CLINICAL ARTICLE J Neurosurg 124:51–58, 2016 Molsidomine for the prevention of vasospasm-related delayed ischemic neurological deficits and delayed brain infarction and the improvement of clinical outcome after subarachnoid hemorrhage: a single-center clinical observational study Angelika Ehlert, MD,1 Christoph Schmidt, MD,2 Johannes Wölfer, MD,3 Gerd Manthei, MD,1 Andreas H. Jacobs, MD,4 Roland Brüning, MD,5 Walter Heindel, MD,6 E. Bernd Ringelstein, MD,7 Walter Stummer, MD,3 Ryszard M. Pluta, MD,8 and Volker Hesselmann, MD6,9 1Department of Neurosurgery, Asklepios Hospital St. Georg, Hamburg; Departments of 2Anästhesiology, Intensive Care and Pain Medicine, 3Neurosurgery, 6Radiology, and 7Neurology, University Hospital Münster; 4European Institute of Molecular Imaging, Münster; 5Department of Radiology, Asklepios Hospital Barmbek, Hamburg; 9Asklepios Hospital Hamburg North, Hamburg, Germany; and 8Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland OBJECTIVE Delayed ischemic neurological deficits (DINDs) and cerebral vasospasm (CVS) are responsible for a poor outcome in patients with aneurysmal subarachnoid hemorrhage (SAH), most likely because of a decreased availability of nitric oxide (NO) in the cerebral microcirculation. In this study, the authors examined the effects of treatment with the NO donor molsidomine with regard to decreasing the incidence of spasm-related delayed brain infarctions and improving clinical outcome in patients with SAH. METHODS Seventy-four patients with spontaneous aneurysmal SAH were included in this post hoc analysis. Twenty- nine patients with SAH and proven CVS received molsidomine in addition to oral or intravenous nimodipine. Control groups consisted of 25 SAH patients with proven vasospasm and 20 SAH patients without. These patients received ni- modipine therapy alone. Cranial computed tomography (CCT) before and after treatment was analyzed for CVS-related infarcts. A modified National Institutes of Health Stroke Scale (mNIHSS) and the modified Rankin Scale (mRS) were used to assess outcomes at a 3-month clinical follow-up. RESULTS Four of the 29 (13.8%) patients receiving molsidomine plus nimodipine and 22 of the 45 (48%) patients receiving nimodipine therapy alone developed vasospasm-associated brain infarcts (p < 0.01). Follow-up revealed a me- dian mNIHSS score of 3.0 and a median mRS score of 2.5 in the molsidomine group compared with scores of 11.5 and 5.0, respectively, in the nimodipine group with CVS (p < 0.001). One patient in the molsidomine treatment group died, and 12 patients in the standard care group died (p < 0.01). CONCLUSIONS In this post hoc analysis, patients with CVS who were treated with intravenous molsidomine had a sig- nificant improvement in clinical outcome and less cerebral infarction. Molsidomine offers a promising therapeutic option in patients with severe SAH and CVS and should be assessed in a prospective study. http://thejns.org/doi/abs/10.3171/2014.12.JNS13846 KEY WORDS subarachnoid hemorrhage; molsidomine; CVS; DIND; vasospasm; NO; vascular disorders ABBREVIATIONS ACA = anterior cerebral artery; BA = basilar artery; BP = blood pressure; CBF = cerebral blood flow; CCT = cranial computed tomography; CVS = cerebral vasospasm; DIND = delayed ischemic neurological deficit; DSA = digital subtraction angiography; GCS = Glasgow Coma Scale; HES = hydroxyethyl starch; HH = Hunt and Hess; ICA = internal carotid artery; ICP = intracranial pressure; MAP = mean arterial blood pressure; MCA = middle cerebral artery; mNIHSS = modified National Institutes of Health Stroke Scale; mRS = modified Rankin Scale; MTG = molsidomine treatment group; NO = nitric oxide; SAH = subarachnoid hemorrhage; STG = standard therapy group; TCD = transcranial Doppler; VA = vertebral artery. SUBMITTED May 5, 2013. ACCEPTED December 29, 2014. INCLUDE WHEN CITING Published online July 10, 2015; DOI: 10.3171/2014.12.JNS13846. DISCLOSURES The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. ©AANS, 2016 J Neurosurg Volume 124 • January 2016 51 Unauthenticated | Downloaded 09/30/21 12:30 AM UTC A. Ehlert et al. P to 50% of patients suffering from subarachnoid Methods hemorrhage (SAH) develop delayed cerebral in- Patients farction and persistent neurological deficits. In up Uto 25% of cases, delayed strokes are responsible for severe Seventy-four consecutive patients with spontaneous disabilities,9,16 and approximately 75% of patients with aneurysmal SAH (age 16−86 years; mean 54.5 years, SD SAH experience persistent cognitive or mental deficits. 14.7) had been admitted to the intensive care unit of the Depending on the selection of patients, only a minority of University Hospital Münster, Germany, between Janu- survivors recover to a normal quality of life or return to ary 2008 and September 2009. All patients were treated work (6%–60%).1,24 with nimodipine. Twenty-nine consenting patients with Since the implementation of nimodipine in 1983, no CVS received molsidomine in addition to the standard new therapeutic approach for vasospasm-associated de- nimodipine therapy when clinical deterioration was obvi- layed ischemic neurological deficits (DINDs) after SAH ous (molsidomine treatment group [MTG]). The control has achieved general acceptance. Only orally adminis- group receiving standard nimodipine therapy consisted tered nimodipine has been shown to decrease the risk of of 45 patients (standard therapy group [STG]). In this DIND or poor clinical outcome.2,9,16 Despite nimodipine STG, 25 patients had CVS but refused molsidomine ther- treatment, vasospasm-associated infarcts occur in 20%– apy (STG-CVS). Twenty patients presented without CVS 50% of patients with SAH, DINDs in 27%–37% of pa- (STG-noCVS; Fig. 1). Epidemiological characteristics of tients, and severe morbidity in 30%–40% of patients.9,13,17 the patient population are presented in Table 1. The loca- A favorable outcome has been reported in less than 10% tions of the aneurysms are presented in Table 2. of patients with DIND, and the majority of those patients To avoid the inclusion of death events due to reasons (62%) have a poor outcome (severe disability, coma, other than CVS, we excluded from evaluation 9 patients death).17 who died within the first 6 days after SAH because of gen- Arteriographic vasospasm is detected in approximately eralized brain edema, severe hypoxia, massive rebleeding, 60%–70% of patients after SAH, but not all of them de- or a relevant mass shift due to parenchymal hematoma or velop DINDs, possibly because of a sufficient collateral causes directly related to procedures. blood supply.9,16 On the other hand, cerebral vasospasm Within 24 hours of admission, the aneurysms were (CVS), as detected by transcranial Doppler (TCD) ultraso- treated by coil embolization and/or clipping. Patients nography or arteriography, is not present in every patient treated by coiling received aspirin (100 mg/day). In the with DINDs. In these cases, DINDs have been attributed MTG, 20 patients were treated with coil embolization, 6 to decreased blood flow through the microcirculation due patients were treated with clipping, and 3 patients received to a locally reduced availability of nitric oxide (NO).18,19 both clipping and coiling. In the STG, 31 patients were Thus, detectable CVS in the macrocirculation may facili- treated with coil embolization, 12 patients with clipping, tate the development of DINDs but is not necessarily its 1 patient with coiling and clipping, and 1 patient was not main cause. These findings suggest that the impact of ce- treated at all. rebral microcirculation on the development of DINDs and Thirty-six patients received the standard therapy with poor outcome has been underestimated.11,18,19 nimodipine 6 tablets × 60 mg/day orally or via feeding Recently, this concept was further supported by results tube. Thirty-eight patients with deteriorated intestinal ab- of the CONSCIOUS 1–3 trials, which treated CVS pa- sorption received intravenous nimodipine 1–2 mg/hr in tients with endothelin receptor antagonists, and a newly the first days after SAH. TCD ultrasonography was per- published randomized trial investigating the therapeutic formed daily and included mean velocity measurements effect of cilostazol, an inhibitor of phosphodiesterase 3.26 of the internal carotid artery (ICA), the middle cerebral TCD ultrasonography-detectable vasospasm was signifi- artery (MCA), the anterior cerebral artery (ACA), the ver- cantly reduced, but the rate of DINDs and related infarcts tebral arteries (VAs), and the basilar artery (BA). CVS showed only a statistical trend toward improvement, and was diagnosed using 3 methods: 1) TCD ultrasonography, the clinical outcome was not altered,1,15,21 possibly because if the mean flow velocity in the ACA and the MCA was clazosentan acted only on the large conductive cerebral above 140 cm/sec or if it was > 120 cm/sec in the BA arteries. and VA, with a Lindegaard index > 3; 2) arteriography, For years, many treatments of DINDs and CVS after if narrowing > 50% of the vessel diameter, as compared SAH have been tried, including compounds with improved with initial values, was detected and DIND was argued; NO delivery. Several of them showed beneficial effects on or 3) the appearance of clinical symptoms within Day CVS, DIND, or clinical outcome.9,16,19,20 Unfortunately, 3–14, such as loss of consciousness or newly developed