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Transpyloric tube feeding in very low birthweight infants with suspected gastroesophageal reflux: impact on apnea and bradycardia.
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MedLine Citation:
PMID:  19242488     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Our aim was to assess the safety and efficacy of transpyloric tube feeding as a therapeutic option to reduce apnea and bradycardia in hospitalized very low birthweight (VLBW) infants with clinical signs suggestive of gastroesophageal reflux (GER).
STUDY DESIGN: This was a retrospective single-center cohort study of VLBW infants hospitalized from 2001 to 2004 with signs of GER who received transpyloric enteral tube feedings. Apnea (>10 s) and bradycardia (<100 bpm) episodes were compared before and after the initiation of transpyloric feedings. The Wilcoxon signed-rank test was used to compare differences between cardiorespiratory episodes before and after treatment at 1-day and combined 3-day intervals. Events recorded to assess the safety of transpyloric feedings included death, sepsis and necrotizing enterocolitis (NEC).
RESULTS: A total of 72 VLBW infants with a median birthweight of 870 g (ranging from 365 to 1435 g) and gestational age of 26 weeks (from 23 to 31 weeks) were identified. The median weight at initiation of transpyloric feedings was 1297 g (from 820 to 3145 g) and infants received transpyloric feeds for a median duration of 18 days (from 1 to 86 days). After the initiation of transpyloric feedings, a reduction in apnea episodes from 4.0 to 2.5 (P=0.02) and a decrease in bradycardia episodes from 7.2 to 4.5 (P<0.001) was observed when comparing the total number of episodes for the 3 days before and after treatment. Five (6.9%) of the infants developed NEC while receiving transpyloric feedings. None of the infants receiving human milk (P=0.07) and 36% of those receiving hydrolysate-based formula (P<0.01) during transpyloric feeds developed NEC. No infants had late-onset culture-proven sepsis. Seven (9.7%) infants died before hospital discharge.
CONCLUSIONS: Transpyloric feedings, especially when limited to human milk, may safely reduce episodes of apnea and bradycardia in preterm infants with suspected GER. Prospective randomized studies are needed to determine the biological impact of bypassing the stomach, as well as the safety and efficacy of this intervention. The results of such studies could modify the current prevailing safety concerns regarding transpyloric feeding in this population.
Authors:
W F Malcolm; P B Smith; S Mears; R N Goldberg; C M Cotten
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-02-26
Journal Detail:
Title:  Journal of perinatology : official journal of the California Perinatal Association     Volume:  29     ISSN:  1476-5543     ISO Abbreviation:  J Perinatol     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-04-28     Completed Date:  2009-07-24     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  8501884     Medline TA:  J Perinatol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  372-5     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Apnea / prevention & control*
Bradycardia / prevention & control*
Child Development
Cohort Studies
Enteral Nutrition / methods
Enterocolitis, Necrotizing / prevention & control
Female
Follow-Up Studies
Gastroesophageal Reflux / diagnosis,  therapy*
Gestational Age
Humans
Infant, Newborn
Infant, Very Low Birth Weight*
Intensive Care Units, Neonatal
Intubation, Gastrointestinal / methods*
Male
Pregnancy
Probability
Pylorus
Retrospective Studies
Risk Assessment
Statistics, Nonparametric
Time Factors
Treatment Outcome
Weight Gain
Grant Support
ID/Acronym/Agency:
3 U10 HD040492-06S1/HD/NICHD NIH HHS; K23 HD060040/HD/NICHD NIH HHS; K23 HD060040-01/HD/NICHD NIH HHS; U10 HD040492/HD/NICHD NIH HHS; U10 HD040492-06S1/HD/NICHD NIH HHS; UL1 RR024128-01/RR/NCRR NIH HHS
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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Journal Information
Journal ID (nlm-journal-id): 8501884
Journal ID (pubmed-jr-id): 5061
Journal ID (nlm-ta): J Perinatol
ISSN: 0743-8346
ISSN: 1476-5543
Article Information
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nihms-submitted publication date: Day: 17 Month: 2 Year: 2010
Electronic publication date: Day: 26 Month: 2 Year: 2009
Print publication date: Month: 5 Year: 2009
pmc-release publication date: Day: 23 Month: 2 Year: 2010
Volume: 29 Issue: 5
First Page: 372 Last Page: 375
ID: 2827248
PubMed Id: 19242488
DOI: 10.1038/jp.2008.234
ID: nihpa84190
UL1 RR024128-01 ||RR
U10 HD040492-06S1 ||HD
K23 HD060040-01 ||HD
National Center for Research Resources : NCRR
National Institute of Child Health & Human Development : NICHD

TRANSPYLORIC TUBE FEEDING IN VERY LOW BIRTHWEIGHT INFANTS WITH SUSPECTED GASTROESOPHAGEAL REFLUX: IMPACT ON APNEA AND BRADYCARDIA
WF Malcolm, M.D. Affiliation: Department of Pediatrics, Duke University, Durham, NC
PB Smith, M.D., M.H.S. Affiliation: Department of Pediatrics, Duke University, Durham, NC
S Mears, NNP Affiliation: Duke University Medical Center, Durham, NC
RN Goldberg, M.D. Affiliation: Department of Pediatrics, Duke University, Durham, NC
CM Cotten, M.D., M.H.S. Affiliation: Department of Pediatrics, Duke University, Durham, NC
Correspondence: Corresponding Author: William F Malcolm, MD, Assistant Professor, Dept of Pediatrics/Neonatology, Box 3179, Duke University Medical Center, Durham, NC 27710, Office- (919) 681-6026, Pager- (919) 970-7474, Fax- (919) 681-6065, malco002@mc.duke.edu

Introduction

The clinical diagnosis of gastroesophageal reflux (GER) is common among preterm infants having apnea and bradycardia. Earlier studies of preterm infants suggested an association between GER and apnea [13]; however, more recent studies using combined pH and multichannel intraluminal impedance monitoring have challenged these findings. [48] While a temporal relationship between GER and apnea of prematurity remains an ongoing debate, therapeutic interventions including anti-reflux medications and transpyloric tube (TPT) feeding are frequently used in this population with little evidence to support their use. [911]

TPT feeding in preterm infants bypasses the stomach and, theoretically, reduces the potential for GER that occurs secondary to lower esophageal sphincter relaxation or delayed gastric emptying. A recent Cochrane review of nine randomized controlled trials of transpyloric versus gastric feeding in preterm infants concluded that there was no evidence for improved “feeding tolerance” or growth with TPT feeds, but found an increased risk for “gastrointestinal disturbance” requiring cessation of feeds. [12] There was no increased risk for necrotizing enterocolitis (NEC), spontaneous intestinal perforation, aspiration pneumonia, or mortality reported, when allocation bias was controlled. The trials included in the review evaluated TPT feeding as an initial feeding strategy versus gastric feeding for improved growth and feeding tolerance, whereas TPT feeding has not been evaluated as a treatment method for reducing GER episodes or episodes of autonomic instability, such as apnea and bradycardia, occurring in very preterm infants suspected of having GER.

Our objectives in this study were to assess 1) whether or not TPT feedings reduced cardio-respiratory episodes, and 2) the safety of this intervention in a population of VLBW infants with suspected GER.


METHODS

This was a review of all very low birthweight (VLBW, BW<1500 g) infants hospitalized at Duke University Medical Center from January 1, 2001 to December 31, 2004 with signs of GER with gastric feedings, who then received TPT feedings. We identified patients by reviewing the discharge summaries of all VLBW infants having a hospital charge for a TPT from unit stock or for placement of a TPT in the Department of Radiology. Determination of each infant’s GER diagnosis and need for TPT feeding was by the neonatal attending on service. Our unit protocol for treating GER reserves the use of TPT feeding for those infants whose episodes of suspected GER are excessive or severe and who have failed trials of other GER treatments, including: positional changes, changes to the feeding schedule, elemental formulas, and anti-reflux medications, including antacids and metoclopramide.

Transpyloric enteral feeding tubes were placed fluoroscopically by a pediatric radiologist or advanced by the bedside nurse and confirmed by abdominal radiograph. An 8-French, polyurethane, non-weighted feeding tube was inserted by nasoduodenal route regardless of placement method. Feedings were then given continuously by pump.

Episodes of apnea > 10 seconds and bradycardia < 100 beats per minute were recorded by the bedside nurse as alerted by bedside impedance monitoring. We compared cardio-respiratory episodes before and after the initiation of TPT feedings at 1-day and combined 3-day intervals. The Wilcoxon signed-rank test was used to compare differences between daily cardio-respiratory episodes before and after TPT feedings were initiated.

Safety was monitored by noting episodes of death, sepsis, necrotizing enterocolitis, or spontaneous intestinal perforation. Sepsis was determined by positive blood culture, excluding untreated coagulase negative staphylococcus. NEC was defined by radiographic (Bell’s Stage IIA or greater) or surgical evidence. Descriptive statistics were used to summarize safety results, while Fisher’s exact and Kruskal-Wallis tests were used to compare factors of those that developed NEC and those that did not.

Infant socio-demographic, perinatal, and neonatal course history were also documented. This study was approved by Duke University’s Institutional Review Board.


RESULTS

72 VLBW infants with a median birth weight of 870 grams (range 365–1435g) and gestational age of 26 weeks (23–31weeks) were included (Table 1). The median weight at initiation of transpyloric feedings was 1297 grams (820–3145g) and age of 59 days (10–177days). Infants received feeds by this route for a median duration of 18 days (1–86days).

Efficacy Assessments

A reduction in apnea episodes from 4.0 for the combined 3 days prior to treatment to 2.5 episodes for the combined 3 days after initiation of TPT feedings (P = 0.02) was observed (Figure 1). In the immediate day before and after initiating TPT feeds, the number of apnea episodes decreased from 2.4 to 2.0 (P=0.10). We observed a decrease in total bradycardia episodes from 7.2 to 4.5 (P < 0.001) in the 3-day intervals before and after TPT placement and a reduction from 4.6 to 3.2 (P < 0.01) in the immediate day before and after the initiation of TPT feeds.

Safety Assessments

Five (6.9%) of the 72 infants developed NEC while receiving TPT feedings, similar in number when compared to those developing NEC before initiating (9.7%) or after discontinuing (8.3%) TPT feeds (Table 2). The infants that developed NEC during TPT feedings were similar to those that did not develop NEC with respect to birth weight, gestational age, gender, race, age and weight at time of initiating TPT feeding (Table 3). None of the infants receiving human milk during TPT feeding developed NEC (P=0.07) and 36% of those receiving hydrolysate based formula developed NEC (P<0.01).

Seven (9.7%) of the infants died prior to hospital discharge. Two infants died after developing NEC while receiving TPT feeds. Five others died from complications of extreme prematurity and whose death was not temporally related to TPT feeds, including one each from complications of brochopulmonary dysplasia, severe hydrocephalus, pulmonary hypertension, pulmonary hypoplasia, and one who died from congenital heart disease. No infant had an episode of sepsis or spontaneous intestinal perforation while receiving TPT feedings.


DISCUSSION

A definite causal relationship between GER and episodes of apnea and bradycardia remains elusive. It is likely that clinicians overdiagnose GER, attempting to explain a reason for the cardio-respiratory episodes related to immaturity of multiple physiologic functions. While it may be difficult to determine whether or not the cardio-respiratory instability elicited the reflux response, or the reflux of milk into the hypopharynx elicited the cardio-respiratory response, clinicians often seek therapeutic options to reduce these episodes in very low birthweight infants. Agreeing on the best therapeutic approach to this situation, however, has been challenging and has included alterations in optimal nutrition, use of medications with known risks, and even surgery. [13] We have included use of TPT feeding in our approach to the infant with apparent GER and recalcitrant cardio-respiratory instability.

Using the preterm infant as his own control, we found that TPT feeding reduces both apnea and bradycardia when compared to gastric feeds. It is possible that TPT feeds reduce GER episodes by allowing the milk to bypass the stomach thereby reducing obstructive apnea associated with milk refluxed to the proximal esophagus and hypopharynx. However, it may be that TPT feeding simply decreases the gastric distension associated with poorer respiratory function in bolus fed preterm infants. [14] The impact of TPT feeding on acid and non-acid reflux episodes and associated cardio-respiratory events in preterm infants has not been evaluated by randomized controlled trial.

One of the problems of diagnosing and treating GER in preterm infants is the lack of standard practice guidelines. The North American Society for Pediatric Gastroenterology and Nutrition Clinical Practice Guidelines for the evaluation and management of infants and children with suspected GER are not intended to be utilized for the management of neonates less than 72 hours old, premature infants or infants with neurological impairments. [15] Thus, neonatologists often start empiric treatment, though behavioral symptoms and cardio-respiratory signs are often poorly predictive of GER and effective medical treatments have not been determined. [1617]

Misra et al. also described a reduction in GER-associated apnea with TPT feeding in a small number of preterm infants and suggested using bedside-placed TPTs as a diagnostic tool for GER in this population. [18] Regardless of the mechanism for reducing apnea, we feel that this feeding method should be considered as a temporary treatment option in preterm infants with “excessive or severe” apnea or bradycardia events. Its effectiveness in improving these events should be evident within 24–72 hours.

A current systematic review comparing gastric versus TPT feeds in preterm infants have cautioned of a possible increased risk of mortality and feeding intolerance with TPT feeds. The increased mortality, however, disappeared when allocation bias was controlled. There were no differences in NEC, spontaneous perforation, sepsis or aspiration pneumonia. [12] While 7% of the babies in our study population developed NEC while receiving TPT feeds, this was similar to the number who developed NEC before or after receiving TPT feedings. Of note, 40% of the infants in our study received maternal breastmilk (non-donor) during TPT feedings and none of those infants developed NEC, while 15% of the infants received hydrolysate based formula during TPT feeds and over one third of them developed NEC.

This study is limited by the retrospective nature of the data collection and the unblinded evaluation of the bedside nurse to the intervention of TPT feedings. The number of recorded events in this study is likely lower than the true incidence, as bedside impedance monitoring and clinical nursing notation usually underestimates actual events. Lastly, while maturation may account for a decrease in cardio-respiratory events, it is unlikely that a maturational improvement would be significant when comparing both one and three day intervals in a preterm infant who is two months old. A randomized controlled trial would be necessary to properly determine efficacy of this intervention.


CONCLUSION

Transpyloric tube feedings are effective in reducing apnea and bradycardia in preterm infants with suspected GER. This method of feeding appears to be safe enough to warrant a clinical trial in a select population of preterm infants having excessive or severe apnea or bradycardia episodes suspected to be related to GER, particularly if the source of nutrition is human milk. Pivotal prospective studies of treatment methods for GER in preterm babies with clear inclusion criteria and outcome measures are needed to make more uniform evidence-based clinical practice recommendations.


Notes

FN2Financial Disclosure: Dr Malcolm was funded by a diversity supplement through the National Institute of Child Health and Human Development Cooperative Multicenter Neonatal Research Network (grant 3 U10 HD040492-06S1) and the Gerber Foundation


Abbreviations Glossary
VLBW very low birthweight (<1500g)
GER astroesophageal reflux
TPT transpyloric tube
NEC necrotizing enterocolitis

References
1. Herbst JJ,Minton SD,Book LS. Gastroesophageal reflux causing respiratory distress and apnea in newborn infantsJ Pediatr 1979;95:763–768. [pmid: 39984]
2. Spitzer AR,Boyle JT,Tuchman DN,Fox WW. Awake apnea associated with gastroesophageal reflux: A specific clinical syndromeJ Pediatr 1984;104:200–205. [pmid: 6694012]
3. Menon AP,Schefft GL,Thach BT. Apnea associated with regurgitation in infantsJ Pediatr 1985;106:625–629. [pmid: 3981319]
4. Peter CS,Sprodowski N,Bohnhorst B,Silny J,Poets CF. Gastroesophageal reflux and apnea of prematurity. No temporal relationshipPediatrics 2002;109:8–11. [pmid: 11773535]
5. Barrington KJ. Apnea at discharge and gastro-esophageal reflux in the preterm infantJ Perinat 2002;22:8–11.
6. Molloy EJ. Does gastroesophageal reflux cause apnea in preterm infants?Biol Neonate 2005;87:254–61. [pmid: 15711034]
7. Wenzl TG,Schenke S,Peschgens T,Silny J,Heimann G,Skopnik H. Association of apnea and nonacid gastroesophageal reflux in infants: Investigations with the intraluminal impedance techniquePediatr Pulmonol 2001;31:144–149. [pmid: 11180691]
8. Di Fiore JM,Arko M,Whitehouse M,Kimball A,Martin RJ. Apnea is not prolonged by acid gastroesophageal reflux in preterm infantsPediatrics 2005;116:1059–1063. [pmid: 16263989]
9. Kimball AL. Gastroesophageal reflux medications in the treatment of apnea in premature infantsJ Pediatr 2001;138:355–60. [pmid: 11241042]
10. Clark RH. Reported medication use in the neonatal intensive care unit: data from a large national data setPediatrics 2006;117(6):1979–1987. [pmid: 16740839]
11. Malcolm WF,Gantz M,Martin RJ,Goldstein RF,Goldberg RN,Cotten CM,et al. Use of medications for gastroesophageal reflux in extremely low birth weight infants at dischargePediatrics 2008;121(1):22–27. [pmid: 18166553]
12. McGuire W. Transpyloric versus gastric tube feeding for preterm infantsCochrane Database Systematic Review. 2007;(3)
13. Guillet R,Stoll BJ,Cotten CM,Gantz M,McDonald S,Poole WK,et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birthweight infantsPediatrics 2006;117(2):137–42.
14. Blondheim O,Abbasi S,Fox WW,Bhutani VK. Effect of enteral gavage feeding rate on pulmonary functions of very low birth weight infantsJ Pediatr 1993;122:751–5. [pmid: 8496756]
15. Rudolph CD,Mazur LJ,Liptak GS,Baker RD,Boyle JT,Colletti RB,et al. Pediatric gastroesophageal reflux clinical practice guidelinesJ Pediatr Gastroenterol Nutr 2001;32(supplement 2)
16. Snel A,Barnett CP,Cresp TL,Haslam RR,Davidson GP,Malbert TH,et al. Behavior and gastroesophageal reflux in the premature neonateJ Pediatr Gastroenterol Nutr 2000;30:18–21. [pmid: 10630434]
17. Hibbs AM. Metoclopramide for the treatment of gastroesophageal reflux disease in infants: a systematic reviewPediatrics 2006;118(2):746–52. [pmid: 16882832]
18. Misra S,Macwan K,Albert V. Transpyloric feeding in gastroesophageal-reflux-associated apnea in premature infantsActa Paediatrica 2007;96(10):1426–29. [pmid: 17850402]

Figures

[Figure ID: F1]
Figure 1 

Tables
[TableWrap ID: T1] Table 1 

Demographics for study population (n=72)


Gestational Age at birth (weeks) 26 (range 23–31)
Birth weight (grams) 870 (365–1435)
Age at start of TPT feeds (days) 59 (10–177)
Post-conceptual age at start of TPT feeds (weeks) 34 (29–48)
Weight at start of TPT feeds (grams) 1297 (820–3145)
Duration of TPT feeds (days) 18 (1–86)
Race: Black 36 (50%)
 White 31 (43%)
 other 5 (7%)
Male Gender 45 (62%)
Received human milk (non-donor) at start of TPT feeds 29 (40%)
Received milk-based preterm formula at start of TPT feeds 16 (22%)
Received hydrolysate formula at start of TPT feeds 11 (15%)
Received amino acid formula at start of TPT feeds 16 (22%)
CLD (O2 at 36 weeks) 25 (35%)
IVH (Grade 3 or 4) or PVL 15 (21%)

[TableWrap ID: T2] Table 2 

Infants developing NEC during TPT feeds


NEC (n=5) during TPT feed Age at TPT start (days) Wt at TPT start (g) Nutrition during TPT feeds NEC outcome
Patient (GA, BW) Formula: (kcal/oz)
1 (26wks, 1055g) 51 1440 Hydrolysate based 24 Medically treated
2 (27wks, 1095g) 47 1110 Hydrolysate based 24 Surgery, death
3 (26wks, 770g) 71 1293 Hydrolysate based 20 Surgery, death
4 (29wks, 1205g) 33 1450 Hydrolysate based 20 Surgery, short gut
5 (27wks, 915g) 85 1229 Amino acid based 22 Medically treated

[TableWrap ID: T3] Table 3 

Comparison of infants developing NEC vs. no NEC during TPT feeds


NEC infants N = 5 Non-NEC infants N = 67 P value
BW (grams) 1055 854 0.17
GA (weeks) 27 26 0.41
Wt at start of TPT feeds (grams) 1293 1300 0.95
Age at start of TPT feeds (days) 51 59 0.95
(%) Male 80 59 0.64
(%) African-American 80 46 0.56
(%) Receiving human milk 0 44 0.07
(%) Receiving preterm formula 0 22 0.24
(%) Receiving hydrolysate formula 80 11 <0.01
(%) Receiving amino acid formula 20 23 1.00


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Keywords: GERD, Feeding Methods, Infant, Premature, Apnea.

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