Effect of treatment with the Molecular Adsorbents Recirculating System on arterial amino acid levels and cerebral amino acid metabolism in patients with hepatic encephalopathy

BACKGROUND: Liver failure is associated with low concentrations of branched-chain amino acids and high concentrations of most other amino acids. In this study the effect of treatment with the Molecular Adsorbents Recirculating System (MARS) on arterial amino acid levels and cerebral amino acid metabolism was examined in patients with severe hepatic encephalopathy. METHODS: The study included seven patients with hepatic encephalopathy from fulminant hepatic failure (FHF) and five patients with hepatic encephalopathy from acute-on-chronic liver failure (AoCLF). Cerebral blood flow and cerebral arteriovenous differences in amino acids were measured before and after 6 h of treatment with MARS. RESULTS: During MARS treatment, the total arterial amino acid concentration decreased by 20% from 8.92 +/- 7.79 mmol/L to 7.16 +/- 5.64 mmol/L (P < 0.05). The concentration decreased in all amino acids with the exception of the branched-chain amino acids. Fischer's ratio of branched-chain to aromatic amino acids increased from 0.73 +/- 0.47 to 0.91 +/- 0.54 (P < 0.05). A net cerebral efflux of amino acids in patients with FHF (8.94 +/- 8.34 micromol/100 g/min) as well as AoCLF (7.35 +/- 24.97 micromol/100 g/min) was not affected by the MARS treatment. MARS had no effect on the cerebral metabolic rate of any single amino acid in either group. CONCLUSIONS: MARS treatment tends to normalize the arterial amino acid concentrations in patients with hepatic encephalopathy. Even though the overall reduction in plasma amino acids and improvement in amino acid dysbalance may well be beneficial, it was not accompanied by any immediate improvement in cerebral amino acid metabolism in patients with FHF or AoCLF.     

Preconditioning by extracorporeal liver support (MARS) of patients with cirrhosis and severe liver failure evaluated for living donor liver transplantation -- a pilot study.

PURPOSE: The aim of this prospective study was to evaluate the effectiveness of preconditioning molecular adsorbent recirculating system (MARS) treatment on patients with acute-on-chronic liver failure (AoCLF), who were awaiting living donor liver transplantation (LDLT). PATIENTS AND METHODS: Between January and December 2001, 10 consecutive AoCLF patients (with progressive hyperbilirubinemia (>20 mg/dl) and hepatic encephalopathy grade > or =2) were studied. MARS was used in eight of these patients who were evaluated for LDLT during 2001. Three AoCLF patients who received LDLT before clinical use of MARS were used as historical controls. RESULTS: Because of a shortage of donors, only five out of 10 patients considered for LDLT could receive transplants. Three patients were treated with MARS for 8 h the day before receiving LDLT, and all three survived. The remaining two patients who received transplants, and who were not pretreated with MARS, died from sepsis and multi-organ failure within 2 weeks. Four of the patients who did not receive transplants because of donor shortage died despite 1 or 3 MARS treatments, however bilirubin levels and grade of encephalopathy were significantly reduced in these patients. CONCLUSIONS: Results of this small pilot study suggest that MARS, by reducing the severity of jaundice and encephalopathy, might be effective as a bridging option in AoCLF patients awaiting LDLT.     

A 3‐year experience with Molecular Adsorbent Recirculating System (MARS): our results on 63 patients with hepatic failure and color Doppler US evaluation of cerebral perfusion

Abstract In our 3‐year experience, we treated 63 patients with Molecular Adsorbent Recirculating System (MARS). The patients were divided as follows: 10 primary non‐function (PNF) 16%, 10 delayed non‐function (DNF) 16%, 16 Fulminant hepatitis (FH) 24%, 23 acute decompensation of chronic liver disease (ACLF) 38%, and 4 hepatic resection 6%. All patients who underwent MARS treatment had bilirubin >15 mg/dL, Glasgow Coma Score between 9 and 11, ammonium >160 µg/dL and non‐coagulability. The determining factors taken into consideration for the continuation of MARS treatment were: an improvement in Glasgow Coma Score, and a decrease in ammonium and bilirubin. We also monitored hemodynamic parameters, acid–base equilibrium, and blood gas analysis before and after each treatment. In order to determine patients' neurological conditions, we not only took into account the Glasgow Coma Score, which does not give mathematically precise results but also took into account the fact that patients with hepatic coma had lower cerebral mean velocity in the cerebral arteries than patients without encephalopathy. For this reason, in the last 22 patients we monitored cerebral perfusion, determined by mean flow velocity (V_mean) in the middle cerebral artery. Our results were expressed as mean ± SD and we analyzed the differences between mean values for each variable, before and after treatment by means of Student's t‐test. At the end of treatment, we obtained significant P‐values for bilirubin, ammonium, Glasgow Coma Score and creatinine. In 16/20 patients, we could demonstrate a clear correlation between the improvement in clinical conditions (especially neurological status) and improvement in cerebral perfusion, measured by color Doppler US.     

Albumin dialysis has a favorable effect on amino acid profile in hepatic encephalopathy

According to one popular theory, hepatic encephalopathy (HE) is partly caused by an imbalance in plasma amino acid levels. The Fischer's ratio between branched chain amino acids (BCAAs) and aromatic amino acids (AAAs) correlates with the degree of HE; the lower Fischer's ratio, the higher the grade of HE. Extra-corporeal liver support systems, like MARS(R)-albumin dialysis (Molecular Adsorbents Recirculating System), can improve HE. The MARS(R) system uses a hyperosmolar albumin circuit to remove both water-soluble and albumin-bound substances. Plasma levels of neuroactive amino acids were analyzed in 82 consecutive patients with life-threatening liver failure admitted to our ICU. All patients fulfilled our indications for MARS treatment and most also fulfilled the criteria for liver transplantation (LTx). In patients with acute liver failure (ALF), as compared to those with acute decompensation of chronic liver failure (AcOChr), levels of leucine and isoleucine were significantly higher before MARS(R) treatment. In all patients, before MARS(R) treatment the higher the grade of HE grade the lower was the Fischer's ratio and higher were the levels of inhibitory neuroactive amino acids. During MARS(R) treatments the Fischer's ratio increased, and the grade of HE decreased. The increase in Fischer's ratio was mainly due to the decrease in AAAs. The plasma levels of neuroactive amino acids, methionine, glutamine, glutamate, histidine and taurine decreased during MARS(R)-treatment. In this study MARS(R)-albumin dialysis had a favorable effect on the plasma amino acid profile of patients with HE.     

Hepatic and systemic haemodynamic changes after MARS in patients with acute on chronic liver failure

Abstract Hyperdynamic circulation and portal hypertension characterize acute on chronic liver failure (AoCLF), partially because of circulating mediators. Molecular Absorbents Recirculating System (MARS) may remove some of these substances. The objective of this study was to evaluate the effect of MARS on portal pressure, systemic haemodynamic and endogenous vasoactive systems. MARS treatment was performed in four patients with AoCLF (mean age 36.2 ± 3.1 years; Child–Pugh C 11 ± 1.8 points; three AAH and one NASH). Systemic and splanchnic haemodynamic measurements were performed before and after each session. Plasmatic renin activity (PRA) and NE were measured at baseline, at the end of the sessions and 10 days after MARS. All patients had severe portal hypertension (HVPG = 23 ± 7 mmHg) and pronounced hyperdynamic circulation (MAP 77.8 ± 11.7 mmHg; CO 11.2 ± 1.6 L/min; SVRI 478.5 ± 105 dyne s/cm⁵). HVPG decreased at the end of the first session in all patients (23 ± 7 mmHg vs 17.3 ± 9.9 mmHg; P = 0.05; mean decrease 32 ± 24%) because of a decrease in WHVP (40.7 ± 5.6 mmHg vs 34 ± 9.6 mmHg; P = 0.025; mean decrease 18 ± 19%). MARS significantly attenuated hyperdynamic circulation as shown by a decrease in CO (11.2 ± 1.6 L/min vs 9.4 ± 2.1 L/min; mean decrease 12.3%), with an increase in MAP (77.8 ± 11.7 mmHg vs 84.2 ± 8 mmHg; mean increase 9.2%) and in SVRI (478.5 ± 105 dyne s/cm⁵ vs 622 ± 198 dyne s/cm⁵; mean increase 41%). PRA and NE decreased significantly (14.2 ± 17.2 ng/mL/h vs 3.7 ± 3.4 ng/mL/h; 1319 ± 1002 pg/mL vs 617 ± 260 pg/mL, respectively). The NE decrease was correlated to HVPG decrease (r = 1, P = 0.01). MARS decreases portal hypertension and ameliorates hyperdynamic circulation in patients with AoCLF, probably mediated by clearance of vasoactive substances. Further studies are necessary to confirm these results.     

An Australian experience with the molecular adsorbents recirculating system (Mars)

The molecular adsorbents recirculating system (MARS) is a form of artificial extracorporeal liver support which has the potential to remove substantial quantities of albumin-bound toxins postulated to contribute to the pathogenesis of liver cell damage, hemodynamic instability and multi-organ failure in patients with acute liver failure and acute-on-chronic liver failure (AoCLF). We assessed the efficacy of MARS therapy in a cohort of patients with severe liver damage unresponsive to intensive medical therapy. MARS therapy was instituted late in the clinical course of six patients with severely impaired liver function refractory to intensive medical therapy, including four with AoCLF precipitated by sepsis and two with liver dysfunction due to sepsis in the absence of pre-existing chronic liver disease. Outcome measures included markers of hemodynamic stability, renal function, serum bilirubin and bile acid levels, arterial ammonia levels, the arterial ketone body (acetoacetate/beta-hydroxybutyrate) ratio, hepatic encephalopathy grade and the plasma disappearance rate of indocyanine green. The rates of discharge from the intensive care unit and in-hospital mortality were determined. Our findings suggest that MARS treatment might be associated with some clinical efficacy even in patients with advanced multi-organ dysfunction occurring in the setting of severe liver damage and in whom treatment is instituted late in the clinical course. However, the overall survival rate (1/6; 17%) was poor. More data obtained from larger cohorts of patients enrolled in randomized controlled studies will be required in order to identify categories of liver failure patients who might benefit most from MARS treatment and to ascertain the most appropriate timing of intervention.     

Serum amino acids in hepatic encephalopathy--effects of branched chain amino acid infusion on serum aminogram

Encephalopathic patients with cirrhosis of the liver consistently showed elevated levels of the aromatic amino acids, phenylalanine, tyrosine and free tryptophan as well as methionine in serum, whereas levels of the branched chain amino acids, valine, leucine and isoleucine, were depressed. Comatose patients with fulminant hepatitis had markedly elevated levels of all amino acids, the results being greatly different from those of cirrhotic patients. Molar ratios of (valine + leucine + isoleucine)/(phenylalanine + tyrosine) decreased both in cirrhotics with and without encephalopathy and in cases with fulminant hepatitis. Infusion of a commercially available L-amino acid solution in a cirrhotic patient induced a strikingly abnormal aminogram documented in hepatic encephalopathy. Therefore, effects of branched chain amino acid infusion on the deranged amino acid pattern were primarily studied for the purpose of improvement in hepatic encephalopathy by normalization of serum amino acid patterns. Elevated levels of the aromatic amino acids and methionine could be apparently depressed in a cirrhotic patient by this type of infusion but not in a case of fulminant hepatitis probably because of the poor utilization of these amino acids in severely impaired liver.     

Improvement of Multiple Organ Functions in Hepatorenal Syndrome During Albumin Dialysis with the Molecular Adsorbent Recirculating System

Abstract: Recently, significant improvement of renal function and prolongation of survival were reported in hepatorenal syndrome (HRS) patients treated with the Molecular Adsorbent Recirculating System (MARS). As no impact on extrarenal organ function was documented, this trial looked into multiple organ function changes during MARS in HRS patients. Eight HRS patients (4 male, mean age 42. 1 years, range 30–58, all United Network for Organ Sharing [UNOS] status 2A) were treated intermittendly 4–14 times (total 47, mean 5.9 ± 3.4) between 4 and 8 h/single treatment. The following changes were observed pre‐ and posttreatment: bilirubin 466 ± 146 to 284 ± 134 γmol/L, creatinine 380 ± 182 to 163 ± 119 μmol/L, urea 26.4 ± 10.3 to 12.9 ± 4.9 mmol/L, plasma sodium 127.5 ± 7.7 to 137.5 ± 4.8 mmol/L (all p < 0.01). Mean arterial pressure (MAP) increased from 71.9 ± 12.8 to 95.6 ± 7.8 Torr (p < 0.001). Oliguria or anuria, present in all patients, was successfully reverted. Ascites, present in all patients, was not detectable after the treatment period. The hepatic encephalopathy grade decreased from 2.8 ± 0.8 to 0.8 ± 0.7 (p < 0.0001). Child‐Index decreased from 13.25 ± 1.3 to 9.4 ± 1.8 (p < 0.001). The hospital survival rate was 62%. One man underwent successful liver transplantation 18 months after the treatment. We conclude that MARS can improve multiple organ functions in patients with HRS.     

No Net Splanchnic Release of Glutathione in Man during N-Acetylcysteine Infusion

Glutathione and amino acid concentrations were measured in arterial and hepatic vein plasma in four healthy volunteers and two patients with cirrhosis. There was no significant splanchnic efflux of glutathione (95% confidence limits,-0.501 to 0.405 μmol/min). After infusion of N-acetylcysteine (NAC) in a high dose (150 mg/kg body weight primer plus 15 mg/(h × kg BW), corresponding to treatment of acetaminophen overdose, there was no change in the splanchnic glutathione efflux (95% confidence limits,-0.531 to 0.375 μmol/min). NAC increased hepatic plasma flow rate from 0.90 ± 0.531 min^-1 to 0.97 ± 0.11 (mean ± SEM; p < 0.05). The effects of NAC treatment on plasma amino acids corresponded to an increased load on hepatic metabolic N conversion and transamination among non-essential amino acids. Splanchnic uptake of serine, alanine, cystine, isoleucine, and phenylalanine increased after NAC compatible with stimulated hepatic glutathione synthesis. In contrast to the rat, plasma glutathione in man probably originates mainly from extrahepatic tissues.     

Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure.

BACKGROUND & AIMS: High circulating levels of ammonia have been suggested to be involved in the development of cerebral edema and herniation in fulminant hepatic failure (FHF). The aim of this study was to measure cerebral metabolism of ammonia and amino acids, with special emphasis on glutamine metabolism. METHODS: The study consisted of patients with FHF (n = 16) or cirrhosis (n = 5), and healthy subjects (n = 8). Cerebral blood flow was measured by the 133Xe washout technique. Blood samples for determination of ammonia and amino acids were drawn simultaneously from the radial artery and the internal jugular bulb. RESULTS: A net cerebral ammonia uptake was only found in patients with FHF (1.62 +/- 0.79 micromol x 100 g(-1) x min(-1)). The cerebral glutamine efflux was higher in patients with FHF than in the healthy subjects and cirrhotics, -6.11 +/- 5.19 vs. -1.93 +/- 1.17 and -1.50 +/- 0.29 micromol x 100 g(-1) x min(-1), respectively (P < 0.05). Patients with FHF who subsequently died of cerebral herniation (n = 6) had higher arterial ammonia concentrations, higher cerebral ammonia uptake, and higher cerebral glutamine efflux than survivors. Intervention with short-term mechanical hyperventilation in FHF reduced the net cerebral glutamine efflux, despite an unchanged net cerebral ammonia uptake. CONCLUSIONS: Patients with FHF have an increased cerebral glutamine efflux, and short-term hyperventilation reduces this efflux. A high cerebral ammonia uptake and cerebral glutamine efflux in patients with FHF were associated with an increased risk of subsequent fatal intracranial hypertension.     

Persistent retention of acetic acid is associated with complete tumour necrosis in patients with hepatocellular carcinoma undergoing percutaneous acetic acid injection

Background: Ultrasound (US)‐guided percutaneous acetic acid injection therapy (PAIT) is effective for patients with hepatocellular carcinoma (HCC). This study aimed to determine the occurrence and predictive value of persistent intra‐tumoral retention of acetic acid after PAIT. Methods: We prospectively studied 60 (52 M, mean age 68?±?10 years) patients with 72 HCC nodules (45?≤?3?cm) treated with PAIT. The presence of post‐treatment persistent retention of acetic acid, defined as a homogeneous and highly hyperechoid mass in US appearance 3 days after completion of the treatment, was correlated with the treatment response. Results: The mean size of the treated tumour was 2.9?±?1.0?cm (range 1.5–5?cm). Thirty (42%) HCC nodules showed complete tumour necrosis demonstrated by contrast‐enhanced dynamic CT. Complete response was found in 22 (69%) of 32 nodules showing persistent intra‐tumoral retention of acetic acid (P?P?=?0.001). There were no significant differences of the injection volume and treatment sessions between those with and without complete tumour necrosis in either small or large (>3?cm) HCC (P?>?0.1). Multivariate logistic regression analysis showed that persistent retention of acetic acid (odds ratio (OR) 10.4, 95% confidence interval (CI) 3.1–34.7; P?P?=?0.002) were independent factors predicting complete tumour necrosis. Conclusions: The presence of persistent retention of acetic acid is associated with a favourable response and may predict complete tumour necrosis after PAIT.     

Changes in brain ECF amino acids in rats with experimentally induced hyperammonemia

Using microdialysis, we studied brain extracellular fluid (ECF) amino acid metabolism in rats with experimentally induced hyperammonemia and regional elevation of brain ECF ammonia levels. The total brain ECF amino acid level was increased by an elevation of the blood ammonia level. Hyperammonemia elevated brain ECF aromatic amino acids and reduced arterial blood branched chain amino acids. When rats with hyperammonemia were intravenously administered norleucine, the brain ECF norleucine level rose markedly, suggesting increased permeability of the blood-brain barrier. When rats with hyperammonemia were infused with a branched chain amino acid-rich preparation, the elevated brain ECF aromatic amino acids level was not suppressed. Following local intracerebral ammonia infusion, only glutamate levels showed a marked elevation. These results suggest that impairment of the blood-brain barrier related to hyperammonemia increases the inflow of low molecular weight substances including amino acids. Furthermore, the ammonia-induced increase of glutamate in the cerebral ECF suggests that high ammonia levels may increase the excitability of the brain. Thus, ammonia may serve as a key factor in the onset of hepatic encephalopathy.     

Effects of a one-week treatment with acid gastric inhibitors on Helicobacter pylori-infected mice

Abstract

Background: Obesity is one of the main factors of transient elastography (TE) failure, considering body mass index (BMI) ≥28?kg/m² as a limiting factor. The XL probe was designed to overcome this limitation.

Aim: To compare the feasibility of the M and XL probes in patients with BMI ≥ 28?kg/m², to evaluate differences in mean values of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) between the two probes and find predictive factors of TE failure.

Material and methods: Prospective study, including all patients with BMI ≥ 28?kg/m² consecutively admitted for TE.

Results: Included 161 patients. Measurements with M probe were reliable in 69.6% of the patients, with 68.2% of valid measurements in obese population and 58.9% in patients with skin-capsule distance (SCD) >25?mm. In 40 patients (81.6%) with an invalid M probe measurement, a reliable result was obtained with XL probe. We found that SCD >25?mm was the only predictor of M probe failure (OR: 4.9, CI: 1.64–14.63, p?=?.004). In those patients in which TE was possible with both probes (n?=?112), mean CAP was 304?±?49?dB/m² with M probe and 301?±?50?dB/m² with XL probe (p?=?.59). Regarding liver stiffness, a mean value of 7.58?±?3.47?kpas was obtained with the M probe and 6.21?±?3.44?kpas with the XL probe (p?Conclusion: There is a reliable applicability of the M probe in a high number (68.2%) of patients with a BMI ≥30?kg/m². A SCD >25?mm was the only predictive factor of M probe failure. Mean values of LSM with XL probe were lower than those obtained with M probe.     

Improvement in Central Nervous System Functions During Treatment of Liver Failure with Albumin Dialysis MARS—A Review of Clinical,Biochemical, and Electrophysiological Data

The Molecular Adsorbent Recirculating System (MARS) is a nonbiological liver support method based on the principles of dialysis, filtration, and adsorption. It allows the safe and efficient removal of both albumin-bound and water-soluble toxic metabolites, including ammonia, aromatic amino acids, tryptophan, and related phenolic and indolic products, as well as benzodiazepines. A well-documented effect of the treatment is the improvement of the hemodynamic situation of decompensated chronic patients. Systemic vascular resistance, mean arterial pressure, cerebral blood flow, and cerebral oxygen consumption increased significantly. The degree of hepatic encephalopathy decreased significantly. Increased intracranial pressure could be normalized in both chronic and fulminant liver failure. In three randomized clinical trials significant improvement of survival could be demonstrated. In a model of murine neuronal networks cultured on multi-microelectrode array plates and incubated with plasma from liver failure patients, a normalization of the spike and burst pattern could be observed, if plasma samples from MARS-treated patients before and after treatment were compared. In conclusion, MARS significantly improves central nervous system functions. It can serve as a model for the further investigation of the role of protein-bound substances in hepatic encephalopathy and cerebral hemodynamics.     

Plasma and cerebrospinal fluid amino acid patterns in hepatic encephalopathy

Plasma and cerebrospinal fluid amino acid levels were measured in 12 cirrhotic patients in grade 0 hepatic encephalopathy and 17 in grade 3–4 hepatic encephalopathy. In 5 of these patients amino acid determinations were performed during the evolution of the encephalopathy. No correlation was found between the degree of hepatic encephalopathy and the plasma amino acid imbalance. In the CSF of cirrhotic patients without encephalopathy, a significant increase was found in nearly all amino acids, including those known to not easily cross the blood-brain barrier; this suggests the presence of a nonspecific modification of the blood-brain barrier permeability. In patients with severe hepatic encephalopathy, the further increase only in cerebrospinal fluid aromatic amino acids and methionine levels suggests the presence of a selective stimulation of the neutral amino acid transport system across the blood-brain barrier. Finally, the good correlation between glutamine and the sum of neutral amino acids found in the cerebrospinal fluid only in the presence of encephalopathy supports the hypothesis that brain glutamine may stimulate neutral amino acid transport across the blood-brain barrier.This work was supported by grant 500.6/Contr. 70/1743 Ministry of Health, Rome, Italy.     

Contrast-enhanced ultrasonography could be a non-invasive method for differentiating none or mild from severe fibrosis in patients with biopsy proven non-alcoholic fatty liver disease

Objective: The gold standard for diagnosing fibrosis stage in non-alcoholic fatty liver disease (NAFLD) is liver biopsy. The aim of this study was to determine whether contrast-enhanced ultrasonography (CEUS) with transit time measurements could be a non-invasive alternative for differentiating none or mild from severe fibrosis in NAFLD patients. Various serum markers and clinical variables were also evaluated.

Materials and methods: Fifty-eight patients with NAFLD underwent CEUS prior to liver biopsy. All patients were also evaluated according to the Göteborg University Cirrhosis Index (GUCI), the AST-Platelet Ratio Index (APRI), the NAFLD fibrosis score, and the FIB-4 and BARD score.

Results: The hepatic vein arrival time (HV) was shorter in patients with severe fibrosis (25.9?±?4.8 vs 29.5?±?4.7?s, p?=?0.023), and the difference between the hepatic and portal vein (ΔHV–PV) was shorter (2.3?±?2.8 vs 6.4?±?2.8?s, p?p?Conclusions: CEUS and non-invasive scoring systems could exclude severe fibrosis in NAFLD patients.     

MARS therapy in critically ill patients with advanced malignancy: a clinical and technical report

Abstract Background/methods: Molecular Adsorbent Recirculating System (MARS) was used in three consecutive critically ill patients at the Singapore General Hospital with advanced malignancy and acute liver failure (ALF). Case 1 was a male patient with hepatocellular carcinoma (HCC) for which initial right hepatectomy was followed by left hepatectomy 5 months later for recurrent HCC. The postoperative course following second surgery was complicated by severe methicillin‐resistant Staphylococcus aureus (MRSA) sepsis, mild azotaemia and subacute cholestatic liver failure. MARS was used thrice in this patient. Case 2 was a female patient with advanced acute lymphoblastic leukaemia (ALL) with postbone marrow transplantation (BMT) acute haemolytic–uraemic syndrome (HUS) secondary to cyclosporin A (Cy A), cytomegalovirus (CMV) infection, severe nosocomial pneumonia, acute renal failure (ARF) treated with continuous haemofiltration and acute veno‐occlusive disease resulting in Budd–Chiari syndrome. The latter precipitated ALF. MARS was instituted twice. Case 3 was a male patient with advanced, refractory Hodgkin's disease previously treated with multiple courses of chemotherapy. ALF developed secondary to acute viral hepatitis B flare. He was given a trial of MARS once in the ICU. All the three patients eventually died. Results: Mean MARS intradialytic systemic pressures were as follows: systolic pressure range was 95 ± 17 to 128 ± 17 mmHg and diastolic pressure range was 51 ± 5 to 67 ± 7 mmHg. Pressure at albumin dialysate exit point from dialyser 1 (Ae) ranged from 253 ± 11 to 339 ± 15 mmHg and that at albumin dialysate entry point into dialyser 1 (Aa) ranged from 142 ± 11 to 210 ± 6 mmHg. Ultrafiltration (UF) was 633 ± 622 mL over mean treatment duration of 6.3 ± 0.9 h with a total heparin dose of 1583 ± 817 IU. Coagulation status pre‐ and 6‐h post‐MARS was similar: aPTT (P = 0.116) and platelet count (P = 0.753). There were no bleeding complications or circuit thromboses. MARS had a significant de‐uraemization effect (pre‐ and post‐MARS serum creatinine and urea: P = 0.046 and 0.028, respectively) but did not significantly attenuate blood lactate, ammonia or total bilirubin levels. Albumin dialysate (Ae ? Aa) urea and creatinine concentrations appeared to be sharply attenuated after 6 h of MARS. In contrast, the removal of total bilirubin by albumin dialysate from the blood compartment appeared to plateau after 4 h of continuous MARS operation. Conclusions: MARS was well‐tolerated in critically ill patients with advanced and complicated cancer. Low‐dose heparin was safe and did not compromise MARS circuit integrity. Although MARS had a significant de‐uraemization effect, this appeared to be limited by the duration of MARS operation. Our data suggested that such a limit was reached earlier for total bilirubin. More data are needed to confirm the present findings and further delineate the saturation limit of MARS for different toxins that accumulate in ALF. This would affect the optimal duration of MARS therapy.     

Protective effects of regulatory amino acids on ischaemia-reperfusion injury in the isolated perfused rat liver

Objective. Some amino acids (AAs) display potent regulatory activities on cell metabolism, including via anti-oxidative defences. The aim of this study was to evaluate the protective effect of these AAs on warm ischaemia-reperfusion (I/R) injury in the isolated perfused rat liver.

Material and methods. Livers from fasted male Sprague-Dawley rats were isolated and perfused without (control group) or with (AP group) a mixture of regulatory AAs (glutamine, histidine, leucine, methionine, proline, phenylalanine, tryptophan and alanine). After 45 min of perfusion, warm ischaemia was induced for 45 min by clamping the portal vein catheter; thereafter, reperfusion was performed for 30 min.

Results. TNF-α production was significantly lower in the AP group during reperfusion (Control: 39±7 versus AP: 16±2 pg min^?1 g^?1, p<0.05), and lactate dehydrogenase (LDH) release decreased significantly during the last 15 min of reperfusion (Control: 0.13±0.03 versus AP: 0.04±0.02 IU min^?1 g^?1, p<0.05), despite similar levels of oxidative stress. The addition of regulatory AAs was not associated with variations in portal flow, bile flow, hepatic glucose or urea metabolism. However, significant changes in intrahepatic glutamine (Control: 1.4±0.2 versus AP: 2.6±0.5 µmol g^?1, p<0.05) together with higher glutamate release in the AP group (Control: 10.2±5.4 versus AP: 42.6±10.9 nmol min^?1 g^?1, p<0.05) indicated modifications in nitrogen metabolism.

Conclusions. Taken together, the lower TNF-α production, suggesting decreased inflammatory response, the decrease in LDH release in the AP group, demonstrating a better preservation of liver viability, and the increase in hepatic glutamine indicate that AAs play an important role in the liver's response to I/R.     

Impact of mandibular advancement device therapy on cerebrovascular reactivity in patients with carotid atherosclerosis combined with OSAHS

Purpose

Obstructive sleep apnea-hypopnea syndrome (OSAHS) may affect cerebrovascular reactivity (CVR), representing cerebrovascular endothelial function, through complex cerebral functional changes. This study aimed to evaluate the change of CVR after 1-month and 6-month mandibular advancement device (MAD) treatment of patients with carotid atherosclerosis (CAS) combined with OSAHS.

Methods

Patients with carotid atherosclerosis combined with OSAHS who voluntarily accepted Silensor-IL MAD therapy were prospectively enrolled. All patients underwent polysomnographic (PSG) examinations and CVR evaluation by breath-holding test using transcranial Doppler ultrasound at baseline (T0), 1 month (T1), and 6 months (T2) of MAD treatment.

Results

Of 46 patients (mean age 54.4 ± 12.4 years, mean body mass index [BMI] 27.5 ± 4.5 kg/m²), 41 patients (responsive group) responded to the 1-month and 6-month treatment of MAD, an effective treatment rate of 89%. The remaining 5 patients (non-responsive group) were younger (47.4?±?13.5 years) and had a higher BMI (35.8?±?1.8 kg/m²). The responsive group had an improvement of apnea-hypopnea index (AHI) (events/h) from 33.0?±?25.0 (T0) to 12.4?±?10.4 (T1) and 8.7?±?8.8 (T2), P?<?0.001; minimum arterial oxygen saturation (minSpO₂) (%) increased from 79.8?±?9.1 (T0) to 81.8?±?9.4 (T1) and 85.2?±?5.4 (T2), P?<?0.01; longest apnea (LA) (s) decreased from 46.5?±?23.1 (T0) to 33.3?±?22.7 (T1) and 29.4?±?18.5 (T2), P?<?0.001; T90 (%) decreased from 10.3?±?14.9 (T0) to 6.1?±?11.8 (T1) and 3.3?±?7.5 (T2), P?<?0.05. Sleep architecture of these patients also improved significantly. The responsive group had a significant increase in left, right, and mean breath-holding index (BHI): left BHI(/s) from 0.52?±?0.42 (T0) to 0.94?±?0.56 (T1) and 1.04?±?0.64 (T2), P?<?0.01; right BHI(/s) from 0.60?±?0.38 (T0) to 1.01?±?0.58 (T1) and 1.11?±?0.60 (T2), P?<?0.01; mean BHI(/s) from 0.56?±?0.38 (T0) to 0.97?±?0.55 (T1) and 1.07?±?0.59 (T2), P?<?0.01), suggesting improved CVR.

Conclusion

Effective MAD therapy is beneficial for restoring cerebrovascular endothelial function in patients with CAS and OSAHS in a short period (1 month and 6 months).

Trial registration

Clinical trial registration number: NCT03665818. September 11, 2018.

     

Effects of late evening snack including branched‐chain amino acid on the function of hepatic parenchymal cells in patients with liver cirrhosis

Aim: A late evening snack (LES) improves protein‐energy malnutrition due to overnight starvation and the catabolic state in patients with liver cirrhosis. Our aim was to examine whether LES including a branched‐chain amino acid (BCAA) could maintain hepatic reserve and the function of hepatic parenchymal cells in patients with liver cirrhosis, including those in the early stage of disease. Methods: Seventeen patients with liver cirrhosis received LES with a BCAA‐enriched nutrient mixture. During the study period, each patient was instructed on energy and protein intake. Indicators of liver function measured at 6 months included maximum asialoscintigraphic removal (Rmax: indicator of total liver receptors), asialoscintigraphic imaging grade, serum albumin, ammonia, tyrosine and BTR (molar ratio of branched‐chain amino acids to tyrosine). Results: Serum albumin levels, BTR and tyrosine levels of the 17 patients were significantly improved after nutrient treatment. In patients with Rmax of 0.2 or higher, serum albumin level and tyrosine level were significantly improved. Conclusion: LES with BCAA‐enriched nutrient therapy can improve protein malnutrition in patients with liver cirrhosis, and is more useful in the early stages of liver cirrhosis in improving hepatic parenchymal cell mass.