Since its introduction three decades
ago, self-monitoring of blood glucose
(SMBG) using finger-stick
blood samples, test strips, and portable
meters has aided diabetes management,
principally by enabling patients—
particularly those treated with insulin—
to become full partners along with
health professionals in striving for excellent
glycemic control. Over time the use
of glucose meters has become easier and
faster with smaller and smaller blood
samples yielding results in a matter of seconds.
For this reason, glucose meters are
now increasingly used in hospital wards,
intensive care units, and other facilities
such as dialysis units and infusion centers
to provide point-of-care results that
would take much longer through routine
laboratory channels. This technology has
largely taken the guess work out of diabetes
management. Without such technology,
intensive glucose control such as that
achieved in the Diabetes Control and
Complications Trial may not have been
demonstrated to prevent or decrease microvascular
complications; insulin pump
therapy would not really be practical; and
hypoglycemia would remain an even
greater source of anxiety for patients and
their families than it already is.
We have come to rely so much on
finger-stick glucose that it is easy to forget
its limitations. In considering this we will
discuss accuracy, specificity, and, in light
of those, inappropriate usage.
Accuracy
Although there is no universally binding
standard, guidelines issued by the International
Organization for Standardization
(ISO) are widely acknowledged. ISO
guideline 15197 suggests that for glucose
levels 75 mg/dl, a meter should read
within 15 mg/dl of the reference sample,
and for levels 75 mg/dl, the reading
should be within 20%. A meter also
should be able to meet these targets in at
least 95% of the samples tested (1).
Several examples serve to illustrate
the implications of this degree of imprecision.
Assuming a meter does indeed
meet the ISO guideline, then a true glucose
level of 55 mg/dl could in fact yield
an SMBG reading of as low as 40 or as
high as 70 mg/dl, and occasionally (1 time
in 20) a reading beyond those limits.
While a reading of 40 mg/dl is likely to
prompt corrective action that could be
quite appropriate for a true value of 55
mg/dl, the same is not likely to be the case
for a reading of 70 mg/dl, which in many
instances will be regarded by the patient
as reassuring, if not cause for congratulation.
This could be particularly inappropriate—
and hazardous—in a patient with
hypoglycemia unawareness whose glucose
of 55 mg/dl is “on the way down”
rather than stable or increasing.
At the other end of the spectrum, a
true value of 350 mg/dl might register as
low as 280 or as high as 360 mg/dl. Because
all of these values are obviously
much higher than desirable in any circumstance,
it could be argued that this is
of no consequence because they all
should lead to glucose-lowering action.
But this is true only up to a point since in
these days of insulin infusion algorithms
aimed at achieving excellent glycemic
control in intensive care situations and
the use of premeal corrective insulin
doses in patients using multiple dose insulin
regimens, the differences mentioned
could quite conceivably compromise the
success of those respective treatment
strategies. It has been suggested that in
critical care situations the error tolerance
limit for bedside glucose testing should be
5 mg/dl (2).
Common experience tells us that the
majority of patients using meters for
SMBG are unaware of the magnitude of
the potential inaccuracy of results, and we
suspect that many health care providers
also tend to ascribe greater accuracy than
is warranted to portable glucose meter results.
Comparison of results on the same
blood sample obtained by different
meters is instructive. One study found
that the degree of difference between
meter readings widened as the true glucose
concentration increased from 70 to
200 mg/dl, with differences ranging from
5.7 to 32% in more than half of the comparisons
(3). Furthermore, the conversion
of whole blood glucose (measured
using finger-stick test strips) to the
plasma level reported by the devices will
vary depending on hematocrit, which is
typically lower and more variable in hospitalized
and intensive care patients than
in otherwise healthy outpatients (4). Potential
user errors such as applying insufficient
blood to the strip, using strips that
are out of date or exposed to excess moisture
or humidity, or failing to enter the
proper code (required for some but not all
systems) can further compromise
accuracy.
None of these errors is reason enough
for advising against the use of this technology,
but we need to do a better job
educating patients and providers about
the limitations. As an aside, we believe
that finger stick self-monitoring of glucose
by patients who do not have diabetes
but who believe they experience (usually
“reactive”) hypoglycemia is inappropriate
as ameans to establishing a diagnosis. The
likelihood that low glucose levels, documented
by self-monitoring in such patients,
truly represent a pathological
degree of hypoglycemia is extremely
small, yet the practice of encouraging
such monitoring can help perpetuate
a false belief that a disorder of glucose
metabolism underlies the patient’s
symptoms.
Specificity
Enzymatic measurement of glucose concentration
based on hexokinase is the
gold standard widely used in clinical laboratories
(5). Among the enzymes currently
used in test-strip systems are
glucose oxidase, glucose dehydrogenase
nicotinamide adenine dinucleotide
(GDH-NAD), GDH flavin adenine dinucleotide
(GDH-FAD), and GDH pyrroloquinolinequinone
(GDH-PQQ). Sensors
based on glucose oxidase are more substrate-
specific than those based on GDH,
but oxygen, being the recipient of electrons
from glucose oxidase, can negatively
affect the results from glucose
oxidase– based sensors (6). This is not a
problem with GDH-based systems, but
while GDH-FAD and GDH-NAD strips
E d i t o r i a l s
E D I T O R I A L ( S E E F R I A S E T A L . , P . 7 2 8 )
948 DIABETES CARE, VOLUME 33, NUMBER 4, APRIL 2010 care.diabetesjournals.org
are not subject to cross-reactivity from
sugars other than glucose, the same is not
the case with GDH-PQQ, which is nonspecific.
Maltose, galactose, and xylose
will be misinterpreted as glucose by
GDH-PQQ–based sensors (7). This certainly
has clinical relevance in certain
situations.
The potential magnitude of error is
illustrated by a report from Australia (8).
A patient treated with intravenous immunoglobulin
preparations containing maltose
was found to have capillary glucose
readings of 167 and 439 mg/dl using a
GDH-PQQ meter but simultaneous labmeasured
venous plasma glucose levels of
41 and 187 mg/dl, respectively. On its
website, the U.S. Food and Drug Administration
(FDA) draws attention to this
hazard by listing the following items as
being potential “interfering products”
with GDH-PQQ strips: Extraneal (icodextrin)
peritoneal dialysis solution; some
immunoglobulins, including Octagam
5%, WinRho SDF Liquid, Vaccinia Immune
Globulin Intravenous (Human),
and HepaGamB; Orencia (abatacept);
Adept adhesion reduction solution (4%
icodextrin); and BEXXAR radioimmunotherapy
agent (9). Additionally, the FDA
warns that any product containing or metabolized
into maltose, galactose, or xylose
could be a potential hazard in this
respect.
While it is likely that most Diabetes
Care readers will not personally have encountered
problems relating to GDHPQQ
strips, the article by Frias et al. (10)
in this issue illustrates that the possibility
of harm is not merely theoretical. In reviewing
the FDA’s Manufacturer and User
Facility Device Experience (MAUDE) database
(http://www.fda.gov/cdrh/MAUDE.
html) and the medical literature, the authors
identified 82 reported incidents with
death occurring in 20%. The method of reporting
toMAUDEprecludes direct attribution
of cause and effect in the cases where
death ensued, but it seems almost inescapable
that inappropriate insulin treatment
leading to severe and unexpected hypoglycemia
was a—or perhaps the—crucial factor.
Almost 80% of the instances involved
peritoneal dialysis using icodextrin. The authors
declare an interest in that they are employees
of LifeScan, a Johnson & Johnson
Company that manufactures and sells monitoring
systems based on glucose oxidase
strips, but, in our opinion, this does not negate
the import of their report.
A table listing the strips that use
GDH-PQQ is displayed on the FDA website
(9). Accu-Chek (Roche Diagnostics)
and FreeStyle (Abbott Diabetes Care) are
the most commonly used. To be fair, the
manufacturers of these strips have issued
warnings about the interfering sugars.
The FDA advises to “avoid using GDHPQQ
glucose test strips in healthcare facilities”
and cautions that if they are used
“NEVER use them on patients . . . who are
receiving interfering products” (9). Despite
this, serious adverse events continue
to be reported. A possible technical solution
to the problem is the use of mutant
forms of GDH-PQQ involving amino acid
substitution, which have good enzymatic
activity for glucose but reduced reactivity
for other sugars (5).
We would favor the FDA withdrawing
approval for use of GDH-PQQ strips
(other than mutant GDH-PQQ)—rather
than simply advising against their use—in
situations specifically recognized as being
problematical, such as icodextrin peritoneal
dialysis or when maltose-containing
immune globulin is used, and setting a
date for the elimination of their use in
health care facilities in general.
LEANN OLANSKY, MD
LAURENCE KENNEDY, MD, FRCP
From the Department of Endocrinology, Cleveland
Clinic, Cleveland, Ohio.
Corresponding author: Laurence Kennedy, kennedl4@
ccf.org.
DOI: 10.2337/dc10-0077
© 2010 by the American Diabetes Association.
Readers may use this article as long as the work is
properly cited, the use is educational and not for
profit, and the work is not altered. See http://
creativecommons.org/licenses/by-nc-nd/3.0/ for
details.
Acknowledgments—Cleveland Clinic has a
contract with Roche Diagnostics for use of
Accu-Chek glucose strips and meters in hospitalized
patients. No other potential conflicts
of interest relevant to this article were
reported.
