Elina Salmi

S-ketamine anesthesia increases cerebral blood flow in excess of the metabolic needs in humans.

Background:Animal studies have demonstrated neuroprotective properties of S-ketamine, but its effects on cerebral blood flow (CBF), metabolic rate of oxygen (CMRO2), and glucose metabolic rate (GMR) have not been comprehensively studied in humans. Methods:Positron emission tomography was used to quantify CBF and CMRO2 in eight healthy male volunteers awake and during S-ketamine infusion targeted to subanesthetic (150 ng/ml) and anesthetic (1,500–2,000 ng/ml) concentrations. In addition, subjects’ GMRs were assessed awake and during anesthesia. Whole brain estimates for cerebral blood volume were obtained using kinetic modeling. Results:The mean ± SD serum S-ketamine concentration was 159 ± 21 ng/ml at the subanesthetic and 1,959 ± 442 ng/ml at the anesthetic levels. The total S-ketamine dose was 10.4 mg/kg. S-ketamine increased heart rate (maximally by 43.5%) and mean blood pressure (maximally by 27.0%) in a concentration-dependent manner (P = 0.001 for both). Subanesthetic S-ketamine increased whole brain CBF by 13.7% (P = 0.035). The greatest regional CBF increase was detected in the anterior cingulate (31.6%; P = 0.010). No changes were detected in CMRO2. Anesthetic S-ketamine increased whole brain CBF by 36.4% (P = 0.006) but had no effect on whole brain CMRO2 or GMR. Regionally, CBF was increased in nearly all brain structures studied (greatest increase in the insula 86.5%; P < 0.001), whereas CMRO2 increased only in the frontal cortex (by 15.7%; P = 0.007) and GMR increased only in the thalamus (by 11.7%; P = 0.010). Cerebral blood volume was increased by 51.9% (P = 0.011) during anesthesia. Conclusions:S-ketamine–induced CBF increases exceeded the minor changes in CMRO2 and GMR during anesthesia.

Effects of subanesthetic ketamine on regional cerebral glucose metabolism in humans.

Background: The authors have recently shown with positron emission tomography that subanesthetic doses of racemic ket-amine increase cerebral blood flow but do not affect oxygen consumption significantly. In this study, the authors wanted to assess the effects of racemic ketamine on regional glucose metabolic rate (rGMR) in similar conditions to establish whether ketamine truly induces disturbed coupling between cerebral blood flow and metabolism. Methods: 18F-labeled fluorodeoxyglucose was used as a positron emission tomography tracer to quantify rGMR on 12 brain regions of interest of nine healthy male volunteers at baseline and during a 300-ng/ml ketamine target concentration level. In addition, voxel-based analysis was performed for the relative changes in rGMR using statistical parametric mapping. Results: The mean ± SD measured ketamine serum concentration was 326.4 ± 86.3 ng/ml. The mean arterial pressure was slightly increased (maximally by 16.4%) during ketamine infusion (P < 0.001). Ketamine increased absolute rGMR significantly in most regions of interest studied. The greatest increases were detected in the thalamus (14.6 ± 15.9%; P = 0.029) and in the frontal (13.6 ± 13.1%; P = 0.011) and parietal cortices (13.1 ± 11.2%; P = 0.007). Absolute rGMR was not decreased anywhere in the brain. The voxel-based analysis revealed relative rGMR increases in the frontal, temporal, and parietal cortices. Conclusions: Global increases in rGMR seem to parallel ket-amine-induced increases in cerebral blood flow detected in the authors’ earlier study. Therefore, ketamine-induced disturbance of coupling between cerebral blood flow and metabolism is highly unlikely. The previously observed decrease in oxygen extraction fraction may be due to nonoxidative glucose metabolism during ketamine-induced increase in glutamate release.

Effects of xenon anesthesia on cerebral blood flow in humans: a positron emission tomography study.

Background:Animal studies have demonstrated a strong neuroprotective property of xenon. Its usefulness in patients with cerebral pathology could be compromised by deleterious effects on regional cerebral blood flow (rCBF). Methods:15O-labeled water was used to determine rCBF in nine healthy male subjects at baseline and during 1 minimum alveolar concentration (MAC) of xenon (63%). Anesthesia was based solely on xenon. Absolute changes in rCBF were quantified using region-of-interest analysis and voxel-based analysis. Results:Mean arterial blood pressure and arterial partial pressure for carbon dioxide remained unchanged. The mean (± SD) xenon concentration during anesthesia was 65.2 ± 2.3%. Xenon anesthesia decreased absolute rCBF by 34.7 ± 9.8% in the cerebellum (P < 0.001), by 22.8 ± 10.4% in the thalamus (P = 0.001), and by 16.2 ± 6.2% in the parietal cortex (P < 0.001). On average, xenon anesthesia decreased absolute rCBF by 11.2 ± 8.6% in the gray matter (P = 0.008). A 22.1 ± 13.6% increase in rCBF was detected in the white matter (P = 0.001). Whole-brain voxel-based analysis revealed widespread cortical reductions and increases in rCBF in the precentral and postcentral gyri. Conclusions:One MAC of xenon decreased rCBF in several areas studied. The greatest decreases were detected in the cerebellum, the thalamus and the cortical areas. Increases in rCBF were observed in the white matter and in the pre- and postcentral gyri. These results are in clear contradiction with ketamine, another N-methyl-d-aspartate antagonist and neuroprotectant, which induces a general increase in cerebral blood flow at anesthetic concentrations.

Sevoflurane and propofol increase 11C-flumazenil binding to gamma-aminobutyric acidA receptors in humans.

Based on in vitro studies and animal data, most anesthetics are supposed to act via &ggr;-aminobutyric acid type A (GABAA) receptors. However, this fundamental characteristic has not been extensively investigated in humans. We studied 11C-flumazenil binding to GABAA receptors during sevoflurane and propofol anesthesia in the living human brain using positron emission tomography (PET). Fourteen healthy male subjects underwent 2 60-min dynamic PET studies with 11C-labeled flumazenil, awake and during anesthesia. Anesthesia was maintained with 2% end-tidal sevoflurane (n = 7) or propofol at a target plasma concentration of 9.0 ± 3.0 (mean ± sd) &mgr;g/mL (n = 7). The depth of anesthesia was measured with bispectral index (BIS). Values of regional distribution volumes (DV) of 11C-flumazenil were calculated in several brain areas using metabolite-corrected arterial plasma curves and a two-compartment model. Separate voxel-based statistical analysis using parametric DV images was performed for detailed visualization. The average BIS index was 35 ± 6 in the sevoflurane group and 28 ± 8 in the propofol group (P = 0.02). Sevoflurane increased the DV of 11C-flumazenil significantly (P < 0.05) in all brain areas studied except the pons and the white matter. In the propofol group the increases were significant (P < 0.05) in the caudatus, putamen, cerebellum, thalamus and the frontal, temporal, and parietal cortices. Furthermore, the DV increases in the frontal, occipital, parietal, and temporal cortical areas and in the putamen were statistically significantly larger in the sevoflurane than in the propofol group. Our findings support the involvement of GABAA receptors in the mechanism of action of both anesthetics in humans.

Bispectral Index, Entropy, and Quantitative Electroencephalogram during Single-agent Xenon Anesthesia

Background:The aim was to evaluate the performance of anesthesia depth monitors, Bispectral Index (BIS) and Entropy, during single-agent xenon anesthesia in 17 healthy subjects. Methods:After mask induction with xenon and intubation, anesthesia was continued with xenon only. BIS, State Entropy and Response Entropy, and electroencephalogram were monitored throughout induction, steady-state anesthesia, and emergence. The performance of BIS, State Entropy, and Response Entropy were evaluated with prediction probability, sensitivity, and specificity analyses. The power spectrum of the raw electroencephalogram signal was calculated. Results:The mean (SD) xenon concentration during anesthesia was 66.4% (2.4%). BIS, State Entropy, and Response Entropy demonstrated low prediction probability values at loss of response (0.455, 0.656, and 0.619) but 1 min after that the values were high (0.804, 0.941, and 0.929). Thereafter, equally good performance was demonstrated for all indices. At emergence, the prediction probability values to distinguish between steady-state anesthesia and return of response for BIS, State Entropy, and Response Entropy were 0.988, 0.892, and 0.992. No statistical differences between the performances of the monitors were observed. Quantitative electroencephalogram analyses showed generalized increase in total power (P < 0.001), delta (P < 0.001) and theta activity (P < 0.001), and increased alpha activity (P = 0.003) in the frontal brain regions. Conclusions:Electroencephalogram-derived depth of sedation indices BIS and Entropy showed a delay to detect loss of response during induction of xenon anesthesia. Both monitors performed well in distinguishing between conscious and unconscious states during steady-state anesthesia. Xenon-induced changes in electroencephalogram closely resemble those induced by propofol.

Measurement of GABAA receptor binding in vivo with [11C]Flumazenil: A test–retest study in healthy subjects☆☆☆

[(11)C]Flumazenil is widely used in positron emission tomography (PET) studies to measure GABA(A) receptors in vivo in humans. Although several different methods have been applied for the quantification of [(11)C]flumazenil binding, the reproducibility of these methods has not been previously examined. The reproducibility of a single bolus [(11)C]flumazenil measurements was studied by scanning eight healthy volunteers twice during the same day. Grey matter regions were analyzed using both regions-of-interest (ROI) and voxel-based analysis methods. Compartmental kinetic modelling using both arterial and reference region input function were applied to derive the total tissue distribution volume (V(T)) and the binding potential (BP) (BP(P) and BP(ND)) of [(11)C]flumazenil. To measure the reproducibility and reliability of each [(11)C]flumazenil binding parameter, absolute variability values (VAR) and intraclass correlation coefficients (ICC) were calculated. Tissue radioactivity concentration over time was best modelled with a 2-tissue compartmental model. V(T) showed with all methods good to excellent reproducibility and reliability with low VARs (mean of all brain regions) (5.57%-6.26%) and high ICCs (mean of all brain regions) (0.83-0.88) when using conventional ROI analysis. Also voxel-based analysis methods yielded excellent reproducibility (VAR 5.75% and ICC 0.81). In contrast, the BP estimates using pons as the reference tissue yielded higher VARs (8.08%-9.08%) and lower ICCs (0.35-0.80). In conclusion, the reproducibility of [(11)C]flumazenil measurements is considerably better with outcome measures based on arterial input function than those using pons as the reference tissue. The voxel-based analysis methods are proper alternative as the reliability is preserved and analysis automated.

Xenon Does Not Affect γ-Aminobutyric Acid Type A Receptor Binding in Humans

BACKGROUND:The noble gas xenon acts as an anesthetic with favorable hemodynamic and neuroprotective properties. Based on animal and in vitro data, it is thought to exert its anesthetic effects by inhibiting glutamatergic signaling, but effects on γ-aminobutyric acid type A (GABAA) receptors also have been reported. The mechanism of anesthetic action of xenon in the living human brain still remains to be determined. METHODS:We used the specific GABAA receptor benzodiazepine-site ligand 11C-flumazenil and positron emission tomography to study the GABAergic effects of xenon in eight healthy male volunteers. Each subject underwent two dynamic 60-min positron emission tomography studies awake and during approximately one minimum alveolar concentration of xenon (65%). Bispectral index was recorded. Cortical and subcortical gray matter regions were analyzed using both automated regions-of-interest analysis and voxel-based analysis. RESULTS:During anesthesia, the mean ± sd bispectral index was 23 ± 7, and there were no significant changes in heart rate or mean arterial blood pressure. Xenon did not significantly affect 11C-flumazenil binding in any brain region. CONCLUSIONS:Xenon did not affect 11C-flumazenil binding in the living human brain, indicating that the anesthetic effect of xenon is not mediated via the GABAA receptor system.

The effects of xenon anesthesia on the relationship between cerebral glucose metabolism and blood flow in healthy subjects: a positron emission tomography study.

BACKGROUND: General anesthetics can alter the relationship between regional cerebral glucose metabolism (rCMRglc) and blood flow (rCBF). In this positron emission tomography study, our aim was to assess both rCMRglc and rCBF in the same individuals during xenon anesthesia. METHODS: 18F-labeled fluorodeoxyglucose and 15O-labeled water were used to determine rCMRglc and rCBF, respectively, in five healthy male subjects at baseline (awake) and during 1 minimum alveolar anesthetic concentration of xenon. Anesthesia was based solely on xenon. Changes in rCMRglc and rCBF were quantified using region-of-interest and voxel-based analyses. RESULTS: The mean (sd) xenon concentration during anesthesia was 67.2 (0.8)%. Xenon anesthesia induced a uniform reduction in rCMRglc, whereas rCBF decreased in 7 of 13 brain regions. The mean decreases in the gray matter were 32.4 (4.0)% (P < 0.001) and 14.8 (5.9)% (P = 0.007) for rCMRglc and rCBF, respectively. rCMRglc decreased by 10.9 (6.4)% in the white matter (P = 0.030), whereas rCBF increased by 9.2 (7.3)% (P = 0.049). The rCBF/rCMRglc ratio was especially increased in the insula, anterior and posterior cingulate, and in the somatosensory cortex. CONCLUSIONS: In general, the magnitude of the decreases in rCMRglc during 1 minimum alveolar anesthetic concentration xenon anesthesia exceeded the reductions in rCBF. As a result, the ratio between rCMRglc and rCBF was shifted to a higher level. Interestingly, xenon-induced changes in cerebral metabolism and blood flow resemble those induced by volatile anesthetics.

Subanesthetic ketamine does not affect 11C-flumazenil binding in humans.

Positron emission tomography (PET) studies suggest that propofol and inhaled anesthetics increase 11C-flumazenil binding in the living human brain, thus supporting the involvement of &ggr;-aminobutyric acid type A (GABAA) receptors in the mechanism of action of these drugs. Ketamine produces its anesthetic effects primarily by N-methyl-d-aspartate receptor antagonism, but it may also have GABAA receptor agonistic properties. By using PET, we studied the cerebral 11C-flumazenil binding in 10 healthy subjects before and during a subanesthetic racemic ketamine infusion reaching a serum concentration of 350 ± 42 ng/mL. Ketamine did not affect 11C-flumazenil binding to GABAA receptor in the brain, indicating that this mechanism is of minor importance in the actions of subanesthetic ketamine.