Dynamic liver function is an independent predictor of recurrence-free survival after curative liver resection for HCC - A retrospective cohort study.

BACKGROUND: Hepatocellular carcinoma is the fifth most prevalent cancer worldwide. High tumour recurrence is the most common cause of the impaired 5-year survival rate of 26-58% after hepatectomy. The aim of this study was to investigate the impact of preoperative dynamic liver function on long-term outcome. MATERIALS AND METHODS: A total of 146 patients that underwent curative resection for HCC at our department from 2005 to 2016 were analysed. Univariate analysis was calculated using Kaplan-Meier method. Multivariable analysis was carried out with Cox regression. RESULTS: The cumulative 1-, 3-, 5-year survival rates were 83%, 42% and 14%, respectively. Multivariable Cox regression yielded that overall survival depends on disease recurrence, haemoglobin, number of tumours, liver cirrhosis, lymphatic vessel invasion, UICC stage and postoperative complications. The corresponding 1-, 3-, 5-year disease-free survival rates were 73%, 32% and 10%, respectively. Multivariable analysis yielded preoperative liver function capacity (HR 2.421; p = 0.014), vascular invasion (HR 2.116; p = 0.034) and UICC stage (HR 2.200; p = 0.037) as risk factors associated with disease-free survival. A subanalysis with respect to the degree of functional impairment implicated that severity of liver function impairment is correlated with the disease-free survival rate. CONCLUSION: This study shows that preoperative dynamic liver function assessed by LiMAx test as well as severity of underlying liver disease have a significant impact on recurrence-free survival after curative hepatectomy. Patients presenting with impaired liver function should be evaluated for other treatment e.g. liver transplantation or receive closer oncological follow-up.

Hepatic CYP1A2 activity in liver tumors and the implications for preoperative volume-function analysis.

Dynamic liver function assessment by the [13C]methacetin maximal liver function capacity (LiMAx) test reflects the overall hepatic cytochrome P-450 (CYP) 1A2 activity. One proven strategy for preoperative risk assessment in liver surgery includes the combined assessment of the dynamic liver function by the LiMAx test, the volumetric analysis of the liver, and calculation of future liver remnant function. This so-called volume-function analysis assumes that the remaining CYP1A2 activity in any tumor lesion is zero. The here presented study aims to assess the remaining CYP1A2 activities in different hepatic tumor lesions and its consequences for the preoperative volume-function analysis in patients undergoing liver surgery. The CYP1A2 activity analysis of neoplastic lesions and adjacent nontumor liver tissue from resected tumor specimens revealed a significantly higher CYP1A2 activity (median, interquartile range) in nontumor tissues (35.5, 15.9-54.4 µU/mg) compared with hepatocellular adenomas (7.35, 1.2-32.5 µU/mg), hepatocellular carcinomas (0.18, 0.0-2.0 µU/mg), or colorectal liver metastasis (0.17, 0.0-2.1 µU/mg). In nontumor liver tissue, a gradual decline in CYP1A2 activity with exacerbating fibrosis was observed. The CYP1A2 activity differences were also reflected in CYP1A2 protein signals in the assessed hepatic tissues. Volume-function analysis showed a minimal deviation compared with the current standard calculation for hepatocellular carcinomas or colorectal liver metastasis (<1% difference), whereas a difference of 11.9% was observed for hepatocellular adenomas. These findings are important for a refined preoperative volume-function analysis and improved surgical risk assessment in hepatocellular adenoma cases with low LiMAx values. NEW & NOTEWORTHY The cytochrome P-450 (CYP) 1A2-dependent maximal liver function capacity test reflects the overall functional capacity of the liver. To which extent hepatocellular tumors harbor CYP1A2 activity and thus contribute to the maximal liver function capacity test outcome is unknown. We here show that hepatocellular adenomas but not hepatocellular carcinomas or colorectal liver metastasis contain significant residual CYP1A2 activity. These findings are important for an improved preoperative volume-function analysis and an accurate surgical risk assessment in hepatocellular adenoma cases.

Identification of serological markers for pre- and postoperative fasting periods.

BACKGROUND & AIMS: Prolonged preoperative fasting periods lead to catabolic states and decelerate recovery after surgery. Valid plasma markers reflecting the patients' metabolic state may improve tailored nutrition support before surgery. Within this study, we sought to advance the knowledge on fasting time-sensitive plasma markers that allow the metabolic characterisation of surgical patients for an optimised preoperative metabolic preparation. METHODS: Patients scheduled for elective surgery of the upper (n = 23) or lower (n = 27) gastrointestinal tract participated in a prospective observational study. Patients' charateristics and nutritional status were recorded and blood samples were drawn on the day of admission. Further blood samples were collected before skin incision of the surgical procedure, on postoperative day 3 and on the day of discharge. Values of clinical chemistry, electrolytes, hemograms and plasma amino acids were determined and correlated with fasting times. RESULTS: Preoperative fasting times were positively correlated with plasma levels of valine, leucine, serine, α-amino butyric acid, free fatty acids, 3-hydroxy butyric acid and significantly negative correlated with chloride and glutamic acid. Postoperative fasting times were correlated with erythrocytes, leukocytes and plasma levels of albumin, CRP, HDL, asparagine and 3-methylhistidine. The multivariate regression analysis revealed glutamic acid and valine as significant independent predictors of preoperative fasting periods. The regression model showed best performance (sensitivity of 90.91% and specificity of 92.31%) to detect patients fasted for ≥20 h. CONCLUSION: Valine and glutamic acid appear as independent metabolic markers for accurate prediction of prolonged fasting periods, independent of the overall nutritional status, age or BMI of patients.

Non-invasive structure-function assessment of the liver by 2D time-harmonic elastography and the dynamic Liver MAximum capacity (LiMAx) test.

BACKGROUND AND AIM: Accurate assessment of structural and functional characteristics of the liver could improve the diagnosis and the clinical management of patients with chronic liver diseases. However, the structure-function relationship in the progression of chronic liver disease remains elusive. The aim of this study is the combined measurement of liver function by the 13 C-methacetin Liver MAximum capacity (LiMAx) test and tissue-structure related stiffness by 2D time-harmonic elastography for the assessment of liver disease progression. METHODS: LiMAx test and time-harmonic elastography were applied, and the serological scores fibrosis 4 index and aspartate aminotransferase to platelet ratio index were calculated in patients with chronic liver diseases (n = 75) and healthy control subjects (n = 22). In 47 patients who underwent surgery, fibrosis was graded by histological examination of the resected liver tissue. RESULTS: LiMAx values correlated negatively with liver stiffness (r = -0.747), aminotransferase to platelet ratio index (r = -0.604), and fibrosis 4 (r = -0.573). Median (interquartile range) LiMAx values decreased with fibrosis progression from 395 µg/kg/h (371-460 µg/kg/h) in participants with no fibrosis to 173 µg/kg/h (126-309 µg/kg/h) in patients with severe fibrosis. Median liver stiffness increased progressively with the stage of fibrosis from no fibrosis (1.56 m/s [1.52-1.63 m/s]) to moderate fibrosis (1.60 m/s [1.54-1.67 m/s]) to severe fibrosis (1.85 m/s [1.76-1.92 m/s]). CONCLUSION: Our findings show that structural changes in the liver due to progressing liver diseases and reflected by increased tissue stiffness correlate with a functional decline of the organ as reflected by a decreased metabolic capacity of the liver.

Liver Function, Quantified by LiMAx Test, After Major Abdominal Surgery. Comparison Between Open and Laparoscopic Approach.

INTRODUCTION: Major abdominal surgery may lead to a systemic inflammatory response (SIRS) with a risk of organ failure. One possible trigger for a postoperative hepatic dysfunction is an altered hepatic blood flow during SIRS, resulting in a decreased oxygen delivery. This pilot study investigated the role of liver dysfunction measured by the LiMAx test after major abdominal surgery, focussing on open and laparoscopic surgical approaches. METHODS: We prospectively investigated 25 patients (7 females and 18 males, age range 55-72 years) scheduled for upper abdominal surgery. The LiMAx test, ICG-PDR and duplex sonography were carried out preoperatively, followed by postoperative days (PODs) 1, 3, 5 and 10. Laboratory parameters and clinical parameters were measured daily. Clinical outcome parameters were examined at the end of treatment. The population was divided into group A (laparotomy) versus group B (laparoscopy). RESULTS: LiMAx values decreased significantly on POD 1 (290 µg/kg/h, P < 0.001), followed by a significant increase at POD 3 (348 µg/kg/h, P = 0.013). Only INR showed a significant increase on POD 1 (1.26, P < 0.001). Duplex sonography and ICG-PDR revealed a hyper-dynamic liver blood flow. No differences between group A and B were found. CONCLUSIONS: Hepatic dysfunction after major abdominal surgery is evident and underestimated. The LiMAx test provides an adequate tool to determine liver dysfunction. Open and laparoscopic approaches appeared similar in terms of liver dysfunction and postoperative SIRS.

Correlation between plasma endothelin-1 levels and severity of septic liver failure quantified by maximal liver function capacity (LiMAx test). A prospective study.

AIM: To investigate the relationship between the degree of liver dysfunction, quantified by maximal liver function capacity (LiMAx test) and endothelin-1, TNF-α and IL-6 in septic surgical patients. METHODS: 28 septic patients (8 female, 20 male, age range 35-80y) were prospectively investigated on a surgical intensive care unit. Liver function, defined by LiMAx test, and measurements of plasma levels of endothelin-1, TNF-α and IL-6 were carried out within the first 24 hours after onset of septic symptoms, followed by day 2, 5 and 10. Patients were divided into 2 groups (group A: LiMAx ≥100 µg/kg/h, moderate liver dysfunction; group B: LiMAx <100 µg/kg/h, severe liver dysfunction) for analysis and investigated regarding the correlation between endothelin-1 and the severity of liver failure, quantified by LiMAx test. RESULTS: Group B showed significant higher results for endothelin-1 than patients in group A (P = 0.01, d5; 0.02, d10). For TNF-α, group B revealed higher results than group A, with a significant difference on day 10 (P = 0.005). IL-6 showed a non-significant trend to higher results in group B. The Spearman's rank correlation coefficient revealed a significant correlation between LiMAx and endothelin-1 (-0.434; P <0.001), TNF-α (-0.515; P <0.001) and IL-6 (-0.590; P <0.001). CONCLUSIONS: Sepsis-related hepatic dysfunction is associated with elevated plasma levels of endothelin-1, TNF-α and IL-6. Low LiMAx results combined with increased endothelin-1 and TNF-α and a favourable correlation between LiMAx and cytokine values support the findings of a crucial role of Endothelin-1 and TNF-α in development of septic liver failure.

Early diagnosis of sepsis-related hepatic dysfunction and its prognostic impact on survival: a prospective study with the LiMAx test.

INTRODUCTION: Liver dysfunction can derive from severe sepsis and might be associated with poor prognosis. However, diagnosis of septic liver dysfunction is challenging due to a lack of appropriate tests. Measurement of maximal liver function capacity (LiMAx test) has been successfully evaluated as a new diagnostic test in liver resection and transplantation. The aim of this study was to evaluate the LiMAx test during sepsis in comparison to biochemical tests and the indocyanin green test (ICG-PDR). METHODS: We prospectively investigated 28 patients (8 female and 20 male, age range 35 to 80 years) suffering from sepsis on a surgical ICU. All patients received routine resuscitation from septic shock (surgery, fluids, catecholamines, antibiotic drugs). The first LiMAx test and ICG-PDR were carried out within the first 24 hours after onset of septic symptoms, followed by day 2, 5 and 10. Other biochemical parameters and scores determining the severity of illness were measured daily. Clinical outcome parameters were examined after 90 days or at the end of treatment. The population was divided into 2 groups (group A: non-survivors or ICU length of stay (ICU-LOS) >30 days versus group B: survivors and ICU-LOS <30 days) for analysis. RESULTS: Epidemiological baseline characteristics of both groups were similar. Group A patients had significant lower LiMAx and ICG-PDR values than patients in group B. Determination of ICG-PDR by finger probe failed in 14.3% of tests due to insufficient peripheral pulses. Respiratory, renal and hepatic dysfunction (LiMAx and ICG-PDR) were associated with prolonged ICU-LOS. Only LiMAx <100 µg/kg/h and respiratory dysfunction were associated with increased mortality. For LiMAx <100 µg/kg/h receiver operating characteristic-analysis revealed a 100% sensitivity and 77% specificity for death. CONCLUSIONS: Sepsis-related hepatic dysfunction can be diagnosed early and effectively by the LiMAx test. The extent of LiMAx impairment is predictive for patient morbidity and mortality. The sensitivity and specificity of the LiMAx test was superior to that of ICG-PDR regarding the prediction of mortality.

Catecholamine dosing and survival in adult intensive care unit patients.

BACKGROUND: Volume management and vasopressor support remain the gold standard of critical care for patients with shock. However, prolonged therapy with catecholamines in high doses is associated with a negative patient outcome. The aim of the present study was to analyze the administered levels of catecholamines over time with respect to survival, and to identify a cut-off to allow a prediction of survival. METHODS: Consecutively, 9,108 adult patients during 22 months were evaluated. This group included 1,543 patients treated with epinephrine and/or norepinephrine with any dose at any time. Time and dosages of the applied drugs, the sequential organ failure assessment and acute and chronic health evaluation II scores on admission and daily, the length of intensive care unit stay, and the outcomes were recorded. RESULTS: The non-survivors received higher doses of norepinephrine and epinephrine than the survivors (p < 0.001). The receiver operator characteristic curve for the area under the curve with non-survival as the classifier revealed a cut-off level of 294.33 µg/kg for norepinephrine with a sensitivity of 74.73 % and a specificity of 70.48 % and a cut-off for epinephrine of 70.36 µg/kg with a sensitivity of 83.87 % and a specificity of 72.79 %. Dose-dependent time curves using these cut-off values were calculated. CONCLUSIONS: Survival of patients with prolonged therapy with norepinephrine and epinephrine above the evaluated thresholds is poor, whereas short-term application of high-dose catecholamines is not associated with poor outcome. Therefore, it remains for the individual clinician, patients, and their surrogates to decide whether the use of high doses of vasopressors is appropriate in view of the low probability of survival.

The use of bedside electromagnetically guided nasointestinal tube for jejunal feeding of critical ill surgical patients.

BACKGROUND: Gastral nutrition in critically ill surgical patients can be difficult because of gastric paresis and a large number of patients fail to reach required caloric intake. Endoscopic or radiologic placement of nasointestinal tube is frequently performed with delay and may raise the risks for critical ill patients. OBJECTIVE: Bedside placement of electromagnetically guided nasointestinal tube (EGNT) may reduce the risk of x-ray exposure, "time out of ward" and caloric deficit. METHODS: All patients in a surgical intensive care unit with need of post-pyloric feeding tube placement were identified. Data were collected from Cortrak-EGNT-System and x-ray. An analysis of placement success rate, time for tube positioning and delay of enteral feeding when EGNT failed were performed. RESULTS: 70 tubes were placed in 51 patients. After the first trial 79% were placed post-pyloric and 21% gastral. Successful postpyloric placement increased to 90% after the second trial. Placement failure occurred in 10% of all cases. In 3 patients jejunal placement was successful in modified anatomical situs after upper gastrointestinal surgery. After 20 min unsuccessful postpyloric placement, performance was stopped and declared as failure. X-ray findings correlated in 100% with Cortrak data. Time needed for placement varied from 1-20 min (mean 7.6 min). CONCLUSIONS: Bedside positioning of electromagnetically guided nasointestinal tube is safe and effective in critically ill surgical patients. Most placements succeed, even in patients after upper GI surgery. EGNT positioning is time saving and may enhance the caloric intake.

Unplanned discharges from a surgical intensive care unit: readmissions and mortality.

PURPOSE: There is great patient turnover every day on surgical intensive care units (SICUs). Surgical intensive care unit beds are provided for major elective surgery. Emergency admissions trigger unplanned discharges. Those patients are at risk for a worse outcome. MATERIALS AND METHODS: We retrospectively analyzed 2558 patients discharged from a 20-bed SICU within 1 year. They were followed up whether discharged electively or not. Patients readmitted to the SICU were stratified according to reason for readmission. RESULTS: Readmission rate to the SICU was 8.3% (139/1675) in elective discharges, and 25.1% (110/439) in unplanned discharges (P < .001); 50% (125/249) of all readmissions were for surgical complications. Hospital mortality was 2.28% (50/2,197) in patients not readmitted to the SICU and 13.3% (33/249) for those readmitted (P < .001). The mortality rate increased by 4% in readmissions for each year of age (P < .05, OR for death 1.04 for each year of age, 95% CI 1.010-1.071). Respiratory failure as a reason for readmission implied a 44% risk of death (P < .001, OR 11.85, 95% CI 5.11-27.45). CONCLUSIONS: Earlier-than-planned discharge from a SICU leads to a substantially higher readmission rate. Readmission correlates with an elevated risk of death. Most readmissions in a surgical clinic are due to surgical complications. Readmission for respiratory failure accounts for most of the mortality.