Effects of recombinant activated factor VII on coagulation measured by thromboelastography in liver transplantation.

Besides the conventional laboratory tests, thromboelastography (TEG) is used to monitor hemostasis during liver transplantation. A previous pilot study suggested a beneficial effect of recombinant activated factor VII (rFVIIa) on transfusion requirements in liver transplantation. In the present study, we assess the effects of rFVIIa on coagulation variables and TEG. In six study patients, the prothrombin time (PT), the activated partial thromboplastin time (aPTT) and TEG variables [reaction time (r), kinetic time (k), or clot formation time, alpha angle (alpha), and maximal amplitude (MA)] were recorded before and after the administration of a bolus of 80 microg/kg rFVIIa. These patients were compared with six controls who did not receive rFVIIa. In contrast with the control group, a significant shortening of PT (P = 0.028) and aPTT (P = 0.028), r (P = 0.046) and k (P = 0.043) values, and a significant incline of the alpha angle (P = 0.028) were noticed after injection of rFVIIa, whereas MA increased not significantly (P = 0.075). rFVIIa rapidly improved coagulation variables in liver transplant patients including PT and aPTT. Of the TEG variables, r, k and alpha angle significantly improved, and MA showed a trend to increase. These data suggest that rFVIIa not only influences the speed of clot formation, but also the physical properties of the clot, which cannot be detected by routine coagulation tests.

Cost effectiveness of selective decontamination of the digestive tract in liver transplant patients.

OBJECTIVE: To assess the cost effectiveness of selective decontamination of the digestive tract (SDD) in liver transplant patients. DESIGN: Randomised, placebo-controlled, double-blind trial with an integrated economic evaluation. SETTING: Two university hospitals in The Netherlands. Cost effectiveness was assessed from a societal perspective. PATIENTS AND PARTICIPANTS: 58 patients who underwent liver transplantation and received SDD (n = 29) or placebo (n = 29) pre- and postoperatively. INTERVENTIONS: SDD medication and placebo. MAIN OUTCOME MEASURES: Infection episodes, days of infection, costs of SDD and routine cultures, mean other direct medical costs per patient and additional costs of severe infection. RESULTS: Costs of SDD medicine and routine cultures were on average 3,100 US dollars ($US; 1997 values) per patient who underwent SDD. Both preoperatively and postoperatively, costs other than SDD and cultures did not significantly differ between the SDD and the placebo groups (preoperative, $US2,370 vs $US2,590; postoperative, $US25,455 vs $US24,915). Additional postoperative costs of severe infections were $US250 per day per patient. There were no significant differences in the mean number of infection episodes between groups. CONCLUSIONS: SDD leads to the additional costs of SDD medication and routine cultures, whereas no savings in other costs and no improvement in infection episodes are realised. Consequently, SDD may be considered as a nonefficient approach in patients undergoing liver transplantation. The additional costs of severe infection are considerable.

Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study.

BACKGROUND: Large transfusion requirements, i.e., excessive blood loss, during orthotopic liver transplantation (OLT) are correlated with increased morbidity and mortality. Recombinant factor VIIa (rF-VIIa) has been shown to improve hemostasis in a variety of conditions, but has never been studied in liver transplantation. METHODS: We performed a single-center, open-label, pilot study in adult patients undergoing OLT for cirrhosis Child-Pugh B or C, to assess efficacy and safety of rFVIIa. rFVIIa (80 microg/kg) was administered at the start of the operation, to be repeated according to predefined criteria. Packed red blood cells (RBC), fresh-frozen plasma, and platelet concentrates were administered according to predefined criteria. Perioperative transfusion requirements in study patients were compared with matched controls. RESULTS: Six patients were enrolled in the study. All received a single dose of rFVIIa. Transfusion requirements (given as median, with range in parentheses) were lower in the study group than in matched controls: 1.5 (0-5) vs. 7 (2-18) units of allogeneic RBC (P=0.006), 0 (0-2) vs. 3.5 (0-23) units of autologous RBC (P=0.043), total amount of RBC 3 (0-5) vs. 9 (4-40) units (P=0.002). Transfused fresh-frozen plasma was 1 (0-7) vs. 8 (2-35) units (P=0.011). Blood loss was 3.5 L (1.4-5.3) vs. 9.8 L (3.7-35.0) (P=0.004). One study patient developed a hepatic artery thrombosis at day 1 postoperatively. CONCLUSIONS: A single dose of 80 microg/kg rFVIIa significantly reduced transfusion requirements during OLT. Further study is needed to establish the optimally effective and safe dose of rFVIIa in orthotopic liver transplantation.

Increased cancer risk after liver transplantation: a population-based study.

BACKGROUND/AIMS: Development of de novo malignancies emerges as a serious long term complication after liver transplantation. METHODS: We reviewed the medical records of 174 adult one-year survivors for de novo malignancies. The observed cancer rates were compared with the expected cancer rates in the Dutch population. RESULTS: Twenty-one of the 174 patients developed 23 malignancies (12%). Skin and lip cancer accounted for 12 of the 23 malignancies (52%). Only one patient had a B-cell lymphoma. The cumulative risk for de novo malignancy was 6, 20, and 55% at 5, 10, and 15 years after transplantation, respectively. The overall relative risk (RR) as compared with the general population was 4.3 (95% confidence interval 2.4-7.1). Significantly increased RRs were observed for non-melanoma skin cancer (RR 70.0), non-skin solid cancer (RR 2.7), renal cell cancer (RR 30.0), and colon cancer (RR 12.5). Multivariate analysis showed that an age > 40 years and pretransplant use of immunosuppression were significant risk factors. CONCLUSIONS: An increased risk of cancer exists after liver transplantation, for both for skin/lip cancer, and other solid tumors. Older age and the use of immunosuppression are risk factors.

Endotoxins and cytokines during liver transplantation: changes in plasma levels and effects on clinical outcome.

Endotoxins, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6 are believed to have a key role in liver transplantation. The origin and course of these factors is not completely known. In this prospective study of 40 patients, we sought more understanding of the relations between these factors and their effects on clinical outcome by sampling at different sites. Endotoxemia was only present in 20% of the patients. In 75% of these patients, it was present during the anhepatic phase and quickly resolved after reperfusion. Endotoxemia was not related to a clinical adverse event. TNF-alpha was released from the graft after reperfusion, and initial levels after reperfusion were related to predonation levels in the donor. Only levels of TNF-alpha in the recipient before transplantation were found to be predictive of postoperative complications. We conclude that monitoring endotoxins and these cytokines is of very limited value in predicting outcome.

Blood loss in orthotopic liver transplantation: a retrospective analysis of transfusion requirements and the effects of autotransfusion of cell saver blood in 164 consecutive patients.

Liver transplantation is associated with excessive blood loss. In order to identify factors influencing blood loss and to provide a basis for a pilot study to evaluate recombinant activated factor VII as a haemostatic agent, a retrospective study was performed in 164 consecutive patients with cholestatic or noncholestatic liver disease, who underwent orthotopic liver transplantation at a single centre between 1989 and 1996. Transfusion of allogeneic and autologous (cell saver) blood was used as a measurement of blood loss. Transfusion requirements were associated with age, gender, primary disease, Child-Pugh classification, serum levels of activated partial thromboplastin time, antithrombin III, urea and creatinine, platelet number, year of transplantation, length of cold ischaemia time and autologous blood transfusion. Of these variables, Child-Pugh classification (P = 0.001), urea (P = 0.0007), year of transplantation (P = 0.002), cold ischaemia time (P = 0.01) and autologous blood transfusion (P < 0.0001) were independent predictors of transfusion requirements by multivariate analysis. Thus, blood loss and transfusion requirements depend primarily on the severity of liver disease, quality of the donor liver, experience of the transplantation team and use of autologous (cell saver) blood transfusion. These findings emphasize the need for appropriate drug therapy and a critical reappraisal of current transfusion policy.

Routine Doppler ultrasound for the detection of clinically unsuspected vascular complications in the early postoperative phase after orthotopic liver transplantation.

To assess the role of routine Doppler ultrasound in the detection of clinically unsuspected vascular complications in the early postoperative phase after orthotopic liver transplantation (OLT), the findings of 858 routinely performed Doppler ultrasound examinations were analyzed in 268 transplants. At various time intervals after OLT, we encountered 46 abnormal Doppler findings: hepatic artery (thrombosis), portal vein [anastomotic stenosis, (non)occlusive thrombosis or reversed flow], inferior vena cava [anastomotic stenosis with reversed flow, no flow, or (non)occlusive thrombosis], and hepatic veins (to-and-fro flow or stenosis with reversed flow) in 14, 20, 9, and 2 transplants, respectively. Most of these abnormal Doppler findings were confirmed by angiography, cavography, or surgery. The positive predictive value for hepatic artery thrombosis (HAT) was 12 out of 14, or 86%. In the first 2 weeks after OLT, routine Doppler ultrasound revealed 20 of the 46 abnormal findings (43%). Clinically unsuspected complications of the hepatic artery, portal vein, inferior vena cava, and hepatic veins were found in 9 of the 14 (64%), 6 of the 20 (30%), 3 of the 9 (33%), and 2 of the 2 (100%) transplants, respectively. The highest incidence--nine vascular complications--was found on the 1st day. On each of the remaining days (except for the 2nd and 9th days), one or two vascular complications were detected. HAT was found mainly in the 1st week. Vascular complications developed independently or concomitantly. We conclude that routine Doppler ultrasound is very important for the detection of clinically unsuspected vascular complications, particularly HAT, in the first 2 weeks after OLT. We recommend routine Doppler ultrasound of all hepatic vessels every 3 days in the early postoperative phase after OLT. Special attention should be paid to the 1st day.

Donor-specific immunological non-responsiveness after liver transplantation.

Since the rate of immunological losses of liver allograft after the immediate posttransplant period is much lower than in other organs, we studied the immune responses against donor HLA antigens in 18 patients with a good long-term outcome to determine whether the development of a state of immunological non-responsiveness to donor antigens might account for this favorable outcome. The reactivity against donor spleen cells was measured before and 2 years after transplantation. The reactivity in mixed lymphocyte culture (MLC) and the frequencies of cytotoxic T cell precursors (CTLp) were determined. Responses against third-party spleen cells were determined concurrently to exclude a generalized reduction of immunocompetence due to chronic immunosuppressive treatment. Before orthotopic liver transplantation, the majority of patients had normal T cell responses against donor antigens that were comparable to those against third-party antigens. Two years after transplantation, donor-specific MLC non-reactivity had developed in 10 of the 18 (56%) patients. In addition, 15 of 18 (83%) patients had developed donor-specific cytotoxic T cell (CTL) non-responsiveness; 2 had reduced numbers of CTLp against both donor and third-party cells, while the remaining patient had maintained reactivity against donor antigens. In conclusion, donor-specific non-responsiveness is present in the majority of patients 2 years after successful liver transplantation, but occurs predominantly at the CTL level.

Quantification of immunosuppression by flow cytometric measurement of intracellular cytokine synthesis.

The availability of a method to measure the effects of drugs on immune reactivity should be helpful in optimizing treatment after organ transplantation. Since cyclosporine A (CSA) interferes with activation of T cells and cytokine synthesis, production of IL-2 and IFN-gamma might constitute a marker of this drug's effects. We measured the capacity for mitogen-stimulated production of these cytokines in whole blood by using immunostaining of intracellular and membrane antigens, followed by flow cytometry. The percentage of CD4+ T cells producing IL-2 or IFN-gamma was strongly reduced in 20 transplant patients compared with 24 healthy controls. The capacity for IL-2 production of CD4+ and CD8+ cells correlated inversely with CSA blood levels (P values 0.0087 and 0.0396, respectively). IFN-gamma production by CD4+ T cells showed a negative correlation with the prednisolone dose (P = 0.0175) and, for the CD8+ subset, with CSA trough levels (P = 0.0023). These data show that inhibition of T cell cytokine synthesis by CSA and prednisolone can be quantified.

Quantitation of immunosuppression by flow cytometric measurement of the capacity of T cells for interleukin-2 production.

BACKGROUND: Methods to quantitate the effects of immunosuppressive drugs on immune reactivity might be helpful for monitoring immunosuppressive treatment. Cyclosporine (CsA) inhibits the induction of cytokine synthesis in T cells, and measurement of interleukin (IL)-2 production might constitute a parameter of this drug's effect. METHODS: We determined the percentages of CD4+ and CD8+ lymphocytes producing IL-2 upon stimulation by phorbol myristate acetate and calcium ionophore in whole blood culture, using immunostaining of intracytoplasmatic and membrane markers, followed by multiparameter flow cytometry. A total of 38 clinically stable transplant patients on various immunosuppressive protocols were studied. RESULTS: The percentage of CD4+ T cells producing IL-2 was strongly reduced in patients compared with healthy controls (23% [range, 3-68%] vs. 59.0% [range, 41-70%]; P=0.000035). The percentage of CD4+ T cells producing IL-2 was negatively correlated with the CsA level (Rc=-0.0821, P=0.00002297) but not with prednisolone or azathioprine doses. Fewer CD8+ T cells produced IL-2 in transplant patients compared with controls, but the difference failed to reach statistical significance. The percentage of CD8+ T cells capable of producing IL-2 was inversely correlated to CsA levels (Rc=-0.0375, P=0.0011). CONCLUSIONS: These data suggest that the functional effects of CsA in transplant recipients can be quantitatively determined and that the capacity of CD4+ T cells to produce IL-2 upon stimulation constitutes a functional parameter of CsA effects on the immune system. Prospective studies are required to determine whether this method is useful for clinical monitoring.

Gastric mucosal pH is associated with initial graft function but is not a predictor of major morbidity after liver transplantation.

Gastric mucosal pH reflects splanchnic perfusion. Monitoring gastric mucosal pH might be useful in predicting outcome after liver transplantation. Forty patients were included in the study. Gastric mucosal pH and gastric mucosal pH corrected for systemic pH were compared with regard to initial liver function and morbidity. Eighty percent of the patients had at least one episode with a gastric mucosal pH of <7.32, and 84% of these had a concomitant arterial pH of <7.32. No differences in morbidity were found between patients with a gastric mucosal pH of <7.32 and those with a gastric mucosal pH of >7.32. If gastric mucosal pH was corrected for arterial pH, only 49% of the patients had an episode during transplantation with a corrected gastric mucosal pH of <7.32. Comparing these patients with the group that did not have such an episode, we found that flow in the venovenous bypass system was significantly lower (2.9 v 3.4 L/min; P < .02) in the first group. Also alanine aminotransferase and aspartate aminotransferase levels were higher, antithrombin III levels and lidocaine clearance rates were lower, and prothrombin times were longer in the group with corrected gastric mucosal pH of <7.32. No differences with regard to major morbidity and mortality were noted. Gastric mucosal pH during liver transplantation should be corrected for arterial pH. Patients with a corrected gastric mucosal pH of <7.32 are more likely to develop initial liver function tests disturbances, but morbidity is not different from patients with gastric mucosal pH of >7.32.

Poor initial graft function after orthotopic liver transplantation: can it be predicted and does it affect outcome? An analysis of 125 adult primary transplantations.

Donor liver shortage is a persistent problem in liver transplantation. A more liberal donor acceptance policy may be a possible solution. However, this might put recipients at risk for initial poor function or even non-function of the graft. Therefore risk factors for initial graft dysfunction should be identified, preferably by using an uniform definition of primary graft dysfunction or non-function. We retrospectively analysed 125 adult liver transplantations in order to identify risk factors for initial poor function and primary non-function. Donor, recipient pretransplant and surgical parameters were evaluated. Since there is no consensus on the criteria of dysfunction we used two definitions known from literature. No risk factors for postoperative dysfunction could be identified for either of the two definition sets. Furthermore, the definition set that included ALAT, prothrombin time and bile production in the first 72 h to identify poor graft function showed no relation with graft or recipient outcome. The other set, using ASAT and prothrombin time, determined from day 2 to day 7, showed that patients with a primary dysfunction had significantly higher morbidity and mortality compared to patients with a well functioning graft. We conclude that initial poor function after liver transplantation remains unpredictable, irrespective of the way it is defined. Moreover, our analysis shows that initial poor function can also develop in recipients that receive 'non-marginal' grafts without prolonged ischemia times. These results may support a more liberal selection of donor livers.

Low HLA-DR expression on monocytes as a prognostic marker for bacterial sepsis after liver transplantation.

BACKGROUND: Low HLA-DR expression on monocytes is associated with an increased risk of infection after surgery or trauma. We determined the value of this parameter as a marker for sepsis after liver transplantation. METHODS: The percentage of monocytes expressing HLA-DR was determined by flow cytometry before and after liver transplantation in nine patients. Five lung and 20 kidney transplant recipients served as controls. RESULTS: Bacterial sepsis occurred in 5 of 9 liver transplant patients and 0 of 24 control patients. Monocyte HLA-DR expression decreased <50% in all five patients with sepsis. HLA-DR expression dropped before (n=4) or at the time of sepsis (n=1), and remained low for 13 weeks. HLA-DR expression remained >50% in the four liver transplant patients without sepsis. Only 1 of 25 control patients had persistently low monocyte HLA-DR expression. CONCLUSIONS: Monitoring of monocyte HLA-DR expression may be helpful in identifying liver transplant patients who have an increased risk of imminent bacterial sepsis.

Surgical treatment of giant haemangioma of the liver.

BACKGROUND: The treatment of giant symptomatic haemangioma of the liver is still controversial. This retrospective study reviewed the results of surgical treatment. METHODS: Twenty-eight patients with symptomatic giant haemangioma of the liver were treated by liver resection (n = 24) or liver transplantation (n = 4). The median diameter of the haemangiomas was 11 (range 5-20) cm. RESULTS: Complications occurred in five of the 24 patients treated by partial liver resection, although all survived and remain alive and well more than 2 years after surgery. In six patients there was residual haemangioma in the liver remnant which did not enlarge during the 2-year follow-up. In four patients the haemangioma was considered irresectable and liver transplantation was performed. One died after a 'two-stage' liver transplantation; the remaining three patients are alive and well, 1, 4 and 9 years after transplantation. CONCLUSION: Liver resection is the treatment of choice for giant haemangioma of the liver where possible. In selected cases liver transplantation is indicated.

Splenic artery aneurysms in liver transplant patients. Liver Transplant Group.

BACKGROUND/AIMS: The purpose of the study was to investigate the incidence of and risk factors for splenic artery aneurysms in liver transplant patients. METHODS: Medical records and the pre- and 1-year postoperative angiograms of 337 liver transplant patients were reviewed to assess the presence and characteristics of these aneurysms. RESULTS: Forty-five patients with aneurysms were identified (13%): 41 cases in 242 adult patients (17%) and four (4%) in 95 children (p<0.01). The female-to-male ratio was 2:1. The majority of the aneurysms (87%) were located in the distal third of the splenic artery and the majority (87%) of the patients presented multiple aneurysms. In patients without portal hypertension no aneurysms were identified, whereas in 16% of the patients with portal hypertension aneurysms were found (p<0.001). In adult patients the incidence of splenic artery aneurysms was significantly higher in patients with parenchymal diseases than in patients with cholestatic diseases (p<0.0001). Two patients (4%) died due to rupture of the aneurysms. Control angiographies, 1 year after liver transplantation, showed no changes in size and number of the aneurysms, and no new aneurysms were identified. CONCLUSIONS: The incidence of splenic artery aneurysms in liver transplant patients is 13%. They are generally multiple and located in the distal third of the splenic artery. The incidence is higher in women and in patients with parenchymal liver disease and portal hypertension. The incidence of rupture was 4%.

Changes in portal hemodynamics and acute rejection in the first 2 weeks after orthotopic liver transplantation. A prospective Doppler ultrasound study.

RATIONALE AND OBJECTIVES: To analyze changes in Doppler ultrasound variables of the portal vein in relation to liver biopsy findings, the authors performed a prospective study of 316 Doppler ultrasound examinations in the first 2 weeks after orthotopic liver transplantation on 23 patients. METHODS: Recordings were obtained daily from the portal vein (diameter, maximum velocity, and flow). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi-square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection. RESULTS: In our series of 23 patients, acute rejection was diagnosed by liver biopsy in nine of them (39%). Changes in portal vein diameter, maximum velocity, and flow did not correlate consistently with liver biopsy findings, due to a multifactorial origin. Changes in portal hemodynamics were observed in patients with hepatic artery thrombosis, portal vein stenosis, acute rejection, and sepsis. CONCLUSIONS: Although routine screening using Doppler ultrasound proved to be useful for the determination of rapid changes in portal hemodynamics within a short time, serial Doppler ultrasound examinations were not helpful in predicting acute rejection.

Evidence for an increased rate of bacterial infections in liver transplant patients with cytomegalovirus infection.

It has been reported that cytomegalovirus (CMV) infections increase the susceptibility of transplant patients for other opportunistic infections. Most of these studies date back from a time when CMV infection was difficult to diagnose and antiviral treatment not available. We therefore analyzed CMV-related morbidity after OLT in 111 consecutive patients. CMV monitoring was done weekly using the antigenemia assay, a quantitative marker of the viral load, in addition to serology. CMV infection occurred in 66/95 (69%) evaluable patients. Antigenemia was detected in 94% of them. The number of CMV antigen-positive cells was helpful to monitor the course of infection and differentiate CMV disease from other complications. CMV infection was symptomatic in 48/66 (73%) patients. Mild disease occurred in 30 patients, and severe constitutional symptoms or organ involvement in 18. No patient died as a direct result of CMV infection, but mortality between day 30 and 180 tended to be higher in CMV-infected patients (15 vs. 0%, p < 0.1). CMV infection was associated with a 2.45-fold higher incidence of major infections between day 30 and 180 after OLT (p < 0.05). Most of these infections were caused by gram-positive cocci. We conclude that CMV not only causes substantial morbidity, but also increases the risk of bacterial infections.

Doppler ultrasound of the hepatic artery and vein performed daily in the first two weeks after orthotopic liver transplantation. Useful for the diagnosis of acute rejection?

RATIONALE AND OBJECTIVES: To analyze changes in Doppler ultrasound variables in relation to liver biopsy findings for the diagnosis of acute rejection after orthotopic liver transplantation (OLT), the authors performed in a prospective study 316 Doppler ultrasound examinations in the first 2 weeks after OLT on 23 patients. METHODS: Recordings were obtained daily from the hepatic artery (resistive index [RI]) and hepatic vein (damping index [DI]). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi-square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection. RESULTS: Serial Doppler ultrasound examinations showed a significant increase in the RI in 11 of 22 patients (50%); the 23rd patient was excluded because of hepatic artery thrombosis. Despite an agreement in 15 of 22 patients (68%) no statistically significant correlation could be found (positive predictive value 6/11 = 55%; negative predictive value 9/11 = 82%; chi-square = 3.14; P > 0.05). A significant increase in the DI was observed in 14 of 23 patients (61%). However, no statistically significant correlation could be found as well with this parameter (positive predictive value 6/14 = 43%; negative predictive value 6/9 = 67%; chi-square = 0.00; P > 0.05). CONCLUSION: Serial Doppler ultrasound examinations were not helpful in predicting acute rejection.