Treat with confidence. Trusted answers from the American ... GER in... · de Ajuriaguerra M, Radvanyi-Bouvet MF, Huon C, Moriette G. Gastroesophageal reflux and apnea in prematurely

Treat with confidence. Trusted answers from the American Academy of Pediatrics.Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Symptomatic Gastroesophageal Reflux in the Preterm Infant:

Fantasy or Real?

Eric C. Eichenwald, MD, FAAPProfessor of PediatricsPerelman School of MedicineUniversity of PennsylvaniaChief, Division of NeonatologyChildrens Hospital of Philadelphia


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Objectives

Identify the pathophysiology of gastroesophageal reflux (GER) in the preterm infant.

Discuss diagnostic modalities for GER.

Explain the possible causal relationship of GER and apnea of prematurity.

Identify effects of treatment of GER in the preterm infant.


Case

You are taking care of a 3-week-old former 26-week GA 800 g baby, on NCO2 and caffeine. She has recurrent apnea and bradycardia events recorded by the nurses.

Apnea is much worse with feeding, and Ive noticed the baby swallowing a lot with the spells, and she spits up all the time. I think its reflux!o Do something!


Apnea and Reflux: Cause and Effect?

Most (all) premature babies have reflux.

Most premature babies < 32 weeks have apnea.

Does reflux cause or worsen apnea of prematurity?


Ontogeny of GER in Preterm Infants

Adapted from Poets CF, Brockmann PE. Myth: gastroesophageal reflux is a pathological entity in the preterm infant. Semin Fetal Neonatal Med. 2011;16(5):259263.

Prematurity

TLESR

Nasogastric tube

Supine position

Large fluid intake

GER

Immature respiratory responses Apnea

????


Is there a physiologic basis for the connection of GER with

idiopathic apnea of prematurity?


Miller MJ, DiFiore JM. A comparison of swallowing during apnea and periodic breathing in premature infants. Pediatr Res. 1995;37(6):796799.


Davies AM, Koenig JS, Thach BT. Upper airway chemoreflex responses to saline and water in preterm infants. J Appl Physiol (1985). 1988;64(4):14121420.


Laryngeal Stimulation Results in Reflex Apneain Preterm Infants



Methods to Diagnosis GER

pH probe measures for acid reflux in lower esophagus

Esophageal impedance measures electrical esophageal signals occurring with reflux and swallows

Combined impedance/pH probe

Clinical: Can you see it?


Lpez-Alonso M, Moya MJ, Cabo JA, et al. Twenty-four-hour esophageal impedance-pH monitoring in healthy preterm neonates: rate and characteristics of acid, weakly acidic, and weakly alkaline gastroesophageal reflux. Pediatrics. 2006;118(2):e299e308.


Lpez-Alonso M, Moya MJ, Cabo JA, et al. Twenty-four-hour esophageal impedance-pH monitoring in healthy preterm neonates: rate and characteristics ofacid, weakly acidic, and weakly alkaline gastroesophageal reflux. Pediatrics. 2006;118(2):e299e308.


Lpez-Alonso M1, Moya MJ, Cabo JA, et al. Twenty-four-hour esophageal impedance-pH monitoring in healthy preterm neonates: rateand characteristics of acid, weakly acidic, and weakly alkaline gastroesophageal reflux. Pediatrics. 2006;118(2):e299e308.


How is GER Diagnosed in the NICU?

Dhillon AS, Ewer AK. Diagnosis and management of gastro-oesophageal reflux in preterm infants in neonatal intensive care units. Acta Paediatr. 2004;93(1):8893.

Chart1

42

8

50

Series 1

Percent

Sheet1

Series 1

Clinical42

Clinical + Test8

Clinical + Test or Therapy Trial50

To resize chart data range, drag lower right corner of range.


Most Common Clinical Criteria for GER Diagnosis in the NICU

Dhillon AS, Ewer AK. Diagnosis and management of gastro-oesophageal reflux in preterm infants in neonatal intensive care units. Acta Paediatr. 2004;93(1):8893.

Chart1

71

69

48

31

23

19

Series 1

Sheet1

Series 1

Feeding Intolerance71

Apnea69

Bradycardia48

Desaturation31

Milk in Mouth23

Respiratory Problems19



Is there evidence that GER precipitates idiopathic apnea of

prematurity?


No Relationship between GER (pH) and Apnea

de Ajuriaguerra M, Radvanyi-Bouvet MF, Huon C, Moriette G. Gastroesophageal reflux and apnea in prematurely born infants during wakefulness and sleep. Am J Dis Child. 1991 Oct;145(10):11321136.

0

2

4

6

8

10

0 1 2 3 4 5 6 7

GER episodes (number/100 min)

Apn

ea >

10 s

ec (n

umbe

r/ 1

00 m

in)


Proportion of Cardiorespiratory Events Preceded by GER (MII and pH)

Di Fiore J, Arko M, Herynk B, Martin R, Hibbs AM. Characterization of cardiorespiratory events following gastroesophageal reflux in preterm infants. J Perinatol. 2010;30(10):683687.

Chart1

2.7

3.4

2.8

2.9

Series 1

Percent of Events

Sheet1

Series 1

All2.7

Apnea > 10 sec3.4

Desaturation < 85%2.8

Brady < 80 bpm2.9



Proportion of GER Episodes Preceded by Cardiorespiratory Event

Di Fiore J, Arko M, Herynk B, Martin R, Hibbs AM. Characterization of cardiorespiratory events following gastroesophageal reflux in preterm infants. J Perinatol. 2010;30(10):683687.

Chart1

9.1

4.9

9.3

12.6

Column1

% GER Preceded by Cardiorespiratory Event

Sheet1

Column1

All GER9.1

Acid MII4.9

Non-Acid MMI9.3

Acid pH Only12.6



Lower Esophageal Sphincter (LES) Pressure Falls Coincident with Apnea

Omari TI. Apnea-associated reduction in lower esophageal sphincter tone in premature infants. J Pediatr. 2009;154(3):374378.


Case Continued (4 Weeks Later)

The baby is now 33 weeks PMA. She is noted to have repeated apnea, bradycardia, and desaturation with PO feeding.

Her nurse also notes that she spits up occasionally, and then criesacts uncomfortable and is gassy.

The mother tells you her other baby had reflux and got better with an unidentified medication.o Do something!


Relationship of Post-prandial Reflux and Apnea

Slocum C, Arko M, Di Fiore J, Martin RJ, Hibbs AM. Apnea, bradycardia and desaturation in preterm infants before and after feeding. J Perinatol. 2009;29(3):209212.

Total GER (per hr) Acidic GER Non-acidic GER

Pre-feed 2 (011) 2 (0-11) 0 (0-4)Post-feed 4 (0-16) 0 (0-10) 4 (0-11)P-value 0.012


Signs Attributed to GER in Preterm Infants

Apnea and desaturation

Failure to thrive

Feeding intolerance

Nipple aversion

General irritability (especially post-prandial)

Worsening lung disease


Differences of Opinion AmongstSubspecialties on GER Symptoms

Golski CA, Rome ES, Martin RJ. Pediatric specialists' beliefs about gastroesophageal reflux disease in premature infants. Pediatrics. 2010;125(1):96104.

Chart1

636878

516361

687080

465179

465984

606284

Neonatologist

Gastroenterologist

Pulmonologist

% Reporting very or somewhat likely

Sheet1

NeonatologistGastroenterologistPulmonologist

Irritability636878

Failure to Thrive516361

Feeding Intolerance687080

Apnea465179

Wheezing465984

Worsening Lung Disease606284



Temporal Association of RefluxBehaviors and Measured GER

Funderburk A, Nawab U, Abraham S. Temporal association between reflux-like behaviors and gastroesophageal reflux in preterm and term infants.J Pediatr Gastroenterol Nutr. 2016;62(4):556561.


Temporal Association of RefluxBehaviors with Measured GER

Funderburk A, Nawab U, Abraham S. Temporal association between reflux-like behaviors and gastroesophageal reflux in preterm and term infants. J Pediatr Gastroenterol Nutr. 2016;62(4):556561.


Does treatment of clinical reflux affect the incidence of

cardiorespiratory events orother GER symptoms in

preterm infants?


Medications Used for Anti-reflux Treatment in Preterm Infants Pro-kinetic agents

o Metoclopramide (cisapride)

Gastric acid suppressiono Proton pump inhibitorso Histamine antagonists


Anti-reflux Treatment Does Not Improve Apnea

Kimball AL, Carlton DP. Gastroesophageal reflux medications in the treatment of apnea in premature infants. J Pediatr. 2001;138(3):355360.


Cross-over Trial of Metoclopramide for Bradycardia Events

Wheatley E, Kennedy KA. Cross-over trial of treatment for bradycardia attributed to gastroesophageal reflux in preterm infants. J Pediatrics. 2009;155(4):516521.


Efficacy and Safety of Proton Pump Inhibitor in Treatment of GER in Infants < 1 Year Old

Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr. 2009;154(4):514520.

* All infants with severe adverse events required hospitalization.

Lansoprazole(N=81)

Placebo(N=81)

P value

Efficacy (%) 54 54 NS

All Adverse Events (%) 62 46 0.058

Severe Adverse Events (%) 12 2 0.032


Ranitidine Associated with Increased Risk ofSepsis, Necrotizing Enterocolitis, and Death in

Very Low Birth Weight Infants

Terrin G, Passariello A, De Curtis M, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics. 2012;129(1):e40e45.

Chart1

25.38.7

4.40.5

9.81.6

9.91.6

Ranitidine

No Ranitidine

Sheet1

RanitidineNo Ranitidine

Sepsis25.38.7

Pneumonia4.40.5

NEC9.81.6

Death9.91.6



Other Suggested Treatment Strategies in Preterm Infants Body positioning (head-up angle, left lateral)

Change in feeding approach (continuous intra-gastric or trans-pyloric)

Milk thickeners (xanthan gum, starch, rice cereal)

Hydrolyzed protein formulas

None of these have been systematically studied in the preterm population and do not appear to reduce GER behaviors.


Case Continued (4 Weeks Later)

The baby is now 39 weeks PMA. She was transferred 2 weeks ago to a community hospital.

Her mother calls to tell you The docs here finally listened to me, and put her on ranitidine and metoclopramide, and she is SO much better and going home tomorrow!o They are good doctorso They did something!


Use of Reflux Meds in Extremely Low Birth Weight Infants at Discharge in NICHD Network

Malcolm WF, Gantz M, Martin RJ, et al. Use of medications for gastroesophageal reflux at discharge among extremely low birth weight infants. Pediatrics. 2008;121(1):2227.

1.7 45.7%

22.2 90%

Chart1

24.8

19.3

47.6

Series 1

Percent at Discharge

Sheet1

Series 1

All ELBW Infants24.8

Discharged < 42 weeks19.3

Discharged > 42 weeks47.6



Conclusions/AAP Committee on Fetus and Newborn (COFN) Recommendations Little evidence that GER is associated with apnea of

prematurity or other reflux-like behaviors

No evidence that treatment of suspected or proven GER is beneficial in preterm infants, and may be harmful

Broad diagnostic and therapeutic variation in practice

Watchful waiting best approach (new AAP COFN recommendations)


Selected References 1. Poets CF. Gastroesophageal reflux: a critical review of its role in preterm infants. Pediatrics.

2004;113(2):e128e132.2. Dhillon AS, Ewer AK. Diagnosis and management of gastro-oesophageal reflux in preterm infants in

neonatal intensive care units. Acta Paediatr. 2004;93(1):8893.3. Slaughter JL, Stenger MR, Reagan PB, Jadcherla SR. Neonatal histamine-2 receptor antagonist and

proton pump inhibitor treatment at United States childrens hospitals. J Pediatr. 2016;174:6370.4. Golski CA, Rome ES, Martin RJ. Pediatric specialists' beliefs about gastroesophageal reflux disease in

premature infants. Pediatrics. 2010;125(1):96104.5. Peter CS, Sprodowski N, Bohnhorst B, Silny J, Poets CF. Gastroesophageal reflux and apnea of

prematurity: no temporal relationship. Pediatrics. 2002;109(1):811.6. Funderburk A, Nawab U, Abraham S. Temporal association between reflux-like behaviors and

gastroesophageal reflux in preterm and term infants. J Pediatr Gastroenterol Nutr. 2016;62(4):556561.

7. Di Fiore JM, Arko M, Whitehouse M, Kimball A, Martin RJ. Apnea is not prolonged by acid gastroesophageal reflux in preterm infants. Pediatrics. 2005;116(5):10591063.

8. Kennedy KA. Cross-over trial of treatment for bradycardia attributed to gastroesophageal reflux in preterm infants. J Pediatrics. 2009;155(4):516521.


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Slide Number 1Disclaimer Objectives Case Apnea and Reflux: Cause and Effect? Ontogeny of GER in Preterm Infants Is there a physiologic basis for the connection of GER with idiopathic apnea of prematurity? Slide Number 8Slide Number 9Laryngeal Stimulation Results in Reflex Apneain Preterm Infants Slide Number 11Methods to Diagnosis GER Slide Number 13Slide Number 14Slide Number 15How is GER Diagnosed in the NICU? Most Common Clinical Criteria for GER Diagnosis in the NICU Is there evidence that GER precipitates idiopathic apnea of prematurity? No Relationship between GER (pH) and Apnea Proportion of Cardiorespiratory Events Preceded by GER (MII and pH) Proportion of GER Episodes Preceded by Cardiorespiratory Event Lower Esophageal Sphincter (LES) Pressure Falls Coincident with Apnea Case Continued (4 Weeks Later) Relationship of Post-prandial Reflux and ApneaSigns Attributed to GER in Preterm Infants Differences of Opinion AmongstSubspecialties on GER Symptoms Temporal Association of RefluxBehaviors and Measured GER Temporal Association of RefluxBehaviors with Measured GER Does treatment of clinical reflux affect the incidence of cardiorespiratory events orother GER symptoms inpreterm infants?Medications Used for Anti-reflux Treatment in Preterm Infants Anti-reflux Treatment Does Not Improve Apnea Cross-over Trial of Metoclopramide for Bradycardia Events Efficacy and Safety of Proton Pump Inhibitor in Treatment of GER in Infants < 1 Year Old Ranitidine Associated with Increased Risk ofSepsis, Necrotizing Enterocolitis, and Death inVery Low Birth Weight Infants Other Suggested Treatment Strategies in Preterm Infants Case Continued (4 Weeks Later) Use of Reflux Meds in Extremely Low Birth Weight Infants at Discharge in NICHD Network Conclusions/AAP Committee on Fetus and Newborn (COFN) Recommendations Selected References Slide Number 40

Documents

Treat with confidence. Trusted answers from the American ... GER in... · de Ajuriaguerra M, Radvanyi-Bouvet MF, Huon C, Moriette G. Gastroesophageal reflux and apnea in prematurely