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  • Author or Editor: Bon H. Verweij x
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Robert F. Berman, Bon H. Verweij and J. Paul Muizelaar

Object. Abnormal accumulation of intracellular calcium following traumatic brain injury (TBI) is thought to contribute to a cascade of cellular events that lead to neuropathological conditions. Therefore, the possibility that specific calcium channel antagonists might exert neuroprotective effects in TBI has been of interest. The focus of this study was to examine whether Ziconotide produces such neuroprotective effects.

Methods. The authors report that the acceleration—deceleration model of TBI developed by Marmarou, et al., induces a long-lasting deficit of neuromotor and behavioral function. The voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) exerts neuroprotective effects in this model of diffuse brain injury (DBI) in rats. The dose and time of injection of Ziconotide chosen for the present study was based on the authors' previous biochemical studies of mitochondria. Rats were trained in a series of motor and memory tasks, following which they were subjected to DBI using the Marmarou, et al., model. At 3, 5, and 24 hours, all rats were injected with 2 mg/kg Ziconotide for a total cumulative dose of 6 mg/kg Ziconotide. Control brain-injured animals were injected with an equal volume of saline vehicle at each of these time points. The rats were tested for motor and cognitive performance at 1, 3, 7, 14, 21, 28, 35, and 42 days postinjury. Saline-treated rats displayed severe motor and cognitive deficits after DBI. Compared with saline-treated control animals, rats treated with Ziconotide displayed better motor performance during inclined plane, beam balance, and beam walk tests; improved memory while in the radial arm maze; and improved learning while in the Morris water maze.

Conclusions. These results demonstrated that the acceleration—deceleration model, which had been developed by Marmarou, et al., induces severe motor and cognitive deficits. We also demonstrated that Ziconotide exhibits substantial neuroprotective activity in this model of TBI. Improvement was observed in both motor and cognitive tasks, even though treatment was not initiated until 3 hours after injury. These findings support the development of neuronal N-type calcium channel antagonists as useful therapeutic agents in the treatment of TBI.

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Bon H. Verweij, J. Paul Muizelaar and Federico C. Vinas

Object. The poor prognosis for traumatic acute subdural hematoma (ASDH) might be due to underlying primary brain damage, ischemia, or both. Ischemia in ASDH is likely caused by increased intracranial pressure (ICP) leading to decreased cerebral perfusion pressure (CPP), but the degree to which these phenomena occur is unknown. The authors report data obtained before and during removal of ASDH in five cases.

Methods. Five patients who underwent emergency evacuation of ASDH were monitored. In all patients, without delaying treatment, a separate surgical team (including the senior author) placed an ICP monitor and a jugular bulb catheter, and in two patients a laser Doppler probe was placed.

The ICP prior to removing the bone flap in the five patients was 85, 85, 50, 59, and greater than 40 mm Hg, resulting in CPPs of 25, 3, 25, 56, and less than 50 mm Hg, respectively. Removing the bone flap as well as opening the dura and removing the blood clot produced a significant decrease in ICP and an increase in CPP. Jugular venous oxygen saturation (SjvO2) increased in four patients and decreased in the other during removal of the hematoma. Laser Doppler flow also increased, to 217% and 211% compared with preevacuation flow.

Conclusions. Intracranial pressure is higher than previously suspected and CPP is very low in patients with ASDH. Removal of the bone flap yielded a significant reduction in ICP, which was further decreased by opening the dura and evacuating the hematoma. The SjvO2 as well as laser Doppler flow increased in all patients but one immediately after removal of the hematoma.

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Maaike R. Moman, Bon H. Verweij, Joeri Buwalda and Gabriël J. E. Rinkel

Object

Patients treated for aneurysmal subarachnoid hemorrhage (SAH) often report a loss of smell. To discriminate between the effects of aneurysmal rupture and treatment, the authors assessed the occurrence of anosmia after clipping and coiling of unruptured aneurysms as well as after the coiling of ruptured aneurysms.

Methods

The authors interviewed patients in whom an unruptured aneurysm was treated by clipping (32 cases) or endovascular coiling (26 cases) as well as patients with SAH who underwent coil therapy (32 cases). A geographically defined subset of 20 patients per group was invited to undergo olfactory testing.

Results

Nine clip-treated patients (28% [95% CI 14–47%]) in the unruptured group reported having anosmia, and no coil-treated patient in the unruptured group (95% [CI 0–13%]) reported having anosmia; in the SAH group, 7 patients (22% [95% CI 9–40%]) reported having anosmia. Anosmia had improved over time in 3 of the clip-treated patients and in all but 1 of the patients with SAH. Examination revealed olfactory disturbance in 13 (65% [95% CI 41–85%]) of the clip-treated and 8 (42% [95% CI 20–67%]) of the coil-treated patients with unruptured aneurysms, and also in 7 (35% [95% CI 15–59%]) coil-treated patients with SAH. In 20 patients who underwent clip therapy for unruptured aneurysms, 19 (95% [95% CI 75–100%]) had olfactory dysfunction on the side ipsilateral to surgery (anosmia reported by 8 of them).

Conclusions

Both clip treatment and SAH contribute to the occurrence of anosmia, with different chances of improvement. Olfactory dysfunction occurs in almost all patients on the side of surgery and can occur subclinically after coil deployment.

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Bon H. Verweij, J. Paul Muizelaar, Federico C. Vinas, Patti L. Peterson, Ye Xiong and Chuan P. Lee

Object. Oxygen supply to the brain is often insufficient after traumatic brain injury (TBI), and this results in decreased energy production (adenosine triphosphate [ATP]) with consequent neuronal cell death. It is obviously important to restore oxygen delivery after TBI; however, increasing oxygen delivery alone may not improve ATP production if the patient's mitochondria (the source of ATP) are impaired. Traumatic brain injury has been shown to impair mitochondrial function in animals; however, no human studies have been previously reported.

Methods. Using tissue fractionation procedures, living mitochondria derived from therapeutically removed brain tissue were analyzed in 16 patients with head injury (Glasgow Coma Scale Scores 3–14) and two patients without head injury. Results revealed that in head-injured patients mitochondrial function was impaired, with subsequent decreased ATP production.

Conclusions. Decreased oxygen metabolism due to mitochondrial dysfunction must be taken into account when clinically defining ischemia and interpreting oxygen measurements such as jugular venous oxygen saturation, arteriovenous difference in oxygen content, direct tissue oxygen tension, and cerebral blood oxygen content determined using near-infrared spectroscopy. Restoring mitochondrial function might be as important as maintaining oxygen delivery.

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Bon H. Verweij, J. Paul Muizelaar, Federico C. Vinas, Patti L. Peterson, Ye Xiong and Chuan P. Lee

Object. Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose—response curves in preclinical drug testing. This idea was tested in a model of TBI in rats.

Methods. Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose.

Conclusions. The authors established these time-window profiles and dose—response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose—response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.

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Michael Reinert, Bon H. Verweij, Thomas Schaffner, George Mihalache, Gerhard Schroth, Rolf W. Seiler and Cornelis A. F. Tulleken

Object

Patients with complex craniocerebral pathophysiologies such as giant cerebral aneurysms, skull base tumors, and/or carotid artery occlusive disease are candidates for a revascularization procedure to augment or preserve cerebral blood flow. However, the brain is susceptible to ischemia, and therefore the excimer laser–assisted nonocclusive anastomosis (ELANA) technique has been developed to overcome temporary occlusion. Harvesting autologous vessels of reasonable quality, which is necessary for this technique, may at times be problematic or impossible due to the underlying systemic vascular disease. The use of artificial vessels is therefore an alternative graft for revascularization. Note, however, that it is unknown to what degree these grafts are subject to occlusion using the ELANA anastomosis technique. Therefore, the authors studied the ELANA technique in combination with an expanded polytetrafluoroethylene (ePTFE) graft.

Methods

The experimental surgeries involved bypassing the abdominal aorta in the rabbit. Ten rabbits were subjected to operations representing 20 ePTFE graft–ELANA end-to-side anastomoses. Intraoperative blood flow, follow-up angiograms, and long-term histological characteristics were assessed 75, 125, and 180 days postoperatively. Angiography results proved long-term patency of ePTFE grafts in all animals at all time points studied. Data from the histological analysis showed minimal intimal reaction at the anastomosis site up to 180 days postoperatively. Endothelialization of the ePTFE graft was progressive over time.

Conclusions

The ELANA technique in combination with the ePTFE graft seems to have favorable attributes for end-to-side anastomoses and may be suitable for bypass procedures.

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Jochem P. Bremmer, Bon H. Verweij, Catharina J. M. Klijn, Albert van der Zwan, L. Jaap Kappelle and Cornelis A. F. Tulleken

Object

Excimer laser–assisted nonocclusive anastomosis (ELANA) is a technique that can be used for extracranial-to-intracranial (EC-IC) bypasses, without the necessity of temporary occlusion of the donor or recipient artery. Information on predictors of patency of EC-IC bypasses in general and the ELANA bypass in particular is sparse. The authors studied 159 ELANA EC-IC bypasses to find predictors of patency.

Methods

From a prospective database of patients who underwent EC-IC bypass surgery, 143 consecutive patients who underwent a total of 159 ELANA bypasses were studied. The associations of patient characteristics, surgical aspects, and technical aspects specific to the ELANA technique with intraoperative and postoperative bypass patency were studied using logistic regression analysis.

Results

At the end of the operation, 146 (92%) of the 159 bypasses were patent. A first attempt to create a bypass was almost 8 times more likely (OR 7.6, 95% CI 2.1–27.5; p = 0.02) to result in a patent bypass than a second attempt. Administration of a small amount of heparin during the operation was also associated with bypass patency (OR 5.2, 95% CI 1.1–24.9; p = 0.04). One hundred twenty-three (77%) of the 159 bypasses were functional at patency assessments during the 1st month after the operation. Older age (OR 1.043 for every year of increase in age, 95% CI 1.010–1.076; p = 0.01), male sex (OR 2.9, 95% CI 1.3–6.5; p = 0.01), and high intraoperative bypass flow (OR 1.017 for every milliliter per minute increase in flow, 95% CI 1.004–1.030; p = 0.01) were associated with postoperative bypass patency.

Conclusions

Attempts to create a second EC-IC ELANA bypass after the first one are more likely to fail, whereas administration of heparin to the patient during the procedure increases the intraoperative bypass patency rate. Postoperative patency results are better in male and in older patients. Intraoperative bypass flow measurements are essential because high bypass flow is an important determinant of postoperative patency.

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Jochem P. Bremmer, Bon H. Verweij, Albert van der Zwan, Michael M. Reinert, Hendricus J. Mansvelt Beck and Cornelis A. F. Tulleken

Object

Cerebral aneurysms that cannot be treated by clip or coil placement can be treated with high-flow bypass surgery using techniques such as the excimer laser–assisted nonocclusive anastomosis (ELANA). To simplify the technique, a sutureless ELANA (SELANA) was developed in combination with an expanded polytetrafluoroethylene (ePTFE) graft.

Methods

In 18 rabbits a bypass was constructed on the abdominal aorta using the SELANA technique with an ePTFE graft, resulting in 18 bypasses and 36 anastomoses. Short-term effects were analyzed in the first 2 weeks and at 2 and 3 months after the procedure. Patency was evaluated using quantitative ultrasound flowmetry. The anastomotic sites were studied using scanning electron microscopy.

Results

Construction of the bypass using the SELANA technique was easier and faster (15–25 minutes) compared with bypasses made with the ELANA technique (> 90 minutes). At the end of follow-up, 16 of 18 bypasses were patent. Of 36 SELANA anastomoses, 32 could be completed without short temporary occlusion of the recipient vessel. Scanning electron microscopy showed complete coverage of all anastomoses with neointimal repair tissue after 10 days.

Conclusions

The SELANA technique provides further advantages over the conventional ELANA technique in ease of use and shortening of procedure time. The patency rate in this series was 89% and neointima repair tissue at the anastomosis site was complete after 10 days. Further experimental studies of the long-term patency and safety of this technique are necessary before clinical application.

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Tristan P. C. van Doormaal, Albert van der Zwan, Saskia Redegeld, Bon H. Verweij, Cornelis A. F. Tulleken and Luca Regli

Object

The purpose of this study was to assess flow, patency, and endothelialization of bypasses created with the sutureless Excimer Laser Assisted Non-occlusive Anastomosis (SELANA) technique in a pig model.

Methods

In 38 pigs, a bypass was made on the left common carotid artery (CCA), using the right CCA as a graft, with 2 SELANAs. Bypass flow was measured using single-vessel flowmetry. The pigs were randomly assigned to 1 of 12 survival groups (1, 2, 3, 4, 5, 6, 7, and 10 days; 2 and 3 weeks; and 3 and 6 months). One extra animal underwent the procedure and then was killed after 1 hour of bypass patency to serve as a control. Angiography was performed just before the animals were killed, to assess bypass patency. Scanning electron microscopy and histological studies were used to evaluate the anastomoses after planned death.

Results

The mean SELANA bypass flow was not significantly different from the mean flow in the earlier ELANA (Excimer Laser Assisted Non-occlusive Anastomosis) pig study at opening and follow-up. Overall SELANA bypass patency (87%) was not significantly different from the ELANA patency of 86% in the earlier study. Complete SELANA endothelialization was observed after 2–3 weeks, compared with 2 weeks in the earlier ELANA study.

Conclusions

The SELANA technique is not inferior to the current ELANA technique regarding flow, patency, and endothelialization. A pilot study in patients is a logical next step.