Faculty of Health Sciences, The University Of Adelaide, Adelaide, South Australia.

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1 The effectiveness of continuous subcutaneous insulin pumps with continuous glucose monitoring in outpatient adolescents with type 1 diabetes: A systematic review Erin Matsuda RN MSN PNP-BC 1 erin.matsuda@samuelmerritt.edu Patricia Brennan PhD, RN, MS 1 pbrennan@samuelmerritt.edu 1. Samuel Merritt University, Oakland, California USA. Affiliated with the Joanna Briggs Institute, Faculty of Health Sciences, The University Of Adelaide, Adelaide, South Australia. Review question/objective The review question is: Are metabolic outcomes improved in outpatient adolescents (aged 13 to 19 years) with type 1 diabetes on a Continuous Subcutaneous Insulin Infusion (CSII) when continuous glucose monitoring is used, compared to self-glucose monitoring alone? Background Type 1 diabetes is the most common childhood paediatric disease, characterised by impairment of insulin producing βeta-cells in the pancreas 1. Internationally, there is variation in the incidence of type 1 diabetes in paediatric patients. According to the Center for Disease Control and Prevention (CDC) and the SEARCH for Diabetes in Youth Study Group, the overall incidence rate of this autoimmune disease is 24.3/100,000 in those 19 years of age 2. Annually, more than 15,000 children and adolescents are diagnosed in the United States (US) 2. From 1990 to 1999, the World Health Organization (WHO) launched the Multinational Project for Childhood Diabetes (DIAMOND), which was tasked with assessing type 1 diabetes in those 14 years or younger worldwide 3. Finland was discovered to have the highest age-adjusted incidence at 40.9 cases per 100,000/year. The lowest age-adjusted incidence is in China and Venezuela at 0.1 cases per 100,000/year. Globally, the largest increase in incidence is in those aged 10 to 14 years 3, 4. This systematic review will focus on adolescent patients with type 1 diabetes, aged 13 to 19 years who manage their diabetes with an insulin pump. Patients with type 1 diabetes mellitus typically present with a history of polydipsia, polyuria, polyphagia, and weight loss 5. Initial findings include hyperglycemia, glycosuria, and ketones in the blood or urine 5. In 2009, the International Expert Committee deemed a haemoglobin A1C (glycosylated haemoglobin) of 6.5% or higher to be the standard for diagnosis 6. The American Diabetes Association (ADA) as well as the International Diabetes Federation and the European Association Study of Diabetes (EASD) accept this measure as the diagnostic tool for diabetes 6. Haemoglobin A1C is the most commonly used measurement for patients with type 1 diabetes 7. It refers to the measurement of the amount of glucose bound to haemoglobin. It is an average of blood glucose levels for the last 120 days, which is consistent with the average life span of a red blood cell (RBC). Page 1

2 Compensation for the lack of insulin-secreting βeta-cells is accomplished through administration of insulin. For adolescents, insulin dosing is based on pubescent status, age, weight, activity level, and amount of carbohydrates consumed 5. Insulin administration, carbohydrate counting, and correction of hyperglycemia are necessary for maintaining glycemic control. Insulin can be administered through multiple daily injections (MDI) of rapid, intermediate and long-acting insulin 5. Another form of insulin delivery is the Continuous Subcutaneous Insulin Infusion (CSII), also known as an insulin pump, which is designed to meet physiological requirements through programmable basal rates and bolus doses 8. CSII s utilise rapid-acting insulin and establish a basal rate, which replaces the need for long-acting insulin. Bolus dosing is accomplished through adjusting the pump and is utilised to account for nutritional intake as well as hyperglycemia correction. Adjustments are also made for physical activity and exercise, as this can affect glucose levels 9. All patients considered in this systematic review will be utilising insulin pumps. In 2006, the United States had more than 35,000 patients, under the age of 21 years, receiving insulin therapy through an insulin pump 10. In Europe, the percentage of people with type 1 diabetes utilising a CSII is lower, potentially due to variation in health care coverage 11. There are various forms of insulin pumps, all with similar capabilities including a dose calculator for high blood glucose correction and carbohydrate ratios, programming software, and several other features 12. Software and programming is specific to each manufacturer. Basal rate abilities vary in each model from 0.05 units/hour to 30 units/hour 12. Information from the pump can be uploaded to online registries allowing providers to review trends and usage. It is imperative the information is reviewed concurrently with glucose monitoring results in order to ensure appropriate dosing and treatment 12. The intervention considered in this systematic review is the use of continuous glucose monitoring (CGM) in conjunction with a CSII. CGM utilises a sensor placed in the interstitial subcutaneous tissue, which then measures glucose levels. This is accomplished with electrochemical sensors that use glucose oxidase and measure an electric current generated when glucose reacts with oxygen. The sensors are coated with a specialised membrane to make them biocompatible 13. The CGM has programmable high and low levels to alert the user when the limit is being reached. Information regarding continuous glucose levels can then be downloaded and reviewed. Based on the report, providers, patients, and caregivers may assess trends and consider changing basal rates or bolus doses 13. CGM sensors currently do not offer a closed-loop solution. The user must enter insulin dosing information into the pump, taking into account the present glucose level and duration of action of the insulin. Currently, CGMs are regarded as a supplemental method for assessing the effectiveness of glucose control. Existing studies are underway to improve accuracy and communication between the sensor and insulin pump with the goal to develop an artificial pancreas 13. Currently, CGM sensors must be calibrated with a glucometer, as specified by the manufacturer 13. The comparison for this review is the standard of care, self-glucose monitoring (SGM), in patients with insulin pumps 6. SGM is accomplished with a glucometer and blood sample typically obtained from a finger prick. The Diabetes Control and Complications Trial (DCCT) demonstrated frequency of Page 2

3 monitoring improves glycemic control and decreases the risk of comorbidity 14, 15. Data from this significant study continues to contribute to current diabetes management. According to the ADA, children and adolescents should monitor their blood glucose at least three or more times per day 6. Blood glucose data is utilised to calculate appropriate insulin doses. Similar to the CGM, information from the glucometers can be downloaded for assessment of results and trends. However, the result is dependent on the action of the patient to obtain the sample and only represents a specific moment in time whereas the CGM sensor continuously tracks the blood glucose level. Depending on the model, CGM can provide glucose levels every one to ten minutes. The sensor may last for up to 72 hours and results are available in real time 16. This systematic review will address two metabolic outcomes: a decrease in the number of hypoglycemic episodes and a haemoglobin A1C level <7.5%. These outcomes were chosen due to their significance as indicators in the management of type 1 diabetes. Glucose levels should be between 90 mg/dl and 130 mg/dl (5.0mmol/l and 7.2mmol/l) before meals and between 90 mg/dl and 150 mg/dl at night (5.0mmmol/l and 8.3mmol/l) 6. Optimal care of an adolescent with type 1 diabetes mellitus is to safely maintain glycemic control and avoid hypoglycemia. Haemoglobin A1C is an indicator of how well the disease is being managed and should be evaluated every three months. McCulloch recommends the haemoglobin A1C level should be compared to approximately 50 recent blood glucose readings to ensure the accuracy of patient SGM 7. The reliability and validity of this test is based on the evidence discovered by the DCCT demonstrating those with lower haemoglobin A1C levels have fewer complications 14. The target A1C for adolescents, aged 13 to 19 years of age, is <7.5% 6. This is consistent with the National Institute of Clinical Excellence (NICE) and diabetes management guidelines of the Australasian Paediatric Endocrine Group for the Department of Health and Ageing 17, 18. An initial search for a systematic review regarding insulin pumps in adolescents with type 1 diabetes mellitus and concurrent use of CGM was conducted in the Joanna Briggs Institute Library of Systematic Reviews, Cochrane Database of Systematic Reviews, and PubMed. No systematic reviews were found. Keywords type 1 diabetes; insulin pumps; glucose monitoring; outpatient; adolescents Inclusion criteria Types of participants This review will consider studies, which include adolescent patients, aged 13 to 19 years, in the outpatient setting with type 1 diabetes mellitus utilising a cutaneous subcutaneous insulin pump. Types of intervention(s)/phenomena of interest This review will consider studies, which evaluate continuous glucose monitoring compared to self-glucose monitoring alone, in adolescents utilising a continuous subcutaneous insulin infusion. Page 3

4 Types of outcomes This review will consider studies, which include the following outcome measures: number of hypoglycemic episodes (glucose <70mg/dL) and haemoglobin A1C level. Types of studies Experimental studies will be considered: randomised control trials (RCTs). Quasi-experimental studies will be considered only in absence of RCTs or where there are too few RCTs. Search strategy The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilised in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published or translated into English will be considered for inclusion in this review. CSIIs have been available for patient care for several decades. However, the technology of CGM has become accessible more recently. Therefore, studies published between 2002 and 2012 will be considered for inclusion in this review. The databases to be searched include: MEDLINE, CINAHL, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase. The search for unpublished studies will include: Google Scholar, New York Academy of Medicine, American Diabetes Association, Juvenile Diabetes Research Foundation, National Institute of Clinical Excellence (NICE), Australasian Paediatric Endocrine Group for the Department of Health and Ageing, International Diabetes Federation, European Association Study of Diabetes, and the National Guideline Clearinghouse. Initial keywords to be used will be: type 1 diabetes, adolescent, continuous glucose monitor, self-glucose monitor, glucose, monitor, continuous subcutaneous insulin infusion, insulin pump, glycosylated hemoglobin, hemoglobin A1C, hypoglycemia, and log book. Assessment of methodological quality Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardised critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer. Page 4

5 Data collection Data will be extracted from papers included in the review using the standardised data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Data synthesis Quantitative papers will, where possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different quantitative study designs included in this review. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. Conflicts of interest There is no conflict of interest to declare. Acknowledgements Dr. Cecily Cosby- Director of Doctorate of Nursing Practice at Samuel Merritt University Dr. Nancy Donaldson- UCSF Centre for Evidence-based Patient Care Quality Improvement, a JBI Affiliated Centre Dr. Mary Sullivan - Practice Site Advisor. Page 5

6 References [1] Levitsky LL, Misra M. Management of type 1 diabetes mellitus in children and adolescents [Internet]. Waltham: UpToDate; 2011 [cited 2011 APR 3]. Available from: [2] Dabelea D, Bell RA, D'Agostino RB Jr., Imperatore G, Johansen JM, Linder B, et al. Incidence of diabetes in youth in the United States. JAMA: The Journal of the American Medical Association.2007; 297(24): [3] The DIAMOND Project Group. Incidence and trends of childhood type 1 diabetes worldwide, Diabetic Medicine.2006; 23: [4] Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J. Incidence of childhood type 1 diabetes worldwide, diabetes mondiale (DiaMond) project group. Diabetes Care. 2000; 23(10): [5] Silverstein J, Klingensmith G, Copeland K, Plotnick L, Kaufman F, Laffel L, et al. Care of children and adolescents with type 1 diabetes: A statement of the American Diabetes Association. Diabetes Care. 2005; 28(1): [6] American Diabetes Association. Standards of medical care in diabetes Diabetes Care. 2012; 35(1):S11-S63. [7] McCulloch D. Blood glucose self-monitoring in management of diabetes mellitus. [Internet]. Waltham: UpToDate; 2011 [cited 2011 APR 3]. Available from: [8] Plotnick LP, Clark LM, Brancati FL, Erlinger T. Safety and effectiveness of insulin pump therapy in children and adolescents with type 1 diabetes. Diabetes Care.2003; 26: [9] Mehta SN, Wolfsdorf II. Contemporary Management of Patients with Type 1 Diabetes. Endocrinology Metabolism Clinic of North America. 2010; 39: [10] Fisher LK. The selection of children and adolescents for treatment with continuous subcutaneous insulin infusion (CSII). Pediatric Diabetes.2006; 7:4-11. [11] Renard E. Insulin pump use in Europe. Diabetes Technology & Therapeutics.2010; 12:S29-S32. [12] Grunberger G, Bailey TS, Cohen AJ, Flood TM, Handelsman Y, Hellman R, et al. Statement by the America Association of Clinical Endocrinologists consensus panel on insulin pump management. Endocrine Practice.2010; 16(5): [13] Aye T, Block J, Buckingham B. Toward closing the loop: An update on insulin pumps and continuous glucose monitoring systems. Endocrinology and Metabolism Clinics of North America.2010; 39: [14] Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The New England Journal of Medicine.1993; 329: Page 6

7 [15] Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. The New England Journal of Medicine.2005; 353(25): [16] Klonoff DC. Continuous glucose monitoring; Roadmap for 21st century diabetes therapy. Diabetes Care.2005; 28(5): [17] Australasian Paediatric Endocrine Group for the Department of Health and Ageing. Clinical practice guidelines: Type 1 diabetes in children and adolescents. [Internet] Australia: National Health and Medical Research Council Act 2005; [cited 2012 May 20]. Available from: [18] National Institute of Clinical Excellence. Type 1 diabetes in children and young people Understanding NICE guidance- information for the families and carers of children with type 1 diabetes, young people with type 1 diabetes, and the public. London, UK: Oaktree Press Ltd.; Insert page break Page 7

8 Appendix I: Appraisal instruments MAStARI Appraisal instrument this is a test message Insert page break Page 8

9 Appendix II: Data extraction instruments MAStARI data extraction instrument Page 9

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