修回日期: 2013-06-04
接受日期: 2013-07-15
在线出版日期: 2013-09-08
重度胃轻瘫是对常规治疗胃轻瘫药物无效、需进行营养支持以及频繁需要急诊住院治疗的难治性胃轻瘫. 对于重度胃轻瘫治疗方式选择一直是临床医师所面临的难题, 国内外也少见对重度胃轻瘫治疗的文献报道, 本文通过查阅国内外有限的相关重度胃轻瘫治疗文献, 系统阐述了基础治疗、药物治疗以及其他方式治疗重度胃轻瘫的研究进展, 并对重度胃轻瘫治疗方式的研究方向进行了展望.
核心提示: 胃电刺激、手术治疗以及内镜下注射肉毒菌素是目前治疗重度胃轻瘫的主要选择方式, 中医中药治疗重度胃轻瘫往往有意想不到的疗效, 积极开展相关研究工作是寻找治疗重度胃轻瘫新的治疗方式的一项重要选择.
引文著录: 李君玲, 仝小林, 逄冰, 田佳星, 周强, 李敏. 重度胃轻瘫治疗方式的研究进展. 世界华人消化杂志 2013; 21(25): 2537-2543
Revised: June 4, 2013
Accepted: July 15, 2013
Published online: September 8, 2013
Severe gastroparesis is a kind of gastroparesis that is refractory to conventional drug therapy and requires nutritional support and frequently emergency hospitalization. The selection of treatment for severe gastroparesis has always been a dilemma for clinicians. Currently, there have been limited reports on the treatment of severe gastroparesis. This article sums up the primary treatments, drug treatments and other kinds of treatments for severe gastroparesis and discusses the prospects for the treatment of this refractory disease.
- Citation: Li JL, Tong XL, Pang B, Tian JX, Zhou Q, Li M. Treatments for severe gastroparesis. Shijie Huaren Xiaohua Zazhi 2013; 21(25): 2537-2543
- URL: https://www.wjgnet.com/1009-3079/full/v21/i25/2537.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i25.2537
胃轻瘫是一种排除机械性梗阻、以固体胃排空延迟为主要特点的症状群[1], 临床主要表现为恶心、呕吐、早饱以及餐后饱胀等. 特发性胃轻瘫、糖尿病、帕金森氏病、胶原血管病等都是引发胃轻瘫的重要原因[2]. 目前对胃轻瘫的药物治疗主要是促胃动力药物的使用, 如红霉素、胃复安、多潘立酮以及西沙比利等, 疗效证实尚可[3]. 然而, 在胃轻瘫患者当中还存在很多重度胃轻瘫患者, 主要表现为对这些常规治疗药物的无效性, 需进行营养支持以及频繁的急诊住院治疗[4]. 作为重度胃轻瘫的主要临床表现, 频繁的恶心呕吐[5]往往可导致患者电解质紊乱、脱水等, 同时降低工作、生活能力, 给社会和家庭带来沉重的负担[6,7], 对于糖尿病重度胃轻瘫患者来说, 频繁恶心呕吐更使血糖难于控制, 极容易发生危险状况[8,9]. 然而对于重度胃轻瘫患者的治疗方式一直是临床学者所面临的难题, 目前为止, 国内外亦少见相关文献报道, 因此本文查阅国内外有限的重度胃轻瘫相关文献报道, 并对各学者的研究成果作一综述, 以期对临床有所帮助.
对于胃轻瘫患者的饮食建议往往是少食、多餐、低脂低纤维等. 而对于难治性症状反复发作入院、影响正常的营养和药物吸收的重度胃轻瘫患者来说, 营养支持往往是必要的[10]. 目前主要的营养支持包括肠内营养和全胃肠外营养. 肠内营养相对于全胃肠外营养来说具有价格低廉、较少有感染并发症的优势, 通过肠内营养能够为患者提供足够的营养物质以及药物治疗, 并且当患者可以经口服摄入足够的营养物质时, 内镜下的置管可以很容易取出. Schlüter等[11]报道, 一例经胃动力药久治无效、几乎不能进食的糖尿病重度胃轻瘫患者, 安放一根永久性鼻-十二指肠管予以管饲, 患者的营养状态明显好转. 相对于肠内营养来说, 全胃肠外营养很少是胃轻瘫患者所必要的, 除非是肠内营养失败或者小肠、结肠都出现了功能失调, 而一旦实行全胃肠外营养支持, 则必须对患者进行密切的临床和实验室检测以防止代谢紊乱.
对于胃轻瘫患者尤其是糖尿病胃轻瘫患者来说, 控制血糖是至关重要的. 有资料证明高血糖本身具有破坏胃排空的作用[12]. 另一方面, 高血糖也可能降低胃对促胃动力药物如红霉素的作用, 有报道高血糖(>15 mmol/L)可以通过减弱红霉素对胃窦运动的动力作用从而降低红霉素促胃动力作用的效果[13,14], 因此对于每一个胃轻瘫的患者来说, 控制血糖都是一种至关重要的基础治疗方式. 同时, 应注意对于糖尿病胃轻瘫患者, 一些影响胃排空的降糖药物也应停用, 如降糖药物二甲双胍、阿卡波糖等均有胃肠道反应, 而醋酸普兰林肽、胰高血糖样肽-1(glucagon like peptide-1, GLP-1)本身就有延缓胃排空的作用.
多巴胺受体拮抗剂如胃复安、多潘立酮等, 5-羟色胺(5-hydroxytryptamine, 5-HT)受体激动剂如西沙比利等是目前治疗胃轻瘫的常规治疗药物, 同时新的相关药物也正在不断研制, 如舒必利、伊托必利等, 均被许多实验证实具有治疗胃轻瘫的前景[15-17], 然而对于治疗重度胃轻瘫, 目前只有以下少数几种有过临床报道.
大环内酯类红霉素是一种强大的促胃动力药, 在一项由Sturm等[18]对目前常用的促胃动力口服药物(D2受体阻滞剂、西沙必利、红霉素)的系统分析中, 红霉素被认为是对于改善胃排空的最有效的治疗药物. 同时在一项单中心回顾性研究中, DiBaise等[19]发现静脉点滴红霉素治疗14例重度胃轻瘫患者, 仅有1例无效, 其余皆有明显效果. 但是红霉素属于抗生素, 具有快速耐受性, 长期的口服治疗具有局限性. 因此寻找一种具有促胃动力作用而又不具有抗菌性能的红霉素类似物亟待解决. ABT-229是第一种被用于临床实验的胃动素受体激动剂, 遗憾的是, 该实验证实与安慰剂组相比, ABT-229并没有缓解具有胃排空延迟的功能性消化不良患者的临床症状[20-22]. GM-611是由中外制药(Chugai Pharma)实验室发现的一种由红霉素衍生而来的胃动素受体激动剂, 在一项多中心、随机、双盲、安慰剂对照的糖尿病胃轻瘫研究中, McCallum等[23]发现GM-611的10 mg, bid用量对于缓解消化系症状有明显效果, 然而对于这些新生药物治疗重度胃轻瘫的效果仍然有待研究.
胃促生长素(ghrelin)是一种主要由胃黏膜组织产生的生长激素促分泌素受体(growth hormone secretagogue receptor, GHSR)的内源性配体, 参与调节胃肠道动力[24,25]. 已经证实, 在特发性胃轻瘫以及糖尿病胃轻瘫的患者中, 合理使用胃促生长素具有显著的促进胃排空作用[26-28]. 然而, 外源性的胃促生长素具有较短的半衰期[29], 因此限制了用于临床治疗的潜力. TZP-101是一种对人类胃促生长素受体具有很强亲和力的选择性胃促生长素受体激动剂[30], 有研究对23例具有严重恶心呕吐的重度胃轻瘫患者输注不同剂量的TZP-101进行治疗, 通过GCSI进行胃轻瘫疗效评价, 证实TZP-101能够显著改善重度胃轻瘫患者的临床症状, 预测TZP-101将成为治疗重度胃轻瘫非常有潜力的药物[31].
目前越来越多的学者发现心理因素与胃轻瘫疾病之间的重要相关性, 而国外的一些运用抗抑郁药治疗重度胃轻瘫的医案报道也使我们在寻找治疗重度胃轻瘫方式之路上眼前一亮.
3.3.1 米氮平: 米氮平是一种具有去甲肾上腺素作用的抗抑郁药, 他同时具有特异性阻滞5-HT3受体的作用, 因此临床中常用于治疗由癌症放疗后、胃旁路手术后等引起的恶心呕吐的治疗[32-35]. Kim等[36]首先报道了一例对红霉素、胃复安、多潘立酮甚至于幽门注射A型肉毒毒素无效的患者, 在接受米氮平治疗后, 恶心呕吐症状迅速好转的病例, 为临床治疗重度胃轻瘫患者提供了光明的前景.
3.3.2 阿瑞吡坦: 阿瑞吡坦是一种神经激肽-1(neurokinin-1, NK-1)受体拮抗药(即P物质拮抗剂), 该物质通过与大脑中NK-1受体结合, 对该受体进行拮抗, 从而治疗由P物质介导的疾患, 如抑郁症、呕吐等. 在一些由化疗引起的恶心呕吐症状中, 该药物被证实具有较高的有效性并被广泛推荐使用[37,38]. Chong等[39]首次报道以80 mg, qd的阿瑞吡坦治疗疗1例对静脉注射以及口服胃促动力药等治疗方式无效的呕吐剧烈的糖尿病重度胃轻瘫患者, 在使用第1次的24 h内即停止了呕吐, 并且在使用4 mo中均未发生呕吐症状. 该报道的出现为治疗重度胃轻瘫指出了一种新的治疗方式, 不过值得指出的是有报道称[40], 阿瑞吡坦在对正常人的肠道动力方面并没有显示明显的作用, 同时有报道称阿瑞吡坦在治疗化疗后引起的恶心呕吐症状过程中可能会引起一些轻微的不良反应, 如打嗝、疲劳、肝功升高、便秘、头痛以及食欲下降.
在寻找重度胃轻瘫的治疗方法中, 胃电起搏治疗是目前临床研究中最为广泛使用的治疗方式. 早在在20世纪70年代初期, 人们就发现胃肠肌电活动与收缩活动之间的密切关系[41,42], Kelly和La Force[43]运用犬模型证实胃电刺激可以引发引起胃平滑肌的顺行和逆行传导的慢波活动. Familoni等[44]则首次对1例糖尿病重度胃轻瘫的患者进行了为期超过1年的胃电刺激治疗, 在缓解恶心呕吐症状上取得了巨大疗效, 该结果为以后胃电刺激治疗的研究奠定了基础. 2000年, 一种高频、低能量的胃电刺激装置(enterra system)被美国食品与药品管理局(FDA)同意作为具有难治性恶心、呕吐症状的胃轻瘫患者的治疗方式[45]. 大量临床实验研究从胃排空检查、临床症状、患者生活质量、体质量变化、摄取营养方式等各方面变化证实胃电起搏治疗对于治疗重度胃轻瘫的广阔前景[46-50]. 然而, 目前为止, 对于胃电起搏治疗胃轻瘫的机制并不明确, 最为广泛的解释是胃电刺激对中枢神经系统的影响[51-53]. 同时由于胃电刺激属于侵入性治疗方法, 感染成为接受该治疗方式的胃轻瘫患者尤其是糖尿病胃轻瘫患者的主要风险[54,55]. 在Chu等[50]的系统评价报告中, 胃电刺激引起的不良反应, 感染占3.87%, 设备迁移占2.69%, 植入部位疼痛占0.67%. 因此对于进行胃电起搏治疗应谨慎从事, 临时的胃电刺激可以检测患者是否适合进行该项治疗[56]. 此外, 根据胃起搏点的电活动可被外加电流刺激所驱动原理设计的体外胃电起搏为临床提供了一种新的治疗手段[57].
胃窦运动减弱以及由于幽门功能障碍引起的胃出口阻力增加是胃轻瘫患者的一种重要的生理性紊乱[58-60]. 肉毒菌素A是一种胆碱能神经肌肉传递抑制剂, 通过局部注射, 可以治疗包括平滑肌和横纹肌在内的肌肉痉挛性疾病[61]. 肉毒毒素A通过不可逆的干扰乙酰胆碱释放而抑制胆碱能神经递质[62]. 目前, 临床中经常通过在食管下括约肌中注射肉毒毒素A来治疗贲门失弛缓症, 疗效较好[63]. 同时许多临床研究中也证实将其注射于消化道的其他部位也是十分安全的. 许多研究通过在幽门括约肌处注射A型肉毒菌素治疗胃轻瘫[64,65]. 有学者采用内镜下注射肉毒杆菌毒素降低幽门张力以增加胃排空, 改善DGP的症状[10]. Bromer等[66]更是直接对接受肉毒菌素治疗的63例重度胃轻瘫患者进行了一项回顾性研究. 结果显示43%的患者对于肉毒菌素的治疗是有效果的, 同时男性患者与治疗效果具有相关性, 遗憾的是, 呕吐作为重度胃轻瘫的主要症状缓解并不明显.
目前为止, 对于顽固性胃轻瘫患者多考虑外科手术治疗方法, 常用的手术方法主要有幽门成形术、幽门口扩张术、胃大部切除、胃造口等[67]. 对于其疗效还是可以肯定的, Watkins等[68]观察了伴顽固性呕吐的18例DGP患者, 发现全胃或次全胃切除术可以明显缓解严重胃轻瘫导致的难治性呕吐, 有6例患者术后呕吐立刻缓解, 随访6年无1例复发, 生活质量显著提高, 然而值得注意的是, 手术治疗需要经过严格的病例选择并且具有术后感染、营养不良以及肾功能不全的危险, 这就局限了手术治疗的使用范围.
中医学是祖国传统医学宝库, 具有辨证论治、整体治疗及相对廉价、非侵入性等优点, 从中医药中寻找治疗重度胃轻瘫的方法具有广阔前景. 然而目前为止国内尚未有对重度胃轻瘫临床疗效的文献研究, 仅散见对个案治疗的报道, 疗效显著. 周强等[69]报道仝小林教授以附子理中汤为主方加减治疗1例呕吐剧烈、西药治疗5月余无效的糖尿病患者, 6剂吐止, 半月体质量增加1 kg. 魏玉玲等[70]报道以枳术丸加减治疗1例使用止吐药腹泻加重, 使用止泻药而呕吐甚的"食入即吐"同时伴腹泻症状的糖尿病胃轻瘫患者, 症状均有改善. 黄颖秋[71]总结认为许多中药具有促胃动力、胃肠动力及双向调节胃肠动力的作用, 此为中医治疗胃轻瘫的作用基础, 然而中医的辨证论治的治疗思路却是取得整体疗效的根本, 值得学者们进行深入的探究.
目前对于重度胃轻瘫治疗方式较为局限, 胃电刺激、手术治疗以及内镜下注射肉毒菌素是目前治疗重度胃轻瘫的主要选择方式, 然而亦多有感染、营养不良等手术不良反应, 深入探究重度胃轻瘫的发生机制并以此为出发点研发新的治疗方式具有重要意义. 值得注意的是, 中医中药治疗重度胃轻瘫往往有意想不到的疗效, 且具有廉价、无明显不良反应的优势, 遗憾的是目前为止国内外尚未有较为完善的中医药治疗重度胃轻瘫的临床报道及研究工作, 积极开展相关研究工作将是寻找治疗重度胃轻瘫新的治疗方式的一项重要选择.
重度胃轻瘫是对常规治疗胃轻瘫药物无效、需进行营养支持以及频繁需要急诊住院治疗的难治性胃轻瘫. 目前对于重度胃轻瘫的治疗方式是临床医师所面临的难题, 通过查阅国内外相关重度胃轻瘫治疗文献, 对目前国内外治疗重度胃轻瘫的方式做一综述对于临床医师治疗重度胃轻瘫具有重要参考意义.
陆伦根, 教授, 上海交通大学附属第一人民医院消化科
胃电刺激、手术治疗以及内镜下注射肉毒菌素是目前治疗重度胃轻瘫的主要选择方式, 中医中药治疗重度胃轻瘫往往有意想不到的疗效, 积极开展相关研究工作是寻找治疗重度胃轻瘫新的治疗方式的一项重要选择.
2000年, 一种高频、低能量的胃电刺激装置被美国食品与药品管理局(FDA)同意作为具有难治性恶心、呕吐症状的胃轻瘫患者的治疗方式.
本文对国内外散见的治疗重度胃轻瘫的文献报道进行了归纳总结评论.
本文为临床医师治疗重度胃轻瘫提供了一定的参考依据.
本文系统阐述了基础治疗、药物治疗以及其他方式治疗重度胃轻瘫的研究进展, 并对重度胃轻瘫治疗方式的研究方向进行了展望.
编辑: 田滢 电编: 鲁亚静
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