The postreperfusion syndrome (PRS) following revascularization of the liver graft during liver transplantation was described in terms of cardiovascular collapse by Aggarwal et al.1 in 1987. They described a syndrome of severe cardiovascular dysfunction, bradyarrhythmia, decreased mean arterial pressure, and systemic vascular resistance, along with an increased mean pulmonary artery pressure, pulmonary capillary wedge pressure, and central venous pressure. The etiology of this syndrome had been attributed to acute acidosis, hyperkalemia, and hypothermia, and the authors also concluded that vasoactive substances released from the liver graft may be involved.2–5 The incidence of PRS in their prospective study was 30%. The acute increase in serum potassium seen with PRS has been related to the organ preservation fluid being flushed out of the graft at reperfusion.6 A more recent retrospective study of liver transplant recipients by Nanashima et al.7 identified the incidence of PRS to be 29% in their program. These authors also found that PRS was more common in recipients of grafts from older donors and that it was associated with postoperative liver and renal dysfunction.
It would seem to be intuitively obvious that any vascular toxins that might be flushed out of the new liver graft would drain directly into the right heart and would be very likely to cause hemodynamic disturbances. Therefore, many different surgical and anesthetic techniques have been developed to minimize the severity of PRS.8–14 This has included flushing the preservation fluid and other vasoactive molecules from the graft prior to reperfusion, adjusting the reperfusion sequence, and also adding some specific pharmacological interventions.
In this issue of Liver Transplantation, Hilmi et al.15 report on a retrospective analysis of 338 consecutive patients who underwent liver transplantation at their institution, and they found an incidence of PRS of varying degrees of severity in 100% of these patients. There was an incidence of 55% of patients experiencing significant PRS. Significant PRS was defined as severe hemodynamic instability, persistent hypotension (greater than 30% of the anhepatic level), asystole, or significant arrhythmias. They also included the development of significant fibrinolysis requiring pharmacological intervention. The quality of the donor graft was not found to be a significant factor in the development of severe PRS, and the graft warm ischemia time was actually found to be shorter in the severe PRS group compared to the milder group. The adverse outcomes from the development of a significant PRS were an increase in blood and blood products that were transfused and a higher incidence of postoperative allograft loss. Cases have been reported that have shown there is an increased risk to patients with liver failure and raised intracranial pressure who undergo liver transplantation and experience PRS, as an acute rise in intracranial pressure will occur.16
The authors include in their discussion of PRS the cellular basis of ischemia-reperfusion (I/R) injury. This may well be a major factor in graft loss and multiorgan dysfunction post-transplantation, but it may or may not be the cause of the immediate hemodynamic effects seen in the presence of significant PRS. These may be 2 discrete entities. The immediate severe hemodynamic effects of PRS may be the result of the heart and vasculature being transfused from the new graft with a large bolus of acidotic, hyperkalemic, cold fluid containing other vasoactive agents that have an immediate deleterious effect on cardiac function and vascular tone. The severity of these immediate hemodynamic changes found with the more severe incidences of PRS has not been correlated with the severity of the I/R injury. The pathophysiological changes of the I/R injury occur in every liver transplant procedure. They are the result of a cellular response not only to the ischemia time but also to the reperfusion of the liver, which causes a profound local inflammatory response. This increases local tissue damage, causes cell death, and creates a systemic inflammatory response syndrome.
The vascular endothelium is affected adversely by both the ischemia and reperfusion episodes. This results in the activation of neutrophils and platelets, causing adhesion to the endothelium and creating a proinflammatory and prothrombotic surface and a loss of local vasoactive mechanisms.17 The neutrophils are attracted to the endothelium by a multistep cascade of leukocyte rolling, adhesion, and then transendothelium migration. This process is facilitated by an increased permeability of the endothelium, cell adhesion molecules, and inflammatory cytokines.18 The endothelial dysfunction is further enhanced by a depletion of nitric oxide resulting in a vasoconstrictive state. Disruption of cellular calcium homeostasis occurs and causes damage to mitochondria and eventual apoptosis of liver cells and cells of other organ systems. Oxidative stress results in an increase in reactive oxygen species that include superoxide, hydrogen peroxide, and hydroxyl ions. These molecules induce apoptosis and cell necrosis, oxidize proteins and lipids, and damage DNA.19 These free radicals also cause extensive cellular damage in distant sites. The cytoprotective effects of antioxidants are inactivated by the massive oxidant load caused by the I/R syndrome. The vascular dysfunction caused by this cascade of events may result in a “no-reflow” phenomenon in the liver graft and failure or primary nonfunction of the transplanted organ.
How can we develop therapeutic strategies to prevent this I/R syndrome or ameliorate its potentially disastrous effects? Many approaches have been tried in an effort to reduce the injuries caused by reperfusion. These have included the use of free-radical scavengers, vasodilators such as inhaled nitric oxide, prostaglandin E1, and various antioxidants. Ischemic preconditioning is being investigated as a method of preventing I/R induced injury. There has been some success in the animal model demonstrating that by improvement of liver cell resistance to anoxia and reoxygenation, cell death can be prevented.20 A novel approach has been to examine the effects of remote ischemic preconditioning. This approach has shown that there is a humoral and neurogenic component to the activation of leukocytes in the I/R syndrome. In humans, remote ischemic preconditioning applied to the upper arm can protect against neutrophil activation and prevent endothelial dysfunction in the contralateral arm that was exposed to ischemia and reperfusion.21 Remote ischemic preconditioning has also been shown to reduce the incidence of myocardial infarction in patients undergoing coronary artery surgery.22
The reperfusion syndrome is still a major complication in liver transplantation. Whether it is the acute severe hemodynamic changes that may be seen at revascularization or the cellular damage and death from the systemic inflammatory response and cellular cascade that is triggered by the I/R syndrome has not been clearly defined. The experimental evidence for ameliorating this syndrome has to be translated urgently to the clinical practice, and more novel research needs to be performed to prevent this unwanted neutrophil activation.23–25 A recent novel approach by Lang et al.26 of preemptively administering inhaled nitric oxide at 80 ppm has shown some reduction in liver cell apoptosis in a small prospective human study.
Scientific progress in this field has to be accelerated so that more extended criteria donors can be used for liver transplantation with less cellular damage at reperfusion.