Bent Adel Hansen

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.

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.

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.

Hyperventilation restores cerebral blood flow autoregulation in patients with acute liver failure

BACKGROUND/AIMS In patients with acute liver failure loss of cerebral blood flow autoregulation may result from cerebral vasodilatation. Since arterial hypocapnia induces cerebral vasoconstriction, we investigated whether cerebral blood flow autoregulation could be reestablished by mechanical hyperventilation. METHODS Seven consecutive patients (median age 45, range 30-50 years) with acute liver failure and hepatic encephalopathy stage IV entered the study. They were all maintained on mechanical ventilation. Cerebral blood flow autoregulation was evaluated by using transcranial Doppler sonography to assess mean flow velocity (Vmean) in the middle cerebral artery, during a rise in mean arterial pressure by norepinephrine infusion (0.5-10 microg/h). The patients were subsequently hyperventilated for 15 min before cerebral blood flow autoregulation was re-evaluated in the same mean arterial pressure range. RESULTS At baseline PaCO2 (4.0 (3.5-4.9)kPa), all patients had impaired cerebral blood flow autoregulation as Vmean increased from 47 (30-78) to 68 (49-107) cm x s(-1) (p<0.05), as MAP was raised from 82 (60-88) to 106 (89-123) mmHg. During hyperventilation, five of seven patients restored cerebral autoregulation as Vmean remained unchanged at 51 (45-70) cm x s(-1) during a rise in MAP from 84 (65-94) to 110 (89-130) mmHg. Cerebral blood flow autoregulation was not restored in two patients, but hyperventilation reduced the slope of the mean arterial pressure-Vmean correlation. These two patients had renal failure and were treated with intermittent hemodialysis. CONCLUSIONS Cerebral blood flow autoregulation was restored by hyperventilation in five of seven patients with acute liver failure, indicating that cerebral vasodilatation is of pathophysiological importance in dysregulation of cerebral circulation in acute liver failure.

Dissociated cerebral vasoparalysis in acute liver failure A hypothesis of gradual cerebral hyperaemia

BACKGROUND/AIMS Normally, cerebral blood flow responds to changes in the arterial carbon dioxide tension (PaCO2) but not to changes in mean arterial pressure, commonly referred to as the cerebral CO2-reactivity and autoregulation. In patients with fulminant hepatic failure and in the rat with thioacetamide-induced liver failure, autoregulation is absent, presumably due to cerebral vasoparalysis. Since also CO2-reactivity may then be compromised, it was studied in patients with fulminant hepatic failure and rats with thioacetamide-induced liver failure. METHODS In ten patients (median age 32 (range 20-48) years)) and in ten age-matched volunteers, cerebral perfusion was elevated by transcranial Doppler assessed mean flow velocity (V(mean)) in the middle cerebral artery during hypo- and hyper-capnia. In six rats with liver failure and in six control rats, cerebral blood flow was measured repeatedly by the intracarotid 133 Xenon injection technique. RESULTS In the patients and volunteers, PaCO2 was lowered from 33 (23-44) to 28 (23-39) mmHg by hypocapnia and raised to 40 (34-48) mmHg by hypercapnia or 5% CO2 inhalation. During hypocapnia, the CO2-reactivity did not differ significantly between patients and volunteers, 4.0 (1.1-7.4) vs. 3.0 (1.7-5.0)% mmHg(-1), while it was reduced during hypercapnia in the patients, 2.2 (1.8-5.2) vs. 4.6 (3.0-8.0)% mmHg(-1) (p < 0.05). In the rats, PaCO2 was reduced from 39 (37-40) to 30 (29-31) mmHg and then raised to 51 (41-55) mmHg. During hypocapnia, CO2-reactivity was similar in rats with liver failure and in control rats, 2.3 vs 2.7% mmhg(21), respectively. In all rats with liver failure CO2-reactivity was abolished during hypercapnia, while it was 1.5% mmHg(-1) in the control rats (p < 0.01). CONCLUSIONS The finding that cerebral CO2 reactivity is reduced in hypercapnia, while it is preserved in hypocapnia, suggests that gradual dilation of the cerebral resistance vessels develops in fulminant hepatic failure and connects previous morphological studies with changes in the regulation of cerebral blood flow, i.e. impaired cerebral autoregulation and blunted CO2-reactivity.

The brain in acute liver failure. A tortuous path from hyperammonemia to cerebral edema

Acute liver failure (ALF) is a condition with an unfavourable prognosis. Multiorgan failure and circulatory collapse are frequent causes of death, but cerebral edema and intracranial hypertension (ICH) are also common complications with a high risk of fatal outcome. The underlying pathogenesis has been extensively studied and although the development of cerebral edema and ICH is of a complex and multifactorial nature, it is well established that ammonia plays a pivotal role. This review will focus on the effects of hyperammonemia on neurotransmission, mitochondrial function, oxidative stress, inflammation and regulation of cerebral blood flow. Finally, potential therapeutic targets and future perspectives are briefly discussed.

Cerebral blood flow, oxygen metabolism and transcranial Doppler sonography during high-volume plasmapheresis in fulminant hepatic failure.

Objective: The effect of high-volume plasmapheresis on hepatic encephalopathy, cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) was investigated in patients with fulminant hepatic failure (FHF). Methods: Twelve consecutive patients (8 women, 4 men, median age 34 years (range 19–51)) were studied before and after high-volume plasmapheresis with 10–16 litres fresh frozen plasma, while PaCO2 and body temperature were maintained at 30 (23–34) mmHg and 37.6°C (36.6–38.4), respectively. Blood samples from the internal jugular vein and a radial artery allowed calculation of the cerebral arteriovenous oxygen difference (AVDO2) and oxygen extraction (AVDO2 divided by arterial oxygen content). CBF was determined by a xenon-133 clearance method in eight patients and CMRO2 calculated as AVDO2 times CBF. Cerebral perfusion pressure (CPP) was determined as the difference between mean arterial and subdural pressures in eight patients. Results: High-volume plasmapheresis was initiated 22 (6–168) h after the development of hepatic encephalopathy and 11 patients had grade 4 encephalopathy. Following high-volume plasmapheresis the grade of encephalopathy improved in four patients. The CBF increased from a median of 31 (16–86) to 45 (18–97) ml/100 g/min and as oxygen extraction remained unchanged (32 (9–41) vs. 29 (7–39)%), CMRO2 increased from 1.24 (0.96–1.82) to 1.86 (1.00–2.07) ml/100 g/min (P<0.05). The CPP increased from 62 (19–76) to 92 (50–105) mmHg (P<0.01), whereas the intracranial pressure remained unchanged (19 (3–45) vs. 11 (5–33) mmHg). No statistical difference was found between the relative changes in the above parameters in survivors compared to non-survivors. Conclusion: Although the clinical status did not improve in all patients, both CBF and CMRO2 increased after high-volume plasmapheresis. The alleviation of brain oxygen metabolism by high-volume plasmapheresis may reflect partial removal of neuroinhibitory plasma factors.

Outcome following liver transplantation for primary sclerosing cholangitis in the Nordic countries

Background: Primary sclerosing cholangitis (PSC) is the most common indication for liver transplantation in the Nordic countries. Because these patients are difficult to evaluate with regard to timing of liver transplantation, it is important to establish predictors of post‐transplant survival. Methods: Data from two groups of patients receiving liver allografts during 1982–2001 were recorded: (a) PSC patients and (b) comparison patients. Outcome following transplantation has been recorded for all patients. Regression analyses have been performed for PSC patients to analyse predictors of patient and graft survival. Results: A total of 245 PSC and 618 comparison patients received a first liver allograft in the period 1982 until the end of the study. The overall 1‐, 3‐ and 5‐year patient survival rates were 82%, 77% and 75%, and 80%, 77% and 74% in the PSC group and comparison group, respectively. Survival following transplantation has increased with time in both the PSC and the comparison group. Recent year of transplantation, no previous hepatobiliary surgery and a lower MELD score were predictors of survival following transplantation for PSC patients. PSC patients had a higher rate of re‐transplantations (13% versus 8%, P = 0.01). Predictors of re‐transplantation in PSC patients were an episode of early rejection and vascular thrombosis. Conclusion: In PSC patients, year of transplantation, previous hepatobiliary surgery and MELD score are predictors of survival following transplantation and these patients are more frequently in need of re‐transplantation compared to the comparison group.

Glucagon increases hepatic efficacy for urea synthesis

The effect of glucagon on the relation between urea synthesis and blood amino acid concentration was studied in seven healthy volunteers. Alanine was given as prime-continuous infusions and, after 1 hr for equilibration, the urea nitrogen synthesis rate was measured in two periods of about 2 hrs as urinary excretion corrected for accumulation and intestinal hydrolysis. During one of the periods, glucagon was infused to obtain a constant concentration of 200-1200 ng/l. The spontaneous urea synthesis during the alanine infusion was 86-141 mmol/hr and linearly related to the alanine concentrations of 1.33-2.99 mmol/l. The hepatic clearance of alanine-nitrogen to urea-nitrogen, assessed by the ratio between the increase in the urea synthesis rate and alanine concentration, was 23 +/- 4 l/hr (mean +/- S.D.). Glucagon increased the rate of urea synthesis by 35 +/- 11 mmol/hr (p less than 0.02) and decreased the alanine concentration by 0.22 +/- 0.06 mmol/l (p less than 0.01). Glucagon increased the hepatic nitrogen clearance to an average of 42 +/- 13 l/hr (p less than 0.01). The difference between infusion of amino-nitrogen and appearance of urea-nitrogen was +15 +/- 10 mmol/hr during alanine infusion alone and -11 +/- 25 mmol/hr during exogenous glucagon. The loss of nitrogen could be accounted for by depletion of non-alanine amino acids from the blood. Glucagon increases the efficacy of urea synthesis, which may be of importance for catabolism by changing the hepatic contribution to nitrogen homeostasis.

Cerebral perfusion, cardiac output, and arterial pressure in patients with fulminant hepatic failure.

Objective: To evaluate whether changes in cardiac output influence cerebral perfusion directly. In fulminant hepatic failure, the circulation is characterized by wide variations in cardiac output and cerebral blood flow (CBF). Design: A retrospective, interindividual analysis of CBF and cardiac output (part 1) and a prospective evaluation of cerebral perfusion, cardiac output, and arterial pressure during norepinephrine infusion (part 2). Setting: A four‐bed specialist liver failure unit. Patients and Interventions: Twenty patients with fulminant hepatic failure (median age, 43 yrs; range, 17‐54; 13 women) maintained on mechanical ventilation (PaCO2, 33 torr [4.40 kPa]; range, 26‐36 torr [3.47‐4.80 kPa) after development of hepatic encephalopathy, stages 3 to 4, had mean arterial pressure (MAP) and cardiac output determined by radial and pulmonary artery catheters. Cerebral perfusion was measured by the 133Xenon clearance technique (n = 8) and by transcranial Doppler sonography, which was used to measure mean flow velocity (Vmean). CBF and Vmean in patients with high cardiac output (>9 L/min) were compared with those with normal or low cardiac output. In the second part of the study, cerebral autoregulation was evaluated by concomitant measurement of Vmean, cardiac output, and MAP during norepinephrine infusion in nine patients. Measurements and Main Results: Median cardiac output was 8.5 L/min (range, 3.2‐17.3), CBF was 33 mL/100 g/min (12‐77 g/min), and Vmean was 45 cm/sec (22‐65 cm/sec). In patients with elevated cardiac output, MAP, Vmean, and CBF were similar compared with patients with normal cardiac output. Neither CBF nor Vmean correlated to cardiac output. During norepinephrine infusion, Vmean increased from 49 cm/sec (34‐69 cm/sec) to 63 cm/sec (58‐90 cm/sec; p < .05), as MAP increased from 75 mm Hg (54‐105 mm Hg) to 97 mm Hg (90‐128 mm Hg). On average, cardiac output remained unchanged at 5.7 L/min (range, 3.2‐17.3), as it increased in five patients and decreased in four patients. The change in Vmean was related to MAP (r2 = .76; p < .01) but not to cardiac output (r2 = .01). Conclusion: This study shows that CBF correlates to arterial pressure rather than to cardiac output in patients with fulminant hepatic failure. The presence of pressure‐passive cerebral circulation stresses the importance of strict cardiovascular control in securing continuous and sufficient cerebral oxygenation and in avoiding the development of cerebral hyperemia and cerebral edema.