Chest
Volume 153, Issue 6, June 2018, Pages 1368-1377
Journal home page for Chest

Original Research: Critical Care
Vitamin C Pharmacokinetics in Critically Ill Patients: A Randomized Trial of Four IV Regimens

Part of the results from this article has been presented in abstract form (de Grooth HJ, Choo WP, Spoelstra - de Man AM, Swart EL, Oudemans-van Straaten HM. Intensive Care Med Exp. 2016;4(suppl 1):A52).
https://doi.org/10.1016/j.chest.2018.02.025 Get rights and content

Background

Early high-dose IV vitamin C is being investigated as adjuvant therapy in patients who are critically ill, but the optimal dose and infusion method are unclear. The primary aim of this study was to describe the dose-plasma concentration relationship and safety of four different dosing regimens.

Methods

This was a four-group randomized pharmacokinetic trial. Patients who were critically ill with multiple organ dysfunction were randomized to receive 2 or 10 g/d vitamin C as a twice daily bolus infusion or continuous infusion for 48 h. End points were plasma vitamin C concentrations during 96 h, 12-h urine excretion of vitamin C, and oxalate excretion and base excess. A population pharmacokinetic model was developed using NONMEM.

Results

Twenty patients were included. A two-compartment pharmacokinetic model with creatinine clearance and weight as independent covariates described all four regimens best. With 2 g/d bolus, plasma vitamin C concentrations at 1 h were 29 to 50 mg/L and trough concentrations were 5.6 to 16 mg/L. With 2 g/d continuous, steady-state concentrations were 7 to 37 mg/L at 48 h. With 10 g/d bolus, 1-h concentrations were 186 to 244 mg/L and trough concentrations were 14 to 55 mg/L. With 10 g/d continuous, steady-state concentrations were 40 to 295 mg/L at 48 h. Oxalate excretion and base excess were increased in the 10 g/d dose. Forty-eight hours after discontinuation, plasma concentrations declined to hypovitaminosis levels in 15% of patients.

Conclusions

The 2 g/d dose was associated with normal plasma concentrations, and the 10 g/d dose was associated with supranormal plasma concentrations, increased oxalate excretion, and metabolic alkalosis. Sustained therapy is needed to prevent hypovitaminosis.

Trial Registry

ClinicalTrials.gov; No.: NCT02455180 ; URL: www.clinicaltrials.gov

Section snippets

Patients

This randomized factorial pharmacokinetic trial was performed between March 2015 and November 2016 in the mixed medical/surgical ICU of VU University Medical Center in Amsterdam, The Netherlands. The analysts determining the vitamin C and oxalate concentrations were blinded to treatment allocation. The trial protocol was registered at ClinicalTrials.gov before patient inclusion (identifier NCT02455180 ).

The study was approved by the medical ethics committee of VU University Medical Center

Results

Twenty patients (five per dosage regimen) were included and randomized (Fig 1). Baseline characteristics are shown in Table 1. All patients received the allocated study medications. No patients died during the 96-h study period.

Dose-Plasma Concentration Relationship

In this four-group randomized pharmacokinetic trial, 20 patients with multiple organ failure were randomized to receive either 2 or 10 g/d vitamin C administered as a twice daily 15-min bolus infusion or continuous infusion.

Two grams per day resulted in normal plasma concentrations, and 10 g/d resulted in supranormal concentrations. Bolus infusion caused higher 1-h concentrations but also caused trough concentrations that approached the hypovitaminosis cutoff in the 2 g/d dose group. Plasma

Conclusions

The present four-group randomized trial in patients with multiple organ dysfunction found that 2 g/d of IV vitamin C resulted in normal plasma concentrations, whereas supraphysiologic concentrations were achieved with 10 g/d. Although renal losses were substantial, high concentrations can be achieved with higher IV doses in a linear dose-concentration relationship. Sustained vitamin C administration is needed to prevent a decline to hypovitaminosis. Urine oxalate excretion was related to the

Acknowledgments

Author contributions: H.-J. G. and H. M. O.-S. take responsibility for the work as a whole, from inception to published article. H.-J. G., W.-P. M.-C., E. L. S., and H. M. O.-S. contributed to study conception and design. H.-J. G., W.-P. M.-C., A. M. E. S.-M., and H. M. O.-S. were responsible for the inclusion of patients, study procedures, and sample handling. W.-P. M.-C. and A. S. Z. performed the pharmacokinetic modeling. H.-J. G. performed the other analyses. A. R. G. and E. L. S. provided

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  • Cited by (0)

    Drs de Grooth and Manubulu-Choo contributed equally to this manuscript.

    FUNDING/SUPPORT: This study was performed on departmental funding.

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