Diabetic ketoacidosis in children and adolescents with diabetes

Diabetic ketoacidosis (DKA) results from absolute or relative deficiency of circulating insulin and the combined effects of increased levels of the counterregulatory hormones: catecholamines, glucagon, cortisol and growth hormone (1, 2). Absolute insulin deficiency occurs in previously undiagnosed type 1 diabetes mellitus (T1DM) and when patients on treatment deliberately or inadvertently do not take insulin, especially the long-acting component of a basal-bolus regimen. Patients who use an insulin pump can rapidly develop DKA when insulin delivery fails for any reason (3). Relative insulin deficiency occurs when the concentrations of counterregulatory hormones increase in response to stress in conditions such as sepsis, trauma, or gastrointestinal illness with diarrhea and vomiting. The combination of low serum insulin and high counterregulatory hormone concentrations results in an accelerated catabolic state with increased glucose production by the liver and kidney (via glycogenolysis and gluconeogenesis), impaired peripheral glucose utilization resulting in hyperglycemia and hyperosmolality, and increased lipolysis and ketogenesis, causing ketonemia and metabolic acidosis. Hyperglycemia that exceeds the renal threshold (approximately 10 mmol/L 180 mg/dL) although the range in normal and diabetic individuals is very wide) and hyperketonemia cause osmotic diuresis, dehydration, and obligatory loss of electrolytes, which often is aggravated by vomiting. These changes stimulate further stress hormone production, which induces more severe insulin resistance and worsening hyperglycemia and hyperketonemia. If this cycle is not interrupted with exogenous insulin, fluid and electrolyte therapy, fatal dehydration and metabolic acidosis will ensue. Ketoacidosis may be aggravated by lactic acidosis from poor tissue perfusion or sepsis. DKA is characterized by severe depletion of water and electrolytes from both the intra and extracellular fluid compartments; the range of losses is shown in Table 1. Despite their dehydration, patients continue to maintain normal blood pressure and have considerable urine output until extreme volume depletion and shock occurs leading to a critical decrease in renal blood flow and glomerular filtration. At presentation, the magnitude of specific deficits in an individual patient varies depending upon the duration and severity of illness, the extent to which the patient was able to maintain intake of fluid and electrolytes, and the content of food and fluids consumed before coming to medical attention. Consumption of fluids with a high-carbohydrate content (juices or sugar containing soft drinks) exacerbate the hyperglycemia (4). Dehydration Rapid, deep, sighing (Kussmaul respiration) Nausea, vomiting, and abdominal pain mimicking an acute abdomen Progressive obtundation and loss of consciousness Increased leukocyte count with left shift Non-specific elevation of serum amylase Fever only when infection is present The biochemical criteria for the diagnosis of DKA are (5): Hyperglycemia (blood glucose > 11 mmol/L ≅200 mg/dL) Venous pH 33.3 mmol/L (600 mg/dL) arterial pH > 7.30 serum bicarbonate > 15 mmol/L small ketonuria, absent to mild ketonemia effective serum osmolality > 320 mOsm/kg stupor or coma It is important to recognize that overlap between the characteristic features of HHS and DKA may occur. Some patients with HHS, especially when there is very severe dehydration, have mild or moderate acidosis. Conversely, some children with T1DM may have features of HHS (severe hyperglycemia) if high carbohydrate containing beverages have been used to quench thirst and replace urinary losses prior to diagnosis (4). Therapy must be appropriately modified to address the pathophysiology and unique biochemical disturbances of each individual patient. There is wide geographic variation in the frequency of DKA at onset of diabetes; rates inversely correlate with the regional incidence of T1DM. Frequencies range from approximately 15% to 70% in Europe and North America (A) (23–27). DKA at diagnosis is more common in younger children (35 mmol/L suggests concomitant lactic acidosis (E) Corrected sodium = measured Na + 2(plasma glucose −5.6/5.6) (mmol/L) Effective osmolality = (mOsm/kg) 2x(Na + K) + glucose (mmol/L) Correct dehydration Correct acidosis and reverse ketosis Restore blood glucose to near normal Avoid complications of therapy Identify and treat any precipitating event Patients with DKA have a deficit in extracellular fluid (ECF) volume that usually is in the range 5–10% (C)(45, 46). Shock with hemodynamic compromise is rare in pediatric DKA. Clinical estimates of the volume deficit are subjective and inaccurate (53, 54); therefore, in moderate DKA use 5–7% and in severe DKA 7–10% dehydration. The effective osmolality (formula above) is frequently in the range of 300–350 mmol/Kg. Increased serum urea nitrogen and hematocrit may be useful markers of the severity of ECF contraction (44, 55). The serum sodium concentration is an unreliable measure of the degree of ECF contraction for two reasons: (1) glucose, largely restricted to the extracellular space, causes osmotic movement of water into the extracellular space thereby causing dilutional hyponatremia (56, 57) and, (2) the low sodium content of the elevated lipid fraction of the serum in DKA. The latter is not a concern with most modern methods for measuring sodium. Therefore, it is important to calculate the corrected sodium (using the above formula) and monitor its changes throughout the course of therapy. As the plasma glucose concentration decreases after administering fluid and insulin, the measured serum sodium concentration should increase, but it is important to appreciate that this does not indicate a worsening of the hypertonic state. A failure of measured serum sodium levels to rise or a further decline in serum sodium levels with therapy is thought to be a potentially ominous sign of impending cerebral edema (58–60). The objectives of fluid and electrolyte replacement therapy are: Restoration of circulating volume Replacement of sodium and the ECF and intracellular fluid deficit of water Improved glomerular filtration with enhanced clearance of glucose and ketones from the blood Reduction of risk of cerebral edema Despite much effort to identify the cause of cerebral edema its pathogenesis is There is no evidence of an between the rate of fluid or sodium used in the treatment of DKA and the of cerebral edema treatment can be as to based on The after a of the and and by a of the the for and the for and (5, and deficits must be IV or oral fluids that may have been in facility before assessment should be into of deficit and (E). patients who are volume but not in volume should with to the peripheral circulation (E). In the rare patient with DKA who in rapidly circulatory volume with (or in as as a with after each The volume and rate of on circulatory status and, it is clinically indicated, the volume administered typically is 10 hours, and may be repeated if necessary (E). not (E). There are no data to the use of in to in the treatment of DKA. fluid management should be with or for at least hours (C,E) deficit replacement should be with a that has a to or with potassium potassium or potassium (see potassium (C,E) The rate of fluid and should be to hours (5, 55). As the severity of dehydration may be difficult to determine and frequently is or (C) fluid each day at a rate rarely in of the based on age, or body (E) 1 and for of In to clinical assessment of dehydration, of effective osmolality may be to fluid and electrolyte therapy (E). losses should not be to the of replacement but may be necessary in rare circumstances (E). The sodium content of the fluid may to be increased if measured serum sodium is low and does not rise appropriately as the plasma glucose concentration (C) The use of of has been associated with the of metabolic acidosis DKA is caused by a decrease in effective circulating insulin associated with in hormones catecholamines, causes some decrease in blood glucose concentration insulin therapy is to blood glucose and lipolysis and (A) evidence that IV insulin should be the of care (A) insulin hours after fluid replacement after the patient has volume of insulin deficiency one is to insulin in normal 1 unit = 1 of IV (A) An IV is may increase the risk of cerebral edema and should not be used at the of therapy (C) The of insulin should usually at at least until of DKA > bicarbonate > 15 mmol/L of the anion which of blood glucose concentrations If the patient to insulin (e.g., some young children with DKA, patients with HHS, and some children with established the may be decreased to or provided that metabolic acidosis to volume the plasma glucose concentration and after insulin therapy, the plasma glucose concentration typically decreases at a rate of depending on the and of glucose (C) prevent an rapid decrease in plasma glucose concentration and 5% glucose should be to the IV fluid (e.g., 5% glucose in when the plasma glucose to approximately mmol/L or if the rate of is It may be necessary to use 10% or to prevent to insulin to the metabolic acidosis. If very rapidly 5 after fluid glucose before plasma glucose has decreased to mmol/L (E). If biochemical of DKA anion do not the insulin therapy, and causes of impaired response to in insulin (E). In circumstances continuous IV is not hourly or or of a or insulin or insulin is and may be as effective as IV insulin (C) but should not be used in whose peripheral circulation is impaired (E). 1 by insulin or at every or every two If blood glucose to 10 There is no evidence that bicarbonate is necessary or in DKA. or hypertonic at the bedside and the to be In of neurological symptoms, should be cases of recurrent DKA are