Symptomatic Gastroesophageal Reflux in the Preterm Infant: Fantasy or Real?

Transcription

1 Symptomatic Gastroesophageal Reflux in the Preterm Infant: Fantasy or Real? Eric C. Eichenwald, MD, FAAP Professor of Pediatrics Perelman School of Medicine University of Pennsylvania Chief, Division of Neonatology Children s Hospital of Philadelphia

2 Disclaimer Statements and opinions expressed are those of the author and not necessarily those of the American Academy of Pediatrics. Mead Johnson sponsors programs such as this to give healthcare professionals access to scientific and educational information provided by experts. The presenter has complete and independent control over the planning and content of the presentation, and is not receiving any compensation from Mead Johnson for this presentation. The presenter s comments and opinions are not necessarily those of Mead Johnson. In the event that the presentation contains statements about uses of drugs that are not within the drugs' approved indications, Mead Johnson does not promote the use of any drug for indications outside the FDAapproved product label.

3 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.

4 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 I ve noticed the baby swallowing a lot with the spells, and she spits up all the time. I think it s reflux! o Do something!

5 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?

6 Ontogeny of GER in Preterm Infants TLESR Prematurity Nasogastric tube Supine position GER Large fluid intake???? Immature respiratory responses Apnea Adapted from Poets CF, Brockmann PE. Myth: gastroesophageal reflux is a pathological entity in the preterm infant. Semin Fetal Neonatal Med. 2011;16(5):

7 Is there a physiologic basis for the connection of GER with idiopathic apnea of prematurity?

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

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

10 Laryngeal Stimulation Results in Reflex Apnea Treat with confidence. Trusted answers from the American Academy of Pediatrics. in Preterm Infants Davies AM, Koenig JS, Thach BT. Upper airway chemoreflex responses to saline and water in preterm infants. J Appl Physiol (1985). 1988;64(4):

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

12 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?

13 López-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):e299 e308.

14 López-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):e299 e308.

15 López-Alonso M1, 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):e299 e308.

16 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):88 93.

17 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):88 93.

18 Is there evidence that GER precipitates idiopathic apnea of prematurity?

19 No Relationship between GER (ph) and Apnea 10 Apnea >10 sec (number/ 100 min) GER episodes (number/100 min) 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 Oct;145(10):

20 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):

21 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):

22 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):

23 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 cries acts uncomfortable and is gassy. The mother tells you her other baby had reflux and got better with an unidentified medication. o Do something!

24 Relationship of Post-prandial Reflux and Apnea Total GER (per hr) Acidic GER Non-acidic GER Pre-feed 2 (0 11) 2 (0-11) 0 (0-4) Post-feed 4 (0-16) 0 (0-10) 4 (0-11) P-value <0.001 <0.001 Apnea > 5 s Brady < 85 Desat < 85% Pre-feed 7 (0-86) 0 (0-4) 0 (0-25) Post-feed 6 (0-60) 0 (0-4) 0 (0-40) P-value 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):

25 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

26 Differences of Opinion Amongst Subspecialties on GER Symptoms Golski CA, Rome ES, Martin RJ. Pediatric specialists' beliefs about gastroesophageal reflux disease in premature infants. Pediatrics. 2010;125(1):

27 Temporal Association of Reflux Behaviors 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):

28 Temporal Association of Reflux Behaviors 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):

29 Does treatment of clinical reflux affect the incidence of cardiorespiratory events or other GER symptoms in preterm infants?

30 Medications Used for Anti-reflux Treatment in Preterm Infants Pro-kinetic agents o Metoclopramide (cisapride) Gastric acid suppression o Proton pump inhibitors o Histamine antagonists

31 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):

32 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):

33 Efficacy and Safety of Proton Pump Inhibitor in Treatment of GER in Infants < 1 Year Old Lansoprazole (N=81) Placebo (N=81) P value Efficacy (%) NS All Adverse Events (%) Severe Adverse Events (%) * All infants with severe adverse events required hospitalization. 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):

34 Ranitidine Associated with Increased Risk of Sepsis, 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):e40 e45.

35 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.

36 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 doctors o They did something!

37 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):22 27.

38 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)

39 Selected References 1. Poets CF. Gastroesophageal reflux: a critical review of its role in preterm infants. Pediatrics. 2004;113(2):e128 e Dhillon AS, Ewer AK. Diagnosis and management of gastro-oesophageal reflux in preterm infants in neonatal intensive care units. Acta Paediatr. 2004;93(1): Slaughter JL, Stenger MR, Reagan PB, Jadcherla SR. Neonatal histamine-2 receptor antagonist and proton pump inhibitor treatment at United States children s hospitals. J Pediatr. 2016;174: Golski CA, Rome ES, Martin RJ. Pediatric specialists' beliefs about gastroesophageal reflux disease in premature infants. Pediatrics. 2010;125(1): Peter CS, Sprodowski N, Bohnhorst B, Silny J, Poets CF. Gastroesophageal reflux and apnea of prematurity: no temporal relationship. Pediatrics. 2002;109(1): 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): 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): Kennedy KA. Cross-over trial of treatment for bradycardia attributed to gastroesophageal reflux in preterm infants. J Pediatrics. 2009;155(4):

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