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AHCPR Health Technology Assessments. Rockville (MD): Agency for Health Care Policy and Research (US); 1990-1999.
This publication is provided for historical reference only and the information may be out of date.
Foreword
The Office of Health Technology Assessment (OHTA) evaluates the risks, benefits, and clinical effectiveness of new or unestablished medical technologies that are being considered for coverage under Medicare. These assessments are performed at the request of the Health Care Financing Administration (HCFA). They are the basis for recommendations to HCFA regarding coverage policy decisions under Medicare.
Questions about Medicare coverage for certain health care technologies are directed to HCFA by such interested parties as insurers, manufacturers, Medicare contractors, and practitioners. Those questions of a medical, scientific, or technical nature are formally referred to OHTA for assessment.
OHTA's assessment process includes a comprehensive review of the medical literature and emphasizes broad and open participation from within and outside the Federal Government. A range of expert advice is obtained by widely publicizing the plans for conducting the assessment through publication of an announcement in the Federal Register and solicitation of input from Federal agencies, medical specialty societies, insurers, and manufacturers. The involvement of these experts helps assure inclusion of the experienced and varying viewpoints needed to round out the data derived from individual scientific studies in the medical literature.
After OHTA receives information from experts and the scientific literature, the results are analyzed and synthesized into an assessment report. Each report represents a detailed analysis of the risks, clinical effectiveness, and uses of new or unestablished medical technologies considered for Medicare coverage. These Health Technology Assessment Reports form the basis for the Public Health Service recommendations to HCFA and are disseminated widely. Individual reports are available to the public once HCFA has made a coverage decision regarding the subject technology.
OHTA is one component of the Agency for Health Care Policy and Research (AHCPR), Public Health Service, Department of Health and Human Services.
- Thomas V. Holohan, M.D.
- Director
- Office of Health Technology Assessment
- J. Jarrett Clinton, M.D.
- Administrator
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Introduction
Continuous subcutaneous insulin infusion (CSII) therapy was introduced in the late 1970s with the goal of obtaining near-normal blood glucose levels in patients with insulin-dependent diabetes mellitus (IDDM) (1-4) Insulin infusion pumps provided an alternative to the multiple daily injections (MDI) of insulin that are necessary for intensive insulin therapy (IIT) and to conventional insulin therapy (CIT). CSII has the unique feature of delivering regular insulin continuously at preset basal rates and at bolus doses over a 24-hour period. Bolus and basal infusions may be varied many times throughout the day in response to changes in food intake, exercise and unexpected blood sugar fluctuations. This technological feature of infusion pumps represents in theory and advance in the clinical management of IDDM. However, the technology also has some shortcomings. It is more expensive than CIT. Syringe blockage or needle dislodgement can result in hyperglycemia and diabetic ketoacidosis (DKA), and overdelivery can result in hypoglycemia. This assessment is intended to provide the most current knowledge on the safety, clinical efficacy, and cost of CSII, and a description of the types of patients who are most likely to benefit from long-term insulin pump therapy. It also addresses the question of when this technology might be contraindicated.
Background
Diabetes affects approximately 60 million persons worldwide, and it is one of the leading causes of death in many developed countries. It is the third leading cause of death from disease in the United States, with about 300,000 individuals dying annually from its long-term complications.(1) About 5 -10 of the 11 million diabetic individuals in the United States have type-I diabetes or IDDM. Because of a deficiency of endogenous insulin, persons with IDDM not only have uncontrolled hyperglycemia, but develop ketoacidosis if they do not receive exogenous insulin. Without treatment, this acute complication can result in coma and death. One objective of insulin replacement therapy for IDDM patients is the prevention of ketoacidosis. A second objective is the prevention of the obvious consequences of uncontrolled hyperglycemia: polyuria, polyphagia, polydipsia, recurrent infections, and visual blurring.
Conventional insulin therapy usually involves one to two subcutaneous injections each day of mixtures of short and intermediate or long acting insulin. For most patients realistic expectations of CIT are:
- Premeal blood glucose levels of 160-200 mg/dL
- Intermittent positive urine glucose tests
- Infrequent ketonuria
- Glycohemoglobin of 10-11 (HbA(1c) 8 -9) (2).
In the late 1970s circumstantial evidence began to accumulate that suggested that achievement of near normoglycemia might prevent the chronic complications of IDDM, which include retinopathy, nephropathy, and neuropathy. For patients with IDDM, intensive insulin therapy is necessary to achieve this goal. Intensive insulin therapy includes frequent self-monitoring of blood glucose, considerable patient education and motivation, and insulin administration either with multiple daily injections or constant subcutaneous insulin infusion.(5) The desired biochemical objectives of IIT are(2):
- Premeal blood glucose levels of 70-120 mg/dL
- Postmeal blood glucose levels of about 180 mg/dL
- Essentially no glucosuria or positive urine ketones
- Glycohemoglobin of 7 -9 (HbA(1c) 6 -7)
If the patient is pregnant, the objectives of control of glycemia are different(2):
- Premeal blood glucose levels 60-105 mg/dL
- Postmeal blood glucose levels of about 120 mg/dL
- Glycohemoglobin of 5.5-7.0 (HbA(1c) 5.5 - 7)
Achievement of near normoglycemia with administration of insulin by constant infusion was reported in 1978 by Pickup et al in the United Kingdom(3). and in 1979 by a group of investigations at Yale.(4) Constant subcutaneous insulin infusion is essentially an open-loop infusion system; it lacks a blood glucose sensor that could automatically adjust insulin infusion rates with changes in blood glucose levels. An insulin-filled syringe or reservoir is connected to a pump mechanism. Activation of the pump mechanism delivers fixed, small volume pulses of insulin into an attached catheter and needle. Changing the basal rate setting varies the interval between the pulses. Rate controls are calibrated in either units of insulin per hour or units of insulin per day. An important features of CSII is the capability of delivering insulin at a slow continuous basal rate, which simulates postabsorptive insulin secretion, and in premeal boluses, which mimic normal peaks of insulin released after a meal. All insulin pumps are provided with flexible infusion sets, with catheter lengths of 20 or 40 inches to facilitate placement of the pump inside or outside clothing. While pump catheters, needles, and reservoirs have had a history of occlusion, newer catheters and the introduction of a buffered human insulin preparation have resulted in a lesser incidence of occlusion. In order to select the appropriate basal rates for insulin infusion and to select the size and timing of the premeal insulin bolus, patients must monitor their blood glucose level several times a day.
Use of CSII can result in a more flexible lifestyle with regard to meal schedules, work, and recreation. While insulin delivery by pump offers variability in timing and dose selection, there is an implicit shortcoming of the CSII pump that is related to the way insulin is delivered. Pump malfunction may cause decreased or increased flow of insulin that may result in either hyperglycemia or hypoglycemia. If the flow of insulin is interrupted and CSII is not promptly reestablished after the pump user is alerted by a signal of malfunction from the pump, diabetic ketoacidosis can occur. Therefore, in comparison to MDI, CSII may result in an increased incidence of hypoglycemia or ketoacidosis. Regardless of the technique of insulin administration, any attempt to achieve near normoglycemia by CSII or MDI appears to result in a greater frequency of significant hypoglycemia than with conventional insulin therapy. Infection at infusion sites has been reported to be the most frequent albeit minor complication of CSII.
The attainment of metabolic control with CSII depends largely on a high frequency of self-monitoring of blood glucose, which in turn depends on individual motivation and patient education. It has therefore been suggested that individuals with diabetes for whom the insulin pump would not be suitable include children and adolescents, emotionally unstable adults, individuals with a history of severe hypoglycemia without warning symptoms, and those with a history of drug or alcohol abuse. Additional guidelines for patient selection for CSII are listed in Table 1.
Table
Table 1. Patient selection guidelines.
Rationale
Insulin infusion pumps represent an alternative to MDI for metabolic control of blood sugar. Despite the convenience associated with its use, there are reports of syringe blockage, overdelivery, and needle dislodgements; these are shortcomings to be addressed in the evaluation of the insulin pumps.
Literature Review
Many studies concerning the benefits and complications of intensive insulin therapy in general and of continuous subcutaneous insulin infusion have been published in the last 10 years.
Clinical Trials
There have been a number of small clinical trials designed to answer the question of whether achievement of near normoglycemia could prevent or ameliorate diabetic retinopathy and other chronic complications: the Kroc Foundation Study (involving six centers in the United States, Canada, and the United Kingdom), (7,8). the Steno Study Group, (9). the Oslo Study Group, (10,11). and a Danish study.(12) Each compared the effects of CIT and IIT in randomized subjects. Lower levels of glycemia could be achieved in the IIT patients (especially with CSII). Retinopathy, however, did not improve; there was, in fact, a transient deterioration in IIT subjects during the first year of the studies. The weakness of all of the studies is that study subjects already had documented diabetic retinopathy and may have progressed beyond the point where improved control of glycemia could be beneficial.
A large multicenter study, the Diabetes Control and Complications Trial (DCCT) was initiated in 1982 in the United States with the National Instituted of Health (NIH) sponsorship.(13,14) The approximately 1,400 randomized (CIT vs IIT) subjects had either minimal or no evidence of retinopathy at entry. One of the objectives of the now completed feasibility phase of the DCCT was to determine whether both a clinically meaningful and statistically significant difference in the level of blood glucose control (determined by blood glucose and HbA1c measurements) could be achieved between patients who were randomly assigned either to standard treatment (one or two daily injections of intermediate and/or short-acting insulin) or to experimental treatment (intensive regimens directed at achieving near normoglycemia using either CSII or MDI). A total of 278 patients (191 adults and 87 adolescents) were enrolled; the IIT group included 101 adults and 45 adolescents. Increase in the incidence of both hypoglycemia and ketoacidosis had been associated with intensive insulin therapy in earlier studies.(15-20) The IIT group experienced 0.54 episodes of hypoglycemia per patient-year during the first year of the DCCT, as compared with 0.17 episodes per patient-year for the conventional treatment group. Severe hypoglycemic episodes tended to occur in a minority of patients (25 and 10 respectively). The CSII group experienced comparatively lower rates of ketoacidosis and of catheter infections than had been reported from other clinical trials.(21,22) The feasibility phase results also revealed that IIT was significantly better in regulating ketonuria than CIT.
Several recent reports(15,23,24). suggest that complications of diabetes may be prevented or reversed in the early phase of their development by careful control of the blood sugar levels. The DCCT study that is currently in progress is addressing the possible relationship between the maintenance of near normoglycemia by IIT and its effect on the development or progression of chronic complications.
Other Reports
A study at the Virginia Mason Clinic in Seattle(21). compared the frequency of ketoacidosis between 161 users of insulin pumps and a matched group of 165 patients placed on a conventional therapy regimen over 18.5 months. Ketoacidosis occurred in 26 of the 161 patients (16.1) using an insulin pump and in 6 of 165 patients (3.6) using conventional therapy. Constant subcutaneous insulin infusion patients were asked to record failures of their insulin infusion system over a 12-month period. Eighty-six percent reported that malfunctions occurred at least once; 96 of the 927 malfunctions were not in the pump itself, but in the infusion set and were related to configuration of the reservoir (e.g., narrowed outflow channel). They also noted that obstruction of the infusion tubing was the most common problem in infusion set failures.
Mecklenburg and Guinn(22). reported a second study from the same clinic. Their 6-month crossover study included 28 insulin pump patients using two different types of regular insulin. They reported that 61 of the 68 episodes (90) of obstructed tubing occurred with an unbuffered beef-pork insulin, while only 7 episodes (10) occurred with buffered pork insulin. It seems that insulin buffering may reduce the occurrence of insulin precipitation in tubings. A preparation of buffered insulin has been introduced to the market since their study was published. A second problem noted by Mecklenburg and Guinn was that of infection at the injection site. Forty-six (29) of the pump users had episodes of infection while none were observed in the 165 patients on conventional therapy. The most common organism isolated was coagulase-positive Staphylococcus aureus. Patients with a history of infected infusion sites were more likely to be nasal carriers of S. aureus than were pump patients without infected sites. The authors found that discomfort, irritation, or infusion site infection were the most common reasons cited by Virginia Mason Clinic patients for terminating CSII therapy.(25)
Bell et al(26). also compared personal and clinical characteristics of patients who had discontinued with those who had chosen to continue CSII therapy. The main reasons for discontinuing CSII were: interference with lifestyle (40), abscesses at the needle site (40), psychological complications (10), and poor insulin absorption (10).
Discussion and Technology Assessment
A report issued in 1984 by the Office of Health Technology Assessment (OHTA) on the use of CSII in the treatment of IDDM concluded that it was still an experimental procedure.(27) A number of studies published since that date have shown that CSII may be a viable alternative to conventional insulin treatment.
The American Diabetes Association, in a position paper prepared by Edwin D. Bransome, Jr., of the Medical College of Georgia(28). strongly recommends that CSII be accepted as a "recognized therapeutic modality" for the treatment of selected patients with IDDM. The Association provided extensive and credible literature to support the position that CSII is widely accepted by the medical professional community(29-31). and can be used to achieve excellent metabolic control in pregnancy.(32-37) Some of the complications of CSII use (diabetic ketoacidosis and infected infusion sites) may be avoided with improvements in the design of the infusion systems.
An extensive review of controlled trials and other available clinical data on CSII was published by Irsigler et al in 1985.(38) The authors concluded that CSII not only improves metabolic control, but also provides a more flexible lifestyle, reduces the incidence of hypoglycemia, ameliorates pain from neuropathy, and decreases the rate of progression of retinopathy.
Pumps that are currently available on the market carry some of the following features:
- Insulin delivery via a plastic cannula to subcutaneous needle
- Programs for a single basal rate of insulin infusion (units/24h) or several basal rates over a 24-hour period
- Programs for selection of different supplemental preprandial bolus doses of insulin
- Alarm systems to warn the patient in cases of pump malfunction caused by low battery output, empty reservoir, occlusion, or incorrect programming
The January/February 1989 issue of Diabetes Self-Management was devoted to the evaluation of four ambulatory insulin infusion pumps that are commercially available in the United States.(39) The publication discussed the advantages and disadvantages of each pump.
Technology Assessment
The following represents abstracted answers to questions addressed in this assessment from the literature and comments received from interested organizations such as the American Diabetes Association and NIH.
Q: Are CSII devices widely accepted as a safe and clinically effective method of delivering insulin to the diabetic patient?
A: Results from a number of controlled clinical trials have shown that CSII devices are effective in providing near-normoglycemia and in improving metabolic control in patients with IDDM.(21,22) There is as yet no evidence to show that CSII is superior in clinical efficacy to MDI.
Q: What types of external infusion pumps would be considered safe and clinically effective for continuous insulin infusion in treating patients with diabetes mellitus?
A: In its completed report on the safety and efficacy of external infusion pumps, NIH cited a study by the Emergency Care Research Institute in Pennsylvania listing the advantages and disadvantages of four commercially available insulin pumps and recommended seven of them for patient use.(40) Nowhere in the report of the clinical trials is there an endorsement of a particular type of pump.
Q: Which patients having what type and severity of diabetes are most likely to benefit from long-term CSII treatments?
A: The benefits most often cited for patients on CSII center on improvement in individual lifestyles, including flexibility in meal timing and in work and recreational scheduling. Pregnancy in diabetic women requires careful regulation of blood glucose in order to minimize or avoid adverse effect(s) on fetal development. Several reports have identified diabetic women who are pregnant or anticipating pregnancy as the patient population that is most likely to benefit from CSII or IIT.(32-37).
Q: What benefits, risks, or complications are associated in continuous insulin therapy using the CSII infusion pump system?
A: Diabetic ketoacidosis, hypoglycemia, and skin problems involving infections and irritation at infusion sites are risks associated with CSII.(41) The occurrence of these risks is due in part to mechanical problems with the pump infusion system, catheter leakage, and dislodgement of the subcutaneous needle. The American Diabetes Association believes that severe emotional disorder, history of chronic drug abuse and alcohol use, and lack of compliance with previous treatment programs are factors that increase such risks (personal communication, E.D. Bransome, Medical College of Georgia, December 2 and 7, 1988). Clinical complications associated with CSII include transient worsening of retinopathy, which remits with continued treatment.(42)
Q: Are there categories of patients with diabetes mellitus for whom a pump is not suitable or for whom its use is contraindicated?
A: The use of CSII is contraindicated in children and adolescents with diabetes (personal communication, D.S.H. Bell, University of Alabama, Birmingham, January 15, 1989). If children placed on CSII cannot participate in contact sports or activities, they could be regarded by their peers as being handicapped and this could lead to serious psychological problems. Adolescents tend to lack the appropriate motivation for daily blood glucose monitoring necessary for the successful use of CSII.(43) Any form of IIT is also contraindicated for individuals with hypoglycemia unawareness and those with untreated preproliferative or proliferative retinopathy.
Q: Are there different features such as programmability, newer versus older designs, or alarms that should be considered in evaluating these systems?
A: As listed in the reports of Diabetes Self-Management and the Emergency Care Research Institute, (39,40). features to be considered in the evaluation of CSII systems include the presence of adequate alarm systems to warn patients of pump malfunction (occlusion, low battery output, catheter leakage), programmable basal rate, accurate delivery, and a display of the amount of insulin delivered and/or amount remaining, as well as the size and weight of the infusion systems.
Q: What are the implications of the lockout features for the external insulin infusion pumps used to treat diabetes?
A: Each manufacturer reported individual methods for preventing accidental insulin delivery. For example; maximum basal rate and bolus modes, maximum 24 hour total, and maximum 24 hour total and a lockout mode.
Q: Are there unique benefits of the CSII method of treating diabetics in terms of short-and long-term patient outcomes that have been demonstrated?
A: Short-term benefits have been documented for patients who are unable to achieve glycemic control and for those who desire flexibility in their lifestyle. There is considerable evidence that achievement of near normoglycemia in diabetic pregnancies will decrease fetal morbidity and mortality.(32-37)
Q: What is the cost of CSII versus MDI?
A: Insulin pumps cost between $2,000 and $3,500 (personal communication, D.S.H. Bell, University of Alabama, Birmingham, January 25, 1989) with an average lifespan of 5 years; the equipment cost is thus about $500 to $700 per year. There are no reliable figures for costs of maintenance. The cost of changing infusion sets every 2 days approximates $35 per month, while $15 per month is a reasonable estimate for the purchase of syringes. Additional costs include $150 -$200 for the purchase of a home glucose monitoring meter and $60 per month for the purchase of reagent strips. On the other hand, the cost of MDI is $15 per month for syringes, $150 -$200 for home glucose monitoring, and about $60 per month for reagent strips.
The Food and Drug Administration (FDA) states that the portable external infusion pumps are currently being reviewed as premarket notification 510(k) submissions and are being considered substantially equivalent to devices in the generic class of infusion pumps which have been classified into class II (performance standards). FDA has approved the new human buffered insulin labeled for administration with external insulin pumps only.
The American College of Physicians' opinion has not changed regarding the use of external infusion pumps for the treatment of diabetes mellitus since their 1983 evaluation in a Clinical Efficacy Assessment Project. The College states that external insulin infusion pumps are capable of achieving euglycemia or near-normoglycemia and near-normalization of many other metabolic parameters that are commonly abnormal in diabetes. Whether they provide superior control over frequent manual insulin injections has not been resolved.
The American Medical Association recently published its assessment on the safety and efficacy of CSII by portable insulin pumps for controlling insulin-dependent diabetes.(44) According to the report, continuous subcutaneous insulin infusion is considered to be safe and effective for control of IDDM when used by "patients with the technical ability to operate the insulin pump and to perform frequent blood glucose monitoring." Because close regulation of glucose levels in pregnant patients with IDDM is associated with improved neonatal outcomes, the report concludes that intensive insulin therapy using either multiple daily injections or CSII is indicated in IDDM patients who are pregnant or who are attempting to conceive. The report further suggests that CSSI may be beneficial for patients with recent onset diabetes or with hypoglycemia associated with hyperalimentation.
There are indications from the NIH's ongoing DCCT study that near normoglycemia may be attained by either continuous subcutaneous insulin infusion or by multiple daily injections. Treatment by either method seems to lead to higher rates of short-term problems associated with intensive insulin therapy, such as hypoglycemia, when compared with conventional treatment.
Summary
Several controlled clinical trials have shown that CSII is effective in providing near-normoglycemia and in improving metabolic control in patients with insulin-dependent diabetes mellitus. There is as yet no evidence to show that CSII is superior in clinical efficacy to manual MDI therapy. The benefits most often cited for patients on CSII include greater lifestyle flexibility with regard to meal timing, work, and recreational scheduling. The higher risks associated with CSII such as diabetic ketoacidosis, hypoglycemia, and skin problems involving infections and irritation at infusion sites may be averted with improvements in the mechanical design of CSII devices. The overall clinical evidences indicates that CSII is as effective as MDI in attaining normoglycemia in patients with insulin-dependent diabetes mellitus who require intensive therapy.
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- DHHS Publication No. AHCPR 91-0030
- Reassessment of External Insulin Infusion Pumps - AHCPR Health Technology Assess...Reassessment of External Insulin Infusion Pumps - AHCPR Health Technology Assessments
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