Elsevier

Journal of Surgical Research

Volume 109, Issue 2, February 2003, Pages 144-148
Journal of Surgical Research

Shock/Sepsis/Trauma/Critical care
Ascorbic acid dynamics in the seriously ill and injured

https://doi.org/10.1016/S0022-4804(02)00083-5 Get rights and content

Abstract

Background. In addition to the known beneficial effects of ascorbic acid on wound healing and the immune response, it is also a potent extracellular antioxidant. Recent work in septic rats suggests that high-dose ascorbic acid total parenteral nutrition (TPN) supplementation may protect cells from free radical injury and improve survival. In this study, we determined ascorbic acid levels in the immediate post-injury/illness period and evaluated the ability of early short-term high levels of ascorbic acid in TPN to normalize plasma levels.

Materials and Methods. Ascorbic acid levels were determined in 12 critically injured patients and 2 patients with severe surgical infections. Each patient received TPN supplemented with increasing doses of ascorbic acid over a 6-day period. Therapeutic responses were determined by plasma and urine measurements using high-pressure liquid chromatography.

Results. The initial mean ± SEM baseline plasma ascorbic acid concentration was depressed (0.11 ± 0.03 mg/dl) and unresponsive following 2 days on 300 mg/day supplementation (0.14 ± 0.03; P = 1.0) and only approached low normal plasma levels following 2 days on 1000 mg/day (0.32 ± 0.08; P = 0.36). A significant increase was noted following 2 days on 3000 mg/day (1.2 ± 0.03; P = 0.005).

Conclusion. We confirmed extremely low plasma levels of ascorbic acid following trauma and infection. Maximal early repletion of this vitamin requires rapid pool filling early in the post-injury period using supraphysiologic doses for 3 or more days.

Introduction

Ascorbic acid deficiency is characterized by hemorrhage, impaired secretory functions, vasomotor instability, hematologic alterations, impaired wound healing, depressed immune response, and psychological disturbances. The metabolic role of ascorbic acid is related to an oxidation and reduction reaction in which ascorbic acid is reversibly oxidized to dehydroascorbic acid. Ascorbic acid promotes the hydroxylation reaction in a number of biosynthetic pathways 1, 2. Hydroxylation is required to stabilize the triple helical conformation of collagen. Compromised collagen production associated with ascorbic acid deficiency results in impaired wound healing [3].

Ascorbic acid at concentrations ranging from 2.5 to 5 fentamoles has been reported to stimulate the migratory responses of neutrophils and monocytes in vitro [4]. Studies in scorbutic guinea pigs have demonstrated impaired cell-mediated immune mechanisms in vivo, manifested as anergy to mycobacterial antigens 5, 6 and also prolonged survival of skin allografts [7]. Ascorbic acid has also been shown to improve resistance to infection with microbial pathogens [4].

The body pool of ascorbic acid is reported to be about 20 mg/kg body wt 8, 9. Once the body pool is saturated, further oral intakes appear unchanged in the urine 8, 9, 10. Acceptable serum levels are considered to be 0.4 to 1.5 mg/dl 11, 12. In the United States, the recommended adult dietary allowance is 60 mg/day. This amount reportedly maintains the body pool and serum levels of 0.75 mg/dl in normal adults [13]. The American Medical Association/Nutrition Advisory Group recommends 100 mg/day in total parenteral nutrition (TPN).

The ascorbic acid requirement following trauma or infection is not known. Levenson et al. [14], as early as 1946, reported plasma ascorbic acid levels below normal values in severely injured patients. In some patients, plasma levels of ascorbic acid were immeasurable within a few hours following major injury. They also reported that blood levels of ascorbic acid remained subnormal even with daily 1000-mg intramuscular injections through the eighth day, when excretion normalized. Crandon et al. 15, 16 reported that the daily parenteral administration of 100 mg ascorbic acid to surgical patients had no effect until supplements were increased to 300 mg per day. Even then, the buffy coat ascorbic acid levels still remained borderline. Coon [17], Shukla [18], and Mason et al. [19] also suggested that surgical stress resulted in increased ascorbic acid requirements.

Renewed interest in ascorbic acid has surfaced because of its antioxidant free radical scavenging property. Oxygen free radicals cause cell injury through cellular membrane lipid peroxidation and degradation of nucleic acids, leading to increased membrane permeability and cell lysis. Schorah et al. [20] reported ascorbic acid levels to be significantly decreased in critically ill patients, diabetics, and patients with gastritis in whom increased reactive oxygen species have been reported 21, 22, 23. Cowley et al. reported that, during sepsis, uncontrolled oxygen free radical production predisposes to multisystem organ failure and death [24]. Increased free radical levels appear to compromise the antioxidant levels in the critically ill and adversely affect outcome. In this regard, Miyagatani et al. reported that high levels of ascorbic acid (133 mg/kg/h) resulted in an 80% survival (P = 0.05) of septic rats compared to 50% without ascorbic acid [25]. They also noted increased levels of hepatic glutathione, the principal intracellular free radical scavenger, in the high-dose ascorbic acid-treated group. No dose-response data were provided.

Based on the above data, it appears that ascorbic acid at the AMA-recommended intake levels of 100 mg/day would unnecessarily prolong desaturation of ascorbic acid pools. If maximal physiologic responses are dependent on immediate availability of ascorbic acid and if body pool levels are compromised in injured and infected patients, early repletion may have therapeutic benefit. For these reasons, we sought to (i) confirm impaired ascorbic acid levels in the acutely ill and injured; (ii) evaluate plasma and urine levels of ascorbic acid during acute short-term intravenous infusions of increasing ascorbic acid concentrations in TPN; and (iii) determine a time-dose response for normal plasma ascorbic acid concentrations.

Section snippets

Materials and methods

Twelve trauma patients with an injury severity score (ISS) >20 and an additional two patients with serious infection in the intensive care unit (ICU) who required TPN for at least 6 days were entered in the study. The TPN regimen allowed precise control of administered ascorbic acid during the evaluation of ascorbic acid levels throughout the study period. The carryover of ascorbic acid in each 2-day step dose was considered in the analysis of the plasma response and urinary excretion based on

Results

The study population consisted of 10 patients involved in motor vehicle crashes (MVC), one gunshot wound to the abdomen, one fall, and two nontrauma patients with infection. There were 7 males and 7 females in this part of the study. The mean ± SEM age of the group was 39 ± 17 years and the mean weight was 80 ± 19 kg. The ISS for the trauma group was 26 ± 3, indicating severe life-threatening trauma.

The plasma ascorbic acid levels for 12 patients at baseline and on varying levels of TPN are

Discussion

Although we do not know the preinjury nutritional status of the patients in this study, it is reasonable to assume that they were not depleted any more than population studies have indicated, as they had not experienced any long-term debilitating processes prior to hospitalization. Smoking and oral contraceptives, widely used practices in the general population, accelerate ascorbic acid turnover. Trauma, infection, and wound healing, as well as severe stress, are also known to increase the

Conclusions

Our results show that plasma ascorbic acid levels following trauma and during infection are extremely low and are not normalized with 300 or even 1000 mg/day supplemented TPN. Since there is an increased turnover and catabolism of ascorbic acid in the presence of trauma and infection, ascorbic acid at 3000 mg/day should be given for at least the first 3 days following severe stress from trauma and infection. [31]

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