Accuracy of blood-glucose measurements using glucose meters and arterial blood gas analyzers in critically ill adult patients: systematic review

Introduction Glucose control to prevent both hyperglycemia and hypoglycemia is important in an intensive care unit. Arterial blood gas analyzers and glucose meters are commonly used to measure blood-glucose concentration in an intensive care unit; however, their accuracies are still unclear. Methods We performed a systematic literature search (January 1, 2001, to August 31, 2012) to find clinical studies comparing blood-glucose values measured with glucose meters and/or arterial blood gas analyzers with those simultaneously measured with a central laboratory machine in critically ill adult patients. Results We reviewed 879 articles and found 21 studies in which the accuracy of blood-glucose monitoring by arterial blood gas analyzers and/or glucometers by using central laboratory methods as references was assessed in critically ill adult patients. Of those 21 studies, 11 studies in which International Organization for Standardization criteria, error-grid method, or percentage of values within 20% of the error of a reference were used were selected for evaluation. The accuracy of blood-glucose measurements by arterial blood gas analyzers and glucose meters by using arterial blood was significantly higher than that of measurements with glucose meters by using capillary blood (odds ratios for error: 0.04, P < 0.001; and 0.36, P < 0.001). The accuracy of blood-glucose measurements with arterial blood gas analyzers tended to be higher than that of measurements with glucose meters by using arterial blood (P = 0.20). In the hypoglycemic range (defined as < 81 mg/dl), the incidence of errors using these devices was higher than that in the nonhypoglycemic range (odds ratios for error: arterial blood gas analyzers, 1.86, P = 0.15; glucose meters with capillary blood, 1.84, P = 0.03; glucose meters with arterial blood, 2.33, P = 0.02). Unstable hemodynamics (edema and use of a vasopressor) and use of insulin were associated with increased error of blood glucose monitoring with glucose meters. Conclusions Our literature review showed that the accuracy of blood-glucose measurements with arterial blood gas analyzers was significantly higher than that of measurements with glucose meters by using capillary blood and tended to be higher than that of measurements with glucose meters by using arterial blood. These results should be interpreted with caution because of the large variation of accuracy among devices. Because blood-glucose monitoring was less accurate within or near the hypoglycemic range, especially in patients with unstable hemodynamics or receiving insulin infusion, we should be aware that current blood glucose-monitoring technology has not reached a high enough degree of accuracy and reliability to lead to appropriate glucose control in critically ill patients.

Results: We reviewed 879 articles and found 21 studies in which the accuracy of blood-glucose monitoring by arterial blood gas analyzers and/or glucometers by using central laboratory methods as references was assessed in critically ill adult patients. Of those 21 studies, 11 studies in which International Organization for Standardization criteria, error-grid method, or percentage of values within 20% of the error of a reference were used were selected for evaluation. The accuracy of blood-glucose measurements by arterial blood gas analyzers and glucose meters by using arterial blood was significantly higher than that of measurements with glucose meters by using capillary blood (odds ratios for error: 0.04, P < 0.001; and 0.36, P < 0.001). The accuracy of blood-glucose measurements with arterial blood gas analyzers tended to be higher than that of measurements with glucose meters by using arterial blood (P = 0.20). In the hypoglycemic range (defined as < 81 mg/dl), the incidence of errors using these devices was higher than that in the nonhypoglycemic range (odds ratios for error: arterial blood gas analyzers, 1.86, P = 0.15; glucose meters with capillary blood, 1.84, P = 0.03; glucose meters with arterial blood, 2.33, P = 0.02). Unstable hemodynamics (edema and use of a vasopressor) and use of insulin were associated with increased error of blood glucose monitoring with glucose meters.
Conclusions: Our literature review showed that the accuracy of blood-glucose measurements with arterial blood gas analyzers was significantly higher than that of measurements with glucose meters by using capillary blood and tended to be higher than that of measurements with glucose meters by using arterial blood. These results should be interpreted with caution because of the large variation of accuracy among devices. Because blood-glucose monitoring was less accurate within or near the hypoglycemic range, especially in patients with unstable hemodynamics or receiving insulin infusion, we should be aware that current blood glucose-monitoring technology has not reached a high enough degree of accuracy and reliability to lead to appropriate glucose control in critically ill patients.

Introduction
Glucose control to prevent both hyperglycemia and hypoglycemia is important in an intensive care unit [1]. Recent meta-analysis, including results of the NICE-SUGAR study [2], showed that intensive insulin therapy (target blood-glucose control, 80 to 110 mg/dl) was not beneficial and increased the risk of severe hypoglycemia in critically ill patients [3][4][5]. Thus, it is currently recommended that insulin should be used when the glucose concentration exceeds 180 mg/dl, and target glucose concentration should generally be between 144 and 180 mg/dl [6,7] Even though a more-modest target for blood-glucose concentration is now accepted, the importance of glucose monitoring and its accuracy has become clearer. Because the physiological activity of glucose is dependent on its plasma concentration, central laboratory blood-glucose measurement using plasma (Glu-lab) is recommended [8,9]. However, arterial blood gas analyzers (ABGs) and/or glucose meters, not Glu-lab, are commonly used to measure blood-glucose concentrations in critically ill patients, because of their convenience and speed [10]. Because most of these devices were not developed to guide the administration of insulin in critically ill patients, they might not be sufficiently accurate to guide therapy aimed at maintaining blood glucose within a 30-mg/dl range [11]. Therefore, knowledge of their limitations is essential to minimize the possibility of a harmful measurement error. However, no systematic literature review has assessed the agreement of measurements by ABGs and/or glucose meters in critically ill patients.
Accordingly, we performed a systematic review and meta-analysis of selected observational studies on the accuracy of blood-glucose measurements by using ABGs (Glu-ABGs), glucose meters using capillary blood samples (Gluco-C), and glucose meters using arterial blood samples (Gluco-A) in critically ill adult patients.

Electronic database
We performed a systematic literature search (January 1, 2001, through August 31, 2012) to find clinical studies comparing blood-glucose values measured by using ABGs and/or glucose meters with those simultaneously measured with a central laboratory machine in critically ill adult patients. The literature search was performed by using MEDLINE and PubMed electronic databases with the following key words: "intensive care", "critical care," "glucose," "sugar," "glycemic," "insulin," "Bland Altman," "agreement," "validation," "reliability," "accuracy," "correlation," "Clarke grid," and "bias." All articles identified by this search strategy were obtained, and their bibliographies were studied for articles that might have been missed by the electronic database search.

Inclusion and exclusion criteria
Inclusion criteria for the current systematic review were as follows: (a) studies conducted in critically ill adult patients, (b) studies in which the accuracy of glucose monitoring was assessed by using ABGs and/or glucose meters, (c) studies in which Glu-lab values were used as reference values, and (d) articles presenting an appropriate summary of statistics. We excluded nonhuman studies, non-English-language articles, and pediatric studies.

Data extraction and interpretation
Two of the authors (SI and ME) extracted data from selected articles, which were then reviewed by coauthors. We paid particular attention to determine whether the accuracy of blood-glucose monitoring was influenced by types of devices and sites of blood collection. Because the accuracy of blood-glucose monitoring in a hypoglycemic range is important, we performed further assessment of accuracy in a hypoglycemic range, defined as < 81 mg/dl. Additionally, we summarized factors associated with errors of blood-glucose measurements.

Primary outcome
Most of the studies were conducted by using (a) agreement (percentages of blood-glucose values with an acceptable error), and/or (b) bias (mean difference between devices and reference) for evaluation.
Because the International Organization for Standardization (ISO) criteria use agreement within ±20% of Glu-lab at or above 75 mg/dl and within ±15 mg/dl below 75 mg/dl, we defined primary outcome as percentages of bloodglucose values within ±20% of the error of Glu-lab, which involved Zone A of error-grid analysis (agreement within ±20% of Glu-lab at or above 70 mg/dl) and agreement with ISO criteria. We obtained rates of overestimation and underestimation of blood-glucose measurements. We defined proportion of nonagreement < 5% as good quality of blood-glucose measurements according to ISO criteria.

Secondary outcomes
We obtained the proportion of agreement by using criteria other than the previously described criteria. Because many reports showed the bias of each device, we summarized their bias.

Statistical analysis
The current systematic review was performed by following the MOOSE statement for observational studies [12]. Analysis was performed by using Review Manager (Rev-Man) (The Cochrane Collaboration, 2008; The Nordic Cochrane Centre, Copenhagen, Denmark). Heterogeneity was calculated by the I2 test, which shows the rate of variation across studies due to heterogeneity rather than to chance (ranging from 0 (no heterogeneity) to 100 (maximum heterogeneity)) [13]. Given the significant heterogeneity found among the results of the studies, the random-effects model was used [14]. All results are reported with 95% confidence intervals. A P value < 0.05 was taken to indicate statistical significance.

Results
We identified 879 potentially relevant articles by the literature search. We excluded 716 studies because they were animal studies, nonclinical studies, non-Englishlanguage articles, or nonrelated studies. Of the remaining 163 studies, 116 were excluded because they were performed in infant or pediatric populations. Full text reviews were conducted for the remaining 47 articles. In 21 of those 47 studies, the accuracy of blood-glucose monitoring was assessed by using ABGs and/or glucometers with central laboratory methods as references in critically ill adult patients ( Figure 1).
11 studies using 1) International Organization for Standardization criteria, 2) error grid analysis or 3) percentage of values within 20 %of reference value 2 studies using percentage of values within 10 %of reference value 1 study using percentage of values within 20 mg/dL difference from reference value 7 studies using solely bias for evaluation 25.2 mg/dl [16] in Glu-ABGs, between -16 mg/dl [23] and 9.9 mg/dl [22] in Gluco-C, and between -10 mg/dl [23] and 23.0 mg/dl [32] in Gluco-A.
All of the 11 studies were single-center observational studies. Nine of the 11 studies were prospective studies [15][16][17][18][19]21,[23][24][25], and the other two studies were retrospective studies [20,22]. Totally, 580 patients were included in the 11 studies. Various types of central laboratory machines were used in the studies. The two methods for blood-glucose Bias was described as mean difference (95% confidence interval). ABG, arterial blood gas analyzer; Gluco-C, glucose meters using capillary blood samples, Gluco-A, glucose meters using arterial blood samples; Ref, reference; Mean D, mean difference; IQR, interquartile range. a Analysis of merged data from glucometer using capillary and arterial samples.
In the 2,778 assessments in the seven studies, the proportion of nonagreement varied from 1.4% to 27.1%. One study (14.3%) showed a good quality of blood-glucose monitoring [18]. The proportion of nonagreement was 9.3%. Overestimation of blood-glucose concentrations was seen in 4.8% of all assessments.
In the seven studies, 3,086 assessments were done. The proportion of nonagreement varied from 0 to 12.3%. One study (14.3%) showed good quality of blood-glucose monitoring [18]. The proportion of nonagreement was 3.3% (n = 101). Overestimation of blood-glucose values was seen in 1.3% of all assessments.

Meta-analysis to compare the accuracy of devices
In three studies, the accuracy of ABGs and that of glucose meters were compared simultaneously [18][19][20]. Glu-ABGs were significantly more accurate than Gluco-C (odds ratio for nonagreement, 0.04; P < 0.001) (Figure 2A). Glu-ABGs tended to be more accurate, but not significantly more accurate, than Gluco-A (odds ratio for nonagreement, 0.17; P = 0.20) (Figure 2B).

Accuracy of blood-glucose measurements in the hypoglycemic range
The accuracy of point of blood-glucose monitoring in the hypoglycemic range was assessed for Glu-ABGs in two studies [16,19], for Gluco-C in three studies [19,23,24], and for Gluco-A in three studies [19,23,25] ( Table 4). The total number of assessments was 157 (59 assessments for ABGs, 52 assessments for Gluco-C, and 46 assessments for Gluco-A).
For ABGs, 13 of the 59 blood-glucose measurements were outside the agreement range (22.0%), and all of them overestimated blood-glucose values (22.0%). One study by Kanji et al. [19] showed a high level of accuracy of ABGs in the hypoglycemic range (nonagreement, none of 37) [19]. For Gluco-C, 26 of the 77 blood-glucose measurements were outside the agreement range (33.8%).
Overestimation of blood-glucose values was seen in 15 measurements (19.5%). For Gluco-A, 14 of the 71 bloodglucose measurements were outside the agreement range (19.7%). Overestimation of blood-glucose values was seen in eight (11.3%) measurements.

Factors associated with error of blood-glucose measurements
In six studies, risk factors for inaccuracy of glucose measurements were determined (five for Gluco-C, five for Gluco-A, and none for ABGs) [20][21][22][23][24][25] (Table 5). Patient's factors (sex, body mass index, severity of illness, and presence of sepsis and/or diabetes), except for age, were not significantly related to inaccuracy. Young age was significantly associated with increased risk of nonagreement for Gluco-C in one study [23]. No laboratory data (albumin, lactate, PaCO 2 , PaO 2 , pH, and hematocrit) were associated with inaccuracy.   For Gluco-C, low perfusion index [36], use of a vasopressor [22,24] and presence of edema [20,24] were significantly associated with inaccuracy. For Gluco-A, use of a vasopressor [23], low peripheral perfusion, and low mean arterial pressure [21] were associated with inaccuracy.
Studies in which agreement of criteria other than "within 20%" was assessed Our literature review retrieved three studies in which agreement of criteria other than "within 20%" was assessed: one study used within 20 mg/dl from the reference [26], and two studies used within 10% of reference methods for evaluation [27,28] (Table 6). No study showed a good quality of blood-glucose monitoring. One study (n = 20) showed that blood-glucose measurements by Accu-Chek Inform using arterial blood samples were less accurate than those using capillary blood samples (odds ratio for incidence of nonagreement, 2.21; P = 0.02) [27]. Another study showed that accuracy of measurements with glucose meters by using arterial blood samples were significantly varied among devices (incidence of nonagreement (Stat-Strip = reference): Accu-Chek Inform: odds ratio, 5.2; P < 0.001, Precision PCx: odds ratio, 15.2; P < 0.001; SureS-tepFlexx, odds ratio, 4.3; P < 0.001) [28].

Discussion
Although several reviews focused on the accuracy of point of blood-glucose monitoring in critically ill patients [10,37,38], our review is the first systematic review for this issue. Our review shows comparisons among devices and between hypo-and non-hypoglycemic ranges, as well as problems in studies including variation of references and insufficient data for a hypoglycemic range.
Although available data are often heterogeneous and insufficient for meta-analysis, we found that the accuracy of blood-glucose monitoring might vary, especially according to the device, site of blood sampling, and glucose range. With our systematic analysis of the 11 retrieved articles, we considered that, despite the limitation of data, some statements can be made to help establish current knowledge of the accuracy of point of blood-glucose monitoring in critically ill adult patients.

Statement 1: Type of central laboratory machine (reference) is highly variable
The type of central laboratory machine varied among the studies. Although all central machines used in the 11 studies have traceability of blood-glucose monitoring, it is unclear whether these machines are equally accurate. Thus, it is difficult to interpret whether the type of laboratory machine influenced the accuracy of point of bloodglucose monitoring. If the central laboratory machine does not have metrologic traceability for blood-glucose monitoring, it should be the case for quality-insurance programs requirements.

Statement 2:
In few studies was the accuracy of ABGs compared with that of a glucose meter simultaneously In the variation of reference as in statement 1, the study to compare the accuracy among Glu-ABGs, Gluco-C, Definition, Definition of hypoglycemia; No of samples, Number of samples in hypoglycemic range; non-hypo, non-hypoglycemic. ABG, arterial blood gas analyzer; Gluco-C, glucose meters using capillary blood samples; Gluco-A, glucose meters using arterial blood samples; CI, confidence interval; Ref, reference.
and Gluco-A is essentially relevant. However, in only three studies were the accuracies of these three compared [18][19][20].

Statement 3: Accuracy of ABG analyzers might vary among devices
The proportion of nonagreement in Glu-ABGs varied widely (0 to 42.8%). Although five of the six studies showed good quality of Glu-ABGs, and the range of limits of agreements for Glu-ABGs (minimum of 19 mg/dl, maximum of 39 mg/dl) was smaller than those for Gluco-C and Gluco-A, one study showed overestimation by Glu-ABGs in 42.8% of the samples. Although it is unclear whether the type of central laboratory machine, conditions of the measurement, or other unknown mechanisms affected the results of that study, the results suggested that accuracy of Glu-ABGs might vary among devices. Thus, it is recommended that each institution confirm the accuracy of their ABGs for blood-glucose monitoring.
Statement 4: ABGs and a glucose meter using arterial blood were significantly more accurate than a glucose meter using capillary blood Glu-ABGs and Gluco-A were significantly more accurate than Gluco-C. Even when we included studies using criteria other than within 20%, the finding did not change (odds ratio for nonagreement, 0.43; P = 0.01). Thus, for blood-glucose measurements in critically ill adult patients, arterial blood samples should be used rather than capillary blood samples.
Statement 5: Blood-glucose monitoring with ABG analyzers tends to be more accurate than that with glucose meters using arterial blood Our meta-analysis showed that Glu-ABGs tend to be more accurate than Gluco-A (P = 0.20). Additionally, the range of limits of agreements in Glu-ABG was smaller than that in Gluco-A. These results suggest that Glu-ABGs might be more appropriate than Gluco-A. However, it should be noted that the accuracy of Gluco-A varied among studies, as stated earlier, and in only three studies were they compared, and the results were conflicting (odds ratios for error, 0.03 to 3.00). Thus, further studies are needed to determine whether Glu-ABGs, Gluco-A, or both can be recommended for blood-glucose monitoring in a critically ill setting. Statement 6: Information on the accuracy of bloodglucose measurement in the hypoglycemia range is not sufficient Although more than 6,000 samples were assessed for the accuracy of blood-glucose measurements (ABG, 1,360; Glu-C, 2,858; Glu-A, 3,086), about 70 samples were in the hypoglycemic range in each method (ABG, 58; Glu-C, 77; Glu-A, 81). This number of samples is not sufficient to compare between devices and determine the risk factors of error. Therefore, further studies are needed for blood-glucose measurements in the hypoglycemic range.
Statement 7: Blood-glucose monitoring in the hypoglycemic range is less accurate than that in the nonhypoglycemic range Because many studies have shown that even mild hypoglycemia is significantly associated with increase in mortality [39,40], accuracy of blood-glucose monitoring in the hypoglycemic range is important. Although little information is available for the hypoglycemic range, as stated earlier, our results showed that the incidences of errors in the hypoglycemic range were higher than those in the nonhypoglycemic ranges.
Regardless of the method used for blood-glucose monitoring, we should be aware that a greater possibility of errors exists in the hypoglycemic range than in the nonhypoglycemic range. We should confirm blood glucose concentrations by using Glu-lab when we obtain bloodglucose values within or near the hypoglycemic range.
Statement 8: Unstable hemodynamics and insulin infusion might increase the risk of errors in blood-glucose monitoring by using a glucose meter Unstable hemodynamics (low perfusion index, use of a vasopressor, presence of edema, and low mean arterial pressure) and insulin infusion were associated with increased risk of inaccuracy. These factors might decrease peripheral blood-glucose concentrations through microcirculatory disturbance and increased tissue glucose consumption [41,42]. Therefore, physicians should avoid using either Gluco-A and Gluco-C in patients with unstable hemodynamics and/or receiving insulin infusion.

Limitations
Our systematic review has some limitations. Our literature search was performed by using only MEDLINE and PubMed and was performed by only one author. The use of other important databases, such as the Cochrane systematic reviews database, and selection by multiple authors might have made the literature review more comprehensive. We also excluded non-English-language reports, abstracts, and unpublished studies. Thus, some findings may have been missed. However, the selection was done with preset inclusion criteria and a careful search of bibliographies so as to minimize selection bias.

Conclusions
Our literature review showed that ABGs were significantly more accurate than glucose meters using capillary blood and tended to be more accurate than glucose meters using arterial blood. However, these results should be interpreted with caution because of the large variation of accuracy among devices. Because blood-glucose monitoring was less accurate within or near the hypoglycemic range, especially in patients with unstable hemodynamics or receiving insulin infusion, we should aware that current blood-glucose monitoring technology has not reached a high enough degree of accuracy and reliability to lead to appropriate glucose control in critically ill patients.

Key messages
• Accuracy of blood-glucose measurements using arterial blood gas analyzers might vary among devices.
• Blood-glucose monitoring with ABG analyzers tends to be more accurate than that by glucose meters with arterial blood.
• Arterial blood samples should be used rather than capillary blood sample for blood-glucose measurements in adult critically ill patients.
• In the hypoglycemic range, blood-glucose monitoring is more inaccurate than that in the nonhypoglycemic range.
• Unstable hemodynamics and insulin infusion might increase the risk of error in blood-glucose monitoring with a glucose meter.