【经验】如何处理PPIs治疗无效的难治性胃食管反流病？

杰斐逊医学院Philip O. Katz MD教授

纽约教会医院Felice Schnoll-Sussman 博士

难治性胃食管反流病是胃肠病学家最常见到的胃食管反流病（GERD）的临床表现。给难治性胃食管反流病下定义很困难，我们认为，每日服用2次质子泵抑制剂（PPIs）治疗4~8周后烧心和/或反流等典型症状仍无改善者，或PPIs治疗12周后食管外或不典型症状经治仍无改善者，即为难治性胃食管反流病。当患者表现为难治性胃食管反流病时，我们应该思考以下问题：这位患者确实是患有胃食管反流病吗？如果是，PPIs治疗对这位患者确实无效吗？如果患者没有胃食管反流病，那么问题在哪里？如果患者确实是难治性胃食管反流病，治疗措施是什么？

为此类患者治疗的第一个步骤是优化PPI治疗方案，确保患者在每日第一餐（大部分情况下是早餐）和晚餐前30分钟服药。不管患者在服用哪一种PPI，只要是难治性GRED，我们都要确保。鉴于目前许多患者服用PPIs是在睡前，按需，或者随着进餐而改变，这一措施将会改善很多患者的症状。我们很少更换患者的PPIs，而是尽量使患者正在服用的PPIs治疗效果达到最好。

下一个步骤取决于患者的临床表现。如果患者主要症状为烧心、反流，我们会为患者做食管胃十二指肠镜检查，来探查是否存在糜烂性食管炎或另一种会导致此种症状的黏膜疾病（如嗜酸细胞性食管炎）的征象。如果食管镜下发现糜烂或Barrett’s食管，那么患者胃食管反流病可以确诊；如果镜下无异常，那么下一步要做的就是反流监测研究。如果通过食管胃十二直肠镜检查诊断为其它疾病，那么我们应该按照该疾病的治疗方式进行恰当的治疗。如果患者表现为不典型或者食管外的症状，并且已经请耳鼻喉、呼吸科或其它相应的专家会诊过，接下来我们就直接做反流监测。

是否进行反流监测取决于我们预测患者患有GERD的概率。如果我们根据病史预测患者患有GRED的概率很低，那么我们将在行食管胃十二指肠镜检查之前停止PPI治疗7天，如果胃镜检查结果正常，就准备放置监测胶囊（Bravo）。这项检查可以持续48小时或者96小时。如果计划监测96小时，那么我们会考虑让患者在第2个48小时内服用PPI。如果我们预测患者患有GERD的概率很高，我们会利用胃内和食管内的pH电极，进行24小时经鼻pH/阻抗监测。这种情况下，我们会寻找食管持续酸暴露，正常食管酸暴露时的食管过敏，或者与阳性症状相关的非酸性反流。胃内电极能够帮助我们定性评估患者PPI治疗对酸的控制情况。中等或差的胃内pH控制合并持续的食管酸暴露提示应改为或者增加抗分泌治疗。如果患者反流监测结果正常，我们会继续检查评估患者的动力异常、反刍综合征、吞气症、胃轻瘫或功能性烧心的情况。

对难治性GERD患者的治疗必须个体化。有以下治疗措施可供选择：巴氯芬，食管下端括约肌射频消融（Stretta procedure），经口无创胃底折叠术（TIF），磁珠括约肌增强技术（Linx），或Nissen胃底折叠术。我们开展了一项用巴氯芬治疗持续性烧心和/或反流的试验。在本实验中，给予患者初始剂量为5毫克的巴氯芬，每日服用3次，如果患者可以耐受，将剂量增加至10毫克，每日3次。如果治疗2到4周后无效，终止治疗。长期服用巴氯芬会有副作用，因此，对于治疗有效的患者，通常我们会考虑外科手术。

我们团队中有一位对Stretta射频消融治疗非常有经验的专家Philip O. Katz，曾经纳入14位患者进行随机对照研究，比较Stretta射频治疗与安慰剂的效果。治疗效果并不令人满意。考虑到这点，我们并不建议患者行Stretta射频治疗。然而随着新的射频发生器的上市，我们开始重新考虑这种治疗措施。据最新数据显示，对难治性反流的患者我们会考虑使用TIF治疗。

我们研究中心（Felice Schnoll-Sussman）初期的研究结果很令人振奋，然而，我们非常小心，纳入了明确诊断为反流并且没有或者只有小的食管裂孔疝的患者。有趣的发现是，我们大部分的数据来自接受经口内镜下肌切开术（POEM）治疗后出现反流的患者。我们的Linx磁珠抗反流技术经验丰富，早期的数据来自经最大剂量PPIs治疗后烧心反流症状仍无改善的患者，这类患者患有轻度（A级或B级）食管炎，食管裂孔疝小于3cm，食管测压结果正常。对于已证实的难治性反酸烧心，我们推荐这种方法及胃底折叠术。我们对患者食管外症状进行个体化治疗。研究经验告诉我们，对于经PPI治疗无效的难治性声音嘶哑（包括其他的耳鼻喉症状），咳嗽等，手术治疗效果差异很大，即使是那些pH监测结果异常的患者。我们巴氯芬治疗的经验比较少，并且目前为止我们还没有用经口无创胃底折叠术（TIF）或者Linx磁珠抗反流手术治疗过食管外症状。胃底折叠术是我们推荐的治疗措施，因此我们仔细观察相关症状，并且需要患者至少对PPIs治疗是部分有效的。我们将和抗分泌治疗联合，在可能的情况下，致力于彻底消除食管酸暴露，并且会向患者详细申明手术治疗并不是完全之策。

Refractory GERD represents the most common clinical presentation of GERD to gastroenterologists. While difficult to define, we consider a patient to have refractory GERD if symptoms persist despite PPI twice daily for 4 to 8 weeks if the patient has typical symptoms (heartburn and/or regurgitation) or 12 weeks if the symptom is extraesophageal (or atypical). When a patient presents with refractory GERD, we ask ourselves the following questions:

Does the patient really have GERD?

If so, is the patient really refractory to PPIs?

If the patient does not have GERD, what is the problem?

If the patient is truly refractory, what are the treatment options?

The first step in approaching these patients is to optimize PPI therapy, being certain patients are taking the dose 30 minutes before the first meal of the day (breakfast in most cases) and before dinner. We do this regardless of which PPI patients are on if they are refractory. As many patients are taking PPIs at bedtime, as needed, or variably related to a meal, this step will result in symptom improvement in many. We rarely switch PPIs, rather optimizing the one the patient is on.

The next step is dependent on presenting symptoms. If the patient has primarily heartburn and/or regurgitation, we will perform an EGD looking for erosive esophagitis or signs of another mucosal disease that may be responsible for symptoms (eg, eosinophilic esophagitis). If the EGD reveals erosions or Barrett’s esophagus, the diagnosis of GERD is assured; if normal, a reflux monitoring study is the next step. If an alternative diagnosis is made at EGD, we will treat this appropriately. If the patient has atypical or extraesophageal symptoms and has been seen by an ENT, pulmonary, or other appropriate specialist, we move directly to reflux monitoring.

The decision to perform reflux monitoring is based on our pretest probability of GERD. If the history suggests a low pretest probability, we will stop the PPI for 7 days prior to the EGD and be prepared to place a telemetry capsule (Bravo) if the EGD is normal. This test can be performed for either 48 or 96 hours. If a 96-hour study is planned, we will consider having the patient take the PPI for the second 48 hours. If our pretest probability of GERD is high, we will perform a 24-hour transnasal pH/impedance study using an intragastric and intraesophageal pH electrode. In these cases, we are looking for continued esophageal acid exposure, esophageal hypersensitivity to normal esophageal acid exposure, or non-acid reflux with a positive symptom association. The intragastric electrode allows us to make a qualitative assessment of acid control by the patient’s PPI. Fair to poor intragastric pH control coupled with continued esophageal acid exposure will result in either a change or increase in antisecretory therapy. If the patient has a normal reflux monitoring study, we continue the workup to evaluate for a motility abnormality, rumination syndrome, aerophagia, gastroparesis, or functional heartburn.

Treatment of the patient with refractory GERD must be individualized. We consider the following options: baclofen, radiofrequency ablation to the lower esophageal sphincter (Stretta procedure), transoral incisionless fundoplication (TIF), magnetic sphincter augmentation (Linx), or Nissen fundoplication. We use baclofen as a therapeutic trial for continued heartburn and/or regurgitation. We start at 5 mg three times daily, advancing to 10 mg three times daily, if it is tolerated. If there is no response in 2 to 4 weeks, there is no reason to continue. Side effects limit long-term use; so, in those who respond, a surgical procedure is usually considered.

One of us (POK) has experience with Stretta, having treated 14 patients in the original randomized trial comparing Stretta with placebo. The patients had a less than satisfactory response. At this point, we do not offer this procedure to our patients. As experience evolves with the new radiofrequency generator on the market, we are open to reconsidering adding this to our treatment options. Based on new data, we will consider TIF in our patients with refractory regurgitation.

Our center’s (FSS’s) initial experience has been encouraging; however, we are very cautious to include only patients with well-documented reflux and no, or small, hiatal hernias. Interestingly, most of our experience to date has actually been in patients who have developed reflux following the POEM procedure. Our initial experience with Linx has been excellent, and early data are compelling for patients with continued heartburn (and regurgitation) despite maximal PPI therapy, provided the patient has minimal (grade A or B) esophagitis, a hiatal hernia <3 cm and normal esophageal manometry. We offer this and fundoplication to our patients with proven refractory heartburn and regurgitation. Our approach to patients with extraesophageal symptoms is highly individualized. Our experience with surgery in patients with PPI-refractory voice disturbance (and other ENT symptoms) as well as cough, has been variable, even in those with abnormal pH monitoring studies. Our experience with baclofen is minimal and underwhelming, and we have yet to send a patient with primarily extraesophageal symptoms for TIF or Linx. As fundoplication is our favored option at this point, we look carefully at symptom association and demand at least a partial response to PPIs. We will be aggressive with antisecretory therapy, looking to eliminate all esophageal acid exposure, if possible, and carefully counsel patients that surgery is not a guarantee.

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