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CHAPTER 147: Diabetes in Children 971 history of the presenting symptoms, because the differential diagnosis of adrenal salt-wasting crisis includes sepsis, congenital heart disease, and other inborn errors of metabolism. Review gestational age and birth weight as well as maternal history regarding complications of pregnancy, prior pregnancies, miscarriages, spontaneous abortions, and previous infant deaths. Try to obtain results of the newborn screening.  PHYSICAL EXAMINATION Record vital signs and weight and assess hydration and mental status. In addition to performing a complete head-to-toe examination, care fully examine the genitalia. Females may have fusion of the labia and an enlarged clitoris. Males may have normal genitalia or a small phallus or hypospadias. Note any hyperpigmentation, especially in the scrotal or labial folds and around the nipples. DIAGNOSIS The most important laboratory studies are a bedside glucose level and serum electrolyte levels. Although hypoglycemia is rare, poor feeding and vomiting may cause secondary hypoglycemia requiring urgent treatment. The classic electrolyte abnormalities in salt-wasting con genital adrenal hyperplasia are hyponatremia and hyperkalemia. Serum potassium level may be elevated to between 6 and 12 mEq/L, although changes in cardiac function and ECG are unusual. Metabolic acidosis typically accompanies the classic electrolyte abnormalities as a result of aldosterone deficiency and dehydration. Definitive diagnosis depends on analysis of blood hormone levels. If possible, obtain results of a steroid profile prior to treatment, but do not delay treatment in the critically ill neonate. Because the presentation of adrenal salt-wasting crisis is nonspecific, consider alternative diagnoses such as sepsis. Although infants generally tolerate hyperkalemia well, obtain a 12-lead ECG, because hyperkalemic changes may alter emergent therapy and disposition. Imaging studies are not routinely indicated or helpful. TREATMENT Circulatory collapse from cortisol deficiency and dehydration is com mon, so establish IV or IO access rapidly. Administer IV fluids in the form of 10 to 20 mL/kg of normal saline. Fluid loss in congenital adrenal hyperplasia is isotonic, and fluid replacement should be with normal saline. Treat hypoglycemia with 5 mL/kg of 10% dextrose as discussed earlier in “Hypoglycemia. ” Normal pathway of adrenal steroid synthesis Progesterone 17-Hydroxyprogesterone Adrenal androgens Deoxycorticosterone 21-Hydroxylase Cortisosterone 11-Deoxycortisol Cortisol 18-Hydroxyprogesterone Aldosterone 21-Hydroxylase deficiency (absolute) Progesterone 17-Hydroxyprogesterone Adrenal androgens FIGURE 146-3. Normal pathway of adrenal steroid synthesis. Initiate steroid hormone replacement urgently: give hydrocorti sone, 25 milligrams IV/IO to neonates, 50 milligrams to toddlers and school-age children, and 100 milligrams to adolescents. Although mineralocorticoid deficiency in congenital adrenal hyperplasia is pri marily treated by sodium repletion with normal saline, there is some mineralocorticoid effect at these high doses of hydrocortisone. If hyperkalemia results in ECG changes or arrhythmia, treat with IV calcium gluconate (10%), 100 milligrams/kg (1 mL/kg), and sodium bicarbonate, 1 mEq/kg. Do not give insulin and glucose for hyperkalemia in infants because this may result in profound hypoglycemia.

orticoid effect at these high doses of hydrocortisone. If hyperkalemia results in ECG changes or arrhythmia, treat with IV calcium gluconate (10%), 100 milligrams/kg (1 mL/kg), and sodium bicarbonate, 1 mEq/kg. Do not give insulin and glucose for hyperkalemia in infants because this may result in profound hypoglycemia. The administration of normal saline and hydrocortisone is usually sufficient to lower serum potassium levels in the absence of cardiac manifestations. DISPOSITION AND FOLLOW-UP All infants with salt-wasting crisis require admission to the hospital. Infants with signs of shock or severe hyperkalemia with ECG changes should be admitted to the intensive care unit, with endocrinology consultation. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Diabetes in Children Adam E. Vella INTRODUCTION AND EPIDEMIOLOGY Diabetes is subclassified into type 1 and type 2. Type 1 diabetes, previ ously 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 adultonset diabetes , is marked by increasing insulin resistance and most commonly occurs in the overweight adult or adolescent; there is a strong CHAPTER Tintinalli_Sec12_p0669-0996.indd 971 8/2/19 7:59 PM

ecline in insulin production. Type 2 diabetes, formerly referred to as non–insulin-dependent diabetes mellitus or adultonset diabetes , is marked by increasing insulin resistance and most commonly occurs in the overweight adult or adolescent; there is a strong CHAPTER Tintinalli_Sec12_p0669-0996.indd 971 8/2/19 7:59 PM 972 SECTION 12: Pediatrics hyperglycemic hyperosmolar state, which can result in severe total body water, potassium, and phosphorus deficits. Hyperglycemic hyperosmo lar 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 nonfo cal 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. CLINICAL FEATURES 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 conscious ness, consider the development of cerebral edema. See later discussion under “Cerebral Edema. ” Abdominal pain and vomiting often accompany DKA. Distinguish nonspecific abdominal pain or gastroenteritis from more serious intraabdominal disorders such as acute appendicitis. Focal abdominal ten derness, 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 condi tions 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 alco hol, or salicylates. LABORATORY EVALUATION Initial blood studies should include CBC; serum glucose level; serum electrolytes including calcium, magnesium, and phosphate; serum beta-hydroxybutyrate 8; venous blood gas analysis; serum lactate; and urinalysis. Hyperglycemia, metabolic acidosis, and elevated serum betahydroxybutyrate confirm the diagnosis of DKA. 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. 9 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. Depending on the type of laboratory analysis used to measure creatinine, serum acetoacetate may result in a factitious eleva tion in the serum creatinine level, but β-hydroxybutyrate does not. 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.

laboratory analysis used to measure creatinine, serum acetoacetate may result in a factitious eleva tion in the serum creatinine level, but β-hydroxybutyrate does not. 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 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. genetic tendency toward the disease. Gestational diabetes 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. 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 preva lence 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 PATHOPHYSIOLOGY AND CLINICAL FEATURES The fundamental cause of DKA is an absolute or relative insulin defi ciency 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 physi ologic 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 symp toms 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.

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 deple tion 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 Chapters 223 and 224, “Type 1 Diabetes Mellitus” and “Type 2 Diabetes Mellitus, ” respectively, for more discussion of the pathophysiology of diabetes; and Chapter 226, “Ketoacidotic Syndromes. ” Polyuria, polydipsia, and polyphagia are the classic symptom triad of type 1 diabetes. Other common symptoms include weight loss, second ary enuresis, anorexia, vague abdominal discomfort, visual changes, and genital candidiasis in a toilet-trained child. The diagnosis is established by demonstrating hyperglycemia, ketonemia, 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 hyper glycemia without ketonuria to diabetic ketosis (hyperglycemia with ketonuria) to full-blown DKA.  DIABETIC KETOACIDOSIS DKA is a metabolic acidosis (pH <7.30 or serum bicarbonate level of <15 mEq/L) with hyperglycemia (serum glucose level of >200  milligrams/dL [>11 mmol/L]) and ketonemia. 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 diabetes to develop a Tintinalli_Sec12_p0669-0996.indd 972 8/2/19 7:59 PM

evel of <15 mEq/L) with hyperglycemia (serum glucose level of >200  milligrams/dL [>11 mmol/L]) and ketonemia. 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 diabetes to develop a Tintinalli_Sec12_p0669-0996.indd 972 8/2/19 7:59 PM CHAPTER 147: Diabetes in Children 973 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 decrease 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 increase 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 reconsid eration of the cause of a decreased level of consciousness. The develop ment 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. See later discussion under “Cerebral Edema. ” 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 following formula: corrected sodium level = {1.6 × [(serum glucose level – 100)/100]} + measured serum sodium level. The major ketoacid produced is beta-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; beta-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. TREATMENT OF PEDIATRIC DIABETIC KETOACIDOSIS Intensive monitoring and meticulous care of the patient with DKA improve outcome. During treatment, monitor bedside glucose every hour, and check electrolytes and venous blood gases every 2 hours. Provide continuous cardiac monitoring of all children with DKA, as a prolonged QT c interval occurs frequently during DKA and is correlated with ketosis.12 QTc prolongation can lead to life-threatening arrhythmias such as torsades de pointes. Avoid medications that may further prolong the QT interval such as ondansetron. Direct attention to perfusion, electrolyte disturbances, mental status, hyperglycemia, and ketonemia (Table 147-1). Concurrently identify and treat associated infections.  FLUID RESUSCITATION The average fluid deficit is 5% to 10% of body weight but may be greater.

further prolong the QT interval such as ondansetron. Direct attention to perfusion, electrolyte disturbances, mental status, hyperglycemia, and ketonemia (Table 147-1). Concurrently identify and treat associated infections.  FLUID RESUSCITATION The average fluid deficit is 5% to 10% of body weight but may be 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 . 13 Typical protocols historically recommended 0.9% sodium chloride correction at 1.5 times the maintenance level for empiric replacement therapy. However, 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 con trol 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. 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. For symptomatic hypophosphatemia, phosphate can be added to IV fluids in the form of potassium phosphate, providing half of the calculated potassium needs with potassium phosphate and half with potassium chloride.  INSULIN Fluid resuscitation will reduce serum glucose levels somewhat but does not correct 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 unit/kg is no longer considered beneficial and is considered potentially harmful because it has been associated with an increased risk for cerebral edema.

usion. 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 unit/kg is no longer considered beneficial and is considered potentially harmful because it has been associated with an increased risk for cerebral edema. The insulin infusion dosage is 0.1 unit of regular insulin per kilogram per hour . As a rule of thumb, decrease serum glucose by TABLE 147-1 Management of DKA in Children •   20 mL/kg NS bolus over 1 h; repeat if hypotensive.* •   After initial bolus and achievement of normotension, begin NS at 1.5 times maintenance level in the ED.† •   If [K+] is 3.5–5.5 mEq/L and patient is urinating, add 30 mEq potassium per liter (half as potassium chloride and half as potassium phosphate). If initial [K +] is 2.5–3.5 mEq/L, add 40 mEq [K +] per liter; consider adding more if the [K +] is <2.5 mEq/L. •   Begin regular insulin at 0.1 unit/kg/h after IV fluid bolus (if given) is complete. Adjust dose to maintain glucose decline at 50–100 milligrams/dL/h. Do not decrease insulin infusion to <0.05 unit/kg/h because insulin is required to clear ketosis even when glucose has normalized. •   Add dextrose to IV fluids when blood glucose level is <200–250 milligrams/dL (11–14 mmol/L). •   Measure serum electrolyte levels every 2 h; measure serum glucose level every hour. Abbreviations: K = potassium; NS = normal saline (0.9% sodium chloride). *In the setting of hypotension, bolus patient with 20 mL/kg NS repeatedly until normotensive. †Alternatively, calculate fluid deficit and correct 50% over the first 12–16 h. Some authorities recommend a higher calculated sodium concentration of between 0.45% and 0.9% sodium chloride. Tintinalli_Sec12_p0669-0996.indd 973 8/2/19 7:59 PM

of hypotension, bolus patient with 20 mL/kg NS repeatedly until normotensive. †Alternatively, calculate fluid deficit and correct 50% over the first 12–16 h. Some authorities recommend a higher calculated sodium concentration of between 0.45% and 0.9% sodium chloride. Tintinalli_Sec12_p0669-0996.indd 973 8/2/19 7:59 PM 974 SECTION 12: Pediatrics 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 ketoaci dosis, 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 to 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 min utes), 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 milligrams/dL (8.3 to 13.8 mmol/L); do not stop the IV insulin infusion until 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 institu tional variation regarding the preferred SC insulin regimen, so consult with a pediatric endocrinologist about preferred local practices.  BICARBONATE THERAPY FOR ACIDOSIS The routine use of bicarbonate in the treatment of DKA is not recommended because it does not 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 over load, accelerated hypokalemia, hypernatremia, and paradoxical CNS acidosis. 15 Bicarbonate administration should be limited to critically ill patients with a pH of <7.0 and hemodynamic compromise (unre sponsive 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. DISPOSITION AND FOLLOW-UP 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.

uld never exceed a pH of 7.1 or a serum bicarbonate level of 10 mEq/L. DISPOSITION AND FOLLOW-UP 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.  CEREBRAL EDEMA 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. 13 Cerebral edema more commonly develops in children <5 years old and is rare in persons >20 years old (Table 147-2). 13 It is likely that all patients with severe DKA have some degree of subclinical cerebral edema,16 but the specific risk factors associated with overt, life-threatening cerebral edema are young age, severe hyperosmolality, persistent hyponatremia, and severe acidosis. 5,13 Failure of serum sodium level to rise commensurately with the fall in glucose level during therapy may be an important predictor.13 Newer studies refute the belief that overaggressive fluid resuscitation per se is a significant risk factor. 2,17 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. 17 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. 18 The most recent study, which is likely the largest study to date on the topic, was a multicenter, randomized controlled trial that evaluated the fluid type and administration rate in a two-by-two factorial design in children with DKA. 19 The study demonstrated no difference in neurologic outcomes in children based on either fluid type or the rate of administration and suggests that more rapid administration of fluid is likely safe and does not lead to an increased risk of cerebral edema. A vasogenic process has been postulated as the pre dominant mechanism of cerebral edema formation in DKA rather than osmotic cellular swelling. 16,20 A study using perfusion MRI during DKA treatment in children demonstrated increased cerebral blood flow, sug gesting 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. 20 Regardless of the exact mechanism, caution in fluid administration is prudent, particularly in the extremely hyperosmolar 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 147-1). 5 Many children appear to be improving clini cally 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 .

fests itself 6 to 12 hours after the onset of therapy (Figure 147-1). 5 Many children appear to be improving clini cally 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. 13,21 Once respiratory arrest has occurred, mean ingful recovery is unlikely.13 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 TABLE 147-2 Risk Factors, Prevention, and Treatment of Cerebral Edema Factors indicating high risk •  Age  <5 y •  Severe  acidosis •  Severe  hyperosmolality •  Failure  of serum sodium level to rise with therapy Prevention •  Avoid  high-dose insulin therapy •  Early  clinical recognition •  Avoid  administration of sodium bicarbonate Treatment •  5–10  mL/kg of 3% saline over 30 min or mannitol, 0.5–1 gram/kg IV bolus •  Fluid  restriction •  Appropriate  airway management and ventilation Tintinalli_Sec12_p0669-0996.indd 974 8/2/19 7:59 PM

Avoid  high-dose insulin therapy •  Early  clinical recognition •  Avoid  administration of sodium bicarbonate Treatment •  5–10  mL/kg of 3% saline over 30 min or mannitol, 0.5–1 gram/kg IV bolus •  Fluid  restriction •  Appropriate  airway management and ventilation Tintinalli_Sec12_p0669-0996.indd 974 8/2/19 7:59 PM CHAPTER 147: Diabetes in Children 975 30 minutes had improved findings on neurologic examination with no apparent complications.22 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 hyperven tilation may lead to hyperemia and worsening of cerebral edema. 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.  SPECIAL CONSIDERATIONS INSULIN PUMP AND DIABETIC KETOACIDOSIS Because most episodes of DKA are related to inadequate insulin deliv ery, 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. 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, serum ketones are not elevated, 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.

y 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 ketonu ria resolves, and then decrease to 5%, as noted earlier. 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 ø ). 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 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. REFERENCES The complete reference list is available online at www.TintinalliEM.com. No. of children with neurologic deterioration Hours after initiation of therapy 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 FIGURE 147-1. Diabetic ketoacidosis (DKA) and cerebral edema: time between the initiation of therapy and neurologic deterioration in children. Tintinalli_Sec12_p0669-0996.indd 975 8/2/19 7:59 PM