demonstrated increased cerebral blood flow suggesting a difference in the hemodynamic states of dehydrated and resuscitated children with DKA. The authors further noted that the patients with greater dehydration and more profound hypocapnia had an increased risk of cerebral edema, possibly as a result of cerebral hypoperfusion and ischemia prior to treatment.¹² Regardless of the exact mechanism, caution in fluid administration is prudent, particularly in the extremely hyperosmolal child (i.e., osmolarity of >340 mOsm/L).

CLINICAL FEATURES

Cerebral edema typically manifests itself 6 to 12 hours after the onset of therapy (Figure 145–1).⁵ Many children appear to be improving clinically and biochemically prior to deterioration from cerebral edema. Premonitory symptoms occur in as few as 50% of patients and include severe headache, declining mental status, seizures, and papilledema. Unfortunately, respiratory arrest may be the first sign of cerebral edema. Early aggressive intervention based on the clinical evaluation, often before confirmatory CT findings, is vital to prevent respiratory arrest, herniation, and death.^8,13 Once respiratory arrest has occurred, meaningful recovery is unlikely.⁸

TREATMENT

Standard treatment for cerebral edema is mannitol (0.25 to 1 gram/kg IV bolus) and endotracheal intubation if necessary. A recent case series reported improvement after infusion of hypertonic saline. Four children given 10 mL/kg of 3% hypertonic saline infused over 30 minutes had improved findings on neurologic examination with no apparent complications.¹⁴ Limit additional fluid administration to the minimum possible to retain a functioning IV catheter or use a heparin lock to allow immediate IV access as necessary. If the child appears more clinically stable and is still in the ED, give half of normal maintenance fluids until the child reaches the pediatric intensive care unit.

Historically the teaching has been that hyperventilation reduces cerebral blood flow and may worsen cerebral ischemia; however, failure to compensate for the metabolic acidosis through adaptive hyperventilation may lead to hyperemia and worsening of cerebral edema.¹⁵ Avoidance of a normocapnic state in patients with a severe metabolic imbalance certainly seems prudent. Consider cerebral venous sinus thrombosis in the child with clinical symptoms of cerebral edema without obvious findings on CT, as this diagnosis may be missed without contrast administration and is better demonstrated on MRI.

Routine blood studies should include serum glucose level, electrolyte panel including calcium and phosphate, venous blood gas analysis, and urinalysis (Table 145–2). Hyperglycemia, metabolic acidosis, and ketones in the urine confirm the diagnosis of DKA. Obtain venous blood samples rather than arterial for assessing the degree of acidosis and hypocarbia, which avoids an additional painful procedure (or procedures); the pH determined by venous blood gas analysis is only 0.03 less than that measured by arterial blood gas analysis and is an accurate reflection of the acid-base status.¹⁶ Obtain other laboratory studies as clinically indicated.

Several factitious laboratory abnormalities may be seen in DKA. An increased WBC count is common in DKA and should be interpreted in the context of physical findings and results of diagnostic studies for infection. Elevated salivary amylase level in DKA confounds the diagnosis of pancreatitis, and lipase level is more accurate. Depending on the type of laboratory analysis used to measure creatinine, serum ketones may result in a factitious elevation in the serum creatinine level.

The serum glucose level is usually >350 milligrams/dL (19.4 mmol/L), but a glucose level of <300 milligrams/dL (16.6 mmol/L) can be consistent with DKA. Euglycemic DKA may occur in a young, well-hydrated diabetic who is adherent to the insulin regimen but has relative insulin deficiency caused by an intercurrent illness. Even in the absence of hyperglycemia, insulin is needed when acidosis and ketonemia or ketonuria are present.

Change in the serum potassium level is the most critical electrolyte disturbance in DKA. Hypokalemia can be both profound and present despite relatively normal initial laboratory values due to ion shifts in response to acidosis. The average potassium deficit is 3 to 5 mEq/kg (150- to 250-mEq potassium deficit in a 50-kg adolescent), and the initial serum level is often normal or high. Potassium depletion is a result of insulin deficiency (which normally drives potassium into cells), acidemia (which causes the redistribution of potassium out of the cells in exchange for hydrogen), volume contraction, and tissue catabolism. These processes all provide increased potassium available for urinary excretion. Within this context, initial hypokalemia signifies a severe deficit and a potentially dangerous situation that requires potassium supplementation once urine output is established.

Serum bicarbonate is invariably low, and a wide anion gap acidosis from the ketonemia is usually noted. In simple DKA, the bicarbonate level should fall to the extent that the anion gap increases. A decrease in the bicarbonate level less than expected for a given increase in the anion gap in the vomiting patient indicates the presence of an accompanying metabolic alkalosis. Conversely, a fall in the bicarbonate level greater than expected for the increase in the anion gap indicates a concomitant non–anion gap acidosis. This is frequently seen in well-hydrated patients who are still able to excrete the keto anions while retaining chloride or in severely dehydrated patients with accompanying lactic acidosis.

The serum osmolality is increased in DKA, and its rise correlates with the decrease in the level of consciousness at presentation. Osmolarity of >340 mOsm/L often results in a stuporous or comatose state, whereas a serum osmolarity of <300 mOsm/L should prompt reconsideration of the cause of a decreased level of consciousness. The development of cerebral edema may be correlated with the rate of decline in the serum osmolarity; thus, it is critical that fluid deficits be corrected less rapidly in patients with high serum osmolarity.

Sodium deficits average 5 to 10 mEq/kg, but the serum sodium level may be normal because of excessive free water loss. More typically, the serum sodium level is factitiously low because of hyperglycemia, and a corrected value may be arrived at by using the formula corrected sodium level = {1.6 × [(serum glucose level – 100)/100]} + measured serum sodium level.

The major ketoacid produced is β-hydroxybutyrate. Unlike acetoacetate, however, it does not react with the nitroprusside used in urine and serum ketone assays, so measured ketone levels may appear low for the degree of acidosis and do not reflect the true extent of ketonemia. This fact also explains the paradoxical rise in measured ketone levels with therapy: β-hydroxybutyrate is converted to acetoacetate, which reacts more strongly with the assay. Using bedside ketone testing to monitor recovery is further complicated by the persistence of urine ketones after clearance of serum ketones.¹⁷

Intensive monitoring and meticulous care of the patient with DKA improves outcome. Current consensus statements recommend continuous cardiac monitoring of all children with DKA,⁴ and a prolonged QT_c interval occurs frequently during DKA and is correlated with ketosis.¹⁸ QT_c prolongation can lead to life-threatening arrhythmias such as torsade de pointes. Avoid medications that may further prolong the QT interval such as ondansetron if the ECG demonstrates prolongation.

Direct attention to perfusion, electrolyte disturbances, mental status, hyperglycemia and ketonemia (Table 145–3). Concurrently identify and treat associated infections.

FLUID RESUSCITATION

The average fluid deficit is 10% of body weight, but is often greater. Give an initial 20 mL/kg bolus of normal saline if the child is in shock and repeat if needed. Once vital signs have stabilized, resist the desire to correct the fluid deficit too rapidly, especially if there is a high calculated osmolarity (i.e., >340 mOsm/L). Many institutions replace the deficit evenly over 24 to 48 hours; this moderated approach helps to avoid overhydration, pulmonary complications, and possibly cerebral edema. The traditional approach is 50% deficit replacement in the first 8 hours with the rest replaced over the next 16 to 24 hours.

ELECTROLYTE REPLACEMENT

Sodium depletion from vomiting and urinary losses rarely causes a problem by itself and is most often related to the extent of dehydration. The main concern with sodium level lies in its correction: failure of serum sodium level to rise in the treatment of DKA is associated with the development of cerebral edema.⁸ Typical protocols historically recommended 0.9% sodium chloride correction at 1.5 times the maintenance level for empiric replacement therapy. But in an attempt to decrease the risk of cerebral edema, some newer protocols advocate sodium concentrations of 0.66% (typically mixed by the pharmacist) to 0.9% sodium chloride and calculate fluid replacements to tighten control over biochemical parameters.⁴ This approach is effective in ensuring a steady rise in the sodium concentration.

Withhold potassium until hyperkalemia (i.e., potassium level of >6.0 mEq/L) is excluded and the child is urinating. ECG findings may be normal in the face of hyperkalemia, so monitor the serum potassium level. Total body potassium deficits are often large, and both initial rehydration and insulin therapy can cause a precipitous decline in potassium levels due to redistribution.

Initial hypokalemia (i.e., <3.0 mEq/L) indicates a profound deficit, and therapy should be aggressive; insulin will further lower serum potassium, so close monitoring and replacement are essential. The recommended rates of potassium replacement vary widely, but in general, maintenance fluids should contain between 30 and 40 mEq [K⁺] per liter. Consider higher doses for children with demonstrated hypokalemia, although a central line is needed and intensive care unit monitoring is required at most institutions. Monitor serum potassium at least every 2 hours.

Phosphate depletion in DKA is well described, but the value of IV replacement has never been proven. Many authorities recommend half of the potassium replacement in the form of potassium phosphate. In the absence of replacement, one should monitor for symptomatic hypophosphatemia (serum phosphate level of <1 mmol/L, muscular weakness, rhabdomyolysis, respiratory depression). The same rule applies to magnesium replacement. Hypocalcemia, when present, is likely secondary to overaggressive phosphate replacement.

INSULIN IN DKA

Fluid resuscitation will reduce serum glucose levels somewhat, but do not correct the underlying metabolic problem or improve ketonemia or acidosis. After the patient is hemodynamically stable, begin a low-dose insulin infusion. High-dose insulin therapy does not improve the rate of recovery and places the patient at greater risk of hypoglycemia and hypokalemia. A loading bolus of 0.1 units/kg is no longer considered beneficial and is considered potentially harmful because it has been associated with an increased risk for cerebral edema.¹⁹

The insulin infusion dosage is 0.1 unit of regular insulin per kilogram per hour. As a rule of thumb, serum glucose level should decrease by 50 to 100 milligrams/dL/h (2.8 to 5.6 mmol/L) in a slow, controlled fashion to prevent intracerebral osmolar shifts. If improvement of the pH is too slow (<0.03 pH units per hour), the insulin infusion rate can be doubled. Generally, glucose level corrects faster than the ketoacidosis, so add dextrose to the IV fluids when the blood glucose level drops to <250 milligrams/dL (14 mmol/L) without stopping the insulin infusion, with the goal of maintaining a serum glucose level of 150 to 300 milligrams/dL (8.3–16.6 mmol/L) until resolution of the ketoacidosis.

Initiate glucose along with insulin for the patient with euglycemic DKA. If the blood glucose level continues to decline, provide additional glucose before considering adjustment of the insulin drip. If the child is receiving the maximum glucose concentration available (or maximum tolerable concentration if through a peripheral line), then the administration of insulin can be temporarily held for 10 to 15 minutes before restarting the insulin drip at a lower rate. In general, this rate should not be <0.05 units/kg/h. The short half-life of IV insulin (5 to 10 minutes), along with the continued administration of glucose, will correct transient hypoglycemia. Continued insulin administration is the mainstay of therapy and should be maintained until reversal of ketoacidosis.

Do not transition the insulin infusion to SC administration until the pH is >7.30, bicarbonate level is >15 mEq/L, and serum ketones have disappeared. At that point, taper the IV insulin to 0.02 to 0.05 unit/kg/h and initiate multidose SC insulin using a regular insulin (short-acting) at a dose of 0.1 unit/kg every 2 hours to maintain serum glucose between 150 and 200 mg/dL (8.3 to 13.8 mmol/L); stop the IV insulin infusion 1 to 2 hours after initiating SC therapy. Do not simply discontinue insulin therapy altogether when DKA resolves, because DKA will recur without adequate continued serum insulin. There is institutional variation regarding the preferred SC insulin regimen, so consult with a pediatric endocrinologist about preferred local practices.

INSULIN PUMP AND DKA

Because most episodes of DKA are related to inadequate insulin delivery, this implies malfunctioning of the insulin pump. Alternatively, the pump may be functioning correctly but the child may have an intercurrent illness with increased and unmet insulin needs. Either way, shut off the pump and treat the child like any other insulin-dependent diabetic patient with DKA.

BICARBONATE THERAPY FOR ACIDOSIS

The use of bicarbonate in the treatment of DKA is not recommended, because it has never been shown to improve outcome and has been associated with a fourfold increase in the development of cerebral edema.⁵ In addition, bicarbonate therapy can lead to volume overload, accelerated hypokalemia, hypernatremia, and paradoxical CNS acidosis.²⁰ Bicarbonate administration should be limited to critically ill patients with a pH of <7.0 and hemodynamic compromise (unresponsive to fluid resuscitation) from depressed cardiac contractility and poor perfusion. If necessary, depending on the pH and the patient's clinical condition, bicarbonate may be administered slowly at 0.5 to 2.0 mEq/kg over 1 to 2 hours. Correction should never exceed a pH of 7.1 or a serum bicarbonate level of 10 mEq/L.

Most patients with DKA require admission to the intensive care unit, even once stabilized, because of intensive monitoring needs. Furthermore, many hospitals restrict the use of insulin infusions to intensive care settings. Patients with known diabetes who have a pH of >7.35 and a bicarbonate level of >20 mEq/L, have a known and resolving precipitant for DKA and a good clinical appearance, and have a solid social situation and will follow up closely with their primary physicians may be discharged home. In as many as 69% of patients with a starting pH of >7.20 or a serum bicarbonate level of >10 mEq/L, acidosis is corrected within 6 hours.⁶

NEW-ONSET HYPERGLYCEMIA

Many children with new-onset diabetes present with classic symptoms of diabetes such as polydipsia, polyuria, and malaise, and are identified before significant ketoacidosis develops. They are frequently sent from the outpatient physician's office to the ED for management and admission. ED management for these children is less intensive and should be done in coordination with an endocrinologist. In general, children with hyperglycemia but no DKA are only mildly dehydrated, urinary ketones may or may not be present, and the serum pH is >7.3. The speed at which such children descend toward actual DKA is largely a function of hydration status and age. Infants and very young children progress more rapidly because of their inability to access fluids independently and their increased metabolic rate. With appropriate hydration and timely insulin administration, DKA is very unlikely to develop in the hospital in the absence of serious underlying illness.

ED management should be restricted to drawing samples for baseline laboratory studies; providing fluids PO or IV, depending on the need; and possibly administering the first dose of insulin. An acceptable initial dose is 0.1 unit/kg SC of regular insulin. Whether or not children with new-onset diabetes are particularly sensitive to insulin is a matter of debate. Still, monitor serum glucose levels closely—every hour after insulin is administered. Consider admission for education and to establish daily insulin requirements. Daily insulin requirements are generally in the range of 0.5 to 1.0 unit/kg/d in divided doses, two thirds in the morning and one third in the evening.

HYPERGLYCEMIA IN PATIENTS WITH PREDIAGNOSED DIABETES

For a diabetic child with hyperglycemia with or without an intercurrent illness or injury, management should focus on the primary reason for the ED visit. An additional dose of 10% of the child's normal daily insulin dose can be administered as regular insulin SC for simple hyperglycemia.

For children with an intercurrent illness, more specific management guidelines may vary among endocrinologists and also may depend on whether or not urinary ketones are present. An acceptable approach if the child has an intercurrent illness and no urinary ketones is to administer an additional 5% of the daily insulin dose every 4 to 6 hours until the condition resolves. If the child has urinary ketones, administer 10% of the daily dose every 4 to 6 hours until the ketonuria resolves, and then decrease to 5%, as noted above.

HYPERGLYCEMIA IN PATIENTS TAKING INSULIN GLARGINE

Occasionally, a child will present with hyperglycemia without DKA after missing one or more doses of insulin glargine (Lantus). Glargine is a long-lasting once-daily insulin preparation that has no peak effect. Generally, glargine is given at approximately 50% of the daily insulin requirement, with the rest given as a short-acting preparation, so that missing a single dose of glargine is not equivalent to missing all insulin doses for the day.

If the child is off schedule for insulin glargine and does not have DKA, a single injection of neutral protamine Hagedorn (NPH) insulin can be given, followed by resumption of the regular dosing schedule.

If the child is off schedule for insulin glargine and has DKA, treatment is no different from management of other cases of DKA.