Cerebral Metabolic Rate Of O2 Research Articles

Abstract 17490: Impaired Cerebrovascular Oxygen Delivery, Reserve, and Metabolism in Adult Fontan Patients

Introduction: Patients with univentricular hearts undergo a three-stage surgical palliation, culminating in total caval-pulmonary connection (Fontan procedure), maximizing delivery of oxygenated blood to the systemic circulation. Prior brain research in this population has highlighted genetic predisposition, in-utero oxygen delivery, surgical insults, and pre-Fontan cyanosis as possible mechanisms of brain injury, but none have examined the impact of the Fontan repair on brain hemodynamics. Study Purpose: To determine the sufficiency of brain O 2 delivery, cerebrovascular reserve (CVR), brain O 2 extraction fraction (OEF), and cerebral metabolic rate of O 2 (CMRO 2 ) in adult Fontan patients, compared to permeability-surface area (PS) of blood brain barrier (BBB) integrity to water, and endothelin levels. Hypothesis: We hypothesized that brain O 2 delivery, CVR, PS, and CMRO 2 would be decreased in Fontan patients, proportional to endothelin levels, an established surrogate for low cardiac output. Methods: We have enrolled 35 Fontan patients (age 20.8 ± 2.5 years, 21M) and 24 control subjects (age 23.4 ± 4.8 years, 9M) to undergo brain MRI, excluding all subjects with known stroke, seizure, or genetic abnormalities. We collected total cerebral blood flow (CBF), OEF, CVR, and PS using 3T MRI. Results: Table 1 summarizes differences in O 2 delivery, CBF, OEF, CMRO 2 , CVR, PS, and endothelin levels in the study cohort. O 2 delivery, CBF, CVR, and CMRO 2 were decreased in Fontan patients; OEF and PS were not different. Endothelin was increased but uncorrelated with the brain metrics. CMRO 2 was correlated with PS (r 2 = 0.19, p<0.001). Conclusion: Adult survivors of Fontan palliation have decreased brain O 2 delivery and reserve, without compensatory OEF increases, leading to lower CMRO 2 . Decreased CMRO 2 was associated with decreased PS, but not endothelin, suggesting microvascular dysfunction rather than low cardiac output as the fundamental etiology.

Baseline oxygen consumption decreases with cortical depth.

The cerebral cortex is organized in cortical layers that differ in their cellular density, composition, and wiring. Cortical laminar architecture is also readily revealed by staining for cytochrome oxidase-the last enzyme in the respiratory electron transport chain located in the inner mitochondrial membrane. It has been hypothesized that a high-density band of cytochrome oxidase in cortical layer IV reflects higher oxygen consumption under baseline (unstimulated) conditions. Here, we tested the above hypothesis using direct measurements of the partial pressure of O2 (pO2) in cortical tissue by means of 2-photon phosphorescence lifetime microscopy (2PLM). We revisited our previously developed method for extraction of the cerebral metabolic rate of O2 (CMRO2) based on 2-photon pO2 measurements around diving arterioles and applied this method to estimate baseline CMRO2 in awake mice across cortical layers. To our surprise, our results revealed a decrease in baseline CMRO2 from layer I to layer IV. This decrease of CMRO2 with cortical depth was paralleled by an increase in tissue oxygenation. Higher baseline oxygenation and cytochrome density in layer IV may serve as an O2 reserve during surges of neuronal activity or certain metabolically active brain states rather than reflecting baseline energy needs. Our study provides to our knowledge the first quantification of microscopically resolved CMRO2 across cortical layers as a step towards better understanding of brain energy metabolism.

Cerebral Oxygenation and Metabolism in Patients Undergoing Clipping of Cerebral Aneurysm: A Comparative Study between Propofol-based total intravenous anesthesia and Sevoflurane-based inhalational anesthesia.

ABSTRACT Background: Sevoflurane unfortunately increases the cranial blood flow, blood volume, and pressure changes cope with cerebral aneurysmal neuroanesthesia goals. Propofol decreases the brain metabolism, blood flow, preserve cerebral reactivity to carbon dioxide, creates neuroprotective effect during cerebral ischemia. Hypothesis: Propofol-based total intravenous anesthesia would be more appropriate than sevoflurane-based inhalational technique during surgical clipping of cerebral aneurysm. Methods: A prospective, randomized, comparative study on 50 patients subjected for elective clipping of cerebral aneurysm, randomly allocated into two equal groups of 25 patients each: propofol-dormicum total intravenous only group and sevoflurane based inhalational group. Results: Jugular oxygen saturation (primary outcome), cerebral blood flow equivalent, heart rate, mean arterial blood pressure, and end tidal carbon dioxide tension were statistically significantly decreased in propofol group compared to sevoflurane group at basal, just after dura opening, at 1,2,3 hours later, and after scalp closure. Arterio-Jugular oxygen content difference, cerebral extraction ratio of O2, estimated cerebral metabolic rate for O2, serum lactate (mg/dl) showed significant increase in propofol group compared to sevoflurane group at basal, 1, 2, 3 h, and after scalp closure. Duration of surgery, time of recovery, blood loss, blood transfusion, intraoperative complications, urine output, total midazolam consumption, surgeon satisfaction, intensive care unit stay time, and Ramsay sedation scale difference was not significant in between both studied groups during the early postoperative period. Conclusion: Propofol based total intravenous anesthesia has better cerebral oxygenation and neuro anesthesia profile compared to sevoflurane-based inhalational anesthesia during cerebral aneurysm clipping surgery with systemic hemodynamic stability.

Cerebral metabolic rate of oxygen during transition from wakefulness to sleep measured with high temporal resolution OxFlow MRI with concurrent EEG

During slow-wave sleep, synaptic transmissions are reduced with a concomitant reduction in brain energy consumption. We used 3 Tesla MRI to noninvasively quantify changes in the cerebral metabolic rate of O2 (CMRO2) during wakefulness and sleep, leveraging the ‘OxFlow’ method, which provides venous O2 saturation (SvO2) along with cerebral blood flow (CBF). Twelve healthy subjects (31.3 ± 5.6 years, eight males) underwent 45–60 min of continuous scanning during wakefulness and sleep, yielding one image set every 3.4 s. Concurrent electroencephalography (EEG) data were available in eight subjects. Mean values of the metabolic parameters measured during wakefulness were stable, with coefficients of variation below 7% (average values: CMRO2 = 118 ± 12 µmol O2/min/100 g, SvO2 = 67.0 ± 3.7% HbO2, CBF = 50.6 ±4.3 ml/min/100 g). During sleep, on average, CMRO2 decreased 21% (range: 14%–32%; average nadir = 98 ± 16 µmol O2/min/100 g), while EEG slow-wave activity, expressed in terms of -power, increased commensurately. Following sleep onset, CMRO2 was found to correlate negatively with relative -power (r = −0.6 to −0.8, P < 0.005), and positively with heart rate (r = 0.5 to 0.8, P < 0.0005). The data demonstrate that OxFlow MRI can noninvasively measure dynamic changes in cerebral metabolism associated with sleep, which should open new opportunities to study sleep physiology in health and disease.

Oxygen is rocket fuel for the human brain; a radical perspective!

Oxygen is rocket fuel for the human brain; a radical perspective!

Cerebral Hyperperfusion and Metabolic Regulation in Response to Hypoxia: Do ATP‐Sensitive Potassium Channels Play a Role?

ATP‐sensitive K+ channels (K+ATP) mediate hypoxia‐induced cerebral vasodilatation and hyperperfusion in animals, a compensatory mechanism that maintains the oxidative metabolic stability of the brain. We then tested whether K+ATP blockade attenuates the increase in cerebral blood flow (CBF) in humans and leads to a shift towards brain non‐oxidative metabolism during isocapnic hypoxia (IH). Seven men (25 ± 4 yrs.) were exposed to 5‐min of normoxia and IH (10% O2) before (BG) and 3 h after Glibenclamide oral administration (AG – 5 mg). Invasive mean arterial pressure (MAP), radial artery and right jugular venous blood saturation, oxygen (PO2) and carbon dioxide (PCO2) partial pressure, glucose and lactate levels, and internal carotid (ICA) and vertebral (VA) artery blood flow (BF, Doppler ultrasound) were quantified over the last 30 s. In another protocol, 5 male subjects (24 ± 4 yrs.) underwent the same procedures before (BPL) and 3 h after placebo ingestion (APL – 5 mg of starch). CBF ((ICA BF + VA BF)×2 (mL/min)), cerebral metabolic rate of O2 (CMRO2), oxygen‐glucose (OGI) and oxygen‐carbohydrate (OCI) indexes were determined in each trial. IH provoked similar arterial desaturation (ΔBG −18.3 ± 6.0 vs. ΔAG −17.9 ± 3.5%, p = 0.784) and PaO2 reduction (ΔBG −80.6 ± 4.8 vs. ΔAG −77.6 ± 9.0 mmHg, p = 0.351). MAP and PaCO2 remained unchanged under both conditions. Smaller increases in ICA (ΔBG +111 ± 94 vs. ΔAG +66 ± 68 mL/min, p = 0.021) and VA BF (ΔBG +44 ± 38 vs. ΔAG +26 ± 39 mL/min, p=0.035) were observed under K+ATP blockade. IH‐induced increase in CBF (ΔBG +310 ± 215 vs. ΔAG +184 ± 150 mL/min, p = 0.017) was attenuated and followed by a smaller increase in CMRO2 (ΔBG +18.9 ± 14.8 vs. ΔAG +4.5 ± 12.2 mmol/100 g/min, p = 0.015). There was no IH‐induced shift to cerebral non‐oxidative metabolism as OGI and OCI did not change. CBF and metabolic responses to IH did not differ between BPL and APL. Therefore, our findings indicate that K+ATP play a role in the human cerebral hyperemia and maintenance of the brain metabolic stability during isocapnic hypoxia.Support or Funding InformationCNPq, CAPES, FAPERJ, FINEPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Oxygen Affinity of Liposome-Encapsulated Hemoglobin on Cerebral Ischemia and Reperfusion as Detected by Positron Emission Tomography in Nonhuman Primates.

We tested a hypothesis that liposome-encapsulated hemoglobin (LEH) with high oxygen (O2 ) affinity (h-LEH, P50 O2 = 10 mm Hg) may work better than LEH with low O2 affinity (l-LEH, P50 O2 = 40 mm Hg) in cerebral ischemia and reperfusion injury using positron emission tomography (PET) in primates undergoing middle cerebral artery (MCA) occlusion and reperfusion. Cerebral blood flow (CBF), O2 extract fraction (OEF), and cerebral metabolic rate of O2 (CMRO2 ) were successively determined by PET before ischemia, at 2 h of ischemia, immediately after reperfusion, and 3 h after reperfusion. Five minutes after MCA occlusion, 10 mL/kg of h-LEH (n = 6) was intravenously infused and compared with the results from previous data of monkeys treated with l-LEH (n = 6), empty liposome (n = 4), or saline (n = 8) as control. After the series of PET studies, the integrated area of cerebral infarction was determined histologically in 12 coronal brain slices. There was no significant difference in CBF, OEF, or CMRO2 up to 2 h of ischemia. A high CBF with a low OEF tended to be suppressed after reperfusion in LEH-treated monkeys. Three hours after reperfusion, the area of mild CMRO2 reduction (down to -30%) decreased (P < 0.05) and the area of mild CMRO2 increase (up to 30%) expanded in LEH-treated monkeys (P < 0.05) regardless of O2 affinity with no difference in the area of moderate-to-severe reduction (<-30%) or increase (<+30%) in CMRO2 compared to animals treated with empty liposome or saline. Distribution of CMRO2 reduction and histological damages showed that LEH mainly protected the cerebral cortex rather than basal ganglia where neuronal dendritic processes were severely lost. There was little difference between the animals treated with l-LEH or h-LEH both at 10 mL/kg or between treatment with empty liposome or saline. In conclusion, LEH was effective regardless of O2 affinity in preserving CMRO2 and in reducing the area of histological damage in the cerebral cortex, but not in basal ganglia, shortly after occlusion/reperfusion of MCA in monkey.

Management Of Patients With Stroke In Critical Care Units, Considering Osmotic Therapy And Hypothermia

Cytotoxic brain edema is an early complication of stroke which increases the possibility of secondary ischemia. Hypertonic solutions, mannitol and recently hypertonic saline (HS) has been considered for treatment of increased ICP. HS could decrease ICP especially in hypotensive patients with different mechanisms, direct effect on edema, decreasing inflammation which is mediated by attenuation of TNFa and IL-1b stimulation on Na-K-Cl cotransporter 1 and improvement of microcirculation. Improvement of microcirculation is so important for hypertonic solutions to be effective in ischemia especially focal ischemia. Based on the literature, hypertonic saline is more effective in decreasing cerebral edema than the equal volume of mannitol. The optimal dose and duration of therapy needs more trials. Caution should be performed with patients with moderate size hemispheric infarcts on presentation, race and genetic factors regarding osmotic therapy.Hypothermia has been rated as one of the most active modes of neuroprotection based on the results of different trials. Hypothermia in both ways, surface and intravascular, decreases cerebral metabolic rate of O2 and glucose and reduces brain oxygen consumption, inflammation and oxidative stress. Recent data continue to support consideration of therapeutic hypothermia for cerebral ischemia in larger clinical trials of acute ischemic stroke. By increasing the time window to therapy initiation and decreasing the treatment duration, selective intracarotid cold saline administration brings increased feasibility, potentially better outcomes and perhaps fewer complications compared with the whole body cooling. Hypothermia is now recommended as a targeted temperature management with defined protocol which should be started early; it may be performed pharmacologically in combination with other therapies. Applying hypothermia should be considered regarding its cost, using in awaked patients, re-warming protocol, incorporation of thrombolysis and its complications.

The roadmap for estimation of cell-type-specific neuronal activity from non-invasive measurements.

The computational properties of the human brain arise from an intricate interplay between billions of neurons connected in complex networks. However, our ability to study these networks in healthy human brain is limited by the necessity to use non-invasive technologies. This is in contrast to animal models where a rich, detailed view of cellular-level brain function with cell-type-specific molecular identity has become available due to recent advances in microscopic optical imaging and genetics. Thus, a central challenge facing neuroscience today is leveraging these mechanistic insights from animal studies to accurately draw physiological inferences from non-invasive signals in humans. On the essential path towards this goal is the development of a detailed 'bottom-up' forward model bridging neuronal activity at the level of cell-type-specific populations to non-invasive imaging signals. The general idea is that specific neuronal cell types have identifiable signatures in the way they drive changes in cerebral blood flow, cerebral metabolic rate of O2 (measurable with quantitative functional Magnetic Resonance Imaging), and electrical currents/potentials (measurable with magneto/electroencephalography). This forward model would then provide the 'ground truth' for the development of new tools for tackling the inverse problem-estimation of neuronal activity from multimodal non-invasive imaging data.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'.

Dehydration accelerates reductions in cerebral blood flow during prolonged exercise in the heat without compromising brain metabolism.

Dehydration hastens the decline in cerebral blood flow (CBF) during incremental exercise, whereas the cerebral metabolic rate for O2 (CMRO2 ) is preserved. It remains unknown whether CMRO2 is also maintained during prolonged exercise in the heat and whether an eventual decline in CBF is coupled to fatigue. Two studies were undertaken. In study 1, 10 male cyclists cycled in the heat for ∼2 h with (control) and without fluid replacement (dehydration) while internal and external carotid artery blood flow and core and blood temperature were obtained. Arterial and internal jugular venous blood samples were assessed with dehydration to evaluate CMRO2 . In study 2, in 8 male subjects, middle cerebral artery blood velocity was measured during prolonged exercise to exhaustion in both dehydrated and euhydrated states. After a rise at the onset of exercise, internal carotid artery flow declined to baseline with progressive dehydration (P < 0.05). However, cerebral metabolism remained stable through enhanced O2 and glucose extraction (P < 0.05). External carotid artery flow increased for 1 h but declined before exhaustion. Fluid ingestion maintained cerebral and extracranial perfusion throughout nonfatiguing exercise. During exhaustive exercise, however, euhydration delayed but did not prevent the decline in cerebral perfusion. In conclusion, during prolonged exercise in the heat, dehydration accelerates the decline in CBF without affecting CMRO2 and also restricts extracranial perfusion. Thus, fatigue is related to a reduction in CBF and extracranial perfusion rather than CMRO2 .

Acute effect of glucose on cerebral blood flow, blood oxygenation, and oxidative metabolism.

While it is known that specific nuclei of the brain, for example hypothalamus, contain glucose-sensing neurons thus their activity is affected by blood glucose level, the effect of glucose modulation on whole-brain metabolism is not completely understood. Several recent reports have elucidated the long-term impact of caloric restriction on the brain, showing that animals under caloric restriction had enhanced rate of tricarboxylic acid cycle (TCA) cycle flux accompanied by extended life span. However, acute effect of postprandial blood glucose increase has not been addressed in detail, partly due to a scarcity and complexity of measurement techniques. In this study, using a recently developed noninvasive MR technique, we measured dynamic changes in global cerebral metabolic rate of O2 (CMRO2 ) following a 50 g glucose ingestion (N = 10). A time dependent decrease in CMRO2 was observed, which was accompanied by a reduction in oxygen extraction fraction (OEF) with unaltered cerebral blood flow (CBF). At 40 min post-ingestion, the amount of CMRO2 reduction was 7.8 ± 1.6%. A control study without glucose ingestion was performed (N = 10), which revealed no changes in CMRO2 , CBF, or OEF, suggesting that the observations in the glucose study was not due to subject drowsiness or fatigue after staying inside the scanner. These findings suggest that ingestion of glucose may alter the rate of cerebral metabolism of oxygen in an acute setting.

On the limits of cerebral oxygen extraction.

On the limits of cerebral oxygen extraction.

Liposome‐Encapsulated Hemoglobin Ameliorates Ischemic Stroke in Nonhuman Primates: Longitudinal Observation

Liposome-encapsulated hemoglobin (LEH) is protective early after brain ischemia in rats and nonhuman primates, but it remains unclear whether the protection persists and confers any benefits beyond the acute phase of brain ischemia and reperfusion. Ten monkeys underwent middle cerebral artery occlusion, received LEH (2 mL/kg, n = 5) or saline (2 mL/kg, n = 5) 5 min later, and reperfusion 3 h later. Positron emission tomography studies were repeated for the cerebral metabolic rate of O2 (CMRO2 ) as well as glucose (CMRglc) up to 8 days after reperfusion, when the animals were euthanized for morphological studies. There was no difference in O2 metabolism until 3 h after reperfusion, when CMRO2 was significantly better preserved in the cortex, but not in basal ganglia, on Day 0 in LEH-treated monkeys. The extent of cortical infarction (saline 68 ± 10% vs. LEH 38 ± 9%, P < 0.05) and CMRO2 (mild suppression: saline 34 ± 10% vs. LEH 14 ± 4%, P < 0.05) remained significantly better preserved 8 days later, when CMRglc showed a similar pattern of cortical protection (mild suppression: saline 49 ± 15% vs. LEH 37 ± 4%, P < 0.05) in LEH-treated monkeys, together with regained body weight. Somatic weight control, morphological integrity, CMRO2 , and CMRglc were better preserved immediately, as well as 8 days after occlusion and reperfusion of the middle cerebral artery in monkeys receiving LEH early after onset of ischemia.

Cerebral perfusion, oxygenation and metabolism during exercise in young and elderly individuals

We evaluated cerebral perfusion, oxygenation and metabolism in 11 young (22 ± 1 years) and nine older (66 ± 2 years) individuals at rest and during cycling exercise at low (25% W(max)), moderate (50% Wmax), high (75% W(max)) and exhaustive (100% W(max)) workloads. Mean middle cerebral artery blood velocity (MCA V(mean)), mean arterial pressure (MAP), cardiac output (CO) and partial pressure of arterial carbon dioxide (P(aCO2)) were measured. Blood samples were obtained from the right internal jugular vein and brachial artery to determine concentration differences for oxygen (O2), glucose and lactate across the brain. The molar ratio between cerebral uptake of O2 versus carbohydrate (O2-carbohydrate index; O2/[glucose + 1/2 lactate]; OCI), the cerebral metabolic rate of O2 (CMRO2) and changes in mitochondrial O2 tension ( P(mitoO2)) were calculated. 100% W(max) was ~33% lower in the older group. Exercise increased MAP and CO in both groups (P < 0.05 vs. rest), but at each intensity MAP was higher and CO lower in the older group (P < 0.05). MCA V(mean), P(aCO2) and cerebral vascular conductance index (MCA V(mean)/MAP) were lower in the older group at each exercise intensity (P < 0.05). In contrast, young and older individuals exhibited similar increases in CMRO2 (by ~30 μmol (100 g(-1)) min(-1)), and decreases in OCI (by ~1.5) and (by ~10 mmHg) during exercise at 75% W(max). Thus, despite the older group having reduced cerebral perfusion and maximal exercise capacity, cerebral oxygenation and uptake of lactate and glucose are similar during exercise in young and older individuals.

Effect of Hypoxia and Hyperoxia on Cerebral Blood Flow, Blood Oxygenation, and Oxidative Metabolism

Characterizing the effect of oxygen (O(2)) modulation on the brain may provide a better understanding of several clinically relevant problems, including acute mountain sickness and hyperoxic therapy in patients with traumatic brain injury or ischemia. Quantifying the O(2) effects on brain metabolism is also critical when using this physiologic maneuver to calibrate functional magnetic resonance imaging (fMRI) signals. Although intuitively crucial, the question of whether the brain's metabolic rate depends on the amount of O(2) available has not been addressed in detail previously. This can be largely attributed to the scarcity and complexity of measurement techniques. Recently, we have developed an MR method that provides a noninvasive (devoid of exogenous agents), rapid (<5 minutes), and reliable (coefficient of variant, CoV <3%) measurement of the global cerebral metabolic rate of O(2) (CMRO(2)). In the present study, we evaluated metabolic and vascular responses to manipulation of the fraction of inspired O(2) (FiO(2)). Hypoxia with 14% FiO(2) was found to increase both CMRO(2) (5.0±2.0%, N=16, P=0.02) and cerebral blood flow (CBF) (9.8±2.3%, P<0.001). However, hyperoxia decreased CMRO(2) by 10.3±1.5% (P<0.001) and 16.9±2.7% (P<0.001) for FiO(2) of 50% and 98%, respectively. The CBF showed minimal changes with hyperoxia. Our results suggest that modulation of inspired O(2) alters brain metabolism in a dose-dependent manner.

Phenylephrine decreases frontal lobe oxygenation at rest but not during moderately intense exercise

Whether sympathetic activity influences cerebral blood flow (CBF) and oxygenation remains controversial. The influence of sympathetic activity on CBF and oxygenation was evaluated by the effect of phenylephrine on middle cerebral artery (MCA) mean flow velocity (Vmean) and the near-infrared spectroscopy-derived frontal lobe oxygenation (ScO2) at rest and during exercise. At rest, nine healthy male subjects received bolus injections of phenylephrine (0.1, 0.25, and 0.4 mg), and changes in mean arterial pressure (MAP), MCA Vmean, internal jugular venous O2 saturation (SjvO2), ScO2), and arterial PCO2 (PaCO2) were measured and the cerebral metabolic rate for O2 (CMRO2) was calculated. In randomized order, a bolus of saline or 0.3 mg of phenylephrine was then injected during semisupine cycling, eliciting a low (approximately 110 beats/min) or a high (approximately 150 beats/min) heart rate. At rest, MAP and MCA Vmean increased approximately 20% (P<0.001) and approximately 10% (P<0.001 for 0.25 mg of phenylephrine and P<0.05 for 0.4 mg of phenylephrine), respectively. ScO2 then decreased approximately 7% (P<0.001). Phenylephrine had no effect on SjvO2, PaCO2, or CMRO2. MAP increased after the administration of phenylephrine during low-intensity exercise (approximately 15%), but this was attenuated (approximately 10%) during high-intensity exercise (P<0.001). The reduction in ScO2 after administration of phenylephrine was attenuated during low-intensity exercise (-5%, P<0.001) and abolished during high-intensity exercise (-3%, P=not significant), where PaCO2 decreased 7% (P<0.05) and CMRO2 increased 17% (P<0.05). These results suggest that the administration of phenylephrine reduced ScO2 but that the increased cerebral metabolism needed for moderately intense exercise eliminated that effect.

Increased Oxidative-nitrative Stress In The Hypoxic Human Brain

Oxidative stress may be responsible for the reduction in systemic nitric oxide (NO) bioavailability and impaired neurovascular reactivity recently observed in hypoxia (DM Bailey et al., J. Physiol. in-the-press). However, the brain's contribution to these systemic changes in redox homeostasis remains unknown. PURPOSE: The present study determined the trans-cerebral exchange kinetics of oxidative-nitrative stress biomarkers in response to hypoxia. Specifically, we hypothesized that hypoxia would increase the net cerebral output of free radicals that would inactivate NO as indicated by a decrease in the net uptake or consumption of nitrite (NO2) and increased output of 3-nitrotyrosine (3-NT). METHODS: Ten healthy males aged 27 (mean) ± 4 (SD) years were examined in normoxia (N: 20.9%O2) and following 9h passive exposure to hypoxia (H: 12.9%O2). Global cerebral blood flow (CBF) was measured using the Kety-Schmidt technique with paired samples obtained from the radial artery and jugular venous bulb. Global cerebral plasma flow (CPF) was determined as CBF × (1-hematocrit). The serum concentration of spin-trapped a-phenyl-tert-butylnitrone (PBN)-adducts was assessed via X-band electron paramagnetic resonance spectroscopy. Plasma NO2 was determined by ozone-based chemiluminescence using modified tri-iodide reagent and 3-NT via ELISA. Trans-cerebral net exchange was calculated as the arterio-jugular venous concentration difference x CPF. Data were analyzed with a two-way repeated measures ANOVA and post-hoc Bonferroni-corrected paired samples t-tests. RESULTS: Despite a marked reduction in PaO2 (N: 107 ± 6 to H: 46 ± 3 mmHg, P < 0.05), the cerebral metabolic rate for O2 was preserved (N: 2.4 ± 0.5 vs.H: 2.5 ± 0.3 μmol/g/min) due to a trend towards increased CBF (N: 85 ± 15 to H: 94 ± 17 mL/100g/min). Hypoxia increased the net cerebral output of PBN-adducts from -73 ± 192 to -360 ± 253 AU/min/g (P < 0.05). This was associated with an attenuation in the net uptake of NO2 (N: 126.4 ± 93.9 to H: 16.0 ± 46.7 nmol/min/g, P < 0.05) and increased output of 3-NT (N: -3.1 ± 9.0 to H: -10.7 ± 18.2 nmol/min/g, P < 0.05). CONCLUSION: These findings provide direct evidence for increased oxidative-nitrative stress across the hypoxic human brain and suggest that neurovascular NO bioavailability may be subject to redox-regulation.

Continuous monitoring of cerebrovascular pressure reactivity in patients with head injury

Cerebrovascular pressure reactivity is the ability of cerebral vessels to respond to changes in transmural pressure. A cerebrovascular pressure reactivity index (PRx) can be determined as the moving correlation coefficient between mean intracranial pressure (ICP) and mean arterial blood pressure. The authors analyzed a database consisting of 398 patients with head injuries who underwent continuous monitoring of cerebrovascular pressure reactivity. In 298 patients, the PRx was compared with a transcranial Doppler ultrasonography assessment of cerebrovascular autoregulation (the mean index [Mx]), in 17 patients with the PET-assessed static rate of autoregulation, and in 22 patients with the cerebral metabolic rate for O(2). Patient outcome was assessed 6 months after injury. There was a positive and significant association between the PRx and Mx (R(2) = 0.36, p < 0.001) and with the static rate of autoregulation (R(2) = 0.31, p = 0.02). A PRx > 0.35 was associated with a high mortality rate (> 50%). The PRx showed significant deterioration in refractory intracranial hypertension, was correlated with outcome, and was able to differentiate patients with good outcome, moderate disability, severe disability, and death. The graph of PRx compared with cerebral perfusion pressure (CPP) indicated a U-shaped curve, suggesting that too low and too high CPP was associated with a disturbance in pressure reactivity. Such an optimal CPP was confirmed in individual cases and a greater difference between current and optimal CPP was associated with worse outcome (for patients who, on average, were treated below optimal CPP [R(2) = 0.53, p < 0.001] and for patients whose mean CPP was above optimal CPP [R(2) = -0.40, p < 0.05]). Following decompressive craniectomy, pressure reactivity initially worsened (median -0.03 [interquartile range -0.13 to 0.06] to 0.14 [interquartile range 0.12-0.22]; p < 0.01) and improved in the later postoperative course. After therapeutic hypothermia, in 17 (70.8%) of 24 patients in whom rewarming exceeded the brain temperature threshold of 37 degrees C, ICP remained stable, but the average PRx increased to 0.32 (p < 0.0001), indicating significant derangement in cerebrovascular reactivity. The PRx is a secondary index derived from changes in ICP and arterial blood pressure and can be used as a surrogate marker of cerebrovascular impairment. In view of an autoregulation-guided CPP therapy, a continuous determination of a PRx is feasible, but its value has to be evaluated in a prospective controlled trial.

Effect of Moderate Hypercapnic Hypoxia on Cerebral Dopaminergic Activity and Brain O2 Uptake in Intrauterine Growth–Restricted Newborn Piglets

There is evidence that intrauterine growth restriction (IUGR) is associated with altered dopaminergic function in the immature brain. Compelling evidence exists that in the newborn brain, specific structures are especially vulnerable to O2 deprivation. The dopaminergic system is shown to be sensitive to O2 deprivation in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain after IUGR under hypercapnic hypoxia (H/H). Therefore, 18F-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography was used to estimate the aromatic amino acid decarboxylase activity of the brain of seven normal weight (body weight 2078 +/- 434 g) and seven IUGR newborn piglets (body weight 893 +/- 109 g). Two positron emission tomography scans were performed in each piglet. All animals underwent a period of normoxia and moderate H/H. Simultaneously, cerebral blood flow was measured with colored microspheres and cerebral metabolic rate of O2 was determined. In newborn normal-weight piglets, the rate constant for FDOPA decarboxylation was markedly increased in mesostriatal regions during H/H, whereas brain oxidative metabolism remained unaltered. In contrast, moderate H/H induced in IUGR piglets a marked reduction of clearance rates for FDOPA metabolites (p <0.05), which was accompanied by a tendency of lowering the rate constant for FDOPA conversion. Furthermore, IUGR piglets maintained cerebral O2 uptake in the early period of H/H, but during the late period of H/H, a significantly reduced cerebral metabolic rate of O2 occurred (p <0.05). Thus, IUGR is accompanied by a missing activation of dopaminergic activity and attenuated brain oxidative metabolism during moderate H/H. This may indicate endogenous brain protection against O2 deprivation.

Cerebral hemodynamics and metabolism in patients with cerebral arteriovenous malformations: an evaluation using positron emission tomography scanning.

The purpose of this study was to evaluate cerebral hemodynamic and metabolic features in patients with arteriovenous malformations (AVMs) by using positron emission tomography (PET) scanning. Twenty-four patients with supratentorial cerebral AVMs participated in PET studies in which 15O inhalation steady-state methods were used. The authors recorded the values of regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), the regional oxygen extraction fraction (rOEF), and the regional cerebral metabolic rate of O2 (rCMRO2) at three designated regions of interest (ROIs) in each patient. These ROIs included perilesional (ROI-p), ipsilateral remote (ROI-i), and contralateral symmetrical (ROI-c) brain regions. To identify the factors that exert a direct effect on the hemodynamics of brains affected by AVM, we also separated the lesions according to their size and flow type shown on angiograms, and grouped the patients according to the presence or absence of progressive neurological deficits. We then compared the PET parameters at different ROIs in individual patients and evaluated the mean values obtained for all 24 patients according to AVM flow type and size, and the presence or absence of progressive neurological deficits. Overall, mean rCBV and rOEF values were significantly higher in ROI-p than in ROI-c (p = 0.00046 and p = 0.015, respectively). No significant differences were seen between the ROI-i and ROI-c with respect to rCBF, rCBV, and rOEF. Mean rCMRO2 values were similar in the three ROIs; however, the mean rCBF was significantly lower in the ROI-p than in the ROI-c in patients with high-flow AVMs (p = 0.019), large AVMs (p = 0.017), and progressive neurological deficits (p = 0.021). Furthermore, the mean rOEF values were significantly higher in the ROI-p than in the ROI-c in patients with high-flow AVMs (p = 0.005), large AVMs (p = 0.019), and progressive neurological deficits (p = 0.017). The PET studies revealed hemodynamic impairment characterized by decreased rCBF and increased rOEF and rCBV values in the ROI-p of patients with large, high-flow AVMs regardless of whether they exhibited progressive neurological deficits.