08 March 2007
A single blind, randomised, 8 way crossover study to
compare the blood volume and pain perception of capillary
blood sampling
There currently exist a plethora of single use blood sampling devices for obtaining
capillary blood samples, most commonly for use in testing of blood sugar levels in
diabetes. However there are limited numbers of studies comparing the adequacy of
these devices in terms of the blood volume they can generate, and also in terms of the
pain produced during the sampling process. We designed a study to look at eight
devices using these two parameters, with one device serving as a reference (Unistik 3
PC, Owen Mumford Ltd).
Introduction
There are few recent studies which compare capillary blood sampling devices in terms
of the adequacy of blood volume generated, and also with regards to the pain
produced during the sampling procedure. In general, most samples taken for the
purposes of monitoring capillary blood glucose are taken from the distal part of the
fingers, which tend to be more sensitive, but also to more accurately reflect the true
level of blood glucose when compared to samples taken from the arms or abdominal
skin. Therefore a device which can show a consistent reduction in pain compared to
its competitors, whilst still producing adequate blood volume for use by today’s blood
glucose monitoring devices should be welcomed by patients, especially those who are
monitoring blood glucose on a more frequent basis.
08 March 2007
Methods
Inclusion and exclusion criteria
The study was designed as an eight way crossover, single blind, randomised study to
look at blood volume generated (both unassisted and assisted) and pain perception,
comparing eight different devices (with the Unistik 3 PC device as the reference
device) in healthy adult volunteers. Volunteers were selected from a panel who had
offered their services to Simbec Research Ltd for the purposes of investigating new
medicines and devices. All volunteers had to be healthy, between the ages of 18 and
70, with no abnormalities of perception in the fingers (as assessed by a physician), no
evidence of skin disease affecting the digits, no cornification on the distal aspects of
the fingers, no history of diabetes (or evidence of same on screening lab tests), no
abnormalities of platelet count and negative pregnancy tests for the female volunteers.
All volunteers freely gave written informed consent to participate in the study.
Volunteers were excluded if they had taken any prescription or OTC medication
within 2 weeks of starting the study which might affect either pain perception or
blood volume obtained, had any clinically significant medical conditions or
abnormalities in laboratory tests seen at screening (including positive tests for HIV or
Hepatitis B or C), had a positive urine screen for drugs of abuse taken at screening
and in addition for female volunteers they were excluded if they had a positive
pregnancy test during the study (testing was carried out each time they attended).
Study conduct
The study was approved by the local research ethics committee prior to any
recruitment being undertaken. A total of 26 volunteers (age range 18-64: 8 males,
mean age 30.3 years, mean weight 93.7kg, mean height 1.81m: 18 females, mean age
39.7 years, mean weight 71kg, mean height 1.60m) were enrolled into the study,
based on statistical calculations to enable the detection of statistically significant
differences in both blood volume and pain perception. These volunteers were then
randomly assigned to treatment groups according a randomisation code generated by
Simbec Research using the PROC PLAN procedure of SAS (version 9.1.3.). Eight
devices were tested, from 7 different manufacturers (table 1). Environmental
conditions were kept as consistent as possible, with room temperature between 18 and
25°C (recorded in daily temperature log). Devices were randomly assigned to be
tested on one of 8 sites on each volunteer (the medial and lateral aspects of the middle
and ring fingers of each hand), with each device being tested at the same site on that
volunteer on each occasion. There was a minimum 48 hour gap between testing
sessions, to allow recovery of the testing sites. Only two testers (JM and RT) were
used, with one (JM) conducting the majority of the tests.
08 March 2007
TABLE 1: Device Characteristics
Brand
Unistik 3PC
(reference
device)
Unistik 3
(Test 1)
Accu-Chek SafeT-Pro Plus
(Test 2)
BD Genie
(Test 3)
Surgilance
One Step
(Test 4)
Haemolan
ce
(Test 5)
EZ-Lance
(Test 6)
Manufacturer/
distributor
Needle/Blade
Gauge
Top/Side firing
Needle
penetration
depth (mm)
Device firing
(semiautomatic or
manual)
Owen
Mumford
Needle
23G
Side
1.8
Owen
Mumford
Needle
23G
Side
1.8
Becton
Dickinson
Needle
23G
Top
2.25
Surgilance
HaeMedic
Needle
21G
Top
2.2
Needle
21G
Top
1.8
Palco
Labs
Needle
21G
Side
1.8
Semi
automatic
Semiautomatic
Roche
Diagnostics
Needle
23G
Top
Variable (1.3,1.8
or 2.3 – 1.8 used
in this study)
Semi-automatic
Auto
Safety
Lancet
(Test 7)
Vitalcare/
Sinda
Needle
21G
Side
1.8
Semiautomatic
Semiautomatic
Manual
Semiautomatic
Semiautomatic
08 March 2007
Finger pricking was undertaken in standardised fashion. The volunteer washed and
dried their hands prior to the first device being tested. They were then seated behind a
screen (such that they could not see the device being tested), through which they
placed their hand. They were given a sheet with the scoring system for pain (0 – 4, 0
being no pain and 4 being very severe; the scale included half points), which they then
verbally communicated to the person recording pain scores. Devices were tested in
the order prescribed by the randomisation; sites were always tested in order 1-8. The
actual testing itself was carried out as follows: both site and device to be tested were
identified by the tester and a checker. The site was then vigorously rubbed with cotton
wool for 5 seconds and the prescribed device was then held against the site for 3
seconds before triggering the device (this was to limit any pressure effect caused by
devices which were pressure activated). Pain score was obtained by direct questioning
at this time, whilst the unassisted blood volume was being measured. Assisted blood
volume was then recorded, using the method detailed below. Following this any
adverse events such as after bleeding, device malfunction or double puncture were
noted. This sequence was repeated until all 8 devices had been tested. Between 1 and
2 hours after the initial test, a review was carried out to assess residual pain and any
other effects such as bruising at the test site (this was then recorded as an adverse
event).
Measurement of study parameters
Blood volume was measured both unassisted and assisted: unassisted blood volume
was taken to be the volume produced from the initial lancing, collected into a 1µl
capillary tube for a maximum of 15 seconds (more than one tube to be used if
required); assisted blood volume was that volume collected into a 200µl capillary tube
after the finger being tested had been massaged 3 times from the hand towards the
puncture site, following the collection of the unassisted sample.
Pain was measured on a scale of 0 – 4, including half points. A reference copy of this
scale was made available to the volunteers whilst they were undergoing testing. Pain
was assessed on 2 occasions; directly following testing, and between 1 and 2 hours
after testing. Pain was not recorded as an adverse event during this study, since it was
being recorded separately using the above score. The volunteers were directly asked
for the score (0-4) that they felt the device warranted.
Statistical analysis
A statistical analysis plan was written by Simbec Research Ltd and agreed with the
study sponsor prior to database lock. Primary efficacy data was the blood volume
generated by each device compared to the reference device. Primary safety data was
the pain caused by each device when compared to the reference device. Secondary
safety data were those adverse events generated and also laboratory safety data from
haematology, biochemistry and urinalysis screens. Power calculations for this study
were based upon previous data provided by the sponsor, based on their own trials;
however we used a slightly different method to obtain the assisted blood volume and
therefore this affected the power of the study to detect small differences between
devices with regards to this parameter such that differences smaller than 3µl could not
08 March 2007
be considered to have any statistical significance. At the sponsor’s request, additional
analyses were carried out comparing all devices to Test 1 (Unistik 3), and these tables
have also been included in the results section.
Effect
A mean unassisted and assisted blood volume (unassistedmean and assistedmean) was
calculated for each subject and each device (across all visits). Descriptive statistics of
unassistedmean and assistedmean using n, mean, standard deviation, minimum, median
and maximum, by device were presented. Additionally unassistedmean and assistedmean
were subjected to an analysis of variance (ANOVA) using fixed effects for site and
device and a random effect for subject. Point estimates and 95% confidence intervals
were constructed for each of the 7 pair wise comparisons (each test versus reference)
along with the presentation of a p-value. No adjustments for multiple comparisons
were made.
Safety
A maximum pain score (painmax) was calculated for each subject and each device
(across all visits). Descriptive statistics of painmax using n, mean, standard deviation,
minimum, median and maximum, by device was presented. Additionally painmax was
subjected to an analysis of variance (ANOVA) using fixed effects for site and device
and a random effect for subject. Point estimates and 95% confidence intervals were
constructed for each of the 7 pair wise comparisons (each test versus reference) along
with the presentation of a p-value. No adjustments for multiple comparisons were
made.
08 March 2007
Results
Blood Volume
Statistical Analysis of Mean Blood Volume (µl)
Method
LSMeans
LSMean
Difference
Test - Reference
95% C.I. for
Difference
P-Value
Reference
0.41
N/A
N/A
N/A
Test 1
0.34
-0.07
-0.17 – 0.04
0.2311
Test 2
0.33
-0.08
-0.18 – 0.03
0.1581
Test 3
0.40
-0.00
-0.11 – 0.11
0.9645
Test 4
0.41
0.00
-0.10 – 0.11
0.9278
Test 5
0.53
0.13
0.02 – 0.24
0.0203
Test 6
0.32
-0.09
-0.19 – 0.02
0.1165
Test 7
0.26
-0.15
-0.25 – -0.04
0.0079
Reference
10.45
N/A
N/A
N/A
Test 1
9.80
-0.65
-4.05– 2.75
0.7058
Test 2
13.13
2.67
-0.72 – 6.07
0.1217
Test 3
15.82
5.37
1.97 – 8.76
0.0021
Test 4
16.64
6.19
2.79 – 9.58
0.0004
Test 5
14.68
4.22
0.83 – 7.62
0.0151
Test 6
10.46
0.00
-3.40 – 3.40
0.9989
Test 7
6.42
-4.03
-7.43 – -0.63
0.0203
Admin.
Unassisted
Assisted
Reference (R) : Unistik 3PC – Normal; Test 1 : Unistik 3 – Normal; Test 2 : Safe-T-Pro Plus; Test 3 : BD Genie;
Test 4 : Surgilance One Step; Test 5 : Haemolance; Test 6 : EZ-Lance; Test 7 : Auto Safety Lancet (Vitalcare).
Statistical Analysis of Mean Blood Volume (µl) - All Tests & Reference vs. Test 1
Method
Admin.
LSMeans
LSMean Difference
Test/Ref. – Test 1
95% C.I. for
Difference
P-Value
Unassisted
Test 1
0.34
N/A
N/A
N/A
Test 2
0.33
-0.01
-0.12 – 0.10
0.8302
Test 3
0.40
0.06
-0.04 – 0.17
0.2484
08 March 2007
Assisted
Test 4
0.41
0.07
-0.04 – 0.18
0.1979
Test 5
0.53
0.19
0.09 – 0.30
0.0005
Test 6
0.32
-0.02
-0.13 – 0.09
0.7068
Test 7
0.26
-0.08
-0.19 – 0.03
0.1390
Reference
0.41
0.07
-0.04 – 0.17
0.2311
Test 1
9.80
N/A
N/A
N/A
Test 2
13.13
3.32
-0.07 – 6.72
0.0550
Test 3
15.82
6.02
2.62 – 9.41
0.0006
Test 4
16.64
6.84
3.44 – 10.23
0.0001
Test 5
14.68
4.87
1.48 – 8.27
0.0051
Test 6
10.46
0.65
-2.75 – 4.05
0.7050
Test 7
6.42
-3.38
-6.78 – 0.02
0.0511
Reference
10.45
0.65
-2.75 – 4.05
0.7058
Reference (R) : Unistik 3PC – Normal; Test 1 : Unistik 3 – Normal; Test 2 : Safe-T-Pro Plus; Test 3 : BD Genie;
Test 4 : Surgilance One Step; Test 5 : Haemolance; Test 6 : EZ-Lance; Test 7 : Auto Safety Lancet (Vitalcare).
Side-Firing v. Top Firing Devices
Method
Side-Firing
Top-Firing
LSMean Difference
Side-Firing – Top-Firing
95% C.I. for
Difference
P-Value
LSMeans
Unassisted
0.33
0.42
-0.09
-0.14 – -0.03
0.0024
Assisted
9.29
15.07
-5.78
-7.51 – - 4.05
<0.0001
(Side-firing: Reference, Test 1, Test 6, Test 7; Top-firing: Test 2, Test 3, Test 4; Test 5)
08 March 2007
Unassisted blood volume
Blood sampling with the Haemolance (Test 5) device resulted in a mean blood
volume which was statistically significantly higher than the reference device
(p=0.0203). The Auto Safety Lancet (Test 7) device gave a mean blood volume which
was statistically significantly lower than the reference device (p=0.0079).
Assisted blood volume
Blood sampling with the BD Genie (Test 3), Surgilance One Step (Test 4) and
Haemolance (Test 5) devices all resulted in mean blood volumes which were
statistically significantly higher than the Unistik 3PC – Normal device (Reference)
(p = 0.0021, p = 0004 and p = 0.0151, respectively).
Blood sampling with the Auto Safety Lancet (Vitalcare) device (Test 7) resulted in a
mean blood volume which was statistically significantly lower than the Unistik 3PC –
Normal device (Reference) (p = 0.0203).
Pain
Statistical Analysis of Maximum Pain Score
08 March 2007
LSMeans
LSMean
Difference
Test - Reference
95% C.I. for
Difference
P-Value
Reference
2.06
N/A
N/A
N/A
Test 1
1.63
-0.43
-0.68 – -0.18
0.0010
Test 2
2.00
-0.07
-0.32 – 0.18
0.5916
Test 3
1.93
-0.13
-0.38 – 0.12
0.3084
Test 4
2.06
-0.00
-0.26 – 0.25
0.9770
Test 5
2.62
0.56
0.30 – 0.81
<0.0001
Test 6
1.99
-0.08
-0.33 – 0.18
0.5479
Test 7
1.78
-0.28
-0.54 – -0.03
0.0282
Admin.
Reference (R) : Unistik 3PC – Normal; Test 1 : Unistik 3 – Normal; Test 2 : Safe-T-Pro Plus; Test 3 : BD Genie;
Test 4 : Surgilance One Step; Test 5 : Haemolance; Test 6 : EZ-Lance; Test 7 : Auto Safety Lancet (Vitalcare).
Statistical Analysis of Maximum Pain Score - All Tests & Reference vs. Test 1
Admin.
LSMeans
LSMean Difference
Test/Ref. – Test 1
95% C.I. for
Difference
P-Value
08 March 2007
Test 1
1.63
N/A
N/A
N/A
Test 2
2.00
0.36
0.11 – 0.61
0.0054
Test 3
1.93
0.30
0.05 – 0.55
0.0207
Test 4
2.06
0.43
0.17 – 0.68
0.0011
Test 5
2.62
0.99
0.73 – 1.24
<0.0001
Test 6
1.99
0.35
0.10 – 0.61
0.0066
Test 7
1.78
0.15
-0.11 – 0.40
0.2564
Reference
2.06
0.43
0.18 – 0.68
0.0010
Reference (R) : Unistik 3PC – Normal; Test 1 : Unistik 3 – Normal; Test 2 : Safe-T-Pro Plus; Test 3 : BD Genie;
Test 4 : Surgilance One Step; Test 5 : Haemolance; Test 6 : EZ-Lance; Test 7 : Auto Safety Lancet (Vitalcare).
Side-Firing v. Top Firing Devices
Side-Firing
Top-Firing
LSMean Difference
Side-Firing – Top-Firing
95% C.I. for
Difference
P-Value
-0.29
-0.43 – -0.14
0.0001
LSMeans
1.87
2.15
(Side-firing: Reference, Test 1, Test 6, Test 7; Top-firing: Test 2, Test 3, Test 4; Test 5)
The Unistik 3 – Normal (Test 1) and Auto Safety Lancet (Vitalcare) (Test 7) devices
were significantly less painful than the Unistik 3PC – Normal device (Reference) (p =
0.0010 and p = 0.0282, respectively). The Haemolance (Test 5) device was
significantly more painful than the Unistik 3PC – Normal device (Reference)
(p < 0.0001). In the additional analysis carried out to look at all devices versus Test 1,
all devices apart from Test 7 were statistically significantly more painful than Test 1.
Of note, side-firing devices in general were statistically less painful than top-firing
devices.
Adverse Events
There were a total of one hundred and fifty eight (158) adverse events reported during
the study, of which one hundred and fifty two (152) were treatment emergent (onset
post start of device testing). Ten (10) adverse events were reported following testing
with the Unistik 3PC – Normal device (Reference). Nineteen (19) adverse events
were reported following testing with the Unistik 3 – Normal device (Test 1).
Nineteen (19) adverse events were reported following testing with the Safe-T-Pro
Plus device (Test 2). Twenty nine (29) adverse events were reported following testing
with the BD Genie device (Test 3). Twenty eight (28) adverse events were reported
following testing with the Surgilance One Step Device (Test 4). Nineteen (19)
adverse events were reported following testing with the Haemolance device (Test 5).
Nineteen (19) adverse events were reported following testing with the EZ-Lance
08 March 2007
devices (Test 6). Nine (9) adverse events were reported following testing with the
Auto safety Lancet (Vitalcare) device (Test 7).
All treatment emergent events were mild in severity and considered to be almost
definitely related to the device testing. No action was required and all events
completely resolved. The most frequently reported adverse event was Contusion,
Reported Term: ‘Bruising Site X’1 (117 events). Other adverse events reported
following device testing were Post Procedural Haemorrhage, Reported Term: ‘After
Bleeding Site X’1 (34 events) and Device Malfunction (1 event).
1
Where ‘X’ = Device Testing Site Number i.e. 1 to 8.
08 March 2007
Discussion
This study was designed to compare 8 different capillary blood sampling devices with
respect to both blood volume produced (unassisted and assisted) and pain generated
by the devices. One device (Unistik 3PC) was used as the reference device (this
device is no longer available, having been superseded by the Unistik 3 with CZT®).
Seven of the devices were semi-automatic (i.e. the device is fired by pressing a trigger
linked to a needle mounted on a spring, which then fires the needle at a pre-set speed,
retracting it afterwards so it then cannot be used again); one device (Haemolance
(Test 5)) was manually triggered (i.e. the needle is linked directly to a trigger, and the
speed of firing and retraction is totally operator dependent- in this case the device
could technically be used again [although this would be contrary to the
manufacturer’s instructions, and sharps policies in any healthcare facilities], since
there is no lock-out mechanism to prevent re-use. This device has now been
superseded by the Haemolance Plus, which has a semi-automatic action and is nonreusable).
The data obtained for blood volume tend to suggest that top firing devices produce a
greater blood volume than side firing devices. However since most blood glucose
meters available currently will provide results with sample sizes of 0.5-5µl (NHS
Purchasing and Supply Agency Centre for Evidence-Based Purchasing: A guide to
blood glucose meters on the UK market [available as web page or leaflet]) all of the
lancing devices on test would provide an adequate sample for these meters.
Top-firing devices in general produced a statistically significantly higher level of pain
than side-firing devices, although Test 5 (Haemolance) (top-firing) is a manually fired
device and therefore is more dependent on the operator than any of the others; the
relative slowness of the lancet motion on firing compared to the semi-automatic
devices can allow lateral motion of the needle whilst in the tissues, thereby potentially
increasing pain. Analysis of the maximum pain scores showed that in relation to the
reference device, both Test 1 (Unstik 3 normal) and Test 7 (Auto Safety Lancet) were
statistically significantly less painful, and that Test 5 (Haemolance) was statistically
significantly more painful. Test 1 (Unistik 3 Normal) uses the Owen Mumford
Comfort Zone Technology® (based on the pain gate theory of Melzack and Wall),
which uses a series of raised dots around the lancing site to provide an initial nonnoiciceptive sensation, which then acts to mask the pain of lancing and hence
decrease perceived pain; given that Test 1 and the reference device are otherwise
identical, this suggests that there is some benefit in terms of reduction of pain when
using this Comfort Zone Technology®.
Conclusion
All the devices provide an adequate blood volume for use with today’s blood glucose
monitors; side firing devices seem to provide less volume than top firing devices, but
also produce less pain on lancing. The addition of Comfort Zone Technology® to the
Owen Mumford device produced the lowest overall pain score, and a statistically
significant reduction in pain compared to the Unistik 3PC without CZT; this suggests
08 March 2007
that devices using this or similar technology should perhaps be considered as a firstline for blood glucose sampling, particularly in those who are more apprehensive
about undergoing such procedures due to the perceived pain involved.
References:
Fruhstorfer H, European Journal of Pain (2000) 4:301-305 ‘Capillary blood
sampling: the pain of single-use lancing devices’
P Nayyar, AD Batki, H Thomason, GH Thorpe: NHS Purchasing and Supply Agency:
Report 06006 – Lancing Systems (March 2006) (available at
http://www.pasa.nhs.uk/evaluation/docs/pathology/Report_06002.pdf)
http://www.pasa.nhs.uk/evaluation/publications/per/blood_glucose.asp (NHS
Purchasing and Supply Agency: Blood Glucose Meter and lancing devices
evaluations, listing details of various devices evaluated by the Medical Devices
Agency and PASA)
R Melzack, P.D. Wall: ‘Pain mechanisms: A new theory’ Science, 150: 171-9, 1965