Strickland Ben A, Barisano Giuseppe, Abedi Aidin, Shiroishi Mark S, Cen Steven, Emanuel Benjamin, Bulic Sebina, Kim-Tenser May, Nguyen Peggy, Giannotta Steven L, Mack William, Russin Jonathan
1Departments of Neurosurgery.
2Neuroradiology.
J Neurosurg. 2021 Oct 29;136(5):1251-1259. doi: 10.3171/2021.6.JNS211270. Print 2022 May 1.
Aneurysmal subarachnoid hemorrhage (aSAH)-induced vasospasm is linked to increased inflammatory cell trafficking across a permeable blood-brain barrier (BBB). Elevations in serum levels of matrix metalloprotease 9 (MMP9), a BBB structural protein, have been implicated in the pathogenesis of vasospasm onset. Minocycline is a potent inhibitor of MMP9. The authors sought to detect an effect of minocycline on BBB permeability following aSAH.
Patients presenting within 24 hours of symptom onset with imaging confirmed aSAH (Fisher grade 3 or 4) were randomized to high-dose (10 mg/kg) minocycline or placebo. The primary outcome of interest was BBB permeability as quantitated by contrast signal intensity ratios in vascular regions of interest on postbleed day (PBD) 5 magnetic resonance permeability imaging. Secondary outcomes included serum MMP9 levels and radiographic and clinical evidence of vasospasm.
A total of 11 patients were randomized to minocycline (n = 6) or control (n = 5) groups. No adverse events or complications attributable to minocycline were reported. High-dose minocycline administration was associated with significantly lower permeability indices on imaging analysis (p < 0.01). There was no significant difference with respect to serum MMP9 levels between groups, although concentrations trended upward in both cohorts. Radiographic vasospasm was noted in 6 patients (minocycline = 3, control = 3), with only 1 patient developing symptoms of clinical vasospasm in the minocycline cohort. There was no difference between cohorts with respect to Lindegaard ratios, transcranial Doppler values, or onset of vasospasm.
Minocycline at high doses is well tolerated in the ruptured cerebral aneurysm population. Minocycline curtails breakdown of the BBB following aSAH as evidenced by lower permeability indices, though minocycline did not significantly alter serum MMP9 levels. Larger randomized clinical trials are needed to assess minocycline as a neuroprotectant against aSAH-induced vasospasm. Clinical trial registration no.: NCT04876638 (clinicaltrials.gov).
动脉瘤性蛛网膜下腔出血（aSAH）所致血管痉挛与炎症细胞通过通透性增加的血脑屏障（BBB）的转运增加有关。血脑屏障结构蛋白基质金属蛋白酶9（MMP9）血清水平升高与血管痉挛发作的发病机制有关。米诺环素是MMP9的有效抑制剂。作者试图检测米诺环素对aSAH后血脑屏障通透性的影响。
症状发作后24小时内就诊且影像学证实为aSAH（Fisher分级3级或4级）的患者被随机分为高剂量（10mg/kg）米诺环素组或安慰剂组。主要观察指标是血脑屏障通透性，通过出血后第5天（PBD5）磁共振通透性成像中感兴趣血管区域的对比信号强度比进行定量。次要观察指标包括血清MMP9水平以及血管痉挛的影像学和临床证据。
共有11例患者被随机分为米诺环素组（n = 6）或对照组（n = 5）。未报告与米诺环素相关的不良事件或并发症。高剂量米诺环素给药与影像学分析中显著更低的通透性指数相关（p < 0.01）。两组间血清MMP9水平无显著差异，尽管两个队列中的浓度均呈上升趋势。6例患者出现影像学血管痉挛（米诺环素组 = 3例，对照组 = 3例），米诺环素队列中只有1例患者出现临床血管痉挛症状。两组在Lindegaard比值、经颅多普勒值或血管痉挛发作方面无差异。
高剂量米诺环素在破裂脑动脉瘤患者中耐受性良好。米诺环素可减少aSAH后血脑屏障的破坏，较低的通透性指数证明了这一点，尽管米诺环素并未显著改变血清MMP9水平。需要更大规模的随机临床试验来评估米诺环素作为预防aSAH所致血管痉挛的神经保护剂的作用。临床试验注册号：NCT04876638（clinicaltrials.gov）。
