Gastroesophageal Reflux & Apnea of Prematurity

Presented by DR.Bassim Abu Rahmeh . Moderated by DR.Jarir Halazun . PEDIATRICS, January 2002
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Apnea
Definition: Cessation of air flow & will be pathologic if : 1) Prolonged >20 sec 2) If associated with bradycardia, cyanosis, pallor or hypotonia . Classification : -Central: inspiratory effort is absent . -Obstructive : inspiratory effort is persist but airway obstruction is present . -Mixed: obstructive follow or precedes central .
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Apnea

Incidence: Occur frequently in premature infants & the incidence increase with decrease GA .

1) Onset : generally begin at 1 or 2 days after birth . 2) Duration : usually ceased by 37 weeks of gestation 3) Term infants : always abnormal and associated usually with serious illness .

Apnea
Pathogenesis : A -Developmental immaturity . * The occurrence correlate brain stem neural function * Breathing in infant is strongly influenced by sleep state .REM sleep predominate in preterm . B -Chemoreceptor response : * hypoxia in preterm result in transient hyperventilation followed by hypoventilation . * ventilatory response in preterm with apnea to increase in CO2 is decreased .
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Apnea
C -Reflexes : stimulation of post pharynx ,lung inflation, fluid in larynx, chest wall distortion can precipitate apnea in infants. D -Respiratory muscle : 1- Airway obstruction : usually in upper pharynx. 2- Nasal obstruction : mainly in preterm. E -Gastroeophageal reflux : common in preterm ??.
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Gastroesophageal Reflux

and Apnea of Prematurity

Objective
The relationship between GER and apnea has been suspected but difficult to prove . The pathophysiology of AOP is incompletely understood, and GER was suspected as a one of the causes because : 1) AOP occurs most frequently in immediate postprandial period (GER most likely to occur). 2) Data from animal study showed instillation of small amount of liquid into larynx causes apnea . 3) Observation that apneas more likely to occur after episodes of regurgitation documented by PH 7 monitoring and manometry.

Objective
One of the reasons that it may have been difficult to demonstrate the relationship between AOP & GER is that the method applied to detect GER ,namely pH monitoring, is not useful in infant. Other method is used to avoid this problem which is (multiple intraluminal impedance technique MII). It measures intraluminal electrical impedance between a number of closely arranged electrodes during bolus passage . It allows for detection of fluid boluses in antegrade (swallow) as well as retrograde (GER) manner.
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Objective
In this study we recorded the MII in conjunction with cardirespiratory (CR) parameters in a group of preterm infants with AOP . We wanted to test the following hypotheses :

1) There is a close temporal relationship between GER & AOP. 2) Reflux episodes usually precedes rather than follow apneas .

METHODS
Nineteen infants (13 boys ) were enrolled in the study & one infant studied twice . Median GA was 30 w (24-34 w) of birth weight 1150g (600-1865g) & postnatal age at the study was 26 days of weight 1595g (1000-2320g) . At the study they were not on mechanical ventilation & had a clinical evidence of AOP that defined as : * occurrence of at least 2 episodes of apnea (>20s) ,bradycardia(<100/min) & or hypoxemia (sat<80%) over a 2hr period . Infants with secondary apnea were excluded .
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METHODS
Those infants underwent 20 6 hour recordings of MII, and CR signals (breathing movements, nasal airflow, ECG, pulse oxymeter sat, & pulse waveforms ) . Recordings were analyzed in 2 phases independent to each other for GER episodes . First :CR signals were analyzed for blinded to esophageal impedance signals . NOTE: periodic apnea excluded . Second :impedance signals were analyzed blinded to the CR signals for reflux episodes
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METHODS
Intraluminal impedance technique : Impedance catheter consist of 7 metallic cylinders placed 1.5 cm apart from each other around an 8F feeding tube through which infant received formula. The catheters advanced into stomach & pulling them back until impedance measured between the lowest 2 electrodes increase ,indicating reentry to esophagus. RE defined as a decrease in impedance starting in the most distal channel and extending over at least 2 channels .
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METHODS
All RE were then analyzed for any temporal association with a CR events which was considered present if the CR event commenced within +/-20 seconds of the onset of an RE. The frequency of apneas associated with GER was calculated by : number of pauses during these reflux episodes by total time of these episodes & comparing the results with those calculated for reflux free episodes .

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RESULTS
During 118 hours of recording a total of:
524 RE occurred with median rate of 25 per recording (range:8-62) . 2039 apneas occurred with median rate of 67 per recording (range:10-346) . 188 desaturations occurred with median rate of 6 per recording (range:0-25) . 44 bradycardias occurred with median rate of 0 per recording (range:0-24) .
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RESULTS

Apnea frequency during episodes with reflux was not significantly different from that found during refluxfree episodes {0.19/min vs 0.25/min} of (P >.05). Also, there was no correlation between apnea, bradycardia ,or desaturation and RE, ie infants who exhibited high numbers of any of these events were not more likely to have frequent RE (P >.05) . Finally among those apneas that did occur within 20 seconds of an RE , similar numbers occurred before as well as after an RE {2;0-14 vs1;0-17;P> .05} . 16

RESULTS

Only 9 of desaturation were associated with an RE and the frequency of desaturation that occur with GER was again not significantly different from desaturation that occurred during reflux-free epochs .

All 9 desaturations ,however, occurred after an RE , with the reflux reaching the pharyngeal level in 6 of these 9 episodes .
Only 1 of 44 bradycardias occurred within +/-20 sec of an RE ; which was small number to interpret.
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RESULTS
When analysis was restricted to those 345 RE that
reached pharyngeal level (median17/record;3-35): The frequency of apnea in conjunction with these RE was again not significantly different from that found during reflux -free epochs (0.17/min vs 0.19/min) However of those 71 apneas that were associated with an RE reaching the pharyngeal level ;significantly more (45 vs 26 ;P < .05 ) occur after rather than before an RE .
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LIMITATIONS
We excluded periodic apneas because there is evidence that the underlying pathmechnism for this pattern is different than that of AOP & even less likely related to GER. We didnt record esophageal PH because it was technically impossible to combine feeding tube, impedance catheter & pH meter so that to they fit into 8F feeding tube . However such a study has been performed in term infants showing almost 90% of RE in this age group are non acidic, suggesting that MII is more sensitive for GER detection than pH monitoring. 19

LIMITATIONS
MII is a relatively new technique & there is a little experience with it in preterm infants. One infant was studied twice , with recordings being 2 months apart, because AOP symptoms recurred after they had temporarily ceased and therefore entry criteria were met again .

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DISCUSSION
Both CR events & GER were common in these infants
but occurred independent to each other .

Apnea, desaturation, or bradycardia didnt occur more

frequently with reflux than during reflux free epochs.

Thus, in these group of preterm infants with recurrent

episodes of AOP ,the AOP seemed to be unrelated to GER although there was a minority of RE (particularly that reached pharyngeal level) that may have resulted in apnea .
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DISCUSSION
We chose to investigate the relationship between
GER & AOP from respiratory view of point ie by addressing the question of weather a significant proportion of these respiratory events is triggered by GER .

For this reason we enrolled infants with AOP

irrespective weather they had a history of frequent regurgitations .

The lack of relationship between GER & AOP found

in these infants cant suggest that such relationship doesnt exist in individuals . 22

DISCUSSION
However ,our results clearly dont support the
hypothesis that GER is a mechanism involved in a large proportions of apneas in preterm infants .

As a result of that this will argue against the

indiscriminate use of antireflux measures in infants with AOP and occasional regurgitations .

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DISCUSSION
Even those RE that reached the pharyngeal level were
not more likely to be associated with apnea which is in contrast to other work in this field . Our findings are in line with those from Page & Jeffrey who observed that preterm infants studied at term equivalent age respond to the pharyngeal infusion of small volumes of NS or water during sleep with a volume-dependent increase in swallowing frequency ,but not with increased apnea rate . These authors suggested that apnea & bradycardia are predominantly evoked larynx rather than pharynx is stimulated ,which not usually occurred during regurgitation of small amounts of liquid .
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DISCUSSION
Several studies in older infants also failed to
demonstrate a consistent relationship between acidic GER & apnea .

However , potential shortcoming of these studies was

that use ph monitoring to document GER which will identify only acidic reflux (pH<4) .

Gastric acidity depends on the interval at which

neutralizing milk is fed .
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DISCUSSION
It has shown term infants fed in 4 hrs interval had
pH<4 in 42% of the time .

Although we couldnt measure pH, it is likely that this

proportion was even lower in our patients who were fed in 2hour intervals .

In fact also using MII technique showed that only 11%

of RE in term infants with recurrent regurgitations or respiratory symptoms had pH < 4.
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CONCLUSION
Both CR events & GER were common in these infants The study shown that GER does not play a significant role in the pathophysiology of AOP ( ie no temporal relationship ) . This finding may be relevant to practice of giving prokinetics to infants of AOP. The effectiveness of this practice has never been proved & difficult to maintain as our results suggest lacks a pathophysiological basis .
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Thanks

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