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Decompressive craniectomy in acute cerebral ischemia in rats
Neuroscience Letters 370 (2004) 85–90
Decompressive craniectomy in acute cerebral ischemia in rats Is there any benefit in smaller thromboembolic infarcts? Tobias Engelhorna,∗ , Sabine Heilandb , Wolf-Ruediger Schabitzc , Stefan Schwabc , Elmar Buschd , Michael Forstinga , Arnd Doerflera a
Department of Neuroradiology, University of Essen, School of Medicine, Hufelandstrasse 55, D-45122 Essen, Germany b Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany c Department of Neurology, University of Heidelberg, Heidelberg, Germany d Department of Neurology, University of Essen, Essen, Germany Received 27 June 2004; received in revised form 29 July 2004; accepted 31 July 2004
Abstract Early craniectomy has shown to reduce infarction size in experimental large MCA infarction probably due to improved leptomeningeal perfusion. Based on the hypothesis that craniectomy may also be beneficial in smaller MCA infarction we evaluated the effects of craniectomy on infarction size in small thromboembolic cerebral infarction in rats. Therefore, thromboembolic cerebral ischemia was induced in 40 rats by endovascular injection of autologous, fibrin-rich emboli. Twentyone animals with a diffusion-weighted MR imaging (DWI)-derived infarction size of 50–100 mm3 (involving one- to two-third of the MCA territory) at 1 h after injection were randomly assigned to two groups. Eleven animals of group 1 immediately underwent craniectomy, ten animals of group 2 (controls) were not treated. Serial DWI was performed at 4 and 24 h. Infarction size was assessed by TTC-staining at 48 h after emboli injection. As result, prior to treatment, at 1 h after emboli injection, infarction size in groups 1 and 2 was 65.9 ± 16.0 mm3 and 67.9 ± 17.8 mm3 , respectively. At 4 and 24 h, infarction size in group 1 was 73.5 ± 22.1 mm3 and 85.2 ± 24.7 mm3 , and 76.3 ± 21.0 mm3 and 83.4 ± 22.9 mm3 in group 2, respectively. TTC-derived infarction size was 84.0 ± 23.3 mm3 and 82.7 ± 21.5 mm3 , respectively. There was no significant difference between the two groups (P > 0.79). In conclusion, our results demonstrate that for small thromboembolic MCA infarction early craniectomy is not beneficial. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Decompressive craniectomy; MCA occlusion; Thromboembolic stroke; Rat
Ischemic cerebral infarction associated with extensive edema and marked elevation of intracranial pressure (ICP) may cause ischemia of neighboring brain tissue and thus lead to further infarction [12]. This type of stroke, described as “malignant” middle cerebral artery (MCA) infarction, has been well-documented in clinical observations and in autopsy studies [20,22]. Aggressive approaches in treating this type of stroke are restoration of blood flow by thrombolysis [11,21] or decompressing the swollen brain by hemicraniec∗
Corresponding author. Tel.: +49 201 7231545; fax: +49 201 7235959. E-mail address: [email protected] (T. Engelhorn).
0304-3940/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2004.07.092
tomy to prevent herniation and to increase collateral blood supply [3,24]. Craniectomy may interrupt the vicious cycle of malignant MCA infarction by decreasing ICP. This may increase cerebral perfusion and optimize retrograde perfusion of MCA branches via leptomeningeal collaterals: functionally compromised but viable brain may thus be able to survive. Few experimental data have been published on the usefulness of craniectomy in the treatment of acute cerebral ischemia [5–10]. Studies using perfusion- and diffusion-weighted MR (DWI, PWI) to monitor the effects of craniectomy in the
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acute and chronic phase [6,7,9] demonstrated significantly increased cortical cerebral perfusion after craniectomy via improvement of collateral leptomeningeal circulation. Based on these encouraging experimental results we supposed that early craniectomy might also be beneficial in smaller, nonmalignant cerebral infarctions, by decreasing local spaceoccupying effects and thus improving collateral circulation. Therefore, we tested whether craniectomy might also decrease infarction size in smaller cerebral infarctions by injection of autologous, fibrin-rich emboli [14]. DWI was used to select and to match appropriate animals and to monitor the evolution of infarction size. Fourty male Wistar rats weighing 280–320 g were used in the present study. All animals were allowed access to food and water ad libitum. The study was approved by the Institutional Review Board. Anesthesia was induced by injection of 100 mg/kg ketamine hydrochloride. Monitoring of physiological parameters (blood pressure, arterial blood gases, plasma glucose, and body temperature) was done at 15 min before and after emboli injection. Body temperature was measured during anesthesia and controlled with circulation of thermostated air to maintain core temperature at 37 ± 0.5 ◦ C. Clots were prepared as recently described in detail [14]. Before blood aspiration the following reagents had to be prepared: phosphate-buffered saline (PBS), 1 mL of thrombin/PBS solution (1 mg/mL), and 5 mL albumin/PBS solution. Then 0.15 mL of the thrombin solution was filled into a 1 mL syringe. Next, three PE-50 tubes (30 cm) were prefitted at one end with a 22 G needle, and five Petri-dishes (5 mL) were filled with PBS and two dishes with albumin/PBS solution. At this point, arterial blood (0.6 mL) was aspirated via the femoral catheter in a 1 mL syringe. The blood was injected into a syringe that contained 0.15 mL thrombin immediately after aspiration. Immediately after mixing, the blood/thrombin mix was injected into the PE-50 tubes. The tubes were kept at room temperature for approximately 40 min. Under microscopic inspection clots with high fibrin content were selected. These were identified as whitish sections. These clot sections were cut into 1.5 mm-long fragments, and eight selected fragments were transferred into a dish with albumin/PBS solution. One by one, clot fragments were drawn up together with the albumin/PBS solution into a 1 m-long PE 50 catheter. In all animals, a midline incision in the neck was performed. Afterwards, the common carotid artery (CCA) was identified. The bifurcation of the CCA, the external carotid artery (ECA), the internal carotid (ICA), and the pterygopalatine artery (PPA) were prepared and ligated at the origin. Then, the occipital and thyroid artery, which branch off the ECA, and the distal ECA itself were coagulated. The proximal ECA was temporarily clipped and a PE 50 catheter was inserted into the ECA-section between the distal coagulation point and the proximally located clip. The tip of the catheter was advanced towards the carotid bifurcation and fixed. The clip was removed. The distal ECA was intersected and the
proximal ECA including the catheter turned caudal to get the tube into a straight line with the ICA. Then, the emboli were injected during a period of 30 s, so that the clots entered the carotid artery one by one. After the last clot had been injected, the CCA was reopened by releasing the clip. Eight clots were used for MCAO as preliminary experiments demonstrated this number ideal to create ischemia in about one- to two-third of the vessel territory. Animals were examined in a 2.35-T scanner (Biospec 24/40, Bruker, Germany). An actively shielded gradient coil with a 120-cm inner diameter was used. This coil was driven by the standard 150-V/100-A gradient power supply. In this configuration, 180 mT/m could be reached in 180 ms. As a radiofrequency coil, a home-built birdcage resonator with a 40-mm inner diameter was used. DWI was performed 1, 4 and 24 h after emboli injection using a spin-echo echo-planar imaging sequence (repetition time 3 s, echo time 67.7 ms, number of averages 3, 8 different b values from 0 to 1260 s/mm2 , diffusion time 50 ms, duration of diffusion gradient 5 ms, field of view 4 cm × 4 cm, matrix 128 × 64, six slices, and slice thickness 2 mm). The apparent diffusion coefficient was calculated from the diffusion-weighted images, as described elsewhere [13]. A side-by-side difference of apparent diffusion coefficient value from homologous pixels (i.e., the ischemic and normal hemispheres that best define the ischemic lesion volume in vivo) of 29%, which is highly correlated with post-mortem infarct volume, was used to define abnormal ischemic pixels and to calculate the ischemic size. Additionally, according to Pacinos and Watson [23] and former studies [9] infarct size was calculated for the parietal, temporal and basal MCA-supplied cortex and the basal ganglia, respectively. Based on former studies [5–10], complete occlusion of the MCA territory results in infarction size of approximately 150 mm3 at 1 h after MCAO. To include animals with infarction of one- to two-third of the MCA territory, only animals demonstrating a DWI-derived infarction size of 50–100 mm3 at 1 h after emboli injection were included. Hereby, calculation of the ischemic lesion volume was started immediately after the MR examination and took approximately 8 min. Included animals were assigned to one of the following experimental groups by using a computer generated randomization program. Group 1: decompressive craniectomy at 1 h after emboli injection. Group 2: no therapy (controls). Animals with an infarction volume smaller than 50 mm3 or greater than 100 mm3 in the initial DWI were excluded from data analysis. We performed craniectomy under microscopic control by creating a bone flap (10 mm × 5 mm) in the parietal and temporal bone using a dental drill as described in detail recently [5,10]. Forty-eight hours after emboli injection, the brains were removed, and then coronally sectioned into 2-mm
T. Engelhorn et al. / Neuroscience Letters 370 (2004) 85–90
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slices. Slices were incubated in a 2% solution of 2,3,5triphenyltetrazolium chloride (TTC) at 37 ◦ C and fixed by immersion in a 10% buffered formalin solution [2]. Lesion volumes were measured by summing the unstained areas on TTC-stained brain slices. To avoid overestimation of the infarction volume, as described by Lin et al., the corrected infarction volume was calculated [16]. For statistical analysis of all results, commercial software (StatView, Brain Power Inc.) was used. For statistical analysis of infarction volume the unpaired t-test was used and a probability value of P < 0.05 was considered to be significant. The means and standard deviations (S.D.) are presented for both groups. A total of 21 animals (52.5%) demonstrated a DWIderived infarction size between 50 and 100 mm3 at 1 h after emboli injection. Eleven animals underwent decompressive craniectomy and 10 animals served as controls. Nine animals revealed nearly complete or complete MCA infarction with an infarction size >100 mm3 . Ten animals revealed an infarction size less than one third of the MCA territory. We noted no statistically significant differences in the remaining 21 animals among the two groups for any of the intraoperative physiologic parameters. Throughout animal preparation the average body temperature for all animals was 36.7 ± 0.4 (mean ± S.D.). Arterial blood gases (pO2 = 102 ± 16, pCO2 = 35 ± 6, pH = 7.38 ± 0.03) and hematocrit (42 ± 3) remained stable. Subarachnoid or parenchymal hemorrhage was not observed. Fig. 1 demonstrates the DWI-derived infarction size of both groups at 1, 4 and 24 h after emboli injection, repectively. Table 1 demonstrates DWI-derived infarction size of both groups in the different MCA-supplied cortical areas and the basal ganglia. Before treatment, at 1 h after emboli injection, infarction size in group 1 (craniectomy) and group 2 (control) was 65.9 ± 16.0 mm3 and 67.9 ± 17.8 mm3 , respectively. There was
Table 1 DWI-derived infarction size (mm3 ) of both groups (control group shown in brackets) at 1, 4 and 24 h after emboli injection in different MCA-supplied cortical areas and the basal ganglia, respectively, according to Pacinos and Watson [23]
Fig. 1. DWI-derived infarction size of both groups at 1, 4 and 24 h after emboli injection, repectively. There was no significant difference between group 1 (craniectomized animals) and group 2 (controls) at any time point.
Fig. 2. TTC-derived absolute infarction size at 48 h after emboli injection. There was no significant difference between group 1 (craniectomized animals) and group 2 (controls).
Localization
Time after emboli injection 1h
4h
24 h
Parietal cortex 9 ± 7 (9 ± 5) 9 ± 7 (10 ± 6) 8 ± 6 (10 ± 7) Temporal cortex 11 ± 7 (9 ± 6) 14 ± 10 (11 ± 10) 17 ± 12 (14 ± 11) Basal cortex 13 ± 9 (14 ± 9) 16 ± 9 (17 ± 11) 18 ± 12 (19 ± 13) Basal ganglia 35 ± 16 (34 ± 15) 37 ± 19 (37 ± 21) 40 ± 22 (42 ± 25) There was no significant difference between craniectomized animals and controls for the different infarct localizations at any time point.
no significant difference between the two groups (P = 0.87). At 4 and 24 h after emboli injection, infarction size in group 1 was 73.5 ± 22.1 mm3 and 85.2 ± 24.7 mm3 and infarction size in group 2 was 76.3 ± 21.0 mm3 and 83.4 ± 22.9 mm3 , respectively. Still, there was no significant difference between the two groups (P > 0.79). Compared to the initial DWI scan none of the animals demonstrated a decreased DWI-derived infarction size or increased ADC values at 4 h after emboli injection. Fig. 2 demonstrates the TTC-derived infarction size of both groups at 48 h after emboli injection. The TTC-derived infarction size in groups 1 and 2 was 84.0 ± 23.3 mm3 and 82.7 ± 21.5 mm3 , respectively. There was no significant difference between the two groups (P = 0.85). The goal of this experimental study was to analyze, whether there is a benefit of early decompressive craniectomy in the treatment of smaller thromboembolic infarcts. While decompressive craniectomy is recommended and indeed may be an appropriate, lifesaving procedure with low risk in selected patients in the management of severe spaceoccupying MCA infarction, there exists no clinical or ex-
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perimental data about a possible impact of decompressing the brain in case of infarcts involving only one- to two-third of the territory of the MCA [3,24]. Theoretically, in such cases, early decompression of locally swollen brain with subsequent activation of leptomeningeal collaterals may result in reduced infarction size too and could thus be of therapeutical benefit. All recent experimental studies [5–10] showing a benefit of early decompressive craniectomy in MCA occlusion are based on the endovascular suture model described by Longa et al. [17]. This model consistently simulates complete space-occupying MCA territory infarction. However, due to complete occlusion of the origin of the MCA and subsequent complete ischemia of the MCA territory, studies on the effects of decompressive craniectomy in smaller cerebral infarction are hardly possible. Temporary endovascular occlusion of the MCA followed by subsequent reperfusion within a therapeutical time window of approximately 2 h [16,18], combined with early decompressive craniectomy does not simulate the clinical setting. Additionally, there may be an early blood–brain barrier breakdown and the infarcts are mainly restricted to the basal ganglia, a region not amenable for a beneficial decompressive craniectomy [7]. To overcome this problem we used the thromboembolic modell as it occludes only parts of the MCA-supplied territory by fibrin-rich clots. By use of DWI and visual inspection of the circle of Willis, clot material obstructed mainly the ipsilateral MCA. However, clot material extended also into the proximal ACA and in two cases into the PCA as confirmed by microscopic inspection of the basal arteries (these animals were excluded from data analysis). The degree of cerebral blood flow reduction described by Krueger and Busch [14] was 54 ± 14% of the hemisphere and sufficient to fulfil the threshold principle/theory of ischemic stroke: Siesjo [25] defined tissue at risk at relative blood flow values starting from 40 to 55% of control. Recently, Dijkhuizen et al. [4] could show that relative blood flow indices <55% of control resulted in ischemic tissue damage. Although the optimal size and number of clots to occlude one- to two-third of the MCA territory were determined in preliminary experiments, and shape and composition of the clots were highly reproducible, the relatively high variety of infarction size was still a problem. To select appropriate animals based on initial infarction size and to match craniectomized and untreated control animals, early diffusion-weighted magnetic resonance imaging (DWI) at 1 h after emboli injection was used. Hereby, studies in both experimental stroke models [19] and stroke patients [26] have demonstrated that DWI is superior to conventional MRI in detecting early ischemic changes. The ischemic hyperintensity on DWI can be detected as early as 3 min [15] after the onset of ischemia and is due to a reduction of the apparent diffusion coefficient (ADC) of water, presumably related to water movement from the extracellular space to the intracellular spaces caused by energy failure after disturbance of
blood flow [16]. The ischemic hyperintensity demonstrated by DWI can be reversible if the interrupted blood flow is restored rapidly [15,19]. To detect any possible reversibility of initial DWI-derived ischemic lesions after decompressive craniectomy, a second MRI examination was performed at 4 h after emboli injection, respectively. As permanent normalization of DWI lesions does not necessarily indicate complete salvage of brain tissue from ischemic injury and the extend of the ischemic lesion maximizes at 24 h after vessel occlusion [15], a third MRI examination was performed as end point measurement at 1 day after emboli injection. At 4 and 24 h, the temporary evolution of the ischemic lesion in treated animals could be directly compared to controls. Additionally, as MRIindependent measure of the definite infarction size at 48 h after emboli injection, TTC-stained brain sections were used to determine definite infarction size [2]. In the initial DWI examination, only a total of 21 of 40 animals (52.5%) undergoing emboli injection revealed an infarction size of one to two-third of the MCA territory (50–100 mm3 based on former studies) and could be included. Spontaneous reperfusion, i.e. reversibility of the initial DWI-derived ischemic lesion, within a time period of 4 h after emboli injection was not observed neither in treated nor in untreated animals. The presumably low rate of spontaneous reperfusion in our model might be related to the high mean fibrin content. The mean fibrin content in the clots was 72 ± 13% as was shown by histologic examination [14]. As result, this study shows that (1) there is no partial reversibility of the initial ischemic lesion after early decompressive craniectomy in smaller thromboembolic infarcts. Additionally, by directly comparing the DWI-derived ischemic lesion at 4 and 24 h after emboli injection of treated and matched untreated animals, (2) there is no decrease of the definite infarction size due to decompression treatment with 73.5 ± 22.1 mm3 versus 76.3 ± 21.0 mm3 and 85.2 ± 24.7 mm3 versus 83.4 ± 22.9 mm3 , respectively (P > 0.87). The MRIindependent TTC-derived infarction size at 24 h after emboli injection was in the same range with 84.0 ± 23.3 mm3 and 82.7 ± 21.5 mm3 , respectively. One explanation for the failed reduction in infarction size in this study could be the infarct localization. In 71% (15 of 21 included animals), the initial ischemic area was located in the basal ganglia and in 90% (19 animals), 52% (11 animals) and 19% (4 animals) the final ischemic area was located in the basal, temporal and parietal MCA-supplied cortex, respectively, referring to Pacinos and Watson [23]. In a former study of experimental decompressive craniectomy using the suture model and perfusion-weighted magnetic resonance imaging (PWI) to calculate relative cerebral blood flow indices (rCBF), Engelhorn et al. [9] showed that rCBF in the cortex of craniectomized animals was higher compared to controls. However, only parts of the temporal cortex and especially the craniectomy site underlying parietal cortex showed a significant increase in rCBF,
T. Engelhorn et al. / Neuroscience Letters 370 (2004) 85–90
whereby rCBF in basal cortical areas and the basal ganglia did not significantly differ from that measured in control animals. In this study, only 45% (5 animals) and 18% (2 animals) of the 11 included animals undergoing decompressive craniectomy revealed initial ischemia in the temporal and parietal MCA-supplied cortex, respectively. As these parts of the cortex are the areas supposed to profit most from the procedure, the benefit of activating leptomeningeal collaterals to increase rCBF in this study is inevitably small. However, rCBF was not determined in this study. Additionally, a long-time follow-up and determination of a neurological score or histology was not performed. Using the TTCderived infarction size and an established neurological score [1] at 7 days after MCA occlusion, Engelhorn et al. [8] could show that early craniectomized animals reveal a better neurological performance with an average score of 1.6 compared to reperfused animals (1.8), although their average infarction size of 96 ± 30 mm3 was slightly higher compared to reperfused animals (79 ± 59 mm3 ). Therefore, it is to speculate if craniectomized animals could show a better neurological performance compared to untreated controls, although initial infarction size is in the same range. As another handicap, intracranial pressure (ICP) was not directly measured in this study as we abandoned to implant pressure-probes due to reported impreciseness of this technique [20]. As indirect ICP-marker, the MR-derived maximal midline shift to the non-infarcted side at 4 and 24 h after emboli injection did not significantly differ in craniectomized and control animals (data not shown), implicating that there was no or only minor effects on ICP due to craniectomy in small thromboembolic infarcts. In conclusion, our preliminary results demonstrate that early decompressive craniectomy does not reduce infarction size in small thromboembolic MCA infarction.
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Acknowledgement [16]
This study was supported by a grant of the Deutsche Forschungsgemeinschaft DFG (Do 721/1-1). [17]
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Decompressive craniectomy in acute cerebral ischemia in rats Is there any benefit in smaller thromboembolic infarcts? Tobias Engelhorna,∗ , Sabine Heilandb , Wolf-Ruediger Schabitzc , Stefan Schwabc , Elmar Buschd , Michael Forstinga , Arnd Doerflera a
Department of Neuroradiology, University of Essen, School of Medicine, Hufelandstrasse 55, D-45122 Essen, Germany b Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany c Department of Neurology, University of Heidelberg, Heidelberg, Germany d Department of Neurology, University of Essen, Essen, Germany Received 27 June 2004; received in revised form 29 July 2004; accepted 31 July 2004
Abstract Early craniectomy has shown to reduce infarction size in experimental large MCA infarction probably due to improved leptomeningeal perfusion. Based on the hypothesis that craniectomy may also be beneficial in smaller MCA infarction we evaluated the effects of craniectomy on infarction size in small thromboembolic cerebral infarction in rats. Therefore, thromboembolic cerebral ischemia was induced in 40 rats by endovascular injection of autologous, fibrin-rich emboli. Twentyone animals with a diffusion-weighted MR imaging (DWI)-derived infarction size of 50–100 mm3 (involving one- to two-third of the MCA territory) at 1 h after injection were randomly assigned to two groups. Eleven animals of group 1 immediately underwent craniectomy, ten animals of group 2 (controls) were not treated. Serial DWI was performed at 4 and 24 h. Infarction size was assessed by TTC-staining at 48 h after emboli injection. As result, prior to treatment, at 1 h after emboli injection, infarction size in groups 1 and 2 was 65.9 ± 16.0 mm3 and 67.9 ± 17.8 mm3 , respectively. At 4 and 24 h, infarction size in group 1 was 73.5 ± 22.1 mm3 and 85.2 ± 24.7 mm3 , and 76.3 ± 21.0 mm3 and 83.4 ± 22.9 mm3 in group 2, respectively. TTC-derived infarction size was 84.0 ± 23.3 mm3 and 82.7 ± 21.5 mm3 , respectively. There was no significant difference between the two groups (P > 0.79). In conclusion, our results demonstrate that for small thromboembolic MCA infarction early craniectomy is not beneficial. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Decompressive craniectomy; MCA occlusion; Thromboembolic stroke; Rat
Ischemic cerebral infarction associated with extensive edema and marked elevation of intracranial pressure (ICP) may cause ischemia of neighboring brain tissue and thus lead to further infarction [12]. This type of stroke, described as “malignant” middle cerebral artery (MCA) infarction, has been well-documented in clinical observations and in autopsy studies [20,22]. Aggressive approaches in treating this type of stroke are restoration of blood flow by thrombolysis [11,21] or decompressing the swollen brain by hemicraniec∗
Corresponding author. Tel.: +49 201 7231545; fax: +49 201 7235959. E-mail address: [email protected] (T. Engelhorn).
0304-3940/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2004.07.092
tomy to prevent herniation and to increase collateral blood supply [3,24]. Craniectomy may interrupt the vicious cycle of malignant MCA infarction by decreasing ICP. This may increase cerebral perfusion and optimize retrograde perfusion of MCA branches via leptomeningeal collaterals: functionally compromised but viable brain may thus be able to survive. Few experimental data have been published on the usefulness of craniectomy in the treatment of acute cerebral ischemia [5–10]. Studies using perfusion- and diffusion-weighted MR (DWI, PWI) to monitor the effects of craniectomy in the
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acute and chronic phase [6,7,9] demonstrated significantly increased cortical cerebral perfusion after craniectomy via improvement of collateral leptomeningeal circulation. Based on these encouraging experimental results we supposed that early craniectomy might also be beneficial in smaller, nonmalignant cerebral infarctions, by decreasing local spaceoccupying effects and thus improving collateral circulation. Therefore, we tested whether craniectomy might also decrease infarction size in smaller cerebral infarctions by injection of autologous, fibrin-rich emboli [14]. DWI was used to select and to match appropriate animals and to monitor the evolution of infarction size. Fourty male Wistar rats weighing 280–320 g were used in the present study. All animals were allowed access to food and water ad libitum. The study was approved by the Institutional Review Board. Anesthesia was induced by injection of 100 mg/kg ketamine hydrochloride. Monitoring of physiological parameters (blood pressure, arterial blood gases, plasma glucose, and body temperature) was done at 15 min before and after emboli injection. Body temperature was measured during anesthesia and controlled with circulation of thermostated air to maintain core temperature at 37 ± 0.5 ◦ C. Clots were prepared as recently described in detail [14]. Before blood aspiration the following reagents had to be prepared: phosphate-buffered saline (PBS), 1 mL of thrombin/PBS solution (1 mg/mL), and 5 mL albumin/PBS solution. Then 0.15 mL of the thrombin solution was filled into a 1 mL syringe. Next, three PE-50 tubes (30 cm) were prefitted at one end with a 22 G needle, and five Petri-dishes (5 mL) were filled with PBS and two dishes with albumin/PBS solution. At this point, arterial blood (0.6 mL) was aspirated via the femoral catheter in a 1 mL syringe. The blood was injected into a syringe that contained 0.15 mL thrombin immediately after aspiration. Immediately after mixing, the blood/thrombin mix was injected into the PE-50 tubes. The tubes were kept at room temperature for approximately 40 min. Under microscopic inspection clots with high fibrin content were selected. These were identified as whitish sections. These clot sections were cut into 1.5 mm-long fragments, and eight selected fragments were transferred into a dish with albumin/PBS solution. One by one, clot fragments were drawn up together with the albumin/PBS solution into a 1 m-long PE 50 catheter. In all animals, a midline incision in the neck was performed. Afterwards, the common carotid artery (CCA) was identified. The bifurcation of the CCA, the external carotid artery (ECA), the internal carotid (ICA), and the pterygopalatine artery (PPA) were prepared and ligated at the origin. Then, the occipital and thyroid artery, which branch off the ECA, and the distal ECA itself were coagulated. The proximal ECA was temporarily clipped and a PE 50 catheter was inserted into the ECA-section between the distal coagulation point and the proximally located clip. The tip of the catheter was advanced towards the carotid bifurcation and fixed. The clip was removed. The distal ECA was intersected and the
proximal ECA including the catheter turned caudal to get the tube into a straight line with the ICA. Then, the emboli were injected during a period of 30 s, so that the clots entered the carotid artery one by one. After the last clot had been injected, the CCA was reopened by releasing the clip. Eight clots were used for MCAO as preliminary experiments demonstrated this number ideal to create ischemia in about one- to two-third of the vessel territory. Animals were examined in a 2.35-T scanner (Biospec 24/40, Bruker, Germany). An actively shielded gradient coil with a 120-cm inner diameter was used. This coil was driven by the standard 150-V/100-A gradient power supply. In this configuration, 180 mT/m could be reached in 180 ms. As a radiofrequency coil, a home-built birdcage resonator with a 40-mm inner diameter was used. DWI was performed 1, 4 and 24 h after emboli injection using a spin-echo echo-planar imaging sequence (repetition time 3 s, echo time 67.7 ms, number of averages 3, 8 different b values from 0 to 1260 s/mm2 , diffusion time 50 ms, duration of diffusion gradient 5 ms, field of view 4 cm × 4 cm, matrix 128 × 64, six slices, and slice thickness 2 mm). The apparent diffusion coefficient was calculated from the diffusion-weighted images, as described elsewhere [13]. A side-by-side difference of apparent diffusion coefficient value from homologous pixels (i.e., the ischemic and normal hemispheres that best define the ischemic lesion volume in vivo) of 29%, which is highly correlated with post-mortem infarct volume, was used to define abnormal ischemic pixels and to calculate the ischemic size. Additionally, according to Pacinos and Watson [23] and former studies [9] infarct size was calculated for the parietal, temporal and basal MCA-supplied cortex and the basal ganglia, respectively. Based on former studies [5–10], complete occlusion of the MCA territory results in infarction size of approximately 150 mm3 at 1 h after MCAO. To include animals with infarction of one- to two-third of the MCA territory, only animals demonstrating a DWI-derived infarction size of 50–100 mm3 at 1 h after emboli injection were included. Hereby, calculation of the ischemic lesion volume was started immediately after the MR examination and took approximately 8 min. Included animals were assigned to one of the following experimental groups by using a computer generated randomization program. Group 1: decompressive craniectomy at 1 h after emboli injection. Group 2: no therapy (controls). Animals with an infarction volume smaller than 50 mm3 or greater than 100 mm3 in the initial DWI were excluded from data analysis. We performed craniectomy under microscopic control by creating a bone flap (10 mm × 5 mm) in the parietal and temporal bone using a dental drill as described in detail recently [5,10]. Forty-eight hours after emboli injection, the brains were removed, and then coronally sectioned into 2-mm
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slices. Slices were incubated in a 2% solution of 2,3,5triphenyltetrazolium chloride (TTC) at 37 ◦ C and fixed by immersion in a 10% buffered formalin solution [2]. Lesion volumes were measured by summing the unstained areas on TTC-stained brain slices. To avoid overestimation of the infarction volume, as described by Lin et al., the corrected infarction volume was calculated [16]. For statistical analysis of all results, commercial software (StatView, Brain Power Inc.) was used. For statistical analysis of infarction volume the unpaired t-test was used and a probability value of P < 0.05 was considered to be significant. The means and standard deviations (S.D.) are presented for both groups. A total of 21 animals (52.5%) demonstrated a DWIderived infarction size between 50 and 100 mm3 at 1 h after emboli injection. Eleven animals underwent decompressive craniectomy and 10 animals served as controls. Nine animals revealed nearly complete or complete MCA infarction with an infarction size >100 mm3 . Ten animals revealed an infarction size less than one third of the MCA territory. We noted no statistically significant differences in the remaining 21 animals among the two groups for any of the intraoperative physiologic parameters. Throughout animal preparation the average body temperature for all animals was 36.7 ± 0.4 (mean ± S.D.). Arterial blood gases (pO2 = 102 ± 16, pCO2 = 35 ± 6, pH = 7.38 ± 0.03) and hematocrit (42 ± 3) remained stable. Subarachnoid or parenchymal hemorrhage was not observed. Fig. 1 demonstrates the DWI-derived infarction size of both groups at 1, 4 and 24 h after emboli injection, repectively. Table 1 demonstrates DWI-derived infarction size of both groups in the different MCA-supplied cortical areas and the basal ganglia. Before treatment, at 1 h after emboli injection, infarction size in group 1 (craniectomy) and group 2 (control) was 65.9 ± 16.0 mm3 and 67.9 ± 17.8 mm3 , respectively. There was
Table 1 DWI-derived infarction size (mm3 ) of both groups (control group shown in brackets) at 1, 4 and 24 h after emboli injection in different MCA-supplied cortical areas and the basal ganglia, respectively, according to Pacinos and Watson [23]
Fig. 1. DWI-derived infarction size of both groups at 1, 4 and 24 h after emboli injection, repectively. There was no significant difference between group 1 (craniectomized animals) and group 2 (controls) at any time point.
Fig. 2. TTC-derived absolute infarction size at 48 h after emboli injection. There was no significant difference between group 1 (craniectomized animals) and group 2 (controls).
Localization
Time after emboli injection 1h
4h
24 h
Parietal cortex 9 ± 7 (9 ± 5) 9 ± 7 (10 ± 6) 8 ± 6 (10 ± 7) Temporal cortex 11 ± 7 (9 ± 6) 14 ± 10 (11 ± 10) 17 ± 12 (14 ± 11) Basal cortex 13 ± 9 (14 ± 9) 16 ± 9 (17 ± 11) 18 ± 12 (19 ± 13) Basal ganglia 35 ± 16 (34 ± 15) 37 ± 19 (37 ± 21) 40 ± 22 (42 ± 25) There was no significant difference between craniectomized animals and controls for the different infarct localizations at any time point.
no significant difference between the two groups (P = 0.87). At 4 and 24 h after emboli injection, infarction size in group 1 was 73.5 ± 22.1 mm3 and 85.2 ± 24.7 mm3 and infarction size in group 2 was 76.3 ± 21.0 mm3 and 83.4 ± 22.9 mm3 , respectively. Still, there was no significant difference between the two groups (P > 0.79). Compared to the initial DWI scan none of the animals demonstrated a decreased DWI-derived infarction size or increased ADC values at 4 h after emboli injection. Fig. 2 demonstrates the TTC-derived infarction size of both groups at 48 h after emboli injection. The TTC-derived infarction size in groups 1 and 2 was 84.0 ± 23.3 mm3 and 82.7 ± 21.5 mm3 , respectively. There was no significant difference between the two groups (P = 0.85). The goal of this experimental study was to analyze, whether there is a benefit of early decompressive craniectomy in the treatment of smaller thromboembolic infarcts. While decompressive craniectomy is recommended and indeed may be an appropriate, lifesaving procedure with low risk in selected patients in the management of severe spaceoccupying MCA infarction, there exists no clinical or ex-
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perimental data about a possible impact of decompressing the brain in case of infarcts involving only one- to two-third of the territory of the MCA [3,24]. Theoretically, in such cases, early decompression of locally swollen brain with subsequent activation of leptomeningeal collaterals may result in reduced infarction size too and could thus be of therapeutical benefit. All recent experimental studies [5–10] showing a benefit of early decompressive craniectomy in MCA occlusion are based on the endovascular suture model described by Longa et al. [17]. This model consistently simulates complete space-occupying MCA territory infarction. However, due to complete occlusion of the origin of the MCA and subsequent complete ischemia of the MCA territory, studies on the effects of decompressive craniectomy in smaller cerebral infarction are hardly possible. Temporary endovascular occlusion of the MCA followed by subsequent reperfusion within a therapeutical time window of approximately 2 h [16,18], combined with early decompressive craniectomy does not simulate the clinical setting. Additionally, there may be an early blood–brain barrier breakdown and the infarcts are mainly restricted to the basal ganglia, a region not amenable for a beneficial decompressive craniectomy [7]. To overcome this problem we used the thromboembolic modell as it occludes only parts of the MCA-supplied territory by fibrin-rich clots. By use of DWI and visual inspection of the circle of Willis, clot material obstructed mainly the ipsilateral MCA. However, clot material extended also into the proximal ACA and in two cases into the PCA as confirmed by microscopic inspection of the basal arteries (these animals were excluded from data analysis). The degree of cerebral blood flow reduction described by Krueger and Busch [14] was 54 ± 14% of the hemisphere and sufficient to fulfil the threshold principle/theory of ischemic stroke: Siesjo [25] defined tissue at risk at relative blood flow values starting from 40 to 55% of control. Recently, Dijkhuizen et al. [4] could show that relative blood flow indices <55% of control resulted in ischemic tissue damage. Although the optimal size and number of clots to occlude one- to two-third of the MCA territory were determined in preliminary experiments, and shape and composition of the clots were highly reproducible, the relatively high variety of infarction size was still a problem. To select appropriate animals based on initial infarction size and to match craniectomized and untreated control animals, early diffusion-weighted magnetic resonance imaging (DWI) at 1 h after emboli injection was used. Hereby, studies in both experimental stroke models [19] and stroke patients [26] have demonstrated that DWI is superior to conventional MRI in detecting early ischemic changes. The ischemic hyperintensity on DWI can be detected as early as 3 min [15] after the onset of ischemia and is due to a reduction of the apparent diffusion coefficient (ADC) of water, presumably related to water movement from the extracellular space to the intracellular spaces caused by energy failure after disturbance of
blood flow [16]. The ischemic hyperintensity demonstrated by DWI can be reversible if the interrupted blood flow is restored rapidly [15,19]. To detect any possible reversibility of initial DWI-derived ischemic lesions after decompressive craniectomy, a second MRI examination was performed at 4 h after emboli injection, respectively. As permanent normalization of DWI lesions does not necessarily indicate complete salvage of brain tissue from ischemic injury and the extend of the ischemic lesion maximizes at 24 h after vessel occlusion [15], a third MRI examination was performed as end point measurement at 1 day after emboli injection. At 4 and 24 h, the temporary evolution of the ischemic lesion in treated animals could be directly compared to controls. Additionally, as MRIindependent measure of the definite infarction size at 48 h after emboli injection, TTC-stained brain sections were used to determine definite infarction size [2]. In the initial DWI examination, only a total of 21 of 40 animals (52.5%) undergoing emboli injection revealed an infarction size of one to two-third of the MCA territory (50–100 mm3 based on former studies) and could be included. Spontaneous reperfusion, i.e. reversibility of the initial DWI-derived ischemic lesion, within a time period of 4 h after emboli injection was not observed neither in treated nor in untreated animals. The presumably low rate of spontaneous reperfusion in our model might be related to the high mean fibrin content. The mean fibrin content in the clots was 72 ± 13% as was shown by histologic examination [14]. As result, this study shows that (1) there is no partial reversibility of the initial ischemic lesion after early decompressive craniectomy in smaller thromboembolic infarcts. Additionally, by directly comparing the DWI-derived ischemic lesion at 4 and 24 h after emboli injection of treated and matched untreated animals, (2) there is no decrease of the definite infarction size due to decompression treatment with 73.5 ± 22.1 mm3 versus 76.3 ± 21.0 mm3 and 85.2 ± 24.7 mm3 versus 83.4 ± 22.9 mm3 , respectively (P > 0.87). The MRIindependent TTC-derived infarction size at 24 h after emboli injection was in the same range with 84.0 ± 23.3 mm3 and 82.7 ± 21.5 mm3 , respectively. One explanation for the failed reduction in infarction size in this study could be the infarct localization. In 71% (15 of 21 included animals), the initial ischemic area was located in the basal ganglia and in 90% (19 animals), 52% (11 animals) and 19% (4 animals) the final ischemic area was located in the basal, temporal and parietal MCA-supplied cortex, respectively, referring to Pacinos and Watson [23]. In a former study of experimental decompressive craniectomy using the suture model and perfusion-weighted magnetic resonance imaging (PWI) to calculate relative cerebral blood flow indices (rCBF), Engelhorn et al. [9] showed that rCBF in the cortex of craniectomized animals was higher compared to controls. However, only parts of the temporal cortex and especially the craniectomy site underlying parietal cortex showed a significant increase in rCBF,
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whereby rCBF in basal cortical areas and the basal ganglia did not significantly differ from that measured in control animals. In this study, only 45% (5 animals) and 18% (2 animals) of the 11 included animals undergoing decompressive craniectomy revealed initial ischemia in the temporal and parietal MCA-supplied cortex, respectively. As these parts of the cortex are the areas supposed to profit most from the procedure, the benefit of activating leptomeningeal collaterals to increase rCBF in this study is inevitably small. However, rCBF was not determined in this study. Additionally, a long-time follow-up and determination of a neurological score or histology was not performed. Using the TTCderived infarction size and an established neurological score [1] at 7 days after MCA occlusion, Engelhorn et al. [8] could show that early craniectomized animals reveal a better neurological performance with an average score of 1.6 compared to reperfused animals (1.8), although their average infarction size of 96 ± 30 mm3 was slightly higher compared to reperfused animals (79 ± 59 mm3 ). Therefore, it is to speculate if craniectomized animals could show a better neurological performance compared to untreated controls, although initial infarction size is in the same range. As another handicap, intracranial pressure (ICP) was not directly measured in this study as we abandoned to implant pressure-probes due to reported impreciseness of this technique [20]. As indirect ICP-marker, the MR-derived maximal midline shift to the non-infarcted side at 4 and 24 h after emboli injection did not significantly differ in craniectomized and control animals (data not shown), implicating that there was no or only minor effects on ICP due to craniectomy in small thromboembolic infarcts. In conclusion, our preliminary results demonstrate that early decompressive craniectomy does not reduce infarction size in small thromboembolic MCA infarction.
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Acknowledgement [16]
This study was supported by a grant of the Deutsche Forschungsgemeinschaft DFG (Do 721/1-1). [17]
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