Cerebral Metabolism during Propofol Anesthesia in Humans Studied with Positron Emission Tomography

Background: Although the effects of propofol on cerebral metabolism have been studied in animals, these effects have yet to be directly examined in humans. Consequently, we used positron emission tomography (PET) to demonstrate in vivo the regional cerebral metabolic changes that occur in humans during propofol anesthesia.

Methods: Six volunteers each underwent two PET scans; one scan assessed awake-baseline metabolism, and the other assessed metabolism during anesthesia with a propofol infusion titrated to the point of unresponsiveness (mean rate + SD 7.8 + 1.5 mg *symbol* kg1 *symbol* h1). Scans were obtained using the18 fluorodeoxyglucose technique.

Results: Awake whole-brain glucose metabolic rates (GMR) averaged 29 + 8 micro moles *symbol* 100 g1 *symbol* min1 (mean plus/minus SD). Anesthetized whole-brain GMR averaged 13 + 4 micro moles *symbol* 100 g1 *symbol* min1 (paired t test, P < 0.007). GMR decreased in all measured areas during anesthesia. However, the decrease in GMR was not uniform. Cortical metabolism was depressed 58%, whereas subcortical metabolism was depressed 48% (P < 0.001). Marked differences within cortical regions also occurred. In the medial and subcortical regions, the largest percent decreases occurred in the left anterior cingulate and the inferior colliculus.     

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.     

Positron Emission Tomography Study of Regional Cerebral Metabolism in Humans during Isoflurane Anesthesia

Background: Although the anesthetic effects of the intravenous anesthetic agent propofol have been studied in the living human brain using brain imaging technology, the nature of the anesthetic state evident in the human brain during inhalational anesthesia remains unknown. To examine this issue, the authors studied the effects of isoflurane anesthesia on human cerebral glucose metabolism using positron emission tomography (PET).

Methods: Five volunteers each underwent two PET scans; one scan assessed awake-baseline metabolism and the other scan assessed metabolism during isoflurane anesthesia titrated to the point of unresponsiveness (means +/- SD; expired = 0.5 +/- 0.1%). Scans were obtained with a GE2048 scanner (4.5-mm resolution-FWHM) using the18 fluorodeoxyglucose technique.

Results: Awake whole-brain glucose metabolism averaged 6.9 +/- 1.5 mg [center dot] 100 g sup -1 [center dot] min sup -1 (means +/- SD). Isoflurane reduced whole-brain metabolism 46 +/- 11% to 3.6 +/- 0.3 mg [center dot] 100 g sup -1 [center dot] min sup -1 (P less or equal to 0.005). Regional metabolism decreased fairly uniformly throughout the brain, and no evidence of any regional metabolic increases were found in any brain region for any participant. A region-of-interest analysis showed that the pattern of regional metabolism evident during isoflurane anesthesia was not significantly different from that seen when participants were awake.     

Effects of Surgical Levels of Propofol and Sevoflurane Anesthesia on Cerebral Blood Flow in Healthy Subjects Studied with Positron Emission Tomography

Background: The authors report a positron emission tomography (PET) study on humans with parallel exploration of the dose-dependent effects of an intravenous (propofol) and a volatile (sevoflurane) anesthetic agent on regional cerebral blood flow (rCBF) using quantitative and relative (Statistical Parametric Mapping [SPM]) analysis.

Methods: Using H215O, rCBF was assessed in 16 healthy (American Society of Anesthesiologists [ASA] physical status I) volunteers awake and at three escalating drug concentrations: 1, 1.5, and 2 MAC/EC50, or specifically, at either 2, 3, and 4% end-tidal sevoflurane (n = 8), or 6, 9, and 12 [mu]g/ml plasma concentration of propofol (n = 8). Rocuronium was used for muscle relaxation.

Results: Both drugs decreased the bispectral index and blood pressure dose-dependently. Comparison between adjacent levels showed that sevoflurane initially (0 vs. 1 MAC) reduced absolute rCBF by 36-53% in all areas, then (1 vs. 1.5 MAC) increased rCBF in the frontal cortex, thalamus, and cerebellum (7-16%), and finally (1.5 vs. 2 MAC) caused a dual effect with a 23% frontal reduction and a 38% cerebellar increase. In the propofol group, flow was also initially reduced by 62-70%, with minor further effects. In the SPM analysis of the "awake to 1 MAC/EC50" step, both anesthetic agents reduced relative rCBF in the cuneus, precuneus, posterior limbic system, and the thalamus or midbrain; additionally, propofol reduced relative rCBF in the parietal and frontal cortices.     

Positron Emission Tomography Study of Regional Cerebral Metabolism during General Anesthesia with Xenon in Humans

Background: The precise mechanism by which the gaseous anesthetic xenon exerts its effects in the human brain remains unknown. Xenon has only negligible effects on inhibitory [gamma]-aminobutyric acid receptors, one of the putative molecular targets for most general anesthetics. Instead, xenon has been suggested to induce anesthesia by inhibiting excitatory glutamatergic signaling. Therefore, the authors hypothesized that xenon, similar to ketamine and nitrous oxide, increases global and regional cerebral metabolism in humans.

Methods: The regional cerebral metabolic rate of glucose (rcMRGlu) was sequentially assessed in two groups of six volunteers each, using 18F-fluorodeoxyglucose as tracer. In the xenon group, rcMRGlu was determined at baseline and during general anesthesia induced with propofol and maintained with 1 minimum alveolar concentration xenon. In the control group, rcMRGlu was measured using the identical study protocol but without administration of xenon. rcMRGlu was assessed after the plasma concentration of propofol had decreased to subanesthetic levels (< 1.0 [mu]g/ml). rcMRGlu was quantified in 10 cerebral volumes of interest. In addition, voxel-wise changes in rcMRGlu were analyzed using statistical parametric mapping.

Results: Xenon reduced whole-brain metabolic rate of glucose by 26 +/- 7% (from 43 +/- 5 [mu]mol [middle dot] 100 g-1 [middle dot] min-1 to 31 +/- 3 [mu]mol [middle dot] 100 g-1 [middle dot] min-1; P < 0.005) and significantly decreased rcMRGlu in all volumes of interest compared with the control group receiving propofol only. Voxel-based analysis revealed metabolic depression within the orbitofrontal, frontomesial, temporomesial, occipital, dorsolateral frontal, and lateral temporal cortices and thalami. No increases in rcMRGlu were detected during xenon anesthesia.     

Recovery from Sevoflurane Anesthesia: A Comparison to Isoflurane and Propofol Anesthesia

Backgroud: Sevoflurane has a lower blood:gas partition coefficient than isoflurane, which may cause a more rapid recovery from anesthesia; it also might cause faster emergence times than for propofol-based anesthesia. We evaluated a database that included recovery endpoints from controlled, randomized, prospective studies sponsored by Abbott Laboratories that compared sevoflurane to isoflurane or propofol when extubation was planned immediately after completion of elective surgery in adult patients.

Methods: Sevoflurane was compared to isoflurane in eight studies (N = 2,008) and to propofol in three studies (N = 436). Analysis of variance was applied using least squares method mean values to calculate the pooled mean difference in recovery endpoints between primary anesthetics. The effects of patient age and case duration also were determined.

Results: Sevoflurane resulted in statistically significant shorter times to emergence (-3.3 min), response to command (-3.1 min), orientation (-4.0 min) and first analgesic (-8.9 min) but not time to eligibility for discharge (-1.7 min) compared to isoflurane (mean difference). Times to recovery endpoints increased with increasing case duration with isoflurane but not with sevoflurane (patients receiving isoflurane took 4-5 min more to emerge and respond to commands and 8.6 min more to achieve orientation during cases longer than 3 hr in duration than those receiving sevoflurane). Patients older than 65 yr had longer times to orientation, but within any age group, orientation was always faster after sevoflurane. There were no differences in recovery times between sevoflurane and propofol.     

Functional Anatomy of Reaching and Visuomotor Learning: A Positron Emission Tomography Study

The purpose of this study was to identify the functional corticalfields involved in reaching for targets in extrapersonal space,and to identify the specific fields representing visual targetinformation in long-term memory. Ten healthy subjects were askedto learn the positions of seven circular targets that were repeatedlyprojected on a screen. The regional cerebral blood flow wasmeasured with positron emission tomography during a rest state,at an early learning stage, at a later learning stage, and finallyat 30 min after the course of learning had been completed. MeanrCBF change images for each task minus rest were calculatedand fields of significant rCBF changes were identified. In all three task states, cortical fields were consistentlyactivated in the left motor and premotor areas, the posteriorpart of the superior parietal lobule, and the right angulargyrus. When learning of the target positions had been achieved,additional fields appeared bilaterally in the posterior partof the superior parietal lobule, the right superior occipitalgyrus, the left motor and premotor areas, the medial aspectof the superior frontal gyrus, the postcentral gyrus, the superiorpart of the cuneus, the inferior part of the angular gyrus,and the anterior part of the insula. The results indicate thatthere are at least two different types of functional fieldsin the posterior part of the superior parietal lobule; one isactive during reaching for the targets when guided by internalrepresentations of target positions; the other likely representsthe storage sites of visual target information that is addressedin long-term memory.     

PET在全麻机制研究中的应用

正电子发射汁算机断层扫描(PET)是一种功能性影像诊断新技术,能够在体反映机体内的物质代谢、局部血流量、受体密度等理化特性的变化。近年来PET技术已开始应用于全麻机制的研究,并在全麻药物的中枢区域定位、相关受体的功能分析等方面显示出独特的应用价值。     

Positron Emission Tomographic Evaluation of Patients with Head and Neck Cancer Undergoing Occlusion and Removal of the Carotid Artery

We used positron emission tomography (PET) to evaluate cerebral metabolic changes in five patients who underwent resection of the internal carotid artery (ICA) for malignant tumors of the head and neck. These patients received a thorough clinical neurologic examination as well as neuroradiologic evaluation, including computed tomography (CT), magnetic resonance imaging (MRI), and PET of the head, before and after balloon occlusion of the ICA. All five were free of cerebral or peripheral vascular disease. In addition, each patient was evaluated with an electroencephalogram (EEG) before and during the balloon occlusion for signs of ischemic changes. No abnormalities were noted on clinical neurologic examination, CT, MRI, or EEG, either before or after occlusion, and excision of the ICA. The PET examination showed a mean preoperative metabolic rate of 7.52 mg of glucose/min/100 gm of brain tissue and a mean postoperative rate of 6.32 mg/min/100 gm of brain tissue; these values were within the normal range of 5.00 to 9.00 mg of glucose/min/100 gm of tissue observed at this center. Only one subject showed asymmetry of glucose metabolism; this subject had received radiation treatment to one side of the brain after the initial PET evaluation. The results of this study support our clinical experience with occlusion and resection of the ICA in patients with head and neck tumors that in the past have been considered inoperable.     

Dose-dependent Regional Cerebral Blood Flow Changes during Remifentanil Infusion in Humans: A Positron Emission Tomography Study

Background: The current study investigated dose-dependent effects of the [mu]-selective agonist remifentanil on regional cerebral blood flow (rCBF) in volunteers using positron emission tomography (PET).

Methods: Ten right-handed male volunteers were included in a 15O-water PET study. Seven underwent three conditions: control (saline), low remifentanil (0.05 [mu]g [middle dot] kg-1 [middle dot] min-1), and moderate remifentanil (0.15 [mu]g [middle dot] kg-1 [middle dot] min-1). The remaining three participated in the low and moderate conditions. A semi-randomized study protocol was used with control and remifentanil conditions 3 or more months apart. The order of low and moderate conditions was randomized. Cardiovascular and respiratory parameters were monitored. Categoric comparisons between the control, low, and moderate conditions and a pixelwise correlation analysis across the three conditions were performed (P < 0.05, corrected for multiple comparisons) using statistical parametric mapping.

Results: Cardiorespiratory parameters were maintained constant over time. At the low remifentanil dose, significant increases in relative rCBF were noted in the lateral prefrontal cortices, inferior parietal cortices, and supplementary motor area. Relative rCBF decreases were observed in the basal mediofrontal cortex, cerebellum, superior temporal lobe, and midbrain gray matter. Moderate doses further increased rCBF in mediofrontal and anterior cingulate cortices, occipital lobe transition, and caudal periventricular grey. Significant decreases were detected in the inferior parietal lobes. These dose-dependent effects of remifentanil on rCBF were confirmed by a correlation analysis.     

异丙酚在小儿全凭静脉复合麻醉中的应用

目的与方法：在４７例ＡＳＡⅠ级，年龄８－１３．５岁、施择期整形外科手术的小儿，观察异丙酚、芬太尼和琥珀胆碱诱导，以异丙酚－芬太尼和肌松药维持麻醉的效果。结果与结论：用异丙酚诱导麻醉能产生满意的插管条件，并能明显抑制气管的心血管反应，与〉３岁小儿相比，〈３岁小儿的异丙酚讫地用量和和量均明显增高，清醒时间延长。     

Population Pharmacokinetics of Propofol: A Multicenter Study

Background: Target-controlled infusion is an increasingly common type of administration for propofol. This method requires accurate knowledge of pharmacokinetics, including the effects of age and weight. The authors performed a multicenter population analysis to quantitate the effects of covariates.

Methods: The authors analyzed 4,112 samples of 270 individuals (150 men, 120 women, aged 2-88 yr, weighing 12-100 kg). Population pharmacokinetic modeling was performed using NONMEM (NONMEM Project Group, University of California, San Francisco, CA). Inter- and intraindividual variability was estimated for clearances and volumes. The effects of age, weight, type of administration and sampling site were investigated.

Results: The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3).     

Imaging Human Cerebral Pain Modulation by Dose-dependent Opioid Analgesia: A Positron Emission Tomography Activation Study Using Remifentanil

Background: Previous imaging studies have demonstrated a number of cortical and subcortical brain structures to be activated during noxious stimulation and infusion of narcotic analgesics. This study used 15O-water and positron emission tomography to investigate dose-dependent effects of the short-acting [mu]-selective opioid agonist remifentanil on regional cerebral blood flow during experimentally induced painful heat stimulation in healthy male volunteers.

Methods: Positron emission tomography measurements were performed with injection of 7 mCi 15O-water during nonpainful heat and painful heat stimulation of the volar forearm. Three experimental conditions were used during both sensory stimuli: saline, 0.05 [mu]g [middle dot] kg-1 [middle dot] min-1 remifentanil, and 0.15 [mu]g [middle dot] kg-1 [middle dot] min-1 remifentanil. Cardiovascular and respiratory parameters were monitored noninvasively. Across the three conditions, dose-dependent effects of remifentanil on regional cerebral blood flow were analyzed on a pixel-wise basis using a statistical parametric mapping approach.

Results: During saline infusion, regional cerebral blood flow increased in response to noxious thermal stimulation in a number of brain regions as previously reported. There was a reduction in pain-related activations with increasing doses of remifentanil in the thalamus, insula, and anterior and posterior cingulate cortex. Increasing activation occurred in the cingulofrontal cortex (including the perigenual anterior cingulate cortex) and the periaqueductal gray.     

Respiratory Sites of Action of Propofol: Absence of Depression of Peripheral Chemoreflex Loop by Low-dose Propofol

Background: Propofol has a depressant effect on metabolic ventilatory control, causing depression of the ventilatory response to acute isocapnic hypoxia, a response mediated via the peripheral chemoreflex loop. In this study, the authors examined the effect of sedative concentrations of propofol on the dynamic ventilatory response to carbon dioxide to obtain information about the respiratory sites of action of propofol.

Methods: In 10 healthy volunteers, the end-tidal carbon dioxide concentration was varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia (total duration, 1,408 s). In each subject, two control studies, two studies at a plasma target propofol concentration of 0.75 [mu]g/ml (Plow), and two studies at a target propofol concentration of 1.5 [mu]g/ml (Phigh) were performed. The ventilatory responses were separated into a fast peripheral component and a slow central component, characterized by a time constant, carbon dioxide sensitivity, and apneic threshold. Values are mean +/- SD.

Results: Plasma propofol concentrations were approximately 0.5 [mu]g/ml for Plow and approximately 1.3 mg/ml for Phigh. Propofol reduced the central carbon dioxide sensitivity from 1.5 +/- 0.4 to 1.2 +/- 0.3 (Plow;P < 0.01 vs. control) and 0.9 +/- 0.1 l [middle dot] min-1 [middle dot] mmHg-1 (Phigh;P < 0.001 vs. control). The peripheral carbon dioxide sensitivity remained unaffected by propofol (control, 0.5 +/- 0.3; Plow, 0.5 +/- 0.2; Phigh, 0.5 +/- 0.2 l [middle dot] min-1 [middle dot] mmHg-1). The apneic threshold was reduced from 36.3 +/- 2.7 (control) to 35.0 +/- 2.1 (Plow;P < 0.01 vs. control) and to 34.6 +/- 1.9 mmHg (Phigh;P < 0.01 vs. control).