Anesth Analg 2003;96:1467-1472
© 2003 International Anesthesia Research Society
NEUROSURGICAL ANESTHESIA
Electron Paramagnetic Resonance Assessment of Brain Tissue Oxygen Tension in Anesthetized Rats
Huagang Hou, MD*,
Oleg Y. Grinberg, PhD*,
Satoshi Taie, MD
,
Steve Leichtweis, PhD*,
Minoru Miyake, MD PhD,
Stalina Grinberg, MS*,
Haiyi Xie, PhD
,
Marie Csete, MD PhD
, and
Harold M. Swartz, MD PhD*
*Department of Diagnostic Radiology, Dartmouth Medical School, Hanover, New Hampshire;
Department of Anesthesiology and Emergency Medicine, Kagawa Medical University, Kagawa, Japan;
Department of Community and Family Medicine, Psychiatric Research Center, Dartmouth Medical School, Lebanon, New Hampshire; and
Anesthesiology and Cell Biology, Emory University, Atlanta, Georgia
Address correspondence and reprint requests to Dr. Harold M. Swartz, EPR Center for the Study of Viable Systems, 7785 Vail, Room 702, Dartmouth Medical School, Hanover, NH 03755. Address e-mail to hms{at}dartmouth.edu
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Abstract
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The adequacy of cerebral tissue oxygenation (PtO2) is a central therapeutic end point in critically ill and anesthetized patients. Clinically, PtO2 is currently measured indirectly, based on measurements of cerebrovascular oxygenation using near infrared spectroscopy and experimentally, using positron emission tomographic scanning. Recent developments in electron paramagnetic resonance (EPR) oximetry facilitate accurate, sensitive, and repeated measurements of PtO2. EPR is similar to nuclear magnetic resonance but detects paramagnetic species. Because these species are not abundant in brain (or other tissues) in vivo, oxygen-responsive paramagnetic lithium phthalocyanine crystals implanted into the cerebral cortex are used for the measurement of oxygen. The line widths of the EPR spectra of these materials are linear functions of PtO2. We used EPR oximetry in anesthetized rats to study the patterns of PtO2 during exposure to various inhaled and injected general anesthetics and to varying levels of inspired oxygen. Rats anesthetized with 2.0 minimum alveolar anesthetic concentration isoflurane maintained the largest PtO2 (38.0 ± 4.5 mm Hg) and rats anesthetized with ketamine/xylazine had the smallest PtO2 (3.5 ± 0.3 mm Hg) at a fraction of inspired oxygen (FIO2) of 0.21, P < 0.05. The maximal PtO2 achieved under ketamine/xylazine anesthesia with FIO2 of 1.0 was 8.8 ± 0.3 mm Hg, whereas PtO2 measured during isoflurane anesthesia with FIO2 of 1.0 was 56.3 ± 1.7 mm Hg (P < 0.05). These data highlight the experimental utility of EPR in measuring PtO2 during anesthesia and serve as a foundation for further study of PtO2 in response to physiologic perturbations and therapeutic interventions directed at preventing cerebral ischemia.
IMPLICATIONS: Using in vivo electron paramagnetic resonance oximetry, we studied the patterns of cerebral tissue oxygenation (PtO2) during exposure to various inhaled and injected general anesthetics, and to varying levels of inspired oxygen. These data show that inhaled anesthetics result in larger levels of PtO2 in the brain than do several injectable anesthetics. The results highlight the experimental utility of electron paramagnetic resonance in measuring PtO2 during anesthesia and serve as a foundation for further study of PtO2 in response to physiologic perturbations and therapeutic interventions directed at preventing cerebral ischemia.
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Introduction
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Cerebral tissue oxygenation (PtO2) during general anesthesia is affected by regional anatomy, blood flow, and cerebral metabolic rate. Both direct and indirect effects of anesthetics on blood flow and metabolism have been extensively studied and modeled because of their importance in determining adequacy of tissue oxygenation. Current clinical techniques based on near infrared spectroscopy are completely noninvasive but rely on algorithms to estimate tissue oxygenation from measurements of oxy- and deoxyhemoglobin saturation (1). These indirect methods of addressing PtO2 changes during anesthesia are state of the art because measurement of tissue oxygen levels in the brain is usually invasive. Acute direct measurements of PtO2 in different areas of the brain usually require multiple electrode placements, whereas continuous measurements require implanted electrodes or fiberoptic sensors (2,3). These technologies are impractical clinically both because of the difficulty of making repeated measurements and because they are inherently traumatic.
Recently, electron paramagnetic resonance (EPR) oximetry, which is less invasive than multiple electrode placements, has proven successful in making repeated measurements of PtO2 (4,5). This technique uses signals from stable, paramagnetic materials whose EPR spectra reflect local tissue oxygen partial pressure (PO2). For PtO2 measurements in rodent brain, several small lithium phthalocyanine (LiPc) crystals (20–50 µg) are implanted into the regions of interest using 25-gauge needles. The surface area of the implants is 0.5–1.0 mm2. Once implanted, the crystals do not provoke a severe inflammatory response (5), and measurements can be collected noninvasively and repeatedly. The recorded EPR spectrum of the implant reports the mean cerebral PO2 value of tissue over the surface of the implant. This technique provides a rapid, highly accurate (within 1% of the measured value), and direct assessment of tissue PO2 at sites of interest. In our previous preliminary studies, we established the methodology of using EPR oximetry to examine brain oxygen tension during anesthetic exposures (4,6,7), but in those studies, we could not strictly control animal breathing and blood gases, including carbon dioxide partial pressure (PaCO2). Also, the implantation of the LiPc was not made stereotactically, resulting in variation of the location from animal to animal. In the present study, we report the results of EPR measurements of cerebral PtO2 using a variety of anesthetic techniques in rats, under conditions in which ventilation and PaCO2 were tightly controlled, and stereotactic placements of LiPc in cerebral cortex were made. In addition, because the relationship between brain PtO2 and inspired oxygen concentration is largely unknown, we also examined the effect of changing the fraction of inspired oxygen (FIO2) on cerebral PtO2 during the administration of various general anesthetics.
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Methods
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Paramagnetic LiPc Crystals
Oxygen-sensitive LiPc crystals were synthesized in our laboratory. Before implantation, a single crystal of LiPc was inserted into a gas permeable Teflon tube (inside diameter 0.623 mm, wall thickness 0.038 ± 0.004 mm; Zeus Industrial Products, Raritan, NJ). This Teflon tube was folded twice and inserted into a quartz EPR tube open at both ends. Samples were maintained in the cavity (Varian TE102) at 37° ± 0.2°C. PO2 in the perfusing gas was monitored and calibrated by vigorously stirring 100 mL of distilled water equilibrated with O2 and/or N2. The quantitative dependence on PO2 of the EPR spectrum was obtained by measuring the peak-to-peak line width (LW) as a function of PO2 in the perfusing gas, with LW defined as the difference in magnetic field between the maximum and minimum of the first-derivative recording of the signal. To ensure that residence in the tissue did not affect the calibration, at the end of the experiment, the rats were euthanized and the LiPc was removed, and calibration procedures were performed as above. The calibrations were unchanged. The resulting calibrations were fitted to a first-order regression equation, which then was used to convert values of LW measured in biological systems into appropriate values of PO2. The LW of LiPc is a linear function of PO2 and independent of local metabolic processes, the presence of other paramagnetic species, and pH (8). The LiPc crystals equilibrate with local tissue PtO2 in much <30 s, and the response of the LW to changes in PtO2 is stable for at least 30 days in the brain. The high density of unpaired spins combined with a narrow intrinsic LW of LiPc allows measurements of PtO2 in the brain using 5–10 crystals (approximately 20–50 µg) with a diameter of approximately 100 µm and length of 100–500 µm. The spectra reflect the average PO2 on the surface of the crystals (5).
Animal Preparation and Anesthesia
The Dartmouth College Animal Care and Use Program approved all animal protocols. Male Sprague-Dawley rats, weighing 300–450 g (Charles River Laboratories, Wilmington, MA), were used. One week before the PtO2 measurements, rats were anesthetized with ketamine/xylazine (100:10 mg/kg IM), and LiPc crystals were placed via a 25-gauge needle directly into the brain at a depth of 2.0 mm from the surface of the skull, through 1.0-mm drilled holes located 3.0 mm from the midline and 1.0 mm in front of the bregma.
The rats were randomly divided into 5 groups with 5 different anesthetics: ketamine/xylazine (100:10 mg/kg IM), pentobarbital (80 mg/kg intraperitoneally [i.p.]), 
-chloralose/urethane (50:1250 mg/kg i.p.), halothane (1.5%, 2.0 minimum alveolar anesthetic concentration [MAC]), and isoflurane (2.2%, 2.0 MAC). These doses/concentrations were chosen to produce comparable acute levels of anesthesia (4,7,9).
To study the effects of inhaled anesthetics on PO2, anesthesia was induced by using 3.0% isoflurane or 2.5% halothane in 33% oxygen, and for study of injectable anesthetics on PO2, animals were anesthetized by i.p. or muscular injection of a ketamine/xylazine mixture, or -chloralose/urethane mixture, or sodium pentobarbital. After an adequate level of anesthesia was achieved, the trachea was intubated and the lungs were mechanically ventilated with continuous monitoring of inspiratory and expiratory PO2 and partial pressure of carbon dioxide and inhaled anesthetics. A polyethylene arterial catheter (PE-50) was placed in the left femoral artery for continuous monitoring of blood pressure (BP) and periodic blood gas measurements. These procedures were accomplished within 20–30 min of anesthesia induction. Rectal temperature was controlled at 37.0° ± 0.5°C via a heated pad. FIO2 was maintained at 0.33 while establishing vascular and airway access, then the animals were allowed to stabilize for 30 min (FIO2 maintained at 0.21), verified by 2 arterial blood gas analyses. The rats then were exposed for 30 min each to FIO2 of 0.33, 0.50, and 1.0 (rats that received single-dose pentobarbital became too lightly anesthetized to obtain adequate data at an FIO2 of 1.0). Average cortical PtO2 was measured for 30 min after changing to each FIO2. In all rats, ventilation was controlled to maintain PaCO2 between 35 and 40 mm Hg throughout the experiment. Fluid balance was maintained with 1.5 mL/h of saline (i.p.).
At the end of the experiment, the rats were euthanized. Gross and microscopic examination (hematoxylin and eosin staining) of the tissue around the implanted LiPc confirmed that the crystals were in the cerebral cortex and that there was no significant inflammatory infiltrate or necrosis around the LiPc.
EPR and Physiologic Measurements
Spectra of LiPc were obtained by using an EPR spectrometer constructed in our laboratory with a low-frequency (1.2 GHz, "L-band") microwave bridge (5). The rat was placed in the magnet and the head positioned so that the brain was directly under the extended loop resonator, which was adjusted to obtain the maximal signal from the LiPc in the cerebral cortex. Typical settings for the spectrometer were: incident microwave power, 10 mW; magnetic field center, 425 G; scan range, 1 G; and modulation frequency, 27 kHz. Modulation amplitude was set at less than one-third of the EPR LW. Scan time was 2 min, and 3–5 scans were usually averaged to achieve a better signal-to-noise ratio.
Mean arterial BP (MAP) was continuously monitored by using a pressure transducer (Biopac Systems, Santa Barbara, CA). Arterial blood (150 µL) was drawn into a glass capillary and blood gases (arterial oxygen partial pressure [PaO2], PaCO2, and pH) were analyzed (Ciba-Corning Diagnostic Corp., Medfield, MA) every 30 min during EPR measurements.
All data were reported as mean ± SE of the mean. Data were analyzed by using analysis of variance to test differences between anesthetic techniques and between FIO2. A post hoc multiple-comparison procedure was used to test possible pairwise mean differences between different FIO2. Type I error resulting from multiple comparisons was adjusted with the Bonferroni correction. P < 0.05 was considered statistically significant.
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Results
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MAP
Table 1 summarizes the MAP values. BP was not controlled pharmacologically to avoid drugs with direct effects on cerebral vasculature. MAP values are similar to those obtained in our laboratory during prior studies (4), although somewhat smaller than values reported by others (10). MAP during inhaled anesthesia at FIO2 = 0.33 was significantly less than after the 3 injectable anesthetics. At FIO2 = 0.5, MAP in the pentobarbital group was significantly larger than in all other anesthetic groups, except chloralose/urethane, likely reflecting emergence from the single induction dose.
Blood Gases and pH
pH and PaCO2 did not vary among groups (Table 2). With all anesthetics, PaO2 increased with increasing FIO2. At the same FIO2, the only significant difference in PaO2 was the relative hyperoxia achieved during chloralose/urethane anesthesia versus all other anesthetics at FIO2 = 1.0.
EPR Spectra
Representative spectra and a calibration curve for LiPc are shown in Figure 1. The LW of the LiPc is a linear function of PO2 throughout the experimental region. LiPc responds to the PO2 rather than the concentration of oxygen ([O2]) (8).
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Figure 1. Calibration curve of lithium phthalocyanine (LiPc) for oxygen partial pressure (PO2). A, Spectra of electron paramagnetic resonance (EPR) LiPc in air (a) and nitrogen (b). B, Calibration of the line width (LW) of EPR spectra of LiPc to PO2.
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Cerebral PtO2
Table 3 summarizes absolute cerebral PtO2 values derived from EPR measurements. While breathing room air, rats in the isoflurane group maintained the largest PtO2, and rats anesthetized with ketamine had the smallest PtO2. This difference persisted during changes in FIO2, and the values for ketamine/xylazine were significantly less than for all other anesthetics at all levels of FIO2. The values of cerebral PtO2 for isoflurane were significantly larger compared with all other anesthetics at all levels of FIO2.
Figure 2 summarizes the cerebral tissue PtO2 values as a function of PaO2. These varied as a function of both FIO2 and anesthetic, and reflected the relationship between PaO2 and PtO2. At FIO2 = 0.5 or 1.0, for all anesthetics, the PtO2 was significantly larger compared with an FIO2 of 0.21.
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Figure 2. Comparison between cerebral tissue oxygenation (PtO2) and arterial oxygen partial pressure (PaO2), measured in all five groups as described in the text. Data are expressed as mean ± SEM, derived from Tables 2 and 3. KT/XYL = ketamine/xylazine, PB = pentobarbital, CH/UT = chloralose/urethane, HT = halothane, IF = isoflurane.
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Discussion
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In normal rat brain, microelectrode measurement of PtO2 suggests that mean PtO2 is 1.6% or approximately 12 mm Hg (10,11), with considerable regional variation. For example, PtO2 in the pons and fornix ranges from <1 to 3 mm Hg, whereas PtO2 in cortex white matter ranges from approximately 6 to 15 mm Hg (10). Species differences in PtO2 have been reported. Nair et al. (12,13) and Eintrei and Lund (14) used needle electrodes for measuring PtO2 in the cortex of gerbils, cats, and minipigs when the animals were anesthetized with 30–40 mg/kg i.p. sodium pentobarbital or 0.25–0.35 mg · kg-1 · min-1 IV ketamine. With FIO2 of 0.21, they found mean cerebral PtO2 values of 35.4, 38, and 28.5 mm Hg, respectively.
The absolute values obtained by EPR in this study suggest that cerebral PtO2 in rats anesthetized by a variety of anesthetics at FIO2 = 0.21 is quite small, despite maintenance of normal PaCO2, arterial pH, and body temperature. Whether these absolute values are truly hypoxic, however, cannot be assessed from the data because neither neurologic nor histologic assessments were made. Nonetheless, historically in a variety of experimental contexts, animals have been anesthetized using these drugs in these doses without apparent negative neurologic sequelae. In fact, animals were anesthetized with ketamine/xylazine for the purpose of LiPc crystal placement for this study, and recovered without apparent problems. However, the data may suggest caution that supplemental oxygen is warranted in almost all studies with rodents maintained for prolonged anesthetics. Further outcome studies will be required to assess the functional effect of these PtO2 values on neuronal integrity. In human studies, absolute values of brain PtO2 are not measured often enough that the hypoxic threshold is firmly established. However, polarographic microcatheter measurements made in head-injured patients revealed PtO2 values between 3–12 mm Hg with absolute mean of 8.5 mm Hg, and observations from such studies have led to the suggestion that levels <10 mm Hg are likely hypoxic (15).
Data gathered here by EPR demonstrate that the cerebral PtO2 and arterial PaO2 depend on anesthetic type in unperturbed, normal animals. The sensitivity of EPR in resolving these differences among anesthetics suggests that EPR will be a useful tool for further study of therapies directed at preserving or controlling cerebral oxygenation. Although other studies have suggested that PtO2 is better preserved by inhaled anesthetics as opposed to ketamine (4,16), these data provide the most detailed information of PtO2 as a function of anesthetic available.
Cerebral PtO2 is determined by the balance of metabolic rate and delivery of O2. Because cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) were not measured, underlying mechanisms that contributed to PtO2 are not delineated directly by our data, but some inferences may be made. For example, MAP tended to be larger in groups that had smaller cerebral PtO2. MAP in rats maintained with inhaled anesthetics was significantly less than that of rats treated with injectable anesthetics, but all values were well within the limits of cerebral autoregulation. Thus, the differences in systemic BPs evident during this study would not be expected to alter CBF, but CBF was not directly measured. The larger values of PtO2 obtained during inhaled anesthesia versus those with injected anesthetics support the idea that CBF was not compromised by decreased MAP during inhaled anesthesia.
Pertinent data from other studies provide some perspectives on the measurements made in this study. Lebrun-Grandie et al. (17) measured O2 uptake and blood flow in regions of the normal human brain and found, in general, that a given regional blood flow was proportional to O2 consumption. Anesthetics, however, induce complex and considerable variations in O2 consumption and blood flow in both animal models and humans. Inhaled anesthetics, such as isoflurane and halothane, generally increase CBF and decrease in CMRO2 (18). Injectable anesthetics, such as barbiturates, can cause a dose-dependent decrease in CBF and CMRO2 (19). Although the effects of ketamine on CBF and CMRO2 have been investigated in many studies, the results are not consistent. Both increased CBF with ketamine administration (20), and no CBF change have been reported (21). Our recent results using magnetic resonance perfusion imaging indicate that ketamine (50 mg/kg) does not induce significant changes in CBF in rats, compared with isoflurane-anesthetized rats (16). However, the addition of xylazine to ketamine (or to isoflurane) does cause significant reductions in forebrain CBF.
Ketamine/xylazine is a very commonly used anesthetic regimen for laboratory rats undergoing survival surgery. This practice stems from recommendations in the veterinary literature (22,23). In the recommended anesthetics for rodents provided by the veterinary staff at one of our institutions, ketamine alone is not listed, whereas ketamine/xylazine is on the standard regimen list. Xylazine, an -2 agonist, does reduce cerebral PtO2 in a dose-dependent manner when added to ketamine (16), probably via its vasoconstrictive effect. We believe that one of the potentially valuable aspects of our study is to provide information on the effects of this commonly used regimen on rodent cerebral PO2.
The inhaled anesthetics used in this study resulted in larger levels of PtO2 in the brain than the injected regimens. This finding is likely related to the fact that inhaled anesthetics induce a larger ratio of CBF to CMRO2 than injectable anesthetics (24) and deserves further investigation combining EPR with other methodologies. These results also demonstrated a significant difference in brain PtO2 as a function of which inhaled anesthetic was administered, with isoflurane yielding larger PtO2 than equi-MAC concentrations of halothane. It may be that dose-dependent decreases in CMRO2 are larger during the administration of isoflurane than with halothane (18).
In conclusion, in vivo EPR oximetry is sufficiently sensitive to monitor effects of anesthetics and varying FIO2 on the cerebral PtO2 for long experimental protocols. Development of portable EPR magnets and improved biocompatible paramagnetic materials are the current focus of research efforts designed to bring this technology into the clinical arena.
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Acknowledgments
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This study was supported by National Institutes of Health Grant PO1 GM51630 and R01 CA67431; the facilities of the EPR Center for the Study of Viable Systems were used, supported by the National Center for Research Resources and National Institutes of Health Grant P41 RR11602.
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References
|
|---|
- Lovell AT, Owen-Reece H, Elwell CE, et al. Continuous measurement of cerebral oxygenation by near infrared spectroscopy during induction of anesthesia. Anesth Analg 1999; 88: 554–8.[Abstract/Free Full Text]
- Mass AI, Fleckenstein W, De Jong DA, et al. Monitoring cerebral oxygenation: experimental studies and preliminary clinical results of continuous monitoring of cerebrospinal fluid and brain tissue oxygen tension. Acta Neurochir Suppl (Wien) 1993; 59: 50–7.[Medline]
- Hoffman WE, Edelman G. Enhancement of brain tissue oxygenation during high dose isoflurane anesthesia in the dog. J Neurosurg Anesthesiol 2000; 12: 95–8.[ISI][Medline]
- Liu KJ, Hoopes PJ, Rolett EL, et al. Effect of anesthesia on cerebral tissue oxygen and cardiopulmonary parameters in rats. Adv Exp Med Biol 1997; 411: 33–9.[ISI][Medline]
- Swartz HM, Clarkson RB. The measurement of oxygen in vivo using EPR techniques. Phys Med Biol 1998; 43: 1957–75.[ISI][Medline]
- Liu KJ, Bacic G, Hoopes PJ, et al. Assessment of cerebral PO2 by EPR oximetry in rodents: effects of anesthesia, ischemia, and breathing gas. Brain Res 1995; 685: 91–8.[ISI][Medline]
- Taie S, Leichtweis SB, Liu KJ, et al. Effects of ketamine/xylazine and pentobarbital anesthesia on cerebral tissue oxygen tension, blood pressure, and arterial blood gas in rats. Adv Exp Med Biol 1999; 471: 89–98.
- Liu KJ, Gast P, Moussavi M, et al. Lithium phthalocyanine: a probe for electron paramagnetic resonance oximetry in viable biological systems. Proc Natl Acad Sci USA 1993; 90: 5438–42.[Abstract/Free Full Text]
- Orliaguet G, Vivien B, Langeron O, et al. Minimum alveolar concentration of volatile anesthetics in rats during postnatal maturation. Anesthesiology 2001; 95: 734–9.[ISI][Medline]
- Ching M. Comparison of the effects of Althesin, chloralose-urethane, urethane, and pentobarbital on mammalian physiologic responses. Can J Physiol Pharmacol 1984; 62: 654–7.[ISI][Medline]
- Silver I, Erecinska M. Oxygen and ion concentrations in normoxic and hypoxic brain cells. Adv Exp Med Biol 1998; 454: 7–16.[ISI][Medline]
- Nair PK, Buerk DG, Haisey JH. Comparison of oxygen metabolism and tissue PO2 in cortex and hippocampus of gerbil brain. Stroke 1987; 18: 616–22.[Abstract/Free Full Text]
- Nair PK, Whalen WJ, Buerk DG. PO2 of cat cerebral cortex: response to breathing N2 and 100% O2. Microvasc Res 1975; 9: 158–65.[ISI][Medline]
- Eintrei C, Lund N. Effects of increases in the inspired oxygen fraction on brain surface oxygen pressure fields in pig and man. Acta Anaesthesiol Scand 1986; 30: 194–8.[ISI][Medline]
- Kiening KL, Unterberg AW, Bardt TF, et al. Monitoring of cerebral oxygenation in patients with severe head injuries: brain tissue PO2 versus jugular vein oxygen saturation. J Neurosurg 1996; 85: 751–7.[ISI][Medline]
- Lei H, Grinberg O, Nwaigwe CI, et al. The effects of ketamine-xylazine anesthesia on cerebral blood flow and oxygenation observed using nuclear magnetic resonance perfusion imaging and electron paramagnetic resonance oximetry. Brain Res 2001; 913: 174–9.[ISI][Medline]
- Lebrun-Grandie P, Baron JC, Soussaline F, et al. Coupling between regional blood flow and oxygen utilization in the normal human brain. Arch Neurol 1983; 40: 230–6.[Abstract]
- Todd MM, Drummond JC. A comparison of the cerebrovascular and metabolic effects of halothane and isoflurane in the cat. Anesthesiology 1984; 60: 276–83.[ISI][Medline]
- Sokoloff L, Reivich M, Kennedy C, et al. The [14C] deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure and normal values in the conscious and anesthetized albino rat. J Neurochem 1977; 28: 897–916.[ISI][Medline]
- Oren RE, Rasool N, Rubinstein EH. Effects of ketamine on cerebral cortical blood flow and metabolism in rabbits. Stroke 1987; 18: 441–4.[Abstract/Free Full Text]
- Akeson J, Bjorkman S, Messeter K, et al. Cerebral pharmacodynamics of anaesthetic and subanaesthetic doses of ketamine in the normoventilated pig. Acta Anaesthesiol Scand 1993; 37: 211–28.[ISI][Medline]
- Wixson SK, White WJ, Hughes HG, et al. The effects of pentobarbital, fentanyl-droperidol, ketamine-xylazine and ketamine-diazepam on core and surface body temperature regulation in adult male rats. Lab Anim Sci 1987; 37: 743–9.[ISI][Medline]
- Wixson SK, White WJ, Hughes HG, et al. A comparison of pentobarbital, fentanyl-droperidol, ketamine-xylazine and ketamine-diazepam anesthesia in adult male rats. Lab Anim Sci 1987; 37: 726–30.[ISI][Medline]
- Magata Y, Saji H, Choi SR, et al. Noninvasive measurement of cerebral blood flow and glucose metabolic rate in the rat with high-resolution animal positron tomography (PET): a novel in vivo approach for assessing drug action in the brains of small animals. Biol Pharm Bull 1995; 18: 753–6.[ISI][Medline]
Accepted for publication December 26, 2002.
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Abstract
Introduction
