- Email: [email protected]
Relative cerebral blood flow during the secondary expansion of a cortical lesion in rats
Neuroscience Letters 345 (2003) 85–88 www.elsevier.com/locate/neulet
Relative cerebral blood flow during the secondary expansion of a cortical lesion in rats Nikolaus Plesnilaa,*, David Friedricha, Jo¨rg Eriskata, Alexander Baethmanna, Michael Stoffela,b a
Institute for Surgical Research, Ludwig-Maximilians University, Munich, Germany b Department of Neurosurgery, Friedrich-Wilhelms University, Bonn, Germany
Received 21 February 2003; received in revised form 28 March 2003; accepted 28 March 2003
Abstract The size of a cerebral contusion is not finite at the moment of trauma, but liable to secondary increase during the following hours and days. In the present study we investigated whether this phenomenon may be related to changes in cortical blood flow (cCBF). In rats a cortical lesion grew to 140% of its initial volume during the first 24 h after injury. During the time of most rapid lesion expansion (,6 h after the insult) marked hypoperfusion (, 30% of baseline) was found in the ipsilateral hemisphere by laser Doppler scanning fluxmetry. In the pericontusional area cCBF slowly recovered to ,80% of baseline, while in the distant brain not affected by delayed cell death, significant hyperperfusion (,160% of baseline) was observed. Thus, early hypoperfusion might be an important mechanism for secondary lesion expansion. q 2003 Published by Elsevier Science Ireland Ltd. Keywords: Brain injury; Trauma; Contusion; Cerebral blood flow; Laser Doppler
Although it is a common clinical observation that the size of a traumatic cortical contusion expands over time, the spatial and temporal dynamics of this process as well as the underlying mechanisms are poorly understood. Recent studies indicate that lesion expansion is caused by progressive cell death in the healthy brain parenchyma around the necrotic focus of a contusion [4,10,14]. Cell death in this penumbra-like tissue may, among others, be mediated by pathological tissue perfusion [2,13]. Indeed, a number of clinical and experimental studies have shown reduced cerebral blood flow (CBF) in and around contused brain parenchyma [1,3,7,15]. As yet, it has never been shown whether these changes actually correlate locally or temporally to cell death and contusion expansion. Therefore, we have studied the relative cortical CBF (rcCBF) in and around a focal cortical lesion during the time of its most rapid expansion (first 6 h after injury). Male Sprague –Dawley rats (n ¼ 34, 250 –300 g b.w., Charles River, Kisslegg, Germany) were anaesthetized in a * Corresponding author. Institut fu¨r Chirurgische Forschung, LudwigMaximilians Universita¨t, Marchioninistrasse 15, 81366 Munich, Germany. Tel.: þ 49-98-7095-4354; fax: þ49-89-7095-4353. E-mail address: [email protected] (N. Plesnila).
halothane chamber (4%), intubated and mechanically ventilated using 0.8% halothane, 30% O2 and 69% N2O. Body and brain temperature were kept at 37.0 8C with a heating pad and superfusion with warm phosphate buffered saline, respectively. A catheter was placed in the tail artery for monitoring of physiological parameters (Table 1). Thereafter the skull was fixed in a stereotactic frame and a trephination of 4 £ 7 mm was performed over the right parietal cortex. Relative CBF of the exposed cortex was assessed by laser Doppler scanning fluxmetry [5] from 15 min before until 6 h after trauma (n ¼ 7). A laser Doppler probe (Periflux 4001, Perimed AB, Ja¨rfa¨lla, Sweden) was mounted on a computercontrolled micromanipulator (MP-3D, GMS, Kiel, Germany). Using custom made software, we defined a rectangular 6 £ 10 point scanning matrix with a point to point distance of 500 mm. This resulted in a 2500 £ 4500 mm scanning field (Fig. 1). At each position of the scanning field laser Doppler measurements were performed for 3 s at a frequency of 2 Hz. Two seconds were needed to move the probe to the next point and to reach stable laser Doppler values. With a total of 60 points 5 min were needed for a single scan. Cortical brain injury was induced by a cooled copper
0304-3940/03/$ - see front matter q 2003 Published by Elsevier Science Ireland Ltd. doi:10.1016/S0304-3940(03)00396-3
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N. Plesnila et al. / Neuroscience Letters 345 (2003) 85–88
Table 1 CBF during the expansion of a focal lesion Time after focal lesion
n MABP (mmHg) Brain temperature (8C) Arterial pH Arterial pCO2 (mmHg)
230 min
þ1 h
þ6 h
7 93 ^ 4.0 38.0 ^ 0.3 7.42 ^ 0.01 36.1 ^ 1.2
7 93 ^ 3.6 37.6 ^ 0.4 7.41 ^ 0.01 36.4 ^ 1.2
7 85 ^ 2.8 37.7 ^ 0.2 7.36 ^ 0.03 37.3 ^ 2.2
cylinder (Ø 3 mm, 2 68 8C) placed on the exposed brain surface for 15 s [12]. The scanning field started in the middle of the focal lesion (3 mm dorsal and lateral to bregma), and covered half of the lesion and 3 mm of initially unaffected cortical tissue (Fig. 1). In parallel experiments, animals (n ¼ 9 per group) were subjected to the same focal lesion as described above. Five minutes, 4 and 24 h later the animals were sacrificed and 5 mm thick coronal sections at 150 mm intervals were prepared throughout the lesion and stained with cresyl violet. The area of necrosis was measured in all sections containing a lesion using a digital image analysis system (Optimas 5.2, Silver Spring, MD) and necrosis volume was calculated [14] (Fig. 2). All procedures described were in accordance with the national guidelines of Upper Bavaria for the conduct of animal experiments. Measurements within a group were analyzed for statistical significance against baseline by Friedman’s ANOVA on ranks and Dunn’s post hoc test. For testing of statistical significance between groups (P , 0:05), the Kruskal – Wallis test and the Mann – Whitney Rank Sum procedures with Bonferroni’s correction were used (SigmaStat 2.0, Jandel Scientific, Erkrath, Germany). All physiological parameters were within the physiological range and did not change during the whole duration of the experiment (Table 1). Calculation of the necrosis volume revealed that 4 h after
Fig. 1. Schematic drawing of a rat skull showing the localization of the trephination (light grey) and the cortical lesion (dark grey). The magnification shows the cortical surface scanned by laser Doppler fluxmetry. White dots represent the 60 locations (10 rows £ 6 columns) where cortical CBF was measured. The duration of one scan was 5 min.
Fig. 2. Quantification of necrosis volume (mean ^ SD) by histomorphometry (20–30 sections/animal) 5 min, 4 and 24 h after cold lesion. Data are presented as % of the primary lesion volume 5 min after cold injury.
cold injury the cortical lesion expanded to 123.6 ^ 4.2% of its initial volume measured at 5 min after trauma (P , 0:05). During the next 20 h the cortical lesion grew by another 16.5% to a total volume of 140.1 ^ 3.9% of the initial volume (P , 0:01, Fig. 2). Twenty-five minutes before trauma rcCBF was constant throughout the scanned area (Fig. 3). Cold lesion induced a decrease of rcCBF. Within the first 25 min after cold lesion a steady decrease of rcCBF was observed in all scanned areas (Fig. 3). Most interestingly, the drop in rcCBF occurred not only in the area of necrosis but also in areas of normal appearing brain up to 3 mm away from the border of the lesion. Thirty minutes after cold lesion rcCBF started to recover in the areas $ 1 mm away from the border of the necrosis (‘distant penumbra’). In the necrosis proper (‘focus’) and in the peri-necrotic area (, 1 mm from the border of the necrosis, ‘near penumbra’), however, we observed no or only very little recovery of rcCBF during the
Fig. 3. rcCBF after cortical cold lesion in the middle of the cortical lesion (‘focus’), in the peri-contusional area which will undergo secondary necrosis (‘near penumbra’, 0–0.5 mm from the border of the contusion), and in the distant cortex which will not be affected by secondary cell death (‘distant penumbra’, 1–4.5 mm from the border of the contusion; n ¼ 7; see Fig. 1). In order to allow comprehensive data presentation, all scanning points from each of these three regions were pooled and one single mean value was calculated for each experimental animal. Mean values ^ SEM for seven animals are presented for each of the three scanning fields every 5 min for a total of 6 h (360 min).
N. Plesnila et al. / Neuroscience Letters 345 (2003) 85–88
first hour after cold lesion (Fig. 3). During the next hours rcCBF recovered in most areas and reached , 80% of baseline in the necrosis and the near penumbra after 3 h and remained at this level until the end of the observation period at 6 h. In contrast to the necrosis and the near penumbra, the distant penumbra not affected by delayed cell death (areas $ 1 mm from the border of necrosis) showed marked hyperperfusion up to 160% of baseline (P , 0:01). Hyperperfusion started 45 min after cold lesion, reached a peak 4 h post trauma and persisted until the end of the observation time 2 h later (Fig. 3). The main finding of this study is that the expansion of an isolated cortical necrosis to 140% of its initial size during the first 24 h after injury is associated with reduced CBF in the core and the penumbra of the lesion, while marked hyperperfusion is observed in normally appearing brain up to 3 mm away from the border of the lesion. To our knowledge, this is the first time that CBF was recorded with high temporal and spatial resolution during the histologically proven expansion of a cortical focal lesion. A reduction of CBF after brain trauma, in part reaching ischemic levels, was described in patients with contusions [3,9,15] and in experimental studies using animal models where contusions were prominent [1,7,8,11,16,17]. However, these findings are not very surprising because most of the contused brain parenchyma is non-vital already shortly after trauma. In the distant, healthy brain not affected by secondary necrosis we detected marked hyperperfusion of 160% of baseline (Fig. 3). Although similar changes distant from contused brain tissue have been reported by others [8], these findings may not be of particular significance, because the tissue in this area does not perish, as also observed in humans with cerebral contusions [1,3]. The most significant finding in this study is the posttraumatic reduction of rcCBF in peri-contusional tissue (Fig. 3), tissue which is going to die during the secondary expansion of the primary lesion. CBF in this area is maximally reduced to 40% of baseline and remains reduced by more than 50% of baseline for about 2 h (Fig. 3). Similar findings – though with less temporal or spatial resolution and without correlation to the evolution of focal pathology – were demonstrated in other experimental cortical contusion models [1,6,7,11] and are also supported by clinical studies [3,13]. The area of peri-contusional hypoperfused tissue is expanding over time [1] and therefore hypoperfusion in this area is most likely associated with cell death resulting in secondary expansion of contused brain parenchyma (Fig. 2). However, what mechanisms are involved in peri-contusional hypoperfusion is unclear [3,11, 13] and definite proof that hypoperfusion is the direct cause for the secondary expansion of contusions is missing as yet. Further experimental studies correlating therapeutical prevention of peri-contusional hypoperfusion with histopathological outcome should clarify this point. Taken together, the current study shows that a cortical
87
necrosis expands in a delayed manner into the surrounding healthy brain (40% of its initial volume) and that this phenomenon is associated with marked hypoperfusion (, 30% of baseline) in the peri-contusional area and with delayed hyperperfusion (, 160% of baseline) in the distant brain which is not affected by delayed cell death. Because of the close temporal and spatial correlation of necrosis growth and hypoperfusion, we hypothesize that hypoperfusion might be a mechanism or a co-factor for delayed pericontusional cell death. Identification of mechanisms underlying this phenomenon might lead to the development of novel approaches for the management and treatment of patients with cortical contusions.
Acknowledgements This study was supported by the Department of Education and Research of the Federal Republic of Germany (BMBF-Verbund ‘Neurotrauma’ Mu¨ nchen; FKZ: 01 KO 94026 to A.B.) and by the Friedrich Baur Foundation (to N.P.).
References [1] R.M. Bryan Jr., L. Cherian, C. Robertson, Regional cerebral blood flow after controlled cortical impact injury in rats, Anesth. Analg. 80 (1995) 687–695. [2] R. Bullock, W.L. Maxwell, D.I. Graham, G.M. Teasdale, J.H. Adams, Glial swelling following human cerebral contusion: an ultrastructural study, J. Neurol. Neurosurg. Psychiatry 54 (1991) 427 –434. [3] R. Bullock, D. Sakas, J. Patterson, D. Wyper, D. Hadley, W. Maxwell, G.M. Teasdale, Early post-traumatic cerebral blood flow mapping: correlation with structural damage after focal injury, Acta Neurochir. Suppl. (Wien) 55 (1992) 14 –17. [4] M.R. Garnett, A.M. Blamire, R.G. Corkill, B. Rajagopalan, J.D. Young, T.A. Cadoux-Hudson, P. Styles, Abnormal cerebral blood volume in regions of contused and normal appearing brain following traumatic brain injury using perfusion magnetic resonance imaging, J. Neurotrauma 18 (2001) 585–593. [5] A. Heimann, S. Kroppenstedt, P. Ulrich, O.S. Kempski, Cerebral blood flow autoregulation during hypobaric hypotension assessed by laser Doppler scanning, J. Cereb. Blood Flow Metab. 14 (1994) 1100– 1105. [6] K.S. Hendrich, P.M. Kochanek, D.S. Williams, J.K. Schiding, D.W. Marion, C. Ho, Early perfusion after controlled cortical impact in rats: quantification by arterial spin-labeled MRI and the influence of spinlattice relaxation time heterogeneity, Magn. Reson. Med. 42 (1999) 673–681. [7] P.M. Kochanek, D.W. Marion, W. Zhang, J.K. Schiding, M. White, A.M. Palmer, R.S. Clark, M.E. O’Malley, S.D. Styren, C. Ho, Severe controlled cortical impact in rats: assessment of cerebral edema, blood flow, and contusion volume, J. Neurotrauma 12 (1995) 1015–1025. [8] F.F. Madsen, Regional cerebral blood flow after a localized cerebral contusion in pigs, Acta Neurochir. (Wien) 105 (1990) 150–157. [9] D.W. Marion, G.J. Bouma, The use of stable xenon-enhanced computed tomographic studies of cerebral blood flow to define changes in cerebral carbon dioxide vasoresponsivity caused by a severe head injury, Neurosurgery 29 (1991) 869 –873. [10] K. Murakami, T. Kondo, S. Sato, Y. Li, P.H. Chan, Occurrence of
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N. Plesnila et al. / Neuroscience Letters 345 (2003) 85–88
apoptosis following cold injury-induced brain edema in mice, Neuroscience 81 (1997) 231–237. [11] P. Nilsson, B. Gazelius, H. Carlson, L. Hillered, Continuous measurement of changes in regional cerebral blood flow following cortical compression contusion trauma in the rat, J. Neurotrauma 13 (1996) 201 –207. [12] N. Plesnila, J. Schulz, M. Stoffel, J. Eriskat, D. Pruneau, A. Baethmann, Role of bradykinin B2 receptors in the formation of vasogenic brain edema in rats, J. Neurotrauma 18 (2001) 1049–1058. [13] M.L. Schroder, J.P. Muizelaar, M.R. Bullock, J.B. Salvant, J.T. Povlishock, Focal ischemia due to traumatic contusions documented by stable xenon-CT and ultrastructural studies, J. Neurosurg. 82 (1995) 966–971.
[14] M. Stoffel, M. Rinecker, N. Plesnila, J. Eriskat, A. Baethmann, Role of nitric oxide in the secondary expansion of a cortical brain lesion from cold injury, J. Neurotrauma 18 (2001) 425–434. [15] H. Tenjin, S. Ueda, N. Mizukawa, Y. Imahori, A. Hino, T. Yamaki, T. Kuboyama, T. Ebisu, K. Hirakawa, M. Yamashita, Positron emission tomographic studies on cerebral hemodynamics in patients with cerebral contusion, Neurosurgery 26 (1990) 971 –979. [16] P.A. Tornheim, F. McDermott, M. Shiguma, Effect of experimental blunt head injury on acute regional cerebral blood flow and edema, Adv. Neurol. 52 (1990) 377–384. [17] J. Zhuang, J.D. Schmoker, S.R. Shackford, J.A. Pietropaoli, Focal brain injury results in severe cerebral ischemia despite maintenance of cerebral perfusion pressure, J. Trauma 33 (1992) 83–88.
Relative cerebral blood flow during the secondary expansion of a cortical lesion in rats Nikolaus Plesnilaa,*, David Friedricha, Jo¨rg Eriskata, Alexander Baethmanna, Michael Stoffela,b a
Institute for Surgical Research, Ludwig-Maximilians University, Munich, Germany b Department of Neurosurgery, Friedrich-Wilhelms University, Bonn, Germany
Received 21 February 2003; received in revised form 28 March 2003; accepted 28 March 2003
Abstract The size of a cerebral contusion is not finite at the moment of trauma, but liable to secondary increase during the following hours and days. In the present study we investigated whether this phenomenon may be related to changes in cortical blood flow (cCBF). In rats a cortical lesion grew to 140% of its initial volume during the first 24 h after injury. During the time of most rapid lesion expansion (,6 h after the insult) marked hypoperfusion (, 30% of baseline) was found in the ipsilateral hemisphere by laser Doppler scanning fluxmetry. In the pericontusional area cCBF slowly recovered to ,80% of baseline, while in the distant brain not affected by delayed cell death, significant hyperperfusion (,160% of baseline) was observed. Thus, early hypoperfusion might be an important mechanism for secondary lesion expansion. q 2003 Published by Elsevier Science Ireland Ltd. Keywords: Brain injury; Trauma; Contusion; Cerebral blood flow; Laser Doppler
Although it is a common clinical observation that the size of a traumatic cortical contusion expands over time, the spatial and temporal dynamics of this process as well as the underlying mechanisms are poorly understood. Recent studies indicate that lesion expansion is caused by progressive cell death in the healthy brain parenchyma around the necrotic focus of a contusion [4,10,14]. Cell death in this penumbra-like tissue may, among others, be mediated by pathological tissue perfusion [2,13]. Indeed, a number of clinical and experimental studies have shown reduced cerebral blood flow (CBF) in and around contused brain parenchyma [1,3,7,15]. As yet, it has never been shown whether these changes actually correlate locally or temporally to cell death and contusion expansion. Therefore, we have studied the relative cortical CBF (rcCBF) in and around a focal cortical lesion during the time of its most rapid expansion (first 6 h after injury). Male Sprague –Dawley rats (n ¼ 34, 250 –300 g b.w., Charles River, Kisslegg, Germany) were anaesthetized in a * Corresponding author. Institut fu¨r Chirurgische Forschung, LudwigMaximilians Universita¨t, Marchioninistrasse 15, 81366 Munich, Germany. Tel.: þ 49-98-7095-4354; fax: þ49-89-7095-4353. E-mail address: [email protected] (N. Plesnila).
halothane chamber (4%), intubated and mechanically ventilated using 0.8% halothane, 30% O2 and 69% N2O. Body and brain temperature were kept at 37.0 8C with a heating pad and superfusion with warm phosphate buffered saline, respectively. A catheter was placed in the tail artery for monitoring of physiological parameters (Table 1). Thereafter the skull was fixed in a stereotactic frame and a trephination of 4 £ 7 mm was performed over the right parietal cortex. Relative CBF of the exposed cortex was assessed by laser Doppler scanning fluxmetry [5] from 15 min before until 6 h after trauma (n ¼ 7). A laser Doppler probe (Periflux 4001, Perimed AB, Ja¨rfa¨lla, Sweden) was mounted on a computercontrolled micromanipulator (MP-3D, GMS, Kiel, Germany). Using custom made software, we defined a rectangular 6 £ 10 point scanning matrix with a point to point distance of 500 mm. This resulted in a 2500 £ 4500 mm scanning field (Fig. 1). At each position of the scanning field laser Doppler measurements were performed for 3 s at a frequency of 2 Hz. Two seconds were needed to move the probe to the next point and to reach stable laser Doppler values. With a total of 60 points 5 min were needed for a single scan. Cortical brain injury was induced by a cooled copper
0304-3940/03/$ - see front matter q 2003 Published by Elsevier Science Ireland Ltd. doi:10.1016/S0304-3940(03)00396-3
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N. Plesnila et al. / Neuroscience Letters 345 (2003) 85–88
Table 1 CBF during the expansion of a focal lesion Time after focal lesion
n MABP (mmHg) Brain temperature (8C) Arterial pH Arterial pCO2 (mmHg)
230 min
þ1 h
þ6 h
7 93 ^ 4.0 38.0 ^ 0.3 7.42 ^ 0.01 36.1 ^ 1.2
7 93 ^ 3.6 37.6 ^ 0.4 7.41 ^ 0.01 36.4 ^ 1.2
7 85 ^ 2.8 37.7 ^ 0.2 7.36 ^ 0.03 37.3 ^ 2.2
cylinder (Ø 3 mm, 2 68 8C) placed on the exposed brain surface for 15 s [12]. The scanning field started in the middle of the focal lesion (3 mm dorsal and lateral to bregma), and covered half of the lesion and 3 mm of initially unaffected cortical tissue (Fig. 1). In parallel experiments, animals (n ¼ 9 per group) were subjected to the same focal lesion as described above. Five minutes, 4 and 24 h later the animals were sacrificed and 5 mm thick coronal sections at 150 mm intervals were prepared throughout the lesion and stained with cresyl violet. The area of necrosis was measured in all sections containing a lesion using a digital image analysis system (Optimas 5.2, Silver Spring, MD) and necrosis volume was calculated [14] (Fig. 2). All procedures described were in accordance with the national guidelines of Upper Bavaria for the conduct of animal experiments. Measurements within a group were analyzed for statistical significance against baseline by Friedman’s ANOVA on ranks and Dunn’s post hoc test. For testing of statistical significance between groups (P , 0:05), the Kruskal – Wallis test and the Mann – Whitney Rank Sum procedures with Bonferroni’s correction were used (SigmaStat 2.0, Jandel Scientific, Erkrath, Germany). All physiological parameters were within the physiological range and did not change during the whole duration of the experiment (Table 1). Calculation of the necrosis volume revealed that 4 h after
Fig. 1. Schematic drawing of a rat skull showing the localization of the trephination (light grey) and the cortical lesion (dark grey). The magnification shows the cortical surface scanned by laser Doppler fluxmetry. White dots represent the 60 locations (10 rows £ 6 columns) where cortical CBF was measured. The duration of one scan was 5 min.
Fig. 2. Quantification of necrosis volume (mean ^ SD) by histomorphometry (20–30 sections/animal) 5 min, 4 and 24 h after cold lesion. Data are presented as % of the primary lesion volume 5 min after cold injury.
cold injury the cortical lesion expanded to 123.6 ^ 4.2% of its initial volume measured at 5 min after trauma (P , 0:05). During the next 20 h the cortical lesion grew by another 16.5% to a total volume of 140.1 ^ 3.9% of the initial volume (P , 0:01, Fig. 2). Twenty-five minutes before trauma rcCBF was constant throughout the scanned area (Fig. 3). Cold lesion induced a decrease of rcCBF. Within the first 25 min after cold lesion a steady decrease of rcCBF was observed in all scanned areas (Fig. 3). Most interestingly, the drop in rcCBF occurred not only in the area of necrosis but also in areas of normal appearing brain up to 3 mm away from the border of the lesion. Thirty minutes after cold lesion rcCBF started to recover in the areas $ 1 mm away from the border of the necrosis (‘distant penumbra’). In the necrosis proper (‘focus’) and in the peri-necrotic area (, 1 mm from the border of the necrosis, ‘near penumbra’), however, we observed no or only very little recovery of rcCBF during the
Fig. 3. rcCBF after cortical cold lesion in the middle of the cortical lesion (‘focus’), in the peri-contusional area which will undergo secondary necrosis (‘near penumbra’, 0–0.5 mm from the border of the contusion), and in the distant cortex which will not be affected by secondary cell death (‘distant penumbra’, 1–4.5 mm from the border of the contusion; n ¼ 7; see Fig. 1). In order to allow comprehensive data presentation, all scanning points from each of these three regions were pooled and one single mean value was calculated for each experimental animal. Mean values ^ SEM for seven animals are presented for each of the three scanning fields every 5 min for a total of 6 h (360 min).
N. Plesnila et al. / Neuroscience Letters 345 (2003) 85–88
first hour after cold lesion (Fig. 3). During the next hours rcCBF recovered in most areas and reached , 80% of baseline in the necrosis and the near penumbra after 3 h and remained at this level until the end of the observation period at 6 h. In contrast to the necrosis and the near penumbra, the distant penumbra not affected by delayed cell death (areas $ 1 mm from the border of necrosis) showed marked hyperperfusion up to 160% of baseline (P , 0:01). Hyperperfusion started 45 min after cold lesion, reached a peak 4 h post trauma and persisted until the end of the observation time 2 h later (Fig. 3). The main finding of this study is that the expansion of an isolated cortical necrosis to 140% of its initial size during the first 24 h after injury is associated with reduced CBF in the core and the penumbra of the lesion, while marked hyperperfusion is observed in normally appearing brain up to 3 mm away from the border of the lesion. To our knowledge, this is the first time that CBF was recorded with high temporal and spatial resolution during the histologically proven expansion of a cortical focal lesion. A reduction of CBF after brain trauma, in part reaching ischemic levels, was described in patients with contusions [3,9,15] and in experimental studies using animal models where contusions were prominent [1,7,8,11,16,17]. However, these findings are not very surprising because most of the contused brain parenchyma is non-vital already shortly after trauma. In the distant, healthy brain not affected by secondary necrosis we detected marked hyperperfusion of 160% of baseline (Fig. 3). Although similar changes distant from contused brain tissue have been reported by others [8], these findings may not be of particular significance, because the tissue in this area does not perish, as also observed in humans with cerebral contusions [1,3]. The most significant finding in this study is the posttraumatic reduction of rcCBF in peri-contusional tissue (Fig. 3), tissue which is going to die during the secondary expansion of the primary lesion. CBF in this area is maximally reduced to 40% of baseline and remains reduced by more than 50% of baseline for about 2 h (Fig. 3). Similar findings – though with less temporal or spatial resolution and without correlation to the evolution of focal pathology – were demonstrated in other experimental cortical contusion models [1,6,7,11] and are also supported by clinical studies [3,13]. The area of peri-contusional hypoperfused tissue is expanding over time [1] and therefore hypoperfusion in this area is most likely associated with cell death resulting in secondary expansion of contused brain parenchyma (Fig. 2). However, what mechanisms are involved in peri-contusional hypoperfusion is unclear [3,11, 13] and definite proof that hypoperfusion is the direct cause for the secondary expansion of contusions is missing as yet. Further experimental studies correlating therapeutical prevention of peri-contusional hypoperfusion with histopathological outcome should clarify this point. Taken together, the current study shows that a cortical
87
necrosis expands in a delayed manner into the surrounding healthy brain (40% of its initial volume) and that this phenomenon is associated with marked hypoperfusion (, 30% of baseline) in the peri-contusional area and with delayed hyperperfusion (, 160% of baseline) in the distant brain which is not affected by delayed cell death. Because of the close temporal and spatial correlation of necrosis growth and hypoperfusion, we hypothesize that hypoperfusion might be a mechanism or a co-factor for delayed pericontusional cell death. Identification of mechanisms underlying this phenomenon might lead to the development of novel approaches for the management and treatment of patients with cortical contusions.
Acknowledgements This study was supported by the Department of Education and Research of the Federal Republic of Germany (BMBF-Verbund ‘Neurotrauma’ Mu¨ nchen; FKZ: 01 KO 94026 to A.B.) and by the Friedrich Baur Foundation (to N.P.).
References [1] R.M. Bryan Jr., L. Cherian, C. Robertson, Regional cerebral blood flow after controlled cortical impact injury in rats, Anesth. Analg. 80 (1995) 687–695. [2] R. Bullock, W.L. Maxwell, D.I. Graham, G.M. Teasdale, J.H. Adams, Glial swelling following human cerebral contusion: an ultrastructural study, J. Neurol. Neurosurg. Psychiatry 54 (1991) 427 –434. [3] R. Bullock, D. Sakas, J. Patterson, D. Wyper, D. Hadley, W. Maxwell, G.M. Teasdale, Early post-traumatic cerebral blood flow mapping: correlation with structural damage after focal injury, Acta Neurochir. Suppl. (Wien) 55 (1992) 14 –17. [4] M.R. Garnett, A.M. Blamire, R.G. Corkill, B. Rajagopalan, J.D. Young, T.A. Cadoux-Hudson, P. Styles, Abnormal cerebral blood volume in regions of contused and normal appearing brain following traumatic brain injury using perfusion magnetic resonance imaging, J. Neurotrauma 18 (2001) 585–593. [5] A. Heimann, S. Kroppenstedt, P. Ulrich, O.S. Kempski, Cerebral blood flow autoregulation during hypobaric hypotension assessed by laser Doppler scanning, J. Cereb. Blood Flow Metab. 14 (1994) 1100– 1105. [6] K.S. Hendrich, P.M. Kochanek, D.S. Williams, J.K. Schiding, D.W. Marion, C. Ho, Early perfusion after controlled cortical impact in rats: quantification by arterial spin-labeled MRI and the influence of spinlattice relaxation time heterogeneity, Magn. Reson. Med. 42 (1999) 673–681. [7] P.M. Kochanek, D.W. Marion, W. Zhang, J.K. Schiding, M. White, A.M. Palmer, R.S. Clark, M.E. O’Malley, S.D. Styren, C. Ho, Severe controlled cortical impact in rats: assessment of cerebral edema, blood flow, and contusion volume, J. Neurotrauma 12 (1995) 1015–1025. [8] F.F. Madsen, Regional cerebral blood flow after a localized cerebral contusion in pigs, Acta Neurochir. (Wien) 105 (1990) 150–157. [9] D.W. Marion, G.J. Bouma, The use of stable xenon-enhanced computed tomographic studies of cerebral blood flow to define changes in cerebral carbon dioxide vasoresponsivity caused by a severe head injury, Neurosurgery 29 (1991) 869 –873. [10] K. Murakami, T. Kondo, S. Sato, Y. Li, P.H. Chan, Occurrence of
88
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apoptosis following cold injury-induced brain edema in mice, Neuroscience 81 (1997) 231–237. [11] P. Nilsson, B. Gazelius, H. Carlson, L. Hillered, Continuous measurement of changes in regional cerebral blood flow following cortical compression contusion trauma in the rat, J. Neurotrauma 13 (1996) 201 –207. [12] N. Plesnila, J. Schulz, M. Stoffel, J. Eriskat, D. Pruneau, A. Baethmann, Role of bradykinin B2 receptors in the formation of vasogenic brain edema in rats, J. Neurotrauma 18 (2001) 1049–1058. [13] M.L. Schroder, J.P. Muizelaar, M.R. Bullock, J.B. Salvant, J.T. Povlishock, Focal ischemia due to traumatic contusions documented by stable xenon-CT and ultrastructural studies, J. Neurosurg. 82 (1995) 966–971.
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