Haemorheologic Enhancement of Cerebral Perfusion Improves Oxygen Supply and Reduces Aß Plaques Deposition in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a consequence of complex interactions of age-related neurodegeneration and vascular-associated pathologies, affecting more than 44 million people worldwide. For the last decade, it has been suggested that chronic brain hypoperfusion and consequent hypoxia play a direct role in the pathogenesis of AD. However, current treatments of AD have not focused on restoring or improving microvascular perfusion. In a previous study, we showed that drag reducing polymers (DRP) enhance cerebral blood flow and tissue oxygenation. We hypothesised that haemorheologic enhancement of cerebral perfusion by DRP would be useful for treating Alzheimer's disease. We used double transgenic B6C3-Tg(APPswe, PSEN1dE9) 85Dbo/Mmjax AD mice. DRP or vehicle (saline) was i.v. injected every week starting at four months of age till 12 months of age (10 mice/group). In-vivo 2-photon laser scanning microscopy was used to evaluate amyloid plaques development, cerebral microcirculation, and tissue oxygen supply/metabolic status (NADH autofluorescence). The imaging sessions were repeated once a month till 12 months of age. Statistical analyses were done by independent Student's t-test or Kolmogorov-Smirnov tests where appropriate. Differences between groups and time were determined using a two-way repeated measures ANOVA analysis for multiple comparisons and post hoc testing using the Mann-Whitney U test. In the vehicle group, numerous plaques completely formed in the cortex by nine months of age. The development of plaques accumulation was accompanied by cerebral microcirculation disturbances, reduction in tissue oxygen supply and metabolic impairment (NADH increase). DRP mitigated microcirculation and tissue oxygen supply reduction - microvascular perfusion was 29.5 ± 5%, and tissue oxygen supply was 22 ± 4% higher than in the vehicle group (p < 0.05). In the DRP group, amyloid plaques deposition was substantially less than in the vehicle group (p < 0.05). Thus, rheological enhancement of blood flow by DRP is associated with reduced rate of beta amyloid plaques deposition in AD mice.

Drag-Reducing Polymers Improve Vascular Hemodynamics and Tissue Oxygen Supply in Mouse Model of Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic metabolic disease characterised by hyperglycaemia and glucose intolerance caused by impaired insulin action and/or defective insulin secretion. Long-term hyperglycaemia leads to various structural and functional microvascular changes within multiple tissues, including the brain, which involves blood-brain barrier alteration, inflammation and neuronal dysfunction. We have shown previously that drag-reducing polymers (DRP) improve microcirculation and tissue oxygen supply, thereby reducing neurologic impairment in different rat models of brain injury. We hypothesised that DRP could improve cerebral and skin microcirculation in the situation of progressive microangiopathies associated with diabetes using a mouse model of diabetes mellitus. Diabetes was induced in C57BL/6 J mice with five daily consecutive intraperitoneal injections of streptozotocin (50 mg/kg/day). Animals with plasma glucose concentrations greater than 250 mg/dL were considered diabetic and were used in the study following four months of diabetes. DRP (2 ppm) was injected biweekly during the last two weeks of the experiment. Cortical and skin (ear) microvascular cerebral blood flow (mCBF) and tissue oxygen supply (NADH) were measured by two-photon laser scanning microscopy (2PLSM). Cerebrovascular reactivity (CVR) was evaluated by measuring changes in arteriolar diameters and NADH (tissue oxygen supply) during the hypercapnia test. Transient hypercapnia was induced by a 60-second increase of CO2 concentration in the inhalation mixture from 0% to 10%. Compared to non-diabetic animals, diabetic mice had a significant reduction in the density of functioning capillaries per mm3 (787 ± 52 vs. 449 ± 25), the linear velocity of blood flow (1.2 ± 0.31 vs. 0.54 ± 0.21 mm/sec), and the tissue oxygen supply (p < 0.05) in both brain and skin. DRP treatment was associated with a 50% increase in all three parameters (p < 0.05). According to the hypercapnia test, CVR was impaired in both diabetic groups but more preserved in DRP mice (p < 0.05). Our study in a diabetic mouse model has demonstrated the efficacy of hemorheological modulation of blood flow by DRP to achieve increased microcirculatory flows and tissue oxygen supply.

Increases in Microvascular Perfusion and Tissue Oxygenation via Vasodilatation After Anodal Transcranial Direct Current Stimulation in the Healthy and Traumatized Mouse Brain.

Traumatic brain injury (TBI), causing neurological deficit in 70% of survivors, still lacks a clinically proven effective therapy. Transcranial direct current stimulation (tDCS) has emerged as a promising electroceutical therapeutic intervention possibly suitable for TBI; however, due to limited animal studies the mechanisms and optimal parameters are unknown. Using a mouse model of TBI we evaluated the acute effects of the anodal tDCS on cerebral blood flow (CBF) and tissue oxygenation, and assessed its efficacy in long-term neurologic recovery. TBI was induced by controlled cortical impact leading to cortical and hippocampal lesions with reduced CBF and developed hypoxia in peri-contusion area. Sham animals were subjected to craniotomy only. Repetitive anodal tDCS (0.1 mA/15 min) or sham stimulation was done over 4 weeks for four consecutive days with 3-day intervals, beginning 1 or 3 weeks after TBI. Laser speckle contrast imaging (LSCI) revealed that anodal tDCS causes an increase in regional cortical CBF in both traumatized and Sham animals. On microvascular level, using in-vivo two-photon microscopy (2PLSM), we have shown that anodal tDCS induces arteriolar dilatation leading to an increase in capillary flow velocity and tissue oxygenation in both traumatized and Sham animals. Repetitive anodal tDCS significantly improved motor and cognitive neurologic outcome. The group with stimulation starting 3 weeks after TBI showed better recovery compared with stimulation starting 1 week after TBI, suggesting that the late post-traumatic period is more optimal for anodal tDCS.

Resuscitation Fluid with Drag Reducing Polymer Enhances Cerebral Microcirculation and Tissue Oxygenation After Traumatic Brain Injury Complicated by Hemorrhagic Shock.

Traumatic brain injury (TBI) is frequently accompanied by hemorrhagic shock (HS) which significantly worsens morbidity and mortality. Existing resuscitation fluids (RF) for volume expansion inadequately mitigate impaired microvascular cerebral blood flow (mvCBF) and hypoxia after TBI/HS. We hypothesized that nanomolar quantities of drag reducing polymers in resuscitation fluid (DRP-RF), would improve mvCBF by rheological modulation of hemodynamics. METHODS: TBI was induced in rats by fluid percussion (1.5 atm, 50 ms) followed by controlled hemorrhage to a mean arterial pressure (MAP) = 40 mmHg. DRP-RF or lactated Ringer (LR-RF) was infused to MAP of 60 mmHg for 1 h (pre-hospital), followed by blood re-infusion to a MAP = 70 mmHg (hospital). Temperature, MAP, blood gases and electrolytes were monitored. In vivo 2-photon laser scanning microscopy was used to monitor microvascular blood flow, hypoxia (NADH) and necrosis (i.v. propidium iodide) for 5 h after TBI/HS followed by MRI for CBF and lesion volume. RESULTS: TBI/HS compromised brain microvascular flow leading to capillary microthrombosis, tissue hypoxia and neuronal necrosis. DRP-RF compared to LR-RF reduced microthrombosis, restored collapsed capillary flow and improved mvCBF (82 ± 9.7% vs. 62 ± 9.7%, respectively, p < 0.05, n = 10). DRP-RF vs LR-RF decreased tissue hypoxia (77 ± 8.2% vs. 60 ± 10.5%, p < 0.05), and neuronal necrosis (21 ± 7.2% vs. 36 ± 7.3%, respectively, p < 0.05). MRI showed reduced lesion volumes with DRP-RF. CONCLUSIONS: DRP-RF effectively restores mvCBF, reduces hypoxia and protects neurons compared to conventional volume expansion with LR-RF after TBI/HS.

Improvement of Impaired Cerebral Microcirculation Using Rheological Modulation by Drag-Reducing Polymers.

Nanomolar intravascular concentrations of drag-reducing polymers (DRP) have been shown to improve hemodynamics and survival in animal models of ischemic myocardium and limb, but the effects of DRP on the cerebral microcirculation have not yet been studied. We recently demonstrated that DRP enhance microvascular flow in normal rat brain and hypothesized that it would restore impaired microvascular perfusion and improve outcomes after focal ischemia and traumatic brain injury (TBI). We studied the effects of DRP (high molecular weight polyethylene oxide, 4000 kDa, i.v. at 2 µg/mL of blood) on microcirculation of the rat brain: (1) after permanent middle cerebral artery occlusion (pMCAO); and (2) after TBI induced by fluid percussion. Using in vivo two-photon laser scanning microscopy (2PLSM) over the parietal cortex of anesthetized rats we showed that both pMCAO and TBI resulted in progressive decrease in microvascular circulation, leading to tissue hypoxia (NADH increase) and increased blood brain barrier (BBB) degradation. DRP, injected post insult, increased blood volume flow in arterioles and red blood cell (RBC) flow velocity in capillaries mitigating capillary stasis, tissue hypoxia and BBB degradation, which improved neuronal survival (Fluoro-Jade B, 24 h) and neurologic outcome (Rotarod, 1 week). Improved microvascular perfusion by DRP may be effective in the treatment of ischemic stroke and TBI.

Dynamics of cerebral venous and intracranial pressures.

Traumatic brain injury and stroke are both characterized by an ischemic core surrounded by a penumbra of low to hyperemic flows. The underperfused ischemic core is the focus of edema development, but the source of the edema fluid is not known. We hypothesized that flow of edema fluid into the tissue is derived from cerebral venous circulation pressure, which always exceeds intracranial pressure (ICP). As a first step toward testing this hypothesis, the aim of the current study was to determine whether cerebral venous pressure in the normal brain is always equal to or higher than ICP. In studies on 2 pigs, cerebral cortical venous, intracranial (subarachnoid), sagittal sinus, and central venous pressures were monitored with manipulation of ICP by raising and lowering a reservoir above and below the external auditory meatus zero point. The results show that cerebral venous pressure is always higher than or equal to ICP at pressures of up to 60 mmHg. On the basis of these observations, we hypothesize that increased cerebral venous pressure initiated after traumatic brain injury and stroke drives edema fluid into the tissue, which thereby increases ICP and a further increase in cerebral venous pressure in a vicious cycle of brain edema.

Hyperbaric nitrogen and pentobarbital on synaptosomal membrane lipids and free fatty acids.

Nitrogen at high pressures and anesthetics increase lipid monolayer surface pressure and in turn modulates monolayer associated lipolytic enzyme activity that could alter membrane lipids. We tested the hypothesis that nitrogen at pressures of 5 and 10 megapascals (MPa) and pentobarbital induce alterations in synaptosomal membrane phospholipid and free fatty acid (FFA). Rat cortical synaptosomes in Krebs-Henseleit buffer were placed in steel chambers and incubated for four hours at 37 degrees C: at 5 or 10 MPa of O2/balance N2; at one 0.1 MPa on room air, and with 10 mg pentobarbital. Free fatty acids (FFA) were quantified by thin-layer and gas chromatography, and neutral and acidic lipids by high-pressure thin layer chromatography and protein by Biorad colorimetric assay. Statistical analyses were by ANOVA and posthoc analysis by Neuman-Keuls and Kruskal-Wallis tests at p < 0.05. Sphyngomyelin, phosphatidylcholine, phosphatidylethanolamine, cerebroside and cholesterol were unchanged by 5 and 10 MPa nitrogen and pentobarbital. Free fatty acids (16:00, 18:00, 18:01, 20:00, 22:0, 22:01 and 24:01) at 10 MPa were reduced compared to 5 MPa (p < 0.05) but unaffected by pentobarbital. The decrease in synaptosomal membrane FFA at 10 MPa suggests attenuated hydrolysis of membrane phospholipids without detectable alterations in membrane phospholipid composition.

Optimization of epoxyeicosatrienoic acid syntheses to test their effects on cerebral blood flow in vivo.

Epoxyeicosatrienoic acids (EETs), normally present in brain and blood, appear to be released from atherosclerotic vessels in large amounts. Once intravascular, EETs can constrict renal arteries in vivo and dilate cerebral and coronary arteries in vitro. Whether EETs in blood will alter cerebral blood flow (CBF) in vivo is unknown. In the present study, the chemical synthesis of four EET regioisomers was optimized, and their identity and structural integrity established by chromatographic and mass spectral methods. The chemically labile EETs were converted to a sodium salt, complexed with albumin, and infused into anesthetized rats via the common carotid. The objective was to test whether sustained, high levels of intravascular EETs alter CBF. The CBF (cortical H2 clearance) was measured before and 30 min after the continuous infusion of 14,15- (n = 5), 11,12- (n = 5), 8,9- (n = 7) and 5,6-EET (unesterified or as the methyl ester, n = 5 for each). Neither the CBF nor the systemic blood pressure was affected by EETs. Because the infusions elevated the plasma concentrations of EETs about 700-fold above normal levels (1.0 nM), it is unlikely that EETs released from atherosclerotic vessels will alter CBF.

Hyperoxia produces neuronal necrosis in the rat.

Widespread cerebral neuronal necrosis occurred in newborn Sprague-Dawley rats submitted to three hours of pure oxygen (100% O2) at normal atmospheric pressure. Neuronal necrosis (NN) was most severe in the immediate newborn period and less marked with advanced maturation. It was minimal and different in its morphological characteristics in rats 10, 15 and 20 days old, and in adults breathing pure oxygen at normal atmospheric pressure for three hours. In the newborn rat, hyperoxemic NN was different in topography and cytopathology from that induced by hypoxia in the same animals. Hyperoxemic NN was similar to the NN described in human premature infants submitted to episodic hyperoxemia. Neuronal damage with karyorrhexis was most prominent in the subiculum of the hippocampus, thalamus, reticular nuclei of the brain stem and the granular cells of the cerebellum. Ultrastructural studies demonstrated nuclear and cytoplasmic membrane damage in neurons and the cellular accumulation of electron-dense lipid droplets. The pathogenesis of NN produced by hyperoxia in the human premature newborn infant may be related to lipid peroxidation of cell membranes such as that induced by oxygen-free radicals in other experimental and in vitro studies, when the anti-oxidant cellular defenses (mainly enzymes such as superoxide dismutase) are overwhelmed.

Cerebrovascular reserve in patients with carotid occlusive disease assessed by stable xenon-enhanced ct cerebral blood flow and transcranial Doppler.

BACKGROUND AND PURPOSE: Cerebrovascular reserve (CVR) by both transcranial Doppler ultrasonography (TCD) and quantitative cerebral blood flow (CBF) can identify subgroups of patients at increased risk for stroke. A direct comparison of CVR measurements obtained with both technologies in patients with cerebrovascular occlusive disease is lacking. METHODS: CVRs before and after acetazolamide administration (1 g IV) were measured by TCD insonation of the middle cerebral artery (MCA) and CBF obtained with stable xenon CT (Xe/CT) in 38 patients with carotid occlusive disease. Sensitivity/specificity calculations were based on 2 Xe/CT MCA values: an average over 4 levels and the level with the lowest percent change in CBF. Compromised CVR was defined as no reactivity or a decrease in reactivity. RESULTS: Using the analysis of the systolic TCD, we found that velocity changes compared with the average Xe/CT MCA CVR showed a sensitivity of 33%, specificity of 90.6%, positive predictive value of 54.5%, and negative predictive value of 80%. The sensitivity of TCD compared with the lowest Xe/CT CBF CVR was 35.5%, specificity and positive predictive values were 100%, and negative predictive value was 66.7%. The index of validity was between 72% and 76%. CONCLUSIONS: TCD is much less sensitive than Xe/CT CBF in identifying patients with compromised CVR. This may be a result of the inability of TCD to identify patients with compromised reserves when their MCA blood flow comes from collateral sources. The lack of correlation between TCD and Xe/CT CBF for identifying patients with compromised CVR should be considered when stroke risk assessments are made by TCD.

Mechanisms of cerebrovascular O2 sensitivity from hyperoxia to moderate hypoxia in the rat.

Cerebrovascular dilation over PaO2 ranging from hyperoxia to moderate hypoxia is unexplained. We hypothesize that tissue acidosis is the cause. Local cortical cerebral blood flow (LCBF), tissue hydrogen ion concentration [H+]t, and tissue PO2 (PtO2) were measured with microelectrodes in the parietal cortex of 18 rats during a 30-min steady state on 60 to 10% inspired O2 (PaO2, 300 to 40 torr) during 40% N2O analgesia. Five rats kept on 60% O2/40% N2O served as controls. In 18 rats at a PaO2 of 275 +/- 7 torr (mean +/- SEM) and PaCO2 of 35 +/- 1 torr, cerebral values were: LCBF = 129 +/- 23 (mean +/- SEM) ml.100 g-1.min-1; [H+]t = 62 +/- 6 nM; and PtO2 = 25 +/- 3 torr. As PaO2 was reduced from about 300 to 40 torr, changes in these variables in percentage of control with respect to PaO2, were described by the following equations, all at P less than 0.0001: LCBF = 85.9 + 5,572/Pao2; [H+]t = 97.15 + 1,012/PaO2; and PtO2 = 108.8 - 3,492/PaO2. Simultaneous solution of the LCBF and [H+]t equations at various PaO2 revealed a slope of 8.82%/nM. Direct correlation between LCBF in ml.100 g-1.min-1 and [H+]t in nM revealed a linear relationship defined by the equation Y = -7.472 + 1.6705X (r = 0.6426) for [H+]t between 56 and 160 nM (pH = 7.25 and 6.80) but no correlation at [H+]t values between 56 and 32 nM (pH = 7.25 to 7.50). Cerebrovascular tone is directly correlated with [H+]t during progressive, 30-min steady-state reduction in PaO2 from 350 to 40 torr.

Stable xenon does not increase intracranial pressure in primates with freeze-injury-induced intracranial hypertension.

Stable xenon (Xe)-enhanced computed tomography is a potentially valuable tool for high resolution, three-dimensional measurement of CBF in patients. However, reports that Xe causes cerebrovascular dilation and increases intracranial pressure (ICP) have tempered enthusiasm for its use. The effects of 5 min of 33% Xe inhalation on ICP (right and left hemispheres) were studied in eight fentanyl-anesthetized Rhesus monkeys after right-sided cortical freeze injury. ICP, CBF, and physiological variables were monitored for up to 6 h postinsult. The preinjury (control) right hemispheric ICP was 8 +/- 5 mm Hg (mean +/- SD) and left hemispheric ICP was 5 +/- 2 mm Hg. Postinjury observations were classified into low (less than 15 mm Hg) and high ICP (greater than or equal to 15 mm Hg) groups. Both right and left ICP values averaged 9 +/- 3 mm Hg in the low ICP group. In the high ICP group, the right ICP was 20 +/- 4 mm Hg and left ICP was 21 +/- 6 mm Hg. ICP was unchanged by Xe inhalation under control conditions as well as in both low and high ICP groups postinjury. Postinjury, the MABP decreased 10-15 mm Hg in the low ICP group and 10-17 mm Hg in the high ICP group 2-3 min after the start of Xe inhalation (p less than 0.05). These results show that 33% Xe inhalation does not increase ICP in fentanyl-anesthetized monkeys but could decrease MABP in stressed states, presumably because of the anesthetic effects of Xe.

Attenuation of brain free fatty acid liberation during global ischemia: a model for screening potential therapies for efficacy?

Whole brain free fatty acids (FFA) continue to rise appreciably even 1 h after decapitation, which may reflect the evolution of ischemic brain injury at least during global ischemia. If so, the attenuation of FFA liberation by various drugs may reflect their efficacy in ischemic brain injury. Rats were pretreated with either 0.9% NaCl (controls), ketamine, halothane, lofentanil, etomidate, Y-9179, R41-468, Innovar-Vet, pentobarbital, thiopental, or phenytoin and decapitated 15 to 30 min thereafter. The brains were kept normothermic for 10 min until they were frozen in liquid nitrogen. Whole brain FFAs were quantitated gy gas-liquid chromatography. After 10 min of ischemia in controls, total FFAs and arachidonic, stearic, oleic, and palmitic acids increased by 8- to 10-fold. The drugs, in order of decreasing effectiveness in attenuating FFA liberation, fell into the following three groups: (1) phenytoin, thiopental, pentobarbital, and Innovar-Vet; (2) R41-468, Y-9179, and etomidate; and (3) lofentanil, halothane and ketamine. The three groups reduced total FFAs by about 23%, 13%, and 8%, respectively. The effectiveness of drugs in attenuating FFA liberation appears to correlate with their efficacy in ischemic brain injury. However, a cause and effect relationship between FAA liberation and the evolution of ischemic brain injury must be established before accurate predictions of efficacy can be made by this method. The limitations of the proposed method of evaluation are discussed.

Cerebrovascular and cerebrometabolic effects of intracarotid infused platelet-activating factor in rats.

Platelet-activating factor has been implicated in a variety of disease processes including ischemic brain injury and endotoxic shock, but its effects on cerebral blood flow (CBF) and metabolism in normal brain have not been described. The effects of platelet-activating factor on global CBF (hydrogen clearance) and the global cerebral metabolic rate for oxygen (CMRO2) were studied in halothane-N2O anesthetized Wistar rats. Hexadecyl-platelet-activating factor infused into the right carotid artery (67 pmol/min) for 60 min decreased mean arterial pressure (MAP) from 122 +/- 4 (x +/- SEM) to 77 +/- 6 mm Hg and CBF from 159 +/- 12 to 116 +/- 14 ml/100 g/min (p less than 0.002). In contrast, CMRO2 increased from 9.7 +/- 0.9 to 11.7 +/- 1.1 ml/100 g/min after 15 min (p less than 0.05). In controls rendered similarly hypotensive by blood withdrawal and infused with the platelet-activating factor vehicle, CMRO2 was unchanged, whereas CBF transiently decreased then returned to baseline at 60 min. These cerebrovascular and cerebrometabolic effects of PAF are reminiscent of and may be relevant to hypoperfusion and hypermetabolism observed after global brain ischemia and in endotoxic shock.

Local cerebral blood flow measured by xenon-enhanced CT during cryogenic brain edema and intracranial hypertension in monkeys.

We developed a closed-skull model of freeze injury-induced brain edema, a model classically thought to produce vasogenic edema, and observed the natural course of changes in edema and blood flow using xenon-enhanced computed tomography (CT) in five rhesus monkeys before and for up to 6 h post insult. Intracranial pressure (ICP) gradually rose throughout the duration of the experiment. CT scans and CBF images permitted direct observation of the evolution of the lesion and revealed early ischemia in the periphery of the injury zone that progressed over time in association with edema. Frequency histogram analysis of local CBF (ICBF) demonstrated subtle but potentially important changes in distribution of ICBF between and within hemispheres at various times post insult. Changes in ICBF distribution were phasic and dissociated from increases in ICP in the latter stages of injury. The Xe/CT CBF method can be used to evaluate the effects of injury and therapy on CBF in this and other models of acute brain injury.

Uncoupled cerebral blood flow and metabolism after severe global ischemia in rats.

In a rat model of complete global brain ischemia (neck tourniquet) lasting either 3 min or 20 min, we monitored global CBF (sagittal sinus H2 clearance) and CMRO2 for 6 h to test the hypothesis that delayed postischemic hyperemia and uncoupling of CBF and CMRO2 occur depending on the severity of the insult. Early postischemic hyperemia occurred in both the 3-min and 20-min groups (p less than 0.05 vs. baseline values) and resolved by 15 min. Hypoperfusion occurred in the 3-min group between 15 and 60 min postischemia (approximately 23% reduction), and in the 20-min group from 15 to 120 min postischemia (approximately 50% reduction) (p less than 0.05), and then resolved. CMRO2 was not significantly different from baseline at any time after ischemia in the 3-min group. After 20 min of ischemia, however, CMRO2 was decreased (approximately 60%) throughout the postischemic period (p less than 0.05). At 5 min after ischemia, CBF/CMRO2 was increased in both groups but returned to baseline from 60 to 120 min postischemia. In the 3-min group, CBF/CMRO2 remained at baseline throughout the rest of the experiment. However, in the 20-min group, CBF/CMRO2 once again increased (approximately 100%), reaching a significant level at 180 min and remaining so for the rest of the 6-h period (p less than 0.05). These data demonstrate biphasic uncoupling of CBF and CMRO2 after severe (20 min) global ischemia in rats. This relatively early reemergence of CBF/CMRO2 uncoupling after 180 min of reperfusion is similar to that observed after prolonged cardiac arrest and resuscitation in humans.

Mechanisms of cerebrovascular dilation by ether in monkeys.

We hypothesized that when the depth of ether anesthesia is increased from 2 to 5%, cerebral vessels dilate secondary to circulating catecholamine stimulation of cerebral metabolism. Cerebral blood flow (CBF) by 133Xe clearance and cerebral metabolic rate for oxygen (CMRO2) were measured on 2% and then 5% ether in air in two groups of seven monkeys each during mechanical ventilation. Propranolol, 0.5 mg/kg i.v., was infused over 5 min in one group, and the other received saline. All measurements were repeated on 5% and 2% ether. Cerebrovascular resistance (CVR) fell by 30%, from 2.28 +/- 0.61 (mean +/- SD) to 1.51 +/- 0.28 mm Hg ml-1 100 g-1 min-1 (p less than 0.01), with the increase in ether from 2 to 5%. CBF and CMRO2 were unaltered from values of about 45 ml 100 g-1 min-1 and 2.3 ml 100 g-1 min-1, respectively. During 5% ether anesthesia, propranolol had no effect on CBF, CMRO2, or CVR. On 2% ether, it increased CVR twofold, from 1.5 +/- 0.30 to 3.0 +/- 1.0 mm Hg ml-1 100 g-1 min-1, and decreased CBF by 33%, from 48 +/- 8 to 32 +/- 10 ml 100 g-1 min-1. Plasma epinephrine was two-fold higher on 2% compared to 5% ether, both before and after saline or propranolol infusion. In monkeys, cerebrovascular dilation by ether at 5% compared to 2% is not secondary to catecholamine stimulation of CMRO2. It may result from a direct effect of either plasma catecholamines or ether on the cerebrovasculature.

Amelioration of brain damage after 12 minutes' cardiac arrest in dogs.

To determine the efficacy of cerebral microcirculation promoting therapy in postischemic brain failure, 11 dogs awakening from methohexital sodium anesthesia were subjected to 12 minutes of reversible circulatory arrest by ventricular fibrillation. Physiological variables were controlled for six hours after resuscitation, and the dogs were observed for seven days. Six dogs without the special postresuscitative therapy did not awaken, and either died within 36 hours or remained comatose for seven days. In five dogs, a combination of the following measures was applied: (1) mean arterial pressure was raised to 150 to 180 mm Hg with norepinephrine for six hours; (2) heparinization; (3) rapid intra-aortic injection of dextran 40 (10 ml/kg body weight); and (4) normovelemic hemodilution with dextran 40 to a hematocrit reading of 25% to 30%. All five treated dogs awakened within 24 hours and appeared normal on the seventh day. Therapy enhanced constriction of pupils and normalization of the electroencephalogram (P less than .05). Postischemic neurological deficit is at least partially due to impaired reperfusion and can be ameliorated or prevented by blood flowing-promoting therapy.

Hypothermic cardiopulmonary bypass alters oxygen/glucose uptake in the pediatric brain.

OBJECTIVES: Neurologic morbidity related to cardiac surgery has been recognized as a major morbidity. A variety of causes related to cardiopulmonary bypass, including microemboli, nonpulsatile flow, hemodilution, and inflammatory mediation, have been proposed. Because oxygen and glucose are the predominant metabolic substrates for the brain, we sought to examine the uptake of these substrates by the pediatric brain during hypothermic cardiopulmonary bypass. METHODS: Eleven children (median age 5 months, range 1 day-17 years) undergoing a variety of cardiac surgical procedures with the use of hypothermic cardiopulmonary bypass were studied. Cerebral arteriovenous differences for oxygen, glucose, and lactate were obtained before, during, and after bypass. On the basis of the predictable stoichiometric relationship for the oxidation of glucose, the relationship of substrate uptake was expressed as the oxygen/glucose index.Oxygen/glucose index (%) = (arteriovenous oxygen difference [micromol/mL]/arteriovenous glucose difference [micromol/mL] x 6) x 100 RESULTS: All children survived with no obvious neurologic sequelae. During cooling on cardiopulmonary bypass, the oxygen/glucose indexes fell significantly from prebypass values (53% +/- 19% at 28 degrees C and 54% +/- 25% at 24 degrees C vs 117% +/- 70%; P <.05, analysis of variance). This decline resulted from decreased oxygen uptake with stable glucose uptake (P <.05). Although oxygen and glucose uptake both increased with rewarming, the net effect was only a slight increase in oxygen/glucose index (62% +/- 16%). Postbypass oxygen/glucose index exceeded prebypass values (149% +/- 83%). CONCLUSIONS: Hypothermic cardiopulmonary bypass alters the relationship between oxygen and glucose uptake in the pediatric brain. The relationship of these findings to bypass-related neurologic morbidity remains to be explored.

Regional low-flow perfusion provides cerebral circulatory support during neonatal aortic arch reconstruction.

OBJECTIVE: Because of concerns regarding the effects of deep hypothermia and circulatory arrest on the neonatal brain, we have developed a technique of regional low-flow perfusion that provides cerebral circulatory support during neonatal aortic arch reconstruction. METHODS: We studied the effects of regional low-flow perfusion on cerebral oxygen saturation and blood volume as measured by near-infrared spectroscopy in 6 neonates who underwent aortic arch reconstruction and compared these effects with 6 children who underwent cardiac repair with deep hypothermia and circulatory arrest. RESULTS: All the children survived with no observed neurologic sequelae. Near-infrared spectroscopy documented significant decreases in both cerebral blood volume and oxygen saturations in children who underwent repair with deep hypothermia and circulatory arrest as compared with children with regional low-flow perfusion. Reacquisition of baseline cerebral blood volume and cerebral oxygen saturations were accomplished with a regional low-flow perfusion rate of 20 mL x kg(-1) x min(-1). CONCLUSIONS: Regional low-flow perfusion is a safe and simple bypass management technique that provides cerebral circulatory support during neonatal aortic arch reconstruction. The reduction of deep hypothermia and circulatory arrest time required may reduce the risk of cognitive and psychomotor deficits.