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feed manifest as high nasogastric aspirates, diarrhea, and abdominal bloating. This was particularly common in the randomized patients with doubtful gastrointestinal function. There was also a significantly higher incidence of feed-related complications in the EN patients, including complications related to the invasive techniques employed for enteral access. Perhaps most importantly, no significant difference was observed between the two modalities in terms of septic morbidity, in contrast to previous studies. These findings should not be surprising. First, although bacterial translocation occurs in humans and is associated with an increased incidence of septic morbidity, the relative effects of TPN and EN on bacterial translocation and parameters of gut-barrier function such as mucosal architecture and intestinal permeability that are seen in rodents have not been substantiated in human studies.6 Second, the frequently quoted studies reporting increases in septic complications in patients receiving TPN involved only patients with abdominal trauma7,8 who as a group are markedly different in terms of age, physiology, and nutrition status from the majority of patients receiving nutrition support. Third, in previous studies nutrient intakes have often been very different in the TPN and EN groups, with overfeeding and consequent hyperglycemia a common occurrence in the TPN patients. This in itself may predispose to sepsis. To avoid this problem, in our study we set similar energy intake targets of 30 kcal 䡠 kg⫺1 䡠 d⫺1 in both groups, aiming to match but not exceed total energy expenditure. Fourth, our study population included a much higher proportion of malnourished patients, with almost a third having lost 10% or more of their usual body weight and just under half being severely malnourished according to the Nutritional Risk Index. These patients have the most to gain from effective nutrient delivery, which, as we have shown, is provided more readily by TPN than by EN. Previous studies have included too many well-nourished patients who arguably have little to gain from nutrition support but nonetheless are exposed to the associated risks. We have demonstrated that these risks also apply to EN, particularly now that more invasive techniques such as percutaneous endoscopic gastromies and feeding jejunostomies are being increasingly used. Complications include leakage of feed, obstruction, and peritonitis. One patient in our study died as a direct result of percutaneous endoscopic gastrotomy insertion. Such morbidity must be taken into account in any comparative study of the two feeding modalities, although it has unfortunately often gone unreported in the past. TPN and EN are not mutually exclusive. It is our considered opinion that patients requiring adjuvant nutrition support should be fed according to the adequacy of gastrointestinal function. Unlike respiratory or renal function, there is at present no reliable objective measure available to assess this, so the decision must be clinically based. Those patients in whom there is no doubt as to whether or not the gut is functioning should receive EN or TPN, respectively. Where doubt does exist, as is often the case in the critically ill patients in the intensive care unit, optimal nutrition support should be provided by using a combination of the two. Enteral feeding should be commenced at low volumes and increased according to tolerance, which necessitates the close monitoring of intakes by nursing staff. As described earlier, EN may serve to restore or maintain gut-barrier function. This should be supplemented by TPN to ensure an adequate total nutrition intake, which is particularly important in malnourished patients. As stated by Griffiths, “underfeeding is a debt that must eventually be repaid, and like all debts it is made worse when it is compounded.”9 As the delivery of EN increases, the TPN is reduced to avoid the potential risks of overfeeding. A slavish commitment to EN in a patient who is clearly unable to tolerate it is inappropriate and is to be discouraged. It has even been suggested that the increase in splanchnic blood flow induced by EN may actually be detrimental to the critically ill patient.10 Feeding in this way should also dispense with the need for invasive enteral access in the majority of cases. A recent prospective, double-blind, randomized, placebocontrolled study of 120 patients in the intensive care unit demon-

Nutrition Volume 18, Number 6, 2002 strated that 7 d of EN supplemented with TPN significantly increases serum concentrations of the nutritional markers retinolbinding protein and prealbumin when compared with EN plus placebo.11 There was no difference in terms of morbidity or mortality, although this is perhaps not surprising considering the relatively short duration of feeding and the small number of malnourished patients included in the study. It certainly provides further evidence that TPN does not cause an increase in morbidity. In conclusion, the time has come for the EN versus TPN debate to be finally laid to rest. Patients with questionable gastrointestinal function should be fed using a combination of EN and TPN. The enteral feed is increased or decreased according to tolerance, with the TPN adjusted accordingly. It is important that any additional benefit conferred by specific substrates be investigated against a background of optimal nutrition support.

Nicholas Woodcock John MacFie Combined Gastroenterology Unit Scarborough Hospital Scarborough, North Yorkshire, United Kingdom REFERENCES 1. Taylor SJ, Fettes SB, Jewkes C, Nelson RJ. Prospective, randomised, controlled trial to determine the effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients suffering head injury. Crit Care Med 1999;27:2525 2. Heyland DK, MacDonald S, Keefe L, Drover JW. Total parenteral nutrition in the critically ill patient. A meta-analysis. JAMA 1998;280:2013 3. Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr 2001;74:534 4. Lipman TO. Grains or veins: is enteral nutrition really better than parenteral nutrition? A look at the evidence. JPEN 1998;22:167 5. Woodcock NP, Zeigler D, Palmer MD, et al. Enteral versus parenteral nutrition: a pragmatic study. Nutrition 2001;17:1 6. MacFie J. Enteral versus parenteral nutrition: the significance of bacterial translocation and gut barrier function. Nutrition 2000;16:606 7. Moore FA, Feliciano DV, Andrassy RJ, et al. Early enteral feeding, compared with parenteral, reduces postoperative septic complications: the results of a meta-analysis. Ann Surg 1992;216:172 8. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding: effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215:503 9. Griffiths RD. Nutrition in intensive care: give enough but choose the route wisely? Nutrition 2001;17:53 10. Bistrian BR. Effects of enteral and parenteral nutrition in rats infused with tumour necrosis factor. JPEN 1997;21:305 11. Bauer P, Charpentier C, Bouchet C, et al. Parenteral with enteral nutrition in the critically ill. Intern Care Med 2000;26:893

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Antioxidant Activity: Are We Measuring It Correctly? I learned from a recent issue of Nutrition that Dr. Lawrence Machlin had passed away. I was shocked at this news. The article by Dr. Bendich reminded me of the occasions I discussed the role of vitamin E with Larry Machlin. I was pleased to know that he was interested in our work, especially the interaction between

Correspondence to: Etsuo Niki, PhD, Director, Human Stress Signal Research Center, AIST, 1-8-31 Midorigaoka, Ikeda, Osaka 563-8577, Japan. E-mail: [email protected]

Nutrition Volume 18, Number 6, 2002 vitamins E and C. Later, he kindly invited me to the meeting on vitamin C organized by the New York Academy of Sciences.1 It was indeed a big event for me to get to know Larry, and I always enjoyed meeting with him and discussing the role of antioxidant vitamins against oxidative stress. That special issue of Nutrition prompted me to write this article as a tribute to Dr. Machlin. There is now increasing evidence from basic, clinical, and epidemiologic studies showing the involvement of oxidative stress in a variety of diseases, cancer, and aging. For example, oxidative modification of low-density lipoprotein has been implicated in the pathogenesis of atherosclerosis.2 Consequently, the role of antioxidants has received renewed attention. Above all, the natural antioxidants contained in foods and beverages such as vegetables, fruits, tea, and wine have been studied extensively. Further, the development of synthetic antioxidant drugs has been explored.3,4 However, recent epidemiologic and intervention studies have not always supported the beneficial effect of antioxidant vitamins and drugs on coronary disease.5 Various methods have been applied to evaluate the antioxidant activities,6 but it has to be appreciated that there is no simple universal method by which antioxidant activities can be measured accurately and quantitatively. In this editorial, I briefly discuss the difficulties and care that should be taken in the assessment of antioxidant activities. Various kinds of oxidants may induce oxidative damage in vivo. For example, the oxidative modification of low-density lipoprotein, which is accepted as an important initial event in the progression of atherosclerosis, may be induced in vivo by several oxidants such as metal ions, peroxynitrite, myeloperoxidase, hypochlorite, and lipoxygenase. The antioxidant efficacy depends markedly on the type of oxidant. For example, vitamin E may exert potent antioxidant activity against oxidation induced by metal ions and peroxynitrite, but it may have little effect against protein modification induced by hypochlorite or lipid peroxidation induced by lipoxygenase.7 Although there may be several oxidants, oxidation in vivo may be divided into two types: free radical–mediated oxidation and non-radical oxidation. Apparently, one important function of antioxidants is to suppress free radical–mediated oxidation by inhibiting the formation of free radicals and/or by scavenging radicals. The formation of free radicals may be inhibited by reducing hydroperoxides and hydrogen peroxide and by sequestering metal ions. Superoxide dismutase removes superoxide and inhibits the formation of peroxynitrite, which can induce oxidative damage. The activities of antioxidants toward free radicals such as hydroxyl radical, superoxide, and peroxyl radical have been measured by various methods. Two points may be noteworthy. First, the efficacy of radical scavenging is determined not only by the reactivity of the antioxidant toward radical but also by its concentration. Many antioxidants react quite rapidly with hydroxyl radical, but many biological molecules that are much more abundant than antioxidants also rapidly react with hydroxyl radical; hence, it is practically impossible for any antioxidant to scavenge hydroxyl radical effectively. Second, the efficacy of radical scavenging depends on the localization of the antioxidant.8 For example, vitamin C is a potent scavenger for the hydrophilic radical but not for the lipophilic radical. The relative activity of vitamin E decreases more in membranes and low-density lipoprotein than in solution due to restricted mobility, and it becomes less efficient for vitamin E to scavenge radicals because the radical goes deeper into the interior from the surface. Thus, the activity measured in the homogeneous solutions should be treated carefully. Another important issue is the duration of inhibition, or lag phase. The antioxidant activity is often assessed from the lag phase produced by the antioxidant compound or biological fluids. For example, the lag phase observed in the oxidation of isolated low-density lipoprotein initiated by copper often has been measured to evaluate antioxidant capacity.9 It has to be appreciated

Editorial Opinions

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that the lag phase is determined by the rate of chain initiation, i.e., the rate of free radical generation, and the concentration and stoichiometric number of the antioxidant. It is difficult to control the rate of radical generation during the oxidation induced by metal ions such as copper because it depends on hydroperoxides, which are difficult to control. Further, many antioxidants interact with metal ions to activate or deactivate. The interaction with other antioxidants is also important. Therefore, the activity of a single antioxidant should be measured carefully. Another basic question is whether the lag phase really reflects antioxidant capacity. The total antioxidant capacity measured from the lag phase during oxidation under certain conditions reflects the total number of radicals that can be trapped until all the antioxidants are consumed. For example, plasma contains various antioxidants such as vitamin C, uric acid, vitamin E, carotenoids, and ubiquinol. Albumin also may act as an antioxidant under certain circumstances. The lag phase is determined by the concentration and stoichiometric number of each antioxidant. Vitamin C usually acts as the primary radical-scavenging antioxidant. It is doubtful whether all the vitamin C is exhausted in vivo; hence, the concentration of vitamin C should be a better marker than concentrations total antioxidants. In my opinion, the total antioxidant capacity measured from the lag phase in many previous experiments does not accurately reflect practical antioxidant activity. Finally, I re-emphasize that antioxidant activity in vivo is determined by many factors: its reactivity toward radicals, the number of radicals it can trap, the fate of antioxidant-derived radicals, localization of the antioxidant, concentration and mobility in the microenvironment, interaction with other antioxidants, and site of generation and reactivity of the radical. Unless we take these factors into consideration, we cannot correctly evaluate antioxidant activity.

Etsuo Niki, PhD Human Stress Signal Research Center National Institute of Advanced Industrial Science and Technology Ikeda, Osaka, Japan

REFERENCES 1. Niki E. Interaction of ascorbate and tocopherol. In: Burns JJ, Rivers JM, Machlin LJ, eds. Third conference on vitamin C, Vol 498. New York: Annals of the New York Academy of Science, 1987:186 2. Glass CK, Witztum JL. Atherosclerosis. The road ahead. Cell 2001;104:503 3. Thomas CE. Approaches and rationale for the design of synthetic antioxidants as therapeutic agents. In: Packer L, Cadenas, E, eds. Handbook of synthetic antioxidants. New York: Marcel Dekker, 1997:1 4. Noguchi N, Niki E. Phenolic antioxidants: a rationale for design and evaluation of novel antioxidant drug for atherosclerosis. Free Radic Biol Med 2000;28:1538 5. Brown BG, Zhao X-Q, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001; 345:1583 6. Niki E, Noguchi N. Evaluation of antioxidant capacity. What capacity is being measured by which method? IUBMB Life 2000;50:323 7. Noguchi N, Yamashita H, Hamahara J, et al. The specificity of lipoxygenasecatalyzed lipid peroxidation and the effects of radical-scavenging antioxidants. Biol Chem 2002(in press) 8. Niki E. Free radicals in the 1900’s; from in vitro to in vivo. Free Radic Res 2000;33:693 9. Esterbauer H, Puhl SH, Rotheneder M. Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Radic Res Commun 1989;6:67

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