Splanchnic Hemodynamics Research Articles

Efficacy and Safety of Terlipressin Infusion in Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI): A Retrospective Observational Study.

Background Hepatorenal syndrome-acute kidney injury (HRS-AKI) is an event that occurs in chronic liver disease (CLD) and is associated with high morbidity and mortality. Terlipressin, a vasopressin analog, is used for the treatment of portal hypertension-related gastrointestinal (GI) bleeding and is found to be effective in the management of HRS-AKI. Continuous infusion of terlipressin maintains a high mean arterial pressure while reducing adverse events. It is better tolerated and equally effective at lower doses than intravenous boluses in patients with HRS-AKI. Aim of the study This study aimed to evaluate the safety and efficacy of terlipressin infusion at the rate of 4 mg/day in the treatment of HRS-AKI. Methods This retrospective study included patients who had HRS-AKI according to the modified International Club of Ascites (ICA) definition. Patients were started on a continuous intravenous infusion. The included patients received terlipressin 1 mg stat followed by a 4 mg infusion over 24 hours, and the infusion was continued until specific response criteria were met or for a maximum of seven days. Results In total, 136 patients were included in this study. The mean age of the study group was 45 years, the mean Child-Turcotte-Pugh (CTP) score was 11, the mean model for end-stage liver disease (MELD) score was 30, and the mean serum creatinine was 2.46 mg/dl. A response to treatment in the form of reduction of serum creatinine was observed in 94 (69.1%) patients, 30 (22%) patients showed no response, and worsening of creatinine was seen in 12 (8.8%) patients. The mean duration of hospital stay was 7.6 days, the mean serum creatinine was 1.17 mg/dl at the end of treatment, and the mean CTP and MELD scores in treatment responders were nine and 27, respectively. A total of 29 (21.3%) of 136 patients had adverse events during the terlipressin infusion therapy. Conclusion Terlipressin infusion has sustained effects on splanchnic hemodynamics with fewer and less severe adverse events than intravenous bolus doses. Terlipressin infusion at a dose of 4 mg/day appeared to be well tolerated, with similar outcomes to that of 2 mg/day with a significantly lower albumin dose. These findings emphasize the importance of optimizing treatment protocols, particularly those favoring infusion methods, to enhance efficacy and minimize adverse effects.

Cediranib ameliorates portal hypertensive syndrome via inhibition of VEGFR-2 signaling in cirrhotic rats

Portal hypertension (PHT) is a syndrome caused by systemic and portal hemodynamic disturbances with the progression of cirrhosis. However, the exact mechanisms regulating angiogenesis-related responses in PHT remain unclear. Cediranib is a potent inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, exhibiting a greater affinity for VEGFR-2. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague–Dawley rats. Sham-operated rats were controls. BDL and sham rats were randomly allocated to receive Cediranib or vehicle after BDL. On the 28th day, portal hypertension related parameters were surveyed. Cediranib treatment could significantly reduce the portal pressure (PP) in BDL rats, while it did not affect the mean arterial pressure (MAP) in sham groups and BDL groups. Cediranib treatment could significantly affect the stroke volume (SV), cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), superior mesenteric artery (SMA) flow and SMA resistance in BDL groups and BDL with Cediranib groups. Cediranib treatment could improve the mesenteric vascular remodeling and contractility. Cediranib treatment significantly reduced mesenteric vascular density. And phospho-VEGFR-2 was significantly downregulated by Cediranib. On the other hand, phospho-endothelial Nitric Oxide Synthases (phospho-eNOS) expressions were upregulated. Cediranib not only improved splanchnic hemodynamics, extrahepatic vascular remodeling and vasodilation, but also alleviated intrahepatic fibrosis and collagen deposition significantly. Cediranib treatment could reduce intrahepatic angiogenesis between BDL-vehicle and BDL-Cediranib rats. In conclusion, Cediranib could improve extrahepatic hyperdynamic circulation by inhibiting extrahepatic angiogenesis through inhibition of the VEGFR-2 signaling pathway, portal collateral circulation formation, as well as eNOS-mediated vasodilatation and vascular remodeling, and at the same time, Cediranib improved intrahepatic fibrogenesis and angiogenesis, which together alleviate cirrhotic PHT syndrome.

Effect of beta-blockers on multiple haemodynamics in cirrhosis: A cross-over study by MR-imaging and hepatic vein catheterization.

Non-selective beta-blockers (NSBB) are widely used in the treatment of patients with cirrhosis. Only about 50% respond with a sufficient reduction in their hepatic venous pressure gradient (HVPG) and NSBB may induce detrimental cardiac and renal effects in the presence of severe decompensation. We aimed to assess the effects of NSBB on haemodynamics using magnetic resonance imaging (MRI) and to assess if these haemodynamic changes were related to the disease severity and HVPG response. A prospective cross-over study of 39 patients with cirrhosis. Patients underwent hepatic vein catheterization and MRI with assessments of HVPG, cardiac function, systemic and splanchnic haemodynamics before and after propranolol infusion. Propranolol induced significant decreases in cardiac output (-12%) and blood flow of all vascular compartments, with the largest reductions seen in the azygos venous (-28%), portal venous (-21%), splenic (-19%) and superior mesenteric artery (-16%) blood flow. Renal artery blood flow fell by -5% in the total cohort, with a more pronounced reduction in patients without ascites than in those with ascites (-8% vs. -3%, p = .01). Twenty-four patients were NSBB responders. Their changes in HVPG after NSBB were not significantly associated with other haemodynamic changes. The changes in cardiac, systemic and splanchnic haemodynamics did not differ between NSBB responders and non-responders. The effects of acute NSBB blockade on renal flow seem to depend on the severity of the hyperdynamic state, with the largest reduction in renal blood flow in compensated patients compared to decompensated patients with cirrhosis. However, future studies are needed to assess the effects of NSBB on haemodynamics and renal blood flow in patients with diuretic-resistant ascites.

Response Guided Slow Infusion of Albumin, Vasoconstrictors and Furosemide Improves Ascites Mobilization and Survival in Acute on Chronic Liver Failure: A Proof-of-Concept Study.

Background and AimsAcute-on-chronic liver failure (ACLF) with increasing organ failure is associated with poor outcomes. Severely deranged systemic hemodynamics and decreased effective arterial blood volume contribute to tissue damage and organ failure. Response-guided therapy with albumin, vasoconstrictors, and furosemide may help overcome effective hypovolemia, improve diuresis and impact survival.MethodsIn the observation cohort, 230 patients with ACLF (CANONIC criteria) with ascites (≥Grade II) and ACLF ≥Grade I were enrolled. A total of 136 patients (GROUP I) received response-guided (urine sodium >80mmol/day) slow albumin-furosemide infusion ± terlipressin (SAFI ± T), while 94 patients (GROUP II) received standard medical therapy. Twenty-eight-day survival, ascites mobilization (nil or grade 1), and adverse events were noted. In another mechanistic cohort (n = 40), laboratory evidences for improvement in various pathophysiological alterations; gut permeability, endotoxemia, cytokine storm, neutrophil dysfunction, and hemodynamic alterations following SAFI ± T/Noradrenaline (NAdr) were evaluated.ResultsAge, gender, CLIF-C-ACLF, SOFA and MELD scores, ACLF grades and urine sodium were not different between the two groups in the observation cohort. Ascites was mobilized in 102/136 in GROUP I (SAFI ± T) and 23/94 in GROUP II (p < 0.05). Twenty-eight-day survival was significantly higher in GROUP I = 103/136 (75.7%) vs GROUP II = 50/94 (53.2%), (P = <0.001). All those who were unable to reach urine sodium >80 mmol/day died. Four patients in GROUP I developed scrotal gangrene. In the mechanistic cohort, 72% of patients survived with significant improvement in gut permeability, endotoxemia, serum cytokines, neutrophil dysfunction, and hemodynamic alterations.ConclusionAscitic fluid mobilization by response-guided SAFI ± T/NAdr therapy improves survival by improving splanchnic and systemic hemodynamics, decreasing gut congestion, gut permeability, and endotoxemia, improving neutrophil functions, and reducing pro-inflammatory cytokines in circulation.

Midodrine in Liver Cirrhosis With Ascites: A Systematic Review and Meta-Analysis.

Ascites is the most common complication of liver cirrhosis. Midodrine is a vasoconstrictor that improves splanchnic and systemic hemodynamics, reduces ascites, and improves clinical outcomes. Here, we aimed to examine the role of midodrine in cirrhosis-related ascites.Scopus, Embase, PubMed, and PubMed Central databases were searched for relevant randomized controlled trials comparing midodrine with other interventions in patients with cirrhotic ascites on November 25, 2020, using appropriate keywords like “midodrine”, “ascitic cirrhosis”, “peritoneal paracentesis” and suitable Boolean operators. Odds ratio (OR) and mean difference (MD) were used to analyze pool data as appropriate with a 95% confident interval (CI).A total of 14 studies were included in our analysis including 1199 patients. The addition of midodrine resulted in statistically significant improvement in mean arterial pressure (MAP) (MD, 3.95 mmHg; 95% CI, 1.53-6.36) and MELD (Model for End-Stage Liver Disease) score (MD, -1.27; 95% CI, -2.49 to -0.04) compared to standard medical treatment (SMT). There was also a significant improvement in plasma renin activity and plasma aldosterone concentration. However, there was no significant improvement in mortality or serum creatinine compared to SMT. In addition, there was no statistically significant improvement in MAP, plasma renin activity, plasma aldosterone concentration, MELD score, overall mortality, and paracentesis-induced circulatory dysfunction comparing midodrine with albumin.Midodrine alone leads to significant improvement in various clinical parameters in patients with cirrhotic ascites compared to standard medical care. At the same time, it was found to be non-inferior to albumin. Therefore, further well-designed studies need to be carried out on midodrine in addition to albumin for optimal clinical benefits among patients with ascites due to cirrhosis.

Mas-related G protein-coupled receptor type D antagonism improves portal hypertension in cirrhotic rats.

Splanchnic vasodilatation contributes to the development and aggravation of portal hypertension (PHT). We previously demonstrated that in cirrhosis, angiotensin‐ mediates splanchnic vasodilatation through the Mas receptor (MasR). In this study, we investigated whether the recently characterized second receptor for angiotensin‐(1–7), Mas‐related G protein‐coupled receptor type D (MrgD), contributes to splanchnic vasodilatation in cirrhotic and noncirrhotic PHT. Splanchnic vascular hemodynamic and portal pressure were determined in two rat models of cirrhotic PHT and a rat model with noncirrhotic PHT, treated with either MrgD blocker D‐Pro7‐Ang‐(1‐7) (D‐Pro) or MasR blocker A779. Gene and protein expression of MrgD and MasR were measured in splanchnic vessels and livers of cirrhotic and healthy rats and in patients with cirrhosis and healthy subjects. Mesenteric resistance vessels isolated from cirrhotic rats were used in myographs to study their vasodilatory properties. MrgD was up‐regulated in cirrhotic splanchnic vessels but not in the liver. In cirrhotic rats, treatment with D‐Pro but not A779 completely restored splanchnic vascular resistance to a healthy level, resulting in a 33% reduction in portal pressure. Mesenteric vessels pretreated with D‐Pro but not with A779 failed to relax in response to acetylcholine. There was no splanchnic vascular MrgD or MasR up‐regulation in noncirrhotic PHT; thus, receptor blockers had no effect on splanchnic hemodynamics. Conclusion: MrgD plays a major role in the development of cirrhotic PHT and is a promising target for the development of novel therapies to treat PHT in cirrhosis. Moreover, neither MrgD nor MasR contributes to noncirrhotic PHT.

Effect of ingesting a meal and orthostasis on the regulation of splanchnic and systemic hemodynamics and the responsiveness of cardiovascular α1-adrenoceptors.

Postprandial orthostasis activates mechanisms of cardiovascular homeostasis to maintain normal blood pressure (BP) and adequate blood flow to vital organs. The underlying mechanisms of cardiovascular homeostasis in postprandial orthostasis still require elucidation. Fourteen healthy volunteers were recruited to investigate the effect of an orthostatic challenge (60°-head-up-tilt for 20 min) on splanchnic and systemic hemodynamics before and after ingesting an 800-kcal composite meal. The splanchnic circulation was assessed by ultrasonography of the superior mesenteric and hepatic arteries and portal vein. Systemic hemodynamics were assessed noninvasively by continuous monitoring of BP, heart rate (HR), cardiac output (CO), and the pressor response to an intravenous infusion on increasing doses of phenylephrine, an α1-adrenoceptor agonist. Neurohumoral regulation was assessed by spectral analysis of HR and BP, plasma catecholamine and aldosterone levels and plasma renin activity. Postprandial mesenteric hyperemia was associated with an increase in CO, a decrease in SVR and cardiac vagal tone, and reduction in baroreflex sensitivity with no change in sympathetic tone. Arterial α1-adrenoceptor responsiveness was preserved and reduced in hepatic sinusoids. Postprandial orthostasis was associated with a shift of 500 mL of blood from mesenteric to systemic circulation with preserved sympathetic-mediated vasoconstriction. Meal ingestion provokes cardiovascular hyperdynamism, cardiac vagolysis, and resetting of the baroreflex without activation of the sympathetic nervous system. Meal ingestion also alters α1-adrenoceptor responsiveness in the hepatic sinusoids and participates in the redistribution of blood volume from the mesenteric to the systemic circulation to maintain a normal BP during orthostasis.NEW & NOTEWORTHY A unique integrated investigation on the effect of meal on neurohumoral mechanisms and blood flow redistribution of the mesenteric circulation during orthostasis was investigated. Food ingestion results in cardiovascular hyperdynamism, reduction in cardiac vagal tone, and baroreflex sensitivity and causes a decrease in α1-adrenoceptor responsiveness only in the venous intrahepatic sinusoids. About 500-mL blood shifts from the mesenteric to the systemic circulation during orthostasis. Accordingly, the orthostatic homeostatic mechanisms are better understood.

DPP4 inhibitor reduces portal hypertension in cirrhotic rats by normalizing arterial hypocontractility

AimsDipeptidyl peptidase-4 inhibitor (DPP4i), a new antidiabetic agent, is reported to affect the progression of chronic liver diseases. The study aims to investigate the effects of DPP4i on contractile response, splanchnic hemodynamics, and portal pressure in cirrhotic rats. Materials and methodsA rat model of carbon tetrachloride-induced cirrhosis was used in this study. Sixteen rats with cirrhosis were treated with DDP4i sitagliptin for 5 consecutive days. Portal and systemic pressures and portal blood flow were measured. Mesenteric arterioles were isolated, and concentration-response curves to norepinephrine (NE) were evaluated. The expression of NADPH oxidase (Nox)1, Nox2, Nox4, and soluble epoxide hydrolase (sEH) were detected. Reactive oxygen species (ROS) and epoxyeicosatrienoic acid (EET) levels in mesenteric arteries were also measured. Key findingsIn cirrhotic rats, sitagliptin significantly reduced portal blood flow and portal pressure without effects on systemic pressure and reversed the decreased response of mesenteric arterioles to NE in an endothelium-dependent manner. Sitagliptin suppressed the increased Nox4 expression and ROS production. In vitro studies showed that Nox4 inhibitor enhanced arteriolar response to NE and reduced hydrogen peroxide (H2O2) level in cirrhotic rats. Sitagliptin also reduced EET levels and increased sEH expression of mesenteric vessels. Pre-incubation with sEH inhibitor in vitro reversed sitagliptin-induced augmentation of response to NE in cirrhotic rats. SignificanceDPP4 inhibition by sitagliptin in vivo has beneficial effects on portal hypertension in cirrhotic rats through normalizing arterial hypocontractility. DDP4 inhibitor may be a novel strategy in the treatment of patients with cirrhosis and portal hypertension.

Partial splenic embolization is superior to intravenous somatostatin for decreasing portal pressure in cirrhotic patients: a dynamic self-controlled cohort study

Aims The efficacy of somatostatin in altering splanchnic hemodynamics in cirrhotic portal hypertension is still controversial. We aimed to establish the dynamic effect of somatostatin on portal pressure in cirrhotic patients and compared its effect with Partial Splenic Embolization (PSE). Methods Eighteen patients with cirrhotic portal hypertension were prospectively recruited. The wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP) were repeatedly measured at baseline, 1-, 5-, 10- and 20-min after initiating somatostatin infusion. After somatostatin infusion cessation and washout, WHVP and FHVP were measured before and after PSE. The change in all the variables between time points was analyzed. Results Decreased hepatic venous pressure gradient (HVPG) 5-min after initiation of infusion was identified compared with baseline level (19.6%; p-value: .042), which was achieved through elevated FHVP (37.5%; p-value: 9.26e − 04). There was no significant decrease in WHVP at any time point during somatostatin infusion. The HVPG (17.4%; p-value: 1.27e − 04) and WHVP (10.4%; p-value: 3.00e − 03) post-PSE significantly decreased compared to the washout level. No significant distribution differences in the number of patients with HVPG decrease by a percentage relative to the baseline level were identified between the 5-min time point and post-PSE. Conclusion Our study indicates that somatostatin administration does not decrease WHVP within 20 min at clinically recommended doses. While somatostatin did decrease HVPG, this effect was achieved through increased FHVP, providing a possible explanation for its unclear efficacy. In contrast, PSE decreases both the WHVP and the HVPG.

Obeticholic acid ameliorates hepatorenal syndrome in ascitic cirrhotic rats by down-regulating the renal 8-iso-PGF2α-activated COX-TXA2 pathway.

The present study explores the potential of chronic treatment with the Foresaid X receptor (FXR) agonist obeticholic acid (OCA), which inhibits oxidative stress-related pathogenesis, in ascitic cirrhotic rats with hepatorenal syndrome (HRS) developed 6 weeks after bile duct ligation (BDL). Systemic, splanchnic, and renal hemodynamics and pathogenic cascades were measured in ascitic BDL and sham rats receiving 2-weeks of either vehicle or OCA treatments (sham-OCA and BDL-OCA groups), and NRK-52E cells, rat kidney tubular epithelial cells. Chronic OCA treatment significantly normalized portal hypertension, glomerular filtration rate, urine output, renal blood flow; decreased ascites, renal vascular resistance, serum creatinine, and the release of renal tubular damage markers, including urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury moleculae-1 (uKim-1) in BDL-OCA rats. In the BDL group, inhibition of the renal oxidative stress (8-iso-PGF2α)-activated cyclooxygenase-thromboxane A2 [COX-TXA2] pathway, apoptosis, and tubular injury accompanied by a decrease in hyper-responsiveness to the vasoconstrictor 8-iso-PGF2α in perfused kidneys. In vitro experiments revealed that 8-iso-PGF2α induced oxidative stress, release of reactive oxygen species, and cell apoptosis, which were reversed by concomitant incubation with the FXR agonist. Through the inhibition of renal 8-iso-PGF2α production and the down-regulation of the COX-TXA2 pathway, our study suggests that chronic OCA treatment can ameliorate the HRS in ascitic cirrhotic rats. Thus, OCA is an agent with antioxidative stress, antivasoconstrictive, antiapoptotic properties which benefit ascitic, cirrhotic rats with systemic, hepatic, and renal abnormalities.

Ascitis

Ascites is the most common complication in patients with hepatic cirrhosis and portal hypertension and is usually the first manifestation of the disease in most cases. The development of ascites in these patients is the result of a significant impairment in systemic and splanchnic haemodynamics and in renal function. Given that the structural hepatic abnormalities are typically irreversible, most patients with cirrhosis develop repeated episodes of ascites during the course of the disease, which can occasionally be persistent or difficult to control despite continuous treatment. The development of ascites in cirrhosis is a sign of a poor prognosis. The probability of survival 1 and 5 years after the first episode of ascites is 50% and 20%, respectively. This short survival needs to be considered when analysing these patients’ treatment, especially regarding the indication for liver transplantation as the definitive and curative treatment.

Changes in Splanchnic Hemodynamics Contribute to the Cardiovascular Responses Following Activation of Bradykinin‐Sensitive Pericardial Afferents

Sympathetic drive is a major controller of cardiovascular function. The heart performs an important sensory function via a variety of cardiac receptors that modulate cardiovascular responses by both neural and humoral reflexes. Bradykinin‐sensitive sympathetic afferent nerves from the heart can trigger marked increases in efferent sympathetic nerve activity to some cardiovascular target organs such as the kidney, arteries and veins. We reported previously that pericardial injection of bradykinin increased venous tone and cardiac output. The splanchnic vascular compartment plays an important role in control of venous return and cardiac output. This work tested the hypothesis that activation of bradykinin‐sensitive pericardial afferents modulates splanchnic hemodynamics.Sprague Dawley rats were anesthetized with a cocktail of alpha chloralose (80 mg/kg) and urethane (800 mg/kg). Catheters were placed in the femoral artery and vein to record arterial pressure (MAP) and heart rate (HR). A PE10 catheter was placed in the pericardial space for the injection of bradykinin (BK), an agent known to stimulate cardiac sympathetic afferents. The chest was closed and the rats allowed to breathe spontaneously. The portal vein and mesenteric artery were exposed via a midline laparotomy and fitted with transit time flow probes. After stabilization, the blood pressure, heart rate, portal venous flow (PF) and mesenteric flow (MF) responses to pericardial injection of BK or vehicle were recorded.Pericardial injection of saline vehicle had little effect (MAP: 2±2 mm Hg; HR: 13±6 bpm; PF: −5±1%; MF: −3±1%). In contrast, pericardial injection of BK (10 ug/kg) increased MAP (16±3 mm Hg) and HR (28±5 bpm). After an initial transient decrease, PF (10±2%) and MF (5±2%) were increased during the plateau phase of the MAP response (60–120 seconds).We interpret these data to indicate that activation of bradykinin‐sensitive pericardial afferents increases portal venous flow. This finding is consistent with the view that activation of the cardiac sympathetic afferent reflex elicits a venoconstrictor response to increase venous return from the splanchnic compartment.Support or Funding InformationSupported by NIH R01 HL136741‐03, and the Basic Biomedical Sciences program of the Sanford School of Medicine.

To Feed or Not to Feed: A Critical Overview of Enteral Feeding Management and Gastrointestinal Complications in Preterm Neonates with a Patent Ductus Arteriosus.

The management of enteral feeds in preterm infants with a hemodynamically significant patent ductus arteriosus (hs-PDA) is a major challenge for neonatologists due to the fear of gastrointestinal (GI) complications. This review aims to analyze the available evidence on the complex relation between the presence and management of PDA, enteral feeding practices, and GI outcomes in the preterm population. There is limited evidence, based on small and heterogeneous trials, that hs-PDA may affect the splanchnic hemodynamic response to enteral feeds. While the presence of PDA seems a risk factor for adverse GI outcomes, the benefits of feeding withholding during pharmacological PDA treatment are controversial. The lack of robust evidence in support of or against a timely feeding introduction or feeding withholding during pharmacological PDA closure in preterm neonates does not allow to draw any related recommendation. While waiting for further data, the feeding management of this population should be carefully evaluated and possibly individualized on the basis of the infants’ hemodynamic and clinical characteristics. Large, multicentric trials would help to better clarify the physiological mechanisms underlying the development of gut hypoperfusion, and to evaluate the impact of enteral feeds on splanchnic hemodynamics in relation to PDA features and treatment.

Refractory ascites-the contemporary view on pathogenesis and therapy.

Refractory ascites (RA) refers to ascites that cannot be mobilized or that has an early recurrence that cannot be prevented by medical therapy. Every year, 5–10% of patients with liver cirrhosis and with an accumulation of fluid in the peritoneal cavity develop RA while undergoing standard treatment (low sodium diet and diuretic dose up to 400 mg/day of spironolactone and 160 mg/day of furosemide). Liver cirrhosis accounts for marked alterations in the splanchnic and systemic hemodynamics, causing hypovolemia and arterial hypotension. The consequent activation of renin-angiotensin and sympathetic systems and increased renal sodium re-absorption occurs during the course of the disease. Cirrhotic patients with RA have poor prognoses and are at risk of developing serious complications. Different treatment options are available, but only liver transplantation may improve the survival of such patients.

Hyperdynamic circulatory syndrome in a mouse model transgenic for SerpinB3

Introduction and objectivesSerpinB3 is a cysteine protease inhibitor involved in several biological activities. It is progressively expressed in chronic liver disease, but not in normal liver. The role in vascular reactivity of this serpin, belonging to the same family of Angiotensin II, is still unknown. Our aim was to evaluate the in vivo and in vitro effects of SerpinB3 on systemic and splanchnic hemodynamics. Material and methodsDifferent hemodynamic parameters were evaluated by ultrasonography in two colonies of mice (transgenic for human SerpinB3 and C57BL/6J controls) at baseline and after chronic carbon tetrachloride (CCl4) treatment. In vitro SerpinB3 effect on mesenteric microvessels of 5 Wistar-Kyoto rats was analyzed measuring its direct action on: (a) preconstricted arteries, (b) dose–response curves to phenylephrine, before and after inhibition of angiotensin II type 1 receptors with irbesartan. Hearts of SerpinB3 transgenic mice and of the corresponding controls were also analyzed by morphometric assessment. ResultsIn SerpinB3 transgenic mice, cardiac output (51.6±21.5 vs 30.1±10.8ml/min, p=0.003), hepatic artery pulsatility index (0.85±0.13 vs 0.65±0.11, p<0.001) and portal vein blood flow (5.3±3.2 vs 3.1±1.8ml/min, p=0.03) were significantly increased, compared to controls. In vitro, recombinant SerpinB3 had no direct hemodynamic effect on mesenteric arteries, but it increased their sensitivity to phenylephrine-mediated vasoconstriction (p<0.01). This effect was suppressed by inhibiting angiotensin II type-1 receptors. ConclusionsIn transgenic mice, SerpinB3 is associated with a hyperdynamic circulatory syndrome-like pattern, possibly mediated by angiotensin receptors.

Effects of terlipressin infusion during hepatobiliary surgery on systemic and splanchnic haemodynamics, renal function and blood loss: a double-blind, randomized clinical trial

BackgroundTerlipressin, in general, is a vasopressor which acts via V1 receptors. Its infusion elevates mean blood pressure and can reduce bleeding which has a splanchnic origin. The primary outcome was to assess the impact of intraoperative terlipressin infusion on portal venous pressure during hepatobiliary surgery; the 2ry outcomes included effects upon systemic hemodynamics, estimated blood loss, and postoperative renal functions.MethodsThis prospective randomized study involved 50 patients undergoing hepatobiliary surgery who were randomly and equally allocated into terlipressin group, or a control group. The terlipressin group received an initial bolus dose of (1 mg over 30 min) followed by a continuous infusion of 2 μg/kg/h throughout the procedure and gradually weaned over the first four postoperative hours, whereas the control group received the same volumes of normal saline. The portal venous pressure changes were measured directly through a portal vein angiocatheter.ResultsPortal pressure was significantly reduced over time in the terlipressin group only (from 17.88 ± 7.32 to 15.96 ± 6.55 mmHg, p < .001). Mean arterial blood pressure was significantly higher in the terlipressin group. Estimated blood loss was significantly higher in the control group than the terlipressin group (1065.7 ± 202 versus 842 ± 145.5 ml; p = 0.004), and the units of packed RBCs transfused were significantly higher in the control group ((0–2) versus (0–4) p = 0.003). There was no significant difference between groups as regards the incidence of acute kidney injury.ConclusionIntraoperative infusion of terlipressin during hepatobiliary surgery was shown to improve intraoperative portal hemodynamics with subsequent reduction in blood loss.Trial registrationClinical trial number and registry URL: Trial registration number: NCT02718599. Name of registry: ClinicalTrials.gov. URL of registry: https://clinicaltrials.gov/ct2/show/NCT02718599. Date of registration: March 2016. Date of enrolment of the first participant to the trial: April 2016.

The role of splanchnic congestion and the intestinal microenvironment in the pathogenesis of advanced heart failure.

Right-sided heart failure, which is often present in the setting of advanced heart failure, is associated with cardiac cachexia, the cardiorenal syndrome, and adverse outcomes. Improved understanding of venous congestion of the splanchnic circulation, which may play a key role in the pathogenesis of right-sided heart failure, could lead to novel therapeutics to ameliorate heart failure. Here we provide an overview of right-sided heart failure, splanchnic hemodynamics, fluid homeostasis, and the intestinal microenvironment. We review recent literature to describe pathophysiologic mechanisms and possible therapeutics. Several possible mechanisms centered around upregulation of sodium-hydrogen exchanger-3 (NHE3) may form a causal link between right ventricular dysfunction, splanchnic congestion, and worsening heart failure. These include an anaerobic environment in enterocytes, resulting in reduced intracellular pH; increased sodium absorption by the gut via NHE3; decreased pH at the intestinal brush border thus altering the gut microbiome profile; increased bacterial synthesis of trimethylamine N-oxide; and decreased bacterial synthesis of short-chain fatty acids causing abnormal intestinal barrier function. Splanchnic congestion in the setting of right-sided heart failure may serve an important role in the pathogenesis of advanced heart failure, and further exploration of these mechanisms may lead to new therapeutic advances.

Prolonged occlusion of the hepatoduodenal ligament to reduce risk of bleeding and tumor spread during recipient hepatectomy for living donor liver transplantation

Introduction: Prevention of excessive bleeding during liver transplantation (LT) operations presents a major challenge. Compared to deceased donor LT, living donor LT (LDLT) is more vulnerable to bleeding because of additional dissection procedures. We herein introduce our technique for prolonged occlusion of the hepatoduodenal ligament applied to recipient hepatectomy for LDLT. Method: Simulated assessment of splanchnic hemodynamics on prolonged occlusion of the hepatoduodenal ligament showed that patients with cirrhotic liver appeared to tolerate the procedure as like in the patients with normal liver. We accumulated experience on the prolonged Pringle maneuver with curved intestinal clamps. Result: This technique was applied to more than 60 cases of adult LDLT operations from early 2014 until the end of 2018. Initially, application of this technique was limited to patients showing heavy bleeding during perihilar mobilization. Thereafter, this technique was applied at the start of liver mobilization and stopped after complete mobilization of the retro-hepatic vena cava. Recently, this technique was also applied during dissection of the hepatoduodenal ligament. The mean total occlusion duration was 67±13 minutes. No patient suffered from major serosal peritoneal tearing-associated bleeding or hepatic artery problems. Intentional prolonged occlusion over two hours was applied to five patients who had advanced hepatocellular carcinoma. Conclusion: We believe that prolonged occlusion of the hepatoduodenal ligament is a simple effective method to reduce intraoperative bleeding, and that it has potential benefit to reduce the risk of intraoperative tumor spread during LDLT operations.

Prolonged occlusion of the hepatoduodenal ligament to reduce risk of bleeding and tumor spread during recipient hepatectomy for living donor liver transplantation.

Backgrounds/AimsPrevention of excessive bleeding during liver transplantation (LT) operations presents a major challenge. Compared to deceased donor LT, living donor LT (LDLT) is more vulnerable to bleeding because of additional dissection procedures. We herein introduce our technique for prolonged occlusion of the hepatoduodenal ligament applied to recipient hepatectomy for LDLT.MethodsSimulated assessment of splanchnic hemodynamics on prolonged occlusion of the hepatoduodenal ligament showed that patients with cirrhotic liver appeared to tolerate the procedure as like in the patients with normal liver. We accumulated experience on the prolonged Pringle maneuver with curved intestinal clamps.ResultsThis technique was applied to more than 60 cases of adult LDLT operations from early 2014 until the end of 2018. Initially, application of this technique was limited to patients showing heavy bleeding during perihilar mobilization. Thereafter, this technique was applied at the start of liver mobilization and stopped after complete mobilization of the retro-hepatic vena cava. Recently, this technique was also applied during dissection of the hepatoduodenal ligament. The mean total occlusion duration was 67±13 minutes. No patient suffered from major serosal peritoneal tearing-associated bleeding or hepatic artery problems. Intentional prolonged occlusion over two hours was applied to five patients who had advanced hepatocellular carcinoma.ConclusionsWe believe that prolonged occlusion of the hepatoduodenal ligament is a simple effective method to reduce intraoperative bleeding, and that it has potential benefit to reduce the risk of intraoperative tumor spread during LDLT operations.

Beneficial Effects of Adrenal Androgen Supplement in Bleeding Cirrhotic Rats.

Critical illness is accompanied by hypothalamic-pituitary-adrenal axis activation, but adrenal insufficiency characterized by inadequate glucocorticoid synthesis is common in critically ill cirrhotic patients, the "hepato-adrenal syndrome." Adrenal cortex also synthesizes androgen (dehydroepiandrosterone, DHEA). DHEA maintains microcirculation by enhancing vascular endothelial nitric oxide synthase (eNOS) activity. In critical patients of other disease entities, a shift of adrenal steroidogenesis away from androgens toward glucocorticoid has been noted, arousing interests in androgen replacement in critical settings. Nevertheless, this has not been surveyed in cirrhosis with hemorrhage. In this study, liver cirrhosis was induced with common bile duct ligation (BDL) in Spraque-Dawley rats. Sham rats were controls. DHEA or vehicle was injected at the beginning of hemorrhage-transfused procedure, followed by terlipressin injection. Hemodynamic parameters were measured. Then abdominal aorta, superior mesenteric arteries (SMA) and splenorenal shunt (prominent portosystemic collateral vessel in rodents) eNOS and inducible NOS protein expressions were evaluated. In bleeding BDL groups without terlipressin injection, adrenocorticotropic hormone (ACTH) stimulation test was performed to evaluate the DHEA response. The results showed that DHEA significantly elevated mean arterial pressure, cardiac output, and stroke volume of bleeding cirrhotic rats treated with terlipressin and reduced systemic vascular resistance without affecting SMA flow, resistance, and portal pressure. DHEA upregulated abdominal aorta and SMA eNOS expressions. ACTH did not stimulate DHEA synthesis in bleeding BDL rats. In conclusion, androgen deficiency exists in bleeding cirrhotic rats. DHEA augments terlipressin-induced amelioration of shock without influencing splanchnic hemodynamics, possibly rendering it a feasible adjunct to vasoconstrictors in variceal hemorrhage.