Alan 0. Marcus
University of Southern California Medical School, Los Angeles, and Saddleback Memorial Medical Center, Laguna Hills, California
The appropriate delivery of insulin for achieving euglycemia has been the goal of diabetes therapies in cases of both absolute and relative insulin deficiency. The fact that insulin is the most effective therapeutic choice for lowering blood sugars to normal or near-normal levels was established almost 80 years ago. All people with diabetes mellitus need to achieve the well-known goal of glucose control, set around the world at an HbA|C of 6.5%. The fact that achieving this target results in prevention, stabilization, and reversal of complications associated with diabetes is equally well known as a result of multiple landmark interventional studies. These studies all met the most rigorous of scientific criteria and -g have set the standards of glucose control to be achieved. The causes of failure | to achieve both euglycemia and improvements in the adverse outcomes of pa- | tients with diabetes need to be examined, and these factors require rectification.
Investigators and clinicians currently view insulin pumps as the "gold Stan- ?
dard" by which all alternative methods of insulin delivery are gauged. What has a given rise to this opinion that insulin pumps provide the best method of achieving J
norma) blood sugars is the publication of multiple studies documenting improved a
the formulation of insulins. This has happened at the same time as an explosion in knowledge of patients' real-time, retrospective, and average glucose levels, giving impetus to improve the glucocentric environment of the patient.
Improvement in the technology of the pump itself is easily recognized by the reduction in its size from the impractical but seminal idea of a pump the size of a backpack (proposed by Arnold Kadish of Los Angeles) to the current pumps that weigh as little as 3.5 ounces, or less than 100 grams (the MiniMed 508).
Despite this remarkable evolution, the goal is the same: to deliver insulin in a physiological way. The concept of the earliest pumps was to deliver insulin intravenously, but this was modified in subsequent pumps to subcutaneous insulin delivery, which made access—and therefore usage—more feasible, but there were still significant limitations due to (heir weight and size (400 g and approximately 18X7X6 cm). These primitive pumps were big and bulky, limited to one infusion rate (insulin rates were adjusted by dilution of insulin), and required a large expenditure of not only battery power but the energy of the patient and the clinicians to maintain its function. The earliest studies on CSII were done with such pumps, and successes were reported in achieving near euglycemia in both adults and adolescents (3.4).
It should be noted that these successes were possible only through the introduction of technology that allowed for the determination of blood sugars rapidly and accurately by the patient. Self-monitoring of blood glucose (SMBG) allows for the evaluation and correction of insulin delivery in terms of basal rate, bolus, and correction bolus and adjustments to these that result in improved glucose due to precise and effective insulin usage.
As described earlier, the pumps themselves have become lighter and smaller and now have the ability to deliver insulin in varying amounts over various time blocks of the day, repetitively or according to the type or characteristics of a given day (e.g., work day, holiday, exercise, travel, premenstrual, or sick). The bolus delivery of insulin can be programmed to match the requirements or challenge presented by every type of meal (its composition or duration) and to accommodate the individual absorptive and gastrointestinal activity of the patient. The bolus can be initiated by remote control, alleviating the fear that "button pushing" by younger patients will result in inappropriate insulin delivery.
The software that accompanies the actual delivery mechanism of the pump allows for added safety features and the accumulation of information on pump performance and patient usage that can be viewed directly or downloaded. This offers additional possibilities for improvement of outcomes as a result of a heightened understanding of what factors resulted in either normal or abnormal glucose levels. Safety alarms on pumps are now standard and provide the added assurance that the insulin pump is doing and will continue to do its primary job of delivering insulin. These features, together with improvements in education and more continuous glucose monitoring, have resulted in a lower incidence ofdiabetic ketoacidosis (DKA) than with syringe delivery of insulin (5). Additional improvements in the catheters, also called infusion sets, that nonsurgically connect the pump reservoir to the patient and serve as the conduit for the delivery of insulin to the subcutaneous space have also increased the overall acceptance and viability of pump usage. Catheters no longer have the compatibility problems with insulin that in earlier years resulted in catheter binding of insulin and variable delivery; the catheters can be painlessly and effectively inserted by devices such as the Sof-
serter, specifically designed for ihis purpose. Multiple options available among catheters allow for variations in subcutaneous fat, individual patient preference, and appropriateness. The ability since 1995 to disconnect from the pump for swimming, taking saunas, and other pursuits in which a pump is not desired was made possible by advances in infusion sets, specifically, by incorporating a quickrelease feature into their design. Needles—bent or straight—as part of the catheter have been supplemented by catheters of varying dimension and shape to improve comfort and allow for individual choice of the ideal infusion set. An additional advance has been the development by pharmaceutical companies of insulin analogs. These insulins are designed to have specific desired performance characteristics.
The rapid-acting insulins commercially available and in use (lispro and aspart) possess the ideal characteristics for success with pump therapy. They realize the rapidity of insulin action that was the goal of the original intravenous pump delivery systems while retaining the advantages of subcutaneous delivery. Rapidity of action allows for better matching of insulin to meal requirements temporally as well as bmitation of the undesirable "tail effect" of injected insulin that results in increased late postprandial hypoglycemia. These insulins have been proven to reduce hypoglycemia, improve HbA,c levels, and, after 3 months of CSII usage, improve hepatic glucose output in response to glucagon (6-9). Reduction in the "tail effect" of these insulins has not been associated with an increase in the occurrence of DKA. The newer technology of the continuous glucose monitoring system and its usage will provide even more information, pinpointing times and events requiring more or less insulin delivery (10) to achieve a reduction in both hyper- and hypoglycemia. Reduction of events, which will result in optimal glycemic control, is dependent on the individual metabolic characteristics of a given patient and the pharmacodynamics and route of delivery of the insulin (11). When one compares the intrapatient variability of different insulins, it is clear that day-to-day fluctuations in glucose levels are frequently attributable to the insulin formulation utilized and the variability in its glucose-lowering effect in the same person on subsequent days even when all other controllable variables are equal (12). Regular by injection would differ from Regular by CSII in that intrapaLient variability is lowest for Regular insulin administered by CSII, greater for glargine and NPH (considered equal in this respect), and still greater for Lente and Ulcralente, which has the greatest intrapaliem variability whether measured -g by time of onset, duration of action, or glucose-lowering efficacy (13). The effec- |
tive use of insulin is dependent on the reproducibility of its effect. |
If we accept the premise that all patients need to be considered candidates for intensive therapy and that CSII is the most physiological way to administer ?
insulin and to practice intensive therapy, we need to exarnine the methods which a result in successful insulin pump usage. Some points apply to all groups, but an js attempt is made to focus on the individual needs of each patient population and a
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