Rotational ThromboElastometry-guided blood component administration versus standard of care in patients with Cirrhosis and coagulopathy undergoing Invasive ProcEdures (RECIPE): study protocol for a randomised controlled trial.

BACKGROUND: Patients with cirrhosis often undergo invasive procedures both for management of complications of their advanced liver disease, including treatment for hepatocellular carcinoma, as well as underlying comorbidities. Despite a current understanding that most patients with cirrhosis are in a rebalanced haemostatic state (despite abnormalities in conventional coagulation tests, namely INR and platelet count), patients with cirrhosis are still often given prophylactic blood components based on these conventional parameters, in an effort to reduce procedure-related bleeding. Viscoelastic tests such as Rotational Thromboelastometry (ROTEM) provide a global measurement of haemostasis and have been shown to predict bleeding risk more accurately than conventional coagulation tests, and better guide blood product transfusion in a number of surgical and trauma-related settings. The aim of this study is to assess the utility of a ROTEM-based algorithm to guide prophylactic blood component delivery in patients with cirrhosis undergoing invasive procedures. We hypothesise that ROTEM-based decision-making will lead to a reduction in pre-procedural blood component usage, particularly fresh frozen plasma (FFP), compared with standard of care, whilst maintaining optimal clinical outcomes. METHODS: This is a multi-centre randomised controlled trial comparing ROTEM-guided prophylactic blood component administration to standard of care in patients with cirrhosis and coagulopathy undergoing invasive procedures. The primary efficacy outcome of the trial is the proportion of procedures requiring prophylactic transfusion, with the primary safety outcome being procedure-related bleeding complications. Secondary outcomes include the amount of blood products (FFP, platelets, cryoprecipitate) transfused, transfusion-related side effects, procedure-related complications other than bleeding, hospital length of stay and survival. DISCUSSION: We anticipate that this project will lead to improved prognostication of patients with cirrhosis, in terms of their peri-procedural bleeding risk. We hope to show that a significant proportion of cirrhotic patients, deemed coagulopathic on the basis of standard coagulation tests such as INR and platelet count, are actually in a haemostatic balance and thus do not require prophylactic blood product, leading to decreased and more efficient blood component use. TRIAL REGISTRATION: RECIPE has been prospectively registered with the Australia and New Zealand Clinical Trials Registry on the 30th April 2019 ( ACTRN12619000644167 ).

Wide variation in pre-procedural blood product transfusion practices in cirrhosis: a national multidisciplinary survey.

BACKGROUND AND AIMS: Recent guidelines recognize the limitations of standard coagulation tests in predicting bleeding and guiding pre-procedural blood component prophylaxis in cirrhosis. It is unclear whether these recommendations are reflected in clinical practice. We performed a nationwide survey to investigate pre-procedural transfusion practices and opinions of key health care stakeholders involved in managing cirrhosis. METHODS: We designed a 36-item multiple-choice questionnaire to investigate the international normalized ratio and platelet cutoffs utilized to guide pre-procedural transfusion of fresh frozen plasma and platelets in patients with cirrhosis undergoing a range of low and high-risk invasive procedures. Eighty medical colleagues from all mainland States involved in managing patients with cirrhosis were invited by email to participate. RESULTS: Overall, 48 specialists across Australia completed the questionnaire: 21 gastroenterologists, 22 radiologists, and 5 hepatobiliary surgeons. 50% of respondents reported that their main workplace did not have written guidelines relating to pre-procedural blood component prophylaxis in patients with cirrhosis. There was marked variation in routine prophylactic transfusion practices across institutions for the different procedures and international normalized ratio and platelet cutoffs. This variation was present both within and between specialty groups and held for both low and high-risk procedures. For scenarios where the platelet count was ≤ 50 × 109/L, 61% of respondents stated that prophylactic platelet transfusions would be given before low-risk and 62% before high-risk procedures at their center. For scenarios where the international normalized ratio was ≥2, 46% of respondents stated that prophylactic fresh frozen plasma would be routinely given before low-risk procedures and 74% before high-risk procedures. CONCLUSION: Our survey reveals significant heterogeneity of pre-procedural prophylactic transfusion practices in patients with cirrhosis and discrepancies between guidelines and clinical practice.

Procedural bleeding risk, rather than conventional coagulation tests, predicts procedure related bleeding in cirrhosis.

BACKGROUND: Standard coagulation parameters are used to guide prophylactic blood product transfusion prior to invasive procedures in cirrhotic patients despite limited high-quality evidence. AIMS: We aimed to describe coagulation parameters and prophylactic blood product use in cirrhotic patients having invasive procedures, and the influence of both on periprocedural bleeding. METHODS: We conducted a cohort study of cirrhotic patients undergoing invasive procedures at a referral hospital. Procedures were classified into low or moderate-high bleeding risk. Prophylactic blood component was defined as fresh frozen plasma, cryoprecipitate or platelet transfusion prior to procedures. Univariate and multivariate logistic regression was performed to identify factors associated with procedure-related bleeding. RESULTS: We identified 566 procedures in 233 cirrhotic patients. Prophylactic blood product was given before 16% of high-risk and 11% of low-risk procedures (P = 0.18). Eight (8.3%) high-risk procedures were complicated by postprocedural bleeding, six of which occurred in patients without significant coagulopathy. The bleeding rate for low-risk procedures was 0.4%. For patients with international normalized ratio >1.5, platelet count <50 x 109/L, or both, the rate of bleeding was comparable between those given and not given prophylactic blood products (3.1 vs. 1.9%; P = 0.63). After adjusting for age, sex, platelet count, international normalized ratio, acute kidney injury, sepsis and model of end-stage liver disease, the only factor significantly predicting procedure-related bleeding was the procedural bleeding risk category (P < 0.01). CONCLUSIONS: Procedure-related bleeding in cirrhotic patients cannot be accurately predicted by INR or platelet count, nor prevented by blood component prophylaxis using these parameters. Procedure-related bleeding is best predicted by the bleeding risk status of procedures.

Viscoelastic Tests as Point-of-Care Tests in the Assessment and Management of Bleeding and Thrombosis in Liver Disease.

Viscoelastic point-of-care (VET POC) tests provide a global assessment of hemostasis and have an increasing role in the management of bleeding and blood component delivery across several clinical settings. VET POC tests have a rapid turnaround time, provide a better overall picture of hemostasis, predict bleeding more accurately than conventional coagulation tests, and reduce blood component usage and health care costs. Despite commonly having abnormal conventional coagulation tests, most patients with chronic liver disease have a "rebalanced" hemostasis. However, this hemostatic balance is delicate and these patients are predisposed to both bleeding and thromboembolic events. Over recent years, VET POC tests have been increasingly studied for their potential as better functional tests of hemostasis in liver disease patients. This review provides a background on the most common VET POC tests (thromboelastography and rotational thromboelastometry) and discusses the current evidence for these tests in the prediction and management of bleeding and thrombosis in patients with chronic liver disease, and in liver resection and transplant. With the recent publication of several randomized controlled trials, there is growing evidence that VET POC tests may be used to improve bleeding risk assessment and reduce blood product use in liver disease patients outside of the transplant setting. However, consensus is still lacking regarding the VET POC tests' thresholds that should be used to trigger blood product transfusion. VET POC tests also show promise in predicting thrombosis in patients with liver disease, but further research is needed before they can be used to guide anticoagulant therapy.

Efficacy and Safety of Mycophenolate Mofetil in Patients With Autoimmune Hepatitis and Suboptimal Outcomes After Standard Therapy.

BACKGROUND & AIMS: Little is known about outcomes of patients with autoimmune hepatitis (AIH) who have a suboptimal outcome to standard therapy and are then given mycophenolate mofetil as rescue therapy. We evaluated the efficacy and safety of mycophenolate mofetil in patients failed by or intolerant to corticosteroids, with or without azathioprine. METHODS: We performed a retrospective study of 105 patients with AIH who received mycophenolate mofetil therapy after an inadequate response or intolerance to standard therapy (98% received combination therapy with corticosteroids plus thiopurines). Patients were recruited from 17 liver clinics via the Australian Liver Association Clinical Research Network. We reviewed records for baseline demographic features and characteristics of liver disease, initial therapy, mycophenolate mofetil indications, treatment outcome, and side effects. The primary outcome was biochemical remission, defined as levels of alanine and aspartate transferase and IgG level within the normal reference range, with or without normal liver histology within the first 2 years of treatment. RESULTS: The indication for mycophenolate mofetil therapy was non-response to treatment for 40% of cases and intolerance to therapy for 60%. Overall, 63 patients (60%) achieved biochemical remission following a median 12 weeks treatment with mycophenolate mofetil. The proportion of patients who achieved biochemical remission was similar between patients receiving mycophenolate mofetil for non-response to standard therapy (57%) and patients with intolerance to standard therapy (62%). However, a lower proportion of patients with cirrhosis achieved biochemical remission (47%) than patients without cirrhosis (6%) (P = .07). Serious adverse events occurred in 3 patients (2.7%) including 1 death, and 10 patients (9.2%) discontinued mycophenolate mofetil because of adverse events. CONCLUSION: In this retrospective study of patients with AIH who received mycophenolate mofetil as a rescue therapy, we found the drug to be well tolerated and moderately effective, inducing biochemical remission in 60% of subjects. Rates of response are lower and rates of infection are higher in patients with AIH and cirrhosis. Prospective studies of mycophenolate mofetil are warranted for this population.

Enhancement of visual selection during transient disruption of parietal cortex.

Selective attention is critical for guiding human behavior. Recent theories have described the process of attention as a biased competition between sensory inputs, but questions remain concerning the anatomical basis of these competitive mechanisms. Using transcranial magnetic stimulation, we found that disruption of the right parietal cortex improved the perception of relevant stimuli in competitive visual displays. This enhancement of selective attention is consistent with previous observations and suggests a crucial role of the superior parietal lobule and supramarginal gyrus in mediating competition between visual inputs.

Simple metric for scaling motor threshold based on scalp-cortex distance: application to studies using transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a unique method in neuroscience used to stimulate focal regions of the human brain. As TMS gains popularity in experimental and clinical domains, techniques for controlling the extent of brain stimulation are becoming increasingly important. At present, TMS intensity is typically calibrated to the excitability of the human motor cortex, a measure referred to as motor threshold (MT). Although TMS is commonly applied to nonmotor regions, most applications do not consider the effect of changes in distance between the stimulating device and underlying neural tissue. Here we show that for every millimeter from the stimulating coil, an additional 3% of TMS output is required to induce an equivalent level of brain stimulation at the motor cortex. This abrupt spatial gradient will have crucial consequences when TMS is applied to nonmotor regions because of substantial variance in scalp-cortex distances over different regions of the head. Stimulation protocols that do not account for cortical distance therefore risk substantial under- or overstimulation. We describe a simple method for adjusting MT to account for variations in cortical distance, thus providing a more accurate calibration than unadjusted MT for the safe and effective application of TMS in clinical and experimental neuroscience.