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Perioperative management of the liver transplant recipient is a team effort that requires close collaboration between intensivist, surgeon, anesthesiologist, hepatologist, nephrologist, other specialists, and hospital staff before and after surgery. Transplant viability must be reassessed regularly and particularly with each donor organ. Regular discussions with patient and family facilitate realistic determinations of goals based on patient aspirations and clinical realities. Early attention to hemodynamics with optimal resuscitation and judicious vasopressor support, respiratory care designed to minimize iatrogenic injury, and early renal support is key. Preoperative and postoperative nutritional support and physical rehabilitation should remain a focus.

With the evolution of surgical and anesthetic techniques, liver transplantation has become "routine," allowing for modifications of practice to decrease perioperative complications and costs. There is debate over the necessity for intensive care unit admission for patients with satisfactory preoperative status and a smooth intraoperative course. Postoperative care is made easier when the liver graft performs optimally. Assessment of graft function, vigilance for complications after the major surgical insult, and optimization of multiple systems affected by liver disease are essential aspects of postoperative care. The intensivist plays a vital role in an integrated multidisciplinary transplant team.

Caring for critically ill patients with acute and/or chronic liver dysfunction poses a unique challenge. Proper resuscitation and early consideration for transfer to liver transplant centers have resulted in improved outcomes. Liver support devices and cellular models have not yet shown mortality benefit, but they hold promise in the critical care of patients with liver disease. This article reviews pertinent anatomic and physiologic considerations of the liver in critical illness, followed by a selective review of associated organ dysfunction.

The number of simultaneous liver-kidney transplants has been increasing. This surgery is associated with an increased risk of complications, longer duration of surgery and longer ischemia time for the renal allograft. Two patients listed for liver-kidney transplant at our center underwent en bloc combined liver-kidney transplantation using donor splenic artery as inflow. Patient 1 previously underwent cardiac catheterization that was complicated by a bleeding pseudoaneurysm of the right external iliac artery that required endovascular stenting of the external iliac artery and embolization of the inferior epigastric artery. Patient 2 was on vasopressor support and continuous renal replacement therapy at the time of transplant. In this paper, we described a novel technique of en bloc liver-kidney transplant with simultaneous reperfusion of both allografts using the donor splenic artery for renal inflow. This technique is useful for decreasing cold ischemia time and total operative time by simultaneous reperfusion of both allografts. It is a useful technical variant that can be used in patients with severe disease of the iliac arteries.

Liver dysfunction may manifest during systemic illness as a consequence of circulatory compromise — inadequate perfusion, passive congestion, intrahepatic redistribution of blood flow — or as a consequence of hepatocellular or fixed tissue macrophage (Kupffer cell) cytotoxicity. It is probable that hepatic dysfunction exacerbates the hemodynamic sequelae and multisystem dysfunction which results from infection. Certainly, underlying hepatocellular disease such as that caused by steatosis, viral hepatitis which results in changes to the cytoarchitecture will predispose to hepatocellular dysfunction in systemic illness.

Background Select hospitalized patients are actively screened for VREC but VRE isolates may not undergo antibiotic susceptibility testing. We sought to identify predictors of daptomycin (DAP) nonsusceptibility (DNS, MIC > 4) and LNS (MIC > 2) among enteric VRE isolates recovered from patients actively screened for VREC for which antibiotic susceptibility testing was not preformed. Methods This was a retrospective study of consecutive adults admitted to a surgical intensive care unit (ICU) or associated medical unit between June 1, 2017 and March 1, 2018 who had a VRE isolate from active screening. Only index isolates were included. DAP and LZD MICs were determined by Etest. Patient- and antimicrobial-level data, including ambulatory prescriptions, dating back to January 1, 2016 were collected. Multivariable logistic regression models were used to determine predictors of DNS and LNS VRE. Results In total, 64 patients’ VRE rectal isolates were included. Fifty-nine (92.2%) were E. faecium and 50 (78.1%) were from ICU patients. Thirty-seven patients (57.8%) were female and the mean age ± SD was 60 ± 13 years. Five (7.8%) and 20 (31.3%) patients had previous abdominal transplant and VRE infection, respectively. DAP and LZD MIC distributions are shown in the table below. Forty-one (64.1%) VRE isolates were LNS, including five LZD-resistant isolates. Only one (1.6%) isolate was DNS precluding an analysis of DNS predictors; 12 (18.8%) isolates had a DAP MIC > 2 mg/L. Common antimicrobial exposures prior to index VRE isolate included: vancomycin (62.5%), ceftriaxone (64.1%), cefepime (53.1%), metronidazole (50%), and ciprofloxacin (50%). Previous LZD (17.2%) and DAP (15.6%) exposure were less common. In a multivariable model, number of previous cefazolin doses (adjusted odds ratio (aOR) 0.74 95% confidence interval (CI) 0.55–0.95), and previous tobramycin exposure (aOR 0.15, 95% CI 0.02–0.81) were inversely associated with LNS. Previous LZD exposure was not associated with LNS. Conclusion LNS was common amongst VRE isolates in this cohort. Previous LZD exposure was infrequent and not associated with LNS. LZD susceptibility testing among VRE isolates recovered from patients actively screened for VREC warrants clinical consideration. Disclosures All authors: No reported disclosures.

Liver injury results from myriad insults including hepatotoxins and viral infections and congenital abnormalities. Individually or in combination these insults result in liver dysfunction which progresses to liver failure which causes multiple organ systems dysfunction and failure, which further impair liver function and result in death. The severity of liver dysfunction and risk of death calculations can be discerned by assessment of extrahepatic organ function. In addition to addressing individual and population benefit from liver transplantation, risk assessment by MELD can be used to address the risks of nonhepatic surgery. Furthermore, mitigation of liver injury and extrahepatic organ system dysfunction can prolong survival. In particular, attention to hemodynamics to optimize hepatic and renal perfusion and avoiding iatrogenic (ventilator-induced) lung injury and minimizing neuro-intoxicants are key to managing the patient with liver disease who is to undergo nonhepatic surgery.

Patients with end stage liver disease may become critically ill prior to LT requiring admission to the intensive care unit (ICU). The high acuity patients may be thought too ill to transplant; however, often LT is the only therapeutic option. Choosing the correct liver allograft for these patients is often difficult and it is imperative that the allograft work immediately. Donation after cardiac death (DCD) donors provide an important source of livers, however, DCD graft allocation remains a controversial topic, in critically ill patients. Between January 2003-December 2008, 1215 LTs were performed: 85 patients at the time of LT were in the ICU. Twelve patients received DCD grafts and 73 received donation after brain dead (DBD) grafts. After retransplant cases and multiorgan transplants were excluded, 8 recipients of DCD grafts and 42 recipients of DBD grafts were included in this study. Post-transplant outcomes of DCD and DBD liver grafts were compared. While there were differences in graft and survival between DCD and DBD groups at 4 month and 1 year time points, the differences did not reach statistical significance. The graft and patient survival rates were similar among the groups at 3-year time point. There is need for other large liver transplant programs to report their outcomes using liver grafts from DCD and DBD donors. We believe that the experience of the surgical, medical and critical care team is important for successfully using DCD grafts for critically ill patients.

Summary This study sought to determine the procurement factors that lead to development of intrahepatic bile duct strictures (ITBS) and overall biliary complications in recipients of donation after cardiac death (DCD) liver grafts. Detailed information for different time points during procurement (withdrawal of support; SBP

The use of donation after cardiac death (DCD) liver grafts is controversial because of the overall increased rates of graft loss and morbidity, which are mostly related to the consequences of ischemic cholangiopathy (IC). In this study, we sought to determine the factors leading to graft loss and the development of IC and to compare patient and graft survival rates for recipients of DCD liver grafts and recipients of donation after brain death (DBD) liver grafts in a large series at a single transplant center. Two hundred liver transplants with DCD donors were performed between 1998 and 2010 at Mayo Clinic Florida. Logistic regression models were used in the univariate and multivariate analyses of predictors for the development of IC. Additional analyses using Cox regression models were performed to identify predictors of graft survival and to compare outcomes for DCD and DBD graft recipients. In our series, the patient survival rates for the DCD and DBD groups at 1, 3, and 5 years was 92.6%, 85%, and 80.9% and 89.8%, 83.0%, and 76.6%, respectively (P = not significant). The graft survival rates for the DCD and DBD groups at 1, 3, and 5 years were 80.9%, 72.7%, and 68.9% and 83.3%, 75.1%, and 68.6%, respectively (P = not significant). In the DCD group, 5 patients (2.5%) had primary nonfunction, 7 patients (3.5%) had hepatic artery thrombosis, and 3 patients (1.5%) experienced hepatic necrosis. IC was diagnosed in 24 patients (12%), and 11 of these patients (5.5%) required retransplantation. In the multivariate analysis, the asystole-to-cross clamp duration [odds ratio = 1.161, 95% confidence interval (CI) = 1.021-1.321] and African American recipient race (odds ratio = 5.374, 95% CI = 1.368-21.103) were identified as significant factors for predicting the development of IC (P < 0.05). This study has established a link between the development of IC and the asystole-to-cross clamp duration. Procurement techniques that prolong the nonperfusion period increase the risk for the development of IC in DCD liver grafts.

Dickson RC, Pungpapong S, Keaveny AP, Taner BC, Ghabril M, Aranda-Michel J, Satyanarayana R, Bonatti H, Kramer DJ, Nguyen JH. Improving graft survival for patients undergoing liver transplantation. Clin Transplant 2011: 25: E345–E355. © 2011 John Wiley & Sons A/S. Abstract: Liver transplant (LT) outcomes are reported to be improving in non-HCV recipients but not for those infected with HCV. Our aim was to evaluate graft survival and predictors of outcome in HCV and non-HCV patients before and after 2003. Patients with primary LT between February 1, 1998, and December 31, 2005, were included. Patients were divided into Era 1 (1998–2002) and Era 2 (2003–2005) with follow-up through May 31, 2009. Graft survival was compared for HCV, non-HCV, and all patients. There was significant improvement in graft survival in Era 2 for HCV patients. Graft survival in Era 2 of HCV patients was equivalent to non-HCV patients. The most significant improvement between eras was in outcomes of grafts from donors ≥60 yr with three-yr graft survival 58.6 (51.3–65.9) vs. 75.4 (68.9–81.9), p = 0.002. The use of donors ≥60 did not change between eras: 31% vs. 34%; however, utilization in HCV recipients decreased from 36% to 3% (p

A number of conditions can lead to acute liver failure. Determining the cause has important prognostic implications that guide decisions regarding the likelihood of spontaneous recovery, or conversely, the need for transplantation.Neurological deterioration is associated with intracranial hypertension, which requires meticulous management. The decision to employ invasive intracranial pressure monitoring is controversial because of associated risks and the lack of controlled studies. Recent literature addressing the use of intracranial pressure monitoring is reviewed.Even tertiary care units that specialize in liver disease treat acute liver failure patients infrequently. Knowledge of the latest guidelines and treatment protocols can lead to improved patient care.

The objective of this study was to evaluate the use of kinetic therapy beds for automated prone positioning and axial rotation in critically ill nontrauma patients with acute respiratory distress syndrome (ARDS). There were 17 patients with ARDS who underwent automated prone positioning using a kinetic therapy bed. The mean age was 51 + 14 years; 12 were females and 12 were Caucasian. The most common admission diagnosis was sepsis (n = 5). The mean Acute Physiology and Chronic Health Evaluation (APACHE) 2 score was 30 + 9 with mean predicted mortality of 65% + 25%. At the time of prone positioning, all patients met the criteria for ARDS. The mean ratio of PaO2 to FIO2 (P/F ratio) before initiation of prone positioning was 89 + 33 and rose to 224 + 92 after at least 30 minutes of prone positioning (P < .0001). There was no significant change in PaCO2 or mean airway pressure. There were no instances of accidental endotracheal tube and central or peripheral venous or arterial catheter dislodgement. Eleven (65%) patients developed new pressure ulcers, 10 (59%) patients developed new skin tears, and all had conjunctival edema during the course of prone positioning. The median duration of automated prone positioning was 6 (interquartile range [IQR] 3.5-8.5) days. Eleven (65%) patients died during hospitalization and 7 required percutaneous tracheostomy for long-term ventilator support. Automated prone positioning using a kinetic therapy bed is a safe and effective means of improving oxygenation in critically ill patients with ARDS. Larger randomized studies are needed to compare it to conventional ventilation strategies, conventional prone positioning, and to assess the impact on mortality.

To compare mortality, graft loss, and postoperative complications after liver transplant in older patients (or =70 years) with those in younger patients (60 years).Outcomes for 42 patients aged 70 years or older who underwent liver transplant were compared with those of 42 matched controls younger than 60 years. All patients underwent transplants between March 19, 1998, and May 7, 2004. Information was collected on patient characteristics, comorbid conditions, laboratory results, donor and operative variables, medical and surgical complications, and mortality and graft loss.Preoperative characteristics were similar across age groups, except for creatinine (P=.01) and serum albumin (P=.03) values, which were higher in older patients, and an earlier year of transplant in younger patients (P.001). Intraoperatively, older patients required more erythrocyte transfusions (P=.04) and more intraoperative fluids (P=.001) than did younger patients. Postoperatively, bilirubin level (P=.007) and international normalized ratios (P=.01) were lower in older patients, whereas albumin level was higher (P.001). The median follow-up was 5.1 years (range, 0.1-8.5 years). Compared with younger patients, older patients were not at an increased risk of death (relative risk, 1.00; 95% confidence interval, 0.43-2.31; P.99) or graft loss (relative risk, 1.17; 95% confidence interval, 0.54-2.52; P=.70). The frequency of other complications did not differ significantly between age groups, although older patients had more cardiovascular complications.Five-year mortality and graft loss in older recipients were comparable with those in younger recipients, suggesting that age alone should not exclude older patients from liver transplant.

Acute liver failure (ALF) is a syndrome of diverse etiology, in which patients without previously recognized liver disease sustain a liver injury that results in rapid loss of hepatic function. Depending on the etiology and severity of the insult, some patients undergo rapid hepatic regeneration and spontaneously recover. However, nearly 60% of patients with ALF in the US require and undergo orthotopic liver transplantation or die. Management decisions made by clinicians who initially assess individuals with ALF can drastically affect these patients' outcomes. Even with optimal early management, however, many patients with ALF develop a cascade of complications often presaged by the systemic inflammatory response syndrome, which involves failure of nearly every organ system. We highlight advances in the intensive care management of patients with ALF that have contributed to a marked improvement in their overall survival over the past 20 years. These advances include therapies that limit the extent of liver injury and maximize the likelihood of spontaneous recovery and approaches to enable prevention, recognition and early treatment of complications that lead to multi-organ-system failure, the most common cause of death. Finally, we summarize the role of orthotopic liver transplantation in salvage of the most severely affected patients.

Arterial vasodilation is common in end-stage liver disease, and systemic hypotension often may develop, despite an increase in cardiac output. During the preparation for and the performance of orthotopic liver transplantation, expected and transient hypotension may be caused by induction agents, anesthetic agents, liver mobilization, or venous clamping. A mild decrease of the already low systemic vascular resistance is often observed, and intermittent use of short-acting agents for vasopressor support is not uncommon. In this report, we describe a patient with unexpected and prolonged hypotension due to vasodilation during and after orthotopic liver transplantation. The preoperative end-stage liver disease evaluation, intraoperative events, and intensive care unit course were reviewed, and no cause for the vasodilation and prolonged hypotension was evident. The explant pathology report was later available and showed systemic mastocytosis. We hypothesize that the unexpected hypotension and vasodilation were caused by mast cell degranulation and its systemic effects on arterial tone.

Sepsis constitutes the most common cause of death in the ICU. Liver dysfunction is manifested among previously normal subjects with sepsis but even more so in populations with preexisting liver disease. Managing these patients is more challenging. We will review recent literature in sepsis and liver disease, and their bedside application.At the cellular-chemical level, studies showed that platelet aggregation and neutrophil activation occur before and are independent of microcirculatory changes which are apparent in all animal septic models. At the clinical level, early goal-directed therapy, euglycemia, low tidal volume ventilation, and early and appropriately dosed renal replacement therapy among others are all tools to improve sepsis survival. Acknowledgement of liver disease as an immunocompromised host, and identification and treatment of complications can positively change the outcome of sepsis in liver disease.Much has been advanced in the field of sepsis management. Understanding the pathophysiology of liver dysfunction and decompensation of a diseased liver incites questions for future research. Early goal-directed therapy, lactate clearance, glycemic control, low volume ventilation strategies, nutrition, adrenal insufficiency, renal dysfunction, hepatorenal syndrome prevention and treatment are some of the issues in the management of sepsis, with or without liver disease, that are relevant in this review.

OBJECTIVE To determine the safety of percutaneous dilatational tracheostomy (PDT) for solid organ allograft recipients, who have increased risks of bleeding and infection. PATIENTS AND METHODS We reviewed the records of patients who underwent solid organ transplant between January 1, 2001, and September 30, 2005, followed by PDT (using the Ciaglia technique) with direct bronchoscopic guidance. We recorded comorbid conditions, number of days from intubation and transplant, positive end-expiratory pressures, ratios of Pao 2 to fraction of inspired oxygen, coagulation study findings, complications, and procedure-related mortality rates. RESULTS Of the 51 patients in our study, 17 had undergone lung transplant; 32, liver transplant; and 2, kidney transplant. The median age was 55 years (range, 27-73), and 53% of patients were men. The median time from intubation to PDT was 10 days and from transplant to PDT, 22 days. The median ratio of Pao 2 to fraction of inspired oxygen was 293, and the median positive end-expiratory pressure was 5 cm H 2 O. Twenty-one patients were receiving dialysis, and 11 were recovering from sepsis (of these, 8 were receiving vasopressors). Ten had coagulopathies (none of which were associated with bleeding complications). Complications were infrequent (7 periprocedural, 4 postprocedural) and included bleeding, bradycardia, hypotension, tracheal ring fracture, and cannula malfunction. Of the bleeding complications, only 2 were clinically remarkable and required removal of the tracheostomy or surgical revision. No infectious complications or procedure-related deaths were noted. CONCLUSION Percutaneous dilatational tracheostomy was tolerated well in recipients of solid organ allografts and had a relatively low risk of major complications and a low procedure-related mortality rate. This method should be considered an acceptable alternative to surgical tracheostomy.

Peritonitis occurring after liver transplantation (PLT) has been poorly characterized to date. The aims of this study were to define the incidence, risk factors, microbiology profiles, and outcome of nonlocalized PLT. This was a retrospective study of 950 cadaveric liver transplantation (LT) procedures in 837 patients, followed for a mean of 1,086 days (range, 104-2,483 days) after LT. PLT was defined as the presence of at least one positive ascitic fluid culture after LT. There were 108 PLT episodes in 91 patients occurring at a median of 14 days (range, 1-102 days) after LT. Significant risk factors associated with the development of PLT by multivariate analysis included pre-LT model for end-stage liver disease score, duration of LT surgery, Roux-en-Y biliary anastomosis, and renal replacement therapy after LT. Biliary complications, intra-abdominal bleeding, and bowel leak/perforation were associated with 34.3%, 26.9%, and 18.5% of episodes, respectively. Multiple organisms, gram-positive cocci, fungus, and multidrug-resistant bacteria were isolated in 61.1%, 92.6%, 25.9%, and 76.9% of ascitic fluid cultures, respectively. The 28 fungal PLT episodes were associated with bowel leak/perforation and polymicrobial peritonitis. Patients who developed PLT after their first LT had a significantly greater risk of graft loss or mortality compared to unaffected patients. Parameters significantly associated with these adverse outcomes by multivariate analysis were recipient age at LT and bowel leak or perforation after LT. In conclusion, PLT is a serious infectious complication of LT, associated with significant intra-abdominal pathology and reduced recipient and graft survival.

The purpose of this retrospective study was to examine the potential role of cerebral hemodynamic and metabolic factors in the outcome of patients with fulminant hepatic failure (FHF). Based on the literature, a hypothetical model was proposed in which physiologic changes progress sequentially in five phases, as defined by intracranial pressure (ICP) and cerebral blood flow (CBF) measurements. Seventy-six cerebral physiologic profiles were obtained in 26 patients (2 to 5 studies each) within 6 days of FHF diagnosis. ICP was continuously measured by an extradural fiber optic monitor. Global CBF estimates were obtained by xenon clearance techniques. Jugular venous and peripheral artery catheters permitted calculation of cerebral arteriovenous oxygen differences (AVDO2), from which cerebral metabolic rate for oxygen (CMRO2) was derived. A depressed CMRO2 was found in all patients. There was no evidence of cerebral ischemia as indicated by elevated AVDO2s. Instead, over 65% of the patients revealed cerebral hyperemia. Eight of the 26 patients underwent orthotopic liver transplantation—all recovered neurologically, including 6 with elevated ICPs. Of the 18 patients receiving medical treatment only, all 7 with increased ICP died in contrast to 9 survivors whose ICP remained normal (P < 0.004). Hyperemia, per se, was not related to outcome, although it occurred more frequently at the time of ICP elevations. Six patients were studied during brain death. All 6 revealed malignant intracranial hypertension, preceded by hyperemia. In conclusion, the above findings are consistent with the hypothetical model proposed. Prospective longitudinal studies are recommended to determine the precise evolution of the pathophysiologic changes. (Liver Transpl 2005;11:1353–1360.)

OBJECTIVE To examine the frequency and microbial pattern of pneumonia and its effect on survival in the current era of orthotopic liver transplantation (OLT). PATIENTS AND METHODS At the Mayo Clinic in Jacksonville, Fla, the medical records of consecutive patients who underwent their first OLT between February 1998 and January 2001 were retrospectively reviewed through the end of the first year post-transplantation. RESULTS Of 401 study patients, 20 developed pneumonia; estimates of incidence with corresponding 95% confidence interval (CI) at 1 and 12 months were 3% (1%-5%) and 5% (3%-7%), respectively. Pseudomonas aeruginosa was the predominant microorganism identified (in 8 of 14 patients) during the first month after transplantation. Between the second and sixth months, 2 of the 4 cases of pneumonia were due to fungal infections of Aspergillus fumigatus. Cytomegalovirus was associated with Aspergillus in 1 patient. No other viral or Pneumocystis carinii pneumonia was diagnosed. There were only 2 cases of pneumonia between 7 months and 1 year after transplantation, neither of which was fungal. Approximately 40% (95% CI, 14%-58%) of patients with pneumonia died within 1 month after diagnosis. The relative risk of mortality in the first month after onset of pneumonia was estimated to be 24 (95% CI, 10-54), which is strong evidence of increased risk of mortality with pneumonia (P CONCLUSIONS Pneumonia appears to occur less often after OLT than previously reported but still has a substantial negative effect on survival. In the early period after OLT, P aeruginosa continues to be the predominant organism causing pneumonia.

Serious infection due to strains of Pseudomonas aeruginosa that exhibit resistance to all common antipseudomonal antimicrobials increasingly is a serious problem. Colistin was used as salvage therapy for 23 critically ill patients with multidrug-resistant P. aeruginosa infection. Twenty-two patients who had septic shock (n=14) and/or renal failure (n=21) received mechanical ventilatory support at baseline. The most common types of infection were pneumonia (n=18) and intra-abdominal infection (n=5). Colistin was administered for a median of 17 days (range, 7-36 days). Seven patients died during therapy, at a median of 17 days (range, 4-26 days) after initiation of treatment. A favorable clinical response was observed in 14 patients (61%); only 3 patients experienced relapse. Bacteremia was the only significant factor associated with treatment failure (P=.02). One patient manifested diffuse weakness that resolved after temporary cessation of colistin therapy. Colistin provides an important salvage therapeutic option for patients with otherwise untreatable serious P. aeruginosa infection.

Objective: Our objective was to determine if a nasopharyngeal airway (rectal trumpet) could be used as a fecal containment device with less trauma than traditional devices, such as a fecal incontinence pouch or balloon rectal catheter. Design: A single-subject clinical series was used. Setting and Subjects: A nonrandom sample of critically ill adult and geriatric patients (n = 22) with ongoing fecal incontinence who were receiving care in an intensive care and intermediate care unit in a university teaching hospital was used. Instruments: Direct observation, medical record review, a questionnaire, and interviews were used. Methods: The bedside nurses identified patients as study candidates. Clinical findings were documented in the medical record. The nurses providing patient care completed questionnaires. Main Outcome Measures: Main outcome measures were parameters related to efficacy, practicality, and complications of use of the rectal trumpet: stool containment, skin and anal sphincter integrity, patient comfort, and ease of insertion. Results: All 22 patients (100%) had containment or improved containment of stool. Observable healing or restoration of skin integrity occurred in 90% of the patients with acquired skin injury (n = 20). None of the patients suffered any change in tone or damage to the anal sphincter. Although 41% of the patients experienced discomfort with insertion of the rectal trumpet, 86% had no discomfort while it was maintained in position. Insertion of the rectal trumpet was rated as easy by 84% of the responding nurses (n = 63). Conclusions: Use of a rectal trumpet was well tolerated by patients and practical for nurses. Incontinence was contained and no untoward effects were noted. Benefits to the patient included wound healing and improved comfort. (J WOCN 2002;29:193-201.)

The first clinical use of the Excorp Medical Bioartificial Liver Support System (BLSS) in support of a 41-year-old African-American female with fulminant hepatic failure is described. The BLSS is currently in a Phase I/II safety evaluation at the University of Pittsburgh/UPMC System. Inclusion criteria for the study are patients with acute liver failure, any etiology, presenting with encephalopathy deteriorating beyond Parson's Grade 2. The BLSS consists of a blood pump; a heat exchanger to control blood temperature; an oxygenator to control oxygenation and pH; a bioreactor; and associated pressure and flow alarm systems. Patient liver support is provided by 70-100 g of porcine liver cells housed in the hollow fiber bioreactor. The patient exhibited transient hypotension and thrombocytopenia at initiation of perfusion. The only unanticipated safety event was a lowering of patient glucose level at the onset of perfusion with the BLSS that was treatable with intravenous glucose administration. Moderate changes in blood biochemistries pre- and post perfusion are indicative of liver support being provided by the BLSS. While the initial experience with the BLSS is encouraging, completion of the Phase I/II study is required in order to more fully understand the safety aspects of the BLSS.

Background. The potential risk of transmission of porcine endogenous retroviruses (PERV) from xenogeneic donors into humans has been widely debated. Because we were involved in a phase I/II clinical trial using a bioartificial liver support system (BLSS), we proceeded to evaluate the biosafety of this device. Materials and Methods. The system being evaluated contains primary porcine hepatocytes freshly isolated from pathogen-free, purpose-raised herd. Isolated hepatocytes were installed in the shell, which is separated by a semipermeable membrane (100-kD nominal cutoff) from the lumen through which the patients’ whole blood is circulated. Both before and at defined intervals posthemoperfusion, patients’ blood was obtained for screening. Additionally, effluent collected from a clinical bioreactor was analyzed. The presence of viral particles was estimated by reverse transcriptase–polymerase chain reaction (RT-PCR) and RT assays. For the detection of pig genomic and mitochondrial DNA, sequence-specific PCR (SS-PCR) was used. Finally, the presence of infectious viral particles in the samples was ascertained by exposure to the PERV-susceptible human cell line HEK-293. Results. PERV transcripts, RT activity, and infectious PERV particles were not detected in the luminal effluent of a bioreactor. Culture supernatant from untreated control or mitogen-treated porcine hepatocytes (cleared of cellular debris) also failed to infect HEK-293 cell lines. Finally, RT-PCR, SS-PCR, and PERV-specific RT assay detected no PERV infection in the blood samples obtained from five study patients both before and at various times post-hemoperfusion. Conclusion. Although longer patient follow-up is required and mandated to unequivocally establish the biosafety of this device and related bioartificial organ systems, these analyses support the conclusion that when used under standard operational conditions, the BLSS is safe.

A Phase I clinical safety evaluation of the Excorp Medical, Inc, Bioartificial Liver Support System (BLSS) is in progress. Inclusion criteria are patients with acute liver failure of any etiology, presenting with encephalopathy deteriorating beyond Parson's Grade 2. The BLSS consists of a blood pump, heat exchanger to control blood temperature, oxygenator to control oxygenation and pH, bioreactor, and associated pressure and flow alarm systems. Patient liver support is provided by 70-100 g of porcine liver cells housed in the hollow fiber bioreactor. A single support period evaluation consists of 12 hour extracorporeal perfusion with the BLSS sandwiched between 12 hours of pre (baseline) and 12 hours of post support monitoring. Blood chemistries and hematologies are obtained every 6 hours during monitoring periods and every 4 hours during perfusion. Physiologic parameters are monitored continuously. The patient may receive a second treatment at the discretion of the clinical physician. Preliminary evaluation of safety considerations after enrollment of the first four patients (F, 41, acetaminophen induced, two support periods; M, 50, Wilson's disease, one support period; F, 53, acute alcoholic hepatitis, two support periods; F, 24, chemotherapy induced, one support period) is presented. All patients tolerated the extracorporeal perfusion well. All patients presented with hypoglycemia at the start of perfusion, treatable by IV dextrose. Transient hypotension at the start of perfusion responded to an IV fluid bolus. Only the second patient required heparin anticoagulation. No serious or unexpected adverse events were noted. Moderate biochemical response to support was noted in all patients. Completion of the Phase I safety evaluation is required to fully characterize the safety of the BLSS.

Tacrolimus (TAC) and mycophenolate mofetil (MMF) are currently approved immunosuppressants for prevention of rejection in liver transplantation (LTx). They have different modes of action and toxicity profiles, but the efficacy and safety of MMF in primary liver transplantation with TAC has not been determined.An Institutional Review Board-approved, open-label, single-center, prospective randomized trial was initiated to study the efficacy and toxicity of TAC and steroids (double-drug therapy (D)) versus TAC, steroids, and MMF (triple-drug therapy (T)) in primary adult LTx recipients. Both groups of patients were started on the same doses of TAC and steroids. Patients randomized to T also received 1 gm MMF twice a day.Between August 1995 and May 1998, 350 patients were enrolled at a single center-175 in the D and 175 in the T groups. All patients were followed until May 1998, with a mean follow-up of 33.8+/-9.1 months. Using an intention-to-treat analysis, the 1-, 2-, 3-, and 4-year patient survival was 85.1%, 81.6%, 78.6%, and 75.8%, respectively, for D and 87.4%, 85.4%, 81.3%, and 79.9%, respectively, for T. The 4-year graft survival was 70% for D and 72.1% for T. Although the rate of acute rejection in the first 3 months was significantly lower for T than for D (28% for triple vs. 38.9% for double, P=0.03), the overall rate of rejection for T at the end of 1 year was not significantly lower than for the D (38.9% triple vs. 45.2% double). The median time to the first episode of rejection was 14 days for D versus 24 days for T (P=0.008). During the study period, 38 of 175 patients in D received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 103 patients in the T discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. The need for corticosteroids was less after 6 months for T and the perioperative need for dialysis was lower with use of MMF.This final report confirms similar patient survival and graft survival up to 4 years with a trend towards fewer episodes of rejection, lower need for steroids, and better perioperative renal function. However, the complex nature of LTx patients and their posttransplantation course prevents the routine application of MMF.

BACKGROUND: Fever in critically ill patients is often treated with antipyretics or physical cooling methods. Although fever is a host defense response that may benefit some critically ill patients, others may not tolerate the cardiovascular demands associated with fever. OBJECTIVES: To compare antipyretics and physical cooling for their effects on core body temperature and cardiovascular responses in critically ill patients. METHODS: The antipyretic administered was 650 mg of acetaminophen. Physical cooling was accomplished by anterior placement of a cooling blanket at 18 degrees C. Core temperature and cardiovascular responses were measured in 14 febrile (body temperature, 38.8 degrees C) critically ill patients at baseline before treatment and up to 3 hours after treatment. Patients able to receive acetaminophen were randomly assigned to receive either acetaminophen only (n = 5) or acetaminophen in combination with a cooling blanket (n = 3). Patients not able to receive acetaminophen were treated with physical cooling only (n = 6). RESULTS: Mean body temperature decreased minimally from baseline to 3 hours after treatment in the physical-cooling-only group (from 39.1 degrees C to 39.0 degrees C) and in the physical cooling and acetaminophen group (from 39.1 degrees C to 38.6 degrees C), but the mean body temperature increased in the acetaminophen-only group (from 39.2 degrees C to 39.4 degrees C). Other notable findings included a slight increase in systemic vascular resistance index in the physical-cooling-only group and in the physical-cooling-plus-acetaminophen group. CONCLUSIONS: Although the study included only 14 subjects, the findings will provide information for future studies in febrile critically ill patients.

Acute liver failure (ALF) is an uncommon conditionassociated with high morbidity and mortality. We performed a retrospective analysis of patients evaluated for ALF. The aim of our study is to determine the clinical features and outcome of such patients and to assess the validity of King's College Hospital (KCH) prognostic criteria. One hundred seventy-seven patients were evaluated for ALF during a period of 13 years. Mean age was 39 years, and 63% were women. The causes included viral hepatitis (31%), acetantinophen toxicity (19%), idiosyncratic drug reactions (12%), miscellaneous causes (11%), and an indeterminate group (28%). Twenty-five patients (14%) recovered with medical therapy (group 1), 65 patients (37%) died without orthotopic liver transplantation (OLT; group II), and 87 patients (49%) underwent OLT (group III). Patients in group II were older and often had advanced encephalopathy, whereas those in group I had less hyperbilirubinemia and often had hyperacute failure. KCH criteria had high specificity and positive predictive value but low negative predictive value for a poor outcome. We conclude that early prognostication is needed in patients with ALF to assist decision making regarding OLT The fulfillment of KCH criteria usually predicts a poor outcome, but a lack of fulfillment does not predict survival.

Acute liver failure (ALF) is an uncommon conditionassociated with high morbidity and mortality. We performed a retrospective analysis of patients evaluated for ALF. The aim of our study is to determine the clinical features and outcome of such patients and to assess the validity of King's College Hospital (KCH) prognostic criteria. One hundred seventy-seven patients were evaluated for ALF during a period of 13 years. Mean age was 39 years, and 63% were women. The causes included viral hepatitis (31%), acetantinophen toxicity (19%), idiosyncratic drug reactions (12%), miscellaneous causes (11%), and an indeterminate group (28%). Twenty-five patients (14%) recovered with medical therapy (group 1), 65 patients (37%) died without orthotopic liver transplantation (OLT; group II), and 87 patients (49%) underwent OLT (group III). Patients in group II were older and often had advanced encephalopathy, whereas those in group I had less hyperbilirubinemia and often had hyperacute failure. KCH criteria had high specificity and positive predictive value but low negative predictive value for a poor outcome. We conclude that early prognostication is needed in patients with ALF to assist decision making regarding OLT The fulfillment of KCH criteria usually predicts a poor outcome, but a lack of fulfillment does not predict survival.

Objective: To evaluate the relationship between the postoperative Acute Physiology and Chronic Health Evaluation (APACHE) II score and mortality at hospital discharge and at 1 yr in liver transplant recipients. Population: Adult orthotopic liver transplant (OLTX) recipients (n = 599) admitted to the intensive care unit postoperatively at a university hospital. Methods: The cohort was split randomly into development and validation sets. Three models were compared for each end point: a) the original APACHE II slope with the original APACHE II postgastrointestinal surgery intercept; b) the original APACHE II slope with an OLTX-specific intercept generated from the development set; and c) an OLTX-specific slope and intercept generated from the development set. Goodness-of-fit and calibration were assessed by the Hosmer-Lemeshow C statistic (where p > .05 suggests good fit) and standardized mortality ratios. Discrimination was assessed by receiver operator characteristic area under the curve analysis. Measurements and Main Results: Hospital and 1-yr mortality rates were 9.9% and 15.9%, respectively. The APACHE II score was strongly associated with mortality (chi-square, p < .0001), but when used with the original equation, it significantly overestimated hospital mortality (standardized mortality ratio, 0.73 [confidence interval, 0.58-0.99]). Using the OLTX-specific approaches, goodness-of-fit for both hospital and 1-yr mortality was good (p = .2-.57) but discrimination was only moderate (receiver operator characteristic area under the curve, 0.675-0.723). Conclusions: APACHE II is a good predictor of short- and long-term mortality after liver transplantation, especially when using OLTX-specific coefficients. Because fit and calibration were better than discrimination, APACHE II will be most useful in the prediction of risk for groups of patients (e.g., in clinical trials or institutional comparisons) rather than for individuals. This study raises the possibility that APACHE II may be useful for long-term mortality prediction in o ther critically ill populations. The overestimation of mortality using the original equation suggests that orthotopic liver transplantation, by reversing the underlying pathophysiology, may modify risk.

Preclinical safety and efficacy evaluation of a novel bioartificial liver support system (BLSS) was conducted using a D-galactosamine canine liver failure model. The BLSS houses a suspension of porcine hepatocytes in a hollow fiber cartridge with the hepatocytes on one side of the membrane and whole blood flowing on the other. Porcine hepatocytes harvested by a collagenase digestion technique were infused into the hollow fiber cartridge and incubated for 16 to 24 hours prior to use. Fifteen purpose-bred male hounds, 1-3 years old, 25-30 kg, were administered a lethal dose, 1.5 g/kg, of D-galactosamine. The animals were divided into three treatment groups: (1b) no BLSS treatment (n = 6); (2b) BLSS treatment starting at 24-26 h post D-galactosamine (n = 5); and (2c) BLSS treatment starting at 16-18 h post D-galactosamine (n = 4). While maintained under isoflurane anesthesia, canine supportive care was guided by electrolyte and invasive physiologic monitoring consisting of arterial pressure, central venous pressure, extradural intracranial pressure (ICP), pulmonary artery pressure, urinary catheter, and end-tidal CO2. All animals were treated until death or death-equivalent (inability to sustain systolic blood pressure > 80 mmHg for 20 minutes despite massive fluid resuscitation and/or dopamine administration), or euthanized at 60 hours. All animals developed evidence of liver failure at 12-24 hours as evidenced by blood pressure lability, elevated ICP, marked hepatocellular enzyme elevation with microscopic massive hepatocyte necrosis and cerebral edema, elevated prothrombin time, and metabolic acidosis. Groups 2b and 2c marginally prolong survival compared with Group 1b (pairwise log rank censored survival time analysis, p = 0.096 and p = 0.064, respectively). Since survival times for Groups 2b and 2c are not significantly different (p = 0.694), the groups were combined for further statistical analysis. Survival times for the combined active treatment Groups 2b and 2c are significantly prolonged versus Group 1b (p = 0.047). These results suggest the novel BLSS reported here can have a significant impact on the course of liver failure in the D-galactosamine canine liver failure model. The BLSS is ready for Phase I safety evaluation in a clinical setting.

Background Tacrolimus (Tac) and mycophenolate mofetil (MMF) are newly approved immunosuppressive agents. However, the safety and efficacy of the combination of MMF and Tac in primary liver transplantation has not been determined.

This book provides an introduction to recent research and applications of adaptive antennas and receivers. It lays heavy emphasis on methods of dealing with non-homogeneous statistical environments, which are frequently encountered in practice and are not well treated by conventional approaches. A major component of the work reported in this book is based on computer analysis and simulations. Many of the authors have made copies of their programs and algorithm implementations available for the use of the reader. Those programs that care currently available for downloading from the publisher's Web page are described in an appendix at the end of the book. The book also provides extensive references and several appendices. The book's primary value is as a reference for those who are trying to validate, extend, or apply adaptive system technology to real-world conditions.

The liver's role as the largest organ of metabolism and the unique and often critical function of liver-specific enzyme pathways imply a greater risk to the recipient of acquiring a donor metabolic disease with liver transplants versus other solid organ transplants. With clinical consequences rarely reported, the frequency of solid organ transplant transfer of metabolic disease is not known. Ornithine transcarbamylase deficiency (OTCD), although rare, is the most common of the urea cycle disorders (UCDs). Because of phenotypic heterogeneity, OTCD may go undiagnosed into adulthood. With over 5000 liver transplant procedures annually in the United States, the likelihood of unknowingly transmitting OTCD through liver transplantation is very low. We describe the clinical course of a liver transplant recipient presenting with acute hyperammonemia and encephalopathy after receiving a liver graft form a donor with unrecognized OTCD.

Impact of acute renal failure on mortality in end-stage liver disease with or without transplantation. Background Acute renal failure (ARF) is traditionally considered a poor prognostic factor in end-stage liver disease and is associated with a mortality approaching 90%. While the increased use of orthotopic liver transplantation (OLTX) has changed the outcome for patients with end-stage liver disease (ESLD), it is not clear whether this has affected the outcome of patients with ESLD and ARF. Methods We prospectively followed the course of ARF in 177 patients with ESLD being evaluated for OLTX. Of these patients 111 received OLTX. In-hospital mortality was compared to that of 316 ESLD patients without ARF, of these 196 received OLTX. Variables include severity of illness as assessed by APACHE II, co-morbid conditions, oliguria, need for renal replacement therapy, and etiologies of ESLD and ARF. These variables were evaluated with respect to the outcome in-hospital mortality by multiple regression analysis for patients with ARF. Results Mortality was significantly higher in oliguric versus non-oliguric patients and in patients who required renal replacement therapy. Mortality correlated strongly with the number of co-morbid conditions, especially sepsis, encephalopathy, respiratory failure, and DIC. For OLTX recipients who developed ARF, no significant difference in survival occurred whether the ARF was pre-OLTX or post-OLTX. Conclusion ARF was associated with an increased mortality consistent with the known adverse prognostic effect of ARF in ESLD. However, the effect of ARF on mortality was remarkably reduced in patients who received a functioning OLTX. Since expected mortality generated from APACHE II scores was higher in the ARF groups, it is not clear that there is an additional effect of ARF beyond the physiologic derangements captured by APACHE II. ARF per se should not necessarily be a contraindication to liver transplant.

Mononeuropathies associated with orthotopic liver transplantation were evaluated in a prospective manner. Ten percent of liver transplant recipients were noted to have focal peripheral nerve lesions in the postoperative period. The ulnar nerve was most commonly involved, with intraoperative compression or postoperative trauma as possible mechanisms of injury. Other upper extremity mononeuropathies were likely a result of vascular cannulations. No brachial plexus injuries occurred. Diabetes and alcoholism were not risk factors for the development of a mononeuropathy.

We sought to understand the mechanism of metabolic acidosis that results in acute resuscitated endotoxic shock. In six pentobarbital-anesthetized dogs, shock was induced by Escherichia coli endotoxin infusion (1 mg/kg) and was treated with saline infusion to maintain mean arterial pressure > 80 mmHg. Blood gases and strong ions were measured during control conditions and at 15, 45, 90, and 180 min after endotoxin infusion. The mean saline requirement was 1833+/-523 mL over a 3 h period. The total acid load from each source was calculated using the standard base deficit. The mean arterial pH decreased from 7.32 to 7.11 (p < .01); pCO2 and lactate were unchanged. Saline accounted for 42% of the total acid load. However, 52% of the total acid load was unexplained. Although serum Na+ did not change, serum Cl-increased (127.7+/-5.1 mmol/L vs. 137.0+/-6.1 mmol/L; p=.016). We conclude that saline resuscitation alone accounts for more than one-third of the acidosis seen in this canine model of acute endotoxemia, whereas lactate accounts for less than 10%. A large amount of the acid load can be attributed to differential Na+ and Cl- shifts from extravascular to vascular spaces.

Patients with moderate and severe pulmonary hypertension have a very high mortality rate when undergoing orthotopic liver transplantation. Because nitric oxide has been successful in reducing pulmonary artery pressures in certain patients with pulmonary hypertension, the efficacy of NO inhalation (40 and 80 ppm) in 4 patients with pulmonary hypertension associated with liver disease was determined. No clinically significant changes in pulmonary artery pressures or other hemodynamic parameters were observed using either concentration of NO. In conclusion, no pulmonary vasodilatory response from inhalation of NO in 4 patients with severe liver disease and pulmonary hypertension was found.

Thrombelastography (TEG) can be used to monitor hemostasis and guide transfusion therapy during orthotopic liver transplantation. However, data are limited regarding the type and quantity of blood components necessary for TEG-guided blood component transfusion in coagulopathic critically ill patients with liver disease. We evaluated changes in four thrombelastogram variables (reaction time, thrombin constant time, alpha angle, and maximum amplitude) in whole blood samples after 74 separate blood component transfusions in 60 critically ill patients with a coagulopathy and liver disease. Only platelets significantly improved TEG variables in patients who received a single type of blood component. Each unit of platelets decreased the reaction and thrombin constant time by 0.43 (P < 0.05) and 0.82 (P < 0.005) min, respectively, increased the alpha angle by 1.5 degrees (P < 0.005), and the maximum amplitude by 1.4 mm (P < 0.005). In patients who received multiple blood components, cryoprecipitate decreased the thrombin constant time by 0.56 min/U (P < 0.05), and each unit of platelets decreased the thrombin constant time by 0.39 min (P < 0.005), and increased the alpha angle and maximum amplitude by 0.63 degrees (P < 0.05) and 0.99 mm (P < 0.005), respectively. We conclude that platelet transfusions, alone or in combination with other blood components, are most effective for improving abnormal TEG variables in coagulopathic critically ill patients with liver disease.