丹曲林钠治疗蛛网膜下腔出血后脑血管痉挛：一项随机双盲安慰剂对照安全性试验。
Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-controlled safety trial.
机构信息
Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Anesthesia/Critical Care, University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
出版信息
J Neurol Neurosurg Psychiatry. 2015 Sep;86(9):1029-35. doi: 10.1136/jnnp-2014-308778. Epub 2014 Oct 24.
BACKGROUND
Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) in human aneurysmal subarachnoid haemorrhage (aSAH). We evaluated safety, feasibility and tolerability of intravenous dantrolene (IV-D) in patients with aSAH.
METHODS
In this single-centre, randomised, double blind, placebo-controlled trial, 31 patients with aSAH were randomised to IV-D 1.25 mg every 6 h for 7 days (n=16) or equiosmolar free water/5% mannitol (placebo; n=15). Primary safety end points were incidence of hyponatraemia (sNa≤132 mmol/L) and liver toxicity (proportion of patients alanine transaminase, aspartate aminotransferase and AlkPhos >5× upper-limit-of-normal). Secondary end points included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored for clinical/radiological cVSP, delayed cerebral ischaemia (DCI), and 3-month functional outcomes. Quantitative analyses of angiograms and daily transcranial Doppler (TCD) were performed.
RESULTS
Between IV-D versus placebo, no differences were observed in the primary outcomes (hyponatremia 44% vs 67% (p=0.29); liver toxicity 6% vs 0% (p=1.0)). Three patients in the IV-D versus two in the placebo group had severe adverse events possibly attributable to infusion and reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain oedema requiring osmotherapy. The majority of adverse events were not related to infusion (17 vs 5 (RR 2.2; 95% CI 0.7 to 6.7; p=0.16) in IV-D vs placebo). No differences in any categorical cVSP outcomes, DCI, 3-month outcomes or quantitative angiogram and TCD analyses were seen in this small safety trial not powered to detect efficacy.
CONCLUSIONS
In this small trial, IV-D after aSAH was feasible, tolerable and safe.
TRIAL REGISTRATION NUMBER
http://clinicaltrials.gov NCT01024972.
背景
丹曲林钠在动物模型中具有神经保护作用，可能减轻人类蛛网膜下腔出血（aSAH）中的脑血管痉挛（cVSP）。我们评估了静脉内丹曲林钠（IV-D）在 aSAH 患者中的安全性、可行性和耐受性。
方法
在这项单中心、随机、双盲、安慰剂对照试验中，将 31 例 aSAH 患者随机分为 IV-D 组（1.25mg，每 6 小时一次，持续 7 天，n=16）或等渗生理盐水/5%甘露醇（安慰剂；n=15）。主要安全性终点为低钠血症（sNa≤132mmol/L）和肝毒性（丙氨酸氨基转移酶、天冬氨酸氨基转移酶和 AlkPhos 超过正常上限 5 倍的患者比例）的发生率。次要终点包括耐受性、全身低血压和颅内高压。对临床/影像学 cVSP、迟发性脑缺血（DCI）和 3 个月的功能结局进行了评估。对血管造影和每日经颅多普勒（TCD）进行了定量分析。
结果
IV-D 组与安慰剂组在主要结局方面无差异（低钠血症发生率分别为 44%和 67%（p=0.29）；肝毒性发生率分别为 6%和 0%（p=1.0））。IV-D 组有 3 例患者和安慰剂组有 2 例患者出现严重不良事件，可能与输注有关，达到停药标准：1 例 IV-D 患者发生肝毒性；2 例患者各发生需要渗透性治疗的脑水肿。大多数不良事件与输注无关（IV-D 组 17 例，安慰剂组 5 例（RR 2.2；95%CI 0.7 至 6.7；p=0.16））。在这项未设效检测量的小型安全性试验中，在任何分类的 cVSP 结局、DCI、3 个月结局或定量血管造影和 TCD 分析中，均未见差异。
结论
在这项小型试验中，aSAH 后 IV-D 是可行的、耐受的和安全的。
试验注册
http://clinicaltrials.gov NCT01024972。
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