A nuclear magnetic resonance advance. Imaging fluorinated anesthetics in the brain.
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Anesthetics↗
Biomedical subjects
L Litt
Publications and source records attributed to L Litt.
19F NMR calcium changes, edema and histology in neonatal rat brain slices during glutamate toxicity.
Respiring neonatal cerebrocortical slices (350 microns thick), loaded with the free calcium indicator 5F-BAPTA, were perfused in a 20-mm-diameter glass NMR tube with oxygenated artificial CSF, exposed to extracellular glutamate and studied at 4.7 Tesla with 19F NMR spectroscopy. 31P/1H NMR spectra, obtained concurrently, were used to assess slice integrity from determinations of intracellular pH, ATP, PCr, lactate and N-acetylaspartate. 60-min periods were induced of recoverable and nonrecoverable glutamate toxicity-defined from changes in NMR metabolites. In other NMR studies, where 5F-BAPTA was not used, metabolic toxicity was modulated by three glutamate receptor antagonists: dizocilpine, NBQX and kynurenic acid. Outcome measurements were made of edema, determined invasively in isolated slices from % swelling and water content and from histological changes in Nissl stains of slice sections. Edema was (1) detectable in all slices within minutes after onset of glutamate exposure, though never in untreated control slices, and (2) modulated differently by dizocilpine, NBQX and kynurenate. Correlations were observed between edema and NMR decreases in PCr and ATP. Nissl stains of sections from slices treated with the most protective agent, dizocilpine, showed preservation of neuronal processes. As was expected in 7-day-old rats with immature NMDA receptors, 19F NMR spectroscopy revealed only small increases in free intracellular calcium ([Ca2+]i). These occurred late during glutamate exposure and reversed early during glutamate washout. The studies demonstrate that it is possible to study correlations between repeated noninvasive NMR spectra in ensembles of brain slices and invasive measures of early cellular responses.
Animals↗
Modulation of glutamate-induced intracellular energy failure in neonatal cerebral cortical slices by kynurenic acid, dizocilpine, and NBQX.
The severity and rapidity of acute, glutamate-induced energy failure were compared in live cerebral cortical slices. In each experiment 80 live cerebral cortical slices (350 microns thick) were obtained from neonatal Sprague-Dawley rats, suspended and perfused in a nuclear magnetic resonance (NMR) tube, and studied at 4.7 T with interleaved 31P/1H NMR spectroscopy. NMR spectra, obtained continually, were determined as 5-min averages. Slices were perfused for 60 min with artificial cerebrospinal fluid (ACSF) containing either glutamate alone or glutamate mixed with one of three glutamate-receptor antagonists: kynurenate, dizocilpine (MK-801), and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX). Dose-dependent decreases in high-energy phosphates were studied during glutamate exposure (0.5 to 10 mM), with and without antagonist protection. Energy recovery after glutamate exposures was measured during a 60-min washout with glutamate-free, antagonist-free ACSF. Reversible and irreversible energy failures were characterized by changes in intracellular pH, and by changes in relative concentrations of ATP, phosphocreatine (PCr), and inorganic phosphate. No changes were observed in intracellular levels of N-acetylaspartate and lactate. Some special studies were also done using R-(-)-2-amino-5-phosphonovaleric acid (100 microM) and tetrodotoxin (1 mM) to examine glutamate receptor specificity in this tissue model. Dizocilpine (150 microM) best ameliorated the energy failure caused by 2.0 mM glutamate. With dizocilpine the maximum ATP decrease was only 6 +/- 5%, instead of 35 +/- 7%.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Triphosphate↗
Hypercarbia-induced changes in cerebral blood volume in the cat: a 1H MRI and intravascular contrast agent study.
Cerebral blood volume changes with arterial carbon dioxide were monitored by proton T1-weighted MR images following administration of the intravascular contrast agent Gd-DTPA labeled with human serum albumin. Without MR contrast, no significant image intensity changes were observed with PaCO2. Following contrast, regional brain image intensities increased significantly over control (0% inspired CO2) in cortical gray, white, and basal ganglia regions with increasing PaCO2 and returned to control intensities upon return to 0% inspired CO2. Imaging of through-plane and in-plane phantoms was performed to assess flow effects. Signal losses of 2 and 6% (relative to no flow) were observed for bulk velocities of 5 mm/s at TE values of 15 ms. An intravascular contrast agent may be useful for MRI monitoring of local cerebral blood volume changes during cerebral perturbations.
Adipose Tissue↗
Correlated, simultaneous, multiple-wavelength optical monitoring in vivo of localized cerebrocortical NADH and brain microvessel hemoglobin oxygen saturation.
Current forms of brain monitoring, such as electroencephalography (EEG), have had limited clinical utility. The EEG records spontaneous cerebrocortical activity and thus is an indirect indicator of metabolic demand and, to a lesser extent, an indicator of mismatch of supply versus demand. Ischemia modulates EEG activity in ways that can usually be detected, but EEG patterns can be similarly modulated by many other factors, including temperature and pharmacologic manipulation. This in vivo study in physiologically monitored animals evaluated the use of correlated optical spectroscopy, performed with an instrument having a fiberoptic light-guide bundle in contact with the cerebral cortex, for the simultaneous monitoring of cerebrovascular oxygen availability and intracellular oxygen delivery. A highly specific monitor of cerebral intracellular oxygen supply, the cerebrocortical intramitochondrial NADH redox state, was monitored in vivo with a fluorescence technique. Absorption spectroscopy was used concurrently to monitor hemoglobin content (blood volume) and oxygen saturation in the microcirculation. Correlated changes in optical signals from cerebrocortical NADH and hemoglobin were studied in a swine model (n = 7) of nitrogen hypoxia. Measurements were made at four wavelengths with a time-division, multiplexed fluorometer/reflectometer. Because the NADH fluorescence signal at 450 nm is affected by local changes in blood volume, a "corrected" fluorescence signal is usually calculated. In previous studies, where only two wave lengths have been measured, attempts at correction were based on reflectance at the excitation wavelength (366 nm). We compared estimators of changes in microcirculatory blood volume using reflection at two wavelengths: 366 nm and 585 nm, the wavelengths for maximum and isobestic absorption. The results of the studies were as follows: (1) during transient hypoxia, NADH and local hemoglobin saturation signals changed in concert with arterial pulse oximetry, with changes in NADH lagging behind changes in saturation by an average of 5.3 seconds; (2) after hypocapnic ventilation to a mean PaCO2 of 20.2 +/- 0.8 mm Hg, NADH increased by 11.5 +/- 8.7% (as compared with maximal change during anoxia), local hemoglobin saturation decreased by 7.7 +/- 6.4%, and local blood volume decreased by 12.5 +/- 13%, while arterial SpO2 was unchanged; (3) our two measures of local blood volume were closely correlated during carbon dioxide perturbations, but poorly correlated during hypoxic perturbation; and (4) NADH fluorescence provided a more rapid, sensitive indicator of oxygen deprivation than did the EEG. During transient hypoxia, EEG changes occurred 57.4 +/- 10.4 seconds after the onset of decline in local hemoglobin saturation, after NADH had completed 50% of its maximal increase.
Animals↗
Tolerance of low intracellular pH during hypercapnia by rat cortical brain slices: A 31P/1H NMR study.
Metabolic tolerance of low intracellular pH (pH(i)) was studied in well-oxygenated, perfused, neonatal, rat cerebrocortical brain slices (350 microns thick) by inducing severe hypercapnia. In each of 17 separate experiments 80 brain slices (approximately 3.2 g wet weight) were suspended in an NMR tube, perfused with artificial CSF (ACSF), and studied at 4.7 T with 31P and 1H NMR spectroscopy. Spectra obtained every 5 min monitored relative concentrations of lactate or high-energy phosphate metabolites, from which pH(i) and extracellular pH were determined. Unperturbed slice preparations were metabolically stable for > 10 h, with no significant changes occurring in pHi, ATP, phosphocreatine (PCr), inorganic phosphate, or lactate. Different levels of hypercapnia were produced by sequentially perfusing slices with the following different ACSF batches, each having previously been equilibrated with a specific mixture of CO2 in oxygen: (a) 10% CO2, 15 min of perfusion; (b) 30% CO2, 15 min of perfusion; (c) 50% CO2, 15 min of perfusion; (d) 70% CO2, 30 min of perfusion; (e) 50% CO2, 15 min of perfusion; (f) 30% CO2, 15 min of perfusion; and (g) 10% CO2, 15 min of perfusion. At the completion of this protocol slices were again perfused with fresh ACSF that was equilibrated with a 95% O2/5% CO2 gas mixture. In each of five separate 1H and 31P experiments, brain slices were recovered within 2 h after termination of exposure to high CO2. The pHi was determined from measurements of the chemical shift difference between phosphoethanolamine and PCr, using a calibration curve obtained for our preparation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Surface coil spectroscopic imaging: time and spatial evolution of lactate production following fluid percussion brain injury.
Detailed temporal and spatial distributions of lactate production are presented for graded fluid-percussion brain injury in the rat. A one-dimensional proton spin-echo spectroscopic imaging (1D SESI) technique, performed with a surface coil, is presented and evaluated. This technique, which represents a practical compromise, provides spatially localized proton nuclear magnetic resonance (NMR) brain spectra from a series of small voxels (less than 0.15 cm3) in less than 10 min, thus enabling both spatial and temporal monitoring of lactate production. These high-resolution lactate maps are correlated with hyperintense regions observed in T2-weighted images taken 10 h after impact, which, in turn, correlate with histology. The data demonstrate that, following severe trauma there is delayed production and propagation of lactate to regions of the brain that are remote from the trauma site. The extent of lactate production depends on the severity of impact. More significantly, the data show that following severe trauma, local lactate concentrations exceed 15 mumol/g, the concentration that has been claimed as the threshold for brain injury. Therefore high lactate levels cannot be ruled out a priori as a possible factor in brain injury following severe head trauma.
Animals↗
Cerebral uptake and elimination of desflurane, isoflurane, and halothane from rabbit brain: an in vivo NMR study.
The authors used in vivo 19F nuclear magnetic resonance spectroscopy to determine rates of cerebral uptake and elimination of desflurane, isoflurane, and halothane in rabbits. After anesthetizing animals by intramuscular and intravenous injection of methohexital and inhalation of 70% nitrous oxide, intravenous and intraarterial catheters were inserted and a tracheostomy and craniotomy performed. Ventilation was controlled to maintain arterial carbon dioxide tension (PaCO2) from between 35 and 45 mmHg. A 2-2.5-cm diameter circle of dura was exposed, over which a 0.9 x 1.0-cm elliptical surface coil was placed. Cerebral anesthetic concentrations (CC) were estimated from spectra acquired on a 4.7-Tesla spectrometer. Alveolar uptake and elimination also were assessed, using inspired (FI) and end-tidal (denoted FA0 at the end of administration) concentrations measured by gas chromatography. After baseline spectra were obtained, volatile agents were administered for 30 min, followed by a 120-min period of elimination. Our findings demonstrate that cerebral uptake and elimination correlate with solubility: they are most rapid for desflurane, next most rapid for isoflurane, and least rapid for halothane. During administration, cerebral uptake of desflurane (CC/FI = 0.690 +/- 0.049 at 9 min) was approximately 1.7 times faster than isoflurane (CC/FI = 0.691 +/- 0.020 at 15 min) and 3 times faster than halothane (CC/FI = 0.662 +/- 0.040 at 27 min). Similarly, elimination rates for desflurane (CC/FA0 = 0.238 +/- 0.015 at 9 min) were 1.7 times faster than isoflurane (CC/FA0 = 0.236 +/- 0.017 at 15 min) and three times faster than halothane (CC/FA0 = 0.212 +/- 0.033 at 27 min).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
In vivo 19F nuclear magnetic resonance brain studies of halothane, isoflurane, and desflurane. Rapid elimination and no abundant saturable binding.
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Anesthetics↗
Use of oximetry during MR imaging of pediatric patients.
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Child↗
Tolerance of low cerebral intracellular pH in rats during hyperbaric hypercapnia.
BACKGROUND AND PURPOSE: Brain acidosis from cerebral ischemia is characterized by average intracellular pH levels of approximately 5.8-6.2, which appear in turn to worsen cellular injury. We report that the brain is not injured when hypercapnia is used to reduce intracellular pH to about 6.2 during adequate oxygenation. A hyperbaric chamber is needed to achieve intracellular pH values so low because inspired CO2 tensions must be increased to approximately 1 atm. SUMMARY OF REPORT: Using in vivo phosphorus-31 and proton nuclear magnetic resonance spectroscopy, we measured brain intracellular pH and lactate concentration of rats inside a nonmagnetic polycarbonate chamber at a barometric pressure of 1,500 mm Hg. Intubated rats were ventilated with a 50% O2/50% CO2 gas mixture for specific times. All six rats ventilated for 15 minutes with CO2 tensions of approximately 750 mm Hg woke up without neurological impairment, despite a decrease in intracellular pH to about 6.2. Higher CO2 tensions and longer exposures resulted in cardiovascular collapse and sudden death, followed by the postmortem appearance of brain lactate. CONCLUSIONS: Brain intracellular pH values near 6.2 can be induced briefly in vivo in ventilated rats without injury under hyperbaric hypercapnic conditions. If attempts are made to lower brain pH in vivo even further by increasing PCO2 beyond 750 mm Hg, mean arterial blood pressure and cerebral blood flow decrease to values incompatible with life.
Animals↗
Stability of brain intracellular lactate and 31P-metabolite levels at reduced intracellular pH during prolonged hypercapnia in rats.
The tolerance of low intracellular pH (pHi) was examined in vivo in rats by imposing severe, prolonged respiratory acidosis. Rats were intubated and ventilated for 10 min with 20% CO2, for 75 min with 50% CO2, and for 10 min with 20% CO2. The maximum PaCO2 was 320 mm Hg. Cerebral intracellular lactate, pHi, and high-energy phosphate metabolites were monitored in vivo with 31P and 1H nuclear magnetic resonance (NMR) spectroscopy, using a 4.7-T horizontal instrument. Within 6 min after the administration of 50% CO2, pHi fell by 0.57 +/- 0.03 unit, phosphocreatine decreased by approximately 20%, and Pi increased by approximately 100%. These values were stable throughout the remainder of the hypercapnic period. Cerebral intracellular lactate, visible with 1H NMR spectroscopy in the hyperoxic state, decreased during hypercapnia, suggesting either a favorable change in oxygen availability (decreased lactate production) or an increase in lactate clearance or both. All hypercapnic animals awakened and behaved normally after CO2 was discontinued. Histological examination of cortical and hippocampal areas, prepared using a hematoxylin and eosin stain, showed no areas of necrosis and no glial infiltrates. However, isolated, scattered, dark-staining, shrunken neurons were detected both in control animals (no exposure to hypercapnia) and in animals that had been hypercapnic. This subtle histological change could represent an artifact resulting from imperfect perfusion-fixation, or it could represent subtle neurologic injury during the hypercapnia protocol. In summary, extreme hypercapnia and low pHi (approximately 6.5) are well tolerated in rats for periods up to 75 min if adequate oxygenation is maintained.(ABSTRACT TRUNCATED AT 250 WORDS)
Acidosis, Respiratory↗
Absence of abundant binding sites for anesthetics in rabbit brain: an in vivo NMR study.
Using magnetic resonance spectroscopy, the authors tested whether cerebral concentrations of inhaled anesthetics do not increase proportionately at inspired concentrations exceeding 3% 1) because anesthetics bind to and saturate specific sites in the brain or 2) because anesthetic-induced depression of ventilation limits the increase in alveolar anesthetic partial pressure. New Zealand White rabbits were anesthetized with methohexital, 70% nitrous oxide, and local infiltration of 1% lidocaine. Cerebral concentrations of anesthetic were determined from 19F spectra acquired with nuclear magnetic resonance (NMR). Inspired, end-tidal, and arterial anesthetic concentrations, and end-tidal and arterial partial pressure of carbon dioxide were measured. Blood/gas partition coefficients were determined and used to convert arterial anesthetic concentration to partial pressures. In seven spontaneously breathing animals, halothane (1%; n = 5) or isoflurane (0.8%; n = 2) was administered at a constant inspired concentration for 20 min; NMR spectra were acquired between 10 and 20 min. Thereafter, the inspired concentration was increased and the process repeated until apnea occurred. Two additional rabbits were anesthetized with isoflurane and studied similarly but with higher inspired concentrations during mechanical ventilation. In spontaneously breathing animals, ventilatory depression occurred, documented by marked increases in PaCO2, and cerebral concentrations of anesthetic did not increase proportionately at inspired concentrations exceeding 3%. In contrast to an absence of a correlation of inspired and cerebral concentrations during spontaneous ventilation, arterial and cerebral concentrations correlated linearly during both spontaneous and mechanical ventilation (R2 greater than 0.969). These results are consistent with depression of ventilation, rather than binding to specific cerebral sites as an explanation for the nonlinear relationship between cerebral and inspired anesthetic concentrations.
Animals↗
Severe hemorrhage after extracorporeal shock-wave lithotripsy.
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Aged↗
31P and 1H magnetic resonance spectroscopy of acute alcohol cardiac depression in rats.
Cardiac depression in the isolated rat heart perfused with 4% ethanol was correlated with intracellular phosphate energetics and tissue water distributions. Energy metabolites were assessed using 31P magnetic resonance spectroscopy (MRS) and correlated to the mitochondrial redox state using epicardial surface fluorometry. Changes in myocardial water compartmentation were measured by using 1H NMR spectroscopy with an extracellular chemical-shift reagent (DyTTHA) and correlated to results of 2D echocardiography (2DE). During alcohol perfusion there was a significant decrease in developed pressure and in coronary flow. No change was seen in ATP, PCr, pHi, Pi, or NADH. After withdrawal of alcohol from the perfusate cardiac function reverted to control values without a depletion of energy levels. During alcohol perfusion 1H MRS showed a marked redistribution of water from the intra- to the extracellular space, corresponding to a 35% left ventricular wall thinning confirmed by 2DE. The results indicate that acute alcohol cardiac depression is related to a dehydration of myocardial cells, but is not associated with intracellular acidosis or energy depletion.
Acute Disease↗
Effects of acetazolamide on cerebral acid-base balance.
Acetazolamide (AZ) inhibition of brain and blood carbonic anhydrase increases cerebral blood flow by acidifying cerebral extracellular fluid (ECF). This ECF acidosis was studied to determine whether it results from high PCO2, carbonic acidosis (accumulation of H2CO3), or lactic acidosis. Twenty rabbits were anesthetized with pentobarbital sodium, paralyzed, and mechanically ventilated with 100% O2. The cerebral cortex was exposed and fitted with thermostatted flat-surfaced pH and PCO2 electrodes. Control values (n = 14) for cortex ECF were pH 7.10 +/- 0.11 (SD), PCO2 42.2 +/- 4.1 Torr, PO2 107 +/- 17 Torr, HCO3- 13.8 +/- 3.0 mM. Control values (n = 14) for arterial blood were arterial pH (pHa) 7.46 +/- 0.03 (SD), arterial PCO2 (PaCO2) 32.0 +/- 4.1 Torr, arterial PO2 (PaO2) 425 +/- 6 Torr, HCO3- 21.0 +/- 2.0 mM. After intravenous infusion of AZ (25 mg/kg), end-tidal PCO2 and brain ECF pH immediately fell and cortex PCO2 rose. Ventilation was increased in nine rabbits to bring ECF PCO2 back to control. The changes in ECF PCO2 then were as follows: pHa + 0.04 +/- 0.09, PaCO2 -8.0 +/- 5.9 Torr, HCO3(-)-2.7 +/- 2.3 mM, PaO2 +49 +/- 62 Torr, and changes in cortex ECF were as follows: pH -0.08 +/- 0.04, PCO2 -0.2 +/- 1.6 Torr, HCO3(-)-1.7 +/- 1.3 mM, PO2 +9 +/- 4 Torr. Thus excess acidity remained in ECF after ECF PCO2 was returned to control values. The response of intracellular pH, high-energy phosphate compounds, and lactic acid to AZ administration was followed in vivo in five other rabbits with 31P and 1H nuclear magnetic resonance spectroscopy.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetazolamide↗
Effects of acetazolamide on cerebrocortical NADH and blood volume.
Acetazolamide (AZ), a potent carbonic anhydrase inhibitor in human and animal tissues, increases cerebral blood flow (CBF) by acidifying cerebral extracellular fluids. To demonstrate the relationship of increased CBF to brain O2 availability after AZ administration, a compensated fluorometer was used to study changes in the cerebrocortical redox balance in rabbits. Seven rabbits were anesthetized with pentobarbital sodium. Excitation light (366 nm) was conducted to the cerebrocortical surface of each animal by a 4-mm-diam fiberoptic light guide. Fluorescence emissions from cerebrocortical NADH (450 nm) were compared at different inspired O2 (FIO2) tensions. Reflected light (366 nm), which was used to determine a correction to the fluorescence signal, was separately quantitated and interpreted as an index of cerebrocortical blood volume. Reductions in FIO2 from 1.0 to 0.21, 0.14, 0.10, and 0.07 resulted in increases in both tissue blood volume and [NADH]. Intravenous AZ (25 mg/kg) increased cerebrocortical blood volume and reduced the [NADH], even during ventilation with 100% O2. The changes in brain redox balance caused by vasodilation with AZ were compared with those caused by vasodilatation with CO2. The NAD+/NADH redox state was a continuous function of FIO2 at all levels of arterial PCO2 (PaCO2), both before and after AZ administration. The improvement in cerebral O2 delivery caused by AZ-induced vasodilation was comparable to that caused by the vasodilatation that results from a PaCO2 elevation approximately equal to 12-15 Torr above normal. The slope of the relationship between [NADH] and FIO2 was similar at normal, low, and high levels of PaCO2. We conclude that AZ administration and PaCO2 elevation improve cerebral oxygenation by similar mechanisms.
Acetazolamide↗
Comparison of lactate concentration determinations in ischemic and hypoxic rat brains by in vivo and in vitro 1H NMR spectroscopy.
An experimental protocol for the quantitation of lactate is demonstrated for in vivo 1H NMR surface coil spectroscopy. The in vivo lactate concentration can be calculated by comparing the in vivo and in vitro ratios of lactate and N-acetylaspartate (NAA) NMR signals. With this protocol, approximately 25% of lactate present in the hypoxic or ischemic rat brain is observed by NMR.
Animals↗