A Multimodal Concept in Patients after Severe Aneurysmal Subarachnoid Hemorrhage: Results of a Controlled Single Centre Prospective Randomized Multimodal Phase I/II Trial on Cerebral Vasospasm

Abstract

Objective: Recent publications suggest that a combination of head-shaking and cisternal irrigation might reduce symptomatic cerebral vasospasm after subarachnoid hemorrhage (SAH). The present clinical prospective randomized phase I/II study was initiated in order to analyze the prophylactic effect of intracisternal lysis in combination with kinetic treatment followed by intrathecal nimodipine lavage.

Methods: Twenty patients with aneurysmal SAH, WFNS grade 2 to 5 (GCS 13-3) and Fisher grade 3 or 4 were included in this prospective randomized study which had been approved by the local Ethics Research Committee. Following insertion of a ventricular drain, securing of the aneurysm by a microsurgical or endovascular route and the insertion of two lumbar catheters, intracisternal lysis with urokinase 120 000 IU/d was performed for 48 h in the patients of the study group. Intrathecal pressure was monitored by the second lumbar catheter. After intracisternal lysis, intrathecal nimodipine lavage was applied for 7 d. For comatose patients kinetic head-rotation was also performed. Vasospasm was clinically identified with a focus on delayed neurological deficits (DINDs) by daily transcranial Doppler (TCD), computerized tomography (CT), perfusion CT (pCT) and cerebral angiography (DSA).

Results: There was no DIND in the study group among the patients who were awake, while two DINDs occurred in the control group. The pooled TCD flow velocities over an average period of 14 d revealed no statistically significant difference between the groups. Vasospasm-related infarction on CT was seen in two patients of the control group. Evident vasospasm on DSA appeared in three patients of the study group compared with 7 patients in the control group. Moreover there was a neurological improvement in the study population as measured by mRS at 3-month follow-up (P=0.266). In two consecutive patients randomized to the study group a paresis of the lower extremities of unknown origin occurred. As a result of these complications the study was stopped in accordance with the local Ethics Research Committee guidelines.

Conclusion: A multimodal approach with translumbar lysis in combination with kinetic therapy followed by intrathecal nimodipine lavage proved to be effective against cerebral vasospasm and for clinical outcome. However, due to the observed complications with the occurrence of paraparesis in two patients of the study group the trial was stopped. Nevertheless, the promising preliminary results suggest a further development of the clinical protocol using a modified multimodal concept to prevent and treat cerebral vasospasm after severe SAH.

Zusammenfassung

Hintergrund: In aktuellen Studien konnte gezeigt werden, dass eine Kombination von kinetischer Therapie und zisternaler Spülung zu einer Reduktion des zerebralen Vasospasmus nach aneurysmatischer Blutung führt. Die vorliegende prospektive, randomisierte Phase I/II Studie wurde konzipiert, um den Effekt der Kombination aus zisternaler Lyse und kinetischer Therapie gefolgt von intrathekaler Nimodipin Spülung zu analysieren.

Methoden: 20 Patienten nach aneurysmatischer Subarachnoidalblutung WFNS Grad 2–5 (GCS 13-3), Fisher Grad 3 oder 4 wurden nach Bewilligung der Ethikkommission in diese Studie eingeschlossen. Nach Anlage einer externen Ventrikeldrainage (EVD) und Versorgung des Aneurysmas chirurgisch oder endovaskulär wurden zwei lumbale Katheter angelegt. Über einen der lumbalen Katheter wurden die Patienten der Studiengruppe mit 120 000 IE/T Urokinase für 48 Stunden behandelt, während der andere zur intrathekalen Druckmessung diente. Die intrathekale Therapie wurde dann durch eine Nimodipin-Applikation ersetzt und für 7 Tage weitergeführt. Die komatösen Patienten wurden parallel mit kinetischer Therapie behandelt. Der Vasospasmus wurde identifiziert über das Auftreten von verzögert auftretenden neurologischen Defiziten (DIND) sowie durch transkranielle Dopplersonografie (TCD), Perfusions CT (pCT) und digitale Subtraktionsangiografie (DSA).

Resultate: Das Auftreten von DINDs wurde ausschließlich bei 2 Patienten in der Studiengruppe beobachtet. Ein Vasospasmus-assoziierter Infarkt im CT wurde ausschließlich bei zwei Patienten in der Studiengruppe dokumentiert. Evidenter Vasospasmus in der DSA zeigte sich bei 3 Patienten in der Studiengruppe und 7 Patienten in der Kontrollgruppe. Die Patienten der Studiengruppe zeigten eine verbesserte neurologische Erholung gemessen am mRS zum Zeitpunkt der Entlassung und nach 3 Monaten. Aufgrund von zwei in Serie aufgetretenen ausgeprägten Paraparesen unklarer Ätiologie wurde die Studie frühzeitig abgebrochen.

Schlussfolgerung: Das multimodale Konzept mit intrathekaler Lyse begleitet von kinetischer Therapie, gefolgt von intrathekaler Nimodipin-Applikation konnte einen positiven Effekt auf den zerebralen Vasospasmus und das Outcome der Patienten aufweisen. Dennoch musste die Studie aufgrund von zwei unklaren Paraparesen frühzeitig abgebrochen werden. Aufgrund der vielversprechenden Resultate sollte jedoch an einem multimodalen Konzept in modifizierter Form festgehalten werden.

Key words

subarachnoid hemorrhage - cerebral vasospasm - multimodal concept

Schlüsselwörter

Subarachnoidalblutung - Zerebraler Vasospasmus - Multimodales Konzept

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