chronic lung disease (CLD), cerebral palsy, and mental retardation
are well known complications of extreme prematurity, less
well known is the increased prevalence of feeding dysfunction.
At the Mount Washington Pediatric Hospital in Baltimore, 41%
of infants born at less than 25 weeks gestation receive surgically
placed feeding tubes for feeding problems.1
According to a study done as part of the Nationwide Inpatient
Sample, 48,000 anti-reflux surgeries have been done over the
period from 1996 to 2003.2
Almost half of those were in infants less than one year old,
and the incidence was found to have almost doubled during
that period. Dysfunctional swallow associated with immaturity,
brain damage, and poor respiratory reserve seen in infants
with CLD, as well as GER, are believed to be causal factors
leading to feeding dysfunction in extremely premature infants.
While GER is essentially seen in all newborn infants and improves
with maturation, the condition is believed to contribute to
several important consequences, including: CR events, reflux
aspiration, feeding aversion, and swallowing dysfunction.3,4
These events increase length of hospitalization, worsen CLD,
and may increase the risk of sudden death.
In the Collaborative Home Infant Monitoring Evaluation (CHIME)
study (involving the largest longitudinal physiologic dataset
of infants), persistent obstructive apneas were shown to be
common beyond term in the recovering premature infant, and
were associated with poor developmental outcome.5,6
GER may be suspected as a cause of persistent CR events at
a gestational age (GA) when most premature infants have outgrown
their apnea of prematurity. CR events induced by GER may be
mediated through vagal reflexes or reflux aspiration. Acute
pulmonary aspiration is often suspected in infants with CLD
when they develop new signs of apnea, respiratory distress,
and chest X-ray changes. Acute aspirations occur with both
nipple feedings and gavage feedings, suggesting GER. In infants
with CLD, GER may become "non-physiologic" because of increased
transient lower esophageal sphincter relaxation,7
and may be especially associated with increased work of breathing
and intra-abdominal pressures. Also, "non-physiologic" GER
may be further complicated by swallowing/laryngeal dysfunction
preventing airway protection.
However, obtaining direct proof of aspiration due to GER or
proving an association of a GER event with a CR event is,
at present, very elusive. Esophageal pH monitoring explores
only the esophageal consequences of GER, and is accurate only
when the gastric pH is low. Clinical history, pattern of abnormalities
on chest X-ray, and tracheobronchial aspiration during barium
contrast or scintigraphic studies lack sensitivity and/or
specificity. Similarly, determination of fat-laden macrophages
in tracheal aspirates has been shown to be poorly specific,
with about half of both the children presenting with GER and
respiratory symptoms as well as controls testing positive
for macrophages containing fat.8
Each of the studies discussed herein sought to explore new
methods of investigation to associate cardiopulmonary events,
especially aspiration and CR events, with GER. The presence
of tracheal pepsin has been used as a marker of aspiration
in older children, adults, and experimental studies.9-12
Several studies have attempted to correlate CR events with
GER as detected by impedance in diverse pediatric populations.13-18
Results and interpretations of these clinical studies have
been conflicting secondary to major methodological differences,
including subject selection, methods of exploration, and temporal
association statistical analysis.
By identifying the reflux bolus itself in the esophagus and
its pH, the combined impedance-pH probe has the potential
to more accurately establish a temporal correlation with CR
events. Sandhill Scientific, the manufacturer of the combined
impedance pH probe in the US, has developed several statistical
tools to explore symptom association. The symptom index (SI)
is calculated as the number of symptoms with reflux times
100 divided by the total number of symptoms, and is expressed
as a percentage. A second method is the Symptom Associated
Probability (SAP), which is a Fisher exact test. The advantage
of these statistical methods is that a correlation between
reflux and CR events may be established for each individual
Sandhill has released their proprietary software with two
different techniques to statistically correlate GER and respiratory
symptoms for the SAP. In the first method of SAP, the recording
is divided into 2 minute bins, and tested for the presence
of GER in bin n and symptom in bin n+1. A symptom occurring
in the same bin n after a GER event is not counted as being
correlated. Whether this assumption is appropriate or not
is unclear. The second method of SAP is based on research
by Bredenoord et al.19
The recording is divided into two minute bins and tested for
the presence of GER. A symptom is determined to be temporally
correlated if the beginning of a GER event occurs within the
2 minute segment before the symptom. This method seems more
appropriate, and new software with this SAP method has recently
been released by Sandhill.
In summary, further studies are needed in infants suspected
of cardiopulmonary complications of GER as seen in the recovering
premature infant with persistent CLD and/or persistent CR
events. GER should be considered in these infants when they
should have outgrown their CLD and/or apnea of prematurity.
The association of CR events with GER may help determine the
optimal medical and surgical management of GER to improve
E, Nunez J, Mathias K, Lefton-Greif M, Gauda E, Katz
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in premature infants<30 weeks gestation APS-SPR 2006,
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R, Corwin MJ, Hunt CE, et al; Collaborative Home Infant
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U, Mitchell JD, Messina I, Day AS, Bohane TD. Assay
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Gut. 2005 Dec;54(12):1810-1817. Abstract