Intraoperative measurement of the graft oxygenation state in living related liver transplantation by near infrared spectroscopy

Graft oxygenation plays an important role in successful liver transplantation. Intraoperative changes in the oxygenation state of the liver graft were measured by near infrared spectroscopy in 28 cases of living related liver transplantation. Oxygen saturation of hemoglobin in the liver (hepatic SO₂) changed from 81.2%±1.5% (mean±SEM) before donation (in the donor) to 49.7%±4.2% after portal reflow, to 58.4%±5.0% after arterial reflow, and then to 71.4%±3.9% before closure. Mean hepatic SO₂ was positively correlated with portal flow rate as measured by duplex Doppler sonography. Cases with low portal flow rate showed a high coefficient of variation (SD/mean) of hepatic SO₂, indicating heterogeneous tissue oxygenation. Though graft size was expected to affect the graft oxygenation state, hepatic SO₂ was fairly independent of the graft-to-recipient weight ratio. In two cases with markedly low hepatic SO₂, postoperative graft dysfunction occurred. This study suggest that the method of near infrared spectroscopy is reliable and useful for assessing the graft oxygenation state in liver transplantation.     

Extension of the indication for living related liver transplantation from children to adults based on resolution of graft size mismatch in relation to tissue oxygenation and metabolic load: a case report

Abstract  We extended the indication for living related partial liver transplantation from pediatric to adult cases. Our first case was a 49-year-old woman with primary biliary cirrhosis. Her sister's left lobe, weighing 280 g, was employed as a graft, and the graft weight/recipient's body weight ratio was calculated as 0.59 %. To decrease the metabolic load to the relatively small graft, the total bilirubin was decreased from a maximum value of 75.0 mg/dl to the most recent preop-erative value of 36.2 mg/dl by plasma exchange. Intraoperative recovery of tissue oxygenation and its heterogeneity were satisfactory due to a relatively high blood supply. A postoperative decrease in bilirubin and increase in cholesterol esterifi-cation were facilitated, concomitant with regeneration of the graft, which weighed 280 g, to 860 c at 3 weeks. Linear regression analysis with respect to tissue oxygenation and metabolic capacity obtained in pediatric cases were applied to this adult case.     

Delayed oxidation of intramitochondrial pyridine nucleotide oxido reduction state as compared with tissue oxygenation in human liver transplantation

Abstract Intra- and post-operative oxygenation of graft liver and subsequent oxidation of the intramitochondrial redox state of pyridine nucleotide were studied in liver transplantation from living related donors with the arterial ketone body ratio (AKBR), the ratio of oxidized flavoprotein to reduced pyridine nucleotide (FP/PN ratio), and oxygen saturation of hemoglobin in liver tissue (hepatic SO₂). The subjects involved in this study consisted of 20 pediatric patients. Hepatic SO₂ was measured by near-infrared tissue spectroscopy. FP/PN ratio was measured by two-dimensional fluorometric scanning. Tissue oxygenation was normalized at the end of the operation. By contrast, AKBR remained at a low value at the end of the operation. At 24 and 48 h after the operation, the AKBR values increased to near the control value, indicating that it took 24 h for the intramitochondrial redox state to be normalized. The FP/PN ratio also remained at a low value at the end of the operation as compared with the control value. In conclusion, the observed delay in oxidation of the intramitochondrial redox state as compared with tissue oxygenation indicated the transition of the redox state associated with the changes in the metabolic state, and suggested the important role of microcirculation in the normalization of the redox state.     

Insulin and glucagon levels in living related liver transplantation: their interaction with the recovery of graft liver function

Insulin and glucagon have opposite effects on various hepatic functions, including energy metabolism, which is essential for hepatic viability. To evaluate the effects of insulin and glucagon on the recovery of graft liver function, changes in these levels were investigated in relation to arterial ketone body ratio (AKBR) during a 30-h period after graft liver reperfusion in 2i recipients of living related liver transplants. Insulin levels did not change significantly throughout this study, while glucagon levels decreased immediately after reperfusion, indicating a rapid degradation of glucagon by the graft liver. The insulin/glucagon (I/G) ratio increased after reperfusion concomitantly with AKBR. In addition, the I/G ratio was significantly correlated with AKBR after reperfusion. It is concluded that the increase in the I/G ratio was closely related to the recovery of graft liver function as reflected by the AKBR in living related liver transplantation.     

Changes in blood ketone body ratio with reference to graft viability after liver transplantation in rats

Arterial blood ketone body ratio (acetoacetate/3-hydroxybutyrate; KBR), which reflects hepatic mitochondrial redox potential, was measured during a 2-week period after orthotopic liver transplantation in three groups of rats: group 1, the isogenic combination of LEW (RT1¹) graft to LEW recipient as control; group 2, the allogenic combination of ACI (RT1^a) graft to LEW recipient without immunosuppressive treatment; and group 3, the allogenic combination of ACI to LEW with immunosuppressive treatment using cyclosporin (CyA). Isogenic recipients survived indefinitely. Allogenic recipients in group 2 had severe rejection with a mean survival of 10.3±0.54 days, while 77.8% of the allogenic recipients in group 3 survived more than 30 days. KBR of rats surviving more than 2 weeks in groups 1 and 3 gradually increased post-transplantation and was maintained at a high level. By contrast, though KBR in group 2 was restored at 3 days, it gradually fell and remained at a significantly low level (P<0.001). It is suggested that KBR provides an accurate indicator for evaluating metabolic viability of the critically deteriorating liver graft accompanied by severe rejection.     

Left Lobe Auxiliary Liver Transplantation for End‐stage Hepatitis B Liver Cirrhosis

Auxiliary liver transplantation (ALT) for hepatitis B virus (HBV)‐related liver cirrhosis previously showed poor results, because the native liver was a significant source of HBV recurrence and the graft could be rapidly destroyed by HBV infection in an immunosuppressive condition. Four patients with HBV‐related liver cirrhosis were unable to undergo orthotopic liver transplantation because the only available grafts of left lobe were too small. Under entecavir‐based anti‐HBV treatment, they underwent ALT in which the recipient left liver was removed and the small left lobe graft was implanted in the corresponding space. The mean graft weight/recipient weight was 0.49% (range, 0.38%–0.55%). One year after transplantation, the graft sizes were increased to 273% and the remnant livers were decreased to 44%. Serum HBV DNA was persistently undetectable. Periodic graft biopsy showed no signs of tissue injury and negative immunostaining for hepatitis B surface antigen and hepatitis B core antigen. After a mean follow‐up period of 21 months, all patients live well with normal graft function. Our study suggests that ALT for HBV‐related liver cirrhosis is feasible under entecavir‐based anti‐HBV treatment. Successful application of small left livers in end‐stage liver cirrhosis may significantly increase the pool of left liver grafts for adult patients.     

Changes in blood ketone body ratio with reference to graft viability after liver transplantation in rats

Abstract. Arterial blood ketone body ratio (acetoacetate/3-hydroxybutyrate; KBR), which reflects hepatic mitochondria] redox potential, was measured during a 2-week period after orthotopic liver transplantation in three groups of rats: group 1, the isogenic combination of LEW (RT1^l) graft to LEW recipient as control; group 2, the allogenic combination of ACI (RT1^a) graft to LEW recipient without immunosuppressive treatment; and group 3, the allogenic combination of ACI to LEW with immunosuppressive treatment using cyclosporin (CyA). Isogenic recipients survived indefinitely. Allogenic recipients in group 2 had severe rejection with a mean survival of 10. 3 ± 0. 54 days, while 77. 8% of the allogenic recipients in group 3 survived more than 30 days. KBR of rats surviving more than 2 weeks in groups 1 and 3 gradually increased post-transplantation and was maintained at a high level. By contrast, though KBR in group 2 was restored at 3 days, it gradually fell and remained at a significantly low level ( P < 0. 001). It is suggested that KBR provides an accurate indicator for evaluating metabolic viability of the critically deteriorating liver graft accompanied by severe rejection.     

Liver Graft Regeneration in Right Lobe Adult Living Donor Liver Transplantation

Optimal portal flow is one of the essentials in adequate liver function, graft regeneration and outcome of the graft after right lobe adult living donor liver transplantation (ALDLT). The relations among factors that cause sufficient liver graft regeneration are still unclear. The aim of this study is to evaluate the potential predisposing factors that encourage liver graft regeneration after ALDLT. The study population consisted of right lobe ALDLT recipients from Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan. The records, preoperative images, postoperative Doppler ultrasound evaluation and computed tomography studies performed 6 months after transplant were reviewed. The volume of the graft 6 months after transplant divided by the standard liver volume was calculated as the regeneration ratio. The predisposing risk factors were compiled from statistical analyses and included age, recipient body weight, native liver disease, spleen size before transplant, patency of the hepatic venous graft, graft weight-to-recipient weight ratio (GRWR), posttransplant portal flow, vascular and biliary complications and rejection. One hundred forty-five recipients were enrolled in this study. The liver graft regeneration ratio was 91.2 ± 12.6% (range, 58–151). The size of the spleen (p = 0.00015), total portal flow and GRWR (p = 0.005) were linearly correlated with the regeneration rate. Patency of the hepatic venous tributary reconstructed was positively correlated to graft regeneration and was statistically significant (p = 0.017). Splenic artery ligation was advantageous to promote liver regeneration in specific cases but splenectomy did not show any positive advantage. Spleen size is a major factor contributing to portal flow and may directly trigger regeneration after transplant. Control of sufficient portal flow and adequate hepatic outflow are important factors in graft regeneration.     

Factors affecting survival after living‐related liver transplantation

Abstract The purpose of this study was to determine the perioperative factors that influence patient and graft outcome in living‐related liver transplantation (LRLT). Between April 1995 and October 1998, we performed a series of 46 LRLT procedures, including 11 adult cased, at our institute. Mean age and weight of the recipients were 12.0 ± 2.3 years and 23.7 ± 2.6 kg, respectively. Seven out of the 46 patients had renal failure and received hemodialysis therapy before and after LRLT or kidney transplantation. The recipients were divided into two groups: those who survived for 7‐48 months after LRLT (group 1, n = 36), and those who died within 4 months after surgery (group 2, n = 10). Factors analyzed included recipient age and weight, graft/recipient body weight ratio (G/R ratio), emergent vs elective surgery, United Network for Organ Sharing (UNOS) status, presence of preoperative plasmapheresis (PEX) and renal failure, and so on. Recipients in group 1 compared with group 2 had less advanced liver disease (i. e., a lower rate of emergent surgery, 14% vs 50%, and fewer patients with UNOS status 1, 14% versus 70%; P < 0.05 and P < 0.001, respectively). Group 1 recipients also had a lower percentage of preoperative treatment with plasmapheresis (22% vs 70%, P < 0.01). However, neither the G/R ratio nor the presence of renal failure affected the patient survival rate. In conclusion, factors independently associated with reduced patient survival after LRLT include emergent surgery, Child‐Pugh class, UNOS status 1, and preoperative plasmapheresis.     

Short-term changes in cholesterol metabolism in 40 patients with liver transplants from living related donors

After liver transplantation, there remains a need for precise markers for evaluation of grafts. We investigated whether serum cholesterol value can serve as a marker for evaluation of the transplanted liver during follow-up. The effect of liver transplantation involving living related donors was investigated in 40 recipients in terms of lipid metabolism as measured by serum cholesterol. The relationship between cholesterol value after transplantation and liver graft weight/body weight (LW/BW) was also examined. Serum cholesterol increased at 10-20 days post-transplantation in successful cases, stabilizing at a value of more than 100 mg/dl after 4 weeks post-transplantation. In unsuccessful cases, serum cholesterol showed little increase in the 3 weeks after transplantation, and thereafter continued to decline. Cholesterol levels never reached 100 mg/dl in any of the unsuccessful transplantation cases. It took 45 days on average for the serum cholesterol to reach 100 mg/dl in recipients with less than 1% LW/BW ratio graft, but only 10 days in recipients with more than 3% LW/BW ratio graft. Patients who had partial liver transplantation from living related donors showed rapid recovery of cholesterol synthesis. However, patients with liver grafts required an extensive period before normalization of cholesterol synthesis, suggesting a need for long-term follow-up of graft recipients.     

Liver graft-transmitted glioblastoma multiforme. A case report and experience with 13 multiorgan donors suffering from primary cerebral neoplasia

The transmission of donor-related malignancies by organ transplantation is a rather rare event. There has only been one report on the development of a brain tumor metastasis in liver transplantation. From September 1988 to January 1993, 342 donor hepatectomies with subsequent transplantation were performed at our center. The main donor diagnoses included subarachnoidal bleeding (n=128; 37.4%), isolated head injury (n=114; 33.3%), multiple injuries (n=55; 16.1%), primary cerebral neoplasia (n=13; 3.8%), and other (n=32; 9.4%). Primary cerebral neoplasia included glioblastoma (n=4), meningioma (n=3), astrocytoma (n=2), angioma (n=2), neurocytoma (n=1), and ependymoma (n=1). In the group of donors suffering from primary cerebral neoplasia, procured organs other than the liver included kidneys (n=20), combined kidneys and pancreata (n=1), pancreata (n=2) hearts (n=8), combined hearts and lungs (n=1), and single lungs (n=1). Follow-up of the respective graft recipients ranged from 28 to 68 months (median 43 months). Recurrent malignancy was observed once, in a liver graft recipient. The donor, a 48-year-old female, had undergone surgical resection of an intracerebral multiform glioblastoma and died 4 months later of a relapse in the brain stem. The 28-year-old female recipient had undergone transplantation for an autoimmune-hepatitic cirrhosis. Four months later, histopathological examination of an intraperitoneal and intrahepatic mass revealed a poorly differentiated, small-cell pleomorphic cancer, identified as a glioma metastasis by S100-and glial fibrillary acidic protein immunohistochemical staining. The patient died 6 months post-transplantation. On autopsy, no further neoplastic lesions were detected. Our review adds a second reported case of a liver graft-transmitted brain tumor to the literature and the fourth donor-related malignancy after hepatic transplantation in general.     

The relationship of systemic hemodynamics and oxygen consumption to early allograft failure after liver transplantation

The early postoperative hemodynamic data of 88 patients who underwent primary liver transplantation between July 1989 and October 1990 at the University Health Center of Pittsburgh were analyzed to establish the relationship of systemic hemodynamics and oxygen consumption to perioperative allograft function. The 15 patients whose allografts failed within the 1 st month following transplantation were designated as group 1, while 73 patients who retained adequate graft function constituted group 2. Although the cardiac index and oxygen delivery did not differ significantly between the groups, group 1 consistently demonstrated a lower mean arterial pressure, oxygen consumption, arteriovenous oxygen content difference, and arterial ketone body ratio. The etiology of reduced oxygen consumption in group 1 patients is speculative, but the data support the notion that oxygen consumption is a useful, predictive indicator for liver allograft function after transplantation.     

A formula to calculate the standard liver volume in children and its application in pediatric liver transplantation

Due to a lack of available size‐matched liver grafts from children, most pediatric recipients are transplanted with technical variant grafts from adult donors. Size requirements for these grafts are not well defined, and consequences of mismatched graft sizes in pediatric liver transplantation are not known. Existing formulas for calculation of a standard liver volume are mostly derived from adults disregarding the age‐related percentual liver weight changes in children. In this study, we aimed to establish a formula for general use in children to calculate the standard liver volume. In a second step, the formula was applied in pediatric patients undergoing liver transplantation at our institution between 2000 and 2010 (n = 377). Analysis of a large number (n = 388) of autopsy data from children by regression analysis revealed a best fit for two formulas: “Formula 1,” children 0 to ≤1 year (n = 246): standard liver volume [ml] = ?143.062973 +4.274603051 * body length [cm] + 14.78817631 * body weight [kg]; “Formula 2,” children >1 to <16 years (n = 142): standard liver volume [ml] = ?20.2472281 + 3.339056437 * body length [cm] + 13.11312561 * body weight [kg]. In comparison with children receiving size‐matched organs, we found an elevated risk of liver graft failure in children transplanted with a small‐for‐size graft, whereas large‐for‐size organs seem to have no negative impact.     

Effect of prostaglandin E1 on preservation injury of canine liver grafts preserved in UW solution

This study investigated whether prostaglandin E₁ (PGE₁) could reduce hepatic injury to the liver graft caused by harvesting and 24-h preservation in University of Wisconsin (UW) solution in a canine model. The PGE₁-treated group was intravenously administered 0.5 g/kg per minute of PGE₁ for 30 min before harvesting, as well as a concentration of 1 mg/l PGE₁ in the washout and UW solutions. In both the PGE₁-treated and the control group, all recipients survived for 1 week or more after transplantation. Arterial ketone body ratio (AKBR) remained over 1.0 in the early postoperative period. The PGE₁ group showed significant reductions in guanase, GOT, and LDH during the early postoperative period compared to the untreated control group. Histological examination disclosed partial mitochondrial swelling, hepatocyte vacuolation, and necrosis in the control group, while such abnormalities were rarely seen in the PGE₁ group. These results suggest that PGE₁ can effectively reduce hepatic injury to liver grafts preserved in UW solution prior to transplantation.     

Living related liver transplantation in children with hypoxemia related to intrapulmonary shunting

Abstract  Living related liver transplantation (LRLT) was performed in seven children with hypoxemia related to intrapulmonary shunting. Based on the degree of the shunt ratio calculated by technetium ⁹⁹m macroaggregated albumin (MAA) scintigraphy, the seven patients were classified in the moderate (shunt ratio under 40 %, n = 4) or severe group (shunt ratio over 40 %, n = 3). While Pa was maintained over 60 mmHg in the moderate group, that in the severe group continued at a low level of under 40 mmHg in the early postoperative period. However, 48 h after surgery the arterial ketone body ratio recovered to a safe level of 1.0 in both groups. Values of aspartate aminotransferase and serum total bilirubin decreased at a constant rate in both groups. Six patients survived, but one died of portal vein thrombosis on the 53 rd postoperative day. Five of six surviving patients recovered from hypoxemia. We concluded that the transplanted liver can tolerate the stress of severe hypoxemia after LRLT.     

Temporary Auxiliary Partial Orthotopic Liver Transplantation Using a Small Graft for Familial Amyloid Polyneuropathy

Donor shortage is a major issue in liver transplantation. We have successfully performed temporary auxiliary partial orthotopic liver transplantation (APOLT) using a small volume graft procured from a living donor for recipients with familial amyloid polyneuropathy (FAP). The aim of this study was to evaluate this procedure by comparing it with standard living donor liver transplantation (LDLT). We compared 13 recipients undergoing this procedure with 23 recipients undergoing a standard LDLT for the treatment of FAP. The estimated donor graft volume and the graft volume/recipient's standard liver volume ratio were significantly smaller in the temporary APOLT group than in the standard LDLT group. Postoperative complications were comparable, although the hospital stay was longer in the temporary APOLT group. All the patients safely underwent a remnant native liver resection about 2 months after their first operation in the temporary APOLT group. No symptoms related to FAP developed before the remnant liver resection, and no significant differences in graft and patient survival were observed between the two groups. We successfully performed temporary APOLT using a small volume liver graft without postoperative liver failure for FAP. Temporary APOLT for FAP might be a useful alternative procedure for expanding the donor pool for LDLT.     

Auxiliary liver transplantation: how to improve regeneration of the native liver by surgery

The technical factors which could influence regeneration of the native liver (NL) in auxiliary liver transplantation (ALT) for fulminant hepatic failure (FHF) are not well known. We studied NL regeneration according to the location of graft anastomosis in the recipient's portal system (superior mesenteric vein versus portal vein), and graft weight (50 % reduced-size versus full-size graft) in a rat model of ALT with 80 % reduction of the NL, and graft arterialization. NL regeneration was significantly more obvious when the graft was anastomosed on the recipient's superior mesenteric vein, thus establishing venous flow to the NL from the pancreas, the spleen, and the stomach, and when a full-size graft was used. The influence of portal venous flow on NL regeneration, assessed by [³H]-thymidine incorporation, was measurable as early as day 2. Both technical variables in combination resulted in significantly greater regeneration (ratio weight of NL/body weight at day 30: 2.32 ± 0.68 % versus 1.21 ± 0.63 % respectively, P = 0.02). Early preservation of portal flow to the NL is advisable to maximize NL regeneration in ALT. In any case, this regeneration is not impeded by the use of large auxiliary grafts. Received: 11 February 1999 Received after revision: 29 July 1999 Accepted: 1 September 1999     

Graft transection and warm perfusion in situ in canine partial orthotopic liver transplantation

Liver transplantation is now proven therapy for various forms of end-stage liver disease in children; however, the problem of donor liver shortage remains. To investigate the feasibility of graft procurement from living, genetically related adult donors without injury to either donor or recipient, partial orthotopic liver transplantation (PLT) using a graft transected and warm perfused in situ was evaluated in beagles; the viability of the graft was assessed in terms of energy metabolism, including blood ketone body ratio (KBR), as well as of recipient survival. PLT was performed in two groups with venovenous bypass. The left half of the donor liver was transected in situ, flush perfused with 21 lactated Ringer's solution (4°C in group A, 20°C in group B), and immediately implanted into the recipient, who was totally hepatectomized, care having been taken to leave the inferior vena cava intact. Four of seven dogs survived for 5 days or longer (longest, 8 days) in group A and six of eight dogs (longest, 20 days) in group B. Causes of death were gastrointestinal bleeding, intussusception, or infection but not graft dysfunction. In both groups the KBR decreased significantly during the anhepatic period, recovered rapidly to the pre-anhepatic level after revascularization, and was maintained within a normal range thereafter. No significant differences in the time course of changes in KBR were seen between the two groups. These results suggest that a warm-perfused graft does not have a poorer viability than a cold-perfused one, that the concept of PLT with a graft transected and warm perfused in situ is feasible, and that it may be the solution to the problem of donor liver shortage.     

Graft transection and warm perfusion in situ in canine partial orthotopic liver transplantation

Abstract. Liver transplantation is now proven therapy for various forms of end-stage liver disease in children; however, the problem of donor liver shortage remains. To investigate the feasibility of graft procurement from living, genetically related adult donors without injury to either donor or recipient, partial orthotopic liver transplantation (PLT) using a graft transected and warm perfused in situ was evaluated in beagles; the viability of the graft was assessed in terms of energy metabolism, including blood ketone body ratio (KBR), as well as of recipient survival. PLT was performed in two groups with venovenous bypass. The left half of the donor liver was transected in situ, flush perfused with 2 1 lactated Ringer's solution (4°C in group A, 20°C in group B), and immediately implanted into the recipient, who was totally hepatectomized, care having been taken to leave the inferior vena cava intact. Four of seven dogs survived for 5 days or longer (longest, 8 days) in group A and six of eight dogs (longest, 20 days) in group B. Causes of death were gastrointestinal bleeding, intussusception, or infection but not graft dysfunction. In both groups the KBR decreased significantly during the anhepatic period, recovered rapidly to the pre-anhepatic level after revascularization, and was maintained within a normal range thereafter. No significant differences in the time course of changes in KBR were seen between the two groups. These results suggest that a warm-perfused graft does not have a poorer viability than a cold-perfused one, that the concept of PLT with a graft transected and warm perfused in situ is feasible, and that it may be the solution to the problem of donor liver shortage.     

Receiver operating characteristic (ROC) analysis of the ability of arterial ketone body ratio to predict graft outcome after liver transplantation — its sensitivity and specificity

To evaluate the ability of arterial ketone body ratio (AKBR; acetoacetate/3-hydroxybutyrate) to predict graft prognosis after liver transplantation, the diagnostic value as a predictive index was compared between AKBR and conventional liver function tests using receiver operating characteristic (ROC) analysis. The ROC curves were determined for AKBR, GOT, GPT, total bilirubin, serum lactate level, and prothrombin time, all of which were measured on the 1st and 2nd postoperative days in 88 cases of liver transplantation. Comparisons of the areas under the ROC curves between AKBR and other tests revealed the significant superiority of AKBR to other tests in predicting graft death within 1 month after transplantation. The present study suggests that AKBR can be used as an accurate index to predict graft prognosis after liver transplantation.