儿童用对乙酰氨基酚栓会不会惊厥（氨甲环酸惊厥我们还在编专家共识）

儿童用对乙酰氨基酚栓会不会惊厥（氨甲环酸惊厥我们还在编专家共识）说实话，如果你在临床实践中超说明书使用氨甲环酸，而并没有告知患者局部使用氨甲环酸的危险，那就是在拿病人做实验，跟倭寇731部队做的人体实验差不多了，是违法的。有些人说，没有证据证明病人是用了氨甲环酸后死亡的，也许是麻醉药打死的，我当时就问他，怎么样才能证明氨甲环酸导致了患者的死亡呢？这些已经报道的文献不够吗？已经死了那么多病人还不够吗？也想问他，难道别的医生的智商不如你么？难道需要拿人做实验吗，一个一个往人的椎管内打氨甲环酸看病人死不死？如果是这样的话，那岂不是跟倭寇731部队一样了？一石激起千层浪，此文推送后，在骨科医生圈子和麻醉科医生圈子里引起了比较大的反响。有人质疑我对该病例的分析和诊断，也有人质疑我危言耸听，声称自己在脊柱手术中应用很多例，成百上千例，国内其他医生加起来应该上万例或者更多，均未见有问题，有人质疑没有做动物实验，就凭国外麻醉科医生报告的将氨甲环酸误注射入椎管内导致患者

氨甲环酸惊厥，人家已研究到分子水平，我们还在“啊，还有神经毒性啊？” 还编写专家共识，写文章鼓励医生违法超说明书使用呢。

2021年11月9日，我推送了一例腰椎间盘突出症术中使用氨甲环酸导致患者惊厥死亡的病例：

31岁，女性，腰椎间盘突出症，微创椎间孔镜手术，打麻醉，用药不当，术后不到8小时死亡

到今天为止，此文已访问浏览6万多人次。

一石激起千层浪，此文推送后，在骨科医生圈子和麻醉科医生圈子里引起了比较大的反响。

有人质疑我对该病例的分析和诊断，也有人质疑我危言耸听，声称自己在脊柱手术中应用很多例，成百上千例，国内其他医生加起来应该上万例或者更多，均未见有问题，有人质疑没有做动物实验，就凭国外麻醉科医生报告的将氨甲环酸误注射入椎管内导致患者严重后果，死亡率高达50%，并不能证明患者的死亡就是氨甲环酸所为。

在这些质疑中，中国的一些医生，自以为是，不学习就张口质疑他人，即使是我把文献逐个从英文翻译为中文，就像做饭一样，我把饭送到他嘴边，都不愿意张口吃，还继续说没饭吃，没有看到饭可吃一样，不去认真学习和查阅更多的文献。

有些人说，没有证据证明病人是用了氨甲环酸后死亡的，也许是麻醉药打死的，我当时就问他，怎么样才能证明氨甲环酸导致了患者的死亡呢？这些已经报道的文献不够吗？已经死了那么多病人还不够吗？也想问他，难道别的医生的智商不如你么？难道需要拿人做实验吗，一个一个往人的椎管内打氨甲环酸看病人死不死？如果是这样的话，那岂不是跟倭寇731部队一样了？

说实话，如果你在临床实践中超说明书使用氨甲环酸，而并没有告知患者局部使用氨甲环酸的危险，那就是在拿病人做实验，跟倭寇731部队做的人体实验差不多了，是违法的。

对于很多质疑和疑问，我基本上没有详细回应，有几个原因：

1. 在2021年10月20日之前，我跟他们一样的，我对氨甲环酸局部使用的危害也是无知的，临床从没局部使用过，不是因为我知道危险，而是师傅没那么教过，也没听过“大师”们讲他们的临床经验，也没阅读过所谓的专家共识。
2. 他们的质疑范围很广，就我的有限知识，难以完美解答他们的问题，也说服不了他们。
3. 我需要学习，我需要拿具体的文献和实际证据，逐个的来呈现，寻找实锤，才能佐证我的意见。
4. 有些质疑，没法回答，只能选择无视。

下面的这篇文献，我曾经在上面的文章中将摘要翻译为中文。这是一篇比较全面的讲述氨甲环酸临床应用导致惊厥发生的综述性文献，从其临床适应证、氨甲环酸导致惊厥发生的发病率和高危因素，临床表现和诊断 患者中枢神经系统内氨甲环酸的浓度 氨甲环酸相关惊厥发作的分子机制 麻醉药物对氨甲环酸对甘氨酸受体抑制的逆转 氨甲环酸相关惊厥的预防和治疗等方面进行了详细的综述，是一篇了解氨甲环酸神经毒性以及临床不良反应的很好的文章。

此文主要涉及“超剂量、静脉途径全身使用氨甲环酸”所带来的不良反应，讨论了药物浓度、分子水平电生理研究及预防与可行的治疗……并没有涉及变更使用途径的这种“更加严重超说明书使用行为”，仅引用了部分腰麻时误用氨甲环酸后导致的临床表现，以佐证氨甲环酸进入脑脊液后的临床表现。

希望你能转发，让更多的人知道。

Tranexamic Acid–Associated Seizures-Causes and Treatment

氨甲环酸引起惊厥的病因和治疗

原文出处：

Irene Lecker Dian-Shi Wang Paul D Whissell Sinziana Avramescu C David Mazer Beverley A Orser. Tranexamic acid-associated seizures: Causes and treatment. Ann Neurol. 2016 Jan;79(1):18-26. doi: 10.1002/ana.24558. Epub 2015 Dec 15.

Abstract:

Antifibrinolytic drugs are routinely used worldwide to reduce the bleeding that results from a wide range of hemorrhagic conditions. The most commonly used antifibrinolytic drug tranexamic acid is associated with an increased incidence of postoperative seizures. The reported increase in the frequency of seizures is alarming as these events are associated with adverse neurological outcomes longer hospital stays and increased in-hospital mortality. However many clinicians are unaware that tranexamic acid causes seizures. The goal of this review is to summarize the incidence risk factors and clinical features of these seizures. This review also highlights several clinical and preclinical studies that offer mechanistic insights into the potential causes of and treatments for tranexamic acid–associated seizures. This review will aid the medical community by increasing awareness about tranexamic acid–associated seizures and by translating scientific findings into therapeutic interventions for patients.

摘要

抗纤维蛋白溶解药物在全世界范围内广泛使用，以减少因各种出血性疾病引起的出血。最常用的抗纤维蛋白溶解药物氨甲环酸与术后惊厥发作的发生率增加有关。据报道，惊厥发作频率的增加程度令人震惊，因为这些事件与神经系统不良后果、住院时间延长和住院死亡率增加有关。然而，许多临床医生并不知道氨甲环酸会引起惊厥发作。本综述的目的是总结这些惊厥发作的发生率、危险因素和临床特征。本综述还强调了一些临床和临床前研究，这些研究为氨甲环酸相关惊厥的潜在病因和治疗提供了机制上的见解。这篇综述将帮助医学界提高对氨甲环酸相关惊厥的认识，并将科学发现转化为对患者的治疗干预。

Antifibrinolytic drugs are used worldwide to decrease the requirement for blood transfusions reduce the risk of reoperation for bleeding and lower mortality associated with hemorrhage following major trauma.[1–3] The most commonly used antifibrinolytic drugs include tranexamic acid (TXA) ε-aminocaproic acid (EACA) and aprotinin.[1] TXA and EACA are synthetic derivatives of the amino acid lysine that exert their hemostatic effects by binding to plasminogen.[4–6] This binding prevents the conversion of plasminogen to plasmin and reduces the degradation of fibrin-containing blood clots.[4–6] Aprotinin conversely is a serine protease inhibitor that binds directly to plasmin and inhibits its function.[7]

抗纤维蛋白溶解药物在全世界范围内使用，以求减少输血需求，降低因出血而再次手术的风险，降低严重创伤后出血相关的死亡率[1-3]。最常用的抗纤维蛋白溶解药物包括氨甲环酸、ε-氨基己酸和抑肽酶[1]。氨甲环酸和氨基己酸是氨基酸赖氨酸的合成衍生物，通过与纤溶酶原结合发挥止血作用[4-6]。这种结合阻止纤溶酶原转化为纤溶酶，并减少含有纤维蛋白的血凝块的降解[4-6]。相反，抑肽酶，是一种丝氨酸蛋白酶抑制剂，可直接与纤溶酶结合并抑制其功能[7]。

Antifibrinolytic agents are considered to be safe and affordable drugs with few serious adverse effects.[1] However observational clinical trials and case reports have shown that TXA and to a lesser extent EACA but not aprotinin are associated with seizures.[8–34] Most TXA associated seizures occur in patients who have undergone cardiac procedures.[16–18 20 21 24–26 30–32 34] However several case reports indicate that TXA-associated seizures also occur in nonsurgical patients.[10 22 27] Seizures in postoperative cardiac surgery patients have been reported to be associated with a 2-fold increase in hospital length of stay and a 2.5-fold higher mortality rate.[26] An increase in the incidence of delirium and stroke and a reduced quality of life have also been reported.[35]

抗纤维蛋白溶解药物被认为是安全且价格合理的药物，几乎没有严重的副作用[1]。然而，临床观察试验和病例报告表明，氨甲环酸，和小部分病例中使用的氨基己酸，但不是抑肽酶，与惊厥发作相关[8-34]。大多数氨甲环酸相关惊厥发生在接受过心脏手术的患者中[16-18 20 21 24-26 30-32 34]。然而，一些病例报告表明，氨甲环酸相关惊厥也发生在非手术患者中[10 22 27]。据报道，心脏手术后患者发生惊厥使住院时间增加2倍和死亡率增加2.5倍 [26]。还有报告谵妄和中风发病率增加以及生活质量下降[35]。(注：静脉使用氨甲环酸)

The goal of this review is to increase awareness about seizures associated with antifibrinolytic drugs and provide mechanistic-based prevention and treatment recommendations. The review focuses on TXA the most commonly used and widely studied antifibrinolytic drug. First the incidence risk factors and clinical features of TXA-associated seizures are summarized. Next preclinical and clinical studies that offer insights into the underlying causes of seizures are reviewed. In particular a study that measured the concentration of TXA in the cerebral spinal fluid (CSF) of patients undergoing major cardiovascular surgery is considered. The study then compared TXA concentrations in the CSF to TXA concentrations that modulate the activity of neurotransmitter receptors in the brain in vitro. Based on these findings treatment strategies to mitigate TXA-associated seizures in patients are proposed.

本综述目的是提高对抗纤维蛋白溶解药物相关惊厥的认识，并提供基于致病机制的预防和治疗建议。本综述主要讨论最常用和研究最广泛的抗纤维蛋白溶解药物氨甲环酸。首先，总结氨甲环酸相关惊厥的发病率、危险因素和临床特征。接下来，回顾临床前和临床研究，这些研究为惊厥发作的根本原因提供认知。重点提及一项测量接受主要心血管手术患者脑脊液中氨甲环酸浓度的研究。该研究将脑脊液中的氨甲环酸浓度与体外调节大脑神经递质受体活性的氨甲环酸浓度进行比较。基于这些发现，提出了减轻患者氨甲环酸相关惊厥发作的治疗策略。(注：静脉使用氨甲环酸)

Clinical Indications Incidence and Risk Factors

TXA was originally approved by the US Food and Drug Administration for the treatment of patients with hemophilia undergoing dental surgery and for women suffering from heavy menstrual bleeding.[36 37] The clinical indications of TXA have rapidly expanded and now include multiple “off-label” uses including cardiac gastrointestinal and orthopedic surgery as well as treatment of postpartum hemorrhage.[38–41] The World Health Organization (WHO) recently included TXA in its “Model List of Essential Medicines.”[42] The WHO recommended that TXA be used to reduce blood loss in patients undergoing cardiopulmonary bypass procedures in trauma patients with significant hemorrhage and in patients with postpartum hemorrhage.[42]

临床适应证、发病率和危险因素

美国FDA最初批准氨甲环酸用于治疗接受牙科手术的血友病患者和月经大出血的女性患者[36 37] (注：静脉使用氨甲环酸)。现在氨甲环酸的临床适应证迅速扩大，包括多种“超说明书”使用，包括心脏、胃肠道、骨科手术以及产后出血的治疗[38-41]。世界卫生组织（WHO）最近将氨甲环酸列入其“基本药物示范清单”[42]，WHO建议使用氨甲环酸减少体外循环手术患者的失血，严重出血的创伤患者和产后出血患者[42]。(注：静脉使用氨甲环酸)

The broad introduction of TXA into surgical care has resulted in an increased reported incidence of seizures particularly during the early postoperative period after cardiac surgery.[21] Retrospective analyses have shown that the incidence of seizures in postoperative cardiac patients has increased from 0.5–1.0% to 6.4–7.3% with the use of higher doses of TXA.[8 17] Additionally several multicenter retrospective studies confirm increased seizures in postoperative patients who received TXA with an incidence ranging from 0.9% to 2.5%.[16 18 20 26] A single prospective trial found that seizures occurred in 3% (3 of 100 patients) of post–cardiac surgical patients treated with TXA.[34] Although the incidence of TXA-associated seizures after cardiac surgery varies between studies treatment with TXA was a strong independent predictor of seizure.[16 20 26]

氨甲环酸广泛应用于外科治疗，导致惊厥发生率增加，尤其在心脏手术后早期[21]。回顾性研究表明，使用更大剂量的氨甲环酸后(注：静脉使用氨甲环酸)，心脏术后患者的惊厥发作发生率从0.5–1.0%增加到6.4–7.3%[8 17]。此外，一些多中心回顾性研究证实接受氨甲环酸的患者术后惊厥发作增加，发病率从0.9%到2.5%[16 18 20 26]。一项单一前瞻性研究发现，接受氨甲环酸治疗的心脏手术患者中，3%（100名患者中的3名）的患者出现术后惊厥发作[34]。尽管不同研究中，心脏手术后氨甲环酸相关惊厥发作的发生率有所不同，但氨甲环酸治疗是惊厥发作强有力的独立预测因子[16 20 26]。(注：静脉使用氨甲环酸)

Retrospective studies have identified several risk factors for TXA-associated seizures. These include higher doses of TXA such as those recommended in the BART study (Blood conservation using Antifibrinolytics in a Randomized Trial; 80–100mg/kg total dose).[16 20 26 43] Female gender increased age and poor overall health also predispose patientsto seizures.[16 17 20 26] Seizures are observed more frequently in patients older than 70 years and those with a high disease severity score as measured by an APACHE II index (Acute Physiology and Chronic Health Evaluation II)>20.[16 20] Patients with renal dysfunction or prior neurological and cardiovascular disorders are also at increased risk.[16 17 20 26] Other important risk factors for TXA-associated seizures include the type and duration of surgery. Most seizures are reported in patients undergoing “open chamber surgery” (eg aortic valve replacement).[16–18 20] The risk is also increased in patients with deep hypothermic circulatory arrest long cardiopulmonary bypass time or prolonged aortic cross-clamp time.[16 18 20 26]

回顾性研究已明确氨甲环酸相关惊厥发作的几个危险因素，包括更大剂量的氨甲环酸，如BART研究中推荐的剂量（抗纤维蛋白溶解剂血液保护随机研究中，推荐总剂量为80–100mg/kg）[16 20 26 43]、女性、高龄和全身健康状况差也会使患者易患惊厥[16 17 20 26]。根据APACHE II指数（急性生理学和慢性健康评估II)>20衡量，70岁以上的患者和疾病严重程度评分高的患者惊厥发作的发生率更高[16 20]。肾功能不全或先前患有神经和心血管疾病的患者也有更高的风险[16 17 20 26]。氨甲环酸相关惊厥发作的其他重要危险因素包括手术类型和持续时间。据报道，大多数惊厥发作发生在接受“开腔手术”（如主动脉瓣置换术）的患者中[16–18 20]。深低温停循环、长时间体外循环或主动脉阻断时间延长的患者，氨甲环酸引起惊厥发作的风险也会增加[16 18 20 26]。(注：静脉使用氨甲环酸)

Several case reports indicate that seizures are not restricted to cardiac surgery patients. For example a patient with chronic kidney failure who was treated with TXA experienced a convulsive seizure.[10] Another patient who underwent a craniotomy for meningioma hadtonic–clonic convulsions after the administration of TXA.[22] A third patient who was admitted for hemoptysis had a focal seizure after TXA treatment which progressed to a generalized seizure.[27] None of these patients had a history of seizure disorders and no abnormalities were detected on subsequent electroencephalography (EEG) or computed tomographic scans.[10 22 27] Collectively these case studies indicate that a wide range of patients may be vulnerable to TXA-associated seizures. Increasing global “off-label” use of TXA may further increase the incidence of TXA-associated seizures.

一些病例报告表明惊厥发作并不局限于心脏手术患者。例如，一名接受氨甲环酸治疗的慢性肾衰竭患者出现痉挛性发作[10] (注：静脉使用氨甲环酸)。另一名接受脑膜瘤开颅手术的患者在使用氨甲环酸后出现强直-阵挛性痉挛[22] (注：静脉使用氨甲环酸)。第三名因咯血入院的患者在接受氨甲环酸治疗后出现局灶性肌阵挛发作，进而发展为全身性惊厥发作[27] (注：静脉使用氨甲环酸)。这些患者均无惊厥病史，且脑电图（EEG）或CT扫描也未发现异常[10 22 27]。这些病例研究表明，很多患者可能容易发生氨甲环酸相关惊厥(注：静脉使用氨甲环酸)。越来越多的“超说明书”使用氨甲环酸可能会进一步增加氨甲环酸相关惊厥的发病率。

Clinical Features and Diagnosis

A clear understanding of the clinical features of TXA associated seizures will aid in their diagnosis. Reports of patients who received an accidental intrathecal injection of TXA have offered rare insights into the clinical manifestation of TXA-associated seizures[11 13 15 19 23 29]. These patients experienced severe back pain that radiated below the waist with burning pain in the lower limbs and gluteal region[11 13 15 19 23 29]. Involuntary motor activity such as a “jerking” of the lower extremities (referred to as myoclonic movements) and twitching of facial muscles was also observed[11–13 15 19 23]. These abnormal movements rapidly progressed to generalized tonic–clonic seizures[11–13 15 19 23]. Myoclonic movements may serve as a warning sign of impending seizures.

临床特征及诊断

明确了解氨甲环酸相关惊厥的临床特征有助于其诊断。有关蛛网膜下腔内意外注射氨甲环酸的病例报告对氨甲环酸相关惊厥的临床表现提供了少有的可以深入了解的机会[11 13 15 19 23 29]。这些患者严重背痛并向腰部以下放射，下肢和臀部有烧灼痛[11 13 15 19 23 29]。还观察到有非自主的活动，如下肢“抽搐”（肌阵挛）和面部肌肉抽搐[11–13 15 19 23]。这些异常肌肉活动迅速发展为全身性强直-阵挛发作[11-13 15 19 23]。肌阵挛可能是惊厥即将发作的预警信号。

In postoperative cardiac surgery patients TXA associated seizures are typically generalized tonic–clonic events although focal and mixed seizures also occur.[20 24 26] Approximately 20% of the seizure patients experience myoclonic activity.[24] Seizures usually occur within the first 5 to 8 hours after surgery during the period of weaning from intravenous sedation in the intensive care unit.[17 20 24 26] Seizure events typically persist for a few minutes[17 20] and do not progress into status epilepticus.[34] About 30 to 60% of patients have recurrent episodes during the first 24 to 48 hours after surgery.[16 17 20]

在心脏手术后患者中，氨甲环酸相关的惊厥发作通常是全身性强直-阵挛发作，尽管也会发生局灶性和混合性惊厥发作[20 24 26]。这些惊厥发作患者中约有20%经历肌阵挛活动[24]。惊厥通常发生在术后5到8小时内，重症监护病房停用静脉镇静期间[17 20 24 26]。惊厥通常持续几分钟[17 20]，不会发展为癫痫持续状态[34]。大约30%到60%的患者在术后24到48小时内反复发作[16 17 20]。(注：静脉使用氨甲环酸)

The diagnosis of TXA-associated seizures may be facilitated by EEG monitoring in the early postoperative period. EEG monitoring could help distinguish between shivering myoclonic movements and seizures and thereby prevent a misdiagnosis.[17 18 26] EEG monitoring may also detect subclinical seizures that are not apparent by observing sedated patients. Continuous EEG monitoring following cardiac surgery identified 1 patient with EEG evidence of seizure who exhibited no convulsive behaviour.[34] Finally EEG monitoring may be particularly useful for the diagnosis of TXA-associated seizures in patients co-treated with a neuromuscular blocker agent such as rocuronium. These drugs inhibit motor activity and mask the behavioral correlates of network hyperexcitability. In the absence of EEG monitoring the incidence of TXA-associated seizures may be underestimated.

术后早期脑电图监测有助于氨甲环酸相关惊厥的诊断。EEG监测有助于区分颤抖、肌阵挛运动和惊厥，从而防止误诊[17 18 26]。EEG监测还可以通过观察镇静患者发现不明显的亚临床惊厥发作。心脏手术后的连续脑电图监测发现1名患者有惊厥发作的脑电图证据，但未表现出惊厥行为[34]。最后，脑电图监测可能特别有助于诊断与神经肌肉阻滞剂（如罗库溴铵）联合治疗患者的氨甲环酸相关惊厥发作。这些药物抑制运动活动，掩盖网络兴奋性的行为相关性。在缺乏脑电图监测的情况下，氨甲环酸相关惊厥发作的发生率可能被低估。

TXA Concentrations in the Central Nervous System of Patients

The proconvulsant properties of TXA likely result from direct effects on the central nervous system (CNS) as application of TXA to the cortex or injection into the cisterna magna in experimental animals causes generalized seizures.[44–46] In an effort to identify the mechanism underlying TXA-associated seizures the concentration of TXA in the CNS of patients was measured. One study took advantage of a unique clinical scenario where CSF was intermittently sampled during surgery.[47] Specifically an indwelling catheter was inserted into the lumbar intrathecal space of patients undergoing repair of thoracoabdominal aneurysms to allow the CSF to be intermittently drained. The purpose of this procedure is to prevent spinal cord ischemia by decreasing the volume of CSF and reducing intrathecal pressure.[48]

患者中枢神经系统内氨甲环酸的浓度

氨甲环酸致惊厥的特性可能源于对中枢神经系统的直接影响，因为在实验动物中，将氨甲环酸应用于大脑皮层或枕大池内注射会导致全身性惊厥发作[44–46]。为了明确氨甲环酸相关惊厥发作的机制，测定患者中枢神经系统内氨甲环酸的浓度，一项研究结合临床实际场景，在手术过程中间歇性地采集脑脊液[47]。具体的说，就是在接受胸腹动脉瘤修复手术的患者的腰椎蛛网膜下腔内置管，便于间歇性排放和采集脑脊液。该操作的目的是通过减少脑脊液体积和降低硬膜囊内压来预防脊髓缺血[48]。(注：静脉使用氨甲环酸)

Measurements of TXA levels in the CSF from these patients produced unexpected results. After infusion of the drug was discontinued the concentration of TXA in the CSF failed to decline and in some cases continued to increase reaching peak concentration of about 200 μM (Fig 1A).[47] In contrast TXA levels in the serum peaked following cardiopulmonary bypass then rapidly declined after the drug infusion was terminated.[47] The peak serum concentration of TXA (2 mM) was about 10 times higher than the concentration of TXA in the CSF (200 μM). Notably 1 patient with a high TXA concentration in the CSF experienced postoperative seizures. The time course of TXA concentrations in the CSF and serum from this patient is illustrated in the top half of Figure 1A. The average concentrations from the CSF and serum of 4 patients are shown in the bottom half of Figure 1A. These results suggest that seizures could arise due to persistently high concentrations of TXA in the brain during the early postoperative period.

这些患者脑脊液中氨甲环酸水平的测定产生了意想不到的结果(注：静脉使用氨甲环酸，检测通过血脑屏障进入脑脊液的氨甲环酸浓度)。停止输注药物(氨甲环酸)后，脑脊液中氨甲环酸的浓度并没有下降，在某些情况下还继续上升，达到约200μM的峰值浓度（图1A）[47]。相反，血清中氨甲环酸水平在体外循环后达到峰值，然后在停止输注药物后迅速下降[47]。氨甲环酸的血清峰值浓度（2mM）约为脑脊液中氨甲环酸浓度（200μM）的10倍。值得注意的是，1名脑脊液中氨甲环酸浓度高的患者术后惊厥发作。该患者脑脊液和血清中氨甲环酸浓度的时间过程如图1A上半部分所示。图1A下半部分显示了4名患者脑脊液和血清的平均浓度。这些结果表明，惊厥发作可能是由于术后早期大脑中持续高浓度氨甲环酸引起的。

FIGURE 1: Tranexamic acid (TXA) concentrations measured in the cerebral spinal fluid (CSF) and serum of patients cause hyperexcitability in vitro. (A) The time course of TXA levels in the CSF and serum of 1 patient who experienced a seizure is shown on the left. The decline of TXA levels in the brain lags behind that in the blood. The timeline at the bottom of each figure indicates key surgical events during cardiopulmonary bypass (CPB). The red arrow highlights the concentrations when TXA administration was terminated. On the right are the summarized data of TXA concentrations in the CSF and serum during key surgical events (n=4). TXA levels in the serum (2 mM) are 10-fold higher than those in the CSF (200 μM). (B) Clinically relevant concentration of TXA (200 μM) causes hyperexcitability by increasing the frequency of seizure-like events in neocortical slices. *P < 0.05.

图1：在体外，患者脑脊液和血清中测得的氨甲环酸浓度会导致高兴奋性。（A）左侧显示1例惊厥发作患者脑脊液和血清中氨甲环酸水平的时间过程。大脑中氨甲环酸水平的下降滞后于血液中氨甲环酸水平的下降。每个图底部的时间线表示体外循环期间的手术关键时间点。红色箭头突出显示终止给药时氨甲环酸在脑脊液和血清中的浓度。右侧是手术关键时间点脑脊液和血清中氨甲环酸浓度的汇总数据（n=4）。血清中的氨甲环酸水平（2mM）比脑脊液中的氨甲环酸水平（200μM）高10倍。（B）临床相关浓度的氨甲环酸（200μM）通过增加新皮质切片(新切脑片)中惊厥样事件的频率而导致高兴奋性。*P < 0.05。

Molecular Mechanism of TXA-Associated Seizures

Studies of animal models have offered insights into the molecular mechanisms underlying TXA-associated seizures. Application of a clinically relevant concentration of TXA (200 μM) to slices of neocortex markedly increased field responses to excitatory stimuli.[47] TXA also increased the frequency of spontaneous epileptiform field potentials or “seizure-like events” (see Fig 1B).[47] Another study showed that application of TXA (1mM) to mouse amygdala slices caused wide spread neuronal depolarization.[49] Collectively these studies show that TXA directly increases the excitability of neuronal networks. Increasing evidence suggests that this hyperexcitability produced by TXA results from reduced inhibitory neurotransmission or “disinhibition.” γ-Aminobutyric acid type A (GABAA) receptors and glycine receptors are major mediators of inhibition in the CNS.[50 51] These transmitter-gated anion channels which are well-known targets for a variety of proconvulsant and anticonvulsant agents are plausible targets for TXA.[52–56]

氨甲环酸相关惊厥发作的分子机制

动物模型研究为了解氨甲环酸相关惊厥发作的分子机制提供帮助。在新切脑片上应用临床相关浓度的氨甲环酸（200μM）(注：脑脊液内引发惊厥的浓度)显著增加场反应的兴奋性刺激[47]。氨甲环酸还增加了自发癫痫样场电位或“惊厥样事件”的频率（见图1B）[47]。另一项研究表明，使用氨甲环酸（1mM）可使小鼠杏仁核切片神经元广泛去极化[49]。这些研究均表明氨甲环酸直接增加神经元网络的兴奋性。越来越多的证据表明，氨甲环酸产生的这种高兴奋性是抑制性神经传递或“去抑制”减少的结果。γ-氨基丁酸A型（GABAA）受体和甘氨酸受体是中枢神经系统抑制的主要介质[50 51]。这些递质门控阴离子通道，是各种促惊厥剂和抗惊厥剂的已知靶点，也是氨甲环酸的合理靶点[52-56]。

FIGURE 2: Tranexamic acid (TXA) is a competitive antagonist of glycine (Gly) receptors. (A) Glycine and TXA are structural analogues suggesting that TXA competes with glycine at the agonist binding site of glycine receptors. (B) TXA (1mM) inhibits glycine (100 μM)-activated currents in cortical neurons. The concentration–response plots for glycine current recorded in the absence and presence of TXA are shown. The results indicate that TXA is a competitive antagonist of glycine receptors.

图2：氨甲环酸是甘氨酸受体的竞争性拮抗剂。（A）甘氨酸和氨甲环酸结构类似，表明氨甲环酸在甘氨酸受体的激动剂结合位点与甘氨酸竞争。（B）氨甲环酸（1mM）抑制皮层神经元中甘氨酸（100μM）激活的电流。显示在无和有氨甲环酸存在的情况下记录的甘氨酸电流的浓度-反应图。结果表明氨甲环酸是甘氨酸受体的竞争性拮抗剂。

The effects of TXA on GABAA receptors were examined first by Furtmuller and colleagues.[57] They showed that TXA is a competitive antagonist of GABAA receptors and that it inhibits recombinant GABAA receptors (α1b2γ2) with a half-maximal inhibitory concentration (IC50) of 7mM.[57] Other investigators showed that TXA inhibits native GABAA receptors in cortical and spinal cord neurons (IC50=1.5 and 1mM respectively).[47] Collectively these results demonstrated that TXA inhibits GABAA receptors but only at concentrations that are higher than the concentration detected in the CSF of patients (200 μM). GABAA receptors generate 2 distinct forms of inhibition synaptic and tonic which could exhibit different sensitivities to TXA.[58–61] Synaptic currents are fast transient events that are activated by near-saturating concentrations of agonist.[62] In contrast tonic currents are generated by low ambient concentrations of transmitter.[62] Synaptic and tonic currents are mediated by different receptor subtypes that often exhibit different pharmacological properties.[60] Surprisingly the potency of TXA for synaptic currents (IC50=0.8mM) and tonic inhibitory currents (IC50=1mM) was similar.[47 49] Thus although inhibition of GABAA receptors may contribute to TXA-associated seizures higher affinity target receptors are likely to exist in the CNS.

Furtmuller及其同事首先研究了氨甲环酸对GABAA受体的影响[57]。他们的研究表明氨甲环酸是GABAA受体的竞争性拮抗剂，并且它抑制重组GABAA受体（α1b2γ2）的半数抑制浓度（IC50）为7mM[57]。其他研究人员表明氨甲环酸抑制大脑皮质和脊髓神经元中的天然GABAA受体（IC50分别为1.5和1mM）[47]。这些结果共同表明氨甲环酸抑制GABAA受体，但仅当浓度高于患者脑脊液中检测到的浓度（200μM）时。GABAA受体产生两种不同形式的抑制，即突触抑制和强直抑制，它们对氨甲环酸可能表现出不同的敏感性[58–61]。突触电流是快速、短暂的事件，被接近饱和浓度的激动剂激活[62]。相反，强直电流是由低浓度的环境递质产生[62]。突触电流和强直电流由不同的受体亚型介导，这些亚型通常表现出不同的药理学特性[60]。令人惊讶的是，氨甲环酸对突触电流（IC50=0.8mM）和强直抑制电流（IC50=1mM）的效力相似[47 49]。因此，尽管GABAA受体的抑制可能导致氨甲环酸相关惊厥发作，中枢神经系统中可能存在更高亲和力的靶受体。

Our research group searched for novel receptors that are sensitive to clinically relevant concentrations of TXA. Because TXA is a structural analogue of glycine we hypothesized that TXA competitively inhibits glycine receptors (Fig 2A) and this action contributes to seizures. In support of this hypothesis glycine receptor antagonists such as strychnine cause myoclonic movements and twitching particularly in the lower limbs as well as muscle spasms and convulsions.[55 56 63 64] Interestingly the pattern of twitching myoclonus and seizures observed in patients treated with TXA is similar to the pattern of the proconvulsant effects of strychnine.[11 22 27] We found that TXA acts as a competitive antagonist of glycine receptors with an IC50 of 1mM (see Fig 2B).[47] Similar to GABAA receptors glycine receptors generate both synaptic currents and tonic inhibitory currents (Fig 3A).[61] Thus we compared the potency of TXA for inhibition of spontaneous miniature inhibitory postsynaptic currents and a tonic current in spinal cord neurons (see Fig 3C).[47] Tonic glycine current was found to be 10-fold more sensitive to TXA (IC50=90 μM) than synaptic currents.[47] Therefore the potency of TXA is greatest for glycine receptors that generate a tonic inhibitory current (see Fig 3B).

我们的研究小组寻找对氨甲环酸临床相关浓度敏感的新受体。因为氨甲环酸与甘氨酸结构近似，我们假设氨甲环酸竞争性抑制甘氨酸受体（图2A），这种作用有助于惊厥发作。为支持这一假设，甘氨酸受体拮抗剂，如士的宁，会引起肌阵挛和抽搐，尤其是在下肢，以及肌肉痉挛和抽搐[55 56 63 64]。有趣的是，在接受氨甲环酸治疗的患者中观察到的抽搐、肌阵挛和惊厥发作表现与士的宁的引起的抽搐、肌阵挛和惊厥发作表现相似[11 22 27]。我们发现氨甲环酸作为甘氨酸受体的竞争性拮抗剂，IC50为1mM（见图2B）[47]。与GABAA受体相似，甘氨酸受体同时产生突触电流和强直抑制电流（图3A）[61]。因此，我们比较了氨甲环酸抑制脊髓神经元自发微抑制性突触后电流和强直电流的效力（见图3C）[47]。研究发现，强直性甘氨酸电流对氨甲环酸（IC50=90μM）的敏感性是突触电流的10倍[47]。因此，氨甲环酸对产生强直抑制电流的甘氨酸受体的效力最大（见图3B）。

FIGURE 3: Tonic glycine current is highly sensitive to tranexamic acid (TXA) inhibition. (A) Inhibitory receptors are expressed in synaptic and extrasynaptic regions of the neuron. These receptors are composed of different subunits and have distinct pharmacological properties. Extrasynaptic receptors mediate a tonic inhibitory conductance. (B) Summary table of the half-maximal inhibitory concentration (IC50) values for TXA inhibition of synaptic and tonic currents mediated by glycine and γ-aminobutyric acid type A (GABA) receptors. (C) TXA (1 mM) inhibits synaptic and tonic glycine currents in a similar manner as the competitive glycine antagonist strychnine. Synaptic currents were studied by recording miniature inhibitory postsynaptic currents. Tonic currents were evoked by applying a low concentration of glycine (10 mM) similar to the ambient concentration present in the extracellular fluid to the bath solution. SEM=standard error of the mean.

图3：强直甘氨酸电流对氨甲环酸抑制高度敏感。（A）神经元突触和突触外区域表达抑制性受体。这些受体由不同的亚单位组成，具有不同的药理特性。突触外受体介导强直抑制电导。（B）甘氨酸和γ-氨基丁酸A型（GABA）受体介导的氨甲环酸抑制突触电流和强直电流的半数抑制浓度（IC50）值汇总表。（C）氨甲环酸（1mM）抑制突触和强直性甘氨酸电流的方式与竞争性甘氨酸拮抗剂士的宁相似。通过记录微抑制性突触后电流来研究突触电流。强直电流可通过培养液中加入低浓度甘氨酸（10mM）（类似于细胞外液中存在的环境浓度）诱发。SEM=平均值标准差。

Finally others have studied the effects of TXA on the activity of excitatory amino acid receptors.[49 57] Binding assays and electrophysiological studies show that TXA (5mM) does not directly inhibit the N-methyl-D-aspartate[57] or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtypes of glutamate receptors.[49] Thus the proconvulsant properties of TXA are likely mediated by disinhibition of tonic glycine current.

最后，其他人研究了氨甲环酸对兴奋性氨基酸受体活性的影响[49 57]。结合试验和电生理学研究表明，氨甲环酸（5mM）不会直接抑制谷氨酸受体的N-甲基-D-天冬氨酸[57]或α-氨基-3-羟基-5-甲基-4-异恶唑丙酸亚型[49]。因此，氨甲环酸的致惊厥特性可能是由强直性甘氨酸电流的去抑制介导。

Anesthetics Reverse TXA Inhibition of Glycine Receptors

Because the tonic current generated by glycine receptors is highly sensitive to TXA inhibition drugs that reverse this inhibitory effect may mitigate TXA-associated hyperexcitability. There are no commonly used selective glycine receptor agonists that can be administered intravenously to patients in the intensive care unit. However several general anesthetics including the inhalational agents isoflurane sevoflurane and desflurane and the intravenous anesthetic propofol act as positive allosteric modulators of glycine receptors.[65 66] Whole-cell recordings of currents in spinal cord neurons showed that clinically relevant concentrations of isoflurane (150 and 250 μM) and propofol(3 μM) fully reversed TXA inhibition of tonic glycine current[47] In addition field recordings from slices of mouse cortex showed that isoflurane (250 μM) and propofol(1 μM) completely reversed the hyperexcitability produced by TXA.[47] Therefore isoflurane and propofol as well as other anesthetics that increase glycine receptor function might be effective either for treating or for preventing TXA-associated seizures (Fig 4).

麻醉药物对氨甲环酸对甘氨酸受体抑制的逆转

由于甘氨酸受体产生的强直电流对氨甲环酸抑制高度敏感，因此逆转这种抑制作用的药物可减轻氨甲环酸相关的高兴奋性。没有可以给重症监护病房患者静脉注射的常用选择性甘氨酸受体激动剂。但几种全身麻醉剂，包括吸入麻醉剂异氟醚、七氟醚、地氟醚和静脉麻醉剂异丙酚，可作为甘氨酸受体的正变构调节剂[65 66]。脊髓神经元电流的全细胞记录显示，异氟醚的临床相关浓度（150和250μM）和异丙酚（3μM）可完全逆转氨甲环酸对强直性甘氨酸电流的抑制[47]。此外，小鼠脑皮质切片的场电位记录显示异氟醚（250μM）和异丙酚（1μM）完全逆转氨甲环酸产生的高兴奋性[47]。因此，异氟醚和异丙酚以及其他增加甘氨酸受体功能的麻醉剂可能对治疗或预防氨甲环酸相关惊厥发作有效（图4）

Prevention and Treatment of TXA-Associated Seizures

Currently there are no recommended treatments for TXA-associated seizures. Given the low incidence and variable clinical manifestations of TXA-associated seizures randomized controlled clinical trials that compare the efficacy of various anticonvulsants treatments are likely to be impractical. Nevertheless results from animal studies have shown that TXA inhibition of tonic glycine current is rapidly and completely reversed by the general anesthetics isoflurane or propofol.[47] These results suggest that general anesthetics may be useful to consider for the first-line treatment for TXA-associated seizures in patients. For example TXA-associated seizures could be prevented by simply prolonging the delivery of anesthetics during the early postoperative period. Notably patients experience seizures most often in the first few hours after admission to the intensive care unit. At this time TXA levels are either peaking or declining slowly.[47] Incontrast anesthetic levels are declining rapidly in the CNS as drug delivery has been terminated.[67] Thus the anesthetic is no longer available to provide anticonvulsant effects. Consistent with this notion that anesthetics protect against TXA-induced seizures many patients first develop seizures during emergence from propofol sedation.[17 24] Also case reports indicate that propofol is effective for treating seizures in patients who inadvertently received an intrathecal injection of TXA.[15 23] Although treatment with a general anesthetic is likely to be effective these drugs should only be administered under conditions that allow their safe use. This review does not provide specific recommendations regarding doses of anesthetics as treatment of patients during the early postoperative period in the intensive care unit is highly complex. Treatment must be guided by the judgment and skill of the care providers.

氨甲环酸相关惊厥的预防和治疗

目前，没有可推荐的有效治疗氨甲环酸相关惊厥的方法。鉴于氨甲环酸相关惊厥的发病率低且临床表现多变，比较各种抗惊厥药物治疗效果的随机对照临床研究是不切实际的。然而，动物研究结果表明，全身麻醉药异氟醚或异丙酚能迅速完全逆转氨甲环酸对甘氨酸强直电流的抑制作用[47]。这些结果表明，全身麻醉剂可能有用，做为第一线治疗氨甲环酸相关惊厥的发作。例如，仅通过延长术后早期麻醉剂的持续使用时间就可以预防氨甲环酸相关惊厥的发作。值得注意的是，患者通常在转入重症监护病房后的最初几个小时内出现惊厥发作。此时，氨甲环酸水平要么达到峰值，要么缓慢下降[47]。相反，随着麻醉药物的停用，中枢神经系统内麻醉药水平迅速下降[67]。因此，麻醉药不再具有抗惊厥作用。与麻醉药可以防止氨甲环酸诱发的惊厥发作这一概念相一致，许多患者在异丙酚镇静苏醒期间首次出现惊厥发作[17 24]。此外，病例报告表明，异丙酚对蛛网膜下腔内意外注射氨甲环酸患者的惊厥发作有效[15 23]。尽管用全身麻醉药治疗可能是有效的，但这些药物只能在保证安全使用的条件下使用。由于重症监护病房术后早期患者的治疗非常复杂，本综述未提供有关麻醉剂剂量的具体建议。治疗必须以医疗人员的判断和技术为指导。

If the use of propofol or other anesthetics is deemed to be unsafe or if these drugs are unavailable alternative therapies can be considered. A second-line treatment for TXA-associated seizures includes compounds that increase GABAA receptor activity which may compensate for a reduction in glycinergic inhibition. Benzodiazepines (lorazepam midazolam diazepam and clonazepam) which do not modify glycine receptors but rather upregulate GABAA receptor function [68 69] have been used to treat seizures following inadvertent intrathecal injection of TXA[27–29] or after cardiac surgery.[16 26] Lorazepam may be considered for the treatment of seizures rather than other benzodiazepines that have shorter duration of action.

如果认为使用异丙酚或其他麻醉剂不安全，或者没有这些药物，可以考虑其他办法。氨甲环酸相关惊厥的二线治疗包括增加GABAA受体活性的药物，这可能补偿甘氨酸抑制的减少。苯二氮卓类药物（劳拉西泮、咪唑安定、地西泮和氯硝西泮）不修饰甘氨酸受体，而是上调GABAA受体功能[68 69]，已用于治疗意外蛛网膜下腔注射氨甲环酸[27–29]后或心脏手术后的惊厥发作[16 26]。劳拉西泮可用于治疗惊厥发作，而不是其他作用时间较短的苯二氮卓类药物。

Finally reducing the dose of TXA during surgery may be the simplest and most practical strategy to prevent TXA-associated seizures. TXA is a competitive antagonist of glycine and GABAA receptors. Thus a lower dose of TXA is less likely to cause seizures as lower concentrations would be “outcompeted” by endogenous neurotransmitters at the agonist-binding sites of glycine and GABAA receptors. The notion that higher doses of TXA increase the risk of seizures is supported by animal[45] and human studies.[16 20 26] Specifically in cardiac surgery patients the use of higher doses of TXA drastically increased the incidence ofseizures.[16 20 26]

最后，在手术期间减少氨甲环酸剂量可能是预防氨甲环酸相关惊厥发作最简单和最实用的策略。氨甲环酸是甘氨酸和GABAA受体的竞争性拮抗剂。因此，较低剂量的氨甲环酸不太可能引起惊厥发作，因为较低浓度氨甲环酸会被甘氨酸和GABAA受体激动剂结合位点的内源性神经递质“超越”。动物研究[45]和人类研究[16 20 26]均已证实大剂量氨甲环酸可增加惊厥发作风险。具体而言，在心脏手术患者中，大剂量氨甲环酸的使用显著增加了惊厥发作的发生率[16 20 26]。

Lowered TXA dosing should also be considered for patients with renal dysfunction as renal excretion is the major route of TXA elimination. Case reports indicate that patients treated with TXA while undergoing dialysis experience generalized seizures and myoclonic movements.[10 70] Interestingly TXA administered to cardiac surgery patients at doses recommended in the BART Trial resulted in higher than expected plasma concentrations which exceeded the recommended therapeutic levels.[71 72] Consistent with these findings lowering TXA doses reduced the frequency of postoperative seizures.[20] Therefore decreasing the dose of TXA is likely the simplest and most effective strategy to reduce the incidence and/or severity of postoperative seizures. However the benefits of reducing TXA dose need to be balanced against the possibility of reducing the drug’s antifibrinolytic effects.

肾功能不全患者也应考虑降低氨甲环酸剂量，因为肾脏排泄是消除氨甲环酸的主要途径。病例报告表明，接受透析治疗的患者在接受氨甲环酸治疗时会出现全身性惊厥发作和肌阵挛活动[10 70]。有意思的是，以BART试验中推荐的剂量给心脏手术患者使用(注：静脉使用)氨甲环酸会导致高于预期的血浆浓度，超过推荐的治疗水平[71 72]。与这些发现相一致，降低氨甲环酸剂量可降低术后惊厥发作的频率[20]。因此，减少氨甲环酸剂量可能是降低术后惊厥发生率和/或严重程度的最简单和最有效的办法。然而，减少氨甲环酸剂量的好处需要与减少药物抗纤维蛋白溶解作用的可能性相权衡。

Summary and Outstanding Questions

In summary TXA-associated seizures occur most frequently during the early postoperative period after cardiac surgery but also occur in patients undergoing noncardiac surgery and other medical treatments. To reduce the risk of seizures the lowest effective TXA dose should be considered and dosing should be adjusted for clinical conditions such as renal dysfunction. A high index of suspicion is required to detect seizures and EEG monitoring may be considered for patients who experience myoclonic movements or twitching or show evidence of focal seizures. Based on results from preclinical studies general anesthetics including propofol and isoflurane may be considered as the first line for prevention and/or treatment. In high-risk patients terminating the TXA infusion early and/or prolonging the administration of anesthetics may prevent seizures.

总结和待解决的问题

总之，氨甲环酸相关惊厥发作最常发生在心脏手术后早期，但也发生在接受非心脏手术和其他医疗治疗的患者中。为了降低惊厥发作的风险，应考虑最低有效氨甲环酸剂量，并根据临床情况（如肾功能不全）调整剂量。预判惊厥发作需要及早发现高度可疑指标，对于发生肌阵挛活动或抽搐或出现局灶性惊厥发作证据的患者，可考虑进行脑电图监测。根据以前的临床研究的结果，可将包括异丙酚和异氟醚在内的全身麻醉药做为预防和/或治疗的一线药物。在高危患者中，尽早终止氨甲环酸输注和/或延长麻醉药的使用可能会防止惊厥发作。

Although progress has been made in our understanding of the causes underlying TXA-associated seizures many questions remain unanswered. First it is uncertain why cardiac surgery patients are more vulnerable to TXA-associated seizures. One potential factor is the high doses of TXA administered during cardiac surgery.[73] Also cardiac surgery can cause intensive systemic inflammation that increases the permeability of the blood–brain barrier.[74] A jeopardized blood–brain barrier could facilitate the entry of TXA into the CNS. Second it is important to understand the mechanism by which TXA gains entry into the CNS as such knowledge could aid in the development of neuroprotective strategies that reduce TXA penetration. Third it is of interest to know whether TXA dosing should be reduced or avoided in patients with a previous history of a seizure disorder or those with clinical conditions such as traumatic brain injury that damage the blood–brain barrier and predispose to seizures. Also antibiotics such as penicillins and cephalosporins inhibit GABAA receptors and it is unknown whether these drugs exacerbate the proconvulsant properties of TXA.

虽然我们在理解氨甲环酸相关惊厥发作原因方面取得了进展，但许多问题仍然没有答案。首先，尚不清楚为什么心脏手术患者更容易发生氨甲环酸相关癫痫发作。一个潜在因素是心脏手术期间使用大剂量的氨甲环酸[73]。此外，心脏手术可导致剧烈的全身炎症，增加血脑屏障的通透性[74]。受损的血脑屏障可促进氨甲环酸进入中枢神经系统。其次，了解氨甲环酸进入中枢神经系统的机制很重要，因为这些知识有助于制定减少氨甲环酸渗透的神经保护办法。第三，有惊厥病史的患者或有外伤性脑损伤等损害血脑屏障并易惊厥发作临床症状的患者是否应减少或避免使用氨甲环酸，这一点很有意义。此外，青霉素和头孢菌素等抗生素抑制GABAA受体，目前尚不清楚这些药物是否会加剧氨甲环酸的致惊厥特性。

Finally future studies are needed to determine whether antifibrinolytic drugs other than TXA also cause seizures. Interestingly EACA is a structural analogue of the amino acid glycine and case reports show that EACA causes seizures.[33] Our electrophysiological studies demonstrated that EACA acts as a competitive antagonist of glycine receptors(IC50=12mM) in mouse neurons.[47] The potency of EACA for glycine receptors is 10-fold lower than that of TXA; however EACA is often administered at 10-fold higher doses than TXA to patients.[75 76] Aprotinin is structurally distinct from TXA and EACA. We observed that aprotinin does not inhibit glycine currents even at a very high concentration (10mM).[47] Antifibrinolytic drugs remain an important and effective low-cost intervention that reduces blood loss morbidity and mortality. Understanding the cause of TXA-associated seizures recognizing the early warning signs of impending seizures and using anesthetics may reduce the incidence and severity of seizures and lead to better patient outcomes.

最后，还需要进一步的研究来确定除氨甲环酸以外的抗纤维蛋白溶解药物是否也会引起惊厥发作。有意思的是，氨基己酸与甘氨酸氨基酸的结构相近，病例报告表明，氨基己酸也可引起惊厥发作[33]。我们的电生理研究表明，氨基己酸在小鼠神经元中充当甘氨酸受体（IC50=12mM）的竞争性拮抗剂[47]。氨基己酸对甘氨酸受体的效力比氨甲环酸低10倍；然而，氨基己酸给患者的剂量通常比氨甲环酸高10倍[75 76]。抑肽酶在结构上不同于氨甲环酸和氨基己酸。我们观察到抑肽酶即使在非常高的浓度（10mM），也不会抑制甘氨酸电流[47]。抗纤维蛋白溶解药物仍然是一种重要、有效、低成本的干预措施，可减少失血、发病率和死亡率。了解氨甲环酸相关惊厥发作的原因，识别即将发生惊厥发作的早期预警信号，并使用麻醉剂可能会降低惊厥发作的发生率和严重程度，使患者预后更好。

参考文献：略