Topical haemostatic agents in liver surgery: do we need them?

AbstractBackgroundWorldwide, partial liver resections are increasingly being performed for primary or secondary hepatic malignancies. There are various techniques to reduce blood loss druing liver surgery. Several topical haemostatic agents have been developed to improve haemostasis of the resection surface and these agents are used more and more, even although the true effects remain unclear.MethodsThe present literature about the use of topical haemostatic agents in liver surgery was reviewed. Furthermore we conducted a Dutch national survey to explore the use of and belief in these agents in liver surgery.ResultsThe Dutch national survey among surgeons showed that topical haemostatic agents are frequently used not only to lower intra-operative blood loss or shorten time to haemostasis, but even more importantly, to reduce resection surface related complications such as bile leakage, postoperative haemorrhage and abscess formation. Although various topical haemostatic agents have been shown to reduce intra-operative time to haemostasis at the resection surface after liver resections, there is no scientific proof that these topical haemostatic agents really reduce resection surface related complications.ConclusionThis review highlights the need for more randomized clinical trials to investigate the efficacy of topical haemostatic agents in reducing resection surface related complications

Diagnostic performance of preoperative CT in differentiating between benign and malignant origin of suspicious gallbladder lesions

Purpose: To determine diagnostic performance of preoperative CT in differentiating between benign and malignant suspicious gallbladder lesions and to develop a preoperative risk score. Method: All patients referred between January 2007 and September 2018 for suspicion of gallbladder cancer (GBC) or incidentally found GBC were retrospectively analyzed. Patients were excluded when preoperative CT or histopathologic examination was lacking. Two radiologists, blinded to histopathology results, independently reviewed CT images to differentiate benign disease from GBC. Multivariable analysis and internal validation were used to develop a risk score for GBC. Model discrimination, calibration, and diagnostic performance were assessed. Results: In total, 118 patients with 39 malignant (33 %) and 79 benign (67 %) lesions were included. Sensitivity of CT for diagnosing GBC was 90 % (95 % confidence interval [CI]: 76?97). Specificity rates were 61 % (95 % CI: 49?72) and 59 % (95 % CI: 48?70). Three predictors of GBC (irregular lesion aspect, absence of fat stranding, and locoregional lymphadenopathy) were included in the risk score ranging from -1 to 4. Adequate performance was found (AUC: 0.79, calibration slope: 0.89). In patients allocated >0 points, the model showed higher performance in excluding GBC than the radiologists (sensitivity 92 % [95 % CI: 79?98]). Moreover, when allocated >3 points, the risk score was superior in diagnosing GBC (specificity 99 % [95 % CI: 93?100]). Conclusions: Sensitivity rates of CT for differentiation between benign and malignant gallbladder lesions are high, however specificity rates are relatively low. The proposed risk score may facilitate differentiation between benign and malignant suspicious gallbladder lesions

Surgical treatment for non-parasitic liver cysts improves quality of life

BACKGROUND&PURPOSE: Liver cysts occur frequently. Most are harmless, however some carry a significant patient burden. Optimizing treatment strategy is complicated as needs differ between patients. The current study assesses the effect of surgery on quality of life (QoL) of patients with non-parasitic liver cysts. METHODS: A retrospective cohort study of all patients who underwent surgery for non-parasitic liver cysts in three major Dutch medical centers from 1993 to 2017. Patient characteristics and surgery related variables were collected from the electronic patient file. QoL was measured before and after surgery using the EORTC QLQ-C30. Summary scores (SumSc) were calculated and compared to reference values of the general population. Multivariate analysis using logistic regression was performed for identifying outcome related factors. Increase of ≥ 10% in SumSc was defined as clinically relevant. MAIN FINDINGS: Eighty-eight of 132 eligible patients (67%) completed two QoL assessments. Respondents demonstrated significant improvement in the global health status, on all 5 functional scales (all p ≤ 0.005), on all 9 symptom scales after surgery (all p < 0.05), and on SumSc (p < 0.001) to levels similar or better than the general population. Patients with complications demonstrated a significant QoL gain (p < 0.05), and reported a similar postoperative status compared to patients without complications (p = 0.74). QoL gain for patients who underwent open and laparoscopic cyst fenestration were similar (p = 0.08). Multivariate analysis of SumSc found mechanical complaints as significant factor for ≥ 10% SumSc increase (OR 0.11, 95% CI (0.02-0.55). CONCLUSIONS: Surgery is a safe and effective strategy to significantly improve QoL in patients with symptomatic liver cysts

Waitlist mortality of young patients with biliary atresia:Impact of allocation policy and living donor liver transplantation

Patients with biliary atresia (BA) below 2 years of age in need of a transplantation largely rely on partial grafts from deceased donors (deceased donor liver transplantation [DDLT]) or living donors (living donor liver transplantation [LDLT]). Because of high waitlist mortality in especially young patients with BA, the Eurotransplant Liver Intestine Advisory Committee (ELIAC) has further prioritized patients with BA listed before their second birthday for allocation of a deceased donor liver since 2014. We evaluated whether this Eurotransplant (ET) allocation prioritization changed the waitlist mortality of young patients with BA. We used a pre-post cohort study design with the implementation of the new allocation rule between the two periods. Participants were patients with BA younger than 2 years who were listed for liver transplantation in the ET database between 2001 and 2018. Competing risk analyses were performed to assess waitlist mortality in the first 2 years after listing. We analyzed a total of 1055 patients with BA, of which 882 had been listed in the preimplementation phase (PRE) and 173 in the postimplementation phase (POST). Waitlist mortality decreased from 6.7% in PRE to 2.3% in POST (p = 0.03). Interestingly, the proportion of young patients with BA undergoing DDLT decreased from 32% to 18% after ET allocation prioritization (p = 0.001), whereas LDLT increased from 55% to 74% (p = 0.001). The proportional increase in LDLT decreased the median waitlist duration of transplanted patients from 1.5 months in PRE to 0.85 months in POST (p = 0.003). Since 2014, waitlist mortality in young patients with BA has strongly decreased in the ET region. Rather than associated with prioritized allocation of deceased donor organs, the decreased waitlist mortality was related to a higher proportion of patients undergoing LDLT.</p

Gallbladder Cancer:Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

SIMPLE SUMMARY: Knowledge of genetic alterations in gallbladder cancer (GBC) continues to increase. This systematic review provides an overview of frequently occurring genetic alterations in GBC and describes their possible therapeutic implications. We detected three frequently (>5%) altered genes (ATM, ERBB2 and PIK3CA) for which targeted therapies are available in other cancer types. For solid cancers with microsatellite instability or a high tumor mutational burden pembrolizumab is FDA-approved. Altogether, these five biomarkers might be used in future molecular panels to enable precision medicine for patients with GBC. We found only nine clinical trials evaluating targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials. ABSTRACT: Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials

Use of antihypertensive agents and the risk of out-of-hospital cardiac arrest: A case control study

Background: Sudden cardiac arrest (SCA) is a complex multifactorial condition and is commonly caused by ventricular tachycardia/fibrillation (VT/VF). Some antihypertensive agents such as thiazides are associated with increased risk of SCA. Objectives: The aim of this study was to assess the association between different antihypertensive agents and the occurrence of out-of-hospital cardiac arrest (OHCA), taking into account their potential impact on serum potassium levels. Methods: Cases were drawn from the Amsterdam Resuscitation Studies (ARREST) registry and controls from the PHARMO database. This study was performed using 1948 cases who had OHCA with electrocardiogram (ECG)-documented VT/VF for the first time. These cases were matched by age, sex, and OHCA date (index date) to 8347 controls. From this dataset, we included only patients who were current users of antihypertensive agents (the index date fell between start date and end date of prescription + 10%). Antihypertensive therapies were classified according to their potential impact on serum potassium levels to therapies with neutral effect, therapies inducing hypokalemia, therapies inducing hyperkalemia, and therapies with unknown effect. Logistic regression analysis was used to study the association between use of antihypertensive agents and occurrence of OHCA and to control for confounding. Results: We included 1192 cases and 3303 controls who were current users of antihypertensive agents in our analysis. The risk of OHCA was significantly increased with users of antihypertensive therapies inducing hypokalemia (adjusted OR 1.48, 95%CI (1.12- 1.94)) and with users of antihypertensive therapies with unknown effect (adjusted OR 1.42, 95%CI (1.13-1.77)) versus users of antihypertensive therapies with neutral effect. There was no difference in OHCA risk between users of antihypertensive therapies inducing hyperkalemia versus users of antihypertensive therapies with neutral effect (adjusted OR 1.13, 95%CI (0.89-1.43)). Conclusions: The risk of OHCA is significantly increased in patients who were current users of antihypertensive therapies inducing hypokalemia and antihypertensive therapies with unknown effect on serum potassium levels

Controlled DCD Liver Transplantation Is Not Associated With Increased Hyperfibrinolysis and Blood Loss After Graft Reperfusion

BACKGROUND: The specific effect of donation after circulatory death (DCD) liver grafts on fibrinolysis, blood loss, and transfusion requirements after graft reperfusion is not well known. The aim of this study was to determine whether transplantation of controlled DCD livers is associated with an elevated risk of hyper-fibrinolysis, increased blood loss and higher transfusion requirements upon graft reperfusion, compared to livers donated after brain death (DBD). METHODS: A retrospective single-center analysis of all adult recipients of a primary liver transplantation between 2000 and 2019 was performed (total cohort n= 628). Propensity score matching (PSM) was used to balance baseline characteristics for DCD and DBD liver recipients (PSM cohort n= 218). Intra- and postoperative hemostatic variables between DCD and DBD liver recipients were subsequently compared. Additionally, in vitro plasma analyses were performed to compare the intraoperative fibrinolytic state upon reperfusion. RESULTS: No significant differences in median (interquartile range) postreperfusion blood loss (1.2 L [0.5-2.2] vs 1.3 L (0.6-2.2); P= 0.62), RBC transfusion (2 units [0-4) vs 1.1 units [0-3], P= 0.21), or FFP transfusion requirements (0 units [0-2.2] vs 0 units (0-0.9); P= 0.11) were seen in DCD compared to DBD recipients, respectively. Furthermore, plasma fibrinolytic potential was similar in both groups. CONCLUSIONS: Transplantation of controlled DCD liver grafts does not result in higher intraoperative blood loss or more transfusion requirements, compared to DBD liver transplantation. In accordance to this, no evidence for increased hyper-fibrinolysis upon reperfusion in DCD compared to DBD liver grafts, was found

Routine Postoperative Antithrombotic Therapy in Pediatric Liver Transplantation:Impact on Bleeding and Thrombotic Complications

BACKGROUND:  Hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT) are serious causes of morbidity and mortality after pediatric liver transplantation. To reduce thrombotic complications, routine antithrombotic therapy consisting of 1 week heparin followed by 3 months acetylsalicylic acid, was implemented in our pediatric liver transplant program in 2003. This study aimed to evaluate incidences of bleeding and thrombotic complications since the implementation of routine antithrombotic therapy and to identify risk factors for these complications. METHODS:  This retrospective cohort study includes 200 consecutive pediatric primary liver transplantations performed between 2003 and 2016. Uni- and multivariate logistic regression analysis, Kaplan-Meier method, and Cox regression analysis were used to evaluate recipient outcome. RESULTS:  HAT occurred in 15 (7.5%), PVT in 4 (2.0%), and venous outflow tract thrombosis in 2 (1.0%) recipients. Intraoperative vascular interventions (odds ratio [OR] 14.45 [95% confidence interval [CI] 3.75-55.67]), low recipient age (OR 0.81 [0.69-0.95]), and donor age (OR 0.96 [0.93-0.99]) were associated with posttransplant thrombosis. Clinically relevant bleeding occurred in 37%. Risk factors were high recipient age (OR 1.08 [1.02-1.15]), high Child-Pugh scores (OR 1.14 [1.02-1.28]), and intraoperative blood loss in mL/kg (OR 1.003 [1.001-1.006]). Both posttransplant thrombotic (hazard ratio [HR] 3.38 [1.36-8.45]; p = 0.009) and bleeding complications (HR 2.50 [1.19-5.24]; p = 0.015) significantly increased mortality. CONCLUSION:  In 200 consecutive pediatric liver transplant recipients receiving routine postoperative antithrombotic therapy, we report low incidences of posttransplant vascular complications. Posttransplant antithrombotic therapy seems to be a valuable strategy in pediatric liver transplantation. Identified risk factors for bleeding and thrombotic complications might facilitate a more personalized approach in antithrombotic therapy

Opioid use is associated with increased out-of-hospital cardiac arrest risk among 40,000-cases across two countries

AIMS: Opioid use has substantially increased in the last decade and is associated with overdose mortality, but also with increased mortality from cardiovascular causes. This finding may partly reflect an association between opioids and out‐of‐hospital cardiac arrest (OHCA). Therefore, we aimed to investigate OHCA‐risk of opioids in the community. METHODS: We conducted 2 population‐based case–control studies separately in the Netherlands (2009–2018) and Denmark (2001–2015). Cases were individuals who experienced OHCA of presumed cardiac cause. Each case was matched with up to 5 non‐OHCA‐controls according to age, sex and OHCA‐date. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We included 5473 OHCA‐cases matched with 21 866 non‐OHCA‐controls in the Netherlands, and 35 017 OHCA‐cases matched with 175 085 non‐OHCA‐controls in Denmark. We found that use of opioids (the Netherlands: cases: 5.4%, controls: 1.8%; Denmark: cases: 11.9%, controls: 4.4%) was associated with increased OHCA‐risk in both regions (the Netherlands: OR 2.1 [95% CI 1.8–2.5]; Denmark: OR 1.8 [95% CI 1.5–2.1]). The association was observed in both sexes, and in individuals with cardiovascular disease (the Netherlands: OR 1.8 [95% CI 1.5–2.1]; Denmark: OR 1.6 [95% CI 1.5–1.7]) or without (the Netherlands: OR 3.4 [95% CI: 2.4–4.8], P (interaction) < .0001; Denmark: OR 2.3 [95% CI: 2.0–2.5], P (interaction) < .0001). CONCLUSION: Use of opioids is associated with increased OHCA‐risk in both sexes, independently of concomitant cardiovascular disease. These findings should be considered when evaluating the harms and benefits of treatment with opioids

The Survival Paradox of Elderly Patients After Major Liver Resections

The objective of this study is to assess the outcome of liver resections in the elderly in a matched control analysis. From a prospective single center database of 628 patients, 132 patients were aged 60 years or over and underwent a primary major liver resection. Of these patients, 93 could be matched one-to-one with a control patient, aged less than 60 years, with the same diagnosis and the same type of liver resection. The mean age difference was 16.7 years. Patients over 60 years of age had a significantly higher American Society of Anaesthesiologists (ASA) grade. All other demographics and operative characteristics were not different. In-hospital mortality and morbidity were higher in the patients over 60 years of age (11% versus 2%, p=0.017 and 47% versus 31%, p=0.024). One-, 3-, and 5-year survival rates in the patients over 60 years of age were 81%, 58%, and 42%, respectively, compared to 90%, 59%, and 42% in the control patients (p=0.558). Unified model Cox regression analysis showed that resection margin status (hazard ratio 2.51) and ASA grade (hazard ratio 2.26), and not age, were determining factors for survival. This finding underlines the important fact that in patient selection for major liver resections, ASA grade is more important than patient age