Fin Stolze Larsen

Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis

Extracorporeal albumin dialysis (ECAD) may improve severe hepatic encephalopathy (HE) in patients with advanced cirrhosis via the removal of protein or non–protein‐bound toxins. A prospective, randomized, controlled, multicenter trial of the efficacy, safety, and tolerability of ECAD using molecular adsorbent recirculating system (MARS) was conducted in such patients. Patients were randomized to ECAD and standard medical therapy (SMT) or SMT alone. ECAD was provided daily for 6 hours for 5 days or until the patient had a 2‐grade improvement in HE. HE grades (West Haven criteria) were evaluated every 12 hours using a scoring algorithm. The primary endpoint was the difference in improvement proportion of HE between the 2 groups. A total of 70 subjects [median age, 53; 56% male; 56% HE grade 3; 44% HE grade 4; median model for end‐stage liver disease (MELD) 32 (11–50) and CPT 13 (10–15)] were enrolled in 8 tertiary centers. Patients were randomized to ECAD + SMT (n = 39) or SMT alone (n = 31). Groups were matched in demographics and clinical variables. The improvement proportion of HE was higher in ECAD (mean, 34%; median, 30%) versus the SMT group (mean, 18.9%; median, 0%) (P = 0.044) and was reached faster and more frequently than in the SMT group (P = 0.045). Subjects receiving ECAD tolerated treatment well with no unexpected adverse events. Conclusion: The use of ECAD may be associated with an earlier and more frequent improvement of HE (grade 3/4). Because this 5‐day study was not designed to examine the impact of MARS on survival, a full assessment of the role of albumin dialysis awaits the results of additional controlled trials. (HEPATOLOGY 2007.)

Transcranial Doppler is valid for determination of the lower limit of cerebral blood flow autoregulation.

This study validates transcranial Doppler sonography (TCD) for determination of the lower limit of cerebral blood flow (CBF) autoregulation and establishes a relation between global CBF and mean flow velocity (Vmean) in the middle cerebral artery. Methods Relative changes in CBF and in Vmean were compared in 12 normal volunteers (2 women and 10 men; median age, 30 years [range, 21 to 61 years]). Catheters was placed in the left radial artery and in the bulb of the right internal jugular vein, respectively. Baseline CBF was measured by single-photon emission computed tomography scanning; concomitantly, blood samples were drawn for calculation of the cerebral arteriovenous oxygen difference. Then changes in mean arterial pressure (MAP) were induced, and relative changes in global CBF were calculated according to Ficks principle assuming a constant cerebral oxygen metabolism. MAP was increased 30 mm Hg by norepinephrine infusion and was decreased by lower body negative pressure. Vmean was measured in the right middle cerebral artery by a 2-MHz probe, and blood samples were drawn at intervals of 5 mm Hg. Results MAP values between 122 (range, 110 to 140) and 48 (range, 34 to 75) mm Hg were measured. The lower limit of autoregulation (the blood pressure under which autoregulation is off) as determined by Vmean did not differ significantly from that determined by relative changes in global CBF: 91 (range, 41 to 108) and 79 (range, 53 to 113) mm Hg, respectively. A significant correlation between Vmean and relative changes in global CBF was demonstrated below the lower limit of autoregulation (R2=.73, P<.001; CBF=−6.3+1.0· Vmean). Above the lower lim1it both values were stable. Conclusions TCD is valid for determination of the lower limit of CBF autoregulation, and changes in CBF may be reliably evaluated by TCD during changes in cerebral perfusion pressure in normal subjects.

Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute‐on‐chronic liver failure: The RELIEF trial

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 = 95) or to standard therapy (SMT) (n = 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 = 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 = 0.02) and bilirubin (P = 0.001) and a more frequent improvement in HE (from grade II‐IV to grade 0‐I; 62.5% versus 38.2%; P = 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. (HEPATOLOGY 2013)

Autoregulation of Cerebral Blood Flow in Patients Resuscitated From Cardiac Arrest

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 (Vmean) in the middle cerebral artery during a stepwise rise in MAP by use of norepinephrine infusion. Vmean 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, Vmean increased from a median of 33 (range 19 to 73) to 37 (22 to 100) cm/s (P <0.001) 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 (P <0.01). 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.

Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure.

In this prospective study of patients with fulminant hepatic failure (FHF), we tested the hypothesis that arterial hyperammonemia results in cerebral accumulation of the osmotic active amino acids glutamine and alanine, processes that were expected to correlate with intracranial pressure (ICP). By using in vivo brain microdialysis technique together with ICP monitoring in 17 FHF patients (10 females/7 males; median age 49 (range 18 to 66) years), we found that arterial ammonia concentration correlated to brain content of glutamine (r=0.47; P > 0.05) but not to alanine. A persisting high arterial ammonia concentration (above 200 μmol/L) characterized patients who developed high ICP (n=8) while patients who did not experience surges of increased ICP (n=9) had a decline in the ammonia level (P > 0.05). Moreover, brain glutamine and alanine concentrations were higher at baseline and increased further in patients who developed intracranial hypertension compared with patients who experienced no surges of high ICP. Brain glutamine concentration increased 32% from baseline to 6536 (697 to 9712) μmol/L (P > 0.05), and alanine 44% from baseline to 104 (81 to 381) μmol/L (P > 0.05). Brain concentration of glutamine (r=0.59, P > 0.05), but not alanine, correlated to ICP. Also arterial ammonia concentration correlated to ICP (r=0.73, P > 0.01). To conclude, this study shows that persistence of arterial hyperammonemia is associated with profound changes in the cerebral concentration of glutamine and alanine. The elevation of brain glutamine concentration correlated to ICP in patients with FHF.

MELD score as a predictor of liver failure and death in patients with acetaminophen-induced liver injury.

The Model for End‐Stage Liver Disease (MELD) scoring system has been established as a reliable measure of short‐term mortality risk in patients with end‐stage chronic liver disease. The aim of this study was to evaluate the prognostic value of the MELD scoring as a predictor of fulminant hepatic failure (FHF) and death in patients with acetaminophen poisoning. Prospectively, serial measurements of the 3 MELD components—INR, bilirubin, and creatinine—were performed in 460 patients with acetaminophen‐induced liver injury. Starting on the first day after the day of overdose, MELD score was significantly higher in patients who eventually developed hepatic encephalopathy (HE) than in those who did not. HE developed in 63 of 142 patients with a MELD score above 18 at 48‐72 hours after the overdose (positive predictive value 44%) compared with 2 of 182 patients with a MELD score of 18 or below (negative predictive value 99%). Among 124 patients with FHF, a threshold MELD score of 33 on the day after the onset of HE had sensitivity of 60%, specificity of 69%, positive predictive value of 65%, and negative predictive value of 63%. However, the discriminative power of MELD score was not superior to that of INR alone or of the Kings College Hospital criteria. Conclusion: MELD score may be useful as a predictor of FHF in patients admitted with acetaminophen toxicity. However, as a predictor of death from FHF, MELD score did not provide more information than the Kings College Hospital criteria or INR alone. (HEPATOLOGY 2007;45:789–796.)

The effect of indomethacin on intracranial pressure, cerebral perfusion and extracellular lactate and glutamate concentrations in patients with fulminant hepatic failure.

Uncontrolled increase in intracranial pressure (ICP) continues to be one of the most significant causes of early death in patients with acute liver failure (ALF). In this study, we aimed to determine the effects of indomethacin on ICP and cerebral perfusion pressure in twelve patients with ALF and brain edema (9 females/3 males, median age 49,5 (range 21 to 64) yrs.). Also changes in cerebral perfusion determined by transcranial Doppler technique (Vmean) and jugular bulb oxygen saturation (SvjO2) were measured, as well as brain content of lactate and glutamate by microdialysis technique. Finally, we determined the cerebral blood flow autoregulation before and after indomethacin injection. We found that indomethacin reduced ICP from 30 (7 to 53) to 12 (4 to 33) mmHg (P < 0.05). The cerebral perfusion pressure increased from 48 (0 to 119) to 65 (42 to 129) mmHg (P < 0.05), while Vmean and SvjO2 on average remained unchanged at 68 (34 to 126) cm/s and 67 (28 to 82) %, respectively. The lactate and glutamate in the brain tissue were not altered (2.1 (1.8 to 7.8) mmol/l and 34 (2 to 268) μmol/l, respectively) after injection of indomethacin. Cerebral blood flow autoregulation was impaired in all patients before injection of indomethacin, but was not restored after administration of indomethacin. We conclude that a bolus injection of indomethacin reduces ICP and increases cerebral perfusion pressure without compromising cerebral perfusion or oxidative metabolism in patients with ALF. This finding indicates that indomethacin may be valuable as rescue treatment of uncontrolled intracranial hypertension in fulminant hepatic failure.

Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure.

Objective:Hyperlactatemia has been suggested as a prognostic marker in acetaminophen-induced fulminant hepatic failure, and a modification of the King’s College Hospital criteria to incorporate arterial lactate measurements has recently been proposed. The aims of the present study were to further evaluate arterial lactate as a prognostic marker in acetaminophen-induced fulminant hepatic failure and to analyze its relationship to known causes of hyperlactatemia such as multiple organ failure and inflammation. Design:Data were collected early after admission and again at the time of onset of grade 3–4 hepatic encephalopathy from acetaminophen-induced fulminant hepatic failure. Multiple organ failure and inflammatory response were assessed by the sequential organ failure assessment (SOFA) score and manifestation of the severe inflammatory response syndrome (SIRS), respectively. Setting:A specialized liver intensive care unit at a tertiary liver center. Patients:One hundred and one consecutive patients with acetaminophen-induced fulminant hepatic failure and grade 3–4 hepatic encephalopathy. Interventions:None. Measurements and Main Results:Arterial lactate was higher in nonsurvivors than in survivors both early after admission (9.8 ± 6.5 mmol/L vs. 5.2 ± 4.2 mmol/L, p = .00004) and at the time of onset of hepatic encephalopathy (6.9 ± 5.6 mmol/L vs. 3.2 ± 2.0 mmol/L, p < .00001). At both time points, arterial lactate significantly correlated with SOFA score and the number of SIRS components fulfilled. Applying the lactate modification of the King’s College Hospital criteria increased their sensitivity but reduced their specificity to <50%. Conclusions:The study confirmed arterial lactate as a prognostic marker in acetaminophen-induced fulminant hepatic failure. Arterial lactate correlated with SOFA score and with the number of SIRS components fulfilled. The lactate modification of the King’s College Hospital criteria showed no obvious advantages over the existing selection criteria.

High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.

BACKGROUND & AIMS Acute liver failure (ALF) often results in cardiovascular instability, renal failure, brain oedema and death either due to irreversible shock, cerebral herniation or development of multiple organ failure. High-volume plasma exchange (HVP), defined as exchange of 8-12 or 15% of ideal body weight with fresh frozen plasma in case series improves systemic, cerebral and splanchnic parameters. METHODS In this prospective, randomised, controlled, multicentre trial we randomly assigned 182 patients with ALF to receive either standard medical therapy (SMT; 90 patients) or SMT plus HVP for three days (92 patients). The baseline characteristics of the groups were similar. The primary endpoint was liver transplantation-free survival during hospital stay. Secondary-endpoints included survival after liver transplantation with or without HVP with intention-to-treat analysis. A proof-of-principle study evaluating the effect of HVP on the immune cell function was also undertaken. RESULTS For the entire patient population, overall hospital survival was 58.7% for patients treated with HVP vs. 47.8% for the control group (hazard ratio (HR), with stratification for liver transplantation: 0.56; 95% confidence interval (CI), 0.36-0.86; p=0.0083). HVP prior to transplantation did not improve survival compared with patients who received SMT alone (CI 0.37 to 3.98; p=0.75). The incidence of severe adverse events was similar in the two groups. Systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores fell in the treated group compared to control group, over the study period (p<0.001). CONCLUSIONS Treatment with HVP improves outcome in patients with ALF by increasing liver transplant-free survival. This is attributable to attenuation of innate immune activation and amelioration of multi-organ dysfunction.

Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome

Patients with advanced cirrhosis and ascites are characterized by circulatory dysfunction with splanchnic vasodilatation and renal vasoconstriction, which often lead to ascites. The vasoconstrictor terlipressin improves renal function in hepatorenal syndrome (HRS). The aim of this study was to evaluate if terlipressin also improves renal function in patients with ascites without HRS. Twenty‐three patients with cirrhosis participated; 15 with nonrefractory ascites were randomized to either terlipressin (N group, n = 11) or a placebo (P group, n = 4), and 8 had refractory ascites and received terlipressin (R group). The glomerular filtration rate (GFR), sodium clearance (CNa), lithium clearance (CLi), osmolal clearance (COsm), and urine sodium concentration (UNa) were assessed before and after the injection of 2 mg of terlipressin or the placebo. GFR increased in the N group (69 ± 19 versus 92 ± 25 mL/min, P < 0.005) and in the R group (31 ± 19 versus 41 ± 31 mL/min, P < 0.05) after terlipressin. In the N group, terlipressin induced an increase in CNa (0.89 ± 0.21 versus 1.52 ± 1.45 mL/min, P < 0.05), CLi (17.3 ± 8.9 versus 21.5 ± 11.6 mL/min, P < 0.05), and COsm (2.10 ± 0.81 versus 3.06 ± 2.0 mL/min, P < 0.05). In the R group, terlipressin induced an increase in CNa (0.11 ± 0.18 versus 0.35 ± 0.40 mL/min, P < 0.05) and CLi (5.5 ± 4.2 versus 9.5 ± 8.55 mL/min, P < 0.05). UNa increased in both groups after terlipressin (P < 0.005). Plasma norepinephrine (P < 0.05) and renin (P < 0.05) decreased after terlipressin. All parameters remained unchanged after the placebo. Conclusion: The vasopressin 1 receptor agonist terlipressin improves renal function and induces natriuresis in patients with cirrhosis and ascites without HRS. Vasoconstrictors may represent a novel future treatment modality for these patients. (HEPATOLOGY 2007.)