Management of the Potential Organ Donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement.

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.

Predicting dry weight in patients with ascites and liver cirrhosis using computed tomography imaging.

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.

Alpha-fetoprotein and tumour size are associated with microvascular invasion in explanted livers of patients undergoing transplantation with hepatocellular carcinoma.

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.

Obesity, diabetes, and smoking are important determinants of resource utilization in liver resection: a multicenter analysis of 1029 patients.

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.

Effects of hyperglycemia on the development of new-onset diabetes after liver transplantation.

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.

An in vitro study of liposomal curcumin: stability, toxicity and biological activity in human lymphocytes and Epstein-Barr virus-transformed human B-cells.

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, NFkappaB 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 degrees 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 (3)H-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.

Cyclosporin A up-regulates and activates protein kinase C-zeta in EBV-infected and EBV-transformed human B-cells.

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 microM) indicating that this effect may be due to oxidative stress induced by CsA. Indeed, after oxidant H(2)O(2) (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 microM) in H(2)O(2) (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 PKCalpha 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.

Predictors of relapse to alcohol and illicit drugs after liver transplantation for alcoholic liver disease.

BACKGROUND: Alcoholic liver disease (ALD) is a common indication for transplantation worldwide. This study identifies factors predicting posttransplant recidivism. METHODS: Clinical and laboratory data were reviewed. Uni- and multivariate analyses for survival and relapse to alcohol and illicit drugs were performed. RESULT: Between July 1995 and November 2007, 387 patients underwent liver transplantation at our institution. Of these, 147 patients (38%) were found to have ALD. Five patients (3.4%) were excluded because of perioperative mortality. Overall survival was 96.2%, 89.6%, and 84.4% at 1, 3, and 5 years, respectively, with a median follow-up of 41.2 months. Twenty-seven patients (19%) returned to alcohol after transplantation. By univariate analysis, depression was the only significant factor affecting survival (P=0.01), whereas posttransplant relapse to alcohol trended toward significance (P=0.059). Multivariate analysis showed both factors to be independently associated with poor survival (P=0.008 and 0.017, respectively). Factors associated with relapse included less than 12 months of abstinence before transplant (P=0.019) and participation in rehabilitation (P=0.026). Multivariate analysis showed pretransplant abstinence less than 12 months as the only independent factor (P=0.037) associated with alcohol relapse after transplantation. Twenty-five patients (17.2%) had documented drug use after transplantation. Drug abuse before transplantation was the only independent predictor of drug abuse after transplantation (P=0.017). CONCLUSIONS: Excellent results can be obtained in patients undergoing liver transplantation for ALD, though depression and recidivism adversely impact survival. In our series, abstinence less than 12 months was associated with relapse to alcohol. Similarly, those with prior drug abuse are more likely to continue drug use after transplantation.

Seatbelt injury resulting in functional loss of a transplanted kidney.

The transplanted kidney, lying heterotopically in the iliac fossa, is especially vulnerable to damage from blunt trauma, particularly compression by vehicle seatbelt. We present a case wherein a functioning renal allograft lying in the right iliac fossa was severely injured by seatbelt compression, resulting in significant functional compromise and eventual loss. The patient later underwent successful retransplantation with a second living donor kidney. Management of injured renal transplant recipients requires appreciation of mechanisms likely to cause damage to the graft, as well as familiarity with available treatment options, both surgical and nonsurgical. As functional life spans of renal allografts improve, this type of injury will most likely be encountered with increasing frequency.

Successful open pulmonary embolectomy for acute massive pulmonary embolism in a recent kidney transplant recipient.

BACKGROUND: Patients with acute massive pulmonary embolus have a high mortality even with treatment. For patients in whom thrombolytic intervention is contraindicated, surgical pulmonary embolectomy is a viable option. CASE REPORT: We present a patient who, four months after kidney transplantation, developed acute massive PE with cardiac arrest. He underwent surgical pulmonary embolectomy and was discharged two weeks later, with preservation of renal allograft function and long-term survival. CONCLUSIONS: While the mortality risk of surgical embolectomy is high, survival has been greatly improved by the use of cardiopulmonary bypass. Early diagnosis and initiation of aggressive treatment is vital to achieving successful outcomes in patients who would otherwise be unsalvageable.

Cyclosporin A-induced lipid and protein oxidation in human B-cells and in Epstein-Barr virus-infected B-cells is prevented by antioxidants.

The incidence of post-transplant lymphoproliferative disorder (PTLD) has increased since cyclosporin A (CsA) became the mainstay of transplant immunosuppression. We have previously shown that, in addition to its potent immunosuppressive property, CsA-induced oxidative stress plays an important role in Epstein-Barr virus (EBV)-related PTLD. Using lipid hydroperoxide and malondialdehyde as markers of lipid oxidation, and protein carbonyls as markers of protein oxidation, we further investigated the in vitro effect of CsA on human B cells and EBV-infected human B cells. We found that CsA at 500 ng/ml, a relatively safe and effective blood concentration in organ transplant recipients, induced the highest lipid hydroperoxide and malondialdehyde after 10 min of treatment in time- and concentration-related kinetic studies. We also found that treatment with CsA at 500 ng/ml for 10 min increased the EBV-infected B cell protein carbonyl formation as assayed by immunoblot method. CsA-induced lipid and protein oxidation could be inhibited by vitamin E, N-acetyl cysteine, and pyrollidine dithiocarbamate. CsA significantly promoted the EBV-B cell transformation as assayed by colony counting, cell counting, and (3)H-thymidine incorporation. Our recent study provides further evidence to support the hypothesis that CsA exerts direct oxidative stress in EBV-infected as well as non-EBV-infected human B cells. A greater understanding of these cellular and molecular mechanisms may benefit the clinical practice and prevention of PTLD.

Prevalent immunosuppressive strategies in liver transplantation for hepatitis C: results of a multi-center international survey.

To determine current immunosuppression regimens and strategies for acute cellular rejection in hepatitis C virus (HCV) patients after liver transplantation (LT), questionnaires were sent to 264 LT programs worldwide. Surveys from 81 programs were reviewed. In 27 centers (33.8%) the immunosuppression protocol used in HCV differed from non-HCV patients. Tacrolimus-based immunosuppression is utilized in 70 centers (86.42%). Triple therapy using tacrolimus, mycophenolate mofetil and steroids is the most common regimen (41%). Six programs (7.4%) use steroid-free protocols. In nine centers (11%) steroids are discontinued within a week, 56% within 3 months, and 98% within the first year. At 75% of centers, mild rejection is treated by increasing baseline immunosuppression. Moderate rejection is treated by increasing baseline immunosuppression in 38% of centers, steroid bolus in 44%, and either in 16%. For severe rejection, 46% of centers give bolus steroid, and 16% administer antibodies. Among respondents, non-US programs use significantly more cyclosporine than US programs (35.6% vs. 2.8%, P<0.001). Duration of steroid therapy is significantly shorter in US programs than non-US (10.8 vs. 29.4 weeks, P<0.001). There is no consensus regarding the best immunosuppressive regimen and rejection treatments in HCV patients after LT. Our results reveal the most prevalent management practices in this difficult group of patients.

Surgical treatment of a rare primary renal carcinoid tumor with liver metastasis.

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.

The use of Dacron graft for cavo-cavostomy in orthotopic liver transplantation.

The end-to-end "interposition" technique and end-to-side "piggyback" technique are standard approaches to in situ anastomosis during orthotopic liver transplantation. We demonstrate that anastomosis of liver allograft to a Dacron vena cava graft can be a feasible solution if traditional anastomoses cannot be used. A 55-year-old man with end-stage liver failure from alcoholic cirrhosis underwent orthotopic liver transplantation; however, an intraoperative complication during recipient hepatectomy rendered the native vena cava unsalvageable. In addition, the donor vena cava was too short to bridge the caval defect for interposition. We therefore used Dacron for an in situ graft to span the gap, with subsequent anastomosis of the allograft to the prosthetic graft in piggyback fashion. The patient did well postoperatively; his only major complication was late anastomotic stenosis, which was treated successfully with balloon dilatation. Unfortunately the patient became recidivous and expired ten months posttransplant, despite indications of satisfactory allograft function.

Arteriovenous malformation of the pancreas: A case report and review of literature.

Extrahepatic arteriovenous malformations (AVMs) of the gastrointestinal (GI) tract are rare and mostly asymptomatic congenital anomalies. The present case describes a 45-year-old woman with an AVM in the head of the pancreas, which caused massive GI bleeding that recurred after embolization, and which was subsequently treated with a pylorus-preserving Whipple pancreaticoduodenectomy. The authors then review the available literature pertaining to AVMs of the GI tract, the diagnostic modalities that have been used to identify them and the treatment approaches that have been described to date, which range from coil embolization of the feeding artery to radical resection of the affected organ. It is important to remember that these lesions shunt blood between the high-pressure arterial system and the low-pressure portal system, which leads to the much-dreaded consequence of portal hypertension.