Cerebral blood flow decreased by adrenergic stimulation of cerebral vessels in anesthetized newborn pigs with traumatic brain injury

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✓ Changes in cerebral blood flow (CBF), pial arteriolar diameter, and arterial blood pressure, gases, and pH were examined before and for 3 hours after fluid-percussion brain injury in α-chloralose-anesthetized piglets. The brain injury was induced by a percussion of 2.28 ± 0.06 atm applied for 23.7 ± 0.5 msec to the right parietal cortex. Regional CBF was measured with radiolabeled microspheres, and changes in pial arteriolar diameter were monitored in the left parietal cortex using closed cranial windows. Immediately following brain injury, mean blood pressure transiently (for approximately 10 minutes) either increased or decreased and then exhibited a prolonged decrease in all of the animals. The brains showed changes consistent with traumatic brain injury such as subarachnoid hemorrhage, contusions, or reactive axonal swelling; none showed histological evidence of a global alternative pathogenetic mechanism such as hypoxic ischemic damage. While CBF of uninjured control animals did not change over a 3-hour observation period, after brain injury blood flow decreased 30% ± 1% below the baseline level within 10 minutes and remained there for 2 to 3 hours posttrauma. After adrenergic blockade, CBF did not decrease at any time during the 3-hour period in either the uninjured control or the injured animals. Concomitant with the decreased blood flow after brain injury, pial arteriolar diameter decreased 14% below the preinjury level. However, in piglets treated with adrenoceptor antagonists, uninjured control and brain-injured animals did not show a decrease in pial arteriolar diameter. The present results support the hypothesis that increased sympathetic outflow to the cephalic vasculature following the fluid-percussion brain injury causes cerebral vasoconstriction decreasing pial arteriolar diameter and regional CBF.

Abstract

✓ Changes in cerebral blood flow (CBF), pial arteriolar diameter, and arterial blood pressure, gases, and pH were examined before and for 3 hours after fluid-percussion brain injury in α-chloralose-anesthetized piglets. The brain injury was induced by a percussion of 2.28 ± 0.06 atm applied for 23.7 ± 0.5 msec to the right parietal cortex. Regional CBF was measured with radiolabeled microspheres, and changes in pial arteriolar diameter were monitored in the left parietal cortex using closed cranial windows. Immediately following brain injury, mean blood pressure transiently (for approximately 10 minutes) either increased or decreased and then exhibited a prolonged decrease in all of the animals. The brains showed changes consistent with traumatic brain injury such as subarachnoid hemorrhage, contusions, or reactive axonal swelling; none showed histological evidence of a global alternative pathogenetic mechanism such as hypoxic ischemic damage. While CBF of uninjured control animals did not change over a 3-hour observation period, after brain injury blood flow decreased 30% ± 1% below the baseline level within 10 minutes and remained there for 2 to 3 hours posttrauma. After adrenergic blockade, CBF did not decrease at any time during the 3-hour period in either the uninjured control or the injured animals. Concomitant with the decreased blood flow after brain injury, pial arteriolar diameter decreased 14% below the preinjury level. However, in piglets treated with adrenoceptor antagonists, uninjured control and brain-injured animals did not show a decrease in pial arteriolar diameter. The present results support the hypothesis that increased sympathetic outflow to the cephalic vasculature following the fluid-percussion brain injury causes cerebral vasoconstriction decreasing pial arteriolar diameter and regional CBF.

Alterations in cerebral hemodynamics following percussive brain injury may affect brain function recovery processes. Decreased cerebral blood flow (CBF) following brain injury may cause asphyxic/ischemic brain damage, and increased CBF may damage the blood-brain barrier and contribute to elevated intracranial pressure. However, it is not clear how CBF is temporally affected by percussive brain injury. It has been reported that CBF decreases early after the injury4,21,34 but then increases 24 hours postinjury in patients over 3 years of age.3,26,33 In animal models of percussive brain injury, CBF falls acutely in rats2,36,43 and cats;11,28 however, there are also reports that percussive brain injury induces pial arteriolar dilation in cats.13,46 Brain injury has been reported in infants,12,24,41 including the so-called “shaken baby syndrome;” however, in contrast to adults and older children, reports on infant brain injury are very limited, and clinical studies of cerebral hemodynamic changes following brain injury are scarce.

The present study was undertaken to characterize acute changes in cerebral hemodynamics subsequent to fluid-percussion brain injury in an infant animal model. We hypothesized that increased sympathetic outflow to the cephalic vasculature may cause decreases in CBF immediately following brain injury. Our results indicate that CBF and pial arteriolar diameter decrease immediately after injury, and that both decreases are blocked by adrenoceptor antagonists, consistent with the working hypothesis.

Materials and Methods
Animal Preparation

Thirty-three newborn pigs of both sexes, each weighing between 1.1 and 2.1 kg, were initially anesthetized intramuscularly with ketamine hydrochloride (33 mg/kg) and acepromazine (3.3 mg/kg) and maintained throughout the experiments on intravenous α-chloralose (initial dose of 50 mg/kg, followed by hourly doses of 5 mg/kg). Rectal temperature of the animals was maintained between 37° and 38°C by an electric heating pad. The femoral artery and vein were catheterized with a polyethylene (PE)-80 catheter for monitoring blood pressure, blood gases, and pH, and administration of anesthetic or fluid, respectively. The other femoral artery was also catheterized, with a PE-100 catheter, for reference withdrawal of blood during microsphere injections. A polyurethane catheter was placed in the left ventricle via the right carotid artery for microsphere injections to assess CBF changes. It has been demonstrated that ligation of one carotid artery does not affect CBF or its distribution in piglets.22,23

After intubation, the animals were fixed in a head frame and artificially ventilated with air. An opening in the skull 2 cm in diameter was made over the left parietal cortex. The dura was cut and reflected over the skull to expose the cortical surface. A cranial window, made of circular stainless steel with a glass pane and equipped with inlet and outlet ports, was placed into the opening and fixed to the skull with acrylic dental cement. An additional smaller opening 1 cm in diameter was made over the right parietal cortex with the dura intact. A metal adapter (14.5 mm in inner diameter, 17.0 mm in outer diameter, and 12.0 mm high) with a narrow circular wing around it was placed over the opening and fixed to the skull with cement. The whole assembly was secured by four anchor screws inserted into the skull.

The closed cranial window was filled with approximately 500 µl of warmed artificial cerebrospinal fluid (CSF) gassed with 6% CO2/6% O2 in N2. The artificial CSF typically exhibited pCO2 ranging from 35 to 41 mm Hg, pO2 from 42 to 48 mm Hg, and pH from 7.41 to 7.49. Piglet artificial CSF was prepared as follows (in mM): 132.0 NaCl, 3.0 KCl, 1.5 MgCl2, 2.5 CaCl2, 6.6 urea, 3.7 dextrose, and 24.6 NaHCO3. After the fluid-percussion injury device was connected to the brain via the preimplanted adapter, the closed cranial window was illuminated and the microscopic objective (connected to a videocamera) was set above the window. The image of the exposed cortical surface was projected onto a video monitor. Pial arterioles with a diameter of 83 to 123 µm were chosen; their diameters were measured via a dimensional analysis system.

Induction of Fluid-Percussion Brain Injury

The device to produce fluid-percussion brain injury was made by the Department of Bioengineering, Medical College of Virginia.30,31 It consists of a pendulum and a horizontally positioned Plexiglas cylinder (4.5 cm in diameter, 60.0 cm long) equipped with a piston via an O-ring at one end. The other end of the cylinder was connected to an L-shaped stainless steel pipe (either 3.5 cm or 4.0 cm in length, 14.0 mm in outer diameter, and 9.0 mm in inner diameter) attached to a preimplanted adapter mounted over the right parietal cortex. The entire system was filled with 0.9% saline and maintained airtight. Brain injury was caused by striking the piston with the pendulum (weighing 4.8 kg) released at between 23° and 25° from the vertical. By varying the angle from which the pendulum was allowed to swing down, one can regulate the intensity of the impact. The impact was detected by a high-pressure transducer fixed inside the L-shaped pipe close to the brain, and recorded on a storage oscilloscope* as an upward pulse deflection. The height and width of the pulse represented, respectively, the intensity and duration of the impact, expressed in atmospheres and milliseconds. The rebounding pendulum was prevented manually from striking the piston more than once.

Determination of Cerebral Blood Flow

Regional CBF was determined using a maximum of six radiolabeled microspheres, 15 µm in diameter. These microspheres were labeled with different isotopes (46scandium, 95niobium, 103ruthenium, 113tin, 57cobalt, and 109cadmium). A known number of microspheres (ranging from 300,000 to 800,000 spheres) with 1 to 3 million counts were injected into the left ventricle over 1 minute by flushing the vial containing microspheres with 5-ml saline while agitating the vial continuously. Withdrawal of reference blood at a constant rate (1.03 ml/min) from the femoral artery began 15 seconds before microsphere injection and was continued until 1 minute after the injection had been completed. At the end of the experiments, the piglets were killed with saturated KCl. The brain and spinal cord were removed and subdivided into seven regions: the right and left cerebrum, caudate nucleus, diencephalon-mesencephalon, pons, medulla oblongata, and cerebellum. Radioactivity was then measured using a gamma counter. The caudate nucleus and diencephalon-mesencephalon were taken from both hemispheres, and their counts were averaged. The overlapping energies from the nuclides were separated from one another by differential spectroscopy. Blood flow was calculated and expressed in ml/100 gm tissue/minute.

Adrenergic Blockade

We have previously reported that pial arteriolar constriction is induced by the activation of the cephalic vasculature sympathetic system by electrical stimulation of the superior cervical ganglia.6,16 This vasoconstriction is blocked by the intravenous injection of 1 mg/kg of the α2-adrenoceptor antagonist yohimbine. Effects of the antagonist in these studies lasted for more than 1 hour. In addition, these studies indicated that not only yohimbine but also α1-adrenoceptor antagonist prazosin can cross the blood-brain barrier. In order to block the cephalic vasculature adrenergic system chemically in the present study, piglets were injected with both α1- and α2-adrenoceptor antagonists in doses of 1 mg/kg each prior to brain injury. Each antagonist was dissolved with 0.9% saline in the volume of 1 ml and was intravenously injected.

Pathological Examination

Six experimental piglets and one sham-operated control piglet were prepared for pathological examination. None of these received radiolabeled microspheres. After completion of the experiments, the animals were perfused with a saline rinse followed by buffered 4% paraformaldehyde. The brains were examined, sectioned coronally (forebrain), and given one midsagittal cut (hindbrain). After the sections were photographed, blocks were obtained and were embedded in paraffin, sectioned (6 to 8 µm), and treated with hematoxylin and eosin and Bielschowski silver stains for axons. Selected sections were also evaluated with standard immunohistochemical methods for ubiquitin and low molecular weight neurofilaments to aid in the detection of reactive axonal swellings.

Experimental Protocols

Four groups of piglets were used in the present study. Group 1 was an uninjured control group (five piglets); Group 2 received a fluid-percussion brain injury (10 piglets); Group 3 was a control group with adrenergic blockade (four piglets); and Group 4 received brain injury with adrenergic blockade (seven piglets). During a 20-minute stabilization period of the exposed vessels under the cranial window, mean arterial blood pressure (MABP), PaCO2, PaO2, and pH were monitored and maintained within physiological ranges. In the brain-injured groups, changes in pial arteriolar diameter were recorded every 2 minutes for 10 minutes to establish the baseline value. Immediately following percussive brain injury, diameter changes were read every 2 minutes for the first 10 minutes, and then every 10 minutes for an additional 170 minutes. Microspheres were injected once before the brain injury and at 10, 60, 120, and 180 minutes after the injury. Mean arterial blood pressure was monitored on-line, and PaCO2, PaO2, and pH were determined once before and at 60 to 90 minutes and 150 to 180 minutes postinjury. In the uninjured control groups, measurements of pial arteriolar diameter, injections of microspheres, MABP monitoring, and PaCO2, PaO2, and pH measurements were carried out in the same way as those of the brain-injured groups. In the two adrenergic blockade groups, with and without brain injury, microspheres were injected similarly except that additional microspheres were injected once 10 to 15 minutes after intravenous administration of prazosin and yohimbine prior to the brain injury. All relevant parameters for this group were similarly monitored.

Statistical Analysis

Statistical analysis of the major data sets used repeated measurement analysis of variance for four groups over time with contrasts by Fisher probable least significant difference. The 95% level of confidence (p < 0.05) was accepted as statistically significant.

Results
Arterial Blood Pressure, Gases, and pH

The MABP in the uninjured controls (Group 1) decreased progressively over a 3-hour observation period (Table 1). Significantly decreased levels were attained at 60 to 180 minutes, ranging from 8% to 14% below the baseline level with an average of 10% ± 1%. In the other uninjured control group with adrenergic blockade (Group 3), MABP significantly increased following prazosin and yohimbine injections in individual piglets ranging from 12% to 23% above the baseline level with an average of 16% ± 2%. Blood pressure changes in the two brain-injured groups were different from those observed in the uninjured control groups. These animals showed a transient blood pressure change of either increase or decrease lasting up to 10 minutes immediately following the brain injury (not indicated in Table 1). Of the 10 animals in Group 2, five (50%) exhibited a transient MABP decrease and three (30%) showed an increase. These changes averaged, respectively, 27% below and 13% above the preinjury level. Two animals (20%) showed no blood pressure change. In Group 4, treated with prazosin and yohimbine, one animal (14%) showed a transient decrease in MABP and four (57%) exhibited an increase. Blood pressure changes in the former averaged 14% below and in the latter 37% above the preinjury level. The remaining two animals (29%) showed no change in MABP. With regard to the secondary prolonged blood pressure change, the pressure in Group 2 decreased from 12% to 16% with an average of 13% ± 1% below the baseline. In Group 4, MABP initially increased following adrenergic blockade (average 17% ± 4%) but then decreased after the injury, ranging from 11% to 19% below the baseline level (average 17% ± 1%). This value is significantly lower than that recorded in the control groups.

TABLE 1

Mean arterial blood pressure tested at various times in four groups of piglets*

GroupNo. of PigletsBaselineTime After Treatment
2 Min10 Min30 Min 60 Min 90 Min 120 Min 150 Min 180 Min    
1: uninjured control590 ± 3 90 ± 3 88 ± 2 86 ± 4 82 ± 5† 82 ± 5† 83 ± 5† 80 ± 3† 77 ± 5† 
2: brain injury1086 ± 3 78 ± 5† 76 ± 4† 77 ± 4† 75 ± 4† 75 ± 4† 72 ± 4† 73 ± 4† 73 ± 5† 
3: uninjured control with prazosin/yohimbine481 ± 4 94 ± 3† 95 ± 3† 95 ± 4† 93 ± 4† 90 ± 5 88 ± 5 86 ± 4 86 ± 5 
4: brain injury with prazosin/yohimbine784 ± 3 86 ± 8 75 ± 7 70 ± 7† 69 ± 6† 70 ± 5† 68 ± 4† 69 ± 3† 70 ± 4† 

Values are expressed as the mean ± standard error of the mean (mm Hg).

Significance of difference compared to the baseline value: p < 0.05.

As shown in Table 2, levels of PaCO2, PaO2 and arterial pH measured at 60 to 90 minutes and 150 to 180 minutes following brain injury in two groups and those values obtained during the corresponding time period in the two control groups did not differ from their corresponding baseline levels. Percussive impact in Group 2 ranged in intensity from 2.07 to 2.64 atm (average 2.28 ± 0.06 atm) and in duration from 21.1 to 26.5 msec (average 23.7 ± 0.5 msec); in Group 4 intensity ranged from 1.98 to 2.64 atm (average 2.33 ± 0.09 atm) and duration from 19.9 to 26.8 msec (average 23.7 ± 0.7 msec). There was no difference in these values between the two brain-injured groups.

TABLE 2

Arterial blood gas and pH levels tested at various times in four groups of piglets*

GroupNo. of PigletsPaCO2 (mm Hg)PaO2 (mm Hg)pH
Baseline  Posttreat (min)BaselinePosttreat (min)BaselinePosttreat (min)
60–90150–18060–90 150–180 60–90 150–180      
1: uninjured control534 ± 2 36 ± 3 38 ± 3 85 ± 8 83 ± 7 80 ± 6 7.47 ± 0.03 7.46 ± 0.03 7.43 ± 0.07 
2: brain injury1039 ± 1 39 ± 2 40 ± 2 84 ± 3 86 ± 5 81 ± 4 7.49 ± 0.02 7.45 ± 0.01 7.45 ± 0.08 
3: uninjured control with prazosin/yohimbine435 ± 2 36 ± 2 38 ± 3 81 ± 4 82 ± 5 80 ± 5 7.46 ± 0.03 7.47 ± 0.04 7.42 ± 0.06 
4: brain injury with prazosin/yohimbine738 ± 2 37 ± 2 37 ± 3 85 ± 4 83 ± 6 80 ± 6 7.44 ± 0.02 7.38 ± 0.05 7.39 ± 0.05 

Values are means ± standard error of the mean. Posttreat = time after treatment.

Changes in Regional Cerebral Blood Flow

Figure 1 shows changes in regional CBF in the four groups of newborn pigs. In the uninjured control group (Group 1, Fig. 1 upper left), although CBF tended to increase in every brain region over a 3-hour observation period, no significant difference was found between the baseline level and the level at 10, 60, 120, and 180 minutes after sham brain injury. In general, CBF appeared to be higher in the brain-stem regions and cerebellum than in the cerebrum and caudate nucleus. In the 10 animals subjected to fluid-percussion brain injury (Group 2, Fig. 1 upper right), the baseline CBF levels before brain injury were similar to those of Group 1 with a higher flow in the brain-stem regions and cerebellum. Cerebral blood flow in all regions decreased significantly for 2 to 3 hours following the injury. The flow decreases in the right and left cerebrum, caudate nucleus, diencephalon-mesencephalon, pons, medulla oblongata, and cerebellum were, respectively, 30%, 32%, 34%, 29%, 30%, 29%, and 30% with an average of 30% ± 1%. There were no regional differences in blood flow following the brain injury. In all brain regions, levels of blood flow were minimal 10 minutes following the injury and tended to gradually return toward their preinjury levels. Specifically, blood flows in most brain regions at 180 minutes after the injury were not significantly different from the corresponding baseline level.

Fig. 1.
Fig. 1.

Graphs showing regional cerebral blood flow in five uninjured control piglets (Group 1, upper left), in 10 piglets following fluid-percussion brain injury (Group 2, upper right), in four uninjured piglets treated with prazosin and yohimbine (Group 3, lower left), and in seven brain-injured piglets pretreated with prazosin and yohimbine (Group 4, lower right). Arrows indicate time of injury or sham injury (time 0); asterisks indicate significant difference compared to the preinjury baseline value (p < 0.05). All values are means ± standard error of the mean; n = number of piglets.

In contrast to untreated piglets, CBF in prazosin and yohimbine-treated piglets without (Fig. 1 lower left) and with (Fig. 1 lower right) brain injury did not decrease at any time. Rather, in brain-injured animals (Group 4), blood flow of the diencephalon and mesencephalon at 180 minutes and the cerebellum at 10, 120, and 180 minutes significantly increased when compared to the corresponding baseline level.

Alterations in Pial Arteriolar Diameter

Pial arteriolar diameter in five uninjured control animals (Group 1) tended to increase slightly over a 3-hour observation period ranging from 3.0% to 6.4% (average 4.5%) starting 70 minutes after sham brain injury (Fig. 2 upper left). At 100 and 120 minutes the increases in diameter were significant compared to the baseline level. In contrast, pial arteriolar diameter progressively decreased following fluid-percussion brain injury given at time 0 in seven animals (Group 2, Fig. 2 upper right). Arterioles constricted immediately following the injury, then returned toward the baseline level within 10 minutes. This trend was reversed again, and the vasoconstriction once again reached significance 80 minutes through 180 minutes after injury. The vasoconstriction during this period ranged from 11% to 18% below the baseline with an average of 14% ± 1% in seven animals. Pial arterioles in control piglets pretreated with adrenergic blockers (Group 3) initially exhibited a small constriction compared to the preblocker levels, probably due to increased systemic blood pressure; however, their diameters began to increase slightly above the baseline 70 to 180 minutes following the sham-brain injury (Fig. 2 lower left). Animals that were pretreated with prazosin and yohimbine and received brain injury (Group 4) did not exhibit pial arteriolar constriction following the injury (Fig. 2 lower right). Rather, pial arteriolar diameters tended to increase slightly ranging from 2.8% to 4.4% (average 3.1%), as was the case in the Group 1 animals.

Fig. 2.
Fig. 2.

Graphs showing pial arteriolar diameter changes in five uninjured control piglets (Group 1, upper left), in seven piglets following fluid-percussion brain injury (Group 2, upper right), in four uninjured piglets treated with prazosin and yohimbine (Group 3, lower left), and in five brain-injured piglets treated with prazosin and yohimbine (Group 4, lower right). Diameter changes were read every 2 minutes for the first 10 minutes, then every 10 minutes until 180 minutes following the injury or sham injury at time 0 (arrows). Diameters were compared with the baseline value (asterisks = p < 0.05) and expressed as percentage changes (means ± standard error of the mean).

Pathological Analysis

On gross examination, the brain from the control group showed only mild congestion of the subarachnoid vessels over the cerebral convexities. Five of the six brain-injured animals studied had gross evidence of trauma in the form of a thin film of subarachnoid hemorrhage, either over the convexities, pooled at the base of the brain, or both (Fig. 3A). Two brains showed evidence of small acute contusions underlying the fluid-percussion injury site. Two other animals showed hemorrhagic necrosis of portions of the caudal cerebellar hemisphere, consistent with herniation contusion; one of these also showed a small contusion over the crest of the gyrus underlying the percussion site.

Fig. 3.
Fig. 3.

Photographs of brain sections from untreated uninjured piglets after fluid-percussion injury. A: Coronal section through the brain of a Group 2 piglet at the level of the application of the fluid percussion wave. Minimal diffuse subarachnoid hemorrhage is present and a small acute contusion is visible at the crest of a gyrus (arrow). Bar = 5 mm. B: Photomicrograph of piglet brain showing an acute contusion (arrows point to hemorrhages) and underlying pallor of the white matter (arrowhead). The area marked by the asterisk is shown as a higher-power view in C. H & E, bar = 1 mm. C: Irregular reactive swellings in a single axon (arrows). Bielschowski, bar = 10 µm.

Microscopic examination revealed a generally well-preserved histological appearance. The control brain showed only mild acute leptomeningitis related to the surgery. There was no evidence of reactive axonal swellings. Contusions were evident in three animals with fluid-percussion injury (Fig. 3B), with some pallor of the adjacent white matter. The cortex near the contused area showed occasional neurons with eosinophilic change. One animal with a grossly normal hindbrain showed a microscopic vermal hemorrhage and the presence of rare eosinophilic Purkinje cells. Microscopic sections confirmed the presence of hemorrhagic necroses in two cerebella. Axons deep to the area of percussion and in the brain stem showed much more irregular axonal profiles than did axons in the control sections. Some of these showed extremely varicose axonal profiles (Fig. 3C), although no overt axonal retraction balls were found.

Discussion

New findings in the present study are that pial arteriolar diameter and CBF decrease immediately following fluid-percussion brain injury and remain reduced for hours, and these brain injury-induced alterations in cerebral hemodynamics are completely blocked by α-adrenoceptor antagonists. The present paper appears to be the first report of percussive brain injury using a newborn pig model, which is ideal for the study of pediatric head injury.

Decreased CBF observed after brain injury in the present study is consistent with observations reported in both adult and young patients,3,4,21,26,33,34 as well as in monkeys,8 cats,11,28 and rats2,36,43 following brain damage. The reduced CBF in the present experiments correlated well with decreased pial arteriolar diameter. The decreased CBF in humans is particularly noteworthy since it was recorded as early as 1 to 4 hours after brain injury had actually occurred.4,26 It is, however, generally difficult to see the consistent results in human patients, probably due in part to the fact that various medications have usually been administered before CBF determination. Nevertheless, it seems reasonable to believe that CBF in humans decreases for as long as 24 hours following brain injury.33 Contrary to these observations, increased pial arteriolar diameter following fluid-percussion brain injury has been reported in cats.13,46 It is not clear what caused the opposite hemodynamic responses.

Our hypothesis that decreased pial arteriolar diameter and CBF following the fluid-percussion brain injury are induced by activation of the sympathetic nerves to the cephalic vasculature is supported by the following four pieces of evidence. 1) The present study demonstrated that brain injury-induced reductions in arteriolar diameter and CBF were completely blocked by pretreatment of piglets with α-adrenoceptor antagonists. It has been shown that the sympathetic nerves affect the tone of the cerebral vessels via α-adrenergic receptors.6,7,16 In particular, the α2-adrenoceptor antagonist yohimbine blocks pial arteriolar constriction induced by stimulation of the cephalic vasculature sympathetic system for at least 1 hour.6 In addition, sympathetic nerve stimulation has been found to reduce CBF in piglets.45 2) Radioligand binding studies demonstrated that α-adrenoceptors, namely the α2-subtype, are present not only in parenchymal but also in pial arteries from pigs.17,20 3) Levels of norepinephrine in CSF and plasma rise following brain injury.19,27,29,40 Plasma norepinephrine levels peak at 10 seconds postinjury in cats.40 4) Although circumstantial, the present finding that pial arteriolar constriction occurred almost instantaneously following the brain injury suggests that vasoconstriction has a neurogenic origin. Thus, the present results suggested possible beneficial effects of α-adrenergic antagonists in blocking traumatic brain injury-induced reduction of CBF. The acute reduction of CBF following brain injury may result in ischemia, thereby contributing to secondary damage.3,4,42

On the other hand, it has been shown that enhancing the release of central norepinephrine facilitates, while blocking it impairs, functional recovery following brain injury.5,14,15 Accordingly, brain injury decreases brain α1-receptor binding density in rats.38 It was proposed that attenuation of ischemic brain injury by methoxamine, an α1-adrenergic agonist,1 was due to inhibitory effects of norepinephrine on ischemia-induced enhanced glutamate release and Ca++ influx.9,10,25 These events, which activate phospholipase A2 leading to the release of arachidonic acid and increases in prostanoids and activated oxygen, have been suggested as major causes of neuronal death following brain ischemia/reperfusion.35 The present results do not conflict with the above reports since the former deals with the primary cause of the brain injury-induced decreased CBF while the latter is concerned with the consequence of the reduced CBF (or ischemia). Various other vasoactive substances are also released as a result of percussive brain injury and affect cerebral vasomotor tone and levels of CBF.13,28,46 In these studies, altered vasomotor tone and CBF were attenuated when animals were pretreated with indomethacin, free radical scavengers, and opiate antagonists. The release of these vasoactive substances appears to require longer time than the release of norepinephrine, suggesting an involvement of different mechanism(s).

Since hemorrhage often accompanies severe brain injury,4,21 it is possible that decreased pial arteriolar diameter and CBF following brain injury involve hemorrhage-induced vasospasm. However, even though hematomas in either the subdural or the ventricular space can produce vasospasm and regional or global reduction of blood flow,44 it is unlikely that hematoma was a major cause for the decreased CBF in the present study. First, the reduction of pial arteriolar diameter following fluid-percussion brain injury was almost immediate, and that of CBF was evident by 10 minutes postinjury. Hematoma-induced vasoconstriction typically requires days and has not been demonstrated earlier than 4 hours after the blood injection.32 Therefore, the time course of the present hemodynamic changes seems too rapid to be produced by perivascular blood. Second, while CBF in the present piglets decreased in all brain regions tested to almost the same degree, small hematomas were found only around the posterior cerebellum and the ventral medulla. It has been reported that, although reduced CBF occurs around the site of hematoma or lesions following brain injury, decreased blood flow is also seen in brain-stem regions without hematoma, suggesting that the hematoma is not the major cause for the observed CBF reduction.4

In adult cats, brain injury induces biphasic changes in systemic arterial blood pressure that can be characterized by a transient hypertension followed by a prolonged hypotension.39,40 For example, the transient blood pressure increase reached almost 80% above the baseline at 20 seconds and returned to the baseline level by 6 minutes postinjury.30,31 Since this transient blood pressure increase was abolished by the α-adrenoceptor antagonist phentolamine, it was concluded that hypertensive response was induced by activation of the peripheral sympathetic system. In the present study, the majority of animals showed a transient hypotensive response to brain injury and, in animals receiving α-blocking agents, the trend was reversed. The cause of the discrepancy between the effects of brain injury in cats and piglets is not clear. Differences in age, species, or anesthetic agents could be involved.

The present neuropathological findings are consistent with the observations in cats that abnormalities in axonal profiles occur within 1 hour of the brain damage. These axonal abnormalities progressively develop from swelling leading to discontinuity of the axons and the formation of axonal retraction balls by 24 hours.18,37 The axonal retraction ball has been observed in human patients as well as in animal models and is a characteristic morphological finding in traumatic brain injury.

The decreased CBF subsequent to the fluid-percussion brain injury tended to recover toward the preinjury levels in our piglets. This tendency was evident in all brain regions and agrees with the reported observations that the reduced CBF resulting from brain injury is transient, while a secondary CBF increase follows.2,3,26,33

In summary, decreased pial arteriolar diameter and CBF subsequent to the fluid-percussion brain injury are blocked by α-adrenoceptor antagonists suggesting that the observed hemodynamic responses are caused by activation of the sympathetic nerves to the cephalic vasculature resulting in α-adrenergically mediated cerebral vasoconstriction.

Acknowledgments

We acknowledge the technical assistance of Alexander Fedinec, Mildren Jackson, Jill S. Smith, Ellen B. Looney, and Annie M.-J. Shibata.

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    De Langen CDJMulder AH: On the role of calcium ions in the presynaptic alpha-receptor mediated inhibition of [3H]noradrenaline release from rat brain cortex synaptosomes. Brain Res 185:39940819803H]noradrenaline release from rat brain cortex synaptosomes. Brain Res 185:

  • 11.

    Dewitt DSPrough DSTaylor CLet al: Reduced cerebral blood flow, oxygen delivery, and electroencephalographic activity after traumatic brain injury and mild hemorrhage in cats. J Neurosurg 76:8128211992J Neurosurg 76:

  • 12.

    Duhaime AHGennarelli TAThibault LEet al: The shaken baby syndrome. A clinical, pathological and biochemical study. J Neurosurg 66:4094151987J Neurosurg 66:

  • 13.

    Ellis EFWright KFWei EPet al: Cyclooxygenase products of arachidonic acid metabolism in cat cerebral cortex after experimental concussive brain injury. J Neurochem 37:8928961981J Neurochem 37:

  • 14.

    Feeney DMSutton RL: Pharmacotherapy for recovery of function after brain injury. Crit Rev Neurobiol 3:1351971987Crit Rev Neurobiol 3:

  • 15.

    Feeney DMWesterburg VS: Norepinephrine and brain damage: alpha adrenergic pharmacology alters functional recovery after cortical trauma. Can J Psychol 44:2332521990Can J Psychol 44:

  • 16.

    Fletcher AMLeffler CWBusija DW: Effects of hypertension and sympathetic denervation on cerebral blood flow in newborn pigs. Am J Vet Res 50:7547571989Am J Vet Res 50:

  • 17.

    Friedman AHDavis JN: Identification and characterization of adrenergic receptors and catecholamine-stimulated adenylate cyclase in hog pial membranes. Brain Res 183:891021980Brain Res 183:

  • 18.

    Gennarelli TAThibault LEAdams JHet al: Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 12:5645741982Ann Neurol 12:

  • 19.

    Hamill RWWoolf PDMcDonald JVet al: Catecholamines predict outcome in traumatic brain injury. Ann Neurol 21:4384431987Ann Neurol 21:

  • 20.

    Harik SISharmer VKWetherbee JRet al: Adrenergic and cholinergic receptors of cerebral microvessels. J Cereb Blood Flow Metab 1:3293381981J Cereb Blood Flow Metab 1:

  • 21.

    Kuhl DEAlavi AHoffman EJet al: Local cerebral blood volume in head-injured patients. Determination by emission computed tomography of 99mTc-labeled red cells. J Neurosurg 52:309320198099mTc-labeled red cells. J Neurosurg 52:

  • 22.

    Laptook AStonestreet BSOh W: The effect of carotid artery ligation on brain blood flow in newborn piglets. Brain Res 276:51591983Brain Res 276:

  • 23.

    Leffler CWBusija DWFletcher AMet al: Effects of indomethacin upon cerebral hemodynamics in newborn pigs. Pediatr Res 19:116011641985Pediatr Res 19:

  • 24.

    Ludwig SWarman M: Shaken baby syndrome: a review of 20 cases. Ann Emerg Med 13:1041071984Ann Emerg Med 13:

  • 25.

    Lynch MABliss TVP: Noradrenaline modulates the release of [14C]glutamate from dentate but not from CA1/CA3 slices of rat hippocampus. Neuropharmacology 25:493498198614C]glutamate from dentate but not from CA1/CA3 slices of rat hippocampus. Neuropharmacology 25:

  • 26.

    Marion DWDarby JYonas H: Acute regional cerebral blood flow changes caused by severe head injuries. J Neurosurg 74:4074141991J Neurosurg 74:

  • 27.

    McIntosh TK: Pharmacological strategies in the treatment of experimental brain injury. J Neurotrauma 9 ( Suppl 1): S201S2091992McIntosh TK: Pharmacological strategies in the treatment of experimental brain injury. J Neurotrauma 9 (Suppl 1):

  • 28.

    McIntosh TKHayes RLDeWitt DSet al: Endogenous opioids may mediate secondary damage after experimental brain injuryAm J Physiol 253:E565E5741987Am J Physiol 253:

  • 29.

    Meyer JSStoica EPascu Iet al: Catecholamine concentrations in CSF and plasma of patients with cerebral infarction and haemorrhage. Brain 96:2772881973Brain 96:

  • 30.

    Millen JEGlauser FL: Low levels of concussive brain trauma and pulmonary edema. J Appl Physiol 54:6666701983. J Appl Physiol 54:

  • 31.

    Millen JEGlauser FLZimmerman M: Physiological effects of controlled concussive brain trauma. J Appl Physiol 49:8568621980J Appl Physiol 49:

  • 32.

    Miller JDBullock RGraham DIet al: Ischemic brain damage in a model of acute subdural hematoma. Neurosurgery 27:4334391990Neurosurgery 27:

  • 33.

    Muizelaar JPMarmarou ADeSalles AAFet al: Cerebral blood flow and metabolism in severely head-injured children. Part I: Relationship with GCS score, outcome, ICP, and PVI. J Neurosurg 71:63711989J Neurosurg 71:

  • 34.

    Muizelaar JPWard JDMarmarou Aet al: Cerebral blood flow and metabolism in severely head-injured children. Part 2: Autoregulation. J Neursourg 71:72761989J Neursourg 71:

  • 35.

    Nicholls DAttwell D: The release and uptake of excitatory amino acids. Trends Pharmacol Sci 11:4624681990Trends Pharmacol Sci 11:

  • 36.

    Nilsson BNordström CH: Experimental head injury in the rat. Part 3: Cerebral blood flow and oxygen consumption after concussive impact acceleration. J Neurosurg 47:2622731977J Neurosurg 47:

  • 37.

    Povlishock JTBecker DPCheng CLYet al: Axonal change in minor head injury. J Neuropathol Exp Neurol 42:2252421983J Neuropathol Exp Neurol 42:

  • 38.

    Prasad MRTzigaret CMSmith Det al: Decreased α1-adrenergic receptors after experimental brain injury. J Neurotrauma 9:26927919921-adrenergic receptors after experimental brain injury. J Neurotrauma 9:

  • 39.

    Rosner MJ: Systemic response to experimental brain injuryBecker DPPovlishock JT (eds): Central Nervous System Trauma Status Report. Bethesda, Md: National Institutes of Health1985405415Central Nervous System Trauma Status Report

  • 40.

    Rosner MJNewsome HHBecker DP: Mechanical brain injury: the sympathoadrenal response. J Neurosurg 61:76861984J Neurosurg 61:

  • 41.

    Sinal SHBall MR: Head trauma due to child abuse: serial computerized tomography in diagnosis and management. South Med J 80:150515121987South Med J 80:

  • 42.

    Suwanwela CSuwanwela N: Intracranial arterial narrowing and spasm in acute head injury. J Neurosurg 36:3143231972J Neurosurg 36:

  • 43.

    Yamakami IMcIntosh TK: Effects of traumatic brain injury on regional cerebral blood flow in rats as measured with radiolabeled microspheres. J Cereb Blood Flow Metab 9:1171241989J Cereb Blood Flow Metab 9:

  • 44.

    Yonas HSekhar LJohnson DWet al: Determination of irreversible ischemia by xenon-enhanced computed tomographic monitoring of cerebral blood flow in patients with symptomatic vasospasm. Neurosurgery 24:3683721989Neurosurgery 24:

  • 45.

    Wagerle LCDelivoria-Papadopoulos M: Alpha adrenergic receptor subtypes in the cerebral circulation of newborn piglets. Fed Proc 44:10081985 (Abstract)Fed Proc 44:

  • 46.

    Wei EPKontos HADietrich WDet al: Inhibition of free radical scavengers and by cyclooxygenase inhibitors of pial arteriolar abnormalities from concussive brain injury in cats. Circ Res 48:951031981Circ Res 48:

Digitizing oscilloscope, Model 54201A, manufactured by Hewlett Packard, Palo Alto, California.

Radiolabeled microspheres obtained from DuPont Corp., Boston, Massachusetts.

Gamma counter MINAXIγ, Auto-Gamma 5000 series, manufactured by Packard Instrument Co., Downers Grove, Illinois.

This research was supported by Grants HL34059, HL42851, HL42875, and NS25122 from the National Institutes of Health, by the American Lebanese Syrian Associated Charities (ALSAC), and by Cancer Center CORE Grant CA-21765.

Article Information

Address reprint requests to: Masaaki Shibata, Ph.D., Laboratory for Research in Neonatal Physiology, Department of Physiology and Biophysics, University of Tennessee, 894 Union Avenue, Memphis, Tennessee 38163.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Graphs showing regional cerebral blood flow in five uninjured control piglets (Group 1, upper left), in 10 piglets following fluid-percussion brain injury (Group 2, upper right), in four uninjured piglets treated with prazosin and yohimbine (Group 3, lower left), and in seven brain-injured piglets pretreated with prazosin and yohimbine (Group 4, lower right). Arrows indicate time of injury or sham injury (time 0); asterisks indicate significant difference compared to the preinjury baseline value (p < 0.05). All values are means ± standard error of the mean; n = number of piglets.

  • View in gallery

    Graphs showing pial arteriolar diameter changes in five uninjured control piglets (Group 1, upper left), in seven piglets following fluid-percussion brain injury (Group 2, upper right), in four uninjured piglets treated with prazosin and yohimbine (Group 3, lower left), and in five brain-injured piglets treated with prazosin and yohimbine (Group 4, lower right). Diameter changes were read every 2 minutes for the first 10 minutes, then every 10 minutes until 180 minutes following the injury or sham injury at time 0 (arrows). Diameters were compared with the baseline value (asterisks = p < 0.05) and expressed as percentage changes (means ± standard error of the mean).

  • View in gallery

    Photographs of brain sections from untreated uninjured piglets after fluid-percussion injury. A: Coronal section through the brain of a Group 2 piglet at the level of the application of the fluid percussion wave. Minimal diffuse subarachnoid hemorrhage is present and a small acute contusion is visible at the crest of a gyrus (arrow). Bar = 5 mm. B: Photomicrograph of piglet brain showing an acute contusion (arrows point to hemorrhages) and underlying pallor of the white matter (arrowhead). The area marked by the asterisk is shown as a higher-power view in C. H & E, bar = 1 mm. C: Irregular reactive swellings in a single axon (arrows). Bielschowski, bar = 10 µm.

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De Langen CDJMulder AH: On the role of calcium ions in the presynaptic alpha-receptor mediated inhibition of [3H]noradrenaline release from rat brain cortex synaptosomes. Brain Res 185:39940819803H]noradrenaline release from rat brain cortex synaptosomes. Brain Res 185:

11.

Dewitt DSPrough DSTaylor CLet al: Reduced cerebral blood flow, oxygen delivery, and electroencephalographic activity after traumatic brain injury and mild hemorrhage in cats. J Neurosurg 76:8128211992J Neurosurg 76:

12.

Duhaime AHGennarelli TAThibault LEet al: The shaken baby syndrome. A clinical, pathological and biochemical study. J Neurosurg 66:4094151987J Neurosurg 66:

13.

Ellis EFWright KFWei EPet al: Cyclooxygenase products of arachidonic acid metabolism in cat cerebral cortex after experimental concussive brain injury. J Neurochem 37:8928961981J Neurochem 37:

14.

Feeney DMSutton RL: Pharmacotherapy for recovery of function after brain injury. Crit Rev Neurobiol 3:1351971987Crit Rev Neurobiol 3:

15.

Feeney DMWesterburg VS: Norepinephrine and brain damage: alpha adrenergic pharmacology alters functional recovery after cortical trauma. Can J Psychol 44:2332521990Can J Psychol 44:

16.

Fletcher AMLeffler CWBusija DW: Effects of hypertension and sympathetic denervation on cerebral blood flow in newborn pigs. Am J Vet Res 50:7547571989Am J Vet Res 50:

17.

Friedman AHDavis JN: Identification and characterization of adrenergic receptors and catecholamine-stimulated adenylate cyclase in hog pial membranes. Brain Res 183:891021980Brain Res 183:

18.

Gennarelli TAThibault LEAdams JHet al: Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 12:5645741982Ann Neurol 12:

19.

Hamill RWWoolf PDMcDonald JVet al: Catecholamines predict outcome in traumatic brain injury. Ann Neurol 21:4384431987Ann Neurol 21:

20.

Harik SISharmer VKWetherbee JRet al: Adrenergic and cholinergic receptors of cerebral microvessels. J Cereb Blood Flow Metab 1:3293381981J Cereb Blood Flow Metab 1:

21.

Kuhl DEAlavi AHoffman EJet al: Local cerebral blood volume in head-injured patients. Determination by emission computed tomography of 99mTc-labeled red cells. J Neurosurg 52:309320198099mTc-labeled red cells. J Neurosurg 52:

22.

Laptook AStonestreet BSOh W: The effect of carotid artery ligation on brain blood flow in newborn piglets. Brain Res 276:51591983Brain Res 276:

23.

Leffler CWBusija DWFletcher AMet al: Effects of indomethacin upon cerebral hemodynamics in newborn pigs. Pediatr Res 19:116011641985Pediatr Res 19:

24.

Ludwig SWarman M: Shaken baby syndrome: a review of 20 cases. Ann Emerg Med 13:1041071984Ann Emerg Med 13:

25.

Lynch MABliss TVP: Noradrenaline modulates the release of [14C]glutamate from dentate but not from CA1/CA3 slices of rat hippocampus. Neuropharmacology 25:493498198614C]glutamate from dentate but not from CA1/CA3 slices of rat hippocampus. Neuropharmacology 25:

26.

Marion DWDarby JYonas H: Acute regional cerebral blood flow changes caused by severe head injuries. J Neurosurg 74:4074141991J Neurosurg 74:

27.

McIntosh TK: Pharmacological strategies in the treatment of experimental brain injury. J Neurotrauma 9 ( Suppl 1): S201S2091992McIntosh TK: Pharmacological strategies in the treatment of experimental brain injury. J Neurotrauma 9 (Suppl 1):

28.

McIntosh TKHayes RLDeWitt DSet al: Endogenous opioids may mediate secondary damage after experimental brain injuryAm J Physiol 253:E565E5741987Am J Physiol 253:

29.

Meyer JSStoica EPascu Iet al: Catecholamine concentrations in CSF and plasma of patients with cerebral infarction and haemorrhage. Brain 96:2772881973Brain 96:

30.

Millen JEGlauser FL: Low levels of concussive brain trauma and pulmonary edema. J Appl Physiol 54:6666701983. J Appl Physiol 54:

31.

Millen JEGlauser FLZimmerman M: Physiological effects of controlled concussive brain trauma. J Appl Physiol 49:8568621980J Appl Physiol 49:

32.

Miller JDBullock RGraham DIet al: Ischemic brain damage in a model of acute subdural hematoma. Neurosurgery 27:4334391990Neurosurgery 27:

33.

Muizelaar JPMarmarou ADeSalles AAFet al: Cerebral blood flow and metabolism in severely head-injured children. Part I: Relationship with GCS score, outcome, ICP, and PVI. J Neurosurg 71:63711989J Neurosurg 71:

34.

Muizelaar JPWard JDMarmarou Aet al: Cerebral blood flow and metabolism in severely head-injured children. Part 2: Autoregulation. J Neursourg 71:72761989J Neursourg 71:

35.

Nicholls DAttwell D: The release and uptake of excitatory amino acids. Trends Pharmacol Sci 11:4624681990Trends Pharmacol Sci 11:

36.

Nilsson BNordström CH: Experimental head injury in the rat. Part 3: Cerebral blood flow and oxygen consumption after concussive impact acceleration. J Neurosurg 47:2622731977J Neurosurg 47:

37.

Povlishock JTBecker DPCheng CLYet al: Axonal change in minor head injury. J Neuropathol Exp Neurol 42:2252421983J Neuropathol Exp Neurol 42:

38.

Prasad MRTzigaret CMSmith Det al: Decreased α1-adrenergic receptors after experimental brain injury. J Neurotrauma 9:26927919921-adrenergic receptors after experimental brain injury. J Neurotrauma 9:

39.

Rosner MJ: Systemic response to experimental brain injuryBecker DPPovlishock JT (eds): Central Nervous System Trauma Status Report. Bethesda, Md: National Institutes of Health1985405415Central Nervous System Trauma Status Report

40.

Rosner MJNewsome HHBecker DP: Mechanical brain injury: the sympathoadrenal response. J Neurosurg 61:76861984J Neurosurg 61:

41.

Sinal SHBall MR: Head trauma due to child abuse: serial computerized tomography in diagnosis and management. South Med J 80:150515121987South Med J 80:

42.

Suwanwela CSuwanwela N: Intracranial arterial narrowing and spasm in acute head injury. J Neurosurg 36:3143231972J Neurosurg 36:

43.

Yamakami IMcIntosh TK: Effects of traumatic brain injury on regional cerebral blood flow in rats as measured with radiolabeled microspheres. J Cereb Blood Flow Metab 9:1171241989J Cereb Blood Flow Metab 9:

44.

Yonas HSekhar LJohnson DWet al: Determination of irreversible ischemia by xenon-enhanced computed tomographic monitoring of cerebral blood flow in patients with symptomatic vasospasm. Neurosurgery 24:3683721989Neurosurgery 24:

45.

Wagerle LCDelivoria-Papadopoulos M: Alpha adrenergic receptor subtypes in the cerebral circulation of newborn piglets. Fed Proc 44:10081985 (Abstract)Fed Proc 44:

46.

Wei EPKontos HADietrich WDet al: Inhibition of free radical scavengers and by cyclooxygenase inhibitors of pial arteriolar abnormalities from concussive brain injury in cats. Circ Res 48:951031981Circ Res 48:

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