Simple measures

Simple measures can be helpful for the management of patients who experience mild symptoms. These include antacids, avoiding precipitating factors, e.g. spicy foods and alcohol, weight loss (when appropriate), avoiding cigarette smoking, modification of the timing and quantity of meals (e.g. not going to bed with a full stomach), and raising the bed head. Unfortunately, these measures are rarely effective for patients with moderate to severe disease, and most patients who present for surgery cannot be adequately treated with these measures.

H₂-receptor antagonists

When first used in the 1970s, histamine type 2 (H₂)-receptor antagonists, which reduce the production of gastric acid, revolutionised the medical approach to duodenal ulcer disease. However, they were less effective for reflux disease and although they sometimes relieve mild to moderate reflux symptoms, few patients achieve complete relief of symptoms.⁹ With the current widespread availability of proton-pump inhibitors, H₂-receptor antagonists are now rarely used as first-line medical therapy.

Proton-pump inhibitors

Proton-pump inhibitors (omeprazole, lanzoprazole, pantoprazole, rabeprazole and esomeprazole) were introduced into clinical practice in the late 1980s.⁷ Proton-pump inhibitors are much more effective at symptom relief and achieve better healing of oesophagitis than H₂-receptor antagonists. However, in patients with severe oesophagitis (Savary Miller grade 2/3) there is a high treatment failure rate,¹⁰ and many patients who initially achieve good symptom control develop ‘breakthrough’ symptoms at a later date, requiring an increased dose of medication to maintain symptom control. Failure may be due to inadequate acid suppression, although in some cases bile or duodenal refluxate may play a role. In patients who respond well to proton-pump inhibitors, symptoms usually recur rapidly (sometimes in less than 24 hours) following cessation of medication, and for this reason lifelong medical treatment is likely to be required.⁷ The long-term use of proton-pump inhibitors appears generally safe. One study has shown, however, that long-term use can be associated with the development of atrophic gastritis with intestinal metaplasia in patients with concurrent Helicobacter pylori infection.¹¹ Long-term use can also be associated with parietal cell hyperplasia.¹² This latter phenomenon may be the reason why symptoms recur rapidly in some patients on cessation of therapy, and may be another reason why some patients require escalating dosages of proton-pump inhibitors to control their symptoms.

Prokinetic agents

Cisapride is the only prokinetic agent that has been shown to be better than placebo for the treatment of reflux.¹³ It acts by improving acid clearance from the distal oesophagus by accelerating gastric emptying. Its therapeutic benefit is similar to that of the H₂-receptor antagonists. Hence, its clinical role has been limited since proton-pump inhibitors became widely available. An incidence of cardiac arrhythmias in the 1990s led to its withdrawal in most parts of the world.

Selection criteria for surgery

As a general rule, all patients who undergo antireflux surgery should have objective evidence of reflux. This may be the demonstration of erosive oesophagitis on endoscopy or an abnormal amount of acid reflux demonstrated by 24-hour pH monitoring. Neither of these tests is sufficiently reliable to base all preoperative decisions on their outcome,¹⁴ as a number of patients with troublesome reflux will have either a normal 24-hour pH study or no evidence of oesophagitis at endoscopy (and, very occasionally, both). For this reason the tests have to be interpreted in the light of the patient’s clinical presentation, and a final recommendation for surgery must be based on all available clinical and objective information.¹⁴ More recently, impedance monitoring (in combination with pH monitoring) has been used to measure ‘volume’ reflux, although the additional information obtained from this investigation appears unlikely to influence surgical decision-making.¹⁵

Patients selected for surgery fall into two groups: (1) patients who have failed to respond (or have responded only partially) to medical therapy; (2) patients whose symptoms are fully controlled by medications, but who do not wish to continue with medication throughout their lives. The first group represents the large majority of patients. The latter group are more likely to be younger patients who face decades of acid suppression to alleviate their symptoms. In the first group, the response to surgery is usually more certain if the patient has had a good response to acid suppression in the past, or at least has had some symptom relief from medication. In patients who have had no response to proton-pump inhibitors, particularly those presenting with atypical symptoms, their symptoms are often due to something other than reflux, despite concurrent objective evidence of reflux (which may be incidental and/or asymptomatic). Such patients will usually not benefit from antireflux surgery.

Failure of medical treatment can be defined as continuing symptoms of reflux while on an adequate dose of acid suppression. In most countries this means at least a standard dose of a proton-pump inhibitor for a minimum period of 3 months. Proton-pump inhibitors are more effective for the control of the symptom of heartburn than volume regurgitation, and it is the latter symptom that is often the dominant problem in patients who have failed on medical therapy.

Patients can be further subdivided into: (i) those with complicated reflux disease; and (ii) those who have straightforward disease without complications.

Medical versus surgical therapy

The issue of the most appropriate treatment for gastro-oesophageal reflux disease has long been a subject of disagreement between surgeons and gastroenterologists. However, most would agree that a single management strategy is unlikely to be appropriate for all patients. Equally, there is a need for better comparative data for medical versus surgical therapy. Eight randomised trials^19,27–39 have been reported that have investigated this issue, but five of these were completed or commenced before the availability of both laparoscopic antireflux surgery and proton-pump inhibitor medication. All of these trials recruited patients who had reflux symptoms that were well controlled by medical therapy. In the latter trials this entailed complete symptom control with a proton-pump inhibitor at trial commencement, thereby excluding patients with uncontrolled symptoms. Hence, the majority of patients who are currently selected for surgery were excluded from the surgical arms of these trials, i.e. patients with a poor response to a proton-pump inhibitor.

In 1992, Spechler²⁸ reported a trial of 247 patients (predominantly men) randomised to either continuous medical therapy with an H₂ blocker, medical therapy for symptoms only or an open Nissen fundoplication. Overall patient satisfaction was highest following surgery at 1 and 2 years follow-up. However, neither the surgical nor medical treatment investigated is now considered optimal. The longer-term outcomes from this study were published in 2001, with median follow-up of approximately 7 years and with proton-pump inhibitors now used for the medically treated patients.⁴⁰ Follow-up was not complete and only 37 (45%) surgical patients were available for late follow-up, with 23% of the original surgical group lost to follow-up, and 32% died during follow-up. The later results did, however, show reasonable outcomes in both the medically and surgically treated groups. However, 62% of the surgical patients consumed antireflux medications at late follow-up, although when these medications were ceased in both study groups the surgical group had significantly fewer reflux symptoms than the medical group, suggesting that most of the surgical patients did not actually need the medications!

In 2003, Parrilla et al.²⁹ reported a randomised trial that randomised 101 patients with Barrett’s oesophagus. Medical therapy was initially an H₂ blocker and later a proton-pump inhibitor. A satisfactory clinical outcome was achieved at 5 years follow-up in 91% of each group, although medical treatment was associated with a poorer endoscopic outcome. Progression to dysplasia was similar in both groups.

In 2000, Lundell et al.^30,31,39 reported a trial of proton-pump inhibitor medication versus open antireflux surgery. Three hundred and ten patients were randomised, and antireflux surgery achieved a better outcome at up to 3 years follow-up. Later reports of 7 years follow-up in 228 patients, and 12 years follow-up in 124, confirmed that surgery still achieved better reflux control than medication, although dysphagia and various wind-related side-effects were more common after fundoplication.^39,41

Rhodes et al. reported the first randomised trial to compare proton-pump inhibitor medication with laparoscopic Nissen fundoplication; 217 patients were enrolled. Surgery was followed by less oesophageal acid exposure 3 months after treatment and better symptom control at 12 months.^32,33,42 A similar study by Anvari et al. enrolled 104 patients into a trial of proton-pump inhibitor therapy versus laparoscopic Nissen fundoplication.^34–36 Follow-up at 12 months and 3 years demonstrated better control of reflux and better quality of life in the patients who underwent surgery.

In 2009, Lundell et al.³⁷ reported the outcomes for a further multicentre randomised trial of laparoscopic Nissen fundoplication versus esomeprazole proton-pump inhibitor therapy (20–40 mg per day). This trial, which was funded by the pharmaceutical company that provided the medical therapy, enrolled 554 patients and outcomes at up to 3 years have been reported. Similar success rates of approximately 90% were reported for each treatment.

Pros and cons of antireflux surgery

Preoperative investigations

Apart from the assessment of each patient’s general suitability for surgery by determining comorbidities, some specific investigations should be performed before undertaking antireflux surgery.

Antireflux surgery

To the non-surgeon, it might seem that there is a bewildering array of operations available for the treatment of reflux. In fact, the fundoplication introduced by Rudolf Nissen in 1956, or some variant of it, remains overwhelmingly the most popular antireflux operation in the world today. The principles of fundoplication are to mobilise the lower oesophagus, wrap the fundus of the stomach, either partially or totally, around the oesophagus, and then stabilise this new anatomy long term. When the oesophageal hiatus is enlarged, it is narrowed by sutures to prevent paraoesophageal herniation postoperatively and also to prevent the wrap being pulled up into the chest. Complications of reflux such as fibrotic stricturing with shortened oesophagus are seen rarely compared to the past. In the circumstance of true oesophageal shortening, an oesophageal lengthening (Collis) procedure can be undertaken to provide a long enough oesophagus to reach the abdomen. The upper lesser curvature of the stomach is used to produce the new oesophagus and the stomach is then wrapped around this. However, in our experience the Collis procedure is now not indicated or required during primary antireflux surgery.

Complete or partial fundoplication?

Because fundoplication is associated with an incidence of postoperative dysphagia, gas bloat and other gas-related symptoms such as increased flatulence, the relative merits of the Nissen fundoplication procedure versus various partial fundoplication variants have been debated for many years. The introduction of laparoscopic approaches only served to heighten this controversy. On the one hand, the Nissen procedure produces an overcompetent gastro-oesophageal junction, which is the cause of some of the problems with dysphagia and gas bloat. On the other hand, it has been suggested that partial fundoplications reduce the risk of over-competence, but perhaps at the expense of a less durable antireflux repair.

Many prospective randomised trials of Nissen versus a partial fundoplication have been performed. DeMeester et al.⁸⁴ had the distinction of reporting the first randomised study in the field of surgery for reflux disease in 1974. Their trial randomised 45 patients to undergo either a Nissen, Hill or Belsey procedure, and they followed up their patients for 6 months after surgery. The dysphagia and recurrent reflux rates were similar for all three procedures. However, the number of patients was too small to allow a meaningful comparison to be made.

Division/no division of short gastric vessels

Until the 1990s the issue of division versus non-division of the short gastric vessels was rarely discussed. However, following anecdotal reports of increased problems with postoperative dysphagia following laparoscopic Nissen fundoplication without division of the short gastric vessels,^104,105 this aspect of surgical technique became a much debated topic. Routine division of the short gastric vessels during fundoplication, to achieve full fundal mobilisation and thereby ensure a loose fundoplication, is thought by some to be an essential step during laparoscopic (and open) Nissen fundoplication.⁶² This opinion was popularised by the publication of studies that compared experience with division of the short gastric vessels with historical experience with a Nissen fundoplication performed without dividing these vessels.^{62,64,104,105} However, other uncontrolled studies of Nissen fundoplication either with or without division of the short gastric vessels confuse the issue further, as good results have been reported whether these vessels were divided or not.^62,65

Six randomised trials have been reported that investigate this aspect of technique. Luostarinen et al.^106,107 reported the outcome of a small trial of division versus no division of the short gastric vessels during open total fundoplication. Fifty patients were entered into this trial and a later report¹⁰⁷ described outcomes following median 3-year follow-up. Both procedures effectively corrected endoscopic oesophagitis. However, there was a trend towards a higher incidence of disruption of the fundoplication (5 vs. 2) and reflux symptoms (6 vs. 1) in patients whose short gastric vessels were divided, and 9 of 26 patients who underwent vessel division developed a postoperative sliding hiatus hernia, compared to only 1 of 24 patients whose vessels were kept intact. The likelihood of long-term dysphagia or gas-related symptoms was not influenced by mobilising the gastric fundus in this trial.

In 1997 we reported a randomised trial that enrolled 102 patients undergoing a laparoscopic Nissen fundoplication to have a procedure either with or without division of the short gastric vessels.⁵ No difference in overall outcome was demonstrated at initial follow-up of 6 months and the trial failed to show that dividing the short gastric vessels during laparoscopic Nissen fundoplication reduced the incidence or severity of early postoperative dysphagia, or the outcome of any objective investigations. At 5 and 10 years follow-up,^108,109 both procedures were equally durable in terms of reflux control and the incidence of postoperative dysphagia. At 5 years follow-up division of the short gastric vessels was associated, with more flatulence and bloating, and greater difficulties with belching.

Blomqvist et al.^110,111 reported the outcome of a similar trial that enrolled 99 patients. At 12 months and 10 years follow-up, this study also showed that dividing the short gastric vessels did not improve the outcome. A recent meta-analysis of larger data with 12 years follow-up, generated by combining the raw Adelaide and Swedish data, confirmed equivalent reflux control, but more bloating after division of the short gastric vessels.¹¹²

Farah et al.,¹¹³ Kösek et al.¹¹⁴ and Chrysos et al.¹¹⁵ all reported trials that showed equivalent reflux control and postoperative dysphagia irrespective of whether the short gastric vessels were divided or not. However, as with the Adelaide and Swedish data, they also demonstrated an increased incidence of bloating symptoms after division of the short gastric vessels.

Laparoscopic versus open antireflux surgery

Non-randomised comparisons between open and laparoscopic fundoplication generally showed that laparoscopic surgery required more operating time than the equivalent open surgical procedure,^122,123 that the incidence of postoperative complications was reduced, the length of postoperative hospital stay was shortened by 3–7 days, patients returned to full physical function 6–27 days quicker, and overall hospital costs were reduced. The efficacy of reflux control appeared to be similar between the two approaches. Ten randomised controlled trials have been reported that compare a laparoscopic fundoplication with its open surgical equivalent.^124–138 Nine of these investigated a Nissen fundoplication and one study compared laparoscopic versus open posterior partial fundoplication.¹³² The early reports that described follow-up extending up to 12 months confirmed advantages for the laparoscopic approach, albeit less dramatic than the advantages expected from the results of non-randomised studies. More recently, longer-term outcomes from some studies have been reported.^{133,135,137,139,140}

Early reports from smaller trials125–127 that each enrolled 20–42 patients demonstrated equivalent short-term clinical outcomes, shortening of the postoperative stay by about 1 day (3 vs. 4 median), longer operating times (extended by approximately 30 minutes), and an overall reduction in the incidence of postoperative complications following laparoscopic Nissen fundoplication. The reduction in the length of the postoperative hospital stay by only 1 day was unexpected. This was achieved entirely by a shorter hospital stay following open fundoplication, suggesting that at least some of the apparent benefits of the laparoscopic approach have been due to a general change in management policy to encourage earlier oral intake, avoiding nasogastric tubes and encouraging earlier discharge from hospital.

Chrysos et al.¹²⁸ reported 12 months follow-up for a trial that enrolled 106 patients. Both approaches achieved effective reflux control, post-fundoplication dysphagia was similar, and the laparoscopic approach was followed by fewer complications, a quicker recovery and fewer symptoms of epigastric bloating and distension. Similar 12-month postoperative outcomes were demonstrated by Ackroyd et al.¹³⁸ in a trial that enrolled 99 patients.

Håkanson et al.¹³² enrolled 192 patients into a trial of laparoscopic versus open posterior partial fundoplication. Their results were similar to the trials of laparoscopic versus open Nissen fundoplication. Early complications were more common after open surgery, the length of the hospital stay was longer (5 vs. 3 days) and return to work was slower (42 vs. 28 days). However, this was offset by a higher incidence of early side-effects and recurrent reflux in the laparoscopic group. At 3 years follow-up, however, there were no outcome differences, satisfaction with the surgery was similar for the two groups, and the need for re-operative surgery of any sort was not influenced by the choice of technique.

Laine et al.¹²⁴ reported 110 patients randomised to undergo laparoscopic or open Nissen fundoplication. As with the other trials, hospital stay was shorter, being halved from 6.4 to 3.2 days and patients returned to work quicker (37 vs. 15 days), but operating time was also prolonged by 31 minutes. Subsequent reports from this group^137,140 described 11- and then 15-year follow-up in 86 patients. Whilst symptom control and side-effects were similar at late follow-up and 82% of the laparoscopic surgery group were satisfied with the late outcome, the incidence of wrap disruption at endoscopic assessment was significantly higher following open surgery (40% vs. 13%) and there were 10 incisional hernias, all following the open technique. Similar outcomes were reported by Nilsson et al.¹³⁶ in a smaller trial that followed patients for 5 years.

The study that created the most controversy in this area was published by Bais et al. in 2000.¹²⁹ This multicentre study initially enrolled 103 patients. The early (3 months) results of this trial showed a disadvantage for the laparoscopic approach and the trial was stopped early because of an excess of adverse end-points. The investigators were criticised for terminating the trial prematurely,^141,142 as it can be argued that the conclusions were misleading. The decision to stop the trial was based primarily on postoperative dysphagia within the first 3 months. Other studies have reported that most patients who undergo a Nissen fundoplication still have some dysphagia 3 months after surgery,^5,130 but that this dysphagia usually subsides as time passes. Hence, a follow-up period of 3 months is too short for the end-point of dysphagia to be adequately assessed. Subsequent reports of 5- and 10-year follow-up from this trial^133,139 confirmed the validity of this critique. With further enrolment boosting the number of patients to 177, no differences in symptoms or subjective outcome could be demonstrated at late follow-up. In addition, 24-hour pH monitoring confirmed equivalent reflux control. At 10-year follow-up, there was a higher rate of surgical reintervention following open surgery, mainly due to an excess of incisional hernias. Hence, the late results of this trial actually support the application of laparoscopic antireflux surgery.

Complications of laparoscopic antireflux surgery

As experience with laparoscopic approaches for antireflux surgery became standard practice, complications unique to the laparoscopic approach emerged (Box 13.1). These include postoperative paraoesophageal hiatus hernia, re-operation for dysphagia, and gastrointestinal perforation. Nevertheless, the risk of complications should be balanced against the advantages of the laparoscopic approach, as the overall complication rate is reduced following laparoscopic surgery.¹³⁹ The likelihood of complications can be influenced by a number of factors, including surgeon experience and expertise, operative technique and perioperative care. Furthermore, the final outcome of some complications can be moderated significantly by applying appropriate early management strategies.

Radiofrequency

The Stretta procedure¹⁶⁵ used a purpose-built device to apply radiofrequency energy to the muscular layer of the oesophageal wall at the gastro-oeosophageal junction. The device comprised a 30-mm-diameter balloon, four 5.5-mm-long retractable stylet electrodes and a mucosal irrigation system. It was passed over an endoscopically placed guidewire and positioned at the gastro-oesophageal junction. The electrodes were deployed to puncture the oesophageal wall, and radiofrequency energy was applied to cauterise the oesophageal muscle. The Stretta procedure generated fibrosis in the muscle layer with the aim of tightening the gastro-oesophageal junction. In general, patients were only selected for this treatment if they had mild grades of reflux. Whilst short-term follow-up of case series suggested reduced reflux symptoms and reduced oesophageal acid exposure, the magnitude of the reduction in acid exposure was disappointing, and most patients continued to have abnormal reflux after treatment.¹⁷⁰ A randomised trial that compared the Stretta procedure with a sham endoscopy showed no differences at 6 months follow-up.¹⁷¹ The trial demonstrated a large placebo effect in the sham controls, and this should be remembered when considering the outcomes of any antireflux therapy. The company that made the device closed in 2006.

Polymer injection

Polymer injection (and similar procedures) aimed to add bulk to the gastro-oesophageal junction, thereby narrowing it, to reduce reflux. The most popular of these procedures was Enteryx.¹⁶⁶ The procedure entailed endoscopic injection of 5–8 mL of a bioinert polymer into the plane between the circular and longitudinal muscle of the distal oesophagus, to create a ring of polymer just above the gastro-oesophageal junction. Initial reports suggested success rates of 70–80% at 12 months follow-up.¹⁶⁶ However, the results from a randomised sham-controlled trial were also unimpressive, with no difference in acid exposure (11.2% vs. 12.7%) at 3 months follow-up. This trial also demonstrated a significant placebo effect, with 41% of the sham-treated patients able to cease proton-pump inhibitor medication, compared to 68% of the treated group.¹⁷² Unfortunately, there were also some catastrophic complications, including four deaths,^173,174 and the manufacturer withdrew the procedure. A similar product, the Gatekeeper reflux repair system, was also withdrawn from clinical use.¹⁷⁵

Endoscopic suturing

Endoscopic fundoplication

Unlike the previous procedures, the EsophyX (Endogastric Solutions, Washington) procedure aims to construct an actual fundoplication.¹⁷⁹ This procedure requires general anaesthesia and two operators. A standard endoscope is passed through the device (Figs 13.13 and 13.14) and both are passed transorally into the stomach. The endoscope is retroflexed for vision and a screw device anchors tissue at the gastro-oesophageal junction to retract it caudally. A plastic arm (tissue mould) then compresses the fundus against the side of the oesophagus, and polypropylene fasteners are passed between the oesophagus and the gastric fundus to anchor these structures. Multiple fasteners are applied to fashion a 200–300° anterior partial fundoplication.

Some cases series report promising short-term outcomes, with claimed success rates of 55–80% at up to 2 years follow-up,^179,180 but lower success rates for normalisation of oesophageal acid exposure.¹⁷⁹ In general, however, this procedure has been restricted to patients with milder degrees of reflux, i.e. no circumferential ulcerative oesophagitis, Barrett’s oesophagus, hiatus hernia ≥ 3 cm or a body mass index > 30. Whilst most patients recover uneventfully, significant complications have also been reported, including bleeding, pneumoperitoneum and oesophageal perforation. Cadière et al.¹⁷⁹ reported a series of 86 patients, followed for 12 months. Eighty-one per cent of patients were not using proton-pump inhibitor medication and 56% claimed cure of their reflux. Postoperative pH monitoring, however, revealed that only 37% of patients had a normal pH study following the EsophyX procedure. The results from this experience suggest that in some patients a fundoplication can be constructed, but perhaps not reliably. Other experience is also less than satisfactory. We recently reported a three-centre experience of 19 EsophyX procedures.¹⁸¹ Only five patients were able to stop antireflux medication, whereas 10 underwent laparoscopic fundoplication within 12 months for a failed EsophyX procedure. Overall, the published literature suggests EsophyX is much less effective than any type of partial fundoplication,⁴ and less than half of patients treated have objective evidence that reflux has been cured.

A similar approach has also been pursued by Medigus (Omer, Israel), who developed a stapling endoscope for the construction of an anterior partial fundoplication.¹⁸² However, clinical trial data are yet to be reported, and this device has not been commercialised. For now it still seems that a durable partial fundoplication cannot be reliably fashioned using an endoscopic approach. This could be because the endoscopic approaches are unable to repair a hiatus hernia and also fail to anchor the fundus to the diaphragm, both important steps for constructing a stable partial fundoplication.

Overview of endoscopic antireflux surgery

The newer procedures that aim to perform an anterior partial fundoplication appear to be based on more sound principles. However, the results remain disappointing, and this is probably because some key steps used routinely during antireflux surgery are still being ignored when undertaking this approach. It is hard to see how an endoscopic approach can be modified to include repair of a hiatus hernia or accurate anchorage of the fundoplication to the hiatal rim, and for these reasons endoscopic treatments are unlikely to offer a viable alternative to antireflux surgery, even in carefully selected subgroups of patients, in the near future.

Lessons can be learnt from the experience with failed endoscopic antireflux treatments. Before any new endoscopic or surgical treatment for reflux is made widely available, it should first be evaluated in well-designed clinical trials. An appropriate procedure must be as effective as a conventional fundoplication, it should apply the same principles that underpin an effective antireflux operation, and it should be equally safe or safer. Furthermore, surgeons will need to have an appropriate strategy to deal with patients who develop recurrent reflux after these procedures, and any procedure that makes a subsequent laparoscopic fundoplication procedure more difficult or more dangerous will be a problem, particularly if there is a substantial risk of the primary endoscopic procedure failing.

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