Liver transplantation for hepatic metastases of neuroendocrine tumors.
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Biomedical subjects
Publications and source records attributed to W O Bechstein.
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Neurotoxicity represents a serious complication following orthotopic liver transplantation. Neurotoxicity may be evoked by various perioperative factors or develop due to drug-specific toxicity of immunosuppression. We evaluated the incidence of neurotoxicity in 121 patients, 61 randomly assigned to FK506 and 60 to CsA-based immunosuppression. The incidence of moderate or severe neurotoxicity was markedly higher in patients treated with FK506 in the early postoperative period (21.3% vs. 11.7% in patients receiving CsA), after retransplantation (100% vs. 0% in patients receiving CsA), and late (8 of 10 patients; P < or = 0.05 vs. CsA). Furthermore late neurotoxicity was highly associated with severe infections and MOFS, which had a lethal outcome in more than 50% of the patients. Patients who subsequently died developed neurologic symptoms in 67% of the cases. These patients also experienced moderate or severe neurotoxicity significantly more often in the early postoperative period compared with patients with a successful outcome (50% vs. 17.3%; P < or = 0.01). However, various blood and serum parameters, including ALT, bilirubin, urea, creatinine and glucose, when analyzed alone or in multivariate fashion, also correlated significantly with the incidence and severity of early postoperative neurotoxicity, indicating that neurotoxicity following LTX may be caused by various factors and is not exclusively a drug-specific side effect of immunosuppression.
Nephrotoxicity represents a serious side effect of immunosuppression following liver transplantation. In order to compare the nephrotoxic action of CsA and FK506 in a clinical setting, we evaluated the incidence of early and late nephrotoxicity in 121 patients, 60 of whom were randomly assigned to CsA- and 61 to FK506-based immunosuppression. Early postoperative renal insufficiency (between PODs 0 and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (38.3%) and FK506 (42.6%). Early postoperative acute renal failure (ARF) (SCr > 3 mg/dl) was observed in 18.0% of patients in the FK506 treatment group and 18.3% of patients receiving CsA therapy. Approximately half the patients with ARF required hemodialysis (CsA: 11.7%; and FK506: 8.2%). All patients with early postoperative ARF requiring hemodialysis survived for more than one year. New onset of late ARF (between PODs 30 and 365) was observed in 6.6% of patients receiving FK506 therapy and in 1.7% in the CsA treatment group as a result of severe infection with multiple organ failure syndrome (MOFS). There was 100% mortality in patients with late ARF requiring hemodialysis. Etiology and prognosis of early and late ARF seem to be completely different. Early ARF was associated with severe coagulopathy and a rise in bilirubin and free hemoglobin, and was accompanied by impaired liver function. Mean onset of hemodialysis in CsA-treated patients was POD 1 and in FK506-treated patients POD 6, which disclosed a different time course of drug-specific nephrotoxicity of CsA and FK506 in early ARF. In contrast, late ARF occurred in both treatment groups only as a part of the MOFS in association with severe infections, an observation consistent with the assumption of overimmunosuppression rather than a primary nephrotoxic effect. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK506-treated patients, and represented a slowly progressing form of drug-specific nephrotoxicity of CsA and FK506. These preliminary results demonstrate a similar outcome in terms of both early and late nephrotoxicity, but longer follow-up will delineate the overall efficacy and toxicity in humans.
The early outcome of 201 liver grafts transplanted consecutively between September 1988 and November 1991 was investigated retrospectively. Donors were categorized according to their hospitalization periods in an intensive care unit (ICU) prior to harvesting, their causes of death, and the variables generally believed to be critical in liver donation, such as arterial hypotension (n = 69; 34.3%), cardiopulmonary resuscitation (n = 20; 9.9%), elevated serum-aminotransferases (s-AT) (n = 11; 5.5%), or an age over 50 years (n = 16; 8.0%). Ninety-one donors (45.3%) spent less than 24 h in an ICU; 29 donors (14.4%) and 14 donors (7.0%) had hospitalization periods generally considered critical of 4-6 days and more than 6 days, respectively. The most common causes of death were subarachnoidal bleeding (n = 70; 34.8%), isolated head injuries (n = 68; 33.8%), and polytraumata (n = 33; 16.4%). The postischemic hepatocellular damage was evaluated comparing peak post-transplant s-AT, which did not differ significantly between groups; nor did donor and recipient ages or cold ischemia times. Fourteen grafts (7.0%) showed a reversible preservation injury presenting with post-transplant s-AT elevated above 2000 IU/l. Five cases (2.5%) of a primary non-functioning graft (PNF) underwent early retransplantation successfully. Serum-aminotransferases (AST: 4944 +/- 2280 IU/l; ATL: 3186 +/- 1918 IU/l) were significantly (P < 0.01) elevated as compared to primary functioning grafts (AST: 699 +/- 935 IU/l; ALT: 620 +/- 701 IU/l). The donor structure of both groups reflected the distribution of variables in the entire collective. No significant overrepresentations were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Bacterial and fungal infections are a major cause of morbidity and mortality after orthotopic liver transplantation. In the immunocompromised host, infections are thought to arise from the gut, which is almost always colonized with potential pathogens. Using oral selective bowel decontamination (SBD), potential pathogens can be eradicated from the gut and infections prevented. In this catamnestic study we have reviewed gastrointestinal colonization, bacterial and fungal infections, and bacterial resistance to standard antibiotics in our first 206 liver transplant patients while under SBD. With few exceptions, gram-negatives were eradicated from the gastrointestinal tract and secondary colonization was inhibited. In spite of unsatisfactory elimination of Candida, probably because nystatin doses were too low, Candida infections were rare (n = 4) and none was fatal. One and two-year survival rates were 93% and 92%, respectively. The bacterial and fungal infection rate was 27.8% with an infection-related mortality of 1.95%. Infections with aerobic gram-positive bacteria prevailed and only 11 gram-negative and 11 fungal infections occurred; among the latter, Aspergillus and Mucor were the most serious and responsible for three of the six deaths in this series. With regard to the development of resistance, we found an increasing number of enterococci and coagulase-negative staphylococci resistant to ciprofloxacin and imipenem, respectively, but unlikely as a consequence of SBD.
In the present study, a retrospective statistical analysis of laboratory data, clinical data, and perioperative blood requirements from 300 primary orthotopic liver transplantations (OLT) is described. METHODS. OLT was performed using established surgical techniques and total IV anaesthesia. Volume was substituted with red blood cells (RBC) and fresh frozen plasma (FFP) according to haemodynamic data, haemoglobin, and diuresis. Platelet counts, prothrombin time, activated partial thromboplastin time (aPTT), thrombin time, fibrinogen, and antithrombin III were registered but not used as indications for transfusions. Statistics were performed using regression analysis and analysis of variance. RESULTS. The mean intraoperative fluid requirement was 793 ml balanced salt solution, 7.1 units RBC, and 8.4 units FFP; pooled random donor platelets were given only once. During 24 h postoperatively, an average of 1.8 units RBC and 4.6 units FFP had to be transfused. Currently, 278 of the 300 patients (92.7%) are alive. There was no significant correlation between clotting data and intraoperative blood use; for postoperative transfusion rates, the preoperative aPTT and postoperative platelet counts had a significant correlation. Reviewing the basic diseases of the patients, there were significant differences in coagulation status, but no differences in transfusion rates. CONCLUSION. According to the data presented, indications for transfusions in OLT according to clotting data are not valid, since these data do not correlate with the blood requirement. In addition, strategies for pretreatment of patients such as preoperative plasmapheresis are no longer justified with respect to possible side effects.
OBJECTIVE: The authors evaluated the complication rate and outcome of side-to-side common bile duct anastomosis after human orthotopic liver transplantation. SUMMARY BACKGROUND DATA: Early and late biliary tract complications after orthotopic liver transplantation remain a serious problem, leading to increased morbidity and mortality. Commonly performed techniques are the end-to-end choledochocholedochostomy and the choledochojejunostomy. Both techniques are known to coincide with a high incidence of leakage and stenosis of the bile duct anastomosis. The side-to-side bile duct anastomosis has been shown experimentally to be superior to the end-to-end anastomosis. The authors present the results of 316 human liver transplants, in which a side-to-side choledochocholedochostomy was performed. METHODS: Biliary tract complications of 370 transplants in 340 patients were evaluated. Three hundred patients received primary liver transplants with side-to-side anastomosis of donor and recipient common bile duct. Thirty-two patients with biliary tract pathology received a bilioenteric anastomosis, and in eight patients, side-to-side anastomosis was not performed for various reasons. Clinical and laboratory investigations were carried out at prospectively fixed time points. X-ray cholangiography was performed routinely in all patients on postoperative days (PODs) 5 and 42. In patients with suspected papillary stenosis, endoscopic retrograde cholangioscopy and papillotomy were performed. RESULTS: One biliary leakage (0.3%) was observed within the early postoperative period (PODs 0 through 30) after liver transplantation. No stenosis of the common bile duct anastomosis was observed during this time. Late biliary stenosis occurred in two patients (0.6%). T tube-related complications were observed in 4 of 300 primary transplants (1.3%). Complications unrelated to the surgical technique, including papillary stenosis (5.7%) and ischemic-type biliary lesion (3.0%), which must be considered more serious in nature than complications of the anastomosis or T tube-related complications, were observed. Papillary stenosis led to frequent endoscopic interventions and retransplantations in 1.3%. CONCLUSIONS: Side-to-side common bile duct anastomosis represents a safe technique of bile duct reconstruction and leads to a low technical complication rate after human orthotopic liver transplantation. Ischemic-type biliary lesion evoked by preservation injury, arterial ischemia, cholestasis, and cholangitis may represent a new entity of biliary complication, which markedly increases the morbidity after human liver transplantation. Therefore, this complication should be the subject of further research.
Leukocytes play an important role in the development of disseminated intravascular coagulation (DIC). In the reperfusion phase of OLT a DIC-like situation has been described and has been held responsible for the high blood loss during this phase. We investigated the role of leukocytes in the pathogenesis of DIC in OLT by measuring the leukocytic mediators released upon activation (cathepsin B, elastase, TNF, neopterin) and the levels of thrombin-antithrombin III (TAT) complexes, seen as markers of prothrombin activation. Arterial blood samples were taken at 10 different time points during and after OLT. Samples were also taken of the perfusate released from the liver graft vein during the flushing procedure before the reperfusion phase. Aprotinin was given as a continuous infusion (0.2-0.4 Mill. KIU/hr) and its plasma levels were determined. Significantly elevated levels of neopterin (15-fold; P < 0.01), cathepsin B (440-fold; P < 0.01) in the perfusate, as compared with the systemic circulation, as well as their significant increases in the early reperfusion phase suggested that they were released by the graft liver. This was paralleled by elevated levels of elastase (1.3-fold, P < 0.05), TNF (1.5-fold, P = NS), and TAT complexes (1.4-fold; P < 0.1) in the perfusate. Significant correlations could be identified between the parameters of leukocyte activation and TAT complexes, whereas no correlation was observed between any of the parameters investigated and the aprotinin levels. Our results strongly indicate a release of leukocytic mediators from the graft liver during its reperfusion which seems to be related to the parallely increased prothrombin activation. No correlation could be seen between levels of aprotinin and levels of leukocytic mediators.
Neurotoxicity is a serious complication following orthotopic liver transplantation leading to increased morbidity and mortality. Neurotoxicity may be evoked by various perioperative factors, or may be due to drug-specific toxicity of immunosuppression. In the present study we evaluated the incidence of central nervous system (CNS) toxicity occurring within the early postoperative period of 121 patients, 61 randomly assigned to FK 506- and 60 to CsA-based immunosuppression as part of a multicentre study. The incidence of moderate or severe CNS toxicity was higher in patients treated with FK 506 (21.3%) than in patients receiving CsA (11.7%). The duration of symptoms was also greater in patients treated with FK 506 than in patients receiving CsA. The incidence of moderate or severe neurotoxicity after retransplantation was markedly greater in patients treated with FK 506 (100% of the patients).
Nephrotoxicity represents a serious side-effect of immunosuppression following orthotopic liver transplantation. In order to preserve the therapeutic potential of cyclosporin (CsA) and FK 506 in human liver transplantation and to differentiate the nephrotoxic action of either drug in a clinical setting, we evaluated the incidence of early and late nephrotoxicity in 121 patients, 60 randomly assigned to CsA- and 61 to FK 506-based immunosuppression. Early postoperative renal insufficiency (between POD0 and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (36.7%) and FK 506 (42.6%). Early postoperative acute renal failure (ARF; SCr > 3 mg/dl) occurred in 18.3%, regardless of the immunosuppressive management. Approximately 50% of patients with ARF required hemodialysis (CsA: 11.7%; and FK 506: 8.3%). Mean onset of hemodialysis in CsA-treated patients was POD1 and in FK 506-treated patients, POD6, which demonstrated a different time course of drug-specific nephrotoxicity of CsA and FK 506 in early ARF. All patients with early postoperative ARF requiring hemodialysis survived more than 1 year (100% survival). New onset of late ARF (between POD30 and 365), however, occurred in 6.5% under FK 506 and in 1.7% under CsA immunosuppression due to severe infections with the multiple organ failure syndrome. This observation was consistent with the assumption of over-immunosuppression rather than a primary nephrotoxic effect. Mortality of patients with late ARF requiring hemodialysis was 100%. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK 506-treated patients, and represented a slowly progressing form of drug-specific nephrotoxicity. These preliminary results demonstrated a similar outcome in terms of early and late nephrotoxicity, but longer follow-up will delineate its overall efficacy and toxicity in humans.
Fulminant liver failure due to acute viral hepatitis is the most common emergency indication for liver transplantation. The postoperative course is highly correlated with the type and duration of infection. The complication rate is lowest in fulminant hepatitis B patients and highest in subacute hepatitis C/NANB patients.
Liver transplantation for advanced hepatocellular carcinoma is often followed by early tumour recurrence and death. At the beginning of the liver transplantation programme at Berlin Virchow we decided to offer liver transplantation only to patients with solitary tumours not exceeding a maximum diameter of 5 cm or to patients with two or three tumour nodes with a maximum diameter of 4 cm. From September 1988 to October 1993 435 liver transplants were performed in 403 patients. Of these, 32 patients (8%) had a histologically confirmed hepatocellular carcinoma (29 males, 3 females, median age 56 years). The overall actuarial survival according to Kaplan-Meier for the whole series of 32 patients with hepatocellular carcinoma was 82%, 78%, and 78% at 1, 2 and 3 years, respectively. Tumour size alone did not seem to be a relevant factor when comparing patients with tumours up to or larger than 3 cm in diameter. Patients with solitary tumours had a better prognosis than patients with multiple tumours. The largest difference was found between patients with stage I-III (UICC) tumours and those with stage IVA tumours: 1-, 2- and 3-year survival rates were 89% throughout in the former group, while the corresponding figures for patients with stage IVA tumours were 63%, 47% and 47%. Efforts should be made to identify stage IVA tumours preoperatively in order to use the precious resource of scarce donor livers in an optimal way.
In orthotopic liver transplantation (OLT) the graft liver is perfused with arterial blood prior to the opening of the hepatocaval anastomosis. In the present investigation we focused on the reperfusion of the graft liver in order to study the hepatic influence in the regulation of urokinase-type plasminogen activator (u-PA levels). Two different aprotinin schedules were used in 43 patients. We measured u-PA levels in the perfusate and in the corresponding systemic circulation. u-PA levels were higher in the perfusate as compared to systemic blood samples despite the dilution of the perfusate sample by the preservation fluid. This suggests u-PA secretion by the graft liver. In the presence of lower aprotinin levels signs of single-chain u-PA (scu-PA) activation was in the perfusate more prominent than systemically--a difference which was not seen in the presence of higher aprotinin levels. This seems to be an argument for the effectiveness of higher dosed aprotinin application in preventing scu-PA activation.
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