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(Stroke. 1995;26:1279-1284.)
© 1995 American Heart Association, Inc.

Articles

The Sheffield Model of Subarachnoid Hemorrhage in Rats

Julian A. Veelken, MB; Rodney J. C. Laing, MD, FRCS Jan Jakubowski, MD, FRCS

From the Department of Neurosurgery, Royal Hallamshire Hospital, Sheffield, UK.

Correspondence to Jan Jakubowski, MD, FRCS, Department of Neurosurgery, Royal Hallamshire Hospital, Glossop Rd, Sheffield S10 2JF, UK.

	Abstract

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Background and Purpose There is no comprehensive and reliable model available in small animals that is suitable for the study of subarachnoid hemorrhage (SAH). Most of the existing models either require extensive surgery to achieve SAH or neglect the importance of an injury to the vessel and the impact of suddenly raised intracranial pressure (ICP). The presented model is designed to overcome these shortcomings.

Methods Forty-three male Wistar rats were anesthetized. Regional cerebral blood flow was measured using the H₂ clearance method bilaterally in the middle cerebral artery territory. ICP and blood pressure were continuously monitored. Blood gases were kept within physiological limits. SAH was produced by passing a nylon thread up through the right internal carotid artery and piercing a hole in the right anterior cerebral artery. The animals were divided into three experimental groups treated with varied operative techniques. After 3 hours the surviving animals were killed, and SAH was confirmed by postmortem examination.

Results The described method proved to be a reliable way of producing SAH in rats. The onset of SAH was characterized by a sudden increase in ICP. There were some differences in the reduction of regional cerebral blood flow and the survival rate in the experimental groups. This may represent differing degrees of severity of the produced SAH.

Conclusions We present an inexpensive and reliable model of SAH in the rat that allows the early course of biochemical, physiological, and pathological changes to be studied.

Key Words: animal models • intracranial pressure • subarachnoid hemorrhage • rats

	Introduction

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The treatment of subarachnoid hemorrhage (SAH) remains one of the major challenges in neurosurgery. Although there has been technical improvement in surgery, the pathophysiological aspects of SAH are still poorly understood.

In particular, the phenomenon of delayed ischemia, commonly referred to as arterial spasm, is of great importance. There is little information about the effect of the sudden impact of raised intracranial pressure (ICP) on the brain at the onset of hemorrhage. There is no quantitative information on damage to the neural and vascular ultrastructure and to the defense mechanisms.

Scientific investigations of patients with SAH are restricted. A variety of animal models have therefore been established. Various species have been used, including dogs,^{1 2 3} cats,⁴ monkeys,^{5 6 7 8 9} and more recently rats. The most commonly used method of producing SAH in rats is based on the introduction of autologous blood into the subarachnoid space through the cisterna magna.^{10 11 12 13 14 15 16} This technique has several major disadvantages. The model neglects the importance of the injury to the artery in the pathophysiology of SAH. Furthermore, it does not take into account that, at the time of the rupture of the vessel, the brain tissue is exposed to arterial blood pressure that in the systolic phase might be as much as 30 to 50 times higher than the normal ICP.¹⁷

This could have a considerable effect on the brain and may contribute to the problem of delayed ischemia. This situation has been understood by some research workers who produced SAH in rats or other animals by rupturing an intracranial vessel with a variety of techniques.^{18 19} All of these methods required access to the intracranial cavity. Such procedures are invasive, and it is difficult to separate the effects of the surgery from those of the experimental hemorrhage.

In this article, we present a new method of producing SAH in rats in which the severity of the bleed is a much closer analogy to spontaneous SAH in humans. Furthermore, the impact of intracranial surgery on the animal is relatively minimal.

	Materials and Methods

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Forty-three male Wistar rats (weight, 310 to 400 g) were used. General anesthesia was induced with ethyl chloride and maintained with intraperitoneal injections of Hypnorm (containing 0.315 mg · mL^-1 fentanyl and 10 mg · mL^-1 fluanisone) and midazolam. The dose required was 0.5 mg · mL^-1 · h^-1 fentanyl and 5 mg · mL^-1 · h^-1 fluanisone. The rat was placed in the supine position on a heated operating table, with body temperature maintained at between 37°C and 39°C. The operating microscope Carl Zeiss OPMI 6 6H-SF was used. A midline skin incision was made on the neck, a tracheostomy was performed, and the trachea was intubated. The animal was paralyzed with gallamine triethiodide at 35 mg · mL^-1 · h^-1 and mechanically ventilated with a mixture of O₂ and air. Throughout the experiment, frequent checks were made to ensure that the animals were adequately anesthetized by applying a painful stimulus to a paw and observing blood pressure responses. The femoral artery and the vein were dissected and cannulated to allow continuous monitoring of blood pressure, blood gas analysis, and fluid replacement. A silver/silver chloride reference electrode was placed subcutaneously.

The animal was turned to the prone position, and the skull vault was exposed by a midline incision. Temporal muscles were stripped from the side of the skull, and two burr holes were made on each side of the skull, one just in front of the coronal suture and the other 5 mm behind. These burr holes were overlying the anterior and posterior areas supplied by the middle cerebral artery. Platinum iridium wire electrodes (tip diameter, 0.125 mm) were introduced into the cortex. The wires were passed through the overlying temporalis muscles, and both muscles were fixed together with a suture that was passed over the cranial vault, therefore securing the electrodes in the correct position.

A small incision was made in the neck at the cranio-occipital junction, and the spinal process of C1 and the atlanto-occipital membrane were exposed. A small catheter was introduced into the cisterna magna to a depth of 2 to 3 mm. The tube was secured in position with dental acrylate, which was poured into the wound, and the wound was then closed. The catheter was connected to a transducer for continuous monitoring of ICP.²⁰ A steady physiological state was achieved, and the first measurements of cerebral blood flow (CBF) were obtained. The rat was then turned on its back.

The common carotid artery including its bifurcation was exposed and dissected. The external carotid artery was divided, leaving a stump of approximately 3 to 4 mm. The pterygopalatine artery was obliterated by bipolar diathermy. The internal carotid artery was then clamped with a small 5-mm Heifetz aneurysm clip, and the CBF measurements were repeated. The stump of the external carotid artery was reopened, and a 3/0 prolene thread was inserted up through the internal carotid artery for about 2.1 to 2.5 cm. The tip of the thread was not specially prepared other than being squarely amputated with a sharp scalpel blade. A small resistance was usually felt, which had to be overcome. A sudden rise of ICP at this stage indicated that SAH had been achieved.

The animals were divided into three experimental groups. In group 1, the thread was removed as well as the clip from the internal carotid artery, and the stump of the external carotid artery was obliterated. This was followed by removal of the aneurysm clip from the internal carotid artery, therefore restoring normal perfusion (9 animals). In group 2, the thread was withdrawn and the external carotid artery stump obliterated, but the common carotid artery remained clamped (14 animals). In group 3, the thread remained in place, and the common carotid artery remained clamped (15 animals).

CBF was measured immediately after SAH had been achieved and thereafter at hourly intervals for a period of 3 hours or until the death of the animal. Cerebral death was assumed when no CBF could be recorded and the mean blood pressure dropped below 40 mm Hg. The surviving animals were killed 3 hours after the bleed. Postmortem examination was performed to confirm SAH, and the brains were removed for histological examination. A pilot histological study was carried out on 2 animals from each group to look for evidence of ischemia in hippocampal areas and to confirm the presence of blood in the subarachnoid spaces on the cerebral convexity. The remaining brains were preserved and will be the subject of more detailed microstructural studies.

	Results

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The method described proved to be reliable in the induction of SAH. There were five failures (11.5%). A typical example of extensive SAH in group 1 is shown in Fig 1, left. Perforation of the vessel always occurred in the proximal part of the right anterior cerebral artery or at its origin, therefore not compromising the blood supply in the distal part of the vessel, which was maintained from the opposite side. At the point of the perforation there was usually a capping clot (Fig 1, right). There was always blood in the basal cisterns with some spread over the hemispheres. It was not possible to quantify the amount of blood; it appeared, however, that in the animals in group 1 the hemorrhage was more profound than in the two other groups.

View larger version (0K): [in this window] [in a new window]   Figure 1. Photographs show examples of subarachnoid hemorrhage. A good deal of blood is present on the basal cisterns. It spreads throughout the sylvian fissures into the subarachnoid spaces of the hemispheres (left). Right, Evidence of a capping clot is shown on the right side to the optic nerve. Some spread of blood is evident in the temporal subarachnoid spaces.

The surgical manipulation and clipping of the right common carotid artery before the introduction of the thread did not reduce regional CBF (rCBF) in the right hemisphere (Fig 2). The mean±SD values of the physiological variables before induction of SAH in this series were 93.3±10.2 mm Hg for blood pressure and 4.3±2.7 mm Hg for ICP. The rCBFs in the anterior and posterior right hemisphere were 69.9±13.9 and 57.8±10.8 mL · 100 g^-1 · min^-1, respectively; in the left hemisphere, rCBF values were 69.8±12.6 and 61.5 mL · 100 g^-1 · min^-1, respectively.

View larger version (36K): [in this window] [in a new window]   Figure 2. Bar graph shows regional cerebral blood flows (rCBF) before and after clamping of the right common and external carotid arteries prior to subarachnoid hemorrhage (SAH). There is no statistically significant difference between the groups (t test, P>.2). ant indicates anterior; post, posterior.

Subsequent to SAH being produced, the following changes occurred. The ICP rose rapidly to values ranging from 30 to 50 mm Hg, the mean being 31±10.2 mm Hg (Fig 3). This was followed by an increase in systemic blood pressure to a mean value of 118±27.0 mm Hg. The blood gas values remained stable within the physiological range throughout the course of the experiment. The survival rate of the animals is shown in Fig 4. In group 1 none of the animals survived the 3-hour observation period. Six of 9 animals (66.7%) were alive 1 hour after SAH, and all were dead 30 minutes later. There was a drop of CBF in the ipsilateral hemisphere below the level of infarction threshold (28 to 32 mL · 100 g^-1 · min^-1). In the contralateral hemisphere CBFs were reduced to 49.4±20.2 and 42.2±22.3 mL · 100 g^-1 · min^-1, respectively. After 1 hour, only the anterior electrode on the contralateral side recorded borderline values, whereas all other rCBF areas remained well below the infarction threshold. The ICP rose from 4.25±2.6 to 33.3±9.9 mm Hg and 1 hour after the bleed was 23.8±10.6 mm Hg in the surviving animals. Blood pressure dropped after the initial rise to values of approximately 60±22.3 mm Hg, and no animal had a systolic blood pressure over 40 mm Hg after 90 minutes.

View larger version (11K): [in this window] [in a new window]   Figure 3. Graph shows changes in intracranial pressure (ICP). In all three groups there is a statistically significant rise in ICP compared with the baseline values (t test, P<.01). No statistically significant difference was seen between the experimental groups. SAH indicates subarachnoid hemorrhage.

View larger version (10K): [in this window] [in a new window]   Figure 4. Graph shows animal survival rate after subarachnoid hemorrhage (SAH) in three experimental groups. GR indicates group.

In group 2, 93.3% of the rats survived up to 2 hours, and 57% were alive after 3 hours. After induction of the bleed, rCBF fell immediately in the ipsilateral hemisphere to 23.7±18.2 mL · 100 g^-1 · min^-1 anteriorly and 23.3±19.4 mL · 100 g^-1 · min^-1 posteriorly; in the contralateral hemisphere, the values were 57.9±8.1 and 48.5±14.3 mL · 100 g^-1 · min^-1, respectively. Over the subsequent period there was a steady decline of rCBF in both hemispheres (Fig 5, middle), which remained all the time below the infarction threshold in the ipsilateral hemisphere. The ICP rose to 28±11 mm Hg immediately after the bleed. A small continuous reduction was observed over a period of 3 hours but not below 21 mm Hg. The blood pressure in this group rose to 121 mm Hg after SAH and then gradually returned to 95 mm Hg.

View larger version (19K): [in this window] [in a new window]   Figure 5. Graphs show regional cerebral blood flow (rCBF) values before and after subarachnoid hemorrhage (SAH) in three experimental groups. The shaded area represents an infarction threshold. The reduction in the rCBF in the right hemisphere compared with the pre-SAH values and the values in the left hemisphere is statistically significant (t test, P<.05). L indicates left; R, right; ant, anterior; and post, posterior. **First measurements at which difference was statistically significant.

In group 3, 14 of the original 15 animals were alive after 1 hour, 13 after 2 hours, and 10 (67%) after 3 hours. The rCBF after SAH in the right hemisphere fell below the infarction threshold. In the left hemisphere, the reduction in blood flow was less evident. After approximately 2 hours, there was a recovery in the blood flow in the surviving animals in the right hemisphere well above the infarction threshold. This is a recovery of approximately 60% of the pre-SAH values. Some recovery was also observed in the left hemisphere (Fig 5, right). The ICP rose to 34.4±7.9 mm Hg and fell to 16.0±3.3 mm Hg at the end of the experiment. Blood pressure, which rose to 119 mm Hg initially, fell to 111 mm Hg after 3 hours in the surviving animals. Histological examination was performed in two brains from each group. In all animals in groups 1 and 2, there was evidence of bilateral hippocampal ischemia. In group 3, ischemia was noted only on the ipsilateral side (Fig 6, top left and right). All animals showed histological evidence of blood in the subarachnoid space on the convexities of both hemispheres (Fig 6, bottom).

View larger version (208K): [in this window] [in a new window]   Figure 6. Photomicrographs show hematoxylin and eosin staining. Top left, Normal hippocampus and the neurones of the end plate (arrow); top right, evidence of acute ischemic changes showing marked nuclear pyknosis in the neurones of the end-plate zone (arrow); bottom, evidence of subarachnoid blood surrounding the arachnoid vessel (arrow) of the hemispheral convexity.

	Discussion

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The rat model of SAH as described in this article is inexpensive, reliable, and simple to implement. The surgical procedure does not require craniotomy and so avoids cerebral trauma before induction of SAH. It consists predominantly of dissection of the neck. The time needed for the preparation of the model should not exceed 30 to 60 minutes with experience. Perfusion in the distribution of the middle cerebral artery is not affected by clipping of the common carotid on the right side. SAH in our model is produced in a closed skull, which explains the prompt and drastic rise in ICP. Rupture of the intracranial vessel, sudden impact of the arterial pressure on the brain, and the subsequent rise of ICP and blood pressure are important factors in the pathophysiology of SAH. It is not surprising that these phenomena did not occur in those models when blood was injected into the basal cisterns. Even in the series of Kader et al,¹⁹ who produced SAH by transclivian puncture, ICP rose only 2.3 mm Hg above the baseline. As the authors of that article suggest, this might be due to the fact that the opening of the clivus might be a site of decompression. The reactivity of the injured basilar artery may be different from that of the vessels in the anterior circulation, therefore creating a situation similar to that in the rupture of the basilar artery aneurysm. The pathophysiology of a bleed comparable with the rupture of an aneurysm in the anterior part of the circle of Willis has been reproduced in the author's own model in baboons⁶ and by Asano and Sano³ in dogs. Both these experiments fulfill three essential criteria, ie, damage to the artery, an explosive bleed, and sudden rise of ICP. However, these models are expensive, involve fairly major surgical trauma, and in the case of the author's model, raise ethical concern.

Our three different experimental groups probably represent different degrees of brain injury after SAH, which reflect the survival rate of the animals.

When the circulation is anatomically restored as in group 1, there is a substantial increase in the pressure of the blood flow from the carotid artery onto the wall of the injured vessel, producing further leakage of blood and causing more cerebral damage. The impact on the brain is so severe that brain stem failure occurs, and there is a rapid decrease in blood pressure. Cortical perfusion in this group decreases practically to zero. This explains why the animals do not survive.

In group 2, there is no blood supply from the ipsilateral carotid artery, and the brain is perfused from the posterior circulation and the opposite internal carotid artery. The direct pressure of the blood flow on the injured wall is less pronounced. A capping clot is allowed to form and the bleeding stops, thus limiting the degree of irreversible damage to the brain and the brain stem.

In group 3, the thread that is left in the vessel protects the site of the injury, limiting the impact of the hemorrhage. Nevertheless, this introduces another factor: occlusion or partial occlusion of the middle cerebral artery. The effects of SAH and the ischemic injury to the territory of the middle cerebral artery in the right hemisphere are mixed. However, the contralateral hemisphere is only subjected to SAH. Cortical perfusion is best maintained in this group and even shows steady improvement during the observation period.

The most recent animal studies of SAH have focused on the investigation of delayed ischemia. It has been questioned whether a rat model is suitable for such a study, since the anatomy of the brain and the vessels differs from that in humans. Swift and Solomon²¹ failed to find any vasculopathy in rats after SAH. However, it has to be remembered that they also used direct injection of blood into the cisterna magna, not reproducing the important factors of damage to the vessel and the sudden rise of ICP and blood pressure. Our model seems more suitable for studying the immediate changes in the event of SAH. Pathological changes as a function of time in a large series can be studied, or microdialysis techniques might be applied to determine and pharmacologically influence ion shifts in the early stages and prevent cell damage.

The techniques used in groups 2 and 3 may be suitable for chronic survival experiments and will be the subject of further studies.

Received April 5, 1994; revision received March 20, 1995; accepted March 20, 1995.

	References

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Veelken, J. A. Articles by Jakubowski, J. Search for Related Content PubMed PubMed Citation Articles by Veelken, J. A. Articles by Jakubowski, J.