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 microg x kg(-1) x min(-1)), and moderate remifentanil (0.15 microg x kg(-1) x min(-1)). The remaining three participated in the low and moderate conditions. A semirandomized 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. CONCLUSION: Remifentanil induced dose-dependent changes in relative rCBF in areas involved in pain processing. At moderate doses, rCBF responses were additionally detected in structures known to participate in modulation of vigilance and alertness. Insight into the mechanisms of opioid analgesia within the pain-processing neural network may lead to a better understanding of antinociception and opioid treatment.     

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 F-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 microg/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 micromol x 100 g x min to 31 +/- 3 micromol x 100 g x min; 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. CONCLUSIONS: Xenon induces metabolic depression in the human brain, suggesting that the inhibition of the glutamatergic system is likely to be of minor significance for the anesthetic action of xenon in vivo.     

Positron emission tomography study of regional cerebral blood flow and flow-metabolism coupling during general anaesthesia with xenon in humans

Background: The effects of xenon on regional cerebral blood flow (rCBF)are controversial. Moreover, the precise sites of action atwhich xenon exerts its effects in the human brain remain tobe established. Methods: rCBF was sequentially assessed by H₂¹⁵O positron emission tomographyin six volunteers. rCBF was determined at baseline and duringgeneral anaesthesia induced with propofol and maintained withone minimum alveolar concentration xenon. rCBF measurementswere started after the calculated plasma concentration of propofolhad decreased to subanaesthetic levels (<1.0 µg ml^–1).Changes in rCBF were calculated for 13 cerebral volumes of interestby measurement of a semi-quantitative perfusion index (PI).In addition, voxel-wise changes in rCBF were analysed usingstatistical parametric mapping. Results: Xenon had only minor effects on PI in grey matter volumes ofinterest. In contrast, PI was increased in white matter [from1.01 (0.11) to 1.24 (0.15) kcnt ml^–1 MBq^–1, P=0.05,mean (SD)]. Voxel-based analysis showed an increase of rCBFin white matter and a relative decrease of rCBF during xenonanaesthesia in distinct grey matter regions, particularly theorbito- and mesiofrontal cortex, cingulate gyrus, thalamus,hippocampus and bilateral cerebellum (P<0.05 corrected).When correlating PI with cerebral metabolic rate of glucose(previously obtained in another group of six volunteers using¹⁸F-fluorodeoxyglucose as tracer), the flow–metabolismcoupling was preserved during xenon anaesthesia. Conclusions: Xenon exerted distinct regional effects on CBF: relative decreasesin several cortical, subcortical, and cerebellar areas wereaccompanied by an increase in white matter. Flow–metabolismcoupling was not impaired during xenon anaesthesia.     

Effects of dose-dependent levels of isoflurane on cerebral blood flow in healthy subjects studied using positron emission tomography

Background:  In this study, we tested the hypothesis that escalating drug concentrations of isoflurane are associated with a significant decline in cerebral blood flow (CBF) in regions sub-serving conscious brain activity, including specifically the thalamus.
Methods:  Nine human volunteers received three escalating drug concentrations: 0.2, 0.4 and 1.0 MAC end-tidal inhalation. During waking, baseline and the three levels of sedation, a     O PET scan was performed.
Results:  Isoflurane decreased the bispectral index (BIS) values dose-dependently. Cardiovascular and respiratory parameters were maintained constant over time. No significant change in global CBF was observed. Throughout all three MAC levels of sedation, isoflurane caused an increased regional cerebral blood flow (rCBF) in the anterior cingulate and decreased rCBF in the cerebellum. Initially, isoflurane (0 vs. 0.2 MAC) significantly increased relative rCBF in the medial frontal gyrus and in the nucleus accumbens. At the next level (0.2 vs. 0.4 MAC), relative rCBF was significantly increased in the caudate nucleus and decreased in the lingual gyrus and cuneus. At the last level (0.4 vs. 1 MAC), relative rCBF was significantly increased in the insula and decreased in the thalamus, the cuneus and lingual gyrus. Compared with flow distribution in awake volunteers, 1 MAC of isoflurane significantly raised relative activity in the anterior cingulate and insula regions. In contrast, a significant relative flow reduction was identified in the thalamus, the cerebellum and lingual gyrus.
Conclusions:  Isoflurane, like sevoflurane, induced characteristic flow redistribution at doses of 0.2–1.0 MAC. At 1 MAC of isoflurane, rCBF decreased in the thalamus. Specific areas affected by both isoflurane and sevoflurane included the anterior cingulate, insula regions, cerebellum, lingual gyrus and thalamus.     

Acupuncture of LI-4 in anesthetized healthy humans decreases cerebral blood flow in the putamen measured with positron emission tomography

To minimize the influence of exogenous factors, 13 volunteers were anesthetized with sevoflurane 1 MAC while exposed to manual acupuncture stimulation of LI-4 (Group 1, n = 7) or a placebo point in the space between the third and fourth metacarpals (Group II, n = 6). During anesthesia (baseline) and anesthesia + acupuncture, one H2(15)O scan was performed, respectively. Group I demonstrated a significant decrease in regional cerebral blood flow in the right medial frontal gyrus (20%) and in the left putamen (17%). In Group II regional cerebral blood flow was decreased in the right medial frontal gyrus (22%); in the putamen no significant changes were observed. These data suggest that needle penetration of the skin affects the medial frontal gyrus, whereas acupuncture of LI-4 influences the putamen.     

Combined effects of propofol and mild hypothermia on cerebral metabolism and blood flow in rhesus monkey: a positron emission tomography study

Purpose Propofol reduces the cerebral metabolic rate for oxygen (CMRO₂), regional CMRO₂ (rCMRO₂), cerebral blood flow (CBF), and regional CBF (rCBF), but maintains the coupling of cerebral metabolism and blood flow. Under mild to moderate hypothermia, the coupling is maintained, while rCBF is reduced, but no direct measurement of rCMRO₂ has yet been reported. This study aimed to evaluate the effects of propofol under normothermic and mild hypothermic temperatures upon rCMRO₂, rCBF, and their regional coupling, through direct measurement by positron emission tomography. Methods Rhesus monkeys were anesthetized with 65% nitrous oxide and propofol. Then rCBF and rCMRO₂ were measured under four sets of conditions: infusion of a low-propofol dose (12 mg·kg⁻¹·h⁻¹) at normothermic temperatures (38°C), a high dose (25 mg·kg⁻¹·h⁻¹) at normothermic temperatures, a low dose under mild hypothermia (35°C), and a high dose under mild hypothermia. The ratio of rCBF/rCMRO₂ was calculated from these data. Results Reductions in CMRO₂ and rCMRO₂ in most regions were associated with two factors: the higher propofol dose and the induction of hypothermia, but there was no interaction between these factors. Concerning blood flow, no significant reduction was observed, except for CBF by the induction of hypothermia. The ratio of rCBF/rCMRO₂ was constant in this study setting. Conclusion During propofol anesthesia, it is possible to reduce cerebral metabolism throughout the entire brain as well as in any brain region by increasing the propofol dose or inducing hypothermia. The concurrent use of these two interventions has an additive effect on metabolism, and can be considered as safe, as their combination does not impair the coupling of cerebral metabolism and blood flow.     

Effects of xenon on cerebral blood flow and autoregulation: an experimental study in pigs

We have investigated the effects of xenon on regional cerebral blood flow (rCBF) and autoregulation in pigs sedated with propofol 4 mg kg-1 h-1. Balloon-tipped catheters were placed into the descending aorta and inferior vena cava of 15 Gottingen Minipigs for manipulation of arterial pressure and blood sampling. rCBF was measured using the sagittal sinus outflow technique. Xenon was adjusted randomly to end- tidal fractions (FE'Xe) of 0, 0.30, 0.50 and 0.70. After baseline measurements of heart rate (HR), mean arterial pressure (MAP), rCBF, sagittal sinus pressure (SSP) and calculation of regional cerebrovascular resistance (rCVR) at each respective FE'Xe, autoregulation was tested in the MAP range 60-120 mm Hg. Increasing FE'Xe had no effect on HR, MAP, rCBF or SSP. rCVR increased with increases in MAP, regardless of FE'Xe. Autoregulation was not impaired. We conclude that xenon inhalation had no effect on rCBF and autoregulation in our model, which could suggest that xenon is an adequate adjunct for neurosurgical anaesthesia.      

A positron emission tomography study of cerebral blood flow and oxygen metabolism in healthy male volunteers anaesthetized with eltanolone

Background: The effects of eltanolone anaesthesia in humans on regional cerebral blood flow, regional cerebral metabolic rate of oxygen and oxygen extraction ratio were to be evaluated using positron emission tomography (PET).
Methods: Six healthy male volunteers were studied. Series of PET-measurements with ¹⁵O and H₂¹⁵O were carried out in the awake state (baseline) (n=6), during eltanolone anaesthesia (n= 5) and during early recovery (n=5), when the subjects were oriented with respect to person, place and time. Eltanolone was given as a programmed infusion.
Results: Cerebral blood flow (rCBF) was reduced in almost all cortex regions studied by 31216% (meanSD, P < 0.01). During recovery KBF increased to 10926% of pre-anaesthetic baseline levels ( P < 0.01). Eltanolone in the doses administered lowered oxygen metabolism (rCMRO₂) by 528% ( P < 0.01) in cortex regions. During recovery rCMRO₂ increased to 9013% of baseline ( P < 0.01). The oxygen extraction (OER) in cortical regions decreased by 32223% ( P < 0.01) during anaesthesia and returned to 82210% of baseline ( P < 0.01) during recovery. Less reduction in cortical blood flow during eltanolone anaesthesia was seen in the uncus ( P < 0.01), though no differences in the depression of oxygen metabolism were seen. Oxygen extraction remained homogeneous throughout the brain.
Conclusion: Eltanolone anaesthesia was shown to reduce cerebral oxygen metabolism and cerebral blood flow in healthy volunteers. There were no signs of ischaemic effects.     

Effects of xenon on cerebral blood flow and cerebral glucose utilization in rats

BACKGROUND: The effects of xenon inhalation on mean and local cerebral blood flow (CBF) and mean and local cerebral glucose utilization (CGU) were investigated using iodo-[14C]antipyrine and [14C]deoxyglucose autoradiography. METHODS: Rats were randomly assigned to the following groups: conscious controls (n = 12); 30% (n = 12) or 70% xenon (n = 12) for 45 min for the measurement of local CBF and CGU; or 70% xenon for 2 min (n = 6) or 5 min (n = 6) for the measurement of local CBF only. RESULTS: Compared with conscious controls, steady state inhalation of 30 or 70% xenon did not result in changes of either local or mean CBF. However, mean CBF increased by 48 and 37% after 2 and 5 min of 70% xenon short inhalation, which was entirely caused by an increased local CBF in cortical brain regions. Mean CGU determined during steady state 30 or 70% xenon inhalation remained unchanged, although local CGU decreased in 7 (30% xenon) and 18 (70% xenon) of the 40 examined brain regions. The correlation between CBF and CGU in 40 local brain structures was maintained during steady state inhalation of both 30 and 70% xenon inhalation, although at an increased slope at 70% xenon. CONCLUSION: Effects of 70% xenon inhalation on CBF in rats are time-dependent. During steady state xenon inhalation (45 min), mean values of CBF and CGU do not differ from control values, and the relation of regional CBF to CGU is maintained, although reset at a higher level.     

Cerebral blood volume,blood flow,and oxygen metabolism in cerebral ischaemia and subarachnoid haemorrhage: An in-vivo study using positron emission tomography

Summary A characteristic sequence of metabolic and haemodynamic changes has been shown to occur in the brain as cerebral perfusion pressure is reduced in experimental animals. Increased cerebral blood volume (CBV) occurs initially, followed by a fall in blood flow (CBF) and, finally, a fall in oxygen metabolism (CMRO₂). By measuring CBV, CBF, and CMRO₂ with positron emission tomography in patients with vasospasm associated with subarachnoid haemorrhage and in patients with arteriosclerotic occlusion or stenosis of extraparenchymal cerebral arteries, we have demonstrated the presence of similar changes distal to such lesions in man. These findings suggest the presence of a local decrease in perfusion pressure. This study demonstrates the utility of positron emission tomography in the assessment of cerebral circulation and metabolism in man. Measurements of regional CBV must be included for a complete assessment of the dynamics of the cerebral circulation.Presented at the Symposium on Cerebral Veins, Graz, Austria, 1982.     

Local cerebral blood flow measured by stable xenon CT during fentanyl-diazepam anesthesia

We assessed the local cerebral blood flow (LCBF) in 40 patients under fentanyl-diazepam anesthesia. The measurement of LCBF was made using 50%–70% stable xenon with 20 min of inhalation interval and a shuttle method for computed tomography imaging. All patients were anesthetized with 5.95±1.76 μg·kg⁻¹ fentanyl and 0.22±0.07 mg·kg⁻¹ diazepam under mechanical ventilation during CBF measurement. The values and distribution of LCBF on non-affected hemisphere appeared to be unaltered by fentanyldiazepam anesthesia. We also assessed the cerebral carbon dioxide reactivity in 6 patients. The cerebral carbon dioxide reactivity, expressed as percentage change in LCBF per unit change in arterial carbon dioxide partial pressure, was 5.39±1.07, and there were no significant differences of reactivity among regions studied. In conclusion, we showed reference values of LCBF and carbon dioxide reactivity, measured by stable xenon-enhanced computed tomography, in patients under fentanyl-diazepam anesthesia. Carbon dioxide reactivity was preserved in all regions including gray matter, white matter, and basal ganglia.     

Measurement of regional cerebral blood flow with H2 15O positron emission tomography during matas test

Summary The authors carried out a Matas test with a regional cerebral blood flow (rCBF) study using H₂ ¹⁵O positron emission tomography (PET) for three cases of large internal carotid artery aneurysms. There is a likely correlation between the cerebral blood flow (CBF) reduction rate obtained by PET, and the mean stump pressure available from a conventional balloon occlusion test. The advantages of this noninvasive and quantitative method are presented in comparison with other methods.     

Measurement of cerebral blood flow and volume with positron emission tomography during isoflurane administration in the hypocapnic baboon

Using positron emission tomography, cerebral blood flow (CBF) and cerebral blood volume (CBV) were measured after the addition of isoflurane (1.3 vols %, end-tidal concentration) to neuroleptanesthesia (fentanyl/droperidol) in hypocapnic baboons. The study was designed to determine whether isoflurane, when administered during hypocapnia, acted as a cerebral vasodilator to increase either CBF or CBV. Mean arterial pressure was maintained within 10% of preisoflurane levels with an angiotensin infusion. In the first protocol (A), CBF and CBV were measured as close together in time as possible in order to detect divergent effects of isoflurane on these variables. When PaCO2 was reduced from 40 mmHg to 25 mmHg, CBF decreased from 44 +/- 4 to 31 +/- 4 ml.100 g-1.min-1 (P less than 0.05) and CBV decreased from 3.1 +/- 0.3 to 2.6 +/- 0.3 ml/100 g (P less than .05). Neither CBF nor CBV was significantly changed by the addition of isoflurane. In the second protocol (B), serial CBV scans were performed frequently during the addition of isoflurane in a fashion designed to detect transient changes in CBV at the time isoflurane was first added to the breathing circuit. Induction of hypocapnia again reduced CBV from 3.1 +/- .3 to 2.7 +/- .2 ml/100 g, (P less than .05) and addition of isoflurane did not change CBV. From these results the authors conclude that in the normal hypocapnic baboon the addition of 1.3% isoflurane does not significantly change cerebral blood flow or volume.     

应用SPECT研究地氟醚麻醉对人脑血流分布的影响

目的研究吸入不同浓度地氟醚麻醉下健康志愿者脑血流(CBF)分布的动态变化。方法选择9名志愿者,每位志愿者分别在清醒、吸入0.5和1.0MAC地氟醚后采用单光子发射计算机断层成像(SPECT)仪进行扫描,观察地氟醚麻醉下人局部脑血流(rCBF)的动态变化。结果全脑CBF计数在清醒时为127.5±23.1,吸入0.5MAC地氟醚麻醉后全脑CBF计数为130.8±25.4,吸入1.0MAC地氟醚后为128.8±22.9,三组间比较差异无显著意义;额叶、顶叶、颞叶、枕叶、中脑、小脑、丘脑、海马、基底核、扣带回和舌回等脑区rCBF计数差异也均无显著意义。结论在保持PETCO2和MAP稳定且在正常范围时,吸入地氟醚麻醉不影响人脑内血流量的分布。     

Assessment of skeletal muscle ventricle tissue blood flow using positron emission tomography

In this pilot study, we assessed the feasibility of using positron emission tomography (PET) imaging for in vivo measurement of skeletal muscle ventricle (SMV) tissue blood flow. In 4 dogs, with SMVs prepared from their latissimus dorsi muscle, we quantified SMV tissue blood flow by PET and related it to the tissue flow measured by radiolabeled microspheres under similar physiologic conditions. The tissue blood flow was estimated in SMVs wrapped around a mandrel (not in circulation) at rest and during SMV stimulation (30 and 90 contraction-cycles/min). SMV tissue perfusion was heterogeneous, especially during SMV contraction. Furthermore, there was a linear relationship between SMV tissue flows estimated by PET and those measured by microspheres. We conclude that in vivo imaging of SMV is feasible by PET. Quantification of SMV tissue blood flow by PET has promise as a means of assessing changes in blood flow, but further technical progress needs to be made before absolute flows can be reliably measured.     

Regional cerebral blood flow and metabolism in reversible ischemia due to vasospasm. Determination by positron emission tomography

Regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of oxygen (rCMRO2) were measured by positron emission tomography (PET) in four patients with subarachnoid hemorrhage and hemiparesis due to cerebral vasospasm. With resolution of the vasospasm, two patients recovered and two remained hemiparetic. Contralateral to the hemiparesis, rCBF was slightly higher in the two patients who eventually recovered (15.0 and 16.2 ml/100 gm/min) than in the two who remained hemiparetic (12.0 and 11.7 ml/100 gm/min). The rCMRO2 measurements showed similar differences, with values of 1.34 and 2.60 ml/100 gm/min in the patients who recovered, and 0.72 and 1.66 ml/100 gm/min in those who did not. These preliminary findings indicate that with PET studies it may be possible to prospectively differentiate patients with neurological deficits due to reversible ischemia from patients with irreversible infarction.     

Quantitative measurements of prostatic blood flow and blood volume by positron emission tomography.

Prostatic blood flow was measured with 15oxygen-water by positron emission tomography using a 1-compartment model. A dynamic study method was applied to 9 normal subjects, 6 with benign prostatic hypertrophy (BPH) and 11 with advanced stages C to D2 prostatic adenocarcinoma. Prostatic blood flow was 15.7 +/- 7.5 ml. per minute per 100 gm. in normal controls, 17.7 +/- 5.2 ml. per minute per 100 gm. in BPH patients and 29.4 +/- 7.8 ml. per minute per 100 gm. in prostatic cancer patients. Prostatic blood flow negatively correlated well with age in the normal subjects. Prostatic blood volume was also estimated by the steady state method using 15oxygen-carbon monoxide. Prostatic blood volume was 8.1 +/- 2.6% in normal controls, 8.9 +/- 1.1% in BPH patients and 6.1 +/- 2.1% in prostatic cancer patients. Blood flow in the prostatic cancer tissue was higher than that in the normal (p < 0.001) or BPH (p < 0.01) tissue. A significant difference in prostatic blood volume was also observed between BPH and cancer tissues (p < 0.02).