Normal lower limit

1 2 4 8 16 24 36 48 72 (hrs) Times after injury

FIGURE 8.9 Serum vitamin C levels in burn and trauma patients. Vitamin C levels decrease in the serum of burn and trauma patients in the early hours after injury. Although much of this may be the result of urinary excretion, the early drop in vitamin C is due to vitamin C consumption in metabolic processes and compartmentalization to areas of greater need. (From Tanaka, H. et al., Arch. Surg., 135, 326, 2000. With permission.)

The normal skin of aged and young rats showed no difference in ascorbic acid content. However, a 59% decrease in ascorbic acid content was observed in wound tissues of aged animals compared to its content in young adult wounds.60

Several investigators have reported that the ascorbic acid level significantly decreased in critically ill patients, and those with trauma and burns, suggesting the consumption of vitamin C6162 (Figure 8.9). Miyagatani et al. reported that high levels of ascorbic acid (133 mg/kg/h) result in an 80% survival of septic rats compared to 50% without high-dose ascorbic acid supplementation.63 They also noted increased levels of hepatic glutathione, the principal intracellular free radical scavenger, in the rat administered high-dose ascorbic acid, suggesting that vitamin C replenishes the scavenging activity of glutathione.

lung injury and ards (adult respiratory distress syndrome)

Adult respiratory distress syndrome (ARDS) is a pulmonary response to a variety of hypermetabolic life-threatening processes, such as trauma and sepsis. The inflammatory response of the lung in ARDS appears to be mediated, at least in part, by oxygen free radicals, suggesting that supplementing with free radical scavengers could help this disease process. Nathens reported that supplemental tocopherol (vitamin E) 3000 IU and 3000 mg intravenous ascorbic acid during 28 d of an intensive care unit (ICU) stay could attenuate alveolar inflammatory response, decrease the multiple organ failure score, and lessen ICU length of stay.64 Ascorbate may play a role in the prevention of lung oxidant injury, not only as an oxidant scavenger but also as an inhibitor of PMN (polymorphonuclear) leukocyte influx to the pulmonary tissue.65,66

paraquat intoxication

Paraquat (an ingredient of Gramoxone) is a potent producer of oxygen radical injury resulting in organ failure. The effects of the ascorbic acid administered after paraquat intoxication (LD50 of Gramoxone), and of ascorbic acid pretreatment followed by the LD50 of paraquat have been reported.67 Ascorbic acid treatment increases the content of polyunsaturated fatty acids in the lung considerably (i.e., the pulmonary membrane fluidity decreases significantly in response to ascorbic acid). In the liver homogenate, the membrane fluidity is significantly increased by ascorbic acid pretreatment and significantly decreased by simultaneous ascorbic acid treatment. In renal tissue, the result of ascorbic acid pretreatment exhibits a similar, but more significant, result to that of the paraquat treatment. The administration of ascorbic acid together with paraquat does not cause a substantial change in the fluidity index compared to the control.67

brain injury

Reactive oxygen species (ROS) have been shown to play a role in the pathophysiology of brain injury. Elangovan et al. reported that chronic oxidative stress exacerbates brain damage following closed head injury. They compared neurological recovery, edema, levels of low molecular weight antioxidants (LMWA), and markers of lipid peroxidation.68 Diabetic rats under chronic oxidative stress showed greater neurological dysfunction associated with further lipid peroxidation following closed head injury. Vitamin C has also been demonstrated to attenuate amyotrophic lateral sclerosis and mitochondrial encephalomyopathy.69 70

ischemia-reperfusion injury

Ischemia-reperfusion injury (IRI) is a damaging process of tissues brought about by rapid oxidative activity after a prolonged period of ischemia due to inadequate blood flow. It is thought to be caused in large part by oxygen radicals. Rhee reported on the effects of antioxidants on hepatic IRI. They induced IRI by clamping the porta hepatis for 30 min. Vitamin C and vitamin E administration lowered the malondi-aldehyde levels and protected against catalase exhaustion. They concluded that antioxidants protected the liver tissue against IRI.71 Similarly, vitamin C effects have been evaluated in myocardial infarction. The effect on infarction was estimated with Evans blue and triphenyl tetrazolium. The results demonstrated that vitamin E and ascorbic acid effectively reduced myocardial necrosis after ischemia.72

thermal injury and oxygen radicals

After burn injury, a cascade of biochemical and physiologic events bring about not only further local damage but also a systemic response (Chapter 11). While some of this response is the result of local cytokines and other inflammatory mediators, current research suggests that oxygen radicals play an important role in increased vascular permeability, lipid peroxidation of the cell membrane, and initiation of local and systemic inflammation after burn injury.73-76 In 1989, Friedl and associates proved that thermal injury in rats causes a release of histamine by mast cells, leading to an increase in xanthine oxidase activity for the first 15 min following thermal trauma.77 They also demonstrated that increased vascular permeability is not entirely due to histamine effects. Instead, it results from damage to the microvascular endothelial cells caused by oxygen free radicals, produced by the breakdown of xanthine by xanthine oxidase to produce hypoxanthine.78

Increased xanthine oxidase (XO) was well described in an animal model of burn injury.79 Hydroxyl radicals (OH-), released from the hypoxanthine-xanthine oxidase system during the dermal ischemia of the early phase of burn injury (within 2 h after injury), may play a major role in lipid peroxidation at the burn injury site.

Tanaka et al. induced burn injuries on the backs of rats and measured the value of tissue malondialdehyde (MDA) concentration to determine the oxidative injury in this burn model.80 Although a number of degradation products have been reported to measure lipid peroxidation, MDA by the thiobarbituric acid assay is the most commonly used technique.79 The MDA is a final metabolite, which is the unsaturated fatty acid peroxidized by attacks from free radicals and is considered to be an index of the production of oxygen radicals within the burn tissue (Figure 8.10). In this study, they found that tissue MDA concentration increased rapidly 30 min after injury and then reached a peak value 1 or 2 h after infliction of the injury. This would suggest that not only are free radical moieties involved with the original free radical damage of burns, but that this process continues for some time period after the original injury.

Many drugs have been reported to significantly attenuate this phenomenon in several burn models by preburn administration of antioxidants such as catalase, Mn-SOD, GSH (glutathione), vitamin E, desferoxamine, allopurinol, and lodoxamine.78,81,82 Unfortunately, burn injury is not anticipated; thus, prophylactic administration of these

FIGURE 8.10 Changes lymphatic malondialdehyde (MDA) on burn hindpaw. The MDA (a lipid free radical end product) concentration of the lymph flow increased immediately after thermal injury and reached peak values 2 to 4 h after injury. The vitamin C administration group showed significantly lower values than that of control group. (*: P < 0.05 compared to the burn-vitamin-C administration group. (From Matsuda, T., J. Burn Care. Rehabil, 14, 624, 1993. With permission.)

FIGURE 8.10 Changes lymphatic malondialdehyde (MDA) on burn hindpaw. The MDA (a lipid free radical end product) concentration of the lymph flow increased immediately after thermal injury and reached peak values 2 to 4 h after injury. The vitamin C administration group showed significantly lower values than that of control group. (*: P < 0.05 compared to the burn-vitamin-C administration group. (From Matsuda, T., J. Burn Care. Rehabil, 14, 624, 1993. With permission.)

drugs is not feasible in a clinical setting. No clinically effective drug has been reported to date.

laboratory studies of vitamin c and burn injury

Applying the biochemical paradigm of vitamin C as a free radical scavenger, Tanaka evaluated the effectiveness of vitamin C on the early phase of burn injuries in several experimental models.

First, he studied 70% body surface area burn models in guinea pigs, which like humans, cannot synthesize vitamin C internally. In this guinea pig model, a dose of 170 mg/kg/24 h of vitamin C lessened increased vascular permeability in second-degree burns, and 340 mg/kg/24 h of vitamin C caused the same result in third-degree burns.82,83 In the following study, the same animal model was used to examine the duration for continuous administration of vitamin C. This experiment revealed that a minimum of 8 h of continuous administration was needed to inhibit increased vascular permeability in third-degree burns (70%), with stable cardiac output and reduction in the water content of burn skin.84

More direct evidence of vitamin C efficacy on lipid peroxidation was found in lymph from burned canine hind paws.85,86 Normally, extracellular fluid that leaks from blood vessels into the interstitial space immediately after burn injury is returned to the body fluids through the lymph vessels. By cannulation to these lymph vessels from the burn area, one may understand the direct changes within the cell that occur at a burn injury site. The degree of the increased protein leak was significantly less in the burned hind paws in the vitamin C administration group. In contrast, the control group demonstrated increased lymph flow accompanied by an increase in lymph-to-plasma-protein ratio, indicating that capillary permeability had increased in these burned hind paws. As seen in Figure 8.10, the MDA values of lymph flow were significantly reduced in the group administered vitamin C compared with the control group.

clinical studies of vitamin c and burn injury

Based on this laboratory data, Tanaka et al. conducted clinical studies in humans. First, he examined the safety of continuous large-dose administration (66 mg/kg/h x 24 continuous hours; = 4.6 g/h in a 70 kg man) of vitamin C to 20 healthy adult volunteers.87 This study revealed no abnormalities in liver function, kidney function, or blood clotting system for 7 d after administration of this dose, clearly indicating that high-dose vitamin C administration to humans appears to be safe.

The dose of vitamin C used in this study is fourfold higher than that used in guinea pigs. The optimum dose of vitamin C in humans has not been determined, but in a canine model of 50% total body surface area (TBSA) burn, similar benefits were observed using a dose of 66 mg/kg/h. It was speculated that large mammals may need larger doses of vitamin C, because they have more complex oxygen free radical generating systems.88

Finally, a clinical prospective randomized study was conducted in severe burn patients.89 The study included consecutive patients with burns of more than 30% of their body surface area (BSA) who were admitted within 2 h postburn to the hospital. Inclusion criteria included those patients who were at least 15 yr but less than 70 yr of age. Patients having liver dysfunction or kidney dysfunction at the time of admission were excluded. Thirty-nine patients who met the criteria were used as subjects of this study during the 5-yr period. Nineteen patients were in the group administered vitamin C; 20 patients comprised the control group. The profiles of the two groups were similar regarding age, gender, body weight, and type of thermal injury, burn size (TBSA), percent of full thickness burn, and the presence of smoke inhalation. The experimental endpoints included the 24 h resuscitation fluid infusion volume, urinary output, changes in body weight, blood pressure, pulse, central venous pressure, hematocrit, total protein, albumin, MDA concentration in the blood, XOD (xanthine oxidase) activity in the blood, and changes in blood gases. These parameters were measured continuously over a period of 96 h. Furthermore, fluid infusion volume during the first 24 h was started immediately after admission using lactated Ringer's solution (L/R) according to the Parkland formula. The hourly infusion volume of the L/R was adjusted to maintain stable hemodynamic parameters (SBP > 90 mmHg) and urine output (0.5 to 1.0 ml/kg/h).

The results of this study are summarized in Figure 8.11. The 24-h resuscitation fluid volume requirement in the CTRL group was 5.5 ± 3.1 ml/kg/% burn, whereas the VC (vitamin C) group required only 3.0 ± 1.7 ml/kg/% burn, representing a 45.5% reduction in fluid requirements (P < 0.004), while adequate stable hemody-namic parameters and urine output were maintained. Burn wound edema at 24 h showed a significant reduction in the group administered vitamin C at 3.2 ± 1.3 ml/g per dry weight compared with 6.3 ± 1.6 ml/g per dry weight for the control group. Furthermore, by suppressing the increased vascular permeability, protein leakage

24 hr total infusion 24 hr volume retained fluid ml/kg/%burn ^ ml/kg/%burn

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