Diabetes mellitus is one of the most common endocrinopathies in dogs, with an estimated prevalence of 0.3% to 1.2%.1–3 Specific portable blood glucose monitors (PBGMs) (AlphaTRAK 2, Zoetis) are designed and validated for use in veterinary patients and are capable of rapid patient-side blood glucose (BG) measurements using either capillary or venous blood.4,5 There are limitations to this method of monitoring, including patient discomfort, reduced compliance, technician or clinician availability, and the need for some BG curves to be performed in a veterinary clinic, potentially resulting in stress-induced hyperglycemia.
Continuous interstitial glucose monitoring systems avoid the need for repeated sample collection by utilizing a small sensor that detects glucose in the interstitial fluid and stores the data in an attached recording device.6–9 IG is closely associated with BG but the relationship between them is complex.10–12 While originally the glucose sensors had to be directly attached to a recording device, “flash” glucose monitor systems (FGMS) allow for the results to be collected by scanning the FGMS with a reader. FGMSs are routinely used by human patients with diabetes mellitus (FreeStyle Libre 14-day system, Abbott).13–15 These devices utilize a small sensor filament that is embedded 5 mm underneath the skin. Once implanted, the FGMS sensor measures IG concentrations every minute with readings automatically stored every 15 minutes. Readings can be obtained throughout the day by scanning the implanted device at least once every 8 hours. The sensor device can remain in place for up to 14 days and accurately reads IG concentrations between 40 and 500 mg/dL.16
Numerous studies have utilized FGMSs placed in the cervical region to monitor glucose concentrations in dogs.17–23 When monitoring stable diabetics or dogs in ketoacidosis, FGMS have repeatedly been shown to be an acceptable clinical alternative to PBGMs or biochemical analyzers.17,18,22 FGMS can also identify overnight glucose nadirs and generate glucose curves that lead to insulin dosing recommendations similar to PBGM-generated curves in stable diabetic dogs.20
While the sensor is generally placed on the dorsal aspect of the neck, this location may not be feasible in a patient either due to their size, neck wrappings or bandages, skin lesions, or skin condition.19 In euglycemic dogs, FGMSs were clinically accurate when placed on the dorsal neck, lower back, thorax, and abdomen, but there was variation among the different sites.24 Similarly, in a small group of diabetic cats, FGMS sensor location did not significantly impact clinical accuracy.25 However, in humans, IG sensors placed on the abdomen reported differing IG measurements and had unacceptable clinical accuracy when compared with those placed in the approved upper arm location.15 Skin thickness may also affect FGMS performance and varies greatly among dogs.26 Previously, skin thickness in dogs has been shown to impact FGMS results when compared with a PBGM, with reduced bias and greater clinical accuracy observed with thicker skin (> 5 mm).27
The purpose of this study was to determine whether sensor location impacts the performance of FGMS measurements in a model of rapidly induced hypoglycemia. Our hypothesis was that the FGMS sensor placed over the hip would perform with acceptable clinical and analytical accuracy when compared with the traditional neck sensor site.
Materials and Methods
Animals
Twenty-four apparently healthy colony mixed breed dogs were subjects in a teaching laboratory for veterinary students. All dogs had a complete physical examination performed by a veterinarian (C.A.P.) before the start of the laboratory. Institutional animal care and use committee approval was acquired for the study protocol (IACUC #2022-0172)
Skin thickness
Before FGMS application, a mobile ultrasound device (MyLabTM30Gold VET, Esaote) and transducer (LA435c) were used to measure the thickness of the skin in both sensor sites (dorsal neck/between the scapulae and over hip) as previously described.26 Three measurements were obtained for each site by a board-certified veterinary radiologist (J. Nagy).
Glucose data collection
The protocol was similar to that of a previous study.21 Food was withheld from the dogs for 16 hours before data collection while free access to water was maintained. One hour before data collection, dogs had 2 FGMS (FreeStyle Libre 14-day system) sensors placed—1 on the dorsal cervical region/in between the scapulae (sensor A), and 1 over the dorsolateral coxofemoral joint (off center on the right side; sensor B). The 2 locations were prepared similarly: the areas were clipped and cleaned with isopropyl alcohol and the sensors adhered to the skin with an additional 2 to 4 drops of tissue adhesive (Vetbond, 3M Animal Care Products). All sensors were placed by a licensed veterinary technician (M. Hervey). For the hour directly after sensor placement, no readings could be obtained due to sensor acclimation time. In addition to 2 FGMSs, each dog had a 22 g X 1-1/4” catheter (Cardinal Health Monoject) placed in their cephalic vein.
At baseline, before insulin administration, approximately 2 mL of blood was withdrawn from the cephalic IV catheter and discarded using a syringe designated the “dead space syringe.” Then, 1 mL of blood was drawn from the catheter and 1 drop was used to measure blood glucose with a PBGM (AlphaTRAK). Concurrently, an FGMS reader was waved over the sensors placed on the dorsal neck and hip to obtain interstitial glucose concentrations from each. After these initial readings, a 0.3 U/kg dose of regular human insulin (Humulin R, Eli Lilly and Company) was injected through the intravenous catheter. After insulin administration, interstitial glucose and blood glucose concentrations were measured as previously described every 10 minutes for a total of 90 minutes. At baseline, and again at 90 minutes, a small sample of blood was used to measure PCV via hematocrit tubes.
In addition to sample collection and analysis, students were responsible for recognizing clinical and biochemical evidence of hypoglycemia and intervening if deemed necessary. Throughout the entirety of the 90-minute study period, heart rate and mentation were monitored and when hypoglycemia or suggestive clinical signs (dullness, anxiety, and ataxia) were noted, students could administer a bolus of 50% dextrose solution (Vedco) or feed a commercial dog food (ProPlan puppy chicken and rice, Purina). The dextrose was first diluted with sterile water to reach a 20% concentration and administered via a catheter at a replacement dose to correct a hypothetical glucose deficit of 60 mg/dL in the extracellular (intravascular and interstitial) space. The “60 mg/dL deficit” refers to a decrease in plasma glucose from 100 to 40 mg/dL. Estimated extracellular fluid volume was used for the calculation because glucose rapidly distributes into both the plasma and interstitial fluid when administered IV. A total of 100 mg/dL was used as “normal” BG concentration and 40 mg/dL was designated as “hypoglycemia needing correction.” Students administered the dextrose dose as a single bolus, not as a continuous infusion. All dogs received a 5 mg dose of dexamethasone (VetOne) administered SC (median dose of 0.2 mg/kg body weight) that served as a 1-time replacement dose of glucocorticoid activity after insulin administration. The selection and timing of these interventions were largely left to the discretion of the students while under supervision by C.A.P., S.E.W., and J.B.E. Multiple interventions of dextrose and food, but not dexamethasone, could be administered if persistent hypoglycemia was noted after initial attempted correction. There were no set values for heart rate and mentation that would prompt intervention, but student groups were required to interpret trends in these parameters as they pertained to their specific dog and to act accordingly. Any glucose reading at or below 40 mg/dL required intervention.
After data collection, the IV catheter and glucose sensors were removed from each dog once their blood glucose concentrations stabilized and they clinically appeared euglycemic.
Statistical analysis
Continuous data were assessed for normality using Anderson-Darling tests and visual inspection of Q-Q plots. Parametric data are presented as mean (±SD) and nonparametric data are presented as median (minimum–maximum).
Glucose concentrations were compared between 2 sensor locations (between the scapulae/on the neck [site A] and the dorsolateral hip [site B]). Bland-Altman plots were constructed to compare the FGMS sites directly. Bias and 95% limits of agreement were calculated using a statistical software program (Prism, Version 5, GraphPad Software). Passing-Bablok regression compared the 2 FGMS locations and the 95% confidence bounds were calculated with the bootstrap (Bca) method.28
As previously described,18 accuracy was assessed according to ISO 15197:2013 criteria (“ISO criteria”; BSI Standards Publication, in vitro diagnostic test system-Requirements for BG monitoring system for self-testing in managing diabetes mellitus; EN ISO 15197:2013) as previously described.18,21 The mean absolute relative difference (MARD), median absolute relative difference (mARD), mean relative difference (MRD), and mean absolute difference (MAD) were calculated for each paired sample between FGMS sites as well as between the site B sensor and the PBGM. For timepoints when either the site A IG or BG concentration was ≤ 100 mg/dL, the percentage of paired IG concentrations from sensor site B within 15 mg/dL was recorded. For IG or BG concentrations > 100 mg/dL, the percentage of paired IG concentrations from site B within ±15% was recorded. According to the ISO criteria, at least 95% of the site B FGMS readings must adhere to these limitations for the device to be considered analytically accurate. To assess clinical accuracy, Parkes consensus error grids for type 1 diabetes were constructed comparing site B glucose to those from both the site A sensor and the PBGM. These grids divide paired glucose measurements into 5 “zones” depending on the degree of difference and associated risk posed to the patient. The zones are (1) no effect on clinical action, (2) altered clinical action unlikely to affect the outcome, (3) altered action likely to affect the outcome, (4) altered action could carry substantial patient risk, and (5) altered action could be dangerous to the patient. According to the ISO criteria, 99% of measured glucose results must fall within zones A and B. This analysis was performed with an open-access statistical software package Error Grid Analysis package.29 The cervical sensor location (sensor site A) was used as the reference standard, as this is the current conventional location for FGMS placement on dogs. The PBGM was used as an additional reference standard because this device monitors blood glucose concentrations with good clinical accuracy and is typically utilized for both in-house glucose curves and serial glucose monitoring in hospitalized patients at the authors’ institution.4,5,18,20
The mean skin thickness ±SD was calculated for each FGMS site, and sites were compared using a paired t test.
Results
Among the colony dogs, ages ranged from 2 to 6 years (median: 4 years) and weights ranged from 18.2–36.7 kg (median: 27.4 kg). Ten were male castrated and 14 were female (2 intact, 12 spayed). The body condition score was measured on a 9-point scale, and the median score was 5 (range = 5–6).
Out of a possible 240 paired FGMS measurements, a total of 209 were available for comparison. One dog removed sensor B (hip) twice and completed the study with only sensor A (neck) in place. There were no other issues associated with placing IV catheters nor FGMSs in any dog. Of the 31 missed readings, 21 (68%) of them were due to non-specific technical errors while the remaining 10 were due to a failure to correctly attach an FGMS to the hip of 1 subject (resulting in 10 “missed” readings). A single FGMS reading was “low,” consistent with an interstitial glucose concentration of ≤ 40 mg/dL. The initial median IG concentrations were 115 mg/dL (88–136 mg/dL) and 111.5 mg/dL (89–127 mg/dL). For the PBGMs values, all 240 measurements were available. Two results were outside the normal range of the device, with a single result reading “high” and another low (corresponding to BG concentrations ≥750 mg/dL and ≤ 20 mg/dL, respectively). The high reading was considered an error (as a spontaneous BG of >750 mg/dL, while all other measurements were either in the euglycemic or hypoglycemic range seemed highly unlikely) and was paired with 1 FMGS reading of 79 mg/dL and the other FGMS displaying “error.” The median initial PBGM measurement was 111 mg/dL (86–125 mg/dL).
The IG nadir (sensors A + B) was typically at the 50-minute time point whereas the BG nadir (PBGM) was typically earlier at 20 minutes. The changes in interstitial and blood glucose after insulin administration were followed over time (Figure 1).
Median interstitial glucose (IG) and blood glucose (BG; blue circle) concentrations in 24 healthy dogs after administration of 03 u/kg regular insulin IV. IG was measured via flash glucose monitoring system (FGMS) sensors placed on the dorsal neck (FGMS A, red square) and hip (FGMS B, black triangle). Glucose concentration nadirs typically occurred at the 20-minute time point for BG and at the 50-minute time point for IG.
Citation: American Journal of Veterinary Research 84, 6; 10.2460/ajvr.23.02.0024
There was a significant moderate positive correlation in IG measurements between the 2 FGMS sites (r = 0.731, P = < .001). A Bland-Altman plot revealed a constant bias of 5.6 mg/dL with 95% limits of agreement between −26.3 to 37.5 mg/dL. A proportional bias was not observed (Figure 2). Most of the divergence between the sites was seemingly random.
Bland-Altman plot (A) and Passing-Bablok regression (B) analysis comparing glucose measurements from flash glucose monitoring system (FGMS) placed on the neck and hip of 24 healthy dogs in which hypoglycemia was induced. There was a constant bias of 5.6 mg/dL with 95% limits of agreement of −26.3 to 37.5 mg/dL between FGMS locations, but a proportional bias was not apparent. There was a correlation between FGMS locations (r = 0.731; intercept = −2.676; slope = 0.971; P = < .001). FGMS = flash glucose monitoring system.
Citation: American Journal of Veterinary Research 84, 6; 10.2460/ajvr.23.02.0024
Data relevant to the ISO criteria for analytical accuracy (MARD, MAD, mARD, and MRD between sensor sites) are presented (Table 1). The number of paired readings when sensor B was within 15 mg/dL of the reference (sensor A) when the IG was ≤ 100 mg/dL was 100/142 (70.4%). This was below the > 95% mandated by ISO criteria. The number of paired readings when sensor B was within 15% of sensor A and the IG was > 100 mg/dL was 36/67 (53.7%) This was also below the > 95% mandated by ISO criteria.
Analytical accuracy of an FGMS placed on the hip (Libre site B) compared with the neck (Libre site A) and to the point of care blood glucose monitor (PBGM) in 24 healthy dogs in which hypoglycemia was induced.
| Libre site B vs A | Libre site B vs PBGM | |
|---|---|---|
| Low range (reference method BG < 100 mg/dL) | ||
| n | 142 | 158 |
| MAD (mg/dL) | 11.3 | 20.4 |
| Percent of values within ± 15 mg/dL of the BG value | 70.4 | 49.0 |
| High range (reference method BG ≥ 100 mg/dL) | ||
| n | 67 | 60 |
| MARD (%) | 15.9 | 21.6 |
| mARD (%) | 13.0 | 17 |
| MRD (%) | 9.8 | −15.2 |
| Percent of values within ± 15% of the BG value | 53.7 | 48.3 |
The Parkes consensus error grid describing the clinical accuracy of sensor B (as compared with the sensor A location) is shown. When comparing the sites, 100% of paired samples were within zones A and B (174/209 [83%] and 35/209 [17%], respectively) (Figure 3) meeting the minimum of 99% defined by ISO criteria for clinical accuracy.
Parkes consensus error grids comparing glucose measurements from the neck and hip FGMS sites (3a) and comparing the hip sensor site to a point of care blood glucose monitor (PBGM) (3b) in 24 healthy dogs in which hypoglycemia was induced. Zones are categorized as follows: (A) no effect on clinical action, (B) altered clinical action unlikely to affect outcome, (C) altered action likely to affect outcome, (D) altered action could carry substantial patient risk, and (E) altered action could be dangerous to the patient. When comparing the hip and neck sites, 100% of paired samples were within zones A and B (174/209 [83.25%] and 35/209 [16.75%], respectively). When comparing the hip site and the PBGM, 84.4% of paired samples were within zones A and B (136/219 [62%] and 48/219 [22%], respectively), with 34/219 (15.6%) within zone C.
Citation: American Journal of Veterinary Research 84, 6; 10.2460/ajvr.23.02.0024
Data relevant to the ISO criteria for analytical accuracy between sensor site B and the PBGM are also presented in Table 1. The number of paired readings when sensor B was within 15 mg/dL of the PBGM when glucose was ≤ 100 mg/dL was 77/158 (49%). The number of paired readings when sensor B was within 15% of the PBGM and glucose was > 100 mg/dL was 29/60 (48%) In both scenarios, this was below the > 95% mandated by ISO criteria. When using a Parkes consensus error grid to assess clinical accuracy, 88% of paired samples between site B and the PBGM were within zones A and B (136/219 [62%] and 48/219 [22%], respectively) (Figure 3) failing to meet the minimum 99% defined by ISO criteria for clinical accuracy.
There was no significant difference in skin thickness between FGMS sites (mean ± SD) location A: 2.1 ± 0.3 mm; location B: 2.1 ± 0.1 mm; P = .91).
Discussion
In this study of non-diabetic dogs with rapidly changing blood glucose, there was a correlation between glucose concentration readings from FGMS sensors placed between the scapulae and over the hip of dogs. There was no evidence of proportional bias and only a relatively small constant bias of 5.6 mg/dL between sites. However, the 95% limits of agreement were relatively wide (−26.3 to 37.5 mg/dL) and most of the variation between the 2 sites appeared random. When using the neck site (site A) as a reference standard, the hip site (site B) failed to meet ISO criteria for analytical accuracy. However, Parkes error grid analysis suggested the variation between the sites would be unlikely to have a major detrimental effect on clinical decision-making.
These findings reflect those of a previous study by Koenig et al in which continuous glucose monitoring systems were applied to multiple different locations on dogs undergoing a glycemic clamp procedure.24 In that study, the differences in values between the PBGM and IG sites during euglycemia were minimal, but they were much more pronounced during BG fluctuations and hyper- or hypoglycemia.24 In those dogs, the lateral thorax was found to be the most accurate IG monitoring site, while in diabetic cats the dorsal neck was proposed to be so.25 The study in cats assessed 3 total sites (knee, neck, and thorax), which all performed similarly.25 This cat study had a relatively small sample size (n = 18) and neither study utilized FGMSs. In humans, regional differences in abdominal and forearm IG have been identified with CGMS and FGMS.15,30
In the current study, FGMS site B met the ISO criteria for clinical accuracy (assessed using a Parkes error grid) when compared with the reference standard site A. When compared with site A, 83% and 17% of paired samples from site B were within zones A and B, respectively. This is similar to results from previous studies, where cervical FGMS sensors performed with satisfactory clinical accuracy when compared with PBGM.17,18,20,22 In these prior studies, however, FGMS failed to meet ISO criteria for analytical accuracy when compared with a reference standard, and the same was found with the novel hip FGMS site in our study. Interestingly, in a study previously performed by our group using the same model of rapidly induced hypoglycemia in healthy dogs, FGMS placed on the neck were shown to be neither clinically nor analytically accurate compared with blood glucose measured with a clinical biochemical analyzer.21 In that study, a direct comparison between the FGMS and PBGM was not made. The novel hip FGMS sensor site in our study failed in both clinical and analytical accuracy when compared with PBGM. Our intention, however, was to compare a novel sensor location (hip) to the conventional location (neck). It should be noted that the ISO criteria are intended to compare blood glucose meters in humans and not glucose meters to CGMS or FGMS and that the differences between BG and IG likely contribute to variation between sample types.
One such contributing factor to the discrepancy between the BG and IG is the physiologic “lag time” between the blood and interstitial space, which has been estimated to be anywhere between 5–20 minutes.10–12,24,31 IG is under the control of complex feedback mechanisms dependent on blood glucose concentration and may be the more clinically accurate metric by which to judge insulin dosing.32–34 The delay between these 2 compartments is likely accentuated by large sudden changes in blood glucose, and IG monitoring systems are less accurate with rapid fluctuations.21,24 This lag time is also manifested in the delayed nadir recorded with IG (approximately 50 minutes) compared with BG (20 minutes), which we previously observed using this model of rapidly induced hypoglycemia in healthy dogs.21
There was minimal variation in skin thickness among all dogs, and there was no significant difference between sites. A previous study indicated that an FGMS may be less accurate in dogs with skin < 5 mm, but it is possible that the small sample size and the existence of concurrent endocrinopathies in that study population affected the results.27 However, in our study, due to the lack of variation in skin thickness between sites, we were unable to assess its effect on FGMS readings.
This study is not without limitations. One limitation is the lack of biochemical analyzer BG measurements obtained via the hexokinase method as a reference standard. In prior studies, PBGM has performed satisfactorily when monitoring BG,4,5 and has previously served as a gold standard in studies of IG sensor location and diabetic monitoring.18,20,25 In clinical practice, however, the cervical site for FGMS placement is essentially the only location used in small animals, and so this location served as our “clinical” reference standard. With this approach, we aimed to determine whether the hip site would result in the same clinical decisions as the cervical site and could thus serve as a clinically equivalent sensor location if the conventional neck site is not feasible. Another limitation is that in our study is that we studied non-diabetic dogs with hypo- or euglycemia, which is not the typical scenario for which glucose monitoring is used. The relationship between interstitial glucose and blood glucose is complex, and the mechanisms involved may be altered in states of prolonged insulin deficiency and hyperglycemia.11,12 A study further evaluating the performance of the FGMS sensor hip site in diabetic patients is the necessary next step to determine the true potential clinical utility of this site. There was no standardization of the population or interventions, and a small number of technical errors impacted data collection.
In this model of rapidly induced hypoglycemia in healthy dogs, variation in glucose concentration measurements between FGMS sensors placed in the traditional location between the scapulae and an alternative location over the hip occurred. The differences were seemingly random in nature as the absolute bias was relatively low and there was no evidence of proportional bias. However, the variation observed was unlikely to have led to decisions that would have adversely affected the clinical outcome. Placing FGMS over the hips of dogs may be an acceptable alternative to placement between the scapulae, but further research is needed to determine whether the FGMS hip site is capable of similar accuracy when used in diabetic, hyperglycemic dogs.
Acknowledgments
No external funding was received for this study. The data from this study was presented as an abstract at the 2022 ACVIM Forum.
The authors declare no conflict of interest.
Institutional Animal Care and Use Committee (IACUC) or Other Approval Declaration.
Approved by the Texas A&M University IACUC (#2022-0172).
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