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Current
Diabetes Reviews
ISSN: 1573-3998
Current Diabetes Reviews
Volume 4, Number 3, August 2008
Contents
Continuous Glucose Monitoring Systems: Toys or Tools
Guest Editor: Christophe De Block
Editorial Pp. 157-158
Minimally-Invasive and Non-Invasive Continuous Glucose Monitoring
Systems: Indications, Advantages, Limitations and Clinical
Aspects Pp. 159-168
Christophe De Block, Jan Vertommen, Begoña Manuel-y-Keenoy
and Luc Van Gaal
[Abstract]
Implantable Continuous Glucose Sensors
Pp. 169-174
Eric Renard
[Abstract]
Continuous Glucose Monitoring: Physiological
and Technological Challenges Pp. 175-180
Gérard Reach and Carine Choleau
[Abstract]
Continuous Glucose Monitoring Time Series and
Hypo/Hyperglycemia Prevention: Requirements, Methods, Open
Problems Pp. 181-192
Giovanni Sparacino, Andrea Facchinetti, Alberto Maran
and Claudio Cobelli
[Abstract]
Evaluating Clinical Accuracy of Continuous Glucose
Monitoring Systems: Continuous Glucose –Error Grid Analysis
(CG-EGA) Pp. 193-199
William L. Clarke, Stacey Anderson and Boris Kovatchev
[Abstract]
Evaluating Clinical Accuracy of Continuous Glucose
Monitoring Devices: Other Methods Pp. 200-206
Iris M.E. Wentholt, August A. Hart, Joost B.L. Hoekstra
and J. Hans DeVries
[Abstract]
Use of Continuous Glucose Monitoring in Patients
with Type 1 Diabetes Pp. 207-217
Samuel L. Ellis, Ramachandra G. Naik, Kate Gemperline
and Satish K. Garg
[Abstract]
Clinical Use of Real-Time Continuous Glucose
Monitoring Pp. 218-222
Tadej Battelino and Jan Bolinder
[Abstract]
Continuous Glucose Monitoring: Is it Helpful
in Pregnancy? Pp. 223-226
Elizabeth Z. Byrne, Howard C. Zisser and Lois Jovanovic
[Abstract]
The Importance of Strict Blood Glucose Control
with Insulin Therapy in the Intensive Care Unit Pp.
227-233
Ingeborg van den Heuvel, Ilse Vanhorebeek and Greet Van
den Berghe
[Abstract]
Glucose Control and Use of Continuous Glucose
Monitoring in the Intensive Care Unit: A Critical Review
Pp. 234-244
Christophe De Block, Begoña Manuel-y-Keenoy, Peter
Rogiers, Philippe Jorens and Luc Van Gaal
[Abstract]
Hyperglycaemia and the Ischaemic Brain: Continuous
Glucose Monitoring and Implications for Therapy Pp.
245-257
Louise E. Allport, Tracey A. Baird and Stephen M. Davis
[Abstract]
Algorithms for Intravenous Insulin Delivery Pp. 258-268
Susan S. Braithwaite and Stephen Clement
[Abstract]
The Future of Continuous Glucose Monitoring: Closed Loop
Pp. 269-279
Roman Hovorka
[Abstract]
Abstracts
[Back to top]
Editorial: Translating Continuous Glucose Monitoring
Systems: Toys or Tools
Diabetic complications can be reduced by achieving
good metabolic control, which for insulin-requiring diabetic
subjects, requires frequent self-monitoring of blood glucose
(SMBG). However, SMBG represents only a snapshot of the glucose
concentration and it does not provide trend information, nor
does it reflect glycaemic fluctuations. In contrast, accurate
and reliable devices sensing glucose on a (near)-continuous
basis provide information about the direction, magnitude,
duration, frequency of glycaemic fluctuations, and may facilitate
specific therapeutic adjustments that need to be made to avoid
hypo- and hyperglycaemic excursions, thereby improving metabolic
control. Particularly patients with brittle diabetes, hypoglycaemia
unawareness, gastroparesis, pregnant women, or pump users,
who are motivated to participate in their diabetes care and
are technologically adept, may benefit from continuous glucose
monitoring (CGM).
In this special issue of Current Diabetes Reviews,
leading researchers review the current evidence for CGM. This
issue begins with a review of the indications, advantages,
technical and clinical aspects of minimally invasive (needle-type
glucose electrodes, and microdialysis-based systems), and
non-invasive CGM sensors [1]. Next, an overview is given of
fully implantable glucose monitoring systems (IGMS) (e.g.
I.V. sensors for hospital use, e.g. ICU) [2]. Long-term use
reducing impact of invasiveness due to implantation, less
frequent calibration needs because of a more stable tissue
environment around the sensor and potential easier inclusion
in a closed-loop insulin delivery system are the expected
benefits of IGMS.
Although CGM systems may represent a breakthrough for glucose
monitoring, the patient and the treating physician must be
aware of the limitations of current CGM systems, that originate
from physiological and technical aspects. Most of the systems
monitor invasively glucose in the subcutaneous tissue. It
is important to realize that there are discrepancies between
blood and interstitial glucose concentration, which may affect
the quality of the system calibration and thereby the accuracy
of the data, as reviewed in the next article [3].
A clinically important task in diabetes management is the
prevention of hypo/hyperglycemic events, as discussed in the
next manuscript. By complex mathematical trend analysis, real-time
CGM sensors can serve as a tool to predict impending glucose
excursions for 20-30 minutes ahead, thereby providing alarm
signals of hypo- and hyperglycaemic values warning the patient
to take preventative actions [4].
The next two papers review criteria for evaluation of CGM
accuracy and clinical performance. Clarke et al.
describe the Continuous Glucose-Error Grid Analysis (CG-EGA),
which reports point- and rate-accuracy for each of the relevant
glycemic ranges; hypo-, eu-, and hyperglycemia [5]. Wentholt
et al. discuss pros and cons of other methods to
analyse accuracy, including regression analysis and correlation
coefficient, relative difference measures, Bland Altman plot,
ISO criteria, combined curve fitting, and epidemiological
analyses. In this paper, recommendations for much needed head-to-head
studies are given [6].
Next, three papers critically review the current clinical
evidence of CGM sensors in type 1 diabetes and in diabetic
pregnancy [7-9]. As written, only a few short-term randomized
controlled trials using real-time CGM have provided us with
evidence in favour of improved metabolic control, reductions
in HbAic, reductions in hypo-
and hyperglycaemic episodes, and improved quality-of-life
[7,8]. In a mini-review, the likely advantages of using CGM
in pregnancy, aiming to improve a patient’s overall
glucose profile, thereby decreasing the risks of poor fetal
outcomes, are described [9].
The next three papers review the importance of strict blood
glucose control in critically ill patients [10-12]. Implementation
of a strict glycemic control protocol, which is primordial
to obtain normoglycemia, in the intensive care unit is feasible
and cost-effective, but asks for careful consideration of
some practical aspects, such as prevention of hypoglycaemia,
training of nurses and selection of accurate blood glucose
measurement tools. CGM devices and closed-loop systems are
being developed and might be of great benefit to overcome
these issues. Novel insights into post-stroke hyperglycaemia
derived from CGM are also discussed in greater detail [12].
In a next article, Braithwaite et al. describe algorithms
for intravenous insulin infusion [13]. Specific distinguishing
algorithm design features and choice of parameters may be
important to establish freedom from hypoglycemia, eliminate
the need for administration of concentrated dextrose during
euglycemia, control variability within the treatment course
of individual patients, achieve adaptability to differing
blood glucose targets, and minimize variability of glycemic
control between treatment courses of different patients or
patient populations. Areas for future work include the reduction
of nursing burden, the development of a theory that will account
for lag time of interstitial monitoring and pharmacodynamic
delay of insulin action, and management strategies for the
narrow euglycemic range [13].
The last article of this hot topic issue focuses on the future
applications of CGM sensors, namely the incorporation of CGM
in a closed-loop [14]. Closed-loop systems consist of a CGM
system, a control algorithm, and an insulin pump, and can
be divided according the way they handle meal delivery into
“fully closed-loop” or “closed-loop with
meal announcement” systems. Given the current research
focus, this review centres on the scsc closed-loop approach,
which has the greatest potential for a near-future commercial
exploitation as recognised by the JDRF-funded Artificial Pancreas
Project. Other approaches utilising intraperitoneal or intravenous
sensing/delivery are also discussed. The most important question
is what is achievable with existing technologies now and when
the first generation of closed-loop systems will find its
way into the clinical practice.
In conclusion, a broad overview of current evidence and practice
with CGM is given. If a CGM system would prove to be accurate,
reliable under different conditions and with sufficient longevity
under daily life conditions, these “toys” may
become “tools” and could reduce the incidence
of long-term diabetic complications, may reduce hospitalisations
due to diabetic ketoacidosis or due to hypoglycemic coma,
and their associated economic costs. If all this would prove
to be the case, then CGM systems are cost-efficient as well,
and will be reimbursed by several health care systems. If
a reliable and long-lasting CGM system could be used in the
future to construct a (semi-) closed loop system, a step towards
the artificial pancreas, this would represent a major breakthrough
in diabetes care.
Keywords: Continuous glucose monitoring,
Diabetes
Abbreviations: CGM: Continuous glucose monitoring,
SMBG: Self-monitoring of blood glucose
REFERENCES
[1] De Block C, Vertommen J, Manuel-y-Keenoy B, Van Gaal L.
Minimally-invasive and non-invasive continuous glucose monitoring
systems: indications, advantages, technical and clinical aspects.
Curr Diabetes Rev 2008; 3: 159-168
[2] Renard E. Implantable continuous glucose sensors. Curr
Diabetes Rev 2008; 3: 169-174.
[3] Reach G, Choleau C. Continuous glucose monitoring: physiological
and technological challenges. Curr Diabetes Rev 2008; 3: 175-180.
[4] Sparacino G, Facchinetti A, Maran A, Cobelli C. Continuous
glucose monitoring time series and hypo/hyperglycemia prevention:
requirements, methods, open problems. Curr Diabetes Rev 2008;
3: 181-192.
[5] Clarke WL, Anderson S, Kovatchev B. Evaluating clinical
accuracy of continuous glucose monitoring devices: continuous-glucose
error-grid analysis. Curr Diabetes Rev 2008; 3: 193-199.
[6] Wentholt IME, Hart AA, Hoekstra JBL, deVries JH. Evaluating
clinical accuracy of continuous glucose monitoring devices:
other methods. Curr Diabetes Rev 2008; 3: 200-206.
[7] Ellis SL, Naik RG, Gemperline K, Garg SK. Use of continuous
glucose monitoring in patients with type 1 diabetes. Curr
Diabetes Rev 2008; 3: 207-217.
[8] Battelino T, Bolinder J. Clinical use of real-time continuous
glucose monitoring. Curr Diabetes Rev 2008; 3: 218-222.
[9] Byrne EZ, Zisser HC, Jovanovic L. Continuous glucose monitoring:
is it helpful in pregnancy? Curr Diabetes Rev 2008; 3: 223-226.
[10] van den Heuvel I, Vanhorebeek I, Van den Berghe G. The
importance of strict blood glucose control with insulin therapy
in the intensive care unit. Curr Diabetes Rev 2008; 3: 227-233.
[11] De Block C, Manuel-y-Keenoy B, Rogiers P, Jorens P, Van
Gaal L. Glucose control and use of continuous glucose monitoring
in the intensive care unit: a critical review. Curr Diabetes
Rev 2008; 3: 234-244.
[12] Allport LE, Baird TA, Davis SM. Hyperglycaemia and the
ischaemic brain: continuous glucose monitoring and implications
for therapy. Curr Diabetes Rev 2008; 3: 245-257.
[13] Braithwaite SS, Clement S. Algorithms for intravenous
insulin delivery. Curr Diabetes Rev 2008; 3: 258-268.
[14] Hovorka R. The future of continuous glucose monitoring:
closed loop. Curr Diabetes Rev 2008; 3: 269-279
Dr. Christophe De Block
Department of Endocrinology-Diabetology
Antwerp University Hospital (UZA), Wilrijkstraat 10
B-2650 Edegem
Belgium
Tel: 32–3–821.32.75
Fax: 32–3–825.49.80
E-mail: christophe.deblock@ua.ac.be
or christophe.de.block@uza.be
[Back to top]
Minimally-Invasive and Non-Invasive Continuous Glucose Monitoring
Systems: Indications, Advantages, Limitations and Clinical
Aspects
Christophe De Block, Jan Vertommen, Begoña Manuel-y-Keenoy
and Luc Van Gaal
Accurate and reliable devices sensing glucose on a (near)-continuous
basis may facilitate specific therapeutic adjustments that
need to be made to avoid hypo- and hyperglycaemic excursions,
thereby improving metabolic control. Current continuous glucose
monitoring (CGM) systems indicate the glucose level, the direction
and magnitude of change of glucose levels, and can be used
to assess glycaemic variability. In addition, real-time CGM
sensors can serve as a tool to predict impending glucose excursions,
thereby providing alarm signals of hypo- and hyperglycaemic
values warning the patient to take preventative actions. Quality
of life may also improve by using CGM via reducing
the fear of hypo-glycaemia.
Particularly patients with brittle diabetes, hypoglycaemia
unawareness, gastroparesis, pregnant women, or pump users,
who are motivated to participate in their diabetes care and
are technologically adept, may benefit from CGM.
However, to successfully implement CGM in daily practice,
these devices must be accurate and reliable, and one must
be aware of the limitations of current CGM systems, that originate
from physiological and technical aspects. Whether CGM succeeds
in improving metabolic control, reducing hypoglycaemic episodes,
and improving quality of life in the majority of patients
remains to be proven. Should this be the case, real-time CGM
may reduce chronic diabetic complications, and avoid hospitalisations,
thereby reducing health care costs.
In this article we will review indications, advantages, limitations,
clinical and technical aspects of current minimally-invasive
and non-invasive CGM sensors.
[Back to top]
Implantable Continuous Glucose Sensors
Eric Renard
Department, Lapeyronie Hospital, CHU Montpellier, and
CNRS UMR 5232, Montpellier, France Abstract: Because of the
limits of wearable needle-type or microdialysis-based enzymatic
sensors in clinical use, fully implantable glucose monitoring
systems (IGMS) represent a promising alternative. Long-term
use reducing impact of invasiveness due to implantation, less
frequent calibration needs because of a more stable tissue
environment around the sensor and potential easier inclusion
in a closed-loop insulin delivery system are the expected
benefits of IGMS. First ex-periences with subcutaneous and
intravenous IGMS have been recently collected in pilot studies.
While no severe adverse events have been reported, biointerface
issues have been responsible for the failures of IGMS. Tissue
reactions around implanted subcutaneous devices and damages
of intravenous sensors due to shearing forces of blood flow
impaired IGMS function and longevity. In functioning systems,
accuracy of glucose measurement reached satisfactory levels
for average durations of about 120 days with subcutaneous
IGMS and 259 days with intravenous sensors. Moreover, sensor
information could help to improve time spent in normal glucose
range when provided to patients wearing subcutaneous IGMS
and allowed safe and effective closed-loop glucose control
when intravenous sensors were connected to implanted pumps
using intra-peritoneal insulin delivery. These data could
open a favourable perspective for IGMS after improvement of
bio-interface conditions and if compatible with an affordable
cost.
[Back to top]
Continuous Glucose Monitoring: Physiological and Technological
Challenges
Gérard Reach and Carine Choleau
Over the past decade, several continuous glucose monitoring
systems have been developed, representing remarkable technological
achievements. Most of the systems monitor glucose invasively
in the subcutaneous tissue. It is important to realize that
there are discrepancies between blood and interstitial glucose
concentration, which (1) may impact the quality of the system
calibration and thereby the accuracy of the data, (2) may
jeopardize the specificity and the sensitivity of hypoglycaemic
alarms based on these systems and (3) must be considered in
the design of closed-loop insulin delivery systems. The aim
of this review is to make the point that the challenge of
developing a continuous glucose monitoring system is not only
technological, but must also take into account the physiology
of glucose in alternate sites where it is sensed.
[Back to top]
Continuous Glucose Monitoring Time Series and Hypo/Hyperglycemia
Prevention: Requirements, Methods, Open Problems
Giovanni Sparacino, Andrea Facchinetti, Alberto Maran
and Claudio Cobelli
A clinically important task in diabetes management is
the prevention of hypo/hyperglycemic events. The availability
of continuous glucose monitoring (CGM) devices allow to develop
new strategies, but new problems have also emerged. In this
contribution, we discuss three major challenges which, in
practical real time CGM applications, should be dealt with:
filtering to enhance the signal-to-noise ratio, ahead-of-time
prediction of glucose concentration, and generation of hypo/hyper-alerts.
For all these challenges, some techniques, with a different
degree of sophistication, have been proposed recently in the
literature, but several issues remain open.
[Back to top]
Evaluating Clinical Accuracy of Continuous Glucose Monitoring
Systems: Continuous Glucose –Error Grid Analysis (CG-EGA)
William L. Clarke, Stacey Anderson and Boris Kovatchev
Continuous Glucose Sensors (CGS) generate rich and informative
continuous data streams which have the potential to improve
the glycemic condition of the patient with diabetes. Such
data are critical to the development of closed loop systems
for automated glycemic control. Thus the numerical and clinical
accuracy of such must be assured.
Although numerical point accuracy of these systems has been
described using traditional statistics, there are no requirements,
as of yet, for determining and reporting the rate (trend)
accuracy of the data generated. In addition, little attention
has been paid to the clinical accuracy. of these systems.
Continuous Glucose-Error Grid Analysis (CG-EGA) is the only
method currently available for assessing the clinical accuracy
of such data and reporting this accuracy for each of the relevant
glycemic ranges, - hypoglycemia, euglycemia, hyperglycemia.
This manuscript reviews the development of the original Error
Grid Analysis (EGA) and describes its inadequacies when used
to determine point accuracy of CGS systems. The development
of CG-EGA as a logical extension of EGA for use with CGS is
described in detail and examples of how it can be used to
describe the clinical accuracy of several CGS are shown. Information
is presented on how to obtain assistance with the use of CG-EGA.
[Back to top]
Evaluating Clinical Accuracy of Continuous Glucose Monitoring
Devices: Other Methods
Iris M.E. Wentholt, August A. Hart, Joost B.L. Hoekstra
and J. Hans DeVries
With more and more continuous glucose monitoring devices
entering the market, the importance of adequate accuracy assessment
grows. This review discusses pros and cons of Regression Analysis
and Correlation Coefficient, Relative Difference measures,
Bland Altman plot, ISO criteria, combined curve fitting, and
epidemiological analyses, the latter including sensitivity,
specificity and positive predictive value for hypoglycaemia.
Finally, recommendations for much needed head-to-head studies
are given. This paper is a revised and adapted version of
How to assess and compare the accuracy of continuous
glucose monitors?, Diabetes Technology and Therapeutics
2007, in press, published with permission of the editor.
[Back to top]
Use of Continuous Glucose Monitoring in Patients with Type
1 Diabetes
Samuel L. Ellis, Ramachandra G. Naik, Kate Gemperline
and Satish K. Garg
The prevalence of type 1 diabetes continues to increase
worldwide at a rate higher than previously projected, while
the number of patients achieving American Diabetes Association
(ADA) glycated hemoglobin (A1c) goals remains suboptimal.
There are numerous barriers to patients achieving A1c targets
including increased frequency of severe hypo-glycemia associated
with lowering plasma glucose as measured by lower A1c values.
Continuous glucose monitoring (CGM) was first approved for
retrospective analysis and now has advanced to the next step
in diabetes management with the approval of real-time glucose
sensing. Real-time CGM, in short term studies, has been shown
to decrease A1c values, improve glucose variability (GV),
and minimize the time and number of hypoglycemic events in
patients with type 1 diabetes. These products are approved
for adjunctive use to self-monitoring of blood glucose (SMBG),
but future long-term studies are needed to document their
safety, efficacy, ability to replace SMBG as a tool of monitoring,
and ultimately utility into closed-loop insulin delivery systems.
New algorithms will need to be developed that account for
rapid changes in the glucose values, so that accuracy of the
sensor data can be maintained. In addition, for better clinical
care and usage, algorithms also need to be developed for both
patients and the providers to guide them for their ongoing
diabetes care.
[Back to top]
Clinical Use of Real-Time Continuous Glucose Monitoring
Tadej Battelino and Jan Bolinder
Maintaining near-normal glycaemia in all patients with
diabetes mellitus (DM) has become a standard and a well accepted
recommendation. Unfortunately, most people with DM do not
achieve this clinical goal because of marked glycaemic fluctuations
and hypoglycaemia. Real-time continuous glucose monitoring
(RT-CGM) has been introduced recently into clinical practice
offering more knowledge about current glucose concentration
and trend and enabling people with DM to intervene and prevent
unwanted glucose excursions by acting upon real-time and predictive
alarms.
Several RT-CGM devices proved to be sufficiently accurate
and feasible for routine use. Observational reports with The
Guardian and Paradigm RT by Medtronic, the STS by DexCom,
FreeStyle Navigator by Abbott and GlucoDay by Menarini established
initial clinical benefit. Five randomised controlled trials
(RCT) demonstrated significantly improved glucose variability
or metabolic control, one of them showing a statistically
significant and clinically meaningful decrease of HbA1c with
a 3 months use of the Guardian RT (Medtronic, Northridge,
CA).
The great potential of RT-CGM devices to improve daily glucose
control and quality of life in people with DM can only be
developed further through RCTs, clarifying in more details
the optimal clinical use and the most beneficial indications
for this novel technique.
[Back to top]
Continuous Glucose Monitoring: Is it Helpful in Pregnancy?
Elizabeth Z. Byrne, Howard C. Zisser and Lois Jovanovic
The effects of diabetes in pregnancy were first noticed
in the beginning of the 19th
century. Today approximately seven percent of all pregnancies
in the United States are affected by gestational diabetes.
Since becoming more knowledgeable of the disease, the medical
community has developed diagnostic criteria for detecting
gestational diabetes and has created treatment options for
lowering the risk of adverse fetal outcomes. A pregnancy affected
by diabetes is associated with macrosomia, fetal malformations,
spontaneous preterm delivery, and labor complications. These
risks can be minimized by tight glycemic control through diet,
insulin, and attentive monitoring of blood glucose levels.
Although most pregnant diabetic women currently monitor their
diabetes using self-monitoring blood glucose, the technology
of continuous glucose monitoring (CGM) offers a myriad of
benefits. This mini-review looks at the advantages of using
CGM in pregnancy which includes decreasing the risks of poor
fetal outcomes, improving a patient’s overall glucose
profile, helping start or adjust insulin treatment, adjusting
current screening protocol and developing a normoglycemic
target for gestational diabetic women to aim for during their
pregnancy. With the use of CGM, the complications of diabetic
pregnancies first seen nearly two centuries ago will become
a problem of the past.
[Back to top]
The Importance of Strict Blood Glucose Control with Insulin
Therapy in the Intensive Care Unit
Ingeborg van den Heuvel, Ilse Vanhorebeek and Greet Van
den Berghe
Two randomised controlled trials have shown that maintenance
of blood glucose levels below 110 mg/dl with intensive insulin
therapy reduces mortality and morbidity of surgical and medical
critically ill patients. An absolute reduction in the risk
of death of 3-4 % is expected in intention-to-treat analysis,
but the survival benefit increases when treatment is continued
for at least a few days. Future studies set up to confirm
the survival benefit and assign it as statistically significant
in an intention-to-treat medical patient population should
be adequately powered with inclusion of at least 5000 patients.
For the observed benefits of intensive insulin therapy strict
maintenance of normoglycaemia is primordial, whereas gly-caemia-independent
actions of insulin have minor, organ-specific impact. Pathophysiological
mechanisms underlying the clinical effects are currently being
unravelled further and might help to find new strategies for
further improving outcome.
Implementation of a strict glycemic control protocol in the
intensive care unit is feasible and cost-effective, but asks
for careful consideration of some practical aspects, such
as prevention of hypoglycaemia, training of nurses and selection
of accurate blood glucose measurement tools. Continuous blood
glucose monitoring devices and closed-loop systems are under
development and might be of great benefit to overcome these
issues.
[Back to top]
Glucose Control and Use of Continuous Glucose Monitoring in
the Intensive Care Unit: A Critical Review
Christophe De Block, Begoña Manuel-y-Keenoy, Peter
Rogiers, Philippe Jorens and Luc Van Gaal
Stress hyperglycemia recently became a major therapeutic
target in the Intensive Care Unit (ICU) since it occurs in
most critically ill patients and is associated with adverse
outcome, including increased mortality. Intensive insulin
therapy to achieve normoglycemia may reduce mortality, morbidity
and the length of ICU and in-hospital stay. However, obtaining
normoglycemia requires extensive efforts from the medical
staff, including frequent glucose monitoring and adjustment
of insulin dose. Current insulin titration is based upon discrete
glucose measurements, which may miss fast changes in glycemia
and which does not give a full picture of overall glycemic
control. Recent evidence suggests that continuous monitoring
of glucose levels may help to signal glycemic excursions and
eventually to optimize insulin titration in the ICU.
In this review we will summarise monitoring and treatment
strategies to achieve normoglycemia in the ICU, with special
emphasis on the possible advantages of continuous glucose
monitoring.
[Back to top]
Hyperglycaemia and the Ischaemic Brain: Continuous Glucose
Monitoring and Implications for Therapy
Louise E. Allport, Tracey A. Baird and Stephen M. Davis
Hyperglycaemia following acute stroke is both common
and prolonged, regardless of diabetes status. A substantial
body of evidence, derived from animal and human literature,
has demonstrated that post-stroke hyperglycaemia has a deleterious
effect upon clinical and radiological stroke outcomes. Whether
intensive glycaemic manipulation positively influences the
fate of ischaemic tissue remains to be shown. This article
provides an overview of the prevalence, aetiology, and mechanisms
of tissue injury arising as a result of post-stroke hyperglycaemia,
as well as exploring the evidence from glucose-lowering treatment
trials to date. Additionally, novel insights into post-stroke
hyperglycaemia derived from continuous glucose monitoring
are discussed.
Stroke is a leading cause of death worldwide and the commonest
cause of long-term disability amongst adults. Increasing evidence
suggests that disordered physiological variables following
acute ischaemic stroke adversely affect outcomes. Of these,
post-stroke hyperglycaemia (PSH) is the most frequently recognised
abnormality and is documented in up to 50% of patients at
the time of stroke presentation [1]. Importantly, a significant
proportion of hyperglycaemic acute stroke patients (~50%)
have undiagnosed disorders of glucose metabolism, including
diabetes [2,3]. Animal and human data have repeatedly demonstrated
that PSH negatively impacts upon the fate of ischaemic brain
tissue, with greater infarct growth, higher mortality and
more severe disability being consistent findings amongst hyperglycaemic
stroke subjects. For these reasons, PSH represents an attractive
physiological target for acute stroke therapies with potential
application across broad time windows, stroke subtypes and
stroke severity. In addition to providing an overview of the
adverse effects of hyper-glycaemia following acute ischaemic
stroke, this article aims to summarise the evidence from current
glucose-lowering treatment trials as well as exploring continuous
glucose monitoring and the implications for future glycaemic
manipulation.
[Back to top]
Algorithms for Intravenous Insulin Delivery
Susan S. Braithwaite and Stephen Clement
This review aims to classify algorithms for intravenous
insulin infusion according to design. Essential input data
include the current blood glucose (BGcurrent
), the previous blood glucose (BGprevious),
the test time of BGcurrent
(test timecurrent), the test
time of BGprevious (test
timeprevious), and the previous
insulin infusion rate (IRprevious).
Output data consist of the next insulin infusion rate (IRnext)
and next test time. The classification differentiates between
“IR” and “MR” algorithm types, both
defined as a rule for assigning an insulin infusion rate (IR),
having a glycemic target. Both types are capable of assigning
the IR for the next iteration of the algorithm (IRnext)
as an increasing function of BGcurrent,
IRprevious, and rate-of-change
of BG with respect to time, each treated as an independent
variable. Algorithms of the IR type directly seek to define
IRnext as an incremental
adjustment to IRprevious.
At test timecurrent, under
an IR algorithm the differences in values of IRnext
that might be assigned depending upon the value of BGcurrent
are not necessarily continuously dependent upon, proportionate
to, or commensurate with either the IRprevious
or the rate-of-change of BG. Algorithms of the MR type create
a family of IR functions of BG differing according to maintenance
rate (MR), each being an iso-MR curve. The change of IRnext
with respect to BGcurrent
is a strictly increasing function of MR. At test timecurrent
algorithms of the MR type use IRprevious
the rate-of-change of BG to define the MR, multiplier, or
column assignment, which will be used for patient assignment
to the right iso-MR curve and as precedent for IRnext.
Bolus insulin therapy is especially effective when used in
proportion to carbohydrate load to cover anticipated incremental
transitory enteral or parenteral carbohydrate exposure. Specific
distinguishing algorithm design features and choice of parameters
may be important to establish freedom from hypoglycemia, eliminate
the need for administration of concentrated dextrose during
euglycemia, control variability within the treatment course
of individual patients, achieve adaptability to differing
blood glucose targets, and minimize variability of glycemic
control between treatment courses of different patients or
patient populations. Areas for future work include the reduction
of nursing burden, the development of a theory that will account
for lag time of interstitial monitoring and pharmacodynamic
delay of insulin action, and management strategies for the
narrow euglycemic range. It is hoped that hypoglycemia and
variability of control will become negligible problems, and
that fear of hypoglycemia no longer will deflect investigators
and caregivers from providing optimal glycemic management.
[Back to top]
The Future of Continuous Glucose Monitoring: Closed Loop
Roman Hovorka
Improvements in accuracy of real-time continuous glucose
monitoring facilitate the development of closed-loop systems
consisting of a continuous glucose monitor, a control algorithm,
and an insulin pump. Closed-loop systems can be divided according
to the way meal delivery is handled as “fully closed-loop”
or “closed-loop” with meal announcement systems.
Depending on the subcutaneous (sc) or intravenous (iv) body
interface, three major types of closed-loop systems are recognised,
(i) sc sensing and sc delivery system, (ii) the iv sensing
and intraperitoneal delivery system, and (iii) the iv glucose
sensing and iv insulin delivery system. Given the current
research focus, this review centres on the sc-sc closed-loop
approach, which has the greatest potential for a near-future
commercial exploitation as recognised by the JDRF Artificial
Pancreas Project. Other approaches utilising intraperitoneal
or intravenous sensing/delivery are also discussed. Closed-loop
systems may revolutionise diabetes management but their introduction
is likely to be gradual starting from simpler applications
such as hypoglycaemia prevention or overnight glucose control
progressing to more complex approaches such as 24/7 glucose
control. The most important question is what is achievable
with existing technologies and when the first generation of
closed-loop systems will find its way into clinical practice.
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