Brain metabolic correlates of hypoxic-ischemic cerebral necrosis in mid-gestational sheep fetuses: significance of hypotension

Mid-gestational sheep fetuses exposed to marked hypoxia for 2 h remain brain intact if MABP is maintained above 30 mm Hg. On the other hand, similarly hypoxic fetuses, if they experience reductions in MABP below 30 mm Hg, develop foci of necrosis that predominantly affect hemispheric white matter and neostriatum. Cortex damage is more restricted and is usually associated with more massive underlying white matter damage. The present study examines the brain metabolic basis for the important role of hypotension in brain injury development in marked hypoxia. Sheep fetuses rendered hypoxic by respiring their ewes with 11% oxygen (fetal PaO2 = 8-12 mm Hg) in which MABP was maintained above 30 mm Hg showed increases in brain lactic acid concentrations to 7-13 mumol/g but unaltered energy charge. In contrast, fetuses that sustained MABP reductions below 30 mm Hg showed increases in lactic acid concentrations in vulnerable structures to 16-24 mumol/g accompanied by marked decreases in energy charge. The vulnerable structures also showed reductions in fructose concentrations but a variable behavior of other brain metabolites including phosphocreatine, glycogen, and glucose. Thus, the present findings suggest a relation between hypotension during marked hypoxia, low energy charge, lactic acid accumulation in brain at high concentrations, and fetal brain injury. The ewes of hypoxic hypotensive fetuses received pentobarbital at lower doses than did those of fetuses that maintained blood pressure. This suggests that pentobarbital plays an important role in protecting the fetal brain from asphyxia by extending the hypoxic fetus's ability to maintain blood pressure in addition to reducing its brain metabolism.     

Hypoxic-ischemic cerebral necrosis in midgestational sheep fetuses: physiopathologic correlations

Thirty-eight midgestational sheep fetuses were exposed 120 min to marked hypoxia. The brains in eight that reduced their mean arterial blood pressure to less than 30 mm Hg were markedly damaged. In these same fetuses the serum lactic acid concentrations were elevated during exposure to hypoxia to excessively high values (greater than 15 mM) and remained elevated for a prolonged period during recovery. Twenty-one fetuses exposed to the same magnitude of hypoxia that maintained their blood pressure unchanged showed less marked elevations of serum lactate concentrations and remained brain-intact. Greater quantities of pentobarbital administered to the ewes during hypoxia seemed to protect the brain from hypoxia and this effect was dose-dependent. Exposure of midgestational sheep fetuses to marked hypoxia associated with reductions in cerebral blood flow due to decreased blood pressure and impaired cerebral autoregulation caused major focal cerebral necrosis.     

Common carotid artery stump pressure in the gerbil stroke model.

In 106 slightly anaesthetised adult mongolian gerbils one common carotid artery (CCA) was ligated and the blood pressure in the distal and in the proximal stump was monitored for 8 minutes. The mean distal CCA stump pressure of the 39 nonsurvivors was 15 (+/- 6) mm Hg, that of the 25 survivors with retinocerebral infarcts was 25 (+/- 6) mm Hg, and that of the 42 intact survivors was 31 (+/- 7) mm Hg. The corresponding mean arterial blood pressures (MABP), as measured in the proximal CCA stump, were 81 (+/- 12) mm Hg, 84 (+/- 13) mm Hg, and 87 (+/- 11) mm Hg, respectively. There were no differences between the samples concerning sex, body weight, rectal temperature, arterial blood gases, arterial pH, and haematocrit. Measurements in a second series of 10 awake gerbils showed that the mean values of MABP, heart rate, and respiratory rate of the nonsurvivors were less than those of the survivors during 90 minutes after CCA ligation. It is inferred that in the mongolian gerbil the lower threshold of the arterial blood pressure for the development of brain infarcts ranges within 22 and 25 mm Hg, that is, within the values found in monkeys and cats. The longlasting depression of respiration and circulation in the nonsurvivors is considered to be related to the phenomenon of diaschisis .     

Increases in oxygen consumption without cerebral blood volume change during visual stimulation under hypotension condition.

The magnitude of the blood oxygenation level-dependent (BOLD) signal depends on cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2). Thus, it is difficult to separate CMRO2 changes from CBF and CBV changes. To detect the BOLD signal changes induced only by CMRO2 responses without significant evoked CBF and CBV changes, BOLD and CBV functional magnetic resonance imaging (fMRI) responses to visual stimulation were measured under normal and hypotension conditions in isoflurane-anesthetized cats at 4.7 T. When the mean arterial blood pressure (MABP) decreased from 89+/-10 to 50+/-1 mm Hg (mean+/-standard deviation, n=5) by infusion of vasodilator sodium nitroprusside, baseline CBV in the visual cortex increased by 28.4%+/-8.3%. The neural activity-evoked CBV increase in the visual cortex was 10.8%+/-3.9% at normal MABP, but was negligible at hypotension. Positive BOLD changes of +1.8%+/-0.5% (gradient echo time=25 ms) at normal MABP condition became prolonged negative changes of -1.2%+/-0.3% at hypotension. The negative BOLD response at hypotension starts approximately 1 sec earlier than positive BOLD response, but similar to CBV change at normal MABP condition. Our finding shows that the negative BOLD signals in an absence of CBV changes are indicative of an increase in CMRO2. The vasodilator-induced hypotension model simplifies the physiological source of the BOLD fMRI signals, providing an insight into spatial and temporal CMRO2 changes.     

Brain interstitial adenosine and sagittal sinus blood flow during systemic hypotension in piglet

We sampled, using the brain dialysis technique, interstitial fluid adenosine from the frontal cortex of newborn piglets subjected to hemorrhagic hypotension while measuring sagittal sinus blood flow, cerebrovascular resistance (CVR), and cerebral O2 delivery. In group 1 (n = 8), MABP was reduced in successive steps from 76 to 30 mm Hg with decrements of approximately 10 mm Hg. At 60 mm Hg, CVR decreased by 19% (p less than 0.001), but sagittal sinus blood flow and interstitial fluid adenosine remained unchanged. At 50 mm Hg, both sagittal sinus blood flow and CVR decreased by 19% (p less than 0.001) and interstitial fluid adenosine rose 4.7-fold (p less than 0.05). At 40 and 30 mm Hg, sagittal sinus blood flow decreased further but CVR remained steady, whereas interstitial fluid adenosine rose 10- and 16-fold, respectively. In group 2 (n = 7), an abrupt reduction of MABP from 80 to 47 mm Hg produced no change in sagittal sinus blood flow and a 29% decrease in CVR (p less than 0.01). Interstitial fluid adenosine increased twofold (p less than 0.01). In group 3 (n = 7), an abrupt reduction of MABP from 79 to 40 mm Hg decreased sagittal sinus blood flow and CVR by 24 and 30%, respectively (p less than 0.01). Interstitial fluid adenosine rose threefold (p less than 0.01). In groups 1, 2, and 3, the increases in interstitial fluid adenosine accompanied decreases in cerebral O2 delivery. In group 4 (n = 7), artificial CSF with a PO2 of 152 mm Hg was perfused through the brain dialysis cannula during graded hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of combined hypoxemia and cephalic hypotension on fetal cerebral blood flow and metabolism

The effect of hypoxemia and cephalic hypotension, alone and in combination, on hemispherical CBF and metabolism was examined in seven chronically catheterized fetal sheep. Hypoxemia was induced by lowering the maternal inspired oxygen fraction and cephalic hypotension was generated by partial occlusion of the fetal brachiocephalic artery. CBF was measured with radionuclide-labeled microspheres. During control, the arterial blood oxygen content (CaO2) was 3.2 +/- 1.0 (SD) mM and CBF averaged 131 +/- 21 (SD) ml min-1 100 g-1. The cephalic perfusion pressure (PP, mean cephalic arterial-sagittal venous) was 40 +/- 4 mm Hg and cerebral vascular resistance (CVR, PP/CBF) was 0.31 +/- 0.06 mm Hg ml-1 min 100 g. During induced hypoxemia, CaO2 was 1.4 +/- 0.7 mM and CBF was elevated to 223 +/- 60 ml min-1 100 g-1. PP was not different from control and CVR was lower at 0.19 +/- 0.04 mm Hg ml-1 min 100 g, reflecting cerebral vasodilation. With cephalic hypotension alone (PP = 21 +/- 4 mm Hg; CaO2 = 3.4 +/- 0.9 mM), CBF fell to 83 +/- 23 ml min-1 100 g-1 and there was no significant change in CVR (0.26 +/- 0.05 mm Hg ml-1 min 100 g). During combined hypoxemia and hypotension (CaO2 = 1.5 +/- 0.8 mM and PP = 18 +/- 4 mm Hg), CBF was significantly greater than during hypotension alone (100 +/- 6 ml min-1 100 g). CVR was 0.19 +/- 0.05 mm Hg ml-1 min 100 g, identical to that measured in normotensive hypoxemia and significantly less than found during hypotension alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral carbohydrate metabolism during severe ischemia in fetal sheep

The effect of cephalic hypotension on brain metabolism was studied in 10 unanesthetized, normoxic (PaO2 greater than 17 mm Hg), late-gestation fetal lambs. Perfusion pressure (cephalic arterial minus sagittal venous pressure) was 40 +/- 1 mm Hg (SEM) during control and was reduced to 10 +/- 1 by occlusion of the Grachio-cephalic artery. Cerebral blood flow was measured with microspheres, and arterial and sagittal vein blood samples were analyzed for oxygen content, glucose, and lactate. During the occlusion, oxygen consumption decreased from 125 +/- 8 to 95 +/- 4 (p less than 0.05) (all values mumol 100 g-1 min-1), and glucose uptake increased from 20 +/- 3 to 25 +/- 1 (p less than 0.05). During the control period, there was no net lactate flux; during the occlusion, lactate excretion was 5.7 +/- 1.4 (p less than 0.005). The control glucose and oxygen uptakes demonstrated a normal 6:1 molar ratio; however, during the occlusion, 9.4 mumol 100 g-1 glucose min-1 were taken up in excess of expected aerobic glucose metabolism. If all of this glucose were anaerobically metabolized to lactate, three times the measured efflux would be produced. The transport properties of the fetal blood-brain barrier may be important factors in perinatal brain injury.     

Hemorrhagic infarct induced by arterial hypertension in cat brain following middle cerebral artery occlusion

The purpose of this experiment was to determine whether an acute rise in brain perfusion pressure causes hemorrhagic transformation of an infarct without a reopening of the occluded artery. We raised the blood pressure of 22 cats by aortic obstruction 5-24 hours after transorbital middle cerebral artery clipping; hemorrhagic infarcts were induced in 11. Mean arterial blood pressure increased by 57.2 +/- 16.9 mm Hg (mean +/- SD) in the 11 cats with hemorrhagic infarcts and by 40.4 +/- 16.9 mm Hg in the 11 remaining cats with pale brain infarcts (p less than 0.05). Induction of hypertension increased regional cerebral blood flow in the ischemic cortical gray matter more in three cats with hemorrhagic infarcts than in seven with pale infarcts. Our results demonstrate that hemorrhagic transformation of an infarct can be induced by a rapid increase in perfusion pressure to brain tissue already exposed to focal ischemia. We also suggest that the restoration of blood flow through leptomeningeal collaterals plays an important role in the pathogenesis of hemorrhagic infarction in cases without reopening of occluded arteries.     

Prostanoids determine the range of cerebral blood flow autoregulation of newborn piglets

To assess whether prostanoids have a role in setting the blood pressure limits of cerebral blood flow autoregulation in newborn animals, we measured cerebral blood flow and prostanoid concentrations in blood from the sagittal sinus over a wide range of mean systemic blood pressures (17-117 mm Hg) in eight newborn piglets treated with 30 mg/kg i.v. ibuprofen and in eight vehicle-treated piglets. Blood pressure was adjusted by inflating balloon-tipped catheters placed at the aortic isthmus and root to induce hypertension and hypotension, respectively, 80 minutes apart in each piglet. Cerebral blood flow and concentrations of prostaglandins E and F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2 in blood from the sagittal sinus and left subclavian artery were measured 20 minutes before (baseline) and during each blood pressure adjustment. In vehicle-treated piglets, cerebral blood flow was constant at blood pressures between 50 and 90 mm Hg (r = 0.06, p = 0.85). When blood pressure was reduced to less than 50 mm Hg, thromboxane B2 concentration in the sagittal sinus increased by 597 +/- 42% and concentrations of the prostaglandins increased by an average of 308 +/- 45% (p less than 0.05). When blood pressure was raised to greater than 90 mm Hg, concentrations of the prostaglandins increased by an average of 46 +/- 11%, with no change in the concentration of thromboxane B2. Treatment with ibuprofen reduced the baseline concentrations of all prostanoids and prevented their changing during hypotension and hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebrovascular effects of sodium nitroprusside in the anaesthetized baboon: a positron emission tomographic study.

The effects of sodium nitroprusside (SNP), a potent hypotensive agent, on cerebral blood flow (CBF) have been extensively studied in clinical and experimental situations but the results remain controversial. Whereas its properties would predict a dilatation of cerebral blood vessels, most studies report either no change or a decrease in CBF. The aim of this study was to investigate the effects of SNP on CBF, cerebral blood volume (CBV), and cerebral oxygen metabolism (CMRO2), by means of positron emission tomography in the anaesthetized baboon. Measurements were performed during normotension (mean arterial pressure (MABP): 97+/-16 mm Hg) and repeated following SNP-induced hypotension (MABP: 44+/-9 mm Hg). Sodium nitroprusside led to an increase in CBF and CBV (+30% and +37%, respectively, P<0.05), whereas no change in CMRO2 was noted. Linear regression analysis of CBF values as a function of MABP confirmed that CBF increases when MABP is reduced by SNP. The comparison between these cerebrovascular changes and those found during trimetaphan-induced hypotension in our previously published studies further argues for a direct dilatatory effect of SNP on cerebral blood vessels.     

Delayed hemorrhagic hypotension exacerbates the hemodynamic and histopathologic consequences of traumatic brain injury in rats.

Alterations in cerebral autoregulation and cerebrovascular reactivity after traumatic brain injury (TBI) may increase the susceptibility of the brain to secondary insults, including arterial hypotension. The purpose of this study was to evaluate the consequences of mild hemorrhagic hypotension on hemodynamic and histopathologic outcome after TBI. Intubated, anesthetized male rats were subjected to moderate (1.94 to 2.18 atm) parasagittal fluid-percussion (FP) brain injury. After TBI, animals were exposed to either normotension (group 1: TBI alone, n = 6) or hypotension (group 2: TBI + hypotension, n = 6). Moderate hypotension (60 mm Hg/30 min) was induced 5 minutes after TBI or sham procedures by hemorrhage. Sham-operated controls (group 3, n = 7) underwent an induced hypotensive period, whereas normotensive controls (group 4, n = 4) did not. For measuring regional cerebral blood flow (rCBF), radiolabeled microspheres were injected before, 20 minutes after, and 60 minutes after TBI (n = 23). For quantitative histopathologic evaluation, separate groups of animals were perfusion-fixed 3 days after TBI (n = 22). At 20 minutes after TBI, rCBF was bilaterally reduced by 57% +/- 6% and 48% +/- 11% in cortical and subcortical brain regions, respectively, under normotensive conditions. Compared with normotensive TBI rats, hemodynamic depression was significantly greater with induced hypotension in the histopathologically vulnerable (P1) posterior parietal cortex (P < 0.01). Secondary hypotension also increased contusion area at specific bregma levels compared with normotensive TBI rats (P < 0.05), as well as overall contusion volume (0.96 +/- 0.46 mm(3) vs. 2.02 +/- 0.51 mm(3), mean +/- SD, P < 0.05). These findings demonstrate that mild hemorrhagic hypotension after FP injury worsens local histopathologic outcome, possibly through vascular mechanisms.     

Cerebral blood flow and tissue oxygen saturation in immediate and progressive ischemia in rat brain.

The aim of the present study was to investigate whether immediate ischemia is more harmful to the brain than progressive ischemia. To do so, we examined the correlation between the degree and the process of ischemia using hypobaric hypotension technique, which was used to reduce systemic blood pressure acutely or progressively below the lower threshold of CBF regulation, in rat brain. In Wistar rats (n = 21), global ischemia using bilateral carotid arteries occlusion coupled with hypobaric hypotension was induced by lowering mean arterial blood pressure (MABP) progressively to 55, 45 and 35 mmHg or immediately to 35 mm Hg. Local cerebral blood flow (ICBF) by laser Doppler (LD) flowmetry and tissue hemoglobin oxygen saturation (HbSO2) by a microspectrophotometric method were measured at 25 corresponding locations using a 'scanning' technique which employs a computer-controlled micromanipulator. Regional CBF (rCBF) and rHbSO2 were determined by calculation of the median value from the 25 ICBF and IHbSO2 data. In the 'progressive' group, rCBF and rHbSO2 decreased gradually and reached 12.2 +/- 15.8 LD-units and 44.9% +/- 13.4% at 35 mm Hg of MABP, respectively. In the 'immediate' group, both parameters dropped suddenly to 7.86 +/- 10.6 LD-units (p < 0.01 vs. CBF of the progressive group) and 22.5% +/- 15.5% (p < 0.001 vs. tissue HbSO2 of the progressive group) from the control at 35 mmHg. These data suggested that cerebral ischemia is better tolerated if it is induced gradually. CBF recorded by LD-scanning technique and HbSO2 value by microspectrophotometric method correlated well in the ischemic condition, indicating that HbSO2 can be preserved if CBF is decreased gradually.     

Comparative study on pathogenesis of selective cerebral lesions in carbon monoxide poisoning and nitrogen hypoxia in cats

Summary Since in a previous study hypoxia and subsequent hypotension were considered to be essential for the pathogenesis of carbon monoxide encephalopathy (CO-encephalopathy), experiments were conducted to see whether a combination of nitrogen hypoxia and subsequent systemic hypotension of similar degree and duration as in the previous experimental CO poisoning could induce the same lesion in the CNS of cats. The partial pressure of blood oxygen was reduced to less than 26 mm Hg by increasing the concentration of nitrogen in N₂/O₂ gas to be inhaled in 1.5 h and then the aortic blood pressure (BP) was reduced to 60–80 mm Hg by blood depletion and ganglion-blockage for 1 h. In 11 of the 15 cats, lesions were produced in the CNS which were similar by light and electron microscopy to those in CO-encephalopathy. In control groups which were treated by hypoxemia only, hypotension only or a combination of CO₂-gas inhalation and hypotension without hypoxemia, such lesions were not found in the cerebral white matter.Considering the pathogenesis of lesions in the cerebral white matter in both nitrogen hypoxia and CO-poisoning, two factors, i.e., hypoxemia and subsequent systemic hypotension, are common and essential. Further, the enormous vasodilation in the cerebral white matter induced by hypoxemia and subsequent drop in BP seem to cause a more severe circulatory disturbance in the cerebral white matter than in the cortex.Supported by the Nissan Science Foundation     

Hypoxia, hyperoxia, ischemia, and brain necrosis

BACKGROUND: Human brains show widespread necrosis when death occurs after coma due to cardiac arrest, but not after hypoxic coma. It is unclear whether hypoxia alone can cause brain damage without ischemia. The relationship of blood oxygenation and vascular occlusion to brain necrosis is also incompletely defined. METHODS: We used physiologically monitored Wistar rats to explore the relationship among arterial blood oxygen levels, ischemia, and brain necrosis. Hypoxia alone (PaO2 = 25 mm Hg), even at a blood pressure (BP) of 30 mm Hg for 15 minutes, yielded no necrotic neurons. Ischemia alone (unilateral carotid ligation) caused necrosis in 4 of 12 rats, despite a PaO2 > 100 mm Hg. To reveal interactive effects of hypoxia and ischemia, groups were studied with finely graded levels of hypoxia at a fixed BP, and with controlled variation in BP at fixed PaO2. In separate series, focal ischemic stroke was mimicked with transient middle cerebral artery (MCA) occlusion, and the effect of low, normal, and high PaO2 was studied. RESULTS: Quantitated neuropathology worsened with every 10 mm Hg decrement in BP, but the effect of altering PaO2 by 10 mm Hg was not as great, nor as consistent. Autoradiographic study of cerebral blood flow with 14C-iodoantipyrine revealed no hypoxic vasodilatation during ischemia. In the MCA occlusion model, milder hypoxia than in the first series (PaO2 = 46.5 +/- 1.4 mm Hg) exacerbated necrosis to 24.3 +/- 4.7% of the hemisphere from 16.6 +/- 7.0% with normoxia (PaO2 = 120.5 +/- 4.1 mm Hg), whereas hyperoxia (PaO2 = 213.9 +/- 5.8 mm Hg) mitigated hemispheric damage to 7.50 +/- 1.86%. Cortical damage was strikingly sensitive to arterial PaO2, being 12.8 +/- 3.1% of the hemisphere with hypoxia, 7.97 +/-4.63% with normoxia, and only 0.3 +/- 0.2% of the hemisphere with hyperoxia (p < 0.01), and necrosis being eliminated completely in 8 of 10 animals. CONCLUSIONS: Hypoxia without ischemia does not cause brain necrosis but hypoxia exacerbates ischemic necrosis. Hyperoxia potently mitigates brain damage in this MCA occlusion model, especially in neocortex.     

Preservation of single-flash visual evoked potentials at very low cerebral oxygen delivery in preterm infants

Single-flash visual evoked potentials (VEPs) were recorded in 32 preterm infants (mean gestational age: 29 weeks) during extreme physiologic conditions within the first day of life. The VEP configuration was normal in all patients at the onset of the investigation. Hypoxic episodes (PaO2 less than 3 kPa) caused rapid and consistent attenuation of the VEP mostly with an instantaneous recovery after normalization of PaO2. In contrast, VEP amplitude and latency were unaffected during episodes with low cerebral blood flow (4.5 ml/100 gm/min) and correspondingly low oxygen delivery to the brain (1 ml/100 gm/min), severe hypocapnia (PaCO2 1.6 kPa), and severe arterial hypotension (MABP 10 mm Hg), provided that the arterial oxygen tension was greater than 5 kPa. Absence of N1 was observed soon after the development of severe intracranial hemorrhage; however, this abnormality was short in duration. We conclude that the neurons generating VEPs are supported sufficiently during extreme physiologic episodes, except during severe hypoxia. The recovery time may be proportional to the cerebral insult.     

Attenuated pressor responses to amino acids in the rostral ventrolateral medulla after swimming training in conscious rats

The cardiovascular effects of microinjection of the amino acids glutamate and glycine within the rostral ventrolateral medulla (RVLM) after swimming training (ST) in unrestrained awake rats were investigated. Unilateral microinjection of l-glutamate (5, 20 and 50 mM, in 100 nl) produced a dose dependent increase in mean arterial pressure (MAP) in control (C) (16+/-5 mm Hg; 29+/-6 mm Hg; 43+/-6 mm Hg) and swim (SW) (1+/-1 mm Hg; 16+/-2 mm Hg; 25+/-3 mm Hg) groups. However, the magnitude of this response was lower in the swim group. Prazosin injection produced hypotension and tachycardia in both groups (C=-43+/-3 mm Hg/98+/-16 bpm; SW=-61+/-5 mm Hg/115+/-32 bpm). In the SW group the hypotension caused by prazosin was greater compared to C group, but the tachycardia was not different between them. After prazosin, glutamate response in RVLM was blocked in both groups as well. When glycine (10 mM or 1 M, in 100 nl) were microinjected into the RVLM of C group we observed two different effects: decrease in MAP with the lower dose and an increase in MAP with the higher dose (10 mM=-13+/-2 mm Hg; 1 M=47+/-6 mm Hg). However, after ST the hypertensive response to glycine was blunted with no alterations in the hypotensive response (10 mM=-14+/-1 mm Hg; 1 M=18+/-4 mm Hg). These findings suggest that RVLM is involved in the modulation of the sympathetic outflow to the cardiovascular system during exercise training.     

Quantitative measurement of blood flow velocity in feline pial arteries during hemorrhagic hypotension and hypercapnia

Due to methodologic difficulties, few investigations have been made on the blood flow velocity in the cerebral microcirculation. Using a newly developed video camera method, we simultaneously measured the blood flow velocity and diameter of pial arteries during hemorrhagic hypotension, after blood pressure recovery, and during CO2 inhalation in cats. When the mean arterial blood pressure was lowered from 129.7 +/- 6.6 to 71.5 +/- 4.1 mm Hg, the blood flow velocity inevitably decreased from 36.6 +/- 5.3 to 27.0 +/- 3.9 mm/sec (p less than 0.001). The calculated blood flow rate [pi X (diameter/2)2 X flow velocity] was preserved in cases with concomitant vasodilation. Conversely, the blood flow velocity increased from 25.3 +/- 5.1 to 31.0 +/- 5.4 mm/sec (p less than 0.001) after mean arterial blood pressure recovery from 67.1 +/- 3.7 to 129.8 +/- 5.8 mm Hg. The blood flow rate was again preserved in vessels with a vasoconstrictive response. Each pial artery apparently dilated or constricted in proportion to the decrease or increase in flow velocity during blood pressure changes, maintaining a constant cerebral blood flow. This indicated the importance of the pial arteries in the mechanisms of cerebral blood flow autoregulation. During 5% CO2 inhalation, the blood flow velocity increased markedly from 25.4 +/- 4.6 to 37.2 +/- 10.0 mm/sec (p less than 0.05), while the pial artery diameter (85.0 +/- 13.7 microns) increased by 9.6 +/- 1.5% (p less than 0.01). The increased flow velocity might be attributable to preferential dilatation of small arterioles or intraparenchymal vessels during hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Response of the cerebral circulation to profound hypocarbia in neonatal lambs

Hyperventilation to extremely low arterial carbon dioxide tension (PaCO2) has been used in the management of persistent pulmonary hypertension in newborn infants. With progressive hypocarbia, cerebral vasoconstriction occurs, raising the concern that extreme hypocarbia may result in cerebral oxygen deprivation. Therefore, I evaluated regulation of the cerebral circulation during acute hypocarbia in 10 newborn lambs. Whole-brain and regional blood flows measured using radioactive microspheres, arterial and venous (sagittal sinus) blood gases, and oxygen contents were measured in each lamb at four arterial carbon dioxide tensions. Whole-brain oxygen delivery, oxygen consumption, and fractional oxygen extraction were calculated. Finally, arterial and venous lactate concentrations were measured to assess cerebral lactate production. Whole-brain blood flow (CBF) decreased in a nonlinear fashion as PaCO2 ranged from 46 to 12 mm Hg [In(CBF) = 0.025(PaCO2) + 3.38; r = 0.70, p less than 0.001]. Similar responses were demonstrated for all regional blood flows examined. Cerebral fractional oxygen extraction (E) increased in a nonlinear fashion [In(1-E) = 0.023(PaCO2)-1.37; r = 0.80, p less than 0.001], and cerebral metabolic rate for oxygen was unchanged with hypocarbia. Cerebral venous lactate concentration increased significantly (3.49 +/- 0.23 vs. 2.01 +/- 0.22 mM, p less than 0.001) during severe hypocarbia (PaCO2 of less than 22 mm Hg), and the arterial-venous lactate concentration difference became negative. These results demonstrate uniform responses of whole-brain and regional blood flows and stable cerebral oxygen consumption during moderate and severe hypocarbia. Although there is evidence for cerebral lactate production during severe hypocarbia, this is not likely to indicate cerebral hypoxia as oxygen consumption does not change.     

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.     

A study of experimental cyanide encephalopathy in the acute phase —Physiological and neuropathological correlation

Summary A study was performed to elucidate the significance of various physiological factors contributing to the pathogenesis of experimental cyanide encephalopathy, such as the systemic arterial blood pressure, venous pressure, common carotid blood flow and local blood flow of the cerebral grey and white matters, and blood gas including pH. The histology and topography of the brain damage was also analysed. Twenty-one cats were divided into four groups. The animals in groups 1, 2 and 3 were subjected to continuous infusion of 0.2% sodium cyanide solution and to the ensuing hypotension below 100 mm Hg by administering a ganglion-blocking drug and by respiratory arrest. Severe damage developed in the deep cerebral white matter, corpus callosum, pallidum and substantia nigra, but the damage of the cerebral cortex and hippocampus was not remarkable. The animals in group 4 that were subjected to cyanide infusion without significant hypotension (above 100 mm Hg), but to the same degree of acidosis as that of the the other groups, had similar morphological changes, but to a lesser degree. On the basis of our physiological and morphological findings, we speculated that the pathophysiological factors of tissue hypoxia and subsequent hypotension operated in cyanide leucoencephalopathy. The topographic selectivity seemed to be related to the characteristic cerebral vascular system, and the severity of the white matter lesions was related to the intensity of both hypoxia and hypotension during cyanide infusion, but not to the extent of acidosis, total dose of cyanide or duration of its infusion per se.Supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (No. 58770280)