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Purpose: The 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., Methods: Seven 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., Results: The 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., Conclusion: The 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.

Patients with FHF have a high risk of cerebral edema and intracranial hypertension. The pathophysiological background for this phenomenon is not completely settled, but alteration in CBF as well as cerebral metabolism seems to be of importance. Mechanical hyperventilation has a prompt effect on intracranial pressure. This effect is assumed to be caused by the hypocapnia induced alkalosis which produces vasoconstriction and thereby a decrease in CBF and cerebral blood volume. It has been stated that hyperventilation may be harmful to patients with FHF, but only few studies have addressed the effect of hyperventilation upon cerebral metabolism. In the present clinical studies we evaluated the effect of short-term mechanical hyperventilation upon cerebral circulation and metabolism in patients with FHF. Although global CBF was reduced in patients with FHF it tightly matched the cerebral oxidative requirements. Already in the early phase of FHF there was a prominent cerebral efflux of glutamine that could not be accounted for by cerebral ammonia uptake. Moderate hyperventilation reduced global CBF without compromising cerebral oxidative metabolism. In addition, moderate hyperventilation restored cerebral autoregulation in most patients with FHF, and normalised the cerebral nitrogen balance during short-term interventions. Studies of global and regional cerebral carbon dioxide reactivity showed normal global as well as regional cerebral carbon dioxide reactivity in almost all patients with FHF. However, cerebral perfusion in frontal brain regions as well as basal ganglia is low in FHF as compared to healthy subjects, which may make these regions at risk of hypoperfusion during pronounced hyperventilation. It is concluded that moderate short-term hyperventilation does not compromise cerebral oxidative metabolism. Recommendation of its prolonged use in FHF awaits further studies. Furthermore, the data of this thesis demonstrates that alterations in cerebral glutamine and ammonia metabolism precedes increases of CBF, which seems to be a phenomenon that takes place later during the disease course, i.e., immediately before intracranial pressure is rising.

More than two thirds of carcinomas of the uterine cervix are caused by human papilloma virus (HPV) types 16 and 18, and 90% of all genital warts are caused by HPV 6 and 11. In June 2006, the US Food and Drug Administration accepted the first prophylactic HPV vaccine against HPV 6, 11, 16 and 18 to be offered to girls and young women. This new vaccine is also now available in Denmark. Questions concerning economics, ethics, organization, and vaccine monitoring need to be discussed in connection with the establishment of a vaccine program. In addition, information to the general population as well as to health care providers and decision-makers should have been given a high priority.

Cerebral blood flow autoregulation is lost in patients with severe liver cirrhosis. The cause of this is unknown. We determined whether autonomic dysfunction was related to impaired cerebral autoregulation in patients with cirrhosis. Fourteen patients with liver cirrhosis and 11 healthy volunteers were recruited. Autonomic function was assessed in response to deep breathing, head-up tilt and during 24-h Holter monitoring. Cerebral autoregulation was assessed by determining the change in mean cerebral blood flow velocity (MCAVm, transcranial Doppler) during an increase in blood pressure induced by norepinephrine infusion (NE). The severity of liver disease was assessed using the Child-Pugh scale (class A, mild; class B, moderate; class C, severe liver dysfunction).NE increased blood pressure similarly in the controls (27 (24-32) mmHg) and patients with the most severe liver cirrhosis (Child-Pugh C, 31 (26-44) mmHg, p=0.405 Mann-Whitney). However, the increase in MCAVm was greater in cirrhosis patients compared to the controls (Child-Pugh C, 26 (24-39) %; controls, 3 (-1.3 to 3) %; respectively, p=0.016, Mann-Whitney). HRV during deep breathing was reduced in the cirrhosis patients (Child-Pugh C, 6.0+/-2.0 bpm) compared to the controls (21.7+/-2.2 bpm, p=0.001, Tukey' test). Systolic blood pressure fell during head-up tilt only in patients with severe cirrhosis. Our results imply that cerebral autoregulation was impaired in the most severe cases of liver cirrhosis, and that those with impaired cerebral autoregulation also had severe parasympathetic and sympathetic autonomic dysfunction. Furthermore, the degree of liver dysfunction was associated with increasing severity of autonomic dysfunction. Although this association is not necessarily causal, we postulate that the loss of sympathetic innervation to the cerebral resistance vessels may contribute to the impairment of cerebral autoregulation in patients with end-stage liver disease.

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. Fischer's 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 micromol/100 g/min) as well as AoCLF (7.35 +/- 24.97 micromol/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.

Hyperammonemia and hyperventilation are consistent findings in patients with fulminant hepatic failure (FHF), which may interfere with cerebral glucose and oxygen metabolism. The aim of the present study is to evaluate whether cerebral oxidative metabolism is preserved early in the course of FHF and whether hyperventilation has an influence on this. We included 16 patients with FHF, 5 patients with cirrhosis of the liver, and 8 healthy subjects. Concomitant blood sampling from an arterial catheter and a catheter in the jugular bulb and measurement of cerebral blood flow by the xenon 133 wash-out technique allowed calculation of cerebral uptake of glucose (CMRgluc) and oxygen (CMRO2). Both CMRgluc and CMRO2 were reduced in patients with FHF compared with those with cirrhosis and healthy subjects, i.e., 11.8 +/- 2.7 v 18.3 +/- 5.5 and 28.5 +/- 6.6 micromol/100 g/min (P <.05) and 86 +/- 18 v 164 +/- 42 and 174 +/- 27 micromol/100 g/min (P <.05). Arteriovenous difference in oxygen and oxygen-glucose index were normal in patients with FHF. Institution of mechanical hyperventilation did not affect glucose and oxygen uptake and hyperventilation did not affect lactate-pyruvate ratio or lactate-oxygen index. In conclusion, we found that cerebral glucose and oxygen consumption are proportionally decreased in patients with FHF investigated before clinical signs of cerebral edema. Our data suggest that cerebral oxidative metabolism is retained at this stage of the disease without being compromised by hyperventilation.

The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been suggested to mediate septic encephalopathy through an effect on cerebral blood flow (CBF) and metabolism. The effect of an intravenous bolus of endotoxin on global CBF, metabolism, and net flux of cytokines and catecholamines was investigated in eight healthy young volunteers. Cerebral blood flow was measured by the Kety-Schmidt technique at baseline (during normocapnia and voluntary hyperventilation for calculation of subject-specific cerebrovascular CO reactivity), and 90 minutes after an intravenous bolus of a reference endotoxin. Arterial TNF-alpha peaked at 90 minutes, coinciding with a peak in subjective symptoms. At this time, CBF and Paco were significantly reduced compared to baseline; the CBF decrease was readily explained by hypocapnia. The cerebral metabolic rate of oxygen remained unchanged, and the net cerebral flux of TNF-alpha, interleukin (IL)-1beta, and IL-6 did not differ significantly from zero. Thus, high circulating levels of TNF-alpha during human endotoxemia do not induce a direct reduction in cerebral oxidative metabolism.

Background: The optimal arterial carbon dioxide tension (P(a)CO(2)) in patients with acute bacterial meningitis (ABM) is unknown and controversial. The objective of this study was to measure global cerebral blood flow (CBF), cerebrovascular CO(2) reactivity (CO(2)R), and cerebral metabolic rates (CMR) of oxygen (O(2)), glucose (glu), and lactate (lac), in patients with ABM and compare the results to those obtained in healthy volunteers., Methods: We studied 19 patients (17 of whom were sedated) with ABM and eight healthy volunteers (controls). CBF was measured during baseline ventilation and hyperventilation with single-photon emission computed tomography (SPECT) (14 patients) and/or the Kety-Schmidt technique (KS) (11 patients and all controls). In KS studies, CMR was measured by multiplying the arterial to jugular venous concentration difference (a-v D) by CBF., Results: CBF did not differ significantly among groups, although a larger variation was seen in patients than in controls. CO(2)R was not significantly different among groups. At baseline, patients had significantly lower a-v DO(2), CMR(O(2)), CMR(glu), and CMR(lac) than controls. CMR(O(2)) did not change between hyperventilation compared to baseline ventilation, whereas CMR(glu) increased., Conclusion: In patients with acute bacterial meningitis, we found variable levels of CBF and cerebrovascular CO(2) reactivity, a low a-v DO(2), low cerebral metabolic rates of oxygen and glucose, and a cerebral lactate efflux. In these patients, a ventilation strategy guided by jugular bulb oximetry and/or repeated CBF measurements may be more optimal in terms of cerebral oxygenation than a strategy aiming at identical levels of P(a)CO(2) for all patients.

Background & Aims: High circulating levels of ammonia have been suggested to be involved in the development of cerebral edema and herniation in fulminant hepatic failure (FHF). The aim of this study was to measure cerebral metabolism of ammonia and amino acids, with special emphasis on glutamine metabolism., Methods: The study consisted of patients with FHF (n = 16) or cirrhosis (n = 5), and healthy subjects (n = 8). Cerebral blood flow was measured by the 133Xe washout technique. Blood samples for determination of ammonia and amino acids were drawn simultaneously from the radial artery and the internal jugular bulb., Results: A net cerebral ammonia uptake was only found in patients with FHF (1.62 +/- 0.79 micromol x 100 g(-1) x min(-1)). The cerebral glutamine efflux was higher in patients with FHF than in the healthy subjects and cirrhotics, -6.11 +/- 5.19 vs. -1.93 +/- 1.17 and -1.50 +/- 0.29 micromol x 100 g(-1) x min(-1), respectively (P < 0.05). Patients with FHF who subsequently died of cerebral herniation (n = 6) had higher arterial ammonia concentrations, higher cerebral ammonia uptake, and higher cerebral glutamine efflux than survivors. Intervention with short-term mechanical hyperventilation in FHF reduced the net cerebral glutamine efflux, despite an unchanged net cerebral ammonia uptake., Conclusions: Patients with FHF have an increased cerebral glutamine efflux, and short-term hyperventilation reduces this efflux. A high cerebral ammonia uptake and cerebral glutamine efflux in patients with FHF were associated with an increased risk of subsequent fatal intracranial hypertension.

Patients with fulminant hepatic failure (FHF) frequently develop cerebral edema and intracranial hypertension. The aim of this study was to evaluate circulating S-100b and neuron-specific enolase (NSE) levels as markers of neurological outcome in patients with FHF. In a subgroup of patients, the cerebral flux of S-100b and NSE was measured. We included 35 patients with FHF, 6 patients with acute on chronic liver disease (AOCLD), 13 patients with cirrhosis of the liver without hepatic encephalopathy, and 8 healthy subjects. Blood samples were obtained from catheters placed in the radial artery and internal jugular bulb. The net cerebral flux of S-100b and NSE was measured, and the effect of short-term hyperventilation, as well as the effect of high-volume plasmapheresis, on circulating levels of these two biomarkers was determined. Blood levels of S-100b were greater in patients with FHF and AOCLD than patients with cirrhosis and healthy subjects (median, 0.39 microg/L; range, 0.02 to 10.31 microg/L; and 1.11 microg/L; range, 0.19 to 4.84 microg/L v 0.05 microg/L; range, 0.02 to 0.27 microg/L; and 0.09 microg/L; range, 0.02 to 0.15 microg/L, respectively; P <.05, ANOVA). Among patients with FHF, blood levels of NSE tended to be greater in patients who subsequently developed cerebral herniation than in survivors (median, 10.5 microg/L; range, 5.2 to 15.9 microg/L v 5.1 microg/L; range, 2.8 to 12 microg/L; P =.05). There was no net cerebral flux of S-100b or NSE. Short-term hyperventilation had no effect on any of these measures, whereas high-volume plasmapheresis reduced circulating S-100b levels from 0.45 microg/L (range, 0.19 to 10.31 microg/L) to 0.42 microg/L (range, 0.11 to 6.35 microg/L; P =.01). In conclusion, blood levels of S-100b were elevated in almost all patients with FHF and AOCLD, but were unrelated to survival. Conversely, NSE showed a clear tendency toward greater circulating levels in patients with FHF who subsequently developed cerebral herniation than in survivors. This finding encourages further evaluation of NSE as a marker of neurological outcome in FHF.

The present study investigated the circulating levels and cerebral fluxes of calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and neuropeptide Y (NPY) and their relation to cerebral blood flow (CBF) during normoventilation and hyperventilation in patients with fulminant hepatic failure (FHF). Sixteen patients with FHF were studied and compared to six patients with cirrhosis of the liver. CBF was measured by the (133)Xe wash-out technique. Blood samples were obtained simultaneously from the artery and internal jugular bulb. Concentrations of CGRP and VIP were higher in FHF than in cirrhosis, 87 (55-218) vs. 29 (21-42) pmol/L, and 11 (6-29) vs. 5 (3-9)pmol/L, respectively. NPY was normal, none of the measures were related to CBF, and there was no detectable net brain fluxes. Hyperventilation did not alter any of the measures. CGRP and VIP in FHF seem to reflect hemodynamic changes in the systemic rather than in the cerebral circulation., (Copyright 2001 Harcourt Publishers Ltd.)

Mechanical hyperventilation is often used to postpone or ameliorate intracranial hypertension in patients with fulminant hepatic failure (FHF). Because such treatment may critically reduce cerebral blood flow (CBF), bedside techniques to monitor CBF are warranted. In this study, we evaluated the efficacy of transcranial Doppler (TCD) sonography of the middle cerebral artery (MCA) and internal jugular bulb saturation (svJO(2)) to determine relative changes in CBF during mechanical hyperventilation in 8 patients with FHF (median age, 40 years; range, 20 to 54 years). We found that TCD and svJO(2) decreased during hyperventilation in parallel with CBF, determined by the xenon 133 ((133)Xe) washout technique. Quantitatively, the TCD method was less accurate to determine carbon dioxide (CO(2)) reactivity compared with svJO(2) and the (133)Xe technique. This indicates a slight change in MCA diameter during hyperventilation. We conclude that TCD and svJO(2) monitoring may give valuable information on relative changes in CBF during hyperventilation. However, the TCD method appears less accurate for quantitative estimation of CO(2) reactivity in patients with FHF.

Mechanical hyperventilation is often instituted in patients with acute bacterial meningitis when increased intracranial pressure is suspected. However, the effect on regional cerebral blood flow (CBF) is unknown. In this study, we measured regional CBF (rCBF) in patients with acute bacterial meningitis before and during short-term hyperventilation. In 17 patients with acute bacterial meningitis, absolute rCBF (in ml/100 g min-1) was measured during baseline ventilation and hyperventilation by single-photon emission computed tomography (SPECT) using intravenous 133Xe bolus injection. Intravenous 99mTc-HMPAO (hexamethylpropyleneamine oxime) was subsequently given during hyperventilation. In 12 healthy volunteers, rCBF was measured by SPECT and 99mTc-HMPAO during spontaneous ventilation. Using standard templates to identify regions of interest (ROIs), we calculated rCBF in percentage of cerebellar (99mTc-HMPAO images) or mean hemispheric (133Xe images) flow for each ROI, the degree of side-to-side asymmetry for each ROI, and the anterior-to-posterior flow ratio. On 133Xe images, absolute rCBF decreased significantly during hyperventilation compared to baseline ventilation in all regions, but the relative rCBF did not change significantly from baseline ventilation (n=14) to hyperventilation (n=12), indicating that the perfusion distribution was unchanged. On 99mTc-HMPAO images (n=12), relative rCBF and the anterior-to-posterior flow ratio were significantly lower in patients than in controls in the frontal and parietal cortex as well as in the basal ganglia. Focal perfusion abnormalities were present in 10 of 12 patients. Regional cerebral blood flow abnormalities are frequent in patients with acute bacterial meningitis. Short-term hyperventilation does not enhance these abnormalities.

Hyperventilation is frequently used to prevent or postpone the development of cerebral edema and intracranial hypertension in patients with fulminant hepatic failure (FHF). The influence of such therapy on regional cerebral blood flow (rCBF) remains, however, unknown. In this study the CBF-distribution pattern was determined within the first 12 hours after development of hepatic encephalopathy (HE) stage 4 before and during hyperventilation. Ten consecutive patients (median age 48 [range 33-57] years) with FHF and 9 healthy controls (median age 54 [24-58] years) had rCBF determined by single photon emission computed tomography (SPECT) using intravenous injection of 133Xenon. For determination of high resolution CBF pattern, the patients were also studied with 99mTc-hexa-methylpropyleneamine oxime (HMPAO) in the hyperventilation condition. There was no significant difference in the rCBF distribution pattern during normoventilation as compared with hyperventilation. The anterior to posterior (AP) ratio was significantly lower in patients as compared with healthy controls. After hepatic recovery and disappearance of HE, 3 patients had restored normal rCBF distribution pattern as compared with healthy controls. We conclude that in sedated patients with FHF, a relatively lower rCBF is found in the frontal regions and in the basal ganglia as compared with posterior regions. This rCBF-distribution pattern was not aggravated during hyperventilation. It is speculated that this change of rCBF in patients with FHF may render the frontal brain regions more susceptible to hypoxia. The relative frontal rCBF decrease was shown to be reversible with hepatic recovery and alleviation of HE.