Gastroesophageal reflux disease: exaggerations, evidence and clinical practice

Ferreira, Cristina Targa; Carvalho, Elisa de; Sdepanian, Vera Lucia; Morais, Mauro Batista de; Vieira, Mário César; Silva, Luciana Rodrigues

doi:10.1016/j.jped.2013.05.009

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Review Article • J. Pediatr. (Rio J.) 90 (02) • Mar-Apr 2014 • https://doi.org/10.1016/j.jped.2013.05.009 copy

Gastroesophageal reflux disease: exaggerations, evidence and clinical practice^☆ ☆ Please cite this article as: Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.

Authorship SCIMAGO INSTITUTIONS RANKINGS

OBJECTIVE:

there are many questions and little evidence regarding the diagnosis and treatment of gastroesophageal reflux disease (GERD) in children. The association between GERD and cow's milk protein allergy (CMPA), overuse of abdominal ultrasonography for the diagnosis of GERD, and excessive pharmacological treatment, especially proton-pump inhibitors (PPIs) are some aspects that need clarification. This review aimed to establish the current scientific evidence for the diagnosis and treatment of GERD in children.

DATA SOURCE:

a search was conducted in the MEDLINE, PubMed, LILACS, SciELO, and Cochrane Library electronic databases, using the following keywords: gastroesophageal reflux; gastroesophageal reflux disease; proton-pump inhibitors; and prokinetics; in different age groups of the pediatric age range; up to May of 2013.

DATA SYNTHESIS:

abdominal ultrasonography should not be recommended to investigate gastroesophageal reflux (GER). Simultaneous treatment of GERD and CMPA often results in unnecessary use of medication or elimination diet. There is insufficient evidence for the prescription of prokinetics to all patients with GER/GERD. There is little evidence to support acid suppression in the first year of life, to treat nonspecific symptoms suggestive of GERD. Conservative treatment has many benefits and with low cost and no side-effects.

CONCLUSIONS:

there have been few randomized controlled trials that assessed the management of GERD in children and no examination can be considered the gold standard for GERD diagnosis. For these reasons, there are exaggerations in the diagnosis and treatment of this disease, which need to be corrected.

Gastroesophageal reflux disease; Gastroesophageal reflux; Proton pump inhibitors; Proton pump inhibitors/therapeutic use; Infant; Child

Author/country	Method	Results	Observations
Cavataio F et al. ¹⁸ Cavataio F et al. ¹⁹Italy	pH-monitoring to differentiate primary GERD and GERD secondary to CMPA	Suggests that a specific phasic pH pattern occurs in CMPA - slow and progressive decrease in pH after challenge test with milk	Other studies did not reproduce these findings
Ravelli AM et al. ²² Italy	Electrogastrography and electrical impedance tomography to study infants with GERD and CMPA	Significant difference between the parameters of infants with GERD (equal to controls) and with CMPA (gastric dysrhythmia and delayed gastric emptying)	Patients with CMPA have motility disorders that induce GERD. This study separated the patients into two groups and assessed the differences (GERD x CMPA)
Garzi A et al.²⁶ Italy	Ultrasonography to study gastric emptying in infants with GERD and CMPA - and ten normal controls-with formula and protein hydrolyzate	Improvement in gastric emptying with hydrolyzed formula in patients with GERD and CMPA	All patients with GERD and CMPA had delayed gastric emptying
Nielsen et al.¹⁷	48-hour pH-metry and endoscopy Day 1- elimination diet Day 2 - challenge test	No difference in the parameters of reflux in pH-monitoring, but observed an association between GERD and CMPA	Incapacity of pH-monitoring to detect episodes of non-acid reflux, particularly in infants who are often breastfed
Nielsen et al.²⁷	Analysis of UGIT biopsies to verify whether there was a different inflammatory pattern in patients with GERD secondary to CMPA	Histology did not identify the group with GERD by CMPA	Older children with a mean age of 7.8 years
Semeniuk J et al. ²⁸ Poland	Esophageal manometry in patients with primary GERD and GERD secondary to CMPA	There were no differences between the two groups
Semeniuk J et al. ²⁹ Poland	Endoscopy in patients with primary GERD (group 1) and secondary to CMPA (group 2)	Esophagitis of varying degrees in 33% of group 1 and in 47% of group 2
Semeniuk J et al. ³⁰ Poland	Measurement of serum gastrin in GERD and GERD associated with CMPA	Serum concentrations were similar in primary and secondary GERD
Farahmand F et al. ³¹	Patients with GERD received omeprazole. Non-responders underwent an elimination diet.	One third of patients with GERD responded to elimination diet that excluded dairy products	Clinical study
Borrelli O et al. ¹⁵ Italy/United Kingdom	48-hour pH-metry-MII Day 1 - amino acid formula Day 2- challenge with cow's milk	The number of reflux episodes and weakly acid episodes increased in the challenge,	They concluded that pH-monitoring did not appear in previous studies, as what most often occurs are postprandial weakly acidic reflux episodes.

Authors/year	PPI/time	Design	Age/n	Results/observations
Tolia V et al.⁶⁹	Lansoprazole 15 or 30 mg, eight to 12 weeks	Open, multicentric Phase I/II study	Children aged 1 to 11 years n = 66	Considered safe and well tolerated 78% healed EE in week eight, and 100% in week 12
				AE: headache, constipation.
Gremse D et al. ⁷⁰	Lansoprazole 15 or 30 mg Studies carried out five days after beginning of use	Open, multicentric Phase I/II study Pharmacokinetics and dynamics	Children aged 1 to 11 years n = 66	Pharmacokinetic properties similar to adults/lansoprazole increases mean intragastric pH in 24 hours and the % of time in which pH is above 3 or 4
Gunasekaran et al. ⁷¹	Lansoprazole 15 or 30 mg Studies carried out five days after beginning of use	Open, multicentric	Adolescents aged 12 to 17 years	Pharmacokinetic properties similar to adults/lansoprazole 15 mg or 30 mg 1x/day used for five days increases the intragastric pH, relieves symptoms, and is well tolerated
		Phase I/II study
		Pharmacokinetics and dynamics	n = 63
				AE: allergies, diarrhea, rash, dizziness.
Fiedorek S et al. ⁷²	Lansoprazole 15 or 30 mg eight weeks	Open	Adolescents aged 12 to 17 years	Lansoprazole 15 and 30 mg reduced symptoms of adolescents with NERD and EE, respectively. Both doses were considered safe
		Phase I/II study	n= 64 NERD (15 mg)
		Efficacy and safety	n= 23 EE (30 mg)
				AE: headache, abdominal pain, nausea and dizziness.
Gold BD et al. ⁷³	Esomeprazole 20 and 40 mg Eight weeks	Multicentric, randomized, and double-blinded non placebo-controlled	Adolescents aged 12 to 17 years	Esomeprazole decreased symptoms in both groups
			n = 148	AE: headache, 8%; abdominal pain, 3%; nausea, 2%; diarrhea, 2%. No severe AE
Orenstein SR et al. ⁵³	Lansoprazole four weeks	Multicentric, double-blinded, parallel, placebo-controlled.	Infants aged 1 to 12 months n = 162	54% of response in the two groups
Tolia V et al.⁷⁴	Esomeprazole oral route 5 or 10 mg/day < 20 kg 10 or 20 mg/day > 20 kg 0.2 or 1 mg/kg/day Eight weeks	Multicentric, randomized, parallel and double-blinded (for dose).	1 to 11 yearsn = 109	GERD confirmed endoscopically or histologically
				Healing of macro or microscopic erosive esophagitis
Baker R et al. ⁷⁵	Pantoprazole delayed release oral suspension	Multicentric, randomized, and double-blinded.	1 to 5 years. n = 60	GERD confirmed endoscopically or histologically
	0.3; 0.6 and 1.2 mg/kg			Improvement of symptoms
	Eight weeks			AE did not increase with higher doses
Winter et al.⁵¹	Pantoprazole delayed-release oral granules	Randomized, double-blinded, placebo-controlled (treatment and withdrawal)	1 to 11 months n = 106	Patients with GERD symptoms
				In blind phase, no differences between the withdrawal of pantoprazole or placebo due to lack of efficacy
	1.2 mg/kg/day
	Four weeks of pantoprazole and four weeks double-blind pantoprazole x placebo			Safe and well tolerated
Tammara BK et al. ⁷⁶	Pantoprazole 0.6 mg/kg 1.2 mg/lg	Multicentric, open, randomized. Pharmacokinetics	Study 1 - 1 month to 12 months n = 43	Exposure increases with increasing dose, but there is great individual variation.
Study 1	Oral granules		Study 2 - 1 year to < 6 years	Exposure was similar to adults.
Study 2	Measurements performed at least after five consecutive doses		n = 17	Well tolerated.
Ward RM et al. ⁷⁷	Delayed-release pantoprazole tablets	Multicentric, open, randomized.	6 to 16 years.	Patients with GERD have the same systemic exposure of adults.
	20 or 40 mg/day		n = 38	No serious adverse effects.
	Measurements performed 12 hours after a single dose and two to four hours after multiple doses	Pharmacokinetics and safety
Sandström M et al. ⁷⁸	Esomeprazole IV 1x/day Four days	Multicentric, open, randomized, Phase I	0 to 17 years.	Clearance increases with weight and age.
				Well tolerated
				31 patients with AE
		Pharmacokinetics and tolerability IV	n = 57	No severe AE
Kukulka M et al. ⁷⁹	MR dexlansoprazole 30 or 60 mg for seven days	Multicentric, parallel, open, Phase I Pharmacokinetics and safety	2 to 17 years. n = 36	Pharmacokinetics similar to adults Mild adverse effects (33.3%)
Winter H et al. ⁸⁰	Esomeprazole 2.5 to 10 mg/day Four weeks	Multicentric, randomized, double-blinded, placebo-controlled (treatment and withdrawal)	1 to 11 months n = 98	There was no statistical difference in treatment interruption due to worsening of symptoms between esomeprazole and placebo
Hassall et al.⁴⁶	Omeprazole 0.7 to 3.5 mg/kg/day 21 months	Prospective, open, long-term to test maintenance dose.	1 to 16 years with healed EE n= 32 (completed the study)	Remission was achieved with continuous use of omeprazole in most patients. 60% required more than half of the dose required for healing

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[1] * Corresponding author. E-mail: cristinatarga@terra.com.br (C.T. Ferreira).