No abstract

on behalf of the RELIEF study group Acute-on-chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n 5 95) or to standard therapy (SMT) (n 5 94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per-protocol (PP) analysis (PP population n 5 156). Up to 10 6-8-hour MARS sessions were scheduled. The main endpoint was 28-day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28-day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44-1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P 5 0.02) and bilirubin (P 5 0.001) and a more frequent improvement in HE (from grade II-IV to grade 0-I; 62.5% versus 38.2%; P 5 0.07) was observed in the MARS group. Severe adverse events were similar. Conclusion: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE.

Cerebral edema leading to cerebral herniation (CH) is a common cause of death in acute liver failure (ALF). Animal studies have related ammonia with this complication. During liver failure, hepatic ammonia removal can be expected to determine the arterial ammonia level. In patients with ALF, we examined the hypotheses that high arterial ammonia is related to later death by CH, and that impaired removal in the hepatic circulation is related to high arterial ammonia. Twenty-two patients with ALF were studied retrospectively. In addition, prospective studies with liver vein catheterization were performed after development of hepatic encephalopathy (HE) in 22 patients with ALF and 9 with acute on chronic liver disease (AOCLD). Cerebral arterial-venous ammonia difference was studied in 13 patients with ALF. In all patients with ALF (n ‫؍‬ 44), those who developed CH (n ‫؍‬ 14) had higher arterial plasma ammonia than the non-CH (n ‫؍‬ 30) patients (230 ؎ 58 vs. 118 ؎ 48 mol/L; P F .001). In contrast, galactose elimination capacity, bilirubin, creatinine, and prothrombin time were not different (NS). Cerebral arterial-venous differences increased with increasing arterial ammonia (P F .001). Arterial plasma ammonia was lower than hepatic venous in ALF (148 ؎ 73 vs. 203 ؎ 108 mol/L; P F .001). In contrast, arterial plasma ammonia was higher than hepatic venous in patients with AOCLD (91 ؎ 26 vs. 66 ؎ 18 mol/L; P F .05). Net ammonia release from the hepatic-splanchnic region was 6.5 ؎ 6.4 mmol/h in ALF, and arterial ammonia increased with increasing release. In contrast, there was a net hepatic-splanchnic removal of ammonia (2.8 ؎ 3.3 mmol/h) in patients with AOCLD. We interpret these data that in ALF in humans, vast amounts of ammonia escape hepatic metabolism, leading to high arterial ammonia concentrations, which in turn is associated with increased cerebral ammonia uptake and CH. (HEPATOL-OGY 1999;29:648-653.)

Background and Purpose-Under normal circumstances, autoregulation maintains cerebral blood flow (CBF) constant within a wide range of mean arterial pressure (MAP). It remains unknown whether patients resuscitated from cardiac arrest have preserved CBF autoregulation. In this study, CBF autoregulation was investigated within the first 24 hours after resuscitation from cardiac arrest. Methods-Eighteen patients and 6 healthy volunteers had relative changes in CBF determined by transcranial Doppler mean flow velocity (V mean ) in the middle cerebral artery during a stepwise rise in MAP by use of norepinephrine infusion. V mean was plotted against MAP, and a lower limit of autoregulation was identified by double regression analysis based on the least-squares method. Results-In patients, V mean increased from a median of 33 (range 19 to 73) to 37 (22 to 100) cm/s (PϽ0.001) during a norepinephrine-induced rise in MAP from 78 (46 to 118) to 106 (60 to 149) mm Hg. Eight of 18 patients had impaired CBF autoregulation, and in 5 of the 10 patients with preserved CBF autoregulation, the lower limit of autoregulation could be identified. The lower limit of CBF autoregulation was 76 mm Hg (41 to 105 mm Hg) in the volunteers and 114 mm Hg (80 to 120 mm Hg) in the 5 patients with preserved autoregulation (PϽ0.01). Conclusions-We conclude that in a majority of patients in the acute phase after cardiac arrest, cerebral autoregulation is either absent or right-shifted. These results indicate that MAP should be kept at a higher level than commonly accepted to secure cerebral perfusion. We recommend, however, that further randomized clinical trials are performed to determine whether sympathomimetic drugs improve neurological outcome. (Stroke. 2001;32:128-132.)