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For how long should medical treatment be continued?
S.R. Orenstein (Pittsburgh)
The simple answer to the question posed in the title is: "until it is cured or requires surgery".
Ascertaining the success of medical treatment, or deciding that it has failed and requires surgery, are, however, rather complex issues. The complexity arises, first, from ambiguity regarding what constitutes optimal medical therapy (which components of conservative therapy are included? Should both a prokinetic and an acid suppressor be used? Should a proton pump inhibitor be used in children?). Second, the complexity results from different responses to therapy by the various manifestations of reflux. Third, the complexity is caused by the need to use invasive testing to evaluate persistence of disease. Fourth, the complexity results from maturational issues - different responses in infants and in older children.
In this discussion, I will not deal with the components of medical therapy, but my personal biases are that "conservative therapy" (advice regarding positioning and feeding) is a very helpful underpinning for reflux therapy, particularly in infants; that a prokinetic agent should usually be used for reflux disease, with an H2 blocker added in those patients with esophagitis; that H2-blocker therapy may be optimized with higher than previously used doses [1]; and that proton pump therapy in children should be reserved for intractable symptoms and used on a temporary basis, often prior to a decision for surgery. I will evaluate the evidence regarding both the success and failure of medical therapy for reflux disease in children, attempting to address the various symptomatic presentations individually and to identify when invasive testing is needed. Due to the different natural history of reflux disease in infants and in older children, these two developmental groups will be discussed separately.
Infants
Success of medical therapy - discontinuing therapy
How one determines the success of medical therapy for reflux disease in infants varies with the presenting manifestations of the reflux. In infants with regurgitation and failure to thrive, controlling regurgitation enough to allow adequate weight gain is the measure of treatment success and persistence of adequate weight gain when therapy is withdrawn indicates "cure" of the problem. Data are limited, but clinical experience suggests that this problem usually resolves between 8 and 12 months, the period when regurgitation frequency is markedly reduced in normal infants.
In contrast to the nutritional consequences of regurgitation, which can be monitored noninvasively when therapy is withdrawn, esophagitis due to reflux cannot
be observed directly. Discontinuing therapy therefore requires: 1) assumptions that esophagitis resolves in concert with observable signs (such as crying or regurgitation); or 2) assumptions that the timing of its persistent resolution can be predicted by pharmacologic studies (largely in adults); or 3) invasive evaluation. Thus one should treat esophagitis for at least 2 or 3 months and until the observable signs have resolved, or until invasive evaluation (esophageal histology) demonstrates resolution.
Apnea, one of the most threatening symptoms of reflux, is essentially confined to infancy. The decision that therapy of the reflux has been successful and can be terminated is undertaken in a more conservative manner than such a decision to terminate therapy for other manifestations of reflux in infants, because of the importance of assuring that apnea will not recur when therapy is discontinued. A decision to terminate therapy in infants with reflux-associated apnea utilizes knowledge of the maturational time course of infantile apnea of any cause, as well as the knowledge of the particular infant's symptoms since initiation of antireflux therapy. A conservative plan is to continue therapy until the infant is older than 6 months and no apnea has occurred for 2 months. Evidence that other signs of reflux are eliminated is also supportive. Infants who have been monitored should not have both the pharmacologic therapy for reflux and the monitor discontinued simultaneously.
Infants with other respiratory manifestations definitely attributable to reflux often require fundoplication for adequate control. However, many such infants deserve a trial of aggressive medical therapy before consigning them to surgery, to allow those who are able to avoid surgery to do so. If medical therapy does result in complete resolution of the respiratory symptoms for a period of time, it is reasonable to attempt to discontinue pharmacologic therapy, but to keep surgical therapy in reserve for those who are unable to remain off therapy.
Failure of medical therapy - advancing to surgical therapy
Surgical therapy is warranted in three general situations. These are, in decreasing order of necessity: 1) symptom hazard: when the danger of persistent reflux is so great that primary fundoplication is preferable to relying on imperfect medical therapy; 2) symptom intractability: when medical therapy fails to resolve serious symptoms; or 3) medication dependence: when medical therapy resolves serious symptoms, but is unable to be withdrawn without resumption of the symptoms. Because the natural history of infantile reflux disease is to resolve in the first year or so of life, surgery should be postponed until after that time, if possible.
Symptom hazard has often been cited as a reason for primary surgical therapy for reflux-associated apnea in infants [2], but pediatric gastroenterologists have managed large numbers of such infants without surgery and without adverse outcome [31. Many infants who have experienced a cyanotic episode or ALTE, apparently due to reflux, can have their risk for subsequent such episodes markedly reduced by very careful nursing practices (e.g., cautious feeding, diligent burping and prone positioning) as well as by pharmacologic intervention. Nonetheless, occasional infants with recurrent severe reflux-associated apneic episodes may demonstrate the
intractability which would prompt surgical intervention. The utility of cardiorespira-tory monitoring in the meantime is ambiguous, although often used, in this situation as in many others; the awake, obstructive, postprandial apnea associated with reflux is particularly unlikely to be detected early by such monitoring.
Two other situations in which symptom hazard may prompt primary fundoplication are Barrett's esophagus and reflux stricture; since both of them are uncommon in infants, they will be considered in the section on older children.
Symptom intractability should not be used as the sole justification for surgery until comprehensive medical therapy (a prokinetic agent, an acid-lowering agent in adequate doses and aggressive conservative management) has been used for at least several months, or if persistent symptoms produce unacceptable hazard. Esophagitis does not resolve in most patients with less than 2 or 3 months of therapy, and related respiratory symptoms may take at least that long [4]. Even esophagitis which has been documented to persist for 12 months or more of treatment in infancy may resolve as the infant becomes a toddler (author's personal experience). A coexisting large hiatal hernia [5,6] or other anatomic defect may prompt earlier surgery including fundoplication. Infants who are particularly likely to manifest symptom intractability during medical therapy of reflux are infants with chronic respiratory disease [7,8] such as bronchopulmonary dysplasia or cystic fibrosis, infants with neurologic disease, infants with other congenital anomalies [7,9] and infants who require gastrostomy feedings [10]. One may reasonably decide after several months of therapy in these patients that the disease is intractable, particularly if the symptoms are producing chronic morbidity. Several groups have attempted to determine whether medical intractability could be predicted by a pH probe study, thus justifying primary surgical therapy. These surgeons have retrospectively identified several parameters of 24-h pH probe monitoring which have "predicted the need for surgery": frequency greater than 34 [11] or ~45 [12] reflux episodes per day, daily reflux duration greater than 27% of the monitored time [13], sleep reflux duration greater than ~4 min/day [14,15] and frequency of prolonged episodes (lasting longer than 5 min) greater than 20 per day [13]. The logic is often circular, however, since the pH probes were considered in the decision for surgery and using the authors' decision that surgery was required as the gold standard is suspect, since some of the authors report a rather large number of patients "requiring" surgery. Other groups studying adults and children have found that the pH probe was a poor predictor of intractability [16-18]. One must conclude, with the group from Salt Lake City, that "the clinical history and the patient's response to medical treatment remain the most important factors in the decision for or against surgery" [15].
Medication dependence generally should not be used as the sole justification for surgery in infants, because of the natural history of infantile reflux to resolve by 2 years of age.
Older children
Success of medical therapy - discontinuing therapy
The natural history of reflux disease in older children is similar to that in adults; unlike most infants, many older children will not achieve persistent resolution of reflux-associated symptoms. However, since some reflux disease does resolve after a course of therapy, even in older children, most reflux disease is initially treated for at least 6-12 weeks, based on the usual course of healing of esophagitis. When such therapy is used empirically, it should not be continued longer than the 6-12 weeks (if the symptoms persist during 3 months of therapy, or return after its discontinuation, endoscopic evaluation is required). If esophagitis has been documented prior to starting medical therapy, a longer course of treatment may be used if the symptoms persist and treatment can be discontinued based on symptom resolution.
Symptoms other than esophagitis, such as chronic respiratory symptoms (e.g., asthma, recurrent pneumonia, hoarseness), may also be treated with at least 6-12 weeks of therapy; the medications are withdrawn after this period if the symptoms have resolved. Recent evidence in adults suggests that treatment ameliorates the symptoms of esophagitis more rapidly than any associated respiratory symptoms, which may take months to respond and which may require high-dose proton pump therapy [4]. If the symptoms recur when medication is withdrawn, more protracted medical therapy may be required, or surgery may be considered.
Failure of medical therapy - advancing (retreating?) to surgical therapy
Recent work in adults has suggested that primary surgical therapy could be a therapeutic option for severe or complicated esophagitis, with greater efficacy than medical therapy persisting for up to 2 years [19-21]. Analysis has suggested that such an approach is of more benefit to younger adults than to older ones [20] and an age threshold in the sixth decade has been identified. Extrapolating such data, it is possible to conclude that primary surgical therapy might be of even more benefit in older children, particularly since relatively long-term function has been documented for fundoplication [22-25], modulating earlier concerns regarding the stability of fundoplication. The development of laparoscopic techniques may further support early fundoplication for children. Modulating such a conclusion is the possibility that ongoing research will provide new medications which are more effective, safe and economical than those now available, and will allow our pediatric patients to avoid the surgeon's knife.
Symptom hazard can be cited as justification for primary surgical intervention in children with Barrett's specialized epithelium [26] and in children with strictures [27-29]. Although some experts argue that adults with these findings might be managed without surgery, the anticipated long duration of disease, the concerns about lifetime proton pump use in young children and the probable additional need for preventing duodenogastroesophageal reflux in these settings argue for primary surgery for children with these presentations.
Symptom intractability during therapy is readily justified as a reason for fundoplication in the older child. Children particularly likely to require surgery for this reason are those with chronic or recurrent respiratory symptoms, neurologic disease and provocative anatomic abnormalities such as esophageal atresia or a large hiatal hernia [7,30-33]. Some might even recommend primary fundoplication prior to medical therapy in such children, but primary aggressive medical therapy has several advantages. First, it should help the surgeon by decreasing esophageal inflammation in those patients who will eventually come to surgery. Second, it may allow a few patients to avoid surgery if their symptoms resolve completely and do not recur. Third, intractability of symptoms during aggressive medical therapy should raise concerns that the diagnosis of a reflux-associated symptom might have been incorrect.
For the reasons noted above in support of primary surgical therapy, medication dependence may be used more often than in the past to justify surgery in older children. If anticipated requirement for medical therapy in a child is lifelong, the relative efficacy and safety of fundoplication make it a very reasonable alternative. Medication dependence is best used to justify surgery in a child who is at least 18 to 24 months old, who has been treated for at least 3 months and who has been demonstrated to relapse after withdrawal of medication at least once, and preferably twice. Such an irreversible decision should be made in consultation with a family well-informed as to the relative risks and benefits.
References
reflux. Arch Dis Child 1989;64:1421-1426.
31. Stringel G. Gastrostomy with antireflux properties. J Pediatr Surg 1990;25:1019-1021.