ISPAD Clinical Practice Consensus Guidelines

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1 Peiatric Diabetes 2006: 7: All rights reserve Copyright # Blackwell Munksgaar 2006 Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Introuction With this issue of Peiatric Diabetes, the first chapters of the Clinical Practice Consensus Guielines of the International Society for Peiatric an Aolescent Diabetes (ISPAD) are publishe. Sequential chapters will be publishe in subsequent issues of Peiatric Diabetes. Finally, the complete set of these guielines will be publishe as a future compenium. In 2003, the total chil population of the worl (0 14 yr) was estimate to be 1.8 billion, of whom 0.024% have iabetes. This means that chilren aroun the worl have iabetes, with new cases iagnose each year (1). This very large number of chilren nee help with injections of insulin in orer to survive an live a full life without restrictions or isabling complications an without being stigmatize for their iabetes. In 1993, members of ISPAD formulate the Declaration of Kos, proclaiming their commitment to Ôpromote optimal health, social welfare, an quality of life for all chilren with iabetes aroun the worl by the year Although all the aims an ieals of the Declaration of Kos were not reache by 2000, we believe that slowly, by small steps, the worlwie care of chilren with iabetes mellitus is improving. ISPAD publishe its first set of guielines in 1995 (2) an its secon in 2000 (3). Since then, the acceptance of intensive therapy for chilren, even for very young chilren, has increase worlwie. Insulin pump usage has risen in all age groups in countries where this treatment moality can be affore. However, intensive therapy requires an investment in better an more comprehensive eucation for the caregivers in orer for it to be successful. The ISPAD Consensus Guielines 2000 have been translate into 11 languages, inicating the nee for a truly international ocument. In , national guielines for chilhoo iabetes were release: the Australian Clinical Practice Guielines from the National Health an Meical Research Council (writing committee chair, Martin Silink)(4) an in the Unite Kingom, the National Institute for Clinical Excellence Clinical Guielines (group leaer, Stephen Greene) (5). Both these publications are truly evience-base in that they eal with the boy of evience in a systematic approach, graing each reference, an builing the case for each recommenation. In 2003, the Canaian Diabetes Association publishe Clinical Practice Guielines with chapters both on type 1 iabetes mellitus (T1DM) an type 2 iabetes mellitus (T2DM) in chilren an aolescents (6). In 2005, the American Diabetes Association (ADA) publishe their statement on the care of chilren an aolescents with T1DM (7). This thir eition of ISPAD s Consensus Guielines, now entitle ÔClinical Practice Consensus Guielines, is much larger an has been enriche by reference to an resources in the above-mentione national guielines. In the Introuction to previous ISPAD Guielines, the acknowlege intention was for the next version of our guielines to be reference. We have use the ADA system for graing eviences (Table 1) (8). Whenever possible, the reference for a statement or recommenation has been inclue, but as reaers will note, a vast majority of the recommenations an suggestions will have the grae E (expert consensus or clinical experience). The Guielines are base on a wie consensus of clinical practice. They were rafte by international writing teams, moifie by experts in ifferent specialties from many countries, ebate at the annual ISPAD meeting in 2005 by the members, an reviewe by members via the internet an the ISPAD website. As far as possible, significant input by iniviuals has been acknowlege. Many thanks to those numerous iniviuals who have contribute but whose names coul not be inclue. As was the same in the 2000 Guielines, the eition places eucation at the center of clinical management. Eucation is the vehicle for optimal self-management, the key to success. New chapters have been ae on T2DM in chilren an aolescents, monogenic iabetes, an exercise. We hope, therefore, that the Guielines will be wiely consulte an will be use to improve awareness among governments, state healthcare proviers, an the general public of the serious long-term implications of poorly manage iabetes an of the essential resources neee for optimal care assist iniviual caregivers in managing chilren an aolescents with iabetes in a prompt, safe, consistent, equitable, an stanarize manner in accorance with the current views of experts in the fiel. 341

2 Hanas et al. Table 1. The evience graing system for Clinical Practice Recommenations of the American Diabetes Association (ADA) (8) Level of evience A B C E Description Clear evience from well-conucte, generalizable, ranomize, controlle trials that are aequately powere, incluing: Evience from a multicenter trial Evience from a meta-analysis incorporating quality ratings Compelling non-experimental evience (i.e., Ôall or none rule) evelope by the Center for Evience-Base Meicine at Oxfor* Supportive evience from well-conucte, ranomize, controlle trials that are aequately powere, incluing: Evience from a well-conucte trial at one or more institutions Evience from a meta-analysis that incorporate quality ratings in the analysis Supportive evience from well-conucte cohort stuies incluing: Evience from a well-conucte prospective cohort stuy or registry Evience from a well-conucte meta-analysis of cohort stuies Supportive evience from a well-conucte case control stuy Supportive evience from poorly controlle or uncontrolle stuies incluing: Evience from ranomize clinical trials with 1 major or 3 minor methoological flaws that coul invaliate the results Evience from observational stuies with high potential for bias (such as case series with comparison with historical controls) Evience from case series or case reports Conflicting evience with the weight of evience supporting the recommenation Expert consensus or clinical experience *Either all patients ie before therapy, at least some survive with therapy, or some patients ie without therapy, an none ie with therapy (e.g., the use of insulin in the treatment of iabetic ketoaciosis). As in 2000, Ôthese Guielines are not strict protocols nor are they the final wor. Iniviual clinical jugment an ecision making also require the family s values an expectations to be consiere, with the best outcomes being reache by consensus. Ragnar Hanas, Kim Donaghue, Georgeanna Klingensmith, Peter GF Swift Eitors of the ISPAD Clinical Practice Consensus Guielines Ragnar Hanas, MD, PhD Department of Peiatrics Uevalla Hospital S Uevalla, Sween [email protected] References 1. IDF. Incience of iabetes. Diabetes Atlas 2006: LARON Z. Consensus Guielines for the Management of Insulin-Depenent (Type 1)Diabetes (IDDM) in Chilhoo an Aolescence. Lonon: Freun Publishing House, SWIFT PGF. (e.). ISPAD (International Society for Peiatric an Aolescent Diabetes) Consensus Guielines for the Management of Type 1 Diabetes Mellitus in Chilren an Aolescents. Zeist, Netherlans: Meforum, APEG. (Australasian Paeiatric Enocrine Group). Australian Clinical Practice Guielines: Type 1 Diabetes in Chilren an Aolescents. Australia: Australia Government, National Health an Meical Research Council, National Collaborating Centre for Women s an Chilren s Health. Type 1 Diabetes: Diagnosis an Management of Type 1 Diabetes in Chilren an Young People. Lonon: RCOG Press, CANADIAN DIABETES ASSOCIATION. Clinical Practice Guielines for the prevention an management of iabetes in Canaa. Can J Diab 2003: 27(Suppl. 2): S84 S SILVERSTEIN J, KLINGENSMITH G, COPELAND K et al. Care of chilren an aolescents with type 1 iabetes: a statement of the American Diabetes Association. Diabetes Care 2005: 28: AMERICAN DIABETES ASSOCIATION. Summary of revisions for the 2006 Clinical Practice Recommenations. Diabetes Care 2006: 29(Suppl. 1): S Peiatric Diabetes 2006: 7:

3 Peiatric Diabetes 2006: 7: All rights reserve # 2006 The Authors Journal compilation # Blackwell Munksgaar 2006 Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Definition, epiemiology an classification Authors: Maria E. Craig, University of NSW, University of Syney, The Chilren s Hospital at Westmea, Australia Anrew Hattersley, Institute of Biomeical an Clinical Sciences, Peninsula Meical School, Exeter, UK Kim Donaghue, University of Syney, The Chilren s Hospital at Westmea, NSW, Australia [email protected] Acknowlegements: Denis Daneman, Zvi Laron, Shin Amemiya, Shigetaka Sugihara, Tatsuhiko Urakami, Gun Forsaner Eitors: Kim Donaghue, Ragnar Hanas, Georgeanna Klingensmith, Peter Swift Definition Diabetes mellitus (DM) is a group of metabolic iseases characterize by chronic hyperglycaemia resulting from efects in insulin secretion, insulin action, or both. The abnormalities in carbohyrate, fat, an protein metabolism that are foun in iabetes are ue to eficient action of insulin on target tissues. If ketones are present in the bloo or urine, treatment is urgent because ketoaciosis can evolve rapily. Diagnostic criteria for iabetes in chilhoo an aolescence Diagnostic criteria for iabetes are base on bloo glucose measurements an thepresenceorabsence of symptoms (E) (1, 2). Three ways to iagnose iabetes are possible an each, in the absence of unequivocal hyperglycaemia, must be confirme, on a subsequent ay, by any one of the three methos givenintable1. Diabetes in chilren usually presents with characteristic symptoms such as polyuria, polyipsia, blurring of vision, an weight loss, in association with glycosuria an ketonuria. In its most severe form, ketoaciosis, or rarely a non-ketotic hyperosmolar state, may evelop an lea to stupor, coma, an in absence of effective treatment, eath. The iagnosis is usually confirme quickly by measurement of a marke elevation of the bloo glucose level. In this situation, if ketones are present in the bloo or urine, treatment is urgent. Waiting another ay to confirm the hyperglycaemia may be angerous in allowing ketoaciosis to evolve rapily. In the absence of symptoms or presence of mil symptoms of iabetes, hyperglycaemia etecte incientally or uner conitions of acute infective, traumatic, circulatory, or other stress may be transitory an shoul not in itself be regare as iagnostic of iabetes. The iagnosis of iabetes shoul not be base on a single plasma glucose concentration. Diagnosis may require continue observation with fasting an/or 2-h postpranial bloo glucose levels an/or an oral glucose tolerance test (OGTT). An OGTT shoul not be performe if iabetes can be iagnose using fasting, ranom, or postpranial criteria, as excessive hyperglycaemia can result using a fasting OGTT in these circumstances. It is rarely inicate in making the iagnosis of type 1 DM (T1DM) in chilhoo an aolescence (E) (2). If oubt remains, perioic re-testing shoul be unertaken until the iagnosis is establishe or refute. Impaire glucose tolerance an impaire fasting glycaemia Impaire glucose tolerance (IGT) an impaire fasting glycaemia (IFG) are intermeiate stages in the natural history of isorere carbohyrate metabolism between normal glucose homeostasis an iabetes (E) (3, 4). IFG an IGT are not interchangeable an represent ifferent abnormalities of glucose regulation. IFG is a measure of isturbe carbohyrate metabolism in the basal state, while IGT is a ynamic measure of carbohyrate intolerance after a stanarize glucose loa. Patients with IFG an/or IGT are now referre to as having pre-iabetes, inicating the relatively high risk for evelopment of iabetes in these patients (A) (5, 6). They can be observe as intermeiate stages in any of the isease processes liste in Table 2. IFG an IGT may be associate with the metabolic synrome (MS), which inclues obesity (especially abominal or visceral obesity), yslipiaemia of the high-triglycerie an/or low-high ensity lipoprotein (HDL) type, an hypertension. 343

4 Craig et al. Table 1. Criteria for the iagnosis of iabetes mellitus (1, 2) (E) Symptoms of iabetes plus casual plasma glucose concentration 11.1 mmol/l (200 mg/l).* Casual is efine as any time of ay without regar to time since the last meal. or Fasting plasma glucose 7.0 mmol/l (126 mg/l). Fasting is efine as no caloric intake for at least 8 h. or 2-h postloa glucose 11.1 mmol/l (200 mg/l) uring an oral glucose tolerance test (OGTT). The test shoul be performe as escribe by the Worl Health Organization (WHO) (2), using a glucose loa containing the equivalent of 75 g anhyrous glucose issolve in water or 1.75 g/kg of boy weight to a maximum of 75 g (3). *Corresponing values (mmol/l) are 10.0 for venous whole bloo an 11.1 for capillary whole bloo. Corresponing values are 6.3 mg/l for both venous an capillary whole bloo. Iniviuals who meet the criteria for IGT or IFG may be euglycaemic in their aily lives as shown by normal or near-normal glycate haemoglobin levels, an those with IGT may manifest hyperglycaemia only when challenge with an OGTT. Categories of fasting plasma glucose (FPG) are efine as follows: FPG, 5.6 mmol/l (100 mg/l) ¼ normal fasting glucose. FPG mmol/l ( mg/l) ¼ IFG. FPG 7.0 mmol/l (126 mg/l) ¼ provisional iagnosis of iabetes (the iagnosis must be confirme, as escribe above uner Diagnostic criteria ). The corresponing categories when the OGTT is use are as follows: 2-h postloa glucose, 7.8 mmol/l (140 mg/l) ¼ normal glucose tolerance. 2-h postloa glucose mmol/l ( mg/ L) ¼ IGT. 2-h postloa glucose mmol/l (200 mg/l) ¼ provisional iagnosis of iabetes (the iagnosis must be confirme, as escribe above). Pathogenesis of T1DM Iniviuals have an absolute eficiency of insulin secretion an are prone to ketoaciosis. Most cases are primarily ue to T-cell meiate pancreatic islet b-cell estruction, which occurs at a variable rate an becomes clinically symptomatic when approximately 90% of pancreatic b-cells are estroye (C) (7). Serological markers of an autoimmune pathologic process, incluing islet cell, glutamic aci ecarboxylase (GAD), islet antigen (IA)-2, IA-2b, or insulin autoantiboies (IAAs), are present in 85 90% of iniviuals when fasting hyperglycaemia is etecte (B) (8, 9). Susceptibility to autoimmune T1DM is etermine by the interaction of multiple genes. Human leucocyte antigen (HLA) genes having the strongest known association, with linkage to DQA an DQB genes, which can be either preisposing or protective (B) (10 12). Iniviuals at increase risk of eveloping T1DM can often be ientifie by measurement of iabetes-associate autoantiboies, genetic markers, an intravenous glucose tolerance testing (B) (13 16). The environmental triggers (chemical an/or viral) which initiate pancreatic b-cell estruction remain largely unknown, but the process usually begins months to years before the manifestation of clinical symptoms (B) (15, 16). In geographical areas where T1DM occurs with lower incience, there is a higher rate of iabetic ketoaciosis (DKA) at presentation (17, 18) When the clinical presentation is typical of T1DM (often associate with DKA) but antiboies are absent, then the iabetes is classifie as T1B (iiopathic). Other forms of iabetes shoul also be consiere as shown in Table 2. Epiemiology of T1DM More than half of iniviuals with T1DM are iagnose before the age of 15 yr (B) (19). In most western countries, T1DM accounts for more than 90% of chilhoo an aolescent iabetes. Type 2 DM (T2DM) is becoming more common an accounts for a significant proportion of youthonset iabetes in certain at-risk populations (B) (20). Epiemiological incience stuies efine the onset of T1DM by the ate of the first insulin injection because of the variable time between the onset of symptoms an iagnosis (B) (21). The incience of T1DM varies greatly between ifferent countries, within countries, an between ifferent ethnic populations (B). Annual incience rates for chilhoo T1DM (0 14 yr age group) comparing ifferent countries of the worl are shown in Figure 1 ( per ) (21, 22). 344 Peiatric Diabetes 2006: 7:

5 Consensus Guielines Table 2. Aetiological classification of isorers of glycaemia I. Type 1 b-cell estruction, usually leaing to absolute insulin eficiency A. Autoimmune B. Iiopathic II. Type 2 May range from preominantly insulin resistance with relative insulin eficiency to a preominantly secretory efect with or without insulin resistance III. Other specific types A. Genetic efects of b-cell function E. Drug or chemical inuce Chromosome 12, HNF-1a (MODY3) Vacor Chromosome 7, glucokinase (MODY2) Pentamiine Chromosome 20, HNF-4a (MODY1) Nicotinic aci Chromosome 13, insulin promoter factor (IPF)-1 (MODY4) Glucocorticois Thyroi hormone Chromosome 17, HNF-1b (MODY5) Diazoxie Chromosome 2, NeuroD1 (MODY6) b-arenergic agonists Mitochonrial DNA mutation Thiazies Chromosome 11, KCNJ11 (Kir6.2), ABCC8 [sulphonylurea receptor 1 (SUR1)] Dilantin a-interferon Others Others B. Genetic efects in insulin action F. Infections Type A insulin resistance Congenital rubella Leprechaunism Cytomegalovirus Rabson Menenhall synrome Coxsackie B4 Lipoatrophic iabetes Others Others G. Uncommon forms of immune-meiate iabetes C. Diseases of the exocrine pancreas Stiff-man synrome Pancreatitis Anti-insulin receptor antiboies Trauma/pancreatectomy Autoimmune polyenocrine synrome eficiencies Neoplasia I an II Cystic fibrosis Others Haemochromatosis H. Other genetic synromes sometimes Fibrocalculous pancreatopathy associate with iabetes Others Down s synrome D. Enocrinopathies Klinefelter s synrome Acromegaly Turner s synrome Cushing synrome Wolfram s synrome Glucagonoma Friereich s ataxia Phaeochromocytoma Huntington s chorea Hyperthyroiism Laurence Moon Biel synrome Somatostatinoma Myotonic ystrophy Alosteronoma Others IV. Gestational iabetes Porphyria Praer Willi synrome Others HNF, hepatocyte nuclear factor; MODY, maturity-onset iabetes of the young. In Europe, incience rates show a close correlation with the frequency of HLA susceptibility genes in increase in those younger than the age of 5 yr (B) (33 35). the general population (B) (23 26). A seasonal variation in the presentation of new In Japan, the incience of T1DM is extremely low at per an has a ifferent an unique cases is well escribe, with the peak being in the winter months (B) (32, 36, 37). HLA association compare with Caucasians (27). In aition, a slowly progressive form of T1DM is common (28). Gener ifferences in incience are foun in some, but not all, populations (B) (21, 29 32). A well-ocumente rise in the incience has been note in many countries, an in some reports, Despite familial aggregation, there is no recognizable pattern of inheritance. The risk of iabetes to an ientical twin of a patient with T1DM is about 36% (B) (38); for a sibling, the risk is approximately 4% by the age of 20 yr (B) (39, 40) an 9.6% by the age of 60 yr (B) (41), compare with 0.5% for the general population. The risk is higher in siblings of there has been a isproportionately greater probans iagnose at a younger age (B) (40, 42). Peiatric Diabetes 2006: 7:

6 Craig et al. Finlan Sarinia Canaa Sween UK (Scotlan) New Zealan Kuwait Australia UK (Northern Irelan) Norway Canaa (Calgary) UK (Oxfor) USA (White) USA (African-American) Puerto Rico (USA) Denmark Spain Malta Germany Icelan Netherlans Italy (Liguria) Belgium Estonia USA (Hispanic) Luxembourg Cyprus Bulgaria Greece Austria Czech Republic Slovak Republic Hungary Portugal Libya Slovenia Algeria France Suan Lithuania Polan Latvia Brazil Russia Croatia Argentina Israel Romania Chile Maceonia Cuba Japan Korea China (H.K.) Paraguay Pakistan Columbia Thailan China (Zunyi) Fiji Fig. 1. Annual incience rates for type 1 iabetes mellitus (T1DM) (0 14 yr age group) comparing ifferent countries in the worl [moifie from the International Diabetes Feeration Atlas (80)]. 346 Peiatric Diabetes 2006: 7:

7 Consensus Guielines T1DM is two to three times more common in the offspring of iabetic men ( %) compare with iabetic women ( %) (B) (40, 42 47). Classification The etiological classification recommene by the American Diabetes Association (ADA) (E) (1) an the Worl Health Organization (WHO) expert committee on the classification an iagnosis of iabetes (E) (2) is shown in Table 2 with minor moification. Classifying types of iabetes The ifferentiation between T1DM, T2DM, an monogenic iabetes has important implications for both therapeutic ecisions an eucational approaches. Regarless of the type of iabetes, however, the chil who presents with severe fasting hyperglycaemia, metabolic erangements, an ketonaemia will require insulin therapy initially to reverse the metabolic abnormalities (48). The possibility of other types of iabetes shoul be consiere in the chil who has the following: An autosomal ominant family history of iabetes. Associate conitions such as eafness, optic atrophy, or synromic features. Marke insulin resistance or requires little or no insulin outsie the partial remission phase. A history of exposure to rugs known to be toxic to b-cells or cause insulin resistance. Measurement of fasting insulin or C-peptie is useful in the iagnosis of T2DM in chilren. Fasting insulin an C-peptie levels are usually normal or elevate, although not as elevate as might be expecte for the egree of hyperglycaemia (E) (49). If patients are treate with insulin, measuring C-peptie when the glucose is sufficiently high (.8 mmol/l) to stimulate C-peptie will etect if enogenous insulin secretion is still occurring. This is rare outsie the honeymoon perio (2 3 yr) in chilren with T1DM (E). T2DM is more completely iscusse in a later chapter. Characteristic features of youth-onset T1DM in comparison with T2DM an monogenic iabetes are shown in Table 3. Maturity-onset iabetes of the young Maturity-onset iabetes of the young (MODY) was escribe as a isorer with the following characteristics: onset before 25 yr of age, autosomal ominant inheritance, non-ketotic DM (50, 51). These classical efinitions given to MODY are no longer very helpful, as T2DM occurs in chilren an will often meet all these criteria (B, C) (52). In aition, efining the molecular genetics has shown that there are marke ifferences between genetic subgroups within these ol, broa categories, making it much more appropriate to use the genetic subgroups, an approach that has been supporte by the ADA an WHO in their guielines on classification (E) (Table 2). There is great variation in the egree of hyperglycaemia, nee for insulin, an risk for future complications (B) (53), see chapter, The iagnosis an management of monogenic iabetes in chilren. Table 3. Clinical characteristics of T1DM, T2DM an monogenic iabetes in chilren an aolescents T1DM T2DM Monogenic Characteristics Genetics Polygenic Polygenic Monogenic Age Throughout chilhoo Usually pubertal (or later) Often postpubertal except MODY2 an neonatal Onset Most often acute, rapi Variable; from slow, mil (often insiious) to severe iabetes Variable Associations Autoimmunity Yes No No Ketosis Common Rare Rare in MODY, common in neonatal iabetes Obesity Reflects the backgroun risk Very common Acanthosis nigricans No Yes No Frequency (% of all Usually 90%1 Most countries,10%?1 3% iabetes in young people) (Japan 60 80%) Parent with iabetes 2 4% 80% 90% Reflects the backgroun risk MODY, maturity-onset iabetes of the young; T1DM, type 1 iabetes mellitus; T2DM, type 2 iabetes mellitus. Peiatric Diabetes 2006: 7:

8 Craig et al. Neonatal iabetes Insulin-requiring hyperglycaemia in the first 3 6 months of life is known as neonatal DM. This rare conition (1 in births) may be associate with intra-uterine growth retaration (C) (54, 55). Approximately half of the cases are transient an have been associate with paternal isoisomy an other imprinting efects of chromosome 6 (B, C) (55, 56), see chapter, The iagnosis an management of monogenic iabetes in chilren. In patients with transient neonatal DM, permanent iabetes may appear later in life (C) (57). Permanent cases have been associate with pancreatic aplasia, activating mutations of KCNJ11, which is the gene encoing the aenosine-triphosphatesensitive potassium channel subunit Kir6.2 (7p15- p13), as well as ABCC8 [sulphonylurea receptor 1 (SUR1)], also in the same chromosome region (57, 58); mutations of the insulin promoter factor-1 (IPF-1) (chromosome 7) in which there is pancreatic aplasia; complete glucokinase eficiency (chromosome 7) (C) (59); mutations of the FOXP3 gene (Tcell regulatory gene) as part of the IPEX synrome (C) (60). Mitochonrial iabetes Mitochonrial iabetes is commonly associate with sensorineural eafness an is characterize by progressive non-autoimmune b-cell failure. Maternal transmission of mutate mitochonrial DNA can result in maternally inherite iabetes. Although several mutations have been implicate, the strongest evience relates to a point substitution at nucleotie position 3243 (A to G) in the mitochonrial trna [leu (UUR)] gene (B) (61, 62). Cystic fibrosis an iabetes Cystic fibrosis (CF)-relate iabetes (CFRD) is primarily ue to insulin eficiency, but insulin resistance uring acute illness, seconary to infections an meications (bronchoilators an glucocorticois), may also contribute to IGT an iabetes. Screening recommenations vary from testing a ranom bloo glucose level annually in all chilren with cystic fibrosis 14 yr ol to performing an OGTT annually in all those.10 yr ol (63, 64), but conventional measures such as FPG, OGTT, an haemoglobin A1c (HbA1c) may not be appropriate tools for the iagnosis of iabetes in patients with CF (B) (65). Insulin therapy initially may only be neee uring respiratory infections ue to acute or chronic infective episoes, but eventually, insulin therapy is frequently necessary. Initially, insulin oses are small (supplemental rather than total insulin replacement). In some patients, early insulin therapy prior to symptoms of hyperglycaemia may provie metabolic effects beneficial to growth, weight, an pulmonary function (66, 67) (B). Drug-inuce iabetes In neurosurgery, large oses of examethasone are frequently use to prevent cerebral oeema (e.g., examethasone 24 mg/). The aitional stress of the surgery may a to the rug-inuce insulin resistance an cause a relative insulin eficiency, sufficient to cause a transient form of iabetes. This will be exacerbate if large volumes of intravenous extrose are given for iabetes insipius. An intravenous insulin infusion is the optimal way to control the hyperglycaemia, which is usually transient. In oncology, protocols which use L-asparaginase, high-ose glucocorticois, cyclosporin, or tacrolimus (FK506) may be associate with iabetes. L-Asparaginase usually causes a reversible form of iabetes (B) (68). Tacrolimus an cyclosporin may cause a permanent form of iabetes, possibly ue to islet cell estruction (C) (69). Often the iabetes is cyclical an associate with the chemotherapy cycles, especially if associate with large oses of glucocorticois. Following transplantation, iabetes most frequently occurs with the use of high-ose sterois an tacrolimus; the risk is increase in patients with pre-existing obesity (B) (70, 71). Diabetes can also be inuce by the use of atypical antipsychotics incluing olanzapine, risperiol, quetiapine, an ziprasione, in association with weight gain (72). CFRD tens to occur late in the isease, typically in aolescence an early aulthoo. Cirrhosis, if present, may contribute to insulin resistance. The onset of CFRD is a poor prognostic sign an is associate with increase morbiity an mortality. Poorly controlle iabetes will interfere with immune responses to infection an promote catabolism (E) (63, 64). Stress hyperglycaemia Stress hyperglycaemia has been reporte in up to 5% of chilren presenting to an emergency epartment. Acute illness or injury, traumatic injuries, febrile seizures, an elevate boy temperature (.39 C) were ientifie as the most common associate features (73). 348 Peiatric Diabetes 2006: 7:

9 Consensus Guielines The reporte incience of progression to overt iabetes varies from 0 to 32% (B, C) (74 79). Chilren with inciental hyperglycaemia without a serious concomitant illness were more likely to evelop iabetes than those with a serious illness (77). Islet cell antiboies (ICAs) an IAAs testing ha a high positive an negative preictive value for T1DM in chilren with stress hyperglycaemia (77). Recommenations Diagnostic criteria for iabetes are base on bloo glucose measurements an the presence or absence of symptoms (E) (1, 2). The iagnosis is usually confirme quickly by measurement of a marke elevation of the bloo glucose level. In this situation, if ketones are present in the bloo or urine, treatment is urgent. Waiting another ay to confirm the hyperglycaemia may be angerous in allowing ketoaciosis to evolve rapily (E). An OGTT shoul not be performe if iabetes can be iagnose using fasting, ranom or postpranial criteria, as excessive hyperglycaemia can result. It is rarely inicate in making the iagnosis of T1DM in chilhoo an aolescence (E) (2). Severe hyperglycaemia etecte uner conitions of acute infection, trauma, surgery, respiratory istress, circulatory, or other stress may be transitory an require treatment but shoul not in itself be regare as iagnostic of iabetes (E). Measurement of iabetes-associate autoantiboy markers, e.g., ICAs, GAD, IA-2, IAAs an/or HbA1c may be helpful in some situations. There is currently insufficient evience to support the routine use of the HbA1c for the iagnosis of iabetes (E) (1). Measurement of fasting insulin or C-peptie is useful in the iagnosis of T2DM in chilren. Fasting insulin an C-peptie levels are usually normal or elevate, although not as elevate as might be expecte for the egree of hyperglycaemia (E) (49). This article is a Chapter in the ISPAD Clinical Practice Consensus Guielines of the International Society for Peiatric an Aolescent Diabetes (ISPAD, The complete set of these Guielines will later be publishe as a compenium. Aitional comments, clarifications or corrections shoul be irecte to the Corresponing Author. References 1. AMERICAN DIABETES ASSOCIATION. Diagnosis an Classification of Diabetes Mellitus. Diabetes Care 2005: 28: S37 S WORLD HEALTH ORGANIZATION. Definition, Diagnosis an Classification of Diabetes Mellitus an its Complications. Part 1: Diagnosis an Classification of Diabetes Mellitus. Geneva: WHO/NCD/NCS/99.2, RASILAINEN S, YLIPAASTO P, ROIVAINEN M et al. Mechanisms of beta cell eath uring restricte an unrestricte enterovirus infection. J Me Virol 2004: 72: DAHLQUIST GG, FORSBERG J, HAGENFELDT L, BOMAN J, JUTO P. Increase prevalence of enteroviral RNA in bloo spots from newborn chilren who later evelope type 1 iabetes: a population-base case-control stuy. 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Only multiple autoantiboies to islet cells (ICA), insulin, GAD65, IA- 2 an IA-2beta preict immune-meiate (Type 1) iabetes in relatives. J Autoimmun 1999: 12: SKYLER JS, KRISCHER JP, WOLFSDORF J et al. Effects of oral insulin in relatives of patients with type 1 iabetes: The Diabetes Prevention Trial Type 1. Diabetes Care 2005: 28: VERGE CF, GIANANI R, KAWASAKI E et al. Preiction of type I iabetes in first-egree relatives using a combination of insulin, GAD, an ICA512bc/IA-2 autoantiboies. Diabetes 1996: 45: DUNGER DB, SPERLING MA, ACERINI CL et al. European Society for Paeiatric Enocrinology/Lawson Wilkins Peiatric Enocrine Society consensus statement on iabetic ketoaciosis in chilren an aolescents. Peiatrics 2004: 113: e133 e140. Peiatric Diabetes 2006: 7:

10 Craig et al. 18. LEVY-MARCHAL C, PATTERSON CC, GREEN A. Geographical variation of presentation at iagnosis of type I iabetes in chilren: the EURODIAB stuy. European an Diabetes. Diabetologia 2001: 44(Suppl. 3): B75 B VANDEWALLE CL, COECKELBERGHS MI, DE L et al. Epiemiology, clinical aspects, an biology of IDDM patients uner age 40 years. Comparison of ata from Antwerp with complete ascertainment with ata from Belgium with 40% ascertainment. The Belgian Diabetes Registry. Diabetes Care 1997: 20: PINHAS-HAMIEL O, ZEITLER P. The global sprea of type 2 iabetes mellitus in chilren an aolescents. J Peiatr 2005: 146: KARVONEN M, VIIK-KAJANDER M, MOLTCHANOVA E, LIBMAN I, LAPORTE R, TUOMILEHTO J. Incience of chilhoo type 1 iabetes worlwie. Diabetes Moniale (DiaMon) Project Group. Diabetes Care 2000: 23: INTERNATIONAL DIABETES FEDERATION. Diabetes Atlas. Secon En, Brussels: IDF DORMAN JS, BUNKER CH. HLA-DQ locus of the human leukocyte antigen complex an type 1 iabetes mellitus: a HuGE review. Epiemiol Rev 2000: 22: GILLESPIE KM, BAIN SC, BARNETT AH et al. The rising incience of chilhoo type 1 iabetes an reuce contribution of high-risk HLA haplotypes. Lancet 2004: 364: ILONEN J, REIJONEN H, GREEN A et al. Geographical ifferences within Finlan in the frequency of HLA-DQ genotypes associate with type 1 iabetes susceptibility. Eur J Immunogenet 2000: 27: KUKKO M, VIRTANEN SM, TOIVONEN A et al. Geographical variation in risk HLA-DQB1 genotypes for type 1 iabetes an signs of beta-cell autoimmunity in a highincience country. Diabetes Care 2004: 27: SUGIHARA S, SAKAMAKI T, KONDA S et al. Association of HLA-DR, DQ genotype with ifferent beta-cell functions at IDDM iagnosis in Japanese chilren. Diabetes 1997: 46: OHTSU S, TAKUBO N, KAZAHARI M et al. Slowly progressing form of type 1 iabetes mellitus in chilren: genetic analysis compare with other forms of iabetes mellitus in Japanese chilren. Peiatr Diabetes 2005: 6: KARVONEN M, PITKANIEMI M, PITKANIEMI J, KOHTAMAKI K, TAJIMA N, TUOMILEHTO J. Sex ifferences in the incience of insulin-epenent iabetes mellitus: an analysis of the recent epiemiological ata. Worl Health Organization DIAMOND Project Group. Diabetes Metab Rev 1997: 13: GALE EA, GILLESPIE KM. Diabetes an gener. Diabetologia 2001: 44: CUCCA F, GOY JV, KAWAGUCHI Y et al. A male-female bias in type 1 iabetes an linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nat Genet 1998: 19: WEETS I, KAUFMAN L, VAN er AB et al. Seasonality in clinical onset of type 1 iabetes in Belgian patients above the age of 10 is restricte to HLA-DQ2/DQ8- negative males, which explains the male to female excess in incience. Diabetologia 2004: 47: EURODIAB ACE STUDY GROUP. Variation an trens in incience of chilhoo iabetes in Europe. Lancet 2000: 355: KARVONEN M, PITKANIEMI J, TUOMILEHTO J. The onset age of type 1 iabetes in Finnish chilren has become younger. Diabetes Care 1999: 22: ONKAMO P, VAANANEN S, KARVONEN M, TUOMILEHTO J. Worlwie increase in incience of type I iabetes the analysis of the ata on publishe incience trens. Diabetologia 1999: 42: GREEN A, BRUTTI G, PATTERSON CC et al. Variation an trens in incience of chilhoo iabetes in Europe. Lancet 2000: 355: LEVY-MARCHAL C, PATTERSON C, GREEN A. Variation by age group an seasonality at iagnosis of chilhoo IDDM in Europe. The EURODIAB ACE Stuy Group. Diabetologia 1995: 38: OLMOS P, A HERN R, HEATON DA et al. The significance of the concorance rate for type 1 (insulin-epenent) iabetes in ientical twins. Diabetologia 1988: 31: HARJUTSALO V, PODAR T, TUOMILEHTO J. Cumulative incience of type 1 iabetes in 10,168 siblings of Finnish young-onset type 1 iabetic patients. Diabetes 2005: 54: STECK AK, BARRIGA KJ, EMERY LM, FIALLO-SCHARER RV, GOTTLIEB PA, REWERS MJ. Seconary attack rate of type 1 iabetes in Colorao families. Diabetes Care 2005: 28: LORENZEN T, POCIOT F, HOUGAARD P, NERUP J. Longterm risk of IDDM in first-egree relatives of patients with IDDM. Diabetologia 1994: 37: GILLESPIE KM, GALE EA, BINGLEY PJ. High familial risk an genetic susceptibility in early onset chilhoo iabetes. Diabetes 2002: 51: Anon. Familial risk of type I iabetes in European chilren. The Euroiab Ace Stuy Group an The Euroiab Ace Substuy 2 Stuy Group. Diabetologia 1998: 41: DORMAN JS, STEENKISTE AR, O LEARY LA, MCCARTHY BJ, LORENZEN T, FOLEY TP. Type 1 iabetes in offspring of parents with type 1 iabetes: the tip of an autoimmune iceberg? Peiatr Diabetes 2000: 1: EL HASHIMY M, ANGELICO MC, MARTIN BC, KROLEWSKI AS, WARRAM JH. Factors moifying the risk of IDDM in offspring of an IDDM parent. Diabetes 1995: 44: LORENZEN T, POCIOT F, STILGREN L et al. Preictors of IDDM recurrence risk in offspring of Danish IDDM patients. Danish IDDM Epiemiology an Genetics Group. Diabetologia 1998: 41: WARRAM JH, KROLEWSKI AS, GOTTLIEB MS, KAHN CR. Differences in risk of insulin-epenent iabetes in offspring of iabetic mothers an iabetic fathers. N Engl J Me 1984: 311: SILVERSTEIN J, KLINGENSMITH G, COPELAND K et al. Care of chilren an aolescents with type 1 iabetes: a statement of the American Diabetes Association. Diabetes Care 2005: 28: AMERICAN DIABETES ASSOCIATION. Type 2 iabetes in chilren an aolescents. Peiatrics 2000: 105: FAJANS SS, BELL GI, POLONSKY KS. Molecular mechanisms an clinical pathophysiology of maturity-onset iabetes of the young. N Engl J Me 2001: 345: OWEN K, HATTERSLEY AT. Maturity-onset iabetes of the young: from clinical escription to molecular genetic characterization. Best Pract Res Clin Enocrinol Metab 2001: 15: AMERICAN DIABETES ASSOCIATION. Type 2 iabetes in chilren an aolescents. American Diabetes Association. Diabetes Care 2000: 23: EHTISHAM S, HATTERSLEY AT, DUNGER DB, BARRETT TG. 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11 Consensus Guielines 55. METZ C, CAVE H, BERTRAND AM et al. Neonatal iabetes mellitus: chromosomal analysis in transient an permanent cases. J Peiatr 2002: 141: HERMANN R, LAINE AP, JOHANSSON C et al. Transient but not permanent neonatal iabetes mellitus is associate with paternal uniparental isoisomy of chromosome 6. Peiatrics 2000: 105: GLOYN AL, PEARSON ER, ANTCLIFF JF et al. Activating mutations in the gene encoing the ATP-sensitive potassium-channel subunit Kir6.2 an permanent neonatal iabetes. N Engl J Me 2004: 350: MASSA O, IAFUSCO D, D AMATO E et al. KCNJ11 activating mutations in Italian patients with permanent neonatal iabetes. Hum Mutat 2005: 25: NJOLSTAD PR, SOVIK O, CUESTA-MUNOZ A et al. Neonatal iabetes mellitus ue to complete glucokinase eficiency. N Engl J Me 2001: 344: BENNETT CL, CHRISTIE J, RAMSDELL F et al. The immune ysregulation, polyenocrinopathy, enteropathy, X- linke synrome (IPEX) is cause by mutations of FOXP3. Nat Genet 2001: 27: VAN DEN OUWELAND JM, LEMKES HH, RUITENBEEK W et al. Mutation in mitochonrial trna(leu)(uur) gene in a large peigree with maternally transmitte type II iabetes mellitus an eafness. Nat Genet 1992: 1: REARDON W, ROSS RJ, SWEENEY MG et al. Diabetes mellitus associate with a pathogenic point mutation in mitochonrial DNA. Lancet 1992: 340: YANKASKAS JR, MARSHALL BC, SUFIAN B, SIMON RH, RODMAN D. Cystic fibrosis ault care: consensus conference report. Chest 2004: 125: 1S 39S. 64. MORAN A, HARDIN D, RODMAN D et al. Diagnosis, screening an management of cystic fibrosis relate iabetes mellitus: a consensus conference report. Diabetes Res Clin Pract 1999: 45: DOBSON L, SHELDON CD, HATTERSLEY AT. Conventional measures unerestimate glycaemia in cystic fibrosis patients. Diabet Me 2004: 21: DOBSON L, HATTERSLEY AT, TILEY S, ELWORTHY S, OADES PJ, SHELDON CD. Clinical improvement in cystic fibrosis with early insulin treatment. Arch Dis Chil 2002: 87: NOUSIA-ARVANITAKIS S, GALLI-TSINOPOULOU A, KARA- MOUZIS M. Insulin improves clinical status of patients with cystic-fibrosis-relate iabetes mellitus. Acta Paeiatr 2001: 90: PUI CH, BURGHEN GA, BOWMAN WP, AUR RJ. Risk factors for hyperglycemia in chilren with leukemia receiving L-asparaginase an prenisone. J Peiatr 1981: 99: DRACHENBERG CB, KLASSEN DK, WEIR MR et al. Islet cell amage associate with tacrolimus an cyclosporine: morphological features in pancreas allograft biopsies an clinical correlation. Transplantation 1999: 68: MAES BD, KUYPERS D, MESSIAEN T et al. Posttransplantation iabetes mellitus in FK-506-treate renal transplant recipients: analysis of incience an risk factors. Transplantation 2001: 72: AL UZRI A, STABLEIN DM, COHN A. Posttransplant iabetes mellitus in peiatric renal transplant recipients: a report of the North American Peiatric Renal Transplant Cooperative Stuy (NAPRTCS). Transplantation 2001: 72: LEVITT KATZ LE, SWAMI S, ABRAHAM M et al. Neuropsychiatric isorers at the presentation of type 2 iabetes mellitus in chilren. Peiatr Diabetes 2005: 6: VALERIO G, FRANZESE A, CARLIN E, PECILE P, PERINI R, TENORE A. High prevalence of stress hyperglycaemia in chilren with febrile seizures an traumatic injuries. Acta Paeiatr 2001: 90: SHEHADEH N, ON A, KESSEL I et al. Stress hyperglycemia an the risk for the evelopment of type 1 iabetes. J Peiatr Enocrinol Metab 1997: 10: BHISITKUL DM, VINIK AI, MORROW AL et al. Preiabetic markers in chilren with stress hyperglycemia. Arch Peiatr Aolesc Me 1996: 150: VARDI P, SHEHADE N, ETZIONI A et al. Stress hyperglycemia in chilhoo: a very high risk group for the evelopment of type I iabetes. J Peiatr 1990: 117: HERSKOWITZ-DUMONT R, WOLFSDORF JI, JACKSON RA, EISENBARTH GS. Distinction between transient hyperglycemia an early insulin-epenent iabetes mellitus in chilhoo: a prospective stuy of incience an prognostic factors. J Peiatr 1993: 123: SCHATZ DA, KOWA H, WINTER WE, RILEY WJ. Natural history of inciental hyperglycemia an glycosuria of chilhoo. J Peiatr 1989: 115: HERSKOWITZ RD, WOLFSDORF JI, RICKER AT et al. Transient hyperglycemia in chilhoo: ientification of a subgroup with imminent iabetes mellitus. Diabetes Res 1988: 9: Incience an trens of chilhoo Type 1 iabetes worlwie Diabet Me 2006: 23: Peiatric Diabetes 2006: 7:

12 Peiatric Diabetes 2007: 8: All rights reserve # 2007 The Authors Journal compilation # 2007 Blackwell Munksgaar Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Phases of iabetes Couper JJ, Donaghue KC. Phases of iabetes. Peiatric Diabetes 2007: 8: Jennifer Couper a Kim Donaghue b a University of Aelaie, South Australia, Australia b University of Syney, The Chilren s Hospital at Westmea, NSW, Australia Corresponing author: Kim Donaghue, The Chilren s Hospital at Westmea, Locke Bag 4001, Westmea, NSW 2145, Australia The Chilren s Hospital at Westmea, Australia. Tel: ; [email protected] Acknowlegments: Denis Daneman, Desmon Schatz Eitors of the ISPAD Clinical Practice Consensus Guielines ; Kim Donaghue, Ragnar Hanas, Georgeanna Klingensmith, Peter Swift Type 1 iabetes mellitus (T1DM) is characterize by Preclinical iabetes. Presentation of iabetes. Partial remission or honeymoon phase. Chronic phase of lifelong epenency on aministere insulin. Preclinical iabetes Preclinical iabetes refers to the months or years preceing the clinical presentationoft1dmwhenantiboies can be etecte as markers of beta-cell autoimmunity: Islet cell autoantiboies. Glutamic aci ecarboxylase autoantiboies (65K isoform). IA2 (also known as ICA512 or tyrosine phosphatase) autoantiboies. Insulin autoantiboies. In aition to these immunological an genetic markers [human leukocyte antigen (HLA) genotype an INS genotype], the risk of T1DM can be further refine by measurement of insulin release in response to an intravenous glucose loa [intravenous glucose tolerance test (IVGTT)]. Risks of progression to iabetes Genetic markers conferring increase or ecrease risk inclue: a) HLA DR3-DQA1*0501-DQB1* 0201 (susceptible genotype). 44 b) HLA DR4-DQA1*0301-DQB1* 0302 (susceptible genotype). c) HLA DR2-DQA1*0102-DQB1* 0602 (protective genotype). Islet autoimmunity can be transient an one raise islet antiboy alone has little prognostic value (1 3). If an iniviual is uner 45 yr an oes not have HLA DR2-DQA1*0102-DQB1* 0602 then: Impaire first phase insulin release on IVGTT (efine as an insulin response less than the 10th percentile for age an sex-matche controls) confers a 60% risk over the next 5 yr (4). Two or more islet antiboies raise without impaire first phase insulin release confer a 25 50% risk over the next 5 yr (5, 6). Neither screening of any population nor intervention in the preclinical phase shoul occur outsie the context of efine clinical stuies (7). Iniviuals who screen positive for genetic or immunological markers of T1DM shoul have access to appropriate counselling an to centres participating in intervention an other efine stuies. Intervention stuies shoul be registere as part of an international network of investigation an information about ongoing stuies shoul be reaily available (7, 8). The one proven environmental trigger of T1DM is congenital rubella (9, 10). Other potential environmental triggers are enteroviral infections (11), casein (12), an cereals (gluten or non gluten) (13, 14). Low levels of intercurrent infection an improve hygiene may be associate with increase risk (15). The hypothesis of acceleration (rather than triggering) of beta-cell

13 Phases of iabetes estruction because of overloa of the beta-cell with risk factors such as rapi growth an weight gain in early life can explain the increasing incience of chilhoo iabetes an the younger age of onset (16). International networks following chilren at increase genetic risk from birth are investigating potential trigger an protective factors (8). Presentation of T1DM Prospective follow-up of high-risk subjects shows that iagnosis of T1DM can be mae in asymptomatic iniviuals in the majority of cases (4). In the Diabetes Prevention Trial Type 1 (DPT-1), when high-risk iniviuals were followe, 73% of participants who were iagnose with iabetes were asymptomatic (4). A chil presenting with a classical history of increasing polyuria, polyipsia, an weight loss over 2 6 wk presents a straightforwar iagnosis. However, failure to consier the possibility of iabetes or atypical presentations may result in late iagnosis. Some chilren have a rapi onset of symptoms an present within ays in iabetic ketoaciosis (DKA); others have a slow onset over several months. Urinary Ôipstick testing for glycosuria an ketonuria provies a simple an sensitive tool for excluing iabetes with less typical presentation. A bloo glucose measurement (plasma glucose.11.1 mmol/l) confirms the iagnosis. The bloo glucose measurement shoul be a laboratory estimation rather than a home glucose monitor or besie reaing. Clinical presentation of iabetes can vary from nonemergency presentations (e.g., polyipsia, polyuria, weight loss, enuresis) to severe ehyration, shock an DKA (17, 18) (E). Non-emergency presentations Non-emergency presentations of iabetes inclue: Recent onset of enuresis in a previously toilet-traine chil, which may be misiagnose as a urinary tract infection or the result of excessive flui ingestion. Vaginal caniiasis, especially in prepubertal girls. Vomiting, which may be misiagnose as gastroenteritis. Chronic weight loss or failure to gain weight in a growing chil. Irritability an ecreasing school performance. Recurrent skin infections. Emergency presentations The usual emergency presentation of DKA in a chil or aolescent inclues: Severe ehyration. Frequent vomiting. Continuing polyuria espite the presence of ehyration. Weight loss because of flui loss an loss of muscle an fat. Flushe cheeks because of the ketoaciosis. Acetone etecte on the breath. Hyperventilation of DKA (Kussmaul respiration) is characterize by a high respiratory rate an large tial volume of each breath, which gives it a sighing quality. Disorere sensorium (isoriente, semicomatose or rarely comatose). Shock (rapi pulse rate, poor peripheral circulation with peripheral cyanosis). Hypotension (a late sign an rare in chilren with DKA). Diagnostic ifficulties leaing to late iagnosis The following situations may result in a late iagnosis of DKA: Very young chilren may present in severe ketoaciosis because of a more rapi onset of severe insulin eficiency (19) an because the iagnosis was not consiere early. Hyperventilation of ketoaciosis may be misiagnose as pneumonia or asthma (cough an breathlessness istinguish these conitions from DKA). Abominal pain associate with ketoaciosis may simulate an acute abomen an lea to referral to a surgeon. Polyuria an enuresis may be misiagnose as a urinary tract infection. Polyipsia may be thought to be psychogenic. Vomiting may be misiagnose as gastroenteritis or sepsis. If a chil is iagnose with iabetes in the presence of symptoms immeiate referral to a centre with expertise in the care of such chilren is manatory, because prompt iagnosis of iabetes in chilren is important in preventing rapi eterioration into ketoaciosis. Severe ketoaciosis, if untreate, is fatal. Therapy is urgent an referral to specialize services is essential (E). Differentiating between T1DM an type 2 iabetes mellitus (T2DM) at iagnosis Features suggesting the iagnosis of type 2 iabetes mellitus (T2DM) rather than T1DM at iagnosis are (20, 21): Obesity. Age greater than 10 yr. Strong family history of T2DM. Acanthosis nigricans. High-risk racial or ethnic group. Unetectable pancreatic autoantiboies. Normal to high C-Peptie levels. Peiatric Diabetes 2007: 8:

14 Couper an Donaghue Partial remission or honeymoon phase in T1DM In approximately 80 percent of chilren an aolescents, insulin requirements ecrease transiently following initiation of insulin treatment (22). The efinition of the partial remission phase has been uncertain but a recent efinition is when the patient requires less than 0.5 units of insulin per kg of boy weight per ay an has an HbA1c,7% (22). The partial remission phase commences within ays or weeks of the start of insulin therapy an may last for weeks to months. During this phase bloo glucose levels are frequently stable within the normal range, espite fluctuations in iet an exercise. It is important for the families to be avise of the transient nature of the partial remission phase so as to avoi the false hope that the iabetes is spontaneously isappearing. Several stuies have shown intensive therapy preserves c-peptie, leas to better control (measure by A1c), an often a ecrease in insulin ose (18, 23). Intervention trials from iagnosis are in progress as part of an international network of intervention trials to preserve beta-cell function either in the preclinical phase or from iagnosis (8). In a few chilren an aolescents, requirements for insulin may ecrease to the point of being able to withraw insulin therapy temporarily an still maintain normoglycaemia. As low ose subcutaneous insulin therapy oes not prolong resiual beta-cell function in the preclinical phase, continuing insulin seems unlikely to provie any other avantage other than maintaining establishe iabetes routines for the chil. Ketoaciosis at presentation (17) an young age (14) reuce the likelihoo of a remission phase. Parents an chilren with T1DM shoul be informe that the remission phase of iabetes is transient an oes not inicate total remission of iabetes (18) (E). Chronic phase of lifelong epenence on insulin The progression from the partial remission phase into the chronic phase of lifelong epenence on insulin is usually a graual ecrease in resiual beta-cell function but clinically seems to be accelerate by an intercurrent illness. At present, exogenous insulin replacement remains the only form of replacement therapy for chilren an aolescents with T1DM, although some other experimental treatments are uner investigation. Transplantation Islet transplantation has become more successful since the introuction of less beta-cell toxic immunosuppressive agents an refine techniques to harvest aequate numbers of viable beta-cells (24). The numbers of subjects who remain insulin-inepenent fall with follow-up an several onor pancreases are require for aequate beta-cell numbers in the transplant (25). The Emonton protocol, which is a glucocorticoi-free immunosuppressant regimen, has been use in several centres with goo clinical outcomes in those with full an partial graft function, namely, protection from severe hypoglycaemia an less labile bloo glucose levels (26) The inuction of immunologic tolerance without the nee for chronic immunosuppressive therapy is a major goal an the potential use of haematopoietic stem cell therapy for inuction of tolerance an islet cell regeneration in vivo an neogenesis in vitro are rapily expaning research irections. Pancreas transplantation provies high rates of graft survival at 1 yr but there are significant surgical risks an the requirement for long-term immunosuppression preclues its use in chilren an aolescents (26, 27). Prevention of iabetes the evience The evience on intervention trials to elay or prevent the onset of T1DM is liste in: European Nicotinamie Diabetes Intervention Trial, a multinational quasiranomize placebo-controlle, ouble-bline intervention stuy, emonstrate that nicotinamie i not elay or prevent the onset of T1DM in high-risk, first-egree relatives (27, 28) (A). The National Institutes of Health DPT-1 emonstrate in a ranomize controlle trial that low ose subcutaneous insulin therapy i not elay or prevent the onset of clinical iabetes in high-risk, first-egree relatives (4) (A). Prevention recommenations an principles Health care professionals shoul be aware that there are no interventions shown to elay or prevent the onset of T1DM. Neither screening of any population nor intervention in the preclinical phase shoul occur outsie the context of efine clinical stuies (7) (E). This article is a Chapter in the ISPAD Clinical Practice Consensus Guielines of the International Society for Peiatric an Aolescent Diabetes (ISPAD, The complete set of these Guielines will later be publishe as a compenium. Aitional comments, clarifications or corrections shoul be irecte to the Corresponing Author. The evience graing system use in the ISPAD Guielines is the same as that use by the American 46 Peiatric Diabetes 2007: 8: 44 47

15 Phases of iabetes Diabetes Association. See the Introuction of the ISPAD Clinical Practice Consensus Guielines in Peiatric Diabetes 2006: 7: References 1. COLMAN PG, STEELE C, COUPER JJ et al. Islet autoimmunity in infants with a Type I iabetic relative is common but is frequently restricte to one autoantiboy. Diabetologia 2000: 43: KIMPIMAKI T, KULMALA P, SAVOLA K et al. Natural history of beta-cell autoimmunity in young chilren with increase genetic susceptibility to type 1 iabetes recruite from the general population. J Clin Enocrinol Metab 2002: 87: KNIP M. Natural course of preclinical type 1 iabetes. Horm Res 2002: 57: DIABETES PREVENTION TRIAL-TYPE 1 DIABETES STUDY GROUP. Effects of insulin in relatives of patients with type 1 iabetes mellitus. N Engl J Me 2002: 346: BINGLEY PJ, CHRISTIE MR, BONIFACIO E et al. Combine analysis of autoantiboies improves preiction of IDDM in islet cell antiboy-positive relatives. Diabetes 1994: 43: VERGE CF, GIANANI R, KAWASAKI E et al. Preiction of type I iabetes in first-egree relatives using a combination of insulin, GAD, an ICA512bc/IA-2 autoantiboies. Diabetes 1996: 45: AMERICAN DIABETES ASSOCIATION. Prevention of type 1 iabetes mellitus. Diabetes Care 2003: 26: GINSBERG-FELLNER F, WITT ME, FEDUN B et al. Diabetes mellitus an autoimmunity in patients with the congenital rubella synrome. Rev Infect Dis 1985: 7(Suppl. 1): S170 S MCINTOSH ED, MENSER MA. A fifty-year follow-up of congenital rubella. Lancet 1992: 340: HYOTY H, HILTUNEN M, KNIP M et al. A prospective stuy of the role of coxsackie B an other enterovirus infections in the pathogenesis of IDDM. Chilhoo Diabetes in Finlan (DiMe) Stuy Group. Diabetes 1995: 44: AKERBLOM HK, VIRTANEN SM, ILONEN J et al. Dietary manipulation of beta cell autoimmunity in infants at increase risk of type 1 iabetes: a pilot stuy. Diabetologia 2005: 48: NORRIS JM, BARRIGA K, KLINGENSMITH G et al. Timing of initial cereal exposure in infancy an risk of islet autoimmunity. JAMA 2003: 290: ZIEGLER AG, SCHMID S, HUBER D, HUMMEL M, BONIFACIO E. Early infant feeing an risk of eveloping type 1 iabetes-associate autoantiboies. JAMA 2003: 290: FILIPPI C, VON HERRATH M. How viral infections affect the autoimmune process leaing to type 1 iabetes. Cell Immunol 2005: 233: DAHLQUIST G. Can we slow the rising incience of chilhoo-onset autoimmune iabetes? The overloa hypothesis. Diabetologia 2006: 49: BOBER E, DUNDAR B, BUYUKGEBIZ A. Partial remission phase an metabolic control in type 1 iabetes mellitus in chilren an aolescents. J Peiatr Enocrinol Metab 2001: 14: THE DIABETES CONTROL AND COMPLICATIONS TRIAL RESEARCH GROUP. Effect of intensive therapy on resiual beta-cell function in patients with type 1 iabetes in the iabetes control an complications trial. A ranomize, controlle trial. Ann Intern Me 1998: 128: KESKINEN PK. First-phase insulin response in young healthy chilren at genetic an immunological risk for type I iabetes. Diabetologia 2002: 45: AMERICAN DIABETES ASSOCIATION. Type 2 iabetes in chilren an aolescents. Peiatrics 2000: 105: AMERICAN DIABETES ASSOCIATION. Screening for type 2 iabetes. Diabetes Care 2003: 26: LOMBARDO F, VALENZISE M, WASNIEWSKA M et al. Twoyear prospective evaluation of the factors affecting honeymoon frequency an uration in chilren with insulin epenent iabetes mellitus: the key-role of age at iagnosis. Diabetes Nutr Metab Clin Exp 2002: 15: DE BEAUFORT CE, HOUTZAGERS CM, BRUINING GJ et al. Continuous subcutaneous insulin infusion (CSII) versus conventional injection therapy in newly iagnose iabetic chilren: two-year follow-up of a ranomize, prospective trial. Diabet Me 1989: 6: SHAPIRO AM, LAKEY JR, RYAN EA et al. Islet transplantation in seven patients with type 1 iabetes mellitus using a glucocorticoi-free immunosuppressive regimen. N Engl J Me 2000: 343: RYAN EA, LAKEY JR, PATY BW et al. Successful islet transplantation: continue insulin reserve provies longterm glycemic control. Diabetes 2002: 51: SHAPIRO AM, RICORDI C, HERING BJ et al. International trial of the Emonton protocol for islet transplantation. N Engl J Me 2006: 255: ODORICO JS, SOLLINGER HW. Technical an immunosuppressive avances in transplantation for insulinepenent iabetes mellitus. Worl J Surg 2002: 26: GALE EA, BINGLEY PJ, EMMETT CL, COLLIER T. European Nicotinamie Diabetes Intervention Trial (ENDIT) Group. European Nicotinamie Diabetes Intervention Trial (ENDIT): a ranomise controlle trial of intervention before the onset of type 1 iabetes. Lancet 2004: 363: Peiatric Diabetes 2007: 8:

16 Peiatric Diabetes 2006: 7: All rights reserve # 2006 The Authors Journal compilation # Blackwell Munksgaar 2006 Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines The iagnosis an management of monogenic iabetes in chilren Authors: Anrew Hattersley, Institute of Biomeical an Clinical Sciences, Peninsula Meical School, Exeter, UK Jan Bruining, Sophia Chilren s Hospital, Rotteram, the Netherlans Julian Shiel, Department of Chil Health, University of Bristol, Bristol, UK Pal Njolsta, Department of Chil Health, University of Bergen, Bergen, Norway Kim Donaghue, The Chilren s Hospital at Westmea, University of Syney, NSW, Australia [email protected] Eitors: Kim Donaghue, Ragnar Hanas, Georgeanna Klingensmith, Peter Swift Definition Monogenic iabetes results from the inheritance of mutation or mutations in a single gene. It may be ominantly or recessively inherite or may be a e novo mutation an, hence, a spontaneous case. In chilren, almost all monogenic iabetes results from mutations in genes that regulate b-cell function, although iabetes can rarely occur from mutations resulting in very severe insulin resistance (C) (1). Diagnosis Why iagnose monogenic iabetes? The majority of patients with genetically proven monogenic iabetes are initially incorrectly iagnose as having type 1 iabetes mellitus (T1DM) or type 2 iabetes mellitus (T2DM) (2) (C). It is important to correctly iagnose monogenic iabetes as it can preict the clinical course of the patient, explain other associate clinical features, an, very important, guie the most appropriate treatment. In aition, making a iagnosis will have implications for other family members often correcting the iagnosis an treatment for other iabetic family members, as well as allowing appropriate genetic counseling. Clinical presentation of monogenic iabetes Clinical presentations in chilren when a iagnosis of monogenic iabetes shoul be consiere are iscusse below an inclue the following: 352 (i) Neonatal iabetes an iabetes iagnose within the first 6 months of life. (ii) Familial iabetes with an affecte parent. (iii) Mil ( mmol/l) fasting hyperglycemia, especially if young or familial. (iv) Diabetes associate with extra pancreatic features. When to suspect a iagnosis of T1DM in chilren may not be correct? Features in chilren initially thought to have T1DM that shoul suggest a possible iagnosis of monogenic iabetes are shown below. None of these are absolute an shoul be consiere as together, rather than in isolation (C) (3). (i) A iagnosis of iabetes before 6 months (B) [in T1DM:,1% (4)]. (ii) Family history of iabetes with a parent affecte (C) [in T1DM: 2 4% (5)]. (iii) Evience of enogenous insulin prouction outsie the Ôhoneymoon phase (after 3 yr of iabetes), with etectable C-peptie (.200 nmol/l) when glucose level is.8 mmol/l (E) (in T1DM: 1 5%). (iv) When pancreatic islet autoantiboies are absent, especially if measure at iagnosis (C) [in T1DM: 3 30% (6 8)]. The great variation in antiboy prevalence in series probably represents ifferences in assays an means it is har to apply publishe series irectly into clinical practice. Absent antiboies shoul lea to other investigation/consieration rather than leaing irectly to genetic tests (E). When to suspect a iagnosis of T2DM in chilren may not be correct? Features in chilren initially thought to have T2DM that shoul suggest a possible iagnosis of monogenic iabetes are shown below. It shoul be note that most T2DM in youth will meet the former classification for maturity-onset iabetes of the young (MODY) [iagnose,25, autosomal ominant inheritance an non-insulin epenent (C) (9 12)]. (i) Not markely obese or iabetic family members who are of normal weight [in T2DM: 20% (12)].

17 Consensus Guielines (ii) Acanthosis nigricans not etecte [in T2DM: 10% (9)]. (iii) Ethnic backgroun with a low prevalence of T2DM, e.g., European Caucasian (in T2DM: 0 45%). (iv) No evience of insulin resistance with fasting C-peptie within the normal range [in T2DM: 0 20% (9 12)]. Making a iagnosis of monogenic iabetes As well as having clinical features that are unusual for T1DM an T2DM, a patient on whom a iagnosis of monogenic iabetes is mae shoul also have the features of a specific genetic subtype of monogenic iabetes (E). The features of the more common monogenic iabetes are given below. While in T1DM an T2DM iabetes there is no single iagnostic test, this is not the case in monogenic iabetes where in.80% of cases, a molecular genetic iagnosis can be mae by DNA testing (C). Molecular genetic testing is offere in most European countries an the USA, but many labs will test patients from other countries (for example, www. iabetesgenes.org an These tests are expensive (up to V500/$600) but can have a big impact on management of the proban an other family members, for whom it will be cheaper, as the mutation is known (V100/$120). Some recently escribe monogenic iabetes genes like Kir6.2 testing in patients iagnose less than 6 months may be available as research tests for no charge (see Approval from the patient s insurance company shoul be sought prior to sening DNA when applicable. Given the limite resources available, it is vital that these tests are use in situations where they are likely to be positive an will alter clinical care. This will involve careful clinical selection an performing physiological tests like C-peptie an autoantiboy measurement, as well as testing other family members before performing molecular genetic tests (E). Specific subtypes of monogenic iabetes an their management Neonatal iabetes an iabetes iagnose within the first 6 months of life There is goo evience that iabetes iagnose in the first 6 months is not T1DM, as autoantiboies are rare an human leukocyte antigen (HLA) genotyping shows HLA haplotypes actually protective for T1DM in these patients (B) (4). Neonatal iabetes is another area which has rapily move from a clinical to a molecular genetic classification (13, 14). Neonatal iabetes is insulin-requiring iabetes, which is usually iagnose in the first 3 months of life. Clinically, two subgroups have been recognize: transient neonatal iabetes mellitus (TNDM) that resolve at a meian of 12 wk an then i not require any treatment, although as many as 50% of cases woul ultimately relapse (B) (15, 16); in contrast to permanent neonatal iabetes mellitus (PNDM), which require continual insulin treatment from iagnosis onwar. For most patients with both types of neonatal iabetes, the molecular etiology can now be efine. The majority of patients with TNDM have an abnormality of imprinting of the ZAC an HYMAI genes on chromosome 6q (B) (14, 15), while the most common known cause of PNDM are mutations in the KCNJ11 gene encoing the Kir6.2 subunit of the b-cell K ATP channel (B) (17, 18). However, TNDM an PNDM are foun with activating mutations in KCNJ11 (Kir 6.2) an ABCC8 [sulfonylurea receptor (SUR) 1]; some of these are amenable to treatment with sulfonylurea rugs which stimulate enogenous insulin secretion (19). If both parents are glucose intolerant, homozygous or compoun heterozygous mutations in glucokinase are most frequent (20, 21). Differential iagnosis. When iabetes is iagnose in the neonatal perio, it is ifficult to tell if it is likely to be transient or permanent, although the features in Table 1 can help ifferentiate the possible ifferent subtypes an can be use to guie molecular genetic testing. TNDM from imprinting anomalies on 6q24. Imprinte anomalies of the 6q24 locus involving the ZAC an HYAMI genes are the most common cause of neonatal iabetes an result in TNDM (B) (14, 15, 22). The commonest 6q24anomalies are inherite paternal uplications or paternal uniparental isomy, although methylation anomalies are being more frequently ientifie (E) (16). Diabetes associate with this is typically iagnose within the first week an resolves aroun 12 wk (B) (15). In approximately 50% of cases, iabetes will reoccur uring the peiatric agerange(b)(15).apart from macroglossia, seen in 23%, there are no nonpancreatic features (B) (15). Initial glucose values can be very high (range: mmol/l) an, therefore, insulin is use initially, although the ose can rapily be reuce. Once patients have relapse, they shoul remain uner annual follow up ue to the risk of iabetes relapsing. On relapse, patients are not insulin epenent an can be treate with iet initially, although subsequently, they often nee insulin (E) (14). The response to oral treatments such as sulfonylureas or metformin is uncertain. PNDM, TNDM an iabetes iagnose in the first 6 months of life ue to Kir6.2 mutations. Kir6.2 mutations are the secon most common cause of Peiatric Diabetes 2006: 7:

18 Hattersley et al. Table 1. Characteristics of iabetes presenting in the first 6 months of life [moifie from reference (13)] Gene, clinical synrome, inheritance PNDM/TNDM Number of cases escribe (% in consanguineous or isolate populations) Meian birth weight in grams (SDS) Age of iagnosis in weeks, meian (range) Pancreatic appearance Other features ZAC/HYAMI, imprinting efect on 6q24 Kir6.2 (KCNJ11), spontaneous ominant (10%) EIF2AK3, Wolcott Rallison synrome, recessive FOXP3, IPEX synrome, X linke TNDM ffi150, rare 2100 (22.94) 0.5 (0 4) Normal Macroglossia (23%) PNDM, TNDM (10%) ffi100, rare (21.73) 6 (0 260) Normal Developmental elay (20%), epilepsy (6%), DKA (30%) PNDM 30 (90)? 13 (6 65) Atrophy of pancreas (?), exocrine ysfunction (25%) Epiphyseal ysplasia (90%), osteopenia (50%), acute liver failure (75%), evelopmental elay (80%), hypothyroiism (25%) PNDM 14, rare 2860 (21.2) 6 (0 30)? Only boys affecte, chronic iarrhea with villous atrophy (95%); pancreatic an thyroi autoantiboies (75%), thyroiitis (20%), eczema (50%); anemia (30%) an often ie young (1 yr) GCK (glucokinase), recessive PNDM 6 (85) 1720 (22.75) Normal Parents have fasting hyperglycemia, as heterozygotes IPF1, recessive PNDM 2 (50) 2140 (22.97) Absent Parents may have early-onset iabetes, as heterozygotes TNDM 2, rare 1900 (23.21) Atrophy Renal evelopmental isorers HNF-1b, ominant (60%) spontaneous PTF1A, recessive PNDM 3 (100) 1390 (23.8) Atrophy Severe neurological ysfunction an cerebellar hypoplasia DKA, iabetic ketoaciosis; HNF, hepatocyte nuclear factor; IPEX, immunoysregulation, polyenocrinopathy, enteropathy, X-linke; IPF1, insulin promoter factor 1; PNDM, permanent neonatal iabetes mellitus; SDS, stanar eviation score; TNDM, transient neonatal iabetes mellitus. 354 Peiatric Diabetes 2006: 7:

19 Consensus Guielines mutations in patients with iabetes iagnose in the first 6 months of life (B) (17, 18). While some (10%) have a remitting form of iabetes that may later relapse, the majority have PNDM (C) (23). Most patients have isolate iabetes, although neurological features are seen in 20% of patients. Despite being a heterozygous mutation, most have no family history, as 90% of cases are spontaneous mutations. The most severe efect is very marke evelopmental elay of motor an social function an generalize epilepsy often with hypsarrhythmia, as seen in West synrome (C) (17). This has been calle the evelopmental elay, epilepsy, an neonatal iabetes (DEND) synrome (18). More common is the intermeiate DEND synrome where patients have less severe evelopmental elay an o not have epilepsy (18). Patients with Kir6.2 mutations have all the clinical features of insulin epenency, as 30% of them present with ketoaciosis, an they usually o not have etectable C-peptie an, thus, are treate with insulin (C) (18). It has recently been shown that these patients can not only be successfully treate with oral sulfonylureas but can also get better glycemic control without an increase in hypoglycemia. The oses neee are high when calculate on a per kg boy weight basis compare with aults, with patients typically neeing 0.5 mg/kg/glibenclamie/, although some may nee as much as 1 mg/kg/ (C) (24 29). With time, many patients have been able to reuce their oses of sulfonylureas but maintain excellent glycemic control (E). Wolcott Rallison synrome. Wolcott Rallison synrome is a rare autosomal recessive conition characterize by early-onset iabetes, epiphyseal ysplasia, renal impairment, acute hepatic failure, an evelopmental elay (B) (30, 31). It is associate with mutations in EIF2AK3 (32). Diabetes usually presents in infancy but may appear later. It is associate with ß-cell loss, leaing to insulin eficiency without autoimmune pathology. Insulin treatment is require. Wolcott Rallison synrome shoul be consiere in any patient with iabetes in the first 3 yr who has epiphyseal ysplasia or acute severe hepatic failure (C, E) (30). Other causes of neonatal iabetes. In Table 1, the clinical features of other causes of neonatal iabetes are outline. Scanning the pancreas to assess if it is present an its size, checking for exocrine pancreatic function an pancreatic autoantiboies [foun in the immunoysregulation, polyenocrinopathy, enteropathy, X-linke (IPEX) synrome] are the most useful iagnostic tests before proceeing to molecular genetic testing (E). All other causes nee to be treate with insulin. Some peiatricians consier that these patients are easiest to manage on subcutaneous insulin pumps. In patients with pancreatic aplasia, exocrine pancreatic supplements will be require. Familial iabetes The most common causes of familial iabetes or familial hyperglycemia are shown in Table 2. Chilren an young aults with iabetes an a strong family history of iabetes: hepatocyte nuclear factor 1 alpha gene mutations (MODY3). The possibility of monogenic iabetes shoul be consiere whenever a parent has iabetes, even if he/she is thought to have T1DM or T2DM (E). The most common form of monogenic iabetes which results in familial iabetes (known in the past as MODY) are hepatocyte nuclear Table 2. Characteristics of common forms of monogenic iabetes an hyperglycemia Inheritance Number of families ientifie in UK Typical age of presentation in peiatric clinic (range) Typical glucose level at presentation (range) mmol/l Other clinical features HNF-1a (MODY3) HNF-4a (MODY1) Glucokinase (MODY2) Dominant (4 18) 17 (11 26) Large increment in an OGTT (at 2 0 h usually.5 mmol/l), low renal threshol, progressive hyperglycemia with age, sensitive to sulfonylureas Dominant (5 18) 15 (9 20) Similar to HNF-1a but renal Dominant (may not be iagnose in parents as mil) threshol normal (0 18) 11 (5.5 16) Usually inciental fining at iagnosis, fasting glucose in the range of mmol/l, small increment in an OGTT (at 2 0 h usually,3.5 mmol/l), little eterioration in glycemia with age HNF, hepatocyte nuclear factor; MODY, maturity-onset iabetes of the young; OGTT, oral glucose tolerance test. Peiatric Diabetes 2006: 7:

20 Hattersley et al. factor (HNF)-1a mutations (B) (33). The clinical characteristics of patients with HNF-1a mutations are as follows: (i) Young-onset iabetes that shows characteristics of not being insulin epenent, e.g., not eveloping ketoaciosis in the absence of insulin, goo glycemic control on a small ose of insulin, or etectable C-peptie measure when on insulin, with glucose.8 mmol/l outsie a normally expecte honeymoon perio (3 yr) (E). (ii) Family history of iabetes. This may be treate with insulin an consiere to be ÔT1DM. This woul typically be iagnose in the age of 20, 30, or 40 yr. There may also be an affecte granparent although often they are iagnose after 45 yr (C). (iii) Oral glucose tolerance tests (OGTTs) in early stages ten to show a very large glucose increment, usually.5 mmol/l (34). Some subjects may have a normal fasting value but still rise into the iabetic range at 2 h (34) (B). (iv) Glycosuria at relatively normal bloo glucose levels is often seen, as these patients have a low renal threshol (B) (34). (v) Marke sensitivity to sulfonylureas resulting in hypoglycemia, espite poor glycemic control before starting sulfonylureas (C) (35, 36). Treatment. Patients with HNF-1a gene mutations can initially be treate with iet although they will have marke postpranial hyperglycemia following a high carbohyrate meal, as the b-cell efect results in insufficient increase in insulin secretion with hyperglycemia (37). Most patients will nee pharmacological treatment, as they show progressive eterioration in glycemic control throughout life an are at risk of consierable microvascular an macrovascular complications (B,C) (38). The first treatment to be use in chilren who are not controlle on insulin shoul be low-ose sulfonylureas, which results in a four-fol greater lowering of glucose than metformin (A) (39). These patients are extremely sensitive to sulfonylureas, an as long as they o not have problems with hypoglycemia, they can be maintaine on these for many ecaes (C) (35). Glycemic control by sulfonylureas is often better than that achieve by insulin, especially in chilren an young aults (40). The ose of sulfonylureas shoul initially be low (one-quarter of the normal starting ose in aults) to avoi hypoglycemia (E). If there is hypoglycemia espite ose titration of a once- or twice-aily sulfonylurea preparation such as gliclazie, a slowrelease preparation or meal time oses with a shortacting agent like nateglinie may be consiere (C) (41). Chilren an young aults with iabetes an a strong family history of iabetes: HNF-4a gene mutations (MODY1). Diabetes ue to mutations of the HNF-4a gene are consierably less common (Table 2) than iabetes ue to mutations of the HNF-1a gene but has similar characteristics, except that there is no low renal threshol an the age of iagnosis may be later (C) (42). HNF-4a mutations shoul be consierewhenhnf-1a sequencing is negative but the clinical features were strongly suggestive of HNF-1a (42). Patients are often sensitive to sulfonylureas (C) (43). Other causes of familial iabetes. A hanful of families with autosomal ominant non-insulinepenent iabetes have been escribe with mutations in insulin promoter factor 1 (IPF1) (MODY4) (44), NeuroD1 (MODY6) (45, 46) an, recently, the carboxyl ester lipase (CEL) gene (MODY7) (47), but these are so unusual, they o not nee to be teste for in chilren with iabetes except in a research setting (E) or when there are aitional phenotypes, such as pancreatic exocrine ysfunction (47). Mil fasting hyperglycemia: ue to glucokinase mutations (MODY2) The fining of raise fasting bloo glucose in the range of mmol/l is unusual in chilren an young aults. This always raises concern that they may be about to evelop T1DM or that the patient has T2DM. However, a consierable proportion of these patients with persistent mil fasting hyperglycemia will have a heterozygous mutation in the glucokinase gene. The phenotype associate with glucokinase mutations is remarkably similar for all mutations. The following features suggest a iagnosis of a glucokinase mutation: (i) The fasting hyperglycemia is persistent an stable over a perio of months or years (34). (ii) Hemoglobin A1c is typically just below or just above the upper limit of normal range ( %). (iii) In an OGTT, the increment (2-h glucose fasting glucose) is small (typically,3.5 mmol/l), although because of the variability of the OGTT, this shoul not be consiere an absolute criterion (34). (iv) Parents may have ÔT2DM or may not be iabetic. On testing, one parent will have a milly raise fasting bloo glucose, in the range of mmol/ L, as this is an autosomal ominant conition (C) (34). Testing of apparently unaffecte parents fasting glucose is important when consiering a iagnosis of a glucokinase mutation (E). Treatment. The fasting hyperglycemia oes not eteriorate significantly an the glucose is regulate at the higher set point (34). This is rarely associate with 356 Peiatric Diabetes 2006: 7:

21 Consensus Guielines any microvascular or macrovascular complications even when no treatment is given throughout life (C) (48). An important point is that these patients o not nee treating in the peiatric age range. There is very little, if any, response to either oral hypoglycemic agents or insulin (E). Exogenous insulin results in reuction of enogenous insulin secretion an so the egree of glycemia will be maintaine, explaining why these chilren can be treate with insulin without significant hypoglycemia. Genetic synromes associate with iabetes When iabetes in a chil is associate with other multi-system isease, the possibility of a monogenic synrome that explains all features shoul be consiere. The Online Menelian Inheritance in Man (OMIM) website [access via the National Center for Biotechnology Information (NCBI) website, nlm.nih.gov/entrez/query.fcgi] can help with clinical features an enables one to know if the gene has been efine an, hence, molecular genetic testing is available. For escribe an previously unescribe synromes, assistance can be obtaine through the International Society for Peiatric an Aolescent Diabetes (ISPAD) rare iabetes collection (access via the link on the ISPAD web page or through www. iabetesgenes.org). The most common genetic synromes which inclue iabetes are liste below: Diabetes insipius, iabetes mellitus, optic atrophy, eafness synrome (Wolfram synrome). Wolfram synrome is an autosomal recessive synrome in which the association of iabetes with progressive optic atrophy uner 16 yr of age is iagnostic (49). The synrome is more common in countries where consanguineous marriages are frequent. Other features are bilateral sensorineural eafness, iabetes insipius, ilate renal tracts, an truncal ataxia or more protean neurological signs, with the complete phenotype seen in 75% of patients, with increasing prevalence with age. The orer of appearance of the neurological symptoms may vary even within families. The meian age of eath in Wolfram synrome is 30 yr (49). Mutations in the gene for Wolfram synrome (WFS1) are present in at least 90% of patients with clinical Wolfram synrome (50 52). The iabetes is non-autoimmune, insulin eficient, an presents at a mean age of 6 yr (49). Patients require insulin treatment from the time of iagnosis, but autoantiboies are not present (C) (49). Thiamine-responsive megaloblastic anemia (Roger s synrome). Thiamine-responsive megaloblastic anemia is a rare, recessive genetic synrome of early-onset megaloblastic anemia (which respons to thiamine), an it is associate with iabetes an sensorineural eafness. This results from mutations in the gene SLC19A2 (53). The iabetes, which is insulin eficient in nature, is responsive to thiamine in some patients, although all seem to evelop an insulin requirement in the long term (C) (54). Deafness is unresponsive to thiamine. Renal cysts an iabetes synrome ue to a HNF-1b mutation. Although initially escribe as a subgroup of familial iabetes (MODY5), it is now clear that patients with mutations in HNF-1b rarely present with isolate iabetes (55). Renal evelopmental isorers, especially renal cysts an renal ysplasia, are present in almost all patients with mutations or gene eletions (56). They may be iagnose in utero an precee the iagnosis of iabetes (B). Other features which may be present in chilren inclue uterine an genitalia evelopmental anomalies, hyperuricemia, gout, an abnormal liver function tests (55). A iagnosis of HNF-1b shoul be consiere in any chil with iabetes who also has non-iabetic renal isease. Patients with HNF-1b mutations, unlike patients with HNF-1a mutations, are not sensitive to sulfonylureas an, therefore, usually require insulin treatment (57). Pancreatic size is reuce, reflecting a reuction in both the enocrine an exocrine pancreas, an subclinical exocrine eficiency is present in most patients (58), but it is uncertain if this shoul be treate if it is asymptomatic. Mitochonrial iabetes. Maternal transmission of mutate or elete mitochonrial DNA can result in maternally inherite iabetes, although they are not usually in the peiatric age range. Despite that several mutations an eletions have been implicate, the strongest evience relates to a point substitution at nucleotie position 3243 (A G) in the mitochonrial trna [leu (UUR)] gene (B) (59). An ientical mutation occurs in the mitochonrial myopathy, encephalopathy, lactic aciosis, an stroke-like synrome, an there may be some overlap between these synromes in family members. Mitochonrial iabetes is commonly associate with sensorineural eafness an short stature. The iabetes is characterize by progressive non-autoimmune b-cell failure an may progress to neeing insulin treatment rapily. Insulin-resistance synromes: type A insulin resistance, leprechaunism, Rabson Menenhall synrome an lipoystrophy. The key features of all insulin-resistance synromes are acanthosis nigricans, anrogen excess, an massively raise insulin concentrations in the absence of obesity (1). The more severe the insulin resistance an the earlier the onset, the more likely is iabetes (C) (1). A summary of some of the key clinical features is shown below [aapte from Musso et al. (1)] in Table 3. Treatment of severe insulin resistance is very ifficult. Most patients with iabetes have poor glycemic control an frequently evelop long-term Peiatric Diabetes 2006: 7:

22 Hattersley et al. Table 3. Characteristics of common insulin-resistance synromes Gene involve Insulin levels Anrogen excess an hypertrichosis Synrome Onset Clinical features Acanthosis nigricans Yes marke [[[, PCOS [[[ Insulin receptor, usually recessive Leprechaunism Congenital Abnormal facies, large genitalia, small for gestational age, an growth retaration; rarely survive infancy Yes marke [[, PCOS [[[ Insulin receptor, usually recessive Yes marke [[[, PCOS [[[ Insulin receptor, usually recessive [[, PCOS 1/2 [[ Total: seipin an AGPAT2 (recessive); partial: lamin AC an PPARG (ominant) Yes may be marke Rabson Menenhall Congenital Extreme growth retaration, abnormal entition Type A Aolescence Insulin resistance in absence of obesity Lipoystrophy Congenital or Loss of subcutaneous aolescence fat partial or total PCOS, polycystic ovarian synrome. complications(c) (1). Approaches use inclue the use of the insulin sensitizers, metformin, an glitazones, but their impact is limite when the insulin resistance is very severe. Insulin is the main stay of treatment, an 500 U insulin an insulin pumps are usually require (1). In partial lipoystrophy, metformin may have benefit an insulin is not require in the early stages (C) (60). In total lipoystrophy, the response of iabetes to recombinant lipoystrophy (61) can be ramatic but is only available on a research basis. Recommenations Avances in molecular genetics have le to the ientification of the genes associate with many clinically ientifie subgroups of iabetes. The ientification of genes has explaine clinical heterogeneity in conitions efine on the basis of when they were iagnose, e.g., neonatal iabetes an MODY. Now molecular genetics is being use as a iagnostic test which can help efine the iagnosis an treatment of chilren with iabetes. As these tests are expensive, genetic testing shoul be limite to those who on clinical grouns are likely to be positive (E). This article is a Chapter in the ISPAD Clinical Practice Consensus Guielines of the International society for peiatric an Aolescent iabetes (ISPAD, The complete set of these Guielines will later be publishe as a compenium. Aitional comments, clarifications or corrections shoul be irecte to the Corresponing Author. References 1. MUSSO C, COCHRAN E, MORAN SA et al. Clinical course of genetic iseases of the insulin receptor (type A an Rabson-Menenhall synromes): a 30-year prospective. Meicine (Baltimore) 2004: 83: MOLLER AM, DALGAARD LT, POCIOT F, NERUP J, HANSEN T, PEDERSEN O. Mutations in the hepatocyte nuclear factor-1alpha gene in Caucasian families originally classifie as having Type I iabetes. Diabetologia 1998: 41: LAMBERT AP, ELLARD S, ALLEN LI et al. Ientifying hepatic nuclear factor 1 alpha mutations in chilren an young aults with a clinical iagnosis of type 1 iabetes. Diabetes Care 2003: 26: IAFUSCO D, STAZI MA, COTICHINI R et al. Permanent iabetes mellitus in the first year of life. Diabetologia 2002: 45: TILLIL H, KOBBERLING J. Age-correcte empirical genetic risk estimates for first-egree relatives of IDDM patients. Diabetes 1987: 36: HATHOUT EH, SHARKEY J, RACINE M et al. Diabetic autoimmunity in infants an pre-schoolers with type 1 iabetes. Peiatr Diabetes 2000: 1: BORG H, MARCUS C, SJOBLAD S, FERNLUND P, SUNDKVIST G. Insulin autoantiboies are of less value compare with islet antiboies in the clinical iagnosis of autoimmune type 1 iabetes in chilren oler than 3 yr of age. Peiatr Diabetes 2002: 3: Peiatric Diabetes 2006: 7:

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24 Hattersley et al. 44. STOFFERS DA, FERRER J, CLARKE WL, HABENER JF. Early-onset type-ii iabetes mellitus (MODY4) linke to IPF1. Nat Genet 1997: 17: MALECKI MT, JHALA US, ANTONELLIS A et al. Mutations in NEUROD1 are associate with the evelopment of type 2 iabetes mellitus. Nat Genet 1999: 23: KRISTINSSON SY, THOROLFSDOTTIR ET, TALSETH B, et al. MODY in Icelan is associate with mutations in HNF- 1alpha an a novel mutation in NeuroD1. Diabetologia 2001: 44: RAEDER H, JOHANSSON S, HOLM PI et al. Mutations in the CEL VNTR cause a synrome of iabetes an pancreatic exocrine ysfunction. Nat Genet 2006: 38: VELHO G, BLANCHE H, VAXILLAIRE M et al. Ientification of 14 new glucokinase mutations an escription of the clinical profile of 42 MODY-2 families. Diabetologia 1997: 40: BARRETT TG, BUNDEY SE, MACLEOD AF. Neuroegeneration an iabetes: UK nationwie stuy of Wolfram (DIDMOAD) synrome. Lancet 1995: 346: STROM TM, HORTNAGEL K, HOFMANN S et al. Diabetes insipius, iabetes mellitus, optic atrophy an eafness (DIDMOAD) cause by mutations in a novel gene (wolframin) coing for a preicte transmembrane protein. Hum Mol Genet 1998: 7: INOUE H, TANIZAWA Y, WASSON J et al. A gene encoing a transmembrane protein is mutate in patients with iabetes mellitus an optic atrophy (Wolfram synrome). Nat Genet 1998: 20: HARDY C, KHANIM F, TORRES R et al. Clinical an molecular genetic analysis of 19 Wolfram Synrome kinres emonstrating a wie spectrum of mutations in WFS1. Am J Hum Genet 1999: 65: LABAY V, RAZ T, BARON D et al. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associate with iabetes mellitus an eafness. Nat Genet 1999: 22: OZDEMIR MA, AKCAKUS M, KURTOGLU S, GUNES T, TORUN YA. TRMA synrome (thiamine-responsive megaloblastic anemia): a case report an review of the literature. Peiatr Diabetes 2002: 3: BINGHAM C, HATTERSLEY AT. Renal cysts an iabetes synrome resulting from mutations in hepatocyte nuclear factor-1{beta}. Nephrol Dial Transplant 2004: 19: BELLANNE-CHANTELOT C, CLAUIN S, CHAUVEAU D et al. Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset iabetes of the young type 5. Diabetes 2005: 54: PEARSON ER, BADMAN MK, LOCKWOOD CR et al. Contrasting iabetes phenotypes associate with hepatocyte nuclear factor-1alpha an -1beta mutations. Diabetes Care 2004: 27: BELLANNE-CHANTELOT C, CHAUVEAU D, GAUTIER JF et al. Clinical spectrum associate with hepatocyte nuclear factor- 1beta mutations. Ann Intern Me 2004: 140: VAN DEN OUWELAND JM, LEMKES HH, RUITENBEEK W et al. Mutation in mitochonrial trna (Leu) (UUR) gene in a large peigree with maternally transmitte type II iabetes mellitus an eafness. Nat Genet 1992: 1: OWEN KR, DONOHOE M, ELLARD S, HATTERSLEY AT. Response to treatment with rosiglitazone in familial partial lipoystrophy ue to a mutation in the LMNA gene. Diabet Me 2003: 20: PETERSEN KF, ORAL EA, DUFOUR S et al. Leptin reverses insulin resistance an hepatic steatosis in patients with severe lipoystrophy. J Clin Invest 2002: 109: Peiatric Diabetes 2006: 7:

25 Peiatric Diabetes 2007: 8: All rights reserve # 2007 The Authors Journal compilation # 2007 Blackwell Munksgaar Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Diabetes eucation Swift PGF. Diabetes eucation. Peiatric Diabetes 2007: 8: Peter GF Swift Corresponing author: Peter GF Swift, Chilrens Hospital, Leicester Royal Infirmary, Leicester, UK. Tel: ; [email protected] Acknowlegements: Karen Cullen, Julie Knowles, Kath Price, Sherian Walron Eitors of the ISPAD Clinical Practice Consensus Guielines ; Kim Donaghue, Ragnar Hanas, Georgeanna Klingensmith, Peter GF Swift Eucation is the keystone of iabetes care an structure self-management euction is the key to a successful outcome. Aapte from ISPAD Consensus Guielines 2000 (1). National peiatric guielines emphasize the importance of eucation but o not inclue specific chapters on eucation an eucational principles (2 5). Publications that provie useful guielines on eucation in iabetes inclue National Stanars for Diabetes Self-management Eucation (6), Position Statement on Structure Eucation (7), Guiance on the Use of Patient-Eucation Moels for Diabetes (8), an the International Curriculum for Diabetes Health Professional Eucation (9). A efinition of Diabetes Eucation has been propose: The process of proviing the person with the knowlege an skills neee to perform iabetes selfcare, manage crises an to make lifestyle changes to successfully manage the isease. (10) Eucation may be seen as an interface between clinical practice an research. Research into iabetes an eucational methos is important in improving clinical practice (2, 5, 6, 10, 11), an this shoul be the responsibility of each nation/state an be a national priority (7, 12). Eucational programs must be carefully planne an have specific aims an learning objectives, which are share with people with iabetes, carers, an their families (8). It has remaine contentious whether eucational interventions per se are beneficial in iabetes care, particularly in chilren an aolescents because eucational, psychosocial an psychotherapeutic interventions are frequently combine for the purpose of improving knowlege, skills an self-efficacy across various aspects of iabetes self-management (13). Nevertheless, systematic reviews of psychoeucational interventions conclue that they have small to meium beneficial effects on glycemic control (13, 14) an somewhat greater effect on psychological outcomes (15). The effects are greater for chilren than for aults (15) an are most effective when integrate into routine care, when parents are involve, empowerment principles are involve, an problem solving, goal setting, an self-efficacy are promote (14, 16). The Diabetes Control an Complications Trial provie unequivocal evience that intensification of management reuces microvascular complications an that intensification requires effective iabetes selfmanagement. Most importantly, effective self-management requires frequent an high levels of eucational input an continuing support (6, 10, 11, 17, 18). Relate to this is evience that health care professionals engage in eucation who are perceive by young people as being motivating may encourage greater aherence to therapy (19). This high level of motivation an enthusiasm in eucational intervention is likely to improve biomeical outcomes by itself an makes interpretation of eucational research a complex science (20). In contrast, those people who o not receive eucation or o not continue to have eucational contacts are more likely to suffer iabetes-relate complications (6, 18, 21, 22). It is a concern, however, that parents an aolescents often express satisfaction about services receive (5) even when there may be large gaps in eucation, psychological support, an self-management techniques accounting for relatively unsatisfactory an variable metabolic control (23). 103

26 Swift Universal principles Every young person has a right to comprehensive expert structure eucation which shoul empower them an their families to take control of their iabetes. (1, 5, 7) Chilren an aolescents, their parents, an other care proviers shoul all have easy access to an be inclue in the eucational process (5). Diabetes eucation shoul be elivere by health care professionals with a clear unerstaning of the special an changing nees of young people an their families as they grow through the ifferent stages of life (1). Diabetes eucation nees to be aaptable an personalize so that it is appropriate to each iniviual s age, stage of iabetes, maturity, an lifestyle; culturally sensitive; an at a pace to suit iniviual nees (1, 2, 4, 5). The priorities for health care professionals in iabetes eucation may not match those of the chil an family. Thus, iabetes eucation shoul be base on a thorough assessment of the person s attitues, beliefs, learning style, ability an reainess to learn, existing knowlege, an goals (1). Eucators (octors, nurses, ieticians, an other health care proviers) shoul have access to continuing specialize training in iabetes eucation an eucational methos (2, 6, 7, 9, 10). Diabetes eucation nees to be a continuous process an repeate for it to be effective (2, 4, 5, 8 10). Content an organization of eucation program It is wiely accepte that iabetes cannot be successfully manage without behavioral moification (24, 25). Health professionals nee to unerstan that eucation per se with acquisition of knowlege is unlikely to alter behavior, particularly in those iniviuals where iabetes appears to be overwhelmingly ifficult. There is, therefore, a nee for training the iabetes team not only in the principles of teaching an structure eucation but also in behavioral change management, incluing counselling techniques (24 26). The importance of structure eucation (7) programs is consiere in a variety of contexts, an there is evience, mainly from ault iabetes, that it is more effective than informal unstructure eucation in improving metabolic control (11, 13 16, 27, 28). In peiatric iabetes, structure eucational programs have been less well publicize, an because of the nature of the problems, have focuse more on psychosocial interventions. The evience for efficacy of these interventions, nearly all from North America, has been extensively reviewe in various texts (13 16) but some others are in an early stage of evelopment (29). There are four key criteria that characterize a structure eucational program (7): (i) has a structure, agree, written curriculum; (ii) uses traine eucators; (iii) is quality assure; (iv) is auite. To put this into practice, it has been recommene that (1 8): Structure eucation shoul be available to all people with iabetes at the time of initial iagnosis, or when it is appropriate for them, an then as require on an ongoing basis, base on a formal, regular iniviual assessment of nee. Eucation shoul be provie by an appropriately traine interisciplinary team: the team shoul have a soun unerstaning of the principles governing teaching an learning. Interisciplinary teams proviing eucation shoul inclue, as a minimum, a iabetes specialist nurse an a ietician. Sessions shoul be hel in a location accessible to iniviuals an families, whether in the community or in the inpatient center. Eucational programs shoul use a variety of teaching techniques, aapte wherever possible to meet the ifferent nees, personal choices, learning styles of young people with iabetes an parents, as well as local moels of care. The principles of eucation in chilren (Table 1) have been aapte from iscussions with teachers an reference (29). Moreover, the principles that govern quality in teaching shoul be recognize by iabetes eucators (Table 2) (29, 30). Specifically in iabetes care, the following guielines (1) may act as a template on which to evelop an appropriate eucational curriculum an, inee, they have been quote extensively elsewhere (2, 4, 5). Primary (level 1) eucation At iagnosis: survival skills (i) Explanation of how the iagnosis has been mae an reasons for symptoms; (ii) Simple explanation of the uncertain cause of iabetes. No cause for blame; (iii) The nee for immeiate insulin an how it will work; (iv) What is glucose? Normal bloo glucose (BG) levels an glucose targets; 104 Peiatric Diabetes 2007: 8:

27 ISPAD guielines Table 1. Principles an practice of eucation in chilren 1. Motivation The learner nees to an/or have a esire to learn 2. Context Where is the learner now? Where oes the learner want to be later? 3. Environment Learner centere, comfortable, trusting Enjoyable/entertaining/interesting/ open 4. Significance Meaningful, important, links or joins up Rewar or gain 5. Concepts Simple to complex in gentle steps (short attention span) 6. Activity Constantly interactive Practical (fitting into real life) Goal setting an problem solving 7. Reinforcement Repetition, review, summarize 8. Reassess, evaluate, auit 9. Move forwar (continuing eucation) (v) Practical skills: insulin injections; bloo an/or urine testing an reasons for monitoring; (vi) Basic ietetic avice; (vii) Simple explanation of hypoglycemia; (viii) Diabetes uring illnesses. Avice not to omit insulin prevent iabetic ketoaciosis; (ix) Diabetes at home or at school incluing the effects of exercise; (x) Ientity cars, necklets, bracelets, an other equipment; (xi) Membership of a Diabetes Association an other available support services; (xii) Psychological ajustment to the iagnosis; (xiii) Details of emergency telephone contacts. Methos of elivering primary levels of eucation an the use of eucational resources will epen on local experience an facilities. It will be ominate initially by iniviual (family) teaching. Health professionals shoul learn to incorporate an eliver the eucation using behavioral approaches, which are learner centere an not iactic (24, 31, 32). Initial learning shoul be reinforce by written guielines an booklets, which shoul be appropriate to the chil s age an maturity (see Appenix Resource). Written materials for parents shoul use appropriate language an a style that is easily comprehensible (it is suggeste that this shoul be at the level of a popular local or tabloi newspaper). Seconary (level 2) continuing eucational curriculum Continuing curriculum (i) Pathophysiology, epiemiology, classification, an metabolism; (ii) Insulin secretion, action, an physiology; (iii) Insulin injections, types, absorption, action profiles, variability, an ajustments; (iv) Nutrition: foo plans; qualitative an quantitative avice on intake of carbohyrate, fat, proteins an fiber; coping with special events an eating out; growth an weight gain; iabetic foos ; sweeteners an rinks; (v) Monitoring, incluing glycate hemoglobin an clear (agree) targets of control; (vi) Hypoglycemia an its prevention, recognition, an management incluing glucagon; (vii) Intercurrent illness, hyperglycemia, ketosis, an prevention of ketoaciosis; (viii) Problem solving an ajustments to treatment; (ix) Goal setting; (x) Micro- an macrovascular complications an their prevention. The nee for regular assessment; (xi) Exercise, holiay planning, an travel, incluing eucational holiays an camps; (xii) Smoking, alcohol, an rugs; (xii) School, college, employment, an riving vehicles; Table 2. Qualities looke for by the UK Office for Stanars in Eucation, OFSTED (29, 30) Lessons shoul be purposeful with high expectations conveye Learners shoul be given some opportunities to organize their own work (overirection by teachers nees to be guare against) Lessons shoul elicit an sustain learners interest an be perceive by pupils to be relevant an challenging The work shoul be well matche to the learners abilities an learning nees Learners language shoul be evelope an extene (teachers questioning skills play a part here) A variety of learning activities shoul be use Goo orer an control shoul be largely base on skilful management of learner s involvement in the lesson an mutual respect Peiatric Diabetes 2007: 8:

28 Swift (xiv) Sexuality, contraception, pregnancy, an chilbirth; (xv) Upates on research. Continuing eucation will take place most often in an ambulatory (outpatient, omiciliary, community) setting (2, 4, 5, 33). Where staffing levels, expertise, an local circumstances o not permit this, eucational programs may be carrie out in the hospital environment, either by iniviual teaching or in groups an, whenever possible, in a protecte environment conucive to learning (33, 34). The eucational program shoul utilize appropriate patient-centere, interactive teaching methos for all people involve in the management of iabetes, particularly the affecte chil or aolescent (33). Higher levels of iabetes eucation shoul be groune in a realistic unerstaning of self-management as both eucational an psychosocial issues are important eterminants of success (13, 29, 33). Newer technology may be attractive to young people incluing vieos, CDs, computer games, text messaging for information (35), telephone reminers an support (36) but is use most effectively in interactive moes (5, 8, 13, 16). Group eucation may be more cost-effective an enhance by peer group (27, 28, 33) or school frienships (29), although there is evience that eucation irecte at iniviual nees is equally effective as group eucation (5, 8, 37). There is anecotal evience that benefit may be gaine from participation in organize Diabetes Association meetings an in holiay or camping experiences (38, 39). Evience from group iscussions with young people suggest that eucation using these newer technologies is attractive, but there is little scientific evience to support its wiesprea use (5). In contrast, traitional, intensive, iniviualize outpatient eucation in specialize clinics has been shown in some situations to prouce excellent results in terms of glycemic control (40, 41). When eucation is viewe as an important factor in empowerment, both for parents an aolescents, it shoul enable young people to use knowlege an practical skills in problem solving an self-care to be in control of goal setting for better care an to have influence over their own lives in making informe ecisions about their iabetes (31, 32, 42, 43). Matching an ajusting insulin profiles to quantifie foo intake an exercise levels have become an important part of moern intensifie management with multiple injection treatment, the availability of analogue insulins, an infusion pumps. Higher levels of eucation an unerstaning are require for these interventions to be successful an require more time, skill, an greater resources from the eucational team (41, 44, 45). Changing insulin regimens per se oes not improve metabolic control (11, 23). In contrast, by aressing the total management package utilizing comprehensive structure eucation, there is more likelihoo of success (6, 7, 13 18, 27, 28, 46), especially if the eucators are highly motivate (20). Eucation an age group Diabetes eucation nees to be aaptable an appropriate to each iniviual s age an maturity (1, 47). Infants an tolers Total epenence on parents an care proviers for injections, foo, an monitoring an the requirement of a trusting attachment between infant an caregivers (48); Mothers may feel increase stress, iminishe boning, an epressive feelings (48, 49), but this applies to many chronic iseases (50); Unpreictable erratic eating an activity levels; Difficulties in istinguishing normal infant behavior from iabetes-relate moo swings (49); Injections an BG checks seen as pain inflicte by caregivers (49); Hypoglycemia is more common. Severe hypoglycemia may be more harmful (see chapter on Hypoglycemia). Eucation on prevention, recognition, an management is therefore a priority. Age-specific targets for BG shoul be iscusse (see chapter on Monitoring). There is conflicting evience on the behavioral characteristics of preschool chilren with iabetes (48, 51) an whether iabetes outcomes epen on eucation per se. But parents report the importance of eucation an nonjugmental support from a team (49, 52). School-age chilren Ajusting to the change from home to school, eveloping self-esteem, an peer relationships (47, 53); Learning to help with an eveloping skills in injections an monitoring; Progressive recognition an awareness of hypoglycemic symptoms (54); Increasing unerstaning an self-management; Aapting iabetes to school programs, school meals, exercise, an sport (53); Incluing monitoring of BG levels an injections in the school setting; 106 Peiatric Diabetes 2007: 8:

29 ISPAD guielines Avising parents on the graual evelopment of the chil s inepenence, with progressive stepwise han over of appropriate responsibilities (1, 47). School-age chilren have expresse issatisfaction that health professionals talk to parents an not to them (5). There is some evience that focuse ageappropriate eucational interventions are effective in chilren an families (5, 13, 14, 16, 47, 55). Aolescents (See chapter on Aolescence for references) Accepting the critical role of continue parental involvement an yet promoting inepenent, responsible self-management appropriate to the level of maturity an unerstaning; Unerstaning that knowlege about iabetes in aolescents is preictive of better self-care an (metabolic) control, but the association is moest; Discussing emotional an peer group conflicts; Teaching problem-solving strategies for ealing with ietary iniscretions, illness, hypoglycemia, sports, smoking, alcohol, rugs, an sexual health; Negotiating targets, goals, an priorities an ensuring that the tasks taken on by the aolescent are unerstoo, accepte, an achievable; Unerstaning that omission of insulin is not uncommon. The opportunity shoul be graspe for nonjugmental iscussion about this; Developing strategies to manage transition to ault services. Summary an recommenations Eucation is the key to successful management of iabetes (1 10). (E) There is evience that eucational interventions in chilhoo an aolescent iabetes have a moestly beneficial effect on glycemic control an a stronger effect on psychosocial outcomes (13 16). (A) To maximize the effectiveness of both conventional iabetes treatment an the avances in iabetes management an technology (especially self-monitoring of BG, analogue insulins, an insulin pumps), it is avisable that quality-assure structure eucation is available to all young people with iabetes an their caregivers (2, 4, 5, 7). (E) Health care professionals require appropriate specialize training in the principles an practice of teaching an eucation (24, 26, 29, 30) to implement successfully behavioral approaches to eucation esigne to empower young people an caregivers in promoting self-management (24, 31, 32). (E,C) The content an elivery of structure eucation nee regular review to enable it to evolve to suit iniviuals, local practice, an the changes in iabetes management an technology (2, 6, 7, 10, 16). (E) Eucational interventions that have been shown to be most effective are most likely tobe base on clear theoretical psychoeucational principles (13 16) (A) be integrate into routine clinical care (e.g., as an ajunct to intensive insulin management) (13, 14, 16, 44, 45) (A,C) involve the continuing responsibility of parents an other caregivers throughout aolescence (4, 5, 29, 33, 55) (B) make use of cognitive behavioral techniques most often relate to problem solving, goal setting, communication skills, family conflict resolution, coping skills, an stress management (13 16) (A) utilize new technologies in iabetes care as one of the vehicles for eucational motivation (13, 16, 35, 36) (A). Evaluation of eucational programs is essential an shoul focus on outcomes such as the patient s achievement of self-selecte iabetes care goals, improve psychosocial aaptation, an enhance selfefficacy in aition to glycemic control (13 16) (E). This article is a Chapter in the ISPAD Clinical Practice Consensus Guielines of the International Society for Peiatric an Aolescent Diabetes (ISPAD, The complete set of these Guielines will later be publishe as a compenium. Aitional comments, clarifications, or corrections shoul be irecte to the Corresponing Author. The evience graing system use in the ISPAD Guielines is the same as that use by the American Diabetes Association. See the Introuction of the ISPAD Clinical Practice Consensus Guielines. Peiatric Diabetes 2006: 7: References 1. ISPAD CONSENSUS GUIDELINES. The Management of Type 1 Diabetes in Chilren an Aolescents. Swift PGF, e. Zeist, The Netherlans: Publ Meforum, SILVERSTEIN J, KLINGENSMITH G, COPELAND K et al. Care of chilren an aolescents with type 1 iabetes: a statement of the American Diabetes Association (ADA Statement). Diabetes Care 2005: 28: Type 1 iabetes in chilren an aolescents, Canaian Diabetes Association e-guielines [WWW ocument] URL 4. AUSTRALIAN PAEDIATRIC ENDOCRINE GROUP. Clinical practice guielines: Type 1 iabetes in chilren an aolescents [WWW ocument] URL hanbook_final.pf 5. NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE UK (NICE). Type 1 iabetes: iagnosis an management of type 1 iabetes in chilren, young people an aults [WWW ocument] URL pf/cg015niceguieline.pf Peiatric Diabetes 2007: 8:

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Cheltenham, UK: Nelson Thornes Lt: ANDERSON RM, FUNNELL M, CARLSON A, SALEH-STATIN N, CRADOCK S, SKINNER TC. Facilitating self-care through empowerment, chapter 4. In: Snoek FJ, Skinner TC, es. Psychology in Diabetes Care. Chichester, UK: John Wiley, 2000: ANDERSON RM, FUNNELL M, BUTLER P, ARNOLD MS, FITZGERALD JT, FESTE C. Patient empowerment: results of a ranomise control trial. Diabetes Care 1995: 18: VON SENGBUSCH S, MULLER-GODEFFROY E, HAGER S et al. Mobile iabetes eucation an care: intervention for chilren an young people with type 1 iabetes in rural areas of northern Germany. Diabet Me 2005: 23: FORSANDER GA, SUNDELIN J, PERSSON B. Influence of the initial management regimen an family social situation on glycemic control an meical care in chilren with type 1 iabetes. Acta Paeiatr 2000: 89: FRANKLIN VL, WALLER A, PAGLIARI C, GREENE SA. A ranomize controlle trial of Sweet Talk, a textmessaging system to support young people with iabetes. Diabet Me 2006: 23: HOWELLS L, WILSON AC, SKINNER TC et al. A ranomize control trial of the effect of negotiate telephone support on glycaemic control in young people with Type 1 iabetes. Diabet Me 2002: 19: RICKHEIM PL, WEAVER TW, FLADER JL, KENDALL DM. Assessment of group versus iniviual iabetes eucation: a ranomize stuy. Diabetes Care 2002: 25: SWIFT PGF, WALDRON S. Have iabetes, will travel. Pract Diabetes 1990: 7: VYAS S, MULLEE MA, KINMONTH A-L. British Diabetic Association. Holiays what are they worth? Diabet Me 1987: 5: DORCHY H. Insulin regimens an insulin ajustments in young iabetic chilren, aolescents an young aults: personal experience. Diabetes Metab (Paris) 2000: 26: NORDFELDT S, LUDVIGGSON J. Severe hypoglycemia in chilren with IDDM: a prospective population stuy. Diabetes Care 1997: 20: WILLIAMS GC, FREEDMAN ZR, DECI EL. Supporting autonomy to motivate patients with iabetes for glucose control. Diabetes Care 1998: 21: Peiatric Diabetes 2007: 8:

31 ISPAD guielines 43. ANDERSON RM, FITZGERALD JT, FUNNELL M, FESTE C. Diabetes Empowerment Scale (DES): a measure of psychosocial efficacy. Diabetes 1997: 46: 269A. 44. GREY M, BOLAND EA, DAVIDSON M et al. Coping skills training for youth with iabetes mellitus has longlasting effects on metabolic control an quality of life. J Peiatr 2000: 137: BOLAND EA, GREY M, OESTERLE A et al. Continuous subcutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, an enhance coping in aolescents with type 1 iabetes. Diabetes Care 1999: 22: DEAKIN TA, CADE JE, WILLIAMS R et al. Structure patient eucation: the iabetes X-PERT Programme makes a ifference. Diabet Me 2006: 23: FOLLANSBEE DS. Assuming responsibility for iabetes management: what age? What price? Diabetes Euc 1989: 15: WYSOCKI T, HUXTABLE K, LINSCHEID TR, WAYNE W. Ajustment to iabetes mellitus in preschoolers an their mothers. Diabetes Care 1989: 12: HATTON DL, CANAM C, THORNE S, HUGHES AM. Parents perception of caring for an infant or toler with iabetes. J Av Nurs 1995: 22: EISER C. Chronic Chilhoo Disease: An Introuction to Psychological Theory an Research. New York: Cambrige University Press, NORTHAM E, ANDERSON P, ADLER R, WERTHER G, WARNE G. Psychosocial an family functioning in chilren with insulin-epenent iabetes at iagnosis an one year later. J Peiatr Psychol 1996: 21: KUSHION W, SALISBURY PJ, SEITZ KW, WILSON BE. Issues in the care of infants an tolers with insulinepenent iabetes mellitus. Diabetes Euc 1991: 17: Diabetes care in the school an ay care setting. ADA Position Statement. Diabetes Care 2004: 27(Suppl. 1): S GONDER-FREDERICK L, COX D, KOVATCHEV B et al. A biopsychobehavioral moel of risk of severe hypoglycemia. Diabetes Care 1997: 20: LAFFEL LM, VANGSNESS L, CONNELL A et al. Impact of ambulatory, family-focuse teamwork intervention on glycemic control in youth with type 1 iabetes. J Peiatr 2003: 142: Appenix Resource In aition to the references in the text, several other sources of further reaing an information may be useful 1. IDF Diabetes Eucation moules. To view or orer free book an CD-ROM with teaching slies, 2. Structure Patient Eucation. Guiance booklet from the Patient Eucation Working Group, 3. Diabetes Eucation Stuy Group of the European Association for the Stuy of Diabetes (EASD). See Basic Curriculum for Health Professionals on Diabetes Therapeutic Eucation, 4. Psychology in Diabetes Care. Snoek FJ, Skinner TC, es. Eitions 1 (2000) an 2 (2005). Chichester, UK: John Wiley & Sons. See Chapters on Chilren; Aolescents; Behaviour Change, 5. Hanas R. Type 1 Diabetes in Chilren, Aolescents an Young Aults: How to Become an Expert on Your Own Diabetes, 3r en. Lonon: Class Publishing, or 6. Peter Chase H. Unerstaning Diabetes, 11th en Daneman D, Frank M, Perlman K. When a chil has iabetes. In association with Canaian Diabetes Association A valuable resource for families an professionals: Peiatric Diabetes 2007: 8:

32 Peiatric Diabetes 2007: 8: All rights reserve # 2007 The Authors Journal compilation # 2007 Blackwell Munksgaar Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Insulin treatment Bangsta H-J, Danne T, Deeb LC, Jarosz-Chobot P, Urakami T, Hanas R. Insulin treatment. Peiatric Diabetes 2007: 8: Hans-Jacob Bangsta a Thomas Danne b Larry C Deeb c Przemyslawa Jarosz-Chobot Tatsuhiko Urakami e an Ragnar Hanas f a Department of Peiatrics, Ulleval University Hospital, Oslo, Norway b Kinerkrankenhaus auf er Bult, Diabetes-Zentrum fur Kiner un Juenliche, Hannover, Germany c Department of Peiatrics, University of Floria College of Meicine, Tallahassee, FL, USA Department of Peiatric Enocrinology an Diabetes, Katowice, Polan e Department of Peiatrics, Nihon University School of Meicine, Tokyo, Japan f Department of Peiatrics, Uevalla Hospital, Uevalla, Sween Corresponing author: Ragnar Hanas, MD, PhD, Department of Peiatrics, Uevalla Hospital, S Uevalla, Sween. Tel: ; fax: ; [email protected] Eitors of the ISPAD Clinical Practice Consensus Guielines : Ragnar Hanas, Kim Donaghue, Georgeanna Klingensmith, an Peter Swift Insulin therapy starte in 1922 using regular insulin before each main meal an one injection at night, usually at 1 AM. With the evelopment of intermeiatean long-acting insulin, most patients move to one or two injections per ay after By 1960, a stuy showe that patients who were iagnose between 1935 an 1945 an using one or two injections per ay ha a much higher risk of retinopathy after 15 yr of iabetes compare with those iagnose before 1935 using multiple aily injections (MDI) (61 vs. 9%) (1) (C). There are no ranomize controlle stuies comparing the longer term outcomes of using oler more traitional insulins with newer regimens when both groups receive equal eucational input. But the fact that the traitional insulins have certain clinical limitations has le to the evelopment of new analogues, rapi an long acting. These insulins represent some improvement in the care of iabetes, but the extent of benefit in a clinical long-term setting is not fully establishe. Data in aults are not reaily transferable to peiatric patients of ifferent age-groups (2), but in chilren an aolescents, as in aults (3) (A), rapi-acting insulin (aspart) is rapily absorbe an eliminate (4). Higher maximum insulin concentrations in aolescents vs. chilren were reporte both for insulin aspart an for human regular insulin (5) (A) but not with glulisine (6) (A). The results from one stuy (5) are in-line with the relatively impaire insulin sensitivity 88 an higher insulin concentrations reporte in healthy aolescents (7, 8) (B). Such finings highlight the necessity to stuy the effects of these new insulins in all age-groups separately. The ifferent rapi-acting analogues have ifferent chemical properties, but no significant ifference in time of action an uration has been reporte (9). Their avantages compare with regular (soluble) insulin are still uner ebate. The Cochrane review from 2006 state that in patients with type 1 iabetes mellitus (T1DM), the weighte mean ifference (WMD) of hemoglobin A1c (HbA1c) was 20.1% in favor of insulin analogue [20.2% when using continuous subcutaneous insulin infusion (CSII)] (10) (A). In chilren an aolescents, bloo glucose control has not been shown to be significantly improve with these analogues (10 14) (A). A reuction in hypoglycemia has been reporte, both for lispro (11, 12, 15) (A) (16) (B) an for aspart (17, 18) (A). In the Cochrane review, the WMD of the overall mean hypoglycemic episoes per patient per month was 20.2 (95% confience interval: 21.1 to 0.7) (10) in favor of rapi-acting insulin analogues. In aolescents, a significantly reuce rate was foun with analogues (14), but no ifference was foun in prepubertal chilren (11, 13). The meian incience of severe hypoglycemia for aults was 26.8 episoes/100 patient years vs for regular insulin (10) (A). In the

33 inclue peiatric stuies, there was no ifference foun in prepubertal chilren (10, 11) or aolescents (14). The basal insulin analogues have ifferent moes of action. Insulin glargine is a clear insulin, which precipitates in situ after injection, whereas insulin etemir is acylate insulin boun to albumin. These analogues have reuce ay-to-ay variability in absorption compare with neutral protamine Hageorn (NPH) insulin, with etemir having the lowest within-subject variability in one stuy (19) (A). So far, the reuction in hypoglycemia but not in HbA1c is the most prominent feature (20) (A), both for glargine (21 24) (A) (25) (B) (26, 27) (C) an for etemir (28, 29) (A) (30) (B) (31) (C). Parental fear of severe hypoglycemia, especially at nighttime, is an impeiment to achieving morning bloo glucose control. Lower boy mass inex (z-score) has been reporte for etemir (29) (C). In ranomize trials, better bloo glucose control has been obtaine using MDI an pumps compare with a twice aily treatment (32, 33). The Diabetes Control an Complications Trial (DCCT) prove convincingly that intensive insulin therapy, incluing a heavy multiisciplinary approach in aolescents with multiple injections or pumps, resulte in a lower rate of long-term complications (33) (A). A further analysis showe that even when comparing patients with the same HbA1c levels, intensive insulin therapy with MDIs or CSII resulte in fewer complications, especially at higher levels of HbA1c (34) (A). Although this has not been stuie in the same way in younger chilren, there is reason to believe that the results apply also to them, limite only by the risk of increasing the risk of severe hypoglycemia (E). However, in a cross-sectional clinical setting, HbA1c, hypoglycemia, an iabetic ketoaciosis (DKA) were not associate with the number of injections per ay in peiatric populations (35) (B). Insulin pump therapy is at present the best way to imitate the physiological insulin profile. Insulin is infuse subcutaneously at a preprogramme basal rate an boluses are ae to counterbalance the intake of carbohyrates. CSII has mostly been compare with MDI with NPH as the long-acting insulin (36, 37) (A) (38 40) (B) (41 46) (C). A reuction in hypoglycemia an improve bloo glucose control has been reporte. One ranomize stuy has recently confirme these finings when glargine was the basal insulin in use (47) (B). Several stuies have compare the use of analogues an regular insulin in pumps (48) (A) (12) (B). Insulin pumps from the onset have been foun to result in superior metabolic control when compare with one to two injections per ay (32) (A) but not with MDI (49) (C). However, in the stuy comparing MDI with CSII, iabetes treatment satisfaction was higher with CSII (50) (C). Unequivocal evience for the benefit of MDI, the analogues, an CSII treatment in chilren is lacking. Carefully structure ranomize stuies are neee. The fact that these moalities are more expensive than conventional treatment has been an obstacle to the implementation of the use of them in many countries. This implies that the new practical recommenations of the International Society for Peiatric an Aolescent Diabetes (ISPAD) have to be applicable for the total iabetes community worlwie. The DCCT stuy an its follow-up Epiemiology of Diabetes Interventions an Complications (EDIC) stuy confirme that an improvement in long-term glucose control, as obtaine with intensifie insulin therapy, incluing heavy support an eucation, can reuce the incience of complications an elay the progression of existing complications in T1DM, also in peiatric patients (33, 50, 51) (A). A rapily increasing numbers of centers aroun the worl are introucing the basal-bolus concept of intensive insulin treatment alreay from the onset of iabetes. Improvements in glycemic control, particularly when provie by intensive insulin treatment with MDI or pump therapy, reuce the risks of vascular complications (A). There is no reason to believe that this is not the case also in younger chilren (E). In all age-groups, as close to physiological insulin replacement as possible an optimal glycemic control must be the aim; the attainment of this aim shoul inclue the consieration of an intensive insulin regimen (E). Insulin availability ) Chilren an aolescents with T1DM are epenent on insulin for survival an shoul have access to aequate amounts of at least regular an NPH insulin. ) ISPAD an the International Diabetes Feeration are working towars making insulin available for all chilren an aolescents with iabetes an promoting universal insulin labeling. Insulin treatment must be starte as soon as possible after iagnosis (usually within 6 h if ketonuria is present) to prevent metabolic ecompensation an DKA (A). Insulin formulation an species Consensus Guielines ) Many formulations of insulin are available; most have some role in the management of T1DM (Table 1). ) Currently, chilren are prescribe human insulins instea of porcine or bovine insulin because of low immunogenicity, but in many countries, these are being supercee by analogues. Peiatric Diabetes 2007: 8:

34 Bangsta et al. Table 1. Types of insulin preparations an suggeste action profiles accoring to the manufacturers Insulin type Onset of action (h) Peak of action (h) Duration of action (h) Rapi-acting analogues (aspart, glulisine, an lispro) Regular/soluble (short-acting) Intermeiate-acting analogues Semilente (pork) NPH IZS lente type Basal analogues Glargine 2 4 None 24* Detemir Long-acting analogues Ultralente type IZS, insulin zinc suspension; NPH, neutral protamine Hageorn insulin. *The uration of action may be shorter than 24 h (65) (A). ) Porcine or bovine preparations may be cheaper an more reaily available in some parts of the worl. They are not inferior in clinical efficacy to human insulins (52) (A). Some locally manufacture preparations have greater immunogenicity, an high titer antiboies may alter pharmacoynamics by acting as insulin-bining proteins. This is particularly relevant when using oler bovine insulins. However, animal species insulins are being withrawn from the market, an major manufacturers are moving towars prouction of analogue insulins only. At the same time, the prouction of zinc-containing insulin (lente) is about to be terminate by the largest insulinproucing companies. The time action of most insulins is ose epenent in that a smaller ose has a shorter uration of effect an earlier peak (53, 54) (C) an (E). There is some evience that lispro (55) an aspart (56) (C) have the same time action irrespective of ose. The results of these stuies are obtaine from a relatively small number of ault subjects, an the results in chilren may result in ifferent profiles of action. Regular insulin (short acting) ) Regular soluble insulin (usually ientical to human insulin) is still use as an essential component of most aily replacement regimens in many parts of the worl either combine with: intermeiate-acting insulin in twice aily regimen or as premeal bolus injections in basal-bolus regimens (given min before meals) together with intermeiate-acting insulin twice aily or a basal analogue given once or twice aily. Rapi-acting insulin analogues Several novel insulin analogues have been evelope. Three rapi-acting types are currently available for chilren (aspart, glulisine, an lispro). They have a rapi onset an shorter uration of action than regular insulin (Table 1). The rapi-acting analogues: Can be given immeiately before meals because there is evience that the rapi action not only reuces postpranial hyperglycemia but nocturnal hypoglycemia may also be reuce (11, 12, 15) (A) (16) (B). Offer the useful option of being given after foo when neee (e.g., infants an tolers who are reluctant to eat) (57) (B). Give a quicker effect than regular insulin when treating hyperglycemia, with or without ketosis, incluing sick ays (E). Are most often use as pranial or snack boluses in combination with longer acting insulins (see basal-bolus regimens). Are most often use in insulin pumps. Intravenous insulin Regular insulins are best suite for intravenous (i.v.) therapy an are use in the following crisis situations: DKA. Control of iabetes uring surgical proceures. Rapi-acting insulin can also be given i.v. (58) (C). However, the effect is not superior to that of regular insulin an it is more expensive. All chilren shoul have rapi-acting or regular insulin available for crisis management. Intermeiate-acting insulins The action profiles of these insulins make them suitable for twice aily regimens an for prebe osage in basal-bolus regimens. 90 Peiatric Diabetes 2007: 8:

35 Two principal preparations exist: ) Isophane NPH insulins. ) Crystalline zinc acetate insulin (IZS or lente insulins). Isophane insulins are mostly use in chilren, mainly because of their suitability for mixing with regular insulin in the same syringe, vial, or cartrige without interaction. Note: When regular insulin is mixe with lente preparations, it reacts with excess zinc, blunting its short-acting properties (59) (B). Basal insulin analogues The new basal insulin analogues are glargine an etemir. They show a more preictable insulin effect with less ay-to-ay variation compare with NPH insulin. (60) (A) (61) (B). In most countries, the two basal analogues have not been formally approve for chilren younger than 6 yr. However, there is a report on successful use of glargine in chilren age from,1 to 5 yr (62) (C). Basal analogues are more expensive (approximately 150 to 100%). Glargine Lack of an accumulation effect of glargine given on consecutive ays has been shown in one stuy (63) (C). The effect of glargine lasts for up to 24 h; however, a waning effect can be seen approximately 20 h after injection (64) (A). Some chilren report a burning sensation when injecting glargine because of the aci ph (65) (C). Detemir A stuy with etemir in aults foun the time of action to be between 6 an 23 h when oses between 0.1 an 0.8 U/kg were given (66) (A). In a peiatric stuy, 70% of the patients use etemir twice or three times aily (29) (A). In aults, stuies with etemir have shown weight reuction or less weight gain (31) (C), which has been observe also in chilren an aolescents (29) (C). Traitional long-acting insulins ) Ultralente TM an Ultratar TM insulins were esigne to have uration of more than 24 h to meet basal insulin requirements an, therefore, coul be use in basal-bolus injection regimens. Their action profile in chilren appears to be extremely variable (53), with ose accumulation effect (E). If available, basal insulin analogues are superior to traitional long-acting insulins (E). Premixe insulin preparations Premixe insulins (fixe ratio mixtures of premeal an basal insulins) are popular in some countries, particularly for prepubertal chilren on twice aily regimens. Although they reuce potential errors in rawing up insulin, they remove the flexibility offere by separate ajustment of the two types. Such flexibility is especially useful for chilren with variable foo intake. Recently, premixe insulins have also become available with rapi-acting analogues. Biphasic insulin aspart 30 (30% aspart an 70% aspart boun to NPH) given for three main meals combine with NPH at betime was equally efficient as premixe human insulin (70% NPH), given for morning an betime with regular insulin for lunch an inner (67). ) There is no clear evience that premixe insulins in young chilren are less effective but some evience of poorer metabolic control when use in aolescents (35). ) Premixe insulins with regular (or rapi-acting) insulin:nph in ifferent ratios, e.g., 10:90, 15:85, 20:80, 25:75, 30:70, 40:60, 50:50 are available in various countries from ifferent manufacturers. ) Premixe insulins are suitable for use in pen injector evices. ) Premixe insulins may be useful to reuce the number of injections when compliance (or aherence) with the regimen is a problem. Inhale insulin ) This new form of insulin therapy has been investigate in chilren oler than 12 yr as part of a stuy in aults (68) (B) but is not approve for clinical use in chilren. Insulin concentrations Consensus Guielines ) The most wiely available insulin concentration is 100 IU/mL (U100). ) Treatment with U40 (40 IU/mL), U50 or other concentrations such as U500 are also acceptable subject to availability an special nees. ) Care must be taken to ensure that the same concentration is supplie each time new supplies are receive. ) Very young chilren occasionally require insulin ilute with iluent obtaine from the manufacturer, but special care is neee in ilution an rawing up the insulin into the syringe. Rapi-acting insulin can be ilute to U10 or U50 with sterile NPH iluent an store for 1 month (69, 70) (C) for use in pumps for infants or very young chilren. Peiatric Diabetes 2007: 8:

36 Bangsta et al. Storage of insulin Regulatory requirements state that the insulin prouct must retain at least 95% of its labele potency at the expiration ate (71). At room temperature (77 F), insulin will lose,1.0% of its potency over 30. In contrast, insulin store in a refrigerator will lose,0.1% of its potency over 30 (71) (C). Storage recommenations are more often base on regulatory requirements regaring sterility than loss of potency (71). The iniviual manufacturerôs storage recommenations an expiration ates must be ahere to. These usually recommen that: Insulin must never be frozen. Direct sunlight or warming (in hot climates) amages insulin. Patients shoul not use insulin that has change in appearance (clumping, frosting, precipitation, or iscoloration). Unuse insulin shoul be store in a refrigerator (4 8 C). After first usage, an insulin vial shoul be iscare after 3 months if kept at 2 8 C or 4 wk if kept at room temperature. However, for some insulin preparations, manufacturers recommen only of use in room temperature (71) (E). In hot climates where refrigeration is not available, cooling jars, earthenware pitcher (matka) (72) (C), or a cool wet cloth aroun the insulin will help to preserve insulin activity. In chilren on small oses of insulin, 3-mL cartriges instea of 10-mL vials shoul be chosen to avoi wasting of insulin. It is essential that a small supply of spare insulin shoul be reaily available to all chilren an aolescents so that the supply remains uninterrupte. Injection sites The usual injection sites are given below: ) Abomen (the preferre site when faster absorption is require an it may be less affecte by muscle activity or exercise); ) Front of thigh/lateral thigh (the preferre site for slower absorption of longer acting insulins); ) Buttocks (upper outer quarant may be useful in small chilren); ) Lateral aspect of the arm (in small chilren with little subcutaneous fat, intramuscular injection is more likely an it may cause unsightly bruising). Cleaning or isinfection of skin is not necessary unless hygiene is a real problem. Infection at injection sites is rare (73) (C). Chilren an aolescents shoul be encourage to inject consistently within the same site (abomen, thigh, buttocks, an arm) at a particular time in the ay, but must avoi injecting repeately into the same spot to prevent lipohypertrophy. Problems with injections ) Local hypersensitivity reactions to insulin injections are uncommon but when they o occur, formal ientification of the insulin (or, more rarely, preservative) responsible may be possible with help from the manufacturers. A trial of an alternative insulin preparation may solve the problem. If true allergy is suspecte, esensitization can be performe using protocols available from the manufacturers. Aing a small amount of corticosterois to the insulin may help (74) (C). ) Lipohypertrophy with the accumulation of fat in lumps unerneath the skin are common in chilren (75). ) Lipoatrophy is now uncommon since the introuction of highly purifie insulins but has been escribe also with the newer analogues (76, 77) (C). ) Painful injections are a common problem in chilren. Check angle, length of the neele, an epth of injection to ensure that injections are not being given intramuscularly an that the neele is sharp. Reuse neeles can cause more pain (78) (A). Inwelling catheters (Insuflon Ò ) can ecrease injection pain (79) (A). ) Leakage of insulin is common an cannot be totally avoie. Encourage slower withrawal of neele from skin, stretching of the skin after the neele is withrawn, or pressure with clean finger over the injection site. ) Bruising an bleeing are more common after intramuscular injection or tight squeezing of the skin. Use of thinner neeles has shown significantly less bleeing at the injection site (80) (B). ) Bubbles in insulin shoul be remove whenever possible. If the bubble is not big enough to alter the ose of insulin, it shoul not cause problems. When using insulin pens, air in the cartrige can cause rops of insulin appearing on the tip of the pen neele if withrawn too quickly (81) (C). Insulin absorption ) Insulin activity profiles show substantial variability both ay to ay in the same iniviuals an between iniviuals, particularly in chilren (5, 53). ) The onset, peak effect, an uration of action epen on many factors that significantly affect the spee an consistency of absorption. 92 Peiatric Diabetes 2007: 8:

37 ) Young people an care proviers shoul know the factors that influence insulin absorption such as: Age (young chilren, less subcutaneous fat!faster absorption) (E) Fat mass (large subcutaneous fat thickness (82) (B) an lipohypertrophy (83) (B)!slower absorption). Dose of injection (larger ose!slower absorption) (53) (C). Site an epth of subcutaneous injection (abomen faster than thigh (84) (A); no goo ata exist on absorption from thigh vs. buttock). Subcutaneous vs. intramuscular injection (intramuscular injection!faster absorption in thigh), also with rapi-acting analogues (85) (B). Acciental intramuscular injections can cause variable glucose control (E). Exercise (leg injection an leg exercise!faster absorption) (86) (B). Insulin concentration, type, an formulation (lower concentration!faster absorption) (87) (B). Ambient an boy temperature (higher temperatures!faster absorption) (82) (B). In general, the absorption spee of rapi-acting analogues is less affecte by the above-mentione factors (88 90) (B, B, A). There is no significant ifference in the absorption of glargine from abomen or thigh (91) (B). Exercise oes not influence glargine absorption (92) (A). There is a risk of hypoglycemia if injecting glargine intramuscularly, particularly in young an lean iniviuals (93) (C). Note: Faster absorption usually results in shorter uration of action (see page 90). Aministration of insulin Devices for insulin elivery Insulin syringes. ) Plastic fixe-neele syringes with small ea space are preferable to glass syringes. ) Syringes are available in a variety of sizes in ifferent countries, ensuring accurate ose elivery, but it is esirable to have small syringes with 1 U per mark (e.g., 0.3 ml) available for small chilren. ) Plastic fixe-neele syringes are esigne for single use. However, many persons with iabetes successfully reuse them without significant increase in risk of infection (94) (B). Reuse shoul be iscourage if there is concern about hygiene or injection pain, as they become less sharp when reuse (78) (A). ) Insulin syringes must have a measuring scale consistent with the insulin concentration (e.g., U100 syringes). ) Syringes must never be share with another person because of the risk of acquiring bloo-borne infection (e.g., hepatitis, HIV). ) It is avisable that all chilren an aolescents with iabetes shoul know how to aminister insulin by syringe because other injection evices may malfunction. Insulin must be aministere by syringes (or other injection evices) calibrate to the concentration of insulin being use. Disposal of syringes. ) Appropriate isposal proceures are manatory. Consensus Guielines Specifically esigne an labele Ôsharps containers may be available from pharmacies an iabetes centers. Special neele clippers (e.g., Safeclip Ò ) may be available to remove the neele an make it unusable. Without a Ôsharps container, syringes with neeles remove may be store an ispose of in opaque plastic containers or tins for garbage collection. Pen injector evices. ) Pen injector evices containing insulin in prefille cartriges have been esigne to make injections easier an more flexible. They eliminate the nee for rawing up from an insulin vial, the ose is iale up on a scale, an they may be particularly useful for insulin aministration away from home, at school or on holiays. ) Special pen injection neeles of small size (5 6 mm) an iameter are available an may cause less iscomfort on injection (80) (B). ) Pen injectors of various sizes an types are available from the pharmaceutical companies. Some pens can be set to ½ unit increments. Availability is a problem in some countries an although pen injectors may improve convenience an flexibility, they are a more expensive metho of aministering insulin. ) Pen injector evices are useful in chilren on multiple injection regimens or fixe mixtures of insulin but are less acceptable when free mixing of insulins is use in a two- or three-ose regimen (E). Neele length. ) The traitional neele length of mm (27 G) has been replace by thinner neeles that are 5 8 mm long (30 31 G). A two-finger pinch technique is recommene for all types of injections to ensure a strict subcutaneous injection, avoiing intramuscular injection (95) (C). Peiatric Diabetes 2007: 8:

38 Bangsta et al. ) With 5 6 mm neeles, the injections can be given perpenicularly without lifting a skin fol if there is enough subcutaneous fat, which often is the case in girls (at least 8 mm as the skin layers often are compresse when injecting perpenicularly) (96) (C). Lean boys, however, have a thinner subcutaneous fat layer, especially on the thigh (96, 97) (C). When injecting into the buttocks, the subcutaneous fat layer is usually thick enough to inject without lifting a skin fol. ) There is a risk of intraermal injections if 5 6 mm neeles are not fully inserte into the skin. Subcutaneous inwelling catheters. ) Such catheters (e.g., Insuflon) inserte using topical local anesthetic cream may be useful to overcome problems with injection pain at the onset of iabetes (79) (A). ) Insuflon is use in an increasing number of centers for introuction of MDI. ) The use of Insuflon oes not affect metabolic control negatively (100) (B). In chilren with injection problems, HbA1c has been lowere by using Insuflon (99) (B). ) The use of a basal analogue an a short- or rapiacting insulin at the same injection time in an Insuflon is not avisable in case of possible interaction of the two insulins (for mixing with glargine, see page 95). ) Insuflons shoul be replace every 2 4 to prevent scarring an a negative effect on insulin absorption (100) (B) (101) (C). Automatic injection evices. ) Automatic injection evices are useful for chilren who have a fear of neeles. Usually, a loae syringe is place within the evice, locke into place, an inserte automatically into the skin by a spring-loae system. ) The benefits of these evices are that the neele is hien from view an the neele is inserte through the skin rapily. ) Automatic injection evices for specific insulin pen injectors are available (102) (B). Jet injectors. ) High-pressure jet injection of insulin into the subcutaneous tissue has been esigne to avoi the use of neele injection. ) Jet injectors may have a role in cases of neele phobia. ) The use of jet injectors has resulte in metabolic control similar to both conventional injections (103) an CSII (104), but problems with have inclue a variable epth of penetration, elaye pain, an bruising (105) (B). Subcutaneous insulin infusion pumps. ) The use of external pumps is increasing an is proving to be acceptable an successful (36, 37) (A) (38, 40 46) (C) (39) (E), even in young infants (42) (C). Ranomize stuies in the preschool group have faile to show better glycemic control (36, 106) (A). ) The positive effects on glycemic control an hypoglycemia in non-ranomize observational stuies have probably been influence by the patient selection in these stuies, such as goo compliance an/or poor metabolic control. Pump therapy has also been foun effective in recurrent ketoaciosis (107, 108). This highlights the importance of iniviualizing the ecision of the metho of therapy for every situation. ) An insulin pump is an alternative to treatment with MDI (incluing basal analogues) if HbA1c is persistently above the iniviual goal, hypoglycemia is a major problem, or quality of life nees be improve (109) (E). ) Insulin pump use is increasing in the younger agegroup, as clinicians become more comfortable with CSII as a more physiological insulin replacement therapy (E). ) The newer generation of Ôsmart pumps that automatically calculate meal- or correction-boluses base on insulin-to-carbohyrate ratios an insulin sensitivity factors have enable alternate proviers, such as granparents, nannies, an aycare workers, to participate in iabetes management tasks (E). ) Insulin pump treatment may be hazarous when eucation an aherence to therapy is inaequate because of the smaller epot of subcutaneous insulin an the suen rise in ketones when insulin supply is interrupte. Pump stops for 5 h in ault patients resulte in b-ketone (beta-hyroxybutyrate) levels of approximately mmol/l but not in DKA (110) (B). Results in chilren an aolescents seem to be similar (111) (C). ) Patients using insulin pumps, especially younger chilren, will benefit from being able to measure b-ketones (E). ) For patients using insulin pump, an prone to ketosis, it may help to give a small ose of basal insulin before betime (E). ) Patients must be instructe on treatment of hyperglycemia, giving insulin with a pen or syringe in case of suspecte pump failure (hyperglycemia an elevate ketone levels). ) Rapi-acting analogue insulins are use in most pumps (E), an a meta-analysis has shown a 0.26% lower HbA1c level when comparing with human regular insulin (24) (A). Regular insulin is less often use in pumps but works well if rapi-acting insulin is not available. 94 Peiatric Diabetes 2007: 8:

39 ) There is no ifference in action effect (112), pump stops or catheter cloggings when using insulin lispro or aspart in pumps (113). ) Lower percentage of basal insulin an more than seven aily boluses are an option for better metabolic control when using pumps (114) (C). The use of pumps requires special eucation for users but oes not nee to be restricte to centers with 24 h access to pump expertise. The pump user or the family shoul be taught how to switch to multiple injections with pens or syringes in case of emergency. Injection technique ) Injections by syringe are usually given into the eep subcutaneous tissue through a two-finger pinch of skin at a 45 angle. A 90 angle can be use if the s.c. fat is thick enough (see page 94). ) Pen injector technique requires a careful eucation incluing the nee to ensure that no airlock or blockage forms in the neele. A wait of 15 s after pushing in the plunger helps to ensure complete expulsion of insulin through the neele (81) (B). Self-injection. ) It shoul be emphasize that a proportion of people with iabetes have a severe long-lasting islike of injections, which may influence their glycemic control (E). For these iniviuals, an injection ai, Insuflon (99) (B), or insulin pump therapy may improve compliance (E). ) There is great iniviual variation in the appropriate age for chilren to self-inject (115) (B). ) The appropriate age relates to evelopmental maturity rather than to chronological age. ) Most chilren oler than 10 yr either give their own injections or help with them (115) (B) ) Younger chilren sharing injection responsibility with a parent or other care provier may help prepare the evice or help push the plunger an, subsequently, uner supervision, be able to perform the whole task successfully. ) Self-injection is sometimes triggere by an external event such as overnight stay with a frien, school excursion, or iabetes camp. ) Parents or care proviers shoul not expect that self-injection will automatically continue an shoul accept phases of non-injection with the nee for help from another person. ) Younger chilren on multiple injection regimens may nee help to inject in sites ifficult to reach (e.g., the buttocks) to avoi lipohypertrophy. Regular checking of injection sites, injection technique, an skills remain a responsibility of parents, care proviers, an health professionals. Self-mixing of insulin. When a mixture of two insulins is rawn up (e.g., regular mixe with NPH), it is most important that there is no contamination of one insulin with the other in the vials. To prevent this, the following principles apply: ) There is no uniformity of avice but most often it is taught that regular (clear insulin) is rawn up into the syringe before clouy insulin (intermeiate or long acting). ) Vials of clouy insulin must always be gently rolle (not shaken) at least 10, preferably 20, times (116) (B) to mix the insulin suspension before carefully rawing it up into the clear insulin. ) If the clouy insulin is of lente type, the mixture must be aministere immeiately, otherwise the regular component interacts with zinc, which blunts the action (59, 117) (C). ) Insulins from ifferent manufacturers shoul be use together with caution, as there may be interaction between the buffering agents. ) NPH an lente insulins shoul never be mixe. ) Rapi-acting insulin analogues may be mixe in the same syringe as NPH immeiately before injections (118) (B) (119) (C). Immeiate injection of a mixture of Ultralente an Humalog has been foun not to iminish the Humalog effect (120) (C). ) The manufacturer recommens that glargine shoul not be mixe with any other insulin before injection, but there is some evience that it can be mixe with insulin lispro an aspart without affecting the bloo-glucose-lowering effect (121) (B) or HbA1c (122) (C). ) The manufacturer recommens that etemir shoul not be mixe with any other insulin before injection. There are no available stuies on this. Insulin regimens Consensus Guielines No insulin injection regimen satisfactorily mimics normal physiology. ) The choice of insulin regimen will epen on many factors incluing age, uration of iabetes, lifestyle (ietary patterns, exercise scheules, school, work commitments, etc.), targets of metabolic control, an, particularly, iniviual patient/family preferences. Peiatric Diabetes 2007: 8:

40 Bangsta et al. ) The basal-bolus concept (i.e., a pump or intermeiate-acting insulin/long-acting insulin/basal analogue once or twice aily an rapi-acting or regular boluses with meals an snacks) has the best possibility of imitating the physiological insulin profile. ) At least two injections of insulin per ay (mixing short/rapi-acting an basal insulin) are avisable in most chilren. ) Most regimens inclue a proportion of short- or rapi-acting insulin an intermeiate-acting insulin, long-acting or basal analogue, but some chilren may, uring the partial remission phase, maintain satisfactory metabolic control on intermeiate- or long-acting insulins alone (i.e., an HbA1c close to the normal range). Whatever insulin regimen is chosen, it must be supporte by comprehensive eucation appropriate for the age, maturity, an iniviual nees of the chil an family. Principles of insulin therapy Aim for appropriate insulin levels throughout the 24 h to cover basal requirements an higher levels of insulin in an attempt to match the glycemic effect of meals. Frequently use regimens ) Two injections aily of a mixture of short- or rapian intermeiate-acting insulins (before breakfast an the main evening meal). ) Three injections aily using a mixture of short- or rapi- an intermeiate-acting insulins before breakfast; rapi or regular insulin alone before afternoon snack or the main evening meal; intermeiate-acting insulin before be or variations of this. ) Basal-bolus regimen of the total aily insulin requirements, 40 60% shoul be basal insulin, the rest prepranial rapi-acting or regular insulin. injection of regular insulin min before each main meal (breakfast, lunch; an the main evening meal); intermeiate-acting insulin or basal/long-acting analogue at betime or twice aily (mornings an evenings). injection of rapi-acting insulin analogue immeiately before (or after) (11, 57) (A) each main meal (breakfast, lunch, an main evening meal); intermeiate-acting insulin or basal/long-acting analogue at betime, probably before breakfast an occasionally at lunchtime or twice aily (mornings an evenings). Insulin pump regimens are regaining popularity with a fixe or a variable basal ose an bolus oses with meals. Note: None of these regimens can be optimize without frequent assessment by bloo glucose monitoring (BGM). Daily insulin osage Daily insulin osage varies greatly between iniviuals an changes over time. It, therefore, requires regular review an reassessment. Dosage epens on many factors such as: ) Age; ) Weight; ) Stage of puberty; ) Duration an phase of iabetes; ) State of injection sites; ) Nutritional intake an istribution; ) Exercise patterns; ) Daily routine; ) Results of BGM (an glycate hemoglobin); ) Intercurrent illness. Guielines on osage: ) During the partial remission phase, the total aily insulin ose is often,0.5 IU/kg/ay. ) Prepubertal chilren (outsie the partial remission phase) usually require insulin of IU/kg/ay. ) During puberty, requirements may rise substantially above 1 an even up to 2 U/kg/ay. The Ôcorrect ose of insulin is that which achieves the best attainable glycemic control for an iniviual chil or aolescent without causing obvious hypoglycemia problems, an the harmonious growth accoring to weight an height chilren s charts. Distribution of insulin ose The istribution of insulin ose across the ay shows great iniviual variation. Regarless of moe of insulin therapy, oses shoul be aapte base on the aily pattern of bloo glucose. ) Chilren on twice aily regimens often require more (perhaps 2/3) of their total aily insulin in the morning an less (perhaps 1/3) in the evening. ) On this regimen, approximately 1/3 of the insulin ose may be short-acting insulin an approximately 2/3 may be intermeiate-acting insulin although these ratios change with greater age an maturity of the young person. 96 Peiatric Diabetes 2007: 8:

41 ) On basal-bolus regimens, the nighttime intermeiate-acting insulin may represent between 30 (typical for regular insulin) an 50% (typical for rapi-acting insulin) of total aily insulin. Approximately 50% as rapi-acting or approximately 70% as regular insulin is ivie up between three an four premeal boluses. When using rapi-acting insulin for premeal boluses, the proportion of basal insulin is usually higher, as short-acting regular insulin also provies some basal effect. ) Glargine is often given once a ay, but many chilren may nee to be injecte twice a ay or combine with NPH to provie aytime basal insulin coverage (25, 123) (C). ) Glargine can be given before breakfast, before inner or at betime with equal effect, but nocturnal hypoglycemia occurs significantly less often after breakfast injection (64) (A, ault stuy). ) When transferring to glargine as basal insulin, the total ose of basal insulin nees to be reuce by approximately 20% to avoi hypoglycemia (123) (C). After that, the ose shoul be iniviually tailore. ) Detemir is most commonly given twice aily in chilren (29) (A) an (E). ) When transferring to etemir from NPH, the same oses can be use to start with (E). Insulin ose ajustments Soon after iagnosis: ) Frequent avice by members of the iabetes care team on how to make grauate alterations of insulin oses at this stage is of high eucational value. ) Insulin ajustments shoul be mae until target bloo glucose levels an target HbA1c are achieve. ) If frequent BGM is not possible, urinary tests are useful, especially in the assessment of nocturnal control. Later insulin ajustments: ) On twice aily insulin regimens, insulin osage ajustments are usually base on recognition of aily patterns of bloo glucose levels over the whole ay or for a number of ays or on recognition of glycemic responses to foo intake or energy expeniture ) On basal-bolus regimens, flexible or ynamic ajustments of insulin are mae before meals an in response to frequent BGM. In aition, the aily bloo glucose pattern shoul be taken into account. The rapi-acting analogues may require postpranial bloo glucose tests approximately 2 h after meals to assess their efficacy. Frequently, insulin is ose base on foo consumption (carbohyrates) an on eviation from a target glucose. Many newer Consensus Guielines insulin pumps allow programming algorithms for these automatic ajustments for ambient bloo glucose an carbohyrate intake. Health care professionals have the responsibility to avise parents, other care proviers, an young people on ajusting insulin therapy safely an effectively. This training requires regular review, reassessment, an reinforcement. Avice for persistent eviations of bloo glucose from target ) Elevate bloo glucose level before breakfast!increase preinner or prebe intermeiateor long-acting insulin. (Bloo glucose tests uring the night are neee to ensure that this change oes not result in nocturnal hypoglycemia.) ) Rise in bloo glucose level after a meal!increase premeal rapi-acting/regular insulin. ) Elevate bloo glucose level before lunch/inner meal!increase prebreakfast basal insulin or increase ose of prebreakfast regular/rapi-acting insulin if on basal-bolus regimen. When using rapi-acting insulin for basal-bolus regimen, the ose or type of basal insulin may nee to be ajuste in this situation. ) When using carbohyrate counting, persistent elevations of bloo glucose may require ajustment in ratios for carbohyrate (insulin-to-carbohyrate ratio). ) Correction oses can be use accoring to the Ô1800 rule, i.e., ivie 1800 by total aily insulin ose to get the results in mg/l that 1 U of rapiinsulin will lower the bloo glucose. For the results in mmol/l, use the Ô100 rule, i.e. ivie 100 by total aily insulin ose (C) an (E). For regular insulin, a Ô1500 rule can be use for results in mg/l an a Ô83-rule for results in mmol/l. However, correction oses shoul always be ajuste iniviually before aministration, epening on other factors affecting insulin resistance, such as exercise. ) Rise in bloo glucose level after evening meal!increase pre-evening meal regular/rapi-acting insulin. In aition: ) Unexplaine hypoglycemia requires re-evaluation of insulin therapy. ) Hyper- or hypoglycemia occurring in the presence of intercurrent illness requires a knowlege of Ôsick ay management. ) Day-to-ay insulin ajustments may be necessary for variations in lifestyle routine, especially exercise or ietary changes. Peiatric Diabetes 2007: 8:

42 Bangsta et al. ) Various levels of exercise require ajustment of iabetes management. ) Special avice may be helpful when there are changes in routine, travel, school outings, eucational holiays/iabetes camps, or other activities that may require ajustment of insulin oses. ) During perios of regular change in consumption of foo (e.g., Ramaan), the total amount of insulin shoul not be reuce but reistribute accoring to the amount an timing of carbohyrate intake. However, if total calorie intake is reuce uring Ramaan, the aily amount of bolus insulin for meals usually nees to be reuce, e.g., to 2/3 or 3/4 of the usual ose (E). Dawn phenomenon ) Bloo glucose levels ten to rise in the hours of the morning (usually after 5 AM) prior to waking. This is calle the awn phenomenon. In iniviuals without iabetes, the mechanisms inclue increase nocturnal growth hormone secretion, increase resistance to insulin action, an increase hepatic glucose prouction. These mechanisms are more potent in puberty. ) Pump stuies (124) (B) (125) (C) have shown that younger chilren often nee more basal insulin before minight than after (reverse awn phenomenon). With a basal-bolus analogue regimen, this can be achieve by giving regular instea of rapi-acting insulin for the last bolus of the ay (nighttime bloo glucose levels nee to be checke) (E). ) In iniviuals with T1DM, fasting hyperglycemia is preominantly cause by waning insulin levels, thus exaggerating the awn phenomenon. Morning hyperglycemia can, in some cases, be precee by nighttime hypoglycemia, being seen less often in pump therapy compare with MDI (126) (B). ) Correction of fasting hyperglycemia is likely to require an ajustment of the insulin regimen to provie effective insulin levels throughout the night an the early morning by the use of: intermeiate-acting insulin later in the evening or at betime; a longer acting evening insulin/basal insulin analogue; changeover to insulin pump treatment. This article is a Chapter in the ISPAD Clinical Practice Consensus Guielines of the ISPAD ( The complete set of these Guielines will later be publishe as a compenium. Aitional comments, clarifications, or corrections shoul be irecte to the corresponing author (R.H.). The evience graing system use in the ISPAD Guielines is the same as that use by the American Diabetes Association. See the Introuction of the ISPAD Clinical Practice Consensus Guielines in Peiatric Diabetes 2006: 7: References 1. JOHNSSON S. Retinopathy an nephropathy in iabetes mellitus: comparison of the effects of two forms of treatment. Diabetes 1960: 9: SIEBENHOFER A, PLANK J, BERGHOLD A, NARATH M, GFRERER R, PIEBER TR. Short acting insulin analogues versus regular human insulin in patients with iabetes mellitus. Cochrane Database Syst Rev 2004: CD BRUNNER GA, HIRSCHBERGER S, SENDLHOFER G et al. Post-pranial aministration of the insulin analogue insulin aspart in patients with type 1 iabetes mellitus. Diabet Me 2000: 17: DANNE T, DEISS D, HOPFENMULLER W, VON SCHUTZ W, KORDONOURI O. Experience with insulin analogues in chilren. Horm Res 2002: 57 (Suppl. 1): MORTENSEN HB, LINDHOLM A, OLSEN BS, HYLLEBERG B. Rapi appearance an onset of action of insulin aspart in paeiatric subjects with type 1 iabetes. Eur J Peiatr 2000: 159: DANNE T, BECKER RH, HEISE T, BITTNER C, FRICK AD, RAVE K. Pharmacokinetics, pranial glucose control, an safety of insulin glulisine in chilren an aolescents with type 1 iabetes. Diabetes Care 2005: 28: ACERINI CL, CHEETHAM TD, EDGE JA, DUNGER DB. Both insulin sensitivity an insulin clearance in chilren an young aults with type I (insulinepenent) iabetes vary with growth hormone concentrations an with age. Diabetologia 2000: 43: AMIEL SA, SHERWIN RS, SIMONSON DC, LAURITANO AA, TAMBORLANE WV. Impaire insulin action in puberty. A contributing factor to poor glycemic control in aolescents with iabetes. N Engl J Me 1986: 315: PLANK J, WUTTE A, BRUNNER G et al. A irect comparison of insulin aspart an insulin lispro in patients with type 1 iabetes. Diabetes Care 2002: 25: FORD-ADAMS ME, MURPHY NP, MOORE EJ et al. Insulin lispro: a potential role in preventing nocturnal hypoglycaemia in young chilren with iabetes mellitus. Diabet Me 2003: 20: DEEB LC, HOLCOMBE JH, BRUNELLE R et al. Insulin lispro lowers postpranial glucose in prepubertal chilren with iabetes. Peiatrics 2001: 108: TUBIANA-RUFI N, COUTANT R, BLOCH J et al. 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43 Consensus Guielines Results of a multicenter trial. German Humalog-CSII Stuy Group. Diabetes Care 1999: 22: RUTLEDGE KS, CHASE HP, KLINGENSMITH GJ, WALRAVENS PA, SLOVER RH, GARG SK. Effectiveness of postpranial Humalog in tolers with iabetes. Peiatrics 1997: 100: HELLER SR, COLAGIURI S, VAALER S et al. Hypoglycaemia with insulin aspart: a ouble-blin, ranomise, crossover trial in subjects with type 1 iabetes. Diabet Me 2004: 21: HOME PD, LINDHOLM A, RIIS A. Insulin aspart vs. human insulin in the management of long-term bloo glucose control in type 1 iabetes mellitus: a ranomize controlle trial. European Insulin Aspart Stuy Group (In Process Citation). Diabet Me 2000: 17: HEISE T, NOSEK L, RONN BB et al. Lower withinsubject variability of insulin etemir in comparison to NPH insulin an insulin glargine in people with type 1 iabetes. Diabetes 2004: 53: HERMANSEN K, FONTAINE P, KUKOLJA KK, PETERKOVA V, LETH G, GALL MA. 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45 Consensus Guielines 78. CHANTELAU E, LEE DM, HEMMANN DM, ZIPFEL U, ECHTERHOFF S. What makes insulin injections painful? BMJ 1991: 303: HANAS R, ADOLFSSON P, ELFVIN-AKESSON K et al. Inwelling catheters use from the onset of iabetes ecrease injection pain an pre-injection anxiety. J Peiatr 2002: 140: ARENDT-NIELSEN L, EGEKVIST H, BJERRING P. Pain following controlle cutaneous insertion of neeles with ifferent iameters. Somatosens Mot Res 2006: 23: GINSBERG BH, PARKES JL, SPARACINO C. The kinetics of insulin aministration by insulin pens. Horm Metab Res 1994: 26: SINDELKA G, HEINEMANN L, BERGER M, FRENCK W, CHANTELAU E. Effect of insulin concentration, subcutaneous fat thickness an skin temperature on subcutaneous insulin absorption in healthy subjects. Diabetologia 1994: 37: YOUNG RJ, HANNAN WJ, FRIER BM, STEEL JM, DUNCAN LJ. Diabetic lipohypertrophy elays insulin absorption. Diabetes Care 1984: 7: BANTLE JP, NEAL L, FRANKAMP LM. 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46 Bangsta et al BODE B, WEINSTEIN R, BELL D et al. Comparison of insulin aspart with buffere regular insulin an insulin lispro in continuous subcutaneous insulin infusion: a ranomize stuy in type 1 iabetes. Diabetes Care 2002: 25: SIEGMUND T, AMELUNXEN S, KAISER M, SCHUMM- DRAEGER P. Pump compatibility of insulin aspart compare to insulin Lispro with respect to catheter complications an ermal/subcutaneous irritations in patients (P) with type 1 iabetes (T1D) unergoing continuous subcutaneous insulin infusion (CSII) therapy. Diabetes 2005: 54 (Suppl. 1): A105 (Abstract) JAROSZ-CHOBOT P, BATTELINO T, KORDONOURI O, PANKOWSKA E, DANNE T, GROUP PS. The PePump survey: inication for CSII an number of aily boluses are associate with HbA1c in 1086 chilren with T1 DM from 17 countries. Peiatr Diabetes 2005: 6 (Suppl. 3): 14 (Abstract) WYSOCKI T, HARRIS MA, MAURAS N et al. Absence of averse effects of severe hypoglycemia on cognitive function in school-age chilren with iabetes over 18 months. Diabetes Care 2003: 26: JEHLE PM, MICHELER C, JEHLE DR, BREITIG D, BOEHM BO. Inaequate suspension of neutral protamine Hagenorn (NPH) insulin in pens. Lancet 1999: 354: (See comments) PERRIELLO G, TORLONE E, DI SANTO S et al. Effect of storage temperature of insulin on pharmacokinetics an pharmacoynamics of insulin mixtures injecte subcutaneously in subjects with type 1 (insulin-epenent) iabetes mellitus. Diabetologia 1988: 31: HALBERG I, JACOBSEN L, DAHL U. A stuy on selfmixing insulin aspart with NPH insulin in the syringe before injection. Diabetes 1999: 48 (Suppl. 1): A104 (Abstract 448) JOSEPH SE, KORZON-BURAKOWSKA A, WOODWORTH JR, EVANS M, HOPKINS D, JANES JM, AMIEL SA. The action profile of lispro is not blunte by mixing in the syringe with NPH insulin. Diabetes Care 1998: 21: BASTYR EJ III, HOLCOMBE JH, ANDERSON JH, CLORE JN. Mixing insulin lispro an ultralente insulin. Diabetes Care 1997: 20: KAPLAN W, RODRIGUEZ LM, SMITH OE, HAYMOND MW, HEPTULLA RA. Effects of mixing glargine an short-acting insulin analogs on glucose control. Diabetes Care 2004: 27: FIALLO-SCHARER R, CHASE P, HORNER B, MCFANN K, WALRAVENS P, GARG S. The mixing of rapi-acting insulin (RAI) analogues (Humalog Ò or NovoLog Ò ) with insulin glargine (IG) in youth with type 1 iabetes (T1D). Diabetes 2005: 54 (Suppl. 1): A451 (Abstract 1879-P) TAN CY, WILSON DM, BUCKINGHAM B. Initiation of insulin glargine in chilren an aolescents with type 1 iabetes. Peiatr Diabetes 2004: 5: CONRAD SC, MCGRATH MT, GITELMAN SE. Transition from multiple aily injections to continuous subcutaneous insulin infusion in type 1 iabetes mellitus. J Peiatr 2002: 140: BOLAND E, AHERN J, VINCENT M. Pumps an kis: basal requirements for excellent metabolic control. Diabetes 2002: 51 (Suppl. 2): A3 (Abstract) LUDVIGSSON J, HANAS R. Continuous subcutaneous glucose monitoring improve metabolic control in peiatric patients with type 1 iabetes: a controlle crossover stuy. Peiatrics 2003: 111: Peiatric Diabetes 2007: 8:

47 Peiatric Diabetes 2007: 8: All rights reserve # 2007 The Authors Journal compilation # 2007 Blackwell Munksgaar Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Diabetic ketoaciosis Wolfsorf J, Craig ME, Daneman D, Dunger D, Ege J, Lee WRW, Rosenbloom A, Sperling MA, Hanas R. Diabetic ketoaciosis. Peiatric Diabetes 2007: 8: Joseph Wolfsorf a Maria E Craig b Denis Daneman c Davi Dunger Julie Ege e WR Warren Lee f Arlan Rosenbloom g Mark A Sperling h an Ragnar Hanas i a Division of Enocrinology, Chilren s Hospital Boston, MA, USA b School of Women s an Chilren s Health, University of New South Wales, Syney, Australia c University of Toronto, The Hospital for Sick Chilren, Toronto, Canaa Department of Paeiatrics, University of Cambrige, Aenbrooke s Hospital, Cambrige, UK e Department of Paeiatrics, John Racliffe Hospital, Oxfor, UK f Enocrinology Service Department of Paeiatric Meicine, KK Chilren s Hospital, Singapore g Division of Enocrinology, Department of Peiatrics, University of Floria College of Meicine, Gainesville, FL, USA h Department of Peiatric Enocrinology, Chilren s Hospital, University of Pittsburgh, PA, USA i Department of Peiatrics, Uevalla Hospital, Uevalla, Sween Corresponing author: Ragnar Hanas, MD, PhD, Department of Peiatrics, Uevalla Hospital, S Uevalla, Sween. Tel: ; [email protected] Eitors of the ISPAD Clinical Practice Consensus Guielines ; Ragnar Hanas, Kim Donaghue, Georgeanna Klingensmith, Peter Swift Diabetic ketoaciosis (DKA) results from absolute or relative eficiency of circulating insulin an the combine effects of increase levels of the counterregulatory hormones: catecholamines, glucagon, cortisol, an growth hormone (1, 2). Absolute insulin eficiency occurs in previously uniagnose type 1 iabetes mellitus (T1DM) an when patients on treatment eliberately or inavertently o not take insulin, especially the long-acting component of a basal-bolus regimen. Patients who use an insulin pump can rapily evelop DKA when insulin elivery fails for any reason. Relative insulin eficiency occurs when the concentrations of counter-regulatory hormones increase in response to stress in conitions such as sepsis, trauma, or gastrointestinal illness with iarrhea an vomiting. The pathophysiology of DKA in chilren is summarize in Fig. 1. The combination of low serum insulin an high counter-regulatory hormone concentrations results in an accelerate catabolic state with increase glucose prouction by the liver an kiney (via glycogenolysis an gluconeogenesis), impaire peripheral glucose 28 utilization resulting in hyperglycemia an hyperosmolality, an increase lipolysis an ketogenesis, causing ketonemia an metabolic aciosis. Hyperglycemia that excees the renal threshol [approximately 10 mmol/l (180 mg/l), although the range in normal an iabetic iniviuals is very wie)] an hyperketonemia causes osmotic iuresis, ehyration, an obligatory loss of electrolytes, which often is aggravate by vomiting. These changes stimulate further stress hormone prouction, which inuces more severe insulin resistance an worsening hyperglycemia an hyperketonemia. If this cycle is not interrupte with exogenous insulin an flui an electrolyte therapy, fatal ehyration an metabolic aciosis will ensue. Ketoaciosis may be aggravate by lactic aciosis from poor tissue perfusion or sepsis. DKA is characterize by severe epletion of water an electrolytes from both the intra- an extracellular flui (ECF) compartments; the range of losses is shown in Table 1. Despite their ehyration, patients continue to maintain normal bloo pressure an have consierable urine output until extreme volume epletion leas to a critical ecrease in renal bloo

48 Consensus Guielines Pathophysiology of Diabetic Ketoaciosis (DKA) Absolute insulin eficiency or Stress, infection or insufficient insulin intake Counter-regulatory hormones Glucagon Cortisol Catecholamines Growth Hormone Lipolysis Glucose utilization Proteolysis Protein synthesis Glycogenolysis Gluconeogenic substrates FFA to liver + + Gluconeogenesis Ketogenesis Hyperglycemia Alkali reserve Aciosis Lactate Glucosuria (osmotic iuresis) Loss of water an electrolytes Decrease flui intake Dehyration Hyperosmolarity Impaire renal function Fig. 1. Pathophysiology of iabetic ketoaciosis. Copyright # 2006 American Diabetes Association. From Diabetes Care, Vol. 29, 2006; Reprinte with permission from The American Diabetes Association. flow an glomerular filtration. At presentation, the magnitue of specific eficits in an iniviual patient varies epening upon the uration an severity of illness, the extent to which the patient was able to maintain intake of flui an electrolytes, an the content of foo an fluis consume before coming to meical attention. Consumption of fluis with a highcarbohyrate content (juices or sugar containing soft rinks) exacerbates the hyperglycemia (3). Clinical manifestations of DKA Dehyration Rapi, eep, sighing (Kussmaul respiration) Nausea, vomiting, an abominal pain mimicking an acute abomen Progressive obtunation an loss of consciousness Increase leukocyte count with left shift Non-specific elevation of serum amylase Fever only when infection is present Definition of DKA The biochemical criteria for the iagnosis of DKA are (4): Hyperglycemia (bloo glucose. 11 mmol/l [200 mg/l]) Venous ph, 7.3 or bicarbonate, 15 mmol/l Ketonemia an ketonuria Partially treate chilren an chilren who have consume little or no carbohyrates may have, on rare occasion, only moestly increase bloo glucose concentrations (Ôeuglycemic ketoaciosis ) (5, 6). Table 1. Losses of fluis an electrolytes in iabetic ketoaciosis (DKA) an maintenance requirements in normal chilren Average (range) losses per kg 24-h maintenance requirements Water 70 ml (30 100) *10 kg 100 ml/kg/24 h kg 1000 ml 1 50 ml/kg/24 h for each kg from kg 1500 ml 1 20 ml/kg/24 h for each kg.20 Soium 6 mmol (5 13) 2 4 mmol Potassium 5 mmol (3 6) 2 3 mmol Chlorie 4 mmol (3 9) 2 3 mmol Phosphate ( ) mmol 1 2 mmol Data are from measurements in only a few chilren an aolescents (41, 42, 80 82). In any iniviual patient, actual losses may be less or greater than the ranges shown in the Table (E). Three methos for etermining maintenance water requirements in chilren are commonly use: *the Holliay Segar formula (143) (shown in this Table), a simplifie Holliay Segar formula (see below), an a formula base on boy surface area for chilren more than 10 kg (1500 ml/m 2 /24 h) (144). Maintenance electrolyte requirements in chilren are per 100 ml of maintenance IV flui (144, 145). Simplifie metho base on Holliay Segar:,10 kg 4 ml/kg/h; kg ml/kg/h for each kg between 11 an 20;.20 kg ml/kg/h for each kg.20. Peiatric Diabetes 2007: 8:

49 Wolfsorf et al. Type 2 iabetes mellitus (T2DM), associate with increase rates an severity of obesity, in some centers now accounts for as much as one half of newly iagnose iabetes in chilren age yr, epening on the socioeconomic an ethnic composition of the population (7). Acute ecompensation with DKA has been recognize to occur at the time of iagnosis in as many as 25% of chilren with T2DM (7). This is more likely in those of African-American escent, less so in Hispanic, an least in Canaian First Nation teenagers (8 13). The majority of new cases of iabetes in Japanese chilren an aolescents are etecte in asymptomatic iniviuals by routine urine screening (14, 15); however, overall, approximately 5% of patients with T2DM have DKA at the time of iagnosis (16). The severity of DKA is categorize by the egree of aciosis (17): Mil: venous ph, 7.3 or bicarbonate, 15 mmol/l Moerate: ph, 7.2, bicarbonate, 10 mmol/l Severe: ph, 7.1, bicarbonate, 5 mmol/l Hyperglycemic hyperosmolar state (HHS) also may occur in young patients with T2DM (18, 19). The criteria for HHS inclue (2): Plasma glucose concentration mmol/l (600 mg/l) Arterial ph Serum bicarbonate. 15 mmol/l Small ketonuria, absent to mil ketonemia (serum b-hyroxybutyrate (SEM) mmol/l (2)) Effective serum osmolality. 320 mosm/kg Stupor or coma It is important to recognize that overlap between the characteristic features of HHS an DKA may occur. Some patients with HHS, especially when there is very severe ehyration, have mil or moerate aciosis. Conversely, some chilren with T1DM may have features of HHS (severe hyperglycemia) if highcarbohyrate-containing beverages have been use to quench thirst an replace urinary losses prior to iagnosis (3). Therapy must be appropriately moifie to aress the pathophysiology an unique biochemical isturbances of each iniviual patient. Frequency of DKA At isease onset There is wie geographic variation in the frequency of DKA at onset of iabetes; rates inversely correlate with the regional incience of T1DM. Frequencies range from approximately 15% to 70% in Europe an North America (A) (20 24). DKA at iagnosis is more common in younger chilren (,5 yr of age), an in chilren whose families o not have reay access to meical care for social or economic reasons (A) (6, 24, 25). In chilren with establishe iabetes (recurrent DKA) The risk of DKA in establishe T1DM is 1 10% per patient per year (A, C) (26 29). Risk is increase in (28): Chilren with poor metabolic control or previous episoes of DKA Peripubertal an aolescent girls Chilren with psychiatric isorers, incluing those with eating isorers Chilren with ifficult or unstable family circumstances (e.g., parental abuse) Chilren who omit insulin (30) (C) Chilren with limite access to meical services Insulin pump therapy (as only rapi-acting or short-acting insulin is use in pumps, interruption of insulin elivery for any reason rapily leas to insulin eficiency) (29) (C) Management of DKA Emergency assessment Perform a clinical evaluation to confirm the iagnosis an etermine its cause. Carefully look for evience of infection. In recurrent DKA, insulin omission or failure to follow sick ay or pump failure management guielines accounts for almost all episoes, except for those because of acute severe febrile or gastrointestinal illness. Weigh the patient. (If boy surface area is use for flui therapy calculations, measure height or length to etermine surface area.) This weight shoul be use for calculations an not the weight from a previous office visit or hospital recor. Assess clinical severity of ehyration. Clinical assessment of ehyration is imprecise, inaccurate, an generally shows only fair to moerate agreement among examiners. It shoul be base on a combination of physical signs. The three most useful iniviual signs for assessing ehyration in young chilren an preicting at least 5% ehyration an aciosis are: s prolonge capillary refill time (normal capillary refill is s) s abnormal skin turgor (Ôtenting or inelastic skin) s abnormal respiratory pattern (hyperpnea) (31) Other useful signs in assessing egree of ehyration inclue ry mucus membranes, sunken eyes, absent tears, weak pulses, an cool extremities. More signs of ehyration ten to be associate with more severe ehyration (31). 30 Peiatric Diabetes 2007: 8: 28 43

50 Consensus Guielines s 10% ehyration is suggeste by the presence of weak or impalpable peripheral pulses, hypotension, an oliguria. Assess level of consciousness [Glasgow coma scale (GCS) see Table 2] (32). Obtain a bloo sample for laboratory measurement of serum or plasma glucose, electrolytes (incluing bicarbonate or total carbon ioxie), bloo urea nitrogen, creatinine, osmolality, venous (or arterial in critically ill patient) ph, pco 2, hemoglobin an hematocrit or complete bloo count (an increase white bloo cell count in response to stress is characteristic of DKA an is not inicative of infection (22). The white cell count nee not be measure unless there is evience of concurrent infection), calcium, phosphorus, an magnesium concentrations (if possible), HbA1c. Perform a urinalysis for ketones. Measurement of bloo b-hyroxybutyrate concentration, if available, is useful to confirm ketoaciosis an may be use to monitor the response to treatment (33, 34). Obtain appropriate specimens for culture (bloo, urine, throat), if there is evience of infection. If laboratory measurement of serum potassium is elaye, perform an electrocariogram (ECG) for baseline evaluation of potassium status (35, 36). In the chil with establishe iabetes (recurrent DKA) an suspecte insulin omission, it may be useful to obtain a bloo sample for etermination of serum free insulin concentration (even when chilren have been treate exclusively with biosynthetic human insulin, anti-insulin antiboies may be present in the serum an interfere with insulin immunoassays. Thus anti-insulin antiboies must be eliminate before the concentration of free (active) insulin is etermine (27)) before insulin is aministere because the history of recent insulin aministration may not be available or accurate (37). Supportive measures Secure the airway an empty the stomach by continuous nasogastric suction to prevent pulmonary aspiration in the unconscious or severely obtune patient. A peripheral intravenous (IV) catheter shoul be place for convenient an painless repetitive bloo sampling. An arterial catheter may be necessary in some critically ill patients manage in an intensive care unit. A cariac monitor shoul be use for continuous electrocariographic monitoring to assess T waves for evience of hyper- or hypokalemia (35, 36). Give oxygen to patients with severe circulatory impairment or shock. Give antibiotics to febrile patients after obtaining appropriate cultures of boy fluis. Catheterization of the blaer is usually not necessary, but if the chil is unconscious or unable to voi on eman (e.g., infants an very ill young chilren) the blaer shoul be catheterize. Where shoul the chil be manage? The chil shoul receive care in a unit that has: Experience nursing staff traine in monitoring an management Written guielines for DKA management in chilren Access to laboratories for frequent an timely evaluation of biochemical variables A specialist/consultant peiatrician with training an expertise in the management of DKA shoul irect inpatient management. Table 2. Glasgow coma scale or score. The GCS consists of three parameters an is score between 3 an 15 (32); 3 being the worst an 15 the best. One of the components of the GCS is the best verbal response, which cannot be assesse in non-verbal young chilren. A moification of the GCS was create for chilren too young to talk. Best eye response Best verbal response Best verbal response (non-verbal chilren) Best motor response 1. No eye opening 1. No verbal response 1. No response 1. No motor response 2. Eyes open to pain 3. Eyes open to verbal comman 4. Eyes open spontaneously 2. No wors, only incomprehensible souns; moaning an groaning 3. Wors, but incoherent* 4. Confuse, isoriente conversation 5. Orientate, normal conversation 2. Inconsolable, irritable, restless, cries 3. Inconsistently consolable an moans; makes vocal souns 4. Consolable when crying an interacts inappropriately 5. Smiles, oriente to soun, follows objects an interacts *Inappropriate wors, no sustaine conversational exchange. Attention can be hel; respons in a conversational manner, but shows some isorientation. 2. Extension to pain (ecerebrate posture) 3. Flexion to pain (ecorticate posture) 4. Withrawal from pain 5. Localizes pain 6. Obeys commans Peiatric Diabetes 2007: 8:

51 Wolfsorf et al. Immeiate assessment Clinical History Polyuria Polyipsia Weight loss (Weigh) Abominal pain Tireness Vomiting Confusion Clinical Signs Assess ehyration Deep sighing respiration (Kussmaul) Smell of ketones Lethargy/rowsiness ± vomiting Diagnosis Confirme Diabetic Ketoaciosis (DKA) Contact Senior Staff Biochemical Features & Investigations Ketones in urine Elevate bloo glucose Aciemia Bloo gases, urea, electrolytes Other investigations as inicate Shock (reuce peripheral pulses) Dehyration >5% Minimal ehyration Reuce conscious level/coma Not in shock Tolerating oral flui Aciotic (hyperventilation) Vomiting Resuscitation Airway ± NG tube Breathing (100% oxygen) Circulation (0.9% saline ml/kg over 1-2 h. & repeat until circulation is restore) but o not excee 30 ml/kg IV Therapy Calculate flui requirements Correct over 48 hours Saline 0.9% ECG for abnormal T-waves A KCL 40 mmol per litre flui Therapy Start with SC insulin Continue oral hyration No improvement Continuous insulin infusion 0.1 unit/kg/hour Critical Observations Hourly bloo glucose Hourly flui input & output Neurological status at least hourly Electrolytes 2 hourly after start of IV therapy Monitor ECG for T-wave changes Aciosis not improving Re- ev aluate IV flui calculations Insulin elivery system & ose Nee for aitional resuscitation Consier sepsis Bloo glucose 17 mmol/l or bloo glucose falls >5 mmol/l/hour IV Therapy Change to 0.45% saline + 5% glucose Ajust soium infusion to promote an increase in measure serum soium Improvement Clinicallywell, tolerating oral fluis Transition to SC Insulin Start SC insulin then stop IV insulin after an appropriate interval Aapte from Dunger et al. Karger Pub NG, nasogastric, SC,subcutaneous Neurological eterioration WARNING SIGNS: heaache, slowing heart rate, irritability, ecrease conscious level, incontinence, specific neurological signs Exclue hypoglycaemia Is it cerebral eema? Management Give mannitol g/kg Restrict IV fluis by one-thir Call senior staff Move to ICU Consier cranial imaging only after patient stabilise Fig. 2. Algorithm for the immeiate assessment an management of iabetic ketoaciosis (DKA). 32 Peiatric Diabetes 2007: 8: 28 43

52 Chilren with severe DKA (long uration of symptoms, compromise circulation, or epresse level of consciousness) or those who are at increase risk for cerebral eema (e.g.,,5 yr of age, severe aciosis, low pco 2, high bloo urea nitrogen) shoul be consiere for immeiate treatment in an intensive care unit (peiatric, if available) or in a unit that has equivalent resources an supervision, such as a chilren s war specializing in iabetes care (C,E) (4, 38). In a chil with establishe iabetes, whose parents have been traine in sick ay management, hyperglycemia an ketosis without vomiting or severe ehyration can be manage at home or in an outpatient health care facility (e.g., emergency war), provie an experience iabetes team supervises the care (C,E) (17, 39, 40). Chilren an aolescents with DKA shoul be manage in centers experience in its treatment an where vital signs, neurological status an laboratory results can be monitore frequently Clinical an biochemical monitoring Successful management of DKA an HHS emans meticulous monitoring of the patient s clinical an biochemical response to treatment so that timely ajustments in treatment can be mae when inicate by the patient s clinical or laboratory ata (E). There shoul be ocumentation on a flow chart of hour-by-hour clinical observations, IV an oral meications, fluis, an laboratory results. Monitoring shoul inclue the following: Hourly (or more frequently as inicate) vital signs (heart rate, respiratory rate, bloo pressure) Hourly (or more frequently as inicate) neurological observations (Glasgow coma score) for warning signs an symptoms of cerebral eema (see below) s s s s s s heaache inappropriate slowing of heart rate recurrence of vomiting change in neurological status (restlessness, irritability, increase rowsiness, incontinence) or specific neurologic signs (e.g., cranial nerve palsies, abnormal pupillary responses) rising bloo pressure ecrease oxygen saturation Amount of aministere insulin Hourly (or more frequently as inicate) accurate flui input (incluing all oral flui) an output Capillary bloo glucose shoul be measure hourly (but must be cross-checke against laboratory venous glucose, as capillary methos may be inaccurate in the presence of poor peripheral circulation an aciosis) Laboratory tests: serum electrolytes, glucose, bloo urea nitrogen, calcium, magnesium, phosphorus, hematocrit, an bloo gases shoul be repeate 2 4 hourly, or more frequently, as clinically inicate, in more severe cases Urine ketones until cleare or bloo b-hyroxybutyrate (BOHB) concentrations, if available, every 2 h (34) If the laboratory cannot provie timely results, a portable biochemical analyzer that measures plasma glucose, serum electrolytes an bloo ketones on fingerstick bloo samples at the besie is a useful ajunct to laboratory-base eterminations. Calculations: s s s Anion gap ¼ Na 2 (Cl 1 HCO 3 ): normal is 12 2 mmol/l j Consensus Guielines In DKA the anion gap is typically mmol/l; an anion gap.35 mmol/l suggests concomitant lactic aciosis (E) Correcte soium ¼ measure Na ([plasma glucose 2 5.6]/5.6) mmol/l Effective osmolality ¼ 2 3 (Na 1 K) 1 plasma glucose mosm/kg Goals of therapy Correct ehyration Correct aciosis an reverse ketosis Restore bloo glucose to near normal Avoi complications of therapy Ientify an treat any precipitating event Fluis an salt. Patients with DKA have a eficit in ECF volume that usually is in the range 5 10% (C) (41, 42). Shock with hemoynamic compromise is rare in peiatric DKA. Clinical estimates of the volume eficit are subjective an inaccurate (43, 44); therefore, in moerate DKA use 5 7% an in severe DKA 7 10% ehyration. The effective osmolality (formula above) is frequently in the range of mmol/kg. Increase serum urea nitrogen an hematocrit may be useful markers of the severity of ECF contraction (40, 45). The serum soium concentration is an unreliable measure of the egree of ECF contraction for two reasons: (1) glucose, largely restricte to the extracellular space, causes osmotic movement of water into the extracellular space thereby inucing ilutional hyponatremia (46, 47), an (2) the low soium content of the elevate lipi fraction of the serum in DKA. The latter is not a concern with most moern methos for measuring soium. Therefore, it is important to calculate the correcte soium (using the above formula) an monitor its changes throughout the course of therapy. As the plasma glucose concentration ecreases after aministering flui an insulin, the measure serum soium concentration shoul increase, but it is important to appreciate that this Peiatric Diabetes 2007: 8:

53 Wolfsorf et al. oes not inicate a worsening of the hypertonic state. A failure of measure serum soium levels to rise or a further ecline in serum soium levels with therapy is thought to be a potentially ominous sign of impening cerebral eema (48 50). The objectives of flui an electrolyte replacement therapy are: Restoration of circulating volume Replacement of soium an the ECF an intracellular flui eficit of water Improve glomerular filtration with enhance clearance of glucose an ketones from the bloo Reuction of risk of cerebral eema Principles of water an salt replacement Despite much effort to fin the cause of cerebral eema it remains a mystery. There is no convincing evience of an association between the rate of flui or soium aministration use in the treatment of DKA an the evelopment of cerebral eema (51). No treatment strategy can be efinitively recommene as being superior to another base on evience. The principles escribe below were evelope after a comprehensive review of the literature an were accepte an enorse by a panel of expert physicians representing the Lawson Wilkins Peiatric Enocrine Society (LWPES), the European Society for Paeiatric Enocrinology (ESPE), an the International Society for Peiatric an Aolescent Diabetes (ISPAD) (4, 52). Begin with flui replacement before insulin therapy. Volume expansion (resuscitation) is require only if neee to restore peripheral circulation. Subsequent flui aministration (incluing oral fluis) shoul rehyrate evenly over 48 h at a rate rarely in excess of times the usual aily maintenance. Water an salt eficits must be replace (A). IV or oral fluis that may have been given in another facility before assessment shoul be factore into calculation of eficit an repair (E). If neee to restore peripheral circulation, volume expansion (resuscitation) shoul begin immeiately with 0.9% saline (E). s s The volume an rate of aministration epens on circulatory status an, where it is clinically inicate, the volume aministere typically is ml/kg over 1 2 h, an may be repeate, if necessary (E). Use crystalloi not colloi (E). There are no ata to support the use of colloi in preference to crystalloi in the treatment of DKA. Subsequent flui management (eficit replacement) shoul be with 0.9% saline or Ringer s acetate for at least 4 6 h (C,E) (45, 49, 53 55). s s s Thereafter, eficit replacement shoul be with a solution that has a tonicity equal to or greater than 0.45% saline with ae potassium chlorie, potassium phosphate, or potassium acetate (see below uner potassium replacement) (C,E) (45, 49, 53, 56, 57). The rate of flui (IV an oral) shoul be calculate to rehyrate evenly over 48 h (C, E) (4, 45). As the severity of ehyration may be ifficult to etermine an frequently is uner- or overestimate (C) (44), infuse flui each ay at a rate rarely in excess of times the usual aily maintenance requirement base on age, weight, or boy surface area (E) (4). See Table 3 for examples of calculations. In aition to clinical assessment of ehyration, calculation of effective osmolality may be valuable to guie flui an electrolyte therapy (E). Urinary losses shoul not routinely be ae to the calculation of replacement flui, but may be necessary in rare circumstances (E). The soium content of the flui may nee to be increase if measure serum soium is low an oes not rise appropriately as the plasma glucose concentration falls (C) (48, 58). The use of large amounts of 0.9% saline has been associate with the evelopment of hyperchloremic metabolic aciosis (59, 60). Insulin therapy DKA is cause by a ecrease in effective circulating insulin associate with increases in counter-regulatory hormones (glucagon, catecholamines, growth hormone, cortisol). Although rehyration alone causes some ecrease in bloo glucose concentration (61, 62), insulin therapy is essential to normalize bloo glucose an suppress lipolysis an ketogenesis (A) (63). DKA is cause by either relative or absolute insulin eficiency. Begin with 0.1 U/kg/h. 1 2 h AFTER starting flui replacement therapy. Extensive evience inicates that Ôlow ose IV insulin aministration shoul be the stanar of care (A) (64). Start insulin infusion 1 2 h after starting flui replacement therapy, i.e., after the patient has receive initial volume expansion (E,C) (65). Correction of insulin eficiency s Dose: 0.1 unit/kg/h (for example, one metho is to ilute 50 units regular [soluble] insulin in 50 ml normal saline, 1 unit ¼ 1 ml) (64, 66) 34 Peiatric Diabetes 2007: 8: 28 43

54 Table 3. Shows an alternative example of flui volumes for the subsequent phase of rehyration Boy weight kg s s DKA: give maintenance 1 5% of boy weight/24 h Maintenance ml/24 h ml/24 h ml/h After initial resuscitation, an assuming 10% ehyration, the total amount of flui shoul be given over 48 h. The Table gives volumes for maintenance an rehyration per 24 h an per hour. If flui has been given for resuscitation, the volume shoul not be subtracte from the amount shown in the Table. Fluis given orally (when patient has improve) shoul be subtracte from the amount in the table. The Table is base on maintenance volumes accoring to Darrow (146). For boy weights.32 kg, the volumes have been ajuste so as not to excee twice the maintenance rate of flui aministration. Route of aministration IV (A) An IV bolus is unnecessary (67), may increase the risk of cerebral eema (65), an shoul not be use at the start of therapy (C) The ose of insulin shoul usually remain at 0.1 unit/kg/h at least until resolution of DKA (ph. 7.30, bicarbonate. 15 mmol/l an/or closure of the anion gap), which invariably takes longer than normalization of bloo glucose concentrations (B) (68). If the patient emonstrates marke sensitivity to insulin (e.g., some young chilren with DKA, patients with HHS, an some oler chilren with establishe iabetes), the ose may be ecrease to 0.05 unit/kg/h, or less, provie that metabolic aciosis continues to resolve. During initial volume expansion the plasma glucose concentration falls steeply (61) (C). Thereafter, an after commencing insulin therapy, the plasma glucose concentration typically ecreases at a rate of 2 5 mmol/l/h, epening on the timing an amount of glucose aministration (C) (69 75). To prevent an unuly rapi ecrease in plasma glucose concentration an hypoglycemia, 5% glucose shoul be ae to the IV flui (e.g., 5% glucose in 0.45% saline) when the plasma glucose falls to approximately mmol/l ( mg/l), or sooner if the rate of fall is precipitous (B). s It may be necessary to use 10% or even 12.5% extrose to prevent hypoglycemia while continuing to infuse insulin to correct the metabolic aciosis. If bloo glucose falls very rapily (.5 mmol/l/h) after initial flui expansion consier aing glucose even before plasma glucose has ecrease to 17 mmol/l (E). If biochemical parameters of DKA (ph, anion gap) o not improve, reassess the patient, review insulin therapy, an consier other possible causes of impaire response to insulin; e.g., infection, errors in insulin preparation (E). In circumstances where continuous IV aministration is not possible, hourly, or 2-hourly subcutaneous (SC) or intramuscular (IM) aministration of a short- or rapi-acting insulin analog (insulin lispro or insulin aspart) is safe an may be as effective as IV regular insulin infusion (C) (70, 76 79), but shoul not be use in subjects whose peripheral circulation is impaire (E). s s Consensus Guielines Initial ose SC: 0.3 unit/kg, followe 1 h later by SC insulin lispro or aspart at 0.1 unit/kg every hour, or units/kg every 2 h. If bloo glucose falls to,14 mmol/l (250 mg/l) before DKA has resolve (ph still,7.30), a 5% glucose an continue with insulin as above. s When DKA has resolve an bloo glucose is,14 mmol/l (250 mg/l), reuce SC insulin lispro or aspart to 0.05 unit/kg/h to keep bloo glucose 11 mmol/l (200 mg/l) until resolution of DKA. If the bloo glucose concentration ecreases too quickly or too low before DKA has resolve, increase the amount of glucose aministere. Do not ecrease the insulin infusion. Peiatric Diabetes 2007: 8:

55 Wolfsorf et al. Potassium replacement Chilren with DKA suffer total boy potassium eficits of the orer of 3 6 mmol/kg (41, 42, 80 82). The major loss of potassium is from the intracellular pool. Intracellular potassium is eplete because of transcellular shifts of this ion cause by hypertonicity (increase plasma osmolality causes solvent rag in which water an potassium are rawn out of cells) an glycogenolysis an proteolysis seconary to insulin eficiency cause potassium efflux from cells. Potassium is lost from the boy from vomiting an as a consequence of osmotic iuresis. Volume epletion causes seconary hyperalosteronism, which promotes urinary potassium excretion. Thus, total boy epletion of potassium occurs, but at presentation serum potassium levels may be normal, increase, or ecrease (83). Renal ysfunction, by enhancing hyperglycemia an reucing potassium excretion, contributes to hyperkalemia (83). Aministration of insulin an the correction of aciosis will rive potassium back into the cells, ecreasing serum levels (84). The serum potassium concentration may ecrease abruptly, preisposing the patient to cariac arrhythmias. Even with normal or high levels of serum potassium at presentation, there is always a total boy eficit of potassium. Begin with 40 mmol potassium/l in the infusate or 20 mmol potassium/l in the hypokalemic patient receiving flui at a rate.10 ml/kg/h. Replacement therapy is require regarless of the serum potassium concentration (A) (85, 86). If the patient is hypokalemic, start potassium replacement at the time of initial volume expansion an before starting insulin therapy. Otherwise, start replacing potassium after initial volume expansion an concurrent with starting insulin therapy. If the patient is hyperkalemic, efer potassium replacement therapy until urine output is ocumente (E). If immeiate serum potassium measurements are unavailable, an ECG may help to etermine whether the chil has hyper- or hypokalemia (C) (35, 36). Flattening of the T wave, wiening of the QT interval, an the appearance of U waves inicate hypokalemia. Tall, peake, symmetrical, T waves an shortening of the QT interval are signs of hyperkalemia. The starting potassium concentration in the infusate shoul be 40 mmol/l. Subsequent potassium replacement therapy shoul be base on serum potassium measurements (E). s If potassium is given with the initial rapi volume expansion, a concentration of 20 mmol/ L shoul be use. Potassium phosphate may be use together with potassium chlorie or acetate; e.g., 20 mmol/l potassium chlorie an 20 mmol/l potassium phosphate or 20 mmol/l potassium phosphate an 20 mmol/l potassium acetate (C,E). Potassium replacement shoul continue throughout IV flui therapy (E). The maximum recommene rate of IV potassium replacement is usually 0.5 mmol/kg/h (E). If hypokalemia persists espite maximum rate of potassium replacement, then the rate of insulin infusion can be reuce. Phosphate Depletion of intracellular phosphate occurs in DKA an phosphate is lost as a result of osmotic iuresis (41, 42, 80). Plasma phosphate levels fall after starting treatment an this is exacerbate by insulin, which promotes entry of phosphate into cells (87 89). Total boy phosphate epletion has been associate with a variety of metabolic isturbances (90 92). Clinically significant hypophosphatemia may occur if IV therapy without foo intake is prolonge beyon 24 h (41, 42, 80). Prospective stuies have not shown clinical benefit from phosphate replacement (A) (93 98). Severe hypophosphatemia in conjunction with unexplaine weakness shoul be treate (E) (99). Aministration of phosphate may inuce hypocalcemia (C) (100, 101). Potassium phosphate salts may be safely use as an alternative to or combine with potassium chlorie or acetate, provie that careful monitoring of serum calcium is performe to avoi hypocalcemia (C) (100, 101). Aciosis Severe aciosis is reversible by flui an insulin replacement; insulin stops further ketoaci prouction an allows ketoacis to be metabolize, which generates bicarbonate (A). Treatment of hypovolemia improves tissue perfusion an renal function increasing the excretion of organic acis. Controlle trials have shown no clinical benefit from bicarbonate aministration (B,C) ( ). Bicarbonate therapy may cause paraoxical CNS aciosis (106, 107); rapi correction of aciosis with bicarbonate causes hypokalemia (106, 108, 109), an failure to account for the soium being aministere an appropriately reucing the NaCl concentration of the fluis can result in increasing osmolality (106). Nevertheless, there may be selecte patients who may benefit from cautious alkali therapy. These inclue: patients with severe aciemia (arterial ph, 6.9) in whom ecrease cariac contractility an peripheral vasoilatation can further impair tissue perfusion, an patients with life-threatening hyperkalemia (E) (110). 36 Peiatric Diabetes 2007: 8: 28 43

56 Consensus Guielines There is no evience that bicarbonate is either necessary or safe in DKA. Bicarbonate aministration is not recommene unless the aciosis is profoun an likely to affect aversely the action of arenaline/epinephrine uring resuscitation (A). If bicarbonate is consiere necessary, cautiously give 1 2 mmol/kg over 60 min (E). Complications of therapy Inaequate rehyration Hypoglycemia Hypokalemia Hyperchloremic aciosis Cerebral eema Introuction of oral fluis an transition to SC insulin injections Oral fluis shoul be introuce only when substantial clinical improvement has occurre (mil aciosis/ketosis may still be present) (E). When oral flui is tolerate, IV flui shoul be reuce (E). When ketoaciosis has resolve, oral intake is tolerate, an the change to SC insulin is planne, the most convenient time to change to SC insulin is just before a mealtime (E). To prevent reboun hyperglycemia the first SC injection shoul be given min (with rapiacting insulin) or 1 2 h (with regular insulin) before stopping the insulin infusion to allow sufficient time for the insulin to be absorbe (E). With intermeiate- or long-acting insulin, the overlap shoul be longer an the IV insulin graually lowere. For example, for patients on a basal-bolus insulin regimen, the first ose of basal insulin may be aministere in the evening an the insulin infusion is stoppe the next morning (E). The ose an type of SC insulin shoul be accoring to local preferences an circumstances. After transitioning to SC insulin, frequent bloo glucose monitoring is require to avoi marke hyperglycemia an hypoglycemia (E). Morbiity an mortality In national population stuies, the mortality rate from DKA in chilren is % (C,B) (111, 112). Cerebral eema accounts for 60 90% of all DKA eaths (C,B) (50, 113). From 10% to 25% of survivors of cerebral eema have significant resiual morbiity (C,B) (50, 113, 114). Other rare causes of morbiity an mortality inclue: Hypokalemia Hyperkalemia Severe hypophosphatemia Hypoglycemia Other central nervous system complications (isseminate intravascular coagulation, ural sinus thrombosis, basilar artery thrombosis) Peripheral venous thrombosis Sepsis Rhinocerebral or pulmonary mucormycosis Aspiration pneumonia Pulmonary eema Ault respiratory istress synrome (ARDS) Pneumothorax, pneumomeiastinum an SC emphysema Rhabomyolysis Acute renal failure Acute pancreatitis (115) Cerebral eema The incience of cerebral eema in national population stuies is % an the mortality rate is 21 24% (50, 113, 114). Demographic factors that have been associate with an increase risk of cerebral eema inclue: Younger age (C) (116) New onset iabetes (B) (112) (C) (116) Longer uration of symptoms (C) (117) These risk associations may reflect the greater likelihoo of severe DKA. In aition, epiemiological stuies have ientifie several potential risk factors at iagnosis or uring treatment of DKA. These inclue: Greater hypocapnia at presentation after ajusting for egree of aciosis (C) (50, 118) Increase serum urea nitrogen at presentation (C) (50) More severe aciosis at presentation (C) (65, 119) Bicarbonate treatment for correction of aciosis (C) (50, 120) An attenuate rise in measure serum soium concentrations uring therapy (C) (48 50) Greater volumes of flui given in the first 4 h (65) Aministration of insulin in the first hour of flui treatment (65) Warning signs an symptoms of cerebral eema inclue: Heaache & slowing of heart rate Change in neurological status (restlessness, irritability, increase rowsiness, incontinence) Specific neurological signs (e.g., cranial nerve palsies) Rising bloo pressure Decrease O 2 saturation Peiatric Diabetes 2007: 8:

57 Wolfsorf et al. Clinically significant cerebral eema usually evelops 4 12 h after treatment has starte, but can occur before treatment has begun (50, 114, ) or, uncommonly, may evelop as late as h after the start of treatment (C,B) (50, 116, 125). Symptoms an signs are variable. A metho of clinical iagnosis base on besie evaluation of neurological state is shown below (C) (126): Diagnostic criteria. Abnormal motor or verbal response to pain Decorticate or ecerebrate posture Cranial nerve palsy (especially III, IV, an VI) Abnormal neurogenic respiratory pattern (e.g., grunting, tachypnea, Cheyne-Stokes respiration, apneusis) Major criteria. Altere mentation/fluctuating level of consciousness Sustaine heart rate eceleration (ecrease more than 20 beats per minute) not attributable to improve intravascular volume or sleep state Age-inappropriate incontinence Minor criteria. Vomiting Heaache Lethargy or not easily arousable Diastolic bloo pressure. 90 mm Hg Age,5 yr One iagnostic criterion, two major criteria, or one major an two minor criteria have a sensitivity of 92% an a false positive rate of only 4%. A chart with the reference ranges for bloo pressure an heart rate, which vary epening on height, weight, an gener, shoul be reaily available, either in the patient s chart or at the besie. Have mannitol or hypertonic saline at the besie an the ose to be given calculate beforehan. In case of profoun neurological symptoms, mannitol shoul be given immeiately. Treatment of cerebral eema Initiate treatment as soon as the conition is suspecte. Give mannitol g/kg IV over 20 min an repeat if there is no initial response in 30 min to 2 h (C,E) ( ). Reuce the rate of flui aministration by one-thir. Hypertonic saline (3%), 5 10 ml/kg over 30 min, may be an alternative to mannitol, especially if there is no initial response to mannitol (C) (130, 131). s Mannitol or hypertonic saline shoul be available at the besie. Elevate the hea of the be. Intubation may be necessary for the patient with impening respiratory failure, but aggressive hyperventilation (to a pco 2, 2.9 kpa [22 mm Hg]) has been associate with poor outcome an is not recommene (C) (132). After treatment for cerebral eema has been starte, a cranial CT scan shoul be obtaine to rule out other possible intracerebral causes of neurologic eterioration (10% of cases), especially thrombosis ( ) or hemorrhage, which may benefit from specific therapy. Prevention of recurrent DKA Management of an episoe of DKA is not complete until its cause has been ientifie an an attempt mae to treat it. All cases of recurrent DKA are preventable Insulin omission, either inavertently or eliberately, is the cause in most cases (C, A) (28, 30). The most common cause of DKA in insulin pump users is failure to take extra insulin with a pen or syringe when hyperglycemia an hyperketonemia or ketonuria occur (E). Home measurement of bloo BOHB concentrations, when compare with urine ketone testing, ecreases iabetes-relate hospital visits (both emergency epartment visits an hospitalizations) by the early ientification an treatment of ketosis (137). Bloo BOHB measurements may be especially valuable to prevent DKA in patients who use a pump because interrupte insulin elivery rapily leas to ketosis (E). s There may be issociation between urine ketone an serum BOHB concentrations, which may be increase to levels consistent with DKA when a urine ketone test is negative or shows only trace or small ketonuria (138). There usually is an important psychosocial reason for insulin omission. s s s an attempt to lose weight in an aolescent girl with an eating isorer, a means of escaping an intolerable or abusive home situation, clinical epression or other reason for inability of the patient to manage the iabetes unassiste. An infection that is not associate with vomiting an iarrhea is selom the cause when the patient/ family is properly eucate in iabetes management an is receiving appropriate follow-up care by 38 Peiatric Diabetes 2007: 8: 28 43

58 Consensus Guielines a iabetes team with a 24-h telephone helpline (B) ( ). A psychiatric social worker or clinical psychologist shoul be consulte to ientify the psychosocial reason(s) contributing to evelopment of DKA (E). Insulin omission can be prevente by schemes that provie eucation, psychosocial evaluation an treatment combine with ault supervision of insulin aministration (B) (142). s Parents an patients shoul learn how to recognize an treat impening DKA with aitional rapior short-acting insulin an oral fluis (E) s Patients shoul have access to a 24-h telephone helpline for emergency avice an treatment (B) (139) s When a responsible ault aministers insulin there may be as much as a tenfol reuction in frequency of recurrent DKA (B) (142). This article is a Chapter in the ISPAD Clinical Practice Consensus Guielines of the International Society for Peiatric an Aolescent Diabetes (ISPAD, The complete set of these Guielines will later be publishe as a compenium. 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60 Consensus Guielines 63. LUZI L, BARRETT EJ, GROOP LC, FERRANNINI E, DEFRONZO RA. Metabolic effects of low-ose insulin therapy on glucose metabolism in iabetic ketoaciosis. Diabetes 1988: 37: KITABCHI AE. Low-ose insulin therapy in iabetic ketoaciosis: fact or fiction? Diabetes Metab Rev 1989: 5: EDGE J, JAKES R, ROY Y et al. The UK case-control stuy of cerebral oeema complicating iabetic ketoaciosis in chilren. Diabetologia 2006: 49: SCHADE DS, EATON RP. Dose response to insulin in man: ifferential effects on glucose an ketone boy regulation. J Clin Enocrinol Metab 1977: 44: LINDSAY R, BOLTE RG. The use of an insulin bolus in low-ose insulin infusion for peiatric iabetic ketoaciosis. Peiatr Emerg Care 1989: 5: SOLER NG, FITZGERALD MG, WRIGHT AD, MALINS JM. Comparative stuy of ifferent insulin regimens in management of iabetic ketoaciosis. Lancet 1975: 2: MARTIN MM, MARTIN AA. Continuous low-ose infusion of insulin in the treatment of iabetic ketoaciosis in chilren. J Peiatr 1976: 89: FISHER JN, SHAHSHAHANI MN, KITABCHI AE. Diabetic ketoaciosis: low-ose insulin therapy by various routes. N Engl J Me 1977: 297: LIGHTNER ES, KAPPY MS, REVSIN B. Low-ose intravenous insulin infusion in patients with iabetic ketoaciosis: biochemical effects in chilren. Peiatrics 1977: 60: KAPPY MS, LIGHTNER ES. Low-ose intravenous insulin in the treatment of iabetic ketoaciosis. Am J Dis Chil 1979: 133: DROP SL, DUVAL-ARNOULD JM, GOBER AE, HERSH JH, MCENERY PT, KNOWLES HC. Low-ose intravenous insulin infusion versus subcutaneous insulin injection: a controlle comparative stuy of iabetic ketoaciosis. Peiatrics 1977: 59: EDWARDS GA, KOHAUT EC, WEHRING B, HILL LL. Effectiveness of low-ose continuous intravenous insulin infusion in iabetic ketoaciosis. A prospective comparative stuy. J Peiatr 1977: 91: BURGHEN GA, ETTELDORF JN, FISHER JN, KITABCHI AQ. Comparison of high-ose an low-ose insulin by continuous intravenous infusion in the treatment of iabetic ketoaciosis in chilren. Diabetes Care 1980: 3: SACKS HS, SHAHSHAHANI M, KITABCHI AE, FISHER JN, YOUNG RT. Similar responsiveness of iabetic ketoaciosis to low-ose insulin by intramuscular injection an albumin-free infusion. Ann Intern Me 1979: 90: UMPIERREZ GE, LATIF K, STOEVER J et al. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with iabetic ketoaciosis. Am J Me 2004: 117: UMPIERREZ GE, CUERVO R, KARABELL A, LATIF K, FREIRE AX, KITABCHI AE. Treatment of iabetic ketoaciosis with subcutaneous insulin aspart. Diabetes Care 2004: 27: DELLA MANNA T, STEINMETZ L, CAMPOS PR et al. Subcutaneous Use of a Fast-Acting Insulin Analog: An alternative treatment for peiatric patients with iabetic ketoaciosis. Diabetes Care 2005: 28: BUTLER A, TALBOT N, BURNETT C, STANBURY J, MACLACHLAN E. Metabolic stuies in iabetic coma. Trans Assoc Am Phys 1947: 60: DANOWSKI T, PETERS J, RATHBUN J, QUASHNOCK J, GREENMAN L. Stuies in iabetic aciosis an coma, with particular emphasis on the retention of aministere potassium. J Clin Invest 1949: 28: DARROW D, PRATT E. Retention of water an electrolyte uring recovery in a patient with iabetic aciosis. J Peiatr 1952: 41: ADROGUE HJ, LEDERER ED, SUKI WN, EKNOYAN G. Determinants of plasma potassium levels in iabetic ketoaciosis. Meicine (Baltimore) 1986: 65: DEFRONZO RA, FELIG P, FERRANNINI E, WAHREN J. Effect of grae oses of insulin on splanchnic an peripheral potassium metabolism in man. Am J Physiol 1980: 238:E TATTERSALL RB. A paper which change clinical practice (slowly). Jacob Holler on potassium eficiency in iabetic aciosis (1946). Diabet Me 1999: 16: NABARRO JD, SPENCER AG, STOWERS JM. Treatment of iabetic ketosis. Lancet : 1: GUEST G. Organic phosphates of the bloo an mineral metabolism in iabetic aciosis. Am J Dis Chil 1942: 64: GUEST G, RAPOPORT S. Electrolytes of bloo plasma an cells in iabetic aciosis an uring recovery. Proc Am Diabetes Assoc 1947: 7: RILEY MS, SCHADE DS, EATON RP. Effects of insulin infusion on plasma phosphate in iabetic patients. Metabolism 1979: 28: ALBERTI KG, EMERSON PM, DARLEY JH, HOCKADAY TD. 2,3-Diphosphoglycerate an tissue oxygenation in uncontrolle iabetes mellitus. Lancet : 2: KNOCHEL JP. The pathophysiology an clinical characteristics of severe hypophosphatemia. Arch Intern Me 1977: 137: O CONNOR LR, WHEELER WS, BETHUNE JE. Effect of hypophosphatemia on myocarial performance in man. N Engl J Me 1977: 297: GIBBY OM, VEALE KE, HAYES TM, JONES JG, WARDROP CA. Oxygen availability from the bloo an the effect of phosphate replacement on erythrocyte 2,3-iphosphoglycerate an haemoglobin-oxygen affinity in iabetic ketoaciosis. Diabetologia 1978: 15: KELLER U, BERGER W. Prevention of hypophosphatemia by phosphate infusion uring treatment of iabetic ketoaciosis an hyperosmolar coma. Diabetes 1980: 29: WILSON HK, KEUER SP, LEA AS, BOYD AE 3r, EKNOYAN G. Phosphate therapy in iabetic ketoaciosis. Arch Intern Me 1982: 142: BECKER DJ, BROWN DR, STERANKA BH, DRASH AL. Phosphate replacement uring treatment of iabetic ketosis. Effects on calcium an phosphorus homeostasis. Am J Dis Chil 1983: 137: FISHER JN, KITABCHI AE. A ranomize stuy of phosphate therapy in the treatment of iabetic ketoaciosis. J Clin Enocrinol Metab 1983: 57: CLERBAUX T, REYNAERT M, WILLEMS E, FRANS A. Effect of phosphate on oxygen-hemoglobin affinity, iphosphoglycerate an bloo gases uring recovery from iabetic ketoaciosis. Intensive Care Me 1989: 15: BOHANNON NJ. Large phosphate shifts with treatment for hyperglycemia. Arch Intern Me 1989: 149: ZIPF WB, BACON GE, SPENCER ML, KELCH RP, HOPWOOD NJ, HAWKER CD. Hypocalcemia, hypomagnesemia, an transient hypoparathyroiism uring Peiatric Diabetes 2007: 8:

61 Wolfsorf et al. therapy with potassium phosphate in iabetic ketoaciosis. Diabetes Care 1979: 2: WINTER RJ, HARRIS CJ, PHILLIPS LS, GREEN OC. Diabetic ketoaciosis. Inuction of hypocalcemia an hypomagnesemia by phosphate therapy. Am J Me 1979: 67: HALE PJ, CRASE J, NATTRASS M. Metabolic effects of bicarbonate in the treatment of iabetic ketoaciosis. BMJ (Clin Res E) 1984: 289: MORRIS LR, MURPHY MB, KITABCHI AE. Bicarbonate therapy in severe iabetic ketoaciosis. Ann Intern Me 1986: 105: OKUDA Y, ADROGUE HJ, FIELD JB, NOHARA H, YAMASHITA K. Counterprouctive effects of soium bicarbonate in iabetic ketoaciosis. J Clin Enocrinol Metab 1996: 81: GREEN SM, ROTHROCK SG, HO JD et al. Failure of ajunctive bicarbonate to improve outcome in severe peiatric iabetic ketoaciosis. Ann Emerg Me 1998: 31: ASSAL JP, AOKI TT, MANZANO FM, KOZAK GP. Metabolic effects of soium bicarbonate in management of iabetic ketoaciosis. Diabetes 1974: 23: OHMAN JL Jr, MARLISS EB, AOKI TT, MUNICHOODAPPA CS, KHANNA VV, KOZAK GP. The cerebrospinal flui in iabetic ketoaciosis. N Engl J Me 1971: 284: SOLER NG, BENNETT MA, DIXON K, FITZGERALD MG, MALINS JM. Potassium balance uring treatment of iabetic ketoaciosis with special reference to the use of bicarbonate. Lancet 1972: 2: LEVER E, JASPAN JB. Soium bicarbonate therapy in severe iabetic ketoaciosis. Am J Me 1983: 75: NARINS RG, COHEN JJ. Bicarbonate therapy for organic aciosis: the case for its continue use. Ann Intern Me 1987: 106: CURTIS JR, TO T, MUIRHEAD S, CUMMINGS E, DANE- MAN D. Recent trens in hospitalization for iabetic ketoaciosis in Ontario chilren. Diabetes Care 2002: 25: EDGE JA, FORD-ADAMS ME, DUNGER DB. Causes of eath in chilren with insulin epenent iabetes Arch Dis Chil 1999: 81: EDGE JA, HAWKINS MM, WINTER DL, DUNGER DB. The risk an outcome of cerebral oeema eveloping uring iabetic ketoaciosis. Arch Dis Chil 2001: 85: LAWRENCE SE, CUMMINGS EA, GABOURY I, DANEMAN D. Population-base stuy of incience an risk factors for cerebral eema in peiatric iabetic ketoaciosis. J Peiatr 2005: 146: HADDAD NG, CROFFIE JM, EUGSTER EA. Pancreatic enzyme elevations in chilren with iabetic ketoaciosis. J Peiatr 2004: 145: ROSENBLOOM AL. Intracerebral crises uring treatment of iabetic ketoaciosis. Diabetes Care 1990: 13: BELLO FA, SOTOS JF. Cerebral oeema in iabetic ketoaciosis in chilren. Lancet 1990: 336: 64 (Letter) 118. MAHONEY CP, VLCEK BW, DELAGUILA M. Risk factors for eveloping brain herniation uring iabetic ketoaciosis. Peiatr Neurol 1999: 21: DURR JA, HOFFMAN WH, SKLAR AH, EL GAMMAL T, STEINHART CM. Correlates of brain eema in uncontrolle IDDM. Diabetes 1992: 41: BUREAU MA, BEGIN R, BERTHIAUME Y, SHAPCOTT D, KHOURY K, GAGNON N. Cerebral hypoxia from bicarbonate infusion in iabetic aciosis. J Peiatr 1980: 96: DEEB L. Development of fatal cerebral eema uring outpatient therapy for iabetic ketoaciosis. Pract Diab 1989: 6: GLASGOW AM. Devastating cerebral eema in iabetic ketoaciosis before therapy. Diabetes Care 1991: 14: (Letter) 123. COUCH RM, ACOTT PD, WONG GW. Early onset fatal cerebral eema in iabetic ketoaciosis. Diabetes Care 1991: 14: FIORDALISI I, HARRIS GD, GILLILAND MG. Prehospital cariac arrest in iabetic ketoaciemia: why brain swelling may lea to eath before treatment. J Diabetes Complications 2002: 16: EDGE JA. Cerebral oeema uring treatment of iabetic ketoaciosis: are we any nearer fining a cause? Diabetes Metab Res Rev 2000: 16: MUIR AB, QUISLING RG, YANG MC, ROSENBLOOM AL. Cerebral Eema in Chilhoo Diabetic Ketoaciosis: Natural history, raiographic finings, an early ientification. Diabetes Care 2004: 27: FRANKLIN B, LIU J, GINSBERG-FELLNER F. Cerebral eema an ophthalmoplegia reverse by mannitol in a new case of insulin-epenent iabetes mellitus. Peiatrics 1982: 69: SHABBIR N, OBERFIELD SE, CORRALES R, KAIRAM R, LEVINE LS. Recovery from symptomatic brain swelling in iabetic ketoaciosis. Clin Peiatr (Phila) 1992: 31: ROBERTS MD, SLOVER RH, CHASE HP. Diabetic ketoaciosis with intracerebral complications. Peiatr Diabetes 2001: 2: CURTIS JR, BOHN D, DANEMAN D. Use of hypertonic saline in the treatment of cerebral eema in iabetic ketoaciosis (DKA). Peiatr Diabetes 2001: 2: KAMAT P, VATS A, GROSS M, CHECCHIA PA. Use of hypertonic saline for the treatment of altere mental status associate with iabetic ketoaciosis. Peiatr Crit Care Me 2003: 4: MARCIN JP, GLASER N, BARNETT P et al. Factors associate with averse outcomes in chilren with iabetic ketoaciosis-relate cerebral eema. J Peiatr 2002: 141: KANTER RK, OLIPHANT M, ZIMMERMAN JJ, STUART MJ. Arterial thrombosis causing cerebral eema in association with iabetic ketoaciosis. 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62 Consensus Guielines 140. DROZDA DJ, DAWSON VA, LONG DJ, FRESON LS, SPERLING MA. Assessment of the effect of a comprehensive iabetes management program on hospital amission rates of chilren with iabetes mellitus. Diabetes Euc 1990: 16: GREY M, BOLAND EA, DAVIDSON M, LI J, TAMBORLANE WV. Coping skills training for youth with iabetes mellitus has long-lasting effects on metabolic control an quality of life. J Peiatr 2000: 137: GOLDEN MP, HERROLD AJ, ORR DP. An approach to prevention of recurrent iabetic ketoaciosis in the peiatric population. J Peiatr 1985: 107: HOLLIDAY MA, SEGAR WE. The maintenance nee for water in parenteral flui therapy. Peiatrics 1957: 19: FRIEDMAN AL. Peiatric hyration therapy: historical review an a new approach. Kiney Int 2005: 67: HENDRICKS K, DUGGAN C., es. Manual of Peiatric Nutrition, 4th en. Hamilton, Ontario: BC Decker, DARROW DC. The physiologic basis for estimating requirements for parenteral fluis. Peiatr Clin North Am 1959: 6: Peiatric Diabetes 2007: 8:

63 Peiatric Diabetes 2007: 8: All rights reserve # 2007 The Authors Journal compilation # 2007 Blackwell Munksgaar Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Management of chilren with iabetes requiring surgery Betts P, Brink SJ, Swift PGF, Silink M, Wolfsorf J, Hanas R. Management of chilren with iabetes requiring surgery. Peiatric Diabetes 2007: 8: Peter Betts a, Stuart J Brink b, Peter GF Swift c, Martin Silink, Joseph Wolfsorf e, Ragnar Hanas f a Southampton University Hospitals Trust, Southampton, UK; b Department of Peiatrics, Tufts University School of Meicine, Boston, MA, USA; c Chilrens Hospital, Leicester Royal Infirmary, Leicester LE1 5WW, UK; Institute of Enocrinology, The Chilren s Hospital at Westmea, Syney, Australia; e Division of Enocrinology, Chilren s Hospital, Boston, MA, USA; f Department of Peiatrics, Uevalla Hospital, Uevalla, Sween Corresponing author: Ragnar Hanas, MD, PhD Department of Peiatrics Uevalla Hospital S Uevalla Sween [email protected] Eitors of the ISPAD Clinical Practice Consensus Guielines ; Ragnar Hanas, Kim Donaghue, Georgeanna Klingensmith, an Peter GF Swift. When chilren with iabetes require surgery or other proceures requiring seation or anesthesia, optimal management shoul maintain aequate hyration an near to normal glycemia, while minimizing the risk of hypoglycemia. The stress of surgery may cause acute hyperglycemia, which increases the risk of postoperative infection (1, 2) (B). Evience-base controlle stuies of perioperative care in chilren have not been conucte, but a review of management has recently been publishe in the anesthesiology literature (3); our current guielines are consistent with the recommenations in that reference. Perioperative management of type 1 iabetes in aults is reviewe in a separate reference (4). The current revise guielines are base on those of the ISPAD Consensus Guielines 2000 with aitions an amenments from the Australian Clinical Practice Guielines: Type 1 Diabetes in Chilren an Aolescents (5), an the Canaian Diabetes Association: Clinical Practice Guielines for the Prevention an Management of Diabetes in Canaa (6). As there are few relevant scientific papers on management uring surgery, the recommenations are mostly base on expert consensus. Glycemic targets for surgery In the past, aults with iabetes have ha an increase risk of postoperative woun infections 242 (approximately 10-fol in a stuy of patients in 1973) (7) (C). However, when bloo glucose (BG) is maintaine between 6.8 an 9.3 mmol/l ( mg/l), there is no ifference in the risk of postoperative woun infections after major vascular surgery (8) (B). Maintaining BG levels below 11 mmol/l (200 mg/l) for the first two postoperative ays ecrease the risk of sternal woun infections after heart surgery from 2.4 to 1.5% (9) (C). Improve postoperative glycemic control [plasma glucose levels of mmol/l ( mg/l)] using continuous intravenous (IV) insulin infusion significantly ecrease mortality an morbiity in patients who require postoperative intensive care an mechanical ventilation after major surgery (10) (A). With this egree of tight glycemic control, 5.2% of subjects experience hypoglycemic episoes compare with 0.8% in the control group; however, none of the episoes was severe (11) (A). The safe implementation of such intensive glycemic control with a continuous IV insulin infusion requires a written protocol an staff training to ensure effectiveness an to minimize the risk of hypoglycemia. To achieve optimal glycemic control, insulin osage may nee to be increase on the ay of major surgery an for approximately 2 after surgery. This is best achieve by continuous IV insulin infusion even after the resumption of oral feeing (12) (C).

64 Surgery in chilren with iabetes Appropriate perioperative glycemic targets for brief an minor surgical proceures are less clear. To ate, no intervention stuies have assesse the impact of ifferent BG levels on morbiity or mortality in these circumstances. However, a few stuies in aults that compare ifferent methos of achieving glycemic control uring minor an moerate surgery i not show any averse effects of maintaining perioperative glycemic levels between 5 an 11 mmol/l ( mg/l) (13, 14) (A) (15) (B). Because the ata in aults show averse effects of hyperglycemia, an support tight perioperative control of glucose in patients unergoing major surgery, it seems reasonable to aim for BG levels between 5 an 10 mmol/l ( mg/l) uring surgical proceures in chilren (E). The benefits of tight glycemic control must be weighe against the risk of perioperative hypoglycemia, which may not be recognize uring anesthesia; however, this risk can be mitigate by frequent capillary BG monitoring. (iii) The elective surgery shoul be scheule as the first case on a surgical list, preferably in the morning (E). (iv) Centers performing surgical proceures on chilren with iabetes shoul have available written protocols for postoperative management of iabetes on the wars where chilren are amitte (E). (v) IV access, infusion of glucose, an frequent BG monitoring is essential in all situations when general anesthesia is given. Glucose 5% is usually sufficient; glucose 10% may be necessary when there is a risk of hypoglycemia (E). (vi) Elevate bloo ketone (beta-hyroxybutyrate, BOHB) an BG concentrations require extra insulin an possibly IV fluis for correction. Such correction also requires the consieration of elay an rescheuling of an elective surgical proceure. A besie meter for BOHB levels works well in a hospital setting an may suffice for monitoring (16) (B, E). Chilren with type 1 iabetes or type 2 treate with insulin requiring a major surgical proceure Must be amitte to hospital for general anesthesia (GA). Nee insulin, even if fasting, to avoi ketoaciosis. Shoul receive a glucose infusion when fasting for more than 2 h before an anesthetic to prevent hypoglycemia. Shoul be carefully monitore via capillary BG measurement for hyperglycemia as stress cause by surgery may cause hyperglycemia an increase insulin requirements. Anesthesia may cause vasoilatation an rop the bloo pressure (BP). If there is an unexpecte acute event (bleeing, rop in BP), normal saline 0.9% (NS) or Ringer s lactate must be infuse rapily. In this case, potassium-containing fluis must not be infuse rapily. Recommenations It is helpful in the management of chilren with iabetes unergoing surgery to ivie proceures into two categories: (i) Minor surgery or proceures that require a brief GA (or heavy seation), usually of less than 1-h uration, an that shoul not have a major impact on glycemic control. Examples inclue enoscopies, jejunal biopsy, aenotonsillectomy, grommet insertion, or repeate short proceures such as in oncology or burns wars. The chil will usually be ischarge from hospital on the ay of proceure. (ii) Major surgery that requires more prolonge general GA is associate with greater risks of metabolic ecompensation, an the chil is unlikely to be ischarge from hospital on the ay of proceure. Although the majority of surgical proceures are elective, both types of proceure may occur as emergencies. (i) Whenever possible, surgery on chilren an aolescents with iabetes shoul be performe in centers with appropriate personnel an facilities to care for chilren with iabetes (E). (ii) To ensure the highest levels of safety, careful liaison is require between surgical, anesthetic, an chilren s iabetes care teams before amission to hospital for elective surgery an as soon as possible after amission for emergency surgery (E). Elective surgery This shoul be performe when the iabetes is uner the best possible control. If glycemic control is uncertain or poor; Consier amission to hospital prior to surgery for assessment an stabilization of glycemic control. If control remains problematic; Surgery shoul be cancelle an rescheule. Peiatric Diabetes 2007: 8:

65 Betts et al. Scheuling of surgery Proceures are preferably scheule first on surgical lists, ieally in the morning. Amit to hospital in the afternoon prior to surgery for major operations, but in appropriate circumstances, it is possible to amit early on the ay of surgery for both minor an major operations (E). Evening prior to surgery Frequent BG monitoring is important especially before meals an snacks an at betime (measure bloo ß-hyroxybutyrate an/or urinary ketone concentration if BG is mmol/l) (E). Give the usual evening or betime insulin(s) an betime snack. Ketosis or severe hyperglycemia will necessitate correction, preferably by overnight IV insulin infusion, an might elay surgery. Major elective surgery (that requires, at a minimum, overnight hospital stay postoperatively) Proceures preferably shoul be first on the list, ieally, in the morning. No soli foo for at least 6 h prior to surgery. Clear fluis (incluing breast milk) may be allowe up to 4 h before surgery (check with anesthetist). Omit the usual morning insulin ose. At least 2 h before surgery start, an IV insulin infusion with glucose 5% (10% if there is concern about hypoglycemia) (see Table 1) (4) (E). If BG is high (.14 mmol/l, 250 mg/l), use 0.5 NS or NS without glucose an increase insulin supply, but a 5% extrose when BG falls below 14 mmol/l (250 mg/l). Monitor BG hourly before surgery an every min uring the operation an until the chil awakens from anesthesia (E). Monitor BG hourly for 4 h after surgery or for as long as the patient is receiving IV insulin. Aim to maintain BG between 5 an 10 mmol/l ( mg/l) an use correction rates of IV insulin uring surgery (E). With IV insulin, a suitable ratio of insulin to glucose for prepubertal chilren is typically 1 unit per 5 g of IV glucose an for aolescents 1 unit per 3 g of IV glucose (3) (E). The ose is ajuste base on BG response. Once the patient is awake, it shoul be possible to ajust the IV insulin to maintain BG in the ieal range, mmol/l ( mg/l), without excessive risk of hypoglycemia (Table 1) (E). When oral intake is not possible, the IV infusion shoul continue for as long as necessary. Minor surgery (where ischarge home usually occurs later in the ay of surgery) Proceures preferably shoul be first on a surgical list, ieally in the morning. Aim for BG 5 10 mmol/l ( mg/l) uring an after surgery (E). Algorithms for ifferent types of insulin regimens are suggeste below. For more etail, see Rhoes et al. (3). No soli foo for at least 6 h prior to GA. Clear fluis (incluing breast milk) are allowe up to 4 h before anesthesia (check with anesthetist). Patients treate with twice aily insulin regimens Morning operations scheule h to h. At h, give 50% of the usual morning ose of intermeiate-acting insulin (NPH, lente). Omit the short- or rapi-acting insulin unless neee to correct hyperglycemia. Commence IV fluis (use glucose 5 10%, as necessary, to prevent hypoglycemia). After surgery, start oral intake or continue IV glucose epening on the chil s conition. Give small oses of short- or rapi-acting insulin (base on the chil s usual correction factor), if neee, to reuce hyperglycemia or to balance foo intake. The inner or evening ose of insulin is given as usual. Alternatively, IV insulin infusion may be starte at h (see below). If IV insulin has been use, continue the insulin infusion until lunch an then given a small ose of short- or rapi-acting insulin to last until the inner or evening insulin ose. If the chil is fully recovere, it may be possible to ischarge the chil from hospital later in the ay. Afternoon operations scheule for h to h. At h, give 50% of the usual ose of intermeiate-acting insulin (NPH, lente) an the usual ose of short- or rapi-acting insulin. Alternatively, give 30 40% of the usual morning insulin ose of short- or rapi-acting insulin (but no intermeiate- or long-acting insulin) an use an IV insulin infusion beginning at least 2 hours before surgery (Table 1). Allow the chil to eat a light breakfast. Clear fluis may be allowe up to 4 hours before anesthesia. Start IV fluis (an IV insulin infusion, if applicable) 2 hours before surgery or no later than miay (Table 1). Thereafter, procee as for morning operations (above). 244 Peiatric Diabetes 2007: 8:

66 Surgery in chilren with iabetes Table 1. Infusion guie for surgical proceures Maintenance flui guie Glucose 5% glucose; 10% if there is concern about hypoglycemia. If BG is high (.14 mmol/l, 250 mg/l), use 0.5 normal saline or normal saline without glucose an increase insulin supply but a 5% extrose when BG falls below 14 mmol/l (250 mg/l). Soium Saline % (20 40 mmol Na/L) with glucose is wiely use. There is evience that the risk of acute hyponatremia may be increase when using hypotonic maintenance solutions (i.e.,,0.9% NaCl) in hospitalize chilren (18) (C). Many centers, therefore, use saline % ( mmol Na/L). A compromise woul be to give 0.45% saline with 5% glucose, carefully monitor electrolytes, an change to 0.9% saline if plasma-na is falling. Potassium Monitor electrolytes. After surgery, a potassium chlorie 20 mmol to each liter of intravenous flui. Some centers a potassium routinely only if infusion is require for more than 12 h. Example of calculation of maintenance requirements (19) (C, E), (tables for this vary between centers, use one that is locally agree an establishe). Boy weight Flui requirement/24 h For each kg between 3 9 kg 100 ml/kg For each kg between kg A an aitional 50 ml/kg For each kg over 20 kg A an aitional 20 ml/kg Max 2000 ml female, 2500 ml male Insulin infusion A soluble insulin 50 units to 50 ml normal saline 0.9%, making a solution of 1 unit insulin/ml; attach to syringe pump an label clearly Start infusion at ml/kg/h (i.e., U/kg/h) if bloo glucose is,6 7 mmol/l, 0.05 ml/kg/h if 8 12 mmol/l, ml/kg/h between 12 an 15 mmol/l an 0.1 U/kg/h if.15 mmol/l. Aim to maintain BG between 5 an 10 mmol/l, epening of the type of surgery, by ajusting insulin infusion hourly BG must be measure at least hourly when the patient is on IV insulin. Do not stop the insulin infusion if BG, 5 6 mmol/l (90 mg/l) as this will cause reboun hyperglycemia. Reuce the rate of infusion. The insulin infusion may be stoppe temporarily if BG,4 mmol/l (55 mg/l) but only for min. BG, bloo glucose. Patients on basal-bolus insulin regimens (17) Morning operations scheule for h to h. Chilren on basal bolus regimens benefit from not iscontinuing their basal insulin before minor surgical proceures as IV insulin will isrupt their usual basal insulin supply when restarting subcutaneous (SC) insulin injections. This is particularly relevant for chilren requiring repeate proceures. Consier the nee for reuction (by 20 30%) of the preceing evening long-acting insulin if there is a pattern of low BG values in the morning. If the general anesthesia is short (,1 h), give 50% of the usual morning ose of intermeiate-acting insulin ose (NPH, lente) or % of the ose if the patient takes long-acting insulin (glargine, etemir, ultratar) at h an commence IV fluis containing glucose 5% (10% if risk of hypoglycemia). Do not give short- or rapi-acting insulin in the morning unless necessary to correct hyperglycemia. Alternatively, IV regular insulin infusion may be starte at breakfast time (omitting all types of morning SC insulin). Perform BG measurements before, uring, an immeiately after GA (at least hourly) an, if necessary, increase glucose concentration of IV fluis to 10% to prevent hypoglycemia. Ajust glucose infusion an insulin (by SC injection of rapi-acting insulin or IV infusion) to maintain perioperative BG in the range 5 10 mmol/l (E). In the postoperative perio, supplemental mimorning short-/rapi-acting insulin may be given if require (10 25% of total aily ose) an, when tolerate, a light meal. Later in the ay, the aim is to resume normal meals an premeal insulin oses as soon as the chil is able to tolerate oral fees. Afternoon operations scheule for h to h. The patient is usually allowe to eat breakfast an rink clear fluis until 4 h preoperatively. At breakfast, give the usual ose of rapi-acting or 50 60% of the usual short-acting insulin an usual ose of basal intermeiate- or long-acting insulin (if usually given at this time). Commence IV fluis containing glucose 5% (10% if risk of hypoglycemia) at a maintenance rate approximately 2 h after breakfast. Peiatric Diabetes 2007: 8:

67 Betts et al. Measure capillary BG hourly an, if necessary, ajust the glucose concentration of IV fluis to prevent hypoglycemia. Give supplemental IV insulin, if neee, to keep perioperative BG concentrations in the target range. After surgery, IV insulin or aitional short-/rapiacting insulin may be require until normal eating is resume. Later, if tolerate, resume meals an the chil s usual insulin at the appropriate times. a small oses of rapi-acting insulin. Give bolus ose an foo when the chil can eat again. Emergency surgery Diabetic ketoaciosis may present as an Ôacute abomen. Acute illness may precipitate iabetic ketoaciosis (with severe abominal pain). Patients on insulin pumps The iabetes team shoul etermine the approach epening on the iniviual patient an proceure. When a chil on continuous subcutaneous insulin infusion (CSII) goes to the operating theatre, it is important to secure the SC infusion site to prevent islogement an interruption of insulin supply uring the proceure. If the general anesthesia is short (approximately,1 h), the pump can be continue at the basal rate, keeping IV glucose 5% infusion at the maintenance rate (see below). Do not give a morning/meal bolus ose unless necessary to correct hyperglycemia. Monitor BG levels hourly preoperatively an at least half hourly uring GA. When necessary, correction oses can be given with the pump preoperatively an postoperatively. Alternatively, give extra IV insulin to keep perioperative BG within target. A meal bolus is given when the patient is reay to eat. Alternatively, CSII can be iscontinue an a continuous IV insulin an glucose infusion commence, as escribe above, until feeing has been satisfactorily establishe. Minor proceures requiring fasting simplifie proceure For short proceures (with or without seation or anesthesia) an when rapi recovery is anticipate, a simplifie protocol may be formulate by personnel experience in the anesthesia for chilren with iabetes an may inclue the following alternatives: Early morning proceure (e.g., h to h): elay insulin an foo until immeiately after completion of the proceure. Twice aily insulin: give 50% of usual insulin ose (NPH/lente an short-/rapi-acting) or give repeate small oses of short-/rapi-acting insulin (20 50% of morning short-/rapi-acting ose). Basal/bolus or CSII: give usual basal insulin/ continue basal rate in the morning an, if neee, No flui foo or meication by mouth; in some emergency situations the stomach must be emptie by a nasogastric tube. Secure IV access. Check weight, measure serum electrolytes, BG, bloo gases, an bloo ß-hyroxybutyrate or urinary ketones before anesthesia. If ketoaciosis is present, follow protocol for iabetic ketoaciosis an elay surgery until circulating volume an electrolyte eficits are correcte. If there is no ketoaciosis, start IV fluis an insulin infusions as for elective surgery. Type 2 iabetes For those iniviuals who have type 2 iabetes an are treate with insulin, follow the insulin guielines as for elective surgery, epening on type of insulin regimen. Patients on oral treatment Metformin: iscontinue 24 h before the proceure for elective surgery, if,24 h since the last ose for emergent surgery, it is essential to maintain hyration with IV fluis before, uring, an after surgery. Sulfonylureas or thiazoliineiones: stop for the ay of surgery. Monitor BG hourly an if greater than 10 mmol/l (180 mg/l) treat with IV insulin, as for elective surgery, to normalize levels, or SC insulin if it is a minor proceure. References 1. GOLDEN SH, PEART-VIGILANCE C, KAO WH, BRANCATI FL. Perioperative glycemic control an the risk of infectious complications in a cohort of aults with iabetes. Diabetes Care 1999: 22: POMPOSELLI JJ, BAXTER JK 3r, BABINEAU TJ et al. Early postoperative glucose control preicts nosocomial infection rate in iabetic patients. JPEN J Parenter Enteral Nutr 1998: 22: RHODES ET, FERRARI LR, WOLFSDORF JI. Perioperative management of peiatric surgical patients with iabetes mellitus. Anesth Analg 2005: 101: GLISTER BC, VIGERSKY RA. Perioperative management of type 1 iabetes mellitus. Enocrinol Metab Clin North Am 2003: 32: Peiatric Diabetes 2007: 8:

68 Surgery in chilren with iabetes 5. APEG. (AUSTRALASIAN PAEDIATRIC ENDOCRINE GROUP). Australian Clinical Practice Guielines: Type 1 Diabetes in Chilren an Aolescents, Australian Government: National Health an Meical Research Council, CANADIAN DIABETES ASSOCIATION. Clinical Practice Guielines for the prevention an management of iabetes in Canaa. Can J Diab 2003: 27(Suppl. 2): S84 S CRUSE PJ, FOORD R. A five-year prospective stuy of 23,649 surgical wouns. Arch Surg 1973: 107: HJORTRUP A, RASMUSSEN BF, KEHLET H. Morbiity in iabetic an non-iabetic patients after major vascular surgery. Br Me J (Clin Res E) 1983: 287: ZERR KJ, FURNARY AP, GRUNKEMEIER GL, BOOKIN S, KANHERE V, STARR A. Glucose control lowers the risk of woun infection in iabetics after open heart operations. Ann Thorac Surg 1997: 63: VAN DEN BERGHE G, WOUTERS P, WEEKERS F et al. Intensive insulin therapy in the critically ill patients. N Engl J Me 2001: 345: VAN DEN BERGHE G, WOUTERS PJ, BOUILLON Retal. Outcome benefit of intensive insulin therapy in the critically ill: insulin ose versus glycemic control. Crit Care Me 2003: 31: KAUFMAN FR, DEVGAN S, ROE TF, COSTIN G. Perioperative management with prolonge intravenous insulin infusion versus subcutaneous insulin in chilren with type I iabetes mellitus. J Diabetes Complications 1996: 10: HEMMERLING TM, SCHMID MC, SCHMIDT J, KERN S, JACOBI KE. Comparison of a continuous glucoseinsulin-potassium infusion versus intermittent bolus application of insulin on perioperative glucose control an hormone status in insulin-treate type 2 iabetics. J Clin Anesth 2001: 13: CHRISTIANSEN CL, SCHURIZEK BA, MALLING B, KNUDSEN L, ALBERTI KG, HERMANSEN K. Insulin treatment of the insulin-epenent iabetic patient unergoing minor surgery. Continuous intravenous infusion compare with subcutaneous aministration. Anaesthesia 1988: 43: RAUCOULES-AIME M, LUGRIN D, BOUSSOFARA M, GASTAUD P, DOLISI C, GRIMAUD D. Intraoperative glycaemic control in non-insulin-epenent an insulin-epenent iabetes. Br J Anaesth 1994: 73: REWERS A, MCFANN K, CHASE HP. Besie monitoring of bloo beta-hyroxybutyrate levels in the management of iabetic ketoaciosis in chilren. Diabetes Technol Ther 2006: 8: KILHAM H, ISAACS D. (es). Enocrinology an iabetes. In: The Chilren s Hospital at Westmea Hanbook: Clinical Practice Guielines in Paeiatrics, 4th en. Australia: McGraw-Hill Australia Pty Lt, 2004: CHOONG K, KHO ME, MENON K, BOHN D. Hypotonic versus isotonic saline in hospitalise chilren: a systematic review. Arch Dis Chil 2006: 91: Peiatric Diabetes 2007: 8:

69 Peiatric Diabetes 2007: 8: All rights reserve # 2007 The Authors Journal compilation # 2007 Blackwell Munksgaar Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Microvascular an macrovascular complications Donaghue KC, Chiarelli F, Trotta D, Allgrove J, Dahl-Jorgensen K. Microvascular an macrovascular complications. Peiatric Diabetes 2007: 8: Kim C Donaghue a, Francesco Chiarelli b, Daniela Trotta b, Jeremy Allgrove c an Knut Dahl-Jorgensen a The Chilren s Hospital at Westmea, University of Syney, Syney, Australia; b Department of Paeiatrics, University of Chieti, Chieti, Italy; c Department of Paeiatric Enocrinology an Diabetes, Royal Lonon Hospital, Lonon, UK Department of Peiatrics, Ullevål University Hospital an Faculty of Meicine, University of Oslo, Oslo, Norway Corresponing author: Kim C Donaghue MB BS PhD The Chilren s Hospital at Westmea, Locke Bag 4001, Westmea, NSW 2145, Australia [email protected] Acknowlegements: Esko Wiltshire, Gisela Dahlquist, Kenneth Lee Jones, Ena Roche, Amina Balafrej, an Riccaro Bonfanti. Eitors of the ISPAD Clinical Practice Consensus Guielines : Kim Donaghue, Ragnar Hanas, Georgeanna Klingensmith, an Peter Swift. The long-term vascular complications of iabetes inclue retinopathy, nephropathy, neuropathy, an macrovascular isease. The outcomes are the following: Visual impairment an blinness ue to iabetic retinopathy. Renal failure an hypertension ue to iabetic nephropathy. Pain, paresthesiae, muscle weakness, an autonomic ysfunction ue to iabetic neuropathy. Cariac isease, peripheral vascular isease, an stroke ue to macrovascular isease. Clinically evient iabetes-relate vascular complications shoul be rare in chilhoo an aolescence. However, early functional an structural abnormalities may be present a few years after the onset of the isease. There has been a eclining incience of complications reporte in many areas with specialize clinics (1 3). This has occurre over a perio of time uring which there have been major changes in iabetes management, ientification of putative risk factors, an the avent of regular screening for complications. There is no evience that this is a worlwie occurrence: in areas where health care is not optimal, a greater risk of complications will remain. Interventional stuies of intensive glycemic control The Diabetes Control an Complications Trial (DCCT) was a multicenter, ranomize controlle clinical trial involving 1441 patients with type 1 iabetes conucte in North America from 1983 to 1993 (4). At recruitment, 195 were pubertal aolescents (age yr): there were no chilren (5). After completion of the DCCT (a meian of 7.4 yr in the aolescent group) an hence the en of ranomization to the two treatment groups (intensive an conventional treatments), the Epiemiology of Diabetes Interventions an Complications (EDIC) stuy continue to follow patients (6). After 4 yr, there was no significant ifference in hemoglobin A1c (HbA1c) between the former intensive an conventional treatment groups. The DCCT provie unequivocal evience that intensive iabetes treatment an improve glycemic control conferre a significant risk reuction for microvascular complications compare with conventional treatment (5) (A). The EDIC stuy has shown that this positive effect continue after ranomization, i.e., there was a memory effect of the improve glycemic control. In aition, it showe a positive effect of intensive therapy for reuction in macrovascular isease (7) (A). 163

70 Donaghue et al. Table 1. Screening, risk factors, an interventions for vascular complications: the levels of evience for risk factors an interventions pertaining to ault stuies, except for improve glycemic control. For clarity, references for these evience levels are inclue in the text Retinopathy Nephropathy When to commence screening? Screening methos Risk factors Potential intervention Annually from age 11 yr with 2 yr of iabetes uration an from 9 yr with 5 yr of uration (E) Annually from age 11 yr with 2 yr of iabetes uration an from 9 yr with 5 yr of uration (E) Funal photography or myriatic ophthalmoscopy (less sensitive) (E) Urinary albumin/creatinine ratio or first morning albumin concentration (E) Neuropathy Unclear History an physical examination Macrovascular After the age of isease 12 yr (E) Lipi profile every 5 yr an bloo pressure annually (E) Hyperglycemia (A), Improve glycemic high bloo pressure (B), control (A) an lipi abnormalities (B), laser therapy (A) an higher BMI (C) High bloo pressure (B), lipi abnormalities (B), an smoking (B) Hyperglycemia (A) an higher BMI (C) Hyperglycemia (A), high bloo pressure (A), lipi abnormalities (B), higher BMI (B), an smoking (B) Improve glycemic control (A), ACEI an AIIRA (A), an bloo pressure lowering (B) Improve glycemic control (A) Improve glycemic control (A), bloo pressure control (B), an statins (A) ACEI, angiotensin-converting enzyme inhibitors; AIIRA, angiotensin II receptor antagonists; BMI, boy mass inex. In the aolescent cohort, intensive treatment compare with conventional treatment reuce the risk an progression of backgroun retinopathy by 53%, clinical neuropathy by 60%, an microalbuminuria by 54%. The ifference in HbA1c was 8.1 vs. 9.8%. The benefits of intensive therapy persiste in the former aolescent cohort uring the EDIC stuy: the previously intensively manage group ha 74% less retinopathy, 48% less microalbuminuria, an 85% less albuminuria (6). Compare with conventional treatment, intensive treatment in the total age group reuce the risk of clinical neuropathy by 60%. Cariovascular events were reuce by 50% in the previously intensively treate group compare with that of the control group uring a mean 17 yr follow-up (7). The DCCT confirme that improve glycemic control may initially worsen iabetic retinopathy. However, within yr, the avantage of intensive treatment is evient (8 10). In the DCCT, the longterm benefits of intensive insulin treatment greatly outweighe the risk of early retinal eterioration. Ophthalmological monitoring is recommene before initiation of intensive treatment an at 3-month intervals for 6 12 months thereafter for patients with long-staning poor glycemic control, particularly if Table 2. Target levels for ifferent parameters to reuce the risk of microvascular an cariovascular iseases in chilren an aolescents with type 1 iabetes; the levels of evience pertain to ault stuies Parameter Target level Evience grae Hemoglobin A1c (Diabetes Control an 7.5% without severe hypoglycemia A Complications Trial stanar) Low-ensity lipoprotein cholesterol,2.6 mmol/l A High-ensity lipoprotein cholesterol.1.1 mmol/l C Triglyceries,1.7 mmol/l C Bloo pressure,90th percentile by age, sex, an height C/B Boy mass inex,95th percentile (non-obese) E Smoking None A Physical activity.1 h of moerate physical activity aily B Seentary activities,2 h aily B Healthy iet Caloric intake appropriate for age an E normal growth Fat,30% of caloric intake an saturate fat,10% of caloric intake Fiber intake g aily Increase intake of fresh fruit an vegetables 164 Peiatric Diabetes 2007: 8:

71 Table 3. Recommene threshol values for ifferent parameters for intervention an the primary prevention; the levels of evience pertain to ault stuies Threshol value Type of intervention Evience grae Bloo pressure.90th percentile for age, Lifestyle intervention B gener, an height Bloo pressure.90th percentile espite ACEI E lifestyle intervention Bloo pressure.95th percentile Lifestyle intervention an ACEI A LDL cholesterol.2.6 mmol/l Dietary intervention A/C LDL cholesterol.3.4 mmol/l an one or more cariovascular isease risk factors Statins A/C ACEI, angiotensin-converting enzyme inhibitors; LDL, low-ensity lipoprotein. Consensus Guielines retinopathy severity is at or past the moerate nonproliferative stage at the time of intensification (E). Other risk factors for the evelopment of complications Longer uration of iabetes, oler age, an puberty are risk factors for complications (11). The prepubertal years of iabetes uration have a significantly lesser impact especially further from the onset of gonaarche (12) (B). For the same iabetes uration, age an puberty increase the risk for retinopathy an elevate albumin excretion rate (AER) (13) (B). Smoking is associate with an increase risk of eveloping persistent microalbuminuria or macroalbuminuria (4, 14). The evience for the effect of smoking on retinopathy is less clear. Type 1 iabetes an smoking interact to prouce excess cariovascular morbiity an mortality (15) (B). Hypertension has a greater impact on cariovascular isease (CVD) in iabetic patients than in non-iabetic iniviuals (16). Bloo pressure control (,140/80 mmhg in aults) is effective in ecreasing cariovascular morbiity an mortality in iabetes (17) (A). Dyslipoproteinemia is associate with microalbuminuria an retinopathy evelopments in the DCCT/ EDIC (18, 19). This inclue higher total an lowensity lipoprotein (LDL) cholesterol an higher triglycerie levels for microalbuminuria, as well as larger LDL particle size an apoprotein B in men (B). Family history of complications increases the risk for nephropathy (20) an retinopathy (21) (B). Higher boy mass inex (BMI) is a risk factor for retinopathy (22), neuropathy (23), microalbuminuria (24), an CVD (25) (B). Lifestyle issues seentary men with iabetes have higher mortality than active iniviuals (26) (B). Diabetic retinopathy Aolescents have a higher risk of progression to vision-threatening retinopathy compare with ault patients with iabetes (27, 28). The progression may be rapi, especially in those with poor glycemic control (29). Hence, aolescence is the time when efforts shoul be irecte to screening for early signs of iabetic retinopathy an moifiable risk factors. Regression of retinopathy can also occur (27, 28, 30). Progression of retinopathy Backgroun retinopathy is characterize by microaneurysms specific to iabetic retinopathy; hemorrhages both pre-retinal an intraretinal; soft an har exuates involving microinfarction an protein an lipi leakages, respectively; intraretinal microvascular abnormalities an ilatation; an constriction an tortuosity of vessels. Backgroun retinopathy is not vision threatening an oes not invariably progress to proliferative retinopathy. Preproliferative retinopathy is characterize by vascular obstruction, progressive intraretinal microvascular abnormalities, an infarctions of the retinal nerve fibers causing cotton wool spots. Proliferative retinopathy is characterize by neovascularization in the retina an/or vitreous posterior surface. The vessels may rupture or blee into the vitreoretinal space which is vision threatening. Encasement in connective tissue results in ahesions, which can cause hemorrhage an retinal etachment. High-risk characteristics for visual loss are the location an extent of neovascularization an signs of vitreous or pre-retinal hemorrhage (31). Maculopathy is characterize by ecrease vascular competence an microaneurysm formation, which prouce exuation an swelling in the central retina. Assessment of retinopathy The most sensitive etection methos for retinopathy are stereoscopic funal photography an fluorescein angiography. Seven-fiel stereoscopic funus photography provies greater sensitivity for etecting both backgroun an proliferative retinopathies compare Peiatric Diabetes 2007: 8:

72 Donaghue et al. with irect ophthalmoscopy (28, 32, 33) (A). Fluorescein angiography reveals functional abnormalities (vascular permeability) as well as structural abnormalities in the bloo vessels, whereas funal photography reveals only structural abnormalities. Other techniques use in the etection of iabetic retinopathy inclue inirect ophthalmoscopy an monochromatic single-fiel photography. In aults with iabetes, myriasis reuce the technical failure rate over non-myriatic funal photography but i not improve sensitivity an specificity for etection of iabetic retinopathy or reuce the nee for referral compare with unilate funal photography of a single fiel (34). In an incient cohort, after 6 yr of uration with HbA1c of 8.7%, 7-fiel stereoscopic funal photography etecte early retinopathy (one microaneurysm or hemorrhage) in 8% of chilren less than 11 yr an 12% of prepubertal chilren. This compares with retinopathy etection in 25% of aolescents oler than 11 yr an 29% of pubertal aolescents (13) (B). Screening from age 11 yr with 2 yr of iabetes uration or from 9 yr with 5 yr of uration will capture most retinopathy eveloping in chilren an aolescents (E). Laser treatment for retinopathy Once sight-threatening retinopathy has been etecte, the treatment options are limite. Panretinal photocoagulation, commonly known as Ôlaser therapy, consists of multiple iscrete outer retinal burns throughout the mi an far peripheral areas but sparing the central macula. It has been proven to reuce the progression of visual loss by more than 50% in patients with proliferative retinopathy (31, 35) (A). However, photocoagulation is not inicate for eyes with mil or moerate non-proliferative retinopathy (36). Sie effects of treatment are ecrease night an peripheral visions an subtle changes in color perception. Complications of laser therapy are vitreal an choroial hemorrhages or visual sequelae of misplace burns. Diabetic nephropathy Diabetic nephropathy is efine as persistent proteinuria greater than 500 mg/24 h or albuminuria greater than 300 mg/24 h an is usually associate with hypertension an a iminishing glomerular filtration rate (37). Enstage renal failure may occur many years later an requires ialysis or kiney transplantation. Diabetic nephropathy is a major cause of morbiity an mortality among young aults with type 1 iabetes (38, 39). Assessment of incipient nephropathy The first clinical sign is microalbuminuria. This is efine (37) as any of those below: AER between 20 an 200 mg/min or AER mg/24 h in 24-h urine collections. Albumin concentration (AC) mg/l (in early morning urine sample). Albumin/creatinine ratio (ACR) mg/mmol or mg/g (spot urine) in males an mg/ mmol in females (because of lower creatinine excretion). Other efinitions have also been use in longituinal stuies. Microalbuminuria is confirme by fining two or all three samples abnormal over a perio of 3 6 months. Persistent microalbuminuria has been shown to preict the progression to en-stage renal failure (2, 30, 31, 40 42) an is associate with an increase risk of macrovascular isease (43, 44) (B). An increase of AER within the microalbuminuric range ientifies patients at risk of progression to renal amage (24, 45, 46) (B). Loss of nocturnal ipping on 24-h bloo pressure monitoring is an early marker of iabetic renal isease preceing microalbuminuria (47). Microalbuminuria can also regress (48), especially in aolescents (24, 49). Progression to microalbuminuria is precee by renal hypertrophy (50) (B). Confouners exercise increases the AER in noniabetic iniviual an increases it more markely uring iabetes. Even moerate exercise may interfere with the interpretation of ata (37). For interpretation of persistently elevate AER values, especially in chilren with short iabetes uration, it is essential to exclue other causes of albuminuria such as immunoglobulin A or other types of nephritis common in chilhoo. In an incient cohort, after 6 yr of uration, early elevation of AER (greater than 7.5 mg/min) was etecte in 5% of chilren younger than 11 yr an 5% of prepubertal chilren: no microalbuminuria was etecte. This compare with early elevation of AER in 25% aolescents oler than 11 yr an 26% of pubertal aolescents. (13). Screening from age 11 yr with 2 yr of iabetes uration an from 9 yr with 5 yr of uration will capture most evolving microalbuminuria in chilren an aolescents (E). Antihypertensive treatment for prevention of nephropathy Effective antihypertensive therapy in patients with nephropathy prolongs the time to en-stage renal isease (51) (B). A recent prospective stuy has shown improve prognosis of renal function from 5 to 7 yr from onset of nephropathy to a meian of 21.7 yr (52), preominantly ue to aggressive antihypertensive treatment, with smaller contributions from improve glycemic control an smoking cessation (B). 166 Peiatric Diabetes 2007: 8:

73 Bloo pressure values between the 90th an 95th percentiles are efine as prehypertension (53, 54). Protocols an reference values for 24-h ambulatory bloo pressure monitoring in chilren have also been publishe (21, 47). Angiotensin-converting enzyme inhibitors (ACEI) are recommene for use in chilren an aolescents with hypertension (55). They have been effective an safe in chilren in short-term stuies (28, 56). The clinical beneficial effect of angiotensin II receptor antagonists (AIIRA) in hypertension is similar to that observe with ACEI but have not been use extensively in chilren. ACEI an AIIRA reuce progression from microalbuminuria to macroalbuminuria an increase the regression rate to normoalbuminuria (57) (A). For those with microalbuminuria, ACEI an AIIRA reuce the oubling of serum creatinine. While ACEI reuces all-cause mortality, AIIRA use was associate with higher all-cause mortality compare with placebo (A). Despite the above evience mainly in aults, there are still some concerns regaring the use of ACEI in protecting long-term renal function in young iniviuals without hypertension. In meta-analysis of iniviual patient ata, the beneficial effects were more moest in those with the lowest levels of microalbuminuria (58) (A). Young people with microalbuminuria woul potentially be taking ACEI for ecaes. Sie effects inclue cough, hyperkalaemia, heaache, an impotence (57). Furthermore, an increase in major congenital malformations has recently been reporte after first-trimester exposure to ACEI but not with other antihypertensive agents in noniabetic women (59). Diabetic neuropathy Diabetes can affect the somatic an autonomic nervous systems. The somatic neuropathies associate with iabetes fall into the following two broa categories: Focal neuropathies inclue mononeuropathies such as carpal tunnel synrome, palsy of the peroneal nerve, palsy of the thir cranial nerve, an proximal nerve conitions (e.g., iabetic amyotrophy). Diabetic sensorimotor polyneuropathy is the most common generalize neuropathy, an, for this reason, the simplifie term Ôiabetic neuropathy is commonly use. It is a polyneuropathy because of the iffuse amage to all peripheral nerve fibers motor, sensory, an autonomic. Such amage occurs insiiously an progressively an is characterize at first by sensory loss an later by loss of motor function, in a stocking an glove istribution. Autonomic neuropathy can cause postural hypotension, vomiting, iarrhea, blaer paresis, impotence, sweating abnormalities, impaire light reflex, impotence, an retrograe ejaculation. Abnormal heart rate responses an prolonge QT intervals have been associate with increase risk of suen eath (60). Assessment of neuropathy Clinical assessment involves history taking especially of numbness, persistent pain, or paresthesia an physical examination of ankle reflexes an vibration an light touch sensations (by conventional neurological examination or by grauate monofilaments). Autonomic nerve tests inclue heart rate response to eep breathing, staning from a lying position, Valsalva maneuver, heart rate variation at rest, QT interval, postural changes in bloo pressure, an pupillary responses to light an ark aaptation. Peripheral nerve tests inclue quantitating vibration an thermal iscrimination threshols an nerve conuction. These are mostly use in research settings. Age- an gener-specific normal ranges nee to be applie where relevant when interpreting results. Nerve function test abnormalities have not ecrease in an aolescent population in which retinopathy an microalbuminuria have ecrease over the same time: peripheral nerve abnormalities actually increase (3). This is probably ue to the increasing BMI which has occurre over the same time (B). Macrovascular isease Consensus Guielines The mortality an morbiity of CVD are markely increase in iabetic iniviuals compare with that in non-iabetic population (61) (B). Hypertension has a greater impact on CVD in iabetic patients than in non-iabetic iniviuals (16). Bloo pressure control (,140/80 mmhg in aults) reuces cariovascular morbiity an mortality in iabetes (17) (A). A family history of early CVD (before 55 yr of age), lipi isturbances, type 2 iabetes, hypertension (10), an smoking place the iniviual with iabetes at higher risk (B). Atherosclerosis starts in chilhoo an aolescence as shown by intima meia thickness of the carotis an aorta (62) an silent coronary atherosclerosis measure by intravascular ultrasoun in young aults with chilhoo-onset iabetes (9) (B). Silent coronary atherosclerosis (9) an cariovascular events (7) are strongly associate with poor glycemic control (A). Cholesterol plays an important role in the initiation an progression of atherosclerosis (53). Well-controlle type 1 iabetes is not associate with gross bloo lipi isturbances, but more avance lipoprotein subclass examinations reveal atherogenic profiles (18). Poor glycemic control was associate with a potentially more atherogenic lipoprotein profile (63). Peiatric Diabetes 2007: 8:

74 Donaghue et al. Changes in lipis associate with increase cariovascular risk are also associate with central obesity in type 1 iabetes (as well as type 2 iabetes) (64). Iniviuals with type 1 iabetes are as much at risk for hypercholesterolemia as the non-iabetic population. The prevalence approache 50% of young aults in one stuy (65). The prevalence of elevate nonhigh-ensity lipoprotein cholesterol was 25% in a stuy of iniviuals younger than 21 yr of age with type 1 iabetes (66). In aults, statins are effective in the primary an seconary preventions of major cariovascular events, stroke, an limb revascularization in patients with iabetes (67) (A). The Heart Protection Stuy was a 5-yr interventional stuy of 5963 patients with iabetes, in which 10% ha type 1 iabetes. This effect was inepenent of glycemic control an cholesterol levels. Short-term trials have shown that simvastatin, lovastatin, an pravastatin are effective an safe in chilren an aolescents (68 70). No significant sie effects were observe in terms of growth, pubertal Tanner graing, testicular volume, menarche, enocrine function parameters, or liver or muscle enzymes. The efficacy an safety of statins in chilren with type 1 iabetes still nee to be etermine in ranomize trials, as oes the age at which treatment shoul be initiate. Special attention shoul be pai to symptoms associate with muscles an connective tissues, as there is an increase risk of rhabomyolysis (71). Screening for an prevention of complications Screening for iabetes complications aims to etect subclinical complications, which may be treate to elay progression to clinical isease. Improvement in glycemic control will reuce the risk for onset an progression of iabetes vascular complications (A). Initial eye examination shoul occur shortly after iagnosis to etect cataracts or major refractive errors that require treatment for binocular vision (E). Screening for retinopathy an microalbuminuria shoul start from 11 yr with 2 yr of iabetes uration an from 9 yr with 5 yr of uration an after 2 yr of iabetes uration in an aolescent (13) (E). Minimum assessment for retinopathy shoul be by ophthalmoscopy through ilate pupils by an experience observer (E). The frequency of retinopathy screening in general shoul occur annually but shoul be more frequently if there are high-risk features for visual loss. For those with uration less than 10 yr, minimal backgroun retinopathy on funal photography an reasonable glycemic control, biennial assessment by funal photography, can occur (27) (E). Laser treatment reuces the rate of visual loss for vision-threatening retinopathy (A). Annual screening for microalbuminuria shoul be unertaken by any of the methos below (13): First morning urine samples (AC). Spot urine: ACR. Time urine collections (AER). Time overnight urine collections are generally easier for aolescents an are less subject to the effects of exercise an posture. Because of biological variability, two of three consecutive collections shoul be use as evience of microalbuminuria. Confouners are exercise an menstrual bleeing. Abnormal screening tests shoul be repeate, as microalbuminuria may isappear an not be persistent. When persistent microalbuminuria is confirme, screening for retinopathy, neuropathy, an lipi abnormalities is also recommene (E). ACEI are recommene for use in chilren with hypertension (55) (E). They have been effective an safe in chilren in short-term stuies (28, 56) but are not safe uring pregnancy. ACEI or AIIRA agents shoul be use in patients with persistent microalbuminuria to prevent progression to proteinuria (E) in aolescents. Bloo pressure shoul be measure at least annually. (E) Confirmation of hypertension may be assiste by 24-h ambulatory bloo pressure measurements (E). Bloo pressure values shoul be compare with age-appropriate centile charts (55). Bloo pressure shoul be maintaine at less than the 95th centile for age as in all chilren with hypertension (55) (E). Screening for fasting bloo lipis shoul be performe soon after iagnosis (when iabetes stabilize) in all chilren with type 1 iabetes oler than 12 yr (E). If normal results are obtaine, this shoul be repeate every 5 yr. If there is a family history of hypercholesterolemia, early CVD, or if the family history is unknown, screening shoul start at 2 yr of age (8) (E). Target level for LDL cholesterol shoul be lower than 2.6 mmol/l. If interventions to improve metabolic control an ietary changes cannot help reach the target level, statins shoul be consiere, although long-term safety is not establishe (55) (E). Cessation of smoking/never initiating smoking will reuce progression of microalbuminuria an CVD (52) (B). References 1. BOJESTIG M, ARNQVIST HJ, HERMANSSON G, KARLBERG BE, LUDVIGSSON J. Declining incience of nephropathy in insulin-epenent iabetes mellitus. N Engl J Me 1994: 330: Peiatric Diabetes 2007: 8:

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76 Donaghue et al. 36. FERRIS F. Early photocoagulation in patients with either type I or type II iabetes. Trans Am Ophthalmol Soc 1996: 94: MOGENSEN CE, KEANE WF, BENNETT PH et al. Prevention of iabetic renal isease with special reference to microalbuminuria. Lancet 1995: 346: ROSSING P: The changing epiemiology of iabetic microangiopathy in type 1 iabetes. Diabetologia 2005: 48: RUGGENENTI P, REMUZZI G. Kiney failure stabilizes after a two-ecae increase: impact on global (renal an cariovascular) health. Clin J Am Soc Nephrol 2007: 2: MATHIESEN ER, OXENBOLL B, JOHANSEN K, SVENDSEN PA, DECKERT T. Incipient nephropathy in type 1 (insulinepenent) iabetes. Diabetologia 1984: 26: MOGENSEN CE, CHRISTENSEN CK. Preicting iabetic nephropathy in insulin-epenent patients. N Engl J Me 1984: 311: VIBERTI GC, HILL RD, JARRETT RJ, ARGYROPOULOS A, MAHMUD U, KEEN H. Microalbuminuria as a preictor of clinical nephropathy in insulin-epenent iabetes mellitus. Lancet 1982: 1: BORCH-JOHNSEN K, ANDERSEN PK, DECKERT T. The effect of proteinuria on relative mortality in type 1 (insulin-epenent) iabetes mellitus. Diabetologia 1985: 28: VALDORF-HANSEN F, JENSEN T, BORCH-JOHNSEN K, DECKERT T. Cariovascular risk factors in type I (insulin-epenent) iabetic patients with an without proteinuria. Acta Me Scan 1987: 222: AMIN R, TURNER C, VAN AKEN S et al. The relationship between microalbuminuria an glomerular filtration rate in young type 1 iabetic subjects: The Oxfor Regional Prospective Stuy. Kiney Int 2005: 68: COUPER JJ, CLARKE CF, BYRNE GC et al. Progression of borerline increases in albuminuria in aolescents with insulin-epenent iabetes mellitus. Diabet Me 1997: 14: LURBE E, SOROF JM, DANIELS SR. Clinical an research aspects of ambulatory bloo pressure monitoring in chilren. J Peiatr 2004: 144: PERKINS BA, FICOCIELLO LH, SILVA KH, FINKELSTEIN DM, WARRAM JH, KROLEWSKI AS. Regression of microalbuminuria in type 1 iabetes. N Engl J Me 2003: 348: RUDBERG S, DAHLQUIST G. Determinants of progression of microalbuminuria in aolescents with IDDM. Diabetes Care 1996: 19: ZERBINI G, BONFANTI R, MESCHI F et al. Persistent renal hypertrophy an faster ecline of glomerular filtration rate precee the evelopment of microalbuminuria in type 1 iabetes. Diabetes 2006: 55: PARVING HH. Impact of bloo pressure an antihypertensive treatment on incipient an overt nephropathy, retinopathy, an enothelial permeability in iabetes mellitus. Diabetes Care 1991: 14: ASTRUP AS, TARNOW L, ROSSING P, PIETRASZEK L, RIIS HP, PARVING HH. Improve prognosis in type 1 iabetic patients with nephropathy: a prospective follow-up stuy. Kiney Int 2005: 68: STEINBERG D. Atherogenesis in perspective: hypercholesterolemia an inflammation as partners in crime. Nat Me 2002: 8: YOSHINO G, KAZUMI T, IWAI M et al. Recommenation for strict control of plasma triglycerie in iabetic subjects. Diabetes Care 1988: 11: NATIONAL HIGH BLOOD PRESSURE EDUCATION PROGRAM WORKING GROUP ON HIGH BLOOD PRESSURE IN CHILDREN AND ADOLESCENTS. The fourth report on the iagnosis, evaluation, an treatment of high bloo pressure in chilren an aolescents. Peiatrics 2004: 114(Suppl. 2): WELLS T, FRAME V, SOFFER B et al. A ouble-blin, placebo-controlle, ose-response stuy of the effectiveness an safety of enalapril for chilren with hypertension. J Clin Pharmacol 2002: 42: STRIPPOLI GF, CRAIG M, DEEKS JJ, SCHENA FP, CRAIG JC. Effects of angiotensin converting enzyme inhibitors an angiotensin II receptor antagonists on mortality an renal outcomes in iabetic nephropathy: systematic review. BMJ 2004: 329: ACE INHIBITORS IN DIABETIC NEPHROPATHY TRIALIST GROUP. Shoul all patients with type 1 iabetes mellitus an microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of iniviual patient ata. Ann Intern Me 2001: 134: COOPER WO, HERNANDEZ-DIAZ S, ARBOGAST PG et al. 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77 Peiatric Diabetes 2007: 8: All rights reserve # 2007 The Authors Journal compilation # 2007 Blackwell Munksgaar Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Other complications an associate conitions Koronouri O, Maguire AM, Knip M, Schober E, Lorini R, Holl RW, Donaghue KC. Other complications an associate conitions. Peiatric Diabetes 2007: 8: Olga Koronouri, Ann M Maguire, Mikael Knip, Eith Schober, Renata Lorini, Reinhar W Holl, an Kim C Donaghue Corresponing author: Kim C Donaghue [email protected] Acknowlegements: Thomas Kapellen, Arlan Rosenbloom, an Houssam El-Sabban. Eitors of the ISPAD Clinical Practice Consensus Guielines : Kim Donaghue, Ragnar Hanas, Georgeanna Klingensmith, an Peter Swift. Impaire growth an evelopment Monitoring of growth an evelopment an the use of percentile charts is a crucial element in the care of chilren an aolescents with iabetes. Increase height at iagnosis of type 1 iabetes mellitus (T1DM) has been frequently reporte (1 4). The precise mechanism for this an whether or not this increase height is maintaine is unclear. Some stuies report that poorly controlle patients show a ecrease in height stanar eviation score over the next few years, while better controlle patients maintain their height avantage (3, 4). Others have not shown this relationship with iabetic control (1). In a recent stuy from Australia, chilren treate with moern regimens (iagnose after 1990) maintaine their increase height better than chilren iagnose before 1991 (2). Although the meian haemoglobin A1c (HbA1c) i not iffer significantly, those iagnose after 1990 ha a significantly higher number of insulin injections per ay. Poor gain of height an weight, hepatomegaly (nonalcoholic steatosis hepatis) an late pubertal evelopment (Mauriac s synrome) have been reporte in chilren with persistently poorly controlle iabetes. Insulin insufficiency, coeliac isease an other gastrointestinal isorers shoul be consiere in this setting. Growth hormone (GH) levels are high in poorly controlle iabetes mellitus, but insulin-like growth factor (IGF)-1 levels are ecrease. Thus, GH therapy is contrainicate in the chilren with poorly controlle T1DM. The possible uses of IGF-1 in T1DM are the subject of consierable investigation. Once the chil or aolescent has reache a satisfactory weight after iagnosis, excessive weight gain may inicate high energy intake, an this may be relate to excessive exogenous insulin. Excessive weight gain is more common uring an after puberty (5). The Diabetes Control an Complications Trial an other stuies have reporte increase weight gain as a sieeffect of intensive insulin therapy with improve metabolic control (6 8). As obesity is a moifiable cariovascular risk factor, careful monitoring an management of weight gain shoul be emphasize in iabetes care. Girls seem to be more at risk of being overweight an eveloping eating isorers as well. In association with increase weight is the risk of hyperanrogenism an polycystic ovarian synrome (9). It is important to remember to reuce the ose of insulin when pubertal evelopment is complete because increase oses of insulin are require uring the aolescent growth spurt. Associate autoimmune conitions Islet cell antiboies (ICA) as well as autoantiboies to insulin, the 65-kDa isoform of glutamic aci ecarboxylase (GAD65) an/or the protein tyrosine phosphatase-relate molecules islet antigen-2 (IA-2) (ICA512) an IA-2b (phogrin) are observe in the overwhelming majority of chilren en route to clinical T1DM (10, 11). A higher proportion of chilren with T1DM also have other etectable organ-specific autoantiboies 171

78 Koronouri et al. [e.g., thyroi, tissue transglutaminase (ttg), arenal] than chilren from the general population. Family members of chilren with iabetes are more likely to have autoantiboies an other manifestations of autoimmune isease than the general population (12, 13). Hypothyroiism Primary hypothyroiism cause by autoimmune thyroiitis occurs in approximately 3 8% (14) or 0.9 per 100 patient years (15) of chilren an aolescents with iabetes. Antithyroi antiboies have been shown to occur uring the first years of iabetes in up to 25% of iniviuals with iabetes (16 20) an to be preictive for the evelopment of clinical or compensate hypothyroiism (20). Thyroi antiboies are observe more frequently in girls than in boys, often emerging along with pubertal maturation (20). Clinical features may inclue the presence of a painless goitre, increase weight gain, retare growth, tireness, lethargy, col intolerance an braycaria. Diabetic control may not be significantly affecte. Hypothyroiism is confirme by emonstrating a low free thyroxine an a raise thyroi stimulating hormone (TSH) concentration. Compensate hypothyroiism may be etecte in an asymptomatic iniviual with a normal thyroxine level an a moestly increase TSH. The treatment is base on replacement with oral L-thyroxine (T 4 ) sufficient to normalize TSH levels an usually this allows regression of the goitre if present. Hyperthyroiism Hyperthyroiism is less common than hypothyroiism in association with iabetes (18, 21), but still more common than in the general population. It may be because fo Grave s isease or the hyperthyroi phase of Hashimoto s thyroiitis. Hyperthyroiism shoul be consiere if there is unexplaine ifficulty in maintaining glycaemic control, weight loss without loss of appetite, agitation, tachycaria, tremor, heat intolerance, thyroi enlargement or characteristic eye signs. Treatment of hyperthyroiism consists of antithyroi rugs such as carbimazole or propylthiouracil. Beta-arenergic blocking rugs are helpful uring the acute phase of thyrotoxicosis to control tachycaria an agitation. Treatment options for persistent or recurrent hyperthyroiism inclue surgery or raioactive ioine. Coeliac isease Coeliac isease occurs in 1 10% of chilren an aolescents with iabetes or 0.7 per 100 patient years (15, 22 30). Coeliac isease is often asymptomatic (26, 28, 31) an not necessarily associate with poor growth or poor iabetic control (although it shoul be exclue in such situations). Any chil with gastrointestinal signs or symptoms incluing iarrhoea, abominal pain, flatulence, yspeptic symptoms, recurrent aphthous ulceration, unexplaine poor growth or anaemia shoul be investigate. Uniagnose coeliac isease has also been associate with increase frequency of hypoglycaemic episoes an a progressive reuction in insulin requirement over a 12-month perio prior to iagnosis (32). The screening for coeliac isease is base on the etection of immunoglobulin (Ig)A antienomysial (EMA) antiboies an IgA antiboies against ttg. Although experience with a recently introuce assay for ttg antiboies suggests that ttg may be more sensitive than EMA (91 vs. 86%), the latter is slightly more specific for coeliac isease (100 vs. 96%) (33). Antigliain antiboies might be more sensitive for coeliac isease than EMA an ttg antiboies in very young chilren (,2 yr), although their specificity remains moest. IgA eficiency (which is present in 1:500 iniviuals) shoul be exclue when screening for coeliac isease by measuring the total IgA level. IgA antiboies may not be etecte in IgA eficiency, resulting in a false-negative test. If the chil is IgA eficient, then IgG antigliain an IgG ttg antiboies shoul be use for screening (34). It is important to remember that coeliac isease is more common in those with IgA eficiency than in the general population (1.7% compare with 0.25%) (35). In the presence of an elevate antiboy level, a small bowel biopsy is neee to confirm the iagnosis of coeliac isease (Marsh classification) (36). A gluten-free iet normalizes the bowel mucosa an frequently leas to isappearance of antiboies but may not necessary lea to improve metabolic control (37). In an asymptomatic chil with proven coeliac isease, a gluten-free iet can be consiere justifie with the aim of reucing the risk of subsequent gastrointestinal malignancy an conitions associate with subclinical malabsorption (i.e., osteoporosis an iron eficiency). While this is a pruent recommenation, there is no literature ocumenting the long-term benefit of a gluten-free iet in asymptomatic chilren iagnose with coeliac isease by routine screening. One paeiatric case series has shown an increase in height for weight following the introuction of a gluten-free iet (31). Another emonstrate a nonsignificant increase in boy mass inex an a nonsignificant reuction in HbA1c (38). Some stuies have emonstrate short-term benefits in other patient groups in terms of improve well-being an increase bone mineral ensity (39 41). 172 Peiatric Diabetes 2007: 8:

79 The risk of coeliac isease is negatively an inepenently associate with age at the onset of iabetes, with a threefol higher risk being seen in chilren age, 4 yr than in those age. 9 yr, an girls have a higher risk of having both iseases (42). Chilren with proven coeliac isease shoul be referre to a paeiatric gastroenterologist an receive support from a paeiatric ietician with experience of gluten-free iets. Vitiligo Vitiligo is an acquire pigmentary isorer characterize by a loss of melanocytes, resulting in white spots or leucoerma (43). It is a common autoimmune conition associate with T1DM an is present in about 6% of iabetic chilren (44). Treatment is ifficult an multiple therapies have been trie with little success. Primary arenal insufficiency (Aison s isease) Up to 2% of patients with T1DM have etectable antiarenal autoantiboies (16, 45, 46). Aison s isease is occasionally associate with T1DM in the autoimmune polyglanular synromes (APS I an II). APS 1 is associate with mucocutaneous caniiasis an hypoparathyroiism an is cause by a mutation in the autoimmune regulator gene on chromosome 21q22.3 (47, 48). APS II is more common in aults but is also seen in chilren in association with autoimmune thyroiitis (49). The conition is suspecte by the clinical picture of frequent hypoglycaemia, unexplaine ecrease in insulin requirements, increase skin pigmentation, lassitue, weight loss, hyponatraemia an hyperkalaemia. The iagnosis is base on the emonstration of a low cortisol response to an arenocorticotropic hormone (ACTH) test. Treatment with a glucocorticoi is urgent an lifelong. In some cases, the therapy has to be supplemente with a mineralocorticoi. In asymptomatic chilren with positive arenal antiboies etecte on routine screening, a rising ACTH level suggests a failing arenal cortex an the evelopment of primary arenal insufficiency. The immunoysregulation polyenocrinopathy X- linke synrome is another rare isorer associate with iabetes in early infancy, severe enteropathy an autoimmune symptoms because of a clear genetic efect (FOX-P3) (50). Lipoystrophy (lipoatrophy an lipohypertrophy) Lipoatrophy is now seen infrequently with the use of human insulin. Recent case reports have escribe lipoatrophy also occurring in patients on insulin pumps treate with lispro insulin, an in patients treate with Lantus (51 53), it is still a rare sie-effect. Lipohypertrophy is a frequent complication of insulin therapy. It has been foun in up to 48% of those with T1DM an has associate with higher HbA1c, more injections an longer uration but not the neele length (54 56). Non-rotation of injection sites has been consistently reporte as an inepenent risk factor for lipohypertrophy (54, 56). Not only is it unsightly but insulin may also be absorbe erratically an unpreictably from these areas (57, 58). Necrobiosis lipoiica iabeticorum These are well-circumscribe, raise, reish lesions sometimes progressing to central ulceration, usually seen in the pretibial region. The reporte prevalence in chilren varies from 0.06 to 10% (44, 59). The aetiology is not clearly unerstoo. Necrobiosis lipoiica iabeticorum has been associate with unerlying microvascular complications (60, 61). A wie variety of treatments have been use over the years in aults incluing topical, systemic or intra-lesional sterois, aspirin, cyclosporin, mycophenolate, becaplermin, excision an grafting, laser surgery, hyperbaric oxygen, topical granulocyte macrophage colony-stimulating factor an photochemotherapy with topical psoralen an ultraviolet-a raiation (62 69). None has been proven useful in controlle clinical trials, an many of these treatments have significant sie-effects. Limite joint mobility Consensus Guielines Limite joint mobility (LJM) is the earliest clinically apparent long-term complication of T1DM in chilhoo. It is a bilateral painless, but obvious, contracture of the finger joints an large joints, associate with tight waxy skin. Following its initial escription associate with short stature, an early microvascular complications, it was recognize to be a common feature of both T1DM an type 2 iabetes mellitus, with a wie range of limitation, affecting 30% of youngsters an correlating with iminishe stature (70, 71). Changes begin in the metacarpophalangeal an proximal interphalangeal joints of the fifth finger an exten raially with involvement of the istal interphalangeal joints as well. Involvement of larger joints inclues not particularly the wrist an elbow but also the ankles an cervical an thoracolumbar spine. The limitation is only milly isabling even when severe. A simple examination metho is to have the patient attempt to approximate palmar surfaces of the interphalangeal joints (72). Passive examination is Peiatric Diabetes 2007: 8:

80 Koronouri et al. essential to confirm that inability to o so is because of LJM. With rare exception, LJM appears after the age of 10 yr. The interval between the etection of mil LJM an the progression to moerate or severe changes in those who progress beyon mil changes, ranges from a few months to 4 yr, following which stabilization occurs (71). Skin biopsy specimens have shown active fibroblasts an extensive collagen polymerization in the rough enoplasmic reticulum (73). The biochemical basis for LJM is likely glycation of protein with the formation of avance glycation en proucts. This results in increase stiffness of the periarticular an skin collagen with ecrease range of motion. Fluorescence of skin collagen, reflecting the accumulation of stable en proucts of the glycation reaction, with increase cross-linking, ehyration an conensation of collagen, increases linearly with age but with abnormal rapiity in T1DM, correlating with the presence of retinopathy, nephropathy an LJM (74). LJM is associate with a three- to fourfol risk for retinopathy, nephropathy an neuropathy (71, 75, 76). Although cross-sectional stuies showe no relationship to iabetes control as measure by HbA1c, longituinal stuy of average HbA1c from onset of iabetes showe that for every unit increase in average HbA1c, there was an approximately 46% increase in the risk of eveloping LJM (77). There has been a more than fourfol reuction in frequency of LJM between the mi-1970s an the mi-1990s in chilren (78) an a lesser ecline in aults (79), with a marke ecrease in severity in the fewer chilren who are affecte, most likely the result of improve glucose control uring this era. Oeema Generalize oeema because of water retention is a rare complication of insulin therapy. Oeema may be seen uring establishment of improve glycaemic control after prolonge perios of poor metabolic control, particularly if there has been significant omission of insulin (80, 81). The oeema spontaneously resolves over a perio of ays to weeks with continue goo glycaemic control. Recommenations Monitoring of growth an physical evelopment an the use of growth charts is an essential element in the continuous care of chilren an aolescents with T1DM (E). Screening of thyroi function by analysing circulating TSH an antiboies is recommene at the iagnosis of iabetes an, thereafter, every secon year in asymptomatic iniviuals without goitre or in the absence of thyroi autoantiboies. More frequent assessment is inicate otherwise (E). Screening for coeliac isease shoul be carrie out at the time of iagnosis an every secon year thereafter. More frequent assessment is inicate if the clinical situation suggests the possibility of coeliac isease or the chil has a first-egree relative with coeliac isease (E). Chilren with T1DM etecte to have coeliac isease on routine screening shoul be referre to a paeiatric gastroenterologist an on confirmation of the iagnosis shoul receive support from a paeiatric ietician with experience of gluten-free iets (E). Routine clinical examination shoul be unertaken for skin an joint changes. Regular screening by laboratory or raiological methos is not recommene. There is no establishe therapeutic intervention for lipoystrophy, necrobiosis lipoiica or LJM (E). References 1. BOGNETTI E, RIVA MC, BONFANTI R, MESCHI F, VISCARDI M, CHIUMELLO G. Growth changes in chilren an aolescents with short-term iabetes. Diabetes Care 1998: 21: DONAGHUE KC, KORDONOURI O, CHAN A, SILINK M. Secular trens in growth in iabetes: are we winning? Arch Dis Chil 2003: 88: GUNCZLER P, LANES R. Poor metabolic control ecreases the growth velocity of iabetic chilren. Diabetes Care 1999: 22: HOLL RW, GRABERT M, HEINZE E, SORGO W, DEBATIN KM. Age at onset an long-term metabolic control affect height in type-1 iabetes mellitus. Eur J Peiatr 1998: 157: HOLL RW, HEINZE E, SEIFERT M, GRABERT M, TELLER WM. Longituinal analysis of somatic evelopment in paeiatric patients with IDDM: genetic influences on height an weight. Diabetologia 1994: 37: DCCT RESEARCH GROUP. The effect of intensive treatment of iabetes on the evelopment an progression of long-term complications in insulin-epenent iabetes mellitus. The Diabetes Control an Complications Trial Research Group. N Engl J Me 1993: 329: HOLL RW, GRABERT M, SORGO W, HEINZE E, DEBATIN KM. Contributions of age, gener an insulin aministration to weight gain in subjects with IDDM. Diabetologia 1998: 41: THON A, HEINZE E, FEILEN KD et al. Development of height an weight in chilren with iabetes mellitus: report on two prospective multicentre stuies, one crosssectional, one longituinal. Eur J Peiatr 1992: 151: CODNER E, SOTO N, LOPEZ P et al. Diagnostic criteria for polycystic ovary synrome an ovarian morphology in women with type 1 iabetes mellitus. J Clin Enocrinol Metab 2006: 91: ATKINSON MA, EISENBARTH GS. Type 1 iabetes: new perspectives on isease pathogenesis an treatment. Lancet 2001: 358: Peiatric Diabetes 2007: 8:

81 Consensus Guielines 11. EISENBARTH GS, GOTTLIEB PA. Autoimmune polyenocrine synromes. N Engl J Me 2004: 350: SOUGIOULTZOGLOU F, FALORNI A, KASSI G, BROZZETTI A, KARAMITSOS D, KOLIAKOS GG. Coincience of high antiislet an antithyroi autoantiboy titles in firstegree relatives of patients with type 1 iabetes. Exp Clin Enocrinol Diabetes 2005: 113: SUMNIK Z, KOLOUSKOVA S, MALCOVA H et al. High prevalence of coeliac isease in siblings of chilren with type 1 iabetes. Eur J Peiatr 2005: 164: HANSEN D, BENNEDBAEK FN, HOIER-MADSEN M, HEGEDUS L, JACOBSEN BB. A prospective stuy of thyroi function, morphology an autoimmunity in young patients with type 1 iabetes. Eur J Enocrinol 2003: 148: GLASTRAS SJ, CRAIG ME, VERGE CF, CHAN AK, CUSUMANO JM, DONAGHUE KC. The role of autoimmunity at iagnosis of type 1 iabetes in the evelopment of thyroi an celiac isease an microvascular complications. Diabetes Care 2005: 28: DE BLOCK CE, DE LEEUW IH, VERTOMMEN JJ et al. 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