- Email: [email protected]
Insulin therapy in children and adolescents with diabetes
DIABETES RESEARCH A N D CLINICAL PRACTICE
9 3S (2011) S114–S117
Insulin therapy in children and adolescents with diabetes Assimina Galli-Tsinopoulou * 4th Department of Pediatrics, Faculty of Medicine, Aristotle University, Papageorgiou General Hospital, Thessaloniki, Greece
AR TI C L E
I NF O
A B S T R A C T
Keywords:
Diabetes type 1 constitutes a growing problem for many children and adolescents world-
Insulin therapy
wide. Diabetic children and adolescents are dependent on insulin for survival. Today, in-
Diabetes mellitus
sulin treatment, either in the classic insulin forms or in the form of insulin analogs, is
Children
widely used in the pediatric diabetic population. New methods of insulin administration
Adolescents
like the continuous subcutaneous insulin infusion systems (pumps) have been developed to ameliorate metabolic control and reduce diabetic complications. © 2011 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
Since the isolation of insulin by Best and Batting in 1922 [1], insulin therapy consists of the primary and lifelong treatment for children and adolescents with type 1 diabetes mellitus (T1DM). Diabetic children and adolescents are dependent on insulin for survival. The most important challenges when treating diabetic children are achieving metabolic control, eliminating the symptoms of hyperglycemia and preventing diabetic ketoacidosis, all in the context of a child’s or adolescent’s normal physical and emotional growth [2]. At the same time, insulin administration enhances physical growth and puberty development [3], given that many children with long duration of diabetes present delay in growth (stature and weight) and delayed onset of puberty [4]. Moreover, insulin treatment in children increases the ability for physical exercise and decreases infection frequency and gravity [5]. All these increase quality of life and longevity for patients with T1DM. Until recently, there was some controversy in the published research concerning the effect of insulin administration in the prevention of chronic complications of T1DM. Researchers also argued on whether attaining optimal blood glucose levels accentuated or anticipated the micro- and
* Correspondence to: Assimina Galli-Tsinopoulou, PhD, Assistant Professor in Pediatric Endocrinology, 4th Department of Paediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, GR-56403 Thessaloniki, Greece. Tel./fax: +30 2310 991537. E-mail address: [email protected], [email protected]
macro-vascular complications of T1DM. However, studies like the DCCT, the Kumamoto and the UKPDS [6–8], managed to erase every doubt on possible contribution of insulin treatment on the diabetic complications. The DCCT study [6] demonstrated an important reduction in the prevalence of all microvascular complications in patients with optimal metabolic control. More specifically, the prevalence of diabetic retinopathy decreased by 76%, proteinuria by 56%, microalbuminuria by 46% and neuropathy by 61%. In the 1990s the classic insulin forms were besided by the newly developed short and long acting insulin analogs; their use was also permitted in children and adolescents. These new analogs can improve the lifestyle and reduce the chance of poor glycemic control in children with T1DM [9]. Today, insulin administration in children with T1DM has more flexibility than in the previous decades. There is the ability of choosing between different types of insulin analogs (in both action and duration), the application of different regimens (2/3/4 injections daily with the combination various types of insulin) and there are also alternative ways for insulin delivery, like the use of continuous subcutaneous insulin infusion pumps.
2.
Classic insulin forms
2.1.
Regular insulin (short acting)
Regular soluble insulin (usually identical to the human insulin) is still used as an essential component of most daily replacement regimens in many parts of the world, either
0168-8227/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
DIABETES RESEARCH A N D CLINICAL PRACTICE
combined with: intermediate-acting insulin in twice daily regimens or as pre-meal bolus injections in basal-bolus regimens (administered 20–30 min before meals) together with intermediate-acting insulin twice daily or a basal analog given once or twice daily [10].
2.2.
Intermediate acting insulins
Due to their action profiles, these insulins are suitable for twice daily regimens and for pre-nocturnal dosage as a basal-bolus. Two principal preparations exist: Isophane NPH (neutral protamine Hagedorn) insulins and the crystalline zinc acetate insulin (insulin zinc suspensions, IZS or Lente insulins). IZS was first developed in the 30’s in an effort to reduce the number of daily injections [11]. NPH was developed in the 50’s and are mostly used in children, mainly because of their suitability for mixing with regular insulin in the same syringe, vial or cartridge without interaction. The use of Lente type insulins is discontinued in most countries worldwide [10].
3.
Insulin analogs
3.1.
Rapid acting insulin analogs
The newly used rapid insulin analogs derived from the replacement of two amino-acids on the human insulin molecule with others, which have the ability to alter the duration of the molecule’s action. Such analogs are: the aspart (NovoRapid® , Novo Nordisk), the lispro (Ilis, Humalog® , EliLilly) and the glulisine (IGlu, Apidra™, Sanofi-Aventis). These analogs have a rapid onset of approximately 15 minutes, peak at 1–3 hours and are characterized by a shorter duration of 4–5 hours. Their advantage is the reduction of postprandial hyperglycemia as well as nocturnal hypoglycemia [12]. Thus, rapid acting insulin analogs also reduce the total number of hypoglycemic episodes [13]. Furthermore, they can be injected after food consumption when needed and their use is also common in insulin pumps [14].
3.2.
Basal long acting insulin analogs
The new basal long acting insulin analogs like glargine (IGlarg, Lantus, Sanofi-Anentis) or detemir (IDet, Levemir, Novo Nordisk) cover the lapse of the previous medium or long action insulins, which have raised many problems, such as: glargine’s action is initiated 2–4 hours after administration, without demonstrating a peak and might last for up to 24 hours [10,15]. Detemir has a quicker onset (1–2 hours) and a similar duration, but tends to limit up at approximately 6–12 hours after administration. A common feature of these insulin analogs is that action duration is dependent on the dosage. The use of basal insulin analogs by children has not been approved in the majority of countries. However, recent research has demonstrated successful use of glargine in children aged 1 to 5 years old [16]. Many children have reported a burning sensation after the administration of glargine, as a result of an acute pH change, however, glargine has been demonstrated to significantly reduce hypoglycemic episodes
9 3S (2011) S114–S117
S115
and improving HbA1c levels [14,17]. In comparison to intermediate acting insulins, prenocturnal glargine administration has been suggested to cause significant reduction in the blood glucose fasting levels, compared to the use of NPH [18]. Detemir on the other hand, excels in comparison with NPH in improving glycemic control and reducing the frequency of hypoglycemic episodes, particularly the nocturnal ones [19]. Between detemir and glargine, research on children and adolescents has showed that the first demonstrates a more reproducible pharmacokinetic profile than the latter [20]. In addition, unlike the other long-acting analogs, detemir remains liquid even after subcutaneous injection [21].
3.3.
Premixed insulin preparations
The premixed insulins consist of fixed ratio mixtures of a rapid and an intermediate insulin. Their use is common in some countries particularly in prepubertal children, on regimens with twice a day injections [10]. Although they reduce potential errors in the procedure of preparing insulin syringes, they remove the flexibility offered by the separate adjustment of the two types. Such flexibility is important in children with variable food consumption, however premixed insulins are useful in populations incapable of learning a more intensive treatment regime. Biphasic insulin aspart 30 (30% aspart and 70% aspart bound to NPH) given for the three main meals combined with NPH before bedtime was equally efficient as premixed human insulin (70% NPH) given for morning and bedtime with regular insulin for lunch and dinner [10,22]. The Hvidøre study demonstrated poorer metabolic control with the use of premixed insulins in adolescents [23].
4.
Regimens
The daily dosage of insulin depends on various factors such as age, body weight, stage of puberty, duration and phase of diabetes, state of injection sites, nutritional intake and distribution, exercise patterns, daily routine, results of blood glucose monitoring (and glycated hemoglobin) and intercurrent illness [10]. Insulin administration in children and adolescents can either be conventional with two mixed insulin injections every 12hours (rapid and medium acting insulins), intensive with three rapid acting insulin injections, or injections of rapid acting insulin analogs with every meal and one medium/long acting insulin analog injection before bedtime. All forms and combinations are adapted to the patient’s age, stage of puberty, dietary and physical exercise habits. In infants and prepubertal children, the daily dosage of insulin ranges from 0.5 to 1.0 μg/kg body weight, whereas during puberty it is increased to 1.5–2.0 μg/kg body weight. During the honeymoon period, the total daily insulin dosage is often <0.5 μgu/kg. The correct dosage for each child/adolescent must attain the following characteristics: (a) achieve the best feasible metabolic control without provoking hypoglycemia, and (b) ensure the adequate and harmonious growth, according to the growth charts for weight and height.
S116
DIABETES RESEARCH A N D CLINICAL PRACTICE
The intensive four injection regimen is preferred and used by the majority of children because it provides flexibility, given that both children and adolescents demonstrate differences in the quantity and quality of daily food intake and physical activity [24]. It should be noted that the application of basal rhythm, meal and corrective dosages during the intensive, multiple injections regimen have a lot of resemblances with the physiologic endogenous excretion of insulin by the pancreas.
5.
Administration of insulin
5.1.
Insulin syringes – pens
Today, the classic syringes of insulin are used only in cases of very young children where free mixture of insulins is administered. Syringes are available in a variety of sizes, ensuring accurate dosage delivery; however it is desirable to have small syringes with 1 unit per mark (e.g. 0.3 ml) for use in small children. “Pen” type insulin administration appliances (Pens) are children and adolescent-friendly and they have been proved to be very useful in intensive regimens with the use of insulin analogs. Pens have suitable gradation and in their majority they have the possibility to regulate even half a unit, by bringing very small and thin needles (5–6 mm, 31G). For children with needle phobia there are special pens that eject the needles and others that operate through high pressure systems instead of needles. Small children with small body surface and decreased subcutaneous fat under intensive regimens tend to use the same places for injection, driven by the pain. For these children there are special catheters, the Insuflon, via which insulin infusion might take place. The use of Insuflon does not affect metabolic control negatively [25]. On the contrary, when used in children with injection problems, HbA1c was significantly lowered with the use of Insuflon [26]. However, it is advisable that all children and adolescents with diabetes should know how to administer insulin by syringe because other injection devices might malfunction. 5.1.1. Education When the proper insulin regimen is chosen, it must be supported by comprehensive education appropriate for the age, maturity and individual needs of the child and family. An important factor for the injection procedure is the adequate education of parents and guardians. The suitable age for “auto-injection” varies for each child and is related much more to the intellectual maturity than to the chronological age. Most children ≥10 years old inject themselves alone or with some help during the procedure. Younger children share the injection responsibility with their parents but must participate in the appliance preparation or even many times carry out all the procedure themselves, under supervision. The need of “auto-injection” is often aroused by incidents like an overnight’s stay at a friend’s house, a school trip or summer camp. Also younger children in multiple injection regimens might need help, when they should perform the injection in body areas where they do not reach, so as to avoid fat-hypertrophy.
5.2.
9 3S (2011) S114–S117
Continuous subcutaneous insulin infusion
Continuous subcutaneous insulin infusion (CSII) consists of an intensive insulin therapy method, which initially began during the 80’s, however its use was spread widely particularly after the DCCT study [8]. All scientific committees with endocrinological orbit and diabetes mellitus interest agree in the use of pumps after suitable education. The International Society of Pediatric and Adolescent Diabetes (ISPAD), the European Society of Pediatric Endocrinology (ESPE) and the Lawson Wilkins Pediatric Endocrine Society (LWPES) in agreement with the American Diabetic Association (ADA) and the European Association for the Study of Diabetes (EASD), established a joint consensus statement regarding the use of insulin pumps in children and adolescents with T1DM [26]. According to this consensus statement, there is no age-related limit and each DM1 child can continue pump insulin therapy regardless of his age. The use of CSII is advisable in children and adolescents with serious and frequent hypoglycemic episodes, with wide fluctuations of blood glucose levels regardless of the HbA1c , in patients with bad glycemic control (high HbA1c ), in children and adolescents with micro-vascular complications, and in the cases that although a good glycemic control is achieved, the insulin therapy influences the quality of life of the patient. Moreover, pump administration is beneficial for children and adolescents, especially in the following cases: in preschool children and particularly infants and neonates, adolescents with appetite disorders, in children and adolescents with increased dawn phenomenon, in children with needle phobia, in pregnant adolescents, in individuals prone to ketoacidosis, as well as in competitive sports athletes [27]. Various factors are important for insulin therapy to be successful, and these include motive, education and the individual’s ability to accept the particular insulin therapy method. Undoubtedly, there is the need for further randomized studies in children and adolescents in order to show whether the use of CSII excels over the multiple injections regimen in improving glycemic control and reducing the frequency of hypoglycemic episodes.
6.
Conclusions
Conclusively, secure and appropriate administration of insulin in children and adolescents requires a priori knowledge of a child’s and adolescent’s body and physiological responses on behalf of doctors and health professionals, and must coincide with adequate patient and family education. Alterations in the patients’ physique and body as a result of the hormonal flood that takes place, renders children and adolescents into “special cases” and indicate the need of continuous changes and readjustments of the insulin therapy. Insulin demonstrates wide fluctuations between days in the same individual, but also among different patients, particularly among children. Insulin onset, peak and duration of action depends on various factors, such as the lack of subcutaneous fat in very young children, the increased fat mass in girls particularly in puberty, and the increased muscular mass observed during adolescence. Intramuscular instead of
DIABETES RESEARCH A N D CLINICAL PRACTICE
subcutaneous injection leads to faster absorption and action, but also shorter duration of action. Other factors influencing insulin action are games/exercise patterns – integral element of children and adolescents’ life – as well as the body’s core and environmental temperatures. It is supported that the action of the new rapid and long acting insulin analogs is less influenced by these factors.
Conflict of interest
[14]
[15]
[16]
The author has no conflicts of interest to report. [17]
references [18] [1] Banting FG, Best CH, Collip JB, Campell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 1922;12:141–6. [2] Stylianou C, Kelnar C. The introduction of successful treatment of diabetes mellitus with insulin. The James Lind Library 2008; (www.jameslindlibrary.org). [3] d’Annunzio G, Cortona L, Vitali L, Pessino P, Lorini R. Final height attainment in girls and boys with insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 1994;24:187–93. [4] Elamin A, Hussein O, Tuvemo T. Growth, puberty, and final height in children with Type 1 diabetes. J Diabetes Complications 2006;20:252–6. [5] Roberts L, Jones TW, Fournier PA. Exercise training and glycemic control in adolescents with poorly controlled type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2002; 15(5):621–7. [6] White NH, Cleary PA, Dahms W, Goldstein D, Malone J, Tamborlane WV. Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT). J Pediatr 2001;139:804–12. [7] Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23:B21–9. [8] The Diabetes Control and Complication Trial research group. The effect of intensive treatment of diabetes on the development of progression of long-term complications in insulin dependent diabetes mellitus. N Eng J Med 1993; 329:977–86. [9] Crotty S, Reynolds SL. The new insulins. Pediatr Emerg Care 2007;23:903–5. [10] Bangstad H-J, Danne T, Deeb LC, Jarosz-Chobot P, Urakami T, Hanas R. Insulin treatment in children and adolescents with diabetes. Pediatr Diabetes 2009;10:82–99. [11] Hirsch I. Insulin analogs. New Engl J Med 2005;352:174–83. [12] American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care 2007;30:S4–36. [13] Danne T, Mortensen HB, Hougaard P, Lynggaard H, Aanstoot HJ, Chiarelli F, et al. Persistent differences among centers
[19]
[20]
[21] [22]
[23]
[24] [25]
[26]
[27]
9 3S (2011) S114–S117
S117
over 3 years in glycemic control and hypoglycaemia in a study of 3,805 children and adolescents with type 1 diabetes from the Hvidore Study Group. Diabetes Care 2001;24:1342–7. Danne T, Aman J, Schober E, Deiss D, Jacobsen JL, Friberg HH, et al. A comparison of postprandial and preprandial administration of insulin aspart in children and adolescents with type 1 diabetes. Diabetes Care 2003;26:2359–64. Hamann A, Matthaei S, Rosak C, Silvestre L. A randomized clinical trial comparing breakfast, dinner, or bedtime administration of insulin glargine in patients with type 1 diabetes. Diabetes Care 2003;26:1738–44. Dixon B, Peter Chase H, Burdick J et al. Use of insulin glargine in children under age 6 with type 1 diabetes. Pediatr Diabetes 2005;6:150–4. Jackson A, Ternand C, Brunzell C, Kleinschmidt T, Dew D, Milla C, et al. Insulin glargine improves hemoglobin A1c in children and adolescents with poorly controlled type 1 diabetes. Pediatr Diabetes 2003;4:64–9. Brunetti P, Muggeo M, Cattin L, Arcangeli A, Pozzilli P, Provenzano V, et al. Incidence of severe nocturnal hypoglycemia in patients with type 1 diabetes treated with insulin lispro or regular human insulin in addition to basal insulin glargine. Nutr Metab Cardiovasc Dis 2010;20:519–26. Johansen OE, Vanberg PJ, Kilhovd BK, Jørgensen AP. Changing basal insulin from NPH to detemir or glargine in patients with type 1 diabetes and a history of severe hypoglycemia. Vasc Health Risk Manag 2009;5:121–8. Danne T,Datz N, Endahl L, Haahr H, Nestoris C, Westergaard L, et al. Insulin detemir is characterized by a more reproducible pharmacokinetic profile than insulin glargine in children and adolescents with type 1 diabetes: results from a randomized, double-blind, controlled trial. Pediatr Diabetes 2008;9:554–60. Crotty S, Reynolds SL. The new insulins. Pediatr Emerg Care 2007;23:903–5. Mortensen H, Kocova M, Teng LY, Keiding J, Bruckner I, Philotheou A. Biphasic insulin aspart vs. human insulin in adolescents with type 1 diabetes on multiple daily insulin injections. Pediatr Diabetes 2006;7:4–10. Mortensen HB, Robertson KJ, Aanstoot HJ, Danne T, Holl RW, Hougaard P, et al. Insulin management and metabolic control of type 1 diabetes mellitus in childhood and adolescence in 18 countries. Hvidøre Study Group on Childhood Diabetes. Diabet Med 1998;15:752–9. Kaufman FR. Intensive management of type 1 diabetes in young children. Lancet 2005;365:737–8. Hanas R, Adolfsson P. Insulin pumps in pediatric routine care improve long-term metabolic control without increasing the risk of hypoglycemia. Pediatr Diabetes 2006; 7:25–31. Burdick P, Cooper S, Horner B, Cobry E, McFann K, Chase HP. Use of a subcutaneous injection port to improve glycemic control in children with type 1 diabetes. Pediatr Diabetes 2009;10:116–9. Eugster EA, Francis G, Lawson Wilkins Drug and Therapeutics Committee. Position Statement: continuous subcutaneous insulin infusion in very young children with type 1 diabetes. Pediatrics 2006;118:e1244–9.
9 3S (2011) S114–S117
Insulin therapy in children and adolescents with diabetes Assimina Galli-Tsinopoulou * 4th Department of Pediatrics, Faculty of Medicine, Aristotle University, Papageorgiou General Hospital, Thessaloniki, Greece
AR TI C L E
I NF O
A B S T R A C T
Keywords:
Diabetes type 1 constitutes a growing problem for many children and adolescents world-
Insulin therapy
wide. Diabetic children and adolescents are dependent on insulin for survival. Today, in-
Diabetes mellitus
sulin treatment, either in the classic insulin forms or in the form of insulin analogs, is
Children
widely used in the pediatric diabetic population. New methods of insulin administration
Adolescents
like the continuous subcutaneous insulin infusion systems (pumps) have been developed to ameliorate metabolic control and reduce diabetic complications. © 2011 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
Since the isolation of insulin by Best and Batting in 1922 [1], insulin therapy consists of the primary and lifelong treatment for children and adolescents with type 1 diabetes mellitus (T1DM). Diabetic children and adolescents are dependent on insulin for survival. The most important challenges when treating diabetic children are achieving metabolic control, eliminating the symptoms of hyperglycemia and preventing diabetic ketoacidosis, all in the context of a child’s or adolescent’s normal physical and emotional growth [2]. At the same time, insulin administration enhances physical growth and puberty development [3], given that many children with long duration of diabetes present delay in growth (stature and weight) and delayed onset of puberty [4]. Moreover, insulin treatment in children increases the ability for physical exercise and decreases infection frequency and gravity [5]. All these increase quality of life and longevity for patients with T1DM. Until recently, there was some controversy in the published research concerning the effect of insulin administration in the prevention of chronic complications of T1DM. Researchers also argued on whether attaining optimal blood glucose levels accentuated or anticipated the micro- and
* Correspondence to: Assimina Galli-Tsinopoulou, PhD, Assistant Professor in Pediatric Endocrinology, 4th Department of Paediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, GR-56403 Thessaloniki, Greece. Tel./fax: +30 2310 991537. E-mail address: [email protected], [email protected]
macro-vascular complications of T1DM. However, studies like the DCCT, the Kumamoto and the UKPDS [6–8], managed to erase every doubt on possible contribution of insulin treatment on the diabetic complications. The DCCT study [6] demonstrated an important reduction in the prevalence of all microvascular complications in patients with optimal metabolic control. More specifically, the prevalence of diabetic retinopathy decreased by 76%, proteinuria by 56%, microalbuminuria by 46% and neuropathy by 61%. In the 1990s the classic insulin forms were besided by the newly developed short and long acting insulin analogs; their use was also permitted in children and adolescents. These new analogs can improve the lifestyle and reduce the chance of poor glycemic control in children with T1DM [9]. Today, insulin administration in children with T1DM has more flexibility than in the previous decades. There is the ability of choosing between different types of insulin analogs (in both action and duration), the application of different regimens (2/3/4 injections daily with the combination various types of insulin) and there are also alternative ways for insulin delivery, like the use of continuous subcutaneous insulin infusion pumps.
2.
Classic insulin forms
2.1.
Regular insulin (short acting)
Regular soluble insulin (usually identical to the human insulin) is still used as an essential component of most daily replacement regimens in many parts of the world, either
0168-8227/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
DIABETES RESEARCH A N D CLINICAL PRACTICE
combined with: intermediate-acting insulin in twice daily regimens or as pre-meal bolus injections in basal-bolus regimens (administered 20–30 min before meals) together with intermediate-acting insulin twice daily or a basal analog given once or twice daily [10].
2.2.
Intermediate acting insulins
Due to their action profiles, these insulins are suitable for twice daily regimens and for pre-nocturnal dosage as a basal-bolus. Two principal preparations exist: Isophane NPH (neutral protamine Hagedorn) insulins and the crystalline zinc acetate insulin (insulin zinc suspensions, IZS or Lente insulins). IZS was first developed in the 30’s in an effort to reduce the number of daily injections [11]. NPH was developed in the 50’s and are mostly used in children, mainly because of their suitability for mixing with regular insulin in the same syringe, vial or cartridge without interaction. The use of Lente type insulins is discontinued in most countries worldwide [10].
3.
Insulin analogs
3.1.
Rapid acting insulin analogs
The newly used rapid insulin analogs derived from the replacement of two amino-acids on the human insulin molecule with others, which have the ability to alter the duration of the molecule’s action. Such analogs are: the aspart (NovoRapid® , Novo Nordisk), the lispro (Ilis, Humalog® , EliLilly) and the glulisine (IGlu, Apidra™, Sanofi-Aventis). These analogs have a rapid onset of approximately 15 minutes, peak at 1–3 hours and are characterized by a shorter duration of 4–5 hours. Their advantage is the reduction of postprandial hyperglycemia as well as nocturnal hypoglycemia [12]. Thus, rapid acting insulin analogs also reduce the total number of hypoglycemic episodes [13]. Furthermore, they can be injected after food consumption when needed and their use is also common in insulin pumps [14].
3.2.
Basal long acting insulin analogs
The new basal long acting insulin analogs like glargine (IGlarg, Lantus, Sanofi-Anentis) or detemir (IDet, Levemir, Novo Nordisk) cover the lapse of the previous medium or long action insulins, which have raised many problems, such as: glargine’s action is initiated 2–4 hours after administration, without demonstrating a peak and might last for up to 24 hours [10,15]. Detemir has a quicker onset (1–2 hours) and a similar duration, but tends to limit up at approximately 6–12 hours after administration. A common feature of these insulin analogs is that action duration is dependent on the dosage. The use of basal insulin analogs by children has not been approved in the majority of countries. However, recent research has demonstrated successful use of glargine in children aged 1 to 5 years old [16]. Many children have reported a burning sensation after the administration of glargine, as a result of an acute pH change, however, glargine has been demonstrated to significantly reduce hypoglycemic episodes
9 3S (2011) S114–S117
S115
and improving HbA1c levels [14,17]. In comparison to intermediate acting insulins, prenocturnal glargine administration has been suggested to cause significant reduction in the blood glucose fasting levels, compared to the use of NPH [18]. Detemir on the other hand, excels in comparison with NPH in improving glycemic control and reducing the frequency of hypoglycemic episodes, particularly the nocturnal ones [19]. Between detemir and glargine, research on children and adolescents has showed that the first demonstrates a more reproducible pharmacokinetic profile than the latter [20]. In addition, unlike the other long-acting analogs, detemir remains liquid even after subcutaneous injection [21].
3.3.
Premixed insulin preparations
The premixed insulins consist of fixed ratio mixtures of a rapid and an intermediate insulin. Their use is common in some countries particularly in prepubertal children, on regimens with twice a day injections [10]. Although they reduce potential errors in the procedure of preparing insulin syringes, they remove the flexibility offered by the separate adjustment of the two types. Such flexibility is important in children with variable food consumption, however premixed insulins are useful in populations incapable of learning a more intensive treatment regime. Biphasic insulin aspart 30 (30% aspart and 70% aspart bound to NPH) given for the three main meals combined with NPH before bedtime was equally efficient as premixed human insulin (70% NPH) given for morning and bedtime with regular insulin for lunch and dinner [10,22]. The Hvidøre study demonstrated poorer metabolic control with the use of premixed insulins in adolescents [23].
4.
Regimens
The daily dosage of insulin depends on various factors such as age, body weight, stage of puberty, duration and phase of diabetes, state of injection sites, nutritional intake and distribution, exercise patterns, daily routine, results of blood glucose monitoring (and glycated hemoglobin) and intercurrent illness [10]. Insulin administration in children and adolescents can either be conventional with two mixed insulin injections every 12hours (rapid and medium acting insulins), intensive with three rapid acting insulin injections, or injections of rapid acting insulin analogs with every meal and one medium/long acting insulin analog injection before bedtime. All forms and combinations are adapted to the patient’s age, stage of puberty, dietary and physical exercise habits. In infants and prepubertal children, the daily dosage of insulin ranges from 0.5 to 1.0 μg/kg body weight, whereas during puberty it is increased to 1.5–2.0 μg/kg body weight. During the honeymoon period, the total daily insulin dosage is often <0.5 μgu/kg. The correct dosage for each child/adolescent must attain the following characteristics: (a) achieve the best feasible metabolic control without provoking hypoglycemia, and (b) ensure the adequate and harmonious growth, according to the growth charts for weight and height.
S116
DIABETES RESEARCH A N D CLINICAL PRACTICE
The intensive four injection regimen is preferred and used by the majority of children because it provides flexibility, given that both children and adolescents demonstrate differences in the quantity and quality of daily food intake and physical activity [24]. It should be noted that the application of basal rhythm, meal and corrective dosages during the intensive, multiple injections regimen have a lot of resemblances with the physiologic endogenous excretion of insulin by the pancreas.
5.
Administration of insulin
5.1.
Insulin syringes – pens
Today, the classic syringes of insulin are used only in cases of very young children where free mixture of insulins is administered. Syringes are available in a variety of sizes, ensuring accurate dosage delivery; however it is desirable to have small syringes with 1 unit per mark (e.g. 0.3 ml) for use in small children. “Pen” type insulin administration appliances (Pens) are children and adolescent-friendly and they have been proved to be very useful in intensive regimens with the use of insulin analogs. Pens have suitable gradation and in their majority they have the possibility to regulate even half a unit, by bringing very small and thin needles (5–6 mm, 31G). For children with needle phobia there are special pens that eject the needles and others that operate through high pressure systems instead of needles. Small children with small body surface and decreased subcutaneous fat under intensive regimens tend to use the same places for injection, driven by the pain. For these children there are special catheters, the Insuflon, via which insulin infusion might take place. The use of Insuflon does not affect metabolic control negatively [25]. On the contrary, when used in children with injection problems, HbA1c was significantly lowered with the use of Insuflon [26]. However, it is advisable that all children and adolescents with diabetes should know how to administer insulin by syringe because other injection devices might malfunction. 5.1.1. Education When the proper insulin regimen is chosen, it must be supported by comprehensive education appropriate for the age, maturity and individual needs of the child and family. An important factor for the injection procedure is the adequate education of parents and guardians. The suitable age for “auto-injection” varies for each child and is related much more to the intellectual maturity than to the chronological age. Most children ≥10 years old inject themselves alone or with some help during the procedure. Younger children share the injection responsibility with their parents but must participate in the appliance preparation or even many times carry out all the procedure themselves, under supervision. The need of “auto-injection” is often aroused by incidents like an overnight’s stay at a friend’s house, a school trip or summer camp. Also younger children in multiple injection regimens might need help, when they should perform the injection in body areas where they do not reach, so as to avoid fat-hypertrophy.
5.2.
9 3S (2011) S114–S117
Continuous subcutaneous insulin infusion
Continuous subcutaneous insulin infusion (CSII) consists of an intensive insulin therapy method, which initially began during the 80’s, however its use was spread widely particularly after the DCCT study [8]. All scientific committees with endocrinological orbit and diabetes mellitus interest agree in the use of pumps after suitable education. The International Society of Pediatric and Adolescent Diabetes (ISPAD), the European Society of Pediatric Endocrinology (ESPE) and the Lawson Wilkins Pediatric Endocrine Society (LWPES) in agreement with the American Diabetic Association (ADA) and the European Association for the Study of Diabetes (EASD), established a joint consensus statement regarding the use of insulin pumps in children and adolescents with T1DM [26]. According to this consensus statement, there is no age-related limit and each DM1 child can continue pump insulin therapy regardless of his age. The use of CSII is advisable in children and adolescents with serious and frequent hypoglycemic episodes, with wide fluctuations of blood glucose levels regardless of the HbA1c , in patients with bad glycemic control (high HbA1c ), in children and adolescents with micro-vascular complications, and in the cases that although a good glycemic control is achieved, the insulin therapy influences the quality of life of the patient. Moreover, pump administration is beneficial for children and adolescents, especially in the following cases: in preschool children and particularly infants and neonates, adolescents with appetite disorders, in children and adolescents with increased dawn phenomenon, in children with needle phobia, in pregnant adolescents, in individuals prone to ketoacidosis, as well as in competitive sports athletes [27]. Various factors are important for insulin therapy to be successful, and these include motive, education and the individual’s ability to accept the particular insulin therapy method. Undoubtedly, there is the need for further randomized studies in children and adolescents in order to show whether the use of CSII excels over the multiple injections regimen in improving glycemic control and reducing the frequency of hypoglycemic episodes.
6.
Conclusions
Conclusively, secure and appropriate administration of insulin in children and adolescents requires a priori knowledge of a child’s and adolescent’s body and physiological responses on behalf of doctors and health professionals, and must coincide with adequate patient and family education. Alterations in the patients’ physique and body as a result of the hormonal flood that takes place, renders children and adolescents into “special cases” and indicate the need of continuous changes and readjustments of the insulin therapy. Insulin demonstrates wide fluctuations between days in the same individual, but also among different patients, particularly among children. Insulin onset, peak and duration of action depends on various factors, such as the lack of subcutaneous fat in very young children, the increased fat mass in girls particularly in puberty, and the increased muscular mass observed during adolescence. Intramuscular instead of
DIABETES RESEARCH A N D CLINICAL PRACTICE
subcutaneous injection leads to faster absorption and action, but also shorter duration of action. Other factors influencing insulin action are games/exercise patterns – integral element of children and adolescents’ life – as well as the body’s core and environmental temperatures. It is supported that the action of the new rapid and long acting insulin analogs is less influenced by these factors.
Conflict of interest
[14]
[15]
[16]
The author has no conflicts of interest to report. [17]
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