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Continuous Subcutaneous Insulin Infusion
A Comprehensive Review of Insulin Pump Therapy
M. James Lenhard, MD;
Grafton D. Reeves, MD
Arch Intern Med. 2001;161:2293-2300.
ABSTRACT
A tremendous amount of data suggest that near-normal glycemic control
prevents or delays complications of diabetes, which has led to a dramatic
increase in continuous subcutaneous insulin infusion (CSII) or insulin pump
use. In this article, the data supporting CSII in type 1 diabetes is reviewed,
and the advantages and disadvantages of CSII are analyzed. In addition, CSII
use in specific situations is examined, including during childhood and pregnancy
and while exercising. The published articles suggest that CSII provides better
glycemic control than does conventional therapy and comparable to or slightly
better control than multiple daily injections. The use of CSII may be especially
indicated during pregnancy or for preconception care and for diabetes presenting
in childhood or adolescence.
INTRODUCTION
The Diabetes Control and Complications Trial (DCCT) demonstrated a dramatic
reduction in the frequency and severity of complications of diabetes mellitus
type 1 in adolescents and young adults by achieving and maintaining glucose
control in the near-normal range.1 Comparable
but less dramatic results were demonstrated in the UK Prospective Diabetes
Study for people with type 2 diabetes.2 These
studies established intensive management of diabetes as the standard of care,
which has rekindled an interest in external insulin infusion pumps, referred
to as continuous subcutaneous insulin infusion (CSII). The patients treated
with CSII in the DCCT demonstrated slightly better glycemic control than those
treated with multiple daily injections, and CSII therapy was well tolerated.3
Consequently, the popularity of CSII has increased dramatically. Approximately
50 000 to 70 000 adults in the United States are thought to be using
CSII, representing about 8% of the adult population with type 1 diabetes.4-5 In addition, the number of insulin
pump users is estimated to have doubled over the last 5 years.4
Despite this surge in popularity, a comprehensive review of CSII has not appeared
in the literature for many years, although brief reviews have been published
in textbooks.6-7 Continuous subcutaneous
insulin infusion seems to be the most physiologic method of delivering insulin
subcutaneously to achieve near-normal glycemic control. With patients and
their families demanding to use CSII, this review is an attempt to describe
the best uses, special considerations, and problems associated with CSII therapy.
DATA SOURCES
All articles found in MEDLINE from 1979 to 2000 that contained the words
"CSII" or "insulin pump" were read. There were 991 articles listed, although
some articles appeared on both lists. Review articles were included and differences
among conclusions explored. Both reviewers abstracted data independently.
PRINCIPLES AND BACKGROUND
Insulin pumps were introduced in the late 1970s. There was initial excitement
over this new technology,8-9 but
within a few years their popularity waned because their size, safety, and
efficacy became troublesome issues.10-11
Insulin pumps had a resurgence in popularity in late 1993 after the DCCT results
were published. The new pumps are smaller, more efficacious, and easier to
use. There are presently 3 manufacturers of insulin pumps in the United States:
Disetronic Medical Systems Inc (St Paul, Minn); MiniMed Technologies (Sylmar,
Calif); and Animas (Frasier, Pa). The new pumps are small, weighing around
400 g, and they all operate similarly. The insulin pump contains an insulin-filled
cartridge or a syringe connected to a catheter that is inserted into the subcutaneous
tissue (Figure 1). The pump continuously
delivers predetermined basal rates to meet nonprandial insulin requirements.
The devices allow programming of many different basal infusion rates, although
the average patient requires only 4 to 6 different rates (Figure 2). It also infuses a bolus to cover mealtime or snack time
insulin requirements.
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Figure 1. A, Examples of 3 insulin infusion
pumps; B and C, 2 subcutaneous catheter infusion sets that may be used for
continuous subcutaneous insulin infusion.
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Figure 2. A typical profile of basal insulin
infusion rates used in continuous subcutaneous insulin infusion. It is very
common for people with diabetes to require a higher basal infusion of insulin
in the predawn hours. Many people are more active in the late afternoon and
more sedentary after dinner, requiring downward and upward adjustments, respectively.
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MISCONCEPTIONS
Therapy using CSII is not well understood by the public, patients with
diabetes, or even some health care providers. There is no surgery involved.
The subcutaneous catheter is manually inserted, typically in less than 5 minutes.
The pump is not an artificial pancreas. While patients who use CSII may sleep
later in the morning because their levels are better controlled for longer
duration, appropriate adjustments in the insulin infusion rates must be made.
They cannot ignore their calorie- and carbohydrate-restricted diets. The patient
needs to self-monitor blood glucose levels as much as if not more than patients
who rely on multiple daily injections (MDI). While there is good evidence
that CSII will provide better glycemic and metabolic control than MDI, with
fewer dangerous glycemic excursions, there is often a misconception that it
will completely eliminate episodes of severe hypoglycemia or hyperglycemia.
ADVANTAGES OF CSII
Glycemic Control
Intensive diabetes management with CSII provides better glycemic control
than does conventional management, which is usually defined as 2 or fewer
injections per day and 2 self-monitored blood glucose checks.12-13
It also provides as good and often better glycemic control than intensive
diabetes management with MDI.14-30
In addition to lowering the levels of glycosylated hemoglobin, CSII has been
shown to decrease glycemic variability31-32
and lower fasting glucose values.16, 29, 33-35
Hypoglycemia
Hypoglycemia is a serious risk associated with intensive therapy and
occurs with both CSII and MDI. Early studies suggested that the risk of hypoglycemia
with CSII was greater or similar to that of conventional diabetes management 36-37 and MDI.38-39
More recently, however, reports have suggested that severe hypoglycemia may
be reduced by CSII as much as 4-fold compared with MDI treatment40-41
with no reduction in glycemic control. This decrease in hypoglycemic events
has been accompanied by an increase in self-reported warning symptoms of hypoglycemia,
as well as by an increase in counterregulatory hormonal responses to hypoglycemia.42-43 Severe hypoglycemia has now become
an accepted indication for initiation of CSII therapy.
Other Metabolic Factors and Diabetes Complications
Intensive diabetes management with CSII improves glycemic control. The
improved control is associated with fewer diabetic and metabolic complications.
Treatment with CSII also improves or slows the progression of diabetic nephropathy,44-46 peripheral and autonomic
neuropathy,47-49
retinopathy,50-54
hypertriglyceridemia and hypoalphalipoproteinemia,55-56
and diabetic changes in transplanted kidneys.57
Lifestyle Flexibility
The improvement in lifestyle may be the most important reason to the
patient who chooses CSII. The ability to increase flexibility in moment-to-moment
living is the reason most frequently cited by individuals who have chosen
CSII.58 It allows the patient to modify insulin
availability hour by hour, which makes possible the performance of activities
that would otherwise be risky: skipping or delaying meals, sleeping late on
weekends, or engaging in vigorous exercise.59
This increased flexibility may be fueling the upsurge in patient demand for
CSII more than any other factor.
DISADVANTAGES OF CSII
As recently as 1990, some authorities asserted that "the use of CSII
is discouraged in routine clinical practice," suggesting instead that it be
limited to specific subsets of patients with type 1 diabetes.60
While earlier reports of increased and unexplained mortality among CSII users61 have largely been explained,11
there are several risks associated with CSII.
Diabetic Ketoacidosis
There is no subcutaneous depot of long-acting insulin with CSII. If
the flow of the regular, short-acting insulin is interrupted, ketonemia and
diabetic ketoacidosis can develop more rapidly and more frequently with CSII
than with other treatments.21, 36, 62
The interruption of insulin may be intentional, to allow patients to participate
in certain activities, or unintentional, caused by catheter occlusion, catheter
disinsertion, battery failure, depleted insulin supply, and other causes.63-65 Many times, the interruption
of insulin is a result of patient error and inadequate training, particularly
when patients do not take the emergency steps necessary in the event of unexplained
hyperglycemia.6 In experimental settings where
insulin delivery was intentionally interrupted, plasma-free insulin values
fell to very low levels (4-8 mU/L) within a 6-hour period, accompanied by
large increases in blood glucose, plasma 3- -hydroxybutyrate, and free
fatty acid values.66
Hypoglycemia
While hypoglycemia generally occurs less frequently with CSII than with
MDI, concern has been expressed about hypoglycemia resulting from unintentional
insulin delivery, or "pump runaway." While this event has occurred,67 it is exceedingly rare and, to our knowledge, has
not been found in the United States in the last 10 years. Technological advances
in the microprocessor components and insulin delivery alarms of the currently
marketed insulin pumps now make the occurrence of such an event extremely
unlikely.
Catheter Site Infection and Contact Dermatitis
The most common complication associated with CSII is infection at the
infusion site36, 67-68;
this is one of the most common causes listed for discontinuation of CSII.69 Most cases of infection have been bacterial, usually Staphylococcus or Streptococcus
species,70 although Rhizomucor cellulitis has been found.71 Presumably,
almost any pathogen could be a cause. There are conflicting reports as to
whether CSII users are chronic carriers of Staphylococcus.70, 72 Occasionally, the
infection may lead to cellulitis or abscess formation requiring surgical debridement.
The annual rate of catheter site infection has been estimated at 7.3 to 11.3
events per 100 years of patient follow-up.3
Additionally, occasional cases of contact dermatitis attributed to the components
of the infusion sets and tape have been described.73-74
On very rare occasions, the contact dermatitis persists despite changing the
type of tape and/or catheter, and is so severe that CSII must be discontinued.
Weight Gain
The most common metabolic adverse effect of improved glycemic control
is weight gain, largely attributable to reducing glycosuria. Participants
in the DCCT who used intensive management gained about 10 pounds (4.5 kg)
more than the conventional treatment group,1
although there was no difference in the weight gained between patients using
CSII and those using MDI.3
Cost
The insulin pump and the supplies needed to begin therapy average about
$5000. The infusion set and catheters must be purchased regularly for as long
as CSII is used, at a yearly cost of approximately $1500. Most insurance companies,
including Medicare and Medicaid, cover the cost of CSII treatment after medical
approval. We are not aware of any detailed studies of the cost-benefit analysis
of CSII.
Prevention of Disadvantages
To minimize the risk of ketoacidosis, patients must check their blood
glucose levels at least 4 times a day to prevent the development of severe
diabetic ketoacidosis. Frequent self-monitoring of blood glucose levels will
also allow for early recognition of hypoglycemia. A change of catheter site
every 2 to 3 days will minimize the risk for developing skin infections. The
application of a local antibiotic ointment to mild skin infections will usually
cure them, and creams with aloe, vitamin E, or corticosteroids may be helpful
for contact dermatitis. Weight gain does not have to occur with CSII. Exercise
and close attention to caloric intake can result in weight maintenance and,
if necessary, weight reduction.
SPECIAL CONSIDERATIONS WITH CSII THERAPY
Choice of Insulin for CSII
Phosphate-buffered insulin demonstrates a decreased incidence of catheter
obstruction, and therefore is the preferred insulin for CSII.75
There are currently 2 insulin preparations available that contain a phosphate
buffer. Velosulin (Novo Nordisk, Princeton, NJ) is buffered regular insulin,
and lispro insulin (Lilly, Indianapolis, Ind) is an insulin analogue modified
to provide very fast action. While only Velosulin has a Food and Drug Administration
indication for CSII, lispro insulin has some clear advantages: lispro CSII
has resulted in less severe and fewer cases of hypoglycemia and better glycemic
control than Velosulin CSII.75-78
However, since lispro is more rapidly absorbed, there is a concern that the
interruption of lispro insulin infusion may lead to more rapid metabolic deterioration
than an interrupted infusion with buffered regular insulin. Consensus is lacking.
One study showed no temporal difference.79
Another study showed that with lispro metabolic deterioration occurred 1.5
to 2 hours earlier and was associated with a larger decrease in blood pH.80 Thus, CSII with lispro insulin seems to provide better
glycemic control and fewer and less severe instances of hypoglycemia than
CSII with buffered regular insulin, although diabetic ketoacidosis may develop
more rapidly.
CSII Use in Children and Adolescents
In contrast to the adult population with type 1 diabetes, there is scarce
data on the use of CSII in the adolescent and childhood populations (especially
childhood). The literature includes few studies, all very limited in scope;
none are randomized, and most involve adolescents. Most of the studies are
small, usually 25 or fewer subjects, and short in duration, usually 12 months
or less.81-90
In addition to nonrandomization, a limited number of subjects, and a relatively
short duration, the 3 CSII studies in the childhood diabetic population have
other major limitations. Two involve only toddlers,91-92
and the others involve only children with newly diagnosed diabetes.93-94
The results of the few studies in the adolescent and childhood diabetes
population are contradictory. Most of the studies, especially the more recent
ones, demonstrate that insulin pump therapy provides as good or better metabolic
and glycemic control than MDI and that it is as well or better tolerated.3, 81-86
Earlier studies, however, demonstrated that it did not provide better control
and was not well tolerated.87-88
Recent studies demonstrate that CSII is associated with lower or comparable
rates of complications such as hypoglycemia, ketoacidosis, and weight gain
than are MDI,85, 89-90,95
while earlier studies demonstrated more complications.87-88
Notwithstanding the scarcity of information and some variance in the findings
on the safety and efficacy of CSII in the pediatric diabetes population, children
and adolescents with diabetes and their parents are demanding to use the pump
because they perceive it to be the safest, easiest, and the most physiologic
method of delivering insulin subcutaneously to achieve near-normal glycemic
control.
CSII Use During Pregnancy
The association between excessive maternal hyperglycemia in women with
type 1 diabetes and the risk of fetal anomalies is well accepted.96-97 In addition to striving for preconception
euglycemia, euglycemic or near euglycemic control should be the goal throughout
pregnancy. Hypoglycemia increases during the first trimester of pregnancy.
This may be due in part to attempts at improved metabolic control, the passive
diffusion of glucose across the placenta, and alterations in the counterregulatory
responses of epinephrine, growth hormone, and glucagon.98
Kimmerle et al99 reported rates of severe hypoglycemia,
defined as coma, seizure, or incapacitation requiring the help of others,
to be as high as 41% in pregnant women with diabetes. With the advantages
of CSII in decreasing hypoglycemia and improving glycemic variability, it
is logical to assume that CSII would be beneficial for pregnant women with
diabetes. As with early studies of CSII efficacy for glycemic control in nonpregnant
patients, some of the earlier studies of CSII during pregnancy demonstrated
no significant improvement in glycemic control, perinatal morbidity, or length
of hospitalization.100 Subsequent studies,
however, suggest that CSII is superior to conventional therapy97, 101
and at least comparable to MDI102-104
in achieving metabolic goals in pregnancy. Several aspects of CSII suggest
that even if glycemic control is only comparable to MDI, pregnant women may
prefer CSII because of its several advantages. These include increased ease
of treating morning sickness and hyperemesis gravidarum, reductions in glycemic
excursions and hypoglycemia, ease of treating the dawn phenomenon that increases
during pregnancy, and improved management in the postpartum period when insulin
requirements may fluctuate.105 Three studies
have found comparable results for pregnant women with type 2 or gestational
diabetes,104-106
although this area has not been well studied.
CSII Use for Type 2 Diabetes
The data on CSII therapy in type 2 diabetes is rather scarce compared
with data for treating type 1 diabetes, although the enthusiasm for implementing
CSII with type 2 diabetes has increased.107
Several short-term trials have demonstrated improvement in glycemic control
at 6 months,108-109 improved -cell
function and first-phase insulin secretion,110-111
and improvement in the altered metabolic milieu associated with type 2 diabetes.112-113 There is only 1 randomized trial
comparing CSII with conventional insulin therapy.114
In this 4-month trial involving 20 subjects, CSII achieved superior glycemic
control, with comparable insulin doses and similar amounts of weight gain.
Ultimately, CSII may prove to be of significant benefit to patients with type
2 diabetes, but the paucity of data makes it impossible to draw any conclusions
at present. The many publications detailing the successful use of the experimental
implantable insulin pump in type 2 diabetes gives hope that these results
can be extended to CSII.115
CSII and Exercise
Habitual physical activity has significant benefit to the patient with
diabetes, and CSII may make it easier for the patient to maintain glycemic
parameters acutely during exercise because of its ability to readily alter
the rate of insulin delivery.116 Although CSII
has not always led to significant improvement in postexercise hyperglycemia,117 insulin sensitivity and aerobic exercise capacity
have been shown to improve with CSII.118-119
Several studies have suggested that CSII may be superior to conventional insulin
therapy in improving cardiac function in subjects with cardiac autonomic neuropathy.119-120 And while regular exercise is certainly
to be encouraged, adequate training of the CSII user is essential to allow
safe changes in the basal infusion rate and to avoid disrupting the catheter
site during brisk physical activity.121
Psychological and Social Implications of CSII
The use of CSII may evoke psychological issues to a greater degree than
conventional diabetes therapy.122 An emotional
and psychosocial assessment is necessary prior to initiating CSII to prevent
discontinuation and ensure proper use of the pump.
Several aspects of CSII are unique, and therefore may present barriers
to successful glycemic control. Since the pump is visible to others, some
patients express difficulty with body image and their self-perceived attractiveness.123 Other people feel inconvenienced explaining CSII
to others and consider it an invasion of their privacy.124
Although CSII may help provide exceptional metabolic control, this mechanical
dependency may invoke feelings of vulnerability and fear of device failure.122 Patient and family education prior to initiation
of CSII helps to minimize this.122 Patient
selection is vital to patient tolerance of CSII. It is not always possible
to predict whether CSII will be successful.95
While some studies have shown CSII to be associated with significantly less
anxiety and depression and improved family social dynamics,125
other studies have suggested that these benefits are most notable in patients
who asked to remain on CSII after completion of the study.126-127
In effect, these studies self-selected those patients who were likely to express
the greatest satisfaction and least psychological discomfort with CSII. There
are few data on the psychological effect of CSII in children and adolescents,
with studies showing both an improved sense of control over their life for
some patients128 and an increase in anxiety
for others.129
Patient Selection and Implementation of CSII
Several excellent texts and articles on the strategies and procedures
of initiating CSII have been published and provide a detailed "how to" guide
for the health care practitioner.7, 130-135
Beginning CSII involves more than merely changing the method of insulin delivery.
Patients should participate in a formal educational program. A dietitian should
instruct the patient in proper meal planning and carbohydrate counting, whereby
the patient calculates the quantity of insulin to take at each meal based
on the amount of carbohydrates to be consumed. A diabetes educator should
instruct the patient in insulin pump management. And a psychologist and/or
social worker should assess motivation, cognitive and problem-solving skills,
maturity level, financial stability, and social support systems. It may be
difficult to successfully implement CSII without the assistance of ancillary
health care providers and a team approach. The successful implementation of
CSII may be as dependent on a motivated, flexible, and skilled health care
team as it is on the patient.
There are no universally applicable criteria for determining which patients
will do well on CSII. Table 1
lists some characteristics that may help determine which patients will be
successful. The current model is that the motivated, relatively stable patient
is the best candidate for CSII. A different school of thought, however, holds
that the patient with poorly controlled diabetes who may, in addition, not
possess the highest level of motivation, cognitive skills, or social support
may benefit to an even greater degree than the more enfranchised patient.
There is currently no data to support this opinion, but relevant research
is being conducted.
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Characteristics to Consider When Evaluating a Potential CSII User*
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SUMMARY
Continuous subcutaneous insulin infusion has proven to be extremely
effective in treating type 1 diabetes. It provides glycemic control superior
to that of conventional therapy and comparable or slightly superior to MDI.
It also decreases the frequency and/or severity of hypoglycemic reactions
and increases lifestyle flexibility. With good compliance and proper attention
to details, the disadvantages and risks of CSII can be minimized.
Some specific patient situations may be especially attractive for the
use of CSII, including pregnancy or preconception care and diabetes presenting
in childhood or adolescence. For the successful use of CSII, a skilled and
motivated health care delivery team is required, and a thorough evaluation
and training of the CSII candidate is necessary prior to implementation. There
is also a need for ongoing close contact between the pump user and the health
care team.
AUTHOR INFORMATION
Accepted for publication March 29, 2001.
We thank Zoe Meyers of Disetronic Medical Systems Inc (St Paul, Minn),
and the librarians at the Christiana Care Medical Library, Wilmington, Del,
especially Joan Smith, for assistance with the literature search.
The photographs were expertly taken at the Medical Photography section
at Christiana Hospital.
Corresponding author and reprints: M. James Lenhard, MD, Diabetes
and Metabolic Diseases Center, Section of Endocrinology, Christiana Care Health
Services, 700 Lea Blvd, Suite 300, Wilmington, DE 19802 (e-mail: JLenhard{at}ChristianaCare.org).
From the Diabetes and Metabolic Diseases Center, Section of Endocrinology,
Christiana Care Health Services (Dr Lenhard), and the Division of Pediatric
Endocrinology, DuPont Hospital for Children (Dr Reeves), Wilmington, Del;
and Jefferson Medical College, Thomas Jefferson University, Philadelphia,
Pa (Drs Lenhard and Reeves).
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