Several reasons may be responsible for the failure of drugs as antireflux therapy (Table 2). Probably the by far most important factor is inadequate inhibition of acid secretion. This may be due to administration of H2-recptor antagonists which do not produce sufficient acid suppression to control reflux symptoms and achieve healing of peptic lesion. Furthermore, also standard doses of PPI are not effective either in about 10-20% of subjects. Thus as a logical consequence PPI should be administered as first line treatment, and in case of insufficient responses at standard doses, PPI doses should be doubled (given b.i.d.). In symptomatic reflux reflux disease, lack of compliance is a relatively rare phenomena since interruption of therapy leads to reoccurrence of symptoms. Some patient still will not show adequate responses even to doubled or tripled doses, a scenario more frequently observed in NERD than in ERD patients.
Table 2. Factors which may play a role for therapeutic failure of medical therapy in gastro-oesophageal reflux disease
• insufficient acid inhibition o ineffective drug (e.g., H2-blockers instead of PPI) o inadequate dosing (PPI dose to low)
• wrong diagnosis (e.g., functional disease instead of reflux disease)
• predominant biliary reflux (after gastric surgery) PPI = proton pump inhibitors
In oesophagitis patients one always assumes that lesions found at endoscopy will also be responsible for a symptom profile which suggests reflux disease; however, detection of minor lesions is not an infrequent observation in patients undergoing endoscopy for other reasons (e.g., work-up for diarrhoea). Thus, there is a population with asymptomatic reflux oesophagitis which has not been characterized well enough until now. It can be speculated that such patients may have upper abdominal or retro-sternal symptoms for other reasons, but thought to be related to ERD; under these circumstances PPI therapy even at higher doses might fail. Another reason for PPI failure may occur in patients after gastric surgery which by itself resulted in profound reduction of acid secretion; in such patients a predominant biliary but only little acid reflux may be the underlying mechanism for generating oesophageal lesions and/ or symptoms but which will not well respond to acid inhibitory therapy. In general however, unresponsiveness to individually tailored PPI therapy is a minor problem in ERD .
Failure to PPI in NERD is a much greater problem. It is well established that demonstration of pathological reflux by pH-metry is associated with much better results of acid suppression thus demonstrating that proven exaggerated acid reflux will be also - analogous to ERD - a predictor for treatment success. In patients with symptoms suggestive of GERD but a reflux
pattern quantitatively within the normal range, the suggested diagnosis is functional heartburn . It is unclear so far whether episodes with heartburn are induced by minute episodes of acid reflux or whether other mechanisms apply (e.g., motor events). Therefore, it is also unproven that acid suppression will benefit those patients. In studies with combined intra-oesophageal impedance and pH monitoring (which allows separate analysis of acid, non-acid, and air regurgitation) it has been shown that in patients with GERD the number of acid reflux episodes can be well reduced by PPI treatment but non-acid reflux persists to the same extent. This observation may explain why some patients report no change in symptoms under the conditions of acid suppression although they well respond to therapy in terms of acidic reflux because they link non-acid reflux to treatment failure. These patients will subsequently not benefit from dose escalation either. Furthermore, many patients with aerophagia and air eructation will often be referred to specialists under the diagnosis of refractory reflux disease after they had (expectedly) not responded to PPI treatment; these patients will not gain any benefit from acid suppressants and have otherwise to be regarded as a demanding population in general. One important rule should be obeyed: transfer of NERD patients refractory to high PPI doses to antireflux surgery should be avoided since functional diseases do not respond to operative procedures but this will lead to an even more complex symptomatology (surgeons should only be involved if a
pathophysiological condition can be unequivocally identified which can be corrected by surgery).
Finally, there is some overlap in patients with GERD and those who otherwise would be assumed to have non-cardiac chest pain (NCCP). A subgroup will also improve when given PPI (which suggests that acid reflux may play a central role) but a significant portion will not (e.g., with motor disorders of the oesophagus) but may subsequently respond to tricyclic antidepressants. Since symptoms are sometimes indistinguishable between reflux disease and NCCP, some patients with refractory retrosternal symptoms may belong to the group of NCCP patients.
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