ISPAD Clinical Practice Consensus Guidelines d Department of Pediatric Endocrinology and Diabetes, Katowice, Poland

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1 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: ; ragnar.hanas@vgregion.se 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

2 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:

3 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:

4 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:

5 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:

6 ) 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:

7 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:

8 ) 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:

9 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:

10 ) 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:

11 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. 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