QT interval prolongation by acute gastrointestinal bleeding in patients with cirrhosis.

BACKGROUND & AIMS: QT interval prolongation is frequent in cirrhosis, and stressful conditions could further prolong QT. We aimed to test this hypothesis and, if it proved correct, to assess its prognostic meaning. METHODS: We reviewed the clinical records of 70 consecutive cirrhotic and 40 non-cirrhotic patients with acute gastrointestinal bleeding. All patients had been evaluated before bleeding (T0) and were re-evaluated at the time of bleeding (T1) and 6 weeks afterwards (T2). RESULTS: QT corrected by heart rate (QTc) lengthened at T1, returning towards baseline values at T2 (mean ± SEM; from 415.9 ± 4.3 to 453.4 ± 4.3 to 422.2 ± 5.7 ms, P < 0.001) in cirrhotics; contrariwise, QTc did not change in non-cirrhotic patients. The 6-week mortality was 29.6% among cirrhotic patients, while no control patient died. At T1, patients who died had longer QTc (P = 0.001) and higher model of end-stage liver disease (MELD) score (P < 0.001) than survivors. MELD and QTc independently predicted survival. Their areas under the ROC curve were 0.88 (CI 95% 0.78-0.95) and 0.75 (CI 95% 0.63-0.85) respectively; the best cut-off values were MELD ≥20 and QTc ≥ 460 ms. Based on these factors, the 6-week mortality was: 0% for patients without risk factors, 32.1% for those with one risk factor and 70.6% for those with both (P < 0.001). CONCLUSIONS: Acute gastrointestinal bleeding further prolongs QTc in cirrhosis. This abnormality independently predicts bleeding-induced mortality. The combined measurement of QTc interval and MELD can clearly identify three patient strata at increasing risk of bleeding-related mortality, thus improving the decision-making for these patients.

Treatments for hepatocellular carcinoma in elderly patients are as effective as in younger patients: a 20-year multicentre experience.

OBJECTIVES: The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. We compared the presenting features and outcome of HCC in elderly (>or=70 years) and younger patients (<70 years). DESIGN: Multicentre retrospective cohort study and nested case-control study. Patients 614 elderly and 1104 younger patients from the ITA.LI.CA database, including 1834 HCC cases consecutively diagnosed from January 1987 to December 2004. Both groups were stratified according to treatment: hepatic resection, percutaneous procedures, transarterial chemoembolisation (TACE). Survival was assessed in the whole population and in each treatment subgroup. Age, sex, aetiology, cirrhosis, comorbidities and cancer stage (CLIP score) were tested as predictors of survival. In each subgroup, differences in patient survival were also assessed after adjustment and matching by propensity score. RESULTS: Ageing was associated with a higher prevalence of comorbidities, better liver function and CLIP score. Regardless of age, two-thirds of patients underwent radical treatments or TACE. Elderly patients underwent more ablative procedures and fewer resections or TACE sessions. The survival of elderly and younger patients was comparable in each treatment subset, and was predicted by CLIP score. This result was confirmed by the propensity analysis. CONCLUSIONS: The overall applicability of radical or effective HCC treatments was unaffected by old age. However, treatment distribution differed, elderly individuals being more frequently treated with percutaneous procedures and less frequently with resection or TACE. Survival was unaffected by age and primarily predicted by cancer stage, assessed by the CLIP system, both in the overall population and in treatment subgroups.

Cannabinoid type 1 receptor antagonism delays ascites formation in rats with cirrhosis.

BACKGROUND & AIMS: Endocannabinoids contribute to hemodynamic abnormalities of cirrhosis. Whether this favors renal sodium retention and ascites formation is unknown. We determined whether cannabinoid type 1 receptor antagonism prevents sodium retention and ascites formation in preascitic cirrhotic rats. METHODS: Once renal sodium handling was impaired, rats with carbon tetrachloride-induced cirrhosis were randomized to receive either vehicle or rimonabant (3 [group 1] or 10 [group 2] mg x kg(-1) x day(-1)) for 2 weeks. Natriuresis, sodium intake, and sodium balance were measured daily. At the end of the protocol, systemic hemodynamics, renal blood flow, ascites volume, and liver fibrosis were assessed. RESULTS: A significant reduction in ascites formation (group 1: 54%; group 2: 10%; vehicle: 90%) and volume (group 1: 1.6 +/- 0.3 mL; group 2: 0.5 mL; vehicle: 5.5 +/- 0.8 mL) occurred in treated rats. Rimonabant significantly improved sodium balance during week 2 (group 1: 0.98 +/- 0.08 mmol; group 2: 0.7 +/- 0.08 mmol; vehicle: 3.05 +/- 0.11 mmol). Both treated groups showed lower cardiac output and higher mean arterial pressure, peripheral vascular resistance, and renal blood flow (P < .05). Liver fibrosis was reduced in group 2 by 30% (P < .05 vs vehicle). Mean arterial pressure inversely correlated with sodium balance (R = -0.61; P = .003), but not with fibrosis score. CONCLUSIONS: Rimonabant improves sodium balance and delays decompensation in preascitic cirrhosis. This is achieved though an improvement in systemic and renal hemodynamics, although it cannot be excluded that the antifibrotic effect of the drug may play a role.

A comparison of kaolin-activated versus nonkaolin-activated thromboelastography in native and citrated blood.

Thromboelastography can be performed with native or citrated blood (a surrogate to native blood in healthy controls, surgical and cirrhotic patients). Activators such as kaolin are increasingly used to reduce the time to trace generation. To compare kaolin-activated thromboelastography with nonkaolin-activated thromboelastography of native and citrated blood in patients with liver disease, patients undergoing treatment with warfarin or low-molecular weight heparin and healthy volunteers. We studied thromboelastography parameters in 21 healthy volunteers (group 1) and 50 patients, including 20 patients with liver cirrhosis with a nonbiliary aetiology (group 2), 10 patients with primary biliary cirrhosis or primary sclerosing cholangitis (group 3), 10 patients on warfarin treatment (group 4) and 10 patients with enoxaparin prophylaxis (group 5). Thromboelastography was performed using four methods: native blood (kaolin-activated and nonkaolin-activated) and citrated blood (kaolin-activated and nonkaolin-activated). For all thromboelastography parameters, correlation was poor (Spearman correlation coefficient < 0.70) between nonkaolin-activated and kaolin-activated thromboelastography, for both citrated and native blood. In healthy volunteers, in patients with liver disease and in those receiving anticoagulant treatment, there was a poor correlation between nonkaolin-activated and kaolin-activated thromboelastography. Kaolin-activated thromboelastography needs further validation before routine clinical use in these settings, and the specific methodology must be considered in comparing published studies.

QT interval correction in patients with cirrhosis.

INTRODUCTION: QT interval prolongation is a common electrophysiological abnormality in patients with cirrhosis. As QT interval varies with the heart rate, many QT correction formulas have been proposed, the Bazett's one being the most criticized because it over-corrects the QT interval and may be misleading. This study focused on the QT-RR relationship in patients with cirrhosis to derive a population-specific QT correction formula. METHODS: One hundred cirrhotic patients of different etiology and severity and 53 healthy controls comparable for age and sex were enrolled. The QT-RR relationship was analyzed in patients by five regression analysis models to derive the population-specific QT-RR equation. The QTc was calculated and compared with those calculated by four common QT correction formulas (Bazett, Fridericia, Framingham, and Hodges). The correlation coefficient QTc-RR was calculated as a measure of the independence of QTc from the original RR interval. RESULTS: In patients the QT-RR relationship was best described by the power equation "QT = 453.65 x RR1/3.02" (R2 = 0.41), similar to the Fridericia's formula. Bazett's formula led to the longest QTc (P < 0.0001), which was still significantly influenced by the RR interval (R = -0.39; P < 0.0001), while the estimated equation led to a QTc value not influenced by RR (R = -0.014). CONCLUSION: Bazett's correction should be avoided in patients with cirrhosis because it still provides a rate-dependent QTc value and might be misleading, particularly when assessing the overall preoperative cardiac risk and the effect of drugs affecting the QT interval. In its place, our formula or that of Fridericia can be confidently employed.

The effects of unfractionated heparin, low molecular weight heparin and danaparoid on the thromboelastogram (TEG): an in-vitro comparison of standard and heparinase-modified TEGs with conventional coagulation assays.

To investigate the effects of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and danaparoid (DPD) added to whole blood in vitro on standard and heparinase-modified thromboelastogram (TEG) parameters compared with conventional assays of coagulation. The effects of UFH, LMWH and DPD on standard TEG parameters were compared with the prothrombin time, activated partial thromboplastin time, thrombin time and anti-activated factor X (anti-FXa) activity, at concentrations of these anticoagulants ranging from 0.025 to 1 U/ml. In the second part of the study, the effects of very low concentrations (0.005-0.05 U/ml) of UFH, LMWH and DPD on the difference between standard and heparinase-modified TEG parameters were compared with the prothrombin time, activated partial thromboplastin time, thrombin time and anti-FXa activity. Standard TEG parameters were outside the reference range at lower concentrations of UFH, LMWH and DPD than most conventional coagulation assays were able to detect. Only anti-FXa activity was more sensitive to the presence of these anticoagulants than the standard TEG alone. The lowest concentration of UFH, LMWH and DPD used in this study (0.005 U/ml) caused significant differences between the standard and heparinase-modified alpha-angles of the TEG. In addition, the difference between standard and heparinase-modified TEG parameters distinguished between low concentrations (0.005-0.05 U/ml) of UFH with greater sensitivity than anti-FXa activity, but were less sensitive to LMWH and DPD. The standard TEG is more sensitive to UFH, LMWH and DPD than most conventional coagulation tests, with the exception of anti-FXa activity. Calculation of the difference between standard and heparinase-modified TEG parameters greatly increases the sensitivity of the assay for the effects of these anticoagulants, and is more sensitive to very low quantities of UFH than anti-FXa activity.

Combined mechanical and pharmacologic thrombolysis for portal vein thrombosis in liver-graft recipients and in candidates for liver transplantation.

Portal vein thrombosis (PVT) is an uncommon cause for presinusoidal portal hypertension and can occur even in liver-graft recipients. Interventional radiology by percutaneous approach may represent a valid and less invasive alternative to surgical treatment. We describe three cases of PVT (2 liver-transplant patients and a cirrhotic patient candidate for liver transplantation) treated by combined mechanical and pharmacologic thrombolysis. The Arrow-Trerotola device was used along with the infusion of urokinase by way of a percutaneous-transhepatic approach. In all cases, a recanalization of the portal system was obtained and maintained during the follow-up. The best result was achieved when mechanical thrombectomy was performed before urokinase infusion. The combined locoregional treatment with mechanical thrombectomy and pharmacologic thrombolysis appears to be a promising approach for PVT because of its rapid and durable effect and its ability to reduce the dose of urokinase required to achieve recanalization.

Thromboelastography with citrated blood: comparability with native blood, stability of citrate storage and effect of repeated sampling.

Thromboelastography (TEG) with recalcified citrate blood is used as an alternative to native blood, but there is insufficient data regarding sample reliability and stability over time. Thus, TEG parameters of freshly drawn native blood were compared with those of recalcified citrated blood without celite in 10 healthy subjects, and the effect of repeated sampling over 240-min storage was evaluated. All TEG parameters following citrate storage remained stable between 30 min [clot formation time (k) = 7.2 +/- 0.6 min; maximum amplitude (ma) = 48.5 +/- 1.9 mm] and 2 h (k = 7.1 +/- 0.6 min; ma = 46.2 +/- 2.5 mm) after initial sampling, but were not comparable with native blood (k = 9.3 +/- 0.7 min; ma = 43.5 +/- 2.5 mm) at any time point. TEG parameters of repeatedly sampled citrated blood had a significant overall hypercoagulable trend throughout 4 h following sampling. In conclusion, in order to achieve reproducible results, citrated blood without celite may be utilized between 30 min and 2 h following sampling, but in normal subjects the TEG parameters following citrate storage are not comparable with native blood, possibly because of incomplete inhibition of the activation of the coagulation cascade. Thus, citrated blood can be used as a surrogate of native blood in assessing coagulation using TEG, but if repeated sampling is used the trend in hypercoagulability must be considered.

Muscle circulation contributes to hyperdynamic circulatory syndrome in advanced cirrhosis.

BACKGROUND/AIMS: Muscle wasting likely influences blood flow to muscle districts in advanced cirrhosis. Thus, we assessed systemic hemodynamics and femoral artery blood flow corrected by muscle mass of the lower limb in 13 patients (Child-Pugh classes B and C) and 11 healthy controls. METHODS: Systemic hemodynamics were assessed by transthoracic electrical bioimpedance, femoral artery blood flow by duplex-Doppler and muscle mass by magnetic resonance imaging. RESULTS: As expected, patients exhibited increased cardiac index and reduced peripheral vascular resistance. Femoral artery blood flow did not differ between patients and controls. However, when this parameter was indicized by the muscle mass of the lower limb, which was reduced in patients (median: 3391; range: [2546-4793] vs 5118 [3562-7077]cm3, p=0.0006), it proved almost doubled in patients (91.1 [59.9-119.4] vs 50.5 [38.6-69.8]microl/min cm3; p=0.0001). Patient femoral blood flow indicized by muscle mass correlated inversely with peripheral vascular resistance (r= -0.65; p=0.017) and directly with cardiac index (r=0.57; p=0.042). CONCLUSIONS: Vasodilation of muscle districts contributes to the reduced peripheral vascular resistance in advanced cirrhosis. Our findings provide a stronger rationale for the use of non-selective vasoconstrictors to treat hemodynamic-dependent complications of cirrhosis, such as hepatorenal syndrome.

Effect of chronic beta-blockade on QT interval in patients with liver cirrhosis.

BACKGROUND/AIMS: QT interval prolongation is frequent in cirrhosis, predicts a poor prognosis and may trigger severe ventricular arrhythmias. Our aim was to evaluate the effect of chronic beta-blockade on QT prolongation. METHODS: Clinical and laboratory evaluation, ECG and hepatic vein pressure gradient (HVPG) measurement were performed in 30 cirrhotic patients before and 1-3 months after prophylactic nadolol. QT was corrected for heart rate by the cirrhosis-specific formula and other formulas. RESULTS: QT(cirrhosis) was prolonged in 10 patients (33%); HVPG was increased in all cases. QT(cirrhosis) was correlated with the Child-Pugh score (r=0.40; p=0.027). Nadolol shortened QT interval only with the Bazett formula (p=0.01), remaining unchanged with the other formulas. The QT interval shortened only if prolonged at baseline (from 473.3+/-5.5 to 458.4+/-6.5 ms; p=0.007), while it lengthened when normal (from 429.8+/-3.1 to 439.3+/-2.9 ms; p=0.01). QTc changes were directly related to the baseline value (p<0.001). HVPG decreased from 19.4+/-0.8 to 15.6+/-1.3 mmHg (p=0.004). The HVPG changes did not correlate with QTc changes. CONCLUSIONS: Chronic beta-blockade shortens the QT interval only in patients with prolonged baseline values, and this is likely due to a direct cardiac effect.

Daily profile of circulating C-type natriuretic peptide in pre-ascitic cirrhosis and in normal subjects: relationship with renal function.

OBJECTIVE: To investigate whether the C-type natriuretic peptide (CNP) has a role in the regulation of fluid and sodium homeostasis in normal subjects and in pre-ascitic cirrhotic patients. MATERIAL AND METHODS: The daily profile of CNP plasma levels was assessed by serial measurements (0700 h, 0900 h, 1800 h, 2300 h) in 10 pre-ascitic cirrhotic outpatients (age 56+/-4 years) and in 10 age-matched healthy controls (54+/-2 years) on a normal sodium diet (150 mmol/day) while carrying on their usual activities (mobile from 0700 h to 2200 h), after an equilibration period of 5 days. Daily diuresis and natriuresis were also monitored. RESULTS: Mean daily CNP was comparable in cirrhotic and healthy subjects (3.64+/-0.32 versus 3.20+/-0.20 pg/ml; p=0.139); CNP concentration showed a tendency towards a circadian fluctuation in healthy subjects (p=0.053) but not in patients (p=0.171). Mean daily CNP concentration significantly correlated with 24-h natriuresis (r=0.709; p=0.022) and urine volume (r=0.745; p=0.013) in patients but not in healthy subjects. CONCLUSIONS: CNP plasma levels appear to play a role in the water-sodium balance regulation in patients with pre-ascitic cirrhosis.

QT interval in patients with non-cirrhotic portal hypertension and in cirrhotic patients treated with transjugular intrahepatic porto-systemic shunt.

BACKGROUND/AIMS: A prolonged QT interval is frequent in chronic liver disease and its aetiology remains unsettled. The study's aim was to assess the role of portal hypertension in the pathogenesis of QT prolongation. METHODS: We measured the QT interval in: (1) 10 patients with non-cirrhotic portal hypertension (NCPH) and preserved liver function; (2) 19 cirrhotic patients before, 1-3 and 6-9 months after transjugular intrahepatic porto-systemic shunt (TIPS) insertion. RESULTS: Baseline corrected maximum QT interval (QTcmax) was prolonged (>440 ms) in eight NCPH and 16 cirrhotic patients, and its value did not differ between the two groups (453+/-8 vs. 465+/-6 ms, P=NS). No patients showed an abnormal baseline QT dispersion. In cirrhotic individuals, QTcmax further increased 1-3 months after TIPS (P=0.042), thereafter remaining steadily elevated. QT dispersion only increased at the second post-TIPS determination (P=0.030). Such changes occurred despite no deterioration of liver function, plasma electrolytes and haemoglobin. CONCLUSIONS: QT interval is frequently prolonged in patient with both non-cirrhotic and cirrhotic portal hypertension and portal decompression by TIPS worsens this abnormality. These results suggest that the porto-systemic shunting is responsible for the altered ventricular repolarisation possibly through a dumping into the systemic circulation of splanchnic-derived cardioactive substances.