The effects of the acute administration of arterial vasoconstrictors on renal plasma flow (RPF) and urinary sodium excretion (UNaV) in cirrhotic patients with ascites with or without hepatorenal syndrome (HRS) are still controversial. As a consequence, vasoconstrictors are not actually used in the treatment of renal sodium retention or HRS in these patients, regardless of the several lines of evidence suggesting that these renal functional abnormalities are related to a marked arterial vasodilation. The lack of an orally available effective arterial vasoconstrictor probably represents a further reason for this omission. Consequently, the present study was made to evaluate the acute effects of the oral administration of midodrine, an orally available ␣-mimetic drug, on systemic and renal hemodynamics and on UNaV in cirrhotic patients with ascites. Mean arterial pressure (MAP), heart rate (HR), cardiac index ( The improvement in systemic hemodynamics, which was also maintained during the the 3-to 6-hour period after midodrine administration, was accompanied by a significant increase in RPF (541.5 ؎ 43.1 vs. 385.7 ؎ 39.9 mL · min ؊1 ; P F .005), GFR (93.1 ؎ 6.5 vs. 77.0 ؎ 6.7 mL · min ؊1 ; P F .025), and UNaV (92.7 ؎ 16.4 vs. 72.2 ؎ 10.7 Eq · min ؊1 ; P F .025). In addition, a decrease in PRA (5.33 ؎ 1.47 vs. 7.74 ؎ 2.17 ng · mL ؊1 · h; P F .05), ADH (1.4 ؎ 0.2 vs. 1.7 ؎ 0.2 pg · mL ؊1 ; P F .05), and NOx (33.4 ؎ 5.0 vs. 49.3 ؎ 7.3 mol ؊1 ; P F .05) was found. In patients with HRS, the effects of the drug on the systemic hemodynamics was smaller and shorter. Accordingly, regardless of a significant decrease in PRA (15.87 ؎ 3.70 vs. 20.70 ؎ 4.82 ng · mL ؊1 · h; P F .0025) in patients with HRS, no significant improvement was observed in RPF, GFR, or UNaV. In conclusion, the acute oral administration of midodrine is associated with a significant improvement in systemic hemodynamics in nonazotemic cirrhotic patients with ascites. As a result, renal perfusion and UNaV also improve in these patients. By contrast, midodrine only slightly improves systemic hemodynamics in patients with type 2 HRS, with no effect on renal hemodynamics and renal function. (HEPATOLOGY 1998;28:937-943.)It has been hypothesized that a peripheral arterial vasodilation is the main factor in the pathogenesis of the functional renal abnormalities in patients with cirrhosis. 1-3 Arterial vasodilation is thought to be related to an excess of local or systemic vasodilators such as glucagon, prostacyclin, substance P, vasoactive intestinal peptide, bile acids, and nitric oxide. [3][4][5][6][7] The localization of arterial vasodilation as well as its link with renal sodium retention are also debated. Clinical and experimental studies suggest that the reduction of arterial vascular resistance occurs mainly in the splanchnic area, whereas in many other vascular beds, i.e., in the renal vascular bed, arterial resistance is normal or even increased in cirrhosis with ascites. 8,9 The reflex activation of the neurohumoral pressor systems, sympathetic nervous ...

Antioxidant agents have the potential to reduce ischemia/reperfusion damage to organs for liver transplantation (LT). In this prospective, randomized study, we tested the impact of an infusion of N-acetylcysteine (NAC) during liver procurement on post-LT outcomes. Between December 2006 and July 2009, 140 grafts were transplanted into adult candidates with chronic liver disease who were listed for first LT, and according to a sequential, closed-envelope, single-blinded procedure, these patients were randomly assigned in a 1/1 ratio to an NAC protocol (69 patients) or to the standard protocol without NAC [71 patients (the control group)]. The NAC protocol included a systemic NAC infusion (30 mg/kg) 1 hour before the beginning of liver procurement and a locoregional NAC infusion (300 mg through the portal vein) just before cross-clamping. The primary endpoint was graft survival. The graft survival rates at 3 and 12 months were 93% and 90%, respectively, in the NAC group and 82% and 70%, respectively, in the control group (P ¼ 0.02). An adjusted Cox analysis showed a significant NAC effect on graft survival at both 3 months [hazard ratio ¼ 1.65, 95% confidence interval (CI) ¼ 1.01-2.93, P ¼ 0.04] and 12 months (hazard ratio ¼ 1.73, 95% CI ¼ 1.14-2.76, P 0.01). The incidence of postoperative complications was lower in the NAC group (23%) versus the control group (51%, P < 0.01). In the subgroup of 61 patients (44%) receiving suboptimal grafts (donor risk index > 1.8), the incidence of primary dysfunction of the liver was lower (P ¼ 0.09) for the NAC group (15%) versus the control group (32%). In conclusion, the NAC harvesting protocol significantly improves graft survival. The effect of NAC on early graft function and survival seems higher when suboptimal grafts are used. Liver Transpl 19:135-144, 2013. V C 2012 AASLD.Received April 3, 2012; accepted July 7, 2012.Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; DRI, donor risk index; GSH, glutathione; ICU, intensive care unit; INR, international normalized ratio; IRI, ischemia/reperfusion injury; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; NAC, N-acetylcysteine; PDF, primary dysfunction; PNF, primary nonfunction; POD, postoperative day.Francesco D'Amico contributed to the study concept and design, the acquisition and analysis of data, and the supervision of the study and manuscript. Alessandro Vitale contributed to the analysis and interpretation of data, the drafting of the manuscript, and the statistical analysis. Anna Chiara Frigo contributed to the statistical analysis. Umberto Cillo contributed to the analysis and interpretation of data and the supervision of the study. Alessandra Bertacco contributed to the acquisition and analysis of data and the critical revision of the manuscript. Donatella Piovan, Domenico Bassi, Rafael Ramirez Morales, Pasquale Bonsignore, Enrico Gringeri, Michele Valmasoni, Greta Garbo, Enrico Lodo, Francesco Enrico D'Amico, Michele Scopelliti, Amedeo Carraro, ...

1 The effects of pinacidil (10, 30, 50,M) on contractility (+dP/dt,,), coronary perfusion pressure (cP), and ECG intervals (PR, QRS, QT) have been studied on constant-flow perfused guinea-pig hearts, driven at four frequencies (2.5, 3, 3.5, 4 Hz).2 Pinacidil decreased +dP/dt,,,, cP and the QT interval in a dose-dependent manner, whereas the PR interval was increased. QRS duration was not modified. All these effects were independent of driving frequency. Pinacidil decreased the interval from Q-wave to T-wave peak (QTpeak) to a greater extent than the QT interval, thus decreasing the QTpeak/QT ratio. This effect, unlike that on QT interval, was more evident at the highest frequency of stimulation. 3 In 4 out of 20 hearts treated with pinacidil sustained ventricular fibrillation (VF) occurred following a short run of premature ventricular beats (R on T phenomenon). 4 In separate experiments, an attempt to induce VF electrically was made at drug concentrations ranging from 1OpM to 1OM (8 experiments for each concentration). In control conditions and at the lowest concentration of pinacidil tested (1OpM) VF could never be induced; in the presence of 30pMm pinacidil VF was induced in 5 out of 8 experiments. Drug concentrations higher that 50 gM permitted the induction of VF in every case. 5 Although the concentrations of pinacidil producing ventricular fibrillation are 30-40 times higher than those found in patients under long term treatment with this agent, it is suggested that caution should be used in prescribing this drug, at least in patients suffering from myocardial ischaemia.

The effect of flecainide on the QRS interval was studied in 10 patients who were receiving long-term oral treatment (50 to 150 mg twice daily) for arrhythmias that were refractory to other drugs. Total and free drug plasma levels and QRS durations were measured at intervals after the morning administration. Free drug plasma levels were linearly correlated with QRS duration in each patient and the slope of the line was widely variable in the population studied. Even after the data from one patient with an unusually high slope (0.454) was excluded from the analysis, the slope range was 0.0284 to 0.144. Pharmacodynamic variability could not be explained by heart rate changes, active metabolites, electrolyte disturbances, or free drug concentration. None of the pharmacokinetic parameters measured (average steady-state concentration, fluctuation of maximum and minimum concentrations, time to peak concentration, final half-life, and protein binding) showed an intersubject variability greater than 4.4 times. Our findings suggest that the determination of flecainide free plasma concentration may not be sufficient to forecast electrophysiologic effects in individual patients.

The pharmacokinetics of ajmaline were studied in 10 patients with suspected paroxysmal atrioventricular block who received a 1 mg/kg intravenous dose over 2 minutes for diagnostic purposes (ajmaline test). Plasma concentration decay followed a triexponential time course with a final half-life much longer (7.3 +/- 3.6 hours) than that previously found by other investigators (about 15 minutes). Mean total plasma clearance and renal clearance were 9.76 ml/min/kg and 0.028 ml/min/kg, respectively. Although most of the dose was eliminated through the extrarenal route (only 3.5% of the intravenous dose was recovered in urine), no fluorescent metabolites could be detected either in plasma or urine. The steady-state volume of distribution averaged 6.17 L/kg, and plasma protein binding ranged between 29 and 46%. Three patients developed a transient atrioventricular block after ajmaline administration. In the remainder, the drug prolonged atrio-His bundle (AH interval), His bundle-ventricular (HV interval) and intraventricular (QRS interval) conduction times. Corrected ventricular repolarisation time (QTc interval) showed less marked changes, which were biphasic at times. The mean maximum ajmaline-induced increase in HV interval was 98%, in QRS was 58%, in AH was 30%, and in QTc was 17%. In most cases the time course of electrocardiographic changes lagged behind that of plasma concentrations, suggesting a delayed equilibrium of plasma concentrations with the site of action (hysteresis). Despite that, the pharmacokinetic-pharmacodynamic model, which accounted for hysteresis, failed to fit the experimental data adequately.(ABSTRACT TRUNCATED AT 250 WORDS)