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Intracarotid air embolism in the baboon: Effects on cerebral blood flow and the electroencephalogram
BRAIN RESEARCH
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INTRACAROTID AIR EMBOLISM IN THE BABOON: EFFECTS ON CEREBRAL BLOOD FLOW AND THE ELECTROENCEPHALOGRAM
B. S. MELDRUM*,J.-J. PAPY ANDR. A. VIGOUROUX Ddpartement de Neurophysiologie Appliqude, Institat de Neurophysiologie et de Psychophysiologie, C.N.R.S., Marseilles 9 (France) and M.R.C. Neuropsychiatry Unit, Medical Research Council Laboratories, Carshalton, Surrey (Great Britain)
(Accepted July 23rd, 1970)
INTRODUCTION The cerebral effects of the intracarotid injection of air have been studied by numerous authors4, 7,a,le,la,la,22. These studies have aided the identification and therapy of cerebral air embolism occurring in patients undergoing open-heart surgery. Cerebral air embolism also provides a convenient experimental model of transient cerebral ischaemia. Naquet and his collaborators1,17-19 have emphasized that the effects on the EEG can be divided into immediate effects which are generalized, transient and of an anoxic nature, and secondary effects beginning 1-12 h after the embolism, which are of a focal, irritative nature and may lead on to status epilepticus. These late focal abnormalities predominate at the junction of the anterior, middle and posterior cerebral arterial territories in the parieto-occipital region. Neuropathological changes (identified after 24 h or more) occur in the same region. Various hypotheses relating to effects on cerebral vasculature and general and local changes in blood flow have been proposed to explain the immediate, generalized effect on the EEG, the late irritative phenomena, and the focal neuropathology. By means of serial arteriography Naquet and Vigourouxla demonstrated a marked prolongation of the arterial circulation time in the ipsilateral hemisphere immediately after intracarotid embolism. It was suggested that secondary, local reductions in blood flow might underlie the late phenomena. However, quantitative studies covering immediate and late effects on cerebral blood flow have not been reported. The present work describes the investigation in the baboon of the immediate and late effects of intracarotid air injection on cerebral blood flow as estimated by isotope clearance. This work has been the subject of a communication to the Physiological Society2 and the French EEG Society15.
* In receipt of an Anglo-FrenchMedical ExchangeBursaryfrom the CIBA Foundation. Brain Research, 25 (1971) 301-315
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METHODS
For this study 21 adolescent baboons (Papio papio) from Senegal, weighing 3-6 kg, were used in a total of 34 experiments. The animals were lightly anaesthetized with pentobarbitone (30-45 mg/kg) and one or both common carotid arteries were exposed. With the body supine, the head was fixed in a stereotaxic apparatus (Modble visuel, La Pr6cision Cin6matographique, Asnibres), which formed part of a specially constructed chair providing mountings for ionizing radiation detectors. EEG activity was recorded on a 4-channel EEG recorder (Alvar) by means of needle electrodes placed symmetrically in the scalp to give &onto-parietal and parietooccipital derivations. In 4 experiments arterial blood pressure was recorded from a femoral arterial cannula by means of a Barovar pressure transducer and a Beckman dynograph. Cerebral blood flow was estimated by means of isotope washout curves, using the method of Ingvar and Lassen 12. Xenon 133 (Radiochemical Centre, Amersham, Great Britain) dissolved in normal saline, with an activity of 150-600 #Ci in 1-1.5 ml, was injected into one carotid artery by means of a fine hypodermic needle, in a period of 6-10 sec. The g a m m a emission from the Xenon lz3 was detected by 3 extracranial probes (D.C.S. 20N2SZT, Construction Radiophonique du Centre, France) each containing a sodium iodide crystal scintillator and a photo-multiplier. These were connected separately to 3 integrating counting systems (MDI.11 with MILl. f1,
Fig. 1. Dorsal view of baboon's head held in the stereotaxic apparatus with 3 scintillation probes mounted bilaterally above the fronto-parietal cortex (middle cerebral artery territory) and in the midline above the parieto-occipital region.
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Construction Radiophonique du Centre), with a linear galvanometric write-out on metallized paper (190 Diamatic, Chauvin Arnoud). The overall time constant of integration was 3 sec. The 3 probes were mounted so that one was in the midline over the anterior occipital territories (see Fig. l) and the other two were placed symmetrically laterally over the fronto-parietal regions, to record from the middle cerebral artery territory. The high tension supplies were adjusted for optimal recording of the Xenon emission at 81 keV. Background counts were negligible (approx. 20/sec). Three recording ranges were employed (1,000, 3,000 and 10,000 counts/sec), the ranges being selected for each probe immediately at the end of the Xenon injection. The 'linear' washout curves, as recorded for 10-12 min after the Xenon injection, were redrawn on semilogarithmic paper. This revealed 2 exponential components. Extrapolation of the slow component (SC) to the origin, followed by subtraction of this component from the early part of the curve, yielded the rapid component (RC). One or 2 control injections of Xenon were given approx. 15 or 30 min before the embolism. Either 5-15 sec before the embolism or 3 min afterwards a further injection of Xenon was given. Subsequent injections were at intervals from 20 min to 24 h after the embolism. The air embolism (2-5 ml) was given as quickly as possible (1-3 sec) via a fine hypodermic needle in one carotid artery. The EEG was continuously recorded before, during, and for 30-60 min after the embolism and subsequently at various intervals up to 24 h. The animal was either returned to its cage 4-8 h after the embolism and its behaviour observed the following day or subjected to perfusion-fixation of the brain. When observations of blood flow and EEG at 24 h were required the animal was re-anaesthetized. Some animals were given a second air embolism 2 or 3 weeks later. In 2 control animals a similar sequence of observations was made in the absence of any deliberate air embolism. In 3 animals washout curves were recorded with the extracranial tissues and vault of the skull removed on one side, leaving the dura intact. In some experiments the rectal temperature was recorded. RESULTS
Cerebral blood flow Control observations. Semilogarithmic conversion of the Xenon laa clearance curves gave 2 exponential components. The rapid one declined with a half-time of 51.3 ± 1.0 sec (mean ± S.E.M., N = 100) and the slow one declined with a halftime of 8 min 8 sec ± 17.5 sec (mean ± S.E.M., N = 100). In the baboon it is not practical to inject the isotope exclusively via the internal carotid artery so that clearance curves derived from probes external to the scalp contain an element derived from the extracranial tissues. To evaluate the importance of this, experiments were performed with the skin, muscle and bony vault of the skull Brain Research, 25 (1971) 301-315
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removed on one side. Clearance curves from the side where the probe was separated from the cerebral hemisphere only by the dura mater were identical in form with those recorded from the opposite side. Values for the half-time of the rapid component in 2 such experiments were identical on the two sides and in a third experiment were slightly less on the side of the craniotomy (mean for 3 craniotomies 48 sec). The slow component had a longer half-time on the side of the craniotomy in 2 experiments, but was shorter in the third (mean -- 9 min 26 sec). This suggests that the values for the half-time of isotope clearance can be used to derive normal cerebral blood flow measurements (in ml blood/min) using an experimentally derived value for the partition coefficient for Xenon between blood and white or grey matter 1°,12,14,21. However, because of difficulties of interpretation after cerebral air embolism (arising from the lack of the requisite 'steady state situation' in respect to cerebral blood flow) the observations are presented directly in terms of half-times of clearance for the rapid and slow components. No consistent differences for either rapid or slow components were observed between the three probes. In 2 animals not subjected to air embolism multiple observations of isotope clearance were made. In one animal the mean control value for the half-time of the rapid component was 37.7 sec and subsequent mean values were 40, 36.7 and 38.7 sec (at 1, 2 and 3 h). In the other animal the control was 61 sec and subsequent values were 61.3, 56.3 and 53.3 sec (at 20 min, 40 min and 2 h). The rectal temperature of the animals was between 33.0°C and 35.5°C directly before the embolism. Immediate effects of air embolism. When air (2-5 ml) was injected into one carotid artery a few seconds after Xenon 133, the clearance curves were invariably modified (see Table I and Figs. 2 and 3). The severest effect, seen in 5 animals, was an almost total arrest of clearance, giving a plateau on the linear clearance curve and on the derived semilogarithmic plot. In animals with intact skulls this plateau was followed after 55-210 sec by a resumption of the slow component and in one animal with a craniotomy (001) the plateau lasted 320 sec. The most usual effect was an arrest of the fast component with no change or a slight slowing in the slow component. No resumption of the fast component could be detected in 10 out of 14 experiments providing satisfactory records at the time of the embolism. Resumption of the fast component was seen in 3 animals 30-50 sec after the embolism. In general nearly identical effects of the embolism were observed at all 3 probes. However, in one animal (328) complete abolition of the fast component was observed at the posterior probe but records from the anterior probes showed only a marked slowing (Fig. 3B). Delayed effects of embolism. The results of 21 experiments in which isotope clearance curves were obtained before embolism and at various intervals up to 24 h afterwards are summarized in Table II. For Xenon injections 3 min after the embolism the half-time of the rapid component was not significantly altered. (This was equally true considering the average of all experiments or comparing the control and 3-min values separately for each animal.) At subsequent intervals up to 24 h the rapid
Brain Research, 25 (1971) 301-315
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Brain Research, 25 (1971) 301-315
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components showed no significant changes, although considerable individual variations were recorded. The true increase in SC half-time immediately after the embolism is greater than that indicated by the '0' value because the initial plateaus have been ignored in calculating the average half-times. Between 20 min and 3 h after the embolism the SC half-time is increased by a little more than a third. Xenon clearances were studied at 24 h in 2 out of the 3 animals showing severe neurological abnormality (see below). In one (336) both RC and SC half-times remained normal (control 42.3 sec and 6 min 42 sec; 24 h, 40.2 sec and 6 min 36 sec). In the other (376) an increase of the RC half-time was observed (control, 41.7 sec and 6 min 33 sec; 24 h, 70.0 sec and 6 min 47 sec). In one baboon (001) determination of the clearance at 40 min failed, probably because of cerebral circulatory arrest in the presence of marked brain swelling (observed at post mortem shortly afterwards).
Arterial blood pressure Arterial pressure was recorded before, during and after the intracarotid injection of 4 ml of air in 4 experiments. The least effective embolism (associated with minor EEG changes lasting 5 sec, and a rapid component with a half-time of 90 sec) produced no immediate or delayed changes in arterial pressure. In the other 3 experiments, the embolism abolished the rapid component o f the clearance curve and produced EEG silence within 10-20 see. In all 3 cases a rise in mean arterial pressure was observed immediately after the embolism. The smallest rise was from 80 to 90 mm Hg after 6 min; the largest rise was from 120 to 180 mm Hg after 1 min. This was accompanied by a bradycardia whose severity matched the change in arterial pressure. A return to normal arterial pressures was observed after 6-15 min. In the following 2 h only minor variations in blood pressure were seen. EEG
Control observations. The depth of anaesthesia was assessed on the basis of the EEG and graded as q- = very light (with predominant fast activity), + q- = medium (mixed fast and slow rhythms), q--+-q- = deep (predominantly slow rhythms) and + + q- q- ----very deep (with isolated bursts of activity on a relatively flat background). For animals with clearance curves recorded at the time of the embolism these gradings are presented in Table I. Immediate effects of embolism. After a latency of 5-30 sec the EEG showed a bilateral silence in 11 out of 21 records taken during embolism. The duration of this silence varied between 4 and 80 sec, except that one animal (001) failed to show any recovery. In a few animals silence was preceded by high amplitude rhythmic delta activity at 3-4 c/sec, i.e., faster than the pre-existing slow activity (see Fig. 4A). A very severe E E G depression with marked slowing, with a latency similar to that for silence, was seen in 5 animals not showing silence. Silence was followed by severe Brain Research, 25 (1971) 301-315
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depression lasting from 2 min to more than 3 h. The minimum time for recovery of the control EEG after silence was 40 min. Recovery following severe depression alone followed a similar time course to recovery after silence followed by severe depression. In 3 animals only a brief slowing, lasting about 20-60 sec, was observed (see Fig. 4B) and in 2 animals there were no EEG changes. The EEG changes observed were in general symmetrical. In a few experiments recovery was slower on the side of the embolism and in some was delayed bilaterally posteriorly. Neurological changes. Usually no abnormalities were observed directly after the embolism in the anaesthetized animal. Occasionally a spasm of the limbs contralateral to the embolism was seen 3-15 sec after the air injection. Respiratory depression sometimes occurred 5-20 min after the embolism and on 4 occasions artificial respiration was employed for 5-15 min. Adequate spontaneous respiration was resumed in all except one case (001). The day after the embolism most animals were neurologically normal, but 3 (320, 336, 376) showed a severe spastic quadriplegia and were incapable of maintaining an erect posture or performing coordinated movements. In one of these (320) tactile stimulation provoked generalized myoclonic jerking. This was the only definite epileptic manifestation observed in 15 experiments with recovery of consciousness. One animal (304) showed marked motor disability throughout the following day but had largely recovered at 48 h. Other animals showed mild locomotor disorders 18-24 h after the embolism but they were fully recovered after 36-48 h. DISCUSSION In the early years of open-heart surgery several authorsT, 20 suggested that recording the EEG was not a good monitoring procedure for the occurrence of cerebral air embolism. More recently the value of the EEG in the recognition of severe cases of air embolism has been established 1. In the present study immediate EEG changes were observed after embolism in the majority of cases, but the severity of such changes did not correlate well with the magnitude of the immediate effects on cerebral blood flow. Air embolism more readily modified cerebral blood flow than it did the EEG, which sometimes remained unaffected in the presence of moderate or severe changes in isotope clearance. (Slight changes in isotope clearance probably indicated that the quantity of air reaching the brain was less than intended due to faulty injection.) The precise interpretation of isotope clearance curves is still disputable. Numerous authors have adopted the view that the fast and slow mono-exponential clearance curves correspond to mean blood flow respectively in grey and white matter10,11,za. In our experiments the injection of isotope via the common carotid artery implies that clearance from extracranial tissues could modify the slow component but, because of its slow rate, it is unlikely to influence the rapid component. The RC half-time observed in control measurements (51.3 see) is similar to values recorded for grey matter by other authorsg, 14.
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The abolition of both the rapid and slow clearances immediately after embolism must imply that cerebral cortical blood flow has been arrested by the intracarotid injection of air. Cerebral ischaemia thus accounts for the generalized EEG silence commonly seen within 10-30 sec. In nearly all animals the half-time of the rapid clearance apparently returned to normal within 3 min. Return of the EEG to normal was slower than might be expected if the effect of air embolism were only a reduction in cerebral blood flow for periods of 30-180 sec. However, similar relatively brief periods of hypoxia in cats were shown by Freeman and Ingvar 6 to lead to an abolition of the normal relationship between cerebral blood flow and the EEG. Thus fairly prolonged slowing of the EEG is not incompatible with prompt restoration of overall cerebral blood flow. These authors also showed 6 that such transient cerebral hypoxia leads to abolition of the normal autoregulatory mechanism, so that cerebral blood flow passively follows changes in blood pressure. Our measurements of arterial blood pressure are in agreement with previous studies4,7, 20. The rise in blood pressure 1-6 min after embolism is probably due to ischaemia of brain stem centres 5. The reduction in cerebral blood flow immediately after embolism cannot be attributed to a fall in blood pressure but must be due to the mechanical effects of the air bubbles. The rise in blood pressure will facilitate the absorption or passage of the air and thus contribute to the restoration of blood flow. There are 3 technical difficulties relating to the clearance curves obtained by injecting Xenon after the injection of air. Firstly, the theory underlying the calculation of blood flow from half-times of isotope clearance assumes a steady state, i.e., constant flow throughout the period of clearance. This was inevitably not the case when air was injected immediately after Xenon, so that the half-times cannot be used for the calculation of absolute blood flows. However, they provided unequivocal evidence for generalized arrest of flow. Secondly, Xenon may diffuse into small bubbles of air remaining in the vessels. This would prolong the slow clearance curve, but would not modify the rapid clearance. Such an effect could contribute to the longer SC half-times seen up to 4 h after air embolism. Thirdly, Xenon injected after the embolism will not saturate brain tissue in areas in which there is no, or minimal, blood flow. Small cortical areas affected in this way will thus cease to contribute to the RC. The lack of change in RC half-times 3 min-24 h after embolism means only that flow was normal in a large proportion of the cortex. The presence of reduced blood flow in restricted areas of the cortex cannot be excluded. This factor combined with the use of rather wide collimation and the occurrence of Compton scatter with gamma emission could contribute to the lack of any clear difference between blood flow measurements derived from a posterior probe (over the cortical areas which are normally most severely affected by air embolism) and probes over the middle cerebral artery territory. We did not observe the late irritative phenomena described by Naquet and colleagues8,17-19, presumably because of the use of barbiturate anaesthesia. Nevertheless, the emboli did produce cortical lesions in this series of experimentsL Whatever physiological events are associated with the irritative phenomena at 1-12 h, with the Brain Research, 25 (1971) 301-315
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severe neurological signs sometimes seen at 24 h and with the focal neuropathology it is clear that a sustained generalized reduction of cortical blood flow does not usually occur. We cannot assess the possible role of localized perivascular oedema, localized reduction in blood flow or increased capillary permeability~. The time course of increased capillary permeability described by Lee and Olszewski 13 (30 min--4 h) is similar to the time course of prolonged SC observed by us. Isotope clearance measurements have shown unequivocally that intracarotid air embolism leads immediately to a severe generalized reduction in blood flow that is adequate to account for the immediate effects on the EEG on the basis of cerebral ischaemia. They have not provided any explanation for the later neurological, EEG and neuropathological features which are largely focal. However, because the ischaemic lesions (a) are largely restricted to the boundary zones of the major arterial territories2, 8 (Brierley and Meldrum, unpublished results), and (b) because they can be detected in an early stage of their development within 30-60 min of the embolism2 (Brierley and Meldrum, unpublished results), it is probable that the lower perfusion pressures in this region allow the bubbles to persist long enough to produce a critical, focal ischaemia. SUMMARY (1) Cerebral blood flow has been measured by means of isotope clearance curves before, during and after intracarotid air embolism in baboons (Papio papio) anaesthetized with pentobarbitone. The EEG was recorded before, during and after embolism. (2) Control clearance curves have been analysed in terms of two mono-exponential components, one rapid (half-time = 51.3 sec 4- 1.0 sec) and one slow (half-time : 8 min 8 sec 4- 17.5 see). (3) The injection of 2-5 ml of air into one carotid artery produced an immediate diminution or abolition of cerebral blood flow. This affected principally the component with a rapid half-time which ceased to be measurable for at least 30 sec. The slow component was less severely affected; in a small proportion of cases it was severely reduced or abolished for 55-320 see. Determinations at intervals from 3 min to 24 h after the embolism, yielded normal half-times for the rapid component (with variable individual changes). (4) These findings are interpreted as showing that there was a generalized arrest of cerebral cortical blood flow in the affected hemisphere immediately after the embolism. This was restored to normal within 3 rain for the majority of the cortex. Some difficulties in the interpretation of isotope clearance curves after local disturbances of cerebral circulation are discussed. (5) The EEG usually showed bilateral depression or silence within 30 sec of the embolism, but sometimes no major changes were observed in spite of prominent changes in blood flow. EEG recovery was markedly delayed (30-120 min) compared with the prompt restoration of normal blood flow. Emboli producing severe im-
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mediate effects on blood flow tended to be associated with more prolonged EEG changes. P h e n o m e n a of an epileptic nature were only rarely observed. (6) It is concluded that following an air embolism fine bubbles disperse throughout the cerebral hemispheres and produce an immediate generalized reduction of cerebral blood flow, which is accompanied by E E G signs of generalized cerebral anoxia. I n most of the cortex, flow is restored to n o r m a l within 3 min by the absorption or passage o f the bubbles. In small foci, where the cerebral perfusion pressure is lowest (i.e., at the b o u n d a r y zones between the arterial territories), the bubbles obstruct local flow for sufficient time to produce ischaemic lesions. ACKNOWLEDGEMENTS
We t h a n k Dr. R. N a q u e t and Dr. J. B. Brierley for help a n d advice, Mr. P. Rage for skilled assistance with the nucleonic equipment, and Mr. A. L. J o h n s o n for advice o n statistical methods.
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15 MELDRUM,B. S., PAPY, J. J., VIGOUROUX,R. A., ET RAGE, P., Effets de l'embolie gazeuse intracarotidienne sur le d6bit circulatoire c6r6bral chez le babouin, Rev. neurol., 121 (1969) 362. 16 MEYER, J. S., GOTOH, F., AND TAZAKI, Y., Circulation and metabolism following experimental cerebral embolism, J. Neuropath. exp. Neurol., 21 (1962) 4-24. 17 NAQUET, R., Epileptic activity evoked b~¢ air embolism in cat, monkey and man. In Z. SERViT (Ed.), Proc. Int. Symp. Comp. Cell. PathophysioL Epilepsy, Liblice, Excerpta Medica, Amsterdam, 1966, pp. 89-102. 18 NAQUET,R., ARFEL, G., CHOUX, M., DUBOIS,D., ET RICHE, D., l~tude exp6rimentale de l'embolie gazeuse par voie carotidienne chez le chat, Electroenceph. clin. Neurophysiol., 20 (1966) 181-196. 19 NAQUET R., ET VIGOUROUX,R. P., Embolies exp6rimentales par voie carotidienne chez le babouin (Papio papio), Rev. neuroL, 144 (1966) 339-360. 20 REDO, S. F., The effects of intra-arterial air injection on the electroencephalogram, electrocardiogram, arterial and venous blood pressure, Surg. Forum, 9 (1958) 166-171. 21 VEALL,N., AND MALLEYr, B. L., The partition of trace amounts of xenon between human blood and brain tissue at 37°C, Phys. Med. Biol., 10 (1965) 375-380. 22 VILLARET, M., ET CACrIERA, R., Les Embolies Cdr~brales: l~tude de Pathologie Exp~rimentale sur les Embolies Solide et Gazeuse du Cerveau, Masson, Paris, 1939, pp. 1-105. 23 WILKINSON,I. M. S., BULL, J. W. D., DU BOULAY,G. H., MARSHALL,J., ROSS RUSSELL,R. W. AND SYMON, L., Regional blood flow in the normal cerebral hemisphere, J. Neurol. Neurosurg. Psychiat., 32 (1969) 367-378.
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301
INTRACAROTID AIR EMBOLISM IN THE BABOON: EFFECTS ON CEREBRAL BLOOD FLOW AND THE ELECTROENCEPHALOGRAM
B. S. MELDRUM*,J.-J. PAPY ANDR. A. VIGOUROUX Ddpartement de Neurophysiologie Appliqude, Institat de Neurophysiologie et de Psychophysiologie, C.N.R.S., Marseilles 9 (France) and M.R.C. Neuropsychiatry Unit, Medical Research Council Laboratories, Carshalton, Surrey (Great Britain)
(Accepted July 23rd, 1970)
INTRODUCTION The cerebral effects of the intracarotid injection of air have been studied by numerous authors4, 7,a,le,la,la,22. These studies have aided the identification and therapy of cerebral air embolism occurring in patients undergoing open-heart surgery. Cerebral air embolism also provides a convenient experimental model of transient cerebral ischaemia. Naquet and his collaborators1,17-19 have emphasized that the effects on the EEG can be divided into immediate effects which are generalized, transient and of an anoxic nature, and secondary effects beginning 1-12 h after the embolism, which are of a focal, irritative nature and may lead on to status epilepticus. These late focal abnormalities predominate at the junction of the anterior, middle and posterior cerebral arterial territories in the parieto-occipital region. Neuropathological changes (identified after 24 h or more) occur in the same region. Various hypotheses relating to effects on cerebral vasculature and general and local changes in blood flow have been proposed to explain the immediate, generalized effect on the EEG, the late irritative phenomena, and the focal neuropathology. By means of serial arteriography Naquet and Vigourouxla demonstrated a marked prolongation of the arterial circulation time in the ipsilateral hemisphere immediately after intracarotid embolism. It was suggested that secondary, local reductions in blood flow might underlie the late phenomena. However, quantitative studies covering immediate and late effects on cerebral blood flow have not been reported. The present work describes the investigation in the baboon of the immediate and late effects of intracarotid air injection on cerebral blood flow as estimated by isotope clearance. This work has been the subject of a communication to the Physiological Society2 and the French EEG Society15.
* In receipt of an Anglo-FrenchMedical ExchangeBursaryfrom the CIBA Foundation. Brain Research, 25 (1971) 301-315
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METHODS
For this study 21 adolescent baboons (Papio papio) from Senegal, weighing 3-6 kg, were used in a total of 34 experiments. The animals were lightly anaesthetized with pentobarbitone (30-45 mg/kg) and one or both common carotid arteries were exposed. With the body supine, the head was fixed in a stereotaxic apparatus (Modble visuel, La Pr6cision Cin6matographique, Asnibres), which formed part of a specially constructed chair providing mountings for ionizing radiation detectors. EEG activity was recorded on a 4-channel EEG recorder (Alvar) by means of needle electrodes placed symmetrically in the scalp to give &onto-parietal and parietooccipital derivations. In 4 experiments arterial blood pressure was recorded from a femoral arterial cannula by means of a Barovar pressure transducer and a Beckman dynograph. Cerebral blood flow was estimated by means of isotope washout curves, using the method of Ingvar and Lassen 12. Xenon 133 (Radiochemical Centre, Amersham, Great Britain) dissolved in normal saline, with an activity of 150-600 #Ci in 1-1.5 ml, was injected into one carotid artery by means of a fine hypodermic needle, in a period of 6-10 sec. The g a m m a emission from the Xenon lz3 was detected by 3 extracranial probes (D.C.S. 20N2SZT, Construction Radiophonique du Centre, France) each containing a sodium iodide crystal scintillator and a photo-multiplier. These were connected separately to 3 integrating counting systems (MDI.11 with MILl. f1,
Fig. 1. Dorsal view of baboon's head held in the stereotaxic apparatus with 3 scintillation probes mounted bilaterally above the fronto-parietal cortex (middle cerebral artery territory) and in the midline above the parieto-occipital region.
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Construction Radiophonique du Centre), with a linear galvanometric write-out on metallized paper (190 Diamatic, Chauvin Arnoud). The overall time constant of integration was 3 sec. The 3 probes were mounted so that one was in the midline over the anterior occipital territories (see Fig. l) and the other two were placed symmetrically laterally over the fronto-parietal regions, to record from the middle cerebral artery territory. The high tension supplies were adjusted for optimal recording of the Xenon emission at 81 keV. Background counts were negligible (approx. 20/sec). Three recording ranges were employed (1,000, 3,000 and 10,000 counts/sec), the ranges being selected for each probe immediately at the end of the Xenon injection. The 'linear' washout curves, as recorded for 10-12 min after the Xenon injection, were redrawn on semilogarithmic paper. This revealed 2 exponential components. Extrapolation of the slow component (SC) to the origin, followed by subtraction of this component from the early part of the curve, yielded the rapid component (RC). One or 2 control injections of Xenon were given approx. 15 or 30 min before the embolism. Either 5-15 sec before the embolism or 3 min afterwards a further injection of Xenon was given. Subsequent injections were at intervals from 20 min to 24 h after the embolism. The air embolism (2-5 ml) was given as quickly as possible (1-3 sec) via a fine hypodermic needle in one carotid artery. The EEG was continuously recorded before, during, and for 30-60 min after the embolism and subsequently at various intervals up to 24 h. The animal was either returned to its cage 4-8 h after the embolism and its behaviour observed the following day or subjected to perfusion-fixation of the brain. When observations of blood flow and EEG at 24 h were required the animal was re-anaesthetized. Some animals were given a second air embolism 2 or 3 weeks later. In 2 control animals a similar sequence of observations was made in the absence of any deliberate air embolism. In 3 animals washout curves were recorded with the extracranial tissues and vault of the skull removed on one side, leaving the dura intact. In some experiments the rectal temperature was recorded. RESULTS
Cerebral blood flow Control observations. Semilogarithmic conversion of the Xenon laa clearance curves gave 2 exponential components. The rapid one declined with a half-time of 51.3 ± 1.0 sec (mean ± S.E.M., N = 100) and the slow one declined with a halftime of 8 min 8 sec ± 17.5 sec (mean ± S.E.M., N = 100). In the baboon it is not practical to inject the isotope exclusively via the internal carotid artery so that clearance curves derived from probes external to the scalp contain an element derived from the extracranial tissues. To evaluate the importance of this, experiments were performed with the skin, muscle and bony vault of the skull Brain Research, 25 (1971) 301-315
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B.S. MELDRUM et aL
removed on one side. Clearance curves from the side where the probe was separated from the cerebral hemisphere only by the dura mater were identical in form with those recorded from the opposite side. Values for the half-time of the rapid component in 2 such experiments were identical on the two sides and in a third experiment were slightly less on the side of the craniotomy (mean for 3 craniotomies 48 sec). The slow component had a longer half-time on the side of the craniotomy in 2 experiments, but was shorter in the third (mean -- 9 min 26 sec). This suggests that the values for the half-time of isotope clearance can be used to derive normal cerebral blood flow measurements (in ml blood/min) using an experimentally derived value for the partition coefficient for Xenon between blood and white or grey matter 1°,12,14,21. However, because of difficulties of interpretation after cerebral air embolism (arising from the lack of the requisite 'steady state situation' in respect to cerebral blood flow) the observations are presented directly in terms of half-times of clearance for the rapid and slow components. No consistent differences for either rapid or slow components were observed between the three probes. In 2 animals not subjected to air embolism multiple observations of isotope clearance were made. In one animal the mean control value for the half-time of the rapid component was 37.7 sec and subsequent mean values were 40, 36.7 and 38.7 sec (at 1, 2 and 3 h). In the other animal the control was 61 sec and subsequent values were 61.3, 56.3 and 53.3 sec (at 20 min, 40 min and 2 h). The rectal temperature of the animals was between 33.0°C and 35.5°C directly before the embolism. Immediate effects of air embolism. When air (2-5 ml) was injected into one carotid artery a few seconds after Xenon 133, the clearance curves were invariably modified (see Table I and Figs. 2 and 3). The severest effect, seen in 5 animals, was an almost total arrest of clearance, giving a plateau on the linear clearance curve and on the derived semilogarithmic plot. In animals with intact skulls this plateau was followed after 55-210 sec by a resumption of the slow component and in one animal with a craniotomy (001) the plateau lasted 320 sec. The most usual effect was an arrest of the fast component with no change or a slight slowing in the slow component. No resumption of the fast component could be detected in 10 out of 14 experiments providing satisfactory records at the time of the embolism. Resumption of the fast component was seen in 3 animals 30-50 sec after the embolism. In general nearly identical effects of the embolism were observed at all 3 probes. However, in one animal (328) complete abolition of the fast component was observed at the posterior probe but records from the anterior probes showed only a marked slowing (Fig. 3B). Delayed effects of embolism. The results of 21 experiments in which isotope clearance curves were obtained before embolism and at various intervals up to 24 h afterwards are summarized in Table II. For Xenon injections 3 min after the embolism the half-time of the rapid component was not significantly altered. (This was equally true considering the average of all experiments or comparing the control and 3-min values separately for each animal.) At subsequent intervals up to 24 h the rapid
Brain Research, 25 (1971) 301-315
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AIR EMBOLISM AND CEREBRAL BLOOD FLOW
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Brain Research, 25 (1971) 301-315
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AIR EMBOLISM AND CEREBRAL BLOOD FLOW
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Brain Research, 25 (1971) 301-315
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components showed no significant changes, although considerable individual variations were recorded. The true increase in SC half-time immediately after the embolism is greater than that indicated by the '0' value because the initial plateaus have been ignored in calculating the average half-times. Between 20 min and 3 h after the embolism the SC half-time is increased by a little more than a third. Xenon clearances were studied at 24 h in 2 out of the 3 animals showing severe neurological abnormality (see below). In one (336) both RC and SC half-times remained normal (control 42.3 sec and 6 min 42 sec; 24 h, 40.2 sec and 6 min 36 sec). In the other (376) an increase of the RC half-time was observed (control, 41.7 sec and 6 min 33 sec; 24 h, 70.0 sec and 6 min 47 sec). In one baboon (001) determination of the clearance at 40 min failed, probably because of cerebral circulatory arrest in the presence of marked brain swelling (observed at post mortem shortly afterwards).
Arterial blood pressure Arterial pressure was recorded before, during and after the intracarotid injection of 4 ml of air in 4 experiments. The least effective embolism (associated with minor EEG changes lasting 5 sec, and a rapid component with a half-time of 90 sec) produced no immediate or delayed changes in arterial pressure. In the other 3 experiments, the embolism abolished the rapid component o f the clearance curve and produced EEG silence within 10-20 see. In all 3 cases a rise in mean arterial pressure was observed immediately after the embolism. The smallest rise was from 80 to 90 mm Hg after 6 min; the largest rise was from 120 to 180 mm Hg after 1 min. This was accompanied by a bradycardia whose severity matched the change in arterial pressure. A return to normal arterial pressures was observed after 6-15 min. In the following 2 h only minor variations in blood pressure were seen. EEG
Control observations. The depth of anaesthesia was assessed on the basis of the EEG and graded as q- = very light (with predominant fast activity), + q- = medium (mixed fast and slow rhythms), q--+-q- = deep (predominantly slow rhythms) and + + q- q- ----very deep (with isolated bursts of activity on a relatively flat background). For animals with clearance curves recorded at the time of the embolism these gradings are presented in Table I. Immediate effects of embolism. After a latency of 5-30 sec the EEG showed a bilateral silence in 11 out of 21 records taken during embolism. The duration of this silence varied between 4 and 80 sec, except that one animal (001) failed to show any recovery. In a few animals silence was preceded by high amplitude rhythmic delta activity at 3-4 c/sec, i.e., faster than the pre-existing slow activity (see Fig. 4A). A very severe E E G depression with marked slowing, with a latency similar to that for silence, was seen in 5 animals not showing silence. Silence was followed by severe Brain Research, 25 (1971) 301-315
B . S . MELDRUM et al.
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depression lasting from 2 min to more than 3 h. The minimum time for recovery of the control EEG after silence was 40 min. Recovery following severe depression alone followed a similar time course to recovery after silence followed by severe depression. In 3 animals only a brief slowing, lasting about 20-60 sec, was observed (see Fig. 4B) and in 2 animals there were no EEG changes. The EEG changes observed were in general symmetrical. In a few experiments recovery was slower on the side of the embolism and in some was delayed bilaterally posteriorly. Neurological changes. Usually no abnormalities were observed directly after the embolism in the anaesthetized animal. Occasionally a spasm of the limbs contralateral to the embolism was seen 3-15 sec after the air injection. Respiratory depression sometimes occurred 5-20 min after the embolism and on 4 occasions artificial respiration was employed for 5-15 min. Adequate spontaneous respiration was resumed in all except one case (001). The day after the embolism most animals were neurologically normal, but 3 (320, 336, 376) showed a severe spastic quadriplegia and were incapable of maintaining an erect posture or performing coordinated movements. In one of these (320) tactile stimulation provoked generalized myoclonic jerking. This was the only definite epileptic manifestation observed in 15 experiments with recovery of consciousness. One animal (304) showed marked motor disability throughout the following day but had largely recovered at 48 h. Other animals showed mild locomotor disorders 18-24 h after the embolism but they were fully recovered after 36-48 h. DISCUSSION In the early years of open-heart surgery several authorsT, 20 suggested that recording the EEG was not a good monitoring procedure for the occurrence of cerebral air embolism. More recently the value of the EEG in the recognition of severe cases of air embolism has been established 1. In the present study immediate EEG changes were observed after embolism in the majority of cases, but the severity of such changes did not correlate well with the magnitude of the immediate effects on cerebral blood flow. Air embolism more readily modified cerebral blood flow than it did the EEG, which sometimes remained unaffected in the presence of moderate or severe changes in isotope clearance. (Slight changes in isotope clearance probably indicated that the quantity of air reaching the brain was less than intended due to faulty injection.) The precise interpretation of isotope clearance curves is still disputable. Numerous authors have adopted the view that the fast and slow mono-exponential clearance curves correspond to mean blood flow respectively in grey and white matter10,11,za. In our experiments the injection of isotope via the common carotid artery implies that clearance from extracranial tissues could modify the slow component but, because of its slow rate, it is unlikely to influence the rapid component. The RC half-time observed in control measurements (51.3 see) is similar to values recorded for grey matter by other authorsg, 14.
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B.s. MELDRUMet a[.
The abolition of both the rapid and slow clearances immediately after embolism must imply that cerebral cortical blood flow has been arrested by the intracarotid injection of air. Cerebral ischaemia thus accounts for the generalized EEG silence commonly seen within 10-30 sec. In nearly all animals the half-time of the rapid clearance apparently returned to normal within 3 min. Return of the EEG to normal was slower than might be expected if the effect of air embolism were only a reduction in cerebral blood flow for periods of 30-180 sec. However, similar relatively brief periods of hypoxia in cats were shown by Freeman and Ingvar 6 to lead to an abolition of the normal relationship between cerebral blood flow and the EEG. Thus fairly prolonged slowing of the EEG is not incompatible with prompt restoration of overall cerebral blood flow. These authors also showed 6 that such transient cerebral hypoxia leads to abolition of the normal autoregulatory mechanism, so that cerebral blood flow passively follows changes in blood pressure. Our measurements of arterial blood pressure are in agreement with previous studies4,7, 20. The rise in blood pressure 1-6 min after embolism is probably due to ischaemia of brain stem centres 5. The reduction in cerebral blood flow immediately after embolism cannot be attributed to a fall in blood pressure but must be due to the mechanical effects of the air bubbles. The rise in blood pressure will facilitate the absorption or passage of the air and thus contribute to the restoration of blood flow. There are 3 technical difficulties relating to the clearance curves obtained by injecting Xenon after the injection of air. Firstly, the theory underlying the calculation of blood flow from half-times of isotope clearance assumes a steady state, i.e., constant flow throughout the period of clearance. This was inevitably not the case when air was injected immediately after Xenon, so that the half-times cannot be used for the calculation of absolute blood flows. However, they provided unequivocal evidence for generalized arrest of flow. Secondly, Xenon may diffuse into small bubbles of air remaining in the vessels. This would prolong the slow clearance curve, but would not modify the rapid clearance. Such an effect could contribute to the longer SC half-times seen up to 4 h after air embolism. Thirdly, Xenon injected after the embolism will not saturate brain tissue in areas in which there is no, or minimal, blood flow. Small cortical areas affected in this way will thus cease to contribute to the RC. The lack of change in RC half-times 3 min-24 h after embolism means only that flow was normal in a large proportion of the cortex. The presence of reduced blood flow in restricted areas of the cortex cannot be excluded. This factor combined with the use of rather wide collimation and the occurrence of Compton scatter with gamma emission could contribute to the lack of any clear difference between blood flow measurements derived from a posterior probe (over the cortical areas which are normally most severely affected by air embolism) and probes over the middle cerebral artery territory. We did not observe the late irritative phenomena described by Naquet and colleagues8,17-19, presumably because of the use of barbiturate anaesthesia. Nevertheless, the emboli did produce cortical lesions in this series of experimentsL Whatever physiological events are associated with the irritative phenomena at 1-12 h, with the Brain Research, 25 (1971) 301-315
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severe neurological signs sometimes seen at 24 h and with the focal neuropathology it is clear that a sustained generalized reduction of cortical blood flow does not usually occur. We cannot assess the possible role of localized perivascular oedema, localized reduction in blood flow or increased capillary permeability~. The time course of increased capillary permeability described by Lee and Olszewski 13 (30 min--4 h) is similar to the time course of prolonged SC observed by us. Isotope clearance measurements have shown unequivocally that intracarotid air embolism leads immediately to a severe generalized reduction in blood flow that is adequate to account for the immediate effects on the EEG on the basis of cerebral ischaemia. They have not provided any explanation for the later neurological, EEG and neuropathological features which are largely focal. However, because the ischaemic lesions (a) are largely restricted to the boundary zones of the major arterial territories2, 8 (Brierley and Meldrum, unpublished results), and (b) because they can be detected in an early stage of their development within 30-60 min of the embolism2 (Brierley and Meldrum, unpublished results), it is probable that the lower perfusion pressures in this region allow the bubbles to persist long enough to produce a critical, focal ischaemia. SUMMARY (1) Cerebral blood flow has been measured by means of isotope clearance curves before, during and after intracarotid air embolism in baboons (Papio papio) anaesthetized with pentobarbitone. The EEG was recorded before, during and after embolism. (2) Control clearance curves have been analysed in terms of two mono-exponential components, one rapid (half-time = 51.3 sec 4- 1.0 sec) and one slow (half-time : 8 min 8 sec 4- 17.5 see). (3) The injection of 2-5 ml of air into one carotid artery produced an immediate diminution or abolition of cerebral blood flow. This affected principally the component with a rapid half-time which ceased to be measurable for at least 30 sec. The slow component was less severely affected; in a small proportion of cases it was severely reduced or abolished for 55-320 see. Determinations at intervals from 3 min to 24 h after the embolism, yielded normal half-times for the rapid component (with variable individual changes). (4) These findings are interpreted as showing that there was a generalized arrest of cerebral cortical blood flow in the affected hemisphere immediately after the embolism. This was restored to normal within 3 rain for the majority of the cortex. Some difficulties in the interpretation of isotope clearance curves after local disturbances of cerebral circulation are discussed. (5) The EEG usually showed bilateral depression or silence within 30 sec of the embolism, but sometimes no major changes were observed in spite of prominent changes in blood flow. EEG recovery was markedly delayed (30-120 min) compared with the prompt restoration of normal blood flow. Emboli producing severe im-
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mediate effects on blood flow tended to be associated with more prolonged EEG changes. P h e n o m e n a of an epileptic nature were only rarely observed. (6) It is concluded that following an air embolism fine bubbles disperse throughout the cerebral hemispheres and produce an immediate generalized reduction of cerebral blood flow, which is accompanied by E E G signs of generalized cerebral anoxia. I n most of the cortex, flow is restored to n o r m a l within 3 min by the absorption or passage o f the bubbles. In small foci, where the cerebral perfusion pressure is lowest (i.e., at the b o u n d a r y zones between the arterial territories), the bubbles obstruct local flow for sufficient time to produce ischaemic lesions. ACKNOWLEDGEMENTS
We t h a n k Dr. R. N a q u e t and Dr. J. B. Brierley for help a n d advice, Mr. P. Rage for skilled assistance with the nucleonic equipment, and Mr. A. L. J o h n s o n for advice o n statistical methods.
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