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      Mortality in People With Type 1 Diabetes, Severe Hypoglycemia, and Impaired Awareness of Hypoglycemia Referred for Islet Transplantation

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          Abstract

          Severe hypoglycemia (SH) is believed to be responsible for 4% to 10% of deaths in individuals with type 1 diabetes (T1D). 1 Treatment recommendations for people with SH and impaired awareness of hypoglycemia (IAH) incorporate a tiered, 4-stage algorithm that includes educational, technological, and transplantation interventions. 2 However, applicability of islet transplantation is restricted by limited supply of donor organs, need for immunosuppression, and strict eligibility criteria. This is the first report of mortality in people referred to a national islet transplantation program, whether or not they received a transplant. All referrals between 2005 and 2016 to Australian islet transplant centers (St Vincent's Hospital, Melbourne; Westmead Hospital, Sydney; Royal Adelaide Hospital, Adelaide) were retrospectively reviewed. Major inclusion criteria for islet transplantation include: age, 18 to 65 years; T1D, longer than 5 years; recurrent SH; IAH; failed intensive insulin therapy. Exclusion criteria include: creatinine clearance less than 75 mL/min per 1.73 m2; proteinuria greater than 300 mg/d; weight greater than 80 kg; active psychiatric illness; pregnancy. 3 Of 321 people (66% female) referred for islet transplantation, 40 received 1 or more transplant, 15 were on the active waiting list, and 266 were considered unsuitable for transplant (Table 1). There were a total of 11 deaths, resulting in an overall mortality rate of 3.4%. Table 2 shows characteristics of the deceased individuals. Most were women with long-duration T1D and suboptimal glycemic control, using multiple daily injections. Use of continuous subcutaneous insulin infusion (CSII) is limited in Australia; however, the transplant program mandates that CSII is considered and/or trialed before proceeding to transplant. There were no differences in baseline demographics or diabetes-related characteristics between the deceased and transplant group (data not shown). TABLE 1 Mortality rates in people referred for islet transplantation TABLE 2 Characteristics of deceased individuals referred for islet transplantation (n = 11) Ten of 11 deceased individuals were unsuitable for transplantation due to renal impairment (stage 3 chronic kidney disease) (3), mental illness (3), previous renal transplant (1), gastroparesis (1), active smoking (1), and acute myeloid leukemia (1). Only 1 person was on the active waiting list and died after presumed deliberate insulin overdose, despite undergoing formal assessment for psychiatric illness. Eight of 11 deaths were hypoglycemia-related: 3 from deliberate insulin overdose in individuals with known depression; 3 from “dead-in-bed” syndrome; 1 from myocardial infarction following hypoglycemia; and 1 after an unintentional insulin overdose. There was 1 death due to diabetic ketoacidosis. The 2 nondiabetes-related deaths were due to septic shock after bowel perforation and acute myeloid leukemia. Suicide constitutes 4.4% of deaths in the general population with T1D younger than 40 years in Australia. 5 Severe hypoglycemia and IAH is known to be associated with poorer psychological well-being, 6 and the high suicide rate of 27% evident within our cohort demonstrates the need for psychological support and intervention. All patients undergo assessment by a psychiatrist prior to transplantation. Renal impairment is another common reason that people are not suitable for transplant. Cause of death in these individuals was predominantly hypoglycemia-related. Compromised renal function further increases risk of hypoglycemia as well as mortality, including death from unintentional insulin overdose. Reduced clearance of insulin was possibly a contributing factor to hypoglycemia in these cases. Our mortality rate may be an underestimate as some deaths may not have been identified. Linkage to the National Death Registry is in progress. It is difficult to compare our mortality rates as there are no specific reports of mortality in the T1D population with SH and IAH, and no reports from other islet transplant programs. Currently, approximately 80% of islet transplant referrals do not receive transplant for medical or psychosocial reasons in Australia. The Australian islet transplant program is actively promoted using educational means to raise awareness within the endocrine community about the indications for transplant and the population in whom transplantation may be beneficial. Highly specialized multidisciplinary clinics with expertise in managing problematic hypoglycemia should be considered to support these high-risk patients who are not suitable for transplant. This report affirms that individuals referred for islet transplantation represent a highly vulnerable group of T1D patients, at risk of SH and its sequelae, including death. Those who do not receive transplant have higher mortality rates than transplanted individuals despite concerns of transplant-associated risks relating to the procedure and long-term immunosuppression. According to the Collaborative Islet Transplant Registry, 819 islet transplants have been performed worldwide. 7 As our eligibility criteria are similar to other major transplant centers contributing to the Collaborative Islet Transplant Registry, it is possible that over 200 people referred for islet transplantation may have died either before receiving a transplant, or after being assessed and found to be unsuitable. Our national database has now been extended to include all patients referred to the islet transplant program.

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          Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation.

          Currently, the major indications for solitary islet transplantation are recurrent severe hypoglycemia and labile glucose control. Quantifying these problems remains subjective. We have developed a scoring system for both hypoglycemia and glycemic lability, established normative data, and used them in patients who have undergone islet transplantation. A composite hypoglycemic score (HYPO score) was devised based on the frequency, severity, and degree of unawareness of the hypoglycemia. In addition, using 4 weeks of glucose records, a lability index (LI) was calculated based on the change in glucose levels over time and compared with a clinical assessment of glycemic lability. A mean amplitude of glycemic excursions (MAGE) was also calculated based on 2 consecutive days of seven readings each day. These scores were determined in 100 randomly selected subjects with type 1 diabetes from our general clinic to serve as a control group and in patients before and after islet transplantation. The mean age of the control diabetic subjects was 38.4 +/- 1.3 years (+/-SE), with a duration of diabetes of 21.5 +/- 1.1 years. The median HYPO score in the control subjects was 143 (25th to 75th interquartile range: 46-423). The LI in the diabetic control subjects was 223 (25th to 75th interquartile range: 130-329 mmol/l(2)/h.week(-1)). The LI correlated much more closely than the MAGE with the clinical assessment of lability. A HYPO score of > or = 1,047 (90th percentile) or an LI > or = 433 mmol/l(2)/h.week(-1) (90th percentile) indicated serious problems with hypoglycemia or glycemic lability, respectively. The islet transplant patients (n = 51) were 42.1 +/- 1.4 years old, with a duration of diabetes of 25.7 +/- 1.4 years. Islet transplant patients had a mean HYPO score of 1,234 +/- 184 pretransplant, which was significantly higher than that of the control subjects (P < 0.001), which became negligible posttransplantation with the elimination of hypoglycemia. The median LI pretransplant was 497 mmol/l(2)/h.week(-1) (25th to 75th interquartile range: 330-692), significantly higher than that of control subjects (P < 0.001), and fell to 40 (25th to 75th interquartile range: 14-83) within a month after the final transplant. In those who had lost graft function, the LI rose again. The HYPO score and LI provide measures of the extent of problems with hypoglycemia and glycemic lability, respectively, complement the clinical assessment of the problems with glucose control before islet transplantation, and will allow comparison of selection of subjects for transplants between centers.
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            Evidence-Informed Clinical Practice Recommendations for Treatment of Type 1 Diabetes Complicated by Problematic Hypoglycemia

            Problematic hypoglycemia, defined as two or more episodes per year of severe hypoglycemia or as one episode associated with impaired awareness of hypoglycemia, extreme glycemic lability, or major fear and maladaptive behavior, is a challenge, especially for patients with long-standing type 1 diabetes. Individualized therapy for such patients should include a composite target: optimal glucose control without problematic hypoglycemia. Therefore, we propose a tiered, four-stage algorithm based on evidence of efficacy given the limitations of educational, technological, and transplant interventions. All patients with problematic hypoglycemia should undergo structured or hypoglycemia-specific education programs (stage 1). Glycemic and hypoglycemia treatment targets should be individualized and reassessed every 3–6 months. If targets are not met, one diabetes technology—continuous subcutaneous insulin infusion or continuous glucose monitoring—should be added (stage 2). For patients with continued problematic hypoglycemia despite education (stage 1) and one diabetes technology (stage 2), sensor-augmented insulin pumps preferably with an automated low-glucose suspend feature and/or very frequent contact with a specialized hypoglycemia service can reduce hypoglycemia (stage 3). For patients whose problematic hypoglycemia persists, islet or pancreas transplant should be considered (stage 4). This algorithm provides an evidence-informed approach to resolving problematic hypoglycemia; it should be used as a guide, with individual patient circumstances directing suitability and acceptability to ensure the prudent use of technology and scarce transplant resources. Standardized reporting of hypoglycemia outcomes and inclusion of patients with problematic hypoglycemia in studies of new interventions may help to guide future therapeutic strategies.
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              Severe hypoglycaemia and its association with psychological well-being in Australian adults with type 1 diabetes attending specialist tertiary clinics.

              To investigate severe hypoglycaemia (SH) in adults with type 1 diabetes and its associations with impaired awareness of hypoglycaemia (IAH), clinical, psychological and socio-demographic factors.
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                Author and article information

                Journal
                Transplant Direct
                Transplant Direct
                TXD
                Transplantation Direct
                Lippincott Williams & Wilkins
                2373-8731
                November 2018
                23 October 2018
                : 4
                : 11
                : e401
                Affiliations
                [1 ] Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, Australia.
                [2 ] Department of Medicine, St Vincent's Hospital, The University of Melbourne, Australia.
                [3 ] Department of Nephrology, St Vincent's Hospital Melbourne, Australia.
                [4 ] Department of Endocrinology, University of Sydney at Westmead Hospital, Sydney, Australia.
                [5 ] Department of Renal Medicine, Westmead Hospital, Sydney, Australia.
                [6 ] Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Australia.
                [7 ] St Vincent's Institute of Medical Research, Melbourne, Australia.
                [8 ] Westmead Institute of Medical Research, University of Sydney at Westmead Hospital, Sydney, Australia.
                Author notes
                [*]Correspondence: Melissa H. Lee, MBBS, Department of Medicine, University of Melbourne St Vincent's Hospital Melbourne, 4th Floor, Clinical Sciences Bldg, 29 Regent St, Fitzroy, Victoria 3065, Australia. ( melissa.lee@ 123456svha.org.au ).
                Article
                TXD50317 00001
                10.1097/TXD.0000000000000841
                6233662
                30534592
                08e0c44d-ac03-4fd9-b216-b6e419e425ce
                Copyright © 2018 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                : 17 April 2018
                : 3 June 2018
                : 18 September 2018
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