GERD Infant

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Gastroesophageal Reflux: A Critical Review of Its Role in Preterm Infants Christian F. Poets, MD From the Department of Neonatology, University of Tuebingen, Tuebingen, Germany ABSTRACT There is widespread concern about gastroesophageal reflux (GER) in preterm infants. This article reviews the evidence for this concern. GER is common in infants, wh..

    Gastroesophageal Reflux: A Critical Review of Its Role in Preterm Infants

    Christian F. Poets, MD

    From the Department of Neonatology, University of Tuebingen, Tuebingen, Germany

ABSTRACT There is widespread concern about gastroesophageal reflux (GER)in preterm infants. This article reviews the evidence for thisconcern. GER is common in infants, which is related to theirlarge fluid intake (corresponding to 14 L/day in an adult) andsupine body position, resulting in the gastroesophageal junction’sbeing constantly "under water." pH monitoring, the standardfor reflux detection, is of limited use in preterm infants whose gastric pH is >4 for 90% of the time. New methods such asthe multiple intraluminal impedance technique and micromanometriccatheters may be promising alternatives but require carefulevaluation before applying them to clinical practice. A criticalreview of the evidence for potential sequelae of GER in preterminfants shows that 1) apnea is unrelated to GER in most infants,2) failure to thrive practically does not occur with GER, and3) a relationship between GER and chronic airway problems hasnot yet been confirmed in preterm infants. Thus, there is currentlyinsufficient evidence to justify the apparently widespread practiceof treating GER in infants with symptoms such as recurrent apneaor regurgitation or of prolonging their hospital stay, unlessthere is unequivocal evidence of complications, eg, recurrentaspiration or cyanosis during vomiting. Objective criteria thathelp to identify those presumably few infants who do requiretreatment for GER disease are urgently needed.

    Abbreviations: GER, gastroesophageal reflux • CMA, cow milk protein allergy • TLESR, transient lower esophageal sphincter relaxation • GERD, gastroesophageal reflux

    disease • MII, multiple intraluminal impedance • AOP, apnea of prematurity • NICU, neonatal intensive care unit

     Gastroesophageal reflux (GER) is common in preterm infants,occurring on average 3 to 1,2 5 times per hour, but to what extentis it a clinical problem? A recent survey of current practiceestimated that 19% of preterm infants admitted to US teachinghospitals received 3 cisapride. Thus, many neonatologists seemto consider GER indeed a problem, but what is the evidence?This article revisits the pathogenesis of GER in preterm infantsand discusses methods for reflux detection, cow milk proteinallergy (CMA) as a potential differential diagnosis, and clinicalproblems potentially resulting from GER.

PATHOGENESIS OF GER IN INFANTS Reflux may occur when the lower esophageal sphincter relaxes.In an upright adult, gas will exit the stomach during thesetransient lower esophageal sphincter relaxations (TLESRs), causingbelching. In a subject lying supine, however, the gastroesophageal junction is constantly under water, and liquid instead of gaswill enter the esophagus. The quantity of the reflux dependson the fluid volume inside the stomach. The volume of fluidgiven to an infant (180 mL/kg per day) would correspond to adaily intake of 14 L/day in an adult. GER in an otherwise healthyinfant may simply serve as a pop-off

4valve to cope with thishigh volume. Thus, GER may be a completely normal phenomenonin infants, and its frequent occurrence in this age group maybe merely a result of their age-specific body position and highfluid intake. Whether GER will become clinically relevant willthen depend on the quality (eg, pH) and the quantity of the refluxate. 5These theoretical considerations were recently confirmed inpreterm infants. Using a micromanometric transducer devicealso incorporating a pH catheter and a feeding tube, 5 Omari etal studied TLESR in 36 preterm infants, 14 of whom had symptomaticGER, ie, GER disease (GERD). They found that both symptomaticand asymptomatic infants had 92% and 94%, respectively, of theirreflux episodes associated with TLESR. The latter were triggeredby gastric distension (eg, feeding) and abdominothoracic straining(eg, during motion). TLESRs were equally common in infants withand without GERD, the only group difference being a higher proportionof acid GER (16.5% vs 5.9%) in symptomatic infants. Acid GERwas reduced by low-volume feeds and shorter feeding intervals.The authors concluded that infants with GERD do not have moreTLESRs but some anatomic or sensory variation that increasesthe likelihood for liquid and/or acid 5 reflux to occur duringTLESR. One factor that increases this likelihood is a feeding tube.Using the multiple intraluminal impedance technique, a pH-independentmethod for reflux detection (see below), we studied the frequencyof GER with and without an 8-French nasogastric tube passing through the lower esophageal sphincter. We found that the frequencyof GER almost doubled when the tube ended inside the stomachinstead of the esophagus, ie, when lower 6 esophageal sphinctercompetence was likely impaired. A traditional view has been that infants with GERD have delayedgastric emptying, 5allowing more time for reflux to occur aftera meal. Recently, however, both Omari et al 7 and Ewer et alshowed that gastric emptying was not delayed in infants withGERD. This finding has practical consequences as it questionsthe rationale for prokinetics in the treatment of GERD. Afterthe recent withdrawal of cisapride, there is now increasing interest in the use of erythromycin, which binds to neural motilinreceptors and stimulates antral contractions and, in lower doses,induces antral migrating motor complexes, which 8 are importantfor gastric emptying. Although 2 recent randomized, controlledtrials reported a more rapid achievement of full oral feedsin infants who were treated with 9,10 erythromycin (1012 mg/kgper day), there remain several concerns with this practice, including the potential to induce cardiac arrhythmias, pyloricstenosis, or septicemia from 9 multiresistant organisms. Also,a recent developmental study on the effects of erythromycinon migrating motor complexes showed that these were inducedonly in 11 infants with gestational ages of 32 weeks or older.Delayed feeding advancements resulting in prolonged parenteralnutrition, however, are a problem mainly in infants who areborn well before 32 weeks’ gestation. Thus, the role ofdelayed gastric emptying in promoting GER and the potentialusefulness of erythromycin in treating the physiologically slowgastrointestinal motility in this age group remain at presentunclear.

METHODS FOR REFLUX DETECTION Reflux detection requires continuous measurements; that 1 or2 reflux episodes occur during a 10-minute radiologic, scintigraphic,or sonographic investigation does not allow 12 any conclusion asto whether a patient has GERD. For this reason, pH monitoringhas

become the "gold standard" for reflux detection. With theintroduction of antimony pH electrodes, this technique has becomeeasy to use and also allows measurements at multiple sites,eg, in both the stomach and the esophagus, or above the loweresophageal 13 sphincter and at the pharyngeal level. The maindisadvantage of pH monitoring is that it relies on gastric acidity:GER cannot be detected when gastric pH is >4. This is relevant in infants, particularly those who are born preterm, who mayhave gastric pH values >4 13,14 for >90% of the time, makingit almost impossible to detect GER by this technique. A potential solution to this dilemma is the multiple intraluminalimpedance (MII) technique, which has recently become commerciallyavailable. This technique is based on the intraluminal measurementof electrical impedance between a number of closely arrangedelectrodes during a bolus passage. Electrical impedance is definedas the ratio 15between voltage and current and is inversely proportionalto electrical conductivity. The underlying principle of MIIis to record changes in impedance in the gastrointestinal lumenthat are caused by the passage of a bolus, with air having alow conductivity and yielding an impedance increase and liquidhaving a high conductivity yielding an 16 impedance decrease.On the basis of the temporal sequence of these changes in impedance,it can be identified whether a change in impedance is causedby a bolus moving in an antegrade (eg, swallow) or a retrograde(reflux, belching) direction. The 17 technique has been used tostudy upper and lower gastrointestinal motility in adults.In infants, it has been used mainly for GER detection, for whichit has been shown to be extremely sensitive, detecting bolusvolumes as small as 0.1 mL, and to yield 18,19 reproducible results.Its major drawback is that analysis is currently extremely time- consuming,but semiautomatic analysis tools, which may solve this problem,are under 20 15 development. A recent review of this technique isavailable. An additional potential alternative is the micromanometric feedingassembly combined 5,21with an antimony micro pH electrode developedby Omari et al. This assembly, however, requires a catheteracross the lower esophageal sphincter, which may interfere 5 withsphincter competence, increasing the likelihood of GER. 22A practical approach to reflux detection was recently suggestedby James and Ewer. These authors performed acid tests in oropharyngealsecretions. Litmus testing for acid (1 or more positive acidtests) was found to have 89% sensitivity and 80% specificity compared with 24-hour pH monitoring. The authors suggested thatthe demonstration of 2 or more positive acid tests in oropharyngealsecretions is sufficient to initiate positional 23 treatment ininfants with symptoms suggestive of GERD. The scientific evidencefor this suggestion, however, remains scant, but given the prevailinguncertainty regarding the diagnosis of GERD, it may be a reasonablecompromise.

CMA AS A DIFFERENTIAL DIAGNOSIS That recurrent vomiting in a preterm infant can be a symptomof an underlying anatomic, metabolic, infectious, or centralnervous disorder is widely known; an extensive review of theseunderlying conditions is beyond the focus of this article. Inaddition, vomiting, feeding problems, failure to thrive, andirritability, the leading symptoms of GERD, are characteristicof CMA. This disorder affects between 0.3% and 7.5% of terminfants, 24 usually within the first 4 months of life. Recently,it has also been described in preterm infants, who shared thesame symptoms and also had the eosinophilic inflammation ofthe 25 antral mucosa characteristic of CMA in older infants.Although the incidence of CMA

     at this age is yet unknown, theauthors suggested that CMA should be considered in 25 preterm infantswith recurrent vomiting and irritability. Confirmation ofthis diagnosis (and treatment) consists of a trial of cow milkproteinfree formula. It has to be kept in mind, however,that some infants are also allergic to hydrolysate and willrespond only to an amino acidbased formula. More dataon the relevance of this potential underlying diagnosis in preterminfants with recurrent vomiting are required.

    POTENTIAL CLINICAL PROBLEMS RESULTING FROM GER Apnea Problems that are frequently cited in conjunction with GER areapnea, failure to thrive, 26and airway problems such as recurrentaspiration or wheezing. Preterm infants often exhibit bothapnea and GER, and the belief that the latter is an underlyingcause of apnea of prematurity (AOP) is evident from the factthat it was the most frequent indication for 3 the widespreaduse of cisapride in preterm newborns (see above). The evidencefor this proposed relationship, however, is largely circumstantialand includes the observation 27that AOP occurs frequently in theimmediate postprandial period, ie, when GER is most likelyto occur. It also includes data from animal studies that showthat apnea can be induced by the instillation of small amountsof liquid into the larynx, resulting in 28stimulation of laryngealchemoreceptors, and the observation that apneas are more 29 likelyto occur after episodes of regurgitation. The latter observationis supported further 30,31by anecdotal reports of apneic spells occurringimmediately after a reflux episode. Most studies that attemptedto document a temporal relationship between apnea and GER, 3238 however,failed to do so. We recently addressed this issue by performing simultaneousrecordings of MII and cardiorespiratory signals in 19 preterminfants with AOP. The frequency of apnea occurring within 20seconds of a reflux episode was not significantly differentfrom that during reflux-free epochs (0.19 vs 0.25/min). Thesame was true for desaturations and bradycardias, which areoften considered more likely than central apneas to be associated with GER. Only 9 (4.8%) desaturations were associated with areflux episode, and the frequency of desaturation occurringwith GER was again not significantly different from that occurringduring reflux-free epochs. Also, only 1 of 44 bradycardias occurredwithin ?20 seconds of a reflux episode. Thus, both cardiorespiratoryevents and GER were 1 common in these infants but were not temporallyrelated. 39 Similarly, Page and Jeffery observed that preterm infantswho were studied at term- equivalent age responded to the pharyngealinfusion of small volumes of 0.9% saline or water during sleepwith a volume-dependent increase in swallowing frequency butnot with an increased apnea rate. These authors suggested thatapnea and bradycardia are predominantly evoked when the larynxrather than the pharynx is stimulated, which does 39 not usuallyoccur during regurgitation of small amounts of liquid. Finally,treatment 401,39,40with cisapride or metoclopramide had no effect onAOP. Infants in these studies, however, were not selectedbecause they had symptoms suggestive of GER-related apnea. Thus,there may be the occasional infant with such symptoms, as alsoreported in case 30,31 studies. In the majority of infants withAOP, however, the latter seems to be unrelated to GER and thereforedoes not justify provision of anti-reflux treatment.

    Failure to Thrive 26Failure to thrive, a symptom frequently reported in older infantswith GER, seems rare

41in preterm infants who exhibit this disorder.Khalaf et al, in a cohort study of 150 neonatal intensivecare unit (NICU) residents evaluated by a pH study, did notfind a significant difference in body weight between infantswith and without GER. A recent case-control study from anotherNICU confirmed these findings. Specifically, weekly weight gainand caloric intake were similar between groups. Nonetheless,infants with GER had a significantly longer hospital stay thanthose without (99 vs 70 days; P 42 < .002). Thus, it seemsthat the close attention given to weight gain in NICU residents seems to protect against the failure to thrive often seen inolder infants with GERD but that physicians are still sufficientlyconcerned by GER to keep these infants in the hospital for longerperiods of time. Whether this concern is justified remains tobe proved.

Airway Problems GER may undoubtedly cause pulmonary aspiration, but this isusually a dramatic event that is clinically and radiologicallyapparent. The more controversial issue is whether chronic airwayproblems may be caused by clinically inapparent or "silent"GER. In one of the first studies that addressed this issue ininfants, midesophageal pH, exhaled CO, 2 and breathing movementswere measured in six 2- to 12-month-old infants with stridor;5 of these also had some clinical suspicion of GER. Within 5to 20 minutes after onset of acid reflux, retractions and stridorwere observed in all infants. Stridor improved with medicalmanagement (bethanechol, positioning, feed thickeners) in all5 infants in whom 43 44this was attempted. More recent, Bibi etal studied 116 children, aged 3 to 28 months, with flexiblebronchoscopy including bronchoalveolar lavage and chest radiography;54 of these had tracheo- and/or bronchomalacia. Patients withrecurrent vomiting and/or feeding-related or unexplained cough(24 in the malacia group, 41 in the control group) underwentpH monitoring and barium radiography. Children with airway malaciawere more likely than those without to have GER (70% vs 39%;P < .01) and had higher scores for lipid-laden alveolar macrophagesin their bronchoalveolar lavage fluid (92101 vs 52), suggesting reflux-related recurrent microaspirations in theformer group. Infants with GER were treated with antirefluxtherapy, and an improvement in respiratory symptoms 44 was noted. Several issues remain unclear from these studies. First, assuminga causal relationship, is GER cause or effect of the respiratorysymptoms, ie, does it result in airway narrowing via stimulationof airway receptors and/or recurrent aspiration, or do the large intrathoracic pressure swings caused by the upper airway narrowingfacilitate GER? Although the respiratory response to GER treatmentdescribed above supports the first option, it cannot prove it.It is not even clear whether there is any causal relationship.For example, a recent 1-year follow-up study of 63 infants withGER did not find an 45increased prevalence of airway problemsin this cohort. Also, a comparison between infants with respiratorysymptoms suggestive of GER and those with gastrointestinal symptomsonly found less GER in the upper esophagus in the respiratorythan in the 46control group (eg, a mean reflux index of 0.95 vs4.0). Second, are data from older infants and toddlers transferableto preterm infants? The only study that investigated the relationshipbetween airway problems and GER in this age group studied infantswith bronchopulmonary dysplasia and found less reflux in theupper esophagus in these than in 47those without bronchopulmonarydysplasia. Thus, despite the above data from older infants,there is currently no evidence that GER is a significant contributorto chronic airway problems in preterm infants. Why then treatit?

    CONCLUSION Clearly, there are some preterm infants in whom GER causes seriousproblems, such as aspiration of gastric contents or recurrentcyanosis, or whose recurrent vomiting is related to CMA. Theseinfants undoubtedly warrant treatment, which should involvea stepwise approach, starting with prone or left lateral positioning(under cardiorespiratory 48,49 5monitoring) followed by frequentlow-volume feeds, removal of feeding tubes 6 250 between feeds,feed thickening, possibly histamine-2 receptor antagonists,and finally 25 a trial of cow milk proteinfree formula.They should be viewed separately, however, from the vast majorityof infants who have physiologic GER and do not require treatment. There is currently insufficient evidence to justify the seeminglywidespread practice of treating GER in infants with symptomssuch as recurrent apnea and recurrent regurgitation or prolongingtheir hospital stay. Objective criteria that help to identify those presumably few infants who do require treatment for GERDare urgently needed.


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