Blood Partition Coefficients Research Articles

Pharmacodynamic modeling of thiopental anesthesia.

We have pharmacodynamically modeled the relationship between the thiopental serum concentration and its effects on the electroencephalogram (EEG). Power spectral analysis was used to calculate the spectral edge, a measure of the underlying EEG frequency that characterizes the progressive slowing of the EEG induced by thiopental. Eight male volunteer subjects had venous thiopental serum concentrations measured, and 10 surgical patients had arterial serum concentrations measured. Thiopental was infused at a rate of 75 to 150 mg/min until a burst suppression EEG pattern was evident. Frequent blood samples were obtained during and after the infusion for measurement of serum thiopental concentrations, and the EEG was recorded for subsequent off-line power spectral analysis to calculate the spectral edge. With venous blood sampling, it was not possible to demonstrate significant hysteresis between the thiopental serum concentration and the spectral edge, allowing thiopental concentrations to be directly related to the spectral edge. With arterial blood sampling, significant hysteresis was present, requiring an effect compartment to relate concentration to effect. The half-time for equilibration (mean +/- SD) between concentration and response for the arterial data was 1.2 +/- 0.30 min. This value for Keo is consistent with known values for cerebral blood flow and thiopental brain: blood partition coefficient. Arterial-venous concentration differences cause the apparent lack of hysteresis with venous blood sampling. An inhibitory sigmoid Emax pharmacodynamic model optimally characterized the relationship between thiopental concentrations and the spectral edge. This model allows estimation of the thiopental serum concentration that causes one-half of the maximal EEG slowing (IC50), which is a measure of an individual's sensitivity to thiopental. Except for the hysteresis, there was no statistical difference in the parameters of the inhibitory sigmoid Emax pharmacodynamic model when venous and arterial blood samplings were compared. Arterial blood sampling offers some distinct advantages when pharmacodynamically modeling continuous, rapidly changing measures of drug effect, such as the EEG.

Local cerebral blood flow and partition coefficients measured in cerebral astrocytomas of different grades of malignancy

Local cerebral blood flow and local partition coefficients were measured in patients with different grades of malignant cerebral astrocytomas (n=5) who inhaled 35% stable xenon during computed tomography scanning. Results were compared with those in age-matched normal subjects (n = 5). Mean values for local cerebral blood flow in the gray matter in patients with astrocytomas were decreased throughout the tumor mass and surrounding brain that was apparently free of tumor. Patients with highly malignant glioblastoma multiforme (astrocytoma grade IV; n=2) showed more variable values for local cerebral blood flow and local partition coefficients compared to those with astrocytomas of lower grades (grades I-II; n = 3). Local partition coefficients in gray matter invaded by grade IV astrocytoma were significantly higher than those in gray matter invaded by grade I-III astrocytomas. Local cerebral blood flow and local partition coefficients in the brain tissue surrounding grade IV astrocytomas were reduced to a greater extent than those in more benign tumors.

The tissue-blood partition coefficient of iodoantipyrine in pig brain and its change with age.

The tissue-blood partition coefficient of 125I-labelled iodoantipyrine was measured in pig brain. The mean coefficient for 11 neonatal piglets (aged 0.5 to 4 days) was 0.718 mL/g (SD 0.083). Measurements in a further 11 animals up to 144 days old (at which time pigs are sexually mature), showed that the partition coefficient increased significantly with age, possibly as a result of the accumulation of brain lipid during growth. The change in partition coefficient with age was curvilinear, rising to unity as the animals reached maturity. There were significant differences between the partition coefficients in grey and in white matter, but these were so small relative to the differences between pigs that they could be neglected for all practical purposes. Since the accuracy of measurement of cerebral blood flow (CBF) by the Kety-Schmidt technique depends directly on the partition coefficient of the tracer, it is important to confirm that apparent changes of CBF do not simply reflect alterations in the partition coefficient rather than real changes in blood flow.

Cerebral blood flow and cerebral metabolism in normal and intrauterine growth retarded neonatal piglets.

1. Cerebral blood flow and cerebral metabolism were measured in conscious, normally grown neonatal piglets and in littermates which had undergone intrauterine growth retardation. 2. Cerebral blood flow was measured by the Kety-Schmidt technique using [125I]iodoantipyrine as the tracer. The tissue: blood partition coefficient of this tracer was measured in separate groups of growth retarded and normal animals. Cerebral utilization rates of glucose and oxygen were calculated from the arteriovenous concentration differences on the Fick principle. 3. The mean body weight of the growth retarded animals was about half that of their normally grown littermates, and liver weight was reduced in proportion. Brain weight was slightly but significantly lower in the growth retarded animals. 4. Cerebral blood flow was lower in the growth retarded piglets but the rates of cerebral utilization of oxygen and glucose were not significantly different in the two groups. The fractional extraction of arterial oxygen by the brain was significantly higher in the growth retarded animals. 5. The partition coefficient of iodoantipyrine was significantly lower in the growth retarded animals, being about 75% of the normal value. It is clear that had the partition coefficients been assumed to have been the same in both groups the calculated cerebral blood flows would have been identical. 6. It is concluded that growth retarded neonatal piglets have relatively normal sized brains, with a rate of glucose and oxygen consumption that is not significantly different from normal, despite a reduction in cerebral blood flow of about 35%. Consequently the fractional extraction rate of arterial oxygen by the brain is increased from 50% to 70%.

Determination of the subcutaneous tissue to blood partition coefficient in patients with severe leg ischaemia by a double isotope washout technique.

Knowledge of the tissue to blood partition coefficient (lambda) is essential for calculation of the perfusion coefficient in a single tissue based on measurements of the washout of locally injected isotopes. No measurements of lambda for Xenon in subcutaneous tissue in the leg have been done in patients with occlusive arterial disease. In 12 patients with occlusive arterial disease in the legs lambda for Xenon was determined in subcutaneous tissue in the calf region and foot as the ratio between the washout rate constant of 131I-Antipyrine and 133Xe. A mixture of the two indicators was injected subcutaneously laterally on the calf and in the first interosseous space on the foot. The time until the curves followed a monoexponential course varied between 15 and 45 min in the calf and 5 and 45 min in the foot. The calculated lambda for Xe showed a great variance between individuals in calf as well as foot. Mean value was 3.7 ml X g-1 (range: 1 X 7-10 X 7) in the calf and 2 X 7 ml X g-1 (range: 1 X 2-4 X 9) in the foot. It is concluded that lambda measurements are necessary for determination of subcutaneous blood flow from 133Xe washout curves in these patients. Determination of lambda is especially important when comparisons are made between individuals.

Stable xenon CT cerebral blood flow measurements computed by a single compartment--double integration model in normal aging and dementia.

Programs have been developed, using a single compartmental analysis model, that provide rapid computer derivation for values of both local cerebral blood flows (LCBF) and local tissue: blood partition coefficients (L lambda) using inhaled stable xenon gas (Xes) as the indicator. These programs are planned for utilization of raw data points derived from serial computed tomography scans made between the 3rd and 9th min after 35% Xes inhalation, while concentrations of end-tidal Xes (PEXes) are concurrently monitored. Double integration and least squares fitting permitted estimation of corresponding arterial (assumed from PEXes) and tissue Xes concentrations at each scanning interval during Xes saturation. Derived estimates for L lambda and LCBF values for each region of interest mathematically approximate values saturated to infinity. The method described can be utilized for any freely diffusible indicator. Cross-sectional analysis of results obtained in 13 normal healthy volunteers between 20 and 80 years of age showed no age-related changes in L lambda values but progressive decreases in blood flow of cortex, basal ganglia, and white matter with advancing age. In senile dementia of Alzheimer's type (SDAT, n = 8) L lambda values were likewise found to be unchanged, but cortical and thalamic gray matter LCBF values were significantly reduced compared to age-matched normal volunteers.

Determination of Tissue to Blood Partition Coefficients in Physiologically-Based Pharmacokinetic Studies

The partition coefficient between tissue and blood used in physiologically-based pharmacokinetic modeling analysis was investigated using the concept of clearance. New equations were derived and compared with previously reported equations in constant intravenous infusion and bolus injection methods. The importance of differentiating arterial from venous blood is discussed.

A simplified in vivo autoradiographic strategy for the determination of regional cerebral blood flow by positron emission tomography: theoretical considerations and validation studies in the rat.

A simplified mathematical model is described for the measurement of regional cerebral blood flow by positron emission tomography in man, based on a modification of the autoradiographic strategy originally developed for experimental animal studies. A modified ramp intravenous infusion of radiolabeled tracer is used; this results in a monotonically increasing curvilinear arterial activity curve that may be accurately described by a polynomial of low degree (= zeta). Integrated cranial activity CB is measured in regions of interest during the latter portion of the tracer infusion period (times T1 to T2). It is shown that (See formula: text) where each of the terms A chi is a readily evaluated function of the blood flow rate constant kappa, the brain:blood partition coefficient for the tracer, the cranial activity integration limits T1 and T2, the coefficients of the polynomial describing the arterial curve, and an iteration factor n that is chosen to yield the desired degree of precision. This relationship permits generation of a table of CB vs. kappa, thus facilitating on-line computer solution for blood flow. This in vivo autoradiographic paradigm was validated in a series of rats by comparing it to the classical autoradiographic strategy developed by Kety and associates. Excellent agreement was demonstrated between blood flow values obtained by the two methods: CBF in vivo = CBF classical X 0.99 - 0.02 (units in ml g-1 min-1; correlation coefficient r = 0.966).

Local cerebral blood flow values as estimated with diffusible tracers: validity of assumptions in normal and ischemic tissue.

A theoretical assessment is made of the validity of assumptions underlying the theory for estimating local cerebral blood flow with diffusible tracer in the tissue under normal and ischemic conditions. First, Kety's derivation of equations that have commonly been used for calculating local cerebral blood flow values is examined in order to define the problems and assumptions. Second, the brain:blood partition coefficient of diffusible tracer, lambda, and the diffusion-limited factor, m, under normal and ischemic conditions are reviewed. An examination of the literature suggested that contrary to common belief, lambda appears to change very little in ischemia if the tissue constituents remain unchanged, whereas m does change with ischemia if the diffusible tracer used is greatly diffusion-limited in the exchange between brain and blood. Even when a gas with an m value close to unity is used as the diffusible tracer, the prolonged mean transit time of blood through the ischemic tissue would make it difficult to maintain the exponential assumptions. As part of the ischemic tissue became infarcted, which is the case with most stroke patients, so the assumptions of homogeneous perfusion would become invalid. This inevitably renders it difficult to estimate local cerebral blood flow with diffusible tracer in ischemic tissue containing an infarcted mass.

A method for calculating regional cerebral blood flow from emission computed tomography of inert gas concentrations.

Emission tomography of positron or gamma emitting inert gases allows calculation of regional cerebral blood flow (rCBF) in cross-sectional slices of human brain. An algorithm is presented for rCBF calculations from a sequence of time averaged tomograms using inhaled 133Xe. The approach is designed to avoid loss of information in brain areas with low flow rates. It is based on linearizing and scaling the early isotope distribution picture (recorded from 0 to 2 min) in rCBF units of ml/100 g/min. This is done by calculating the time constant ki for pixels with high count rate using the entire sequence of four 1 min pictures and using a fixed value for the brain:blood partition coefficient, lambda. The method is essentially based on the bolus distribution principle, and it allows the estimation of blood flow in ischemic areas. Application to positron emission tomography is discussed.

Mapping local blood flow of human brain by CT scanning during stable xenon inhalation.

Non-invasive methods are described for estimating local cerebral blood flows (LCBF) and partition coefficients (L lambda) during inhalation of 35% stable xenon gas (Xes) in oxygen during CT scanning. After denitrogenation by 100% oxygen breathing, 35% Xes is breathed for 7-8 minutes to minimize subanesthetic effects. Mean changes in brain Hounsfield units extrapolated to 15 minutes were 7.7 units for white matter and 5.3 units for gray matter. They were measured from volumes 80 cubic mm (10 mm2 area x 8 mm), or larger with an EMI 1010 scanner at 1 minute intervals. These data were used for computing LCBFs and L lambdas. Irradiation measured at the center of brain slices was 1 rad per minute. To calculate L lambdas about 6 exposures are necessary, thereafter, each 1 minute scan provides LCBF measurements for 2 adjacent 8 mm slices. Reproducibility for LCBF was r = 0.85 (P less 0.001). Mean L lambdas were 0.86 +/- 0.08 for gray and 1.34 +/- 0.10 for white matter. Normative mean flows (mls/100 g brain/min) were: basal ganglia = 79.6 +/- 9.3, cortex = 82.3 +/- 8.5, white matter = 29.2 +/- 5.9, midbrain tegmentum = 94.3 +/- 14.8, cerebellar cortex = 80.1 +/- 10.9, dorsal pons = 89.3 +/- 4.7, brachium pontis = 35.0 +/- 4.2. Subject finger exercises produced increases of LCBF in contralateral pre-central and post-central gyri. Eye closure decreased flow values limited to the visual system. Gray matter flow values diffusely decreased in non-REM sleep but increased above normal in REM sleep. Cerebral infarction and hemorrhage resulted in zones of zero flow with borders having reduced lambdas and low flows attributed to edema.

Method for the determination of cerebral blood flow in conscious rabbits

A procedure for the determination of cerebral blood flow by the local clearance method after intracarotid injection of 133Xe in the conscious rabbit is described. The inert radioactive indicator is injected into a permanent nylon catheter equipped with a two-way Gordth's needle inserted into the common carotid artery and filled with heparin, emerging behind the shoulders of the animals. All branches of the homolateral common carotid artery except the internal carotid artery were ligated. Studies of the distribution of colored tracers (dark blue ink) and radioactive tracers ( 99mTc albumin microspheres) show that the main localization of the injected indicator is within the homolateral hemisphere. Brain to blood partition coefficients of 133Xe are worked out for rabbit's gray matter (0.576 ± 0.048) and white matter (0.808 ± 0.023). The slope method for first and second component of the wash-out Xenon curve is used for CBF calculations. CBF determinations in 9 normal rabbits result in 84.27 ± 5.59 and 16.69 ± 2.44 ml/min × 100 g tissue, respectively, for the fast and slow component. Significant changes do not occur in serial determinations within 2 hr.

Abnormality of the xenon brain:blood partition coefficient and blood flow in cerebral infarction: an in vivo assessment using transmission computed tomography.

Xenon-enhanced computed tomography (CT) was used to analyze, in vivo, the patterns of blood flow of cerebral infarction in a nonhuman primate model. Consistent and reproducible results were attained utilizing the numerical data from CT scans obtained during the inhalation of nonradioactive xenon. The spatial resolution of CT defined a morphophysiologic map of the variability in brain:blood partition coefficient and flow rate constant that exist within and around an infarct. Both the flow and the partition coefficient were significantly diminished in the ischemic focus in all animals studied. Although the partition coefficients were normal, the flow was decreased in the other locales sampled in the ipsilateral hemispheres. In the contralateral hemispheres, both flows and partition coefficients were within the range of normal for adolescent baboons.

Nonradioactive iodoantipyrine enhanced cranial computed tomography: preliminary observations.

Nonradioactive 4-iodoantipyrine, an iodinated indicator that freely diffuses across the blood-brain barrier, was serially imaged in vivo using computed tomography (CT). Prominent enhancement was immediately detected in the brain substance of the dog following the intracarotid injection of this contrast medium. An estimate was made of the brain:blood partition coefficient for 4-iodoantipyrine from the CT derived arterial and brain concentration of this iodinated marker. Practical applicability of this technique is limited unless an improved method for getting the 4-iodoantipyrine into solution can be developed. However, this study reinforces the concept that local cerebral blood flow and metabolism can be analyzed by diffusible tracers using CT.

Colon blood flow in the dog: effects of changes in arterial carbon dioxide tension.

A new method for measuring blood flow in the colon using a 133Xenon clearance technique has been developed in the greyhound. Values for 133Xe tissue blood partition coefficient for colon have been established. The mean basal colon blood flow in 35 animals was 39.8 cm3.min-1.100g-1 with a coefficient of variation for repeat measurements of 8.7%. Hypercapnia produced a significant rise in colon blood flow to a mean maximum level of 62.2 cm3.min-1.100g-1 and hypocapnia a significant fall to a mean level of 27.9 cm3.min-1.100g-1. For arterial carbon dioxide tension (PCO2) values between 2 and 12 kPa (15 and 90 mmHg) there was a straight line relationship between colon blood flow and arterial PCO2. When hypercapnia was prolonged for 75 min, the initial rise in colon blood flow was only partially sustained, while prolonged hypocapnia for a similar period resulted in sustained reduction in flow. Mean resting colon oxygen consumption in 35 animals was 1.17 cm3.min-1.100g-1 and this was not significantly affected by hypocapnia. Hypercapnia to arterial PCO2 levels between 8 and 14 kPa (60 and 105 mmHg), however, produced a significant rise in colon oxygen consumption. Since changes in colon blood flow during and after surgery may affect healing of colonic anastomoses, these results may be relevant when considering anaesthetic techniques for patients undergoing colon resection.

Measurement of liver blood flow in the dog using krypton-85 clearance: A comparison with electromagnetic flowmeter measurements

Blood flow in the superficial liver tissue was measured by recording the clearance rate of the β emissions of 85Kr following its injection into the portal vein. The flow values calculated from monoexponential clearance curves were compared to portal venous blood flow simultaneously recorded with a calibrated electromagnetic flow probe in six dogs whose hepatic artery had been ligated. The liver: blood partition coefficient of 85Kr was measured in these dogs and was found to be 0.91. There was a close correlation ( r = 0.95) between the blood flow values obtained from the two techniques over a wide range of flow values. This shows that measurement of liver blood flow in the surface layers of the liver using the 85Kr clearance method provides a true reflection of the blood flow in the liver tissue as a whole.

Computed tomographic measurement of the xenon brain-blood partition coefficient and implications for regional cerebral blood flow: a preliminary report.

The calculation of regional cerebral blood flow requires, in addition to the measurement of the clearance, a knowledge of the regional brain-blood partition coefficient. The usual 133Xe washout techniques do not measure this latter parameter but use published values for normal brain tissue. This may lead to large errors in pathological tissue because the partition coefficient changes significantly in brain tumors. Investigations have begun into the use of CT and stable xenon to produce a cross sectional view of the brain in terms of its brain-blood partition coefficients. Results of experiments using an iodine phantom and xenon inhalation in animals are presented.

A guide for the isolation of the canine brain.

ArticleA guide for the isolation of the canine brain.D D Gilboe, A L Betz, and D A LangebartelD D Gilboe, A L Betz, and D A LangebartelPublished Online:01 Apr 1973https://doi.org/10.1152/jappl.1973.34.4.534MoreSectionsPDF (996 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByThe effect of a free radical scavenger and platelet-activating factor antagonist on FFA accumulation in post-ischemic canine brainNeurochemical Research, Vol. 19, No. 4Recovery of Postischemic Brain Metabolism and Function Following Treatment with a Free Radical Scavenger and Platelet-Activating Factor AntagonistsJournal of Neurochemistry, Vol. 56, No. 1Acute ultrastructural response of hypoxic hypoxia with relative ischemia in the isolated brainActa Neuropathologica, Vol. 78, No. 6Relating Cerebral Ischemia and Hypoxia to Insult IntensityJournal of Neurochemistry, Vol. 50, No. 6The cerebral origin of the alpha rhythmElectroencephalography and Clinical Neurophysiology, Vol. 69, No. 1Evaluation of Artificial Plasma for Maintaining the Isolated Canine Brain28 June 2016 | Journal of Cerebral Blood Flow & Metabolism, Vol. 6, No. 4Cerebral Vascular Resistance following Platelet and Leukocyte Removal from Perfusate28 June 2016 | Journal of Cerebral Blood Flow & Metabolism, Vol. 6, No. 1Quantitation of Local Cerebral Blood Flow and Partition Coefficient without Arterial Sampling: Theory and Validation29 June 2016 | Journal of Cerebral Blood Flow & Metabolism, Vol. 5, No. 2Cerebral Oxygen Utilization as a Gauge of Brain Energy MetabolismCharacterization of the Blood-Brain Barrier: Protein Composition of the Capillary Endothelial Cell MembraneJournal of Neurochemistry, Vol. 41, No. 5Transport of Hexoses and Monocarboxylic AcidsRegional Cerebral Blood Flow Measurement with Fluoromethane and Positron TomographyThe Effect of Severe Hypoxia on Cerebral Glucose FluxEffect of Acute Hyperammonemia on Metabolism and Cerebral Energy StateCytochalasin B inhibition of brain glucose transport and the influence of blood components on inhibitor concentrationBiochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 471, No. 3Metabolism and cerebral energy state: Effect of acute hyperammonemia in beagle dogBiochemical Pharmacology, Vol. 26, No. 24Physiological Aspects of Brain Energy MetabolismEdema Formation in the Isolated Canine Brain: Anoxia vs. IschemiaInhibition of glucose transport into brain by phlorizin, phloretin and glucose analoguesBiochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 406, No. 4Accelerative exchange diffusion kinetics of glucose between blood and brain and its relation to transport during anoxiaBiochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 401, No. 3Effects of anoxia on net uptake and unidirectional transport of glucose into the isolated dog brainBrain Research, Vol. 67, No. 2Kinetics of cerebral glucose transport in vivo: inhibition by 3-O-methylglucoseBrain Research, Vol. 65, No. 2Cerebral metabolite and adenylate energy charge recovery following 10 min of anoxiaBiochimica et Biophysica Acta (BBA) - General Subjects, Vol. 320, No. 3 More from this issue > Volume 34Issue 4April 1973Pages 534-7 https://doi.org/10.1152/jappl.1973.34.4.534PubMed4698616History Published online 1 April 1973 Published in print 1 April 1973 Metrics

Can plasma skimming of inconstancy of regional hematocrit introduce serious errors in regional cerebral blood flow measurements or their interpretation?

Recent reports indicate that in cases of elevated plasma or blood viscosity, red cell velocity through the cerebral microcirculation is unimpaired while plasma transit is retarded. One explanation may be that plasma skimming is increased, with increased shunting of plasma into longer, less direct flow paths, while an increasing proportion of red cells take shorter paths. Such inhomogeneities of flow on a microvascular level can be directly demonstrated in cases of endothelial damage or anoxia, and may produce an altered regional hematocrit. Measurements of regional cerebral blood flow are dependent upon regional hematocrit because this affects the tissue:blood partition coefficient (λ) of diffusible indicators. Hence changes in regional HCT may produce errors in the calculation of regional blood flow unless the value of λ. is corrected to reflect altered HCT. Moreover, no matter what kind of indicator is used, our functional interpretation of regional blood flow measurements is dependent upon our assumption that the ‘blood’ in the region maintains a constant capacity to carry nutrients like oxygen. Thus the lack of a constant relationship between plasma flow and red cell flow may produce errors either in the measurement or interpretation of regional flow measurements. These errors will increase in importance as blood flow is measured in smaller and smaller volumes of brain.

A comparison of the disappearance curves of 133X3 and 85Kr for the measurement of the intrarenal distribution of blood flow.

Krypton-85 and xenon-133 disappearance curves which are used to measure the intrarenal distribution of blood flow have been compared in two groups of animals under normal conditions. The blood flow rates (ml/100 g per min), percentage of initial radioactivity, and regional blood flow (ml/100 g kidney tissue) of the cortex calculated from the krypton-85 decay curves were found to be more elevated than those obtained from the xenon-133 curves. The same conclusions can be drawn from the results obtained for the outer medulla with the exception that the percentage of initial radioactivity was not different when calculated with either method. Among other considerations, the fact that the tissue to blood partition coefficient of krypton is not influenced by the hematocrit and that this radioisotope may be used for the preparation of the autoradiograms leads to the conclusion that it is preferable to use krypton-85 rather than xenon-133 for the measurement of intrarenal distribution of blood flow in animal experimentation.