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Hepatopulmonary syndrome is a liver disease complication characterized by the clinical triad of an advanced chronic liver disease, a pulmonary vascular dilatation, and a reduced arterial oxygenation (hypoxemia: PaO2 less than 70 mm Hg at rest) in the absence of intrinsic cardiopulmonary disease. Precapillary vasodilatation, intrapulmonary angiogenesis and hyperdynamic circulation lead to arteriovenous shunting and reduced gas diffusion. In case of detecting macroscopic shunts, the pulmonary artery branch embolization could be performed. However, the hepatopulmonary syndrome can be cured nowadays by means of liver transplantation only. A 5-year survival in these patients is about 70%. The observed mortality is the highest during the surgery or early after, especially in patients with PaO2 lower than 50 mm Hg. It ranges from 8.5 to 29%. A prolonged oxygenation support is often required after liver transplantation using invasive or non-invasive ventilation, or even extracorporeal membrane oxygenation. In this review, we have focused on the recent advances in this field as described in available literature and have presented a case report of successful liver transplantation in a patient with a severe hepatopulmonary syndrome.

BACKGROUND/AIMS: Small intestinal bacterial overgrowth (SIBO) and hemodynamic changes are common in cirrhosis. We wanted to examine our hypothesis whether SIBO leads to hemodynamic changes in cirrhosis. MATERIALS AND METHODS: A total of 50 patients with cirrhosis and 15 healthy controls were enrolled in a pilot prospective study. All participants underwent the lactulose hydrogen breath test for SIBO and echocardiography with a simultaneous assessment of blood pressure and heart rate. Cardiac output and systemic vascular resistance were calculated. RESULTS: Study participants with SIBO had a lower systolic blood pressure and systemic vascular resistance compared to those without SIBO and to healthy controls (110.2±12.3 mmHg vs. 126.2±21.0 mmHg and 121.2±9.8 mmHg; p=0.005 and p=0.011, respectively; 1312±352 dyn·s·cm(−5) vs. 1704±424 dyn·s·cm(−5) and 1648±272 dyn·s·cm(−5); p=0.001 and p=0.006, respectively), but a higher cardiac output (5.38±1.41 l/min vs. 4.52±1.03 l/min and 4.40±0.68 l/min; p=0.034 and p=0.041, respectively) and C-reactive protein (10.5[1.2–16.5] mg/l vs. 2.8[0.6–9.1] mg/l; p=0.028; no comparison with healthy controls). There were no significant differences between patients without SIBO and healthy controls with regard to systolic blood pressure (p=0.554), systemic vascular resistance (p=0.874), and cardiac output (p=0.795). SIBO was associated with vasodilation and hyperdynamic circulation in decompensated cirrhosis (p=0.002; p=0.012), but not in compensated cirrhosis (p=1.000; p=0.474). CONCLUSIONS: SIBO is associated with hyperdynamic circulation and other hemodynamic changes in cirrhosis and may be a principal factor causing these through systemic inflammation.

Sepsis is a highly complex and often fatal syndrome which varies widely in its clinical manifestations, and therapies that target the underlying uncontrolled immune status in sepsis are needed. The failure of preclinical approaches to provide significant sepsis survival benefit in the clinic is often attributed to inappropriate animal disease models. It has been demonstrated that high mobility group box protein 1 (HMGB1) blockade can reduce inflammation, mortality and morbidity in experimental sepsis without promoting immunosuppression. Within this study, we explored the use of ovine anti-HMGB1 antibodies in a model of ovine septic shock incorporating intensive care supports (OSSICS). Results: Septic sheep exhibited elevated levels of HMGB1 within 12 h after the induction of sepsis. In this study, sepsis was induced in six anaesthetized adult Border Leicester × Merino ewes via intravenous instillation of E. coli and sheep monitored according to intensive care unit standard protocols for 26 h, with the requirement for noradrenaline as the primary endpoint. Septic sheep exhibited a hyperdynamic circulation, renal dysfunction, deranged coagulation profile and severe metabolic acidosis. Sheep were assigned a severity of illness score, which increased over time. While a therapeutic effect of intravenous anti-HMGB1 antibody could not be observed in this model due to limited animal numbers, a reduced bacterial dose induced a septic syndrome of much lower severity. With modifications including a reduced bacterial dose, a longer timeframe and broad spectrum antibiotics, the OSSICS model may become a robust tool for preclinical assessment of sepsis therapeutics.

Whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure in advanced cirrhosis is controversial. Herein, we aimed to evaluate the systemic and splanchnic hemodynamic effects of β-blockers in decompensated vs. compensated cirrhosis and to investigate the influence of systemic hemodynamic changes on survival times in decompensated cirrhosis.Patients with cirrhosis and high-risk esophageal varices, without previous bleeding, were consecutively included and grouped according to the presence or absence of decompensation (ascites with or without overt encephalopathy). Systemic and hepatic hemodynamic measurements were performed before starting β-blockers and again after 1 to 3 months of treatment (short-term).Four hundred and three patients were included (190 decompensated and 213 compensated). At baseline, decompensated patients had higher portal pressure than compensated patients and were more hyperdynamic, with higher cardiac output (CO) and lower arterial pressure. Under β-blockers, decompensated patients had lower portal pressure decrease (10 ± 18% vs. 15 ± 12%; p0.05) and had greater reductions in heart rate (p0.001) and CO (17 ± 15% vs. 10 ± 21%; p0.01). Among patients with decompensated cirrhosis, those who died had a greater decrease in CO with β-blockers than survivors (21 ± 14% vs. 15 ± 16%; p0.05) and CO under β-blockers independently predicted death by competing-risk regression analysis, with good diagnostic accuracy (C-index 0.74; 95% CI 0.66-0.83). Death risk was higher in decompensated patients with CO5 L/min vs. CO ≥5 L/min (subdistribution hazard ratio 0.44; 95% CI 0.25-0.77; p = 0.004).In patients with high-risk varices treated to prevent first bleeding, the systemic hemodynamic response to β-blockers is greater and the portal pressure decrease is smaller in those with decompensated cirrhosis. The short-term effect of β-blockers on CO might adversely influence survival in decompensated cirrhosis.β-blockers are often used to reduce the risk of variceal bleeding in patients with cirrhosis. However, it is not known whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure. Herein, we show that in patients with decompensated cirrhosis the potentially detrimental systemic effects of β-blockers are greater than in compensated patients, while the beneficial pressure lowering effects are reduced. The short-term effect of β-blockers on cardiac output may adversely influence survival in patients with decompensated cirrhosis.

Acute-on-chronic liver disease is a clinical syndrome characterized by decompensated liver fibrosis, portal hypertension and splanchnic hyperdynamic circulation. We aimed to determine whether the alpha-1 agonist phenylephrine (Phe) facilitates endothelial nitric oxide (NO) release by mesenteric resistance arteries (MRA) in rats subjected to an experimental microsurgical obstructive liver cholestasis model (LC). Sham-operated (SO) and LC rats were maintained for eight postoperative weeks. Phe-induced vasoconstriction (in the presence/absence of the NO synthase –NOS- inhibitor L-NAME) and vasodilator response to NO donor DEA-NO were analysed. Phe-induced NO release was determined in the presence/absence of either H89 (protein kinase –PK- A inhibitor) or LY 294002 (PI3K inhibitor). PKA and PKG activities, alpha-1 adrenoceptor, endothelial NOS (eNOS), PI3K, AKT and soluble guanylate cyclase (sGC) subunit expressions, as well as eNOS and AKT phosphorylation, were determined. The results show that LC blunted Phe-induced vasoconstriction, and enhanced DEA-NO-induced vasodilation. L-NAME increased the Phe-induced contraction largely in LC animals. The Phe-induced NO release was greater in MRA from LC animals. Both H89 and LY 294002 reduced NO release in LC. Alpha-1 adrenoceptor, eNOS, PI3K and AKT expressions were unchanged, but sGC subunit expression, eNOS and AKT phosphorylation and the activities of PKA and PKG were higher in MRA from LC animals. In summary, these mechanisms may help maintaining splanchnic vasodilation and hypotension observed in decompensated LC., This study was supported by Ministerio de Economía y Competitividad (SAF2012-38530), CiberCV (CB16/11/00286 and CB16/11/00264), and Fondo Europeo de Desarrollo Regional (FEDER) a way to build Europe, Comunidad de Madrid (B2017/BMD-3676)

OBJECTIVE To report the perinatal outcome of singleton pregnancies complicated by placental chorioangioma diagnosed on prenatal ultrasound. METHODS MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched for studies reporting the outcome of pregnancies complicated by placental chorioangioma. Inclusion criteria were singleton pregnancy diagnosed with placental chorioangioma on prenatal ultrasound, with no other associated structural anomaly. The primary outcome was perinatal mortality. Secondary outcomes included associated non-structural anomalies detected on prenatal ultrasound (including fetal hydrops, anemia, polyhydramnios, signs of hyperdynamic circulation and small-for-gestational-age (SGA) fetus), SGA at birth, composite neonatal morbidity and preterm birth. Outcome was assessed separately in pregnancies undergoing and those not undergoing fetal therapy. Subanalyses were performed according to the presence of hydrops and the size of the tumor in all pregnancies diagnosed with chorioangioma. Random-effects meta-analyses of proportions were used to analyze the data. RESULTS Twenty-eight studies (161 pregnancies) were included. In pregnancies complicated by chorioangioma that did not undergo intervention, intrauterine death occurred in 8.2% (95% CI, 3.8-15.0%), while neonatal death and perinatal death occurred in 3.8% (95% CI, 1.0-8.1%) and 11.1% (95% CI, 5.0-19.4%), respectively. SGA at birth was present in 24.0% (95% CI, 13.5-36.5%) of cases, while preterm birth

It is widely known that liver cirrhosis, regardless of the etiologies is accompanied by severe hemodynamic changes. The principal pathophysiological mechanisms are the hyperdynamic circulation with increased cardiac output, heart rate along with reduced systemic vascular resistance. Thus, counteractive mechanisms may develop that eventually lead to systolic as well as diastolic dysfunction and rhythm disturbances, in order to keep a steady homeostasis in the human body. : Literally, blunted contractile responsiveness to physical or pharmacological stress, impaired diastolic relaxation and electrophysiological changes, primarily QT interval prolongation, do occur progressively in a cirrhotic patient with no known preexisting cardiac disease. This condition is identified as cirrhotic cardiomyopathy (CCM), an entity different from that seen in alcoholic cardiac muscle disease. : For the past decades, clinicians did study and attempt to understand the pathophysiology and clinical significance of this process. Indeed, various factors have been identified acting at the molecular and cellular level. : Electrocardiography, echocardiography and various serum biomarkers are the main tools that help healthcare practitioners to point to the correct diagnosis. : Noteworthy, the subjects that suffer from cirrhotic cardiomyopathy may progress to heart failure during invasive procedures such as surgery, insertion of a transjugular intrahepatic portosystemic shunting (TIPS) and liver transplantation. Besides, several studies have illustrated that CCM is a contributing factor, or even a precipitant, of hepatorenal syndrome (HRS), a conceivable reversible kidney failure in patients with liver cirrhosis and ascites. : The treatment is the same as it is in the patients with liver cirrhosis and heart failure and there is no particular treatment for cirrhotic cardiomyopathy. Hence, it is of utmost importance to clearly comprehend the pathophysiology of this disease in order to design more accurate diagnostic tools and definitive treatments in a way to prevent the complications of cirrhosis and overt heart failure. : The objective of this review is to describe in a comprehensive way the pathological alterations that occur in the cardiovascular system of cirrhotic patients. It will also point the limitations that remain in the diagnosis and treatment strategies and more importantly, this review will alert the clinicians in the modern era to further observe and record additional pathological changes in this subset of patients.

Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1&ndash, 7) (Ang-(1&ndash, 7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients&rsquo, clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1&ndash, 7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1&ndash, 7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1&ndash, 7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1&ndash, 7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.

Cirrhosis with portal hypertension and related complications are associated with a high mortality. Excess of circulating vasodilators and cardiodepressive substances lead to a hyperdynamic circulation with changed myocardial structure and function. The entity cirrhotic cardiomyopathy seems to be involved in different aspects of hepatic decompensation, which focuses on new targets of treatment. Areas covered: This review deals with contemporary aspects of cirrhotic cardiomyopathy, and the literature search was undertaken by PubMed with 'cirrhotic' and 'cardiomyopathies' as MeSH Terms. Cirrhotic cardiomyopathy is defined as the presence of systolic and diastolic dysfunction and electrophysiological abnormalities. The diagnosis is based on contemporary Doppler/Echocardiography measurements or quantitative magnetic resonance imaging. Cirrhotic cardiomyopathy is independent of the etiology of the liver disease but related to severity and survival. Expert commentary: The outcome of invasive procedures and liver transplantation is influenced by the presence of cardiac dysfunction. Therefore, a cautious cardiac evaluation should be included in the patient evaluation prior to liver transplantation. Liver transplantation ameliorates most of the abnormalities seen in cirrhotic cardiomyopathy, but no specific treatment can yet be recommended.

The liver is characterized by two inflow systems: a low-resistance–high-flow system through the portal vein (PV), which accounts for about 70–80% of hepatic blood flow, and a high-resistance–low-flow system with a high oxygen content, through the hepatic artery (HA), which carries about 20% of hepatic blood flow. In normal conditions, the PV drains the blood from the splanchnic territory with a low resistance; the gradient between the PV and the inferior vena cava (IVC) is less than 5 mm Hg, and the flow is 100 mL/min per 100 g of liver mass [1–3]. The hepatic parenchyma has no active role in regulating the hepatic inflow but is a passive recipient of variable amounts of blood flow from the splanchnic circulation. In cirrhotic patients, the augmented splanchnic volume increases portal pressure progressively because of the high intrahepatic resistance. Collateral circulation develops, diverting splanchnic blood to the systemic circulation. The initial systemic vasodilatation is followed by a decrease in central volume causing relative hypovolemia, which leads to sodium retention and plasma volume expansion, resulting in increased cardiac output [4]. A high cardiac output and decreased peripheral vascular resistance and arterial pressure are the features of this hyperdynamic circulation, which worsens the initial endothelial stress. The reduced portal flow, together with an imbalance of coagulation, may lead to the occurrence of portal vein thrombosis (PVT), which may compromise the outcome of orthotopic liver transplantation (OLT). The replacement of the cirrhotic liver with a normal liver relieves the mechanical component of portal hypertension, but the splanchnic circulation is not restored to normal parameters immediately [5]. Following graft reperfusion, portal vein flow (PVF) increases to almost twice that of healthy subjects because of the loss of normal vascular tone and the persistence of abnormal splanchnic hemodynamics [6]. A prospective study on hepatic hemodynamics with different type of liver grafts showed that the PVF is significantly increased following reperfusion, whereas the hepatic artery flow (HAF) is decreased compared with the native situation [7]. When partial grafts are used, the hemodynamic stress is significantly enhanced (Fig. 9.1). The intrahepatic hepatic arterial buffer response (HABR) operates to compensate for PVF changes: the increased PVF reduces the hepatic artery flow by means of the HABR. The PVF/HAF ratio increases after reperfusion; in more than half of patients, PVF accounts for 93% of the total liver flow [8–10]. The extreme increase in PVF observed after living donor liver transplantation (LDLT) and the HABR are responsible for the reduced HAF usually encountered in this setting [11]. The PVF in cirrhotic and transplanted livers is quite different, showing a low flow in cirrhotic recipients with portal hypertension and a relatively high post-reperfusion flow after implantation (Fig. 9.2). In the pioneering experience of Starzl et al. [12], the HA and PV were reconstructed after caval anastomosis, but the liver was reperfused first via the HA, contrary to the current practice of initial portal vein reperfusion. In the particular setting of donation after cardiac death (DCD), the HAF can be restored before the PVF in order to reduce the rate of ischemic biliary tract lesions [13, 14]. With the development of the cava-preserving technique, a temporary portocaval shunt (PCS) has been proposed in order to decrease the splanchnic congestion during the anhepatic phase (Fig. 9.3), thus avoiding the need for a veno-venous bypass [15]. This technique has led to a reduction in intraoperative blood loss and postoperative renal failure [16]. The PCS has also been proposed as a way to decrease the portal inflow in partial grafts, thus avoiding overperfusion in small-for-size grafts, which leads to specific problems such as prolonged cholestasis, ascites, and increased vascular thrombosis rates, potentially leading to graft loss [17–19].

Cirrhotic cardiomyopathy historically has been confused as alcoholic cardiomyopathy. The key points for diagnosis of cirrhotic cardiomyopathy have been well explained, however this entity was neglected for a long time. Nowadays the diagnosis of this entity has become important because it is a factor that contributes significantly to morbidity-mortality in cirrhotic patients. Characteristics of cirrhotic cardiomyopathy are a hyperdynamic circulatory state, altered diastolic relaxation, impaired contractility, and electrophysiological abnormalities, particularity QT interval prolongation. The pathogenesis includes impaired function of beta-receptors, altered transmembrane currents and overproduction of cardiodepressant factors, such as nitric oxide, cytokines and endogenous cannabinoids. In addition to physical signs of hyperdynamic state and heart failure under stress conditions, the diagnosis can be done with dosage of serum markers, electrocardiography, echocardiography and magnetic resonance. The treatment is mainly supportive, but orthotopic liver transplantation appears to improve this condition although the prognosis of liver transplantation in patients with cirrhotic cardiomyopathy is uncertain.

BACKGROUND Liver cirrhosis is a chronic hepatic disease which is associated with cardiovascular abnormalities. Hyperdynamic circulation in liver cirrhosis causes functional and structural cardiac alterations. The prevalence of left ventricle diastolic dysfunction (LVDD) in cirrhotic patients ranges from 25.7% to as high as 81.4% as reported in different studies. In several studies the severity of diastolic dysfunction (DD) correlated with a degree of liver failure and the rate of dysfunction was higher in patients with decompensated cirrhosis compared with compensated. Future directions of the comprehensive assessment of cardiac function in cirrhotic patients might provide a better prognosis for these patients. AIM To clarify the correlation between the severity of liver cirrhosis and left ventricle diastolic dysfunction in the existing literature. METHODS Through January and February of 2019 at Vilnius University we conducted a systematic review of the global existing literature on the prevalence of left ventricle diastolic dysfunction in patients with liver cirrhosis. We searched for articles in PubMed, Medline and Web of science databases. Articles were selected by using adequate inclusion and exclusion criteria. Our interest was the outcome of likely correlation between the severity of cirrhosis [evaluated by Child-Pugh classes, Model For End-Stage Liver Disease (MELD) scores] and left ventricle diastolic dysfunction [classified according to American Society of Echocardiography (ASE) guidelines (2009, 2016)], as well as relative risk of dysfunction in cirrhotic patients. Subgroup analyses were performed to evaluate the ratio and grades of left ventricle diastolic dysfunction with respect to cirrhosis severity. RESULTS A total of 1149 articles and abstracts met the initial search criteria. Sixteen articles which met the predefined eligibility criteria were included in the final analysis. Overall, 1067 patients (out of them 723 men) with liver cirrhosis were evaluated for left ventricle diastolic dysfunction. In our systemic analysis, we have found that 51.2% of cirrhotic patients had left ventricle diastolic dysfunction diagnosed and the grade 1 was the most prevalent (59.2%, P < 0.001) among them, the grade 3 had been rarely diagnosed - only 5.1%. The data about the prevalence of diastolic dysfunction in cirrhotic patients depending on Child-Pugh Classes was available from 5 studies (365 patients overall) and only in 1 research diastolic dysfunction was found being associated with severity of liver cirrhosis (P

Fluid retention is a common and challenging condition in daily clinical practice. The normal fluid homoeostasis in the human body is based on accurately counter-balanced physiological mechanisms. When compromised fluid retention occurs and is seen in pathophysiologically different conditions such as liver cirrhosis, heart and kidney failure, and in preeclampsia. These conditions may share pathophysiological mechanisms such as functional arterial underfilling, which seems to be a mutual element in cirrhosis, cardiac failure, cardiorenal and hepatorenal syndromes, and in pregnancy. However, there are also distinct differences and it is still unclear whether kidney dysfunction or arterial underfilling is the initiating factor of fluid retention or if they happen simultaneously. This review focuses on similarities and differences in water retaining conditions and points to areas where important knowledge is still needed.

Infections and sepsis are more common in cirrhotic than in the general population and constitute the commonest cause of sudden worsening and death. The diagnosis of systemic inflammatory syndrome and sepsis are challenging in cirrhotics due to an underlying a state of hyperdynamic circulation. Further, poor nutritional and bone marrow reserves lead to modest host immune response, the so called immunoparalysis state and the outcome of antibiotic therapy is suboptimal. In this review, a comprehensive description of current and emerging concepts in the pathogenesis and diagnosis of sepsis with importance to current and novel biomarkers for diagnosis of sepsis in cirrhosis is presented. Furthermore, novel treatment options and preventive strategies are discussed to improve the overall survival.

BACKGROUND AND AIMS AG490, the specific inhibitor of JAK2/STAT3 signaling, has been shown to decrease portal pressure, splanchnic hyperdynamic circulation and liver fibrosis in cirrhotic rats. Nonselective betablockers such as propranolol are the only drugs recommended in the treatment of portal hypertension. The aim of this study was to explore the combinative effect of treatment with propranolol and AG490 on portal hypertension. METHODS Rats induced by common bile duct ligation were treated with vehicle, AG490, propranolol, or AG490 + propranolol for 2 weeks. Hemodynamics parameters were assessed. Expressions of phospho-STAT3 protein and its down-regulated cytokines in splanchnic organs were detected by ELISA or western blot. Lipopolysaccharide binding protein (LBP) and IL-6 were assessed by ELISA or western blot. Characterization of liver and mesentery was performed by histological analyses. RESULTS Highly expressed phospho-STAT3 protein in cirrhotic rats could successfully be inhibited by AG490 or AG490 + propranolol treatments but not by propranolol alone. Both AG490 and propranolol significantly reduced portal pressure and hyperdynamic splanchnic circulation, and combination of AG490 and propranolol achieved an additive effect than with either drug alone. AG490, alone or in combination with propranolol, inhibited liver fibrosis, splenomegaly and splanchnic angiogenesis. Increased markers of bacterial translocation (LBP and IL6) were greatly reduced by propranolol but not by AG490. CONCLUSIONS The combination of propranolol and AG490 caused a greater improvement of portal hypertension and might therefore offer a potentially promising therapy in the portal hypertension treatment.

Objective We compared the intraoperative hemodynamic profiles and outcomes of liver transplant (LT) patients receiving preoperative beta-blockers for portal hypertension with those of patients not receiving beta-blockers. Methods Beat-to-beat hemodynamic data were recorded with the use of a lithium dilution cardiac output monitor, including heart rate (HR), cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), SVR index, mean arterial pressure, stroke volume (SV), and SV index. Perioperative data included age, sex, etiology of cirrhosis, Model of End-Stage Liver Disease score, warm and cold ischemia times, and intraoperative blood and blood products replacement. Postoperative data included Acute Physiology and Chronic Health Evaluation II score, Intensive Care National Audit and Research Centre (ICNARC) score, length of intensive care unit stay, renal replacement treatment, and mortality. Results After exclusion, 215 patients not receiving and 93 patients receiving beta-blockers for portal hypertension were included. There was no significant difference between groups in demographic data. HR, CO, and CI were significantly lower in the beta-blocker group (P = .0001). Regarding outcomes, the ICNARC score was significantly higher in the beta-blocker group (P Conclusions Preoperative administration of beta-blockers attenuates the hyperdynamic circulation in LT patients; this is clearly seen through a reduction in intraoperative CO, CI, and HR. This decreased hyperdynamic state was not shown to relate to outcomes in any of the variables except for a higher ICNARC score reported in the group treated with beta-blockers.

Introduction: Cirrhosis is associated with changes in the cardiovascular system, where the circulatory dysfunction is compensated by the development of a hyperdynamic circulation. Endothelial function can be understood as the endothelium capability to release Nitric Oxide (NO) where an impairment in the normal development of this process constitutes a main step in the genesis and progression of atherosclerosis, a major cause of cardiovascular events. In recent years, non-invasive measurements have gained attention, due to the potential complications associated to invasive procedures. Objective: To evaluate endothelial function (EF) in patients with cirrhosis, in different stages of the disease, complemented with hemodynamic measurements. Methods: Individuals were divided in three age groups, according to the severity of their disease. EF was assessed by using the flow mediated dilation technique (FMD), jointly with noninvasive determination of cardiac output (CO), total peripheral resistance (TPR) and arterial compliance (AC). Results: TPR showed a decrease in advanced severity while AC had an increase. Particularly, EF was found to be higher in CHC group, decreasing in CHB and more pronounceably in CHA. Concomitantly, an inverse behavior was observed regarding CO evolution. Conclusion: EF was noninvasively evaluated in cirrhosis, in terms of the progression of the disease. Hyperdynamic states in the more advanced condition were accompanied by a higher vascular reactivity, probably associated with higher peripheral NO release and increased AC.

The term “Small-for-Flow” reflects the pathogenetic relevance of hepatic hemodynamics for the “Small-For-Size” syndrome and posthepatectomy liver failure. We aimed to characterize a large-animal model for studying the “Small-for-Flow” syndrome. We performed subtotal (90%) hepatectomies in 10 female MiniPigs using a simplified transection technique with a tourniquet. Blood tests, hepatic and systemic hemodynamics, and hepatic function and histology were assessed before (Bas), 15 min (t-15 min) and 24 h (t-24 h) after the operation. Some pigs underwent computed tomography (CT) scans for hepatic volumetry (n = 4) and intracranial pressure (ICP) monitoring (n = 3). Postoperative care was performed in an intensive care unit environment. All hepatectomies were successfully performed, and hepatic volumetry confirmed liver remnant volumes of 9.2% [6.2–11.2]. The hepatectomy resulted in characteristic hepatic hemodynamic alterations, including portal hyperperfusion, relative decrease of hepatic arterial blood flow, and increased portal pressure (PP) and portal-systemic pressure gradient. The model reproduced major diagnostic features including the development of cholestasis, coagulopathy, encephalopathy with increased ICP, ascites, and renal failure, hyperdynamic circulation, and hyperlactatemia. Two animals (20%) died before t-24 h. Histological liver damage was observed at t-15 min and at t-24 h. The degree of histological damage at t-24 h correlated with intraoperative PP (r = 0.689, p = 0.028), hepatic arterial blood flow (r = 0.655, p = 0.040), and hepatic arterial pulsatility index (r = 0.724, p = 0.066). All animals with intraoperative PP > 20 mmHg presented liver damage at t-24 h. The present 90% hepatectomy porcine experimental model is a feasible and reproducible model for investigating the “Small-for-Flow” syndrome.

Objective To evaluate preoperatively intended en bloc renal pedicle control for laparoscopic nephrectomy in our hospital, as the safety and efficacy of en bloc renal pedicle control has been approved for laparoscopic nephrectomy but some authors do not advocate the generalised use of it. Methods We reviewed all laparoscopic nephrectomies that were carried out by two laparoscopic surgeons (from January 2015 until April 2017) who had a preoperative intention of en bloc renal pedicle control. By creating a window at the lower pole and another window at upper pole then using the Covidien Endo-GIA™ (45,60 mm vascular reload) to control the pedicle. We analysed patients’ demographic data, nephrectomy indication, intraoperative findings, and intra- and postoperative complications. Patients were followed-up with blood pressure measurements and for the presence or absence of any signs of hyperdynamic circulation. The analysis of data was done using SPSS® version 20 (SPSS Inc., IBM Corp., Armonk, NY, USA). Results We found 38 laparoscopic nephrectomies done for patients with mean (range) age 55.7 (18–94) years and mean (range) body mass index of 29.2 (17–41) kg/m2. The indications for nephrectomy were variable: 22 patients (57.9%) for non-functioning kidney, 14 (36.8%) for renal tumours and two (5.2%) for ureteric tumours. There were 23 left nephrectomies and 15 right nephrectomies performed laparoscopically. There were no conversions to open technique and no intraoperative complications. There was an average blood loss of 75 mL and the mean (range) total laparoscopic time was 85 (45–125) min. All cases had no significant postoperative complications, apart from one who developed a postoperative collection and pleural effusion that required a chest tube and drainage. During the follow-up, none of the patients developed signs of an arteriovenous fistula. Conclusion Pre-intended en bloc renal pedicle control during laparoscopic nephrectomies is safe using the Endo-GIA vascular stapler without significant complications.

Cardiovascular dysfunction in cirrhotic patients is a recognized clinical entity commonly referred to as cirrhotic cardiomyopathy. Systematic inflammation, autonomic dysfunction, and activation of vasodilatory factors lead to hyperdynamic circulation with high cardiac output and low peripheral vascular resistance. Counter acting mechanisms as well as direct effects on cardiac cells led to systolic or diastolic dysfunction and electromechanical abnormalities, which are usually masked at rest but exposed at stress situations. While cardiovascular complications and mortality are common in patients undergoing liver transplantation, they cannot be adequately predicted by conventional cardiac examination including transthoracic echocardiography. Newer echocardiography indices and other imaging modalities such as cardiac magnetic resonance have shown increased diagnostic accuracy with predictive implications in cardiovascular diseases. The scope of this review was to describe the role of cardiac imaging in the preoperative assessment of liver transplantation candidates with comprehensive analysis of the future perspectives anticipated by the use of newer echocardiography indices and cardiac magnetic resonance applications.

This is a detailed protocol describing invasive hemodynamic measurements in cirrhotic rats for the characterization of portal hypertensive syndrome. Portal hypertension (PHT) due to cirrhosis is responsible for the most severe complications in patients with liver disease. The full picture of the portal hypertensive syndrome is characterized by increased portal pressure (PP) due to the increased intrahepatic vascular resistance (IHVR), hyperdynamic circulation, and increased splanchnic blood flow. Progressive splanchnic arterial vasodilation and increased cardiac output with elevated heart rate (HR) but low arterial pressure characterizes the portal hypertensive syndrome. Novel therapies are currently being developed that aim to decrease PP by either targeting IHVR or increased splanchnic blood flow - but side effects on systemic hemodynamics may occur. Thus, a detailed characterization of portal venous, splanchnic, and systemic hemodynamic parameters, including measurement of PP, portal venous blood flow (PVBF), mesenteric arterial blood flow, mean arterial pressure (MAP), and HR is needed for preclinical evaluation of the efficacy of novel treatments for PHT. Our video article provides the reader with a structured protocol for performing invasive hemodynamic measurements in cirrhotic rats. In particular, we describe the catheterization of the femoral artery and the portal vein via an ileocolic vein and the measurement of portal venous and splanchnic blood flow via perivascular Doppler-ultrasound flow probes. Representative results of different rat models of PHT are shown.

Developing medicines for hemodynamic disorders that are characteristic of cirrhosis of the liver is a relevant problem in modern hepatology. The increase in hepatic vascular resistance to portal blood flow and subsequent hyperdynamic circulation underlie portal hypertension (PH) and promote its progression, despite the formation of portosystemic collaterals. Angiogenesis and vascular bed restructurization play an important role in PH pathogenesis as well. In this regard, strategic directions in the therapy for PH in cirrhosis include selectively decreasing hepatic vascular resistance while preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis. The aim of this review is to describe the mechanisms of angiogenesis in PH and the methods of antiangiogenic therapy. The PubMed database, the Google Scholar retrieval system, and the reference lists from related articles were used to search for relevant publications. Articles corresponding to the aim of the review were selected for 2000-2017 using the keywords: "liver cirrhosis", "portal hypertension", "pathogenesis", "angiogenesis", and "antiangiogenic therapy". Antiangiogenic therapy for PH was the inclusion criterion. In this review, we have described angiogenesis inhibitors and their mechanism of action in relation to PH. Although most of them were studied only in animal experiments, this selective therapy for abnormally growing newly formed vessels is pathogenetically reasonable to treat PH and associated complications.

BACKGROUND AND AIMS Patients with cirrhosis and portal hypertension often develop complications relating to hepatic excretory dysfunction. The standard measurement of the hepatic excretion is the constant infusion indocyanine green clearance (ICGCI ) technique. The ICG 15-min retention test (ICG-r15) is faster, more patient friendly, and cheaper. The aims were to compare the ICG-r15 test with the standard method, to assess relations to patient characteristics and survival, and to assess the ICG-r15 level in healthy control subjects. METHODS This study included 68 patients with cirrhosis and portal hypertension (Child class A/B/C:17/37/14). All patients underwent a full liver vein catheterization and hemodynamic evaluation with determination of ICG-r15 and ICGCI as the reference in a subset of 38 patients. Sixteen healthy control subjects were included for compiling a reference interval. RESULTS The ICG-r15 was increased in the cirrhotic patients with increasing values in parallel with liver dysfunction (15/41/58%) in Child class A/B/C compared with 7% in the controls (P

Liver cirrhosis is associated with a wide range of cardiovascular abnormalities including hyperdynamic circulation and cirrhotic cardiomyopathy. The pathogenic mechanisms of these cardiovascular changes are multifactorial and include vascular dysregulations. Aim The present study tested the hypothesis that the systemic vascular hyporesponsiveness in thioacetamide (TAA)-induced liver injury model is dependent on nitric oxide (NO) and cyclooxygenase (COX) derivatives. Main methods Wistar rats were treated with TAA for eight weeks to induce liver injury. Key findings The maximal contractile response in concentration-effect curves to phenylephrine was decreased in aorta from TAA-treated rats, but no differences were found in aorta without endothelium, suggesting an endothelium-dependent mechanism in decreased contractile response. There was no difference in the contractile response with and without L-NAME (N(ω)-nitro- l -arginine methyl ester) in rats with liver injury, showing that the TAA treatment impairs NO synthesis. Pre-incubation of the aorta with indomethacin, a COX-inhibitor, normalized the reduced contractile response to phenylephrine in arteries from TAA group. Also, COX-2 and iNOS (inducible nitric oxide syntase) protein expression was increased in aorta from TAA group compared to control group. Animals submitted to TAA treatment had a reduction in systolic blood pressure. Our findings demonstrated that liver injury induced by TAA caused a decrease in aortic contractile response by a COX-dependent mechanism but not by NO release. Also, it was demonstrated an inflammatory process in the aorta of TAA-treated rats by increased expression of COX-2 and iNOS. Significance Therefore, there is an essential contribution of COX-2 activation in extra-hepatic vascular dysfunction and inflammation present in cirrhosis induced by TAA.

Anesthetic management of the patient with major burn injuries presents numerous challenges. During the acute resuscitation phase, massive crystalloid infusions may be required. Anatomical distortions make airway management and vascular access difficult. With time, pathophysiological changes in cardiovascular function range from initial hypovolemia and impaired perfusion to a hyperdynamic circulation and hypermetabolic state. Pharmacological support of the circulation may be needed. These and other changes profoundly alter response to anesthetic drugs. Effective anesthetic management will depend on knowledge of the continuum of pathophysiological changes, technical skills, proper planning, and availability of proper resources. A team approach is necessary, keeping in mind that perioperative management not only depends on the surgical plan, but also should be compatible with ICU management and goals. This requires close communication with other members of the burn care team, which is one of the most important principles of effective anesthetic management of these challenging patients.

Pulmonary hypertension is a relatively common phenomenon in patients with hepatic cirrhosis and can appear through various mechanisms. The most characteristic scenario that binds portal and pulmonary hypertension is portopulmonary syndrome. However, hyperdynamic circulation, TIPS placement and heart failure can raise the mean pulmonary artery pressure without increasing the resistances. These conditions are not candidates for treatment with pulmonary vasodilators and require a specific therapy. A correct assessment of hemodynamic, ultrasound and clinical variables enables the differential diagnosis of each situation that produces pulmonary hypertension in patients with cirrhosis.

Acute or chronic insults to the liver are usually followed by a tissue repairing process. Unfortunately, this action, in most cases, is not effective enough to restore the normal hepatic structure and function. Instead, fibrogenesis and regenerative nodules formation ensue, which are relatively nonfunctioning. The common final stage of the process is liver cirrhosis with increased intrahepatic resistance to portal venous blood flow. Throughout the entire course, the extrahepatic circulatory dysfunction, including increased splanchnic blood flow, elevated portal venous blood flow and pressure, decreased splanchnic and peripheral vascular resistance, tachycardia, and increased cardiac output, are noted and denoted as portal hypertension with hyperdynamic circulatory dysfunction. When such a condition is established, patients may suffer from fatal complications such as gastroesophageal variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome. The cause of such a circulatory dysfunction is not fully elucidated. Nevertheless, clarification of the pathophysiology definitely contributes to the control of portal hypertension-related complications. Herein, the molecular mechanism of this intriguing disaster is reviewed and discussed.

Objective Hepatopulmonary syndrome (HPS) is characterized by vascular dilatation and hyperdynamic circulation, while portopulmonary hypertension (POPH) is characterized by vasoconstriction with fibrous obliteration of the vascular bed. Vasoactive molecules such as nitric oxide (NO) are candidate factors for cirrhotic complications associated with these diseases. However, oxidative stress balance is not well characterized in HPS and POPH. The present objective is to investigate the oxidative stress and anti-oxidative stress balance and NO pathway balance in patients with potential HPS and POPH. Methods We recruited patients with decompensated cirrhosis (n=69) admitted to our hospital as liver transplantation candidates. Patients exhibiting partial pressure of oxygen lower than 80 mmHg and alveolar-arterial oxygen gradient (AaDO2) ≥15 mmHg were categorized as potentially having HPS (23 of 69 patients). Patients exhibiting a tricuspid regurgitation pressure gradient ≥25 mmHg were categorized as potentially having POPH (29 of 61 patients). Serum reactive oxygen metabolites were measured and anti-oxidative OXY-adsorbent test (OXY) were performed, and the balance of these tests was defined as the oxidative index. The correlation between these values and the clinical characteristics of the patients were assessed in a cross-sectional study. Results Potential HPS patients exhibited no correlation with oxidative stress markers. Potential POPH patients exhibited lower OXY (p=0.037) and higher oxidative index values (p=0.001). Additionally, the vascular NO synthase enzyme inhibiting protein, asymmetric dimethylarginine, was higher in potential POPH patients (p=0.049). The potential POPH patients exhibited elevated AaDO2, suggesting the presence of pulmonary shunting. Conclusion Potential POPH patients exhibited elevated oxidative stress with decreased anti-oxidative function accompanied by inhibited NO production. Anti-oxidants represent a candidate treatment for potential POPH patients.

Cardiovascular complications have emerged as the leading cause of death after liver transplantation, particularly among those with advanced liver cirrhosis. Therefore, a thorough and accurate cardiovascular evaluation with clear comprehension of cirrhotic cardiomyopathy is recommended for optimal anesthetic management. However, cirrhotic patients manifest cardiac dysfunction concomitant with pronounced systemic hemodynamic changes, characterized by hyperdynamic circulation such as increased cardiac output, high heart rate, and decreased systemic vascular resistance. These unique features mask significant manifestations of cardiac dysfunction at rest, which makes it difficult to accurately evaluate cardiovascular status. In this review, we have summarized the current knowledge of heart and liver interactions, focusing on the usefulness and limitations of cardiac evaluation tools for identifying high-risk patients.

Patients with cirrhosis and portal hypertension often develop complications from a variety of organ systems leading to a multiple organ failure. The combination of liver failure and portal hypertension results in a hyperdynamic circulatory state partly owing to simultaneous splanchnic and peripheral arterial vasodilatation. Increases in circulatory vasodilators are believed to be due to portosystemic shunting and bacterial translocation leading to redistribution of the blood volume with central hypovolemia. Portal hypertension per se and increased splanchnic blood flow are mainly responsible for the development and perpetuation of the hyperdynamic circulation and the associated changes in cardiovascular function with development of cirrhotic cardiomyopathy, autonomic dysfunction and renal dysfunction as part of a cardiorenal syndrome. Several of the cardiovascular changes are reversible after liver transplantation and point to the pathophysiological significance of portal hypertension. In this paper, we aimed to review current knowledge on the pathophysiology of arterial vasodilatation and the hyperdynamic circulation in cirrhosis.

The clinical course of cirrhosis is mostly determined by the progressive increase of portal hypertension, hyperdynamic circulation, bacterial translocation and activation of systemic inflammation. Different disease states, encompassing compensated and decompensated cirrhosis and a late decompensated state, are related to the progression of these mechanisms and may be recognised by haemodynamic or clinical characteristics. While these disease states do not follow a predictable sequence, they correspond to varying mortality risk. Acute-on-chronic liver failure may occur either in decompensated or in compensated cirrhosis and is always associated with a high short-term mortality. The increasing severity of these disease states prompted the concept of clinical states of cirrhosis. A multistate approach has been considered to describe the clinical course of the disease. Such an approach requires the assessment of the probabilities of different outcomes in each state, which compete with each other to occur first and mark the transition towards a different state. This requires the use of competing risks analysis, since the traditional Kaplan-Meier analysis should only be used in two-state settings. Accounting for competing risks also has implications for prognosis and treatment efficacy research. The aim of this review is to summarise relevant clinical states and to show examples of competing risks analysis in multistate models of cirrhosis.

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. The presence of portal hypertension has been demonstrated in NAFLD prior to development of inflammation or fibrosis, and is a result of extrahepatic and intrahepatic factors, principally driven by vascular dysfunction. An increased intrahepatic vascular resistance potentially contributes to progression of NAFLD via intralobular hypoxia. However, the exact mechanisms underlying vascular dysfunction in NAFLD remain unknown. This study investigates systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis. Wistar rats were fed a methionine-choline-deficient diet, inducing steatosis, or control diet for 4 weeks. In vivo hemodynamic measurements, aortic contractility studies, and in situ liver perfusion experiments were performed. The mean arterial blood pressure was lower and portal blood pressure was higher in steatosis compared to controls. The maximal contraction force in aortic rings from steatotic rats was markedly reduced compared to controls. While blockade of nitric oxide (NO) production did not reveal any differences, cyclooxygenase (COX) blockade reduced aortic reactivity in both controls and steatosis, whereas effects were more pronounced in controls. Effects could be attributed to COX-2 iso-enzyme activity. In in situ liver perfusion experiments, exogenous NO donation or endogenous NO stimulation reduced the transhepatic pressure gradient (THPG), whereas NO synthase blockade increased the THPG only in steatosis, but not in controls. Alpha-1-adrenergic stimulation and endothelin-1 induced a significantly more pronounced increase in THPG in steatosis compared to controls. Our results demonstrate that severe steatosis, without inflammation or fibrosis, induces portal hypertension and signs of a hyperdynamic circulation, accompanied by extrahepatic arterial hyporeactivity and intrahepatic vascular hyperreactivity. The arterial hyporeactivity seems to be NO-independent, but appears to be mediated by specific COX-2-related mechanisms. Besides, the increased intrahepatic vascular resistance in steatosis appears not to be NO-related but rather to vasoconstrictor hyperreactivity.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare genetic blood disorder that leads to abnormal bleeding due to absent capillaries and multiple abnormal blood vessels known as arteriovenous malformations. A feature of HHT is high-output heart failure due to multiple arteriovenous malformations. High-output heart failure can lead to recurrent epistaxis Kiesselbach area syndrome (REKAS), further exacerbating heart failure through increased blood loss and resultant anemia. We report a patient with HHT who presented with high-output heart failure contributing to REKAS. In patients with REKAS, we propose if anemia is present, REKAS can be avoided by correcting the anemia by increasing the hemoglobin level to greater than 9 to 10 g/dL. This decreases hyperdynamic circulation and reduces pressure in the blood vessels of the nose.