**1. Introduction**

Liver transplantation (LT) has evolved to become a standard therapy for certain end-stage liver diseases [1]. Nowadays, 80% of organs come from donors who have suffered brain trauma (brain-dead donors) [1–4]. Brain death (BD) has been defined as the irreversible loss

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

of brain and brain stem function, usually caused by major hemorrhage, hypoxia or metabolic dysregulation [5, 6]. Hemodynamic events, hormonal changes and inflammation and immune activation occur consequently to BD [6–9]. It has been described that BD markedly reduces the tolerance of liver grafts to preservation and reperfusion injury and reduces graft survival [2–4, 10]. The detrimental consequences of BD have been clinically described; however the underlying mechanisms and their relevance in LT remain poorly understood. Indeed, few studies have evaluated the effect of BD on LT, and most of the experimental studies focused in establishing surgical or pharmacological strategies to reduce liver graft damage associated with transplantation have been performed in the absence of BD [6].

**2. Effects of brain death on liver graft undergoing transplantation**

on hepatic graft undergoing transplantation are presented.

of brain-dead donors [3].

Liver I/R injury is a local proinflammatory response mediated by the immune system. The central nervous system plays a fundamental role in the regulation of molecular markers triggering inflammation and tissue damage, and BD results in a breakdown of these mechanisms, hence initiating the cascade of I/R injury liver transplants and exacerbating the hepatic damage caused by I/R [9]. However, although the detrimental consequences of BD have been clinically described, the underlying mechanisms and their relevance in LT remain poorly understood [6]. Following, systemic events that happen after BD and the specific effects of BD

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BD is followed immediately by an acute and transient rise in blood pressure (Cushing reflex), that is immediately followed by a transient bradycardia communicated through parasympathetic activation [16, 24, 28–31]. Later after BD, deteriorating hemodynamics and a compromised perfusion of abdominal organs is becoming evident. Accordingly, a shift from aerobic to anaerobic metabolism and acidosis is registered, clinically reflected by elevated serum levels of lactate and free fatty acids and promoted by decreasing insulin secretion and hyperglycemia [21, 32, 33]. Alterations of specific mitochondrial functions may lead to an impaired production of ATP and a reduced uptake of substrates for mitochondrial metabolism and eventually limit resistance and survival of cells and organs to damaging insults [34]. It is well known that ATP degradation during hepatic ischemia leads to an acceleration of glycolysis [35]. Although glycolysis is essential for cell survival, it may also be detrimental because of the accumulation of glycolytic products such as lactate [35]. In the liver, the increase in cAMP levels due to ischemia triggers the activation of glycolysis. This causes the accumulation of hexose 6-phosphates, which proceed down the glycolytic pathway to form lactate [35–38]. Some authors [39] have shown that normotensive BD had no influence on the general viability of the liver, as measured by ATP content. In this research work, no differences were found in ATP content in livers from BD-induced rats and control rats, implicating that the phase of BD up to 6 h does not reduce general liver viability. However, it has also been described that the ATP content after 3 h of reoxygenation after graft harvesting was significantly increased in liver biopsies from brain-dead rats, may be because of a stress response, caused by increased catecholamine levels induced by BD and exaggerated reoxygenation times of liver tissues, exacerbating the I/R injury [39].

Hemodynamic instability, hormonal alterations, blood coagulation factor consumption, lung tissue changes, hypothermia, and electrolyte disturbance generated by BD invariably influence hepatic functions. Increased AST and ALT concentrations indicated liver dysfunction in brain-dead pigs and hepatocyte edema, hepatic sinusoid compression, and other microscopic observations in such animals demonstrated damage to liver cells [40, 41]. Also, BD causes time-dependent general dysfunction in rats, as indicated by elevated LDH and creatinine, AST and α-GST levels [42]. The disruption of liver function seems to be due to circulatory collapse and hemodynamic instability [41]. Morphological changes in the liver following BD are even less well defined. Recent experimental findings show that hepatocytes in livers from brain-dead donors show an altered cell membrane permeability and integrity [17, 43]. It has also been reported increased caspase-3 activity indicating that apoptosis occurs in liver tissue

Shortage of donor organs remains a major obstacle to the widespread application of LT in patients with end-stage liver disease [11–14]. To overcome this problem, transplant centers developed strategies to expand the organ donor pool [15]. This shortage could be alleviated by routine use of sub-optimal donor livers including elderly donors, steatotic donors, split livers and donor with viral infections or with malignancy. These sub-optimal livers exhibit a greater risk of organ dysfunction and primary non-function compared with optimal livers, when used as grafts in transplantation [1, 4, 9]. Multiple methods are currently being investigated to minimize the effects of ischemia-reperfusion (I/R) injury to allow the use of sub-optimal liver grafts, including anti-inflammatory approaches to attenuate cytokines, blockade of adhesion molecules, antiapoptotic strategies, among others. However, these studies are performed in non-BD surgical conditions. Only a recent study describes, for the first time, a potential treatment in steatotic liver grafts undergoing LT from cadaveric donors [1].

Since consequences of BD are linked to an inferior graft function and a more potent immune response, studies in animal models could be critical in uncovering its basic mechanisms and to provide a rationale for the development of novel targets that may prevent the deteriorating consequences of BD in clinical practice [16]. Virtually, all experimental organ transplantation studies generally utilize young, healthy living animals as donors; in clinical practice; however, a relatively low percentage of organs are acquired from living sources. Among other variables, the difference between living and brain-dead donors includes the effect of profound physiological and structural derangements [17]. Although a wide variety of animal BD models have been used to study the effect of BD on donor organ quality (without transplantation) [18–26], the lack of standardization of BD models makes difficult to compare results from different research groups. Undoubtedly, there is a need for a more controlled and standardized BD model allowing studies of organs in a situation closely resembling the reality in the intensive care unit [27].

In the first part of this chapter, we highlight the actual knowledge and new insights into the pathophysiology in BD focusing on liver graft undergoing transplantation. Following, the different experimental models reported in literature used to study the effect of BD on quality of optimal and sub-optimal liver grafts are presented, focusing on the strengths and limitations. Since recognize the underlying mechanisms of detrimental effects of BD is a critical question to design therapeutic strategies to protect liver grafts undergoing transplantation, we discuss if the existing BD animal models mimic the clinical findings in transplants with BD donors, and highlight which BD model could be more appropriated.
