Hani P. Grewal

Amelioration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-α polyclonal antibody☆☆☆

Tumor necrosis factor (TNF) is an inflammatory cytokine that may be an important mediator in the development of the systemic sequelae associated with severe acute pancreatitis. The purpose of this study was to determine whether the neutralization of TNF-alpha with a polyclonal antibody could ameliorate selected biochemical parameters of severe pancreatitis in a rat model. Pancreatitis was induced by an antegrade injection of artificial bile into the bile duct. Forty rats were randomized into 4 groups: no surgery (controls), saline infusion to bile duct (sham), placebo treatment in animals with pancreatitis (placebo + Px), and pretreatment with a polyclonal antibody (PAb) in animals with pancreatitis (PAb + Px). Serum TNF-alpha, amylase, calcium, hematocrit, glucose, and ascites volume were measured 2 hours after bile duct infusion. Pretreatment with the PAb produced a significant improvement in all parameters when compared with pancreatitis animals treated with placebo (p < 0.001). In addition, TNF-alpha, which was elevated in animals with pancreatitis, was reduced significantly in treated animals (p < 0.001). These results suggest that TNF-alpha may be an important mediator in the evolution of the systemic manifestations of severe acute pancreatitis.

Donor age affects fibrosis progression and graft survival after liver transplantation for hepatitis C

Background. The use of liver allografts from an older donor (OD) (age >50 years) is a widespread strategy to manage the disparity between supply and demand of organs for liver transplantation. This study determines the effect of OD allografts on fibrosis progression and graft survival after liver transplantation in patients with and without infection caused by hepatitis C virus (HCV). Methods. All patients undergoing liver transplantation at our center from March 1998 to December 2001 were analyzed. Protocol liver biopsies were performed at 1, 16, and 52 weeks after transplantation and yearly thereafter. One liver pathologist scored all biopsy specimens for modified hepatic activity index (0–18) and fibrosis (0–6). Results. A total of 402 patients (167 with HCV and 235 without HCV) underwent liver transplantation during the study period. Among patients with HCV, baseline characteristics of OD recipients were similar to younger donor (YD) (age <50 years) recipients. In patients with HCV, graft survival was shorter in OD graft recipients than in YD recipients (P <0.001). In patients without HCV, graft survival was independent of donor age. In patients with HCV, a fibrosis score of 3 or greater was present in 17% of OD recipients at 4 months and in 26% at 12 months after transplantation, compared with 8% of YD recipients at 4 months and 13% at 12 months (P <0.001). Conclusions. Liver transplantation with OD grafts is associated with rapid progression of fibrosis and decreased graft survival in patients with HCV, but not in patients without HCV. OD grafts should be considered preferentially for patients without HCV.

Liver Transplantation Using Controlled Donation After Cardiac Death Donors: An Analysis of a Large Single-Center Experience

The use of donation after cardiac death (DCD) donors may provide a valuable source of organs for liver transplantation. Concerns regarding primary nonfunction (PNF) and intrahepatic biliary stricture (IHBSs) have limited the enthusiasm for their use. A retrospective analysis of 1436 consecutive deceased donor liver transplants performed between December 1998 and October 2006 was conducted. These included 108 DCD liver transplants, which were compared to 1328 transplants performed with organs from donors meeting the criteria for donation after brain death (DBD). The median follow‐up was 48 months. The 1‐, 3‐, and 5‐year patient survival and graft survival for DCD donors were 91.5%, 88.1%, and 88.1% and 79.3%, 74.5%, and 71.0%, respectively. The 1‐, 3‐, and 5‐year patient survival and graft survival for DBD donors were 87.3%, 81.1%, and 77.2% and 81.6%, 74.7%, and 69.1%, respectively. Patient survival and graft survival were not significantly different between DCD donors less than 60 years old, DCD donors greater than 60 years old, and DBD donors. Causes of graft loss included IHBSs (n = 9), PNF (n = 4), recurrent hepatitis C virus (n = 4), hepatic artery thrombosis (n = 1), rejection (n = 2), and patient death (n = 13). Contrary to previously published data, excellent long‐term patient survival and graft survival can be obtained with DCD allografts, and in our experience, they are equivalent to those obtained from DBD allografts. Liver Transpl 15: 1028–1035, 2009.

Anti-TNFα therapy improves survival and ameliorates the pathophysiologic sequelae in acute pancreatitis in the rat

BACKGROUND Elevated levels of tumor necrosis factor-alpha (TNFalpha) have been measured in a lethal model acute pancreatitis (AP) and may contribute to the pathophysiologic sequelae of the disease. METHODS To determine the significance of anti-TNFalpha therapy on survival and disease manifestations in a clinically relevant model of AP, a rat model was developed using a retrograde pancreatic ductal infusion of bile. Animals were randomized to no treatment (n = 30) or treatment with anti-TNFalpha antibody 15 minutes prior to induction of AP (n = 30). Five treated and 5 untreated rats were killed at various time periods up to 72 hours to provide temporal characterization of TNFalpha activity in AP. RESULTS A burst Of TNFalpha activity in the serum of untreated pancreatitis animals between 1 and 3 hours after induction of the disease is prevented by pretreatment with anti-TNFalpha antibody. CONCLUSIONS These findings provide a plausible mechanism for the improvement in biochemical and histologic parameters as well as in overall survival in an experimental model of acute pancreatitis in the rat.

Surgical technique for right lobe adult living donor liver transplantation without venovenous bypass or portocaval shunting and with duct-to-duct biliary reconstruction.

ObjectiveTo report the authors’ experience with adult living donor liver transplantation (ALDLT) without venovenous bypass and to describe modifications that will allow for a direct duct-to-duct biliary reconstruction. Summary Background DataAdult living donor liver transplantation is being evaluated as a method to alleviate the organ shortage. Descriptions of the procedure have emphasized the use of venovenous bypass, portocaval decompression, and the mandatory use of a Roux-en-Y biliary enteric anastomosis. The authors describe a technique for ALDLT without venovenous bypass, portocaval decompression, or caval clamping in 11 recipients and describe the modifications to the procedure that may allow a duct-to-duct biliary reconstruction in certain cases. MethodsBetween March 1999 and March 2000, 11 ALDLTs were performed at the authors’ institution. All procedures were performed without venovenous bypass, portocaval decompression, or caval clamping. After a modification to the procedure, five of the last six recipients underwent biliary reconstruction with a direct duct-to-duct anastomosis. Data regarding donor, recipient, and graft survival, complications, and graft function were collected. ResultsRecipients comprised five women and six men, mean age 48 years. Donors comprised five women and six men, mean age 36.5 years. Donor to recipient relationships included sibling, spouse, son, and daughter. Indications for transplantation were hepatitis C, hepatitis C with hepatocellular carcinoma, primary biliary cirrhosis, primary sclerosing cholangitis, ethanol, and cryptogenic. No case required venovenous bypass or portocaval shunting. The right hepatic vein of the donor graft was anastomosed to the confluence of the left and middle hepatic veins in all cases. All donors are alive and well, with no adverse complications reported. Recipient and graft survival rates were 91% and 82%, respectively, for ALDLT versus 92% and 92% for recipients of cadaveric organs during the same time period. One recipient died of multiple organ failure and sepsis. Biliary reconstruction was performed by Roux-en-Y hepaticojejunostomy in the six cases. In five of the last six recipients, direct duct-to-duct biliary reconstruction with a T tube was used. No anastomotic leaks or strictures occurred in the patients undergoing duct-to-duct reconstruction. ConclusionsAdult living donor liver transplantation can be performed safely and may help alleviate the organ shortage. Neither venovenous bypass nor portocaval shunting is necessary to perform the procedure, and modifications to both the donor and recipient hepatectomy procedures may allow biliary reconstruction to be performed by a direct duct-to-duct anastomosis in selected cases.

Incidence and outcome of infection by vancomycin-resistant Enterococcus following orthotopic liver transplantation

Vancomycin-resistant Enterococcus (VRE) has become a significant nosocomial pathogen. For this study, the records of 325 patients who underwent orthotopic liver transplantation (OLT) were reviewed. Thirty-four patients were infected by VRE (incidence of 10.5%, 14% in adults vs. 5% in children, P < 0.01). Common features of patients who developed infections with VRE included previous antibiotic use (25 patients, 15 of whom received vancomycin), co-infection by other pathogens (28 patients), and relaparotomy following OLT (20 patients). Pulmonary and/or renal failure preceded infection by VRE in 11 and 4 adult patients, respectively. Biliary complications were exceedingly common in patients infected by VRE (28 patients) and significantly increased the risk of infection by VRE (21.5% vs. 3.1% for patients without biliary complications, P < 0.0001). Mortality associated with VRE infections was high (56% vs. 19% for patients not infected by VRE, P < 0.0005). The most frequent cause of death was sepsis (16 of 19 patient deaths), often polymicrobial. The high incidence of infection by VRE following OLT, the lack of effective antibiotics for the treatment of VRE, and the association of VRE with patient mortality emphasizes the need to define the risk factors associated with VRE infection. We suggest early surgical intervention to treat complications that may predispose patients to infection by VRE.

Risk factors for postimplantation pancreatitis and pancreatic thrombosis in pancreas transplant recipients.

Reperfusion pancreatitis and pancreatic thrombosis are 2 complications of pancreatic transplantation that are associated with both an increased patient morbidity and a decrease in pancreas graft survival rates. These complications are thought to be related to donor factors, procurement and preservation variables, and postimplantation recipient management. We reviewed our experience with 41 consecutive pancreas transplant patients (18 females, 23 males) performed in association with kidney transplants (n = 34), whole (n = 5) and segmental (n = 2). The average cold ischemia time (CIT) was 11.5 hr. Donor and recipient variables were related to two outcomes: (1) postoperative pancreatitis (n = 9) and (2) postoperative pancreatic thrombosis (n = 6). Steroid administration to the donor resulted in significant reduction of postimplantation pancreatitis (P < 0.001). Also, postoperative pancreatitis was significantly less common (P < 0.02) in recipients given calcium channel blockers in the early postoperative period. Pancreatic thrombosis was significantly more common in male recipients (P < 0.04) and was also significantly related to CIT (P < 0.05). These data indicate that proper donor management and pretreatment with high-dose steroids, together with shortening of CIT and postoperative administration of calcium channel blockers, are protective against pancreatic thrombosis and pancreatitis.

A Prospective Comparison of Simultaneous Kidney–Pancreas Transplantation With Systemic-Enteric Versus Portal-Enteric Drainage

ObjectiveTo compare pancreas transplantation with systemic-enteric (SE) versus portal-enteric (PE) drainage in a prospective fashion. Summary Background DataTo improve the physiology of pancreas transplantation, the authors developed a new technique of portal venous delivery of insulin and enteric drainage of the exocrine secretions. MethodsDuring a 26-month period, the authors prospectively alternated 54 consecutive simultaneous kidney and pancreas transplants to either SE (n = 27) or PE (n = 27) drainage. The two groups were well matched for numerous characteristics. Maintenance immunosuppression in both groups consisted of tacrolimus, mycophenolate mofetil, and steroids. ResultsPatient survival rates were 93% SE versus 96% PE; kidney graft survival rates were 93% in both groups. Pancreas transplantation survival (complete insulin independence) was 74% after SE versus 85% after PE drainage with a mean follow-up of 17 months. The mean length of initial hospital stay was 12.4 days in the SE group and 12.8 days in the PE group. The SE group was characterized by a slight increase in the number of readmissions. The incidences of acute rejection (33%) and major infection (52%) were similar in both groups. The incidence of intraabdominal infection was slightly higher in the SE group. However, the early relaparotomy rate was similar between groups. The composite endpoint of no rejection, graft loss, or death was attained in 56% of SE versus 59% of PE patients. ConclusionsThese results suggest that simultaneous kidney and pancreas transplantation with SE or PE drainage can be performed with comparable short-term outcomes.

Choice of surgical technique influences perioperative outcomes in liver transplantation.

OBJECTIVE To examine how the choice of surgical technique influenced perioperative outcomes in liver transplantation. SUMMARY BACKGROUND DATA The standard technique of orthotopic liver transplantation with venovenous bypass (VVB) is commonly used to facilitate hemodynamic stability. However, this traditional procedure is associated with unique complications that can be avoided by using the technique of liver resection without caval excision (the piggyback technique). METHODS A prospective comparison of the two procedures was conducted in 90 patients (34 piggyback and 56 with VVB) during a 2.5-year period. Although both groups had similar donor and recipient demographic characteristics, posttransplant outcomes were significantly better for the patients undergoing the piggyback technique. The effect of surgical technique was examined using a stepwise approach that considered its impact on two levels of perioperative and postoperative events. RESULTS The analysis of the first level of perioperative events found that the piggyback procedure resulted in a 50% decrease in the duration of the anhepatic phase. The analysis of the second level of perioperative events found a significant relation between the anhepatic phase and the duration of surgery and between the anhepatic phase and the need for blood replacement. The analysis of the first level of postoperative events found that the intensive care unit stay was significantly related to both the duration of surgery and the need for blood replacement. The intensive care unit stay was in turn related to the second level of postoperative events, namely the length of hospital stay. Finally, total charges were directly related to length of hospital stay. The overall 1-year actuarial patient and graft survival rates were 94% in the piggyback and 96% in the VVB groups, respectively. CONCLUSIONS These data demonstrate that surgical choices in complex procedures such as orthotopic liver transplantation trigger a chain of events that can significantly affect resource utilization. In the current healthcare climate, examination of the sequence of events that follow a specific treatment may provide a more complete framework for choosing between treatment alternatives.

Long-term outcomes of donation after cardiac death liver allografts from a single center.

Abstract:  Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non‐heart‐beating or donation after cardiac death (DCD) are encouraging. However, long‐term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow‐up >4.5 years. During 1998–2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart‐beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non‐function and biliary complications as compared with SCD and ECD. The overall one‐, two‐, and five‐yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long‐term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.