Fig. 4. End-tidal CO2 levels versus serum bicarbonate concentrations in children with diabetic ketoacidosis. (From Fearon DM, Steele DW. End-tidal carbon dioxide predicts the presence and severity of acidosis in children with diabetes. Acad Emerg Med 2002;9:1373-8; with permission.)
from the intracellular to the extracellular space in DKA results from a combination of factors, including direct effects of low insulin concentrations, intracellular protein and phosphate depletion, and buffering of hydrogen ions in the intracellular fluid compartment . Despite normal or elevated initial potassium concentrations, total body potassium concentrations are depleted, often profoundly, and serum potassium concentrations usually drop rapidly with insulin treatment. The initial serum potassium concentration should not be taken as an indication of total body potassium stores. Serum phosphate concentrations are similarly elevated or normal at presentation but tend to decrease during treatment.
White blood cell counts are frequently elevated in children who have DKA, and the differential may be left shifted. The precise mechanism responsible for leukocytosis in DKA is not fully understood, but elevated catecholamine concentrations may play a role [65,66]. Another contributing factor may be an elevation in proinflammatory cytokines (eg, tumor necrosis factor-a, interleukin-6, interleukin-8, interleukin-1(3) and C-reactive protein caused by DKA. [67-69] Cytokine concentrations are substantially increased during DKA and decrease promptly with the initiation of insulin therapy. C-reactive protein concentrations, although also frequently elevated in patients who have DKA, show a less consistent decrease with treatment . Infection is infrequently the cause of DKA in children , and an elevated or left-shifted white blood cell count need not prompt a search for an infectious process unless fever or other symptoms or signs of infection are present.
Serum amylase or lipase concentrations are elevated in 40% of children who have DKA and in 40% to 80% of adults who have DKA [70-72]. The cause and significance of these elevations, however, are not known. Clinical pancreatitis in children who have DKA is rare, and elevated amylase or lipase concentrations need not prompt further investigation for pancreatitis unless abdominal pain persists after resolution of ketosis.
Treatment of diabetic ketoacidosis
Intravenous fluids (0.9% saline or other isotonic fluids) should be administered as soon as possible to restore adequate perfusion and hemodynamic stability. An intravenous fluid bolus of 10 to 20 mL/kg is often required. In patients who are well perfused and hemodynamically stable, an initial fluid bolus may not be necessary. A recent study indicated that physicians' clinical assessments of the degree of dehydration in children who have DKA correlate poorly with the actual percentage dehydration and often underestimate dehydration severity . Difficulties in clinical estimation of dehydration may result in part from osmotically mediated water movement from the tissues to the intravascular space. This fluid movement results in preservation of intravascular volume and may obscure some of the clinical signs of dehydration. Because severity of dehydration is difficult to estimate clinically, it may be most appropriate to assume an average degree of dehydration for most patients (approximately 7%-9% of body weight [73,74]). This estimated fluid deficit, along with maintenance fluid requirements, should be replaced evenly over a 36- to 48-hour period using 0.45% to 0.9% saline. Because the serum glucose concentration typically decreases to levels near the renal threshold for glucose reabsorption within a few hours of initiating treatment, replacement of ongoing fluid losses from osmotic diuresis is usually unnecessary. Ongoing fluid losses caused by profuse vomiting or diarrhea may need to be replaced on rare occasion.
The serum glucose concentration often decreases substantially with rehydra-tion alone as a result of improvements in the glomerular filtration rate and decreased concentrations of counterregulatory hormones [46,75]. This decline in glucose concentration early in treatment should not be interpreted as an indication of excessive insulin administration.
Insulin is required to resolve acidosis and hyperglycemia via suppression of ketogenesis, gluconeogenesis, and glycogenolysis and promotion of peripheral glucose uptake and metabolism. Insulin should be administered intravenously at a rate of 0.1 U/kg/h . An initial bolus or loading dose of insulin is unnecessary because maximal reductions in ketogenesis and lipolysis are achieved rapidly with the insulin infusion rate specified previously [26,32]. More rapid declines in serum glucose concentration may be achieved with insulin administered at rates in excess of 0.1 U/kg/h, but these higher insulin dosages may increase the frequency of hypoglycemia during therapy [32,75]. The risk of hypokalemia also is greater at higher insulin infusion rates [32,75]. Thus, there seems to be no benefit to higher insulin dosages, and the potential for adverse effects may increase. The use of insulin dosages less than 0.1 U/kg/h have not been studied extensively, but available data suggest that these lower dosages may not suppress ketogenesis adequately .
With insulin treatment, serum glucose concentrations often normalize before ketosis and acidosis have resolved. When the serum glucose concentration declines to approximately 250 to 300 mg/dL, dextrose should be added to the intravenous fluids to avoid hypoglycemia as the insulin infusion is continued to promote resolution of ketosis and acidosis. The two-bag system is an effective and efficient method for administering dextrose in children who have DKA. This system allows a more rapid response to changes in serum glucose concentration and is more cost effective than single-bag methods . Two bags of intravenous fluids with identical electrolyte content but varying dextrose concentrations (usually 0% and 10%) are administered simultaneously. The relative rates of administration of the two fluids can be adjusted to vary the dextrose concentration while maintaining a constant overall rate of administration of fluid and other electrolytes (Fig. 5). Once this system is established, the blood glucose concentration should be maintained between 150 and 250 mg/dL to strike a balance between avoidance of hypoglycemia during treatment and prevention of ongoing fluid losses from osmotic diuresis.
With insulin treatment and resolution of acidosis, there is substantial movement of potassium from the extracellular space to the intracellular space, and serum potassium concentrations may decrease precipitously. Intravenous administration of potassium is essential, and concentrations of 30 to 40 mEq/L intravenous fluids are usually required. Adequate renal function should be ensured before administration of potassium. Potassium chloride may be used alone or in combination with potassium phosphate or potassium acetate. Use of combinations of potassium salts may help to diminish the risk of development of hyper-chloremic acidosis by decreasing the chloride load.
Studies have demonstrated that some degree of hyperchloremic acidosis develops during treatment of DKA in most patients, and the severity of hyper-chloremic acidosis correlates with serum urea nitrogen concentrations . Patients who are less dehydrated and have better preservation of renal function have a greater tendency to develop hyperchloremic acidosis during treatment. This tendency is likely caused by the increased urinary loss of bicarbonate precursors (ketoacid and lactic acid anions) and diminished conversion of these precursors to bicarbonate with insulin administration [47,78].
Whether phosphate replacement should be given routinely in children who have DKA is controversial. It is known that 2,3-diphosphoglycerate levels in red blood cells are decreased in patients who have DKA, and hypophosphatemia may result in persistence of low 2,3-diphosphoglycerate levels. This situation theoretically may lead to reduced tissue oxygen delivery, particularly during therapy when correction of acidosis increases the affinity of hemoglobin for oxygen,
reversing the Bohr effect [79,80]. Occurrence of this effect to a degree that would be clinically relevant, however, has been difficult to demonstrate [80,81]. Conversely, although hypocalcemia can result from phosphate replacement, symptomatic hypocalcemia has been documented mainly with aggressive or rapid phosphate replacement and is uncommon when phosphate is administered slowly in more modest concentrations [81,82]. It is difficult to make a strong case either in favor of or against phosphate replacement. Case reports, however, have documented rhabdomyolysis and hemolytic anemia as results of severe hypophosphatemia during DKA [83,84]. Therefore, regardless of whether phosphate replacement is given routinely, it is necessary to monitor serum phosphate concentrations during treatment and administer phosphate replacement if severe hypophosphatemia develops.
Hypomagnesemia is common during DKA treatment and may contribute to hypocalcemia by inhibition of parathyroid hormone secretion [85,86]. Although monitoring of serum calcium and magnesium concentrations is recommended to detect rare cases of severe hypomagnesemia or hypocalcemia, decreases in the concentrations of these electrolytes are usually mild and asymptomatic and rarely require treatment.
Bicarbonate should not be administered routinely in children who have DKA because acidosis usually can be corrected with insulin and fluids alone, and hemodynamic instability that results from acidosis is rare . Most studies have found minimal or no differences in the rapidity of correction of acidosis in patients who have DKA treated with or without bicarbonate [87-89]. One reason for the apparent lack of effect of bicarbonate on rapidity of resolution of acidosis is that bicarbonate administration may cause an increase in hepatic ketone production . It is believed that this increase results from pH-dependent stimulation of ketogenesis via increased mitochondrial uptake of fatty acyl-CoA.
Bicarbonate administration also increases the likelihood of hypokalemia during DKA treatment  and theoretically may increase tissue hypoxia as a result of leftward shifts in the hemoglobin-oxygen dissociation curve . Bicarbonate
Fig. 5. Two-bag system and illustrative typical course. (A) Two-bag system allows independent manipulation of glucose and total fluid volume, because electrolyte content of two bags is identical except for dextrose. (B) Differential rates of two bags modulate glucose delivery, which can be any concentration ranging from 0% to 10%. Total fluid volume is based on a patient's degree of dehydration and ongoing fluid requirement. (C) In this typical course, insulin therapy is instituted as continuous infusion of 0.1 U/kg/h, and total fluid rate is set at 200 mL/h. Because patient is markedly hyperglycemic, no dextrose is given initially. As insulin action lowers patient's glucose level, dextrose is titrated into intravenous fluid without changing administered fluid volume. Glucose titration aims to control rate of blood glucose decline (possible risk factor for cerebral edema) and prevent hypoglyce-mia in the face of continued insulin requirement. Later, when a patient's dehydration and ketosis become partially corrected, insulin and total fluid can be independently adjusted. (From Grimberg A, Cerri RW, Satin-Smith M, et al. The "two bag system'' for variable intravenous dextrose and fluid administration: benefits in diabetic ketoacidosis management. J Pediatr 1999;134:377; with permission.)
treatment also may lead to paradoxic acidosis of the cerebrospinal fluid [53,92]. This phenomenon likely occurs because administration of bicarbonate results in diminished respiratory drive and a rise in the partial pressure of CO2. Although the blood-brain barrier is impermeable to bicarbonate, CO2 crosses the blood-brain barrier readily and generates carbonic acid and cerebrospinal fluid acidosis. Bicarbonate administration also has been associated with an increased risk of cerebral edema in childhood DKA . Routine administration of bicarbonate is not recommended. In rare cases in which hemodynamic instability is believed to be caused by severe acidosis and does not respond to standard measures or in rare cases of symptomatic hyperkalemia, however, bicarbonate administration should be considered.
Specific recommendations for monitoring of children who have DKA are outlined in the report of the European Society for Pediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society international DKA consensus conference [94,95]. Most patients who have DKA should be treated in a pediatric intensive care unit or other unit with similar capacities for managing children who have DKA. Blood glucose concentrations should be measured hourly and electrolyte concentrations should be monitored every 2 to 4 hours. Venous pH measurements are helpful because serum bicarbonate concentrations may not increase over the first several hours despite improvements in acidosis. Arterial blood gas measurements, however, are generally unnecessary. Lack of appropriate improvement in acidosis with treatment suggests inadequate insulin infusion, inadequate rehy-dration, renal failure, sepsis, or other intercurrent condition.
Vital signs and mental status should be monitored hourly, and fluid intake and output should be recorded accurately. Cardiac monitoring is recommended because cardiac arrhythmias may occur during treatment, albeit infrequently. Recent data demonstrated a high frequency of prolonged QT interval corrected for heart rate (QTc) in children who have DKA (N. Kuppermann, MD, personal communication, 2005).
The most frequent complications of DKA treatment are hypoglycemia and hypokalemia. With adequate monitoring of serum glucose and potassium concentrations, however, these complications are usually detected at an early stage, are easily treated, and rarely result in permanent morbidity or mortality. More serious complications of DKA are rare but may be life threatening, including cerebral edema [93,96], pulmonary edema [97-99], CNS hemorrhage or thrombosis , other large vessel thromboses , cardiac arrhythmias caused by electrolyte disturbances [93,102,103], pancreatitis , renal failure , and intestinal necrosis [106-108]. Patients who have DKA are also uniquely sus ceptible to rhinocerebral and pulmonary mucormycosis, a rare fungal infection . Acidosis interferes with an important host defense mechanism against this fungus by disrupting the capacity of transferrin to bind iron. Mucormycosis occurs most frequently in children with longstanding poor blood glucose control. This infection carries a poor prognosis with high mortality rates. Aggressive treatment with antifungal agents and early resection of involved tissue is recommended .
Although severe dehydration and electrolyte depletion likely cause some of the complications of DKA, the mechanisms responsible for several others are not well understood. Recent studies have suggested that (3-OHB may cause pulmonary vascular endothelial dysfunction and that perfusion of rabbit lungs with either (-OHB or AcAc results in edema and hemorrhage . DKA also may cause a prothrombotic state, which may predispose children to CNS and other thromboses [101,112]. Studies have reported increased levels of von Willibrand factor and decreased free protein S and protein C activity in DKA and enhanced platelet aggregation associated with hyperglycemia [112-114]. Case series have suggested that deep venous thromboses may develop in as many as 50% of children with femoral central venous catheters [101,115]. Central venous catheters, particularly femoral venous catheters, should therefore be used with caution in children who have DKA.
Cardiac arrhythmias occur infrequently during DKA treatment and generally have been attributed to electrolyte disturbances. Recent data, however, documented a consistent increase in the QT interval corrected for heart rate (QTc) in children during acute DKA, with 47% of children having a QTc above 450 msec, the threshold generally considered to indicate prolongation of QTc . In the recent study, the increase in QTc did not correlate with electrolyte concentrations, and the frequency of abnormal electrolyte concentrations in the study group was low, which raised the possibility that ketosis per se might have an effect on the myocardium. QTc intervals normalized after treatment of DKA.
The most frequent serious complication of DKA is cerebral edema, which occurs in 0.3% to 1% of pediatric DKA episodes [93,96,116,117]. Symptoms and signs of cerebral edema include headache, altered mental status, recurrence of vomiting, hypertension, inappropriate slowing of the heart rate, and other signs of increased intracranial pressure. Recent studies have documented a 21% to 24% mortality rate for DKA-related cerebral edema and a 21% to 26% rate of permanent neurologic morbidity [93,96].
Although less than 1% of children who have DKA develop symptomatic cerebral edema, studies that used sequential CT scans or other imaging technologies in children who have DKA showed that mild, asymptomatic cerebral edema is likely present in most children who have DKA (Fig. 6) [118-120]. The pathophysiologic mechanisms that cause cerebral edema during DKA remain unclear and have been the source of much controversy. Many investigators have attributed cerebral edema to rapid changes in serum osmolality or overly vigorous fluid resuscitation during DKA treatment. This hypothesis, however, has not been supported by data from clinical studies. In studies that used appropriate multi-
Fig. 6. CT scans of the same patient during DKA treatment (A) and after recovery from DKA (B). Narrowing of the ventricles during DKA indicates cerebral edema, although the patient was asymptomatic. (From Krane EJ, Rockoff MA, Wallman JK, et al. Subclinical brain swelling in children during treatment of diabetic ketoacidosis. N Engl J Med 1985;312:1147-51; with permission.)
Fig. 6. CT scans of the same patient during DKA treatment (A) and after recovery from DKA (B). Narrowing of the ventricles during DKA indicates cerebral edema, although the patient was asymptomatic. (From Krane EJ, Rockoff MA, Wallman JK, et al. Subclinical brain swelling in children during treatment of diabetic ketoacidosis. N Engl J Med 1985;312:1147-51; with permission.)
variate statistical techniques to adjust for DKA severity, an association between the rate of change in serum glucose concentration or the volume or sodium content of fluid infusions and risk for cerebral edema was not demonstrated [93,121,122]. Several case reports also described symptomatic and even fatal cerebral edema that occurred before hospital treatment for DKA [1,123,124]. This information suggests that DKA-related cerebral edema likely cannot be explained simply by osmotically mediated fluid shifts. More recent data suggested that cerebral edema during DKA may be predominantly vasogenic and may result from activation of ion transporters in the blood-brain barrier [118,125]. Cerebral hypoperfusion during DKA or direct effects of ketosis or inflammatory cytokines on blood-brain barrier endothelial cell function might play a role in stimulating this process [69,118,126].
Epidemiologic studies have shown that children at greatest risk for symptomatic cerebral edema are children with high blood urea nitrogen concentrations  at presentation and children who present with more profound hypocapnia [93,122]. A lesser rise in the measured serum sodium concentration during treatment (as the serum glucose concentration falls) also indicates increased risk for cerebral edema [93,127]. More intensive monitoring of neurologic state and vital signs for children who present with these risk factors is recommended.
Clinical studies have not demonstrated a clear beneficial effect of any phar-macologic agent in treating DKA-related cerebral edema. Case reports, however, suggest that prompt administration of mannitol (0.25-1 g/kg) may be beneficial [128,129]. Intubation with associated hyperventilation has been correlated with poorer outcomes of DKA-related cerebral edema . Therapeutic hyperventilation that attempts to decrease pCO2 below a patient's own compensation for metabolic acidosis likely should be avoided in intubated children who have DKA except when absolutely necessary to treat clinically overt elevated intracranial pressure. CNS imaging in patients with suspected cerebral edema is recommended to rule out other causes of altered mental status, such as CNS thromboses; however, treatment for suspected cerebral edema should not be delayed while awaiting imaging studies.
In children, findings of hyperglycemia, increased anion gap acidosis, and ketonuria or ketonemia generally indicate a diagnosis of DKA, and other disorders that result in this constellation of biochemical abnormalities are rare. Occasionally, however, other disorders may have a similar presentation. Rare metabolic defects may cause ketoacidosis, including succinyl-CoA: 3-ketoacid coenzyme A transferase deficiency, a defect in ketolysis, and beta-ketothiolase deficiency, a defect in L-isoleucine catabolism. These conditions, however, are most frequently associated with hypoglycemia or normoglycemia rather than hyperglycemia [30,131-133].
In the setting of gastroenteritis, hyperglycemia may occur when stress hormone concentrations are markedly elevated in response to dehydration. Lactic acidosis results from dehydration, and the combination of hyperglycemia with acidosis initially may suggest a diagnosis of DKA. FFA concentrations also may be elevated, and modest ketonemia occasionally occurs [134-138]. These findings have been documented most frequently in infants and toddlers. In rare cases, extreme elevations in serum glucose concentration (> 800-1000 mg/dL) have been reported in infants with gastroenteritis without diabetes mellitus . Rapid resolution of hyperglycemia with hydration alone can be helpful in differentiating this situation from DKA .
Extreme hyperglycemia and hyperosmolality can occur without ketosis in patients who have diabetes (hyperglycemic hyperosmolar state [HHS]). This condition occurs much more frequently in adults than in children and more frequently in patients who have type 2 diabetes than in persons who have type 1 diabetes. Among pediatric patients, case series have suggested that obese African-American children who have type 2 diabetes may be at greatest risk for HHS [140,141]. HHS also has been documented to occur with increased frequency in patients who are predisposed to dehydration because of limited access to fluids, including infants and children with cognitive deficits [139, 142]. Although HHS has been viewed as a condition separate from DKA, it may be more appropriate to view HHS as one extreme in the various presentations of altered glucose and fat metabolism in patients who have diabetes. DKA with near-normal glucose concentrations (euglycemic DKA) may be viewed as the opposite extreme on this continuum. Where a particular patient falls in this spectrum is determined by the relative concentrations of insulin and counterregulatory hormones and by the states of hydration and nutrition of the patient. The clinical picture in many patients may have elements of DKA and HHS .
The pathogenesis of HHS is similar to that of DKA; however, some important differences should be noted. Hyperglycemia without ketosis generally occurs in patients who retain some ability to produce insulin, most commonly persons who have type 2 diabetes. Ketogenesis and lipolysis are suppressed at lower serum insulin concentrations than the levels required to suppress hepatic glucose production, and patients develop hyperglycemia without ketosis [32,144]. In patients who do not develop ketoacidosis, osmotic diuresis with electrolyte and water loss may persist for prolonged periods and result in profound dehydration. Without ketosis, urinary cation excretion is not necessary to balance ketoanion excretion, and less electrolyte loss relative to free water loss occurs in HHS than in DKA, which contributes to the hyperosmolar state. Nonetheless, because the duration of osmotic diuresis in HHS may be lengthy, patients who have HHS may have greater electrolyte deficits than patients who have DKA . Diminished renal function that results from severe dehydration is particularly important in the pathogenesis of HHS because diminished capacity for glucose excretion is necessary for the development of marked hyperglycemia.
The criteria for diagnosis of HHS include blood glucose concentration more than 600 mg/dL, serum osmolality more than 330 mOsm/kg, and lack of significant ketosis . The serum sodium concentration, when corrected for the blood glucose concentration, is generally above the normal range [146,147]. The clinical presentation of HHS is otherwise similar to that of DKA, with some exceptions. Children who have HHS often have a more prolonged history of polyuria and polydipsia than children who have DKA [140,142]. Because of the absence of ketosis, fruity breath odor is not present, and tachypnea is not a prominent feature, except in patients in whom substantial lactic acidosis occurs.
In adults, approximately 10% to 20% of patients who have HHS present in coma, and other mental status abnormalities at presentation are more frequent than in DKA. Seizures may occur, and focal neurologic deficits (eg, hemiparesis, hemianopsia, chorea-ballismus) also have been described with HHS [139,142, 146,148].
Because HHS occurs infrequently in children, data regarding the optimal approach to treatment are lacking. Some authors have suggested that it may be preferable to delay insulin therapy in patients who have HHS because the serum glucose concentration decreases considerably with rehydration alone . Patients who have HHS are not ketotic, and insulin is not needed for resolution of acidosis . Delaying insulin treatment in these patients may result in more gradual declines in serum glucose concentration and serum osmolality. Use of 0.9% saline for intravenous fluid replacement rather than hypotonic saline also has been recommended to promote a more gradual decline in serum sodium concentration. Because patients with HHS may have had ongoing osmotic diuresis for prolonged periods before presentation, electrolyte deficits may be particularly pronounced. Close monitoring of serum electrolyte concentrations (particularly potassium and phosphate) is recommended . Hypernatremia frequently develops during therapy as the serum glucose concentration declines and water returns to the extravascular tissues. Hypernatremia occasionally may be difficult to treat in patients who have HHS, in part because of ongoing free water losses caused by osmotic diuresis and persistent stimulation of sodium retention by aldosterone .
In contrast to DKA, in which complications occur infrequently and the mortality rate is less than 1%, HHS is associated with more frequent complications and a high mortality rate. Although limited epidemiologic data are available on HHS in children, one report documented a mortality rate of 14% , similar to the approximately 15% to 20% mortality rate of HHS in adults . Thromboembolic complications, including pulmonary emboli and deep venous thromboses, occur frequently in patients who have HHS as a result of severe dehydration and increased blood viscosity . Routine use of anticoagulant therapy, however, is controversial. A malignant hyperthermia-like syndrome with hyperpyrexia and rhabdomyolysis also was described in several children who had HHS . The cause of this syndrome is unclear. Cardiac arrhythmias caused by severe electrolyte disturbances, cerebral edema, and pulmonary edema also may occur [140,141].
DKA occurs frequently in children who have diabetes, particularly at the time of diagnosis. Greater efforts are necessary to promote earlier recognition of new onset of diabetes so that DKA can be prevented and to avoid subsequent occurrences of DKA in children who have established diabetes. Further research is also necessary to understand and prevent cerebral edema, the most serious complication of DKA. International recommendations for DKA treatment in children recently were published and will be helpful in standardizing the treatment of this condition [94,95].
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