Point-of-Care Testing in Liver Disease and Liver Surgery.

The alterations in coagulation and hemostasis that accompany liver disease are complex, and while patients with this disease have traditionally been perceived as having a bleeding diathesis, it is now understood that in stable patients hemostasis is "re-balanced." Hepatic surgery, and particularly liver transplantation, can be associated with large fluid shifts, massive bleeding, and coagulopathy, as well as postoperative thrombosis. Point-of-care tests (POCTs) of coagulation facilitate goal-directed treatments and hemostatic monitoring in dynamic environments where the coagulation status can alter rapidly and often unpredictably. POCTs reflect more accurately the re-balanced hemostatic system than do conventional coagulation tests (CCTs). Viscoelastic POCT-guided transfusion algorithms permit a reduction in blood product administration and are a key component of patient blood management programs. Moreover, viscoelastic POCTs are better able to identify patients with hypercoagulability than CCTs. With thrombosis increasingly recognized to be a problem in patients with liver disease, POCTs hold promise for both individualized bleeding and thrombosis management.

Clinical Utility of Viscoelastic Tests of Coagulation (TEG/ROTEM) in Patients with Liver Disease and during Liver Transplantation.

The concept that patients with stable liver disease are at an increased risk of bleeding, based solely on abnormalities of conventional coagulation tests such as prothrombin time (PT) and international normalized ratio (INR), is now recognized to be an overly simplistic interpretation of an extremely complex situation. These tests are in fact very poor predictors of bleeding in patients with liver disease who undergo invasive or surgical procedures. Commercially available whole blood viscoelastic tests (thromboelastography [TEG] and thromboelastometry [ROTEM]) evaluate the kinetics of coagulation from initial clot formation to final clot strength. These dynamic tests provide a composite picture reflecting the interaction of plasma, blood cells, and platelets, and more closely reflect the situation in vivo than do PT/INR, which are performed on plasma samples and measure isolated end points. Despite prolonged PT/INR and low platelet counts, viscoelastic tests are within normal range in many patients with both acute and chronic liver disease, commensurate with the concept of rebalanced hemostasis, and in keeping with the fact that an increasing number of these patients undergo liver transplantation without the need for blood or blood products. In addition, these tests reveal important additional information, such as the presence of hypercoagulability and a prothrombotic state, and also information about the presence of endogenous heparinoids associated with vascular endothelial damage, due to sepsis or acute inflammation. This review provides an overview of the current literature on the potential clinical utility of viscoelastic tests of coagulation in patients with liver disease.

No increase in blood transfusions during liver transplantation since the withdrawal of aprotinin.

The aims of this study were to determine whether the withdrawal of aprotinin (APRO) led to an increased bleeding risk in patients undergoing orthotopic liver transplantation (OLT). A retrospective analysis compared consecutive patients undergoing OLT and treated with aprotinin (APRO group; n = 100) with a group in which aprotinin was not used (no-APRO group; n = 100). Propensity score matching was then performed for each group to identify 2 matched cohorts. Patients were matched by their primary diagnoses and Model for End-Stage Liver Disease scores. This resulted in 2 matched cohorts with 55 patients in each group. None of the patients in the APRO group had significant fibrinolysis. In the no-APRO group, 23.6% of the patients developed fibrinolysis (P < 0.003). Tranexamic acid was used in 61.5% of the patients (n = 8) in the no-APRO group in whom lysis was present, and this resolved the fibrinolysis in all but 1 of these patients. There were no differences in red blood cell, fresh frozen plasma, platelet concentrate, or cryoprecipitate transfusions between the 2 groups. In conclusion, we have shown a significant increase in the prevalence of fibrinolysis during OLT since the withdrawal of APRO. However, there has been no increase in transfusion requirements.

A prospective cohort study of intrathecal versus epidural analgesia for patients undergoing hepatic resection.

BACKGROUND: The aim of this prospective observational study was to compare peri/post-operative outcomes of thoracic epidural analgesia (TEA) versus intrathecal morphine and fentanyl patient-controlled analgesia (ITM+fPCA) for patients undergoing a hepatic resection (HR). METHOD: Patients undergoing elective, one-stage, open HR for benign and malignant liver lesions, receiving central neuraxial block as part of the anaesthetic, in a high-volume hepato-pancreato-biliary unit, were included in the study. The primary outcome measure was post-operative length of stay (LoS). RESULTS: A total of 73 patients (36 TEA and 37 ITM+fPCA) were included in the study. The median (IQR) post-operative LoS was 13 (11-15) and 11 (9-13) days in the TEA and ITM+fPCA groups, respectively (P = 0.011). There was significantly lower median intra-operative central venous pressure (P < 0.001) and blood loss (P = 0.017) in the TEA group, and a significant reduction in the time until mobilization (P < 0.001), post-operative intra-venous fluid/vasopressor requirement (P < 0.001/P = 0.004) in the ITM+fPCA group. Pain scores were lower at a clinically significant level 12 h post-operatively in the TEA group (P < 0.001); otherwise there were no differences out to day five. There were no differences in quality of recovery or postoperative morbidity/mortality between the two groups. CONCLUSION: ITM+fPCA provides acceptable post-operative outcomes for HR, but may also increase the incidence of intra-operative blood loss in comparison to TEA.

Clinical utility of viscoelastic tests of coagulation in patients with liver disease.

The prothrombin time (PT) and international normalised ratio (INR) are used in scoring systems (Child-Pugh, MELD, UKELD) in chronic liver disease and as a prognostic tool and for dynamic monitoring of hepatic function in acute liver disease. These tests are known to be poor predictors of bleeding risk in liver disease; however, they continue to influence clinical management decisions. Recent work on coagulation in liver disease, in particular thrombin generation studies, has led to a paradigm shift in our understanding and it is now recognised that haemostasis is relatively well preserved. Whole blood global viscoelastic tests (TEG(®) /ROTEM(®) ) produce a composite dynamic picture of the entire coagulation process and have the potential to provide more clinically relevant information in patients with liver disease. We performed a systematic review of all relevant studies that have used viscoelastic tests (VET) of coagulation in patients with liver disease. Although many studies are observational and small in size, it is clear that VET provide additional information that is in keeping with the new concepts of how coagulation is altered in these patients. This review provides the basis for large scale, prospective outcome studies to establish the clinical value of these tests.

Aprotinin and the risk of thrombotic complications after liver transplantation: a retrospective analysis of 1492 patients.

Aprotinin is an antifibrinolytic drug that reduces blood loss during orthotopic liver transplantation (OLT). Case reports have suggested that aprotinin may be associated with an increased risk of thromboembolic complications. Recent studies in cardiac surgery also have suggested a higher risk of renal failure and postoperative mortality. Despite these concerns, no large-scale safety assessment has been performed in OLT. In a retrospective observational study involving 1492 liver transplants, we studied the occurrence of postoperative thromboembolic or thrombotic events and mortality in patients who received aprotinin (n = 907) and patients who did not (n = 585). The overall incidence of hepatic artery thrombosis and central venous complications (pulmonary embolism or inferior vena cava thrombosis) was 3.2% and 0.9%, respectively. In propensity score-adjusted analyses (C-index = 0.79), aprotinin was not associated with an increased risk of hepatic artery thrombosis [odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.50-2.01, P = 0.86]. Although central venous complications were found more frequently in patients receiving aprotinin, the difference was not statistically significant (OR = 2.95, 95% CI = 0.54-16.23, P = 0.32). In addition, no significant differences were found in 1-year mortality (OR = 1.21, 95% CI = 0.86-1.71, P = 0.32). In conclusion, this study did not demonstrate an increased risk of thrombotic complications or mortality when aprotinin is used during OLT.

The prevalence of a heparin-like effect shown on the thromboelastograph in patients undergoing liver transplantation.

It has been known for several decades that thromboelastographic analysis of the blood of patients undergoing liver transplantation may show a heparin-like effect (HLE) at the time of reperfusion. However, the prevalence of HLE and the origin of these heparin-like substances remain largely unstudied. The primary aim of this retrospective observational analysis was to determine the prevalence of the HLE in 211 consecutive patients having liver transplantation in our institution at various stages throughout the transplant. One of the secondary aims was to analyze the prevalence of HLE with respect to the various etiologies of liver disease. Paired Thromboelastograph traces (native and heparinase) were examined at 5 stages of the transplant: the baseline stage, dissection stage, anhepatic stage, reperfusion stage, and end of the case. HLE was defined as a reduction in the reaction and coagulation times of greater than 50% by the addition of heparinase to the sample. Thirty-one percent of patients had evidence of an HLE at baseline, and this increased to 75% after reperfusion of the donor graft. This HLE resolved spontaneously in 47% by the end of the case. Patients with fulminant liver failure were more likely to demonstrate HLE at baseline than those with chronic liver disease (45.8% compared to 29%). There was no difference in the prevalence of HLE after reperfusion. In conclusion, prior to transplantation, there is a significant difference in the prevalence of HLE with respect to etiology. However, this difference disappears after reperfusion as the majority of patients then develop HLE. Although it is clear that there are both endogenous and exogenous sources of heparin contributing to the HLE, the clinical significance of these findings remains unclear.

Thromboelastography-guided recombinant factor VIIa administration in a patient with refractory autoimmune idiopathic thrombocytopenia.

Autoimmune idiopathic thrombocytopenia poses a significant challenge for clinicians in the perioperative period. Repeat platelet transfusions may not result in satisfactory increments in the platelet count and routine coagulation screens may not reflect the degree of abnormal hemostasis. We report the use of point-of-care testing with thromboelastography and platelet counting in managing a patient with refractory autoimmune idiopathic thrombocytopenia, undergoing a splenectomy for active bleeding. These tests were successfully used to monitor the frequency of administration of recombinant factor VIIa (NovoSeven(R), NovoNordisk, Copenhagen, Denmark) with platelet transfusions.

Rational approach to transfusion in liver transplantation.

For over 50 years patients with liver cirrhosis were considered to be at markedly increased risk of bleeding. This dogma was seemingly supported by abnormalities in standard laboratory tests (SLTs), such as the prothrombin time, that were interpreted as indicating a bleeding diathesis. However, publications from the last decade have revealed SLTs to be poor predictors of bleeding and it is now understood that stable patients with cirrhosis have a rebalanced haemostatic system and preserved thrombin generation. Viscoelastic tests (VETs), such as ROTEM® or TEG™ allow dynamic assessment of the entire coagulation process and provide a better illustration of the interactions between pro- and anticoagulants as well as platelets. Despite their documented success in reducing transfusion rates in liver transplantation more than 30 years ago, the adoption of VETs has been met with some resistance and has only recently gained significant momentum. Bleeding risk should be assessed in every patient undergoing invasive intervention and must consider markers of disease severity, underlying coagulation incompetence, anaemia and surgical factors. The recognition that bleeding in this patient cohort is predominantly linked to mechanistic factors such as portal hypertension, rather than primary coagulopathy, has led to a paradigm shift in their perioperative management. Cognizant of their detrimental effect, the use of large volumes of fresh frozen plasma to correct derangements in SLTs has given way to more refined haemostatic management with specific factor concentrates guided by VETs, coupled with measures to minimize portal venous pressure and meticulous surgical hemostasis.

Thrombocytopenia in cirrhosis: Impact of fibrinogen on bleeding risk.

AIM: To investigate the relationship between baseline platelet count, clauss fibrinogen, maximum amplitude (MA) on thromboelastography, and blood loss in orthotopic liver transplantation (OLT). METHODS: A retrospective analysis of our OLT Database (2006-2015) was performed. Baseline haematological indices and intraoperative blood transfusion requirements, as a combination of cell salvage return and estimation of 300 mls/unit of allogenic blood, was noted as a surrogate for intraoperative bleeding. Two groups: Excessive transfusion (> 1200 mL returned) and No excessive transfusion (< 1200 mL returned) were analysed. All data analyses were conducted using IBM SPSS Statistics version 23. RESULTS: Of 322 OLT patients, 77 were excluded due to fulminant disease; redo transplant or baseline haemoglobin (Hb) of < 80 g/L. One hundred and fourteen (46.3%) were classified into the excessive transfusion group, 132 (53.7%) in the no excessive transfusion group. Mean age and gender distribution were similar in both groups. Baseline Hb (P ≤ 0.001), platelet count (P = 0.005), clauss fibrinogen (P = 0.004) and heparinase MA (P = 0.001) were all statistically significantly different. Univariate logistic regression with a cut-off of platelets < 50 × 109/L as the predictor and Haemorrhage as the outcome showed an odds ratio of 1.393 (95%CI: 0.758-2.563; P = 0.286). Review of receiver operating characteristic curves showed an area under the curve (AUC) for platelet count of 0.604 (95%CI: 0.534-0.675; P = 0.005) as compared with AUC for fibrinogen level, 0.678 (95%CI: 0.612-0.744; P ≤ 0.001). A multivariate logistic regression shows United Kingdom model for End Stage Liver Disease (P = 0.006), Hb (P = 0.022) and Fibrinogen (P = 0.026) to be statistically significant, whereas Platelet count was not statistically significant. CONCLUSION: Platelet count alone does not predict excessive transfusion. Additional investigations, e.g., clauss fibrinogen and viscoelastic tests, provide more robust assessment of bleeding-risk in thrombocytopenia and cirrhosis.

Early acute kidney injury after liver transplantation: Predisposing factors and clinical implications.

AIM: To investigate the additional clinical impact of hepatic ischaemia reperfusion injury (HIRI) on patients sustaining acute kidney injury (AKI) following liver transplantation. METHODS: This was a single-centre retrospective study of consecutive adult patients undergoing orthotopic liver transplantation (OLT) between January 2013 and June 2014. Early AKI was identified by measuring serum creatinine at 24 h post OLT (> 1.5 × baseline) or by the use of continuous veno-venous haemofiltration (CVVHF) during the early post-operative period. Patients with and without AKI were compared to identify risk factors associated with this complication. Peak serum aspartate aminotransferase (AST) within 24 h post-OLT was used as a surrogate marker for HIRI and severity was classified as minor (< 1000 IU/L), moderate (1000-5000 IU/L) or severe (> 5000 IU/L). The impact on time to extubation, intensive care length of stay, incidence of chronic renal failure and 90-d mortality were examined firstly for each of the two complications (AKI and HIRI) alone and then as a combined outcome. RESULTS: Out of the 116 patients included in the study, 50% developed AKI, 24% required CVVHF and 70% sustained moderate or severe HIRI. Median peak AST levels were 1248 IU/L and 2059 IU/L in the No AKI and AKI groups respectively (P = 0.0003). Furthermore, peak serum AST was the only consistent predictor of AKI on multivariate analysis P = 0.02. AKI and HIRI were individually associated with a longer time to extubation, increased length of intensive care unit stay and reduced survival. However, the patients who sustained both AKI and moderate or severe HIRI had a longer median time to extubation (P < 0.001) and intensive care length of stay (P = 0.001) than those with either complication alone. Ninety-day survival in the group sustaining both AKI and moderate or severe HIRI was 89%, compared to 100% in the groups with either or neither complication (P = 0.049). CONCLUSION: HIRI has an important role in the development of AKI post-OLT and has a negative impact on patient outcomes, especially when occurring alongside AKI.

Reducing transfusion requirements in liver transplantation.

Liver transplantation (LT) was historically associated with massive blood loss and transfusion. Over the past two decades transfusion requirements have reduced dramatically and increasingly transfusion-free transplantation is a reality. Both bleeding and transfusion are associated with adverse outcomes in LT. Minimising bleeding and reducing unnecessary transfusions are therefore key goals in the perioperative period. As the understanding of the causes of bleeding has evolved so too have techniques to minimize or reduce the impact of blood loss. Surgical "piggyback" techniques, anaesthetic low central venous pressure and haemodilution strategies and the use of autologous cell salvage, point of care monitoring and targeted correction of coagulopathy, particularly through use of factor concentrates, have all contributed to declining reliance on allogenic blood products. Pre-emptive management of preoperative anaemia and adoption of more restrictive transfusion thresholds is increasingly common as patient blood management (PBM) gains momentum. Despite progress, increasing use of marginal grafts and transplantation of sicker recipients will continue to present new challenges in bleeding and transfusion management. Variation in practice across different centres and within the literature demonstrates the current lack of clear transfusion guidance. In this article we summarise the causes and predictors of bleeding and present the evidence for a variety of PBM strategies in LT.

Cirrhotic cardiomyopathy: Implications for the perioperative management of liver transplant patients.

Cirrhotic cardiomyopathy is a disease that has only recently been recognised as a definitive clinical entity. In the setting of liver cirrhosis, it is characterized by a blunted inotropic and chronotropic response to stress, impaired diastolic relaxation of the myocardium and prolongation of the QT interval in the absence of other known cardiac disease. A key pathological feature is the persistent over-activation of the sympathetic nervous system in cirrhosis, which leads to down-regulation and dysfunction of the ß-adrenergic receptor. Diagnosis can be made using a combination of echocardiography (resting and stress), tissue Doppler imaging, cardiac magnetic resonance imaging, 12-lead electrocardiogram and measurement of biomarkers. There are significant implications of cirrhotic cardiomyopathy in a number of clinical situations in which there is an increased physiological demand, which can lead to acute cardiac decompensation and heart failure. Prior to transplantation there is an increased risk of hepatorenal syndrome, cardiac failure following transjugular intrahepatic portosystemic shunt insertion and increased risk of arrhythmias during acute gastrointestinal bleeding. Liver transplantation presents the greatest physiological challenge with a further risk of acute cardiac decompensation. Peri-operative management should involve appropriate choice of graft and minimization of large fluctuations in preload and afterload. The avoidance of cardiac failure during this period has important prognostic implications, as there is evidence to suggest a long-term resolution of the abnormalities in cirrhotic cardiomyopathy.

Individualised oxygen delivery targeted haemodynamic therapy in high-risk surgical patients: a multicentre, randomised, double-blind, controlled, mechanistic trial.

BACKGROUND: Morbidity after major surgery is associated with low oxygen delivery. Haemodynamic therapy aimed at increasing oxygen delivery in an effort to reduce oxygen debt, tissue injury, and morbidity, is controversial. The most appropriate target for this strategy is unclear and might have several off-target effects, including loss of neural (parasympathetic)-mediated cellular protection. We hypothesised that individualised oxygen delivery targeted haemodynamic therapy (goal-directed therapy) in high-risk surgical patients would reduce postoperative morbidity, while secondarily addressing whether goal-directed therapy affected parasympathetic function. METHODS: In this multicentre, randomised, double-blind, controlled trial, adult patients undergoing major elective surgery were allocated by computer-generated randomisation to a postoperative protocol (fluid, with and without dobutamine) targeted to achieve their individual preoperative oxygen delivery value (goal-directed therapy) or standardised care (control). Patients and staff were masked to the intervention. The primary outcome was absolute risk reduction (ARR) in morbidity (defined by Clavien-Dindo grade II or more) on postoperative day 2. We also assessed a secondary outcome focused on parasympathetic function, using time-domain heart rate variability measures. Analyses were done on an intention-to-treat basis. The trial was registered with Controlled Clinical Trials (number ISRCTN76894700). FINDINGS: We enrolled 204 patients between May 20, 2010, and Feb 12, 2014. Intention-to-treat analysis of the 187 (92%) patients who completed the trial intervention period showed that early morbidity was similar between goal-directed therapy (44 [46%] of 95 patients) and control groups (49 [53%] of 92 patients) (ARR -7%, 95% CI -22 to 7; p=0·30). Prespecified secondary analysis showed that 123 (66%) of 187 patients achieved preoperative oxygen delivery (irrespective of intervention). These patients sustained less morbidity (ARR 19%, 95% CI 3-34; p=0·016), including less infectious complications. Goal-directed therapy reduced parasympathetic activity postoperatively (relative risk 1·33, 95% CI 1·01-1·74). INTERPRETATION: Achievement of preoperative oxygen delivery values in the postoperative phase was associated with less morbidity, but this was not affected by the use of an oxygen delivery targeted strategy. Reduced parasympathetic activity after goal-directed therapy was associated with the failure of this intervention to reduce postoperative morbidity. FUNDING: Academy of Medical Sciences and Health Foundation Clinician Scientist Award.

Transfusion and coagulation management in liver transplantation.

There is wide variation in the management of coagulation and blood transfusion practice in liver transplantation. The use of blood products intraoperatively is declining and transfusion free transplantations take place ever more frequently. Allogenic blood products have been shown to increase morbidity and mortality. Primary haemostasis, coagulation and fibrinolysis are altered by liver disease. This, combined with intraoperative disturbances of coagulation, increases the risk of bleeding. Meanwhile, the rebalancing of coagulation homeostasis can put patients at risk of hypercoagulability and thrombosis. The application of the principles of patient blood management to transplantation can reduce the risk of transfusion. This includes: preoperative recognition and treatment of anaemia, reduction of perioperative blood loss and the use of restrictive haemoglobin based transfusion triggers. The use of point of care coagulation monitoring using whole blood viscoelastic testing provides a picture of the complete coagulation process by which to guide and direct coagulation management. Pharmacological methods to reduce blood loss include the use of anti-fibrinolytic drugs to reduce fibrinolysis, and rarely, the use of recombinant factor VIIa. Factor concentrates are increasingly used; fibrinogen concentrates to improve clot strength and stability, and prothrombin complex concentrates to improve thrombin generation. Non-pharmacological methods to reduce blood loss include surgical utilisation of the piggyback technique and maintenance of a low central venous pressure. The use of intraoperative cell salvage and normovolaemic haemodilution reduces allogenic blood transfusion. Further research into methods of decreasing blood loss and alternatives to blood transfusion remains necessary to continue to improve outcomes after transplantation.

Correction of ionized plasma magnesium during cardiopulmonary bypass reduces the risk of postoperative cardiac arrhythmia.

UNLABELLED: We conducted this randomized controlled trial to determine whether the intraoperative measurement and correction of ionized plasma magnesium can reduce the risk of cardiac arrhythmia after cardiopulmonary bypass. Eighty-five patients presenting for coronary artery bypass grafting were randomly assigned either to the magnesium-corrected group, which received magnesium sulfate on the basis of measured levels of ionized plasma magnesium (n = 43), or to the control group, in which magnesium levels were identified but not corrected (n = 42). Ionized magnesium was determined with an ion-selective electrode with minimal delay, and further samples were taken for laboratory analysis of total plasma magnesium. All patients had Holter electrocardiogram monitoring for 72 h after surgery. Total hypomagnesemia (45 patients; 53% of all patients) was more common than ionized hypomagnesemia (11 patients; 13%) before cardiopulmonary bypass. Both total and ionized magnesium levels declined further during the course of cardiopulmonary bypass in the control group. The incidence of ventricular tachycardia in the first 24 h was less frequent in the magnesium-corrected group (3 patients; 7%) than the control group (12 patients, 30%; P < 0.01). Patients in the magnesium-corrected group were more likely to display continuous sinus rhythm (Lown Grade 0) in the first 24 h (14 patients; 34%) than patients in the control group (2 patients, 5%; P < 0.001). Our results suggest that the intraoperative correction of ionized magnesium is associated with a reduction in postoperative ventricular arrhythmia in cardiac surgical patients. IMPLICATIONS: In this study the correction of ionized plasma magnesium during cardiopulmonary bypass was guided by measurements from an ion-selective electrode. This intervention resulted in a reduction in the incidence of postoperative ventricular tachycardia and an increased frequency of continuous sinus rhythm. Ion-selective electrodes constitute a convenient near-patient test, providing a basis for the targeted replacement of ionized plasma magnesium.