tips Children&Teenagers 1 DKA in Infants, Children, and Adolescents:

tips Top International Publications Selection Children&Teenagers 1 DKA in Infants, Children, and Adolescents: a Consensus Statement from the ADA 1 2 Can We Prevent Diabetic Ketoacidosis in Children? 2 3 When Should Determination of Ketonemia be Recommended? 3 4 Treatment of Diabetic Ketoacidosis in Children and Adolescents 4 5 Ketoacidosis at Diabetes Onset is still Frequent: a Multicentre Analysis of 14'664 Patients 5

Diabetic Ketoacidosis in Infants, Children, and Adolescents: a Consensus Statement from the American Diabetes Association. Wolfsdorf J, Glaser N, Sperling MA. American Diabetes Association. Diabetes Care 2006;29:1150 9 1 Considering diabetic ketoacidosis (DKA), the child differs from the adult in a number of characteristics: DKA can be often misdiagnosed in children, especially in infants and toddlers Treatment (delivering fluids and electrolytes) requires a greater precision because of higher basal metabolic rate and large surface area relative to total body mass in children Cerebral and other autoregulatory mechanisms may not be as well developed in younger children predisposing them to cerebral edema (0.5 1% of all episodes of DKA in children), the most common cause of mortality in children with DKA Whereas delay in diagnosis is the major cause of DKA in previously unrecognized disease in younger children, omission of insulin appears to be the leading cause of recurrent DKA in adolescents Pathophysiology of DKA Absolute insulin deficiency or Stress, infection or insufficient insulin intake Counterregulatory hormones Glucagon Cortisol Catecholamines Growth hormone Lipolysis Glucose utilization Proteolysis Protein synthesis Glycogenolysis Gluconeogenic substrates FFA to liver ++ Gluconeogenesis Ketogenesis Hyperglycemia Alkali Reserve Glucosuria (osmotic diuresis) Ketoacidosis Lactic Acidosis Loss of water and electrolytes Dehydration Decreased fluid intake Hyperosmolarity Impaired renal function The severity of DKA is defined by the degree of acidosis: mild, venous ph 7.2 7.3; moderate, ph 7.1 7.2; and severe ph < 7.1 Frequency of DKA There is a wide geographic variation in the frequency of DKA at onset of diabetes; frequency ranges from ~15 to 70% in Europe, Australia, and North America 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 The risk of DKA in children and adolescents with established type 1 diabetes is 1 10 per 100 person-years

1 Precipitating factors Insulin omission, either inadvertently or deliberately is the cause of DKA in most cases Precipitating factors Insulin omission Intercurrent infection Mostly in: Children with poor metabolic control or previous episodes of DKA, peripubertal and adolescent girls, children with clinical depression or other psychiatric disorders (including those with eating disorders), children with difficult or unstable family circumstances, children with limited access to medical services, children on insulin pump therapy Properly educated patient/family Management of DKA The child with severe DKA or at increased risk for cerebral edema should be considered for immediate treatment in an intensive care unit (pediatric if available). A child with established diabetes (whose parents have been trained in sick-day management, hyperglycemia and ketosis) can be managed at home or in an outpatient health care facility Emergency assessment * Perform clinical evaluation to confirm diagnosis Weigh the patient Look for acanthosis nigricans (suggesting insulin resistance and Type 2 diabetes) Assess clinical severity of dehydration Assess level of consciousness Obtain a blood sample for measurement of serum/plasma glucose, electrolytes, urea nitrogen, creatinine, osmolality, venous ph, pco 2, po 2, hemoglobin and hematocrit or complete blood count, calcium, phosphorus, magnesium, HbA 1c and blood β-hydroxybutyrate (β-ohb) Perform a urinalysis for ketones If infection, obtain appropriate specimens If delay in measurement of serum potassium, perform ECG Clinical & biochemical monitoring Hourly vital signs ** Hourly neurological observations ** (warning signs and symptoms of cerebral edema) Amount of administered insulin Hourly accurate fluid input and output ** Hourly capillary blood glucose Laboratory tests: serum electrolytes, glucose, calcium, magnesium, phosphorus and blood gases should be repeated every 2 4 h **. Blood urea nitrogen, creatinine and hematocrit should be repeated at 6 8h intervals until they are normal Urine ketones until cleared If the laboratory can not provide timely results, a portable analyzer that measures plasma glucose, serum electrolytes and blood ketones on fingerstick blood samples is a useful adjunct to laboratory-based determinations * supportive measures are necessary in some critical situations ** or more frequently as indicated

1 Fluid and electrolyte therapy DKA is characterized by severe depletion of water and electrolytes from both the intracellular fluid and extracellular fluid (ECF) compartments The objectives of fluid and electrolyte replacement therapy are restoration of circulating volume, replacement of sodium and the ECF and intracellular fluid deficit or water, restoration of glomerular filtration with enhanced clearance of glucose and ketones from the blood and avoidance of excessive rates of fluid administration so as not to exacerbate the risk of cerebral edema Replacement procedure for a child (weight 30 kg, surface area 1 m 2 ) with DKA estimated to be 10% dehydrated Approximate duration and rate Fluid composition and volume Sodium Potassium Chloride Phosphate (meq) (meq) (meq) (mmol) Hour 1 (300 ml/h) 300 ml 0.9% NaCl (normal saline) 46 46 Hours 2 4 (125 ml/h); start regular insulin at 0.1 unit.kg -1. h -1 375 ml (normal saline) + 20 meq potassium acetate/l + 20 meq potassium phosphate/l 58 15 58 5.1 Hours 5 48 (125 ml/h); continue regular insulin (0.1 unit. kg -1. h -1 until ph 7.3 or HCO 3 18 meq/l) 5,500 ml (one-half normal saline + dextrose) + 20 meq potassium acetate/l + 20 meq potassium phosphate/l 424 220 424 75 Total in 48 h 6,175 ml fluid 528 235 528 80 Insulin DKA is caused by a decrease in effective circulating insulin associated with increases in counterregulatory hormones. Although rehydration alone causes some decrease in blood glucose concentration, insulin therapy is essential to normalize blood glucose and suppress lipolysis and ketogenesis Potassium, phosphate, acidosis Children with DKA suffer total-body potassium deficits of the order of 3 6 mmol/kg; potassium replacement therapy is required regardless of the serum potassium concentration Depletion of intracellular phosphate occurs in DKA, and phosphate is lost as a result of osmotic diuresis Prospective studies have not shown clinical benefit from phosphate replacement; however severe hypophosphatemia (< 1mg/dl) should be treated even in the absence of symptoms Severe acidosis is reversible by fluid and insulin replacement

1 Cerebral edema Symptomatic cerebral edema occurs in 0.5 1% of pediatric DKA episodes. This complication has a high mortality rate (21 24%) and a substantial percentage of survivors (15 26%) are left with permanent neurological injury The signs and the symptoms of cerebral edema are shown in the below table: Symptoms and signs of cerebral edema Headache Recurrence of vomiting Inappropriate slowing of heart rate Rising blood pressure Decreased oxygen saturation Change in neurological status: - Restlessness, irritability, increased drowsiness, incontinence - Specific neurologic signs, e.g. cranial nerve palsies, abnormal pupillary responses, posturing Several hypotheses have been proposed to account for the occurrence of cerebral edema during DKA but the cause remain poorly understood Children at greatest risk for symptomatic cerebral edema are those who present with high blood urea nitrogen concentrations and those with more profound acidosis and hypocapnia Data are limited regarding the effectiveness of pharmacological interventions for treatment of cerebral edema Prevention Management of an episode of DKA is not complete until its cause has been identified (new onset diabetes: in most cases delayed diagnosis; establish diabetes: in most cases insulin omission; insulin pump users: in most cases failure to take extra insulin when hyperglycemia or hyperketonemia/ketonuria occurs) Home measurement of blood β-ohb, when compared with urine ketone testing, decreases diabetes-related hospital visits by the early identification and treatment of ketosis Blood β-ohb measurements may be especially valuable to prevent DKA in patients who use a pump because interrupted insulin delivery rapidly leads to ketosis

Can We Prevent Diabetic Ketoacidosis in Children? Bismuth E, Laffel L. Pediatr Diabetes 2007;8 Suppl 6:24 33. Review. 2 Background Diabetic ketoacidosis (DKA) is an acute potentially life-threatening complication of diabetes affecting more than 100 000 persons annually in the United States Although major advances have improved diabetes care, DKA remains the leading cause of hospitalization, morbidity, and death in youth with Type 1 diabetes (T1D) Prevention can be accomplished through appropriate education, improved self-care and adherence, and consistent self-monitoring of blood glucose and ketones Epidemiology At diagnosis (onset) There is a wide geographic variation in the frequency of DKA at onset of diabetes (in Europe, Australia and North America it ranges from 15 to 70%). However, rates of DKA at diagnosis are most commonly 25 30% In established diabetes DKA is higher in females, peaks in early teenage years and rarely occurs in anyone diagnosed for less than 2 years Risk factors In evolving T1D, DKA is frequently an indicator of a delay in the recognition of the symptoms of diabetes (more frequent in the very young < 5 years), whereas in established diabetes is often indicative of either insulin omission or suboptimally managed intercurrent illness/stress Prevention Primary prevention DKA as an initial manifestation of T1D could be prevented with: Increased awareness by the lay and medical communities of the symptoms of diabetes Surveillance in high-risk populations potentially identified by family history or genetic susceptibility Secondary prevention Episodes of DKA after diagnosis could be reduced if: Children with diabetes and their families receive comprehensive, ongoing diabetes education Sick-day rules should be reinforced periodically (especially at the start of the school year and during flu season) Patients receiving continuous subcutaneous insulin infusion frequently monitor blood glucose along with urine/ blood ketones (followed by appropriate intervention when needed)

2 Importance of ketone testing β-hydroxybutyrate (β-ohb) is the predominant ketone body produced during a DKA episode Recently, a hand-held device has been developed that allows the determination of β-ohb from capillary blood Testing for ketones remains critical to the prevention of DKA: the ADA recommends blood ketone testing since currently available urine ketone tests are considered not reliable Urine ketone testing: some limitations Nitroprusside- based urinary tests do not react with β-ohb Measurement does not reflect current conditions if the urine has been in the bladder for several hours Strips can lose their accuracy if opened more than 6 months earlier Results can be affected by medications (for example drugs containing sulfhydryl groups) Obtaining a urine sample is sometimes problematic Management of elevated ketone levels Education and awareness of the triggers for hyperglycemia, ketoacidosis and DKA remain crucial for sick-day management and prevention of metabolic decompensation in youth with T1D Triggers for hyperglycemia, ketosis and diabetic ketoacidosis New-onset diabetes Infection Trauma Surgery Emotional stress Errors in insulin administration Pump failure/catheter kinking Intentional manipulation of insulin dosing Pregnancy Myocardial infarction Medications (e.g. steroids) Substance abuse Eating disorders Comorbidities Sick-day rules Cornerstones of sick-day management Never omit insulin (infection induces insulin resistance often necessitating increased or supplemental doses of insulin which dosage should be based on both blood glucose and ketone testing) Ongoing self-blood-glucose monitoring with adult supervision at least every 2 4 h, occasionally every 1 2 h and with results recorded on a log book Monitoring for ketosis every 2 4 h with results recorded on a log book Continuation of monitoring and supplemental insulin through the night Increased intake of salty fluids to combat dehydration associated with hyperglycemia and possible fever Treatment of any underlying illness Anti-emetics if severe vomiting prevents fluid intake Frequent contact with the health-care team to review clinical status

2 Hand-held blood ketone meter can improve self-care management, providing a method to detect metabolic disturbance and correct it if appropriate guidelines are followed: Illness/infection persistent hyperglycemia Check blood ketone level (β-ohb) Less than 0.6 mmol/l 0.6 mmol/l or greater Recheck later in the day (particularly if blood glucose is > 250 mg/dl (13.8 mmol/l) Extra insulin is needed to reduce ketone levels If still < 0.6 mmol/l: continue checking as long as the illness or infection lasts If 0.6 mmol/l: go to the right column of this flow chart Extra fluids help prevent dehydration Call the health care team for advice when the blood ketone level persists >1 mmol/l or when the value is 3 >mmol/l Extra fast-acting analog or regular insulin is given every 2 or 4 hours until ketone levels are < 0.6 mmol/l Flow chart for ketone checking and treatment of illness or infection Conclusions DKA is a serious complication of diabetes and the leading cause of death in children with diabetes DKA at diagnosis may be prevented through earlier recognition of symptoms; in children with established diabetes education remains the most powerful tool to prevent DKA New technologies that can detect the blood ketone β-ohb instead of traditional urine ketones appear to provide opportunity for early identification and treatment of impending DKA leading to reduced need for hospitalization and potential cost-saving

2 Background Diabetic ketoacidosis is a serious complication of diabetes associated with considerable mortality and morbidity β-hydroxybutyrate (β-ohb) accounts for about 75% of ketones, and blood concentration can be determined with a sensor Aims To investigate the frequency and degree of ketonemia in daily life of children/adolescents with diabetes To make a base for recommendations for determination of ketonemia in clinical practice Patients and methods 3 month study period 45 patients (23 boys and 22 girls) aged 4 19 years (mean 11.6 ± 3.5) with Type 1 diabetes since 1 10 years (mean 4.4 ± 3.3 years) treated at the pediatric clinic of Linköping, Sweden Patients (or their parents) were asked to perform eight-point 24-h profiles in 2 weeks with blood glucose and β-ohb measurements using a combined glucose and ketone sensor and fill up a diary with those values, insulin doses, episodes of hypoglycemia, infections etc. Results Main findings of the study were: Most of the measurements revealed no β-ohb concentration at all (only 0.3% of the measurements showed concentrations 1.0 mmol/l) 6000 5735 Distribution of β-ohb values 5000 number of measurements 4000 3000 2000 1000 0 0 896 226 91 41 9 15 11 5 4 17 5 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0-2.0 2.0-3.0 β-hydroxybutyrate

When Should Determination of Ketonemia be Recommended? Samuelsson U, Ludvigsson J. Diabetes Technol Ther 2002;4:645 50 3 Younger children more often had ketonemia (β-ohb concentration 0.2 mmol/l is considered as positive ketonemia) than older children or adolescents Ketonemia in relation to age groups % of children with positive ketonemia 12 10 8 6 4 2 0 102/992 4-7 years p<0.01 164/2645 8-11 years p<0.001 160/3420 12-19 years Ketonemia was more common in the morning than during the rest of the day Slight ketonemia occurred during infection High blood glucose values (> 270 mg/dl [15 mmol/l]) were significantly more often accompanied by β-ohb concentrations 0.2 mmol/l than lower blood glucose values Ketonemia in relation to blood glucose values % of children with positive ketonemia 14 12 10 8 6 4 2 0 0-89 90-179 180-269 270-359 360- Blood glucose (mg/dl) Conclusions High concentrations of β-ohb are rare in diabetic children with reasonably good metabolic control A value > 0.4 mmol/l seems already highly abnormal, therefore the authors recommend that: - Patients retest glucose and ketones when β-ohb levels are > 0.4 mmol/l (especially when the blood glucose values are > 270 mg/dl [15 mmol/l]) - Patients measure β-ohb during infections, periods of high blood glucose values and if they have ketonuria Moreover: - Measurement of ketonemia may be valuable to distinguish ketoacidosis from gastroenteritis in the presence of nausea and vomiting - Monitoring β-ohb should be routine for patients on insulin pump therapy

3 Background Diabetic ketoacidosis (DKA), a crucial pediatric medical emergency, may be defined as a metabolic derangement characterized by hyperglycemia, acidosis and ketonuria It may occur in children with diabetes at onset due to severe insulin deficiency or in established patients from failing to take insulin, acute stress and poor sick-day management A wide range of signs and symptoms may indicate DKA in children: Frequency of signs and symptoms of ketoacidosis* Polyuria, nocturia 88% Thirst, polydipsia 84% Signs of dehydration 78% Abdominal pain, vomiting 14% Acidotic breathing 6% Alteration of consciousness 6% Coma 2% * in the newly diagnosed diabetic children admitted to the Department of Pediatrics of the Universities of Parma and Chieti, Italy, from 1990 2000 The most feared treatment-related complication is cerebral oedema which is frequent in very young children at their first episode of DKA Treatment The cornerstones of the treatment of DKA are rehydration, insulin therapy, and removal of the electrolyte disorders with particular attention to potassium, sodium, and phosphate. First hour Minimum I.V. treatment (rehydration only) Saline solution 0.9% 5 8 ml/kg/hour From the 2 nd hour onwards Complete I.V. treatment (rehydration + insulin) Rehydration Saline Solution 0.9% 1 + Potassium 2 Max. 4 l/m 2 in 24 36 hours 3 Fast-acting insulin Glycemia > 250 mg/dl: 0.1 0.075 IU/kg/hour 4 Glycemia < 250 mg/dl: 0.05 0.025 IU/kg/hour + 10% Glucose Solution 1 ml/kg/hour 5 Protocol for the treatment of DKA 1 If corrected blood sodium levels are >150 meq, 0.45% saline solution may be used. 2 Add K + to the saline solution (if the patient is not anuric) in order to infuse 0.1 0.2 meq/kg/hour (never more than 0.4 meq/kg/hour): the calculated dose must be divided into 50% K-phosphate and 50% K-cloride. 3 Calculation of the volume of liquids to be infused in 24 36 hours, according to body weight and chronological age: kg 14 21 (age: 3 6 years): 2200 ml/m 2 ; Kg 22 29 (age: 7 9 years): 1800 ml/m 2 ; Kg 30 55 (age>10 years): 1500 ml/m 2 4 f ph>7.25: 0.075 IU/Kg/hour should be used. 5 Maintain the combined infusion until beta-hydroxybutyrate blood levels are normalized. Regulate the velocity of the two infusions in order to maintain blood glucose levels within 150-180 mg/dl.

Treatment of Diabetic Ketoacidosis in Children and Adolescents. Vanelli M, Chiarelli F. Acta Biomed 2003;74:59 68. Review. 4 Monitoring Frequent monitoring is a key component of successful treatment Monitoring of DKA a) Clinical Neurological status (pupillary responses, reflexes); cardiac rate; respiratory rate b) Biological blood glucose; blood sodium (*); blood potassium; blood chloride c) Instrumental ECG; blood pressure On admission haemogasanalysis; creatinine blood level; blood β-hydroxybutyrate (β-ohb) and every 3 hours * The value of blood glucose must be corrected, each time, on the basis of blood glucose levels adding to the blood sodium level 2.75 meq every 100 mg/dl of glucose above 100 mg/dl base-line Here below the principal findings regarding the use of blood β-ohb assay in an inpatient setting: β-ohb levels at diagnosis were found to be correlated with HbA 1c values, latency before diagnosis of diabetes, and insulin dose infused during the first hours of treatment In patients with higher values of β-ohb at admission, time to achieve resolution of ketosis is longer than that found in the patients presenting lower values In response to therapy, β-ohb levels begin to decline sooner than urine ketone bodies levels. Furthermore dosage informs on the definitive resolution of ketosis many hours in advance compared with urine ketone bodies test Advantages of using blood β-ohb assay Plan DKA management and insulin therapy since β-ohb seems to be a useful sensitive marker of metabolic decompensation Avoid problems associated with urine determination of ketones (detection of acetoacetate only, unreliability, delay of disappearance ) Monitor hourly patient s ketotic status Forecast the required time to achieve definitive resolution of DKA Reduce the length of stay in the intensive care for the patients with severe DKA by using normalization of β-ohb levels as primary endpoint, thus allowing to save costs

5 Ketoacidosis at Diabetes Onset is still Frequent in Children and Adolescents: a Multicentre Analysis of 14 664 Patients from 106 Institutions. Neu A, Hofer SE, Karges B, et al. Diabetes Care 2009 Jun 23. Aim To analyze the frequency, clinical characteristics and trends associated with the occurrence of diabetic ketoacidosis (DKA) at the onset of Type 1 diabetes mellitus on the basis of long-term follow-up data (13 years). Research design and methods A total of 106 paediatric diabetes centres in Germany and Austria participated in this study Data from 14 664 patients (average of 9.0 years; range 0 17.9 years) with Type 1 diabetes collected between 1995 and 2007 were suitable for evaluation DKA was defined and classified according to the ISPAD (International Society for Pediatric and Adolescents Diabetes) consensus guidelines: mild DKA was 7.2 ph < 7.3; moderate DKA, 7.1 ph < 7.2; severe DKA, ph < 7.1 Results DKA was observed in 21.1% of patients The proportion of severe cases of DKA is high: ~6% of patients with Type 1 diabetes at onset 10 9 8 9.8% Severity of ketoacidosis 25 20 Frequency of ketoacidosis according to years % patients with DKA 7 6 5 4 3 2 1 0 Mild DKA 5.4% Moderate DKA 5.9% Severe DKA DKA (%) 15 10 5 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 year DKA mild DKA moderate DKA severe 2004 2005 2006 2007 Conclusions Data show no significant change in the frequency and magnitude of DKA over the last 13 years: DKA occurring at diabetes onset continues to be an important problem Reinforced efforts aimed at educating patients and practicing physicians are imperative if the situation is to improve

1 Wolfsdorf J et al. American Diabetes Association. Diabetes Care 2006;29: 1150-1159. 2 Bismuth E et al. Pediatr Diabetes 2007;8 Suppl 6:24-33. Review. 3 Samuelsson U et al. Diabetes Technol Ther 2002;4: 645-650. 4 Venelli M et al. Biomed 2003;74: 59-68. Review. 5 Neu A et al. Diabetes Care 2009; Jun 23. A. Menarini Diagnostics Switzerland S.r.l. Eggbühlstrasse 14, CH-8050 Zürich