Concomitant EEG, lactate, and phosphorus changes by 1H and 31P NMR spectroscopy during repeated brief cerebral ischemia.

Pilots of high-performance aircraft are subject to transient loss of consciousness due to cerebral ischemia resulting from sudden high gravitational stress. To assess the effects of gravitational stress-induced blackout on cerebral metabolism and electrical function, we developed an animal model in which global cerebral ischemia is produced repeatedly at short intervals. Rats were prepared by ligation of subclavian and external carotid arteries and the right carotid artery was cannulated bidirectionally to measure circle of Willis and systemic pressures. Ischemia was induced by inflation of an occluder about the left carotid artery. Interleaved 31P and 1H NMR spectra were acquired on a 4.7-T Biospec system simultaneously with EEG recordings. We report results from 20 experiments of 30-min duration in which rats were subject to 30 1-min ischemia:reflow cycles of 10I:50R, 20I:40R, 30I:30R, and 40I:20R [numbers are seconds of ischemia (I) and reflow (R) during each 1-min cycle]. During ischemia the graded delivery of the ischemic insult permitted direct correlations between 2- to 5- and 7- to 20-Hz EEG activity and progressive changes in pH, lactate, ATP, phosphocreatine (PCr) and Pi. The best correlations were found between EEG activity and pH and PCr; correlation coefficients ranged from 0.93 to 0.95. A loss of EEG activity was observed without significant sustained energy loss in all but the most severe cycle.

Evaluation of lactate production and clearance kinetics by 1H NMR in a model of brief repetitive cerebral ischemia.

Pilots of high-performance aircraft are subject to repeated transient cerebral ischemia during high-gravitational stress maneuvers. Previously we have demonstrated that repeated episodes of transient cerebral ischemia and reflow are cumulative and lactate accumulations appear to be exponential. To evaluate the metabolic events determining the kinetics of lactate accumulation, and therefore the rates of substrate utilization, we have used in vivo 1H nuclear magnetic resonance with a 5-s time resolution to measure lactate production and clearance. The individual rates for each animal were then used to predict the accumulation of lactate in the same animal during 30 episodes of ischemia and reflow. Lactate accumulation was modeled as the balance between a zero-order production process during the ischemic period and a first-order clearance process. The predicted lactate accumulation showed excellent agreement with the observed time course, validating the predictive power of the simple model used. The highly reproducible nature of this model and its accuracy in predicting lactate accumulation should enable more accurate studies of the deleterious effects of lactate accumulation in cerebral ischemia by providing a highly reproducible means for generating a specific level of lactate accumulation.

ATP and pH predictors of histologic damage following global cerebral ischemia in the rat.

In vivo changes of high energy phosphates and pH were determined with 31P NMR spectroscopy in rats subjected to symmetric or asymmetric partial global ischemia with reperfusion. Tissue damage was assessed by histology. ATP depletion, following PCr depletion, developed shortly after the onset of ischemia. In prolonged ischemia reperfusion was not followed with full recovery. APT depletion of more than 20% during reperfusion was associated with histologic damage; marked necrosis was associated with 50% reduction. Although during ischemia, severe persisting intracellular acidosis developed sometimes, and it was also associated with tissue damage, it did not appear to elicit tissue damage independently of the ATP depletion. Splitting of the Pi peak was useful in predicting heterogeneous distribution of the necrosis, thus it can reflect a heterogeneous distribution of the intracellular pH.

Middle cerebral artery transcranial Doppler velocity monitoring during orthotopic liver transplantation: changes at reperfusion--a report of six cases.

STUDY OBJECTIVE: To determine the effect of reperfusion of the grafted liver on transcranial Doppler blood flow velocity in the middle cerebral artery in humans during orthotopic liver transplantation. DESIGN: Clinical study. SETTING: University hospital. PATIENTS: 6 patients scheduled for orthotopic liver transplantation. INTERVENTIONS: Middle cerebral artery blood flow velocity (MCAVm) was monitored continuously using a transcranial Doppler (TCD) probe. The TCD measurements were noninvasive. MEASUREMENTS AND MAIN RESULTS: The EME TC2000S TCD probe (Nicolet, Inc., Memphis, TN) was secured to the head using a strap providing continuous measurement of MCAVm. All other data were recorded by a patient monitoring system and a respiratory gas analyzer. Averaged MCAVm increased significantly in 5 of 6 patients (p < 0.001) when pre-reperfusion and post-reperfusion values were compared. Maximum post-reperfusion values for MCAVm, pulsatility index (PI), and systolic Doppler velocity (Vs) were greater than the corresponding immediate pre-reperfusion values (p < 0.05, p < 0.05, and p < 0.001, respectively). The increases in MCAVm cannot be explained on the basis of hypercarbia alone and were observed in the presence of systemic arterial hypotension and abrupt increases in central venous pressure, particularly at the time of graft reperfusion. CONCLUSIONS: MCAVm increased with reperfusion of the grafted liver. These data suggest that multiple factors--including hypercarbia, lactic acidosis, or multiple vasoactive substances released by the grafted liver--may contribute to the observed increases in MCAVm, Vs, and PI.

A mathematical model of the intracerebral steal phenomenon in regional and focal ischaemia.

The objective of the present work was to mathematically estimate the extent and dynamics of intracerebral steal which may occur in response to cerebral vasodilation in regional and focal cerebral ischaemia. To this end, a spatially distributed mathematical model of regional cerebral blood flow (rCBF) was developed. The model contained a parallel system of intracerebral vascular resistances which were connected in series to a lumped extracerebral artery resistance and, for the focal ischaemia model, also a lumped pial collateral resistance. The rCBF was measured at 30 min of ischaemia in the following models: (1) bilateral carotid occlusion in spontaneously hypertensive rats (SHR), and (2) occlusion of the middle cerebral artery (MCA) in normotensive rats. The measured 3-dimensional rCBF data were used to set up the initial values of intracerebral resistance components. Cerebral vasodilation induced by inhalation of CO2 was simulated in the model by decreasing the values of both intracerebral and collateral resistance. Vascular responsiveness was specified to decrease with the ischaemic rCBF. In addition, a long term change in rCBF and resistance distribution was introduced to account for: (1) gradual rise in intracerebral resistance due to ischaemic oedema, and (2) adaptive decrease in collateral resistance. The following were predicted by the mathematical model. (1) At 60% maximum intracerebral dilatation a small intracerebral steal (5-10%) occurs at flow levels below 30-50 ml/100 g/min in both ischaemic models. (2) In focal ischaemia, the steal can be compensated by the 5% to 20% decrease in the collateral vascular resistance. (3) The rate of collateral adaptation overcomes the rate of intracerebral resistance rise and, therefore, eliminates the intracerebral steal after an adequately long period of time (on the order of a few hours). (4) An inverse steal effect can be demonstrated at the end of vasodilatation, provided that the time constant of collateral adaptation selected is longer (about 5:1) than the time constant of the intracerebral resistance rise. We conclude that the prediction of rCBF response to vasodilatation in cerebral ischaemia requires a knowledge of resting rCBF and of the response characteristics of both intracerebral and pial arterial segments.

Risks and benefits of shunting in carotid endarterectomy. The International Transcranial Doppler Collaborators.

BACKGROUND AND PURPOSE: Controversy continues about the pathogenesis of perioperative stroke in carotid endarterectomy and the use of shunting. The purpose of this study was to determine, using transcranial Doppler ultrasonography, the severity of ischemia during clamping of the carotid artery as a basis for analysis of complications in patients operated on with and without shunting. METHODS: In a retrospective study, 11 centers contributed 1,495 carotid endarterectomies monitored with transcranial Doppler. The cases were divided into groups with severe, mild, and no ischemia, and each group was subdivided according to shunt use. The perioperative rate of severe stroke attributable to intraoperative ischemia, in addition to total perioperative stroke, was determined for each subgroup. RESULTS: Severe ischemia occurred in 7.2% of our cases but cleared spontaneously in about half of these. In those with persisting ischemia the rate of severe stroke was very high, while shunting protected against stroke in such cases. If ischemia did not occur, the stroke rate was higher with shunting, although not so high as in unshunted cases with severe ischemia. Slightly more than one third of the severe strokes were due to postoperative cerebral hemorrhage or carotid thrombosis, unrelated to clamp-induced ischemia or shunting. CONCLUSIONS: Carotid endarterectomy complications might be reduced by selectively shunting only for severe persisting ischemia. Monitoring of cerebral ischemia would be essential to selective shunting.

Carotid endarterectomy monitored with transcranial Doppler.

Intraoperative transcranial Doppler monitoring of cerebral ischemia during carotid clamping under general anesthesia was done in 238 carotid artery operations, mostly endarterectomy. Depending on the severity of reduction of middle cerebral artery mean velocity, patients were classified as no, mild, or severe ischemia at clamping. With a carotid shunt, velocity was always in the "no ischemia" category during shunting. For patients with no ischemia, stroke was significantly lower without a shunt (2/175 no shunt versus 2/12 shunt). For mild ischemia, shunting did not affect the stroke rate (1/20 no shunt versus 0/9 shunt). For severe ischemia, strokes were less frequent with a shunt (4/9 no shunt versus 0/13 shunt). Intraoperative electroencephalogram predicted most, but not all severely ischemic cases. Carotid back pressure correlated with Doppler velocity, but transcranial Doppler was more helpful. Transcranial Doppler is a new and valuable technique in carotid surgery.

The contribution of reoxygenation to ischemic brain damage.

This study examined the hypothesis that the level of postischemic reperfusion affects the severity of the resulting neuronal necrosis. In rats, tissue PO2% was monitored as an index of flow (reoxygenation) at four cortical sites by chronically implanted platinum electrodes. Twenty minutes of total global cerebral ischemia was followed by 30 min of reoxygenation. The level of reoxygenation was controlled to maintain the PO2 nearly constant at one or more of the cortical electrodes. Tissue from within 400 microns of each of 19 electrode sites among seven rats was evaluated histologically. There was a positive correlation between reoxygenation level and severity of neuronal damage. Perineuronal lucent halo formation, probably representing astrocyte foot process swelling, was negatively correlated with reoxygenation level. This study demonstrates that ischemic neuronal damage was aggravated by increased reoxygenation but that perineuronal swelling, as evidenced by halo formation, was somewhat ameliorated.

The importance of cerebral ischemia during carotid endarterectomy.

The importance of cerebral ischemia produced by carotid clamping during carotid endarterectomy remains controversial. In an effort to determine the importance of cerebral ischemia during carotid endarterectomy, 369 patients undergoing 431 consecutive carotid endarterectomies were studied by Xenon-133 (133Xe) clearance and electroencephalogram (EEG) monitoring. None of the patients was shunted during the procedures. The severity of ischemia as indicated by 133Xe clearance from the ipsilateral hemisphere during 20 to 30 minutes of carotid occlusion did not predict the appearance of complications in this group of patients (chi 2 = 1.417; P = 0.841). There was a highly significant relationship between the depth of cerebral ischemia as demonstrated by 133Xe clearance and the appearance of abnormalities on the EEG (chi 2 = 42.043, P less than 0.0001). In the subgroup of patients developing abnormalities as shown by EEG, there was a negative correlation (chi 2 = 17.495; P less than 0.002) between reduction in blood flow and the appearance of complications, in that the higher the blood flow during occlusion the more likely the patient developing EEG changes would develop complications.

Experimental brain ischaemia: assessment of injury by magnetic resonance spectroscopy and histology.

Phosphorus magnetic resonance spectroscopy (31P-MRS) was made to measure changes in brain high energy phosphate compounds, adenosine triphosphate (ATP) and phosphocreatine (PCr), inorganic phosphorus (Pi) and intracellular pH (pHi) during a prolonged period of incomplete brain ischaemia produced, in anaesthetized dogs, by bilateral carotid occlusion together with haemorrhagic hypotension for intervals of up to 300 min. Mean arterial blood pressure (MABP) was lowered in a stepwise fashion, until signs of metabolic decompensation (as estimated by MRS) occurred. At that point MABP was varied against further evidence of metabolic decompensation in an attempt to maintain a more constant degree of insult. At the end of the ischaemic period MABP was restored and the animals observed during a 3 h recovery period. At the end of the recovery period the brains were perfusion-fixed for histological examination. A semi-quantitative method of histological evaluation was used to determine the degree of histological damage. This permitted assignment of an 'ischaemic score' to the tissue sampled from each animal. Comparisons were then made between the magnitude of this 'ischaemic score' and the changes in metabolic and physiological variables (ATP, PCr, pHi and MABP) as well as an estimator of phosphorylation potential (PCr/Pi), which were all measured during the ischaemic insult. Histological examination showed a wide variety of neuronal alterations, including dark and pale type injury, which correlated directly with the metabolic derangements brought about by ischaemia. The degree of damage determined from this histological assessment correlated best with the duration and degree of change in PCr/Pi, supporting the use of this ratio as a critical index of cellular energy state. In particular there was a strong linear relationship between the degree of leucocyte recruitment and changes in PCr/Pi. To summarize, metabolic changes, determined by MRS, correlate with the degree of histological damage, and in turn, the classical descriptions of acute ischaemic neuronal injury appear to be validated by MRS determinations of metabolic changes during ischaemia.

Effect of emitted power on waveform intensity in transcranial Doppler.

This study assesses the problem of transcranial Doppler recording failure and seeks to determine the extent to which this can be ameliorated by increased emitted power. We hypothesized that waveform intensity is directly related to the rate and quality of successful recording and may be compared quantitatively among groups of patients. Among a large group of patients recorded at 800 mW/cm2 emitted power, intensity was strongest in white men, weakest in black women, and intermediate in black men and white women. It declined with age in women of either race, but not in men of either race. Analysis of the effect of emitted power on intensity predicted that significant numbers of waveforms recorded at 800 mW/cm2 could not be recorded at the current clinical standards of 100 mW/cm2, the difference being most pronounced in elderly black women. Temporal bone window thickness measured in a series of adult cadaver skulls was least in white men, greatest in black women, and intermediate in black men and white women. The findings of this study support the hypothesis that temporal bone window thickness is an important determinant of recording difficulty and suggest that increased emitted power can significantly increase successful recording, particularly in black and elderly patients. Increased power alone, however, cannot completely solve the recording problem within safe limits.

Biological and neuropsychological characterization of physostigmine responders and nonresponders in Alzheimer's disease.

To assess the efficacy of oral physostigmine for the treatment of Alzheimer's disease, 20 patients were entered into a clinical trial. All patients underwent a dose-finding phase (two weeks), followed by an open trial (two weeks), and a double-blind crossover phase (two weeks drug, two weeks placebo). Extensive neuropsychological testing (Buschke Selective Reminding procedure, category generation, picture recognition, finger tapping) and measurement of systemic cholinergic parameters were measured during each of these phases. Patients were classified as physostigmine responders and nonresponders based on a priori established criteria. Using these, nine patients were found to respond to physostigmine, while 11 were classified as nonresponders. During baseline conditions, responders when compared to nonresponders were found to have higher concentrations of red blood cell (RBC) choline (Ch) and higher ratios of RBC Ch to plasma Ch. Neuropsychological tests were found to fall into one of three categories. The first group of tests were sensitive to drug effects and differentiated physostigmine responders from nonresponders; the second group was found to predict responsiveness; and the third group was neither predictive nor sensitive to drug effects.

Regional cerebral blood flow for singers and nonsingers while speaking, singing, and humming a rote passage.

Two groups of singers (n = 12,13) and a group of nonsingers (n = 12) each produced the national anthem by (1) speaking and (2) singing the words and by (3) humming the melody. Regional cerebral blood flow (rCBF) was measured at rest and during each phonation task from seven areas in each hemisphere by the 133Xe-inhalation method. Intrahemisphere, interhemisphere, and global rCBF were generally similar across phonation tasks and did not yield appreciable differences among the nonsingers and the singers.

Transcranial Doppler in acute brain stem infarction.

Two patients with acute brain stem infarctions were examined angiographically and with the transcranial Doppler. One patient had a patent basilar artery but worsened clinically. The second patient had a thrombosis of the left vertebral artery which was dislodged with the angiographic catheter. Thrombolytic therapy was initiated. Serial transcranial Doppler examinations showed persistent patency of the vertebrobasilar system although the patient failed to improve. The usefulness of the transcranial Doppler in the management of acute stroke is discussed in the context of these patients.

Blood velocity in the middle cerebral artery and regional cerebral blood flow during carotid endarterectomy.

Blood flow velocity in the middle cerebral artery, determined by transcranial Doppler ultrasonography, was monitored during 31 carotid endarterectomies. Electroencephalogram (EEG) was also monitored, and regional cerebral blood flow (rCBF) was measured. The relation between rCBF and mean velocity was dependent on the rCBF level; the correlation was strong if rCBF was less than 20 ml/100 g/min but weak if rCBF was greater than that level. Ipsilateral EEG suppression was related to a rCBF threshold of 9 ml/100 g/min and to a mean velocity threshold of 15 cm/sec; the rCBF threshold was more specific for EEG change. Postischemic hyperemia was evident in measurements of mean velocity but not of rCBF. These disparities between mean velocity and rCBF seemed to be due to three factors: 1) disproportionately high mean velocity in patients with stenosis of the middle cerebral artery, 2) a nonlinear relation between mean velocity and rCBF, and 3) the anatomically different regions of the brain in which mean velocity and rCBF are measured. The velocity measurement appeared to be relatively more sensitive than rCBF to hemodynamic events in the corpus striatum and internal capsule.

Patterns of EEG frequency content during experimental transient ischaemia in subhuman primates.

EEGs were recorded with depth electrodes in 8 monkeys undergoing transient middle cerebral artery ligation. Electrodes measured EEG, cerebral blood flow (CBF), and tissue oxygen simultaneously during and after occlusion. An EEG frequency analysis was performed. Electrode sites were examined microscopically, and infarction size, tissue vacuolization index, and neuronal morphology were described quantitatively. Serial neurological examinations were performed. Two patterns of EEG frequency change were delineated, dependent upon degree of ischaemia. Mild ischaemia, as indicated by less severe clinical deficits, higher CBF during occlusion, and minor pathological changes was associated with large increases in slow EEG activity and decreases in fast EEG activity during occlusion, with recovery of slow activities to baseline, but continued suppression of fast activities 24 h later. Severe ischaemia was associated with suppression of both fast and slow frequencies during occlusion, with slow activities returning to baseline and fast activities remaining suppressed 24 h later. The best quantitative EEG indicator of severity of ischaemia was suppression of slow wave activity during occlusion. The best EEG indicator that an ischaemic event had occurred 24 h previously was continued suppression of fast EEG activities. These data may be helpful in the design of EEG frequency analysis studies for monitoring the time course of human cerebral ischaemia and for retrospective diagnosis of transient ischaemic attacks (TIAs).

The role of tissue acidosis in ischaemic tissue injury: the concept of the pH integral.

Cerebral cortical tissue pH was monitored with an extracellular glass electrode in 32 rats subjected to total global cerebral ischaemia produced by ligation of the basilar and carotid arteries with systemic hypotension for periods of 8 to 60 min. The totality of the ischaemia, and its duration were confirmed by monitoring with a brain tissue O2 electrode. Reperfusion was induced by hypertension and maintained thereafter to exclude delayed ischaemia during 3 h survival after which the rats were sacrificed by perfusion fixation. The severity of tissue pH change was varied by inducing hyperglycaemia in some of the rats. Quantitative counts were made of neurons demonstrating changes reflecting severe ischaemic injury within 500 microns of the electrode tip. For the criterion of an ischaemically injured neuron count greater than 20%, there appeared to be a threshold at about 30 min, and more than 0.8 units change in pH. For quantitative assessment of the ischaemic insult a more satisfactory index was found by combining both time and acidosis as the integral of the pH change during the period of ischaemia. This was found to have a strong correlation with the histologic changes. There was a less strong correlation between the acidosis during reperfusion and the histologic change. Comparing these results with those for 3 rats subjected to 215 min of ischaemia without reperfusion, it appears that most of the effect of acidosis in aggravating ischaemic injury takes place during the first hour of ischaemia with little further aggravation for longer periods.

Prognosis of acute hemiplegia estimated by transcranial Doppler ultrasonography.

Blood velocity in the middle cerebral artery was measured by transcranial Doppler ultrasonography in 15 patients suffering complete hemiplegia of less than 12 hours' duration, presumed due to cerebral ischemia. Among seven patients in whom blood velocity was greater than 30 cm/sec, five made complete or partial useful recovery of the involved hand and arm. Among eight patients in whom blood velocity was less than 30 cm/sec, one recovered completely while the other seven retained permanent total paralysis of the hand and arm.