Use of continuous subcutaneous insulin infusion (CSII) therapy in pediatric diabetes patients in the perioperative period

Diabetes mellitus is one of the most common endocrinopathies encountered in the perioperative period, and the pediatric population is increasingly using continuous subcutaneous insulin infusions for diabetes management. As these patients present for procedures or surgery requiring anesthesia, the anesthesia provider is charged with the task of managing these pumps perioperatively. Here, we review our experience from a large tertiary care academic medical center and propose recommendations for the perioperative management of children and adolescents with diabetes who use insulin pumps.     

Insulin therapies: Current and future trends at dawn

Insulin is a key player in the control of hyperglycemia for type 1 diabetes patients and selective individuals in patients of type 2 diabetes. Insulin delivery systems that are currently available for the administration of insulin include insulin syringes, insulin infusion pumps, jet injectors and pens. The traditional and most predictable method for the administration of insulin is by subcutaneous injections. The major drawback of current forms of insulin therapy is their invasive nature. To decrease the suffering, the use of supersonic injectors, infusion pumps, sharp needles and pens has been adopted. Such invasive and intensive techniques have spurred the search for alternative, more acceptable methods for administering insulin. Several non-invasive approaches for insulin delivery are being pursued. The newer methods explored include the artificial pancreas with closedloop system, transdermal insulin, and buccal, oral and pulmonary routes. This review focuses on the new concepts that are being explored for use in future.     

Optimal Routes for Chronic Insulin Infusion with Portable and Implantable Devices

The optimal route for chronic insulin infusion via portable or implantable pumps is still a subject of controversy. Through the literature reports and personal experience (representing 70 patient-years of continuous treatment), the authors have found that the subcutaneous route is the ideal route in terms of comfort, safety, and cost. However, owing to sluggish and unpredictable insulin resorption, it appears that subcutaneous infusion is often not more effective than intensive conventional insulin therapy. The intravenous route gives the best diabetic control, but with a high risk of infection and obstruction. The intramuscular route, although more efficient than the subcutaneous, can be envisaged for only short periods because of its poor tolerance. The portal route is still at an experimental stage. The authors chose the intraperitoneal route because of the following advantages: near physiological insulin resorption kinetics; better diabetes control than subcutaneous infusion although comparable to intravenous; a 30% reduction of insulin requirements; and satisfactory local tolerance and acceptability with respect to severe asepsy precautions, patient selection, intensive education, and careful medical follow-up. The intraperitoneal route is feasible for portable insulin pumps, but basically more adaptable to implantable devices.     

Closed-loop glycemic control with a wearable artificial endocrine pancreas. Variations in daily insulin requirements to glycemic response

We succeeded in miniaturizing a needle-type glucose monitoring system with characteristics suitable for application in a wearable, closed-loop control system. A wearable artificial endocrine pancreas (12 X 15 X 6 cm, 400 g) consisting of a sensor, a microcomputer system that calculates insulin and glucagon infusion rates, and two roller pumps was developed. Continuous glucose monitoring by a glucose sensor inserted in the subcutaneous tissue of the forearm or abdomen of healthy and diabetic volunteers revealed that glucose concentrations in subcutaneous tissue were 10% lower than, but were highly correlated with, blood glucose concentrations in the range of 49-388 mg/dl. Glycemic control was established in diabetic patients by intravenously infusing insulin in response to measured glucose concentrations on a moment-to-moment basis for a period of several days. By comparing the glycemic control obtained in each patient treated with multiple insulin injections or open-loop subcutaneous insulin infusion, the superiority of feedback control with the system was clearly demonstrated. During continuous glycemic regulation, day-to-day variations of insulin requirements were recognized in both basal insulin infusion and postprandial insulin infusion rates in response to identical meals and exercise. These data suggest the feasibility of long-term glycemic control in diabetic subjects with a wearable artificial endocrine pancreas, and indicate that to overcome changes in individual metabolic characteristics on a moment-to-moment basis, a closed-loop glycemic control system may be essential for ambulatory diabetic patients.     

Impact of new technologies on diabetes care

Technologies for diabetes management, such as continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) systems, have improved remarkably over the last decades. These developments are impacting the capacity to achieve recommended hemoglobin A1c levels and assisting in preventing the development and progression of micro- and macro vascular complications. While improvements in metabolic control and decreases in risk of severe and moderate hypoglycemia have been described with use of these technologies, large epidemiological international studies show that many patients are still unable to meet their glycemic goals, even when these technologies are used. This editorial will review the impact of technology on glycemic control, hypoglycemia and quality of life in children and youth with type 1 diabetes. Technologies reviewed include CSII, CGM systems and sensor-augmented insulin pumps. In addition, the usefulness of advanced functions such as bolus profiles, bolus calculators and threshold-suspend features will be also discussed. Moreover, the current editorial will explore the challenges of using these technologies. Indeed, despite the evidence currently available of the potential benefits of using advanced technologies in diabetes management, many patients still report barriers to using them. Finally this article will highlight the importance of future studies tailored toward overcome these barriers to optimizing glycemic control and avoiding severe hypoglycemia.     

Portable insulin infusion pumps as an alternative means of insulin delivery in type I diabetes. Report on 11 patients

In many cases of type I diabetes it is extremely difficult to maintain adequate long-term diabetic control. Over the last decade a better understanding has been gained of the relationship between hyperglycaemia and the onset of diabetic microvascular disease. Because of this new techniques are being developed to improve diabetic control; one of these is the use of portable 'open loop' insulin infusion pumps. The results achieved in the first 11 patients to use the Auto-Syringe AS-6C insulin infusion pump on an outpatient basis for longer than 4 months are described. A highly significant improvement in fasting blood glucose levels, 2-hour postprandial blood glucose levels, mean blood glucose levels, glycosylated haemoglobin levels and mean glycaemic excursions was noted in all patients. No cutaneous complications developed despite the use of indwelling subcutaneous needles for up to 4 days at a time. Patient acceptability was excellent and none of the patients had any problems in adapting to 24-hour pump use. The importance of correct patient selection and continuous home blood glucose monitoring is stressed. Insulin infusion pumps can provide an alternative and highly efficacious means of maintaining excellent diabetic control in a select group of type 1 diabetics. However, it is essential that the physician be trained in the use of these pumps and that adequate back-up services are available.     

Why intraperitoneal delivery of insulin with implantable pumps in NIDDM?

In the normal state, pancreatic secretion of insulin results in a portal/peripheral gradient with the highest concentrations of insulin in the liver. In diabetic patients with absent or insufficient pancreatic insulin secretion who require exogenous insulin, this normal gradient is lost, resulting in numerous abnormalities. This consideration led to interest in the intraperitoneal delivery of insulin, hoping to produce a therapeutic state more closely resembling normal physiology. The development of implantable insulin pumps, which can deliver insulin intraperitoneally, led to numerous studies on insulin-dependent diabetes mellitus (IDDM) patients, demonstrating that insulin delivered intraperitoneally is rapidly and predictably absorbed with most of it going into the portal system, resulting in hepatic delivery of insulin. Studies in IDDM patients have demonstrated that good glucose control can be achieved with intraperitoneal delivery of insulin from implantable pumps with lesser glycemic fluctuations and, therefore, fewer episodes of hypoglycemia. Furthermore, intraperitoneal insulin results in carbohydrate and particularly lipid metabolism that more closely mimics the normal physiological state than produced by injections of insulin. Thus, implantable insulin pumps are being studied for use in IDDM. Many non-insulin-dependent diabetes mellitus (NIDDM) patients have insufficient pancreatic secretion and require exogenous insulin. Because of alterations in hepatic sensitivity to insulin, increments in insulin delivery to the liver may be even more important in NIDDM than IDDM. Furthermore, insulin resistance, which is an integral part of NIDDM, results in higher physiological levels of insulin, which are required for glucose control, and thus significant peripheral hyperinsulinemia occurs in patients receiving exogenous insulin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat.

Leptin has been shown to improve insulin sensitivity and glucose metabolism in normoinsulinemic healthy or obese rodents. It has not been determined whether leptin may act independently of insulin in regulating energy metabolism in vivo. The present study was designed to examine the effects of leptin treatment alone on glucose metabolism in insulin-deficient streptozotocin (STZ)-induced diabetic rats. Four groups of STZ-induced diabetic rats were studied: 1) rats treated with recombinant methionine murine leptin subcutaneous infusion with osmotic pumps for 12-14 days (LEP; 4 mg x kg(-1) x day(-1), n = 10); 2) control rats infused with vehicle (phosphate-buffered saline) for 12-14 days (VEH; n = 10); 3) pair-fed control rats given a daily food ration matching that of LEP rats for 12-14 days (PF; n = 8); and 4) rats treated with subcutaneous phloridzin for 4 days (PLZ; 0.4 g/kg twice daily, n = 10). Phloridzin treatment normalizes blood glucose without insulin and was used as a control for the effect of leptin in correcting hyperglycemia. All animals were then studied with a hyperinsulinemic-euglycemic clamp (6 mU x kg(-1) x min(-1). Our study demonstrates that leptin treatment in the insulin-deficient diabetic rats restored euglycemia, minimized body weight loss due to food restriction, substantially improved glucose metabolic rates during the postabsorptive state, and restored insulin sensitivities at the levels of the liver and the peripheral tissues during the glucose clamp. The effects on glucose turnover are largely independent of food restriction and changes in blood glucose concentration, as evidenced by the minimal improvement of insulin action and glucose turnover parameters in the PF and PLZ groups. Our results suggest that the antidiabetic effects of leptin are achieved through both an insulin-independent and an insulin-sensitizing mechanism.     

Artificial connection between glucose sensing and insulin delivery: implications of peritoneal administration

The replacement of insulinogenic function in insulin-dependent diabetes has to restore the feedback between intracorporal glucose and insulin. This has been accomplished by the following approaches: (a) the so-called open-loop insulin treatment by means of injections or pumps, employing laboratory or other extracorporal analytical devices and closing the feedback at large intervals only; (b) transplantation of insulin producing tissue and the bioartificial pancreas, employing the natural beta-cell both for glucose sensing and insulin delivery; (c) implanted artificial drug delivery systems providing chemical feedback between intracorporal glucose and insulin release from a nonrefillable reservoir of limited capacity; (d) the intracorporal or paracorporal artificial beta-cell comprising a glucose sensor (electrochemical or other type) that permanently delivers the signal to the computer-controlled insulin pump. This artificial device works on the basis of an algorithm of glucose-dependent insulin provision, compensating for the lack of other regulators, for the site of insulin administration, which is usually posthepatic, and for the kinetic properties of sensing system, e.g., a subcutaneous inserted amperometric electrode. Present experimental studies show that the pharmacodynamics of peritoneally applied insulin may be implemented into a mathematical model of the overall glucose-insulin system. They include absorption nearly as fast as after intravenous application, predominant portal inflow and approximately 30% hepatic removal. Feedback-controlled peritoneal insulin administration by means of an artificial beta-cell working on peripheral-venous blood glucose monitoring results in normal glycemic profiles under basal conditions and during oral glucose loads, if the pharmacodynamic properties of the peritoneal route are implemented into the insulin dosage algorithm.     

Inhalation of insulin in dogs: assessment of insulin levels and comparison to subcutaneous injection

Pulmonary insulin delivery is being developed as a more acceptable alternative to conventional subcutaneous administration. In 15 healthy Beagle dogs (average weight 9.3 kg), we compared insulin distribution in arterial, deep venous, and hepatic portal circulation. Dogs received 0.36 units/kg s.c. regular human insulin (n = 6) or 1 mg (2.8 units/kg) or 2 mg (5.6 units/kg) dry-powder human inhaled insulin (n = 3 and 6, respectively). Postinhalation of inhaled insulin (1 or 2 mg), arterial insulin levels quickly rose to a maximum of 55 +/- 6 or 92 +/- 9 microU/ml, respectively, declining to typical fasting levels by 3 h. Portal levels were lower than arterial levels at both doses, while deep venous levels were intermediate to arterial and portal levels. In contrast, subcutaneous insulin was associated with a delayed and lower peak arterial concentration (55 +/- 8 microU/ml at 64 min), requiring 6 h to return to baseline. Peak portal levels for subcutaneous insulin were comparable to those for 1 mg and significantly less than those for 2 mg inhaled insulin, although portal area under the curve (AUC) was comparable for the subcutaneous and 2-mg groups. The highest insulin levels with subcutaneous administration were seen in the deep venous circulation. Interestingly, the amount of glucose required for maintaining euglycemia was highest with 2 mg inhaled insulin. We conclude that plasma insulin AUC for the arterial insulin level (muscle) and hepatic sinusoidal insulin level (liver) is comparable for 2 mg inhaled insulin and 0.36 units/kg subcutaneous insulin. In addition, arterial peak concentration following insulin inhalation is two times greater than subcutaneous injection; however, the insulin is present in the circulation for half the time.     

The influence of peritoneal dialysis and the use of subcutaneous and intraperitoneal insulin on glucose metabolism and serum lipids in type 1 diabetic patients

Background. Intraperitoneally administered insulin is regarded as the most physiological replacement therapy, leading to lower peripheral insulin concentrations and equal or better glycaemic control than subcutaneous insulin. This two-part study was undertaken to evaluate the effect of CAPD, as well as the use of subcutaneous vs. intraperitoneal insulin on insulin sensitivity, glycaemic control and serum lipids in type 1 diabetes. Methods. Eleven patients with type 1 diabetes mellitus and chronic renal failure participated the studies. Glycated haemoglobin (HbA1c), euglycaemic hyperinsulinaemic clamp, serum lipids, and patient well-being were measured. During CAPD all patients were first treated with subcutaneous insulin and then with intraperitoneal insulin. The metabolic studies were repeated after both treatment periods for at least 3 months. Metabolic studies were performed on six of the patients also before initiation of CAPD. Results. HbA1c rose after the initiation of CAPD (from 8.85±0.54% to 9.58±0.66%, NS) and improved after changing from subcutaneous to intraperitoneally administered insulin (from 9.49±0.43% to 8.13±0.39%, P<0.01). Insulin dose increased by 15% after initiation of CAPD and 128% after switching for subcutaneous to intraperitoneal insulin. Glucose disposal rate enhanced by 39% (P=0.05) and 14% respectively (P <0.01). Initiation of CAPD had no significant effects on serum lipids but intraperitoneally administered insulin reduced HDL cholesterol and increased LDL/HDL ratio significantly. Conclusions. Intraperitoneal insulin therapy offers better glycaemic control and insulin sensitivity than subcutaneous insulin. Deterioration of HbA1c after initiation of CAPD while patients remained on subcutaneous insulin may be partly due to absorbed energy from the dialysate. Intraperitoneal insulin therapy seems to have detrimental effects on serum lipids. The clinical significance in modifying the risk of atherosclerosis remains unclear.     

Effects of interrupted insulin treatment on fetal outcome of pregnant diabetic rats

Streptozocin-induced diabetic female rats became normoglycemic after subcutaneous insertion of insulin-releasing osmotic minipumps. These female rats were mated with normal males from the same Sprague-Dawley substrain. In this substrain, the offspring of diabetic rats show a markedly increased congenital malformation rate compared with fetuses of nondiabetic rats. The pregnant diabetic rats were subjected to removal and insertion of pumps at defined gestational days that marked the beginning or end of a 2- or 4-day period of insulin withdrawal. Evaluation of the offspring on day 20 of pregnancy included fetal/placental weights, estimated number of implants, resorptions, and morphological assessment of congenital malformations. Resorptions occurred in all interruption groups, but malformations were found only in animals with insulin withdrawal on gestational days 4-8, 6-8, 6-10, 8-10, and 8-12. The highest resorption (42%) and malformation (17%) rates were found in the rats subjected to insulin withdrawal during gestational days 6-10. Because manifestly diabetic rats with no insulin treatment showed similar resorption (39%) and malformation (17%) rates, this study suggests that a teratogenic period in diabetic rat pregnancy occurs during gestational days 6-10, a period corresponding to postconceptional wk 2-4 in human pregnancy. Interruption of insulin treatment induced similar maternal weight loss and similar maternal serum concentrations of D-glucose, cholesterol, urea, and creatinine in rats with and without malformed offspring.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin signaling in human visceral and subcutaneous adipose tissue in vivo

In this study, we evaluated the activation of various insulin signaling molecules in human fat in vivo and compared signaling reactions in visceral and subcutaneous fat depots. Paired abdominal omental and subcutaneous fat biopsies were obtained from nonobese subjects with normal insulin sensitivity under basal conditions and 6 and 30 min following administration of intravenous insulin. Insulin receptor phosphorylation was more intense and rapid and insulin receptor protein content was greater in omental than in subcutaneous adipose tissue (P < 0.05). Insulin-induced phosphorylation of Akt also occurred to a greater extent and earlier in omental than in subcutaneous fat (P < 0.05) in the absence of significant changes in Akt protein content. Accordingly, phosphorylation of the Akt substrate glycogen synthase kinase-3 was more responsive to insulin stimulation in omental fat. Protein content of extracellular signal-regulated kinase (ERK)-1/2 was threefold higher in omental than in subcutaneous fat (P < 0.05), and ERK phosphorylation showed an early 6-min peak in omental fat, in contrast with a more gradual increase observed in subcutaneous fat. In conclusion, the adipocyte insulin signaling system of omental fat shows greater and earlier responses to insulin than that of subcutaneous fat. These findings may contribute to explain the biological diversity of the two fat depots.     

Continuous infusion of subcutaneous compared to intravenous insulin for tight glycaemic control in medical intensive care unit patients

The aim of this randomised controlled study was to compare continuous subcutaneous insulin infusion using an insulin pump with the traditional continuous intravenous infusion method for tight glycaemic control. Sixty patients admitted to our University Hospital medical intensive care unit with an initial blood glucose level over 6.1 mmol/l, were enrolled and randomised into two treatment groups: the subcutaneous insulin group received continuous subcutaneous insulin infusion and the intravenous group received insulin by traditional intravenous infusion with infusers. Three patients died in the first 24 hours and were excluded from the final analysis. Insulin therapy was administered to both groups according to the previously designed and used protocol in the department. The target glucose level was 4.4 to 6.1 mmol/l. There was no significant difference in mortality between the groups. However mean blood glucose level was found to be lower (6.56+/-0.82 mmol/l vs. 7.85+/-1.6 mmol/l, P=0.00055) in the subcutaneous insulin group. According to Vogelzang's hyperglycaemic index, better glycaemic control was achieved in the subcutaneous insulin group while there was no significant difference in terms of hypoglycaemic events. Daily insulin bolus and infusion requirements were also significantly lower in the subcutaneous insulin group. Despite the small number of patients involved in this study in a medical intensive care unit, strict blood glucose control using a subcutaneous insulin pump was achieved more efficiently than the traditional intravenous infusion method without increasing hypoglycaemic events.     

Significant hyperkalemia after discontinuation of an insulin pump

Patients with diabetes and insulin pumps may need their insulin therapy modified during surgery. Often, this is done with blood glucose as the end point. Changing insulin therapy can also have profound effects on potassium homeostasis in certain patients. This case demonstrates that changes in insulin therapy warrant not only close monitoring of blood glucose, but also of serum potassium. This patient's comorbidities and treatments that could alter potassium homeostasis are also reviewed.     

Insulin and hypertonic glucose in the management of aseptic fat liquefaction of post‐surgical incision: a meta‐analysis and systematic review

A meta‐analysis and systematic review assessing randomised controlled trials (RCTs) was sought to determine whether subcutaneous injection of insulin with hypertonic glucose promotes healing in postoperative incisions with aseptic fat liquefaction. We searched the Cochrane library, Pubmed, EMBASE, National Science Digital Library (NSDL) and China Biological Medicine Database (CBMdisc) for literature published from 1 January 1990 to 30 September 2011. RCTs that evaluated subcutaneous injection of insulin with hypertonic glucose as a treatment for postoperative wound with fat liquefaction were sought. Wound healing was the primary endpoint. Jadad score and Cochrane Collaboration's tool were used for assessing quality of studies and risk of bias. We abstracted data regarding time to wound healing, cost and adverse effects. The random‐effects inverse variance model was used for all analyses using weighted mean difference and 95% confidence interval. Eight trials (414 participants) were identified that met the inclusion criteria. Subcutaneous injection of insulin with hypertonic glucose significantly reduces time to healing by 6·33 days compared with conventional drainage, with less cost. There was no report concerning adverse effects. Subcutaneous injection of insulin with hypertonic glucose may improve the healing process in postoperative wounds with aseptic fat liquefaction.     

Glucose Sensing in the Peritoneal Space Offers Faster Kinetics Than Sensing in the Subcutaneous Space

The paramount goal in the treatment of type 1 diabetes is the maintenance of normoglycemia. Continuous glucose monitoring (CGM) technologies enable frequent sensing of glucose to inform exogenous insulin delivery timing and dosages. The most commonly available CGMs are limited by the physiology of the subcutaneous space in which they reside. The very same advantages of this minimally invasive approach are disadvantages with respect to speed. Because subcutaneous blood flow is sensitive to local fluctuations (e.g., temperature, mechanical pressure), subcutaneous sensing can be slow and variable. We propose the use of a more central, physiologically stable body space for CGM: the intraperitoneal space. We compared the temporal response characteristics of simultaneously placed subcutaneous and intraperitoneal sensors during intravenous glucose tolerance tests in eight swine. Using compartmental modeling based on simultaneous intravenous sensing, blood draws, and intraarterial sensing, we found that intraperitoneal kinetics were more than twice as fast as subcutaneous kinetics (mean time constant of 5.6 min for intraperitoneal vs. 12.4 min for subcutaneous). Combined with the known faster kinetics of intraperitoneal insulin delivery over subcutaneous delivery, our findings suggest that artificial pancreas technologies may be optimized by sensing glucose and delivering insulin in the intraperitoneal space.     

普外科患者并存糖尿病的围手术期处理

目的明确糖尿病患者围手术期血糖控制的安全方法。方法对87例普外科患者并存糖尿病时围手术期诊断与治疗进行回顾性分析,其中62例采用静脉给药方式,15例应用胰岛素泵。结果术后因高渗性非酮症昏迷死亡1例,切口感染4例,肺部感染2例,无一例发生低血糖昏迷。结论静脉应用普通胰岛素及应用胰岛素泵是围手术期糖尿病患者血糖控制的安全有效的方法。     

Long-term treatment of streptozotocin-induced diabetes by continuous insulin minipump in the Syrian hamster

It is difficult to normalize plasma glucose for a prolonged period of time by s.c. injection in experimental animals. The goal of this study was to determine the feasibility and the dosage of insulin needed to maintain 24-h normoglycemia in streptozotocin-diabetic Syrian hamsters with a s.c.-implanted osmotic minipump. The pumps, which release insulin at a constant rate, were replaced every 14 days with fresh pumps for as long as 52 days. A high insulin dose (1 U/kg/h) was required to normalize plasma glucose and fatty acid concentrations, water and food consumption, urine output, and body weight.     

Intrathecal injection of morphine in the ambulatory treatment of neoplastic pain (lumbar route)

A intrathecal injection of morphine has been given to 26 patients who present a tumor in activity with pain which withstand to heavy analgesic drugs. A intrathecal catheter with a sub-cutaneous tunnel is in connection with a subcutaneous reservoir. The hospitalisation for implantation is short. The mean efficient dosage is 3 mg of morphine chlorhydrate once or twice a day. About 50% of the patients are improved by this technic. In the future subcutaneous computerized pumps shall give better efficiency, shall decrease the dosage of drug, secondary effects and number of injections.