Experiences with MARS liver support therapy in liver failure: analysis of 176 patients of the International MARS Registry

Extracorporeal liver support using the MARS recently has shown remarkable results in several trials. This study aims to extend the basis for analyses by making available the worldwide data with help of an international registry. One hundred and seventy six patients were analysed, main indications are acute-on-chronic liver failure (56%), acute liver failure (22%), primary graft dysfunction (15%), liver failure post liver surgery (4%) and miscellaneous (3%). The predicted survival within the first group based on a mean MELD score of 30.4 pts. and a mean Child score of 12.6 pts. was quite limited. The data suggest an improved survival accompanied by significant improvements of hepatic encephalopathy, mean arterial pressure, serum bilirubin level, creatinine, urea, albumin, INR, ammonia and MELD score. The results are confirming observations of other trials before which have shown MARS therapy to be an effective and safe extracorporeal liver support in liver failure.     

Effect of thoracic blood volume changes on steady state cardiac output.

We have investigated the extent to which shifts of blood volume out of or into the thoracic region influence the steady state cardiac output. The systemic circulation of anesthetized dogs was replaced with an artificial circuit which stimulated the pertinent mechanical characteristics of an intact circulation. As in the normal animal, the steady state venous return was proportional to the pressure gradient for venous return (i.e, mean systemic minus right atrial pressure). Cardiac function was altered either by administration of epinephrine or by changes in left ventricular afterload. At a constant mean aortic pressure of 100 mm Hg, epinephrine administration increased the steady state cardiac output by 55%. Half of this increase resulted from the lowered mean right atrial pressure (caused by improved cardiac function); the remainder resulted from an increased mean systemic pressure (caused by the volume shift to the systemic circulation). Increases in afterload transferred sufficient volume to the heart-lung compartment to reduce significantly the mean systemic pressure and, hence, the steady state venous return. Our results indicate that the heart-lung compartment contains a significant volume which is under cardiac control. In addition to being able to alter the right atrial pressure, the heart can modulate the steady state cardiac output by adjusting the mean systemic pressure. To this degree the heart can adjust its own venous return.     

Betamethasone and the rhesus fetus: multisystemic effects.

In this controlled study of betamethasone administration to pregnant rhesus monkeys, using dosages per gram of fetal body weight similar to those reported in several human clinical studies, the most significant fetal pulmonary changes observed were increases in maximum lung volumes. The fact that comparable increases in peak volumes were demonstrated on saline filling supports our contention that these changes are related primarily to lung structural alterations rather than surfactant effects. Additional findings in the treated animals included reduced fetal head circumference, thymus weight, adrenal weight, placental weight, and maternal postoperative weight and increased fetal hepatic weight. Any of these glucocorticoid-induced changes could portend serious side effects. Further studies are needed to delineate the risk:benefit ratio of such treatment.     

Distribution of interstitial compliance and filtration coefficient in canine lung

Utilizing a modification of the isogravimetric methodology, we have estimated the perivascular interstitial compliance and filtration coefficient in the canine lung. These values averaged 1.8 g/cm H2O and 34 (g/h)/cm H2O, respectively, per 100 g lung wet weight. By studying lungs at both low and high states of inflation (where the alveolar septae are collapsed) we were also able to determine the spatial distribution of both the interstitial compliance and filtration coefficient. We estimate that of the above total interstitial compliance a maximum of 55% is around alveolar septal vessels, 20% around extra-alveolar arteries and 25% around extra-alveolar veins. Of the above total filtration coefficient, 50% represents filtration from alveolar septal vessels, 23% from extra-alveolar arteries, and 27% from extra-alveolar veins. Our results imply that there are finite interstitial compliances communicating with all permeable vessels. Significant pressures can be built up in these spaces, thereby acutely limiting the further formation of interstitial edema.     

Potential cardiotonic agents. 2. Synthesis and pharmacologic properties of 5-(pyri-4-yl)- and 5-phenyl substituted 3-cyano-6-methyl-2-oxaalkylaminopyridines

The authors describe the preparation, the physicochemical properties and the results of evaluation of positive inotropic and vasodilator activities in a series of 5-(4-pyridinyl)- and 5-phenyl-substituted 3-cyano-6-methyl-2-oxaalkylamino-pyridines. Some of the compounds are comparable in their positive inotropic potency to that of amrinone and cause, additionally, a decrease in blood pressure.     

Increase of Octanoate Concentrations During Extracorporeal Albumin Dialysis Treatments

Extracorporeal liver support procedures based on albumin dialysis require the use of pharmaceutical‐grade human serum albumin (HSA). Those preparations contain octanoate, which is added as stabilizer during the production process. For octanoate, a direct involvement in the pathogenesis of liver failure complications as well as an indirect influence by competitive displacement effects at the albumin molecule have been described. During five Single Pass Albumin Dialysis (SPAD) and three Molecular Adsorbent Recirculating System (MARS) treatments the changes of octanoate concentrations in blood and dialysate were investigated. An octanoate increase in patient blood was observed during passage of the filter for both SPAD (585 µmol/L [338–1022 µmol/L]) (median [range]) and MARS (182 µmol/L [71–437 µmol/L]) during the first three hours of treatment. The molar ratio of octanoate/albumin at the blood outflow was significantly higher during SPAD treatments (1.73 [0.86–2.64] vs. 0.54 [0.31–1.1]; P = 0.001) during MARS. Changes of octanoate blood levels during SPAD were significantly higher than during MARS (P < 0.001). The shift of octanoate from the dialysate to the patient was persistent during SPAD (median 67.6 µmol/min), whereas during MARS a decrease over time was observed (from 25.5 to 7.5 µmol/min). During albumin dialysis procedures a transfer of octanoate into patient blood occurs. The time‐course and extent are different between both albumin dialysis procedures. Given the positive clinical effects reported mainly for MARS, the clinical impact of albumin dialysis‐associated transfer of octanoate during extracorporeal liver support needs to be evaluated further.     

Delayed distension of contracted airways with lung inflation in vivo

A deep inspiratory sigh is one of the most severe dynamic stresses that lungs normally experience. It typically is a very transient phenomenon, normally lasting only about 2 to 3 s. The airway response to a deep inspiration has been shown to be different in asthmatic and normal individuals. When airway smooth muscle (ASM) is contracted in normal subjects, a deep inspiration results in a subsequent dilation of the airways. However, in asthmatic subjects, a deep inspiration often results in little change in airway function, and sometimes results in an even further contraction of ASM. The mechanism underlying this difference depends on the dynamic behavior of both ASM and the lung parenchyma. If the contracted muscle had slower dynamic responses than the lung parenchyma, the timing of the deep inspiratory maneuver could affect the airway response. In the present study, we designed an experiment to determine how well matched the dynamic response is of airways to that of the lung parenchyma. The results clearly demonstrate that airways contracted with methacholine dilate at about a rate four times slower than that of the lung parenchyma during rapid lung inflation and deflation. This effect may play a role in the unique response of asthmatic subjects to deep inspiration. The mechanism of this dynamic slowness of contracted airways probably involves intrinsic properties of the smooth-muscle contractile processes.     

Effects of tamoxifen on ischemia-induced angiogenesis in the mouse lung

Obstruction of pulmonary blood flow in the mouse lung causes a prompt angiogenic response, with new systemic vessels from intercostal arteries penetrating the pleura within 5–6 days [Mitzner et al. Am J Pathol 2000; 157(1): 93–101]. Tamoxifen, a triphenylethylene antiestrogen, has been shown to be effective in limiting tumor growth, possibly because of inhibition of angiogenesis. We investigated the effects of tamoxifen on blood vessel development after left pulmonary artery ligation (LPAL). Timed-release pellets of either tamoxifen (free base/15 mg over 21 days) or placebo carrier were implanted subcutaneously in male C57BL/6J mice 6–8 weeks of age. Two days after pellet implantation, the left pulmonary artery was permanently obstructed by suture ligation. New systemic vessel growth was assessed after left ventricular injection of fluorescence labeled microspheres. Tamoxifen slowed the formation of functional blood vessels sevendays after LPAL. By 14 days, however, no difference was observed between tamoxifen and placebo treated mice with systemic perfusion to the left lung reaching a maximum of 3.8% and 4.7% of cardiac output respectively. No change in VEGF mRNA expression was observed until 14 days after LPAL when a small increase (2-fold) was observed in both placebo and tamoxifen treated lungs. However, VEGF protein was elevated in both tamoxifen and placebo lungs 24 h after LPAL (∼4-fold). These changes in VEGF protein may be due to the presence of trapped inflammatory cells observed in lung sections at this early time point. Although tamoxifen appeared to slow the progression of blood vessel formation, it did not affect VEGF mRNA, therefore likely acting through an estrogen receptor-independent mechanism.     

Potential cardiotonic agents. 1. Synthesis and pharmacologic properties of 3-cyano-2-oxaalkylamino-5-(4-pyridinyl)pyridines

Synthesis, physicochemical properties and evaluation of positive inotropic and vasodilator activities are described in a series of substituted 2-amino-3-cyano-5-(4-pyridinyl)pyridines. Some of the 2-oxaalkylamino derivatives showed remarkable positive inotropic activities and, additionally, a decrease in blood pressure. The most potent compounds 11 and 13 have a greater activity than amrinone.