To Investigate the Incidence of Reflux in Patients After Per-oral Endoscopic Myotomy in Achalasia Cardia Patients
Condition: Achalasia Cardia; Gastroesophageal Reflux
MeSH terms: Gastroesophageal Reflux; Esophageal Achalasia
Study type: Observational [Patient Registry]

Summary: 
      Achalasia is a rare motility disorder of the oesophagus that is characterized by aperistalsis
      of the oesophagal body and dysrelaxation of the lower oesophagal sphincter (LES). Current
      treatment is palliative, and the aim of the treatment is to diminish the obstructive function
      of the esophagogastric junction (EGJ). Due to this approach, the most frequent complication
      post-treatment is gastroesophageal reflux (GER). However, not every treated patient develops
      GER symptoms and the mechanism behind the occurrence of GER in treated achalasia are unclear.
      In this study, we aim to Investigate the incidence of reflux in patients after peroral
      endoscopic myotomy in patients with achalasia cardia.
    

Detailed description: 
      1. INTRODUCTION- Achalasia is a rare motility disorder of the oesophagus that is
           characterized by aperistalsis of the oesophagal body and dysrelaxation of the lower
           oesophagal sphincter (LES). Current treatment is palliative, and the aim of the
           treatment is to diminish the obstructive function of the esophagogastric junction (EGJ).
           Due to this approach, the most frequent complication post-treatment is gastroesophageal
           reflux (GER). However, not every treated patient develops GER symptoms and the mechanism
           behind the occurrence of GER in treated achalasia are unclear. In this study, we aim to
           Investigate the incidence of reflux in patients after peroral endoscopic myotomy in
           patients with achalasia cardia.

        2. STUDY OBJECTIVES

           Our hypothesis is those gastroesophageal reflux symptoms in treated patients with
           achalasia are dependent on retention and fermentation of food due to a reduced clearance
           by aperistalsis of the oesophageal body rather than the result of actual acid reflux
           episodes. We expect a difference in gastroesophageal reflux episodes, LES pressure in
           the treated patients with achalasia that experience gastroesophageal reflux symptoms
           compared to the the group that does not encounter gastroesophageal reflux symptoms.

        3. STUDY POPULATION This observational study has a prospective design. Two groups of study
           subjects will be included. Treated patients with achalasia with gastroesophageal reflux
           symptoms and treated patients with achalasia without gastroesophageal reflux symptoms.
           On the baseline, clinical data will be collected regarding medical history, family
           history and medical symptoms related to GER or achalasia.In all the included study
           subjects, several measurements will be done at AIG hospitals, Hyderabad. The duration of
           the study is dependent on the rate of inclusion of the study subjects but, it is
           expected that in 6 months, all study subjects will be included.

        4. DESIGN AND DURATION OF THE STUDY- It will be a prospective observational study for 6
           months.

        5. METHODOLOGY

      5a. SUBJECT RECRUITMENT - Treated patients with idiopathic achalasia visiting the outpatient
      clinic will be asked to participate in the study. Only when a study subject has given
      informed consent, questionnaires concerning demographic and clinical data will be recorded,
      and measurements will be performed.

      5b. RANDOMIZATION AND BLINDING- NO

      5c. STUDY METHODS-

      5d.STUDY PROCEDURE-

      Baseline clinical data will be collected using different questionnaires. The participant will
      be subjected to the GERD Questionnaire to be sure that he or she is allocated to the correct
      study group. For this study, all included study subjects will undergo a few measurements.
      Upper GI endoscopy under conscious sedation will be done, followed by a timed barium
      oesophagogram &. High-resolution manometry will be done. The barium oesophagography is
      performed to gain insight into oesophageal emptying and the width of the oesophagus. After
      peroral endoscopic myotomy has been done, these measurements, including upper GI endoscopy,
      24 hours ambulatory pH and impedance testing, High-resolution oesophageal manometry & Timed
      barium oesophagogram, will be done at 3 months of follow-up.

      5e. Study requirements and timeline

      The measurements will be performed after cessation of PPIs, H2-antagonists and medications
      that can influence intestinal motility for one week. To reduce severe symptoms, patients are
      allowed to take rescue medication in the form of antacids. Furthermore, one day before the
      measurements, the patients will be restricted to a liquid diet to minimize the stasis of food
      in the oesophagus. Study subjects will arrive in the morning at the AIG hospital after an
      overnight fast, with no intake of fluid after midnight except water. If this is not possible,
      the medication should, of course, be ingested before the measurements. Before the first
      measurements, patients must have been fasting for four hours, so also no intake of water. UGI
      endoscopy followed by High-resolution oesophageal manometry later timed barium esophagogram
      will be done.

      The formal investigation for patients with reflux symptoms after one month will be UGI
      endoscopy, High-resolution oesophageal manometry and 24-hour ambulatory pH-impedance
      monitoring. Study subjects go home with the pH-impedance catheter in place and will receive a
      diary to write down their symptoms. During this measurement, the study subject has to drink
      and eat at everyday moments. Still, there is no restriction concerning the food intake,
      except again an overnight fast due to the timed barium oesophagography the next day. The
      following day patients come back to the hospital where the pH-impedance catheter will be
      removed, and a timed barium oesophagography will be performed, which is the last measurement.

      5f. METHODS OF ASSESSMENT-

      A)High-Resolution Manometry (HRM)

      A water-perfused high-resolution manometry assembly with 21 water-perfused sensors spaced at
      1-cm intervals at the position of the esophagogastric junction will be used.

      Each sensor is accurate to within 1mmHg, capable of recording transient pressure changes over
      6000 mmHg/s, and zeroed to atmospheric pressure. The high-resolution manometry assembly will
      be introduced transnasal and positioned to record from hypopharynx to stomach with about five
      intragastric sensors. Data are analyzed using Solar high-resolution manometry software
      (Medical Measurement Systems, Enschede, The Netherlands).

      B) pH- impedance monitoring

      A pH-impedance catheter will be introduced transnasally. A 2.1-mm outer diameter study
      catheter comprised of six electrode pairs measuring intraluminal impedance at 3, 5, 7, 9, 15
      and 17 cm above the LES and an ISFET pH sensor, placed 5 cm above the LES will be used.
      Before and after recording the pH electrode will be calibrated using standard buffers of pH
      seven and pH 1. The catheter will be positioned in such a way that the pH sensor is located 5
      cm above the LES, which is based on manometry readings.

      C) Analysis of the data of the HRM and pH-impedance monitoring

      For analysis of the data obtained with HRM and pH-impedance measurement, MMS software
      (Enschede, The Netherlands) Will be used.The HRM will give insight into the esophageal
      function. It provides information on the contractile activity of the oesophagal body and the
      esophagogastric junction, including the LES. Therefore it helps distinguish transient LES
      relaxation (TLESRs), which occurs in GERD, from pseudo relaxation of the LES by shortening
      the oesophagal body. pH impedance monitoring provides information on oesophagal bolus
      transit. GER is characterized by TLESRs and a retrograde moving decrease in impedance with an
      abrupt drop in pH levels followed by normalization of the impedance and pH. In the case of
      fermentation, there is a slight and longer decrease in impedance and pH. The pH-impedance
      monitoring will also record all reflux episodes, both acid as non-acid, during the 24-hours
      measurement. During the analysis of the data of the pH-impedance monitoring, reflux symptoms
      will be correlated with acid and non-acid reflux episodes. A positive correlation is declared
      if a specific reflux symptom is preceded by a reflux episode within two minutes. The analysis
      will be done manually for all the patients as the risk of false-positive is more with the
      automated analysis. Oesophageal acidification patterns observed during pH-impedance
      monitoring.

        1. Acid reflux with average clearance: rapid pH drop to below 4, drop rate ≥one pH unit per
           second, lasting between 10 s and 5 min.

        2. Acid reflux with delayed clearance: rapid pH drop to below 4, drop rate≥one pH unit per
           second, lasting longer than 5 min.

        3. Acid fermentation: slow pH drop to below 4, drop rate <1 pH unit per minute, prevailing
           longer than 5 min most specific for achalasia cardia. Automated analysis can count these
           refluxes as false positive and can misdiagnose fermentation as reflux after POEM.

        4. Stasis of recently ingested acidic food or drink: pH drops to below four during
           meal/drink, pH below 4 persisting longer than 5 min after meal/drink.

        5. Unclassified: pH drop below 4, not meeting criteria for any of the acid patterns
           described above.

      D) Timed barium esophagram

      A maximal tolerable amount of low-density barium sulphate must be ingested by the study
      subjects in 30-45 s without regurgitation or aspiration. After ingestion of low-density
      barium sulphate, oesophageal stasis will be determined at 1, 2 and 5 minutes with the study
      subject upright in a slight left posterior position. The distance from the tapered distal
      oesophagus to the top of the barium column and the maximal diameter of the oesophagus is
      measured.

      E) Questionnaires

        -  Eckardt score, which is the sum of symptom scores for dysphagia, regurgitation, chest
           pain, and weight loss. Each symptom is scored from 0 to 3. The minimum score is 0, and
           the maximum score is 12. Pre and post values will be recorded.

        -  The validated Achalasia Disease-Specific Quality-of-Life questionnaire (Achalasia-
           DSQoL). Pre and post POEM values will be recorded.

        -  The validated Gastroesophageal Reflux Disease Questionnaire (GERDQ) is a self-assessment
           questionnaire that can be used for the diagnosis and follow-up of gastroesophageal
           reflux disease. It measures both symptoms and the impact of symptoms on a person's daily
           life.

           5g. STOPPING OR DISCONTINUATION CRITERIA- NOT APPLICABLE

           6. OUTCOME MEASURES Three-month post peroral endoscopic myotomy

           7. SAMPLE SIZE CALCULATION- Sample size- 50 patients Expected outcomes - 18- 28 per cent
           is likely to be symptomatic post POEM surgery, and true reflux incidence maybe around 5-
           10 per cent. Considering incidence for GERD population from south India, around 8 per
           cent sample size will be about 50, with the study's power as 80 per cent, with 95 per
           cent confidence interval and 5 per cent margin of error.

           8. STATISTICAL ANALYSIS- Data will be expressed as median and percentile values (5th,
           25th, 75th and 95th percentiles). Depending on the normality of distribution, we will
           use either paired Student's t-test or Mann-Whitney U test for paired comparison.
           Likewise, we will use a one-way analysis of variance with Tukey test or Kruskal-Wallis,
           followed by Dunn's test as appropriate. The upper limit of normal will be defined as the
           95th percentile of expected values. For PSPW index and MNBI thresholds, we will use the
           5th and 25th percentile values. P≤0.05 will be considered statistically significant.

           9. ETHICAL JUSTIFICATION OF THE STUDY All patients of Achalasia patients who undergo
           palliative treatment in the form of peroral endoscopic measurement will be tested after
           the procedure at 3 months. It will give us insight into the true incidence of GERD and
           also will determine their therapy based on the phenotype they fit in.
    

Intervention name(s): Peroral endoscopic myotomy
Intervention type(s): Procedure
Intervention description(s): Peroral endoscopic myotomy involves an initial incision on the internal lining of the oesophagus. This permits entry of the endoscope to within the wall of the oesophagus, where the muscle will be exposed. The inner layer of the muscle near the lower oesophagal sphincter will be cut (this is termed myotomy). At the conclusion of the procedure, the oesophagal incision will be closed with standard endoscopic clips.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Treated achalasia patients with and without gastroesophageal reflux symptoms visiting the
        outpatient clinic of the Gastroenterology Department.
      
Keywords: Achalasia cardia; Peroral endoscopic myotomy; Gastroesophageal Reflux; oesophageal pH study; oesophageal acidification; High resolution manometry