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.
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).
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).
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.
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