EDITORIAL EDITORIAL

April 2008
Volume 83

Mayo Clinic Number 4

Proceedings
Critical Glucose Control: The Devil Is in the Details
in critically ill patients concomitantly receiving sedatives
T his issue of Mayo Clinic Proceedings contains 3 ar-
ticles on maintaining normal glucose levels in hospi-
talized patients.1-3 The report by Desachy et al1 addresses a
and analgesics. Assessment is confounded further if pa-
tients are hemodynamically unstable, have altered mental
concept—reliably measuring glucose in critically ill pa- status, or are also receiving sympatholytic medications.
tients—that is important to understanding the other 2 ar- The systematic review and meta-analysis of periopera-
ticles. The accuracy of point-of-care (POC) glucometers tive glycemic control by Gandhi et al2 in this issue of
and variability of glucose measurement in the intensive Proceedings noted that patients treated with IIT for TGC
care unit (ICU) are where the details meet the devil.1 The had more hypoglycemic episodes. There was a trend to-
potential effect of inaccurate glucose measurements on ward lower mortality with TGC, but
tight glycemic control (TGC) protocols using intensive it was not statistically significant. See also pages
insulin therapy (IIT) must be appreciated. Variability in Because studies vary in frequency of 400, 406, and
measurement technique and results could explain some of glucose monitoring and accuracy of 418
the conflicting opinions about the advisability of aggres- technique used to measure glucose
sive control of glucose levels in critically ill patients.4,5 levels, the effect of different methods is important and must
Recent publications have heightened awareness of the be considered when evaluating results of individual reports
increased morbidity and mortality among hospitalized pa- on the benefits of TGC.
tients with acute illness who have diabetes and those who Tight glycemic control requires frequent and accurate
have hyperglycemia but are not known to have diabetes.6-10 glucose measurements, can be time-consuming, and varies
Agencies that certify and reimburse hospitals increasingly in cost depending on the method used. The goals of moni-
call for glucose management as a benchmark of care.11,12 toring are to ensure that plasma glucose levels are within
Despite the growing impetus for maintaining normal glucose the normal range (often given as 80-110 mg/dL), the pa-
levels in critically ill adults,4,5,13 several experts question the tient is not hypoglycemic, and the brain does not incur the
universal benefit of euglycemia in the heterogeneous popu- consequences of neuroglycopenia.23 Close monitoring of
lation of adults in ICUs.14-20 The only prospective random- the plasma or whole blood glucose levels in ICUs requires
ized controlled trial that has shown a decrease in ICU understanding the monitoring technique used and its limi-
morbidity and mortality with TGC4 has been challenged16 tations. This entails understanding how a POC glucometer
because of its patient population, feeding protocol, mortal- functions, the instrument’s accuracy and precision, and
ity, and timing of IIT initiation. Three more recent prospec- expected standards for accuracy.20,24-26 Clinicians need to be
tive randomized controlled trials failed to duplicate the aware of how bedside glucose monitoring compares with
benefits of that trial.5,21,22 These 3 studies also reported the laboratory-based criterion standard and the potential for
substantial hypoglycemia: glucose levels below 40 mg/dL misleading results to prompt inappropriate therapy. Fi-
(Mayo Clinic reference range, 70-100 mg/dL; to convert to nally, clinicians and those improving glucometers must
mmol/L, multiply by 0.0555) developed in 9.8% to 18.7% appreciate that monitoring glucose in critically ill patients
of patients who received IIT to maintain TGC.5,19,22 Identi- is far more complicated than monitoring glucose in ambu-
fying signs and symptoms of hypoglycemia can be difficult latory patients, and data cannot be extrapolated from one
population to the other.27
Address correspondence to Douglas B. Coursin, MD, B6/319 UW CSC,
Desachy et al1 specifically examine how glucometer
Madison, WI 53792-3272 (dcoursin@wisc.edu). measurements for ICU patients are affected by poor periph-
© 2008 Mayo Foundation for Medical Education and Research eral tissue perfusion, as gauged by pulse oximetry; they

394 Mayo Clin Proc. • April 2008;83(4):394-397 • www.mayoclinicproceedings.com

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 EDITORIAL

found that POC glucose measurements varied from refer- TABLE. Factors Affecting Point-of-Care Blood Glucose
Measurements
ence laboratory results by 20% or more in 15% of capillary
glucose samples and 7% of whole blood samples. Point-of- Blood source: serum, plasma, whole blood
Blood sampling site (capillary blood can differ from venous by as much as
care results more often overestimated than underestimated 70 mg/dL)
glucose values compared with reference laboratory results. Amount of blood on glucometer strip
Patients with a low perfusion index had the most substan- Too much results in spuriously high levels
Too little results in spuriously low levels
tial disagreements. Desachy et al remind us of the limita- Hematocrit (progressive anemia results in spuriously high levels in whole
tions of using capillary samples in critically ill adults and blood assays)
the need for physicians to recognize potential pitfalls. Peripheral hypoperfusion: shock states, vasoconstriction, dehydration,
vasospastic disorders
Point-of-care glucose measurements in hemodynamically Sample processing delay
stable patients have correlated with laboratory reference Substances reported to interfere with glucose measurements
values when arterial samples are measured by reflectance Levodopa
Dopamine
or optical techniques.28,29 In contrast, 2 studies of patients Mannitol
diagnosed as being in shock who required infusions of Acetaminophen
vasoactive drugs to stabilize hemodynamic function indi- Severe unconjugated bilirubin
Severe lipemia
cated that finger-stick test results and bedside glucose mea- Elevated uric acid
surements varied by 30% and 18%, respectively, compared Maltose (present in immunoglobulin solutions)
with laboratory reference values.30,31 Icodextrin (present in peritoneal dialysis fluid)
To examine this variance in glucose measurement in
critically ill patients, Kanji et al25 compared 3 methods of
measuring POC glucose with central laboratory values. ments are commonly made at the bedside using various
The POC measurements consisted of blood gas and chem- POC devices (roughly 25 handheld devices are currently
istry analysis of arterial blood and of glucometer analysis approved by the Food and Drug Administration),35 or
of 2 types of samples: capillary blood obtained by finger samples are transported to a satellite or central laboratory
stick and arterial blood. Each of the 3 POC methods was for analysis. Results differ depending on whether whole
compared by paired assessment with the central laboratory blood (POC) or plasma (reference laboratory) is measured;
values and clinical relevance of the resulting interventions differences are corrected via application of a nomogram.
by changes in an insulin protocol. If the POC blood glucose Various POC techniques depend on application of one of
measurement resulted in the same intervention as the cen- the following principles: photo reflectometry or electro-
tral laboratory measurement, this was scored as agreement. chemical reaction (glucose oxidase, glucose dehydroge-
If the 2 approches to glucose measurement resulted in nase). Clinicians should be aware that the federal standard
different insulin interventions, this was scored as disagree- for POC glucose measurements is ±20% agreement with
ment. Agreement of POC glucometer values with central laboratory results (ie, not very reliable when applied to
laboratory values was less than 80% for all POC methods. critical values in critically ill patients).36
However, agreement was substantially lower during hy- Accurate glucose measurements are mandatory to en-
poglycemia: 26.3% for capillary blood and 55.6% for arte- sure proper insulin dosing; however, many confounding
rial blood using POC glucometer measurements and 64.9% factors affect blood glucose measurements (Table). Such
for blood gas and chemistry samples. Point-of-care capil- confounding factors and attempts to correct or compensate
lary blood measurements overestimated actual blood glu- for potentially misleading results vary in their effect on POC
cose concentrations, and erroneous results could have led results and can produce either overestimations or underesti-
to missed diagnosis of severe hypoglycemia and resulted in mations of glucose levels. Timely availability of glucose
inappropriate continuation of insulin therapy. This possi- values facilitates adjustments in insulin infusions, particu-
bility is of great concern in the ICU because medications larly in unstable situations, such as patients with septicemia
and underlying disease can mask the clinical signs of hy- or at particularly high risk for neuroglycopenic insult, as in
poglycemia, leading to serious complications including acute neurologic injury (eg, patients in the Intraoperative
seizures, hypoglycemia-induced coma, and death.32-34 Hypothermia for Aneurysm Surgery Trial [IHAST]3). As
An ideal ICU glucose sensor would be accurate, fast, glucose measurements are refined and as currently available
easy to use, continuous or nearly continuous, and free of computer-based algorithms are applied to TGC, the thera-
significant interference. Despite the findings by Desachy peutic loop can be closed, achieving safe and consistent
et al, glucose measurements in the ICU are obtained most glucose control in ICUs and surgeries.
often from capillary measurements (usually via finger Using a post hoc analysis of the IHAST patient popula-
stick), followed by venous or arterial samples. Measure- tion, Pasternak et al3 reported on blood glucose measure-

Mayo Clin Proc. • April 2008;83(4):394-397 • www.mayoclinicproceedings.com 395

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EDITORIAL

ments performed when aneurysm clips were applied (ie, a creasingly advocated for the intraoperative period despite
time considered to have high risk for cerebral ischemia) limited or even conflicting data. Some experts continue to
and correlated these measurements with outcome 3 months question the risk vs benefit of routinely targeting euglycemia
after surgery. Patients having intraoperative glucose values (rather than simply avoiding severe hyperglycemia). Soon
in the upper quartile (ie, ≥152 mg/dL) had worse gross we hope to have more robust data from multicenter trials in
neurologic function at 3 months, and those in the upper 2 both broad and specific ICU populations as well as better
quartiles (ie, ≥129 mg/dL) had worse neuropsychological glucose measurement technology. Research protocols raise
function. Although Pasternak et al once again note the questions about which patient population benefits from
potential importance of glucose in modulating patient out- TGC, and the goal for maintenance of blood glucose levels
comes, they also demonstrate the limitations of current remains open to discussion and investigation.
glucose monitoring. Specifically, their report did not iden- The ongoing international, multicenter, open-label, pro-
tify their method for measuring blood glucose values. We spectively randomized Normoglycaemia in Intensive Care
cannot determine whether the data contained the type of Evaluation and Survival Using Glucose Algorithm Regula-
errors likely with POC determinations. The large numbers tion (NICE-SUGAR) trial40 will enroll 6100 adult patients
of patients entered into the IHAST analysis and the fact that by the last quarter of 2008. It compares a TGC group with a
physiology was relatively stable at the time of surgery therapeutic goal of 81 to 108 mg/dL to a control group in
should have overcome some of the limitations in glucose which glucose was maintained at 144 to 180 mg/dL. More
analysis for an entire population and indeed allowed strati- than 99% of patients will have glucose samples obtained
fication of neurologic risk according to glucose concentra- from arterial blood and measured via either POC devices or
tion. However, the IHAST results still might not predict a reference laboratory. Any value below 72 mg/dL will be
outcome for TGC in any given patient because of the immediately corroborated with a reference laboratory
aforementioned errors in POC glucose analysis, because of analysis. All patients will have been in the ICU for longer
the single time point for glucose measurement, and because than 48 hours, and all-cause mortality is the primary end
blood glucose measurements might not accurately reflect point of the study (Simon Finfer, MD, written communica-
brain glucose concentrations in some patients. Given that tion, February 17, 2008).
brain, not blood, glucose levels modulate neurologic out- We hope the results of NICE-SUGAR and other trials
come during ischemia37 and that brain-to-blood glucose will help clinicians achieve optimal glycemic control in
ratios are altered in some specific clinical scenarios (eg, ICU patients, but even then results might not apply to
rapidly fluctuating blood glucose concentrations38 and per- patients in other settings (eg, during surgery). Future re-
haps critical illness and other glucose-intolerant states), we finements in glucose monitoring are likely to provide accu-
need not only better POC blood glucose measurements but rate and nearly continuous glucose measurements. Auto-
also POC brain glucose measurements. mated or closed-loop glucose monitoring systems will
Tremendous interest and ongoing effort are directed likely provide a means for safe and timely adjustments in
toward refining blood glucose measurements, developing insulin infusion and will improve glycemic control with
near-continuous monitors, and ultimately, developing an less frequent hypoglycemia.
artificial pancreas.27,39 Percutaneous, subcutaneous, and in-
travascular approaches are being considered. Intravascular Brenda G. Fahy, MD
devices appear to be the most feasible for critically ill Department of Anesthesiology
patients, in part to achieve extreme accuracy, to minimize University of Kentucky
variability in peripheral perfusion, and to limit variation Lexington
secondary to stress responses. Challenges faced by manu-
facturers developing instruments to measure glucose levels Douglas B. Coursin, MD
almost continuously include, but are not limited to, infec- Departments of Anesthesiology and Medicine
tion risk, thrombotic risk, injury at the access site, calibra- University of Wisconsin
tion requirements, and interference (particularly from sub- Madison
stances administered through adjacent vascular infusion
ports). Several innovations seek to limit these problems 1. Desachy A, Vuagnat AC, Ghazali AD, et al. Accuracy of bedside
and others related to anemia and hypoperfusion with glucometry in critically ill patients: influence of clinical characteristics and
perfusion index. Mayo Clin Proc. 2008;83(4):400-405
unique sensing probes and with repeated provision of the 2. Gandhi GY, Murad MH, Flynn DN, et al. Effect of perioperative insulin
equivalent of plasma glucose assays. infusion on surgical morbidity and mortality: systematic review and meta-
analysis of randomized trials. Mayo Clin Proc. 2008;83(4):418-430.
Tight glycemic control using IIT is increasingly consid- 3. Pasternak JJ, McGregor DG, Schroeder DR, et al, IHAST Investigators.
ered the norm in managing critically ill patients and is in- Hyperglycemia in patients undergoing cerebral aneurysm surgery: its associa-

396 Mayo Clin Proc. • April 2008;83(4):394-397 • www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
 EDITORIAL

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Mayo Clin Proc. • April 2008;83(4):394-397 • www.mayoclinicproceedings.com 397

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