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Editorials and Perspectives: Overview

Brain Death and Organ Damage: The Modulating Effects of Nutrition

Singer, Pierre1,3; Shapiro, Haim2; Cohen, Jonathan1

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doi: 10.1097/01.tp.0000189710.92728.c5
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Abstract

The shortage of organ donors is the main limiting factor to successful organ transplant programs all over the world (1, 2). It is therefore essential to maximize the number of organs from the available donor pool. In this regard, it has become clear that a series of insults, which are initiated by severe brain injury and amplified by brain death, may have a significant negative impact on the quality of organs so that many are lost for transplantation. Hemodynamic instability (3), endocrine disturbances (4), and the release of chemokines and cytokines with important immunological consequences (5), have all been implicated. In addition, during the harvesting, preservation, and reperfusion stages, organs are subject to ischemia-reperfusion injury (6). Strategies to optimize the use of available organs have focused on the importance of hemodynamic stability, replacing hormone deficiencies, and possible dampening of the effects of mediator release.

The use of nutrition as a therapeutic intervention to improve outcomes of critically ill patients in intensive care (7, 8), and more recently, of organ donors (9), has received increasing attention. We review the effects of brain death on the potential organ donor and discuss the theoretical basis for using targeted nutritional therapy to modulate these effects and improve organ preservation and function.

HEMODYNAMIC AND INFLAMMATORY RESPONSE TO MASSIVE BRAIN INJURY AND BRAIN DEATH

Head injury followed by brain death induces a series of deleterious effects on hemodynamic and metabolic homeostasis. Progressive brain herniation, with resultant ischemia of the vagal and cardiomotor nuclei, results in intense sympathetic stimulation (10). This so-called “autonomic storm” produces severe generalized vasoconstriction, which may lead to hypertension, tachycardia, and myocardial ischemia (4). Brain death has been defined as “explosive” when there is a sudden and dramatic increase in intracranial pressure (such as may occur after trauma) and in experimental animals, massive increases (up to 1,000-fold) in the level of epinephrine have been demonstrated (11). These patients typically show the most hyperdynamic responses and severe arteriolar vasoconstriction, myocardial and renal structural damage, ventricular dysfunction, and endothelial damage and activation have been described. Where the rise in intracranial pressure is more gradual, the hyperdynamic response is blunted and only mild ischemic damage to the myocardium is found. Following the “autonomic storm” as herniation is completed, sympathetic tone is lost, resulting in loss of vascular tone which frequently results in cardiovascular collapse (4). Both brain death and hypotension can lead to malperfusion, local and general ischemia, and an increase in oxidative stress, which may have detrimental effects on organ function (12).

As part of the regional response to brain injury and brain death, a large number of cytokines and related compounds are produced. They are thought to contribute to the programmed death (apoptosis) of individual cells, to hemodynamic instability, and by sensitizing donor organs, increase the risks of rejection, poor organ function and primary organ dysfunction (13). These cytokines are present in all organs and their level increases with time and prolonged exposure (14).

EFFECTS OF ISCHEMIA-REPERFUSION INJURY

The ischemia-reperfusion injury incurred in the perioperative period may also contribute significantly to organ damage. Injury is mediated by free radicals and reactive oxidative species, which are produced through four main pathways: the mitochondrial respiratory chain, the NAPDH oxidase enzyme of neutrophils and macrophages (the predominant mechanism in severe sepsis), the ubiquitous xanthine oxidase enzyme, producing massive amounts of free oxygen radicals during the reperfusion phase, and by metallic ions (iron and copper), which are released during cell destruction. Free radicals cause the liberation of NFkB which controls the production of acute phase mediators such as TNF-alpha and IL-2.

NUTRITIONAL STATUS OF THE BRAIN-DEAD ORGAN DONOR

In an experimental rat model of fluid percussion-induced traumatic brain injury, Moinard et al. observed long-lasting anorexia which resulted in muscular atrophy, increased myofibrillar proteolysis demonstrated by an increase in the 3-methylhistidine/creatinine ratio, intestinal atrophy, and renal failure (15). This hypercatabolic state is commonly found after head injury in patients who progress to brain death. Skeletal amino acids are shifted towards gluconeogenesis, a process requiring ATP. The resultant increase in adenosine monophosphate, adenosine and xanthine induces superoxidase and xanthine oxidase activities, thus increasing free radical activity (16). Moinard et al. also found a decrease in hepatic glycogen and ATP content, together with liver atrophy (15). This could impair the resistance of the liver graft to ischemic episodes, which increases free radical production, intracellular acidosis and cell swelling (17–19). Olinda et al. (20) found no difference in the ATP content in liver slices for up to 6 hr after induced brain death in rats compared to controls. IL-1β production in liver slices from brain-dead animals was increased significantly as was nitric oxide when compared to controls. However, the ATP content after 3 hr of re-oxygenation following graft harvesting was significantly increased. These findings are in contradiction to those reported by Novitzky et al. (21) who found the ATP content to be decreased and lactate level increased 6 hr following brain death in baboons. However, these animals received no hemodynamic support and remained hypotensive throughout the study period. By contrast, animals in the Olinda study (20) were maintained normotensive, suggesting that the ATP and lactate abnormalities were induced not directly by brain death but rather by the resultant hypotension.

The metabolic and circulatory disturbances after head injury and leading to brain death also have severe consequences on the energy status and the redox condition of organs. Organ energy status as well as redox status is closely related to nutritional status. A direct relationship between adequate energy status of the liver (as assessed by liver ATP content) and favorable posttransplant outcome has been described.

NUTRITIONAL MODULATION

Preoperative feeding appears to have some advantages on organ function and organ vitality when compared to fasting and can influence the severity of oxidative stress (see Figure 1 in (22)). In a rat model of ischemia-reperfusion induced by mesenteric artery clamping-unclamping, cardiac output was shown to be significantly less in fasted compared to fed animals. In addition, the liver oxidative stress was much lower in the fasted animals. This protective effect of preoperative feeding may be related to preservation of the gut barrier function. The altered intestinal permeability and decreased liver function may predispose to single or even multiple organ dysfunction. It still remains to be demonstrated whether preoperative feeding may have similar beneficial effects in humans. Intravenous administration of vitamin E shortly before surgery in patients undergoing partial liver resection was shown to result in significant improvement in liver enzymes after surgery and a significantly shorter length of ICU stay compared to a control group, suggesting that supplementation reduced the impact of ischemia-reperfusion injury (23). Administration of alpha tocopherol has also been shown to prevent ischemic induced, free radical-mediated rat liver cell injury and to improve survival (24). However, administration of vitamin E after brain death determination and before organ harvesting in an attempt to prevent ischemia/reperfusion injury has not yet been tested.

The reperfusion of cold-preserved livers may result in functional and morphological alterations (25), which are significantly related to glycogen depletion occurring during cold ischemia/reperfusion. It would seem that the provision of glycogen and energy to the donor would be important goals in preventing these changes. However, while some authors (26) suggest that donor nutritional depletion induces de novo protein synthesis which might ameliorate cold ischemia and reperfusion injury in the rat liver, others have found no effect whether the donor was fed or not. These differences are probably explained by differences in methodological techniques, including time of cold ischemia and the type of preservation solution used. Importantly, Domenicali et al. showed that maintaining hepatic glycogen content by glucose supplementation significantly reduced the fasting-associated exacerbation of oxidative stress and liver injury and the ATPase exhaustion seen in rat fatty livers exposed to ischemia-reperfusion injury (27). Glycogen depletion leading to adenosine monophosphate accumulation, increased hypoxanthine and xanthine production, could lead to increased peroxidation. Blocking adenosine degradation has been found to improve graft survival after liver transplantation in rats (28). It is still believed that the higher the ATP and adenosine biphosphate in the liver tissue, the higher the liver energy charge, and the better the function of the liver graft (29, 30).

NUTRITIONAL MODULATION OF CARBOHYDRATES AND LIPIDS

Organ donors fequently receive large infusions of dextrose-containing fluids, which may result in hyperglycemia and a hyperosmolar state. Hyperglycemia, by inducing reactive oxygen species, has an inflammatory effect. The realization that tight glucose control may significantly decrease morbidity and mortality has significantly influenced the care of critically ill patients (31) and those with brain injury (32). The possible beneficial effect of a similar strategy in brain-dead donors requires additional investigation.

The use of lipids in potential donors to improve organ outcome appears to have a strong basis. In addition to providing significant nutritional support in the form of calories, lipids can alter membrane phospholipid composition and modify prostanoid and cytokine production in response to ischemia and reperfusion. The fatty acid composition of currently available lipid emulsions differ in the percentage of long and medium chain triglycerides, and the ratio between polyunsaturated and monounsaturated fatty acids. Recently specific fatty acids, including omega-3 fatty acids, have been added to available formulae. These fatty acids, derived from arachidonic acid and eicosapentoic acid, have been shown to modulate proinflammatory eicosanoid production. When administered to patients with the adult respiratory distress syndrome (33) and acute lung injury (34), these fatty acids together with gamma-linolenic acid resulted in beneficial effects on oxygenation, lung mechanics, length of ventilation and pulmonary neutrophil recruitement. In a tolerance study, we have shown that the administration of IV lipids enriched with fish-oil to heart-beating organ donors was well tolerated and resulted in no biological or clinical side effects in either the donor or recipient (35). The study was mainly focused on renal function and renal survival was similar in both the experimental and an historical control group. Fish-oil administered after kidney transplantation or liver transplantation has been shown to improve creatinine clearance and glomerular blood flow (36, 37).

Zhong observed an increased survival of rat livers injured by ethanol administration and then transplanted when fed with a high fat (35%) versus a low fat (12%) diet (38). The administration of fat also resulted in an increase of ATP content and hepatic energy charge (39).

An infusion of docosahexaenoic acid in isolated rat hearts has been shown to be harmful during ischemia and reperfusion (40). This is in agreement with the finding that fatty acids accumulating in the myocardium during ischemia reperfusion cause myocardial damage (41), resulting in arrhythmias and impaired cardiac pump function. Omega-3-fatty acids may benefit the recovery of cardiac function after cold storage, by attenuating coronary and myocardial preservation injury. Another example of the protective effect of lipids is illustrated by the use of propofol, a general anesthetic agent which is emulsified with long chain triacylglycerols, which has been shown to alter global and cardioplegic ischemia. This protective effect may be related to a decrease in mitochondria pore opening, diminishing oxidative stress (42) or to the reduction of hydrogen peroxide-induced lipid peroxidation (43).

PROTECTIVE EFFECTS OF PROTEIN

Ischemia-reperfusion injury of the kidney, induced by oxygen-derived free radicals, is characterized by a decrease in glomerular filtration rate and may result in acute renal failure with delayed recovery (44). Ischemia and early reperfusion also result in the depletion of renal glycine (45). Yin et al. (46) investigated whether a bolus injection of glycine given before reperfusion plus continuous dietary supplementation afterward could reduce the renal injury. They showed that in rats receiving glycine, postischemic renal function was less impaired and recovered more quickly, whereas tubular injury and cast formation observed in controls was minimized. These effects were probably due to the prevention of hypoxia, as evidenced by increased binding of the in vivo marker of hypoxia pimonidazole in the outer medulla of control but not glycine-fed rats. The positive effects of glycine persisted for up to two weeks as mild leukocyte infiltration and interstitial fibrosis were still observed in control but not in glycine-treated rats. The protective effect glycine is related to enhanced heat shock protein 70 gene expression (47).

Increased synthesis of albumin has been demonstrated in partially hepatectomized rats force-fed with amino acids (48). In addition, hepatocyte mitotic activity was significantly increased when mice were fed with a high compared to a low protein diet following refeeding after starvation (49). Following 70% partial hepatectomy, rats fed with TPN enriched with glutamine, a DNA precursor, had a significantly higher rate of hepatic regeneration compared to unenriched TPN (50).

Glutamine supplementation also improves survival rate after heart transplantation in rats (51). Mean beating time and scoring for beating strength were better if rats received glutamine before the procedure, suggesting that glutamine may induce graft protection from ischemia and reperfusion injury (52).

OXIDATIVE DAMAGE AND ITS NUTRITIONAL TREATMENT

Endogenous antioxidants, substances inhibiting or delaying oxidation, include glutathione, thiols, and albumin. In the critically ill organ donor, the response to ischemia-reperfusion injury may well depend on the antioxidant status. In addition to increased reactive oxidative species, circulating levels of nearly all antioxidant micronutrients are depressed (53). Food is the most important source of antioxidants, many belonging to the phenol family (54). Table 1 summarizes the potentially effective nutritional antioxidants. Few studies have shown the effectiveness of micronutrients as antioxidants. Thus, selenium supplementation in critically ill patients (55) was associated with a significant decrease in the incidence of acute renal failure but no difference in mortality. The addition of copper, zinc and selenium in burns was shown to decrease IL-6 levels and reduce lipid peroxidation and infectious complications (56, 57). In severe brain injury, zinc supplementation was associated with improved visceral protein levels (58).

TABLE 1
TABLE 1:
Effects of various antioxidants on ischemia-reperfusion injury

The damage caused by an acute injury is more pronounced in selenium-deficient states. It appears that correction of the deficit at the time of injury is less effective than supplementation prior to the injury. Dietary selenium was administered to rats for 5 weeks before their hearts were isolated, were subjected to 22.5 min of ischemia, 45 min of reperfusion and their functional recovery assessed. It was found that 1) hearts from selenium deficient animals were more susceptible to ischemia-reperfusion injury (38% vs. 47% recovery of rate pressure product in supplemented animals); and 2) hearts from selenium supplemented animals had improved recovery of cardiac function postischemia, an increased activity of glutathione peroxidase and a greater endogenous activity of thiredoxin reductase (59).

Other antioxidants, such as polyphenolic substances, may also play an important role in preventing ischemia-reperfusion injury. Polyphenolic substances appear to have powerful anti-inflammatory and vasculo-protective properties (60) and therefore are appropriate for the prevention of ischemia-reperfusion injury. In animal models, systemic administration of polyphenolic substances or their extracts from plants, reduces oxidative stress, inflammation, necrosis, apoptosis and mortality due to ischemia-reperfusion (61–64). Two polyphenolic substances are well established: epigallocatechin gallate, and curcumin. These substances inhibit activation of NFκB and inducible-nitric oxide synthetase expression, attenuate injury induced by inflammation, ischemia-reperfusion, and lipid peoxidation (65–68).

Epigallocatechin gallate, a component of green tea, has been shown to have protective effects on the heart (64) and the lung (69) following ischemia-reperfusion after cold preservation. Hepatic ischemia-reperfusion injury is also prevented by green tea extract (70). In addition, several studies have shown that green tea extracts may attenuate cyclosporin A induced oxidative stress in rats (71–73). One-third of all livers available for transplantation are discarded because of steatosis (74). Fiorini et al. (75) administered epigallocatechin gallate intraperitoneally for 2 days or orally for 5 days to animals prior to 15 min of warm ischemia and 24 hr of reperfusion. Epigallocatechin gallate significantly reduced hepatic fat content by 55%, and reduced the level of palmitic acid by 3.5-fold. Interestingly, oral and intraperitoneal epigallocatechin gallate significantly increased hepatic glutathione levels and this may offer protection against the increased concentrations of reactive oxygen species occurring after ischemia-reperfusion. Zhong showed that livers rinsed in preservation solution (University of Wisconsin) containing a green tea extract as epigallocatechin gallate prevented primary graft failure after the transplantation of ethanol-induced fatty livers in rats (76). This cellular protection was attributed to the antioxidant and anti-inflammatory effects of the flavonoids.

Curcumin is the major component of turmeric, and is a major anti-inflammatory agent (77). In a cardiac ischemia-reperfusion model, curcumin has been shown to inhibit NFκB, thus attenuating the ischemia-reperfusion injury and blunting the release of plasma anti-inflammatory cytokines (77, 78). Curcumin also enhances the immuno-suppressive effects of cyclosporine after cardiac rat transplantation (79). In addition, there is a synergy of action between mycophenolate mofetil and bioflavonoids like curcumin, as has been shown in a renal ischemia-reperfusion model (80, 81).

ASSESSMENT OF NUTRITIONAL STATUS

Biochemical markers to assess nutritional status in the brain death organ donors include prealbumin, blood sugar, and serum levels of phosphate, magnesium and calcium (8, 9). Relevant micronutrients related to stress but also to oxidative status are plasma levels of selenium, copper, zinc and vitamin E. Other markers used to assess the oxidative status require specialized laboratories and include measurement of plasma malondialdehyde and F2 isoprostanes, and free fatty acid oxidation (mainly C22:6 (ω-3)), prostaglandins, ATP/ADP concentrations, gluthatione levels, gluthatione peroxidase and superoxide dismutase activity as well as plasma total antioxidant status, antioxidant gap, ascorbic acid for antioxidant protection markers (16, 20, 21, 82).

CONCLUSIONS

The harmful effects of brain death and ischemiareperfusion injury may result in the loss of organs for transplantation. We have shown that there are strong theoretical grounds to suggest that nutritional intervention may modulate some of these effects, especially those due to ischemia-reperfusion. We propose that prospective trials should be planned to test the efficacy of nutritional support in the heart-beating organ donor. These studies should test the effects of micronutrients such as selenium, zinc, copper or vitamin E on the antioxidant status and clinical outcome of harvested organs. Others studies are also mandatory to evaluate the effectiveness of polyphenols, trace elements, fish oil and glutamine, independently and together, in the limitation of ischemia-reperfusion injury. More specifically, curcumin supplementation could prevent heart or renal ischemic injury and epigallocatechin gallate could have potential effects on the prevention of liver or lung preservation injury. The nutritional balance achieved by these means may well aid in optimizing the management of brain-dead donors.

REFERENCES

1. Hertz M,Taylor D, Trulockn E, et al. The registry of the International Society for Heart and Lung Transplantation: nineteenth official report—2002. J Heart Lung Transplant 2002; 21: 950.
2. Sheehy E, Conrad SL, Brigham LE, et al. Estimating the number of potential organ donors in the United States. N Eng J Med 2003; 349: 667.
3. Jenkins DH, Reilly PM, Schwab CW. Improving the approach to organ donation: a review. World J Surg 1999; 23: 644.
4. Smith M. Physiologic changes during brain stem death—lessons for management of the organ donor. J Heart Lung Transplant 2004; 23: S217.
5. Pratschke J, Neuhaus P, Tullius SG. What can be learned from brain-death models? Transplant Int 2005; 18: 15.
6. Chen EP, Bittner HB, Kendall SW, et al. Hormonal and hemodynamic changes in a validated model of brain death. Crit Care Med 1996; 24: 1352.
7. Barr J, Hecht M, Flavin KE, et al. Outcomes in critically ill patients before and after the implementation of an evidence-based nutritional management protocol. Chest 2004; 125: 1446.
8. Griffiths RD. Specialized nutrition support in critically ill patients. Curr Opin Crit Care 2003; 9: 249.
9. Singer P, Cohen J, Cynober L. Effect of nutritional state of brain-dead organ donor on transplantation. Nutrition 2001; 17: 948.
10. Mertes PM, Abassi HE, Jaboin Y, et al. Changes in hemodynamic and metabolic parameters following induced brain death in the pig. Transplantation 1994; 58: 414.
11. Shivalkar B, Van Loon J, Wieland W, et al. Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function. Circulation 1993; 87: 230.
12. Golling M, Mehrabi A, Blum K, et al. Effects of hemodynamic instability on brain death-induced preservation liver damage. Transplantation 2003; 75: 1154.
13. Powner D. Effects of gene induction and cytokine production in donor care. Prog Transpl 2003; 13: 9.
14. Takada M, Nadeau KC, Hancock WW, et al. Effects of explosive brain death on cytokine activation of peripheral organs in the rat. Transplantation 1998; 65: 1533.
15. Moinard C, Neveux N, Royo N, et al. Characterization of the alteration of nutritional state in brain injury induced by fluid percussion in rats. Intensive Care Med 2005; 31: 281.
16. Harvey PRC, Iu S, McKeown CMB, et al. Adenosine nucleotide tissue concentration and liver allograft viability after cold preservation and warm ischemia. Transplantation 1988; 45: 1016.
17. Pikul J, Sharpe MD, Lowndes R, et al. Degree of preoperative malnutrition is predictive of postoperative morbidity and mortality in liver transplant recipients. Transplantation 1994; 57: 469.
18. Morgan GR, Sanabria JR, Clavien PA, et al. Correlation of donor nutritional status with sinusoidal lining cell viability and liver function in the rat. Transplantation 1991; 51: 1176.
19. Clavien PA, Harvey PR, Strasberg SM. Preservation and reperfusion injuries in liver allografts. An overview and synthesis of current studies. Transplantation 1992; 53: 957.
20. Olinda P, van der Hoeven JA, Merema MT, et al. The influence of brain death on liver function. Liver Int 2005; 25: 109.
21. Novitzki D, Wicomb WN, Cooper D, Thaalagard MA. Improved cardiac function following hormonal therapy in brain dead pigs: relevance to organ donation. Transpl Proc 1988; 20: 29.
22. van Hoorn DE, Boelens PG, van Middelaar-Voskuilen MC, et al. Preoperative feeding preserves heart function and decreases oxidative injury in rats. Nutrition 2005; 21: 859.
23. Bartels M, Biesalski HK, Engelhart K, et al. Pilot study on the effect of parenteral vitamin E on ischemia and reperfusion induced liver injury: a double blind randomized, placebo-controlled trial. Clin Nutr 2004; 23: 1360.
24. Marubayashi S, Dohi K, Ochi K, et al. Role of free radicals in ischemic rat liver cell injury: prevention of damage by alpha-tocopherol administration. Surgery 1986; 99: 184.
25. Quintana AB, Guibert EE, Rodriguez JV. Effect of cold preservation/reperfusion on glycogen content of liver. Concise review. Ann Hepatol 2005; 4: 25.
26. Uchida Y, Tamaki T, Tanaka M, et al. de novo Protein synthesis induced by donor nutritional depletion ameliorates cold ischemia and reperfusion injury in rat liver. Transpl Proc 2000; 32: 1657.
27. Domenicali M, Vendímiale G, Serviddio G, et al. Oxidative injury in rat fatty liver exposed to ischemia-reperfusion is modulated by nutritional status. Dig Liver Dis 2005; 37: 689.
28. Tian Ya, Shafer T, Skell A, Schilling MK. Adenosine deaminase inhibition attenuates reperfusion low flow and improves graft survival after rat liver transplantation. Transplantation 2000; 69: 2277.
29. Lanir A, Jenkins RL, Caldwell C, et al. Hepatic transplantation survival: correlation with adenosine nucleotide level in donor liver. Hepatology 1988; 8: 471.
30. Pattou F, Boudjema K, Kerr-Conte J, et al. Enhancement of the quality of hepatic graft by restoration of hepatic glycogen reserves in the donor. Press Med 1992; 21: 2012.
31. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Eng J Med 2001; 345: 1359.
32. Bruno A, Williams LS, Kent TA. How important is hyperglycemia during acute brain infarction. Neurologist 2004; 10: 195.
33. Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentoic acid, gamma-linolenic acid and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 1999; 27: 1409.
34. Singer P, Theilla M, Fisher H, et al. The benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med; in press.
35. Singer P, Zolotarski V, Yussim A, et al. Renal effects of parenteral fish oil administered to heart-beating organ donors and renal-transplant recipients: a tolerance study. Clin Nutr 2004; 23: 597.
36. van der Heide H, Bilo HJG, Tegzess AM, et al. The effects of dietary supplementation with fish oil on renal function in cyclosporine-treated renal transplant recipicents. N Eng J Med 1990; 49: 523.
37. Badalamenti S, Slaerno F, Lorenzano E, et al. Renal effects of dietary supplementation with fish oil in cyclosporine-treated liver transplant recipients. Hepatology 1995; 22: 1695.
38. Zhong Z, Connor HD, Mason RP, et al. Ethanol, not fat accumulation per se, increases free radical production in a low-flow, reflow liver perfusion model. Transplantation 1998; 56: 1431.
39. Yagi T, Ishikawa T, Oishi M, et al. Hepatic energy booster and lipomodulatory effect on postperfusional endotoxemia by intraoperative lipid infusion in porcine liver transplantation. Hepatol Res 2000; 17: 72.
40. Schjott J, Brekke OL, Jynge P, et al. Infusion of EPA and DHA lipid emulsions: effect on heart lipids and tolerance to ischemia-reperfusion in the isolated rat heart. Scand J Clin Lab Invest 1993; 53: 873.
41. Burton KP, Buja LM, Sen A, et al. Accumulation of arachidonate in triacylglycerols and unesterified fatty acids during ischemia and reflow in the isolated rat heart. Am J Pathol 1986; 124: 238.
42. Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc Res 2004; 61: 372.
43. Corcoran TB, Engel A, Sakamoto H, et al. The effects of propofol on lipid peroxidation and inflammatory response in elective coronary artery bypass grafting. J Cardiothorac Vasc Anesth 2004; 18: 592.
44. Weinberger JM. Glutathione and glycine in acute renal failure. Ren Fail 1992; 14: 311.
45. Beck FX, Ohna A, Dorge A, et al. Ischemia-induced changes in cell element composition and osmolyte contents of outer medulla. Kidney Int 1995; 48: 449.
46. Yin M, Zhong Z, Connor HD, et al. Protective effect of glycine on renalinjury induced by ischemia-reperfusion in vivo. Am J Physiol Ren Physiol 2002; 282: F417.
47. Nissim I, Hardy M, Pleasure J, et al. A mechanism of glycine and alanine cytoprotective action: stimulation of stress-induced HSP 70 mRNA. Kidney Int 1992; 42: 775.
48. Kirsch RE, Saunders SJ, Frith LOC, et al. The effect of intragastric feeding with amino acids on liver regeneration after partial hepatectomy in the rat. Am J Clin Nutr 1979; 32: 738.
49. Leduc EH. Mitotic activity in the liver of the mouse during inanition followed by refeeding with different levels of protein. Am J Anat 1949; 84: 397.
50. Yoshida S, Yunoki T, Aoyagi K, et al. Effect of glutamine supplement and hepatectomy on DNA and protein synthesis in the remnant liver. J Surg Res 1995; 59: 475.
51. Kojima R, Tmaki T, Kawamura A, et al. Expression of heat shock proteins induced by L(+)-glutamine infection and survival of hypothermically stored heart grafts. Transpl Proc 1998; 30: 3746.
52. Kjellman UW, Bjork K, Ekroth R, et al. Addition of alpha-ketoglutarate to blood cardioplegia improves cardioprotection. Ann Thorac Surg 1997; 63: 1625.
53. Venardos K, Harrison G, Headrick J, et al. Effects of dietary selenium on gluthatione peroxidase and thiridoxin reductase activity and recovery from cardiac ischemia-reperfusion. J Trace Elem Med Biol 2004; 18: 81.
54. Berger MM. Can oxidative damage be treated nutritionally? Clin Nutr 2005; 24: 172.
55. Anstwurm MWA, Schottdorf J, Schopohl J, et al. Selenium replacement in patients with severe inflammatory response syndrome improves clinical outcome. Crit Care Med 1999; 27: 1807.
56. Heyland DK, Dhaliwal R, Suchner U, et al. Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill. Intensive Care Med 2005; 31: 327.
57. Agay D, Anderson RD, Sandre C, et al. Alterations of antioxidant trace elements (Zn, Se, Cu) and related metaloenzymes in plasma and tissues following burn injury in rats. Burns 2005; 31: 366.
58. Young B, Ott L, Kasarskis E, et al. Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. J Neurotrauma 1996; 13: 25.
59. Hughes DA. Plant polyphenols: modifiers of immune function and risk of cardiovascular disease. Nutrition 2005; 21: 422.
60. Singh D, Chander V, Chopra K. The effect of quercetin, a bioflavonoid on ischemia/reperfusion induced renal injury in rats. Arch Med Res 2004; 35: 484.
61. Kahraman A, Erkasan N, Serteser M, et al. Protective effect of quercetin on renal ischemia/reperfusion injury in rats. J Nephrol 2003; 16: 219.
62. Su JF, Guo CJ, Wei JY, et al. Protection against hepatic ischemiareperfusion injury in rats by oral pretrreament with quercetin. Biomed Environ Sci 2003; 16: 1.
63. Brookes PS, Digerness SB, Parks DA, et al. Mitochodrial function in response to cardiac ischemia-reperfusion-induced gastric mucosal injury in rats. Physiol Res 2001; 50: 501.
64. Varilek GW, Yang F, Lee EY, et al. Green tea polyphenol extract attenuates inflammation in interleukin-2 deficient mice, a model of autoimmunity. J Nutr 2001; 131: 2034.
65. Jian YT, Mai GF, Wang JD, et al. Preventive and therapeutic effects of NFkappa B inhibitor curcumin in rat colitis induced by trinitrobenzenesulfonic acid. World J Gastroenterology 2005; 11: 1747.
66. Martin AR, Villegas I, La Casa C, et al. Revastrol, a polyphenol foundingrapes, suppresses oxidative damage and stimulates apoptosis during early colonic inflammation in rats. Biochm Pharmacol 2004; 67: 1399.
67. Comalada M, Camuesco D, Sierra S, et al. In vivo quercitrin and -inflammatory effect involves release of quercitin, which inhibits inflammation through down-regulation of the NFkappa B pathway. Eur J Immunol 2005; 35: 584.
68. Aneja R, Hake PW, Burroughs TJ, et al. Epigallocatechin, a green tea polyphenol, attenuates myocardial ischemia reperfusion in rats. Mol Med 2004; 10: 55.
69. Omasa M, Fukuse T, Matsuoka K, et al. Effect of green tea extracted polyphenol on ischemia/reperfusion injury after cold preservation of rat lung. Transplant Proc 2003; 35: 138.
70. Zhong Z, Froh M, Connor HD, et al. Prevention of hepatic ischemia/reperfusion injury by green tea extract. Am J Physiol Gastrointest Liver Physiol 2002; 283: G957.
71. Mohamadin AM, El-Beshbishy HA, El-Mahdy MA. Green tea extract attenuates cyclosporine A-induced oxidative stress in rats. Pharmacol Res 2005; 51: 55.
72. Shi SH, Zheng SS, Jia CK, et al. Inhibitory effects of tea polyphenols on transforming growth factor beta 1 expression in rats with cyclosporine A-induced chronic nephrotoxicity. Acta Pharmacol Sin 2004; 25: 98.
73. Chang EJ, Mun KC. Effect of epigallocatechin gallate on renal functionin cyclosporine-induced renal dysfunction nephrotixicity. Transpl Proc 2004; 36: 2133.
74. Marsman WA, Wiesner RH, Rodriguez L, et al. Use of fatty donor liver is associated with diminished early patient and graft survival. Transplantation 1996; 62: 1246.
75. Fiorini RN, Donovan JL, Rodwell D, et al. Short-term administration of Epigallocatechin gallate reduces hepatic steatosis and protects against warm hepatic ischemia/reperfusion injury in steatotic mice. Liver Transpl 2005; 11: 298.
76. Shosches DA. Effect of bioflavonoids quercetin and curcumin on ischemic renal injury: a new class of renoprotective agents. Transplantation 1998; 66: 147.
77. Yeh CH, Chen TP, Wu YC, et al. Inhibition of NF kappa B activation with curcumin attenuates plasma anti-inflammatory cytokines surge and cardiomyocytic apoptosis following cardiac ischemia/reperfusion. Surg Res 2005; 125: 109.
78. Yeh Ch, Lin YM, Wu YC, et al. Inhibition of NF-kappa B activation can attenuate ischemia/reperfusion-induced contractibility impairment via decreasing cardiomyocytic proinflammatory gene up-regulation and matrix metalloproteinase expression. Cardiovasc Pharmacol 2005; 45: 301.
79. Chueh SC, Lai MK, Liu IS, et al. Curcumin even enhances the immunosuppressive activity of cyclosporine in rat allografts and in mixed lymphocyte reactions. Transpl Proc 2003; 35: 1603.
80. Shoskes DA, Jones EA, Shahed A. Synergy of mycophenolate mofetil and bioflavonoids in prevention of immune and ischemic injury. Transplant Proc 2000; 33: 2988.
81. Jones EA, Shoskes DA. The effect of mycophenolate mofetil and polyphenolic bioflavonoids on renal ischemia reperfusion injury and repair. J Urol 2000; 163: 999.
82. Mishra V, Baines M, Wenstone R, Shenkin A. Markers of oxidative damage, antioxidant status and clinical outcome in critically ill patients. Ann Clin Biochem 2005; 42: 269.
Keywords:

Brain death; Organ donor; Nutrition

© 2005 Lippincott Williams & Wilkins, Inc.