Blood Flow-metabolism Coupling Research Articles

A Brief Review of Brain's Blood Flow-Metabolism Coupling and Pressure Autoregulation.

The human brain, depending on aerobic glycolysis to cover its metabolic needs and having no energy reserves whatsoever, relies on a constant and closely regulated blood supply to maintain its structural and functional integrity. Cerebral autoregulation, that is, the brain's intrinsic ability to regulate its own blood flow independently from the systemic blood pressure and cardiac output, is an important physiological mechanism that offers protection from hypoperfusion injury. Two major independent mechanisms are known to be involved in cerebral autoregulation: (1) flow-metabolism coupling and (2) myogenic responses of cerebral blood vessels to changes in transmural/arterial pressure. A third, less prominent component of cerebral autoregulation comes in the form of neurogenic influences on cerebral vasculature. Although fragmentation of cerebral autoregulation in separate and distinct from each other mechanisms is somewhat arbitrary, such a scheme is useful for reasons of simplification and to better understand their overall effect. Comprehension of cerebral autoregulation is imperative for clinicians in order for them to mitigate consequences of its impairment in the context of traumatic brain injury, subarachnoid hemorrhage, stroke, or other pathological conditions.

The Use of Hemodynamic and Cerebral Monitoring to Study Pharmacodynamics in Neonates.

Drugs acting on the cardiovascular and central nervous system often display relatively fast clinical responses, which may differ in neonates compared to children and adults. Introduction of bedside monitoring tools might be of additional value in the pharmacodynamic (PD) assessment of such drugs in neonates. We aim to provide an overview of the frequently used monitoring tools to assess drug effects on the hemodynamic status as well as the cerebral circulation, oxygenation and cerebral metabolism in neonates. The use of blood pressure measurements, heart rate variability, functional echocardiography, nearinfrared spectroscopy and (amplitude-integrated) electroencephalography in neonates is discussed, as well as new parameters introduced by these tools. Based on the 'brain circulation model', the hemodynamic effects on the brain and their interplay are summarized. In this model, 3 processes (i.e. blood processes, vascular smooth muscle processes and tissue processes) and 3 mechanisms (i.e. autoregulation, blood flow metabolism coupling and cerebral oxygen balance) are distinguished, which all may be influenced by drug administration. Finally, propofol, sevoflurane, midazolam and inotropes are used as examples of which PD has been studied using the available hemodynamic and/or cerebral monitoring tools. The implementation of (non-)invasive monitoring tools to document hemodynamic and cerebral PD effects in neonates is of relevance both in a neonatal research and intensive clinical care setting. We highlight the need to integrate these tools in future PD research. Furthermore, besides short-term drug effects, long-term outcome of drug therapy in neonates also warrants further attention.

The coupling of cerebral blood flow and oxygen metabolism with brain activation is similar for simple and complex stimuli in human primary visual cortex

Quantitative functional MRI (fMRI) experiments to measure blood flow and oxygen metabolism coupling in the brain typically rely on simple repetitive stimuli. Here we compared such stimuli with a more naturalistic stimulus. Previous work on the primary visual cortex showed that direct attentional modulation evokes a blood flow (CBF) response with a relatively large oxygen metabolism (CMRO2) response in comparison to an unattended stimulus, which evokes a much smaller metabolic response relative to the flow response. We hypothesized that a similar effect would be associated with a more engaging stimulus, and tested this by measuring the primary human visual cortex response to two contrast levels of a radial flickering checkerboard in comparison to the response to free viewing of brief movie clips. We did not find a significant difference in the blood flow–metabolism coupling (n=%ΔCBF/%ΔCMRO2) between the movie stimulus and the flickering checkerboards employing two different analysis methods: a standard analysis using the Davis model and a new analysis using a heuristic model dependent only on measured quantities. This finding suggests that in the primary visual cortex a naturalistic stimulus (in comparison to a simple repetitive stimulus) is either not sufficient to provoke a change in flow–metabolism coupling by attentional modulation as hypothesized, that the experimental design disrupted the cognitive processes underlying the response to a more natural stimulus, or that the technique used is not sensitive enough to detect a small difference.

Pour ou contre les halogénés en neuroanesthésie pour chirurgie intracrânienne

Isoflurane, desflurane and sevoflurane all preserve cerebrovascular carbone dioxide (CO2) reactivity. They are all concentration-dependant cerebral vasodilatators and decrease cerebral metabolism. Sevoflurane induces the smallest cerebral vasodilatation and preserve cerebral autoregulation up to 1.5CAM, compared to isoflurane and desflurane which impair it upon 1CAM. Propofol has been compared to inhaled agents. Propofol preserve cerebrovascular CO2 reactivity, blood flow-metabolism coupling, cerebral autoregulation and has no vasodilatation effect. None of the three inhaled agents induce any clinical relevant increase of intracranial pressure (ICP), but studies were conducted in patients without any intracranial hypertension (ICHT). However, compared to propofol, ICP and brain swelling were higher with inhaled agents, more with isoflurane compared to sevoflurane. Finally, neuroprotective properties have been described in experimental model for all the inhaled agents but clinical proofs are still lacking. In conclusion, for intracranial surgery without any ICHT inhaled agents can be used as a maintenance anesthetic with a preference for sevoflurane. In case of ICHT or a risk of ICHT during the surgery, propofol is preferred for it slightest effect on ICP and cerebral hemodynamic.

Dopamine therapy promotes cerebral flow-metabolism coupling in preterm infants

Dopamine is widely used to maintain blood pressure in very preterm infants, but it may affect neurovascular regulation as it crosses the immature blood-brain barrier. We contrasted the relationship between cerebral perfusion and oxygen metabolism in preterm infants treated with dopamine because of hypotension with normotensive controls. Prospective observational study in a neonatal intensive care unit. Cerebral metabolic rate of oxygen consumption (CMRO2) was determined via measurements of cerebral blood flow (CBF) and cerebral venous saturation (CSvO2) using near infrared spectroscopy. Twenty-six infants (median gestation 26 weeks) were studied at a median postnatal age of 17 h. Infants were categorised as control (n = 16) or dopamine-treated (DOPA, n = 10). No relationship was found between CBF and CMRO2 in the control group, while a strong positive correlation was found in the DOPA group (R (2) = 0.62, P = 0.01). Cerebral fractional oxygen extraction (CFOE) and CBF showed strong negative correlation in the control infants (R2 = 0.65, P < 0.001), but not in the DOPA group. CSvO2 was lower at decreased CBF (R2 = 0.56, P < 0.001) in the control infants, but not in the DOPA group. Cerebral blood flow-metabolism coupling in the very preterm brain differs strikingly from that in the mature brain, where CBF is coupled to CMRO2. In the very preterm brain, variations of cerebral oxygen extraction, not CBF, sustain CMRO2. In contrast, preterm infants receiving dopamine exhibit flow-metabolism coupling similar to the mature brain. These findings suggest a previously unrecognised role for dopamine in the preterm brain in promoting flow-metabolism coupling.

Assessment of cerebral oxygen supply-demand balance by near-infrared spectroscopy during induction of anesthesia in patients undergoing coronary artery bypass graft surgery: comparison of midazolam with propofol.

Near-infrared spectroscopy (NIRS) continuously measures regional cerebral oxygen saturation (rSO2) noninvasively and has been shown to detect even small changes in cerebral oxygen supply-demand balance. Although widely used, only the effect of midazolam on cerebral blood flow has been studied in humans and evidence is lacking about its effect on cerebral metabolic rate. We therefore evaluated the effect of midazolam on cerebral oxygen supply-demand balance with NIRS. Sixty patients undergoing elective coronary artery bypass graft surgery were randomly allocated into either midazolam (n = 30) or propofol (n = 30) group. rSO2 was recorded before induction while patients were breathing room air as baseline, after pre-oxygenation with 100% oxygen, after administration of either midazolam or propofol, after completion of administration of sufentanil and after tracheal intubation. Hemodynamic variables including cardiac index and mixed venous oxygen saturation were recorded at the same time points. rSO2 and hemodynamic variables were similar between the groups throughout the study period. After pre-oxygenation, rSO2 significantly increased compared to baseline in each group, and did not show any additional increase after administration of either midazolam or propofol and sufentanil in both groups. Midazolam preserves cerebral blood flow-metabolism coupling to a similar degree to propofol as assessed by near infrared spectroscopy.

Nimodipine does not affect the flow-metabolism couple in permanent cerebral ischemia.

Despite widespread investigational and clinical usage of the calcium channel blocker nimodipine, its effects on cerebral physiology in normal and ischemic brain remain poorly understood. In order to gain insight into this subject we examined the effects of nimodipine on glucose metabolism and cerebral blood flow-metabolism coupling in the rat during conditions of reproducible focal ischemia. Nimodipine-treated animals were then matched with vehicle-treated controls for both study conditions. Animals were subjected to permanent occlusion of the middle cerebral artery (MCA) along with occlusion of the common carotid arteries. Five minutes into ischemia, an intravenous infusion of nimodipine (1 micro g/kg per min, n=9) or vehicle ( n=9) was initiated and continued until the end of the study. Seventy-five minutes after the occlusion, [14C]2-deoxyglucose was injected into the venous catheter for the measurement of the local cerebral metabolic rate for glucose (LCMRgl), followed 25 min later by the injection of N-isopropyl-[123I] p-iodoamphetamine for the measurement of local cerebral blood flow (LCBF). The animals were killed at the end of 2 h of ischemia, and the brains were processed for double-labeled autoradiography. In all animals, permanent MCA occlusion produced significant decrements in LCBF, LCMRgl, and LCBF/LCMRgl ratio in both the core of the ischemia as well as regions peripheral to the ischemia within the same cerebral hemisphere when compared with non-ischemic brain. There were no significant differences between the nimodipine-treated and vehicle-treated groups. In conclusion, nimodipine does not appear to alter cerebral blood flow or cerebral metabolism in ischemic brain.

Effects of propofol on cerebral blood flow and the metabolic rate of oxygen in humans.

Effects of propofol on human cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and blood flow-metabolism coupling have not been fully evaluated. We therefore assessed the effects of propofol on total-CBF and CMRO2 in patients without noxious stimuli and neurologic disorders. General anesthesia was induced with midazolam (0.2 mg/kg) and fentanyl (5 microg/kg) in 10 patients (ASA physical status I) undergoing knee joint endoscopic surgery. Epidural anesthesia was also performed to avoid noxious stimuli during surgery. Cerebral blood flow (CBF) and cerebral arteriovenous oxygen content difference (a-vDO2) was measured using the Kety-Schmidt method with 15% N2O as a tracer before and after propofol infusion (6 mg/kg/h for 40 min), and the CMRO2 was also calculated. CBF decreased following propofol infusion from 34.4 ml/100 g/min (range 28.4-52.0) to 30.0 ml/100 g/min (range 20.2-42.4) (P=0.04). Although there was no significant change in a-vDO2, CMRO2 decreased following propofol infusion from 2.7 ml/100 g/min (range 2.2-4.3) to 2.2 ml/100 g/min (range 1.4-3.0) (P=0.04). There was a strong linear correlation between CBF and CMRO2 (r=0.90). Propofol proportionally decreased CBF and CMRO2 without affecting a-vDO2 in humans, suggesting that normal cerebral circulation and metabolism are maintained.

Cerebral blood flow regulation in REM sleep: a model for flow-metabolism coupling.

The pattern of metabolic and circulatory changes occurring during REM sleep in the whole brain is also observed at a regional level in different instances of functional activation. This pattern is characterized by an increase in metabolic rate, blood flow, glucose and oxygen uptake, the increase in glucose uptake generally exceeding oxygen uptake. A model of interpretation is presented, based on the assumption that substantial limitation to oxygen diffusion exists in the brain. According to the model, microregions lying at mid-distance between capillaries may become hypoxic, depending on metabolic rate and blood-cell PO2 difference. At increasing metabolic rates, O2 consumption in pericapillary microregions increases and the PO2 drop becomes steeper. As a consequence, in microregions far from capillaries a decrease in O2 availability occurs, in concomitance with the increase in metabolic rate, so that non-oxidative glucose metabolism develops locally. A similar spatial PO2 pattern forms in the case of arterial hypoxia, when capillary PO2, and then blood-cell PO2 difference, is reduced. The hypoxic microregions are the source of vasodilatatory messages, the consequent vasodilatation increasing average capillary PO2 and then favoring O2 diffusion to the tissue. Oxygen thus appears to be a better candidate than glucose as a mediator of blood flow-metabolism coupling. This is supported by its higher extraction fraction and by the fact that, in physiologic conditions, arterial hypoxia (and not hypoglycemia) acts on cerebral blood flow. Moreover, the diffusion capacity of glucose in the brain is higher than that of oxygen, so that diffusion limitation is more likely to occur for oxygen. The present model allows consistent organization of the stereotyped changes in cerebral blood flow and glucose and oxygen uptake occurring both in REM sleep and in other instances of brain activation.

Physiological and Pathophysiological Roles of Nitric Oxide in the Central Nervous System

Nitric oxide (NO) is produced by three distinct isoforms of nitric oxide synthases in the central nervous system. Here, the roles of nitric oxide in the central nervous system are reviewed under physiological and pathophysiological conditions. Under physiological conditions, NO plays a role in the regulation of cerebral blood flow and autoregulation, blood flow-metabolism coupling, neurotransmission, memory formation, modulation of neuroendocrine functions, and behavioral activity. Impairment of the NO-mediated cerebrovascular vasodilatation occurs during ischemia-reperfusion, diabetes, hypertension, subararchnoid hemorrhage, and various forms of shock. Enhancement of NO production in the brain occurs during stoke, seizures, and acute and chronic inflammatory and neurodegenerative disorders. The alterations of the expression of the various isoforms of nitric oxide synthases under the above conditions are discussed. Moreover, the molecular mechanisms of NO and peroxynitrite induced cellular injury are delineated. Finally, the current strategies available for selective pharmacological manipulation of individual nitric oxide synthase isoforms are discussed.

Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression.

The role of nitric oxide (NO) in cerebral blood flow-metabolism coupling was assessed in SV-129 wild-type (WT) and neuronal (type I) NO synthase (NOS) knockout mice (Kn). Regional cerebral blood flow (rCBF; laser-Doppler flowmetry) was measured over the contralateral cortical barrel field during unilateral mechanical vibrissal deflection (2-3 Hz, 60 s) under urethan anesthesia. The rCBF response was similar in WT and Kn and did not differ when recorded over the intact skull or closed cranial window preparations. Whisker stimulation increased rCBF by 41 +/- 8% (maximum) and 27 +/- 6% (mean) in WT (n = 6) and 41 +/- 7% (maximum) and 26 +/- 6% (mean) in Kn (n = 6) when recorded through a closed cranial window. After superfusion with topical N omega-nitro-L-arginine (L-NNA; 1 mM), the rCBF response was inhibited by approximately 45% in WT mice (P < 0.05), whereas there was no inhibition in Kn. Endothelium-dependent relaxation, assessed by pial vessel dilation in response to topical acetylcholine (100 microM) and inhibition by L-NNA (1 mM), was the same in both groups. Our results suggest that 1) endothelial NO production does not mediate the rCBF coupling to neuronal activity in Kn, 2) the inhibitory effect of L-NNA on the rCBF response to whisker stimulation in WT is a consequence of type I (neuronal) NOS inhibition, and 3) NO-independent mechanisms couple rCBF and metabolism during whisker stimulation in mice lacking expression of neuronal NOS.

Physiological and pathophysiological roles of nitric oxide in the central nervous system.

Nitric oxide (NO) is produced by three distinct isoforms of nitric oxide synthases in the central nervous system. Here, the roles of nitric oxide in the central nervous system are reviewed under physiological and pathophysiological conditions. Under physiological conditions, NO plays a role in the regulation of cerebral blood flow and autoregulation, blood flow-metabolism coupling, neurotransmission, memory formation, modulation of neuroendocrine functions, and behavioral activity. Impairment of the NO-mediated cerebrovascular vasodilatation occurs during ischemia-reperfusion, diabetes, hypertension, subararchnoid hemorrhage, and various forms of shock. Enhancement of NO production in the brain occurs during stoke, seizures, and acute and chronic inflammatory and neurodegenerative disorders. The alterations of the expression of the various isoforms of nitric oxide synthases under the above conditions are discussed. Moreover, the molecular mechanisms of NO and peroxynitrite induced cellular injury are delineated. Finally, the current strategies available for selective pharmacological manipulation of individual nitric oxide synthase isoforms are discussed.

Failure of cerebral blood flow-metabolism coupling after acute subdural hematoma in the rat.

We have used a recently introduced cerebral blood flow tracer, technetium-99-DL-hexamethylpropylene amine oxime, to map regional cerebral blood flow simultaneously with measurements of glucose metabolism ([14C]-2-deoxyglucose technique) using autoradiography. The technique was used to compare the acute effects of middle cerebral artery occlusion with the more complex events that occur after induction of an acute subdural hematoma (SDH) in the rat. Previous studies with this SDH model have shown that an infarction is induced in the cortex under the hematoma. In both models, the core of the infarct zone was associated with a reduction in both flow and metabolism to less than 15% of control values. In both models, the infarct core was surrounded by a band of tissue in which glucose metabolism increases by 60 to 70% and blood flow is reduced by the same amount. Global blood flow after the SDH was reduced by 14%, but remained unchanged after middle cerebral artery occlusion. In the hippocampus, a massive increase in metabolism (up to 157%) after SDH was accompanied by a paradoxical decrease in blood flow (32%). This discrepancy between blood flow and metabolism indicates loss of flow-metabolism coupling and provides a mechanism for infarct recruitment and delayed hippocampal damage after SDH.

Failure of Cerebral Blood Flow-Metabolism Coupling after Acute Subdural Hematoma in the Rat

WE HAVE USED a recently introduced cerebral blood flow tracer, technetium-99-DL-hexamethylpropylene amine oxime, to map regional cerebral blood flow simultaneously with measurements of glucose metabolism ([14C]-2-deoxyglucose technique) using autoradiography. The technique was used to compare the acute effects of middle cerebral artery occlusion with the more complex events that occur after induction of an acute subdural hematoma (SDH) in the rat. Previous studies with this SDH model have shown that an infarction is induced in the cortex under the hematoma. In both models, the core of the infarct zone was associated with a reduction in both flow and metabolism to less than 15% of control values. In both models, the infarct core was surrounded by a band of tissue in which glucose metabolism increases by 60 to 70% and blood flow is reduced by the same amount. Global blood flow after the SDH was reduced by 14%, but remained unchanged after middle cerebral artery occlusion. In the hippocampus, a massive increase in metabolism (up to 157%) after SDH was accompanied by a paradoxical decrease in blood flow (32%). This discrepancy between blood flow and metabolism indicates loss of flow-metabolism coupling and provides a mechanism for infarct recruitment and delayed hippocampal damage after SDH.

Cerebral blood flow-metabolism coupling after administration of soman at nontoxic levels

The effect of soman, an irreversible organophosphorus cholinesterase inhibitor, on regional cerebral blood flow and glucose utilization were studied with a double-tracer, autoradiographic technique in rats. Soman was given at a subtoxic dose of 55 μg/kg SC and variables were measured 45 min later. No changes in arterial blood pressure or signs of toxicity were present in the animals studied. Soman induced a pronounced increase in cerebral blood flow. This change was not accompanied by an increase in cerebral metabolism, with exception of superior colliculi. Brain regions showing the more pronounced (greater than 200% over control) increases in blood flow were motor, sensory and temporal cortex, area 18a of the occipital cortex, claustrum, inferior colliculus and cerebellum. These findings differ from those previously reported for the carbamate cholinesterase inhibitor, physostigmine, and constitute the first demonstration of cerebrovascular effects for an organophosphorus cholinesterase inhibitor, soman, at nonsymptomatic doses.

Effects of two dihydropyridine calcium channel blockers on cerebral metabolism and blood flow in traumatized rat brain

The effect of two dihydropyridine calcium (Ca) channel blocking drugs on cerebral glucose metabolism (LCGU), blood flow (LCBF), and blood flow-metabolism coupling were studied in thermally injured rat brain using quantitative radioautographic techniques. No reversal of the previously noted LCGU depression caused by the freezing lesion (Pappius, 1981) was detected following treatment with either PY-108-068 (PY) or nimodipine (NIM). These results therefore provided no support for the role of Ca in the mechanism of functional disturbances induced by cold injury (Pappius and Wolfe, 1983b), though they do not rule out its involvement. Treatment with PY, but not NIM, reestablished the normal LCBF-LCGU relationship in cortical areas, which has been shown to be disturbed by the freezing lesion and in subcortical and brainstem structures, in which the alteration caused by the injury was not as pronounced. The results suggest that the mechanism that apparently uncouples LCBF from LCGU in injured brain is altered in the presence of PY. However, since NIM did not have the same effect on LCBF, it is not clear whether the effects of PY relate to blockade of Ca channels or some other effect of PY.

Differential effects of methylxanthines on local cerebral blood flow and glucose utilization in the conscious rat.

The aim of this study was to test the effects of the three "classical" methylxanthines, theophylline, caffeine and theobromine, on local cerebral blood flow and glucose utilization. Equimolar doses (1.6 mumol/kg/min i.v.) of theophylline and caffeine produced increases in local cerebral glucose utilization and decreases in local cerebral blood flow. These compounds, therefore, re-set the ratio of cerebral blood flow per unit of glucose utilization at a lower level. These results are interpreted with respect to the known adenosine antagonist properties of caffeine and theophylline. Theobromine, a substance with less significant adenosine antagonist properties, had minimal effects on local cerebral blood flow and glucose utilization at a dose of 1.6 mumol/kg/min i.v. These data may provide supportive evidence for the hypothesis that adenosine plays an important role in cerebral blood flow-metabolism coupling.