Intracranial pressure, blood pressure, and pulse rate after occlusion of a middle cerebral artery in cats TORU HAYAKAWA, M.D., ANDARTHUR G. WALTZ, M.D.
Cerebrovascular Clinical Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota The left middle cerebral artery was occluded in 12 tranquilized but unanesthetized cats with use of a device implanted transorbitally 5 to 7 days earlier. Bilateral epidural pressures, mean aortic blood pressure, and pulse rate were measured at intervals for up to 48 hours after occlusion. The relationships of these measurements to each other and to the extent and severity of cerebral infarcts is described. K E y WOROS 9 cerebral edema 9 cerebral ischemia 9 cerebral infarction 9 Cushing response 9 epidural pressure 9 hemorrhagic infarction 9 vasomotor response
CUTE occlusion of a major cerebral artery can cause cerebral edema; ~,1~ in humans, swelling of the brain may be the chief cause of death early after an ischemic stroke? 9,28 Previous studies of brain swelling and intracranial pressure (ICP) in experimental models of acute focal cerebral ischemia in animals have been complicated by the anesthesia and surgical procedures required for the production of ischemia. During occlusion of one middle cerebral artery (MCA), for example, anesthesia, an open cranium, or drainage of cerebrospinal fluid (CSF) all may influence subsequent changes of ICP. ~2 In addition, the effects of increases of ICP caused by ischemic cerebral edema on such systemic circulatory factors as blood pressure and pulse rate have not been determined. Therefore, we have measured bilateral epidural pressures (EDP), mean aortic blood pressure (MABP), and pulse rate (PR) in cats before and after occlusion of one MCA by a
A
J. Neurosurg. / Volume 43 / October, 1975
device implanted previously, and related the changes of EDP and the systemic factors to the extent and severity of the resulting cerebral infarcts. Materials
and Methods
Thirteen unselected adult cats were used for this study. Sedation and anesthesia, consisting of phencyclidine hydrochloride, 1 mg/kg injected intramuscularly, and sodium pentobarbital, 20 mg/kg injected intraperitoneally, were used for the implantation of a device for occlusion of the left MCA and two devices for measurement of EDP by methods described and illustrated previously. 11,12 In brief, the left MCA was exposed by a transorbital approach and freed from its arachnoid investiture so that a suture could be placed around it at its origin. A single knot was made in the suture and its ends were passed outside the incision through a solid-ended 399
T. H a y a k a w a a n d A. G. W a l t z tube-and-stylet which was apposed to the MCA and fixed to the wall of the orbit with epoxy cement. The optic foramen was sealed around the tube-and-stylet with Silastic sheeting, oxidized cellulose, and contact adhesive, and the orbit was filled with epoxy cement. One shallow stainless steel cylinder with a thin Silastic membrane was implanted with contact adhesive and epoxy cement in a burr hole in each parietal region in such a way that the Silastic membrane was as nearly coplanar with the dura as possible. ~'25 A stainless steel tube that passed from the cylinder outside the incision was sealed with a plastic tube after the cylinder was filled with bubble-free water. The cats were allowed to recover from the anesthesia and surgical procedures after implantation, and food and water were made available. Each cat was examined to be certain that there was no evidence of a neurological deficit, leak of CSF, or intracranial infection related to the implantation procedures. Five to 7 days after implantation of the three devices, each cat was sedated with phencyclidine hydrochloride, 1 mg/kg injected intramuscularly. Procaine hydrochloride, in a 2% solution, was injected into the skin over a femoral artery and a short incision was made through the anesthetized area. A polyethylene catheter was passed through the femoral artery into the abdominal aorta for measurement of MABP and PR with a strain gauge and polygraph. The cat was then placed loosely in a head holder with the body prone and the EDP devices were connected to strain gauges by nondistensible catheters and continuous columns of bubble-free water. The volume of water sufficient to produce a recorded value of 5 mm Hg for EDP on a polygraph was injected into each device from a microliter syringe attached to a side arm. For each subsequent measurement of EDP the device was evacuated and this same volume of water was injected. Although EDP values were recorded as absolute mm Hg, the devices were thus standardized to an original value of 5 mm Hg, which is close to the normal EDP of cats? 1 The left MCA was occluded in 12 of the 13 cats by tightening the suture in the implanted occlusion device; the other cat served as a sham-operated control. Measurements of EDP, MABP, and PR were made at intervals
400
for up to 48 hours: immediately after MCA occlusion; at 30 seconds; at 1, 2, 5, 10, 20, 30, 45, 60, 90, 120, 150, and 180 minutes; hourly thereafter until 12 hours after occlusion; and at 14, 16, 18, 20, 24, 32, and 48 hours. Epidural pressure was measured only at 24 and 48 hours in the sham-operated cat. Additional phencyclidine hydrochloride was injected as necessary for sedation. After 48 hours of observations and measurements, the animals that survived were killed by the intraarterial injection of a saturated solution of potassium chloride. In all cats, 0.5 ml of India ink was injected into the left common carotid artery as soon after death as possible, for verification of MCA occlusion. The brain was removed, inspected grossly, and fixed in 10% formalin. Coronal sections of the fixed brain were made at the levels of the tips of the temporal lobes, the optic chiasm, and the posterior mammillary bodies. The sections were stained with hematoxylin and eosin for histopathological examination. Results
The findings in the 12 experimental cats are summarized in Table 1.
Relationships between EDP and Infarcts Transient bilateral decreases of EDP occurred in nine of the 12 cats (all but Cats 3, 6, and 11) at the time the implanted suture was tightened for MCA occlusion (Fig. 1, Table 1). The decreases ranged from 0.5 to 1.8 mm Hg, and persisted for less than 1 minute in all but Cat 12, in which EDP was still decreased at 2 minutes. Marked increases of EDP to maximum values greater than 30 mm Hg were recorded after MCA occlusion in five of the 12 cats. Two of these, Cats 1 and 5, died before the end of the observation period of 48 hours; tentorial herniation, greater on the side of occlusion, was noted on inspection of the brains of both. All five of these cats had large infarcts on the side of MCA occlusion involving not only the basal ganglia and internal capsule but extensive areas of the cerebral cortex as well (Figs. 2 and 3). Two of the infarcts (in Cats 3 and 4) were hemorrhagic (Fig. 2, Table 1). A small amount of subarachnoid blood was found under the left occipital lobe of Cat 1.
J. Neurosurg. / Volume 43 / October, 1975
o
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20
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177.5
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33.0
58.5
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595
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9
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95w
113w
74:~
82
106
103
1705
* E D P = epidural pressure; M A B P = mean aortic blood pressure; P R = pulse rate; M C A = middle cerebral artery. t Died before 48 hours. ~t Recorded just before death. wRecorded earlier than time of maximal EDP.
24
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Cat No
2
Time of First Value > 10 mm Hg (hrs)
EDP Time of Maximum Value Maximum Value Corresponding MABP at Time of on Side of on Side of Value Opposite Maximum EDP MCA Occlusion MCA Occlusion MCA Occlusion (7o of Initial Value) (hrs) (mm Hg) (ram Hg)
Infarct
moderate
small
small
large
moderate
moderate
moderate
large
large, hemorrhagic
large, hemorrhagic
large
large
EDP, MABP, PR, survival, and characteristics of infarcts in 12 cats with MCA occlusion, listed in order of decreasing maximum values of EDP*
TABLE 1
O
O
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0 o
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T. Hayakawa and A. G. Waltz swelling or herniation of the brain was evident on inspection. The infarcts in the cats that survived the 48 hours of observation (Cats 10 and 11) were relatively small, with little involvement of cortex. No changes of EDP were recorded from the cat that had the surgical procedures without MCA occlusion, and no infarct was found on examination of the brain.
Relationships among EDP, MABP, and PR
FIG. 1. Polygraph recording from Cat 2 showing transient decreases of EDP bilaterally and transient increase of MABP immediately after MCA occlusion. Increases of EDP began relatively soon after MCA occlusion in the five cats that eventually had maximum values greater than 30 mm Hg, with values greater than 10 mm Hg recorded as early as 30 minutes and values greater than 20 mm Hg recorded as early as 21A hours after occlusion (Fig. 2, Table 1). In the two cats with hemorrhagic infarcts EDP was greater during the period of 3 to 6 hours after occlusion than in the other three cats, and EDP values greater than 20 mm Hg were recorded earlier (Figs. 2 and 3). Side-to-side pressure differences developed in all five of these cats; the pressure differences were greater at higher EDP with maximal differences ranging from 5.5 to 15.0 mm Hg (Figs. 2 and 3). Three of the 12 cats had moderate increases of EDP after MCA occlusion to maximum values of 12 to 20 mm Hg (Table 1). In these cats the infarcts involved cerebral cortex but were relatively smaller than those of the cats with greater increases of EDP (Fig. 4). Increases of EDP began later than 12 hours after MCA occlusion, and maximum values were recorded at 20 or 24 hours. Sideto-side pressure differences were small and variable, ranging from 0.5 to 3,5 mm Hg. Little or no change of EDP (all values 10.0 mm Hg or less) and no important side-to-side differences were recorded from four of the 12 cats with MCA occlusion (Table 1). Two of these four (Cats 9 and 12) died within 12 hours of MCA occlusion, about 1 hour after a sudden decrease of MABP (Fig. 5); the infarcts were moderate or large in size, but no 402
In six of the 12 cats, changes of MABP that were between 10% and 15% of the value recorded just before MCA occlusion occurred within 30 seconds of occlusion (Fig. 1). MABP increased in three (Cats 2, 3 and 5); these later had marked increases of EDP. MABP decreased in Cats 4, 7, and 9. There were no consistent changes of PR immediately after MCA occlusion. Cat 1 developed an increase of MABP and a decrease of PR associated with a rapid and severe increase of EDP just before death (Fig. 3). The other four cats with EDP values greater than 30 mm Hg also developed decreases of PR when EDP was high (Fig. 2, Table 1). Increases of MABP were not recorded from these cats; decreases were noted in Cats 4 and 5, but a terminal increase of MABP could have occurred in Cat 5 and not been detected. Cats 9 and 12 each developed severe hypotension just before death (Fig. 5); one of these had an increase of PR, the other a decrease. Cats 10 and 11 each developed moderate increases of MABP within 2 hours of occlusion. In all cats, fluctuations of MABP and PR occurred between the time of MCA occlusion and death or killing, but there were no consistent relationships to changes of EDP or the characteristics of the resulting cerebral infarcts other than those described above. No appreciable changes of MABP or PR were recorded in the cat with the operative procedures but without MCA occlusion. Discussion
Early Changes o f EDP after MCA Occlusion Previous studies of ICP in experimental models of acute focal cerebral ischemia, including those from this laboratory, have not provided reliable information about changes of ICP during the first few hours of ischemia
J. Neurosurg. / Volume 43 / October, 1975
Effects of occlusion of an MCA in cats
FIG. 2. Relationships among EDP, MABP, PR, and the infarct in Cat 4. Note early increases of EDP bilaterally, side-to-side pressure differences, and hemorrhagic changes in the infarct. H & E.
F~G. 3. Relationships among EDP, MABP, PR, and the infarct in Cat 1. Note Cushing response before death and side-to-side pressure differences.
J. Neurosurg. / Volume 43 / October, 1975
403
T. Hayakawa and A. G. Waltz
Ft~. 4. Relationships among EDP, MABP, PR, and the infarct in Cat 8.
FIG. 5. Relationships among EDP, MABP, PR, and the infarct in Cat 9. because of anesthesia, an open cranium, drainage of CSF, or an inappropriate model. 3'6'9'''18'~~ However, the present study has confirmed the findings of previous studies with respect to increases of ICP 24 hours or more after MCA occlusion. ",2~ In particular, side-to-side pressure differences of EDP again have been recorded, and with two exceptions changes of EDP have related well to the ex,404
tent and severity of the resulting cerebral infarcts. Early changes of EDP after MCA occlusion also appear to be related to the extent of cerebral ischemia, and in particular to involvement of cerebral cortex. Larger lesions not only cause greater increases of EDP but increases begin earlier than with smaller lesions, at times less than an hour after occluJ. Neurosurg. / Volume 43 / October, 1975
E f f e c t s of o c c l u s i o n of a n M C A in cats in cats with marked increases of EDP after MCA occlusion. The side-to-side differences probably do not represent pressure gradients in the CSF, as pressure in CSF spaces that are in continuity with one another must be equal, ls,16,~2 It is more likely that side-to-side differences are measured as the brain swells and CSF is displaced from beneath the EDP device, so that the pressure recorded as EDP is a reactive pressure from compression of the lschemia without an Increase o f ICP brain? ~as The reactive pressure will be higher Experimental cerebral ischemia does not than that of the CSF, and may vary from always result in edema that is sufficient to region to region because of local differences cause brain swelling and increases of ICP 6'" in the supporting structures of the brain, even if infarcts develop that are extensive blood volume, edema, or other factors. 23 A enough to involve cerebral cortex as well as more complete discussion of this subject is inthe basal ganglia and internal capsule, as in cluded in a previous report. 11 the present study. CSF pressure in humans likewise is variable after a stroke, and may Relationships among EDP, M A B P , and PR not increase; TM when CSF pressure does inThe transient changes of MABP that occrease, it usually does so because of brain swelling2 Infarcted tissue may become curred immediately after MCA occlusion in edematous without producing increases of six cats may have been due to manipulation of ICP in one or more of several ways: infarcted the artery and its accompanying sympathetic tissue may contain an increased proportion of nerves. Vasomotor instability after the first water yet not swell to an increased volume;~ few minutes of ischemia may have been focal increases of tissue pressure caused by related to effects of hypoxemia or of hemilimited swelling of an infarct may not be spheric ischemia on vasomotor centers, transmitted to the surface of the brain but directly or indirectly through neurogenic inmay be dissipated by the structural com- fluences. Minor fluctuations of MABP and ponents of cerebral tissue; '~,~a or swelling of PR did not appear to affect the outcome of the brain may be compensated for by changes the ischemic process or the extent of the of intracranial blood or CSF volume? 3,~ ~ resulting infarcts. However, vasomotor Focal increases of tissue pressure, however, effects of ischemia may have contributed to the major hypotension with which Cats 9 and may affect local tissue perfusion. T M Death early after the onset of acute focal 12 died. In addition, the moderate increases cerebral iscbemia may not always be related of MABP that occurred after MCA occlusion to edema, swelling, and increases of ICP. In in two cats that had small infarcts suggests a the present study, two cats died within 12 possible partial protective effect of moderate hours of MCA occlusion without increases of hypertension. In contrast to studies by others who used EDP. There was no tentorial herniation, and little swelling of the relatively large infarcts cerebral oil embolizationfl early increases of that were found in their brains on histo- EDP were not generally associated with pathological examination. The cause of death hypertension or tachycardia; when consistent in such situations is unclear, but both cats vasomotor changes occurred in cats with died with hypotension, suggesting direct or in- marked increases of EDP, the changes were direct involvement of vasomotor centers. those of a slowing of the pulse rate. A Alternatively, impairment of respiratory characteristic Cushing response of hypertenfunction, which was not measured, could have sion and bradycardia developed in Cat 1, caused hypoxemia and contributed to the which died with a markedly increased EDP and tentorial herniation. The other four cats death of the cats. with marked increases of EDP also had Side-to-Side Differences o f EDP bradycardia; although hypertension was not Supratentorial side-to-side pressure differ- recorded it may have occurred between ences of EDP, reported previously,1',~~again measurements, or terminally in Cat 5, which have been demonstrated in the present study died with tentorial herniation. sion. Thus, brain swelling from edema adequate to cause increases of ICP can occur after relatively brief periods of cerebral ischemia? .9," Immediate transient decreases of EDP that may occur after MCA occlusion probably are related to decreases of intracranial blood volume caused by decreased perfusion.
J. Neurosurg. / Volume 43 / October, 1975
405
T. H a y a k a w a
Pathogenesis o f Hemorrhagic Infarction The mechanisms involved in the development of hemorrhagic infarcts in the brain after arterial occlusion are obscure. MCA occlusion followed by hypertension may cause hemorrhagic infarcts; s.8~ however, in the present study the two cats that had moderate hypertension after occlusion actually had the smallest infarcts, without hemorrhagic changes. Similarly, cerebral ischemia adequate to cause disruption of endothelial integrity may or may not result in hemorrhagic infarction if the flow of blood is restored to the ischemic region. 5,27 In the present study, two hemorrhagic infarcts were found in the brains of cats with marked increases of E D P (Cats 3 and 4); in these cats, major increases of EDP occurred earlier but the maximum values for EDP were less than those for three other cats that had purely ischemic infarcts. Hemorrhage into the infarct may have accounted for the early increase of E D P ; alternatively, severe ischemia may have predisposed both to massive swelling and endothelial damage resulting in hemorrhage. Hypertension did not appear to be important for the development of hemorrhagic infarction in these cats; the M A B P of Cat 3 was 174 mm Hg 9 hours after M C A occlusion, but in Cat 4 fluctuations of M A B P after occlusion were no greater than those occurring in cats with infarcts not c o n t a i n i n g hemorrhage. N o hemorrhagic infarcts were encountered in the brains of cats without marked increases of EDP; hemorrhagic changes may occur more frequently in large infarcts, or hemorrhage into the infarct may result in a larger lesion. Unfortunately, no specific explanation for the pathogenesis of h e m o r r h a g i c infarcts is provided by the present study. Acknowledgments
Technical assistance and advice were provided by Terry Hansen and Margaret M. Jordan.
References
1. Bartko D, Reulen H J, Koch H, et al: Effect of dexamethasone on the early edema following occlusion of the middle cerebral artery in cats, in Reulen H J, Schiirmann K (eds): Steroids and Brain Edema. Berlin/Heidelberg/New York, Springer-Verlag, 1972, pp 127-137 406
a n d A. G. W a l t z
2. Beks JWF, Kerckhoffs HPM: Relationship between intracranial pressure and water content of the brain in experimental brain oedema. (Abstract) J Neurol Neurosurg Psychiatry 34:109, 1971 3. Brock M, Beck J, Markakis E, et al: Intracranial pressure gradients associated with experimental cerebral embolism. Stroke 3:123-130, 1972 4. Christensen MS, Brodersen P, Olesen J, et al: Cerebral apoplexy (stroke) treated with or without prolonged artificial hyperventilation: 2. Cerebrospinal fluid acid-base balance and intracranial pressure. Stroke 4:620-631, 1973 5. Crowell RM, Olsson Y, Klatzo I, et al: Temporary occlusion of the middle cerebral artery in the monkey: Clinical and pathological observations. Stroke 1:439-448, 1970 6. Dorsch NWC, Symon L: Intracraniai pressure changes in acute ischaemic regions of the primate hemisphere, in Brock M, Dietz H (eds): lntraeraoial Pressure: Experimental and Clinical Aspects. Berlin/Heidelberg/New York, Springer-Verlag, 1972, pp 109-114 7. Frei H J, Wallenfang T, PiSll W, et'al: Regional cerebral blood flow and regional metabolism in cold induced oedema. Aeta Nenrochir (Wien) 29:15-28, 1973 8. Globus JH, Epstein JA, Green MA, et al: Focal cerebral hemorrhage experimentally induced. J Neuropathol Exp Neurol 8:113-116, 1949 9. Halsey JH Jr, Capra NF: The course of experimental cerebral infarction - - the development of increased intracranial pressure. Stroke 3:268-278, 1972 10. Harrison MJG, Brownbill D, Lewis PD, et al: Cerebral edema following carotid artery ligation in the gerbil. Arch Neurol 28:389-391, 1973 11. Hayakawa T, Waltz AG: Changes of epidural pressures after experimental occlusion of middle cerebral artery in cats: Relationships to severity of neurologic deficits, sizes of infarcts, and anesthesia. J Neurol Sei (In press) 12. Hayakawa T, Waltz AG: Immediate effects of cerebral ischemia: Evolution and resolution of neurologic deficits after experimental occlusion of one middle cerebral artery in conscious cats. Stroke 6:321-327, 1975 13. Johnston IH, Rowan JO: Raised intracranial pressure and cerebral blood flow. 4. Intracranial pressure gradients and regional cerebral blood flow. J Neurol Neurosurg Psychiatry 37:585-592, 1974 14. Kogure K, Busto R, Scheinberg P, et al: Energy metabolites and water content in rat brain during the early stage of development of cerebral infarction. Brain 97:103-114, 1974 15. Langfitt TW, Weinstein JD, Kassell NF, et al: Transmission of increased intracranial
J. Neurosurg. / Volume 43 / October, 1975
Effects of occlusion of an MCA in cats
16.
17.
18.
19.
20. 21.
22.
23.
24.
pressure. 1. Within the craniospinal axis. J brain pressure. J Neurasurg 34:38-47, 1971 Neurosurg 21:989-997, 1964 25. Schettini A, Walsh EK: Experimental idenLangfitt TW, Weinstein JD, Kassell NF, et al: tification of the subarachnoid and subpial Transmission of increased intracranial compartments by intracranial pressure pressure. 2. Within the supratentorial space. J measurements, d Neurasurg 40:609-616, 1974 Neurosurg 21:998-1005, 1964 26. Shaw C-M, Alvord EC Jr, Berry RG: Swelling LBfgren J, Zwetnow NN: Cranial and spinal of the brain following ischemic infarction with arterial occlusion. Arch Neural 1:161-177, components of the cerebrospinal fluid pressure-volume curve. Acta Neural Scand 49: 1959 575-585, 1973 27. Sundt TM Jr, Waltz AG: Cerebral ischemia McQueen JD, Jelsma LF, Bacci F, et al: Exand reactive hyperemia: Studies of cortical perimental intracranial hypertension due to blood flow and microcirculation before, durvascular blockade. J Neurosurg 33:156-166, ing, and after temporary occlusion of middle 1970 cerebral artery of squirrel monkeys. Ore Res Ng LKY, Nimmannitya J: Massive cerebral 28:426-433, 1971 infarction with severe brain swelling: a 28. Symon L, Pasztor E, Branston NM, et al: clinicopathological study. Stroke 1:158-163, Effect of supratentorial space-occupying 1970 lesions on regional intracranial pressure and O'Brien MD, Waltz AG: Intracranial pressure local cerebral blood flow: an experimental gradients caused by experimental cerebral study in baboons. J Neural Neurosurg ischemia and edema. Stroke 4:694-698, 1973 Psychiatry 37:617-626, 1974 O'Brien MD, Waltz AG, Jordan MM: 29. Teraura T, Meyer JS, Sakamoto K, et al: Ischemic cerebral edema. Distribution of Hemodynamic and metabolic concomitants of water in brains of cats after occlusion of the brain swelling and cerebral edema due to exmiddle cerebral artery. Arch Neural 30: perimental cerebral infarction. J Neurosurg 456-460, 1974 36:728-744, 1972 Ommaya AK, Hekmatpanah J: Comments to 30. Waltz AG, Sundt TM Jr: The microSession 4: Focal Brain Damage (Experimenvasculature and microcirculation of the ceretal), in Brock M, Dietz H (eds): lntracranial bral cortex after arterial occlusion. Brain 90: Pressure: Experimental and Clinical As681-696, 1967 pects. Berlin/Heidelberg/New York, Springer-Verlag, 1972, pp 135-136 Reulen H J, Kreysch HG: Measurement of This investigation was supported in part by brain tissue pressure in cold induced cerebral USPHS Grant NS-3364. oedema. Aeta Neuraehir (Wien) 29:29-40, Address reprint requests to: Arthur G. Waltz, 1973 M.D., Department of Neurology, Pacific Medical Schettini A, McKay L, Majors R, et al: Ex- Center, P.O. Box 7999, San Francisco, California perimental approach for monitoring surface 94120.
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407
Cerebrovascular Clinical Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota The left middle cerebral artery was occluded in 12 tranquilized but unanesthetized cats with use of a device implanted transorbitally 5 to 7 days earlier. Bilateral epidural pressures, mean aortic blood pressure, and pulse rate were measured at intervals for up to 48 hours after occlusion. The relationships of these measurements to each other and to the extent and severity of cerebral infarcts is described. K E y WOROS 9 cerebral edema 9 cerebral ischemia 9 cerebral infarction 9 Cushing response 9 epidural pressure 9 hemorrhagic infarction 9 vasomotor response
CUTE occlusion of a major cerebral artery can cause cerebral edema; ~,1~ in humans, swelling of the brain may be the chief cause of death early after an ischemic stroke? 9,28 Previous studies of brain swelling and intracranial pressure (ICP) in experimental models of acute focal cerebral ischemia in animals have been complicated by the anesthesia and surgical procedures required for the production of ischemia. During occlusion of one middle cerebral artery (MCA), for example, anesthesia, an open cranium, or drainage of cerebrospinal fluid (CSF) all may influence subsequent changes of ICP. ~2 In addition, the effects of increases of ICP caused by ischemic cerebral edema on such systemic circulatory factors as blood pressure and pulse rate have not been determined. Therefore, we have measured bilateral epidural pressures (EDP), mean aortic blood pressure (MABP), and pulse rate (PR) in cats before and after occlusion of one MCA by a
A
J. Neurosurg. / Volume 43 / October, 1975
device implanted previously, and related the changes of EDP and the systemic factors to the extent and severity of the resulting cerebral infarcts. Materials
and Methods
Thirteen unselected adult cats were used for this study. Sedation and anesthesia, consisting of phencyclidine hydrochloride, 1 mg/kg injected intramuscularly, and sodium pentobarbital, 20 mg/kg injected intraperitoneally, were used for the implantation of a device for occlusion of the left MCA and two devices for measurement of EDP by methods described and illustrated previously. 11,12 In brief, the left MCA was exposed by a transorbital approach and freed from its arachnoid investiture so that a suture could be placed around it at its origin. A single knot was made in the suture and its ends were passed outside the incision through a solid-ended 399
T. H a y a k a w a a n d A. G. W a l t z tube-and-stylet which was apposed to the MCA and fixed to the wall of the orbit with epoxy cement. The optic foramen was sealed around the tube-and-stylet with Silastic sheeting, oxidized cellulose, and contact adhesive, and the orbit was filled with epoxy cement. One shallow stainless steel cylinder with a thin Silastic membrane was implanted with contact adhesive and epoxy cement in a burr hole in each parietal region in such a way that the Silastic membrane was as nearly coplanar with the dura as possible. ~'25 A stainless steel tube that passed from the cylinder outside the incision was sealed with a plastic tube after the cylinder was filled with bubble-free water. The cats were allowed to recover from the anesthesia and surgical procedures after implantation, and food and water were made available. Each cat was examined to be certain that there was no evidence of a neurological deficit, leak of CSF, or intracranial infection related to the implantation procedures. Five to 7 days after implantation of the three devices, each cat was sedated with phencyclidine hydrochloride, 1 mg/kg injected intramuscularly. Procaine hydrochloride, in a 2% solution, was injected into the skin over a femoral artery and a short incision was made through the anesthetized area. A polyethylene catheter was passed through the femoral artery into the abdominal aorta for measurement of MABP and PR with a strain gauge and polygraph. The cat was then placed loosely in a head holder with the body prone and the EDP devices were connected to strain gauges by nondistensible catheters and continuous columns of bubble-free water. The volume of water sufficient to produce a recorded value of 5 mm Hg for EDP on a polygraph was injected into each device from a microliter syringe attached to a side arm. For each subsequent measurement of EDP the device was evacuated and this same volume of water was injected. Although EDP values were recorded as absolute mm Hg, the devices were thus standardized to an original value of 5 mm Hg, which is close to the normal EDP of cats? 1 The left MCA was occluded in 12 of the 13 cats by tightening the suture in the implanted occlusion device; the other cat served as a sham-operated control. Measurements of EDP, MABP, and PR were made at intervals
400
for up to 48 hours: immediately after MCA occlusion; at 30 seconds; at 1, 2, 5, 10, 20, 30, 45, 60, 90, 120, 150, and 180 minutes; hourly thereafter until 12 hours after occlusion; and at 14, 16, 18, 20, 24, 32, and 48 hours. Epidural pressure was measured only at 24 and 48 hours in the sham-operated cat. Additional phencyclidine hydrochloride was injected as necessary for sedation. After 48 hours of observations and measurements, the animals that survived were killed by the intraarterial injection of a saturated solution of potassium chloride. In all cats, 0.5 ml of India ink was injected into the left common carotid artery as soon after death as possible, for verification of MCA occlusion. The brain was removed, inspected grossly, and fixed in 10% formalin. Coronal sections of the fixed brain were made at the levels of the tips of the temporal lobes, the optic chiasm, and the posterior mammillary bodies. The sections were stained with hematoxylin and eosin for histopathological examination. Results
The findings in the 12 experimental cats are summarized in Table 1.
Relationships between EDP and Infarcts Transient bilateral decreases of EDP occurred in nine of the 12 cats (all but Cats 3, 6, and 11) at the time the implanted suture was tightened for MCA occlusion (Fig. 1, Table 1). The decreases ranged from 0.5 to 1.8 mm Hg, and persisted for less than 1 minute in all but Cat 12, in which EDP was still decreased at 2 minutes. Marked increases of EDP to maximum values greater than 30 mm Hg were recorded after MCA occlusion in five of the 12 cats. Two of these, Cats 1 and 5, died before the end of the observation period of 48 hours; tentorial herniation, greater on the side of occlusion, was noted on inspection of the brains of both. All five of these cats had large infarcts on the side of MCA occlusion involving not only the basal ganglia and internal capsule but extensive areas of the cerebral cortex as well (Figs. 2 and 3). Two of the infarcts (in Cats 3 and 4) were hemorrhagic (Fig. 2, Table 1). A small amount of subarachnoid blood was found under the left occipital lobe of Cat 1.
J. Neurosurg. / Volume 43 / October, 1975
o
4~ t~
20
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--
--
--
8
9
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11
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78.0
177.5
9.0
10,0
12.0
20.0
20.0
33.0
58.5
67.0
81.0
192.5
595
125
129
80t
93
107
151t
92
88 50,t
110w
98w
82:[:
75
78
84
81, then 112.+
9
48
48
6
48
48
48
12
48
48
48
14
PR at Time of 9 Survival Maximum EDP (~o of Initial Value) (hrs)
95w
113w
74:~
82
106
103
1705
* E D P = epidural pressure; M A B P = mean aortic blood pressure; P R = pulse rate; M C A = middle cerebral artery. t Died before 48 hours. ~t Recorded just before death. wRecorded earlier than time of maximal EDP.
24
7
90
5
20
a,4
4
6
21/2
3
I
1/2
4
Cat No
2
Time of First Value > 10 mm Hg (hrs)
EDP Time of Maximum Value Maximum Value Corresponding MABP at Time of on Side of on Side of Value Opposite Maximum EDP MCA Occlusion MCA Occlusion MCA Occlusion (7o of Initial Value) (hrs) (mm Hg) (ram Hg)
Infarct
moderate
small
small
large
moderate
moderate
moderate
large
large, hemorrhagic
large, hemorrhagic
large
large
EDP, MABP, PR, survival, and characteristics of infarcts in 12 cats with MCA occlusion, listed in order of decreasing maximum values of EDP*
TABLE 1
O
O
imo
t-
0 o
0
t~
T. Hayakawa and A. G. Waltz swelling or herniation of the brain was evident on inspection. The infarcts in the cats that survived the 48 hours of observation (Cats 10 and 11) were relatively small, with little involvement of cortex. No changes of EDP were recorded from the cat that had the surgical procedures without MCA occlusion, and no infarct was found on examination of the brain.
Relationships among EDP, MABP, and PR
FIG. 1. Polygraph recording from Cat 2 showing transient decreases of EDP bilaterally and transient increase of MABP immediately after MCA occlusion. Increases of EDP began relatively soon after MCA occlusion in the five cats that eventually had maximum values greater than 30 mm Hg, with values greater than 10 mm Hg recorded as early as 30 minutes and values greater than 20 mm Hg recorded as early as 21A hours after occlusion (Fig. 2, Table 1). In the two cats with hemorrhagic infarcts EDP was greater during the period of 3 to 6 hours after occlusion than in the other three cats, and EDP values greater than 20 mm Hg were recorded earlier (Figs. 2 and 3). Side-to-side pressure differences developed in all five of these cats; the pressure differences were greater at higher EDP with maximal differences ranging from 5.5 to 15.0 mm Hg (Figs. 2 and 3). Three of the 12 cats had moderate increases of EDP after MCA occlusion to maximum values of 12 to 20 mm Hg (Table 1). In these cats the infarcts involved cerebral cortex but were relatively smaller than those of the cats with greater increases of EDP (Fig. 4). Increases of EDP began later than 12 hours after MCA occlusion, and maximum values were recorded at 20 or 24 hours. Sideto-side pressure differences were small and variable, ranging from 0.5 to 3,5 mm Hg. Little or no change of EDP (all values 10.0 mm Hg or less) and no important side-to-side differences were recorded from four of the 12 cats with MCA occlusion (Table 1). Two of these four (Cats 9 and 12) died within 12 hours of MCA occlusion, about 1 hour after a sudden decrease of MABP (Fig. 5); the infarcts were moderate or large in size, but no 402
In six of the 12 cats, changes of MABP that were between 10% and 15% of the value recorded just before MCA occlusion occurred within 30 seconds of occlusion (Fig. 1). MABP increased in three (Cats 2, 3 and 5); these later had marked increases of EDP. MABP decreased in Cats 4, 7, and 9. There were no consistent changes of PR immediately after MCA occlusion. Cat 1 developed an increase of MABP and a decrease of PR associated with a rapid and severe increase of EDP just before death (Fig. 3). The other four cats with EDP values greater than 30 mm Hg also developed decreases of PR when EDP was high (Fig. 2, Table 1). Increases of MABP were not recorded from these cats; decreases were noted in Cats 4 and 5, but a terminal increase of MABP could have occurred in Cat 5 and not been detected. Cats 9 and 12 each developed severe hypotension just before death (Fig. 5); one of these had an increase of PR, the other a decrease. Cats 10 and 11 each developed moderate increases of MABP within 2 hours of occlusion. In all cats, fluctuations of MABP and PR occurred between the time of MCA occlusion and death or killing, but there were no consistent relationships to changes of EDP or the characteristics of the resulting cerebral infarcts other than those described above. No appreciable changes of MABP or PR were recorded in the cat with the operative procedures but without MCA occlusion. Discussion
Early Changes o f EDP after MCA Occlusion Previous studies of ICP in experimental models of acute focal cerebral ischemia, including those from this laboratory, have not provided reliable information about changes of ICP during the first few hours of ischemia
J. Neurosurg. / Volume 43 / October, 1975
Effects of occlusion of an MCA in cats
FIG. 2. Relationships among EDP, MABP, PR, and the infarct in Cat 4. Note early increases of EDP bilaterally, side-to-side pressure differences, and hemorrhagic changes in the infarct. H & E.
F~G. 3. Relationships among EDP, MABP, PR, and the infarct in Cat 1. Note Cushing response before death and side-to-side pressure differences.
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T. Hayakawa and A. G. Waltz
Ft~. 4. Relationships among EDP, MABP, PR, and the infarct in Cat 8.
FIG. 5. Relationships among EDP, MABP, PR, and the infarct in Cat 9. because of anesthesia, an open cranium, drainage of CSF, or an inappropriate model. 3'6'9'''18'~~ However, the present study has confirmed the findings of previous studies with respect to increases of ICP 24 hours or more after MCA occlusion. ",2~ In particular, side-to-side pressure differences of EDP again have been recorded, and with two exceptions changes of EDP have related well to the ex,404
tent and severity of the resulting cerebral infarcts. Early changes of EDP after MCA occlusion also appear to be related to the extent of cerebral ischemia, and in particular to involvement of cerebral cortex. Larger lesions not only cause greater increases of EDP but increases begin earlier than with smaller lesions, at times less than an hour after occluJ. Neurosurg. / Volume 43 / October, 1975
E f f e c t s of o c c l u s i o n of a n M C A in cats in cats with marked increases of EDP after MCA occlusion. The side-to-side differences probably do not represent pressure gradients in the CSF, as pressure in CSF spaces that are in continuity with one another must be equal, ls,16,~2 It is more likely that side-to-side differences are measured as the brain swells and CSF is displaced from beneath the EDP device, so that the pressure recorded as EDP is a reactive pressure from compression of the lschemia without an Increase o f ICP brain? ~as The reactive pressure will be higher Experimental cerebral ischemia does not than that of the CSF, and may vary from always result in edema that is sufficient to region to region because of local differences cause brain swelling and increases of ICP 6'" in the supporting structures of the brain, even if infarcts develop that are extensive blood volume, edema, or other factors. 23 A enough to involve cerebral cortex as well as more complete discussion of this subject is inthe basal ganglia and internal capsule, as in cluded in a previous report. 11 the present study. CSF pressure in humans likewise is variable after a stroke, and may Relationships among EDP, M A B P , and PR not increase; TM when CSF pressure does inThe transient changes of MABP that occrease, it usually does so because of brain swelling2 Infarcted tissue may become curred immediately after MCA occlusion in edematous without producing increases of six cats may have been due to manipulation of ICP in one or more of several ways: infarcted the artery and its accompanying sympathetic tissue may contain an increased proportion of nerves. Vasomotor instability after the first water yet not swell to an increased volume;~ few minutes of ischemia may have been focal increases of tissue pressure caused by related to effects of hypoxemia or of hemilimited swelling of an infarct may not be spheric ischemia on vasomotor centers, transmitted to the surface of the brain but directly or indirectly through neurogenic inmay be dissipated by the structural com- fluences. Minor fluctuations of MABP and ponents of cerebral tissue; '~,~a or swelling of PR did not appear to affect the outcome of the brain may be compensated for by changes the ischemic process or the extent of the of intracranial blood or CSF volume? 3,~ ~ resulting infarcts. However, vasomotor Focal increases of tissue pressure, however, effects of ischemia may have contributed to the major hypotension with which Cats 9 and may affect local tissue perfusion. T M Death early after the onset of acute focal 12 died. In addition, the moderate increases cerebral iscbemia may not always be related of MABP that occurred after MCA occlusion to edema, swelling, and increases of ICP. In in two cats that had small infarcts suggests a the present study, two cats died within 12 possible partial protective effect of moderate hours of MCA occlusion without increases of hypertension. In contrast to studies by others who used EDP. There was no tentorial herniation, and little swelling of the relatively large infarcts cerebral oil embolizationfl early increases of that were found in their brains on histo- EDP were not generally associated with pathological examination. The cause of death hypertension or tachycardia; when consistent in such situations is unclear, but both cats vasomotor changes occurred in cats with died with hypotension, suggesting direct or in- marked increases of EDP, the changes were direct involvement of vasomotor centers. those of a slowing of the pulse rate. A Alternatively, impairment of respiratory characteristic Cushing response of hypertenfunction, which was not measured, could have sion and bradycardia developed in Cat 1, caused hypoxemia and contributed to the which died with a markedly increased EDP and tentorial herniation. The other four cats death of the cats. with marked increases of EDP also had Side-to-Side Differences o f EDP bradycardia; although hypertension was not Supratentorial side-to-side pressure differ- recorded it may have occurred between ences of EDP, reported previously,1',~~again measurements, or terminally in Cat 5, which have been demonstrated in the present study died with tentorial herniation. sion. Thus, brain swelling from edema adequate to cause increases of ICP can occur after relatively brief periods of cerebral ischemia? .9," Immediate transient decreases of EDP that may occur after MCA occlusion probably are related to decreases of intracranial blood volume caused by decreased perfusion.
J. Neurosurg. / Volume 43 / October, 1975
405
T. H a y a k a w a
Pathogenesis o f Hemorrhagic Infarction The mechanisms involved in the development of hemorrhagic infarcts in the brain after arterial occlusion are obscure. MCA occlusion followed by hypertension may cause hemorrhagic infarcts; s.8~ however, in the present study the two cats that had moderate hypertension after occlusion actually had the smallest infarcts, without hemorrhagic changes. Similarly, cerebral ischemia adequate to cause disruption of endothelial integrity may or may not result in hemorrhagic infarction if the flow of blood is restored to the ischemic region. 5,27 In the present study, two hemorrhagic infarcts were found in the brains of cats with marked increases of E D P (Cats 3 and 4); in these cats, major increases of EDP occurred earlier but the maximum values for EDP were less than those for three other cats that had purely ischemic infarcts. Hemorrhage into the infarct may have accounted for the early increase of E D P ; alternatively, severe ischemia may have predisposed both to massive swelling and endothelial damage resulting in hemorrhage. Hypertension did not appear to be important for the development of hemorrhagic infarction in these cats; the M A B P of Cat 3 was 174 mm Hg 9 hours after M C A occlusion, but in Cat 4 fluctuations of M A B P after occlusion were no greater than those occurring in cats with infarcts not c o n t a i n i n g hemorrhage. N o hemorrhagic infarcts were encountered in the brains of cats without marked increases of EDP; hemorrhagic changes may occur more frequently in large infarcts, or hemorrhage into the infarct may result in a larger lesion. Unfortunately, no specific explanation for the pathogenesis of h e m o r r h a g i c infarcts is provided by the present study. Acknowledgments
Technical assistance and advice were provided by Terry Hansen and Margaret M. Jordan.
References
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a n d A. G. W a l t z
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J. Neurosurg. / Volume 43 / October, 1975
Effects of occlusion of an MCA in cats
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24.
pressure. 1. Within the craniospinal axis. J brain pressure. J Neurasurg 34:38-47, 1971 Neurosurg 21:989-997, 1964 25. Schettini A, Walsh EK: Experimental idenLangfitt TW, Weinstein JD, Kassell NF, et al: tification of the subarachnoid and subpial Transmission of increased intracranial compartments by intracranial pressure pressure. 2. Within the supratentorial space. J measurements, d Neurasurg 40:609-616, 1974 Neurosurg 21:998-1005, 1964 26. Shaw C-M, Alvord EC Jr, Berry RG: Swelling LBfgren J, Zwetnow NN: Cranial and spinal of the brain following ischemic infarction with arterial occlusion. Arch Neural 1:161-177, components of the cerebrospinal fluid pressure-volume curve. Acta Neural Scand 49: 1959 575-585, 1973 27. Sundt TM Jr, Waltz AG: Cerebral ischemia McQueen JD, Jelsma LF, Bacci F, et al: Exand reactive hyperemia: Studies of cortical perimental intracranial hypertension due to blood flow and microcirculation before, durvascular blockade. J Neurosurg 33:156-166, ing, and after temporary occlusion of middle 1970 cerebral artery of squirrel monkeys. Ore Res Ng LKY, Nimmannitya J: Massive cerebral 28:426-433, 1971 infarction with severe brain swelling: a 28. Symon L, Pasztor E, Branston NM, et al: clinicopathological study. Stroke 1:158-163, Effect of supratentorial space-occupying 1970 lesions on regional intracranial pressure and O'Brien MD, Waltz AG: Intracranial pressure local cerebral blood flow: an experimental gradients caused by experimental cerebral study in baboons. J Neural Neurosurg ischemia and edema. Stroke 4:694-698, 1973 Psychiatry 37:617-626, 1974 O'Brien MD, Waltz AG, Jordan MM: 29. Teraura T, Meyer JS, Sakamoto K, et al: Ischemic cerebral edema. Distribution of Hemodynamic and metabolic concomitants of water in brains of cats after occlusion of the brain swelling and cerebral edema due to exmiddle cerebral artery. Arch Neural 30: perimental cerebral infarction. J Neurosurg 456-460, 1974 36:728-744, 1972 Ommaya AK, Hekmatpanah J: Comments to 30. Waltz AG, Sundt TM Jr: The microSession 4: Focal Brain Damage (Experimenvasculature and microcirculation of the ceretal), in Brock M, Dietz H (eds): lntracranial bral cortex after arterial occlusion. Brain 90: Pressure: Experimental and Clinical As681-696, 1967 pects. Berlin/Heidelberg/New York, Springer-Verlag, 1972, pp 135-136 Reulen H J, Kreysch HG: Measurement of This investigation was supported in part by brain tissue pressure in cold induced cerebral USPHS Grant NS-3364. oedema. Aeta Neuraehir (Wien) 29:29-40, Address reprint requests to: Arthur G. Waltz, 1973 M.D., Department of Neurology, Pacific Medical Schettini A, McKay L, Majors R, et al: Ex- Center, P.O. Box 7999, San Francisco, California perimental approach for monitoring surface 94120.
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