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Keywords:

  • electrical impedance;
  • gastro-oesophageal reflux;
  • oesophagus;
  • pH monitoring;
  • symptoms

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ambulatory reflux monitoring
  5. Impedance monitoring: principles
  6. Measurement of acid and weakly acidic reflux
  7. Paediatric patients
  8. Atypical reflux symptoms
  9. Practical application
  10. Conclusions
  11. References

Abstract  Impedance monitoring is a new technique that can be used to detect the flow of fluids and gas through hollow viscera. With impedance monitoring gastro-oesophageal reflux can be detected independent of its acidity by differences in electrical impedance between the mucosal surface, fluids and gas that surround the catheter. Clinically, it is used in combination with oesophageal pH monitoring, and the combination of impedance-pH monitoring allows recognition of both acidic and weakly acidic reflux episodes. Studies have shown that impedance-pH monitoring is useful in the evaluation of patients with proton pump inhibitor-resistant typical reflux symptoms, as it provides a higher yield in detecting reflux as the cause of a patient’s symptoms compared to pH monitoring alone. It is therefore likely that impedance-pH monitoring will largely replace pH monitoring in the next 5 years and it will become the standard for reflux detection.


Abbreviations:
GORD

gastro-oesophageal reflux disease

SI

symptom index

SAP

symptom association probability

PPI

proton pump inhibitor

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ambulatory reflux monitoring
  5. Impedance monitoring: principles
  6. Measurement of acid and weakly acidic reflux
  7. Paediatric patients
  8. Atypical reflux symptoms
  9. Practical application
  10. Conclusions
  11. References

Measurement of gastro-oesophageal reflux has proven its use in both clinical practice and research. It is currently a widely used technique for evaluation of patients with symptoms that are suggestive of gastro-oesophageal reflux disease (GORD). Furthermore, studies using reflux monitoring have significantly contributed to our understanding of GORD pathophysiology. In the last decade, new evidence supported the replacement of pH monitoring by combined pH-impedance monitoring. In this review, we will focus on the available evidence on the use of impedance monitoring in clinical practice.

Ambulatory reflux monitoring

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ambulatory reflux monitoring
  5. Impedance monitoring: principles
  6. Measurement of acid and weakly acidic reflux
  7. Paediatric patients
  8. Atypical reflux symptoms
  9. Practical application
  10. Conclusions
  11. References

Over the last 30 years, ambulatory measurement of gastro-oesophageal reflux has become a commonly used technique for the evaluation of patients with symptoms suggestive of GORD. Ambulatory reflux monitoring was based on the measurement of intra-oesophageal acidity using a catheter with pH-sensitive electrode placed in the oesophagus. With pH monitoring, reflux is defined as a drop in pH below 4. The number of reflux episodes as well as the acid exposure time (% time with pH < 4) are expressed and considered to be important parameters that are helpful in diagnosing GORD and predicting the success of antireflux therapy. Furthermore, the acid exposure time is positively correlated to the degree of mucosal damage.

Another aspect of ambulatory reflux monitoring is the possibility to correlate the onset of reflux episodes to the symptoms that occurred during the measurement.1 The temporal relationship between symptoms and reflux episodes is usually expressed using the symptom index (SI) or symptom association probability (SAP). A positive SI and/or SAP indicate a high probability that the observed relationship between reflux and symptoms did not occur by chance and thus suggests causality.

Besides the widespread clinical application, acid exposure time measured with pH monitoring is often used as hard endpoint in clinical studies with new drugs and surgical therapies.

Reflux detection with pH monitoring is thus useful but it is also cheap, widely available and reliable. Furthermore, pH monitoring is accurate and reproducible. A practical disadvantage is the discomfort that is brought about by the fact that it is a catheter-based technique. Introduction through a nostril is uncomfortable and often induces retching, besides this a continuous presence of the catheter is felt during the measurement, which sometimes results in a decrease in daily activity and meal consumption during the 24-h measurement.

The most important limitation is the fact that with pH monitoring only acid reflux episodes (pH < 4) can be measured, while it was clear from acid perfusion studies that less acidic substances with a pH of 5 or 6 can also induce the typical sensation of heartburn.2 Furthermore, it was realized that during acid suppressive therapy with PPI’s, the majority of reflux episodes would probably be non-acid, and therefore not detectable with pH monitoring.

In 1991, impedance monitoring was introduced as a new technique to detect flow of fluids and gas through hollow viscera.3 Firstly, it was regarded a potential helpful tool for the evaluation of oesophageal transit but soon its value for reflux detection was also recognized.4,5 It has now become apparent that impedance monitoring offers new opportunities in the field of gastro-oesophageal reflux monitoring. In the next paragraphs, we will go further into the technical details and clinical applications of this emerging new technique.

Impedance monitoring: principles

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ambulatory reflux monitoring
  5. Impedance monitoring: principles
  6. Measurement of acid and weakly acidic reflux
  7. Paediatric patients
  8. Atypical reflux symptoms
  9. Practical application
  10. Conclusions
  11. References

In electrical impedance monitoring, the resistance to electrical flow in an alternating current circuit is measured. In oesophageal impedance monitoring, an alternating current circuit is generated between two ring electrodes separated by a non-conductive catheter. Impedance is inversely related to the conductivity of the medium between the two electrodes. The conductivity of fluids such as saline or gastric juice is high and impedance is low when these substances form the medium. The conductivity of air is almost infinitively low and thus a high impedance is measured when the medium consists of air. When the oesophagus is empty the catheter is in contact with the collapsed luminal walls, resulting in an intermediate impedance level. Placement of a series of electrodes along the catheter makes is possible to evaluate the direction and velocity in which the gaseous or liquid medium is transported through the oesophagus. Thus with oesophageal impedance monitoring, the nature and movement of a substance in the oesophageal lumen can be detected. Gastro-oesophageal reflux thus appears as a liquid (and sometimes also gaseous) bolus moving from the stomach in proximal direction and is detected independent of its acidity.

Measurement of acid and weakly acidic reflux

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ambulatory reflux monitoring
  5. Impedance monitoring: principles
  6. Measurement of acid and weakly acidic reflux
  7. Paediatric patients
  8. Atypical reflux symptoms
  9. Practical application
  10. Conclusions
  11. References

As mentioned, oesophageal impedance monitoring identifies reflux episodes and makes it possible to detect the nature (liquid, gas or mixed liquid-gas) and proximal extent of reflux episodes (Fig. 1). Combined with pH monitoring, one can determine whether a reflux episode is acid (nadir pH < 4), or non-acid (nadir pH > 4). Non-acid reflux is often further separated into weakly acidic (nadir pH 4–7) and weakly alkaline reflux (nadir pH > 7).6

image

Figure 1.  Pure liquid weakly acidic reflux episode (panel A) and acid reflux episode consisting of both a gaseous and liquid component (panel B). The arrows indicate the direction of the refluxate.

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Impedance-pH monitoring can be regarded as an improvement of pH monitoring alone and the indications for which pH monitoring is used are similar for combined pH-impedance monitoring. The total number of reflux episodes (acid and non-acid) can be counted as well as the acid exposure time. Reflux monitoring with impedance measurements is as reproducible as pH monitoring and normal values for non-acid reflux episodes have been reported.7–10 It is now regarded as the most sensitive method for reflux detection.11,12 However, it is questionable whether knowing if a patients has ‘excessive’ non-acid reflux is of any value. Indeed, the number of acid reflux episodes and the acid exposure time are correlated to the degree of mucosal damage and are predictors of response to therapy, but this has not been established for non-acid reflux episodes. As it is uncertain whether ‘excessive’ non-acid reflux can cause damage to the oesophagus or whether it selects patients who will benefit from therapy, not much is expected from comparison to normal values. More is to be expected from investigating the temporal relationship between the onset of symptoms and the occurrence of reflux episodes.

The concept of changes in reflux patterns induced by PPI therapy and the potential value of impedance monitoring was illustrated by a study in which pH-impedance studies were carried out in 12 GORD patients off therapy and repeated while these patients were on omeprazole 20 mg twice daily.13 While PPI therapy induced a large decrease in number of acid reflux episodes, the total number of reflux episodes was similar due to an increase in non-acid reflux episodes. Inhibition of acid secretion thus does not result in a decrease in reflux episodes, only a shift in acidity of the reflux episodes is obtained. Symptoms during the study were produced by both acid and non-acid reflux. Heartburn and acid taste were most often related to acid reflux, but were also related to non-acid reflux and the occurrence of regurgitation was not reduced at all during acid-suppressive therapy.

Sifrim et al. showed that, in ambulatory subjects off PPI-therapy, approximately two-thirds of the reflux episodes are acidic and one-third is weakly acidic (Fig. 2).14,15 On PPI, approximately 90% of all reflux episodes is weakly acidic and <10% of the reflux episodes is acidic.16,17 Weakly alkaline reflux is very rare and usually consists only 1% of the total number of reflux episodes.

image

Figure 2.  Distribution of the occurrence of acid, weakly acidic and weakly alkaline reflux episodes off and on proton pump inhibiting (PPI) therapy. The total number of reflux episodes is not affected by the therapy, only the acidity of the reflux episodes.

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A large multi-centre study in which 24-h pH-impedance monitoring on PPI was carried out in 168 patients with PPI-resistant symptoms showed that from the 144 patients who had symptoms during the measurement, 16 patients (11%) had a positive SI for acid reflux and 53 (37%) had a positive SI for non-acid reflux. Thus, reflux could be identified as the cause of symptoms in 69 patients (48%) based on the pH-impedance data compared to 16 patients based on pH-metry alone.16 These data suggest that combined pH-impedance monitoring makes it possible to identify more patients in whom reflux is the cause of their symptoms under PPI therapy compared to pH-metry alone.

A study in which impedance-pH monitoring was performed in 48 patients after cessation of PPI therapy showed that combined pH-impedance identified reflux as the cause of their symptoms in 37 (77%) of the patients while pH monitoring alone identified reflux as the cause of their symptoms in 32 (67%) patients.18 Combined pH-impedance monitoring is thus also slightly better than pH monitoring alone in patients off PPI. Also, this study shows that symptom association analysis performed separately for acidic and weakly acidic reflux does not result in a higher yield than symptom association analysis for all reflux episodes pooled, independent of pH.

Thus, on PPI, the majority of reflux episodes is weakly acidic and these weakly acidic reflux episodes are responsible for the majority of reflux symptoms while off PPI the majority of reflux episodes is acidic, causing the majority of symptoms.17,19 The question now remains is whether impedance-pH monitoring should be performed ‘on’ or ‘off’ PPI. With pH monitoring, patients with persistent symptoms under PPI-therapy were almost without exception measured after cessation of their antisecretory therapy for at least 7 days. With impedance-pH monitoring, the option of continuation of acid inhibitory therapy exists. Advantage of performing pH-impedance monitoring on PPI is that it allows investigating whether acid-secretion is indeed adequately suppressed or whether there is potential inefficiency of the drug or a lack of compliance. The advantages of performing the measurement off PPI are already mentioned: the native oesophageal acid exposure correlates to the degree of mucosal damage and is a predictor for success of surgery.

Recently, we tried to provide a definite answer to the question whether to measure on or off PPI by studying 30 patients with GORD twice, once with and once without PPI therapy.20 More patients reported reflux symptoms during the measurement off PPI. Symptom association analysis identified 15 and 11 patients with a positive SAP in the measurement off and on PPI respectively. Eight of the 19 patients who had no symptoms or a negative SAP during measurement on PPI had a positive SAP off PPI therapy. In contrast, only four patients with a positive SAP on PPI were missed in the measurement off PPI therapy. The results suggest that a slightly higher yield is obtained by studying patients after cessation of their PPI. The most optimal approach would probably be to perform both a measurement on and one off PPI, but patients will probably not tolerate this.

Besides impedance-pH monitoring for refractory GORD, we reported the use of impedance monitoring as an aid in detection of the cause of reflux symptoms in a patient with achlorhydria due to an autoimmune atrophic gastritis.21 It revealed that no acid reflux episodes occurred in this patient and that her symptoms resulted from weakly acidic reflux.

As described, impedance monitoring can show that a patient’s symptoms are indeed due to weakly acidic reflux episodes. As acid can sensitize the oesophagus to subsequent reflux episodes, for treatment it seems logical, at least from a theoretical point of view, to ensure maximal acid suppression with a high dose of PPI. If this is not helpful, what is next? There are currently no acceptable drugs that effectively reduce the number of reflux episodes. Baclofen reduces the number of acid and weakly acidic reflux episodes by inhibiting the rate of transient lower oesophageal sphincter relaxations but unfavourable side effects make this drug unpopular as a therapy for GORD.22 Targeting visceral hyperalgaesia seems reasonable, for example, by adding a low dose of a cyclic antidepressant. The therapy that results in the most effective reduction in non-acid reflux is antireflux surgery, with a reduction of over 90% of all acid and weakly acidic reflux episodes.23,24 Indeed, patients with symptoms due to non-acid reflux, reflected by a positive SI for non-acid reflux, responded well to antireflux surgery.25 However, the operation also reduces gas reflux, which can result in the sensation of an inability to belch and severe symptoms of bloating and abdominal discomfort.

Paediatric patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ambulatory reflux monitoring
  5. Impedance monitoring: principles
  6. Measurement of acid and weakly acidic reflux
  7. Paediatric patients
  8. Atypical reflux symptoms
  9. Practical application
  10. Conclusions
  11. References

As infants receive frequent milk feeds, and because milk is a potent buffer of gastric acidity, weakly acidic reflux is expected to occur frequently in infants. Indeed oesophageal impedance is feasible and detects more reflux than pH recording alone in paediatric patients.26–28 However, detection of more reflux does not necessarily mean that the child’s symptoms result from these reflux episodes.29 Data suggesting that impedance does offer a clear-cut benefit in paediatric clinical practice are missing. Furthermore, due to ethical difficulties, there are no normal values for weakly acidic reflux episodes in these patients. Because the difficulty of establishing a relationship between symptoms and non-acid reflux in children and infants, the uncertain relationship between oesophageal damage and non-acid reflux and no effect of the study results on treatment, we think impedance monitoring has currently no place in routine paediatric practice.

Atypical reflux symptoms

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ambulatory reflux monitoring
  5. Impedance monitoring: principles
  6. Measurement of acid and weakly acidic reflux
  7. Paediatric patients
  8. Atypical reflux symptoms
  9. Practical application
  10. Conclusions
  11. References

Symptoms such as pain in the throat, astmatiform spells, hoarseness and globus sensation are sometimes called supra-oesophageal reflux symptoms or atypical reflux symptoms, with the assumption that these are the result of gastro-oesophago-pharyngeal reflux. Furthermore, laryngeal erythema, erosions and nodules are often attributed to reflux disease while it has been shown that it is impossible to distinguish reflux-related lesions from lesions that are induced by other causes.30 Indeed, it is possible that gastro-oesophago-laryngeal reflux can damage laryngeal and pharyngeal structures, but it is almost impossible to establish reflux as the causative factor in an individual patient. As mentioned, visual inspection cannot provide a definite answer and reflux monitoring, either with pH or impedance monitoring, is not helpful either. Pathological oesophageal acid exposure and/or a high number of proximal acid or non-acid reflux episodes are not related to acid exposure above the upper oesophageal sphincter and are not indicative for supra-oesophageal reflux disease.31 Although it has been suggested that non-acid reflux episodes can be measured with an impedance catheter in the pharynx, the value of this technique has yet to be clarified.32–34

In case of cough, this is different. Various studies with pH monitoring have shown that a subset of patients indeed has a temporal relationship between acid reflux episodes and cough.35,36 Cough can also be induced by weakly acidic reflux and it has been shown that impedance-pH monitoring has a higher yield in identifying patients with cough due to reflux compared to pH monitoring alone.37,38 Recently, it has been reported that patients with weakly acidic reflux-induced coughing responded favourably to anti-reflux surgery.39,39

Practical application

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ambulatory reflux monitoring
  5. Impedance monitoring: principles
  6. Measurement of acid and weakly acidic reflux
  7. Paediatric patients
  8. Atypical reflux symptoms
  9. Practical application
  10. Conclusions
  11. References

As clinical studies have shown that impedance-pH monitoring is indeed the most optimal way to study gastro-oesophageal reflux, the technique is also ready for widespread clinical use and advised by professional guidelines.40 Impedance-pH reflux monitoring systems are commercially available and offered by several providers, but still significantly more expensive than pH monitoring systems. A system usually consists of portable datalogger, catheters and a workstation on which the data can be stored and analysed. A careful instruction of the patients is most important, and we let them consume three meals and two snacks with beverage at fixed times during the 24-h measurement. Nature and onset of symptoms have to be noted in a symptom diary. Most systems are delivered with software for automatic analysis of the measurement, but the quality varies and we advise to go through the measurement manually as well.41,42

As mentioned above, if the aim of the study is to confirm or exclude GORD as the cause of a patients symptoms, the optimal approach would be to perform a measurement after cessation of PPI’s for at least 7 days. If the aim of the study is to investigate whether a patient’s symptoms are due to incomplete acid suppression, the best way would be to perform a study while the PPI is continued.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ambulatory reflux monitoring
  5. Impedance monitoring: principles
  6. Measurement of acid and weakly acidic reflux
  7. Paediatric patients
  8. Atypical reflux symptoms
  9. Practical application
  10. Conclusions
  11. References

The combination of pH and impedance monitoring can be used to detect acidic and weakly acidic reflux. Hard evidence suggests the usefulness of this new technique in clinical practice and it becomes more and more widespread in motility laboratories of academic and non-academic hospitals. It is likely that impedance-pH monitoring will largely replace pH monitoring in the next 5 years and it will become the standard for reflux detection.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ambulatory reflux monitoring
  5. Impedance monitoring: principles
  6. Measurement of acid and weakly acidic reflux
  7. Paediatric patients
  8. Atypical reflux symptoms
  9. Practical application
  10. Conclusions
  11. References
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