The Interplay between Perioperative Oxidative Stress and Hepatic Dysfunction after Human Liver Resection: A Prospective Observational Pilot Study.

Post-hepatectomy liver failure (PHLF) remains the major contributor to death after liver resection. Oxidative stress is associated with postoperative complications, but its impact on liver function is unclear. This first in-human, prospective, single-center, observational pilot study evaluated perioperative oxidative stress and PHLF according to the ISGLS (International Study Group for Liver Surgery). Serum 8-isoprostane, 4-hydroxynonenal (4-HNE), total antioxidative capacity, vitamins A and E, and intraoperative, sequential hepatic tissue 4-HNE and UCP2 (uncoupling protein 2) immunohistochemistry (IHC) were assessed. The interaction with known risk factors for PHLF and the predictive potential of oxidative stress markers were analyzed. Overall, 52 patients were included (69.2% major liver resection). Thirteen patients (25%) experienced PHLF, a major factor for 90-day mortality (23% vs. 0%; p = 0.013). Post-resection, pro-oxidative 8-isoprostane significantly increased (p = 0.038), while 4-HNE declined immediately (p < 0.001). Antioxidative markers showed patterns of consumption starting post-resection (p < 0.001). Liver tissue oxidative stress increased stepwise from biopsies taken after laparotomy to post-resection in situ liver and resection specimens (all p < 0.001). Cholangiocarcinoma patients demonstrated significantly higher serum and tissue oxidative stress levels at various timepoints, with consistently higher preoperative values in advanced tumor stages. Combining intraoperative, post-resection 4-HNE serum levels and in situ IHC early predicted PHLF with an AUC of 0.855 (63.6% vs. 0%; p < 0.001). This was also associated with grade B/C PHLF (36.4% vs. 0%; p = 0.021) and 90-day mortality (18.2% vs. 0%; p = 0.036). In conclusion, distinct patterns of perioperative oxidative stress levels occur in patients with liver dysfunction. Combining intraoperative serum and liver tissue markers predicts subsequent PHLF. Cholangiocarcinoma patients demonstrated pronounced systemic and hepatic oxidative stress, with increasing levels in advanced tumor stages, thus representing a worthwhile target for future exploratory and therapeutic studies.

Early postoperative arterial lactate concentrations to stratify risk of post-hepatectomy liver failure.

BACKGROUND: Post-hepatectomy liver failure (PHLF) represents the major determinant for death after liver resection. Early recognition is essential. Perioperative lactate dynamics for risk assessment of PHLF and associated morbidity were evaluated. METHODS: This was a multicentre observational study of patients undergoing hepatectomy with validation in international high-volume units. Receiver operating characteristics analysis and cut-off calculation for the predictive value of lactate for clinically relevant International Study Group of Liver Surgery grade B/C PHLF (clinically relevant PHLF (CR-PHLF)) were performed. Lactate and other perioperative factors were assessed in a multivariable CR-PHLF regression model. RESULTS: The exploratory cohort comprised 509 patients. CR-PHLF, death, overall morbidity and severe morbidity occurred in 7.7, 3.3, 40.9 and 29.3 per cent of patients respectively. The areas under the curve (AUCs) regarding CR-PHLF were 0.829 (95 per cent c.i. 0.770 to 0.888) for maximum lactate within 24 h (Lactate_Max) and 0.870 (95 per cent c.i. 0.818 to 0.922) for postoperative day 1 levels (Lactate_POD1). The respective AUCs in the validation cohort (482 patients) were 0.812 and 0.751 and optimal Lactate_Max cut-offs were identical in both cohorts. Exploration cohort patients with Lactate_Max 50 mg/dl or greater more often developed CR-PHLF (50.0 per cent) than those with Lactate_Max between 20 and 49.9 mg/dl (7.4 per cent) or less than 20 mg/dl (0.5 per cent; P < 0.001). This also applied to death (18.4, 2.7 and 1.4 per cent), severe morbidity (71.1, 35.7 and 14.1 per cent) and associated complications such as acute kidney injury (26.3, 3.1 and 2.3 per cent) and haemorrhage (15.8, 3.1 and 1.4 per cent). These results were confirmed in the validation group. Combining Lactate_Max with Lactate_POD1 further increased AUC (ΔAUC = 0.053) utilizing lactate dynamics for risk assessment. Lactate_Max, major resections, age, cirrhosis and chronic kidney disease were independent risk factors for CR-PHLF. A freely available calculator facilitates clinical risk stratification (www.liver-calculator.com). CONCLUSION: Early postoperative lactate values are powerful, readily available markers for CR-PHLF and associated complications after hepatectomy with potential for guiding postoperative care.Presented in part as an oral video abstract at the 2020 online Congress of the European Society for Surgical Research and the 2021 Congress of the Austrian Surgical Society.

Liver failure represents a major complication after liver resection and determines the risk of postoperative death, therefore early anticipation and risk stratification are highly relevant. This study, of 991 patients in three international centres, shows that the maximum lactate blood level within 24 h after surgery is a very strong factor predicting the further course after liver operations. Lactate could potentially aid in clinical decision making such as prophylactic treatment, intensified observation or early discharge of patients.

Systematic review on peri-operative lactate measurements to predict outcomes in patients undergoing liver resection.

Lactate measurements have proven utility as a triage tool, therapeutic guide, and prognostic indicator, with broad use in Acute Care and transplantation. Its value in guiding therapy and predicting outcomes following liver resection is less well-defined. This systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines assessed the relationship between peri-operative lactate levels and morbidity and mortality after liver resection. Seven relevant studies comprising 2573 patients in total were identified. Six studies assessed intra-operative or early postoperative lactate levels, one publication examined pre-operative levels. All studies demonstrated a significant association between peri-operative lactate levels and adverse outcomes. The influence of pre-operative diabetes and cirrhosis on postoperative lactate levels was shown in one study each, no study assessed the association of lactate with post-hepatectomy liver failure according to defined criteria. The heterogeneity of study measurements and end-points precluded a meta-analysis from being performed. Early postoperative lactate >3-3.7 mmol/L is associated with mortality but validation of clear cut-off levels for outcome prediction is pending. Literature suggests lactate is a useful predictive marker for outcomes post liver surgery, especially when measured in the early postoperative phase. Further research is required to standardize the use of lactate measurements in a meaningful therapeutic manner.