The perioperative period of liver transplantation from unconventional extended criteria donors: data from two high-volume centres.

BACKGROUND: As literature largely focuses on long-term outcomes, this study aimed at elucidating the perioperative outcomes of liver transplant patients receiving a graft from two groups of unconventional expanded criteria donors: brain dead aged > 80 years and cardiac dead. METHODS: Data of 247 cirrhotic patients transplanted at two high volume liver transplant centers were analysed. Confounders were balanced using a stabilized inverse probability therapy weighting and a propensity score for each patient on the original population was generated. The score was created using a multivariate logistic regression model considering a Comprehensive Complication Index ≥ 42 (no versus yes) as the dependent variable and 11 possible clinically relevant confounders as covariate. RESULTS: Forty-four patients received the graft from a cardiac-dead donor and 203 from a brain-dead donor aged > 80 years. Intraoperatively, cardiac-dead donors liver transplant cases required more fresh frozen plasma units (P < 0.0001) with similar reduced need of fibrinogen to old brain-dead donors cases. The incidence of reperfusion syndrome was similar (P = 0.80). In the Intensive Care Unit, both the groups presented a comparable low need for blood transfusions, renal replacement therapy and inotropes. Cardiac-dead donors liver transplantations required more time to tracheal extubation (P < 0.0001) and scored higher Comprehensive Complication Index (P < 0.0001) however the incidence of a severe complication status (Comprehensive Complication Index ≥ 42) was similar (P = 0.52). ICU stay (P = 0.97), total hospital stay (P = 0.57), in hospital (P = 1.00) and 6 months (P = 1.00) death were similar. CONCLUSION: Selected octogenarian and cardiac-dead donors can be used safely for liver transplantation.

Red blood cell exchange as an approach for treating a case of severe tacrolimus overexposure.

Immunosuppressive medication dosing errors are not unfrequent and may present a number of challenges to transplant clinicians. Tacrolimus (TAC) is a widely used immunosuppressant with a narrow therapeutic index and potential severe side effects, including neurotoxicity and kidney injury. We herein report a case of 60-year-old woman who underwent deceased-donor liver transplantation at our center and due to inadvertent TAC overexposure was admitted to the Intensive Care Unit because of severe neurologic impairment, kidney injury and arterial hypotension. This case was challenging because TAC is largely bound to erythrocytes, has a high molecular weight, is highly lipophilic, has a high distribution volume and cannot be removed by hemodialysis or plasmapheresis. Based on these considerations, we decided to replace TAC-saturated erythrocytes with blood-bank red cells with the aim to accelerate its clearance. The treatment was effective in decreasing TAC whole blood trough levels within the therapeutic ranges with a significant improvement of the patient's clinical status. Red-blood cell exchange is a potentially safe and effective means of managing severe and symptomatic TAC toxicity.

Balance of pro- and anti-inflammatory cytokines in cirrhotic patients undergoing liver transplantation.

This study was prospectively aimed at having better information about the natural history of serum cytokines in cirrhotic patients undergoing liver transplant surgery and at assessing their ability to set up an appropriate dynamic relationship between pro-inflammation and anti-inflammation. The levels of six cytokines (TNF-α, IL-1, IL-2, IL-6, IL-8, IL-10) were measured in blood samples collected at different time points before, during and after (48 h) the transplant procedure from the radial artery of 62 consecutive cirrhotic patients who underwent orthotopic liver transplantation. IL-1 always stayed within the normal range; IL-2 showed elevated baseline levels but decreased up to half at the end of the study (p<0.0001). IL-6 peaked at the end of surgery and returned to baseline 48 h afterwards. The same happened to IL-8 concentrations. IL-10 levels shown above the normal threshold at baseline, peaked at the end of surgery (p<0.0001) and were halved at the end of the study (p<0.0001). TNF-α peaked at the end of surgery without, however, being different from baseline levels (p=0.6). The physiologic pattern of cytokine release and their dynamic relationship was found to be preserved with a quick return to a balance between pro-inflammation and anti-inflammation as shown by the IL-6/IL-10 and TNF-α/IL 10 ratios (used to assess the inflammatory balance). A correlation was found between perioperative pro-inflammatory cytokine levels and the severity of the liver disease necessitating OLT. In summary, cirrhotic patients can achieve a balanced inflammatory response to surgery which is considered a primary requirement for uneventful grafts and patients' postoperative recovery.

Evaluation of a new software version of the FloTrac/Vigileo (version 3.02) and a comparison with previous data in cirrhotic patients undergoing liver transplant surgery.

BACKGROUND: Reliable cardiac output monitoring is particularly useful in the cirrhotic patient undergoing liver transplant surgery, because cirrhosis of the liver is associated with a vasodilated and high output state, known as cirrhotic cardiomyopathy, that challenges the reliability of pulse contour cardiac output technology. The contractility of the ventricle in cirrhosis is impaired, which is tolerated even though the ejection fraction and cardiac output are elevated because of the low peripheral resistance. However, during surgery the cirrhotic patient can decompensate because of the physiological changes and stress of surgery. Recently, we showed that the FloTrac/Vigileo™ failed to perform in cirrhotic patients undergoing transplant surgery. In response, the company upgraded their software. Therefore, we have assessed the accuracy and reliability of this new third-generation (version 3.02) FloTrac/Vigileo algorithm software in the same setting. METHODS: The cardiac index was measured simultaneously by single-bolus thermodilution (CI(TD)), using a pulmonary artery catheter, and pulse contour analysis, using the FloTrac/Vigileo (CI(V)). Readings were made at 10 time points during and after liver transplant surgery in 21 patients. Comparisons with data from our 2009 study, which used second-generation (version 01.10) software, were also made. RESULTS: Our new data show that version 3.02 software significantly reduced the adverse effect on pulse contour cardiac output reading bias in low peripheral resistance states, and thus improves the overall precision and trending ability of the system. Regression analysis between CI(TD) and CI(V) showed that the correlation was moderate (r =0.67, 95% confidence interval, 0.40 to 0.86). The Bland and Altman analysis showed that bias was 0.4 L.min(-1) · m(-2), and the percentage error was 52% (95% confidence interval, 49% to 55%). Trending ability of the new software also was improved but was still well below the current benchmarks. CONCLUSION: The new software (version 3.02) provided substantial improvements over the previous versions with better overall precision and trending ability. Further algorithm refinements will increase this technology's reliability to be extensively used in the highly complex setting of cirrhotic patients undergoing liver transplantation.

A single-staggered dose of calcineurin inhibitor may be associated with neurotoxicity and nephrotoxicity immediately after liver transplantation.

The aim of the present work was to assess the incidence of neuro-nephrotoxicity after a single-staggered dose of calcineurin inhibitors (CI) with different immunosuppressive approaches. From January to December 2006, all liver transplantation (LT) recipients at risk of renal or neurological complications treated with extracorporeal photopheresis (ECP) + mycophenolate mofetil + steroids and staggered introduction of CI (ECP group) were compared with a historical control group on standard CI-based immunosuppression. The ECP group included 24 patients with a mean model for end-stage liver disease (MELD) score of 19.9 +/- 11.1. The control group consisted of 18 patients with a mean MELD score of 12.5 +/- 5.2 (p = 0.012). In the ECP group CI were introduced at a mean of 9.2 +/- 6.2 d (4-31 d) after LT. Five patients in the ECP group presented acute neuro-nephrotoxicity after the first CI administration on post-transplant d 4, 5, 6, 6, and 14. Overall patient survival at one, six, and 12 months was 100%, 95.8%, and 95.8% in the ECP group vs. 94.4%, 77.7%, and 72.2% in the control group (p < 0.001). In conclusion, we showed that CI toxicity may occur after a single-staggered dose administration, ECP seems to be a valuable tool for managing CI-related morbidity regardless of the concomitant immunosuppressive regimen, being associated with a lower mortality rate in the early post-transplant course.

A novel immunosuppressive strategy combined with preemptive antiviral therapy improves the eighteen-month mortality in HCV recipients transplanted with aged livers.

BACKGROUND: Donor's age and immunosuppression influence the severity of hepatitis C virus (HCV) recurrence. We analyzed the 18-month mortality in 302 consecutive HCV recipients, divided into three groups, with homogeneous immunosuppression and preemptive antiviral therapy in the last group. PATIENTS: Group 1: one hundred thirty-three patients (1996-2000) mainly received a triple therapy (steroids- cyclosporine A [CyA]-azathioprine); first line treatment of biopsy-proven acute rejection (BPAR) was with steroid boluses; second-line with OKT3. Group 2: ninety-one patients (2001-2003) mainly received a double therapy (steroids-CyA) and induction with anti-CD25 antibody; first-line BPAR treatment was increased dose/switch of the calcineurin inhibitor; second-line steroid boluses; third-line extracorporeal photopheresis (ECP). Group 3: seventy-eight patients (2004-June 2006) mainly received a monotherapy (CyA) associated with ECP and induction with anti-CD25 antibody; first-line BPAR treatment was increased dose/switch of calcineurin inhibitor with increased ECP frequency, second-line steroid boluses, and third-line retransplantation. RESULTS: Median donor's age increased from 54 (13-84) years in group 1 to 60 (10-93) years in group 2 and 66 (17-84) years in group 3 (P<0.001). Overall mortality in groups 1, 2, and 3 decreased from 28.6% to 22% and 10.2% respectively (P = 0.003); HCV-related mortality from 7.5% and 12.1% to 1.3%, respectively (P = 0.029). BPAR were 33.8% in group 1 and 9.0% in group 3. Applicability of the preemptive antiviral therapy in group 3 was 69.2%. Sustained viral clearance occurred in 38.9% of 36 patients who completed the protocol. At multivariate analysis, a single-drug immunosuppressive regimen was the only variable independently associated with survival (P=0.05). CONCLUSION: Low and steady immunosuppression combined with preemptive antiviral therapy significantly improved the short-term mortality of HCV recipients transplanted with aged organs. Prolonged follow-up will assess whether this benefit is maintained in the long run.

The role of immunomodulation in ABO-incompatible adult liver transplant recipients.

BACKGROUND: ABO-incompatible (ABO-i) liver transplantation (LT) is a high-risk procedure due to the potential for antibody-mediated rejection (AMR) and cell-mediated rejection. The aim of the current report is to illustrate the results of a retrospective comparison study on the use of immunomodulation with therapeutic plasma exchange (TPE) associated to high-dose immunoglobulins (IVIg) and extracorporeal photopheresis (ECP) in ABO-i adult LT patients. PATIENTS AND METHODS: Between January 1996 and December 2005, 19 patients underwent ABO-i LT. The study was designed for a comparison between two groups of ABO-i LT. Group 1 (control group) consisted of 11 patients treated with TPE only. Group 2 (study group) included eight patients treated with TPE and IVIg. Moreover, all Group 2 patients received acute rejection prophylaxis with ECP. RESULTS: The graft survival at 6, 12, and 18 months was 63.6, 54.4, and 45.5% for Group 1 vs. 87.5, 87.5, and 87.5% for Group 2 (P < or = 0.001). In Group 1 there were 3(27.3%) cases of AMR; 5 (45.4%) biopsy-proven acute rejections (BPAR); 1 (9.1%) chronic rejection and 3 (27.3%) ischemic-type biliary lesions (ITBL). In Group 2 there were no cases of AMR, BPAR, chronic rejection, or ITBL (P = 0.013). CONCLUSION: At median follow-up of 568 days, TPE in combination with IVIg and ECP appears to protect the graft from AMR in ABO-i liver transplantation. Continued patient enrollment will allow validation of these preliminary observations or the opportunity to devise newer AMR-avoidance policies.

Treatment of antibody-mediated rejection with high-dose immunoglobulins in ABO-incompatible liver transplant recipient.

ABO-incompatible liver transplantation (LT) entails high risk of antibody-mediated rejection (AMR) and poor graft survival. Different treatment modalities have been reported, but none with use of a 2-week course of high-dose polyclonal i.v. immunoglobulins (IVIg) associated with plasmapheresis without the use of steroid pulses or monoclonal antibody. A 60-year-old male patient with blood-group O, Caucasian, underwent urgent LT for acute liver failure after hepatectomy for HCV-related hepatocellular carcinoma. He was grafted with a 66-year-old, blood-group A, HCV-positive liver graft. Pretransplant conditioning consisted of plasmapheresis and immunosuppression was triple with tacrolimus (TAC), steroids, and mycophenolate mofetil with anti-IL2-R monoclonal antibodies, plasmapheresis if hemagglutinin level >1:8, and extracorporeal photopheresis. After reduction of liver function tests to baseline, the patient presented a tenfold increase in alanine aminotransferases (ALT) levels 7 days post-transplantation. AMR was confirmed on histology. Treatment consisted of IVIg (1.5 g/Kg/daily for the first 7 days, and 1 g/Kg/daily from day 8 to 14) with a 14-day course of plasmapheresis. No side effect was observed and daily blood IgG levels ranged between 24.4 and 36.4 g/l. At the end of the scheduled course ALT returned to baseline. A control liver biopsy 55 days after LT showed no rejection and replacement of necrosis with fibrous strands. This case may support the role of high-dose IVIg for treatment and/or prophylaxis of severe AMR.

Avoiding calcineurin inhibitors in the early post-operative course in high-risk liver transplant recipients: The role of extracorporeal photopheresis.

The aim of this work is to report on the results of a single-center, prospective study on the feasibility of calcineurin-inhibitor (CNI)-staggered immunosuppression by use of extracorporeal photopheresis (ECP) in liver transplant (LT) recipients at risk of renal and neurological complications. Patients were matched on a 1:1 basis with historical controls on standard CNI immunosuppression. ECP patients were treated with ECP plus antimetabolites and/or steroids, while CNIs were withheld until clinically indicated. Thirty-six patients were evaluated: 18 ECP patients and 18 controls. ECP was tolerated in 100% of cases. CNI were introduced at a median of 8 days (4-55) in 17 ECP patients, while one patient was on a fully CNI-sparing regimen 22 months after LT. Acute rejection occurred in 27.7% patients in ECP (5/18) versus 16.7% in controls (3/18) (P = ns) with a shorter time to rejection in ECP (36 +/- 31.3 days vs. 83.6 +/- 65.6 days; P = ns). All rejection episodes were amenable to medical treatment. Neurological and renal complications occurred in 22.2% (4/18) of patients in either group, but led to in-hospital mortality in 3 patients among controls versus 1 in ECP (P = ns). One-, 6-, and 12-month survival rates were 94.4, 88.1, and 88.1% in ECP versus 94.4, 77.7, and 72.2% among controls (P < 0.0001). ECP seems to allow for management of high-risk LT recipients in the early post-transplant course and reduction of CNI-related mortality. Continued data validation is favored to assess the impact of ECP on long-term graft and patient survival.

Cystatin C as a marker of renal function immediately after liver transplantation.

To verify whether cystatin C may be of some use as a renal function marker immediately after orthotopic liver transplantation (OLT), we compared serum cystatin C (S(Cyst)), serum creatinine (S(cr)), and creatinine clearance (C(cr)) levels with the glomerular filtration rate (GFR). On postoperative days 1, 3, 5, and 7, S(Cyst) and S(cr) was measured in simultaneously drawn blood samples, whereas C(cr) was calculated using a complete 24-hour urine collection. The GFR was determined on the same days by means of iohexol plasma clearance (I-GFR). The correlation between 1/S(Cyst) and I-GFR was stronger than that of 1/S(cr) or C(cr) (P< 0.01). In the case of moderate reductions in I-GFR (80-60 mL/minute/1.73 m), S(cr) remained within the normal range, whereas the increase in S(cyst) was beyond its upper limit; for I-GFR reductions to lower levels (59-40 mL/minute/1.73 m), S(cr) increased slightly, whereas S(cyst) was twice its upper normal limit. When we isolated all of the I-GFR values on days 3, 5, and 7 that were > or = 30% lower than that recorded on the first postoperative day, S(Cyst)(P< 0.0001) and S(cr) (P< 0.01) levels were increased, whereas C(cr) remained unchanged (P = 0.09). Receiver operating characteristic (ROC) area-under-the-curve analysis showed that the diagnostic accuracy of S(cyst) was better than that of S(cr) and C(cr). S(cyst) levels of 1.4, 1.7, and 2.2 mg/L respectively predicted I-GFR levels of 80, 60, and 40 mL/minute/1.73 m. In conclusion, cystatin C is a reliable marker of renal function during the immediate post-OLT period, especially when the goal is to identify moderate changes in GFR.

Use of fenoldopam to control renal dysfunction early after liver transplantation.

With the aim of assessing whether fenoldopam can help to preserve renal function after liver transplantation, we randomized 140 consecutive recipients with comparable preoperative renal function to receive fenoldopam 0.1 microg/kg/minute (group F, 46 patients), dopamine 3 microg/kg/minute (group D, 48 patients), or placebo (group P, 46 patients) from the time of anesthesia induction to 96 hours postoperatively. There were no differences between the groups in intraoperative urinary output or furosemide administration (both P =.1). Daily recordings made during the first 4 postoperative days revealed no significant differences in urinary output (P =.1), serum creatinine (P =.5), the incidence of renal insufficiency (P =.7), the need for loop diuretics (P =.9) or vasoactive drugs (P =.8). In comparison with preoperative levels, creatinine clearance at the end of the study in the patients receiving fenoldopam remained substantially unchanged, whereas it decreased by 39 and 12.3%, respectively, in the subjects receiving placebo or dopamine (P <.001); blood cyclosporine A (CsA) levels were similar in the 3 groups (P =.1). Three subjects died in the intensive care unit (1 in each group, P =.9), 2 of them had renal failure. In conclusion, our results confirm the inefficacy of dopamine in preventing or limiting early renal dysfunction after liver transplantation, and suggest that fenoldopam may preserve creatinine clearance by counterbalancing the renal vasoconstrictive effect of CsA, as it has been reported in previous experimental studies.

Renal failure and abdominal hypertension after liver transplantation: determination of critical intra-abdominal pressure.

There is growing interest in measuring intra-abdominal pressure (IAP) in postsurgical and critically ill patients because increased pressure can impair various organs and functions. The aim of this study was to evaluate the effect of different IAP levels on the postoperative renal function of subjects undergoing orthotopic liver transplantation. IAP was measured every 8 hours with the urinary bladder pressure method for at least 72 hours after surgery. At the end of the study, the patients were classified on the basis of their IAP values: < or = 18 mm Hg (group A), 19 to 24 mm Hg (group B), > or = 25 mm Hg (group C). The three groups were compared in terms of the incidence of acute renal failure (defined as blood creatinine > 1.5 mg/dL or an increase in the same of > 1.1 mg/dL within 72 hours of surgery), hourly diuresis, blood creatinine, the filtration gradient, hemodynamic variations, and outcome. The incidence of renal failure was higher among the subjects in group C (P < .05 versus group A and < .01 versus group B), who also had higher creatinine levels (P < .01), a greater need for diuretics (P < .01) and a worse outcome (P < .05). Receiver Operator Characteristic curve analysis showed that an abdominal pressure of 25 mm Hg had the best sensitivity/specificity ratio for renal failure. An intra-abdominal pressure of > or = 25 mm Hg is an important risk factor for renal failure in subjects undergoing liver transplant.