موارد شایع در برخورد با زردی نوزادان

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موارد شایع در برخورد با زردی نوزادان

دکتر مجید محمدی زادهفوق تخصص نوزادان

ئت علمی دانشگاه علوم پزشکی اصفهانیعضو ه

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اهداف آموزشی جلسهشرکت کنند2گان در پایان جلسه:•

چرخه تولید و دفع بیلی روبین را مرور کرده باشند•تعریف و سیر زردی فیزیولوژیک را در نوزادان ترم و نزدیک ترم بدانند•انواع زردی مرتبط با شیر مادر و درمان آن را بدانند•فاکتورهای خطر زردی نوزادی را بشناسند•تشخیص زردی نوزاد در روزهای اول تولد پیش از ترخیص از بیمارستان و •

چگونگی پی گیری آن پس از ترخیص را بدانندارزش و موارد کاربرد ترانس کوتانئوس بیلی روبینومتری را در زردی •

نوزادی بدانندتشخیص آزمایشگاهی زردی و بررسی های الزم را برای علت زردی بدانند•کلیات درمان زردی را در نوزاد ترم و نزدیک ترم بدانند•اصول حاکم بر فوتوتراپی در منزل را بشناسند•نقش فنوباربیتال در درمان زردی نوزاد را بشناسند•

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neonatal bile pigment metabolism

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enterohepatic Circulation

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PHYSIOLOGIC JAUNDICE

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PHYSIOLOGIC MECHANISMS OF NEONATAL JAUNDICE

Increased bilirubin load on liver cellIncreased erythrocyte volumeDecreased erythrocyte survivalIncreased early labeled bilirubinIncreased enterohepatic circulation of bilirubin

Decreased hepatic uptake of bilirubin from plasmaDecreased ligandinDecreased bilirubin conjugationDecreased uridine diphosphoglucuronosyl transferase activityDefective bilirubin excretionExcretion impaired but not rate limiting

8

TERM NEONATE

• Physiologic jaundice is characterized by a progressive rise in TSB concentration from approximately 2 mg/dL in cord blood to a mean peak of:– 5 to 6 mg/dL between 48 and 120 hours of age in white and African-

American babies, with most infants presenting at 72 to 96 hours of age

– 10 to 14 mg/dL between 72 and 120 hours of age in Asian-American babies

• This is followed by a rapid decline to approximately 3 mg/dL by:– the fifth day of life in white and African-American neonates

– the seventh to tenth day in Asian-American neonates

(phase 1 physiologic jaundice)

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TERM NEONATE

• During the period from the fifth to tenth day of life in white and African-American infants, TSB concentrations decline slowly, reaching the normal adult value of less than 2 mg/dL by the end of that period

(phase 2 physiologic jaundice)

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TERM NEONATE

• The epidemiology is dependent, in part, on the prevalence of formula feeding in a population, with lower peak TSB values occurring among the predominantly formula-fed infants

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PRETERM NEONATE

• physiologic jaundice in premature neonates is more severe than in full-term neonates

• mean peak TSB concentrations reaches 10 to 12 mg/dL by the fifth day of life

• mean peak unconjugated bilirubin concentrations of 10 to 12 mg/dL may be associated with acute bilirubin encephalopathy or kernicterus in certain high-risk low-birthweight neonates

• all degrees of visible jaundice in premature neonates should be monitored closely and investigated fully

12

LATE PRETERM NEONATE

• Late preterm gestation is an important risk factor for the development of severe neonatal hyperbilirubinemia and kernicterus

• Scrupulous attention to screening for jaundice in the newborn nursery, adequate lactation support, parental education and appropriate postdischarge follow-up should facilitate institution of treatment when clinically indicated

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POST-TERM NEONATE

• nearly all postmature neonates and approximately half of all SGA full-term neonates may be expected to have little or no physiologic jaundice

• peak TSB concentrations is less than 2.5 mg/dL

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Mechanisms for phase 1 physiologic jaundice

• It results from the combination of a sixfold increase in the load of bilirubin presented to the liver and a marked deficiency in UGT activity

• The very large increase in bilirubin load appears to result from both increased de novo bilirubin synthesis and enteric reabsorption of unconjugated bilirubin

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Mechanisms for phase 2 physiologic jaundice

• It appears to result from an imbalance in which hepatic uptake of bilirubin remains diminished while the increased bilirubin load presented to the liver persists

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Jaundice Associated with Breast Feeding

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Jaundice Associated with Breast Feeding

• Breast-feeding failure jaundice

• Breast milk jaundice

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PATHOGENESIS OF JAUNDICE ASSOCIATED WITH BREAST-FEEDING

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Prevention of breast-feeding failure jaundice

• encouraging frequent (at least 8 to 12 times per day for the first several weeks) breast feeding

• avoiding supplementation with water or glucose solutions • accessing maternal lactation counseling

• intensive support of the breast-feeding

• mother is necessary, especially in view of early discharge policies in place at many hospitals

• both during birth hospitalization and after hospital discharge, the newborn should be closely monitored for weight gain, adequate urination and stool formation, and the development of jaundice

20

Breast milk jaundice

• occurs after the first 3 to 5 days of life and may last into the third week of life or beyond

• Epidemiologic studies report that 10% to 30% of breast-fed infants in the second to sixth week of life are affected, with some having hyperbilirubinemia into the third month

21

• Interruption of breast feeding is not recommended unless TB concentrations reach levels that might be of danger to the infant

• For such diagnosis, it is necessary to confirm that the TB is primarily unconjugated, that thyroid function tests are normal, and that there is no evidence of urinary infection

• In the situation in which the infant is thriving and the TB does not reach dangerous levels, it may be prudent to observe the infant

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DIAGNOSIS

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Visual assessment

• Cutaneous icterus in the newborn is usually not reflected with TSB concentrations of less than 5 mg/dL

• As the intensity of jaundice increases, clinical icterus progresses in a caudal direction

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Visual assessment

• Because routine daily TSB determinations are not usually performed on full-term or even premature newborns, careful scrutiny of the nursery population several times a day by experienced personnel is essential to detect infants who are becoming jaundiced

• Visual assessment of jaundice, however, is largely subjective, inaccurate, and dependent on observer experience

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Transcutaneous bilirubinometry

• The technique offers an objective measurement of skin color, from which a reading- reflecting the TB- is derived

• Two devices, the BiliChek (Philips Childrens Medical Ventures, Monroeville, PA) and JM-103 Jaundice Meter (Konica Minolta/AirShields JM 103 Jaundice Meter, Draeger Medical AG and Co, Lubeck, Germany) are currently commercially available

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• A number of studies have shown that these instruments provide fairly accurate estimates of TB in term and near-term newborn infants of varying races and ethnicities, generally providing values within 2 to 3 mg/dL of the TB, if the TB is less than 15 mg/dL

• The technology tends to under-read the actual TB measurement and should be regarded as a screening mechanism rather than an accurate reflection of the TB

• The devices have been evaluated as potential

predischarge screening tools to identify infants at risk

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• TcB is a measurement of the yellow color of the blanched skin and subcutaneous tissue, not the serum and should be used as a screening tool to help determine whether the TSB should be measured

• Although TcB measurements provide a good estimate of the TSB level, they are not a substitute for TSB values, and a TSB level should always be obtained when therapeutic intervention is being considered

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• As with any point-of-care test, regular monitoring for appropriate quality assurance by comparison with TSB measurements is necessary

29


• The use of TcB screening reduces the number of blood tests for bilirubin determination compared to visual assessment without compromising detection of infants with significant TB values (eg, >75th percentile)

• There are significant variations among different instruments. When TcB is used clinically as a substitute for TB, values of new instruments should always be compared to TB performed by the laboratory to ensure good correlation

30


• A confirmatory TB should be measured in the following settings :

– When TcB exceeds the 75th percentile on the TB nomogram for phototherapy

– When the TcB exceeds the 95th percentile on the TcB nomogram

– At follow-up after discharge, the TcB >13 mg/dL

– When the TcB value is at 70% of the TSB level recommended for the use of phototherapy

– When therapeutic intervention is being considered. Therapy should be initiated while awaiting confirmatory results

– If the management plan would be altered by considering the TB to be equal to TcB + 3 mg/dL

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• additional studies are warranted to establish a strong and reliable correlation between TcB and TB: – at levels of 15 mg/dL and higher

– during and after phototherapy

– in premature or low-birthweight infants, before its routine use can be advocated

32

Predischarge risk assessment for prediction of subsequent severe hyperbilirubinemia

• Combining a predischarge measurement of TSB or TcB with clinical risk factors might improve the prediction of the risk of subsequent hyperbilirubinemia

• In addition, when interpreted by using the hour-specific nomogram, measurement of TSB or TcB also provides a quantitative assessment of the degree of hyperbilirubinemia

• This provides guidance regarding the need (or lack of need) for additional testing to identify a cause of the hyperbilirubinemia and for additional TSB measurements

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Risk Factors for Development of Severe Hyperbilirubinemia

in Infants of 35 or More Week's GestationMajor risk factorsPredischarge TSB or TcB level in the high-risk zoneJaundice observed in the first 24 hrBlood group incompatibility with positive direct antiglobulin test, other known hemolytic disease (G6PD deficiency), elevated ETCOc

Gestational age 35–36 wkPrevious sibling received phototherapyCephalohematoma or significant bruisingExclusive breastfeeding, particularly if nursing is not going well and weight loss is excessiveEast Asian race[*]

Minor risk factorsPredischarge TSB or TcB level in the high intermediate-risk zoneGestational age 37–38 wkJaundice observed before dischargePrevious sibling with jaundiceMacrosomic infant of a diabetic motherMaternal age ≥25 yrMale genderDecreased riskTSB or TcB level in the low-risk zoneGestational age ≥41 wkExclusive bottle feedingBlack raceDischarge from hospital after 72 hr

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Important Risk Factors for Severe Hyperbilirubinemia

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Hyperbilirubinemia Neurotoxicity Risk Factors

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Other Risk Factors for Severe Hyperbilirubinemia to be Considered

with the Gestational Age and the Pre-discharge TSB or TcB level

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Risk designation of term and near-term well newborns based on their hour-specific serum bilirubin values

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Nomogram of hour-specific transcutaneous bilirubin measurements (mg/dL) for healthy fullterm newborns

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Predischarge risk assessment for prediction of subsequent severe hyperbilirubinemia

• For those infants from whom 2 successive TSB or TcB measurements are obtained, it is helpful to plot the data on the nomogram to assess the rate of rise

• Hemolysis is likely if the TSB/TcB is crossing percentiles on the nomogram and suggests the need for further testing and follow-up

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Algorithm providing recommendations for management and follow-up according to predischarge bilirubin measurements, gestation, and risk factors for subsequent hyperbilirubinemia

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42


43


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Follow up after discharge

• It should be noted that, even with a low predischarge TSB or TcB level, the risk of subsequent hyperbilirubinemia is not zero, so appropriate follow-up should always be provided

• Most infants discharged at 72 hours should be seen within 2 days of discharge

• Earlier follow-up might be necessary for infants who have risk factors for severe hyperbilirubinemia

• Those in the lower risk zones with few or no risk factors can be seen later

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Laboratory Evaluation of the Jaundiced Infant of 35 or More Weeks' Gestation

INDICATIONS ASSESSMENTSJaundice in first 24 hr Measure TcB and/or TSB

Jaundice appears excessive for infant's age Measure TcB and/or TSBInfant receiving phototherapy or TSB rising rapidly (i.e., crossing percentiles [Fig 102-8]) and unexplained by history and physical examination

Blood type and Coombs test, if not obtained with cord bloodComplete blood count and smearMeasure direct or conjugated bilirubinIt is an option to perform reticulocyte count, G6PD, and ETCOc, if availableRepeat TSB in 4–24 hr depending on infant's age and TSB level

TSB concentration approaching exchange evels or not responding to phototherapy

Perform reticulocyte count, G6PD, albumin, ETCOc, if available

Elevated direct (or conjugated) bilirubin level Do urinalysis and urine culture. Evaluate for sepsis if indicated by history and physical examination

Jaundice present at or beyond age 3 wk, or sick infant

Total and direct (or conjugated) bilirubin levelIf direct bilirubin elevated, evaluate for causes of cholestasisCheck results of newborn thyroid and galactosemia screen, and evaluate infant for signs or symptoms of hypothyroidism

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When we search to determine the cause of jaundice

• it appears in the 1st 24–36 hr of life

• 4 mg/dL or greater in cord blood

• serum bilirubin is rising at a rate faster than o.5 mg/dL during a 4-8 hour period

• serum bilirubin is rising at a rate faster than 5 mg/dL/24 hr

• serum bilirubin is 13-15 mg/dL or greater in full-term infants (especially in the absence of risk factors) or 10 mg/dL or greater in preterm infants

• jaundice persists after 10–14 days of life

• direct-reacting bilirubin is >2 mg/dL at any time

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Other factors suggesting a non physiologic cause of jaundice

• family history of hemolytic disease

• vomiting, lethargy, poor feeding, excessive weight loss, apnea, bradycardia, abnormal vital signs (including hypothermia)

• pallor, hepatomegaly, splenomegaly

• signs of kernicterus

• light-colored stools, dark urine positive for bilirubin

• failure of phototherapy to lower bilirubin

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Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation

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Guidelines for exchange transfusionin hospitalized infants of 35 or more weeks' gestation

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HOME PHOTOTHERAPY

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• A physician who considers the use of home phototherapy should limit its use to infants with the following characteristics:

– term infants, older than 48 hours, otherwise healthy – serum bilirubin concentration greater than 14 mg/dL but

less than 18 mg/dL – no elevation in direct-reacting bilirubin concentration – diagnostic evaluation negative

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• Prior to therapy, a diagnostic evaluation should include:

– (1) history and physical examination

– (2) hemoglobin concentration or hematocri

– (3) WBC count and differential coun

– (4) blood smear for red cell morphology platelet

– (5) reticulocyte count

– (6) total and direct-reacting bilirubin concentration

– (7) maternal and infant blood typing Coombs test

– (8) urinalysis including a test for reducing substances

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• Arrangements must be made to measure the infant’s serum bilirubin concentration at least every 12 to 24 hours depending on the previous concentration and the rate of rise

• The supervising physician should be in contact with the family daily during the period of treatment

68

• Subjective symptom descriptions are unreliable in infants and children

• younger than 8 to 12 years of age, and many of the• purported symptoms of GERD in infants and

children are• nonspecific

69

• The diagnosis of GERD is inferred when• tests show excessive frequency or duration of reflux• events, esophagitis, or a clear association of

symptoms• and signs with reflux events in the absence of• alternative diagnoses

70

• Although many tests have been used to diagnose• GERD, few studies compare their utility

• Importantly,• it is not known whether tests can predict an

individual• patient’s response to therapy.

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Tests are useful to:

• document the presence of pathologic reflux or its complications

• establish a causal relation between reflux and symptoms

• evaluate therapy

• exclude other conditions

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• Because no test can address all of these questions:

– they must be carefully selected according to the information sought

– the limitations of each test must be recognized

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History and Physical Examination

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The major role

• to exclude other more worrisome disorders that present with vomiting

• to identify complications of GERD

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Table 2. Warning signals requiring investigation in infant with regurgitation or vomiting

Bilious vomiting Failure to thrive

Consistently forceful vomiting Onset of vomiting after 6 months of life

Diarrhea Constipation

Fever Hepatosplenomegaly

Macro/microcephaly Bulging fontanelle

Abdominal tenderness or distension

Documented or suspected genetic/metabolic syndrome

Lethargy Gastrointestinal bleeding Hematemesis HematocheziaSeizures

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• typical presenting symptoms of reflux disease in childhood vary with age and underlying medical condition

• however, the underlying pathophysiology of GERD is thought to be similar at all ages including the premature infant

77

• Symptoms and signs associated with reflux are• Nonspecific

• Regurgitation, irritability, and vomiting are common in

• infants with physiologic GER or GERD, but• are indistinguishable from regurgitation, irritability,

and• vomiting caused by food allergy, colic and• other disorders.

78

• The severity of reflux or esophagitis found• on diagnostic testing does not directly correlate

with the• severity of symptoms

• As in adults, individual symptoms in children generally

• are not highly predictive of findings of GERD by• objective studies

79

• Because individual symptoms do not consistently correlate

• with objective findings or response to medical• treatment, parent- or patient-reported questionnaires• based on clusters of symptoms have been developed

• However, no symptom or cluster of symptoms has been• shown to reliably predict complications of reflux or to• predict those infants likely to respond to therapy

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Esophageal pH Monitoring

81

• It measures• the frequency and duration of acid esophageal reflux

episodes

• Slow electrode response times (antimony• being the slowest) do not alter the assessment of total• reflux time substantially but may affect the accuracy of• correlation between symptoms and reflux episodes

• Esophageal pH monitoring is insensitive to weakly acid• and nonacid reflux events

82

• By convention, a drop in intraesophageal pH <4.0 is• considered an acid reflux episode

• Although interpretation of pH monitoring data• is simplified by computerized analysis, visual

inspection• of the tracing is required to detect artifacts and

evaluate• possible clinical correlations

83

• Common parameters• obtained from pH monitoring include the total

number• of reflux episodes, the number of reflux episodes

lasting• >5 minutes, the duration of the longest reflux

episode,• and the RI (percentage of the entire record that

esophageal• pH is <4.0)

84

• The RI is the most commonly used summary score

• The normal pediatric ranges previously in general• use were obtained using glass electrodes (65,83),

but such• data poorly correlate with that obtained by the

antimony• electrodes now in common use (84). Moreover,

normal• data depend on the definition of a ‘‘normal

population.’’

85

• specific• ‘‘cutoff’’ values that discriminate between

physiologic• GER and pathologic GERD are suspect; rather, it is

likely• that a continuum exists such that normal ranges

should be• regarded as guidelines for interpretation rather than• absolutes

86

• Abnormal esophageal pH monitoring has not been• shown to correlate with symptom severity in infants

• The clinical utility of pH studies and their• ability to determine a causal relation between specific• symptoms (eg, pain, cough) and reflux remain controversial• in adults (101), and are not validated in• pediatric patients

• the reliability of data obtained by this method to predict improvement• following either medical or surgical antireflux• therapy has not been established

87

• Esophageal pH monitoring provides a quantitative• measure of esophageal acid exposure with

established• normal ranges, but the severity of pathologic acid

reflux• does not correlate consistently with symptom

severity or• demonstrable complications

88

• Esophageal pH• monitoring is useful for evaluating the efficacy of

antisecretory• Therapy

• It may be useful to correlate symptoms• (eg, cough, chest pain) with acid reflux episodes, and to• select those children with wheezing or respiratory symptoms• in which acid reflux may be an aggravating factor

• The sensitivity and specificity of pH monitoring are not• well established

89

• Esophageal pH monitoring may be abnormal• in patients with conditions other than GERD, such

as• gastric outlet obstruction, motility disorders, and

esophagitis• due to other disorders, including eosinophilic

esophagitis

90

Combined Multiple Intraluminal Impedance and pH Monitoring

91

• MII is a procedure for measuring the movement of• fluids, solids, and air in the esophagus

• It is a relatively• New technology that provides a more detailed description• of esophageal events with a more rapid response time• than current pH-monitoring technology

• MII measures• changes in the electrical impedance (ie, resistance)• between multiple electrodes located along an esophageal• catheter

92

• The direction and velocity of a bolus can be• Calculated

• The upward extent• of the bolus and the physical length of the bolus

can also• be evaluated

• MII can detect extremely small bolus• volumes

93

• The combined measurement of pH and• impedance (pH/MII) provides additional information

as to• whether refluxed material is acidic, weakly acidic,

or• Nonacidic

• Normal• values for all of the age groups have not yet been

established

94

• The combination• of pH/MII with simultaneous monitoring of• symptoms using video-polysomnography or manometry• has proven useful for the evaluation of symptom• correlations between reflux episodes and apnea, cough,• other respiratory symptoms and behavioral symptoms

• The technology is especially useful in• the postprandial period or at other times when gastric• contents are non-acidic

• The relation between weakly• acid reflux and symptoms of GERD requires clarification

95

• Whether combined esophageal pH and• impedance monitoring will provide useful

measurements• that vary directly with disease severity, prognosis,• and response to therapy in pediatric patients has• yet to be determined

96

Motility Studies

97

• Esophageal manometry measures esophageal peristalsis,

• upper and lower esophageal sphincter pressures, and

• the coordinated function of these structures during swallowing.

• Manometric studies are useful to confirm a• diagnosis of achalasia or other motor disorders of

the• esophagus that may mimic GERD

98

• Although esophageal manometry has been an• important tool in studying the mechanisms of GERD,• GERD cannot be diagnosed by esophageal manometry

• Esophageal manometry may be abnormal in patients• with GERD, but the findings are not sufficiently sensitive• or specific to confirm a diagnosis of GERD, nor to predict• response to medical or surgical therapy. It may be useful• in patients who have failed acid suppression and who• have negative endoscopy to search for a possible motility• disorder, or to determine the position of the LES to place• a pH probe

99

Endoscopy and Biopsy

101

EVALUATION AND MANAGEMENT OF THE PEDIATRIC PATIENT WITH SUSPECTED GERD

102

• The following sections describe the relation between

• reflux and several common signs, symptoms or symptom

• complexes of infants and children

• The evaluations• appropriate to establish a diagnosis of GERD and

recommendations• for management in each case are outlined

103

Recurrent Regurgitation and Vomiting

• The challenge is to distinguish regurgitation• and vomiting caused by reflux or reflux disease• from vomiting caused by numerous other disorders

• This can be confusing because reflux episodes• sometimes trigger vomiting

• Vomiting associated with reflux is• probably a result of the stimulation of pharyngeal sensory• afferents by refluxed gastric contents

• Laboratory• and radiographic investigation may be necessary to• exclude other causes of vomiting

105

Table 3. Differential diagnosis of vomiting in infants and children

106

Gastrointestinal obstruction InfectiousPyloric stenosisMalrotation with intermittent volvulusIntestinal duplicationHirschsprung diseaseAntral/duodenal webForeign bodyIncarcerated hernia

SepsisMeningitisUrinary tract infectionPneumoniaOtitis mediaHepatitis

Other gastrointestinal disorders Metabolic/endocrineAchalasiaGastroparesisGastroenteritisPeptic ulcerEosinophilic esophagitis/gastroenteritisFood allergyInflammatory bowel diseasePancreatitisAppendicitis

GalactosemiaHereditary fructose intoleranceUrea cycle defectsAmino and organic acidemiasCongenital adrenal hyperplasia

Neurologic ToxicHydrocephalusSubdural hematomaIntracranial hemorrhageIntracranial massInfant migraineChiari malformation

LeadIronVitamins A and DMedications—ipecac, digoxin, theophylline, etc

Renal OthersObstructive uropathyRenal insufficiency

Pediatric falsification disorder (Munchausen syndrome by proxy)Child neglect or abuseSelf-induced vomitingCyclic vomiting syndromeAutonomic dysfunction

CardiacCongestive heart failureVascular ring

107

Approach to the infant with recurrent regurgitation and vomiting

108

Approach to the infant with recurrent regurgitation and weight loss

110

• Malcolm WF, et al. Use of Medications for Gastroesophageal Reflux at Discharge Among Extremely Low Birth Weight Infants. Pediatrics 2008;121;22

111

• GER) occurs commonly in extremely low birth weight (ELBW) infants (birth weight• of 1000 g) and often is considered pathologic enough to warrant treatment with

medications that have not• been proved safe or efficacious for this population. Although information on the best

strategies for diagnosis and• treatment of GER in premature infants is largely extrapolated from studies of term

infants and older children,• clinicians continue to make the diagnosis and to initiate treatment in this high-risk

population with the intent of• improving outcomes.• The effects of GER in premature infants are largely undefined and poorly understood.

Cardiorespiratory compromise• among premature infants frequently is attributed to GER, although studies have failed

to show consistently this• association or a benefit of medical treatment.1–4 Reflux-specific behaviors have also

been shown to be unreliable• indicators of GER in premature infants.5 Despite this uncertainty, GER is a common

clinical diagnosis in NICUs and• has been associated with longer hospital stays and higher hospital costs

112

• The medical treatment of premature infants with the• presumed diagnosis of GER with antireflux medications,• such as H2 receptor blockers and prokinetic agents, is a• common occurrence in US NICUs, during hospitalization• and at discharge. Although studies have been unable to• demonstrate consistently the short-term benefits of antireflux• medications in preterm infants, H2 receptor• blocker therapy was shown to be used commonly for• very low birth weight infants and metoclopramide was• reported to be 1 of the 10 medications prescribed most• commonly in NICUs.8,9 Data on the effects of antireflux• medications on follow-up growth and development are• lacking. The objectives of this study were (1) to determine• the frequency of use of antireflux medications at• hospital discharge among ELBW infants in 16 academic• tertiary centers; (2) to identify risk factors associated• with being discharged from the hospital with antireflux• medications; and (3) to assess the contribution of the• clinical diagnosis of GER, defined on the basis of the use• of antireflux medications at discharge, to growth and• development at corrected ages of 18 to 22 months

114

Recommendations

115

• In infants and toddlers, there is no symptom or group of• symptoms that can reliably diagnose GERD or predict

treatment response

• Esophageal pH monitoring is a valid and reliable measure of esophageal acid

• exposure only.

• Combined multiple esophageal impedance-pH recording is superior

• to pH monitoring alone for evaluation of GER-related symptom

• association

116

• Endoscopic biopsy cannot determine whether esophagitis, if present, is due to reflux

• Absence of histological changes does not rule out reflux disease.

• There may be a role for nuclear scintigraphy to diagnose aspiration

• in patients with chronic refractory respiratory symptoms, but the technique is

• not recommended in patients with other potentially GER-related symptoms

117

• The presence of pepsin in broncho-alveolar lavage fluid is an indicator of

• GER-related aspiration, but its clinical utility remains to be established

• There is no evidence to support an empiric trial of pharmacologic

• treatment in infants and young children with symptoms suggestive of GERD

118

• Thickening of formula results in decreased visible reflux (regurgitation).

• Antireflux surgery should be considered only in children with GERD and failure of

• optimized medical therapy, or long-term dependence on medical therapy where

• compliance or patient preference preclude ongoing use, or life-threatening complications

119

• In the infant with recurrent regurgitation, a thorough history and physical examination

• with attention to warning signs are generally sufficient to allow the clinician to establish

• a diagnosis of uncomplicated GER

120

• In the infant with uncomplicated regurgitation, parental education, reassurance, and

• anticipatory guidance are recommended.

• Thickening of formula can be considered in addition to parental education, reassurance,

• and anticipatory guidance.

• In general, no other intervention is necessary. If symptoms worsen

• or do not resolve by 12 to 18 months of age or ‘‘warning signs’’ develop, referral to a

• pediatric gastroenterologist is recommended

121

• In the regurgitating/vomiting infant with poor weight gain despite adequate energy intake, urinalysis,

• CBC, electrolytes, urea/creatinine, and celiac screening are recommended; UGI series should be

• considered. Recommended dietary management includes a 2-week trial of extensively hydrolyzed/

• amino acid formula, thickened formula, or increased energy density. If dietary managements fails

• and/or if the investigations reveal no abnormalities, referral to a pediatric GI is recommended

122

• In otherwise healthy infants with unexplained crying, irritability, or distressed behavior, there is

• no evidence to support acid suppression

• In the infant or child with reflux esophagitis, initial treatment consists of lifestyle changes and

• PPI therapy. In most cases, efficacy of therapy can be monitored by the degree of symptom relief.

• In the infant with feeding refusal, acid suppression without earlier diagnostic evaluation is

• not recommended

123

• In the vast majority of infants, reflux is not related to pathologic apnea or to apparent

• life-threatening event, although a clear temporal relation exists in individual infants.

• In infants in whom this relation is suspected or if symptoms recur, impedance/pH recording

• in combination with polysomnographic recording may aid in establishing cause and effect

126

• Tipnis NA, Tipnis SM. Controversies in the Treatment of Gastroesophageal Reflux Disease in Preterm Infants. Clin Perinatol. 2009;36: 153–164

127

• GER typically is a physiologic process and is common in• term and premature infants

• When the retrograde movement of gastrointestinal contents

• results in injury to the esophagus or supra-esophageal structures, GER

• is considered pathologic, and the infant is identified as having gastrointestinal reflux

• disease (GERD)

•

128

• The reported incidence of GER varies based on the criteria used• for diagnosis and ranges from 22% to 85% of premature infants

• the true• frequency of peptic esophagitis or pulmonary disease• because of GERD is unknown

• Recent studies• have found that the use of acid-suppression therapy for GERD

in infants younger• than 1 year of age is increasing5 and that nearly 25% of very

low birth weight infants• are treated with reflux medications at discharge

129

• Differentiating between physiologic• and pathologic GER, understanding the

mechanisms that result in the generation of• and the protection against GER, and understanding

the rationale for treatment are• important for the effective management of GERD in

premature infants

130

Mechanisms of GER in preterm infants

131

• The most common mechanism of GER in the preterm infant is transient relaxation of

• the lower esophageal sphincter

• Increased intra-abdominal pressure and decreased• baseline lower esophageal sphincter pressure also

are associated with GER and• may play a more significant role in infants who have

respiratory or neurologic disease

132

Protection from GER in preterm infants

133

• Mechanisms to protect the esophagus from GER are present even in the preterm infant.

• Abnormalities in any of these protection mechanisms can predispose an infant to

• the consequences of GER

134

• Regurgitation of gastric contents into the esophagus triggers• several esophageal and laryngeal reflexes to counteract GER and to protect the• airway from acid exposure.8 Distension of the esophagus by refluxate results in

the• induction of a secondary peristaltic wave that propels the material back into the

stomach• and in reflexive closure of the upper esophageal sphincter to prevent migration of• refluxed material into the posterior pharynx (the esophagopharyngeal closure

reflex). If• refluxate reaches the upper esophagus, however, the upper esophageal sphincter• opens reflexively to allow expulsion of the material into the pharynx, but the

glottis• closes spontaneously to prevent airway aspiration, and the closure is

accompanied• by a period of apnea. Entry of refluxate into the pharynx also results in primary

peristalsis

135

• The esophageal epithelium serves as the main barrier for limiting the effects of

• acid exposure to the esophagus. Intercellular phospholipids and bicarbonate secretion

• from mucous glands in the esophagus and salivary glands neutralize the gastric

• acid in refluxed materials.10 Exposure of the esophageal mucosa to acid and bile

• causes the breakdown of tight junctions, leading to edema and dilatation of the intracellular

• spaces of Disse

136

Clinical features of GER in preterm infants

137

• Many clinical signs and symptoms in preterm infants have been attributed to GER, including:

– apnea, chronic lung disease, poor weight gain and behavioral symptoms

138

Apnea

• Apnea often occurs during or following feeding periods, leading to the assumption that

• apnea occurs as a result of GER. It is postulated that refluxate during the GER episodes

• stimulates laryngeal chemoreflexes.12 Laryngeal stimulation in preterm infants

• results in obstructive, central, and mixed apneas as well as other reflex activities

• including cough, increased swallowing, and arousal

139

Apnea

• Although some suggest a• relation between apnea or bradycardias of prematurity• and reflux (472), most studies do not support reflux as• a cause of pathologic apnea in premature infants

• Several studies using prolonged pH monitoring• or impedance monitoring have failed to demonstrate a temporal relationship• between GER and apnea

• These studies demonstrate that both GER• and apnea do occur together in preterm infants but occur as separate rather

than• simultaneous events, suggesting that common risk factors for both apnea

and GER• are present in these individuals

141

Apnea

• treatment with prokinetic agents has not been• shown to improve apnea.22 The effects of acid

suppression using newer protonpump• inhibitor (PPI) agents have not been studied

142

chronic lung disease

• Current studies in neonates fail to show a clear causal relationship between GER

• and chronic lung disease

143


• Researchers have used the amount of acid exposure in• the esophagus during sleep as a method of assessing

chronic lung disease risk. Jolley• and colleagues found high GER scores in 28 infants

who had BPD, but in most of• these infants exposure to esophageal acid during

sleep was not prolonged. The infants• who had prolonged exposure to esophageal acid

during sleep improved more• with reflux treatment than those who had normal

exposure to esophageal acid during• Sleep (Gastroenterology 1981)

144


• Akinola and colleagues retrospectively reviewed 629 preterm infants of whom

• 137 had pH testing. Sixty-three percent of these infants had abnormal pH scores;

• however, there was no correlation of BPD status with GER status in this cohort (Am J Perinatol 2004)

• Omari• and colleagues found no difference in the

mechanism of GER in infants who had• BPD compared with healthy infants(Gut 2002)

145


• The method used to detect GER may play a role in helping to identify those at risk for

• BPD• The studies involving pepsin may indicate that nonacid• reflux is an important mediator of lung disease in preterm infants

• Although reflux episodes may be more common in• infants with bronchopulmonary dysplasia, there is no• evidence that GERD therapy affects the clinical course• or outcome

• Treatment trials• showing an improvement in pulmonary status are needed to establish

better a relationship• between GERD and BPD

146

Growth

• Failure to thrive is a sign often attributed to GER in infants

• A retrospective case-control• study evaluated the impact of GER on growth and hospital stay in a cohort of

23• preterm infants and an in equal number of control infants The diagnosis of GER

was based on clinical• symptoms. Investigators found no significant difference between patients and

control• infants in average weekly weight gain, caloric intake, grams gained per calorie

given,• or weekly increments gained in length and head circumference (J Pediatr

Gastroenterol Nutr 1998)

• There are• no studies evaluating the efficacy of GERD treatment using growth as a clinical• research end point

147

Behavior

• Several behaviors such as irritability, facial grimacing, head arching, and frequent swallowing have been attributed to GER, particularly in older infants

• case-controlled and placebo-controlled studies have found poor correlation of these behavioral symptoms with GER in preterm infants and have found no difference in symptom scores after treatment with cisapride or omeprazole

• Therefore, it is unlikely that these behavioral symptoms are the result of GER in preterm infants

148

Evaluation of GER in preterm infants

149

• Because GER is a normal physiologic event, the role of diagnostic testing is to determine

• if GER is causing disease and to exclude other pathologic conditions that mimic

• GER

• Therefore the value of specific diagnostic tests varies, depending on the clinical

• presentation.

150

History and physical examination

• History and physical examination alone may be adequate to diagnose GERD and

• initiate management in some cases

• In general, physiologic GER in infants is easy to• recognize, and no treatment is necessary

151

• Common signs and symptoms attributed• to GER include regurgitation (milk in the pharynx),

vomiting, irritability, arching, grimacing,• apnea, bradycardia, desaturation, and respiratory

symptoms. Many of these• clinical features, however, are common to other

disorders such as milk protein allergy;• as discussed previously, studies have failed to

correlate these symptoms with GER,• and treatment has not been shown to be efficacious

152

Radiographic upper gastrointestinal series

• not useful for the diagnosis of GERD

• useful to detect anatomic abnormalities

153

Esophageal pH monitoring

• The• percentage of time in a 24-hour study that the

esophageal pH is less than 4, also called• the ‘‘reflux index’’ (RI), is considered the most valid

measure of reflux because it• reflects the cumulative exposure of the esophagus to

acid. Commonly, an RI greater• than 11% is considered to indicate pathologic GERD

in infants.41 A recent British• study, however, reported variability in the location of

pH catheter and threshold values• for significant RI scores at tertiary referral centers

154

Multichannel intra-esophageal impedance test (MII)

• When combined with esophageal pH monitoring, the MII test allows detection• of both acid and nonacid episodes of GER

• Unfortunately, despite the improved• detection of GER episodes, this new technology has not yet influenced clinical• management in pediatric patients, especially those who have airway

symptoms in• whom a cause–effect relationship is difficult to establish

• More recently, normative• values have been established for acidic and weakly acidic reflux in preterm• Infants

• however, the usefulness of pH/MII testing has not been evaluated in preterm• infants

155

Esophageal pH monitoring

• Esophageal pH monitoring also• may be performed to determine whether an episodic

symptom such as apnea or• pain is caused by GER. In such cases the occurrence

of the symptom and esophageal• pH are monitored simultaneously so that a symptom

index (the percentage of GER• episodes associated with the symptom) can be

evaluated. Studies using prolonged• esophageal pH monitoring show poor correlation

between the severity of symptoms• and response to therapy

156

Upper endoscopy with biopsy

• In one study, 39% of infants• who had a pathologic RI score by pH testing had

normal esophageal biopsies, and• 50% of infants who had histologic esophagitis had

normal esophageal pH scores (Heine RG, et al. J Pediatr 2002)

• Therefore, histology alone was not predictive of GERD in this study

157

Nuclear scintigraphy

• A lack of standardized techniques,• the absence of age-specific normative data, and a

lack of sensitivity limit the value• of this test

• Furthermore, although nuclear scintigraphy identified GER in preterm

• infants, there was no correlation with the proximal extent of the episodes with clinical

• Symptoms (Morigeri C, et al. Eur J Nucl Med Mol Imaging 2008)

158

Empiric therapy without diagnostic evaluation

• In• preterm infants, however, there are no data evaluating the effects of

empiric GERD• therapy before diagnostic testing for traditional GERD-related

symptoms

• Caution• should be used, because the pharmacokinetics and dosing of PPI

drugs are not• well understood in this population

• If a trial of empiric therapy is initiated, it should• be time limited to determine whether there is a symptomatic

response and to evaluate• whether symptoms relapse off drug

159

Treatment of GER in preterm infants

160

• Compared with adults, few studies have evaluated the treatment of GERD in preterm

• Infants

• Most infants who have frequent regurgitation have physiologic reflux, and no

• interventions are required

• It is important to balance the potential risks of GERD with

• those of therapy when deciding on appropriate treatment in the individual patient

161

Nonpharmacologic Treatments

162

• positioning changes

• thickening of feeds

• trial use of hypoallergenic or high-calorie formulas

• alterations in the mode of feeding

163

Positioning

• In a randomized, crossover study of infants younger than 5 months of age, semisupine positioning (sitting) in an infant seat was found to exacerbate GER, whereas the prone position was superior

• More recently, van Wijk and colleagues found faster gastric emptying and less liquid reflux with a strategy of feeding infants in the right decubitus position followed by position change to the left decubitus position 1 hour later (J Pediatr 2007)

• Caution should be used when placing infants in nonsupine positions because of the risk of SIDS

164

Manipulation of feeds

• Thickening of feeds with guar gum or cereals or the use of newer milk-based formulas

• that thicken upon acidification in the stomach reduces the number and height of nonacid

• reflux episodes and regurgitation but does not decrease acid reflux events (Wenzl TG, et al. Pediatrics 2003)

• The• addition of thickeners may result in changes in

formula osmolarity and caloric density,• resulting in excessive caloric intake

165


• A 2-week trial of a hypoallergenic formula (protein• hydrolysate– or amino acid–based) can be

considered to exclude intolerance to cow’s• milk protein as a cause of reflux symptoms

166


• Continuous drip feeding reduces vomiting• and reflux symptoms, but chronic use of indwelling

tubes that cross the gastroesophageal• junction is associated with increased regurgitation

and esophagitis

• This problem may be avoided by intermittent orogastric tube placement

167

Pharmacologic Treatments

168

Acid neutralizers and surface agents

• Oral antacids and surface agents such as alginates have been poorly studied in preterm

• infants

• Because of the risk of• heavy-metal toxicity, chronic antacid use in preterm

infants is not recommended

169

Prokinetic therapies

• Prokinetic agents have limited role in the treatment of GERD in preterm infants because

• of their lack of efficacy demonstrated in large meta-analyses (metoclopramide)

• and potential cardiac (domperidome and cisapride) or neurologic (metoclopramide

• and domperidome) side effects

170


• Bethanachol has been used for treatment, but its efficacy• is questionable, and the side effects generally outweigh

any potential benefit

• Erythromycin increases antral contractility via the motilin receptor but has had mixed

• results in improving reflux scores and feeding tolerance in preterm infants During

• early infancy, however, the use of erythromycin is associated with the development

• of hypertrophic pyloric stenosis and cardiac arrhythmias

171


• Baclofen, a gamma butyric• acid receptor agonist, reduced the frequency of

transient lower esophageal sphincter• relaxation, decreased acid reflux, and accelerated

gastric emptying in a placebo- controlled• study in infants

• The development of baclofen analogues has been hampered

• by neurologic side effects in early adult studies

172

Acid-Suppression therapiesH2-receptor antagonists

• Few randomized clinical trials of H2 receptor antagonists have assessed their impact on the symptoms of GERD in the general infant population or in NICU patients

173


• The pharmacokinetics of ranitidine has been studied in preterm infants and it has been shown to protect against steroid-induced ulcers in patients who have chronic lung disease

174


• Orenstein SR, et al. Aliment Pharmacol Ther. 2003: infants ages 1.3 to 10.5 months were randomized to a higher or lower dose of famotidine, followed by a placebo-controlled withdrawal. Infants receiving both doses had improved emesis frequency compared with placebo.

• Infants receiving the higher dose also had decreased crying time and volume of emesis.

• However, famotidine seemed to cause agitation and a head-rubbing behavior that was attributed to headache

– the authors concluded that further study was warranted

175


• Neither the pharmacokinetic properties of other H2RAs, nor their efficacies in the treatment of signs or symptoms of GERD have been evaluated in preterm infants

176


• Cimetidine is an inhibitor of CYP3A and may cause potentially dangerous increases in the concentrations of drugs that are metabolized by these enzymes, including theophylline, benzodiazepines, beta-blockers and phenytoin

• Ranitidine may interact with some of these drugs to a lesser degree

• Ranitidine can rarely cause leukopenia, neutropenia or thrombocytopenia, which is usually reversible

177

Acid-Suppression therapiesProton-pump inhibitors

– genetic and developmental variability in the expression of cytochrome P450 metabolic pathways may result in differences in the pharmacokinetic properties of PPIs in preterm infants

– the pharmacokinetic and pharmacodynamic properties of lansoprazole and omeprazole have been studied only recently in a small number of neonates

– omeprazole 0.7 mg/kg once daily normalized the RI in six of seven preterm infants who had abnormal pH scores (Omari TI, et al.JPGN 2007)

but no difference was found in the frequency of reflux symptoms in the placebo and omeprazole arms at the end of the treatment

178

Potential risks of (chronic) acid suppression

• Infants:– necrotizing enterocolitis– late-onset sepsis

• Children: – acute gastroenteritis – community-acquired pneumonia

• Adults: – Clostridium difficile, Salmonella, and Campylobacter infections– decreased absorption of calcium and vitamin B12 and hip

fracture

179

Potential risks of (chronic) acid suppression

• The effects of chronic acid suppression on vitamin or mineral absorption have not been evaluated in younger populations, particularly in preterm infants

180

Anti-reflux Surgery

181

• Current medical therapy almost always provides adequate treatment for esophageal

• complications of GER

• The decision to subject a child to the risks of• antireflux surgery requires that outcome will be substantially better than with

medical• Therapy

• Although recent studies suggest that potential risks are associated with long-term medical therapy, these risks are small compared with the potential complications

• of fundoplication surgery

• GERD-related symptoms can persist in• up to two thirds of children who undergo antireflux surgery. Many of these

children• continue to receive GERD medical therapy 2 months following the procedure

182

SUMMARY

183

• GER is common in preterm infants and usually is a physiologic phenomenon with little

• clinical consequence.

• GERD is frequently diagnosed by• inadequate criteria in the preterm infant .

• Correlation of clinical signs and symptoms with GER has been

• poor in most studies

184

• The efficacy of GERD therapy has not been studied systematically

• in preterm infants. Furthermore, GERD therapy, particularly with prokinetic

• agents, acid-suppression therapy, and surgery, is fraught with recognized complications

• and potentially with other complications that currently are unknown. Therefore,

• clinicians must weigh carefully the risks, benefits, and alternatives of GERD therapy

• before initiating treatment.

185

• . Potential alternative diagnoses, pretreatment diagnostic

• testing, and desired treatment outcomes should be considered before initiating

• GERD therapy.

186

• Cessation of GERD therapy should be considered, particularly if treatment

• does not result in the desired clinical outcome

187

• The long-term risk of• GERD in premature infants during adulthood is• controversial

189

• Hibbs AM. Pharmacotherapy for Gastroesophageal Reflux Disease. NeoReviews. 2011, 12(3): e159- 166

190

• associations between GER(D)• and its putative complications in preterm• infants, including apnea and• lung disease, are questionable

• The• appropriate diagnostic modalities for• diagnosing GERD in the term or• preterm neonate in the NICU are• also controversial

191

• Medications for GERD are among• the most commonly prescribed• drugs in the NICU

• The common pharmacologic strategies used to treat gastroesophageal• reflux disease (GERD) in the neonatal intensive care unit (NICU) include• suppression of gastric acid with histamine-2 (H2) receptor antagonists and• proton pump inhibitors (PPIs) and stimulation of gastrointestinal motility• with dopamine receptor antagonists or motilin receptor agonists.

• These• medications are primarily metabolized by hepatic cytochrome P450 (CYP)• enzymes

192

• Although frequently used, none of these drugs has strong

• evidence for efficacy in decreasing the complications of reflux in preterm

• infants or term neonates

• In addition, a few well-conducted, masked,• randomized studies that have accounted for

maturational changes in their• design have raised concerns about the safety of these

medications in• infants

193

• the use of these• medications and clinicians’ beliefs• about their safety and effectiveness• varies extensively

194

• medication failures at the bedside• or in research trials may result• from either a failure of the medication• to achieve its intended action or• from the erroneous application of• drugs to symptoms not caused by• GERD

195

• Conversely, apparent successes• may result from a true drug• effect or from the natural resolution• of symptoms with maturation

196

• because the goal of therapy is• to treat GERD, not physiologic• GER, the gold standard for gauging• therapeutic success must be improvement• in symptoms or complications,• not simply improvement in physiologic• measures

197

• Proposed• complications of reflux in• NICU patients, such as food refusal,• lung disease, failure to thrive, and• pharyngeal or vocal cord edema,• theoretically could stem from the• effect of acid on the esophagus or• airway. Some have argued that due to• either a limited capacity to produce• acid or to frequent buffering of gastric• contents by milk feedings, infants• may experience less acidic GER(D)• than older patients.

198

• Studies simultaneously• monitoring acid and nonacid• GER in infants have shown• that acid GER predominates preprandially• and nonacid GER predominates• postprandially. (13)(14)• . (8)

199

• Although most GER events in infants• are nonacid, (13)(14) studies• of infants referred for suspicion of• GERD indicate that at least some• preterm infants can experience significant• acid GER, as measured by• an esophageal pH of less than 4 for• more than 10% of the time. However,• it is not clear whether acidity• is the mechanism by which reflux• causes complications in infants

200

• Both H2 receptor antagonists and• PPIs share some potential safety concerns.• Gastric acidity may play a role• in host immune defense.H2 receptor• antagonists have been associated• with an increased risk of necrotizing• enterocolitis, (16) although it is not• clear if this is a causal relationship.

201

• In older patients, an• association between acid suppression• and lower respiratory tract infections,• including ventilator-associated pneumonia,• has been proposed but remains• controversial

202

• Acid reduction may decrease calcium• absorption via decreased ionization• of calcium in the stomach.

• Both H2 receptor antagonists and• PPIs are metabolized by the CYP• enzymatic systems in the liver. Potential• drug interactions may exist• with drugs metabolized by these• pathways

203

H2 Receptor Antagonists

• Parietal cells produce a baseline• amount of hydrochloride when they• are not stimulated by histamine. H2• receptor antagonists decrease this production• below physiologic basal secretion• rates and decreasemeal-associated• acid production. In addition, other• substances that stimulate acid production,• such as acetylcholine and gastrin,• have a reduced effect on parietal cells• when H2 receptors are blocked

204

Proton Pump Inhibitors

• No PPIs are currently• labeled for use in infants younger• than 1 year of age

• However, PPI use• in infants increased exponentially• between 1999 and 2004, with the• highest prescription rates in infants• younger than 4 months of age

• Lansoprazole and omeprazole are• the most commonly prescribed PPIs• for infants

205

• Although PPIs have been shown• to decrease gastric acidity in infants• in physiologic studies, there is a paucity• of masked randomized studies in• infants that account for maturational• changes in reflux symptoms

206

• . Orenstein• and associates (42) randomized• outpatient infants who had failed a run-in period of

nonpharmacologic• management to lansoprazole or placebo.• There was no difference in efficacy• between the groupsHowever, there was a• significant increase in serious adverse• events in the lansoprazole group;• among these adverse events, a nonsignificant• increase in lower respiratory• tract infections was seen

207

• The impact of acid• suppression by PPIs or H2 receptor• antagonists on bone health in healthy• neonates or preterm infants who• have osteopenia of prematurity is unknown.

• The off-label use of PPIs in• infants and the possibility of adverse• effect on bones are currently being• tracked by the FDA

208

• Vitamin• B12 absorption is also dependent on• gastric acidity, but the impact of gastric• acid suppression on B12 status in• infants is also unknown

• The relationship between PPI use• and pathogenic or colonizing C difficile• in infants has not been reported.

209

Drugs That Improve Motility

• Drugs that promote gastrointestinal• motility are believed to decrease GER• by increasing gastric emptying, thereby• limiting the amount of liquid available• to reflux into the esophagus. Prokinetics• may also improve esophageal• motility and lower esophageal sphincter• tone.

210

• recent studies have• shown that oral domperidone can increase• the QT interval in neonates

211

metoclopramide

• The Cochrane systematic review of• GERD therapies in children found• both therapeutic benefit and increased• adverse effects with metoclopramide• treatment, although most• of the improvements were in physiologic• measures of GER and not• GERD symptoms

• A systematic• review of metoclopramide therapy• for GERD in infants found insufficient• evidence for either efficacy or• safety in this population

212

• Metoclopramide crosses the bloodbrain• barrier and acts on central dopamine• receptors, which allows for• neurologic adverse effects. Reported complications of metoclopramide in• infants include irritability, drowsiness,• oculogyric crisis, dystonic reaction,• apnea, and emesis. (51) In 2009, the• FDA issued a black-box warning• about the risk of tardive dyskinesia• with prolonged or high-dose metoclopramide• exposure. (52) Tardive• Dyskinesia may persist• after the drug is stopped

• Whether neonates• or preterm infants are at greater or• lesser risk of tardive dyskinesia than• older patients has not been established.

• Metoclopramide may cause lactation and gynecomastia• in neonates.

213

Erythromycin

• Erythromycin is an analog of the• gastrointestinal hormone motilin

• It promotes• gastrointestinalmigratingmotor complexes.

• a standard promotility• dose has not been established in neonates• or preterm infants

• Infants• whose gestational age is greater than• 32 weeks may be better able to respond• to stimulation of the motilin• receptor

214

• Most studies of erythromycin as a prokinetic in preterm infants have focused

• on improving feeding intolerance• and not specifically on treating• GERD

• because long-term adverse events• had not been fully studied, erythromycin• should be reserved for infants• who had severe dysmotility

215

• It is unknown whether an increased risk of HPS• would be seen with the lower doses• and longer duration of therapy likely• to be used to increase motility, although• pyloric stenosis has not been• reported in most of the current trials• in preterm infants

• erythromycin is• an inhibitor of CYP3A. Erythromycin• may increase serum concentrations• of theophylline, digoxin, some benzodiazepines,• sildenafil, phenytoin, and• warfarin

216

• It has a direct proarrhythmic• effect by itself

• It may prolong the QT interval• and predispose the patient to torsades• de pointes

217

Conclusion

• None of the medications commonly• used to treat GERD in the NICU has• been demonstrated to be safe and effective.

• Few rigorously conducted• randomized trials account for maturational• changes in infants and even• fewer focus on clinical symptoms in• neonates or preterm infants

218

• Many of• the masked, randomized trials in infants• have found evidence for harm.

• Therefore, the potential adverse effects• of pharmacologic management of• GERD in the NICU should only be• risked for infants experiencing severe• complications that have been rigorously• linked to reflux and that have not• improvedwith a trial of nonpharmacologic• measures and expectant management

219

• Therapy should be discontinued• promptly if there is no improvement in• the infant’s status. For infants who do• improve with pharmacotherapy, a plan• should be made to assess them off• GERD drugs within a few weeks to• months because maturational changes• may either have been responsible for• the initial improvement or may render• drug therapy unnecessary in the near• future.

220

• avoidance of exposure• to medications that have documented• risk and little evidence for efficacy• should be the preferred approach• to a NICU patient who has suspected• GERD

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