对患者的教育是大多数 NMRS 综合征的治疗基础。 应向患者提供可终止即将发生的 NMRS 或预防复发的物理技术的建议。
即使很多药物可能对预防 NMRS 有效,但几乎无可作为依据的随机临床试验,同时支持使用药物治疗的证据也不充分。[60]Jacobus JR, Johannes BR, Catherine NB, et al. Drugs and pacemakers for vasovagal, carotid sinus and situational syncope. Cochrane Database Syst Rev. 2011;(10):CD004194.http://www.ncbi.nlm.nih.gov/pubmed/21975744?tool=bestpractice.com 因此除可能使用米多君外,无强烈推荐治疗神经介导的(以及直立性)晕厥的药物。[61]Izcovich A, González Malla C, Manzotti M, et al. Midodrine for orthostatic hypotension and recurrent reflex syncope: a systematic review. Neurology. 2014;83:1170-1177.http://www.ncbi.nlm.nih.gov/pubmed/25150287?tool=bestpractice.com
对患者的教育
对患者的教育是治疗所有类型 NMRS 的一个重要因素。[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Mar 9 [Epub ahead of print].http://circ.ahajournals.org/content/early/2017/03/09/CIR.0000000000000499http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com 应告知患者应,虽然 NMRS 一般不致命,[2]Brignole M, Moya A, de Lange FJ, et al; ESC Scientific Document Group. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018 Mar 19. [Epub ahead of print]https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehy037/4939241http://www.ncbi.nlm.nih.gov/pubmed/29562304?tool=bestpractice.com 但这类晕厥易于复发,若不采取预防措施,可导致受伤。此外,了解一些基本病理生理学知识以及对预警症状进行识别和作出反应的必要性可能对患者有益;这不仅可降低损伤风险,最终还可提高治疗依从性。应该教育患者避免一些诱因,例如长时间站立、温暖环境以及应对牙科和医疗环境。[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Mar 9 [Epub ahead of print].http://circ.ahajournals.org/content/early/2017/03/09/CIR.0000000000000499http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com
在适当且安全的情况下可减少或停用导致低血压的药物。[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Mar 9 [Epub ahead of print].http://circ.ahajournals.org/content/early/2017/03/09/CIR.0000000000000499http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com
复发性血管迷走性晕厥易感患者应了解停止发作和降低将来发作易感性的技术(例如物理操作法,用富含电解质的液体补液)。 另外这些患者还应了解盐摄入量增加的价值和潜在风险。 对于情境性晕厥,还应让患者认识到有可能改善或完全避免诱因:例如,通过戒烟抑制咳嗽晕厥,以及通过坐位排尿避免排尿性晕厥。 在某些病例中,脱敏技术(例如,飞行恐惧相关性晕厥)可能也有帮助。 颈动脉窦综合征 (CSS) 患者应避免穿紧领服装或打领带,尽管通常也推荐心脏起搏。
物理技术
1. 身体抗压训练 (PCM)
当首次识别到预警症状时,提倡采用 PCM 防止即将发生的 NMRS 或直立性晕厥。 已证明下蹲、手臂绷紧、腿交叉,以及腿交叉伴下肢肌肉绷紧有效。[62]Krediet CT, van Dijk N, Linzer M, et al. Management of vasovagal syncope: controlling or aborting faints by leg crossing and muscle tensing. Circulation. 2002;106:1684-1689.http://circ.ahajournals.org/content/106/13/1684.fullhttp://www.ncbi.nlm.nih.gov/pubmed/12270863?tool=bestpractice.com[63]Brignole M, Croci F, Menozzi C, et al. Isometric arm counter-pressure maneuvers to abort impending vasovagal syncope. J Am Coll Cardiol. 2002;40:2053-2059.http://www.ncbi.nlm.nih.gov/pubmed/12475469?tool=bestpractice.com 在关于身体抗压训练试验(PC 试验)中,对身体训练进行了评估,发现晕厥事件复发率和总负担有所减少。[64]van Dijk N, Quartieri F, Blanc JJ, et al. Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres Trial (PC-Trial). J Am Coll Cardiol. 2006;48:1652-1657.http://www.ncbi.nlm.nih.gov/pubmed/17045903?tool=bestpractice.com 因此,PCM 应为血管迷走性晕厥治疗策略的重要组成部分。 关于 PCM 对情境性晕厥或颈动脉窦晕厥患者的作用缺乏科学的数据支持,但可能已用于选择性病例。
2. 倾斜训练(站立训练)
倾斜训练的主要目标(称为站立训练更加准确)是提高对直立性压力的神经血管反应。[65]Ector H, Reybrouck T, Heidbüchel H, et al. Tilt training: a new treatment for recurrent neurocardiogenic syncope and severe orthostatic intolerance. Pacing Clin Electrophysiol. 1998;21:193-196.http://www.ncbi.nlm.nih.gov/pubmed/9474671?tool=bestpractice.com 首选方法为站立训练(通常在家),逐渐延长时间超过 10 到 12 周。 推荐开始时长为 3 到 5 分钟,每日两次;然后站立时长每 3 或 4 天逐渐延长到 30 到 40 分钟,每日两次。 美国心脏病学会 (ACC)/美国心脏协会 (AHA)/美国心律协会 (HRS) 认为,直立性训练对于频繁发作的血管迷走性晕厥患者的作用是不确定的。[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Mar 9 [Epub ahead of print].http://circ.ahajournals.org/content/early/2017/03/09/CIR.0000000000000499http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com
非随机研究表明,若坚持进行站立训练,可减少对反射性晕厥的易感性。[66]Di Girolamo E, Di Iorio C, Leonzio L, et al. Usefulness of a tilt training program for the prevention of refractory neurocardiogenic syncope in adolescents: a controlled study. Circulation. 1999;100:1798-1801.http://circ.ahajournals.org/content/100/17/1798.fullhttp://www.ncbi.nlm.nih.gov/pubmed/10534467?tool=bestpractice.com[67]Reybrouck T, Heidbüchel H, Van De Werf F, et al. Long-term follow-up results of tilt training therapy in patients with recurrent neurocardiogenic syncope. Pacing Clin Electrophysiol. 2002;25:1441-1446.http://www.ncbi.nlm.nih.gov/pubmed/12418741?tool=bestpractice.com[68]Kinay O, Yazici M, Nazli C, et al. Tilt training for recurrent neurocardiogenic syncope: effectiveness, patient compliance, and scheduling the frequency of training sessions. Jpn Heart J. 2004;45:833-843.http://www.ncbi.nlm.nih.gov/pubmed/15557724?tool=bestpractice.com 但依从性通常是一个问题,因为训练过程既耗时又枯燥。此外,随机对照试验 (RCT) 效果不佳,表明该方法可能并无起初期望的功效;因此需进一步研究。[69]On YK, Park J, Huh J, et al. Is home orthostatic self-training effective in preventing neurally mediated syncope? Pacing Clin Electrophysiol. 2007;30:638-643.http://www.ncbi.nlm.nih.gov/pubmed/17461874?tool=bestpractice.com[70]Gurevitz O, Barsheshet A, Bar-Lev D, et al. Tilt training: does it have a role in preventing vasovagal syncope? Pacing Clin Electrophysiol. 2007;30:1499-1505.http://www.ncbi.nlm.nih.gov/pubmed/18070305?tool=bestpractice.com
药物治疗
血容量扩张是对需药物疗法的大多数血管迷走性晕厥或直立性晕厥患者推荐的一个重要手段。 传统方法包括高盐饮食及富含电解质的运动饮料。 主要的安全担心为可能会诱发高血压。 幸运的是,这在年轻患者中比较罕见,但对老年人患者是个值得关注的问题。 增加盐和液体摄入的禁忌证包括高血压、肾病、心力衰竭或心功能障碍病史。
如果需要使用处方药扩充血容量,可以使用氟氢可的松。[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Mar 9 [Epub ahead of print].http://circ.ahajournals.org/content/early/2017/03/09/CIR.0000000000000499http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com 不良反应包括高血压和低钾血症。 然而,关于氟氢化可的松效力的临床证据较弱。[71]Scott WA, Pongiglione G, Bromberg BI, et al. Randomized comparison of atenolol and fludrocortisone acetate in the treatment of pediatric neurally mediated syncope. Am J Cardiol. 1995;76:400-402.http://www.ncbi.nlm.nih.gov/pubmed/7639169?tool=bestpractice.com[72]Salim MA, Di Sessa TG. Effectiveness of fludrocortisone and salt in preventing syncope recurrence in children: a double-blind, placebo-controlled, randomized trial. J Am Coll Cardiol. 2005;45:484-488.http://www.ncbi.nlm.nih.gov/pubmed/15708690?tool=bestpractice.com 第 2 项晕厥预防试验 (POST II) 是一项评估氟氢可的松对血管迷走神经性晕厥效果的多中心、随机、安慰剂对照研究,其结果表明,相比于安慰剂组,氟氢可的松组的晕厥发作未显著减少。[73]Sheldon R, Morillo CA, Krahn A, et al. A randomized clinical trial of fludrocortisone for the prevention of vasovagal syncope (POST II). Can J Cardiol. 2011;27(suppl 5):S335-S336.http://www.onlinecjc.ca/article/S0828-282X(11)01050-6/fulltext
在对预防血管迷走性晕厥有效的其他药物中,β 受体阻滞剂仍然被广泛使用,尽管缺乏有力的证据支持。 起初提倡使用 β 受体阻滞剂减少肾上腺素激增的影响,预防反射性晕厥 - 往往先发,而且可能是迷走血管性诱因的组成部分。 积极的支持性证据大部分来自小规模的观察性研究及一项小型随机对照试验。[74]Mahanonda N, Bhuripanyo K, Kangkagate C, et al. Randomized double-blind, placebo-controlled trial of oral atenolol in patients with unexplained syncope and positive upright tilt table test results. Am Heart J. 1995;130:1250-1253.http://www.ncbi.nlm.nih.gov/pubmed/7484777?tool=bestpractice.com 一项大型随机对照临床试验 (POST I) 表明,在所有年龄范围的患者中,β受体阻滞剂并未显示出具有显著统计学意义的益处。[75]Sheldon R, Connolly S, Rose S, et al. Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation. 2006;113:1164-1170.http://circ.ahajournals.org/content/113/9/1164.fullhttp://www.ncbi.nlm.nih.gov/pubmed/16505178?tool=bestpractice.com
另外血管收缩剂和静脉收缩剂也可能预防直立不耐受相关性晕厥。 依替福林(肾上腺素)是一种中度的α及β受体激动剂,在迷走血管国际研究 (VASIS) 中表明对预防血管迷走性晕厥无效。[76]Sutton R, Brignole M, Menozzi C, et al. Dual-chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibitory syncope: pacemaker versus no therapy: a multicenter randomized study. The Vasovagal Syncope International Study (VASIS) investigators. Circulation. 2000;102:294-299.http://circ.ahajournals.org/content/102/3/294.fullhttp://www.ncbi.nlm.nih.gov/pubmed/10899092?tool=bestpractice.com 米多君是此类适应症的主要药物。 尽管米多君在体位性低血压患者中进行了最广泛的研究,[77]Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med. 1993;95:38-48.http://www.ncbi.nlm.nih.gov/pubmed/7687093?tool=bestpractice.com 但研究也表明它对血管迷走神经性晕厥有效。[78]Ward CR, Gray JC, Gilroy JJ, et al. Midodrine: a role in the management of neurocardiogenic syncope. Heart. 1998;79:45-49.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1728578/pdf/v079p00045.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/9505918?tool=bestpractice.com[79]Perez-Lugones A, Schweikert R, Pavia S, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J Cardiovasc Electrophysiol. 2001;12:935-938.http://www.ncbi.nlm.nih.gov/pubmed/11513446?tool=bestpractice.com 晕厥预防试验 4 (POST IV) 是一项正在进行的多中心、随机、安慰剂对照试验,评估米多君对复发性晕厥发作的效果。[80]ClinicalTrials.gov. Clinical trial NCT01456481: Assessment of midodrine in the prevention of vasovagal syncope - the Prevention of Syncope Trial IV (POST 4). August 2016. https://clinicaltrials.gov (last accessed 21 April 2017).https://clinicaltrials.gov/ct2/show/NCT01456481?term=NCT01456481&rank=1 另外,有学者提议将哌甲酯用于对米多君不耐受的患者,[81]Grubb BP, Kosinski D, Mouhaffel A, et al. A. The use of methylphenidate in the treatment of refractory neurocardiogenic syncope. Pacing Clin Electrophysiol. 1996;19:836-840.http://www.ncbi.nlm.nih.gov/pubmed/8734752?tool=bestpractice.com 尽管其价值不明。
其他几个药物分类也被提倡使用,但最大价值仍然不明。 其中最重要的为选择性 5-羟色胺再摄取抑制剂 (SSRI)。[82]Grubb BP, Wolfe DA, Samoil D, et al. Usefulness of fluoxetine hydrochloride for prevention of resistant upright tilt induced syncope. Pacing Clin Electrophysiol. 1993;16:458-464.http://www.ncbi.nlm.nih.gov/pubmed/7681197?tool=bestpractice.com 推测在中枢神经系统中 5-羟色胺过敏反应可能会诱发 NMRS;SSRI 预治疗可减少这种异常反应的发生。 但临床试验结果是混合的。
过去还多次提倡使用丙吡胺、纯抗胆碱能(例如东莨菪碱)及茶碱,但有利的证据并不可信。
关于氟氢可的松及米多君对情境性晕厥或颈动脉窦晕厥患者的血容量扩充作用,目前缺乏科学的数据,但可能已用于特定病例。
心脏起搏
心脏起搏可能对治疗伴心动过缓的颈动脉窦综合征有效,防止心动过缓诱发型晕厥。 然而,由于持续存在的血管抑制反应,患者可能仍然存在症状。 起搏对难治性血管迷走性晕厥患者的有效性不确定。 直观认为,可通过起搏预防严重心动过缓(心动抑制性晕厥)。 三项非盲试验表明了起搏的效力,[76]Sutton R, Brignole M, Menozzi C, et al. Dual-chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibitory syncope: pacemaker versus no therapy: a multicenter randomized study. The Vasovagal Syncope International Study (VASIS) investigators. Circulation. 2000;102:294-299.http://circ.ahajournals.org/content/102/3/294.fullhttp://www.ncbi.nlm.nih.gov/pubmed/10899092?tool=bestpractice.com[83]Connolly SJ, Sheldon R, Roberts RS, et al. The North American Vasovagal Pacemaker Study (VPS). A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol. 1999;33:16-20.http://www.ncbi.nlm.nih.gov/pubmed/9935002?tool=bestpractice.com[84]Ammirati F, Colivicchi F, Santini M; Syncope Diagnosis and Treatment Study Investigators. Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope: a multicenter, randomized, controlled trial. Circulation. 2001;104:52-57.http://circ.ahajournals.org/content/104/1/52.fullhttp://www.ncbi.nlm.nih.gov/pubmed/11435337?tool=bestpractice.com 然而,随后 2 项使用起搏器治疗的试验发现,两个治疗组均未显示出获益。[43]Raviele A, Giada F, Menozzi C, et al. A randomized, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. The Vasovagal Syncope and Pacing Trial (SYNPACE). Eur Heart J. 2004;25:1741-1748.http://eurheartj.oxfordjournals.org/content/25/19/1741.fullhttp://www.ncbi.nlm.nih.gov/pubmed/15451153?tool=bestpractice.com[85]Connolly SJ, Sheldon R, Thorpe KE, et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA. 2003;289:2224-2249.http://jama.jamanetwork.com/article.aspx?articleid=196492http://www.ncbi.nlm.nih.gov/pubmed/12734133?tool=bestpractice.com 一项关于难治性血管迷走性晕厥患者(但无其他疾病)的随机交叉研究显示,与常规起搏器相比(CLS 关),双腔闭环刺激(CLS 开)可使晕厥复发率降低。[86]Russo V, Rago A, Papa AA, et al. The effect of dual-chamber closed-loop stimulation on syncope recurrence in healthy patients with tilt-induced vasovagal cardioinhibitory syncope: a prospective, randomised, single-blind, crossover study. Heart. 2013;99:1609-1613.http://www.ncbi.nlm.nih.gov/pubmed/23723446?tool=bestpractice.com 然而,对文献的系统性综述表明,并无充分证据支持起搏器治疗的使用。[60]Jacobus JR, Johannes BR, Catherine NB, et al. Drugs and pacemakers for vasovagal, carotid sinus and situational syncope. Cochrane Database Syst Rev. 2011;(10):CD004194.http://www.ncbi.nlm.nih.gov/pubmed/21975744?tool=bestpractice.com ACC/AHA/HRS 关于晕厥患者的评估和管理指南确实建议,对“年龄在 40 岁及以上、有复发性血管迷走性晕厥且有长时间自发性心脏停博”的一小部分患者,可考虑采用双腔起搏。[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Mar 9 [Epub ahead of print].http://circ.ahajournals.org/content/early/2017/03/09/CIR.0000000000000499http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com