Interaction between vitamin C and point of care glucose monitoring. are we overly wary of it or is it a valid concern?

This editorial intends to revisit the interaction between vitamin C and point of care (POC) glucose monitoring on the backdrop of a recent study performed by Juan et al. in the relevant topic¹. The authors have aimed to determine if high dose vitamin C interferes with POC glucose measurement leading to erroneous results by conducting a single centered, retrospective, observational case series study.

Vitamin C, also known as ascorbic acid, is a water-soluble vitamin synthesized by the majority of mammals, but not by humans. It has been implicated historically in the treatment of scurvy² but its utility in clinical practice has witnessed a massive resurgence lately. Role of vitamin C along with hexose transporters (Gluts) have been the subject of interest in cancer treatment as well. Vitamin C exist in reduced and oxidized forms; namely ascorbic acid and dehydroascorbic acid (DHA). Gluts and DHA have been proposed as potential targets for synergistic pharmacological targets in certain cancers³. Data emanating from the efficacy of vitamin C in sepsis has sparked enthusiasm in a significant quarter of medical professionals. The prevailing literature generally do not consider that vitamin C in an aqueous solution is rapidly oxidized to dehydroascorbic acid (DHA), a molecule that is very similar to glucose. The effect that vitamin C has on the activation of neutrophils in sepsis is very interesting, considering that neutrophils do not incorporate ascorbic acid, they only transport DHA⁴. The basis for use of vitamin C in sepsis and respiratory failure or acute respiratory distress syndrome (ARDS) is primarily based on its antioxidant property, ability to downregulate cytokine activity, and blunt neutrophil accumulation in the alveoli and subsequent damage to the alveolar-capillary interface^2,5. In a retrospective before-after study by Marik et al., early use of vitamin C along with thiamine and corticosteroids in severe sepsis and septic shock was shown to prevent progressive organ dysfunction⁶. Patients in this study received 1500 mg of vitamin C every 6 h intravenously for four days or till discharge from the intensive care unit (ICU)⁷. Fowler III et al. used a 96-hour infusion of vitamin C at 50 mg/kg every 6 h in a randomized, double-blind, placebo-controlled multicenter trial⁸. This study did not reveal significant improvement in organ dysfunction or attenuation of inflammatory markers but did show an improvement in 28-day all-cause mortality with the use of vitamin C (29.8 vs 46.3%, p-value of .03). It also revealed greater ICU free days (1.7 vs 7.7 days, a p-value of .03) and improved hospital free days (22.6 vs 15.5 days, a p-value of .04) in the patient cohort receiving vitamin C⁸. Thus, it becomes obvious that clinicians and researchers enthused by the prospect of vitamin C adding to the current armory of the fight against sepsis have caused an upsurge in its use. Besides, vitamin C has also been found to be advantageous in patients with burn by its ability to decrease endothelial improve urinary output⁷. With the outbreak of coronavirus disease 2019 (COVID 19), researchers have scoured every possible prevailing resource to tackle the virus.

The use of vitamin C, often in intravenous form, has garnered an optimistic utility all across the globe. Results of an ongoing randomized controlled trial clinicaltrials.gov (Identifier NCT 04264533) is expected by the end of September 2020 which if favorable, can consolidate the trend of using vitamin C further in COVID 19 pneumonia and ARDS⁹. As much as we are excited about the tantalizing prospect of vitamin C being an important adjunct in sepsis, ARDS, burn, and COVID 19, it is an obligation of the medical fraternity to subject vitamin C to intense scrutiny for possible adverse effects. The study by Juan et al. will add to the existing literature about vitamin C and POC glucose monitoring and fortify safety measures in the patient care.

Juan et al.¹ conducted a retrospective, single-center, observational study that included 82 eligible septic patients admitted to the emergency ICU of their hospital in China. Patients received a daily dose of vitamin C ranging from 50 mg/kg to 200 mg/kg at a constant rate of 1 gm/hour. 50 to 100 mg/kg/24 h was classified as low dose vitamin C while 100–200 mg/kg/24 h was classified as high dose vitamin C (hDVC). These patients received at least 3 days of hDVC. This study compared paired values of POC glucose with laboratory glucose (LG) measurement 15 min prior and after the infusion of hDVC. The study duration lasted 3 years from January 2016 to December 2019.

The glucose oxidase-peroxidase colorimetric method was used for POC glucose measurement while the hexokinase spectrometric method was used for LG measurement. It should be noted in the context of this study that that blood for POC and LG utilize venous blood samples. Accuracy of paired POC glucose measurement and LG values and detection of any clinically significant difference in these paired values were the primary endpoint. Wilcoxon’s matched paired test was used to detect any such difference. The secondary endpoint of the study was the accuracy of POC glucose measurement based on different renal functions.

Out of 141 septic patients admitted to the emergency ICU and treated with hDVC, only 82 patients were included in the final study. The median amount of vitamin C was reported to be 100 mg/kg/day while the median duration was 9 days. 35 patients received a high dose while 47 of the study participants received a lower dose. Results indicated that POC glucose measurement was lower than the LG values both before and after the administration of hDVC in all 35 subjects. Paired values of POC glucose and LG values in terms of relative difference percentages were higher with hDVC (17.86 ± 35.68% vs −12.43% ± 21.44%, p-value .01)¹. Parkes Consensus Error Grid Analysis showed a larger difference between LG and POC glucose measurement in patients on renal replacement therapy or renal impairment per se.

Amidst the growing excitement surrounding the utility of vitamin C in various aforementioned clinical practice scenarios, issues of fictitious hyperglycemia have raised some eyebrows. There have been reports of falsely elevated POC glucose as compared to LG measurement in burn patients that received infusion of vitamin C¹⁰. This discrepancy has been reported to range from the mean value of vitamin C of 138 mg/dL- 225 mg/dL. The mean POC glucose range was 225 ± 71 mg/dL and it was significantly higher than mean LG 138 ± 41 mg/dL on hdVC (p = .002)⁷. Glucose and vitamin C have similar molecular structures with both bearing 6-carbon molecules. Oxidation of ascorbic acid by glucose oxidase and dehydrogenase generates electric current measured as glucose¹¹. Falsely elevated POC glucose can trigger an inappropriately aggressive treatment response leading to patient morbidity and mortality¹⁰. Comparative studies of most commonly used POC glucose monitoring devices have shown that unphysiologic ascorbic acid concentration can erroneously increase glucose measurement by more than 30% irrespective of the technology used¹².

In the study by Juan et al., surprisingly significantly lower value was obtained for POC glucose as compared to LG values before hdVC infusion (158.08 ± 62.08 mg/dL vs 186.25 ± 71.50 mg/dL, p < .001) or after hdVC treatment (142.90 ± 58.91 mg/dL vs 186.74 ± 72.74 mg/dL, p < .001. This result is different from spurious higher values of POC glucose reported in the studies and case reports published so far^10–12. Juan et al. opine that the colorimetric method used in their study principally differs in mechanism from studies that used glucose dehydrogenase pyrroloquinoline quinine for POC glucose measurement¹. The use of this different technology might have spuriously yielded lower value as opposed to fictitious hyperglycemia reported so far¹.

It should be a general notion to the readers that the use of the hexokinase method for measuring serum glucose is not affected by ascorbic acid, thus it does not cause factitious hyperglycemia in patients subjected to the administration of high doses of ascorbic acid. Authors of this study have also concluded that erroneous POC glucose reading is induced by hDVC only as compared to low dose but a smaller sample size and lack of definite serum vitamin C measurement are two major limiting factors for this observation¹. Based on the Parkes Consensus Error Grid analysis of the data, authors have also deduced that worse kidney function would result in greater inaccuracy in POC glucose monitoring. This finding is consistent with the preexisting notion that water solubility and urinary excretion of vitamin C in septic patients depend on their renal function¹³.

As the enthusiasm surrounding the clinical utility of vitamin C continues to soar, it would be prudent to meticulously analyze associated fallacies. Adopting a precautionary approach while interpreting POC glucose reading in patients on hDVC seems to be necessary. Data obtained from Juan et al. has laid a good foundation for a larger randomized controlled trial to further verify the effects of hDVC on POC and laboratory glucose measurement.

Transparency

Declaration of funding

This paper was not funded.

Declaration of financial/other relationships

SS has been part of the speakers bureau for Theravance Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

None stated.