Practical implementation of automated closed-loop insulin delivery: A French position statement.

Automated closed-loop (CL) insulin therapy has come of age. This major technological advance is expected to significantly improve the quality of care for adults, adolescents and children with type 1 diabetes. To improve access to this innovation for both patients and healthcare professionals (HCPs), and to promote adherence to its requirements in terms of safety, regulations, ethics and practice, the French Diabetes Society (SFD) brought together a French Working Group of experts to discuss the current practical consensus. The result is the present statement describing the indications for CL therapy with emphasis on the idea that treatment expectations must be clearly defined in advance. Specifications for expert care centres in charge of initiating the treatment were also proposed. Great importance was also attached to the crucial place of high-quality training for patients and healthcare professionals. Long-term follow-up should collect not only metabolic and clinical results, but also indicators related to psychosocial and human factors. Overall, this national consensus statement aims to promote the introduction of marketed CL devices into standard clinical practice.

Practical implementation, education and interpretation guidelines for continuous glucose monitoring: A French position statement.

The use by diabetes patients of real-time continuous interstitial glucose monitoring (CGM) or the FreeStyle Libre® (FSL) flash glucose monitoring (FGM) system is becoming widespread and has changed diabetic practice. The working group bringing together a number of French experts has proposed the present practical consensus. Training of professionals and patient education are crucial for the success of CGM. Also, institutional recommendations must pay particular attention to the indications for and reimbursement of CGM devices in populations at risk of hypoglycaemia. The rules of good practice for CGM are the precursors of those that need to be enacted, given the oncoming emergence of artificial pancreas devices. It is necessary to have software combining user-friendliness, multiplatform usage and average glucose profile (AGP) presentation, while integrating glucose and insulin data as well as events. Expression of CGM data must strive for standardization that facilitates patient phenotyping and their follow-up, while integrating indicators of variability. The introduction of CGM involves a transformation of treatment support, rendering it longer and more complex as it also includes specific educational and technical dimensions. This complexity must be taken into account in discussions of organization of diabetes care.

Indication, organization, practical implementation and interpretation guidelines for retrospective CGM recording: A French position statement.

AIM: The benefits of retrospective continuous glucose monitoring (retroCGM) recording have been widely explored in clinical studies, and many diabetes physicians routinely use this examination. However, the method of interpretation of CGM recordings has never been precisely described. METHOD: An expert French panel of physicians met for two days to discuss several aspects of retroCGM use and to produce a position statement. RESULTS: The guidelines cover the indications for retroCGM, the general organization and practical implementation of CGM recordings, a description of the different devices available and guidelines for the interpretation of retroCGM recordings. CONCLUSION: This consensus document should help clinicians in the proper use of retroCGM.

Enhanced growth of Staphylococcus aureus after nitric oxide supplementation during simulated extracorporeal circulation.

BACKGROUND: Several factors contribute to postoperative bacterial infections in cardiac surgery. Long operation times and the use of extracorporeal circulation increase the risk of infection. Nitric oxide has been shown to possess a broad spectrum antimicrobial effect. METHODS: In this study, we investigated the effect of nitric oxide on S. AUREUS growth in whole blood during simulated extracorporeal circulation. RESULTS: S. AUREUS growth increased 6.2-fold after 180 min SECC in the presence of nitric oxide. Leukocyte counts remained unchanged without any differences between the groups. We observed a steady increase in markers of oxidative stress and activity of the innate immune system. Myeloperoxidase levels increased 8-fold, and C3a and terminal complement complex by 2-fold after 180 min. CONCLUSION: S. AUREUS growth is not due to the effect of nitric oxide on the innate immune system but from its effect on the bacteria itself. It has been shown that nitric oxide stimulates the expression of inducible lactate dehydrogenase, specific to S. AUREUS, which improves its resistance to oxidative stress, and may give S. AUREUS a survival advantage resulting in increased growth.

A reduction in severe hypoglycaemia in type 1 diabetes in a randomized crossover study of continuous intraperitoneal compared with subcutaneous insulin infusion.

AIM: Continuous intraperitoneal insulin infusion (CIPII) with the DiaPort system using regular insulin was compared to continuous subcutaneous insulin infusion (CSII) using insulin Lispro, to investigate the frequency of hypoglycemia, blood glucose control, quality of life, and safety. METHODS: In this open, randomized, controlled, cross-over, multinational, 12-month study, 60 type 1 diabetic patients with frequent hypoglycemia and/or HbA1c > 7.0% with CSII were randomized to CIPII or CSII. The aim was to obtain the best possible blood glucose while avoiding hypoglycemia. RESULTS: The frequency of any hypoglycemia was similar (CIPII 118.2 (SD 82.6) events / patient year, CSII 115.8 (SD 75.7) p = 0.910). The incidence of severe hypoglycemia with CSII was more than twice the one with CIPII (CIPII 34.8 events / 100 patient years, CSII 86.1, p = 0.013). HbA1c, mean blood glucose, and glucose fluctuations were not statistically different. Treatment-related severe complications occurred mainly during CIPII: port infections (0.47 events / patient year), abdominal pain (0.21 events / patient year), insulin underdelivery (0.14 events / patient year). Weight gain was greater with CSII (+ 1.5 kg vs. - 0.1 kg, p = 0.013), quality of life better with CIPII. CONCLUSIONS: In type 1 diabetes CIPII with DiaPort reduces the number of severe episodes of hypoglycemia and improves quality of life with no weight gain. Because of complications, indications for CIPII must be strictly controlled. CIPII with DiaPort is an alternative therapy when CSII is not fully successful and provides an easy method of intraperitoneal therapy.

Treatment of diabetes mellitus using an external insulin pump in clinical practice.

Before the initiation of insulin pump therapy, patients must be aware of the different aspects of this form of intensive insulin therapy. Most healthcare professionals recommend a sequential approach to inform patients about CSII. Factors that need to be considered in choosing an insulin pump include its safety features, durability of the device, tolerability and comfort of the catheter, user-friendliness, technical features and appearance. The initial insulin requirements need to be individualized for the given patient, using different methods to determine the appropriate dosages for the basal rate and prandial boluses. Glycaemic targets and algorithms for insulin dose adaptation need to be learned by the patients to enable them to avoid and/or correct hypo- and hyperglycaemia/ketosis episodes. Patients are also advised on how to carry out frequent self-monitoring of blood glucose-and of ketone bodies, if necessary. Insulin pumps are now able to deliver a range of basal rates and boluses that increase the flexibility of CSII. One specific issue is the approach to meal-planning, based on carbohydrate-counting or the equivalent: this method of so-called 'flexible insulin therapy' can improve metabolic control (for instance, by diminishing postprandial excursions) as well as the quality of life of patients. Evaluation of the knowledge and practices of the patient can be made through a continuous educational programme carried out by experienced nurses and physicians at the start of therapy and during follow-up. In addition, it may be necessary to identify the reasons for lack of improvement in metabolic control after several months of therapy, which include pump malfunction, cannula problems, miscalculated insulin dosages and insufficient metabolic control in specific clinical situations with a high risk of metabolic deterioration (illness, exercise, concomitant drugs). Annual assessment of the patient using an itemized checklist is required to verify the continued efficacy and safety of insulin pump therapy, two main factors of success with CSII treatment.

One-year efficacy and safety of Web-based follow-up using cellular phone in type 1 diabetic patients under insulin pump therapy: the PumpNet study.

AIM: Conventional follow-up of type 1 diabetic patients treated with continuous subcutaneous insulin infusion (CSII) was compared with intensive coaching using the Web and the cellular phone network for retrospective data transmission and short message service (SMS). METHODS: Thirty poorly controlled patients (HbA1c 7.5-10%) were enrolled in a bicenter, open-label, randomized, 12-month, two-period, crossover study. After a 1-month run-in period, 15 patients were randomly assigned to receive weekly medical support through SMS based upon weekly review of glucose values, while 15 patients continued to download self-monitored blood glucose (SMBG) values on a weekly basis without receiving SMS. After 6 months, patients crossed over to the alternate sequence for 6 additional months. Visits at the clinic were maintained every 3 months. RESULTS: Patients with long-standing inadequately controlled diabetes (24 +/- 13 years) were included. A non-significant trend to reduction in HbA(1c) (-0.25+/-0.94%, P<0.10) and mean glucose values (-9.2+/-25 mg/dl, P=0.06) during the 6-month SMS sequence was observed as compared with the no-SMS period. No safety issue (hypoglycemia, glucose variability) was reported. Adherence to SMBG was not affected by the trial. Quality of life analysis suggests a significant improvement in DQOL global score, as well as the DQOL satisfaction with life subscale, during the SMS sequence. CONCLUSIONS: Long-term telemedical follow-up of insulin pump-treated patients using a cellular phone-, SMS- and Web-based platform is feasible, safe, does not alter quality of life and associated with a trend toward improved metabolic control.

Continuous intraperitoneal insulin infusion does not increase the risk of organ-specific autoimmune disease in type 1 diabetic patients: results of a multicentric, comparative study.

AIM: The purpose of this national multicenter prospective study by the French EVADIAC group was to investigate the possibility that continuous intraperitoneal insulin infusion using an implanted pump (CIpii) increases the risk of autoimmune disease in type 1 diabetic patients as it increased anti-insulin immunogenicity. METHODS: Prevalence of clinical (Hashimoto's disease, hyperthyroidism, gastric atrophic disease and vitiligo) and subclinical (presence of anti-thyroperoxidase antibodies, anti-intrinsic factor antibodies, abnormal TSH levels) autoimmune diseases was estimated by comparing two groups of patients already treated by either CIpii (n=154) or external pump (CSII) (n=121) for an average of 6 years. Incidence of autoimmune disease was determined by comparing the same measurements one year after inclusion. RESULTS: No significant difference was observed for the total prevalence of clinical and subclinical auto-immune thyroid and gastric di-seases (35.6% and 3.2% respectively in the CIpii group versus 40.4% and 2.6% in the CSII group). No significant difference for the incidence of clinical and subclinical auto-immune diseases was observed: 7.2% and 0% in CIpii and 7.3% and 1.7% in CSII. CONCLUSION: As previously shown AIA (anti-insulin antibodies) levels were higher in CIpii than in CSII (32.9% vs 20.2%, P<0.0001) but no correlation was observed with either clinical or subclinical autoimmune disease. This large-scale study eliminates the possibility that CIpii increases the risk of autoimmune disease.

Value and limitations of the Continuous Glucose Monitoring System in the management of type 1 diabetes.

The CGMS (Continuous Glucose Monitoring System) is a portable device allowing continuous measuring of glucose. It provides recordings of at least 72 h, during which 288 measures/day are performed. Results are visualised in the form of a set of curves, illustrating the variations in blood glucose levels over time. The quality of the records has often been questioned by several authors. Some of the system's physiologically related limitations can be explained by the less than perfect coincidence of variations in glucose levels observed in the interstitial tissue, where CGMS measurings are done, and in the blood, where calibrations are performed. Other limitations, such as defects in accuracy or in reproducibility of tracings or premature curtailments of recordings, are due to technical weaknesses which were considerably improved during the past few years, particularly with regard to the quality of the electrodes providing a more stable signal over time. In clinical practice, CGMS is a tool for investigating the glycaemic patterns of diabetic patients in conjonction with SMBG. It allows the identification of overlooked hyper- or hypoglycaemia. Generally well accepted, it is a usefull tool to analyse the nocturnal period, or any situation where glucose checks are rare. The visual nature of its results provides a facilitating support in the discussion between the patient and the care-provider during consultations or educational sessions. CGMS utilisation was proposed for guiding treatment adjustment. At present, it is still difficult to state with certainty that this tool allows effective improvement in the metabolic control of patients with type 1 diabetes, in view of the paucity of controlled studies showing an impact on HbA1c values or on the frequency of hypoglycaemia, even if such a tendency emerges from most non-controlled intervention trials.

Advantages to using capillary blood beta-hydroxybutyrate determination for the detection and treatment of diabetic ketosis.

Ketone body determination is indicated in all diabetic patients when the risk of ketotic decompensation exists. New methods of screening for ketosis, in particular capillary blood ketone body determination, provide analytical, technical and clinical advantages compared to the conventional ketonuria. It is proposed that a diabetic patient with hyperglycaemia (capillary blood glucose > 2.50 g.l(-1)) and capillary blood ketone bodies exceeding 0.5 mmol.l(-1) requires therapeutic management. For values greater than 3 mmol.l(-1) or in case of more serious clinical symptoms, hospitalisation is indicated, considering the high probability of ketoacidotic decompensation. The advantages of capillary blood ketone body determination including easy use, and rapid and objective results may improve management of the diabetic patient, especially in emergency situations. However, prescription by a physician of capillary blood ketone body determination should be offered to targeted populations that have a high risk of ketoacidotic decompensation, after providing education to patients that is above all aimed at preventing this metabolic complication. In this context of determining ketone bodies in capillary blood, the term "capillary blood ketone bodies" is therefore preferable to the term "capillary blood beta-hydroxybutyrate determination". Indeed, it appears more appropriate, simple, descriptive and significant both for health-care staff and for patients.

What are capillary blood ketone levels in type 1 diabetic patients using CSII in normal conditions of insulin delivery?

OBJECTIVE: The aim of the study was to determine the normal level of capillary ketonemia in type 1 diabetic patients on continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: A total of 36 type 1 diabetic patients treated by external pump were studied for 2 to 3 weeks. Patients were instructed to self monitor capillary glucose and capillary ketone bodies at least 4 times per day with a handheld Medisense Optium meter and check for urinary ketone bodies in the morning and when blood glucose exceeded 2.5 g/l with a semiquantitative test. Data were collected and analysed for each period of time defined as the time interval between two changes of the infusion site. A period was considered "normal" when no problem causing any impairment in insulin delivery was detected. RESULTS: 186 periods of 2.1 +/- 0.9 days were recorded; 119 were considered normal. 1281 coupled values of glucose and betahydroxybutyrate were analysed during the so called normal periods. Mean percentage of ketonemia of 0, 0.1, 0.2, > or =0.3 mmole/l were 81.3%, 13%, 3.7% and 2% respectively whereas mean glucose level (g/l) was 1.49 +/- 0.7, 1.48 +/- 0.7, 1.59 +/- 0.8 and 1.89 +/- 0.9 respectively. Only 0.9% of betahydroxybutyrate values were > or =0.3 mmole/l when blood glucose exceeded 2.5 g/l. CONCLUSION: Our study indicates that ketonemia self monitoring can be a valuable tool to screen insulin deficiency in patients on CSII with a low risk of false positive if we consider a threshold of 0.3 mmole/l for ketone bodies.

Nitric oxide and inflammatory response in simulated extracorporeal circulation.

BACKGROUND: Simulated extracorporeal circulation (SECC) induces inflammatory reaction. Nitric oxide (NO) has pro-and anti-inflammatory properties. NO role in SECC-related inflammatory response is unclear. The aim of this study was to clarify if NO affects the foreign-surface induced leukocyte activation during SECC. METHODS: Human blood was circulated through SECC during 3 hours. Control group C was ventilated with oxygen/air mixture and the study group with oxygen/air mixture and NO. Leukocyte activation was measured as serum levels of myeloperoxidase (MPO), human neutrophil lipocalin (HNL), lactoferrin (LF), interleukin-1-beta (IL-1 beta) and interleukin-10 (IL-10). Oxygen free radical production capacity was evaluated with chemiluminescence. NO metabolites nitrite/nitrate were estimated in serum. RESULTS: Leukocyte granule release increased over time. Addition of NO significantly increased MPO, HNL and LF release. The average difference increased with SECC duration. NO addition did not significantly affect measured interleukins concentration or oxygen free radical production capacity. NO metabolites increased significantly in the NO circuits. CONCLUSIONS: Results indicate that NO addition during SECC is pro-inflammatory and has no effect on oxygen free radical production and interleukin release.

Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience.

OBJECTIVE: To report a long-term multicentre experience with implantable insulin pumps in type 1 diabetic patients, and to test safety and accuracy of the systems following improvements in infused insulin solutions and peritoneal catheter. RESEARCH DESIGN AND METHODS: Forty MiniMed Implantable Pumps model 2001 were consecutively implanted over a two-month period in type 1 diabetic volunteers. The systems were equipped by a new compliant sideport catheter and were refilled at 45-day intervals with HOE 21 PH ETP insulin batches showing enhanced physical stability in vitro. Safety was assessed from the incidence of acute adverse events and effectiveness from quarterly HbA(1c) assays. Accuracy of delivery was measured at each pump refill by comparing residual insulin in the pump reservoir with expected amount according to programmed infusion. The study lasted until pump battery depletion or premature pump explantation. RESULTS: Cumulated experience was 106 patient-years. Premature explantations occurred in 3 cases, due to one electronic pump failure and two "pump-pocket" infections. Near-normal insulin delivery was sustained until expected battery depletion in 13 cases. Forty underdelivery events occurred in 24 pumps, but 36 among them were related to pump slowdowns due to insulin aggregation in pumps that were promptly solved by an outpatient NaOH rinse procedure. Only 4 underdeliveries were caused by catheter obstructions that required laparoscopy to remove peritoneal tissue overgrowth around the catheter. Over pump lifetime, HbA(1c) was 7.2 +/- 0.2% in the 13 patients with no underdelivery and 7.7 +/- 0.5% in the other ones. Only one severe hypoglycemia and one ketoacidosis occurred during the whole study. CONCLUSION: Our current experience with improved implantable pumps and insulin solutions shows both long-term safety and effectiveness of this treatment in type 1 diabetic patients following improvement in infused insulin solutions and catheter. This therapy may be a good alternative for patients that experience frequent severe hypoglycemia with intensive subcutaneous insulin therapy.

Comparison of blood glucose stability and HbA1C between implantable insulin pumps using U400 HOE 21PH insulin and external pumps using lispro in type 1 diabetic patients: a pilot study.

BACKGROUND: To assess the efficacy on blood glucose control of continuous peritoneal insulin infusion from implantable pump (CPII) compared with continuous subcutaneous infusion using insulin lispro (CSII-IL) in type 1 diabetic patients. METHODS: Fourteen type 1 diabetic patients (5 males and 9 women, age 50.6 +/- 12.8, diabetes duration 28.0 +/- 13.4 years) were treated with CSII-IL and CPII. Capillary blood glucose (BG) was monitored and recorded at least 4 times per day during 2 study periods of 45 days: using CSII-IL (period A), and from 45th to 90th day after implantation (period B). HbA1C was measured at the end of each period. RESULTS: Both daily BG levels (145 +/- 18 vs 153 +/- 17 mg/dl, p<0.01) and preprandial BG levels (139 +/- 20 vs 147 +/- 22 mg/dl, p<0.05) were lower in period B. Although postprandial BG values tended to be lower in period B, this reduction did not reach statistical significance (149 +/- 20 vs 157 +/- 16 mg/dl, p=0.07). Meanwhile, SD of all BG values was lower with CPII (69 +/- 11 vs 79 +/- 17 mg/dl, p<0.01) and HbA1c levels were lower at the end of period B (7.3 +/- 0.9 vs 7.8 +/- 0.9%, p=0.04). Low blood glucose index was comparable during both periods (2.8 +/- 1.6 vs 3.1 +/- 1.5, p=0.4). CONCLUSION: CPII may provide a better BG control and stability than CSII-IL. However, a long-term randomized prospective study is needed to confirm these improvements.

[Indication of CGMS (Continuous Glucose Monitoring System) in the functionnal investigations of adult type 1 diabetic patients]. / Intérêt du CGMS (Continuous Glucose Monitoring System) dans l'exploration du diabète de type 1 de l'adulte.

The Minimed CGMS (Continuous Glucose Monitoring System) is a holter-style electroenzymatic sensor allowing 3-days continuous monitoring of interstitial glucose fluctuations. This device gathers wide informations about the fluctuations of glucose over the day, in a more detailed (288 measurements) but less accurate way than those obtained from glucose self-monitoring. Its utilisation has been proposed for the analysis of nocturnal glucose control, to detect asymptomatic hypoglycemia or dawn phenomenon, and could be useful in the adjustment of type 1 diabetes therapy. Thus, its use could contribute to an improvement in glucose control, especially in patients with low compliance to self-monitoring. CGMS graphs can be used as an individual teaching support, or illustrate characteristic situations during collective educational sessions. The period chosen for the CGMS record, the duration of the record and the instructions given to the patients are of major importance to obtain accurate and reproductive graphs, that can be used in clinical practice.

Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the Development of Pump Therapy in Diabetes.

OBJECTIVE: To compare the efficacy of 2 intensified insulin regimens, continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI), by using the short-acting insulin analog lispro in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 41 C-peptide-negative type 1 diabetic patients (age 43.5+/-10.3 years; 21 men and 20 women, BMI 24.0+/-2.4 kg/m2, diabetes duration 20.0+/-11.3 years) on intensified insulin therapy (MDI with regular insulin or lispro, n = 9, CSII with regular insulin, n = 32) were included in an open-label randomized crossover study comparing two 4-month periods of intensified insulin therapy with lispro: one period by MDI and the other by CSII. Blood glucose (BG) was monitored before and after each of the 3 meals each day. RESULTS: The basal insulin regimen had to be optimized in 75% of the patients during the MDI period (mean number of NPH injections per day = 2.65). HbA1c values were lower when lispro was used in CSII than in MDI (7.89+/-0.77 vs. 8.24+/-0.77%, P<0.001). BG levels were lower with CSII (165+/-27 vs. 175+/-33 mg/dl, P<0.05). The SD of all the BG values (73+/-15 vs. 82+/-18 mg/dl, P<0.01) was lower with CSII. The frequency of hypoglycemic events, defined as BG levels <60 mg/dl, did not differ significantly between the 2 modalities (CSII 3.9+/-4.2 per 14 days vs. MDI 4.3+/-3.9 per 14 days). Mean insulin doses were significantly lower with CSII than with MDI (38.5+/-9.8 vs. 47.3+/-14.9 U/day. respectively, P< 0.0001). CONCLUSIONS: When used with external pumps versus MDI, lispro provides better glycemic control and stability with much lower doses of insulin and does not increase the frequency of hypoglycemic episodes.

Improvement of HbA1c and blood glucose stability in IDDM patients treated with lispro insulin analog in external pumps.

OBJECTIVE: To compare the efficacy of the short-acting insulin analog lispro (LP) with that of regular insulin in IDDM patients treated with an external pump. RESEARCH DESIGN AND METHODS: Thirty-nine IDDM patients (age, 39.4 +/- 1.5 years; sex ratio, 22M/17W; BMI, 24.4 +/- 0.4 kg/m2; diabetes duration, 22.5 +/- 1.6 years) who were treated by external pump for 5.1 +/- 0.5 years were involved in an open-label, randomized, crossover multicenter study comparing two periods of 3 months of continuous subcutaneous insulin infusion with LP or with Actrapid HM, U-100 (ACT). Boluses were given 0-5 min (LP) or 20-30 min (ACT) before meals. Blood glucose (BG) was monitored before and after the three meals every day. RESULTS: The decrease in HbA1c was more pronounced with LP than with ACT (-0.62 +/- 0.13 vs. -0.09 +/- 0.15%, P = 0.01). BG levels were lower with LP (7.93 +/- 0.15 vs. 8.61 +/- 0.18 mmol/l, P < 0.0001), particularly postprandial BG levels (8.26 +/- 0.19 vs. 9.90 +/- 0.20 mmol/l, P < 0.0001). Standard deviations of all the BG values (3.44 +/- 0.10 vs. 3.80 +/- 0.10 mmol/l, P = 0.0001) and of postprandial BG values (3.58 +/- 0.10 vs. 3.84 +/- 0.10 mmol/l. P < 0.02) were lower with LP. The rate of hypoglycemic events defined by BG < 3.0 mmol/l did not significantly differ between LP and ACT (7.03 +/- 0.94 vs. 7.94 +/- 0.88 per month, respectively), but the rate of occurrences of very low BG, defined as BG < 2.0 mmol/l, were significantly reduced with LP (0.05 +/- 0.05 vs. 0.47 +/- 0.19 per month, P < 0.05). At the end of the study, all but two (95%) of the patients chose LP for the extension phase. CONCLUSIONS: When used in external pumps, LP provides better glycemic control and stability than regular insulin and does not increase the frequency of hypoglycemic episodes.