Systematic comparison of routine laboratory measurements with in-hospital mortality: ICU-Labome, a large cohort study of critically ill patients.

BACKGROUND: In intensive care unit (ICU) patients, many laboratory measurements can be deranged when compared with the standard reference interval (RI). The assumption that larger derangements are associated with worse outcome may not always be correct. The ICU-Labome study systematically evaluated the univariate association of routine laboratory measurements with outcome. METHODS: We studied the 35 most frequent blood-based measurements in adults admitted ≥6 h to our ICU between 1992 and 2013. Measurements were from the first 14 ICU days and before ICU admission. Various metrics, including variability, were related with hospital survival. ICU- based RIs were derived from measurements obtained at ICU discharge in patients who were not readmitted to the ICU and survived for >1 year. RESULTS: In 49,464 patients (cardiothoracic surgery 43%), we assessed >20·106 measurements. ICU readmissions, in-hospital and 1-year mortality were 13%, 14% and 19%, respectively. On ICU admission, lactate had the strongest relation with hospital mortality. Variability was independently related with hospital mortality in 30 of 35 measurements, and 16 of 35 measurements displayed a U-shaped outcome-relation. Medians of 14 of 35 ICU-based ranges were outside the standard RI. Remarkably, γ-glutamyltransferase (GGT) had a paradoxical relation with hospital mortality in the second ICU week because more abnormal GGT-levels were observed in hospital survivors. CONCLUSIONS: ICU-based RIs for may be more useful than standard RIs in identifying ICU patients at risk. The association of variability with outcome for most of the measurements suggests this is a consequence and not a cause of a worse ICU outcome. Late elevation of GGT may confer protection to ICU patients.

Evidence against a role for platelet-derived molecules in liver regeneration after partial hepatectomy in humans.

Background and Aim: Blood platelets have been shown to stimulate liver regeneration after partial hepatectomy in animal models and humans, but the molecular mechanisms involved are unclear. It has been proposed that growth factors and angiogenic molecules stored within platelets drive platelet-mediated liver regeneration, but little direct evidence in support of this mechanism is available. Methods: We assessed levels of relevant platelet-derived proteins (vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor, platelet-derived growth factor, thrombospondin, and endostatin) in platelet-rich and platelet-poor plasma taken at various perioperative time points from patients undergoing a (extended) right partial hepatectomy (n = 17) or a pylorus-preserving pancreatico-duodenectomy (n = 10). In addition, we collected intraoperative samples from the efferent and afferent liver veins prior to and after completion of liver resection. Twenty-four healthy controls were included to establish reference ranges for the various tests. Results and Conclusions: Although we demonstrate perioperative changes in platelet and plasma levels of the proteins assessed, the changes observed in patients undergoing partial hepatectomy largely mirror the changes observed in patients undergoing a pylorus-preserving pancreatico-duodenectomy. In addition, no change in the growth factor levels in platelet-rich plasma between afferent and efferent liver veins was observed. Thus, the absence of an intra- or postoperative consumption of platelet-derived proteins in patients undergoing partial hepatectomy argues against a role of release of these molecules in stimulation of liver regeneration. Relevance for patients: In depth knowledge of the mechanism underlying platelet-mediated liver regeneration may facilitate development of targeted therapeutic interventions for patients with failing liver regeneration, which for example may occur following a partial hepatectomy. Although the prevailing dogma is that platelet stimulate liver regeneration by release of growth factors stored within platelets, data in this manuscript argue against this mechanism and suggest other pathways to be responsible.

No evidence for increased platelet activation in patients with hepatitis B- or C-related cirrhosis and hepatocellular carcinoma.

INTRODUCTION: Cancer is a major risk factor for developing venous thromboembolism (VTE). Plasma hypercoagulability is an established risk factor for cancer-related VTE. In addition, thrombocytosis and hyperreactive platelets have been implicated in VTE and cancer progression. Cirrhosis is associated with changes in platelet number and function. The platelet activation status of patients with cirrhosis and hepatocellular carcinoma has not yet been established. Here we assessed the platelet activation status in patients with hepatitis-related cirrhosis in presence or absence of HCC. MATERIALS AND METHODS: We performed a cross-sectional study including thirty-eight consecutive patients with hepatitis B- or C- related liver cirrhosis in presence or absence of HCC. We studied basal and agonist-induced platelet activation using flow cytometry. In addition, we studied the plasma levels of von Willebrand factor (VWF) and the VWF-cleaving protease ADAMTS13. Twenty healthy volunteers served as controls. RESULTS: We found no evidence of basal platelet activation in patients with cirrhosis compared to controls. However, we found reduced agonist-induced platelet activation in patients. No differences in the basal and agonist-induced platelets activation status between patients with or without HCC were detected. Plasma levels of VWF were increased and the levels of ADAMTS13 activity were decreased in patients compared to controls. No differences between the levels of VWF and ADAMTS13 in patients with or without HCC were detected. CONCLUSIONS: HCC development or recurrence in patients with hepatitis B- or C-related cirrhosis does not appear to be associated with platelet activation and changes in pivotal proteins in primary hemostasis.

Levels of angiogenic proteins in plasma and platelets are not different between patients with hepatitis B/C-related cirrhosis and patients with cirrhosis and hepatocellular carcinoma.

Increasing evidence suggests that levels of angiogenic proteins within blood platelets change at the earliest stages of cancer development and may thus provide a promising diagnostic and prognostic tool. Patients with cirrhosis have increased risk of developing hepatocellular carcinoma (HCC). We aimed to study whether development of HCC in hepatitis-related cirrhosis results in changes in platelet levels of angiogenic proteins. We studied the intraplatelet levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), endostatin, platelet factor 4 (PF4) and thrombospondin type 1 (TSP-1) in 38 consecutive patients with hepatitis B- or C-related liver cirrhosis with or without HCC in addition to plasma levels of the same proteins. Twenty healthy volunteers were included to establish reference values for the various tests. Intraplatelet levels of VEGF, bFGF, HGF and endostatin were significantly higher in patients compared to controls. Intraplatelet levels of PDGF, PF4 and TSP-1 were comparable between patients and controls. Plasma levels of VEGF, bFGF and endostatin were comparable between patients and controls. Plasma levels of PDGF, PF4 and TSP-1 were decreased in patients, but this difference disappeared when levels were corrected for platelet count. Intraplatelet and plasma levels of all proteins assessed were comparable between patients with and without HCC. In conclusion, the intraplatelet levels of some angiogenic proteins are elevated in cirrhosis, but do not discriminate between patients with and without HCC. Thus, intraplatelet levels of angiogenic proteins do not seem useful as diagnostic or prognostic biomarker of HCC in cirrhotic patients.

Early elevated serum gamma glutamyl transpeptidase after liver transplantation is associated with better survival.

BACKGROUND: Gamma glutamyl transpeptidase (GGT) is a membrane bound enzyme that plays a key role in the synthesis of the antioxidant glutathione. Epidemiological studies have linked high GGT with an increased risk of morbidity and cardiovascular mortality. In contrast, GGT is usually elevated in liver transplant recipients that experience good outcomes. AIMS: To study if and how GGT is correlated with mortality following liver transplantation. METHODS: We analyzed the prognostic relevance of serum GGT levels during the early and late postoperative period after liver transplantation in 522 consecutive adults. We also studied alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels. RESULTS: Early after transplantation, the peak median (interquartile range) GGT levels were significantly higher in patients who survived more than 90 days compared to non-survivors: 293 (178-464) vs. 172 (84-239) U/l, p<0.0001. In contrast, late after transplantation, GGT levels were significantly lower in patients who survived more than 5 years than those who did not ( p<0.01). The pattern of GGT levels also differed from those of alanine aminotransferase, aspartate aminotransferase, and total bilirubin early after transplantation, while these patterns were congruent late after transplantation. Kaplan-Meier survival analysis showed that early after transplantation the higher the GGT levels, the better the 90-day survival ( p<0.001). In contrast, late after transplantation, higher GGT levels were associated with a lower 5-year survival ( p<0.001). CONCLUSIONS:   These paradoxical findings may be explained by the time-dependent role of GGT in glutathione metabolism. Immediate postoperative elevation of GGT may indicate a physiological systemic response while chronic elevation reflects a pathological response.

Immediate postoperative low platelet count is associated with delayed liver function recovery after partial liver resection.

OBJECTIVE: To evaluate whether a low postoperative platelet count is associated with a poor recovery of liver function in patients after partial liver resection. BACKGROUND: Experimental studies in rodents have recently suggested that blood platelets play a critical role in the initiation of liver regeneration. It remains unclear whether platelets are also involved in liver regeneration in humans. METHODS: In a series of 216 consecutive patients who underwent partial liver resection for colorectal liver metastases, we studied postoperative mortality and liver dysfunction in relation to the immediate postoperative platelet count. All patients had normal preoperative liver function and none of them had liver fibrosis or cirrhosis. Delayed postoperative recovery of liver function was defined as serum bilirubin >50 micromol/L or prothrombin time >20 seconds at any time point between postoperative day 1 and 5. RESULTS: Patients with a low (<100 x10(9)/L) immediate postoperative platelet count had worse postoperative liver function, higher serum markers of liver injury, and increased mortality compared with patients with normal platelet counts (>100/L). A low immediate postoperative platelet count was identified as an independent risk factor of delayed postoperative recovery of liver function (OR, 11.5; 95% CI, 1.1-122.4; P = 0.04 in multivariate analysis). CONCLUSION: After partial liver resection, a low platelet count is an independent predictor of delayed postoperative liver function recovery and is associated with increased risk of postoperative mortality. These clinical findings are in accordance with the accumulating evidence from experimental studies, indicating that platelets play a critical role in liver regeneration.

Bleeding in liver surgery: prevention and treatment.

Intraoperative blood loss and transfusion of blood products are negatively associated with postoperative outcome after liver surgery. Blood loss can be minimized by surgical methods, including vascular clamping techniques, the use of dissection devices, and the use of topical hemostatic agents. Preoperative correction of coagulation tests with blood products has not been shown to reduce intraoperative bleeding and it may, in fact, enhance the bleeding risk. Maintaining a low central venous pressure has been shown to be effective in reducing blood loss during partial liver resections, and volume contraction rather than prophylactic transfusion blood products seems justified in patients undergoing major liver surgery. Although antifibrinolytic drugs have proved to be effective in reducing blood loss during liver transplantation, systemic hemostatic drugs are of limited value in reducing blood loss in patients undergoing partial liver resections.