Perioperative fluid management and outcomes in adult deceased donor liver transplantation - A systematic review of the literature and expert panel recommendations.

BACKGROUND: Fluid management practices during and after liver transplantation vary widely among centers despite better understanding of the pathophysiology of end-stage liver disease and of the effects of commonly used fluids. This reflects a lack of high quality trials in this setting, but also provides a rationale for both systematic review of all relevant studies in liver recipients and evaluation of new evidence from closely related domains, including hepatology, non-transplant abdominal surgery, and critical care. OBJECTIVES: To develop evidence-based recommendations for perioperative fluid management to optimize immediate and short-term outcomes following liver transplantation. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. METHODS: Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. Studies included those evaluating the following postoperative outcomes: acute kidney injury, respiratory complications, operative blood loss/red cell units required, and intensive care length of stay. PROSPERO protocol ID: CRD42021241392 RESULTS: Following expert panel review, 18 of 1624 screened studies met eligibility criteria for inclusion in the final quantitative synthesis. These included six single center RCTs, 11 single center observational studies, and one observational study comparing centers with different fluid management techniques. Definitions of interventions and outcomes varied between studies. Recommendations are therefore based substantially on expert opinion and evidence from other clinical settings. CONCLUSIONS: A moderately restrictive or "replacement only" fluid regime is recommended, especially during the dissection phase of the transplant procedure. Sustained hypervolemia, based on absence of fluid responsiveness, elevated filling pressures and/or echocardiographic findings, should be avoided (Quality of Evidence: Moderate | Grade of Recommendation: Weak for restrictive fluid regime. Strong for avoidance of hypervolemia). Mean Arterial Pressure (MAP) should be maintained at >60-65 mmHg in all cases (Quality of Evidence: Low | Grade of Recommendation: Strong). There is insufficient evidence in this population to support preferential use of any specific colloid or crystalloid for routine volume replacement. However, we recommend against the use of 130/.4 HES given the high incidence of AKI in this population.

Understanding controls on Margalefidinium polykrikoides blooms in the lower Chesapeake Bay.

A time-dependent model of Margalefidinium polykrikoides, a mixotrophic dinoflagellate, cell growth was implemented to assess controls on blooms in the Lafayette River, a shallow, tidal sub-tributary of the lower Chesapeake Bay. Simulated cell growth included autotrophic and heterotrophic contributions. Autotrophic cell growth with no nutrient limitation resulted in a bloom but produced chlorophyll concentrations that were 45% less than observed bloom concentrations (~80 mg Chl m-3 vs. 145 mg Chl m-3) and a bloom progression that did not match observations. Excystment (cyst germination) was important for bloom initiation, but did not influence the development of algal biomass or bloom duration. Encystment (cyst formation) resulted in small losses of biomass throughout the bloom but similarly, did not influence M. polykrikoides cell density or the duration of blooms. In contrast, the degree of heterotrophy significantly impacted cell densities achieved and bloom duration. When heterotrophy contributed a constant 30% to cell growth, and dissolved inorganic nitrogen was not limiting, simulated chlorophyll concentrations were within those observed during blooms (maximum ~140 mg Chl m-3). However, nitrogen limitation quenched the maximum chlorophyll concentration by a factor of three. Specifying heterotrophy as an increasing function of nutrient limitation, allowing it to contribute up to 50% and 70% of total growth, resulted in simulated maximum chlorophyll concentrations of 90 mg Chl m-3 and 180 mg Chl m-3, respectively. This suggested that blooms of M. polykrikoides in the Lafayette River are fortified and maintained by substantial heterotrophic nutritional inputs. The timing and progression of the simulated bloom was controlled by the temperature range, 23 °C to 28 °C, that supports M. polykrikoides growth. Temperature increases of 0.5 °C and 1.0 °C, consistent with current warming trends in the lower Chesapeake Bay due to climate change, shifted the timing of bloom initiation to be earlier and extended the duration of blooms; maximum bloom magnitude was reduced by 50% and 65%, respectively. Warming by 5 °C suppressed the summer bloom. The simulations suggested that the timing of M. polykrikoides blooms in the Lafayette River is controlled by temperature and the bloom magnitude is determined by trade-offs between the severity of nutrient limitation and the relative contribution of mixotrophy to cell growth.

International Liver Transplantation Consensus Statement on End-stage Liver Disease Due to Nonalcoholic Steatohepatitis and Liver Transplantation.

Nonalcoholic steatohepatitis (NASH)-related cirrhosis has become one of the most common indications for liver transplantation (LT), particularly in candidates older than 65 years. Typically, NASH candidates have concurrent obesity, metabolic, and cardiovascular risks, which directly impact patient evaluation and selection, waitlist morbidity and mortality, and eventually posttransplant outcomes. The purpose of these guidelines is to highlight specific features commonly observed in NASH candidates and strategies to optimize pretransplant evaluation and waitlist survival. More specifically, the working group addressed the following clinically relevant questions providing recommendations based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system supported by rigorous systematic reviews and consensus: (1) Is the outcome after LT similar to that of other etiologies of liver disease? (2) Is the natural history of NASH-related cirrhosis different from other etiologies of end-stage liver disease? (3) How should cardiovascular risk be assessed in the candidate for LT? Should the assessment differ from that done in other etiologies? (4) How should comorbidities (hypertension, diabetes, dyslipidemia, obesity, renal dysfunction, etc.) be treated in the candidate for LT? Should treatment and monitoring of these comorbidities differ from that applied in other etiologies? (5) What are the therapeutic strategies recommended to improve the cardiovascular and nutritional status of a NASH patient in the waiting list for LT? (6) Is there any circumstance where obesity should contraindicate LT? (7) What is the optimal time for bariatric surgery: before, during, or after LT? (8) How relevant is donor steatosis for LT in NASH patients?

Analysis of ischemia/reperfusion injury in time-zero biopsies predicts liver allograft outcomes.

Ischemia/reperfusion injury (IRI) that develops after liver implantation may prejudice long-term graft survival, but it remains poorly understood. Here we correlate the severity of IRIs that were determined by histological grading of time-zero biopsies sampled after graft revascularization with patient and graft outcomes. Time-zero biopsies of 476 liver transplants performed at our center between 2000 and 2010 were graded as follows: nil (10.5%), mild (58.8%), moderate (26.1%), and severe (4.6%). Severe IRI was associated with donor age, donation after circulatory death, prolonged cold ischemia time, and liver steatosis, but it was also associated with increased rates of primary nonfunction (9.1%) and retransplantation within 90 days (22.7%). Longer term outcomes in the severe IRI group were also poor, with 1-year graft and patient survival rates of only 55% and 68%, respectively (cf. 90% and 93% for the remainder). Severe IRI on the time-zero biopsy was, in a multivariate analysis, an independent determinant of 1-year graft survival and was a better predictor of 1-year graft loss than liver steatosis, early graft dysfunction syndrome, and high first-week alanine aminotransferase with a positive predictive value of 45%. Time-zero biopsies predict adverse clinical outcomes after liver transplantation, and severe IRI upon biopsy signals the likely need for early retransplantation.

Dysnatremia and mortality: do sweat the small stuff...

Marked dysnatremia is associated with increased mortality in patients admitted to intensive care. However, new evidence suggests that even mild deviations from normal and simple variability of sodium values may also be significant. Should these findings prompt clinicians to re-evaluate the approach to fluid management in this setting? Sodium disorders, on one hand, are known to result from overzealous administration or restriction of free water or sodium ions. However, they are also associated with a range of co-morbidities and drug treatments that alter water loss and sodium handling in the nephron independently of prescribed fluid regimens. Moreover, powerful neuroendocrine and inflammatory responses to surgery, trauma and other acute illness may induce or intensify such changes, altering the response to administered fluids. These observations suggest that both patient and treatment variables contribute, but the extent to which sodium disturbances are preventable and whether prevention improves outcome are unknown. Dysnatremia certainly reflects underlying systemic disorders, but how important is fluid management as a cause, and does it contribute independently to poorer outcomes through osmotic or other mechanisms? Although total fluid volume and doses of potassium and glucose are regularly adjusted in critically ill patients, sodium is usually delivered at standard concentrations as long as serum values lie within an acceptable range. It may be prudent to pay closer attention to these values, especially when abnormal, when fluctuating or when an adverse trend is present. More frequent measurements of sodium in blood, urine and drainage fluids, and appropriate adjustment of the sodium content of prescribed fluids, may be indicated. Until more light can be shed on the pathophysiology of dysnatremia in the critically ill, we should assume that better control of plasma sodium levels may yield better outcomes.

Anesthesia for liver transplantation in US academic centers: institutional structure and perioperative care.

Investigators at a single institution have shown that the organization of the anesthesia team influences patient outcomes after liver transplant surgery. Little is known about how liver transplant anesthesiologists are organized to deliver care throughout the United States. Therefore, we collected quantitative survey data from adult liver transplant programs in good standing with national governing agencies so that we could describe team structure and duties. Information was collected from 2 surveys in a series of quantitative surveys conducted by the Liver Transplant Anesthesia Consortium. All data related to duties, criteria for team membership, interactions/communication with the multidisciplinary team, and service availability were collected and summarized. Thirty-four of 119 registered transplant centers were excluded (21 pediatric centers and 13 centers not certified by national governing agencies). Private practice sites (26) were later excluded because of a poor response rate. There were minimal changes in the compositions of the programs between the 2 surveys. All academic programs had distinct liver transplant anesthesia teams. Most had set criteria for membership and protocols outlining the preoperative evaluation, attended selection committees, and were always available for transplant surgery. Fewer were involved in postoperative care or were available for patients needing subsequent surgery. Most trends were associated with the center volume. In conclusion, some of the variance in team structure and responsibilities is probably related to resources available at the site of practice. However, similarities in specific duties across all teams suggest some degree of self-initiated specialization.

Optimizing cost-effectiveness in perioperative care for liver transplantation: a model for low- to medium-income countries.

Although liver transplantation (LT) is a highly effective treatment, it has been considered too costly for publicly funded health systems in many countries with low to medium average incomes. However, with economic growth and improving results, some governments are reconsidering this position. Cost-effectiveness data for LT are limited, especially in perioperative care, and the techniques and costs vary widely between centers without overt differences in outcomes. Anesthesiologists working in new programs find it difficult to determine which modalities are essential, which are needed only in exceptional circumstances, and which may be omitted without effects on outcomes. We investigated key elements of preoperative evaluations, intraoperative management, and early postoperative care that might significantly affect costs in order to develop a best-value approach for new programs in resource-limited health systems. We identified all modalities of care commonly used in anesthesia and perioperative care for adult LT along with their costs. Those considered to be universally accepted as minimum requirements for safe care were excluded from the analysis, and so were those considered to be safe and low-cost, even when evidence of efficacy was lacking. The remaining items were, therefore, those with uncertain or context-restricted value and significant costs. A systematic review of the published evidence, practice surveys, and institutional guidelines was performed, and the evidence was graded and summarized. With respect to costs and benefits, each modality was then cited as strongly recommended, recommended or optional, or no recommendation was made because of insufficient evidence. Sixteen modalities, which included preoperative cardiovascular imaging, venovenous bypass, pulmonary artery catheterization, high-flow fluid warming devices, drug therapies for hemostasis, albumin, cell salvage, anesthetic drugs, personnel (staffing) requirements, and early extubation, were assessed. Only high-flow fluid warming was strongly recommended. The recommended modalities included preoperative echocardiography, cell salvage, tranexamic acid and early extubation. Six others were rated optional, and there was insufficient evidence for 5 modalities. We conclude that some costly techniques and treatments can be omitted without adverse effects on outcomes.

Effects of phlebotomy and phenylephrine infusion on portal venous pressure and systemic hemodynamics during liver transplantation.

BACKGROUND: A regimen of fluid restriction, phlebotomy, vasopressors, and strict, protocol-guided product replacement has been associated with low blood product use during orthotopic liver transplantation. However, the physiologic basis of this strategy remains unclear. We hypothesized that a reduction of intravascular volume by phlebotomy would cause a decrease in portal venous pressure (PVP), which would be sustained during subsequent phenylephrine infusion, possibly explaining reduced bleeding. Because phenylephrine may increase central venous pressure (CVP), we questioned the validity of CVP as a correlate of cardiac filling in this context and compared it with other pulmonary artery catheter and transesophageal echocardiography-derived parameters. In particular, because optimal views for echocardiographic estimation of preload and stroke volume are not always applicable during liver transplantation, we evaluated the use of transmitral flow (TMF) early peak (E) velocity as a surrogate. METHODS: In study 1, the changes in directly measured PVP and CVP were recorded before and after phlebotomy and phenylephrine infusion in 10 patients near the end of the dissection phase of liver transplantation. In study 2, transesophageal echocardiography-derived TMF velocity in early diastole was measured in 20 patients, and the changes were compared with changes in CVP, pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and calculated systemic vascular resistance (SVR) at the following times: postinduction, postphlebotomy, preclamping of the inferior vena cava, during clamping, and postunclamping. RESULTS: Phlebotomy decreased PVP along with CO, PAP, PCWP, CVP, and TMF E velocity. Phenylephrine given after phlebotomy increased CVP, SVR, and arterial blood pressure but had no significant effect on CO, PAP, PCWP, or PVP. The change in TMF E velocity correlated well with the change in CO (Pearson correlation coefficient 95% confidence interval 0.738-0.917, P< or =0.015) but less well with the change in PAP (0.554-0.762, P< or =0.012) and PCWP (0.576-0.692, P< or =0.008). TMF E velocity did not correlate significantly with CVP or calculated SVR. CONCLUSION: Phlebotomy during the dissection phase of liver transplantation decreased PVP, which was unaffected when phenylephrine infusion was used to restore systemic arterial pressure. This may contribute to a decrease in operative blood loss. CVP often increased in response to phenylephrine infusion and did not seem to reflect cardiac filling. The changes in TMF E velocity correlated well with the changes in CO, PAP, and PCWP during liver transplantation but not with the changes in CVP.

Aprotinin and the risk of thrombotic complications after liver transplantation: a retrospective analysis of 1492 patients.

Aprotinin is an antifibrinolytic drug that reduces blood loss during orthotopic liver transplantation (OLT). Case reports have suggested that aprotinin may be associated with an increased risk of thromboembolic complications. Recent studies in cardiac surgery also have suggested a higher risk of renal failure and postoperative mortality. Despite these concerns, no large-scale safety assessment has been performed in OLT. In a retrospective observational study involving 1492 liver transplants, we studied the occurrence of postoperative thromboembolic or thrombotic events and mortality in patients who received aprotinin (n = 907) and patients who did not (n = 585). The overall incidence of hepatic artery thrombosis and central venous complications (pulmonary embolism or inferior vena cava thrombosis) was 3.2% and 0.9%, respectively. In propensity score-adjusted analyses (C-index = 0.79), aprotinin was not associated with an increased risk of hepatic artery thrombosis [odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.50-2.01, P = 0.86]. Although central venous complications were found more frequently in patients receiving aprotinin, the difference was not statistically significant (OR = 2.95, 95% CI = 0.54-16.23, P = 0.32). In addition, no significant differences were found in 1-year mortality (OR = 1.21, 95% CI = 0.86-1.71, P = 0.32). In conclusion, this study did not demonstrate an increased risk of thrombotic complications or mortality when aprotinin is used during OLT.