Download CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII)

Vuk Vrhovac Institute, University Clinic for Diabetes,
Endocrinology and Metabolic Diseases
Dugi dol 4a, HR-10000 Zagreb, Croatia
E-mail: [email protected]
Review
CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII)
Manja Prašek, Tomislav Bo‘ek, @eljko Metelko
Key words: continuous subcutaneous insulin infusion (CSII),
type 1 diabetes mellitus, absorption variability,
insulin analog, hypoglycemia, ketoacidosis, blood
glucose self-monitoring
SUMMARY
Intensive diabetes management can be achieved in children,
adolescents and adults either with the use of continuous
subcutaneous insulin infusion or with multiple daily injections.
The goals of intensive diabetes management established by the
Diabetes Control and Complications Trial are to achieve near
normal glycemia, to avoid short-term crises such as
hypoglycemia requiring third part assistance or intervention, to
minimize longterm complications, and to improve the quality
and length of life in persons suffering from diabetes. The
importance of tight metabolic control in patients with diabetes
was also demonstrated by the results of United Kingdom
Prospective Diabetes Study, and emphasized in the Saint
Vincent Declaration. Disadvantages of multiple daily injections
are the need for patients to take three or even more injections per
day by syringe or pen, resulting in poor compliance, and to use
modified insulins, intermediate or long-acting insulins (NPH,
Lente, Ultra-lente) that must be injected to reach basal
concentration of insulin to keep blood glucose within normal
limits between meals. It has been clearly shown that absorption
of modified insulins vary from 19% to 55% in the same
individual, which could be the reason for blood glucose
variability. Conversely, the absorption of soluble, short-acting
Diabetologia Croatica 32-3, 2003
insulins that are used in continuous subcutaneous insulin infusion
varies by less than 3% daily. As the result of continuous
subcutaneous insulin infusion – insulin pump therapy and use of
a continuous glucose sensor, achievement of the main goals in
diabetes treatment could rather become a matter of fact. During
recent years continuous subcutaneous insulin infusion has
reached widespread recognition, as it has become the mode of
intensive diabetes treatment for more than 200 000 diabetic
patients worldwide.
HISTORICAL OVERVIEW AND PRESENT
WORLDWIDE SITUATION
Intensive diabetes management can be achieved in
children, adolescents and adults either with the use of
continuous subcutaneous insulin infusion (CSII) or
with multiple daily injections (MDI). The goals of
intensive diabetes management established by the
Diabetes Control and Complications Trial (DCCT) (1)
are to achieve near normal glycemia, to avoid shortterm crises such as hypoglycemia requiring third part
assistance or intervention, to minimize longterm
complications, and to improve the quality and length of
life in persons suffering from diabetes. The importance
of tight metabolic control in patients with diabetes was
also demonstrated by the results of United Kingdom
Prospective Diabetes Study (UKPDS) (2), and
emphasized in the Saint Vincent Declaration (3).
Disadvantages of MDI are the need for patients to take
three or even more injections per day by syringe or pen,
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M. Prašek, T. Bo‘ek, @. Metelko / CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII)
resulting in poor compliance, and to use modified
insulins, intermediate or long-acting insulins (NPH,
Lente, Ultra-lente) that must be injected to reach
basal concentration of insulin to keep blood glucose
within normal limits between meals. It has been clearly
shown that absorption of modified insulins vary from
19% to 55% in the same individual, which could be the
reason for blood glucose variability (4,5). Conversely,
the absorption of soluble, short-acting insulins that are
used in CSII varies by less than 3% daily (5,6). As the
result of continuous subcutaneous insulin infusion
(CSII)-insulin pump therapy and use of a continuous
glucose sensor, achievement of the main goals in
diabetes treatment could rather become a matter of
fact. During recent years CSII has reached widespread
recognition, as it has become the mode of intensive
diabetes treatment for more than 200 000 diabetic
patients worldwide (7).
approximately 0.5% of type I diabetic patients in
Denmark are treated with CSII (29). In contrast, in the
USA approximately 16% of type I diabetic patients are
estimated to use CSII as a mode of intensive treatment
(30), whereas in Sweden the rate of CSII treatment is
about 8% (29). In Germany, as many as 10% of patients
with type 1 diabetes use insulin pumps (31).
Figure 1. History of pumps: (A) early insulin pump
designed by Arnold Kadish; (B) early portable insulin
pump; (C) modern insulin pump.
(A)
The use of CSII was first reported in 1978 by John
Pickup et al. (8). This new technology was devised and
developed as a research procedure to enable testing of
the connections between diabetes control and diabetes
related complications. In the following years, its
efficacy and beneficial effect on the development of
most of the late diabetic complications were in a short
time confirmed by many studies (8-25).
In the early insulin pump era, serious side effects were
reported, such as ketoacidosis, hypoglycemia and
mortality (26). As the result of these findings, the use of
CSII decreased or was stagnant. In 1993, the Diabetes
Control and Complications Trial (DCCT) reported
significant reduction in the rate and severity of
complications in type I diabetics due to the
achievement of glucose control to near normal values
(1). DCCT pointed to CSII as a slightly but
significantly better method in maintaining strict
glycemic control compared to other modes of
intensified treatment (27). Since the publication of
DCCT, in the last 10 years there has been an increase in
the use of CSII, especially in the USA as well as in many
other countries. Today there are more than 200,000
diabetic patients using CSII as a daily mode of their
intensive diabetes treatment (7).
On the other hand, there are countries like the
United Kingdom where insulin pump technology was
developed but the use of CSII is still quite uncommon
(28), considering the advantages or benefits of CSII.
According to the study conducted by Noergaard,
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(B)
(C)
BASIC INFORMATION ON INSULIN
PUMPS
Recent technologic advancements have made insulin
pumps an increasingly attractive option for patients
with diabetes. New pumps are smaller and easier to
operate, and they can accurately deliver microdoses of
insulin. Also, they have become more reliable, with
alarm system for malfunction.
Current insulin pumps consist of a reservoir filled
with insulin, a small battery operated pump, and a
computer chip for controlling insulin delivery. Insulin is
M. Prašek, T. Bo‘ek, @. Metelko / CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII)
Figure 2. Examples of 3 insulin infusion pumps (A);
subcutaneous catheter infusion set that may be used
for CSII (B).
(A)
dosages and to ensure that insulin is delivered. Insulin
pumps manufactured by five different companies are
currently available on the market: Animas, Deltec,
Disetronic Medical Systems, Medtronic MiniMed, and
Sooil Corporation Ltd.
INDICATIONS FOR USE OF CSII
(PREREQUISITES FOR CSII)
CSII is used in selected type 1 diabetic patients to
achieve strict blood glucose control. To achieve
favorable CSII outcomes it is essential to identify
appropriate candidates.
Indications for CSII (30):
(B)
delivered to the body through an infusion set. A thin
flexible plastic tube is attached to the pump, and at the
other end of the tube there is a catheter. The catheter
is inserted under the skin, near the abdomen to deliver
insulin to the body. The insulin pump is about the size
of a deck of cards, weighs about 100 grams (3 ounces),
and can be worn on a belt or carried in a pocket. The
pump is programmed to deliver small amounts of
insulin continuously throughout the day and night
(’basal’ dose in the range of 0.1-1.0 U/h) to meet
nonprandial insulin requirements. Extra doses of
insulin (’bolus’ doses) are delivered at meal times and
at times when blood glucose is too high based on the
user’s programming to cover mealtime or snack time
insulin requirements. Patients can choose to receive a
bolus of rapid acting insulin before, during or after the
meal, and so called square-wave bolus – a bolus
released evenly over a preset period of time, commonly
30 minutes to 2 hours.
Most of the currently used pumps have an
opportunity for setting several basal rates (average
patients require 4-6 different rates). Frequent blood
glucose monitoring is essential to determine insulin
Diabetologia Croatica 32-3, 2003
history of hypoglycemia unawareness or
history of unpredictable, recurring hypoglycemic events requiring assistance
hemoglobin A1c levels greater than 7%
failure of maintaining strict glycemic control
with MDI
dawn phenomenon: glucose levels exceeding
8-9 mmol/L in the morning
pronounced day-to-day blood glucose level
variability
pregnancy (strict glycemic control is obligatory
before conception to prevent the occurrence
of fetal anomalies and spontaneous abortion,
and therefore it is recommendable to start
insulin pump therapy even before pregnancy)
need of flexibility in lifestyle (necessary for
shift workers, business travelers, workers in a
safety-sensitive job, etc.)
low insulin requirements, below 20 U/day
Indications for use of CSII in children and adolescents
•
hypoglycemia
•
dawn phenomen
•
hemoglobin A1c greater than 7%
•
failure of maintaining strict glycemic
control with MDI
•
pronounced day-to-day blood glucose
level variability
•
flexibility in lifestyle (skipping or delaying
meals, sleeping late on weekends)
•
low insulin requirements, below 20 U/day
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M. Prašek, T. Bo‘ek, @. Metelko / CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII)
Candidates for CSII (as well as children’s parents)
should be motivated to achieve near normal glucose
level, willing to perform frequent blood glucose selftesting and to learn about pump therapy, need to have
technical skills and precision on performing blood
glucose monitoring and handling insulin pump device.
Patients must have realistic expectations about the
influence of insulin pump device on their life (4-6
blood glucose measurements a day). They need to be
aware that CSII is not a cure, it is a tool in achieving
strict blood glucose control, to minimize the risk of
acute diabetes complications, and to prevent or delay
the onset of late diabetes related complications.
CONTRAINDICATIONS – CSII
NONELIGIBLE PATIENTS
Patients who are not ready to perform 4-6 blood
glucose measurements daily and are not willing for
close cooperation with the diabetes health care team
consisting of a physician, a nurse and a dietitian, are not
eligible for CSII. Patients with notable psychologic
disturbance have a tendency to worse glycemic control
using CSII. Patients with major psychiatric disorders
such as psychosis and severe depression should be
excluded from screening procedure for initiation of
CSII. CSII should be avoided in patients who are
concerned and worried even after education and
counseling about daily activities such as sexual
relationships, contact sports as well as in patients who
would feel physically and emotionally uncomfortable
wearing insulin pump device (7).
STARTING INSULIN PUMP THERAPY –
BASAL INFUSION AND PREPRANDIAL
INFUSION
The best candidates for CSII are individuals who are
practicing diabetes self-management, including
frequent monitoring of blood glucose level, recording
blood glucose and insulin levels in a logbook, visiting
medical team on a regular basis, and counting
carbohydrates. Besides, patients who show poor control
using MDI, and become frustrated and discouraged
resulting in tendency to develop poor habits of
monitoring and medical follow up, may be very
succesful with CSII (30).
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When pump therapy is initiated, the total daily
insulin dose should be reduced by 25%-30%, and 50%
be used as basal dose and 50% as total bolus dose (32).
Children and adolescents may begin with 40% as basal
and 60% as bolus dose (33). The basal dose is divided
by 24 to get units per hour (U/h). The recommendation
is to start with a single basal rate, and if needed to add
second basal rate according to glucose self-monitoring
values. The monitoring pattern indicates proper timing
and rate of insulin to be administered. To determine
bolus doses, the patient’s meal content must be taken
in consideration: the patient is given either fixed-meal
diet on which to adjust the bolus doses or the
carbohydrate-to-insulin ratio for use in calculating meal
boluses according to food intake. For the first 2-4
weeks, until basal rates are established, snacks are
avoided. Adjustments of basal and bolus doses are
based on blood glucose measurement taken before
meals, 2 hours after meals, at bedtime, at midnight,
and at 3 a.m. The basal rate is increased or decreased
by 0.1 U/h to keep the premeal and overnight blood
glucose levels within a 2-mmmol/L glucose excursion
from baseline. If the glucose level rises by more than 2
mmol/L at prebreakfast measurement compared to 3
a.m. measurement, a second basal rate must be
established (about 1.5 times the first basal rate that
starts at 00.00 h) for 4 to 6 hours, and is started 2-3
hours before the usual breakfast time. The basal rate is
adjusted during the day only if there are significant
glucose excursions occurring in case of delaying meals
or not eating. To perform a fine basal rate adjustment,
the patient should delay or skip a meal and keep
monitoring of blood glucose every 2 hours in fasting
state. 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
(30,33).
Bolus doses are adjusted on the basis of glucose
measurements performed 2 hours postmeal. The
patients must be well educated to adjust his or her
insulin boluses or carbohydrate-to-insulin ratio every 2
days in order to keep glucose levels within reasonable
excursions (<10 mmol/L) 2 hours postmeal (30).
M. Prašek, T. Bo‘ek, @. Metelko / CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII)
CALCULATING INSULIN
REQUIREMENTS
MONOMERIC INSULIN – THE PUMP
INSULIN OF CHOICE
It is essential for patients on CSII to know how to
count carbohydrates before starting pump therapy,
because the insulin pump device delivers bolus doses
to compensate for the carbohydrate intake at each
meal. To define a meal bolus – the amount of insulin
that must be taken to compensate for the eaten
carbohydrates, the patient has to calculate his insulincarbohydrate ratio. The insulin-carbohydrate ratio tells
the patient how much insulin he has to administer to
compensate for a specific amount of carbohydrates.
The ratio will vary from meal to meal and is under the
influence of patient’s weight, age, physical activity,
insulin sensitivity as well as of the presence of other
diseases or diabetes related complications. There are
several methods of calculating insulin-carbohydrate
ratio. This ratio varies from 1U/5 g carbohydrate to
1U/25 g carbohydrate (33).
The pump insulin of choice is monomeric insulin.
Several lately published studies have revealed that the
use of insulin analog lispro in comparison to regular
insulin for CSII significantly reduces blood glucose
level and hemoglobin A1c (HbA1c) (34-38). Moreover,
slightly but significantly less lispro insulin than regular
insulin was required, but no difference in the incidence
of hypoglycemic events was reported. Aspart insulin
has recently been indicated to be as effective as
buffered regular insulin and lispro when used in CSII
therapy (39). In the same study the insulin analogs had
an advantage over buffered regular insulin in terms of
improvement of postprandial glycemic control.
Postprandial glycemic control as well as fasting plasma
glucose and mean plasma glucose highly correlate with
HbA1c, as reported in the American Diabetes
Association position statement (40). Several studies in
nondiabetic and type 2 diabetic subjects have shown an
increased risk of mortality and myocardial infarction to
be associated with isolated postprandial hyperglycemia
(41-47).
PATIENTS ON CSII NEED TO BE WELL
EDUCATED AND ACQUIRE
PROFICIENCY IN BASIC
INSTRUCTIONS
With all candidates for insulin pump therapy, the risk
of its use and risk prevention should be discussed in
depth. This includes the risk of hyperglycemia and its
possible development into ketosis and diabetic
ketoacidosis, site infections as well as hypoglycemia
awareness, prevention and treatment. The patients
need to be aware of potential mechanical problems and
problem solving strategies such as air bubbles, kinked
infusion set, dislodged tubing that could cause lacking
of expected insulin delivery, etc. Bode et al. point out
that for the widespread use of CSII, an excellent
educational set-up for patients and for medical staff is
essential to increase favorable effects and to diminish
side effects of CSII (33). All recent reports suggest
that CSII shows greatest efficacy in patients who are
well-trained in the management of intensive insulin
treatment and who remain inadequately controlled
because of frequent unpredictable hypoglycemia or a
pronounced dawn phenomenon (7).
Diabetologia Croatica 32-3, 2003
Some patients using lispro insulin in their pumps
were found to have developed erratic and
unpredictable glucose fluctuations because of insulin
lispro precipitation in infusion catheters (48,49). Upon
switching from lispro insulin to aspart insulin or
buffered regular insulin, the problem resolved without
repeated catheter blockages. It was confirmed that
instability of lispro insulin was not in connection with
any particular infusion catheter or type of insulin pump
(48).
The rapid action of insulin analogs provides patients
greater flexibility in their mealtime insulin needs
because the bolus can be administered just before
meals, resulting in improved compliance and better
quality of life for patients using CSII therapy.
GLYCEMIC CONTROL DURING CSII
According to the results of DCCT, patients who used
CSII had the mean HbA1c value lower by 0.2%-0.4%
and improved lifestyle fexibility compared to patients
on MDI therapy (50).
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A recent meta-analysis of 12 randomized controlled
trials (13-15,51-59), which compared CSII to
intensified insulin injection regimens, shows a mean
difference in blood glucose concentration of 0.9
mmol/L (95% CI 0.5-1.2) and HbA1c difference of
0.5% (0.2-0.7) in favor of CSII (7). Glycemic control
according to the value of HbA1c was significantly
improved after starting CSII therapy, as shown by other
investigators (33,60-62). Glycemic control in patients
on CSII is affected by several factors, as observed by
Bode et al. (63). The frequency of blood glucose selfmonitoring is the one with greatest impact on glycemic
control. Other factors with a significant effect on
glycemic control are: 1) recording of insulin and blood
glucose values in a logbook (HbA1c 7.4% in those who
record versus 7.8% in those who do not) (63); 2) dietary
practices – carbohydrate counting (HbA1c 7.2% in
those who count carbohydrates, 7.4% in those on a
fixed-meal diet, and 8% in those on an undefined diet,
p>0.001) (63); and 3) use of insulin lispro versus
buffered insulin in the pump (HbA1c=7.3% versus
7.7%, p<0.001) (64).
Besides lowering the levels of glycosylated
hemoglobin, CSII has been shown to decrease
variability in the blood glucose level (6,65) and to lower
fasting glucose level (13,16,66-68).
BLOOD GLUCOSE SELF-MONITORING
As reported by Bode et al., the frequency of blood
glucose monitoring is the most important factor for
successful treatment with insulin pumps (63). They
have found that patients who monitor blood glucose
levels three or more times a day have lower mean
HbA1c level compared to patients who monitor it once
or twice daily (7.2% versus 8%; p<0.001). They suggest
that each additional blood glucose measurement
corresponds to a 0.2% decrease in HbA1c (p<0.0002).
To achieve strict blood glucose control it is neccesary to
perform 4 to 6 blood glucose measurements daily.
DISADVANTAGES OF CSII
Hypoglycemia (disadvantage or indication for
use of CSII?)
CSII therapy has been shown to decrease the
incidence of severe hypoglycemia as compared to MDI
therapy as a result of greater reproducibility and
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flexibility of insulin administration during CSII
therapy. In DCCT, the incidence of severe
hypoglycemia was three times greater in the group of
patients on intensive diabetes treatment, with similar
rates for multiple insulin injections and CSII (27).
Much of the DCCT-associated hypoglycemia may have
been due to unfamiliarity with the management of
strict blood glucose control. This conclusion is based
on the fact that the rates of hypoglycemia halved
during the study. In contrast to DCCT, according to
the experience of Bode et al., CSII is associated with a
lower occurrence of hypoglycemia requiring assistance
(69), and in some cases with restored hypoglycemia
awareness. It is important to emphasize that the
number of hypoglycemic episodes remained
significantly lower in years 2, 3 and 4 of pump use (26,
39 and 36 episodes per 100 patient/years, respectively),
without increase in HbA1c value (69). Moreover, a
reduction in hypoglycemia has been shown by other
investigators (60,61). Several factors are substantial for
this decrease in severe hypoglycemia: better
pharmacokinetic delivery of insulin, the ability to
control blood glucose over a desired although higher
target range for patients prone to hypoglycemia, and
markedly reduced insulin requirements compared to
MDI therapy (33).
Ketoacidosis
A patient on CSII does not have a subcutaneous
depot of long acting insulin. If the flow of short acting
insulin is interrupted, diabetic ketoacidosis can
develop more rapidly and more frequently (as it has
been reported in some early studies) with CSII
compared to other modes of treatment (70-73). The
cause of interruption of insulin administration may be
either intentional, because of some patient activities,
or unintentional, caused by catheter occlusion,
catheter disinsertion, battery failure, or depleted
insulin supply (74-76). In many cases ketoacidosis
occurs as a result of patient error and inadequate
training, particularly in patients who do not perform
emergency steps in the event of unexplained
hyperglycemia (77). Most studies show that with
proper education and pump practice, there is no
difference in the frequency of ketoacidosis between
CSII and injection therapy (61,62,69,78).
M. Prašek, T. Bo‘ek, @. Metelko / CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII)
Infusion site infections
Infection at the infusion site is probably more
common in CSII than in MDI therapy. The organisms
that are mainly causing infusion site infections are
Staphylococcus aureus, S. epidermidis and Mycobacterium
fortuitum (79-81). Occasionally, the infection may lead
to cellulitis or abscess formation requiring surgical
treatment. The annual rate of infusion site infection
has been estimated to 7.3-11.3 events per 100 years of
patient follow up (50). The risk of infusion site
infections can be reduced by changing the infusion set
every 2-3 days, not reusing cannulas, washing hands
before insertion, and covering the implanted needle
with a sterile dressing.
THE COST-EFFECTIVENESS OF CSII
COMPARED TO MDI IN THE
MANAGEMENT OF DIABETES
It is well known that for the application and
reimbursement of CSII therapy appropriately screened
candidates are necessary. The ability to identify eligible
candidates for CSII and to sustain their participation in
therapy is a hard issue to achieve positive outcomes
reported by the DCCT (1).
Many persons with type I diabetes mellitus are now
exploring whether CSII is a treatment option for them.
Unfortunately, despite the initial enthusiasm about
this mode of intensive treatment, according to the
literature, about 50% of these diabetics discontinue
CSII within a period of 2 years of its initiation (82-84).
According to the protocol used in the DCCT, to
initiate intensive therapy subjects were hospitalized.
The estimated cost for initiating CSII in the DCCT
was about 2900 USD per subject (27,85). Total
estimated annual cost for sustaining CSII was about
5800 USD per subject per year (27,85). In the study
performed by Sanfield et al. (86), participants were
followed for 2.5 years, discontinuation rate was 3%, and
the estimated cost for screening, CSII initiation and
follow-up was about 2431 USD. Through the
structured screening protocol 37% of patients were
identified as noneligible candidates for CSII. Once the
CSII has been initiated, only 3% of elected individuals
discontinue this therapy within 2.5 years of initiation.
The most recently published study suggests that CSII
Diabetologia Croatica 32-3, 2003
is most cost-effective in patients who had more than
two severe hypoglycemic events per year and who
required admission to hospital at least once a year (87).
USE OF CSII IN SPECIFIC GROUPS OF
DIABETIC PATIENTS
CSII and pregnancy
A connection between maternal hyperglycemia in
women with type 1 diabetes and the risk of consecutive
congenital fetal anomalies is well known (88,89).
Euglycemic or near euglycemic control is the goal
throughout pregnancy as well as during the
preconception period. One of the main indications for
use of insulin pump therapy is hypoglycemia, the
occurrence of which increases during the first trimester
of pregnancy. In the study of Kimmerle et al. (90), a
very high rate of severe hypoglycemia of 41% was
recorded in pregnant women with diabetes. Severe
hypoglycemia was defined as coma, seizure or
incapacitation requiring third part assistance.
Considering the efficacy of CSII in reducing
hypoglycemia and improving glucose excursions, there
is every reason for its use in pregnant women with
diabetes.
In spite of the at least comparable effect to MDI (9193), there are several advantages that suggest the use
of CSII in pregnancy, i.e. increased ease of treating
morning sickness and hyperemesis gravidarum,
reduction in glycemic excursions and hypoglycemia,
ease of treating the dawn phenomenon that increases
during pregnancy, and improvement in the postpartum
period when fluctuation of insulin requirements may
occur (94).
CSII in children and adolescents
In the last years, there has been a dramatic increase in
the use of CSII in children and adolescents suffering
from diabetes. The DCCT recommendations for strict
metabolic control and development in pump
technology have resulted in a tremendous increase in
the number of insulin pump users in the USA, from 500
in 1997 to more than 7 500 in 2001 (30). A recently
published study (95) analyzed 161 patients (aged 18
months to 18 years) and has reported a decrease in
HbA1c by 0.6%-0.7% as well as a decrease in the
number of severe hypoglycemia episodes. The
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continuation rate was 98%. In spite of lower HbA1c
value, the rate of severe hypoglycemic events (seizure
or coma) was significantly lower. In a lately published
study that included 95 patients, mean age 12 years and
median duration of follow-up 28 months, the mean
HbA1c value upon starting pump therapy was
significantly lower than before it (7.75% vs. 8.1%,
p<0.001) (96). The number of hypoglycemic events
was reduced upon the introduction of pump therapy
(12 vs. 17; rate ratio 0.46, CI 0.21-1.01). The incidence
of diabetic ketoacidosis and emergency department
visits was similar before and after the start of insulin
pump therapy. According to the above mentioned
results, it is to conclude that insulin pump therapy
significantly improves glycemic control and reduces
hypoglycemic events in children and adolescents, with
no difference in the number of diabetic ketoacidosis
episodes. One of the considerable benefits of CSII in
infants and toddlers is reduction in the risk of severe
hypoglycemia (97).
COMPARISON OF CSII AND MDI WITH
GLARGINE
Glargine is an insulin analog proposed as long acting,
peakless insulin designed to meet basal insulin
requirements. The theoretical advantage of CSII is its
ability to deliver insulin more physiologically resulting
in greater stability of blood glucose level than it could
be achieved with MDI. One of the most significant
features of CSII is basal rate preprogramming to meet
the physiologic insulin needs, therefore mostly several
basal rates are necessary. This feature is in particular
helpful
during
the
night
when
insulin
pharmacokinetics and the dawn phenomenon may
modify basal insulin requirements (98). The study
performed by King (99) showed the patients on MDI
(lispro insulin and glargine) to be for a significantly
longer time out of the target sensor glucose ranges (3.811.1 mmol/L) compared to the group of patients on
CSII (50.7% vs. 20.9%, p=0.04). The patients treated
with glargine had a 3-fold increase in the time exposed
to glucose values below 3.8 mmoL/L compared to CSII
patients, and 2-fold increase in the time exposed to
glucose values greater than 11.1 mmol/L. The mean
number of nocturnal basal rate setting was 2.4 ± 0.7 in
the CSII group. The group of patients on MDI with
glargine had no possibility to change basal rates.
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The ideal basal insulin should be administered at a
variable rate to satisfy changes in daily insulin
requirements. CSII seems to be the only current
method of basal insulin delivery achieving this variable
rate (99).
OUR EXPERIENCE WITH THE USE OF
CSII
At the end of the 1980s, we carried out a study to
compare the efficacy and safety of MDI and CSII
introduced in outpatient conditions during a one-year
randomized crossover trial. After a 3-month run-in
period, 39 type 1 diabetic patients were allocated
either to MDI or CSII. During the first 6 months,
HbA1c values decreased significantly in both groups
(MDI from 7.2% ± 1.9% to 6.5% ± 1.0%, p<0.05; CSII
from 7.4% ± 0.9% to 5.9% ± 0.8%, p<0.001). After
crossover HbA1c values decreased again on CSII (from
6.9% ± 1.3% to 6.1% ± 0.8%, p<0.05), however, in the
group of patients who were switched from CSII to
MDI, HbA1c values significantly increased (from 6.1%
± 0.5% to 7.4% ± 1.2%, p<0.001). Although the rate
of severe hypoglycemia requiring assistance was twice
as high during pump therapy (0.94/patient-years)
compared to MDI (0.47/patient-years), the total
number of hypoglycemic coma was the same (4 both).
The rate of severe episodes of ketosis was 6-fold
(2.05/patient-years vs. 0.37/patient-years) and the
incidence of diabetic ketoacidosis 2.5-fold in CSII
compared with MDI (0.28/patient-years vs.
0.11/patient-years) (100,101).
CONTINUOUS INTRAPERITONEAL
INSULIN INFUSION (CIPII) IMPLANTABLE INSULIN PUMPS
These are insulin pums that are located within the
body to deliver insulin intravenously or intraperitoneally. Despite their use for almost 20 years now,
the number of patients using this mode of intensive
diabetes management remains low, about one
thousand, worldwide. The advantages of implanted
insulin pumps include: the pump is out of sight, there
is no need for catheter insertion, and ease of insulin
delivery to great veins or into peritoneal cavity. The
use of implanted insulin pumps is limited by their
relative invasiveness, cost and reported high frequency
of complications during pump therapy (101-105). The
M. Prašek, T. Bo‘ek, @. Metelko / CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII)
use of implanted insulin pumps in comparison to
CSII/MDI improves glycemic control (the level of
HbA1c was lower by 0.6%), and the number of severe
hypoglycemic events was reduced, as suggested by
some investigators (106-109).
According to so-called Dutch experience, very poor
glycemic control and repeated admissions to the
hospital due to diabetes are indications with good
reason for implantable insulin pumps (110).
CONCLUSION
The future of CSII seems to be promising. CSII in
comparison
to
MDI
has
better
insulin
pharmacokinetics, less variability in insulin absorption,
and decreased risk of hypoglycemia. The main
advantages of CSII are improvement in glycemic
control, reduced risk of hypoglycemic events, and
lifestyle flexibility. The improvement in lifestyle is one
of the most important advantages of CSII allowing
patients to perform activities that would otherwise be
risky, such as skipping or delaying meals, sleeping late
on weekends, or engaging in vigorous exercise. Notable
disadvantages
of
CSII
include
increased
implementation cost, infusion site infections, and the
risk of ketoacidosis.
Because of its advantages it is to expect that CSII
technology may be used in 40% of type 1 diabetic
patients and about 5% of those suffering from type 2
diabetes (33).
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