This document was developed through the collaborative efforts of the Society of Critical Care Medicine, the American College of Chest Physicians, and the Association of Organ Procurement Organizations. Under the auspices of these societies, a multidisciplinary, multi-institutional task force was convened, incorporating expertise in critical care medicine, organ donor management, and transplantation. Members of the task force were divided into 13 subcommittees, each focused on one of the following general or organ-specific areas: death determination using neurologic criteria, donation after circulatory death determination, authorization process, general contraindications to donation, hemodynamic management, endocrine dysfunction and hormone replacement therapy, pediatric donor management, cardiac donation, lung donation, liver donation, kidney donation, small bowel donation, and pancreas donation. Subcommittees were charged with generating a series of management-related questions related to their topic. For each question, subcommittees provided a summary of relevant literature and specific recommendations. The specific recommendations were approved by all members of the task force and then assembled into a complete document. Because the available literature was overwhelmingly comprised of observational studies and case series, representing low-quality evidence, a decision was made that the document would assume the form of a consensus statement rather than a formally graded guideline. The goal of this document is to provide critical care practitioners with essential information and practical recommendations related to management of the potential organ donor, based on the available literature and expert consensus.

This document was developed through the collaborative efforts of the Society of Critical Care Medicine, the American College of Chest Physicians, and the Association of Organ Procurement Organizations. Under the auspices of these societies, a multidisciplinary, multi-institutional task force was convened, incorporating expertise in critical care medicine, organ donor management, and transplantation. Members of the task force were divided into 13 subcommittees, each focused on one of the following general or organ-specific areas: death determination using neurologic criteria, donation after circulatory death determination, authorization process, general contraindications to donation, hemodynamic management, endocrine dysfunction and hormone replacement therapy, pediatric donor management, cardiac donation, lung donation, liver donation, kidney donation, small bowel donation, and pancreas donation. Subcommittees were charged with generating a series of management-related questions related to their topic. For each question, subcommittees provided a summary of relevant literature and specific recommendations. The specific recommendations were approved by all members of the task force and then assembled into a complete document. Because the available literature was overwhelmingly comprised of observational studies and case series, representing low-quality evidence, a decision was made that the document would assume the form of a consensus statement rather than a formally graded guideline. The goal of this document is to provide critical care practitioners with essential information and practical recommendations related to management of the potential organ donor, based on the available literature and expert consensus.

BACKGROUND/AIMS In cirrhotic patients, ascites may increase weight and adversely impact liver transplant candidacy. METHODOLOGY In this study we used linear and volume measurements from abdominal CT imaging to estimate dry weight of transplant candidates using multivariable linear regressions. We reviewed 200 scans. For males there were 81, 26, and 41 scans with no/small, moderate, and large ascites, respectively, and 41, 6, and 5 scans of females with no/small/moderate, and large ascites respectively. RESULTS In males without ascites, subxiphoid subcutaneous fat volume had the strongest correlation with weight (r = 0.826); the best prediction utilized four variables including height, subcutaneous subxiphoid fat volume, and intraabdominal and subcutaneous umbilicus fat volumes (r = 0.923, r2 = 0.852, SEE = 15.15, p < 0.001). In females, subcutaneous fat volume above the umbilicus had the best correlation (r = 0.815); incorporating height and anterior subxiphoid fat thickness increased predictive accuracy (r = 0.892, r2 = 0.796, SEE = 15.37, p < 0.001). These regressions consistently under-predicted scale weight in patients with moderate and large ascites (5.92 +/- 25.50 pounds and 11.21 +/- 19.34 pounds in males, and 2.29 +/- 23.76 and 8.37 +/- 11.44 in females). CONCLUSIONS Equations to estimate patient weight regardless of ascites may offer a more accurate representation of size than scale weight in transplant candidates with ascites.

BACKGROUND:To determine factors associated with outcomes and microvascular invasion (MVI) in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC).METHODS:Between July 1996 and August 2008 at the Universities of Kentucky or Tennessee, LT recipients were retrospectively analysed.RESULTS:One hundred and one patients had HCC in the explanted liver; one patient was excluded because of fibrolamellar histology. Seventy-nine (79%) were male and 81 (81%) were older than 50. HCC was incidental in 32 patients (32%). Median follow-up was 31 months. Ten patients (10%) developed recurrence, which was associated with poor survival (P= 0.006). Overall 1-, 3-, and 5-year survival rates were 87%, 69% and 62%, respectively. Excluding patients with lymph node metastasis (LNM) or MVI yielded 91%, 81% and 75% survival at the same time points. MVI was independently associated with recurrence (OR 28.40, 95% CI 1.77-456.48, P= 0.018) and decreased survival (OR 4.70, 95% CI 1.24-17.80, P= 0.023), and LNM with decreased survival (OR 6.05, 95% CI 1.23-29.71, P= 0.027). Tumour size (OR 4.1, 95% CI 1.2-13.5, P= 0.013) and alpha-fetoprotein (AFP) > 100 (OR 5.0, 95% CI 1.4-18.1, P= 0.006) were associated with MVI.CONCLUSIONS:MVI greatly increases the risk of recurrence and death after LT for HCC, and is strongly associated with tumour size and AFP > 100.

Compared to a surgical shunt, a transjugular intrahepatic portosystemic shunt (TIPS) is a less invasive means of lowering portal venous pressure in patients with cirrhosis experiencing complications of portal hypertension, with relatively low procedure-related morbidity. Presently, the most common indications for TIPS placement are acute variceal bleeding and refractory ascites. The number of other indications is growing, but many are still controversial. We present a patient with partial portal vein thrombosis (PVT) who received TIPS to maintain portal vein patency when it was suspected that complete PVT was imminent. The TIPS was able to preserve the remaining portal flow until successful liver transplantation (LT) 3 months later.

OBJECTIVE:To investigate independent contributions of obesity, diabetes, and smoking to resource utilization in patients following liver resection.SUMMARY BACKGROUND DATA:Despite being highly resource-intensive, liver resections are performed with increasing frequency. This study evaluates how potentially modifiable factors affect measures of resource utilization after hepatectomy.METHODS:The American College of Surgeons' National Surgical Quality Improvement Program (ACS NSQIP) public-use database was queried for patients undergoing liver resection. Resource variables were operative time (OT), intraoperative transfusion, length of stay (LOS), ventilator support at 48 hours, and reoperation. Bivariable and multivariable linear and logistic regressions were performed.RESULTS:There were 1029 patients identified. Most resections involved less than a hemiliver (599 patients, 58.2%). Mean BMI was 28.0 +/- 6.0. Mean OT was 253 +/- 122 minutes (range, 27 to 794) but varied by procedure (P < 0.001). Mean LOS was 8.7 +/- 10.7 days (range, 0 to 202). Morbid obesity added 48 minutes to OT (P = 0.018), 1.1 units to transfusions (P = 0.049), 2.2 days to LOS (P < 0.001), and accounted for delayed ventilator weaning (odds ratio, 4.5; P = 0.022). Underweight patients had shorter OT, but stayed 3.3 days longer than normal weight patients (P < 0.001). Insulin-treated patients with diabetes had longer OT (P < 0.001), increased transfusions (P < 0.001), and delayed ventilator weaning (odds ratio, 6.7; P < 0.001), while orally-treated patients with diabetes showed opposite trends. Smokers stayed 1.9 days longer (P < 0.001), with increased risk of prolonged ventilation (odds ratio, 3.3; P = 0.002) and reoperation (odds ratio, 2.3; P = 0.015).CONCLUSION:Obesity, diabetes, and smoking are each associated with important components of healthcare expenditure. Education and prevention programs are needed to limit their impact on overall resource utilization.

We have reported that cyclosporine (CsA) has direct effect to promote Epstein-Barr virus (EBV) transformation of human peripheral blood B lymphocytes. In this article, we have reported that CsA promoted EBV-infected, human B-cell transformation as assayed by three methods of colony number counting, cell number counting, and 3 H-thymidine incorporation. At first, we sought to correlate the three methods in EBV-infected human B-cell transformation, observing that they are convenient correlate with each other, and only vary in the degree when transformed cells are compared to the controls. Based on these pilot experiments, the three assay methods were then applied to CsA-treated and nontreated, EBV-infected human B cells to investigate whether CsA treatment promoted EBV-infected human B-cell transformation. We observed that CsA treatment increased colony formation above the control value of 28 4.5/well to 49 +/- 4.3 (colonies/well; n = 5; P < .05). CsA treatment increased the cell number from the control of 33,025 1900 to 50,925 4194 (cells/well; n = 5; P < .05). CsA treatment increased 3 H-thymidine incorporation from the control result of 12,481 1341 to 26,514 5464 (CPM/well; n = 5; P < .05). In conclusion, CsA promoted EBV-B-cell transformation in three correlated assay methods in vitro using a model of posttransplant lymphoproliferative disorder.

Background. Protein Kinase C (PKC) is a family of enzymes that plays a key role in cell signaling pathways leading to cellular activation and proliferation. Conventional PKC (cPKC) is dependent on calcium for activation. We have proposed that cyclosporin A (CsA), despite being a calcineurin inhibitor, will activate PKC in B cells, thus promoting Epstein-Barr virus (EBV)-induced transformation. Here we show that CsA promoted atypical PKC isoform PKC-zeta in B cells.Materials and methods. Western-blot was used to assay PKC-zeta protein level in EBV-B cells. Confocal microscopy was used to assay PKC-zeta translocation from cytosol to cell membrane, a known process of PKC activation.Results. CsA (500 ng/mL) time dependently increased PKC-zeta from control of 7055 units to 7145, 10,805, 10,914, and 12,705 units, respectively, after 15 min, 1 h, 12 h, and 24 h of incubation in EBV-transformed human B-cell line (LCL). CsA increased PKC-zeta expression was inhibited 50% by Vit.E (40 mu M) indicating that this effect may be due to oxidative stress induced by CsA. Indeed, after oxidant H2O2 (0.1 mM) treatment, PKC-zeta protein level in LCL cells increased 124%, 257%, 349%, and 359% after 15 min, 1 h, 12 h, and 24 h of culture compared with control. Addition of Vit.E (40 mu M) in H2O2 (0.1 mM) treatment and then with Vit.E in the culture decreased PKC-zeta level in LCL cells 26%,20%,41%, and 60% after 15 min, 1 h, 12 h, and 24 h of culture. In confocal microscopy in Jurkat T cell line, phorbol 12-myristate 13-acetate (PMA) activated cPKC isoform PKC alpha after 30 min treatment and activated PKC-zeta after 60 min treatment. CsA inhibited PMA activation of PKC-alpha but not PKC-zeta. CsA alone did not activate PKC-alpha or PKC-zeta in Jurkat T cells. In LCL and in EBV-infected human B-cells, PMA stimulated PKC-alpha activation after 30 min treatment and stimulated PKC-zeta activation after 60 min treatment. CsA inhibited PMA activation of PKC-alpha but not PKC-zeta. In addition, CsA activated PKC-zeta in the EBV-transformed and EBV-infected human B cells.Conclusion. These experiments show that CsA-induced oxidative stress caused PKC-zeta up-regulation in LCL cells, and show the differential effect of CsA in the PKC signaling pathways in T cells versus B cells. CsA-induced PKC-zeta activation may be an important signaling step in EBV-induced post-transplant lymphoproliferative disorders. (C) 2009 Elsevier Inc. All rights reserved.

Curcumin is a multi-functional and pharmacologically safe natural agent. Used as a food additive for centuries, it also has anti-inflammatory, anti-virus and anti-tumor properties. We previously found that it is a potent inhibitor of cyclosporin A (CsA)-resistant T-cell co-stimulation pathway. It inhibits mitogen-stimulated lymphocyte proliferation, NFκB activation and IL-2 signaling. In spite of its safety and efficacy, the in vivo bioavailability of curcumin is poor, and this may be a major obstacle to its utility as a therapeutic agent. Liposomes are known to be excellent carriers for drug delivery. In this in vitro study, we report the effects of different liposome formulations on curcumin stability in phosphate buffered saline (PBS), human blood, plasma and culture medium RPMI-1640 + 10% FBS (pH 7.4, 37 °C). Liposomal curcumin had higher stability than free curcumin in PBS. Liposomal and free curcumin had similar stability in human blood, plasma and RPMI-1640 + 10% FBS. We looked at the toxicity of non-drug-containing liposomes on 3H-thymidine incorporation by concanavalin A (Con A)-stimulated human lymphocytes, splenocytes and Epstein-Barr virus (EBV)-transformed human B-cell lymphoblastoid cell line (LCL). We found that dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) were toxic to the tested cells. However, addition of cholesterol to the lipids at DMPC:DMPG:cholesterol = 7:1:8 (molar ratio) almost completely eliminated the lipid toxicity to these cells. Liposomal curcumin had similar or even stronger inhibitory effects on Con A-stimulated human lymphocyte, splenocyte and LCL proliferation. We conclude that liposomal curcumin may be useful for intravenous administration to improve the bioavailability and efficacy, facilitating in vivo studies that could ultimately lead to clinical application of curcumin.

CONTEXT:New-onset diabetes after transplantation (NODAT) has been associated with cardiovascular and thrombotic complications, acute rejection, and infection in transplant recipients. NODAT in kidney transplantation is well described; however, data are lacking in liver transplant recipients. OBJECTIVE:To evaluate the incidence of new-onset diabetes within 6 months postoperatively in adult liver transplant recipients. DESIGN, PARTICIPANTS, SETTING, AND INTERVENTIONS: Patients who underwent a liver transplantation at our institution between January 2004 and December 2005 were retrospectively evaluated. NODAT was defined according to the diagnostic criteria of the American Diabetes Association/World Health Organization, persistent hyperglycemia (serum glucose > or = 200 mg/dL occurring 2 weeks after initial steroid induction and persisting for more than 2 weeks), or the need for hypoglycemic agents upon discharge. MAIN OUTCOMES:Incidence of NODAT within 6 months after transplantation in patients with poor glycemic control within the first 2 weeks after transplantation, acute rejection episodes, infections, hospital readmissions, and cardiovascular and thrombotic events. RESULTS:Forty-five patients were evaluated. Within the first 6 months after transplantation, NODAT developed in 11 (24%). Acute rejection, infection, hospital readmissions, cardiovascular events, and thrombotic events did not differ between the groups. CONCLUSION:Elevated fasting levels of blood glucose during the first 2 weeks after liver transplantation may be associated with an increased incidence of NODAT and may have predictive value. More studies are needed to determine the effects of recognition and treatment of hyperglycemia in recent transplant recipients.

We present a case of massive bleeding secondary to vaginal varices complicating portal hypertension in a patient awaiting orthotopic liver transplantation (OLT). The vagina is among the rarest of locations reported for portal hypertensive varices causing hemorrhage; in fact, our patient represents only the seventh such case since the first report by Kreek in 19671-5 and the only case in which the initial and definitive management was OLT. A 58-year-old white female, gravida 3, para 3, was referred to our transplant center for liver transplant evaluation for nonalcoholic steatohepatitis. Her past medical history included diabetes mellitus type 2 and nephrolithiasis, and her surgical history was notable for a total abdominal hysterectomy performed 17 years earlier for endometriosis as well as open cholecystectomy, bilateral tubal ligation, and renal lithotripsy. On physical examination, she had mild ascites but was otherwise unremarkable. Upon completion of the transplant evaluation, she was activated on the transplant waiting list. Approximately 1 year after she was listed, the patient underwent routine computed tomography imaging, which showed a small, cirrhotic liver without ascites, and patent vasculature. Three months later, she presented with a sudden onset of significant vaginal bleeding. Vaginal varices were identified by direct visualization, and after a 3-unit transfusion of packed red blood cells, she underwent emergent suture ligation of the varices with cessation of bleeding. However, bleeding recurred after an asymptomatic interval of 2 weeks. Shortly after her return to the hospital, the patient became hypotensive and was discovered to have a hematocrit of 22%. She was aggressively resuscitated and taken emergently to the operating room for examination under anesthesia. Actively bleeding varices were again seen at the upper aspect of the vaginal cuff; these were suture-ligated and packed, with cessation of bleeding. In all, she received 4 units of packed red blood cells, 1 unit of fresh frozen plasma, and a six-pack of platelets during this admission, with return of hemodynamic stability and no additional hemorrhage. During this time, placement of a transjugular intrahepatic portosystemic shunt (TIPS) was considered, but in light of the patient's recent stability, this was not performed, and she was discharged to the care of her primary physician. Ten days later, the patient again developed hemodynamically significant vaginal hemorrhage. At this time, she was evaluated with reconsideration of TIPS placement. Computed tomography imaging showed a patent splenic vein but also the new finding of portal vein thrombosis, which was then confirmed by carbon dioxide angiogram; TIPS placement was therefore precluded. Pelvic varices were appreciated adjacent to the bladder and vagina (Fig. 1). Of note, no thrombosis of the iliac venous system on either side was observed. Abdominal and pelvic angiography was performed the next day to rule out an arteriovenous malformation. Although none was seen, thrombosis of the portal vein was again visualized, along with retrograde flow in the superior mesenteric vein and enlarged mesenteric venous collaterals draining into numerous pelvic varices. Hypertrophy of the inferior mesenteric vein was also noted, with probable retrograde flow (Figs. 2 and 3). Venous phase computed tomography scan demonstrating prominent varices (V) adjacent to the bladder (Bl) and vagina (Va). Packing can be seen within the vaginal vault. R indicates rectum. Angiogram showing the dilated inferior mesenteric vein (IMV) and vaginal varices (V). Angiogram showing the inferior mesenteric vein (IMV) and superior mesenteric vein (SMV) in continuity with vaginal varices (V). Fortunately, a liver allograft became available 2 days later, and the patient underwent successful OLT. During transplantation, a 5-cm organized thrombus was removed from the portal vein, with return of brisk portal flow. Portal vein continuity was able to be restored by end-to-end anastomosis between the donor and recipient portal veins. During the operation, the patient again developed significant vaginal hemorrhage, which necessitated gynecology consultation at the conclusion of the transplantation. The gynecologists performed additional suture ligation of the varices while the patient was still in the operating room. She had no additional episodes of vaginal hemorrhage during her uneventful postoperative recovery. Bl, bladder; IMV, inferior mesenteric vein; OLT, orthotopic liver transplantation; R, rectum; SMV, superior mesenteric vein; TIPS, transjugular intrahepatic portosystemic shunt; V, varices; Va, vagina. The pathophysiologic effects of cirrhosis can lead to serious complications in patients awaiting OLT. Portal hypertension, which frequently accompanies end-stage liver disease, can be caused by anything that compromises portal-systemic drainage. In a patient with cirrhosis, this is typically due to increased vascular resistance within the liver,6 although outflow and inflow impairments (such as portal vein thrombosis in our patient) can also be contributory. The formation of venous collaterals to decompress the portal system occurs as a direct consequence of increased portal pressure, typically in one or more areas in which there is native communication between portal and systemic circulation (distal esophagus/proximal stomach, rectum, umbilicus, and retroperitoneum). Varices are essentially venous collaterals in these transition zones that have become prominently dilated. Varices are most commonly found in the esophagogastric region, and the presence of these varices poses a high risk of developing hemorrhage, up to 30% within 2 years.6 Numerous ectopic locations have been reported as well, including the small bowel, colon, and biliary tree.7 The anatomy of the vagina and uterus makes them unlikely locations to develop varices for two reasons. First, the uterus has an extensive venous plexus, which primarily drains into the uterine veins and later the hypogastric veins (part of systemic circulation). The vagina also has a venous plexus, which similarly drains into the hypogastric veins via bilateral vaginal veins. The plexuses are in communication with each other and with the vesical and hemorrhoidal plexuses. Second, the nearest and only native communication between these networks and portal drainage is the superior portion of the hemorrhoidal plexus. Although anorectal varices may occur in up to 44% of patients with cirrhosis,8 the combined span of the vaginal and uterine plexuses provides numerous venues for decompressing venous hypertension, without the consequence of varix formation. We present a case of hemorrhagic vaginal varices complicating portal hypertension in a patient awaiting OLT, a problem that is rarely described in the literature. With one exception, all reported cases of vaginal variceal hemorrhage occurred in patients who had previously undergone hysterectomy; at 19 years, our patient had the longest interval between hysterectomy and onset of hemorrhage among these cases. In 2005, Orlando et al.5 described the 2 most recent cases and conducted a thorough review of the literature. They hypothesized that the loss of the uterine venous plexus creates the possibility of prominent venous congestion in the vaginal network, ultimately leading to variceal development. Only one reported patient with bleeding vaginal varices had not undergone hysterectomy, although she had a history of cervical cancer treated with radiotherapy 17 years earlier.4 Because a well-known effect of radiation is decreased vascularity,9 focused radiation to the cervix may have had the same result as hysterectomy in terms of disrupting communication between the vaginal and uterine venous plexuses. It appears that in certain patients, the vaginal plexus alone may not be sufficient to decompress severe portal hypertension, and this can result in venous engorgement and development of vaginal varices with hemorrhagic potential. The therapeutic approach to bleeding vaginal varices in a patient with cirrhosis does not differ greatly from the approach to varices in any other location. Initial management is usually directed toward the local control of bleeding using suture ligation, banding, or sclerotherapy, together with compression dressing and simultaneous correction of any underlying coagulopathy. Temporizing measures such as TIPS are also beneficial in reducing variceal pressure and possibly improving other complications of portal hypertension. Liver transplantation remains the definitive treatment for end-stage liver disease and severe portal hypertension resulting in bleeding varices and provides excellent outcome. As we identify potential risk factors for developing this complication, it may be advisable to consider including a thorough gynecologic examination as part of the transplant evaluation process for patients with cirrhosis with a previous hysterectomy. Early recognition of vaginal varices may allow for surveillance and preemptive therapy before life-threatening hemorrhage occurs. However, if this type of patient indeed presents with otherwise unexplained vaginal bleeding, varices must be a diagnostic consideration.

BACKGROUND:Carcinoid tumors are characteristically low grade malignant neoplasms with neuroendocrine differentiation that arise in various body sites, most commonly the lung and gastrointestinal tract, but less frequently the kidneys, breasts, ovaries, testes, prostate and other locations. We report a case of a carcinoid of renal origin with synchronous single liver metastases on radiological studies.CASE PRESENTATION:A 45 year-old patient who presented with abdominal pain was found on CT scan to have lesions in the right ovary, right kidney, and left hepatic lobe. CA-125, CEA, and CA 19-9 were within normal limits, as were preoperative liver function tests and renal function. Biopsy of the liver mass demonstrated metastatic neuroendocrine tumor. At laparotomy, the patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, radical right nephrectomy with lymphadenectomy, and left hepatectomy. Pathology evaluation reported a right ovarian borderline serous tumor, well-differentiated neuroendocrine carcinoma of the kidney (carcinoid) with 2 positive retroperitoneal lymph nodes, and a single liver metastasis. Immunohistochemistry revealed that this lesion was positive for synaptophysin and CD56, but negative for chromogranin as well as CD10, CD7, and CD20, consistent with a well-differentiated neuroendocrine tumor. She is doing well one year after her initial surgery, with no evidence of tumor recurrence.CONCLUSION:Early surgical intervention, together with careful surveillance and follow-up, can achieve successful long-term outcomes in patients with this rare malignancy.

We read with great interest the report by Elias et al.1 of endovascular exclusion of a hepatic artery pseudoaneurysm (HAP) using a polytetrafluoroethylene-covered stent (Jomed NV). The authors commented that “surgical intervention to and around the hepatic artery” is the most common cause of HAP. However, with liver transplantation, the hepatic artery is by definition manipulated, and it has been our experience as well as others' that a local infection, particularly from bile leaks adjacent to the artery, is the most common etiology of HAP.2, 3 Therefore, it would have been helpful if the authors had provided additional details of the postoperative course, including presence or absence of local infection. We also note with interest that this patient had an active infectious source (osteomyelitis requiring amputation) just 2 weeks prior to transplantation. We believe that the optimum approach in a patient with mycotic aneurysm will be a procedure that will resect or exclude the pseudoaneurysm and resolve the bile leak or other cause of local infection. Although there are a few case reports of polytetrafluoroethylene-covered stents being used to treat mycotic pseudoaneurysms in the femoral, pulmonary, and renal arteries and thoracic aorta,4 the experience is limited, and stents seem to be advisable when the patient is at high risk for surgery. Thomas Johnston*, Hoonbae Jeon*, Roberto Gedaly*, Dinesh Ranjan*, * Department of Surgery, University of Kentucky, Lexington, KY.