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Juergen Konczalla, Volker Seifert, Juergen Beck, Erdem Güresir, Hartmut Vatter, Andreas Raabe and Gerhard Marquardt

OBJECTIVE

Outcome analysis of comatose patients (Hunt and Hess Grade V) after subarachnoid hemorrhage (SAH) is still lacking. The aims of this study were to analyze the outcome of Hunt and Hess Grade V SAH and to compare outcomes in the current period with those of the pre–International Subarachnoid Aneurysm Trial (ISAT) era as well as with published data from trials of decompressive craniectomy (DC) for middle cerebral artery (MCA) infarction.

METHODS

The authors analyzed cases of Hunt and Hess Grade V SAH from 1980–1995 (referred to in this study as the earlier period) and 2005–2014 (current period) and compared the results for the 2 periods. The outcomes of 257 cases were analyzed and stratified on the basis of modified Rankin Scale (mRS) scores obtained 6 months after SAH. Outcomes were dichotomized as favorable (mRS score of 0–2) or unfavorable (mRS score of 3–6). Data and number needed to treat (NNT) were also compared with the results of decompressive craniectomy (DC) trials for middle cerebral artery (MCA) infarctions.

RESULTS

Early aneurysm treatment within 72 hours occurred significantly more often in the current period (in 67% of cases vs 22% in earlier period). In the earlier period, patients had a significantly higher 30-day mortality rate (83% vs 39% in the current period) and 6-month mortality rate (94% vs 49%), and no patient (0%) had a favorable outcome, compared with 23% overall in the current period (p < 0.01, OR 32), or 29.5% of patients whose aneurysms were treated (p < 0.01, OR 219). Cerebral infarctions occurred in up to 65% of the treated patients in the current period.

Comparison with data from DC MCA trials showed that the NNTs were significantly lower in the current period with 2 for survival and 3 for mRS score of 0–3 (vs 3 and 7, respectively, for the DC MCA trials).

CONCLUSIONS

Early and aggressive treatment resulted in a significant improvement in survival rate (NNT = 2) and favorable outcome (NNT = 3 for mRS score of 0–3) for comatose patients with Hunt and Hess Grade V SAH compared with the earlier period. Independent predictors for favorable outcome were younger age and bilateral intact corneal reflexes. Despite a high rate of cerebral infarction (65%) in the current period, 29.5% of the patients who received treatment for their aneurysms during the current era (2005–2014) had a favorable outcome. However, careful individual decision making is essential in these cases.

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Erdem Güresir, Hartmut Vatter, Patrick Schuss, Ági Oszvald, Andreas Raabe, Volker Seifert and Jürgen Beck

Object

The object of this study was to describe the rapid closure technique in decompressive craniectomy without duraplasty and its use in a large cohort of consecutive patients.

Methods

Between 1999 and 2008, supratentorial rapid closure decompressive craniectomy (RCDC) was performed 341 times in 318 patients at the authors' institution. Cases were stratified as 1) traumatic brain injury, 2) subarachnoid hemorrhage, 3) intracerebral hemorrhage, 4) cerebral infarction, and 5) other. A large bone flap was removed and the dura mater was opened in a stellate fashion. Duraplasty was not performed—that is, the dura was not sutured, and a dural substitute was neither sutured in nor layed on. The dura and exposed brain tissue were covered with hemostyptic material (Surgicel). Surgical time and complications of this procedure including follow-up (> 6 months) were recorded. After 3–6 months cranioplasty was performed, and, again, surgical time and any complications were recorded.

Results

Rapid closure decompressive craniectomy was feasible in all cases. Complications included superficial wound healing disturbance (3.5% of procedures), abscess (2.6%) and CSF fistula (0.6%); the mean surgical time (± SD) was 69 ± 20 minutes. Cranioplasty was performed in 196 cases; the mean interval (± SD) from craniectomy to cranioplasty was 118 ± 40 days. Complications of cranioplasty included epidural hematoma (4.1%), abscess (2.6%), wound healing disturbance (6.1%), and CSF fistula (1%).

Compared with the results reported in the literature for decompressive craniectomy with duraplasty followed by cranioplasty, there were no significant differences in the frequency of complications. However, surgical time for RCDC was significantly shorter (69 ± 20 vs 129 ± 43 minutes, p < 0.0001).

Conclusions

The present analysis of the largest series reported to date reveals that the rapid closure technique is feasible and safe in decompressive craniectomy. The surgical time is significantly shorter without increased complication rates or additional complications. Cranioplasty after a RCDC procedure was also feasible, fast, safe and not impaired by the RCDC technique.

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Erdem Güresir, Patrick Schuss, Hartmut Vatter, Andreas Raabe, Volker Seifert and Jürgen Beck

Object

The aim of this study was to analyze decompressive craniectomy (DC) in the setting of subarachnoid hemorrhage (SAH) with bleeding, infarction, or brain swelling as the underlying pathology in a large cohort of consecutive patients.

Methods

Decompressive craniectomy was performed in 79 of 939 patients with SAH. Patients were stratified according to the indication for DC: 1) primary brain swelling without or 2) with additional intracerebral hematoma, 3) secondary brain swelling without rebleeding or infarcts, and 4) secondary brain swelling with infarcts or 5) with rebleeding. Outcome was assessed according to the modified Rankin Scale (mRS) at 6 months (mRS Score 0–3 favorable vs 4–6 unfavorable).

Results

Overall, 61 (77.2%) of 79 patients who did and 292 (34%) of the 860 patients who did not undergo DC had a poor clinical grade on admission (World Federation of Neurosurgical Societies Grade IV–V, p < 0.0001). A favorable outcome was attained in 21 (26.6%) of 79 patients who had undergone DC. In a comparison of favorable outcomes in patients with primary (28.0%) or secondary DC (25.5%), no difference could be found (p = 0.8). Subgroup analysis with respect to the underlying indication for DC (brain swelling vs bleeding vs infarction) revealed no difference in the rate of favorable outcomes. On multivariate analysis, acute hydrocephalus (p = 0.009) and clinical signs of herniation (p = 0.02) were significantly associated with an unfavorable outcome.

Conclusions

Based on the data in this study the authors concluded that primary as well as secondary craniectomy might be warranted, regardless of the underlying etiology (hemorrhage, infarction, or brain swelling) and admission clinical grade of the patient. The time from the onset of intractable intracranial pressure to DC seems to be crucial for a favorable outcome, even when a DC is performed late in the disease course after SAH.

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Hartmut Vatter, Michael Zimmermann, Veronika Tesanovic, Andreas Raabe, Volker Seifert and Lothar Schilling

Object. The disturbed balance between nitric oxide and endothelin (ET)—1 in the cerebrovasculature seems to play a major role in the development of cerebral vasospasm after subarachnoid hemorrhage. Endothelin-1 represents the contractile part in this balance. In addition to the prevailing ETA receptor—dependent contractile effect, ET-1 also has ETB receptor—mediated vasodilatory attributes. The aim of the present study was to define the actual selectivity of clazosentan, the first putative highly ETA receptor—selective antagonist clinically proven to be effective in the treatment of vasospasm in the cerebrovasculature.

Methods. Rat basilar artery ring segments with endothelial function were used for the measurement of isometric force. Concentration effect curves were constructed by cumulative application of sarafotoxin S6c, ET-1, or big ET-1 in the presence or absence of clazosentan (10−9 to 10−6 M) after a precontraction was induced by prostaglandin F. The inhibition by clazosentan was estimated by the value of the affinity constant (pA2).

The relaxation induced by sarafotoxin S6c, ET-1, and big ET-1 was inhibited in a competitive manner by clazosentan, yielding pA2 values of 7.1, 6.7, and 6.5, respectively. The selectivity to the ETA receptor in the cerebrovascular system was approximately two logarithmic units.

Conclusions. The present investigation shows a competitive inhibition of ETB receptor—mediated relaxation in cerebral vessels by clazosentan in therapeutically relevant concentrations. Thus, additional clinical trials should be undertaken to evaluate clazosentan concentrations in cerebrospinal fluid. Furthermore, the present data may be taken to describe the pharmacological properties for an ET receptor antagonist specifically tailored for the treatment of pathological conditions of impaired cerebral blood flow.

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Hartmut Vatter, Michael Zimmermann, Veronika Tesanovic, Andreas Raabe, Lothar Schilling and Volker Seifert

Object. The central role of endothelin (ET)—1 in the development of cerebral vasospasm after subarachnoid hemorrhage is indicated by the successful treatment of this vasospasm in several animal models by using selective ETA receptor antagonists. Clazosentan is a selective ETA receptor antagonist that provides for the first time clinical proof that ET-1 is involved in the pathogenesis of cerebral vasospasm. The aim of the present investigation was, therefore, to define the pharmacological properties of clazosentan that affect ETA receptor—mediated contraction in the cerebrovasculature.

Methods. Isometric force measurements were performed in rat basilar artery (BA) ring segments with (E+) and without (E−) endothelial function. Concentration effect curves (CECs) were constructed by cumulative application of ET-1 or big ET-1 in the absence or presence of clazosentan (10−9, 10−8, and 10−7 M). The inhibitory potency of clazosentan was determined by the value of the affinity constant (pA2).

The CECs for contraction induced by ET-1 and big ET-1 were shifted to the right in the presence of clazosentan in a parallel dose-dependent manner, which indicates competitive antagonism. The pA2 values for ET-1 were 7.8 (E+) and 8.6 (E−) and the corresponding values for big ET-1 were 8.6 (E+) and 8.3 (E−).

Conclusions. The present data characterize clazosentan as a potent competitive antagonist of ETA receptor—mediated constriction of the cerebrovasculature by ET-1 and its precursor big ET-1. These functional data may also be used to define an in vitro profile of an ET receptor antagonist with a high probability of clinical efficacy.

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Hartmut Vatter, Juergen Konczalla, Stefan Weidauer, Christine Preibisch, Michael Zimmermann, Andreas Raabe and Volker Seifert

Object

The key role in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH) is increasingly assigned to endothelin (ET)-1. Constriction of the cerebrovasculature by ET-1 is mainly mediated by the ETA receptor but is putatively altered during the development of cerebral vasospasm. Therefore, the aim in the present study was to characterize these alterations, with the emphasis on the ETA receptor.

Methods

Cerebral vasospasm was induced using the rat double-hemorrhage model and proven by perfusion weighted magnetic resonance imaging. Rats were killed on Day 5 after SAH, and immunohistochemical staining for ETA receptors was performed. The isometric force of basilar artery ring segments with (E+, control group) and without (E−, SAH group) endothelial function was measured. Concentration effect curves (CECs) for ET-1 were constructed by cumulative application in the absence and presence of the selective ETA receptor antagonist clazosentan (10−8 or 10−7 M).

Results

The CEC for E+ segments was significantly shifted to the left after SAH by a factor of 3.7, whereas maximum contraction was unchanged. In E− segments, the CECs were not shifted during cerebral vasospasm but the maximum contraction was significantly enhanced. The inhibitory potency of clazosentan yielded a pA2 value of 8.6 ± 0.2. Immunohistochemical staining of the smooth-muscle layer showed no significant increase of ETA receptor expression, but positive staining occurred in the endothelial space after SAH.

Conclusions

The present data indicate an enhanced contractile effect of the smooth-muscle ETA receptors in cases of cerebral vasospasm. The inhibitory potency of clazosentan on this contraction is increased. Furthermore, some evidence for an ETA receptor and an endothelium-dependent vasoactive effect after SAH is provided.