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(Stroke. 1997;28:632-638.)
© 1997 American Heart Association, Inc.

Articles

Early Reperfusion in the Anesthetized Baboon Reduces Brain Damage Following Middle Cerebral Artery Occlusion

A Quantitative Analysis of Infarction Volume

Alan R. Young, PhD; Omar Touzani, PhD; Jean-Michel Derlon, MD; Giuliano Sette, MD; Eric T. MacKenzie, PhD; Jean-Claude Baron, MD

From INSERM U 320, Cyceron (A.R.Y., G.S., J.-C.B.), Biomedical Cyclotron Unit of Caen (A.R.Y., O.T., J.-M.D., G.S., E.T.M., J.-C.B.), University of Caen-CNRS UMR 6551 (O.T., E.T.M.), France; and Dipartimento di Scienze Neurologiche I°Clinica Neurologica–Universita "La Sapienza," Rome, Italy.

Correspondence to Dr Alan R. Young, Jules Horowitz Campus INSERM U 320 Cyceron, Biomedical Cyclotron Unit of Caen, Blvd Henri Becquerel, BP 5229, 14074 Caen Cedex, France. E-mail young{at}cyceron.fr.

	Abstract

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Background and Purpose Because in humans the clinical benefits of reperfusion remain controversial, it is important to determine whether reperfusion per se reduces infarct volume. In the nonhuman primate, mostly semiquantitative assessments of infarction have been performed. When ischemic volumes have been calculated, it has been for the acute or subacute stages of experimental stroke and may thus not adequately reflect the total volume of consolidated infarction.

Methods Anesthetized baboons were subjected to 6 hours of either reversible or permanent middle cerebral artery occlusion (MCAO). Approximately 4 weeks later, the brains were processed for neuropathological examination to allow assessment of the final infarct volume determined by the difference of healthy tissue between occluded and nonoccluded hemispheres.

Results Reversible MCAO resulted in a small essentially subcortical infarction (mean±SD, 0.58±0.31 cm³) in 6 of 10 baboons: the infarct (pannecrosis) was restricted to the head of the caudate nucleus, internal capsule, and putamen; 4 of 10 baboons showed no evidence of macroscopic infarction. Permanent MCAO produced a larger subcortical infarct in all 7 baboons studied (2.37±1.32 cm³; P=.0006 by Wilcoxon-Mann-Whitney test); the lesion was more extensive and encompassed the external capsule and, in 2 baboons, the adjacent insular cortex.

Conclusions We conclude that under optimal experimental conditions, an ischemic episode of 6 hours in duration is well tolerated in the anesthetized adolescent baboon, with 4 animals showing no signs of macroscopic brain damage. Thus, early reestablishment of cerebral blood flow after a focal ischemic insult is not detrimental but indeed is beneficial in terms of the final infarct volume (both at the subcortical and cortical levels) produced by occlusion of a major cerebral artery. The data further suggest a feasible time window in which to initiate and continue therapeutic interventions.

Key Words: cerebral ischemia • middle cerebral artery occlusion • reperfusion • stroke, experimental • baboons

	Introduction

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Whether early reperfusion to restore blood flow through a partially ischemic brain is beneficial, or indeed detrimental, to the final tissue outcome remains debatable (see Reference 1¹ for review). Although previous studies in the rat^{2 3 4 5 6 7 8} and cat^{9 10} have shown that early reperfusion reduces infarct volume, the literature is sparse with regard to equivalent studies performed in the nonhuman primate.^{11 12 13} We have addressed the issue in terms of the final infarct volume produced after either temporary (to mimic the clinical situation of early spontaneous or thrombolytic-induced recanalization) or permanent middle cerebral artery occlusion (MCAO) in the anesthetized baboon. As part of a larger program mainly centered on positron emission tomography imaging,^{14 15 16} the present investigation was carried out because previous studies in the nonhuman primate lacked a quantitative assessment of infarct volume performed in the chronic stage and thus would be judged inconclusive by present-day standards. In addition, it was felt that by doing such a study, one would obtain information relevant to the issue of early thrombolysis in humans.^{17 18 19 20 21 22} Our hypothesis was that early reperfusion of the MCA after a 6-hour ischemic episode would not exacerbate, but would indeed ameliorate, the extent of cerebral infarction produced by permanent MCAO.

	Materials and Methods

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The baboons (Papio anubis; body weight, 7 to 16 kg) were housed in individual cages maintained at 24°C with 50% relative humidity on a 12-hour/12-hour light/dark cycle and were fed commercial chow supplemented with fresh fruits and water ad libitum. All experiments were carried out in the framework of the French national legislation that governs animal experimentation. The research protocols were approved by the scientific council of our institution (Cyceron); a team of veterinary surgeons, external to the programs of research, was responsible for the animals' health and welfare. Following techniques previously described,^{14 15 16} the baboons were anesthetized, curarized, and ventilated with 67% nitrous oxide in oxygen under etomidate (0.3 mg·kg^-1·h^-1; Hypnomidate). Reversible MCAO was performed in 11 baboons (1 died at day 3 because of postoperative complications) and permanent MCAO in 7 others (no mortality). Two hours before the occlusion, all baboons received a perfusion of heparin (50 IU/h IV) over 10 hours to minimize the possible complications of reperfusion in those baboons subjected to clip removal. During surgical interventions, anesthesia was supplemented with isoflurane (0.5% to 1.5%; Forene).

The transorbital approach to the right MCA was used.^{14 15 16 23} After enucleation, a small craniectomy was performed using a saline-cooled surgical drill to expose the right MCA. The dura mater was opened, and the arachnoid was dissected to allow the placement of two microvascular clips, one on the proximal part of the main MCA trunk and the other on the orbitofrontal branch. The only variability encountered in the anatomic presentation was in the more or less proximal origin of the orbitofrontal artery. This artery was unique in all our cases and bifurcated after a short common trunk into two secondary branches: one lateral following the cortical orbital surface of the frontal lobe and the other medial, recurrent toward the interhemispheric fissure and presumably giving rise to the lenticulostriate perforating arteries. In all cases, the two clips were placed in the following way: one small clip at the origin of the orbital frontal artery, proximal to both the lateral (cortical) and medial branches; and a larger clip on the main MCA trunk (M1), just distal to the origin of the orbitofrontal artery and therefore proximal to the origin of more lateral division branches (temporal and lateral frontal) of the MCA. Warmed saline was used to reduce the possibility of vascular spasm during these procedures. The occlusion and reperfusion phases were verified by Doppler sonography.

The orbit was reconstructed approximately 8 hours after the placement of the microvascular clips in both temporary and permanently occluded baboons. During the time that the MCA was exposed to atmospheric pressure, the craniectomy was covered with a hemostatic collagen compress, and the orbit was lightly packed with a compress soaked in warm saline. There was no evidence of brain herniation in either group at the time of reconstruction. Reconstruction of the orbit was performed under aseptic conditions as follows: the craniectomy was covered by an absorbable collagen-coated mesh (Vicryl Collagène, Ethicon) and held in place with tissue adhesive (Histoacryl, B. Braun Melsungen AG) applied to the calvarium; the mesh was then covered with a nonexothermic glass ioner luting cement (GC Fuji I, GC Corporation). Thereafter, a silicon prosthesis (diameter, 14 to 16 mm) was positioned in the orbit, and 1-cm squares of hemostatic collagen compresses (Panegen, Laboratoires Fournier) were loosely applied around it. Rifamycine local antibiotic (Rifocine, Merrell Dow) was then applied to the orbit, and a tarsorrhaphy was performed. These procedures allowed a complete postoperative recovery in all baboons (except 1) and permitted long-term survival.

During the recovery phase, the baboons received 250 mL of concentrated human erythrocytes (preceded by 2 mg dexamethasone IM; Soludecadron) to maintain normal levels of hematocrit and prevent the adrenocortical insufficiency that may occur during prolonged infusions of etomidate²⁴ ; the baboons were then placed on antibiotic therapy (15 mg/kg IM daily; Kefandol) for 5 days.

Physiological (arterial pressure, heart rate, and temperature) and biochemical (PaCO₂, PaO₂, pH, hematocrit, hemoglobin, and arterial glucose levels) parameters were monitored to maintain optimal conditions during and after the occlusion.

Approximately 4 weeks later, the baboons were deeply anesthetized with 2% to 3% isoflurane, curarized, and ventilated. Heparin (5000 IU) was administered intravenously. The baboons were placed in a supine position, the thorax was opened through a midline incision, and a cannula was inserted into the ascending aorta through the left ventricle. After incision of the right atrium and clamping of the descending aorta, heparinized saline (5 L) was perfused at the baboon's mean arterial pressure until the perfusate from the right atrium was bloodless. Thereafter, 8 L of FAM (formaldehyde 40%, glacial acetic acid, and absolute methanol in the ratio of 1:1:8) was perfused at the same pressure to fix the brain in situ. After decapitation, the head was placed in the FAM fixative at 4°C for a minimum of 24 hours. The brain was removed from the skull and immersion-fixed in FAM for a further 4 weeks before being transferred to a 70% solution of methanol.

On the basis of data obtained from MRI scans taken approximately 1 week before euthanasia, a single block of tissue was identified, cut, and embedded in paraffin wax. Coronal sections 15 µm thick were taken with reference to a stereotaxic atlas of the baboon's brain²⁵ and stained with hematoxylin and eosin. An image analyzer (Biocom RAG 200) was used to map the contour of healthy tissue. The area of the lesion was subsequently calculated after subtraction of the surface area of the macroscopically healthy tissue on the affected side from the contralateral hemisphere. On any given coronal section, ventricular surface areas were subtracted before the calculation of noninfarcted tissue. For each baboon, the infarct volume was calculated by integration over 10 equidistant slices that encompassed the whole lesion²⁶ (Fig 1).

View larger version (55K): [in this window] [in a new window]   Figure 1. Illustrative topographical distribution of ischemic damage in 2 baboons after reversible and permanent middle cerebral artery occlusion (MCAO). The figure shows representative coronal sections taken from -9 mm through to +33 mm from the point of bregma. The shaded area represents macroscopic infarction. Note that the infarct volume is calculated for individual baboons over 10 equidistant brain slices, which encompassed the rostrocaudal extension of the lesion (see "Materials and Methods").

Statistical Methods
The physiological and biochemical data were analyzed by ANOVA followed by Scheffé's test. A comparison of the infarct volumes between permanently and transiently occluded baboons was carried out by Wilcoxon-Mann-Whitney nonparametric test. Mean±SD values are given throughout the text and figures.

	Results

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On recovery from anesthesia, a slight contralateral hemiparesis in the upper limb and visual field defects with neglect were generally noted, but neurological improvement was readily discernible within 24 to 48 hours. However, further analysis and quantification of these effects were not conducted. During the days after MCAO, the baboons were alert and exhibited normal feeding and grooming behavior.

After release of the clip in the cohort of baboons subjected to temporary MCAO, arterial pH values were significantly lower (P<.01, ANOVA followed by Scheffé's test) when compared with the final measurement made in the chronic stage. Apart from this finding, there were no further meaningful changes in any of the remaining physiological or biochemical parameters measured in either group either during or after the period of occlusion.

Fig 1 illustrates schematically the distribution of pannecrosis in 2 baboons after temporary or permanent MCAO. Reperfusion resulted in a smaller and topographically less extensive lesion. Of the 10 baboons subjected to 6 hours of occlusion, 4 showed no evidence of gross macroscopic infarction (see Fig 2). The remaining 6 animals in this group had only a mild to moderate infarction volume (mean±SD, 0.58±0.31 cm³; range, 0 to 0.90 cm³) located in the head of the caudate nucleus and anterior putamen (see Fig 2 for illustration). In the permanently occluded group of baboons, there was a consolidated infarction that covered the entire basal ganglia region (2.37±1.32 cm³; range, 1.21 to 4.63 cm³; P=.0006 by Wilcoxon-Mann-Whitney test), and in some instances (2 baboons, Nos. PAH7 and PA62) the ipsilateral insular cortex was clearly involved as well (Fig 2). Fig 3 shows the distribution of infarct volumes for all baboons studied. As illustrated, there was no overlap in infarct volumes between the two groups.

View larger version (70K): [in this window] [in a new window]   Figure 2. Representative digitized images of coronal brain sections taken at the level of the basal ganglia region after permanent or 6-hour reversible middle cerebral artery occlusion (MCAO). The original sections (15 µm thick) were taken and stained with hematoxylin and eosin. Permanent occlusion produced a large area of consolidated infarction in all baboons and resulted in an extensive lesion that encompassed the external capsule (ec) and with some involvement of the parasylvian cortex (pc). Six-hour occlusion resulted in macroscopically intact brain sections in 4 baboons (PA85, PA86, PA264, and PAL4). In the remaining baboons in this group, reversible MCAO produced a lesion that was smaller, relatively uniform in size, and normally restricted to the head of the caudate nucleus (c), internal capsule (ic), and putamen (p). Calibration bar equals 1 cm.

View larger version (11K): [in this window] [in a new window]   Figure 3. Distribution of individual infarct volumes after reversible or permanent middle cerebral artery occlusion. Four baboons in the 6-hour group had no macroscopically evident infarction (see Fig 2); 6 other baboons in the same group had only a small discrete infarct (see Fig 2). There was no overlap of the distribution of infarct volumes between the permanently and transiently occluded groups (P=.0006 by nonparametric Wilcoxon-Mann-Whitney test). Mean±SD values are shown.

	Discussion

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The findings of the present study show that it is possible to limit the degree of final infarction volume by reperfusion 6 hours after MCAO in the anesthetized baboon. The study further extends previous reports on other species in the literature, although our data would suggest that the evolution toward infarction in the nonhuman primate is much less rapid than that noted in the rat⁶ or cat.^{27 28} In rodents, a consolidated infarction is the rule after 1 to 2 hours of MCAO. We believe that the evolution of ischemic processes in the nonhuman primate is probably more closely related to that observed in humans.

To our knowledge, there has been no previous study in the nonhuman primate that has evaluated and compared, in a systematic manner and in a reliable and reproducible experimental model of focal ischemia, the effects of permanent and temporary MCAO on quantitative infarct volumes studied in the chronic stage. Qualitative descriptions of infarct size after reversible focal ischemia have, however, been reported in the literature.^{29 30 31 32 33} Some earlier studies in baboons have cast some doubt as to the benefits of early reperfusion after MCAO. For example, Selman and coworkers³⁴ reported that 6 hours of MCAO followed by reperfusion resulted in a neurological deficit that was worse than the neurological deficit produced by permanent MCAO. In that study, the occlusion was achieved in awake baboons through the use of an inflatable balloon cuff placed around the MCA. This procedure resulted in two deaths within 48 hours (related to malignant intracranial hypertension), and postmortem examination revealed severe basal ganglia and cortical destruction with evidence of gross swelling of the hemisphere. Conversely, Hadley and colleagues³⁵ reported that in baboons anesthetized with sodium thiopental and subjected to 6 hours of temporary MCAO, almost half of the animals showed no gross evidence of infarction; comparative data in permanently occluded baboons were not reported, however. Nehls et al¹² performed a similar investigation of temporary (6 hours) MCAO in Papio anubis anesthetized with nitrous oxide and fentanyl. There were no operative deaths, and infarction was found in only 4 of 6 baboons (this included an infarction volume that measured only 0.7% of the hemisphere) and was restricted to the basal ganglia/thalamus regions; again, no control group with permanent MCAO was reported. Jones and coworkers³⁶ used the snare-ligature technique to address the problem of the relationships between the duration of an ischemic episode, the severity of ischemia, and the resulting infarct size in awake monkeys. These authors reported that in general the longer the occlusion, the larger the infarct. Overall however, the semiquantitative results from these investigations have suggested that reperfusion could be of importance in limiting the extent of ischemic damage subsequent to the occlusion of a major cerebral artery.

Nonetheless, there is a considerable difference in the extent of ischemic damage produced and mortality when different models of MCAO are used. If one assumes that the studies are performed with the technical expertise necessary to ensure that little or no damage is produced to the underlying tissue or perforating arterioles despite the method chosen to occlude the MCA, then other factors must be implicated to explain the discordance in the literature. Although the balloon-cuff^{11 30 34} or snare-ligature³⁶ methods may be more demanding technically when compared with the placement of microvascular clips,^{12 16 32 33 35} all procedures appear to produce a consistent infarction even though the infarct volume differs somewhat depending on the methods used. However, one consistent finding is that the size of infarct produced after MCAO is greater when unanesthetized animal models are used.^{29 34 36} As such, it becomes difficult to ascertain whether it is the procedure used to occlude the artery that results in these variations between studies or whether it is the anesthetic that provides a large degree of neuroprotection.

One possible explanation is that "stress-related exacerbation" of the infarct, due to immobilization, may take place in the unanesthetized models. In such models, it is common that the PaCO₂ reaches hypocapnic levels, which in turn may further reduce values of cerebral blood flow and the cerebral metabolic rate for oxygen in already jeopardized brain regions.³⁷ Furthermore, long periods of immobilization (7 to 9 hours) are know to increase blood-brain barrier permeability,³⁸ and shorter periods of up to 1 hour significantly increase the release of noradrenaline.³⁹

Although they did not compare temporary with permanent MCAO, del Zoppo and associates¹¹ are one of the few groups who have measured infarct volumes (which were based on both CT procedures and classic histological procedures) after cerebral ischemia. In awake baboons, temporary MCAO for 3 hours (by the balloon-cuff technique) produced infarct volumes equivalent to 3.2±1.5 cm³ (by CT scan at day 10) and 3.9±1.9 cm³ (by morphometric neuropathology at day 14). These values are considerably greater than those reported in the present study. Such a large infarction after a comparatively short period of occlusion may be related to the potentially deleterious effects of selective but repeated cerebral angiographic procedures, which were performed to demonstrate the effectiveness of balloon inflation and subsequent patency of the MCA. Other differences between our present investigation and that of Del Zoppo et al are as follows: (1) We used heparin to limit potential secondary events after clip removal. (2) Erythrocytes and dexamethasone were administered to maintain a constant hematocrit level (the adrenocortical insufficiency induced by prolonged etomidate infusions can expand intravascular volume²⁴ ). (3) Our studies were carried out using light anesthesia, which could possibly limit a stress-related immobilization exacerbation of final infarction volume.

In summary, the present study provides the first quantitative evidence from the nonhuman primate that reperfusion, even after 6 hours of cerebral ischemia, can indeed save brain tissue that would otherwise be destined to infarction if left untreated. Furthermore, we have shown that even subcortical tissue may be salvaged by relatively early reperfusion and that this tissue is not irreversibly damaged by brief periods of ischemia, as is widely believed at present. Reperfusion (even under optimal experimental conditions) may not, however, prevent some degree of selective neuronal loss or "incomplete infarction"^{40 41} in that part of the ipsilateral hemisphere saved from pannecrosis.

Our data further agree with the clinical findings of stroke, albeit actual quantitative measurements of infarct volumes are difficult to undertake in humans. There is, however, other indirect evidence to support the beneficial effects of early reperfusion. Transcranial Doppler techniques to measure blood velocity in the MCA territory and x-ray CT-scanning procedures to determine the extent of brain swelling after infarction in the MCA territory revealed that in patients whose symptomatic MCA blood velocity increased, there was a better chance of recovery.⁴² The authors concluded that early reperfusion is not associated with a worsening of acute ischemia-induced swelling and indeed may lead to a better clinical outcome. Ringelstein and collaborators⁴³ likewise used CT-scanning techniques to measure infarct size in 34 stroke patients; they reported that the more rapidly recanalization of the MCA occurred (either by spontaneous reperfusion or induced by the administration of tissue plasminogen activator), the smaller the size of the infarct. The authors also pointed out that when recanalization took longer than 8 hours, the lesions always extended to the cortex. In addition, through the use of positron emission tomography, Marchal and colleagues⁴⁴ noted that in stroke patients in whom hyperperfusion with little or no metabolic alteration was noted (indicative of a spontaneous recanalization), there was systematically a better neurological outcome; these results were subsequently confirmed by Baird et al¹⁷ using the SPECT technique. Nonetheless, all these data obtained in humans offer only indirect evidence for the benefits of reperfusion.

We provide evidence to show that reperfusion after 6 hours of MCAO significantly limits the volume of consolidated infarction by approximately 85% when compared with findings in baboons subjected to permanent occlusion of the MCA. We have further shown that there is no overlap between the infarct volumes found after permanent MCAO and those obtained after a 6-hour period of occlusion with subsequent reperfusion. This study convincingly demonstrates that the evolution of ischemia toward infarction in the primate brain is a slower process than has often been thought in the past.

Although we show that reperfusion at 6 hours significantly reduces infarct volume, this situation does not exclude the possibility that the residual damage could be further reduced by limiting the potentially deleterious effects of reperfusion. For instance, a recent report by Mori et al¹³ has shown that the administration of a lipid peroxidation inhibitor, tirilazad mesylate, can significantly reduce the volume of infarction (40% in the basal ganglia region) noted after 3 hours of temporary MCAO in the unanesthetized baboon. Such studies give rise to the speculation that thrombolysis and a combination of drug therapies (eg, free radical scavengers plus a neuroprotective agent) may provide the best answer for the treatment of stroke. Although we acknowledge that the data reported in the present study may not be readily extrapolated to the clinical situation, they nonetheless suggest a feasible time window in which to initiate and continue therapeutic interventions.

	Acknowledgments

 
These studies were supported by grants from the Ministry of Research and Technology (89-C-0690) and La Fondation pour la Recherche Medicale. We would like to warmly thank Florence Mézenge for her excellent work in preparing the brain specimens, and a special mention goes to Gilles Huguet for his assistance with the care of the animals.

Received August 12, 1996; revision received November 6, 1996; accepted November 7, 1996.

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