Flemming Tofteng

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.)

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.

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.

Effect of treatment with the Molecular Adsorbents Recirculating System on arterial amino acid levels and cerebral amino acid metabolism in patients with hepatic encephalopathy

Background: Liver failure is associated with low concentrations of branched‐chain amino acids and high concentrations of most other amino acids. In this study the effect of treatment with the Molecular Adsorbents Recirculating System (MARS) on arterial amino acid levels and cerebral amino acid metabolism was examined in patients with severe hepatic encephalopathy. Methods: The study included seven patients with hepatic encephalopathy from fulminant hepatic failure (FHF) and five patients with hepatic encephalopathy from acute‐on‐chronic liver failure (AoCLF). Cerebral blood flow and cerebral arteriovenous differences in amino acids were measured before and after 6 h of treatment with MARS. Results: During MARS treatment, the total arterial amino acid concentration decreased by 20% from 8.92 ± 7.79 mmol/L to 7.16 ± 5.64 mmol/L (P < 0.05). The concentration decreased in all amino acids with the exception of the branched‐chain amino acids. Fischers ratio of branched‐chain to aromatic amino acids increased from 0.73 ± 0.47 to 0.91 ± 0.54 (P < 0.05). A net cerebral efflux of amino acids in patients with FHF (8.94 ± 8.34 μmol/100 g/min) as well as AoCLF (7.35 ± 24.97 μmol/100 g/min) was not affected by the MARS treatment. MARS had no effect on the cerebral metabolic rate of any single amino acid in either group. Conclusions: MARS treatment tends to normalize the arterial amino acid concentrations in patients with hepatic encephalopathy. Even though the overall reduction in plasma amino acids and improvement in amino acid dysbalance may well be beneficial, it was not accompanied by any immediate improvement in cerebral amino acid metabolism in patients with FHF or AoCLF.

Brain hypoxanthine concentration correlates to lactate/pyruvate ratio but not intracranial pressure in patients with acute liver failure

BACKGROUND & AIMS The pathogenesis of cerebral edema in acute liver failure is suggested, in in vitro and animal studies, to involve a compromised oxidative metabolism with a decrease in cerebral ATP levels and an increase in purine concentrations. In this study we hypothesize that the cerebral concentrations of hypoxanthine, inosine, and lactate/pyruvate (LP) ratio are increased and correlated in patients with acute liver failure. Furthermore, we expect the purines and L/P ratio to correlate with intracranial pressure (ICP) (positively), and cerebral perfusion pressure (CPP) (negatively). METHODS In 17 patients (aged 18-60 years) with acute liver failure and severe hyperammonemia (182 ± 36 μM (mean ± SD)), cerebral microdialysis was performed, and ICP and CPP were monitored. Microdialysate concentrations of hypoxanthine, inosine, lactate, and pyruvate were measured. RESULTS The hypoxanthine concentration was 23.0 ± 12 μM in early samples and 11.7 ± 6.8 μM in late samples (normal level ~2.0 μM). The inosine concentration was 7.2 ± 7.1 μM and 2.8 ± 1.6 μM, and the LP ratio was 55.8 ± 21.6 and 45.6 ± 20.8, respectively (normal level ~18). Hypoxanthine correlated significantly to LP ratio (r(2)=0.40, p<0.01) while inosine did not. The purine levels and L/P ratio did not correlate to ICP or CPP, nor did they differ between patients with high ICP (>20 mmHg, n=9) and patients without (n=8). CONCLUSIONS This study shows that the high cerebral LP ratio correlates to the hypoxanthine level in patients with acute liver failure. However, these metabolic alterations were not related to the development of intracranial hypertension.

Cerebral Blood Flow and Metabolism During Infusion of Norepinephrine and Propofol in Patients With Bacterial Meningitis

Background and Purpose— In patients with severe bacterial meningitis, norepinephrine is often infused to increase mean arterial pressure (MAP). This increases cerebral blood flow (CBF), but it is unknown if this increase is caused by impaired cerebral autoregulation or by a cerebral effect of norepinephrine through increased cerebral metabolism. The latter possibility implies a CBF–metabolism coupling. This has not been studied during meningitis. We studied the effect of norepinephrine and propofol on CBF and oxidative metabolism in patients with severe bacterial meningitis. Methods— In seven patients with pneumococcal meningitis and 7 healthy subjects, norepinephrine was infused intravenously; patients also underwent intravenous propofol infusion. Global CBF was measured by the Kety–Schmidt technique; cerebral oxidative metabolism and net flux of norepinephrine and epinephrine were calculated from measured arterial-to-jugular venous concentration differences (a-vD). Results— During norepinephrine infusion, MAP increased from a median value of 79 (range, 70 to 89) to 99 (98 to 129) mm Hg in patients, and from 87 (72 to 103) to 123 (112 to 132) mm Hg in controls. CBF increased in patients (51 [48 to 60] to 59 [54 to 77] mL/100 g per minute) but remained unchanged in controls. The cerebral metabolic rate of oxygen (CMRO2) decreased in patients and remained unchanged in controls. No cerebral net flux of norepinephrine or epinephrine was found at any time in the 2 groups. During propofol infusion, CMRO2, and the a-vDO2 decreased whereas CBF was unchanged. Conclusions— In patients with severe bacterial meningitis, norepinephrine increases both MAP and CBF but not CMRO2, indicating impaired autoregulation. Propofol reduces CBF relatively less than cerebral metabolism, suggesting a resetting of the CBF–CMRO2 relationship.

Management of patients with fulminant hepatic failure and brain edema

Cerebral edema in acute liver failure is associated with a poor prognosis. Optimization of cerebral perfusion pressure and blood flow plays a key role in contemporary management of these patients. However, understanding of the pathophysiology of brain edema is required for optimal patient management. This review explains the relationships between cerebral perfusion and edema and summarizes therapies that are currently used in patients with acute liver failure to prevent and reduce intracranial pressure.

Cerebral oxygenation determined by near-infrared spectrophotometry in patients with fulminant hepatic failure

BACKGROUND/AIMS In severe cases of acute liver failure (ALF), cerebral hyperperfusion may result in high intracranial pressure and brain damage. The aim of this study was to determine if near-infrared spectrophotometry (NIRS) could detect a raise in cerebral blood flow and oxygenation induced by noradrenaline (NA) infusion. METHODS In seven ALF patients (five females and two males; median age 49 years (range 20-70)) changes in cerebral concentration of oxy-(deltaHbO(2)) and total-haemoglobin (deltaHbT) were compared to the jugular bulb saturation (SvjO(2)) and cerebral blood flow velocity (Vmean) during NA infusion. RESULTS Mean arterial pressure increased from 68 (64-86) to 103 (87-118) mmHg and the cerebral perfusion pressure from 61 (53-79) to 95 (74-110) mmHg (P<0.05), while the intracranial pressure (7 (6-15) mmHg) was not significantly changed. In six patients cerebral deltaHbO(2) and deltaHbT increased 2.7 (0.3-9.6) and 2.0 (0.3-14.8) micromol l(-1), respectively, but cerebral oxygenation decreased in one patient. SvjO(2) increased from 68 (55-76) to 74 (64-78) % (P<0.05) concomitant with an increase in Vmean from 47 (34-65) to 68 (50-86) cm s(-1) (P<0.05). deltaHbO(2) covariated with changes in SvjO(2) during NA in all but one patient. CONCLUSIONS In ALF patients, a change in cerebral perfusion was detected by NIRS. The combination of NIRS and transcranial Doppler sonography may be valuable non-invasive techniques to detect cerebral hyperperfusion before intracranial hypertension becomes manifest.

Circulating levels of vasoactive peptides in patients with acute bacterial meningitis

PurposeThe underlying mechanisms for cerebral blood flow (CBF) abnormalities in acute bacterial meningitis (ABM) are largely unknown. Putative mediators include vasoactive peptides, e.g. calcitonin-gene related peptide (CGRP), vasoactive intestinal peptide (VIP), and endothelin-1 (ET-1), all of which may be affected by therapeutic interventions used in the intensive care unit. We measured arterial levels as well as the net cerebral flux of these peptides in patients with ABM, and in healthy volunteers undergoing interventions relevant to intensive care.MethodsSeven patients with severe ABM and sepsis and fifteen healthy volunteers were included after informed consent. The net cerebral fluxes of vasoactive peptides were measured by the Kety-Schmidt technique in ABM patients (baseline study only), as well as in volunteers at baseline, during voluntary hyperventilation, after an intravenous injection of lipopolysaccharide (LPS), and during norepinephrine infusion.ResultsThe arterial levels of CGRP, but not of VIP or ET-1, were elevated in patients with ABM, but no net cerebral flux was present. CGRP levels decreased during hyperventilation and after LPS injection. No net cerebral flux of VIP occurred in any group at any time. A cerebral efflux of ET-1, which occurred in volunteers at baseline, was neither present in volunteers after LPS injection nor in patients with ABM.ConclusionThe arterial concentration of the vasodilatory peptide, CGRP, but of neither VIP nor the vasoconstrictor ET-1, is elevated in patients with ABM and sepsis. A constitutive cerebral output of ET-1 appears to be present in healthy humans, but is abolished after LPS injection.

Assessment of response to beta-blockers by expression of βArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients

BACKGROUND & AIMS Non-selective beta-blockers (NSBB) are first choice for prevention of variceal bleeding. But possible deleterious effects in refractory ascites and frequent non-response are clinical drawbacks. Since levels of vasoactive proteins in antrum mucosa reflect vascular dysfunction in cirrhosis, these expression levels might also reflect hemodynamic response to NSBB. METHODS Biopsies from the gastric and duodenal mucosa of 25 patients with cirrhosis were collected and the hepatic venous pressure gradient (HVPG) was measured before and after an acute propranolol challenge. Transcription and protein expression of Ras homolog family member A (RhoA), Rho-kinase (ROCK)2, beta-arrestin2 (βArr2), endothelial nitric oxide synthase (eNOS) and the phosphorylation of downstream effectors VASP and moesin were analyzed using PCR and Western blot. Further 21 patients on NSBB were evaluated on their follow up for events of variceal bleeding defined as non-response. RESULTS Ten patients showed HVPG <10mmHg, further seven patients showed significant hemodynamic response to NSBB, whereas eight patients were non-responders. The mucosal transcription of vasoactive proteins was higher in antrum mucosa compared to corpus and duodenum. The transcriptional levels of vasoactive proteins were higher in patients with HVPG >10mmHg and HVPG >16mmHg. Interestingly, mRNA levels of RhoA and ROCK2 were lower in patients with large varices at endoscopy. Moreover, RhoA and ROCK2 transcription correlated with the decrease of HVPG after acute NSBB challenge. Finally, acute and long-term non-responders showed lower expression of βArr2 in antrum mucosa. CONCLUSION This study shows for the first time that the expression of βArr2 in antrum mucosa biopsies might reflect the hemodynamic response to NSBB and their long-term protective effect. This finding might offer an easy approach at upper endoscopy to facilitate the decision to treat with NSBB if varices are present.