Glucose Measurement in the ICU: Regulatory Intersects Reality*

Rice, Mark J. MD; Smith, John L. PhD; Coursin, Douglas B. MD

doi: 10.1097/CCM.0000000000002274
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Division of Multispecialty Adult Anesthesiology Department of Anesthesiology Vanderbilt University Medical Center Nashville, TN

NIVG Consulting, LLC Portland, OR

Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI

*See also p. 567.

Supported, in part, by Vanderbilt University Medical Center, the University of Wisconsin School of Medicine and Public Health, and NIVG Consulting, LLC. Dr. Smith received funding from LifeScan, AgaMatrix, Masimo/Cercacor Laboratories, and Insulet for expert witness services; and received funding from Zyomed Corp. for consulting services. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Article Outline

Over the past 2 decades, there has been a dramatic increase in the number of ICU patients who have known or previously unrecognized dysglycemia. We define dysglycemia as hypoglycemia, hyperglycemia, and/or marked variability in glucose levels during a critical illness. A large body of literature has evolved regarding the risks and benefits of normalization of glucose in the critically ill and the potential for unintended consequences related to achieving that goal (1).

Core to the management of dysglycemic patients, whether they have type 1 or type 2 diabetes (or one of its variants) or abnormal glucose homeostasis related to stress or associated pathology, is the need for timely and accurate glucose measurements. There are a number of challenges related to obtaining accurate glucose results in the ICU environment. Related to these challenges, the Food and Drug Administration (FDA) has recently issued a proposal calling for stricter application of glucose measurement standards in the critically ill (2) and has raised various questions about timeliness, cost, and realistic glucose analysis. Briefly, the FDA has proposed criteria for increased accuracy for prescription point-of-care (POC) glucose measurements for critically ill patients (“critically ill” has not been defined by the FDA) that are listed in Table 1. Please refer to recent review articles by Klonoff et al (3) and Rice and Coursin (4) for background regarding the specifics of the regulatory issues.

There is an abundance of literature regarding the inaccuracies surrounding ICU glucose measurements using POC meters (5–7). Two of these studies (6, 7) have even reported potential inaccurate dosing of insulin therapy and the resulting serious consequences from these erroneous measurements. Therefore, it is imperative that we trust our glucose meters and the methods they use to make these measurements in our critically ill patients.

A major issue with glucose measurement in this population is the sample site. Most ICU measurement, at least in the United States, is done with capillary blood (i.e., fingertip) (8), although arterial and venous blood samples are thought to be more accurate. Kuwa et al (9) reported the differences in glucose values from concurrently measured capillary, arterial, and venous blood samples. Also, Critchell et al (10) have reported similar findings, although it is unclear if the source of the inaccuracy may be the sample site, accuracy of the device itself, or both. Although the exact reason is unknown, it is generally believed that measurement of glucose from fingertip blood samples is not as accurate as more traditional blood sites (arterial or venous).

There is only one POC glucose meter currently approved for use in critically ill patients (Nova StatStrip; Nova Biomedical, Waltham, MA). In this issue of Critical Care Medicine (11), the manufacturer of this device has sponsored a multicenter trial that measured the accuracy and validity of glucose measurements across a wide spectrum of ICU patients. This five-center, international study compared venous and arterial blood glucose samples measured with a central laboratory device (CLD) to results for samples acquired simultaneously and measured using the POC Nova StatStrip meter (Nova Biomedical). They reported that this device yielded acceptable accuracy when compared with the CLD as measured by both the Clinical & Laboratory Standards Institute Point-of-Care Testing 12-A3 standards and when plotted on a Parkes error grid.

It is crucial to point out that all samples reported were obtained from either arterial or venous blood. Although capillary blood samples were obtained during the study, interestingly, the results and comparisons to CLD from these samples were not reported. It is important to note that this device is not approved for capillary blood measurement in the critically ill population. This study is in line with a 2014 article by Karon et al (12) that reported the StatStrip device to have acceptable accuracy when judged against CLSI POCT12-A3 standards, which are not as stringent as the recent FDA-proposed guidelines. As is the case with many of the blood samples reported in this issue of Critical Care Medicine by DuBois et al (11), the vast majority (95%) of the samples were arterial.

As noted above, the vast majority of glucose sample measurements in the ICU are performed using a fingertip capillary blood sample and measured on POC devices (8). Despite the lack of data from this current study (11), which could support such a practice, we suspect that this remains the current approach independent of which glucose meter is used in real world ICUs. The current study device and all other commercially available POC devices are not approved for use in the critically ill “for measuring capillary samples.”

Why are samples measured with POC meters potentially different than those sent to a central laboratory for analysis? There are four major sources of error with POC glucose measurement and these are summarized in Table 2.

One potential source of error with fingertip glucose sampling is not discussed in the literature to our knowledge, but may be a major foundation of measurement inaccuracy noted with capillary blood. This surrounds the practice of “milking the finger” when drawing blood from the fingertip. We know that this practice increases the amount of interstitial fluid (ISF) in the fingertip pool of blood. Although ISF and blood are thought to be well equilibrated in the dense capillary bed of the fingertip, it has not been established that they will show identical glucose concentrations, so this dilution is a potential error source.

This dilution also reduces the hematocrit of this sample. Although some POC glucose meters correct for hematocrit levels, this could result in an inaccurate result. Additionally, ISF has lower sodium and potassium concentrations (13) and could also introduce measurement error. Some POC devices, which make hematocrit corrections based on the conductivity of a blood sample applied to a test strip, make those calculations based on normal electrolyte concentrations, and lower levels in a sample diluted with ISF could be a source of error. A supplier of blood collection devices (14) warns that milking may also lead to hemolysis of the blood sample as well as dilution with tissue fluid.

Although DuBois et al (11) report here that one POC measurement technology using arterial and venous blood meets several accuracy standards, we are concerned this methodology fails to address the vast majority of real world ICU patients, where most sampling is done with fingertip blood samples. Since capillary samples were reported to have been collected during the study, the authors could go a long way (perhaps in a future publication) to resolve the outstanding question about accuracy of these measurements by reporting the results and comparing them to the CLD measurements. We believe that even though the device is not yet approved for these measurements (using capillary blood), reporting these results under a research umbrella is acceptable.

In summary, we have several recommendations as follows:

1. This study should be repeated and reported with capillary samples. The authors say that they collected the samples. Is there a possibility they made the measurements and chose not to report them?

2. Healthcare professionals should be cautioned about milking the finger for blood samples. We would suggest detailed studies be done on this common practice to quantify the impact of this practice, especially in the critically ill population.

3. FDA should consider relaxing ICU glucose measurement accuracy standards per a recent recommendation (3). Having a POC result in a few minutes compared to an hour with the central laboratory measurement may be the better patient-centric pathway. There is no question that quick results are more advantageous in caring for patients, especially ICU patients who may have rapidly changing glucose values.

4. If there is any doubt as to the accuracy of the POC glucose result, a sample should be sent urgently to the central laboratory for confirmation.

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REFERENCES

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13. Fogh-Andersen N, Altura BM, Altura BT, et al. Composition of interstitial fluid. Clin Chem. 1995; 41:1522–1525
14. Niwinski N. Capillary blood collection: Best practices. Franklin Lakes, NJ, Becton, Dickinson, and Company, 2009. USA, Lab Notes - Volume 20, No. 1, Available at: http://www.bd.com/vacutainer/labnotes/Volume20Number1/. Accessed December 20, 2016

blood chemical analysis; clinical laboratory techniques; glucose, hyperglycemia; hypoglycemia; point-of-care systems

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