Summary
Objective. To study the effects of clazosentan, a new selective endothelin receptor subtype A antagonist, on cerebral perfusion and cerebral oxygenation following severe aneurysmal subarachnoid haemorrhage (aSAH).
Methods. All 12 patients treated at our institution in the context of a phase IIa, multicenter, randomized trial on clazosentan’s safety and efficacy in reducing the incidence of angiographic cerebral vasospasm were included in this substudy. The phase IIa study (n = 34) consisted of two parts: a double-blind, randomized Part A (clazosentan 0.2 mg/kg/h versus placebo) and an open-label Part B (clazosentan 0.4 mg/kg/h for 12 h followed by 0.2 mg/kg/h) for patients with established vasospasm. In parallel to the phase IIa study protocol, which included assessment of vasospasm by angiography and transcranial Doppler sonography, we determined regional cerebral blood flow (rCBF), cerebrovascular resistance, and regional tissue oxygenation.
Results. Cerebral perfusion was comparable between treatment groups during the early post-bleeding period (rCBF placebo, 22.6 ± 3.5 ml/100 g/min versus rCBF clazosentan, 23.9 ± 1.1 ml/100 g/min). By the time of control angiography (day 8 after aSAH), rCBF decreased by 50% in the placebo group (11.3 ± 6.7 ml/ 100 g/min) while it remained stable in the clazosentan group (23.5 ± 12.9 ml/100 g/min). During Part B of the study, all 3 patients who developed haemodynamically relevant vasospasm during placebo treatment, showed a sustained improvement in rCBF upon conversion to clazosentan.
Conclusions. These preliminary data suggest that clazosentan reduces the extent of vasospasm-associated impairment of cerebral perfusion following aSAH. Furthermore, clazosentan may exert beneficial actions on overt vasospasm-associated hypoperfusion.
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Abbreviations
- Acom:
-
anterior communicating artery
- aSAH:
-
aneurysmal subarachnoid haemorrhage
- CPP:
-
cerebral perfusion pressure
- CT:
-
computerized tomography
- CVR:
-
cerebral vascular resistance
- DIND:
-
delayed ischaemic neurological deficit
- GCS:
-
Glasgow Coma Scale
- H&H:
-
Hunt and Hess
- ICA:
-
internal carotid artery
- ICP:
-
intracranial pressure
- LI:
-
Lindegaard index
- MAP:
-
mean arterial pressure
- MCA:
-
middle cerebral artery
- Pcom:
-
posterior communicating artery
- rCBF:
-
regional cerebral blood flow
- SD:
-
standard deviation
- sXe-CT:
-
stable Xenon computerised tomography
- TCD:
-
transcranial Doppler sonography
- TD-rCBF:
-
thermal diffusion regional cerebral blood flow
References
T Bertsch S Kuehl F Muehlhauser S Walter B Hodapp S Rossol J Schmeck A Ragoschke S Schutt M Fritzinger P Horn P Vajkoczy NW Wellner K Fassbender (2001) ArticleTitleSource of endothelin-1 in subarachnoid haemorrhage Clin Chem Lab Med 39 341–345 Occurrence Handle11388659 Occurrence Handle10.1515/CCLM.2001.053 Occurrence Handle1:CAS:528:DC%2BD3MXktFOltLc%3D
BL Clyde DK Resnick H Yonas HA Smith AM Kaufmann (1996) ArticleTitleThe relationship of blood velocity as measured by transcranial doppler ultrasonography to cerebral blood flow as determined by stable xenon computed tomographic studies after aneurysmal subarachnoid haemorrhage Neurosurgery 38 896–904 Occurrence Handle8727814 Occurrence Handle10.1097/00006123-199605000-00008 Occurrence Handle1:STN:280:DyaK283ovVOnsQ%3D%3D
HH Dietrich RG Dacey SuffixJr (2000) ArticleTitleMolecular keys to the problems of cerebral vasospasm Neurosurgery 46 517–530 Occurrence Handle10719847 Occurrence Handle10.1097/00006123-200003000-00001 Occurrence Handle1:STN:280:DC%2BD3c7ot1OltA%3D%3D
T Hayashi A Suzuki J Hatazawa I Kanno R Shirane T Yoshimoto N Yasui (2000) ArticleTitleCerebral circulation and metabolism in the acute stage of subarachnoid haemorrhage J Neurosurg 93 1014–1018 Occurrence Handle11117843 Occurrence Handle1:STN:280:DC%2BD3M%2FnslKnsg%3D%3D
Hirata Y, Matsunaga T, Ando K, Furukawa T, Tsukagoshi H, Marumo F (1990) Presence of endothelin-1-like immunoreactivity in human cerebrospinal fluid. Biochem Biophys Res Commun
JW Hop GJ Rinkel A Algra J van Gijn (1997) ArticleTitleCase-fatality rates and functional outcome after subarachnoid haemorrhage: a systematic review Stroke 28 660–664 Occurrence Handle9056628 Occurrence Handle1:STN:280:DyaK2s3gvFehug%3D%3D
S Itoh T Sasaki A Asai Y Kuchino (1994) ArticleTitlePrevention of delayed vasospasm by an endothelin ETA receptor antagonist, BQ-123: change of ETA receptor mRNA expression in a canine subarachnoid haemorrhage model J Neurosurg 81 759–764 Occurrence Handle7931624 Occurrence Handle1:CAS:528:DyaK2MXit1Wis74%3D
S Juvela (2002) ArticleTitlePlasma endothelin and big endothelin concentrations and serum endothelin-converting enuyme activity following aneurysmal subarachnoid haemorrhage J Neurosurg 97 1287–1293 Occurrence Handle12507125 Occurrence Handle1:CAS:528:DC%2BD38Xpsleitro%3D
G Kaptain G Lanzino N Kassell (2000) ArticleTitleSubarachnoid haemorrhage: epidemiology, risk factors, and treatment options Drugs Aging 17 183–199 Occurrence Handle11043818 Occurrence Handle10.2165/00002512-200017030-00003 Occurrence Handle1:STN:280:DC%2BD3cvptFelug%3D%3D
A-L Kwan C-L Lin C-Z Chang H-J Wu S-L Hwong AY Jeng KS Lee (2001) ArticleTitleContinuous intravenous infusion of CGS 26303, an endothelin-converting enzyme inhibitor, prevents and reverses cerebral vasospasm after experimental subarachnoid haemorrhage Neurosurgery 49 422–429 Occurrence Handle11504119 Occurrence Handle10.1097/00006123-200108000-00029 Occurrence Handle1:STN:280:DC%2BD3MvlslOqsQ%3D%3D
D Langleben AM Hirsch E Shalit L Lesenko RJ Barst (2004) ArticleTitleSustained symptomatic, functional, and hemodynamic benefit with the selective endothelin-A receptor antagonist, sitaxsentan, in patients with pulmonary arterial hypertension: a 1-year follow-up study Chest 126 1377–1381 Occurrence Handle15486408 Occurrence Handle10.1378/chest.126.4.1377 Occurrence Handle1:CAS:528:DC%2BD2cXhtValur3E
ER Levin (1995) ArticleTitleEndothelins N Engl J Med 333 356–363 Occurrence Handle7609754 Occurrence Handle10.1056/NEJM199508103330607 Occurrence Handle1:CAS:528:DyaK2MXnvValsLo%3D
S Roux V Breu T Giller W Neidhart H Ramuz P Coassolo JP Clozel M Clozel (1997) ArticleTitleRo 61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm J Pharmacol Exp Ther 283 1110–1118 Occurrence Handle9399983 Occurrence Handle1:CAS:528:DyaK1cXis1Cguw%3D%3D
MD Shaw M Vermeulen GD Murray JD Pickard BA Bell GM Teasdale (2000) ArticleTitleEfficacy and safety of the endothelin, receptor antagonist TAK-044 in treating subarachnoid haemorrhage: a report by the Steering Committee on behalf of the UK/Netherlands/Eire TAK-044 Subarachnoid Haemorrhage Study Group J Neurosurg 93 992–997 Occurrence Handle11117873 Occurrence Handle1:CAS:528:DC%2BD3cXptValsr0%3D
P Vajkoczy P Horn C Bauhuf E Munch U Hubner D Ing C Thome C Poeckler-Schoeninger H Roth P Schmiedek (2001) ArticleTitleEffect of intra-arterial papaverine on regional cerebral blood flow in haemodynamically relevant cerebral vasospasm Stroke 32 498–505 Occurrence Handle11157189 Occurrence Handle1:CAS:528:DC%2BD3MXhtlymsLg%3D
P Vajkoczy P Horn C Thome E Munch P Schmiedek (2003) ArticleTitleRegional cerebral blood flow monitoring in the diagnosis of delayed ischemia following aneurysmal subarachnoid haemorrhage J Neurosurg 98 1227–1234 Occurrence Handle12816269
Vajkoczy P, Meyer B, Weidauer S, Raabe A, Thome C, Ringel F (2005) The selective endothelin A (ETA) receptor antagonist clazosentan (AXV-034343) prevents cerebral vasospasm following severe aneurysmal subarachnoid haemorrhage – a randomized, double-blind, placebo-controlled, multicenter, phase IIa study. J Neurosurg (in press)
AY Zubkov KS Rollins AD Parent J Zhang RM Bryan SuffixJr (2000) ArticleTitleMechanism of endothelin-1-induced contraction in rabbit basilar artery Stroke 31 526–533 Occurrence Handle10657432 Occurrence Handle1:CAS:528:DC%2BD3cXhtV2ns78%3D
M Zuccarello GB Soattin AI Lewis V Breu H Hallak RM Rapoport (1996) ArticleTitlePrevention of subarachnoid haemorrhage-induced cerebral vasospasm by oral administration of endothelin receptor antagonists J Neurosurg 84 503–507 Occurrence Handle8609565 Occurrence Handle1:CAS:528:DyaK28Xit1ynsrk%3D Occurrence Handle10.3171/jns.1996.84.3.0503
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The first two authors contributed equally to the study
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Barth, M., Capelle, HH., Münch, E. et al. Effects of the selective endothelin A (ETA) receptor antagonist Clazosentan on cerebral perfusion and cerebral oxygenation following severe subarachnoid hemorrhage – preliminary results from a randomized clinical series. Acta Neurochir (Wien) 149, 911–918 (2007). https://doi.org/10.1007/s00701-007-1249-3
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DOI: https://doi.org/10.1007/s00701-007-1249-3