Mika Teräs

Effects of Sevoflurane, Propofol, and Adjunct Nitrous Oxide on Regional Cerebral Blood Flow, Oxygen Consumption, and Blood Volume in Humans

Background Anesthetic agents, especially volatile anesthetics and nitrous oxide (N2O), are suspected to perturb cerebral homeostasis and vascular reactivity. The authors quantified the effects of sevoflurane and propofol as sole anesthetics and in combination with N2O on regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV) in the living human brain using positron emission tomography. Methods 15O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine rCBF, rCMRO2 and rCBV, respectively, in eight healthy male subjects during the awake state (baseline) and at four different anesthetic regimens: (1) sevoflurane alone, (2) sevoflurane plus 70% N2O (S+N), (3) propofol alone, and (4) propofol plus 70% N2O (P+N). Sevoflurane and propofol were titrated to keep a constant hypnotic depth (Bispectral Index 40) throughout anesthesia. End-tidal carbon dioxide was strictly kept at preinduction level. Results The mean ± SD end-tidal concentration of sevoflurane was 1.5 ± 0.3% during sevoflurane alone and 1.2 ± 0.3% during S+N (P < 0.001). The measured propofol concentration was 3.7 ± 0.7 &mgr;g/ml during propofol alone and 3.5 ± 0.7 &mgr;g/ml during P+N (not significant). Sevoflurane alone decreased rCBF in some (to 73–80% of baseline, P < 0.01), and propofol in all brain structures (to 53–70%, P < 0.001). Only propofol reduced also rCBV (in the cortex and cerebellum to 83–86% of baseline, P < 0.05). Both sevoflurane and propofol similarly reduced rCMRO2 in all brain areas to 56–70% and 50–68% of baseline, respectively (P < 0.05). The adjunct N2O counteracted some of the rCMRO2 and rCBF reductions caused by drugs alone, and especially during S+N, a widespread reduction (P < 0.05 for all cortex and cerebellum vs. awake) in the oxygen extraction fraction was seen. Adding of N2O did not alter the rCBV effects of sevoflurane and propofol alone. Conclusions Propofol reduced rCBF and rCMRO2 comparably. Sevoflurane reduced rCBF less than propofol but rCMRO2 to an extent similar to propofol. These reductions in flow and metabolism were partly attenuated by adjunct N2O. S+N especially reduced the oxygen extraction fraction, suggesting disturbed flow–activity coupling in humans at a moderate depth of anesthesia.

Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo.

Positron emission tomography permits noninvasive measurement of regional glucose uptake in vivo in humans. We employed this technique to determine the effect of FFA on glucose uptake in leg, arm, and heart muscles. Six normal men were studied twice under euglycemic hyperinsulinemic (serum insulin approximately 500 pmol/liter) conditions, once during elevation of serum FFA by infusions of heparin and Intralipid (serum FFA 2.0 +/- 0.4 mmol/liter), and once during infusion of saline (serum FFA 0.1 +/- 0.01 mmol/liter). Regional glucose uptake rates were measured using positron emission tomography-derived 18F-fluoro-2-deoxy-D-glucose kinetics and the three-compartment model described by Sokoloff (Sokoloff, L., M. Reivich, C. Kennedy, M. C. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada, and M. Shinohara. 1977. J. Neurochem. 28: 897-916). Elevation of plasma FFA decreased whole body glucose uptake by 31 +/- 2% (1,960 +/- 130 vs. 2,860 +/- 250 mumol/min, P less than 0.01, FFA vs. saline study). This decrease was due to inhibition of glucose uptake in the heart by 30 +/- 8% (150 +/- 33 vs. 200 +/- 28 mumol/min, P less than 0.02), and in skeletal muscles; both when measured in femoral (1,594 +/- 261 vs. 2,272 +/- 328 mumol/min, 25 +/- 13%) and arm muscles (1,617 +/- 411 to 2,305 +/- 517 mumol/min, P less than 0.02, 31 +/- 6%). Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.75, P less than 0.005), and arm muscles (r = 0.69, P less than 0.05) but not with glucose uptake in the heart (r = 0.04, NS). These data demonstrate that the glucose-FFA cycle operates in vivo in both heart and skeletal muscles in humans.

Cardiac Positron Emission Tomography/Computed Tomography Imaging Accurately Detects Anatomically and Functionally Significant Coronary Artery Disease

Background— Computed tomography (CT) is increasingly used to detect coronary artery disease, but the evaluation of stenoses is often uncertain. Perfusion imaging has an established role in detecting ischemia and guiding therapy. Hybrid positron emission tomography (PET)/CT allows combination angiography and perfusion imaging in short, quantitative, low-radiation-dose protocols. Methods and Results— We enrolled 107 patients with an intermediate (30% to 70%) pretest likelihood of coronary artery disease. All patients underwent PET/CT (quantitative PET with 15O-water and CT angiography), and the results were compared with the gold standard, invasive angiography, including measurement of fractional flow reserve when appropriate. Although PET and CT angiography alone both demonstrated 97% negative predictive value, CT angiography alone was suboptimal in assessing the severity of stenosis (positive predictive value, 81%). Perfusion imaging alone could not always separate microvascular disease from epicardial stenoses, but hybrid PET/CT significantly improved this accuracy to 98%. The radiation dose of the combined PET and CT protocols was 9.3 mSv (86 patients) with prospective triggering and 21.8 mSv (21 patients) with spiral CT. Conclusion— Cardiac hybrid PET/CT imaging allows accurate noninvasive detection of coronary artery disease in a symptomatic population. The method is feasible and can be performed routinely with <10 mSv in most patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00627172.

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 &mgr;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. Conclusions Both anesthetic agents caused a global reduction of rCBF (propofol > sevoflurane) at the 1 MAC/EC50 level. The effect was maintained at higher propofol concentrations, whereas 2 MAC sevoflurane caused noticeable flow redistribution. Despite the marked global changes, SPM analysis enabled detailed localization of regions with the greatest relative decreases.

Gender and Insulin Sensitivity in the Heart and in Skeletal Muscles: Studies Using Positron Emission Tomography

Good insulin sensitivity is independently associated with a low risk for coronary heart disease, but it is unclear whether this risk factor differs between men and women. We compared insulin sensitivity of glucose uptake directly in muscle and heart tissues between healthy women (age 29 ± 2 years, body mass index [BMI] 22 ± 1 kg/m2, VO2max 39 ± 4 ml · kg−1 · min−1) and men matched for age (31 ± 2 years), BMI (23 ± 1 kg/m2), and VO2max (44 ± 3 ml · kg−1 · min−1) using [18F]fluoro-2-deoxy-D-glucose and positron emission tomography under hyperinsulinemic (insulin infusion rate 1 mU · kg−1 · min−1) normoglycemic conditions. Whole body insulin sensitivity was 41% greater in women (52 ± 6 μmol · kg body wt−1 · min−1) than in men (37 ± 3 μmol · kg body wt−1 · min−1, P < 0.05). This difference was explained by a 47% greater rate of glucose uptake by femoral muscles (113 ± 10 vs. 77 ± 7 μmol · kg muscle−1 · min−1, women vs. men, P < 0.01). Insulin-stimulated glucose uptake rates in the heart were similar in women (738 ± 58) and men (749 ± 62 μmol · kg muscle−1 · min−1). Femoral muscle insulin sensitivity was closely correlated with whole body insulin sensitivity (r = 0.84, P < 0.001). Gender and VO2max together explained 68% of the variation in femoral muscle glucose uptake. We conclude that women are more sensitive to insulin than equally fit men because of enhanced muscle but not heart insulin sensitivity.

Radiotherapy treatment planning and long-term follow-up with [11C]methionine PET in patients with low-grade astrocytoma

PURPOSE To evaluate the feasibility of [(11)C]-methionine positron emission tomography (MET PET) in radiotherapy (RT) treatment planning and long-term follow-up in patients with low-grade glioma. PATIENTS Thirteen patients with low-grade astrocytoma and 1 with anaplastic astrocytoma underwent sequential MET PET and magnetic resonance imaging (MRI) before and 3, 6, 12, and 21-39 months after RT, respectively. Ten patients were studied after initial debulking surgery or biopsy and 4 in the recurrence phase. METHODS A total of 58 PET scans were performed. After transmission scanning, a median dose of 425 MBq of MET was injected intravenously and emission data was acquired 20 min after injection for 20 min. The uptake of MET in tumor area was measured as standardized uptake value (SUV) and tumor-to-contralateral brain SUV ratios were generated to assess irradiation effects on tumor metabolism. Functional imaging with PET was compared with concurrent MRI in designing the RT planning volumes and in assessment of response to RT during a median follow-up time of 33 months. RESULTS In 12 patients (86%), tumor area was clearly discernible in the baseline PET study. In the remaining 2 patients with a suspected residual tumor in MRI, PET showed only a diffuse uptake of MET interpreted as negative in the original tumor area. In the dose planning of RT, MET PET was helpful in outlining the gross tumor volume in 3 of 11 cases (27%), whereas PET findings either coincided with MRI (46%) or were less distinctive (27%) in other cases. In quantitative evaluation, patients with a low tumor SUV initially had significantly better prognosis than those with a high SUV. Tumor-to-contralateral brain uptake ratios of MET discriminated well patients remaining clinically stable from those who have since relapsed or died of disease. CONCLUSION Quantitative MET PET has prognostic value at the time of initial treatment planning of low-grade glioma. Some patients may benefit of RT volume definition with MET PET, which seems to disclose residual tumor better than MRI in selected cases. Stable or decreasing uptake of MET in tumor area after RT during follow-up seems to be a favorable sign.

Clinical Value of Absolute Quantification of Myocardial Perfusion With 15O-Water in Coronary Artery Disease

Background— The standard interpretation of perfusion imaging is based on the assessment of relative perfusion distribution. The limitations of that approach have been recognized in patients with multivessel disease and endothelial dysfunction. To date, however, no large clinical studies have investigated the value of measuring quantitative blood flow and compared that with relative uptake. Methods and Results— One hundred four patients with moderate (30%–70%) pretest likelihood of coronary artery disease (CAD) underwent PET imaging during adenosine stress using 15O-water and dynamic imaging. Absolute myocardial blood flow was calculated from which both standard relative myocardial perfusion images and images scaled to a known absolute scale were produced. The patients and the regions then were classified as normal or abnormal and compared against the reference of conventional angiography with fractional flow reserve. In patient-based analysis, the positive predictive value, negative predictive value, and accuracy of absolute perfusion in the detection of any obstructive CAD were 86%, 97%, and 92%, respectively, with absolute quantification. The corresponding values with relative analysis were 61%, 83%, and 73%, respectively. In region-based analysis, the receiver operating characteristic curves confirmed that the absolute quantification was superior to relative assessment. In particular, the specificity and positive predictive value were low using just relative differences in flow. Only 9 of 24 patients with 3-vessel disease were correctly assessed using relative analysis. Conclusions— The measurement of myocardial blood flow in absolute terms has a significant impact on the interpretation of myocardial perfusion. As expected, multivessel disease is more accurately detected. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00627172.

The second generation HRRT - a multi-centre scanner performance investigation

The high resolution research tomograph (HRRT) is one of the most complex existing positron emission tomographs: it is the only human size scanner capable of decoding the depth of the /spl gamma/-ray interaction in the crystal, using a lutetium LSO/LYSO phoswich detector arrangement. In this study we determined basic scanner hardware characteristics, such as scanner data acquisition stability, and their variability across eleven centres. In addition a subset of the NEMA NU-2001 standards measurements was performed. We found (i) significant variability in the DOI decoding results between centres, (ii) a trend toward an increasing number of detected true coincident events as a function of elapsed time from scanner calibration likely due to a shifting energy spectrum, (iii) a count-rate dependent layer identification, (iv) scatter fraction ranging from /spl sim/ 42% to 54% where the variability was partly related to the shifting of the energy spectrum, (v) sensitivity ranging from /spl sim/5.5% to 6.5% across centres, (vi) resolution of /spl sim/(2.5 mm)/sup 3/, fairly consistent across centres, (vii) image quality which is very comparable to other scanners.

[18F]fluorodeoxyglucose uptake in tumors: kinetic vs. steady-state methods with reference to plasma insulin.

[18F]Fluorodeoxyglucose (FDG) uptake in noncerebral tumors is commonly reported as tissue radioactivity concentration normalized to injected dose and body weight. We studied the feasibility of this approach by imaging 68 tumors in 46 oncologic patients with dynamic FDG-PET and compared kinetic and static methods of quantitation of FDG uptake. Further, the effect of plasma glucose and insulin concentration on the obtained quantitative indexes was analyzed in all patients. The metabolic rate for FDG was strongly associated with normalized uptake value adjusted for injected dose (r = 0.92, p < 0.0001), dose and patient weight (r = 0.91, p < 0.0001), and dose and body surface area (r = 0.94, p < 0.0001). The FDG uptake was not related to plasma glucose concentration under euglycemic (≤6.5 mmol/L) conditions, but was low in two diabetic patients with overt hyperglycemia. Hyperinsulinemia was associated with a low to moderate FDG uptake, probably exerting its action through a metabolic shift of tracer influx to muscle and fat. Our results show that a single scan in the steady-state phase, e.g., 45–60 min from the injection, can be used for assessment of FDG uptake in tumors, making frequent blood sampling during imaging unnecessary. However, glucose concentration in blood must be monitored in patients with known or suspected abnormalities in glucose metabolism.

Carbon-11-methionine and PET in evaluation of treatment response of breast cancer.

Uptake of L-methyl-11C-methionine (11C-methionine) in breast cancer metastases was studied with positron emission tomography (PET). Eight patients with soft tissue metastases were studied twice: before the onset of chemotherapy (4), hormonal therapy (3) or radiotherapy (1) and 3-14 weeks later. The radioactivity concentration of the low molecular weight fraction of venous plasma samples separated by fast gel filtration was used as input function. The input corrected uptake rate of 11C-methionine (Ki) in breast cancer metastases before the treatment ranged between 0.035 and 0.186 1 min-1 and the standardised uptake value (SUV) between 2.0 and 11.4. The uptake of 11C-methionine into the metastases decreased when clinical objective stability or regression of the metastases was later obtained and increased in cases where progressive disease was seen during treatment. We conclude that metabolic changes in the amino acid metabolism detected by PET precede the clinical response, and may be of clinical value in predicting the treatment response.