Brain tissue pressure in focal cerebral ischemia

Transcription

1 J Neurosurg 62:83-89, 1985 Brain tissue pressure in focal cerebral ischemia FAUSTO IANNO'ITI, M.D., JULIAN T. Horr, M.D., AND GRALD P. SCHILK, M.S. Section of Neurosurgery, Department of Surgery, University of Michigan Hospitals, Ann Arbor, Michigan ~" Twenty-three anesthetized cats underwent permanent middle cerebral artery occlusion in a study of the relationships of regional cerebral blood flow, ventricular fluid pressure, brain tissue pressure, and ischemic edema formation. A pressure gradient of 8 mm Hg developed between ischemic tissue and normally perfused tissue during a 4-hour observation period after occlusion. Brain water accumulated as tissue pressure rose, while blood flow in the same area fell. The data suggest, but do not prove, that ischemic brain edema causes tissue pressure to rise focally, and that blood flow to the ischemic zone is compromised further by the resultant hydrostatic pressure gradient. Ky WORDS 9 intracranial pressure 9 brain tissue pressure 9 focal cerebral edema 9 ischemic brain edema p ROGRSSIV neurological deficit occurs in about 15 % of patients with stroke from cerebral arterial occlusion. ~9"24"27 Presumably the ischemic focus accounting for the deficit is an active, progressive, and enlarging one, or it is accompanied by secondary reactions in the surrounding tissue (such as edema formation) which enhance the initial ischemic insult. dema develops in ischemic brain soon after arterial occlusion. It forms initially within glia and neurons, causing the cellular space to swell and the extracellular space to shrink. 3'7'13 The increase in cellular water content has little effect on intracranial pressure (ICP) at first, because brain parenchyma is compliant and the insult is focal. Hours to days later, when the bloodbrain barrier opens and protein-rich fluid extravasates into the ischemic area, water accumulates and the brain swells. Then ICP, measured from the ventricles, rises as edema continues to form. 1~ Intracranial pressure, measured directly from brain tissue, may increase within the ischemic area as soon as cellular water content begins to rise. t~ That tissue pressure elevation likely develops during a period when overall brain compliance is adequate to compensate for the increasing water content in the ischemic zone, and when ICP, measured from the ventricles, remains unaltered. It is now possible to measure ventricular fluid pressure (VFP), brain tissue pressure, cerebral blood flow (CBF), and brain water content regionally in normal animals and in animals with focal cerebral ische- mia.4,5,~ 1,25,26,28,29,32,33 Thus, it is possible to study hydrostatic tissue pressure gradients within ischemic brain parenchyma, if they exist, and to relate those gradients to the process of ischemic brain edema and the effect of edema on perfusion of the ischemic area. In experiments described here, we tested the hypothesis that brain edema, resulting from a focal ischemic event, causes a hydrostatic pressure gradient to develop between normal and ischemic brain. We further suggest that that gradient adversely affects perfusion of the already ischemic tissue. Materials and Methods Preparation and Measurements Twenty-three mongrel cats, each weighing 2.8 to 3.4 kg, were anesthetized with intraperitoneal sodium pentobarbital (30 mg/kg). ach animal underwent tracheostomy, then was paralyzed with intravenous gallamine triethiodide (4 mg/kg), and mechanically ventilated. Cannulas (P-90) were placed in a femoral artery and vein to measure systemic arterial pressure (SAP), to sample arterial blood gases and hematocrit, and to administer fluids or drugs as necessary. Body temperature was monitored and maintained at 37 ~ to 380C using a heating pad. ach animal was placed prone in the sphinx position with the head fixed in a Kopf stereotaxic frame. Arterial Blood Gases. nd-tidal carbon dioxide (T-CO2) was monitored continuously from expired J. Neurosurg. / Volume 62/January,

2 F. Iannotti, J. T. Hoff and G. P. Schielke air by an infrared COz gas analyzer. The SAP and T-CO2 data were displayed on a Gould electrostatic recorder.* Arterial blood was sampled intermittently; PaCO2 ( mm Hg, mean _+ standard deviation), PaO2 (> 100 mm Hg), and ph (7.35 _+ 0.08) were maintained within physiological limits by ventilator adjustment. Ventricular Fluid Pressure. Ventricular fluid pressure was measured with a No. 23 needle inserted stereotaxically through a burr hole into the right lateral ventricle at the coordinates A12, L4.5, H+8 in 23 animals. 3~ The needle was connected by P 50 polyethylene tubing to a P23ID Statham transducer.t The signal was amplified by a pressure processor~ and recorded continuously. The system was zeroed at the level of the interaural line.12 Tissue Pressure. Tissue pressure was measured from the tip of a No. 23 needle (outer diameter = mm, inner diameter = ram). The needle was attached to a Statham pressure transducer by P 50 semirigid tubing through a four-way stopcock. The stopcock was in turn attached to a 1-cc tuberculin syringe held in a Harvard infusion pump.w The system was filled with saline free of air bubbles and leaks which might cause high compliance or pressure artifact. Pressure was measured continuously by the electrostatic recorder. Two tissue pressure needle systems were used in each experiment. A No. 23 tissue pressure needle was inserted stereotaxically through a burr hole into the caudate nucleus at the coordinates Al6, L5, H+4. 3~ The system was zeroed at the level of the interaural line. Saline was injected through the needle by the infusion pump during insertion to prevent air bubble formation at the tip of the needle. The infusion, at a rate of 0.01 ul/sec, was stopped when the needle reached its predetermined position. No more than 0.1 ul was infused during insertion. The burr hole was then sealed with dental acrylic cement to prevent loss of cerebrospinal fluid (CSF). A pulsatile pressure synchronous with ventilation was observed immediately after insertion of the tissue pressure needle. This initial pressure, which was positive and higher than VFP, fell soon thereafter, reaching a steady state after 40 to 60 minutes. The time for equilibration was probably related to delayed dispersion of * Gould electrostatic recorder, Model S 1000, manufactured by Gould, Inc., Instruments Division, 3631 Perkins Ave., Cleveland, Ohio. t P 50 polyethylene tubing and P23ID transducer manufactured by Statham Medical Instruments, Los Angeles, California. :~ Pressure processor, Model , manufactured by Gould, Inc., Instruments Division, 3631 Perkins Ave., Cleveland, Ohio. w Harvard infusion pump, Model 945, manufactured by Harvard Apparatus Co., Inc., The aling Corp., 22 Pleasant St., South Natick, Massachusetts. local pressure caused by penetration of the needle through the brain tissue. Measurements taken prior to reaching steady state were discarded. Pulsatile waveforms were usually maintained for 60 to 90 minutes, after which ventilatory waves began to attenuate and pressure to fall. An infusion of 0.1 to 0.2 ~1 of saline over 10 to 20 seconds usually restored the waveform. Although pressure returned to steady state within 3 to 5 minutes following the infusion, measurements were not taken until at least 15 minutes later. When 0.2 ta was infused during the steady-state period, pressure rose by 1 to 3 mm Hg, but returned to the preinfusion value within 5 minutes. A system was considered inadequate if it did not allow steady-state pressure to be maintained for a period of at least 60 minutes. No more than 0.2 ul/hr per needle was infused in any one experiment. Infusions in the fight and left caudate nuclei were always made simultaneously. Blood Flow. Regional cerebral blood flow (rcbf) was measured by the hydrogen clearance technique in all 23 cats. A 250-u diameter Teflon-coated platinumiridium electrode, with the tip exposed 0.5 to 0.7 mm, was placed stereotaxically 1.0 mm posterior to each tissue pressure probe. ach electrode was polarized mv to a silver-silver chloride reference electrode placed in the temporal muscle. Hydrogen gas (7% to 10%) was administered for about 2 minutes through the inspired air and then discontinued abruptly. The desaturation curves were analyzed by the initial slope method 23 and rcbf was expressed as ml. 100 gm -~. min-l Blood-Brain Barrier. All animals received 8 ml of vans blue dye (2% in 0.9% saline) as an indicator of blood-brain barrier permeability 30 minutes before sacrifice. Middle Cerebral Artery Occlusion The left middle cerebral artery (MCA) was exposed transorbitally through an enlarged optic foramen. 2~ After the dura was opened and the arachnoid around the artery was incised, the artery was occluded with bipolar coagulation. The dural opening was sealed with oxidized cellulose and rapid-drying glue to prevent any CSF leak. Occlusion of each artery was confirmed post mortem. 9 Sham occlusion of the MCA was performed in three animals. The three were sacrificed 4 hours later. xperimental Protocol After control measurements, the MCA was occluded in 20 cats. During occlusion, VFP, tissue pressure, SAP, and T-CO2 were displayed continuously on the recorder. Regional CBF was measured 15 minutes, 60 minutes, and then hourly after occlusion. ight cats were sacrificed after 1 hour of occlusion, and 12 after 4 hours of occlusion. Animals were sacrificed with an overdose of intravenous barbiturate. 9'~2 After sacrifice the whole brain was removed rapidly, 84 J. Neurosurg. / Volume 62/January, 1985

3 Brain tissue pressure in cerebral ischemia wrapped in waxed paper, and chilled at 9~ for 15 minutes. Coronal sections (2 mm thick) were then cut at the level of the tissue pressure probes and placed in kerosene. Samples were taken by a l-ram curette from the area of brain surrounding each tissue pressure probe and placed immediately in a bromobenzene-kerosene column for specific gravity determination. ~4,~7 Water content in the region of the internal capsule adjacent to the caudate nucleus was also measured in six cats after 4 hours of MCA occlusion. Care was taken to avoid sampling of vans blue-stained tissue which might cause calculation errors for water content. 17 Results Neither MCA exposure nor MCA occlusion had a significant effect on arterial blood gases, SAP, or hematocrit in any of the 23 sham-operated or experimental cats during each experiment. Sham Controls In the three sham-operated cats, MCA exposure failed to change rcbf in the ipsilateral caudate nucleus. The rcbf fell slightly from a control level of 36.0 _+ 6.4 to 35.3 _+ 7.2 ml. 100 gm-l.min -~ 15 minutes after sham occlusion and did not change significantly during the ensuing 4 hours of observation. xposure of the MCA caused an immediate decrease in both VFP and tissue pressure. Thirty to 40 minutes after the skull was sealed, pressures returned to control values and remained stable over the 4 hours of observation. No pressure gradient developed at any time during the sham experiments. Water content of the caudate nucleus was not affected by MCA exposure, and alterations in blood-brain barrier were not revealed by vans blue dye tissue staining. MCA Occlusion Threshold for dema Formation. Occlusion of the MCA in all 20 cats caused an immediate fall in rcbf in the ipsilateral caudate nucleus. Measured 10 to 15 minutes after occlusion, rcbf was _ ml. 100 gm -~.min-~, with a range of 5 to 28 ml. 100 gm -~ 9 min-l When this initial rcbf value was correlated with the water content that later developed in the area, a blood flow threshold for the development of edema became apparent (Fig. 1). Water accumulated in the caudate nucleus if the initial rcbf was below 18 ml. 100 gm -~ 9 min -~. The presence of this threshold led to analysis of the relationships of flow and water homeostasis in the 20 cats with MCA occlusion. For the purpose of this study, blood flow reduction which consistently correlated with edema formation was termed "critical ischemia." Critical Ischemia. Values for rcbf, tissue pressure, and VFP were recorded in seven cats sacrificed after 1 hour of severe ischemia. Immediately after occlusion, rcbf decreased approximately 75% and then fell further with time. Ten to 15 minutes after the left MCA I-- LI.I I-- 0 (J ill:: hi l " 8O 78 I 9 Caudote nucleus ipsiloteral to the occlusion 9 Contralateral coudate I I I I i [ [ I I I I I rcbf (ml.lo0 ~-I.min-I ) FIG. 1. Regional cerebral blood flow (rcbf) threshold for edema. The rcbf values immediately after occlusion are related to water content of brain from the same area 1 or 4 hours after arterial occlusion. Note the threshold for edema formation when initial flow was below 18 ml. 100 gm -~. min-l was occluded, tissue pressure in the ischemic area was higher than on the contralateral side. After 1 hour of occlusion, a significant (p < 0.002) pressure gradient between the ischemic and the nonischemic caudate nucleus was evident. In the nonischemic side tissue pressure was equal to VFP. While water content of the nonischemic caudate was 78.90% _+ 0.21%, water content of the ischemic caudate was 80.91% _+ 0.36%, indicating significant (p < 0.001) edema formation. In nine cats with MCA occlusion for 4 hours, rcbf in the ipsilateral caudate decreased from initially to _ ml. 100 gm-l.min -~ by 60 minutes, followed by a slow decline to 5.87 _ ml. 100 gm -~.min -~ terminally (Fig. 2). On the contralateral side, flow fell slightly at the beginning of the ischemic period, then remained stable for 4 hours. In the nine animals sacrificed 4 hours after MCA occlusion, tissue pressure in the ischemic caudate rose progressively, in contrast to the tissue pressure on the normally perfused side. Normal caudate tissue pressure and VFP did not rise significantly during the 4 hours following occlusion (Fig. 3). Water content in the ischemic caudate increased from 78.80% _+ 0.49% to 82.48% _+ 0.72% after 4 hours of ischemia in the same nine animals (Fig. 4). In six of these nine cats, white matter adjacent to the ischemic caudate showed a small though significant (p < 0.05) increase in water content. On the contralateral side neither the caudate nucleus nor the white matter showed any change in water content. Non-Critical Ischemia. The fall in blood flow after occlusion was above the threshold for edema formation in four of the 20 cats. One had occlusion for 1 hour and three had occlusion for 4 hours. After an initial J. Neurosurg. / Volume 62/January,

4 i F. Iannotti, J. T. Haft and G. P. Schielke 60 ' _o 2o 9 Right C0udote 9 Left Coudate 84 Caudote internal Nucleus Capsule 82 7o LU W I- z 80 T 68 z ~ o o I "' //~ t J t 9 I FIG. 2. Critical ischemia level. The regional cerebral blood flow (rcbf) values after left middle cerebral artery occlusion () fell sharply within minutes, then fell further over the 4-hour observation period on the same side. The rcbf tended to fall over the same period on the contralateral side, but the threshold for edema formation was never reached and the downward trend was not significant. modest reduction, rcbf remained stable for 1 hour, then rose spontaneously, possibly indicating the recruitment of collateral circulation in the three cats followed for 4 hours (Fig. 5 left). Since occlusion of the artery was verified at the end of each experiment, incomplete occlusion of the MCA did not account for the failure of caudate ischemia to develop. No difference was found between pre-occlusion flows in this group and those in the group with critical ischemia, indicating that control rcbf prior to occlusion was comparable be w W o- 5 Control ~ 0.25 I y//i L R L [y~ R L FIG. 3. Tissue pressure gradient during critical ischemia. Right ventricular fluid pressure (V), right caudate tissue pressure (R), and left caudate tissue pressure (L) are shown before and after left middle cerebral artery occlusion (). Note the pressure gradient that developed over 4 hours between the left ischemic caudate and the normally perfused right caudate. The ventricular fluid pressure and right caudate tissue pressure did not differ. R k L FIG. 4. Water content of brain tissue. dema formation was apparent only in the ischemic caudate 4 hours after left middle cerebral artery occlusion. tween the two groups. No edema was found at the end of occlusion and no pressure gradients developed (Fig. 5 right). Time Factor in dema Formation. All 20 cats with MCA occlusion (eight for 1 hour, 12 for 4 hours) had a decrease in blood flow initially. Thus, both the 1-hour and the 4-hour groups were subjected initially to the same degree of ischemia. The difference (p < 0.001) in water content of ischemic brain between the two groups (80.90% % versus 82.48% _+ 0.72%) was apparently related to the duration of the ischemic event. More edema developed in cats with occlusion for 4 hours than in those with occlusion for 1 hour. Alterations in Blood-Brain Barrier. Blood-brain barrier permeability, as shown by visible vans blue staining, was preserved in all animals with focal ischemia for up to 4 hours. The absence of a blood-brain barrier defect after 4 hours of continuous ischemia was consistent with previous findings. 1o, 13,22 Water content of the ischemic caudate was correlated with VFP and left tissue pressure was measured immediately before sacrifice. The amount of edema had little effect on VFP (Fig. 6 left). Although accurate pressure/ volume relationships for the intracranial space could not be established because the volume of the edematous area was not measured, it appeared that the increase in volume of edematous tissue was accommodated without a substantial change in VFP 15'16'18 (Fig. 6 left). Tissue pressure reacted differently. An increase in tissue volume caused a parallel increase in tissue pressure (Fig. 6 right). The difference in compliance between the intracranial compartment considered as a whole, and the tissue as a part of the whole, was more evident when the pressure gradient, expressed as tissue pressure minus VFP, was related to the actual water content of the ischemic area (Fig. 7). The maximum pressure gradient corresponded to the maximum degree of edema. 86 J. Neurosurg. / Volume 62/January, 1985

5 Brain tissue pressure in cerebral ischemia ii~ 60 O _o 4O zo 0 9 Riqht Caudate 9 Left Coudate I J J,r~ I 2 3 4,.t Control l 0.25 I FIG. 5. Non-critical ischemia. Left: Regional cerebral blood flow (rcbf) values after left middle cerebral artery occlusion () in three animals observed for 4 hours and in one animal observed for 1 hour. Flow in these four animals fell initially but not below the threshold for edema formation identified in Fig. 1. Right. Ventricular fluid (V) and tissue pressure from the fight (R) and left (L) caudate nuclei are shown in the same four animals. A pressure gradient did not develop when the initial flow reduction was above 18 ml. 100 gm -~.rain-~. Discussion In addition to standard techniques for measuring rcbf, VFP, and brain water content, our current study required accurate recording of hydrostatic pressures from brain parenchyma. We have previously described a reliable means of tissue pressure monitoring in cats, using a fluid-filled No. 23 needle, stereotaxically placed in deep gray or white matter, coupled by low-compliance tubing and connectors to a standard strain gauge and a recording apparatus. 12 When combined in a single experiment, these techniques allowed us to measure VFP, rcbf, and tissue pressure simultaneously from ischemic and normally perfused brain before and after MCA occlusion. The model enabled us to study flow and ICP relationships after a focal ischemic event as well as the degree of edema formation in the ischemic zone terminally. Our purposes were to demonstrate that: 1) severe brain ischemia causes edema formation early; 2) ischemic edema causes focal elevation of hydrostatic pressure, establishing a pressure gradient between ischemic and normally perfused areas; and 3) a pressure gradient adversely affects blood flow in the area of ischemia, possibly by mechanical compression of the capillary bed. Regional CBF and brain water were measured from the caudate nucleus because earlier studies from our laboratory showed that this large, deep structure is most predictably involved when the ipsilateral MCA is occluded proximal to the lateral lenticulostriate artery. 9 Stereotaxic placements of both an rcbf electrode and a tissue pressure needle within 1 mm of each other assured recording from corresponding areas ipsilateral and contralateral to arterial occlusion in the area most likely to be affected by the insult. Reduction in caudate CBF occurred in all 20 animals with MCA occlusion. This initial reduction was severe in 16, and was followed by a further decline over 4 hours. A similar trend followed an early reduction in CBF on the side opposite to the occlusion, but that change was not significant in our study. The fact that 16 A "I- 12 -le A o= I- 15 / 8 O. d. I--- A,= 5 5 8~ 7'8 WATR CONTNT (%) ' 8~ ' 8~ ' 8', FIG. 6. Water content and intracranial pressures. Left: Ventricular fluid pressure (VFP) failed to change even though edema developed in the ischemic left caudate. Right: Left caudate tissue pressure (TP) increased proportionally as edema developed in the same tissue. -4 ~';8 ' ' ' i = I i WATR CONTNT(%) FIG. 7. Water content and pressure gradient. The left caudate tissue-ventricular fluid pressure gradient (TP-VFP) measured immediately prior to sacrifice is related to water content m the ischemic area. The magnitude of the gradient is a function of edema formation. J. Neurosurg. / Volume 62/January,

6 F. Iannotti, J. T. Hoff and G. P. Schielke CBF falls in brain opposite the side of arterial occlusion within 4 hours and is accompanied by increased water content has been shown before. 21 Water content in the ischemic caudate rose significantly within 1 hour of arterial occlusion in seven of eight animals. Tissue water continued to rise over the next 3 hours, provided rcbf was less than 20 ml- 100 gm -I 9 min -l. Similar threshold flow values have been shown in focal ischemia experiments by others, not only for water accumulation, but also for electrical activity and cell membrane ionic transport. 1'2'6"11'18 Water content in the caudate remained unchanged in our study when flow to the ischemic zone exceeded 20 ml. 100 gm -1.min-1. The flow threshold for edema formation found in four of our 20 animals was consistent with earlier studies. 1.2,31 dema after 4 hours of ischemia was more obvious in the gray matter of the caudate than in the white matter of the internal capsule adjacent to it. The current study did not demonstrate significant white matter edema after MCA occlusion, probably because edema did not spread to it during the relatively short observation period after occlusion. 21 dema in the internal capsule might have appeared later, however, when blood-brain barrier permeability had increased and vans blue-labeled albumin and water extravasated from the capillaries in the ischemic caudate.10"13'16 Tissue pressure in the caudate was allowed to reach steady state prior to MCA occlusion. When CSF escaped through the enlarged optic foramen during dissection of the MCA, tissue pressure fell and remained atmospheric until the MCA was occluded and the foramen was sealed. Within 1 hour of sealing, the tissue pressure rose in the ischemic caudate and continued to rise. Conversely, tissue pressure in the normally perfused caudate returned to steady state by 1 hour and then did not rise significantly for the duration of the experiment. As a consequence, a hydrostatic pressure gradient between the ischemic and the normal caudate developed early and increased progressively, reaching nearly 8 mm Hg terminally. That gradient, unassociated with a blood-brain barrier defect, was associated with progressive edema and ischemia in the caudate ipsilateral to the occlusion. Ventricular fluid pressure failed to change, even though tissue pressure was 8 mm Hg higher a few millimeters away. Similar pressure gradients in brain parenchyma have been shown in the presence of vasogenic edema induced by cold injury. ',~s.16 Capillary lumen closing pressure in normal brain parenchyma is about 35 mm Hg, although accurate measurements are lacking Closing pressure in poorly perfused brain may be less. Whether 8 mm Hg of extrinsic pressure on the capillary exerts enough force to affect the flow of blood through its lumen remains speculative. vidence from our experiments implies, however, that mechanical compression of the capillary bed by swollen brain cells does occur, and that it happens early before the blood-brain barrier opens and vasogenic edema develops. We have not yet proven the hypothesis that increasing edema causes tissue pressure to rise and compress the capillary bed enough to affect blood flow adversely. I~ Further experiments designed to manipulate either blood flow to the ischemic zone or the edema process itself may provide additional evidence to support the hypothesis. References 1. Astrup J, Siesj6 B, Symon L: Thresholds in cerebral ischemia--the ischemic penumbra. Stroke 12: , Astrup J, Symon L, Branston NM, et al: Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. Stroke 8:51-57, Branston NM, Strong A J, Symon L: Impedance related to local blood flow in cerebral cortex. J Physiol (Lond) 275:81P-82P, Brock M, Winkelmfiller, Prll W, et al: Measurement of brain-tissue pressure. Lancet 1: , 1972 (Letter) 5. Cervrs-Navarro J, Ferszt R, Artigas J, et at: A modified method for monitoring intracerebral pressure in brain edema, in Cervrs-Navarro J, Ferszt R (eds): Brain dema. Advances in Neurology, Vol 28. New York: Raven Press, 1980, pp Crockard A, Iannotti F, Hunstock AT, et al: Cerebral blood flow and edema following carotid occlusion in the gerbil. Stroke 11: , Fenstermacher JD, Patlak CS: The movements of water and solutes in the brains of mammals, in Pappius HM, Feindel W (eds): Dynamics of Brain dema. Berlin/Heidelberg/New York: Springer-Verlag, 1976, pp Guyton AC, Granger H J, Taylor A: Interstitial fluid pressure. Physiol Rev 51: , HoffJT, Nishimura M, Newfield P: Pentobarbital protection from cerebral infarction without suppression of edema. Stroke 13: , Hossmann KA, Schuier FJ: xperimental brain infarcts in cats. I. Pathophysiological observations. Stroke 11: , Iannotti F, Hoff JT: Ischemic brain edema with and without reperfusion: an experimental study in gerbils. Stroke 14: , Iannotti F, Hoff JT, Schielke GP: Brain tissue pressure: physiological observations in anesthetized cats. J Neurosurg 60: , Klatzo I: Neuropathological aspects of brain edema. J Neuropathol xp Neurol 26:1-14, Marmarou A, Poll W, Shulman K, et al: A simple gravimetric technique for measurement of cerebral edema. J Neurosurg 49: , Marmarou A, Shulman K, Shapiro K, et al: The time course of brain tissue pressure and local CBF in vasogenic edema, in Pappius HM, Feindel W (eds): Dynamics of Brain dema. Berlin/Heidelberg/New York: Springer- Verlag, 1976, pp Marmarou A, Takagi H, Shulman K: Biomechanics of brain edema and effects on local cerebral blood flow, in Cervrs-Navarro J, Ferszt R (eds): Brain dema. Advances in Neurology, Vol 28. New York: Raven Press, 1980, pp Marmarou A, Tanaka K, Shulman K: An improved 88 J. Neurosurg. / Volume 62/January. 1985

7 Brain tissue pressure in cerebral ischemia gravimetric measure of cerebral edema. J Neurosurg 56: , Matsuoka Y, Hossmann KA: Cortical impedance and extracellular volume changes following middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab 2: , Ng LKY, Nimmannitya J: Massive cerebral infarction with severe brain swelling: a clinicopathological study. Stroke 1: , O'Brien MD, Waltz AG: Transorbital approach for occluding the middle cerebral artery without craniectomy. Stroke 4: , O'Brien MD, Waltz AG, Jordan MM: Ischemic cerebral edema. Distribution of water in brains of cats after occlusion of the middle cerebral artery. Arch Neurol 30: , Olsson Y, Crowell RM, Klatzo I: The blood-brain barrier to protein tracers in focal cerebral ischemia and infarction caused by occlusion of the middle cerebral artery. Acta Neuropathol 18:89-102, Pasztor, Symon L, Dorsch NWC, et al: The hydrogen clearance method in assessment of blood flow in cortex, white matter and deep nuclei of baboons. Stroke 4: , Plum F, Posner JB, Alvord C Jr: dema and necrosis in experimental cerebral infarction. Arch Neurol 9: , Reulen HJ, Graham R, Spatz M, et al: Role of pressure gradients and bulk flow in dynamics of vasogenic brain edema. J Neurosurg 46:24-35, Reulen H J, Kreysch HG: Measurement of brain tissue pressure in cold induced cerebral oedema. Acta Neurochir 29:29-40, Ropper AH, Shafran B: Brain edema after stroke. Clinical syndrome and intracranial pressure. Arch Nenrol 41: 26-29, Shulman K, Marmarou A, Weitz S: Gradients of brain interstitial fluid pressure in experimental brain infusion and compression, in Lundberg N, Pontrn U, Brock M (eds): Intracranial Pressure II. Berlin/Heidelberg/New York: Springer-Verlag, 1975, pp Snashall PD, Lucas J, Guz A, et al: Measurement of interstitial "fluid" pressure by means of a cotton wick in man and animals: an analysis of the origin of the pressure. Clin Sci 41:35-53, Snider RS, Niemer WT: A Stereotaxic Atlas of the Cat Brain, ed 2. Chicago: University of Chicago Press, Symon L, Branston NM, Chikovani O: Ischemic brain edema following middle cerebral artery occlusion in baboons: relationship between regional cerebral water content and blood flow at 1 to 2 hours. Stroke 10: , Tulleken CAF, Meyer JS, Ott O, et al: Brain tissue pressure gradients in experimental infarction recorded by multiple wick-type transducers, in Lundberg N, Pontrn U, Brock M (eds): Intracranial Pressure II. Berlin/Heidelberg/New York: Springer-Verlag, 1975, pp Young W: H2 clearance measurement of blood flow: a review of technique and polarographic principles. Stroke 11: , 1980 Manuscript received April 5, Accepted in final form September 4, 1984, This work was supported by Grant NS from the National Institutes of Health, Bethesda, Maryland. This paper was presented at the Annual Meeting of the American Academy of Neurological Surgeons at Pebble Beach, California, on October 25, Present address for Dr. Iannotti: Institute of Neurological Surgery, First Medical College, Via Colli Aminei 21, Naples, Italy. Address reprint requests to: Julian T. Hoff, M.D., Section of Neurosurgery, Department of Surgery, University of Michigan Hospitals, Ann Arbor, Michigan J. Neurosurg. / Volume 62/January,