Why didn’t patient with documented reflux get better with PPI?

There are numerous problems with pH studies; many of these problems have been alluded to in previous blog entries (see below).  Another problem is that these studies are not highly predictive of response to therapy (Gut 2012; 61: 501-506).

This French study from three centers examined 100 consecutive patients (58 females) with an average age of 50 years.  All patients had reflux symptoms, namely regurgitation and/or heartburn.  PPI dosage was not standardized and reflux symptoms were quantified with recall questionnaires.

The authors note that up to 40% of patients with reflux symptoms have inadequate symptom relief with a 4-week course of single dose proton pump inhibitor (PPI) therapy; the aim of their study was to investigate which factors on pH probe-impedance (pH-MII) would predict a response to therapy.

Definition: Nonresponders were patients who had more than 2 days of mild symptoms per week while receiving a standard or double dose of PPI treatment for 4 weeks

Results:

  • No reflux pattern on pH-MII was associated with a response to PPIs. Table 2 in the study looked at multiple factors including SI, SAP, time for acid exposure, and number of reflux events.
  • Lower BMI (≤ 25 kg/m-squared), non-erosive reflux, and normal pH study were associated with poor PPI response
  • Other factors associated with poor PPI response: female gender, irritable bowel syndrome (IBS), and functional dyspepsia.
  • Response rates: 58% of individuals with BMI >25, 71% with esophagitis, 23% with functional dyspepsia, 30% with IBS
  • Among responders, 77% were receiving a single dose PPI

Some of the poor response may be related to the study population.  Only 35% had abnormal acid exposure.  In total, 67% were determined to have abnormal pH studies, though this was due to a large fraction having a positive symptom-reflux association analysis.

However, this study population likely reflects a typical clinical group of patients diagnosed with GERD and demonstrates some of the shortcomings of pH-MII in clinical practice.  Even patients with abnormal pH-MII studies, the presence of functional dyspepsia and IBS were strongly associated with PPI failure.

Previous related blog entries:

HEROES trial

Impedance recommendations from PIG

Gastroesophageal Reflux: I know it when I see it

Treating reflux does not help asthma

Unexplained chest pain

Impedance recommendations from PIG

The ESPGHAN Pediatric Impedance Group (PIG) has published a review/consensus statement on the use of pH-Impedance monitoring (MII-pH) in children (JPGN 2012; 55: 230-34).

Conclusions from this group:

  • MII-pH provides more information than conventional pH probe.  Whether this information will “inform prognosis, or predict response to therapy in pediatric patients has yet to be determined”
  • ‘As long as there is no effective medical therapy for weakly acid and nonacid reflux, the clinical relevance of MII-pH remains debatable’
  • “There are no data on the results of antireflux surgery based solely on the detection of weakly acid and nonacid reflux”
  • MII-pH is investigational technique needing standardization before routine diagnostic use can be recommended.
  • Major indications: need to identify weakly acid and nonacid reflux, persisting symptoms during antireflux treatment, use in identifying rumination syndrome, and research
  • Limitations of MII-pH: high cost, limited contribution to change in medical care, lack of evidence-based parameters for assessment of GER

Related blog entries:

Gastroesophageal Reflux: I know it when I see it

Treating reflux does not help asthma

The Medical Pendulum and Gastroesophageal Reflux

Treatment for rumination and belching

Treatment options for rumination and for belching are limited.  Baclofen improves symptoms and decreases events in both of these disorders (Clin Gastroenterol Hepatol 2012; 10: 379-84).

Rumination is characterized by effortless regurgitation of recently ingested food into the mouth (or beyond). It is easily mistaken for vomiting disorders and motility disturbances.  With rumination, patients have retrograde flow of gastric contents into the esophagus through voluntary, though unintentional, abdominal muscle contractions with increased intragastric pressure increases.

Supragastric belching occurs when air is sucked into the esophagus by decreasing the intrathoracic pressure or by contracting pharyngeal muscles.

Baclofen is an agonist of the γ-aminobutyric acid B (GABA) receptor which results in increased lower esophageal sphincter (LES) pressures and reduced swallowing rates. Baclofen has been shown to improve reflux, mainly by reducing transient LES relaxations (TLESRs) but also by increasing basal LES pressures.

In the majority of patients, the mainstay of treatment has been behavioral which use diaphragmatic breathing to compete/extinguish these behaviors.  There are a shortage of therapists familiar with this approach.  As such, alternative treatments are needed.  In this study, high-resolution manometry-impendance recordings were taken from 16 patients (10 women; mean age 43 years; range 18-89 years); eight of the patients had rumination.  Only 12 patients were included in the final analysis; four patients refused repeat manometry.  Manometry was performed before and after treatment along with recording symptoms.  Both symptoms and manometry recordings improved with Baclofen therapy.  This was a one-week open-label study.  Baclofen was dosed at 10 mg TID.  At baseline the total number of “flow events” was 473; after treatment, this was reduced to 282 events.  In total, rumination events decreased by 68% during treatment.   This improvement correlated with increased LES pressures.

Four of the 12 patients reported mild side effects mainly sleepiness and difficulty concentrating.

Additional references:

  • -Clin Gastroenterol & Hep 2007; 5:772. Review. Supragastric belching usually due to aerophagia and is very frequen (up to 20/hr)t. GERD related belching is less infrequent, has sour taste, usually less loud & after meals. Gum chewing, excessive beverage drinks, rapid eating or drinking,  smoking or using straw for drinking may increase air in the stomach and lead to burping which can be behavioural problem as well.
  • -“Behavioral Treatment of Chronic Belching Due to Aerophagia in a  Normal Adult” Behav Modif 2006; 30; 341
  • -JPGN 2011; 52: 414. Mgt of severe rumination @ Columbus Ohio. n=5. Definitive dx established with AD manometry with typical r-wave pattern (when regurgitates after a meal)
  • -JPGN 2010; 50: 103. Rumination occurring in NL intelligent adolescents. May start with regurgitation and progress to inability to swallow saliva.
  • -Clin Gastro & Hep 2006; 4: 1314. Review of management of rumination/case presentation
  • -Chitkara et al: Teaching diaphragmatic breathing for rumination syndrome. Am J Gastroenterol. 2006 Nov;101(11):2449-52. Review. Can use behavioral interventions such as deep breathing exercises/ diaphragmatic breathing to break the spasms..
  • -Gastroenterology 2006; 130: 1527-28. Review and criteria of rumination.
  • -Pediatrics 2003; 111: 158-62. Review of rumination dx, Rx, & prognosis.
  • -Clin Persp in Gastro 2000; 3 (5): 277.

Additional Baclofen references:

  • -J Pediatr 2006; 149: 436, 468. Baclofen reduces GER. 0.5mg/kg/day
  • -JPGN 2004; 38: 317. Effectiveness of baclofen in neurologically-impaired children w GER. (0.7/kg/day), n=8.
  • -Gastroenterology 2000; 118: 7-13. Use of baclofen to reduce TLESR.
  • -Aliment Pharm Ther 2003; 17: 243-51. Baclofen reduced GER (acid & nonacid). side effects -N, V, dizzy. dose: in adults, start at 5mg tid, increase c 5mg increments every 4th day to 10-20mg tid.

Gastroesophageal Reflux: I know it when I see it

      According to Wikipedia, Justice Potter Stewart, in Jacobellis v. Ohio 378 U.S. 184 (1964) stated the following: I shall not today attempt further to define the kinds of material I understand to be embraced within that shorthand description [“hard-core pornography”]; and perhaps I could never succeed in intelligibly doing so. But I know it when I see it, and the motion picture involved in this case is not that. [Emphasis added.]
     To some extent, ‘I know it when I see it’ has been the mantra about identifying gastroesophageal reflux for advocates for pH-impedance (pH-MII).  Enthusiasts have claimed that pH-MII is vastly superior to pH studies alone for many reasons including the ability to detect more GER episodes than conventional pH studies.  Yet, a major flaw has been a paucity of normative data.  To determine whether there is interobserver and intraobserver agreement in the interpretation of pH-MII, seven expert world groups collaborated on a study to analyze ten pediatric 24-hour tracings (J Pediatr 2012; 160: 441-6).
     Five of these studies were considered easy and five were more challenging due to less obvious features like low baselines, retrograde patterns during swallowing, and moving/crying artifacts.   Among 1242 liquid and mixed GER events, 490 (42%) were scored by the majority of observers.  The authors claim that this is “moderate agreement.”  The automated analysis (AA), not surprisingly, had much better agreement than manual analysis.   With AA there was 94% sensitivity rate and 74% specificity. When looking at AA alone, AA missed 6.5% of events scored by observer consensus and  30% of GER episodes recorded with AA were not detected by majority consensus.
     When looking at each pH-MII recording (Figure 2), there was poor agreement on whether the study was pathologic.  Only five of the studies had uniform agreement that the number of episodes (>73 GER episodes) were either pathologic or not. Those with agreement were all negative studies.  The authors conclude, though, that there was “substantial” agreement based on a mean kappa value of 0.70.
     A comparison to a previous pH-MII publication (Scand J Gastro 2011; 46: 271-6) notes that in this previous study, 83% of pH-MII recordings had a concordant symptom association probability despite underdetection of GER episodes with AA; it was recommended to use ‘AA when the symptom association was positive.  If symptom association was negative, they suggested manual analysis.’
    The conclusions from the current study:
  • ‘In theory, AA is favored over manual analysis due to reproducibility’
  • AA does not seem specific enough to ensure correct marking of GER episodes in infants and children yet
  • Consensus to refine AA needs to be reached …to retain confidence …in impedance

If this is the best that worldwide experts can do with this widespread technology, what does that mean for clinicians in practice?

Additional references:

Recent related posts:

The Medical Pendulum and Gastroesophageal Reflux

Unexplained chest pain

  • -Journal of Gastroenterology and Hepatology 2010;25:817-22. Has some normative pH-MII data.  ‘Can acid (pH) refluxes predict multichannel intraluminal impedance refluxes? A correlation study.’
  • -JPGN 2010; 50: 25. Reflux detected by Impedance does NOT determine fundoplication outcome. n=34.
  • -JPGN 2010; 52: 129. Review. No normative data. Using SAP>95% to correlate symptoms (better than SI or SSI). Main use is to study intractable pts to establish if nonacid reflux is contributing to symptoms.
  • -J Pediatr 2010; 157: 878 (“death of pH probe”), 949. Use of impedance in children. n=225. (70 were discarded). Notes lack of therapeutic possibilities for non-acid reflux.  Symptom index is + if >50%, SAP if >95%. Symptom index is number of symptoms with reflux episode divided by total number of symptom occurrences. SAP, symptom association probability, is a statistical tool that uses 2-minute windows throughout recording to correlate symptom and reflux event.  pH probe 2nd metal for infant -place 2cm above LES.  pH probe 3rd metal for child -place 3cm above LES
  • -Clin Gastro & Hep 2009; 7: 743. n=39 adults. Non-acid reflux events in patients on therapy correlated with acid reflux parameters when patients studied off therapy. Abnormal impedance parameters: total number of reflux events >63 (avg normal was 28). This study relied on # of reflux events more than SAP or SI. SAP or SI is problematic in patients who lack clinical response to PPIs.
  • -Gastroenterology 2009; 136 (suppl 1): S1896. n=143. #of events (not SI or SAP) is then most conservative estimate as well as the one with the highest likelihood of encompassing other symptom assoication parameters.
  • -J Pediatr 2009; 154: 248. n=50. a high # with normal pH had symptom correlation w GER events. (initial cohort was 80 –30 excluded due to problems with study or insufficient symptoms) SAP is superior for correlating symptoms.
  • -Clin Gastro & Hep 2008; 6: 840. Impedance is best tool -D Castell.; -Clin Gastro & Hep 2008; 6: 880.
  • -Clin Gastro & Hep 2008; 6: 482, 521. ‘Impedance/pH is best tool’. Pts who respond to PPIs likely due so due to its effect on chemostimulation; those who continue with symptoms may do so based on mechanostimulation -related to volumes in esophagus not due to acidity.
  • -J Pediatr 2006; 149: 216. Equal frequency of acid and non-acid reflux in 24 pts with asthma. No correlation identified with resp symptoms.
  • -Clin Gastro & Hep 2006; 4: 167. Impedance does not add to pH probe in UNTREATED patients.
  • -JPGN 2002; 34: 511, 519.
  • -Pediatrics 2006; 118: e299, 793. Impedance data in preterm infants. Asymptomatic and affected infants with similar impedance values and both have reflux to upper esophagus.