Anti-reflux therapy — why, when and how

Serial

Therapeutics

Anti-reflux therapy - why, when and how

B. K. Sandhu, A. E. M. Davies Table

During the last 10 years there has been a resurgence of interest in gastroesophageal reflux (GOR). Fresh impetus has been provided by firstly the development of new and better methodologies for evaluating GOR and secondly by the availability of newer and better pharmacological agents such as cisapride for treatment. Development and availability of oesophageal pH monitoring, a more accurate method of diagnosis than barium mealle3 have enabled identification of a number of symptoms not previously known to be caused by reflux, particularly silent reflux.4 Our understanding of the pathophysiology has increased, but the condition has nevertheless become more complex to evaluate and treat. The purpose of this paper is to transform this new understanding into rational therapy for GOR. The definition of GOR is, the involuntary passage of gastric contents into the oesophagus. It does not specify any specific aetiology and may be primary or secondary.

(A)

(B)

Symptoms and clinical presentation (Cl

GOR may occur in normal children but becomes pathological when its frequency and intensity is increased and there is manifestation of associated symptoms. There are three main categories of symptoms in children (Table 1). Vomiting is the most obvious and common symptom of ‘primary’ GOR but vomiting may also be due to ‘secondary’ GOR due to disease processes such as gastroenteritis, urinary tract infection, intestinal obstruction, food allergy and metabolic disease.

Symptoms

of GOR

Oesophageal 1. Specific

symptoms symptoms l Regurgitation l Vomiting l Nausea Failure to thrive l 2. Symptoms due to oesophagitis l Haematemesis and melaena l Dysphagia l Epigastric or retrosternal pain l Heartburn l Symptoms related to anaemia l General irritability l Feeding problems l Oesophageal obstruction due to stricture Respiratory symptoms l Aspiration pneumonia, especially recurrent l Apnoea, especially in the preterm infant l Apparent life-threatening events (ALTEs) and sudden infant death syndrome l Cyanotic episodes l Cough l Stridor l Bronchospasm or wheezing, especially intractable asthma Worsening of existing respiratory l disease eg. cystic fibrosis Neurobehavioural symptoms l Sandifer-Sutcliffe syndrome l Seizure-like events in infants

In secondary GOR, obviously the primary disease should be treated. This is one reason why it is imperative that tests such as oesophageal pH monitoring should not be available without a complete consultation. It is not the intention of this paper to discuss the differential diagnosis of secondary GOR.

Diagnostic tests

B. K. Sandhu MD MINT, Consultant Paediatric Gastroenterologist and A. E. M. Davies MINX, Senior Registrar, Institute of Child Health, Royal Hospital for Sick Children St Michael’s Hill, Bristol BS2 8BJ. Correspondence and requests for offprints to BKS. Current Prrediatrics (1994) 4, 118-122 0 1994 Longman Group Ltd

1

Diagnostic tests and treatments are not indicated for non-pathological reflux, ie, occasional ‘regurgitation’ or ‘spitting’ done by many infants who are well. For 118

ANTI-REFLUX

those whose symptoms suggest pathological reflux there are a number of tests available. Early diagnosis and appropriate treatment can halt unnecessary investigations and prevent complications such as oesophagitis, failure to thrive and respiratory problems.

Lower oesophagealpH monitoring Over the last 10 years, 24-h lower oesophageal pH monitoring has increasingly become established as the ‘gold’ standard for documenting acid GOR. Reflux is a dynamic phenomenon and therefore the ability to monitor over a prolonged time makes the test more physiological and reliable. Several different scoring systems have been developed for pH studies. The most commonly used system is shown in Table 2 with normal values based on studies by Vandenplas and Sacre-Smits.’ A reflux episode is commonly defined as occurring when lower oesophageal pH falls below pH 4. The percentage time pH is less than 4 in the lower oesophagus (often referred to as the reflux index) provides a convenient single summary of the study for clinical purposes. Children with a reflux index of 510% (mild) or lo-20% (moderate) will often be controlled by medical therapy. Those with over 20-30% reflux frequently require surgical intervention (Phase 4). When using pH 4 to indicate reflux it is important to remember that non-acid reflux may occur and will not be detected. The Working Group on GOR of the European Society of Paediatric Gastroenterology and Nutrition (ESPGAN) has recently published a protocol for lower oesophagus pH monitoring6 and this is worthwhile consulting by those carrying out this procedure.

Barium radiography This has been historically used for diagnosing reflux. It only looks at gastro-oesophageal dynamics over a very short period and has been found to give unreliable and often misleading results7 and should not be used for the purpose of diagnosing the severity or presence of GOR. However, it is useful in detecting anatomical abnormalities such as hiatus hernia, oesophageal stricture, gastric outlet obstruction and malrotation. It may also show mucosal abnormalities of severe oesophagitis.

2

Scoring

% of time

system

for oesophageal

pH < 4 for total

period

pH monitoring (the reflux

index)

Total

number normal

of reflux values

-

WHEN

AND

and

Sacre-Smits5

119

Therapy There is a range of treatments available and the treatment plan for each patient will depend on the severity of symptoms, the presence of complications and the presence of any associated illnesses with an arbitrary classification into 4 treatment phases (Table 3). Phase 1 Treatment IA. Position: Allowing the child to sleep with the head elevated by 30” by putting a folded blanket under the mattress has been shown to be effective in treating uncomplicated GGR in about 25% of infants and is now an accepted and essential part of treatment.g 1B. Milk thickening agents: These products are mostly bean gum preparation (Carobel); Nestargel is a carob seed flower containing 3.5% calcium lactate. They increase feed viscosity and have been shown to decrease observed symptoms of regurgitation and vomiting. However, number of reflux episodes decrease but the duration of remaining refluxes is prolonged with no significant change in reflux index.” Thickened feeds may be inappropriate in patients with oesophagitis as oesophageal dysmotilTable

3

Therapy

for GOR

I Phase 1A IB 1C ID Phase

I Positioning - prone, head elevated to 30” Milk thickening agents Dietary advice-frequent feeds of small volume Antacids - Infant Gaviscon

l l l l

2 Prokinetic agents -.cisapride 0.8 mg/kg/day in 3-4 doses given before feeds* If svmptoms oersist. trv domoeridone 1 mg/kg/day,br metociopramide 0.5 mg/kg/day

l l

38

3 HZ-receptor antagonists - cimetidine 30 mg/kg/day - ranitidine IO-15 mg/kg/day omeprazolet Sucralfate 0.25-1.0 g qds

l

l l

Phase

4 Surgery procedure

-

Nissen

fundoplication,

*Doses tDose

of 0.4 mg-1.2 mglkglday schedule currently under

or Thal

-

episodes Vandenplas

HOW

This enables diagnosis of gross and histological oesophagitis as well as diagnosing hiatus hernia, strictures and Barrett’s oesophagus as well as other diseases which may cause epigastric pain or haematemesis. In a patient suspected of reflux associated oesophagitis, histological confirmation of oesophagitis is important, both to show oesophagitis in a child where endoscopy is equivocal or negative, and to confirm that the oesophagitis is due to reflux in the patient where endoscopy is positive.7,8

l

Expected

- WHY,

Endoscopy

Phase 3A Table

THERAPY

may be used. evaluation.

120 CURRENT PAEDIATRICS ity may further delay clearance of thickened refluxed material. ZC. Dietary advice: In older children dietary advice includes normal lowish fat diet and avoidance of carbonated drinks, coffee, cola, tea, chilled drinks or spicy food. In infants, the historical approach of small frequent feeds has advantages but does increase post-prandial periods of reflux. Adequate calories need to be given including compensatory feeds to replace those lost as vomit. ID. Antacids: Antacids such as infant Gaviscon (sodium salt of alginic acid) have been shown to be effective in GOR,” and appear to be relatively safe but the increased sodium load may be inappropriate in preterm babies. The dose is half a dual sachet mixed in each feed for babies less than 4.5 kg, and a complete dual sachet for larger children per feed. Breast fed babies should be given the dose mixed in water after feeds. Phase 2 therapy

Cisapride is a non-dopamine receptor blocking prokinetic drug that acts by enhancing acetylcholine release in the gut. It increases gastrointestinal motility and improves antroduodenal co-ordination. The usual dose is 0.8 mg/kg/day (range 0.4-1.2) in 3-4 doses. It has little effect on acute vomiting. If there is no response to cisapride, domperidone (1 mg/kg/day) or metoclopramide 0.5 mg/kg/day given 6-8 hourly may be worth trying especially in neurologically abnormal children.

Who to treat and how? The Working Group on gastro-oesophageal reflux disease of the European Society of Paediatric Gastroenterology and Nutrition (ESPGAN) of which BKS is a member has very recently published a proposition for the diagnosis and treatment of GOR in children13 and the following recommendations are based on the consensus view of the Working Group. Therapy for patients with uncomplicated GOR - Phase 1 treatment (Fig. 1)

This is suitable for patients who will mostly comprise infants under 1 year of age with regurgitation. These patients do not have any complications such as failure to thrive or haematemesis. Phase 1 treatment: position, milk thickening, dietary recommendations about small frequent feeds and an antacid can be started without carrying out investigations such as lower oesophageal pH monitoring. The diagnosis of GOR in these cases is based on history and examination. There is some disagreement but the Working Group recommended that Phase II treatment, cisapride, could also be used in these patients without performing investigations provided the child had no evidence of complications and other causes of vomiting have been excluded. The dose of cisapride used is 0.2 mg/kg 6-hourly before feeds but higher doses have been used. If the results of the therapeutic trial are unsatisfactory, pH monitoring may be performed to document reflux. If the result shows no significant GOR, the diagnosis should be reconsidered and other investigations may be indicated (scintigra-

Phase 3 treatment 3A. H2 receptor blockers: Cimetidine (30 mg/kg/day)

and ranitidine (10-l 5 mg/kg/day) have been used to treat GOR with oesophageal symptoms. It is not useful to combine antacids with acid secretion inhibiting drugs. 3B: Omeprazole,

a powerful proton pump blocker, has been shown to be effective in treating GORoesophagitis resistant to H2 blocker therapyI’ but the dosage schedule for children is still being evaluated. Sucralfate was shown to be as effective as cimetidine for oesophagitis in children.

Abnormal Mod/severe GOP.

Mild Gem continue

Phase 4 therapy

As GOR in infants may resolve, surgery should only be considered after a full trial of medical treatment. In children with pre-existing neurological abnormalities, or those with apparent life threatening events (ALTE), surgery should be considered earlier. Nissen fundoplication is the usual procedure but other techniques may be used.

Fig. l-Treatment

of patients

with

uncomplicated

GOR.

ANTI-REFLUX

phy if non-acid reflux is suspected). When pH monitoring data are abnormal, the long list of ‘primary’ disorders that may present with GOR needs to be reconsidered. Investigations to look for complications of GOR may be indicated if moderate/severe GOR is present and these include endoscopy for peptic oesophagitis and upper GI barium studies for anatomical malformation; manometry may be helpful to detect achalasia of the cardia or other motility disorders. At this stage the patient should be referred to a specialised centre (Fig. 1). Therapy for patients with suspected oesophagitis (Fig. 2)

For patients presenting with symptoms suggestive of oesophagitis (see Table 1 ), upper gastrointestinal endoscopy with biopsy is the investigation of choice. This should be performed by an experienced paediatric gastroenterologist and should always be a duodeno-gastro-oesophagoscopy. l3 If delayed gastric emptying or non-acid reflux are suspected clinically, then scintigraphy may be useful. If an anatomical malformation is suspected then barium studies may also be appropriate. Minimal oesophagitis (Grade 1-3; mucosal redness) may heal with Phase 1 and Phase 2 therapy alone. H2 blocker (Phase 3a) treatment is indicated for more severe oesophagitis (> Grade 3; mucosal ulceration). Phase 3b (omeprazole) should be tried if 3a is not effective and may be used as an alternative to 3a although experience with this drug in children is still limited and a dosage schedule is still being evaluated. A control endoscopy needs to be performed 4-12 weeks after treatment. If this shows normal oesophageal mucosa, Phase 3 treatment can be stopped Complicated

GOR

1. EndoScOpy

/\ .Severe (mucosal "lceratlon) I

Mmimal I

Phase

L1

& 2

i

Phase 3 1-3 months I

Persistent ulceration

I weat for Investigate

Fig. 2-Treatment

mucosal ?

further prior

for complicated

e Normal Stop Phase Cont. Phase 6-12 months l-3 to

months surgery

GO!?.

3 2

THERAPY

- WHY, WHEN AND HOW

121

but Phase 1 and 2 should be continued for a prolonged period (> 6 months) depending on the clinical situation. The oesophagitis may recur and it is advisable to repeat the endoscopy 3 months after stopping Phase 3 therapy. If there is no improvement despite adequate Phase 3 treatment, underlying anatomical and other problems need to be excluded. It is appropriate to try Phase 3 therapy for another 4-12 weeks. Surgery may be inevitable if medical treatment fails and may be life saving in children with recurrent and life-threatening aspiration particularly in neurologically abnormal children. Children with Barrett’s oesophagus or peptic stricture require fundoplication as initial therapy. Children with GOR needing gastrostomy for feeding are another group that may benefit from surgery. Surgery should be preceded by a full diagnostic work up including pH monitoring, gastric emptying studies, barium studies, endoscopy and manometry. Surgical treatment is not without complications which include ‘gas-bloat’, dumping, retching, intestinal obstruction, wrap hernia and recurrence of reflux.14-15 Therapy for neurologically abnormal children

The association between GOR and cerebral palsy was first reported by Abrahams and Burkitt in 1970,16 who found reflux in 75% of cases. Symptoms of recurrent chest infections, failure to thrive, irritability and vomiting are often accepted as being part of the disability. If fully investigated, a significant portion of those children will be found to have GOR.” Professor Carre (1985), a protagonist of conservative treatment, recognised that a higher proportion of mentally handicapped children with GOR required surgical treatment.18 Natural resolution of GOR is less common in these children and the pathophysiological mechanisms of GOR are complex and include the neurological disease itself causing delayed oesophageal clearance and delayed gastric emptying, effect of being in a wheelchair, constipation etc. The GOR in these children may often be silent.4 In other children GOR may mimic neurological disease resulting in gross dystonic posturing (Sandifer’s syndrome) or seizure-like events which are cured by effective antireflux therapy.” Oesophagitis is common in children with psychomotor retardation and upper GI endoscopy should be carried out if the child is anaemic or if pH monitoring documents severe reflux. The treatment should be energetic (Phase 1, 2 and 3) but response to medical treatment may be disappointing. In contrast to neurologically normal children, response to cisapride (which acts locally and is devoid of CNS effects) is poor” and Phase 2 drugs with some central nervous system action may be worth trying (domperidone). Phase 4 treatment, ie, surgery is indicated particularly in children with severe oesophagitis or recurrent

122

CURRENT PAEDIATRICS

chest infections. If there is delayed gastric emptying, a pyloroplasty may be carried out simultaneously. Therapy for silent GOR and respiratory manifestations

An enormous variety of respiratory abnormalities have been linked to GOR either on the basis of presumed aspiration or via oesophageal - respiratory tree reflexes (Table 1). With the advent of new methodologies it has become clear that reflux may be clinically silent, ie, no history of regurgitation or vomiting, and may present with complications, particularly respiratory ones. Up to three quarters of children with ALTE’s may have pathological GOR.2325 Duration of reflux episodes during sleep may be an important determinant of reflux associated respiratory disease and sudden infant death syndrome23 and hence in these children, analysis of pH monitoring should be directed at determining the duration of reflux episodes during sleep, rather than relying on the conventional reflux index. GOR in these children should be energetically treated with Phase 1, 2 and 3 therapy and pH studies repeated to check that reflux is being prevented. If Phase 3 treatment is not effective then Phase 4 treatment should be sought early. In preterm infants, pulmonary aspiration, apnoea and bronchopulmonary dysplasia have all been linked with GOR.24 Mechanism of the association is unclear but lower oesophageal acidification and laryngeal chemoreflex may be involved. GOR should be considered in infants with non-obstructive xanthine resistant apnoea and treatment with phase 1 therapy may resolve the symptoms.22 GOR may play a role in intractable asthma and chronic lung disease such as cystic fibrosis (CF) and is worthwhile considering. If confirmed, treatment will depend on severity of reflux (Phase l-3). In children who require regular gastrostomy feeding, if a trial of medical treatment is ineffective, Phase 4 therapy should be considered.25

Conclusion Children with typical symptoms of primary GOR without signs of complications can be treated with Phase 1 therapy without prior investigations. 24-h oesophageal pH monitoring is the investigation of choice for diagnosing the presence and severity of GOR. If Phase 1 treatment is ineffective, cisapride should be added (Phase 2). If complications such as oesophagitis and respiratory symptoms occur or silent GOR is suspected, investigations are necessary. Endoscopy is recommended if oesophagitis is suspected and if confirmed, should be treated with Phase 3 therapy in addition to Phase 1 and 2. If Phase 3 therapy fails to control complications particularly in neurologically abnormal children or children with ALTE, Phase 4 therapy is recommended after full evaluation.

References 1. Orenstein SR, Orenstein DM. Gastroesophageal reflux and respiratory disease in children. J Pediatr 1988; 112: 847-858. 2. Boyle JT. Gastro oesophageal reflux in the paediatric patient. Gastroenterol. Clin North Am 1989; 18: 3155337. 3. Tappin DM, King C, Paton JY. Lower oesophageal pH monitoring - a useful clinical tool. Arch Dis Child 1992; 67: 146-148. 4. Booth IW. Silent gastro oesophageal reflux: how much do we miss? Arch Dis Child 1992: 67: 1325-1327. 5. Vandenplas Y, Sacre-Smits L. Continuous 24 hour oesophageal pH monitoring in 285 asymptomatic infants O-15 months old. J Pediatr Gastroenterol Nutr 1987; 6: 220-224. 6. Working Group of ESPGAN. A standardised protocol for the methodology of esophageal pH monitoring and interpretation of the data for the diagnosis of gastroesophageal reflux. Society statement. J Pediatr Gastroenterol Nutr 1992; 14: 4617471. I. Martin PB, Surendra-Kumar D, Sandhu BK. Oesophageal pH, barium studies and clinical symptoms in children. Proceedings of British Paediatric Association Meeting 1992. 8. Black D, Haggitt R, Orenstein S et al. Esophagitis in infants: morphometric histological diagnosis and correlation with measures of gastroesophageal reflux. Gastroenterology 1990; 98: 1408-1414. 9. Orenstein SR, Whitington PF. Positioning for prevention of infant gastroesophageal reflux. Pediatrics 1982; 69: 7688772. 10. Vandenplas Y. Oesophageal pH monitoring for gastroesophageal reflux in infants and children. Ed: J Wiley and Son, England. 11. Buts JD, Barndi C, Otte JB. Double-blind controlled study on the efficacy of sodium alginate in reducing gastroesophageal reflux assessedby 24-h continuous pH monitoring in infants and children. Eur J Pediatr 1987; 146: 1566158. 12. Arguelles-Martin F, Gonzales-Femadex F, Gentles MG, Navro-Marino M. Sucralfate in the treatment of reflux oesophagitis in children: preliminary results. Scan J Gastroenterol24(suppl 150): 43347. 13. Vandenplas Y et al. A proposition for the diagnosis and treatment of gastro oesophageal reflux disease in children. A report from a working group of ESPGAN on gastrooesophageal reflux disease. Pediatr 1993; 152: 704-711. 14. Spitz L, Roth K, Kiely EM et al. Operation for gastro oesophageal reflux associated with severe mental retardation. Arch Dis Child 1993; 68: 347-351. 15. Cilley R. Management of gastroesophageal reflux in children. Curr Opin Pediatr 1991; 3: 483-488. 16. Abrahams P, Burkitt BFE. Hiatus hernia and gastro oesophageal reflux in children and adolescents with cerebral palsy. Australian Paediatric Journal 1980; 6: 4146. 17. Sondheimer JM, Morris BA. Gastroesophageal reflux among severely retarded children. J Pediatr 1979; 97: 710-714. 18. Carre J. Managements of gastroesophageal reflux. Arch Dis Child 1985; 60: 71-75. 19. Puntis JWL, Smith ML, Buick RG, Booth IW. Effect of dystonic movement on oesophageal peristalsis in Sandifer’s syndrome. Arch Dis Child 1989; 64: 1311-1313. 20. Brueton MJ, Clarke GS, Sandhu BK. Effect of cisapride on gastroesophageal reflux in children with and without neurological disorders. Dev Med Child Neurol 1990; 32: 629-632. 21. Veereman-Wauters G, Bochner A, Caillie-Bertrand MV. Gastroesophageal reflux in infants with a history of near-miss sudden infant death. J Pediatr Gastroenterol Nutr 1991; 12: 319-323. 22. See CC, Newman IJ, Berezin S et al. Gastroesophageal reflux induced hypoxaemia in infants with apparent life threatening events. Am J Dis Child 1989; 143: 951-954. 23. Halpern LM, Jolley SG, Tune11WP, Johnson DG, Sterling CG. The mean duration of gastroesophageal reflux during sleep as an indicator of respiratory symptoms from gastroesophageal reflux in children. J Pediatr Surg 1991; 26: 6866690. 24. Newell SJ, Booth IW, Morgan MEI, Durbin GM, McNeish AS. Gastroesophageal reflux in preterm infants. Arch Dis Child 1989; 64: 780-786. 25. Orenstein SR. Controversies in Pediatric Gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1992; 14: 338-348.