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.

Normothermic Perfusion in the Assessment and Preservation of Declined Livers Before Transplantation: Hyperoxia and Vasoplegia-Important Lessons From the First 12 Cases.

BACKGROUND: A program of normothermic ex situ liver perfusion (NESLiP) was developed to facilitate better assessment and use of marginal livers, while minimizing cold ischemia. METHODS: Declined marginal livers and those offered for research were evaluated. Normothermic ex situ liver perfusion was performed using an erythrocyte-based perfusate. Viability was assessed with reference to biochemical changes in the perfusate. RESULTS: Twelve livers (9 donation after circulatory death [DCD] and 3 from brain-dead donors), median Donor Risk Index 2.15, were subjected to NESLiP for a median 284 minutes (range, 122-530 minutes) after an initial cold storage period of 427 minutes (range, 222-877 minutes). The first 6 livers were perfused at high perfusate oxygen tensions, and the subsequent 6 at near-physiologic oxygen tensions. After transplantation, 5 of the first 6 recipients developed postreperfusion syndrome and 4 had sustained vasoplegia; 1 recipient experienced primary nonfunction in conjunction with a difficult explant. The subsequent 6 liver transplants, with livers perfused at lower oxygen tensions, reperfused uneventfully. Three DCD liver recipients developed cholangiopathy, and this was associated with an inability to produce an alkali bile during NESLiP. CONCLUSIONS: Normothermic ex situ liver perfusion enabled assessment and transplantation of 12 livers that may otherwise not have been used. Avoidance of hyperoxia during perfusion may prevent postreperfusion syndrome and vasoplegia, and monitoring biliary pH, rather than absolute bile production, may be important in determining the likelihood of posttransplant cholangiopathy. Normothermic ex situ liver perfusion has the potential to increase liver utilization, but more work is required to define factors predicting good outcomes.

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.

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.

Anesthetic management of hepatic transplantation.

PURPOSE OF REVIEW: The present review describes new trends and ongoing controversies in the anesthetic care of liver transplant recipients. RECENT FINDINGS: Recent studies have improved our knowledge of conditions increasing perioperative risk, such as portopulmonary hypertension and renal failure. Improved surgical and anesthetic management has reduced intraoperative blood loss, as more studies identify an independent association between blood transfusion and poor outcome. New concepts in the coagulopathy of liver failure are emerging, with clear implications for clinical practice, including greater awareness of the risks of intraoperative thromboembolism. Less invasive intraoperative hemodynamic monitoring has been advocated, as has wider use of transoesophageal echocardiography. Early extubation is becoming more routinized. SUMMARY: Anesthetic management still varies widely between liver transplant centers with little data to indicate best practice. Future research should focus on fluid replacement, prevention and treatment of coagulopathy, care of the acutely ill patient and the safety and benefits of early extubation.