Safety of Continuously Infused High Dose Vitamin C

April 19, 2012

This study was done in conjunction with a series of studies by the Matsuda group that involved the use of high doses of infused vitamin C in severely burned subjects.  They had been testing high dose vitamin C as an anti-oxidant in an attempt to diminish the delayed injury that always occurred in severely burned patients. Their initial studies involved rats, guinea pigs and eventually anesthetized dogs to show the efficacy of this technique.  There was some resistance in the medical community to using these rather high doses of vitamin C, especially in patients with such a disturbed fluid and salt balance as those with severe or extensive burns.

This study was done to show that high dose vitamin C was not harmful in normal human subjects with the implication being that it may also be safe in burned subjects.  Interestingly, this therapy has, in the years since performing this study, become a fairly widely used modality for extensively burned subjects and has proven to be very effective in stabilizing the otherwise precariously unbalanced hemodynamic condition of these patients.

The full paper and a link to the PDF are shown below.

Safety of Continuously Infused High dose Vitamin C

The Safety of Continuous Intravenous Infusion Of

High‑dose Vitamin C in Healthy Humans

by

Takayoshi Matsuda, M.D., Hideki Yuasa, M.D., Walid Khabaz, M.D.,

Candice Richardson, Pharm D., Marella Hanumadass, M.D.,

and Robert J. Walter, Ph.D.

Burn Center and Department of Surgery, Cook County Hospital;

Department of Surgery, University of Illinois;

Hektoen Institute for Medical Research, Chicago, IL

Presented at the Twenty‑sixth Annual Meeting of the American

Burn Association, Orlando, Florida, April 20‑23, 1994.

Address all correspondence to:

            Robert J. Walter, Ph D.

Division of Surgical Research

Department of Surgery

Cook County Hospital

627 South Wood Street

Chicago, IL  60612

Tel:  (312)-633-7237 (office)

Fax:  (312)-633-8347

ABSTRACT

Background:  It has been shown that continuous intravenous infusion of vitamin C in high doses (14 mg/kg/hr) decreases postburn capillary permeability and reduces the resuscitation fluid volume requirements by 75% in burned animals. 

Methods:  In the present study, the effects of an 8 hr intravenous infusion of high‑dose vitamin C (0.5, 1.0, and 2.0 gm/hr) were evaluated in 4 healthy adult volunteers. 

Results:  Plasma vitamin C levels ranged from 4 to 16 μg/ml at baseline, and increased to 41-90 μg/ml during the infusion of 0.5 g/hr vitamin C, to 92-152 μg/ml during the 1 g/hr infusion, and to 162-290 μg/ml during the 2 g/ hr infusion.  Plasma vitamin C values decreased rapidly after termination of the infusion and returned to baseline by 16 hours postinfusion.  None of the subjects developed any subjective symptoms.  Vital signs, EKG monitoring, urinalysis, and hematology and chemistry blood tests before, during, and after the vitamin C infusion were all within normal limits. 

Conclusions:  Continuous intravenous infusion of up to 2 g/hr of vitamin C for 8 hrs appeared to have no adverse effects on healthy adult humans.

Key Words: VITAMIN C,  SAFETY,  ANTIOXIDANT,  HIGH‑DOSE

INTRODUCTION

Burn injuries cause increased capillary permeability which results in extensive fluid and protein leakage from the intravascular space.  For extensively burned patients, a massive volume of fluid is required for resuscitation during the first 24 hours postburn in order to prevent hypovolemic shock.  Friedl and associates have demonstrated that increased postburn capillary permeability is due to capillary endothelial damage caused by free radicals generated by the increased activity of xanthine oxidase ¹.  We have previously demonstrated in animal studies that continuous intravenous infusion of a natural antioxidant, vitamin C, in high doses (14 mg/kg/hr) minimizes the burn tissue lipid peroxidation ² and reduces fluid and protein leakage from the intravascular space to the interstitial space ³.  We have also shown that, for guinea pigs with 70% body surface area (BSA) burns, the resuscitation fluid volume requirements can be reduced by 75% with adjuvant administration of vitamin C ⁴.  It has also been reported that the administration of vitamin C must be continued for at least 8 hours in order to maintain adequate hemodynamic stability when the burned animals are resuscitated with a reduced fluid volume ⁵.

Before this high‑dose vitamin C therapy can be advanced to a clinical trial in burned patients, the possible toxicity or adverse side effects of such therapy must be determined.  The present study was undertaken to evaluate the safety of short‑term intravenous infusion of high‑dose vitamin C in healthy human volunteers.

SUBJECTS AND METHODS

Study subjects.  Four (4) healthy male volunteers, ages 28 to 34 years with body weights ranging from 68 to 90 kg, participated in the study.  The experimental protocol was approved by the Institutional Review Board of the Cook County Hospital and each subject signed an informed consent.  There was no financial payment to the volunteers for their participation in the study.  One week prior to the initiation of the study, a complete history was obtained, a physical examination performed, and baseline blood samples drawn.  The history, the physical examination, and all the blood test values were confirmed to be within normal limits before the initiation of the study.  None of the subjects had a history of kidney disease, and none were taking routine vitamin C supplements.

Preparation of Vitamin C Solution.  An injectable vitamin C solution, Cenolate (500 mg/ml; Abbott Laboratories Hospital Products Division, Abbott Park, IL), was diluted with sterile water at a ratio of 1 to 17.44 (vol/vol).  The concentration of vitamin C and sodium in this diluted sodium ascorbate solution was 27.11 mg/ml and 154 mEq/L, respectively.

Dosing Schedule.  Three different doses of vitamin C (i.e., 8 hour infusion of 0.5, 1.0 and 2.0 g/hr) were studied in each of the subjects with one week intervals between each infusion.  In the first week, a loading dose of 0.5 g vitamin C was infused over 20 minutes, followed by a continuous infusion of 0.5 g/hr of vitamin C (0.26 ml/kg/hr) for 8 hours.  In the second and third weeks, 1.0 g/hr and 2.0 g/hr doses of vitamin C were studied, respectively, using an identical scheme.

Conduct of the study.  The study was performed on the Intensive Care Unit of the Burn Center at Cook County Hospital.  On the morning of the study day, the subject was assigned to a bed with ambulation privileges ad libitum.  The subject remained in the Burn Center for approximately 24 hours and then returned to the Burn Center as required for follow‑up data collection.  A regular hospital diet was provided and water was given ad libitum throughout the study period.

A catheter was inserted into a forearm vein for blood drawing and then kept open with a heparin lock for subsequent blood samplings at predetermined intervals during and after the infusion of vitamin C.  After obtaining a blood sample for the baseline measurement, a venous catheter was inserted into the opposite forearm and the vitamin C infusion was initiated.

           

            Monitoring and Data Collection.  Vital signs were measured every hour during the infusion, and every 4 hours thereafter until 12 hours postinfusion.  The subject was placed on a continuous EKG monitor.  Fluid intake and urine output during the study day were recorded.  Urinalysis (specific gravity, pH, sugar, acetone, protein, blood, and microscopic examination) was performed prior to the vitamin C infusion, during the 24‑hour study period (i.e., 8 hours infusion and 16 hours postinfusion), and at 24 hours and 7 days postinfusion.  Hematological tests (CBC and coagulation profile) and blood chemistries (sodium, potassium, chloride, bicarbonate, calcium, glucose, total protein, albumin, globulin, phosphorus, cholesterol, urea nitrogen, creatinine, alkaline phosphatase, SGOT, SGPT, GGT, and LDH) were performed at baseline, at the end of the vitamin C administration, and at 1 and 7 days postinfusion.  Tests for urine and blood as described above were determined in the hospital's central clinical laboratories.

Blood samples for venous blood gases were drawn at baseline, and at 1, 2, 4 and 8 hours during the vitamin C infusion.  These results were determined in the Neonatology Stat Laboratory of Cook County Hospital.  Plasma vitamin C levels were drawn at baseline, and at 1, 2, 4, and 8 hours during the vitamin C infusion, and analyzed in the Burn Center research laboratory using HPLC ⁶.

RESULTS

Each of the four subjects completed the three‑week study for the evaluation of the three different doses of vitamin C.  None of the subjects developed any subjective symptoms that may be related to drug reaction such as headache, dizziness, nausea, vomiting, abdominal pain, or diarrhea.  Vital signs monitored during the study periods remained essentially within normal limits. There were no abnormalities detected in the EKG monitoring.  All the laboratory measurements before, during, and after the vitamin C administration in each of the subjects were within normal limits.  Follow‑up examinations and laboratory tests of all the subjects both one week and one month after the 2 g/hr infusion revealed no abnormalities.

The plasma vitamin C levels of one of the subjects before, during, and after the infusion of the three different doses of vitamin C are shown in Figure 1.  The plasma vitamin C levels of all four subjects at 2 g/hr dose are illustrated in Figure 2.  Plasma vitamin C levels of all the subjects ranged from 4-16 μg/ml prior to the vitamin C infusion.  Levels increased to 41-90 μg/ml during the infusion of 0.5 g/hr vitamin C, to 92-152 μg/ml during the 1 g/hr infusion, and to 162-290 μg/ml during the 2 g/hr infusion.  The plasma vitamin C values of all the subjects decreased rapidly after termination of the infusion, and returned to baseline by 16 hours postinfusion.

DISCUSSION

Vitamin C (ascorbic acid) is a six-carbon, water‑soluble vitamin which is structurally related to glucose and other hexoses ⁷.  Its physiological functions are numerous.  Severe or prolonged deficiency leads to the clinical condition known as scurvy.  The recommended daily dietary allowance of vitamin C for the healthy adult is 60 mg/day ⁸, which will prevent signs of scurvy for at least 4 weeks.  Vitamin C is also a well-known naturally-occurring antioxidant ^9‑11.  We have previously shown that continuous intravenous infusion of vitamin C in high doses (14 mg/kg/hr) decreases burn tissue lipid peroxidation ², minimizes postburn capillary permeability ³, and reduces the resuscitation fluid volume requirements in burned animals by 75% ⁴.  When vitamin C is administered via intravenous infusion, it is impossible to elevate the concentration of vitamin C selectively in the burned area only, instead the concentration of vitamin C in the total extracellular fluid must be elevated to the level required by the burned tissue.  This resulting plasma concentration of vitamin C is dependent upon the dose of vitamin C administered.  The minimum dose of vitamin C that was necessary to achieve the desired therapeutic effects in our animal experiments was 14 mg/kg/hr ⁴.  This dosage, equivalent to 1,000 mg/hr for a 70 kg adult, is very large as compared to the physiological maintenance dose (60 mg/day) and represents a pharmacological dose.

Pauling ¹² has advocated the ingestion of large doses of vitamin C as an antioxidant for health maintenance.  His recommended daily dose is 0.25 to 5 grams for a healthy adult based upon the extrapolation of the rate of vitamin C synthesis observed in animals ¹².  In addition, he recommends an even greater dosage, 5 to 20 g/day, for the treatment of illnesses such as the common cold ¹³.  The efficacy and safety of so‑called "megadose" vitamin C ingestion for the common cold, however, is controversial.  

Rivers, one of the organizers of the "Third New York Academy of Sciences Conference on Vitamin C" held in 1986, concluded ¹⁴ that the use of large quantities of ascorbic acid did not result in the production of calcium‑oxalate stones, increased uric acid excretion, impaired vitamin B12 status, iron overload, systemic conditioning, or increased mutagenic activity in healthy individuals.  The only contraindication regarding the ingestion of large quantities of vitamin C mentioned in that paper ¹⁴ relates to patients with renal impairment and patients on chronic hemodialysis.  Furthermore, any reported criticism of "megadose" vitamin C ingestion has been directed toward chronic or long‑term usage of high-dose vitamin C.  To our knowledge, the safety of short‑term (e.g., 8 to 24 hours) intravenous infusion of high‑dose, neutral pH, vitamin C has not been evaluated elsewhere.  

In the present study, none of the subjects developed any overt symptoms nor abnormal laboratory values associated with the high‑dose vitamin C infusion.  Although the number of subjects studied was small, it appears that continuous intravenous infusion of up to 2 grams per hour of vitamin C for 8 hours is not detrimental to healthy adult humans.

Vitamin C (ascorbic acid) has a low molecular weight (176 g/mol), and passes freely through the glomerular filtration barriers.  Reabsorption of ascorbate from glomerular filtrate in the renal tubules is an active, saturable process ¹⁴.  It has been shown that the reabsorption mechanism is saturated at plasma levels of 8 to 9 μg/ml ^15,16.  Plasma ascorbate in excess of that required to maintain plasma levels at approximately 10 μg/ml is, therefore, efficiently eliminated by the kidney.  The rapid decrease in the plasma ascorbate level after the termination of vitamin C infusion in the present study supports this contention.  The continuous high plasma ascorbate levels depicted during the infusion of vitamin C in the present study suggests that intake has exceeded the elimination capability of the kidneys resulting in elevation of plasma ascorbate levels.

REFERENCES

1.  Freidl HP, Till GO, Trentz O:  Roles of histamine, complement and xanthine oxidase in thermal injury of skin. Amer J Pathol 135:203, 1989.

2.  Matsuda T, Tanaka H, Yuasa H:  The effects of high‑dose vitamin C therapy on postburn lipid peroxidation. J Burn Care Rehabil 14:624, 1993.

3.  Matsuda T, Tanaka H, Hanumadass M:  Effects of high‑dose vitamin C administration on postburn microvascular fluid and protein flux. J Burn Care Rehabil 13:560, 1992.

4.  Matsuda T, Tanaka H, Williams S:  Reduced fluid volume requirement for resuscitation of third degree burns using high dose vitamin C. J Burn Care Rehabil 12:525, 1991.

5.  Tanaka H, Broaderick P, Shimazaki S:  How long do we need to give antioxidant therapy during resuscitation when its administration is delayed for two hours? J Burn Care Rehabil 13:567, 1992.

6.  Dennison DB, Brawley TG, Hunter GL:  Rapid high‑performance liquid chromatographic determination of ascorbic acid and combined ascorbic acid‑dehydroascorbic acid in beverages. J Agr Food Chem 29:927, 1981.

7.  Gilman A, Goodman L, Rall T., eds. The phamacological basis of therapeutics. New York: MacMillan Publishing Co. 1985; 1567‑1568.

8.  Food and Nutrition Board, National Research Council. Recommended dietary allowances. 1989; 10th edition:p 118 Washington, DC. National Academy of Sciences.

9.  Nishikimi M:  Oxidation of ascorbic acid with superoxide anion generated by the xanthine‑xanthine oxidase system. Biochem Biophys Res Comm 63:463, 1975.

10.  Bielski BHJ, Richter HW, Chan PC:  Some properties of the ascorbate free radical. Ann NY Acad Sci 258:231, 1975.

11.  Bodannes RS, Chan PC:  Ascorbic acid as a scavenger of singlet oxygen. FEBS Letters 105:195, 1979.

12.  Pauling L. Vitamin C, the common cold, and the flu. San Francisco: W.H.Freeman and Company, 1976; 145‑146.

13.  Pauling L. Vitamin C, the common cold, and the flu. San Francisco: W.H.Freeman and Company, 1976; 148

14.  Rivers JM:  Safety of high‑level vitamin C ingestion. Ann NY Acad Sci 498:445, 1987.

15.  Hagler L, Herman RH:  Oxalate metabolism.  I. Amer J Clin Nutr 26:758, 1973.

16.  Hagler L, Herman RH:  Oxalate metabolism.  II. Amer J Clin Nutr 26:882, 1973.

FIGURES

 Figure 1.  The plasma vitamin C levels of one of the subjects before, during, and after the infusion of three different doses of vitamin C (i.e., 0.5, 1.0, or 2.0 g/hr).  The plasma vitamin C levels increased rapidly, remained elevated throughout the 8 hour infusion period, and decreased rapidly upon termination of the infusion.

Figure 2.  Plasma vitamin C levels of four subjects infused at a dosage of 2 g/hr.  The plasma vitamin C levels increased to 162 to 290 μg/ml during the infusion period, but decreased rapidly upon termination of the infusion.  Vitamin C levels for each subject are shown as individual data points and the mean of these four data points at each time is shown as a line.

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