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 < 7.3 or bicarbonate < 15 mmol/L Ketonemia and ketonuria. Partially treated children and children who have consumed little or no carbohydrate may have, on rare occasion, only modestly increased blood glucose concentrations ("euglycemic ketoacidosis") (6, 7). Type 2 diabetes mellitus (T2DM), associated with increased rates and severity of obesity, in some centers now accounts for as much as one half of newly diagnosed diabetes in children aged 10 to 21 years, depending on the socioeconomic and ethnic composition of the population (8). Acute decompensation with DKA has been recognized to occur at the time of diagnosis in as many as 25% of children with T2DM (8). This is more likely in those of African-American descent, less so in Hispanic, and least in Canadian First Nation teenagers (9–14). The majority of new cases of diabetes in Japanese children and adolescents are detected in asymptomatic individuals by routine urine screening (15, 16); however, overall, approximately 5% of patients with type 2 diabetes have DKA at the time of diagnosis (17). The severity of DKA is categorized by the degree of acidosis (18): Mild: venous pH < 7.3 or bicarbonate < 15 mmol/L Moderate: pH < 7.2, bicarbonate < 10 mmol/L Severe: pH < 7.1, bicarbonate < 5 mmol/L Hyperglycemic hyperosmolar state (HHS), also referred to as hyperosmolar nonketotic coma, may occur in young patients with T2DM (19–21), but rarely in T1DM subjects. The criteria for HHS include (22): plasma glucose concentration > 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 (< 5 years of age), and in children whose families do not have ready access to medical care for social or economic reasons (A) (7)(27–30). The risk of DKA in established T1DM is 1–10% per patient per year (A, C) (3, 31–34): Risk is increased in (34): children with poor metabolic control or previous episodes of DKA peripubertal and adolescent girls children with psychiatric disorders, including those with eating disorders children with difficult or unstable family circumstances children who omit insulin (33) (C) children with limited access to medical services insulin pump therapy (as only rapid or short-acting insulin is used in pumps, interruption of insulin delivery for any reason rapidly leads to insulin deficiency) (3) (C) Perform a clinical evaluation to confirm the diagnosis and determine its cause Carefully look for evidence of infection. In recurrent DKA, insulin omission or failure to follow sick day or pump failure management guidelines accounts for almost all episodes, except for those caused by acute severe febrile or gastrointestinal illness. Weigh the patient. This weight should be used for calculations and not the weight from a previous office visit or hospital record. Assess clinical severity of dehydration. Clinical assessment of dehydration is imprecise, inaccurate and generally shows only fair to moderate agreement among examiners. It should be based on a combination of physical signs. The three most useful individual signs for assessing dehydration in young children and predicting at least 5% dehydration and acidosis are: prolonged capillary refill time (normal capillary refill is ≤ 1.5-2 seconds) abnormal skin turgor ('tenting' or inelastic skin) hyperpnea (35). Other useful signs in assessing degree of dehydration include: dry mucus membranes, sunken eyes, absent tears, weak pulses, cool extremities. More signs of dehydration tend to be associated with more severe dehydration (35). ≥ 10% dehydration is suggested by the presence of weak or impalpable peripheral pulses, hypotension, and oliguria. Assess level of consciousness (Glasgow coma scale [GCS] - see Table 2) (36). Obtain a blood sample for laboratory measurement of serum or plasma glucose, electrolytes (including bicarbonate or total carbon dioxide), blood urea nitrogen, creatinine, osmolality, venous (or arterial in critically ill patient) pH, pCO2, calcium, phosphorus, and magnesium concentrations (if possible), HbA1c, hemoglobin and hematocrit or complete blood count. Note, however, that an elevated white blood cell count in response to stress is characteristic of DKA and is not necessarily indicative of infection (30). Perform a urinalysis for ketones. Measurement of blood ß-hydroxybutyrate concentration, if available, is useful to confirm ketoacidosis and may be used to monitor the response to treatment (37–39). Obtain appropriate specimens for culture (blood, urine, throat), if there is evidence of infection. If laboratory measurement of serum potassium is delayed, perform an electrocardiogram (ECG) for baseline evaluation of potassium status (40, 41). Secure the airway and if there is deterioration in conscious level, empty the stomach by continuous nasogastric suction to prevent pulmonary aspiration. A peripheral intravenous (IV) catheter should be placed for convenient and painless repetitive blood sampling. An arterial catheter may be necessary in some critically ill patients managed in an intensive care unit. A cardiac monitor should be used for continuous electrocardiographic monitoring to assess T-waves for evidence of hyper or hypokalemia (40, 41). Give oxygen to patients with severe circulatory impairment or shock. Give antibiotics to febrile patients after obtaining appropriate cultures of body fluids. Catheterization of the bladder usually is not necessary, but if the child is unconscious or unable to void on demand (e.g., infants and very ill young children) the bladder should be catheterized. The child should receive care in a unit that has: Experienced nursing staff trained in monitoring and management Written guidelines for DKA management in children Access to laboratories that can provide frequent and timely measurements of biochemical variables Effective osmolality (mOsm/kg) = 2x A specialist/consultant pediatrician with training and expertise in the management of DKA should direct inpatient management. Children with severe DKA (long duration of symptoms, compromised circulation, or depressed level of consciousness) or those who are at increased risk for cerebral edema (e.g., < 5 years of age, severe acidosis, low pCO2, high blood urea nitrogen) should be considered for immediate treatment in an intensive care unit (pediatric, if available) or in a unit that has equivalent resources and supervision, such as a children's ward specializing in diabetes care (C,E) (5, 42). In a child with established diabetes, whose parents have been trained in sick day management, hyperglycemia and ketosis without vomiting or severe dehydration can be managed at home or in an outpatient health care facility (e.g., emergency ward), provided an experienced diabetes team supervises the care (C,E) (18, 43, 44). Successful management of DKA and HHS requires meticulous monitoring of the patient's clinical and biochemical response to treatment so that timely adjustments in treatment can be made when indicated by the patient's clinical or laboratory data (E). There should be documentation on a flow chart of hour-by-hour clinical observations, IV and oral medications, fluids, and laboratory results. Monitoring should include the following: Hourly (or more frequently as indicated) vital signs (heart rate, respiratory rate, blood pressure) Hourly (or more frequently as indicated) neurological observations (Glasgow coma score) for warning signs and symptoms of cerebral edema (see below) headache inappropriate slowing of heart rate recurrence of vomiting change in neurological status (restlessness, irritability, increased drowsiness, incontinence) or specific neurologic signs (e.g., cranial nerve palsies, abnormal pupillary responses) rising blood pressure decreased oxygen saturation Amount of administered insulin Hourly (or more frequently as indicated) accurate fluid input (including all oral fluid) and output. Capillary blood glucose should be measured hourly (but must be cross-checked against laboratory venous glucose, as capillary methods may be inaccurate in the presence of poor peripheral circulation and acidosis). Laboratory tests: serum electrolytes, glucose, blood urea nitrogen, calcium, magnesium, phosphorus, hematocrit, and blood gases should be repeated 2 hourly for the first 12 hours, or more frequently, as clinically indicated, in more severe cases. Urine ketones until cleared or blood ß-hydroxybutyrate (BOHB) concentrations, if available, every 2 hours (38, 39). If the laboratory cannot provide timely results, a portable biochemical analyzer that measures plasma glucose, serum electrolytes and blood ketones on fingerstick blood samples at the bedside is a useful adjunct to laboratory-based determinations. Additional calculations that may be informative: Anion gap = Na − (Cl + HCO3): normal is 12 ± 2 (mmol/L) In DKA the anion gap is typically 20–30 mmol/L; an anion gap >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 < mmol/L mg/dL) before DKA has 5% glucose and continue with insulin as to blood glucose at 11 mmol/L mg/dL) until of DKA. Children with DKA total body potassium deficits of the of to The loss of potassium is from the intracellular potassium is of of this caused by plasma osmolality causes in which water and potassium are of and glycogenolysis and to insulin deficiency cause potassium from is from the body from vomiting and as a of osmotic depletion causes which urinary potassium total body depletion of potassium but at serum potassium levels may be increased or decreased by hyperglycemia and potassium to of insulin and the of acidosis will potassium into the serum levels The serum potassium concentration may decrease the patient to cardiac Replacement therapy is of the serum potassium concentration (A) If the patient is potassium replacement at the time of volume and before insulin therapy. potassium after volume and with insulin therapy. If the patient is potassium replacement therapy until urine output is (E). If immediate serum potassium measurements are an may to determine the child has hyper or hypokalemia (C) (40, 41). of the of the and the of indicate and of the are signs of The potassium concentration in the should be potassium replacement therapy should be based on serum potassium measurements (E). If potassium is with the rapid volume a concentration of mmol/L should be may be used with potassium or mmol/L potassium and mmol/L potassium or mmol/L potassium and mmol/L potassium replacement should continue throughout IV fluid therapy (E). The rate of intravenous potassium replacement is usually (E). If hypokalemia a rate of potassium the rate of insulin can be of intracellular occurs in DKA and is as a of osmotic levels after treatment and this is by insulin, which of into body depletion has been associated with a of metabolic disturbances may occur if intravenous therapy without food intake is prolonged hours have not shown clinical from replacement (A) in with should be treated (E) of may (C) may be used as an to or combined with potassium or provided that monitoring of serum is to (C) acidosis is by fluid and insulin insulin further production and to be which bicarbonate of tissue perfusion and renal thereby the of have shown no clinical from bicarbonate therapy may cause acidosis rapid of acidosis with bicarbonate causes hypokalemia and failure to for the sodium administered and appropriately the concentration of the fluids can in osmolality there may be patients who may from therapy. These include: patients with severe pH < in decreased cardiac and peripheral can further tissue and patients with (E) is not the acidosis is and likely to the of If bicarbonate is considered necessary, (E). acidosis edema fluids should be only when clinical has may be (E). oral fluid is IV fluid should be (E). ketoacidosis has oral intake is and the change to insulin is the most convenient time to change to insulin is before a (E). prevent hyperglycemia the first should be or hours before the insulin to time for the insulin to be (E). or long-acting insulin, the overlap should be and the IV insulin for patients on a basal-bolus insulin the first of insulin may be administered in the and the insulin is the (E). The and type of insulin should be to and to insulin, frequent blood glucose monitoring is to hyperglycemia and (E). In population the rate from DKA in children is to edema accounts for to of all DKA 10% to 25% of of cerebral edema have Other rare causes of and include: Other complications venous or pulmonary edema respiratory and Acute renal failure Acute The incidence of cerebral edema in population is and the rate is The pathogenesis of both its and is and that have been associated with an increased risk of cerebral edema include: (C) onset diabetes (C) duration of symptoms (C) These risk may the of severe DKA. have risk at diagnosis or treatment of DKA. These include: at after for degree of acidosis (C) Increased serum urea nitrogen at (C) More severe acidosis at (C) treatment for of acidosis (C) An rise in measured serum sodium concentrations therapy (C) of fluid in the first hours of insulin in the first of fluid treatment for of the has been in cases of fatal cerebral edema associated with DKA In the degree of edema DKA in children with the degree of dehydration and at presentation, but not with to osmolality or osmotic changes These data have been as the that cerebral edema is to cerebral DKA, and that osmotic DKA treatment do not a slowing of heart rate in neurological status (restlessness, irritability, increased drowsiness, incontinence) neurological signs (e.g., cranial nerve blood pressure saturation cerebral edema usually hours after treatment has but can occur before treatment has may develop as as hours after the of treatment and signs are A of clinical diagnosis based on bedside evaluation of neurological state is shown (C) or response to pain or nerve and respiratory (e.g., level of consciousness heart rate more per not to volume or state or not blood pressure > < 5 years two or one and two criteria have a of and a rate of only A chart with the for blood pressure and heart rate, which depending on and should be available, in the patient's chart or at the treatment as as the is the rate of fluid by Give IV and if there is no response in to 2 hours (C,E) may be an to or a of therapy if there is no response to (C) or hypertonic should be at the bedside the of the may be necessary for the patient with impending respiratory but a < has been associated with poor and is not (C) treatment for cerebral edema has been a cranial should be to causes of neurologic deterioration of especially or which may from specific therapy. of an of DKA is not complete until its cause has been and an made to treat inadvertently or is the cause in most cases The most common cause of DKA in insulin pump is failure to take insulin with a or when hyperglycemia and hyperketonemia or occur (E). measurement of blood concentrations, when to urine decreases hospital emergency and by the and treatment of ketosis measurements may be especially to prevent DKA in patients who use a pump interrupted insulin delivery rapidly leads to There may be between urine only measures and and serum concentrations, which may be increased to levels with DKA when a urine is or shows only or small There usually is an important reason for insulin an to weight in an adolescent with an eating a of an or home clinical or reason for of the patient to the diabetes An infection that is not associated with vomiting and diarrhea is the cause when the is in diabetes management and is appropriate care by a diabetes team with a A psychiatric social or clinical should be to identify the to of DKA (E). omission can be by that provide evaluation and treatment combined with of insulin and patients should to recognize and treat impending DKA with rapid or short-acting insulin and oral fluids (E) Patients should have access to a for emergency and treatment a insulin there may be as much as a in frequency of recurrent DKA DKA is caused by relative or absolute insulin Children and adolescents with DKA should be managed in centers experienced in its treatment and vital neurological status and laboratory results can be frequently with fluid replacement before insulin therapy. is only if to peripheral fluid (including oral should hours at a rate rarely in of the with hours fluid replacement therapy. If the blood glucose concentration decreases or low before DKA has increase the of glucose decrease the insulin with normal or high levels of serum potassium at presentation, there is a total body deficit of with in the or in the patient fluid at a rate > 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