DIABETICMedicine

DOI: 10.1111/dme.12604

Review Article
Utility of ketone measurement in the prevention,
diagnosis and management of diabetic ketoacidosis

S. Misra1,2 and N. S. Oliver1

1
Department of Diabetes, Endocrinology and Metabolism, Imperial College London and 2Clincal Biochemistry and Metabolic Medicine, Imperial Healthcare NHS
Trust, London, UK

Accepted 6 October 2014

Abstract
Ketone measurement is advocated for the diagnosis of diabetic ketoacidosis and assessment of its severity. Assessing the
evidence base for ketone measurement in clinical practice is challenging because multiple methods are available but there
is a lack of consensus about which is preferable. Evaluating the utility of ketone measurement is additionally problematic
because of variability in the biochemical definition of ketoacidosis internationally and in the proposed thresholds for
ketone measures. This has led to conflicting guidance from expert bodies on how ketone measurement should be used in
the management of ketoacidosis. The development of point-of-care devices that can reliably measure the capillary blood
ketone b-hydroxybutyrate (BOHB) has widened the spectrum of applications of ketone measurement, but whether the
evidence base supporting these applications is robust enough to warrant their incorporation into routine clinical practice
remains unclear. The imprecision of capillary blood ketone measures at higher values, the lack of availability of routine
laboratory-based assays for BOHB and the continued cost-effectiveness of urine ketone assessment prompt further
discussion on the role of capillary blood ketone assessment in ketoacidosis. In the present article, we review the various
existing methods of ketone measurement, the precision of capillary blood ketone as compared with other measures, its
diagnostic accuracy in predicting ketoacidosis and other clinical applications including prevention, assessment of severity
and resolution of ketoacidosis.
Diabet. Med. 32, 14–23 (2015)

In the present article, we discuss the biochemical and

Introduction
Diabetic ketoacidosis is a serious, acute complication of
diabetes, associated with significant morbidity and mortality
[1]. It results from the accumulation of ketone bodies
[b-hydroxybutyrate (BOHB also known as 3-hydroxybuty-
rate) and acetoacetate (AcAc)] and accompanying hydrogen
ions, produced after lipolysis of triglycerides in the absence
or deficiency of insulin [2,3]. Diagnosis of ketoacidosis
requires a measure of glycaemia, identification of ketones
and assessment of acid-base status. The recognition that the
accumulation of ketones and resultant ketoacidosis are the
underlying biochemical problem has led to a shift in focus
away from glucose measurement for both diagnosis and
ongoing management. Ketone detection has traditionally
relied on urine assessment using qualitative or semi-quanti-
tative dipsticks; however, the development of point-of-care
hand-held analysers capable of measuring capillary blood
ketones has allowed the rapid assessment of blood ketones at
the bedside and in the home.
Correspondence to: Shivani Misra. E-mail: smisra@imperial.ac.uk
analytical aspects of ketone measurement and critically
review the evidence base for the clinical applications.
Methods of ketone measurement
The main ketoacids are AcAc and BOHB, which usually
circulate in low equimolar concentrations (< 0.5 mmol/l in
healthy adult blood after an overnight fast) [2]. Acetone,
another ketone body, is formed from the spontaneous
decarboxylation of AcAc, is volatile, and present in very
low concentrations. Ketones can currently be measured in
the urine, capillary blood and serum.
Urine ketones
Urine dipsticks (detecting ketones qualitatively or
semi-quantitatively) impregnated with nitroprusside reagent,
react only with AcAc and acetone but not BOHB. During
ketoacidosis, the ratio of AcAc to BOHB favours the latter
and can be as high as 1:10, as BOHB is formed from the
reduction of AcAc [2]. This shift in equilibrium accounts

ª 2014 The Authors.

14 Diabetic Medicine ª 2014 Diabetes UK
 Review article
for the discordant results often encountered between urine
ketone measurement and the severity of ketoacidosis, as
assessed by pH and bicarbonate, as measurement of AcAc in
urine will underestimate the extent of ketonaemia [4]. Urine
ketone concentrations also reflect the total accumulated
since the last void and levels measured may therefore become
uncoupled from real-time changes.
Urine ketone assessment is also limited by the paradoxical
increase in urinary AcAc during resolution of ketoacidosis,
which is attributable to the conversion of excess BOHB back
to AcAc, as acidosis resolves. Laboratory guidelines from the
American Diabetes Association state that for use by patients
in the home setting, control materials would be desirable to
ensure accuracy of test results, but these are not commer-
cially available [4].
These limitations, coupled with the semi-quantitative and
subjective interpretation of the test, the lag time between
serum and urine metabolic changes and difficulties with
serial urine samples in a dehydrated unwell patient, have led
to the suggestion that blood ketone measurement is superior
to urine assessment. This is further supported by the
apparent delay in urine dipstick assessment compared with
blood ketone assessment in those presenting acutely with
hyperglycaemia [5,6] and by the fact that many acutely
unwell patients are unable to provide a urine sample in the
emergency department [7].
Blood ketone measurement
Ketones may be measured in serum, plasma or whole
blood samples using laboratory-based analysers, or in
finger-prick samples using capillary blood. Several different
assay methods (colorimetric, gas chromatography, capillary
electrophoresis and enzymatic) have been described for
specific BOHB detection, but enzymatic methods appear to
be the most widely used [4]. The measurement of AcAc
using nitroprusside in blood is not advocated for diagnos-
tic purposes, as BOHB will not be detected. It is important
to make the distinction between laboratory measurement
of serum BOHB and point-of-care measurement of
capillary ketones (BOHB) in whole blood. This is analo-
gous to the difference between plasma glucose and
capillary blood glucose, and the same advantages and
disadvantages apply.
Serum b-hydroxybutyrate
A variety of enzyme-based assays are available for the
detection of BOHB in serum. The quoted reference method
(Stanbio reagents on Cobas 501 analyser) is linear up to
4.5 mmol/l, but levels above this can be diluted into the
linear range. Coefficients of variation are quoted as being
between 1 and 4%, but higher outside the linear range [8,9].
Many laboratory-based analysers are capable of measuring
BOHB, but it is unclear how many laboratories have the
ª 2014 The Authors.
Diabetic Medicine ª 2014 Diabetes UK
DIABETICMedicine
facility to measure serum BOHB, as until recently its use has
been limited to the investigation of neonatal hypoglycaemia.
The availability of laboratory analysis is essential as it has
the facility to dilute samples outside of the linear range and
to confirm analysis of capillary blood ketone outside the
range of point-of-care devices.
Capillary blood ketones
The measurement of capillary blood ketones at the point of
care has recently been advocated [10]. The advantages of any
point-of-care test apply to this method, in that a rapid
quantitative result can be obtained in real time, allowing
immediate changes in management. This is advantageous in
the diabetes setting, where devices can be used to empower
self-management.
There are currently two approved meters capable of
measuring capillary blood ketone using dry-chemistry meth-
odology: the FreeStyleOptium (Precision Xceed; Abbott
Diabetes Care, Maidenhead, UK) and the Glucomen LX Plus
(Menarini, Florence, Italy). Versions of these meters are also
available for inpatient monitoring with connectivity. The
devices measure BOHB using BOHB dehydrogenase coupled
with electrochemical detection. These methods and older
variants have been evaluated against reference enzymatic
spectrophotometric assays and generally show good correla-
tion [6,11–14]. The Abbott devices are perhaps the most
evaluated.
Older-generation point-of-care devices, such as the Med-
isense Optium (Abbott Diabetes Care), have now been
superseded by newer devices. It is worth noting that many of
the studies underpinning current guidance incorporate data
generated using older devices. The main difference between
older and newer devices is a shorter measurement time, with
smaller capillary blood volume and an improved coefficient
of variation at lower range measurements: 5.9% at
0.68 mmol/l (Precision Xceed pro) vs 8.2–14.6% at concen-
trations below 1 mmol/l (Medisense Optium) [12–16].
Whilst these advances are important developments, the
coefficient of variation outside of the normal range (in the
ketoacidotic range) has not improved considerably. In
addition, evaluations of the newer devices show a loss of
linearity and imprecision at high levels of BOHB, which seem
not to have been reported for earlier versions, except in one
study [17]. Manufacturers quote linearity up to ketone values
of 8 mmol/l, after which a ‘Hi’ reading is reported, but this
contrasts with reports validating meters in clinical settings,
which show a loss of linearity above levels of 3 mmol/l
[18,19].
A recent study also compared the Precision Xceed meter
with a non-enzymatic reference method using liquid chro-
matography tandem mass spectrometry traceable to weighed
standard solutions, using dried blood spots. They found
linearity up to concentrations of 6 mmol/l (r = 0.97), after
which the Abbott method showed saturation, and was
15
DIABETICMedicine Ketone measurement in diabetic ketoacidosis  S. Misra and N. S. Oliver
non-linear; however, inter-individual coefficients of variation
were higher at ~ 6 mmol/l, leading the authors to concur that
capillary blood ketone BOHB levels should not be reported
above 3 mmol/l [20]. This contrasts with the manufac-
turer-stated range of up to 8 mmol/l.
These findings are important if capillary blood ketone
measurement is used to monitor resolution of ketoacidosis in
conjunction with other biochemical variables, as advised in
current guidance, because reported values of > 3 mmol/l
may, in reality, be higher [10]. This is especially important if
higher levels of capillary blood ketone are used to guide level
of care; for example, blood ketones > 6 mmol/l to guide
admission to high dependency areas. Guidance also advo-
cates a target BOHB reduction of 0.5 mmol/l/h, and to
achieve this reliably, levels outside of the range of linearity of
point-of-care devices need to be determined [10].
It could be argued that the absolute value of capillary
blood ketones is not essential for the clinical management of
ketoacidosis and differentiation of high from low levels
would be sufficient, but this needs to confirmed in high-qual-
ity studies that not only assess diagnostic accuracy, but also
clinical utility and impact on patient outcomes.
Most ketone meters also have recommended operational
haematocrit ranges. For the PrecisionXceed the upper limit is
set at 60%, above which it is recommended that capillary
blood ketone measurement is not used; however, dehydra-
tion and hyperosmolality are clinical states nearly always
seen in ketoacidosis, and haematocrits may be well above the
60% threshold. As with any test, these limitations should be
taken into consideration when the measurement is being
made, although it should be noted that bedside ketone
monitoring is one method of several to aid making the
diagnosis.
There are clear potential advantages of capillary blood
ketone measurement over urine ketone assessment, both
biochemically and analytically. A recent systematic review
comparing urine AcAc with blood BOHB (serum or capillary
blood ketones) concluded that blood BOHB assessment was
associated with reduced frequency of hospitalization, shorter
time to recovery from diabetic ketoacidosis and lower costs;
however, only four studies met the inclusion criteria for this
review and the authors acknowledged the quality of evidence
(by National Health and Medical Research Council stan-
dards) underpinning these conclusions was grade ‘C’ or
satisfactory, whilst the studies themselves were heteroge-
neous in terms of design and outcomes assessed [21].
Furthermore, it is important to distinguish between studies
using serum or capillary blood ketone BOHB, as there are
clear practical differences.
The cost and lack of availability of widespread capillary
blood ketone analysis, mean that in some centres urine
ketone testing may still be the favoured choice. Point-of-care
devices must also be compliant with biochemistry laboratory
protocols, to ensure staff training is adequate, that meters
undergo rigorous and frequent quality assurance, that there
16
is a facility to perform laboratory ketone testing when meter
readings are invalid, and that there is sufficient connectivity
to electronic patient records [10]. These standards are a
challenge to maintain, but if capillary blood ketone testing is
to become widespread in and outside of hospital, the
provision of these services must be taken into consideration.
Reassuringly both capillary blood ketone and serum BOHB
measurement have external quality assurance schemes, in
which laboratories can participate. There is therefore infra-
structure in place to ensure quality is maintained [22,23].
Guideline recommendations
Published consensus criteria from the Joint British Diabetes
Societies [10], and American Diabetes Association [24],
identify a role for ketone measurement in the diagnosis of
ketoacidosis, and also advocate its use for monitoring of
ketonaemia resolution, representing a shift in focus from the
traditional variables assessed, such as bicarbonate, glycaemia
and pH. However, the guidance available lacks consensus on
both the method of ketone measurement and the clinical
applications; the Joint British Diabetes Societies recommends
use of capillary blood or urine ketones for diagnosis, and
capillary blood ketones for monitoring severity and resolu-
tion. The American Diabetes Association guidance stipulates
the use of serum and urine ketone measurements for
diagnosis, and direct BOHB measurement for monitoring
resolution, but do not specify how this should be measured.
The laboratory guidelines from the American Diabetes
Association [4] contradict the American Diabetes Associa-
tion ketoacidosis guidance and recommend blood, but not
urine, ketone measurements for diagnosis of ketoacidosis and
state that urine ketone measurement should not be used to
monitor treatment. Meanwhile the International Society for
Pediatric and Adolescent Diabetes clinical practice guidelines
recommend capillary blood ketone use only if laboratory
measures are unavailable [25]. Table 1 provides a summary
of the recommendations.
Clinical applications of ketone
measurement
Diagnosis of ketoacidosis
Biochemically, ketosis and acidosis do not always accom-
pany each other because, in the early stages of ketosis, excess
hydrogen ions may be buffered [15]. Bicarbonate and pH
may be affected by factors such as vomiting, respiratory
compensation and pre-existing acid base disturbances [15]
and, although glucose values have been incorporated into
diagnostic criteria, the recognition of euglycaemic ketoaci-
dosis and the decoupling of ketosis from hyperglycaemia,
means that hyperglycaemia alone cannot be diagnostic of
ketoacidosis [10]. Since ketosis is the underlying abnormality
and given the non-specific nature of changes in bicarbonate
ª 2014 The Authors.
Diabetic Medicine ª 2014 Diabetes UK
 Review article DIABETICMedicine

Table 1 Summary of guidelines advocating the use of ketone assessment in diabetic ketoacidosis

Definition of Ketones in Laboratory

ketoacidosis Ketones for Ketones for monitoring measurement
Guideline (where given) diagnosis severity resolution advocated

American Diabetes Nitroprusside-based No BOHB for monitoring No

Association on  Glucose reactions for resolution. No
management of > 13.8 mmol/l diagnosis. indication of
hyperglycaemic Qualitative whether serum or
crises, 2009 [19]  pH < 7.3 result in urine capillary blood
or serum ketone assessment
 Bicarbonate
< 18 mmol/l

 Urine or serum ke
tones by nitroprus
side reaction
‘positive’

Joint British Diabetes Capillary Yes, a level Yes, aim for a Yes, if values on
Society, 2011 [9]  Glucose blood > 6 mmol/l reduction of at least capillary blood
> 11 mmol/l or ketone measurement 0.5 mmol/l/h BOHB ketone meter ‘
of BOHB as measured in out-of-range’
known diabetes
or, if unavailable, capillary blood
 Bicarbonate semi-quantitative
assessment of urine
< 15 mmol/l and/
AcAc
or pH < 7.3

 Ketones > 3 mmol/

l or > 2+ on urine
dipstick

American Diabetes N/A Urine ketones Not specified Specific BOHB Not specified
Association should not recommended but
laboratory guidance be used to not specified
on ketones in diagnose or whether capillary
diabetes, 2011 [3] monitor ketoacidosis. blood ketone or
Specific BOHB preferred laboratory-based
for diagnosis assessment
International Society Urine ketones No Yes, until urine Yes. Capillary blood
for Paediatric and  Glucose or BOHB ketones cleared ketone assessment
Adolescent Diabetes > 11 mmol/l or if available only if laboratory
guidelines, 2009 BOHB every 2 h unable to provide
[20]  Bicarbonate timely results
< 15 mmol/l and/
or pH < 7.3

 Ketonaemia and
ketonuria

BOHB, b-hydroxybutyrate; AcAc, acetoacetate.

and pH, the focus of diagnosis has shifted to ketone
measurement.
The current guidelines for ketoacidosis diagnosis in the UK
include; ketonaemia > 3 mmol/l or > 2+ ketones on urine
dipstick, blood glucose > 11 mmol/l or known diabetes
mellitus and venous bicarbonate < 15 mmol/l or pH level
< 7.3 [10]. Many previous studies have compared the
sensitivity of capillary ketone testing with that of urine
ketone, bicarbonate, glycaemia and pH in the diagnosis of
ketoacidosis [6,7,9,26–28]. These studies are heterogeneous
and use different numerical thresholds, making comparison
problematic. In addition, there is no clear international
consensus on the diagnostic variables for ketoacidosis, with
the American Diabetes Association suggesting a bicarbonate
level of < 18 mmol/l, no specific numerical thresholds for
ketone measurement and a glucose level of > 14 mmol/l [24].
In a retrospective study of 304 patients, serum BOHB
measurements were compared with serum bicarbonate levels
to determine BOHB levels corresponding to the American
Diabetes Association-recommended bicarbonate threshold of
18 mmol/l [9]. A curvilinear relationship between bicarbon-
ate and BOHB was shown, with a BOHB level of 3.8 mmol/l

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Diabetic Medicine ª 2014 Diabetes UK 17
DIABETICMedicine Ketone measurement in diabetic ketoacidosis  S. Misra and N. S. Oliver
(3 mmol/l in children) corresponding to a bicarbonate level
of 18 mmol/l. That study suggests that a BOHB minimum
concentration of 3.8 mmol/l could be incorporated into
diagnostic criteria, but the authors do not advocate the use of
point-of-care devices, recognizing the limited precision of
such analysers above 3 mmol/l.
In a prospective study, 171 patients presenting to the
emergency department with hyperglycaemia (> 11 mmol/l)
and capillary blood ketone > 0.1 mmol/l were assessed [29].
Ketoacidosis was defined as a glucose level > 11 mmol/l, with
serum BOHB > 0.42 mmol/l and a pH level < 7.3. Urine,
serum and capillary ketones were compared between those
meeting the criteria for ketoacidosis, and those individuals
with ketonaemia alone. Capillary blood ketone had a 72%
sensitivity and 82% specificity for the detection of ketoaci-
dosis, compared with 66 and 78%, respectively, using urine
ketone assessment. Although capillary and serum ketones did
not differ significantly, the correlation between the values was
weak but significant (r = 0.488, p < 0.0001), suggesting that
capillary blood ketone could be an alternative to laboratory
ketone testing, and that it was superior to urine testing in the
recognition of ketoacidosis; however, the threshold for
diagnosis of ketoacidosis was low at 0.42 mmol/l, which is
in the normal range, making it a poor discriminator of
ketoacidosis and comparison with other studies a challenge.
More recently, a study comparing urine ketone assessment
with capillary blood ketone measurement in the diagnosis of
ketoacidosis (defined as glucose ≥14 mmol/l, anion gap > 10
mmol/l, bicarbonate < 18 mmol/l and pH < 7.3 mmol/l)
found that capillary blood ketone had a 98% sensitivity and
78.6% specificity compared with a urine dipstick sensitivity
of 98.1% and a specificity of 35.1% for ketoacidosis [30].
The proposed capillary blood ketone threshold of 1.5 mmol/l
in that study, however, again contrasts with other studies
that set a higher threshold of BHOB for the diagnosis of
ketoacidosis of > 3 mmol/l and, in addition, the study
recommended an optimum threshold of 2 mmol/l on
receiver–operator curve analysis. This highlights the diffi-
culty in comparing studies with differences in the definition
of ketoacidosis and proposed thresholds. The similar sensi-
tivities found for capillary blood ketone and urine testing
may mean that a negative urine dipstick remains a valuable
test in excluding ketoacidosis.
The above-mentioned studies show that blood ketone
measurement has a role to play in the diagnosis of ketoac-
idosis, with high positive predictive values at some thresh-
olds. Further work is needed to address the lack of consensus
on a diagnostic threshold, the wide intra- and inter-individ-
ual variability of the test and the heterogeneity of study
design, which currently make the data difficult to interpret
for clinical practice. This difficulty is further compounded by
the variable levels of capillary blood ketone in people with
hyperglycaemia and euglycaemia without ketoacidosis [31].
The literature suggests there is superior utility in serum
ketone or capillary blood ketone assessment compared with
18
urine ketone assessment, and that the latter, although equally
sensitive in diagnosing ketoacidosis, may be more valuable in
excluding it and has lower specificity [6,32–34]. It is worth
considering that the two methods of measurement reflect not
only different ketone bodies, but also variable time points,
and discrepancies between urine and blood ketones will
reflect either resolving ketonaemia (urine ketones high, but
capillary blood ketone normal), or incipient ketoacidosis
(high capillary blood ketone, with undetectable urine
ketones) [35]. Furthermore, although capillary blood ketone
is superior to urine ketone assessment, it is unclear if it is
the best method to diagnose ketoacidosis in a patient with
haemoconcentration, as laboratory testing is the ‘gold
standard’ and could be used as a diagnostic test to support
a positive urine dipstick. Whatever the sensitivity and
specificity of capillary blood ketone measurement, the
provision of a laboratory-based reference method, through
which higher levels can be diluted, must be available as is the
case with glucose. If the limitations of bedside ketone meters
are fully appreciated, laboratories can be mobilized to
provide alternative methods. Whilst these are not widely
available at present, further research into the area will enable
a case to be made at a local level.
Assessing the severity of ketoacidosis
Although there may be an emerging role for ketone assess-
ment in the diagnosis or identification of ketoacidosis, its role
in the assessment of severity of ketoacidosis is more
controversial. Serum BOHB levels have been correlated with
serum bicarbonate with a modest association; Sheikh-Ali
et al. [9] found a correlation coefficient (r = 0.8) between
initial serum bicarbonate and BOHB in adults, and Fulop
et al. [36] prospectively measured serum BOHB levels from
patients with ketoacidosis and compared them with serum
bicarbonate levels (r = 0.69), anion gap (r = 0.52) and
arterial pH (r = 0.38). The correlations using only initial
measurement of BOHB were weaker suggesting that BOHB
measurements should not be routinely used to assess initial
ketoacidosis severity. Glucose levels are also poorly corre-
lated to BOHB levels [37]. The correlation between capillary
blood ketone and ketoacidosis severity at time of presenta-
tion in 54 patients [30] was substantially weaker, with
correlation coefficients between capillary blood ketone and
pH, bicarbonate and anion gap of 0.33, 0.25 and 0.16,
respectively. Along with other studies [34,38], these findings
suggest capillary blood ketone values cannot reliably assess
ketoacidosis severity.
The guidance from the Joint British Diabetes Society
suggests the presence of biochemical variables such as blood
(capillary or serum unspecified) ketones > 6 mmol/l, bicar-
bonate < 5 mmol/l, pH level < 7.1 or anion gap > 16 mmol/l
should prompt referral to a high dependency unit [10];
however, the poor correlation between BOHB and the other
markers of severity, suggests that capillary blood ketone
ª 2014 The Authors.
Diabetic Medicine ª 2014 Diabetes UK
 Review article
should not be used to guide the level of care, particularly
when the precision of capillary blood ketone measurement is
lost above 3 mmol/l, making the value of 6 mmol/l difficult
to assess in the absence of laboratory confirmation. Other
clinical variables outlined in Joint British Diabetes Societies
guidance [10], such as urine output, haemodynamic stability,
Glasgow Coma score and airway protection may be more
important determinants of level of care.
Monitoring for resolution of ketoacidosis
It is unclear which variables should be monitored to assess
resolution of ketoacidosis. The Joint British Diabetes Soci-
eties guidance states that capillary blood ketones should be
measured serially, while traditionally, pH, bicarbonate, urine
ketones and glycaemia have all been used [10]. The latter is
now considered less of an indicator because of the recogni-
tion of euglycaemic ketoacidosis and because suppression of
lipolysis may require more insulin than is needed to restore
euglycaemia. The limitations of urine ketones have already
been discussed and centre on the paradoxical increase in
urine ketones (AcAc) during ketoacidosis resolution. Several
studies have considered the use of capillary blood ketone to
track ketoacidosis resolution and determine when i.v. insulin
can be switched to s.c. insulin or when patients can be
discharged [17,39].
A small study measured serum BOHB (4-hourly), capillary
blood ketone (hourly) and urine ketones in the resolution of
ketoacidosis, and compared their current endpoint (pH > 7.3
and urine ketones negative) to a proposed new endpoint (pH
> 7.3 and two successive capillary blood ketone < 1 mmol/l),
in a paediatric population with ketoacidosis [8]. Out of 11
samples that had laboratory BOHB values > 6 mmol/l, only
three were reported as ‘Hi’ on the capillary blood ketone
meter, with the remaining reported between 1 and 7 mmol/l
lower than the actual value. The study found a median lag
time of 11 h between their current endpoint for cessation of
i.v. insulin and the proposed capillary blood ketone end-
point, with the latter allowing earlier discharge from a high
dependency unit, suggesting a role for capillary blood ketone
measurement in a paediatric population; however, earlier
discharge was dependent on hourly sampling for ketones, a
resource-intensive exercise.
In another paediatric study comparing serial measure-
ments of capillary blood ketone with serum BOHB and
other biochemical variables such as pH and bicarbonate, a
good correlation was shown between capillary blood
ketone and resolution of ketoacidosis [40]. Uncoupling of
this relationship was observed at higher BOHB concentra-
tions, which may also account for the discrepancy in levels
of ketones, pH and bicarbonate often encountered at
diagnosis.
Since capillary blood ketones cannot reliably be measured
above 6 mmol/l and may be unreliable above 3 mmol/l, it is
difficult to recommend their use in the monitoring of
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Diabetic Medicine ª 2014 Diabetes UK
DIABETICMedicine
ketoacidosis, particularly if a decrement of 0.5 mmol/l per
h is advised, as the coefficient of variation of the meters may
be beyond this. Unless capillary blood ketone measurements
are routinely confirmed with laboratory serum analysis, the
limitations in this context negate its regular use, for
assessment of severity [41].
Prevention of ketoacidosis
While the utility of capillary blood ketone in the acute setting
may be limited by its poor precision at high values and in the
dehydrated patient, there is a promising role in the outpatient
setting to prevent ketoacidosis. Self-monitoring of ketones at
home aims to increase awareness of possible impending
ketoacidosis, offering patients the opportunity to increase
insulin and reduce ketogenesis during hyperglycaemia [42].
A study of young adults and children as part of ‘sick-day’
management at home [43] randomized participants to either
capillary blood ketone or urine ketone assessment in
conjunction with blood glucose monitoring, after intensive
education [43]. After 6 months of follow-up, the 123
participants were more likely to test capillary blood ketones
than urine ketones (90.8 vs 61.3%) and the capillary blood
ketone group were significantly less likely to be admitted for
hospitalization (38 per 100 patient-years vs 75 per 100
patient-years). The outcome in this study was hospital
admission for any cause and not diagnosis of ketoacidosis,
so it cannot be concluded that capillary blood ketone
assessment prevented ketoacidosis. Of the 33 hospital
admissions recorded, the vast majority were related to
hyperglycaemia or ‘metabolic derangement’ but some were
also attributable to hypoglycaemia. While the majority of
participants preferred capillary blood ketone testing to urine
testing, further work is needed to determine if the cost
incurred from providing routine outpatient capillary blood
ketone testing offsets the financial burden of hospital
admission. However, although patient acceptability is an
important factor, if patients complied equally with urine and
capillary blood ketone testing, the difference in hospitaliza-
tion may diminish.
Another study analysed the utility of capillary blood
ketone assessment in an outpatient setting in 15 patients and
found that, in the absence of intercurrent illness, capillary
blood ketone measurements did not exceed 1 mmol/l in spite
of glucose levels up to 33.1 mmol/l [15]. In individuals with
intercurrent illness some individuals noted levels of capillary
blood ketone > 1 mmol/l; however, self-monitoring
prompted increases in insulin dosage and resolution of
ketonaemia. A similar paediatric study examined capillary
blood ketone levels in children with Type 1 diabetes, and
suggested that levels above 0.4 mmol/l should be considered
abnormal [31]. These studies suggest a preventative role for
capillary blood ketone measurement, and larger randomized
studies are required to confirm these findings. Other studies
have examined the role of capillary blood ketone
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DIABETICMedicine Ketone measurement in diabetic ketoacidosis  S. Misra and N. S. Oliver
measurement in detecting interruptions of continuous s.c.
insulin infusion in patients on insulin pump therapy [44].
Sick-day diabetes management requires serial measure-
ment of blood glucose, and ketone measurement provides a
useful adjunct to assessment of glucose in the hyperglycaemic
state but is in no way a substitute. A measure of ketosis in
hyperglycaemia can help to differentiate hyperglycaemia
secondary to a carbohydrate and insulin mismatch from
evolving insulin deficiency. Whilst trends of capillary blood
ketone may be useful, a single reading which may be falsely
high or low could provide false reassurance or cause anxiety
and it is unclear how often capillary blood ketones should be
measured. Ketonuria assessment has limitations but does at
least confirm ketosis over a time period of hours.
It is critical that intensive education accompanies self-mon-
itoring of capillary blood ketones and the added value of
home capillary blood ketone monitoring, in addition to
intensive and structured diabetes education, should be
considered. In the absence of continuing clinical support
there is a risk that home capillary blood ketone testing may
paradoxically increase hospital attendance in patients who
would otherwise self-manage hyperglycaemia. Ketonuria
testing at least, on sick-days with input from specialist
nurses, was shown to potentially reduce admissions, but
capillary blood ketone may also be useful in this context
[45]. Results are awaited on a large study comparing urine
and blood ketone assessment in young people with Type 1
diabetes, although preliminary results suggest the latter may
improve glycaemic control in insulin pump treatment [46].
Cost-effectiveness of capillary blood ketone measurement
The availability of point-of-care technology represents an
exciting technological development, and is often proposed to
be cheaper in the long term than laboratory-based alterna-
tives; however, this argument may not hold true for ketone
assessment as routine laboratory-based analysis is seldom
undertaken. Evidence suggests potential cost-saving in its use
vs urine ketone testing in a paediatric intensive care setting.
Thirty three children with severe ketoacidosis were random-
ized to be monitored either with hourly capillary blood
ketone or urine ketone assessment. The capillary blood
ketone group cleared ketosis between 4 and 9.5 h earlier
than the ketonuria group, meaning an earlier discharge from
the intensive care unit and a saving of nearly 3000 Euros
[47]. Nearly half of the children in the urine monitoring
group, however, did not produce any urine because of
dehydration. In addition, in that study, a good correlation
was found between resolving ketonaemia, pH and glucose
levels. One could therefore argue that resolution of acidosis
and hyperglycaemia could be justifiable endpoints without
incurring the excess cost of ketone measurement.
Calculations of ketone measurement cost-effectiveness
need to take into account the potential cost of providing
20
ketone-testing strips to people with Type 1 diabetes against
the cost of urine ketone strips, which are almost 10 times
cheaper and may be used less frequently. The potential
savings from preventing admission may offset this cost but
we do not yet have these data.
Large, well-designed studies are needed to assess conclu-
sively the utility of capillary blood ketone measurement and
to determine the cost-effectiveness of such an approach. In an
inpatient setting, studies to date suggest that capillary blood
ketone measurement may facilitate early discharge from
higher dependency environments in paediatric patients, and
may be a cost-effective tool; however, the provision of
laboratory-based serum ketone measurement into these
cost-analyses must also be included.
Discussion
As ketones are the primary derangement in ketoacidosis,
their measurement is a logical step to take in unwell people
with diabetes, but clinical practice has jumped an important
step by attempting to validate the test in a point-of-care
capacity before fully appreciating its value with precise
laboratory measurement. Multiple clinical applications are
increasingly reported, with no consensus on thresholds or
frequency of measurement.
Capillary blood ketone measurement represents an ana-
lytical and technological advance on traditional qualitative
or semi-quantitative urine ketone measurement, with many
potential applications. The evidence base evaluating poin-
t-of-care ketone measurements in ketoacidosis is still in its
infancy, with heterogeneous studies published, a paucity of
high-quality randomized diagnostic accuracy studies and
limited data on whether changes in diagnostic accuracy
impact on patient outcome, a common issue when new tests
are introduced [48]. The studies reviewed have been con-
ducted over the last 20 years, with some evaluating early
versions of ketone meters that have now been superseded by
next-generation devices that may or may not be more
accurate. This aspect of the evidence base warrants further
consideration. It is worth questioning why so few studies
have robustly assessed utility. This may reflect the regulatory
frameworks for devices, which do not require efficacy data
for marketing (in contrast to that for medicines), and only
assess safety and minimum performance standards; however,
diagnostic tests in general are commonly inadequately
assessed and proposals to ensure high-quality evaluation
exist, but are not routinely followed [49].
Despite the technological advances, deciding if capillary
blood ketone is a clinically useful improvement needs further
study and, until studies that formally assess clinical utility are
undertaken with associated laboratory measurements that
can provide robust transferable reference ranges, there will
remain confusion over its use, diminishing its value and
implementation.
ª 2014 The Authors.
Diabetic Medicine ª 2014 Diabetes UK
 Review article
For the diagnosis of ketoacidosis, studies are conflicting,
with some showing good correlation of capillary blood
ketones with other biochemical variables such as bicarbonate
and pH levels, whilst others are more limited. Since caution
should be exercised when measuring capillary blood ketones
in dehydrated patients, who are invariably volume-depleted
and have haemoconcentration, the validity of using capillary
blood ketones alone as the measure of ketosis to diagnose
ketoacidosis is questionable. Until there are consensus
criteria on the definition of ketoacidosis and an appropriate
and evidence-based capillary blood ketone threshold, it will
be difficult to design and carry out appropriately powered
prospective studies.
One of the biggest limitations hindering routine use of
capillary blood ketones lies in the poor precision above
3 mmol/l. Ketone levels above this threshold may falsely
underestimate ketonaemia and levels starting above 3 mmol/l
at diagnosis, cannot be reliably tracked for improvements in
ketonaemia as advised in Joint British Diabetes Societies
guidance. This single issue impedes routine use of capillary
blood ketone in ketoacidosis in the absence of labora-
tory-based corroborative analysis. Ketone assessment is,
however, one variable used to diagnose ketoacidosis, and it
could be argued that as long as the above limitations are
considered there is still a place for capillary blood ketone
assessment. Uptake of Joint British Diabetes Societies guid-
ance in the UK has been widespread and it is therefore
important that all clinical users are aware of the pros and cons
of the test [50].
In the same way that glucometers are not routinely used to
diagnose diabetes, but are corroborated with plasma glucose
measurement, capillary blood ketone measurement without
concomitant serum assessment cannot be advocated.
Although many studies show a reasonable correlation
between capillary blood ketones and serum BOHB, this
relationship is uncoupled at values above 3 mmol/l. These
limitations need to be understood by clinical staff undertak-
ing the test and all staff require a suitable level of training to
carry out these tests.
Given the lower concentrations of BOHB involved and the
reduced need for rigid thresholds, the most promising utility
for capillary blood ketone assessment lies in self-management
and ketoacidosis prevention, just as capillary blood glucose
measurement is most potent for self-management, and this
warrants further investigation. Intensive diabetes education
to empower self-management, is often the most useful tool in
preventing ketoacidosis and it will be difficult to delineate the
effects of this from capillary blood ketone testing.
Conclusion
There is undoubtedly a role for the use of capillary blood
ketone assessment in the diagnosis, management and pre-
vention of ketoacidosis, but the heterogeneous studies, often
non-randomized, incorporating small numbers with conflict-
ª 2014 The Authors.
Diabetic Medicine ª 2014 Diabetes UK
DIABETICMedicine
ing results, means that there is a lack of clarity about how
the technology should be applied and what the result means
or offers above more routinely available methods. The
routine use of capillary blood ketones in the absence of a
concomitant laboratory service is not ideal and there is a
danger that a simple point-of-care urine ketone test with
well-known limitations is being replaced with another test
in which limitations are not widely appreciated. Exact
guidance on clinical usage is lacking consensus and a firm
evidence base, and, until these are available, capillary blood
ketone measurement should be used and interpreted with
caution.
Funding sources
None.
Competing interests
None declared.
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