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he results of the Diabetes Control and Com- persons with diabetes attempt to achieve prepran-
436
J Lab Clin Med
Volume 130, Number 4 Bantle and Thomas 437
and painful because of the frequent punctures. For minute samples. Fifteen minutes later (at t = 0), each
all of these reasons, a less-invasive method of mon- subject was provided a breakfast with a calorie level
itoring blood glucose would be desirable. judged to be appropriate for that individual. Eighteen
An alternative m e d i u m to blood for monitoring additional venous blood and dermal interstitial fluid sam-
glucose could be a body tissue or fluid. Subcutane- ples were obtained at 15-minute intervals from 15 to 270
minutes after breakfast. Finger-prick capillary blood sam-
ous tissue or fluid might be used in this regard, but
ples were obtained 30 minutes before breakfast and at
there has been controversy about the accuracy with
every second sampling time thereafter (every 30 minutes).
which subcutaneous glucose concentrations reflect
GCRC nurses collected all samples. One subject, in whom
blood glucose concentrations. 5 Recently T a m a d a et symptomatic hypoglycemia developed during the study,
al. 6 reported that a glucose flux obtained transder- was treated with orally administered carbohydrate. After
mally through the use of a low-level electric current the last samples were obtained, the intravenous catheters
showed a quantitative relationship to serum glucose. were removed and the studies ended. Subjects were pro-
Thus, dermal interstitial fluid might be a good me- vided lunch before they left the GCRC.
dium for glucose monitoring. Dermal interstitial fluid was collected with a sterile,
With this in mind, we used a prototype sampling disposable, 29-gauge hypodermic cannula attached to a
device developed by Integ Inc., St. Paul, Minn., to depth-limiting spacer. A 0.5 mm 3 capillary tube (Drum-
collect minute quantities of dermal interstitial fluid mond Scientific Company, Broomall, Pa.) was attached to
to determine the ability of the dermal interstitial the blunt end of each cannula with heat shrink tubing.
This assembly was loaded into a prototype sampling de-
fluid glucose concentration to accurately predict
vice with a window for observing the capillary tube. The
plasma glucose concentration over a wide range of
sampling device was placed on the skin of a subject's
potential glucose concentrations. Of particular con- forearm and steady pressure was applied. The spacer
cern was the predictive capability of the dermal limited the penetration of the cannula to a maximum
interstitial fluid glucose concentration at times when depth of 1.4 mm. As the cannula penetrated the dermis,
plasma glucose concentration was rapidly rising or the pressure created allowed interstitial fluid to flow into
falling. This was, therefore, a feasibility study under- the capillary tube. The study nurse visually monitored the
taken to determine whether dermal interstitial fluid collection of interstitial fluid through the window in the
might be an acceptable alternative to blood for glu- sampling device. It usually took between 5 and 15 seconds
cose monitoring. to collect a sample. After the sample was collected, the
cannula assembly was removed from the sampling de,rice
METHODS and again visually inspected by the study nurse. A sample
Subjects. Twenty subjects with type I diabetes partici- was deemed acceptable if visual inspection showed that
pated in this study, but data for 3 subjects were excluded the capillary tube was filled and contained no air bubbles
from the analysis for reasons described later. Therefore, or visible blood. A new cannula assembly was used for
data from 17 subjects were included in this report. These collection of each sample.
17 subjects were 8 women and 9 men whose mean age was The study nurse either could not obtain or deemed
41 years (range: 21 to 70 years) and whose mean duration unacceptable a total of 14 interstitial fluid samples. All
of diabetes was 20 years (range: 6 months to 48 years). acceptable samples were numbered and immediately
Nine subjects were known to have retinopathy, 7 to have stored at -70 ° C.
neuropathy, and 2 to have nephropathy. One subject had The protocol for the study was approved by the Uni-
had a kidney transplant. All subjects were receiving sub- versity of Minnesota Committee on the Use of Human
cutaneous insulin therapy. Seven subjects received insulin Subjects in Research. Written informed consent was .ob-
from insulin infusion pumps, 2 subjects took four insulin tained from all subjects.
injections daily, 4 subjects took three insulin injections Laboratory methods. All dermal interstitial fluid sam-
daily, 2 subjects took two insulin injections daily, and 2 pies were transported from the GCRC to the Integ Lab-
subjects took one insulin injection daily. oratory on dry ice and were stored at -70 ° C until analysis.
Study protocol. Each subject was studied on one occa- The samples were identified to Integ personnel only by
sion. Subjects were asked to report to the GCRC before number (i.e., all Integ personnel were masked with regard
breakfast on study mornings. Each subject had a venous to the plasma and capillary glucose values of the intersti-
catheter placed in a forearm vein from which timed blood tial fluid samples). Before glucose analysis, each capillary
samples could be obtained. Baseline samples of venous tube was microscopically reexamined to confirm that the
blood and dermal interstitial fluid were obtained 30 min- samples met the acceptance criteria. Unacceptable sam-
utes and 15 minutes before breakfast, respectively. After ples were excluded from glucose analysis. On microscopic
the second baseline samples were obtained, each subject analysis, the dermal interstitial fluid samples from three
took his or her usual pre-breakfast dose of subcutaneous consecutive subjects were found to contain a contaminant
insulin. Subjects were allowed to adjust their insulin doses that was of indeterminate origin but was thought to orig-
according to the blood glucose values found in their 15- inate in the capillary tubes. Because the nature of the
J Lab Clin Med
438 Bantle and Thomas October 1997
%o
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o ooo
oj o
E 0 o o~ o 0
E o0O o ~
v OO
8 o °°'°,~ o 8
o o°~e°~o °Oo o
72
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o
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Y0
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5
I
10
I
15
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20
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25
Fig. 1. Plasma glucose versus dermal interstitial fluid glucose concentrations for all observations of all
subjects (n = 223); the line shown is the line of identity (x = y).
C~l
O
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0 _
..1 o
0
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E
v
0 o o
0 °o
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"(3
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oo :°°
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0 5 10 15 20 25
Fig. 2. Plasma glucose versus capilla~r blood glucose concentrations for all observations of all subjects
(n = 154); the line shown is the line of identity (x = y).
[275 mg/dl]) control solution were 1.5% and 1.4%, respec- The Chemtrak Level 1 and Level 3 control solutions
tively. Capillary blood glucose concentrations were mea- were used as intermethod controls. The dermal interstitial
sured with the Yellow Springs Instruments 2300 Stat Plus. fluid glucose values were corrected linearly so that the
Dermal interstitial fluid glucose concentrations were values for the Chemtrak Level 1 and the Chemtrak Level
measured in the Integ Inc. laboratory with a manual 3 control solutions obtained at the Biochemistry Labora-
hexokinase method and an unblanked hexokinase re- tory of the University of Minnesota agreed with those
agent and standards (Sigma Diagnostics, St Louis, obtained at the Integ laboratory.
Mo.) according to the manufacturer's instructions. A Statistical analysis. Analysis of the relationship between
proportional adjustment was made in the measurement dermal interstitial fluid and plasma glucose values was
method to compensate for the 0.5 ~1 volume of inter- done so as to take into account the dependence among
stitial fluid samples, which was smaller than the 10 txl repeated measures of glucose for each subject. This was
volume of serum or plasma samples typically analyzed done by multiple regression of the dermal interstitial fluid
with this method. The dermal interstitial fluid samples glucose values (dependent variable) on the plasma glu-
were expressed into microcentrifuge tubes containing cose values (independent variable) as parallel lines with a
hexokinase reagent. The capillary tubes were rinsed common slope and separate intercepts for each subject.
three times with the hexokinase reagent. Each sample There was no evidence of different slopes among subjects.
was read with a spectrophotometer (Genesys 5; Spec- A similar analysis was done for the capillary and plasma
tronic, Milton Roy, Rochester, N.Y.) at 340 nm. For the glucose values. The slopes of these regression lines are
manual hexokinase assay, the interassay coefficient of given in Table I and are adjusted for the repeated mea-
variation for Chemtrak Level 1 control solution was sures. For comparison with the literature, we also pro-
8.0% and for Chemtrak Level 3 control solution was vided correlation coefficients, mean absolute differences,
5.3%. and mean percent differences, although all of these ig-
J Lab Clin Med
440 Bantle and Thomas October 1997
Subject 5 Subject 10
tO
...1
0
tO
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V
E Q
t- 0
i i i 4 t u n i
O 0 50 100 150 200 250
0 50 100 150 200 250
c--
Subject 12 Subject 13
0
c-
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/:...
tO tO
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LO tO
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i i p i i
nored the dependence arising from the repeated measure- [37 to 422 mg/dl]). Comparisons of capillary blood
ments. For Table II, glucose excursions were calculated as glucose with plasma glucose values are provided in
the range from minimum to maximum values. Time to Fig. 2 and Table I. Capillary blood glucose values
peak glucose concentration was estimated for each subject were not better correlated with plasma glucose val-
as the length of time needed for the glucose concentration
ues than were dermal interstitial fluid glucose values,
to reach its largest value. One subject withdrew from the
study early, and the data for this subject were excluded and both the mean absolute difference and mean per-
from Table II, in which the data were based on the cent difference between capillary blood glucose and
remaining 16 subjects. Paired t tests were used to compare plasma glucose values were somewhat greater than the
end points and as the basis for calculations to determine corresponding differences between dermal interstitial
the power of the study to find differences in glucose fluid glucose and plasma glucose values.
excursion, peak glucose concentration, and time to peak Plasma glucose, dermal interstitial fluid glucose,
glucose concentration. and capillary blood glucose values from the four
individual subjects with the largest excursions in
RESULTS plasma glucose are presented in Fig. 3. In all four
The observed values of dermal interstitial fluid subjects, the three glucose curves were similar. Data
glucose and plasma glucose concentrations for all on glucose excursion, peak glucose concentration,
subjects are compared graphically in Fig. 1 and nu- and time to peak glucose concentration for 16 sub-
merically in Table I. Dermal interstitial fluid glucose jects are provided in Table II. There were no signif-
values were highly correlated (r = 0.95,p < 0.0001) icant differences between plasma and dermal inter-
with plasma glucose values across the range of ob- stitial fluid for any of these parameters, although the
served plasma glucose values (2.1 to 23.4 mmol/L difference for peak glucose concentration ap-
J Lab Clin Med
Volume 130, Number 4 Bantle and Thomas 441
proached significance (p = 0.07). To put these re- Our preliminary data suggest that measurement
sults in perspective, the sizes of the differences the of dermal interstitial fluid glucose concentrations
study had power to find were calculated. With 16 can be used to estimate plasma glucose concentra-
subjects, there was an 80% chance (power: r = 0.8) tions. If the performance issues raised in this study
of finding a significant difference between dermal can be resolved, and the collection techniques can
interstitial fluid glucose and plasma glucose values if be performed satisfactorily by patients, this less-
the true differences were larger than 1.3 mmol/L (24 invasive method of glucose monitoring could pro-
mg/dl) in glucose excursion, 0.9 mmol/L (16 mg/dl) vide a new option for patients with diabetes mellitus.
in peak glucose concentration, or 20 minutes: in time
to peak glucose concentration. Conflict-of-interest note: William Thomas is a stockholder in
Integ Inc.
DISCUSSION
Our data demonstrated that dermal interstitial
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