Neuromotor Markers of Esophageal Motility in Feeding Intolerant Infants With Gastroschisis

Abstract

Background:

Feeding problems in neonates with gastroschisis are commonly attributed to foregut dysmotility. However, the dysmotility mechanisms are not well understood.

Objective:

Our aim was to differentiate the pharyngoesophageal motility characteristics in neonates with gastroschisis compared with the controls. Specifically, the characteristics of swallowing, upper esophageal sphincter (UES), esophageal body, and lower esophageal sphincter (LES) were evaluated during basal state and upon provocation.

Patients and Methods:

Surgically repaired and recovered study infants with persistent feeding difficulties (n = 8; 36 ± 2 weeks gestational age) and controls (n = 8; 38 ± 2 weeks gestational age) were evaluated at 40 ± 2 weeks and 42 ± 2.5 weeks postmenstrual age, respectively. The basal and adaptive pharyngoesophageal motility characteristics were evaluated using a specially designed esophageal motility catheter with UES and LES sleeves and pneumohydraulic micromanometric water perfusion system at the crib side. Analysis of variance, chi-square, and t tests were applied; data are shown as mean ± standard deviation, and P < 0.05 was considered significant.

Results:

Birth weight was less in gastroschisis (P < 0.03, vs controls) and length was less at motility study (P < 0.01, vs controls). The study group (vs controls) needed prolonged respiratory support (21 ± 23 vs 1 ± 2 days; P < 0.001) and prolonged gavage feeding (167 ± 100 vs 9 ± 16 days; P < 0.01). Compared with the controls, the gastroschisis group had lower frequency (P < 0.05) and poor propagation of spontaneous swallows (P < 0.001), UES relaxation time was shorter (P < 0.05), rate of relaxation was faster (P < 0.001), and esophageal peristaltic propagation velocity was slower (P < 0.05). Upon esophageal provocation with air and liquids, frequency occurrence of the esophageal reflexes was low (P < 0.05) with respect to primary peristalsis, secondary peristalsis, UES contractile reflex, and LES relaxation reflex.

Conclusions:

In gastroschisis feeding milestones and respiratory milestones were delayed, basal pharyngoesophageal peristaltic failure was common, adaptive peristaltic reflexes were less frequent and failed to occur, and frequency occurrences of UES and LES responses were impaired. These neuromotor markers may provide clues to define the esophageal motor function abnormalities in infants with an abnormality thought to be limited to the intestine.

The incidence and prevalence of gastroschisis is increasing (1). With advances in maternal and fetal therapies and neonatal intensive care, the survival rate among neonates born with abdominal wall defects is increasing (1). Furthermore, the morbidity related to feeding, gastroesophageal reflux disease (GERD), and esophagitis in these infants is high (2,3). GERD has been reported to be around 40% to 50% in a meta-analysis of patients with gastroschisis (4). Enteral feeding tolerance can be difficult or delayed in infants with foregut and abdominal wall malformations despite surgical repair and anatomical modification (1,5,6).

The mechanisms of feeding difficulties, respiratory morbidity, and esophageal dysmotility after surgical repair of the gastroschisis are not well known. The presence of GERD and chronic lung disease may have contributed to recurrent readmissions in foregut malformations or malfunction during childhood (7). Whether this association is due to inadequate aerodigestive adaptive mechanisms is not known. The gap in knowledge about esophageal dysmotility mechanisms may stem from the lack of safe methods to evaluate in these fragile infants. Recently, using micromanometric methods, we characterized basal and adaptive esophageal neuromotor responses in human infants (8–10).

The objectives of the present study were to characterize and differentiate the pharyngoesophageal motility characteristics in neonates with gastroschisis compared with controls. Specifically, the characteristics of swallowing, upper esophageal sphincter (UES), esophageal body, and lower esophageal sphincter (LES) were evaluated during basal state and upon provocation. We accomplished these objectives by defining the basal and adaptive pharyngoesophageal motility characteristics in fully recovered, postsurgical infants with gastroschisis that had persistent feeding intolerance.

PATIENTS AND METHODS

Gastroschisis infants (n = 8, study group) that had recovered from surgery and structurally normal controls (n = 8) that had recovered from transitional neonatal problems participated in this study. By the time of our motility evaluation, the study subjects had recovered from postsurgical issues and were not on any narcotics. They did not have any obstructive bowel pathologies (atresias), because gavage feeds were maintained. Study subjects were on full enteral gavage feeds, and were off parenteral nutrition. In contrast, the controls (n = 8) were feeding orally at the time of evaluation.

Gestational age (GA) was determined by maternal history and obstetric data. Postmenstrual age was calculated by adding chronological age to GA. Subjects were not receiving prokinetics or acid-suppressive therapies at evaluation. Exclusion criteria were: chromosomal disorders and hypoxic ischemic injury. These studies were approved by the institutional review boards at both sites, Nationwide Children’s Hospital of Columbus, OH, and Children’s Hospital of Wisconsin, Milwaukee. Informed consents and Health Insurance Portability and Accountability Act authorization were obtained from parents prior to study.

Standard Clinical Practice Protocol

As part of the standard of clinical care, study infants underwent surgery under general anesthesia when they were physiologically stable. The approach to surgical repair was decided upon by the surgeon, with primary reduction being the preferred method if feasible. As an alternative, staged repair also was considered when infants experienced physiological instability during surgical procedure. Standard postoperative care was administrated as required, including narcotic analgesia for postoperative pain, antibiotics for suspected sepsis, and parenteral nutrition for nutritional support.

Minimal enteral feeding was begun upon the return of bowel sounds in physiologically stable infants that had an absence of gastric aspirates. Physiological stability for the purpose of initiation and maintenance of feeding practice was defined as an ability to maintain vital signs within the normal range for a 24- to 48-hour period, clearance of gastric residual volumes, presence of bowel sounds, and ability to pass stool. After initiation, feeding increments were based on consistent enteral feeding tolerance for a previous 24- to 48-hour period and by the lack of evidence of feeds being held during the same period. Generally, feeds were held if there was a gastric residual volume >50% of the feeding volume, or if there was a bilious aspirate. During such occurrences, routine clinical evaluation was performed and feedings were resumed after physiological stability was ascertained.

Manometric Methods

The esophageal manometry methods adapted for neonates have been described by us before (8–12). Briefly, the catheter assembly was connected to the pneumohydraulic micromanometric water perfusion system via the resistors (Dentsleeve International, Mui Scientific, Ontario, Canada), pressure transducers (TNF-R disposable pressure transducers, Ohmeda, Tewksbury, MA), and amplifiers (UPS 2020, Medical Measurement Systems USA, Dover, NH). The esophageal manometry catheter assembly with dual sleeves and 4 side-ports and a terminal gastric recording port were used. The water perfusion rate was 0.02 mL/min per port for esophageal ports, 0.01 mL/min per port for the pharyngeal port, and 0.04 mL/min per port for the sleeves. All of the studies were done in the same manner, with the transducers at the level of the subject’s esophagus (midaxillary line). The catheter was passed nasally in the supine lying infant without the aid of sedation. Respiratory patterns and vital signs were recorded concurrent with manometry to document subject safety.

Manometric Study Protocol

Manometric Catheter Positioning

Continuous data acquisition and analysis were performed during manometric study based on waveform characteristics, as defined previously (8–12). During pull-through, the high pressure zones of the LES and UES were identified by the presence of a consistent increase in pressure >5.0 mmHg above the baseline for at least 15 seconds, in addition to the changes in pressure with respiration (11).

Manometric Evaluation of Basal and Adaptive Responses

The infants were allowed to adapt to catheter placement for about 30 minutes, and the basal pharyngoesophageal motility was recorded. Data obtained from this period were used to describe the characteristics of swallow, such as the spontaneous swallow frequency, propagation and distribution of primary peristaltic waveforms, peristaltic velocity, and resting UES and LES pressures. All of the measurements were taken at end expiration and data were analyzed as described previously (8–12).

Infusions with graded volumes of air, sterile water, and apple juice were given 3 times via the midesophageal infusion port to evaluate the adaptive responses. Presence of ≥50% peristaltic responses was considered as a response for a specific volume. However, when 2 identical responses were noted with the first 2 infusions, a third infusion was avoided to minimize fluid load. The rationale for the use of these infusions was that the esophagus can be the site of mechanostimulation (air) or acidic stimulation (apple juice, pH 3.7) during gastroesophageal reflux events. Water (pH 7.0) was used as a control infusion. The presence of primary peristalsis, secondary peristalsis, and changes in UES and LES tone were identified. The frequency and characteristics of peristaltic and sphincteric reflex responses were quantified as described before (8,9).

Statistical Analysis

Subject characteristics, manometric data variables, and outcome variables at discharge were compared within and between the groups. Data are shown as mean ± standard deviation, unless stated otherwise. Analysis of variance and chi-square, Mann-Whitney rank sum, or t tests were performed using SPSS 14.0 (SPSS, Chicago, IL). P < 0.05 was considered significant.

RESULTS

Subject, Disease, and Morbidity Characteristics

Eight infants with gastroschisis (3 male; 35.6 ± 2.3 weeks GA) were evaluated at 41.9 ± 2.5 weeks postmenstrual age. Eight controls that were asymptomatic (1 male; 37.6 ± 2.3 weeks GA) were evaluated at 39.8 ± 1.5 weeks postmenstrual age. The median Apgar score in both of the control and study groups at 1 minute was 8 and at 5 minutes was 9. The controls were admitted for respiratory distress and transitional neonatal problems, including sepsis workup and jaundice. All of the controls were discharged on oral feeds. Both groups of subjects received antibiotics for suspected sepsis workup. The characteristics of growth, respiratory, and feeding milestones in controls and study infants are shown in Table 1.

TABLE 1.

Subject and disease characteristics

Subject characteristics	Control (n = 8)	Study (n = 8)	P
Growth characteristics at birth
Gestational age, wk	37.6 ± 2.3	35.6 ± 2.3	NS
Weight, kg	3.0 ± 0.8	2.0 ± 1.1	0.03
Length, cm	48.0 ± 4.6	43.0 ± 5.6	NS
Head circumference, cm	32.2 ± 2.1	30.0 ± 2.4	NS
Growth characteristics at motility study
Postmenstrual age, wk	39.8 ± 1.5	41.9 ± 2.5	NS
Weight, kg	3.4 ± 0.7	2.4 ± 1.1	NS
Length, cm	51.3 ± 1.2	46.1 ± 3.0	0.01
Head circumference, cm	33.9 ± 1.4	33.9 ± 2.2	NS
Feeding milestones
Exclusive gavage feeds, days	5 ± 9	129 ± 129	0.01
Transitional gavage and full oral feeds, days	4 ± 8	57 ± 28	0.04
Total days on gavage feeds	9 ± 16	167 ± 100	0.01
Respiratory milestones
Ventilation, days	1 ± 2	11 ± 11	0.001
NCPAP, days	0 ± 1	11 ± 13	0.02
Total respiratory support, days	1 ± 2	21 ± 23	0.001

NCPAP = nasal continuous positive airway pressure. Values shown as mean ± standard deviation. P values from Mann-Whitney rank sum or t tests.

Characteristics of Spontaneous Swallow-induced Primary Peristalsis

Basal swallow characteristics were analyzed at different levels: frequency occurrence, pattern of propagation, UES and LES tone, and esophageal body waveform characteristics. The frequency and propagation of spontaneous swallows were different between the groups (both P < 0.05, Fig. 1). The characteristics of UES and LES, as well as esophageal body waveform propagation, are described in Table 2.

FIG. 1.

A, Comparison of swallow frequency in control vs gastroschisis and (B) the distribution of swallow propagation rates. Both of these characteristics are impaired in the study group (P < 0.001).

TABLE 2.

Basal characteristics of esophageal motility

Characteristics	Control	Study	P
Resting UES pressure, mmHg	23.8 ± 10.8	30.1 ± 8.2	0.4
UES relaxation time, s	1.5 ± 1.2	0.3 ± 0.1	0.035
Rate of UES pressure fall, mmHg/s	31.2 ± 23.3	112.5 ± 17.8	0.001
Resting LES pressure, mmHg	16.7 ± 5.36	9.2 ± 6.9	0.163
Swallow start to LES relaxation onset, s	1.3 ± 0.3	1.5 ± 0.5	0.45
Amplitude proximal esophagus, mmHg	34.2 ± 11.1	40.0 ± 24.8	0.6
Amplitude distal esophagus, mmHg	46.2 ± 24.9	23.6 ± 9.1	0.1
Proximal to middle esophagus propagating velocity, cm/s	3.0 ± 1.6	0.9 ± 0.2	0.08
Middle to distal esophagus propagating velocity, cm/s	2.1 ± 0.7	0.6 ± 0.3	0.05

UES = upper esophageal sphincter; LES = lower esophageal sphincter. Values shown as mean ± standard deviation. P values from Mann-Whitney rank sum or t tests.

Adaptive Reflex Responses Upon Esophageal Provocation

A total of 292 esophageal infusions (graded volumes of air, water, and apple juice) were given in the control (n = 127 infusions) and in the study (n = 165 infusions) group. Characteristics of peristaltic responses and UES and LES responses evoked upon esophageal provocation are shown in Fig. 2. The frequency recruitment of peristaltic responses (Fig. 3), UES contractile responses (Fig. 4A), and LES relaxation responses (Fig. 4 B) were lower and different in the study group (all P < 0.001).

FIG. 2.

Examples of manometry recording from a control and a study subject are shown. Upon midesophageal stimulation with 1.0 mLwater, robust secondary peristalsis (SP) sequence, upper esophageal sphincter contractile reflex (UESCR), and lower esophageal sphincter relaxation response (LESRR) are noted. The responses are weaker in the study subject. Also, the resting LES tone is low in the study subject. DE = distal esophagus.

FIG. 3.

The frequency recruitment of esophageal peristaltic reflex responses in the control vs study group is shown. Upon midesophageal stimulation, lack of a response (None) was frequent in the study group, and secondary peristalsis (SP) and primary peristalsis (PP) occurred more frequently in the control group.

FIG. 4.

The frequency recruitment of upper (UES) and lower esophageal sphincter (LES) responses in the control vs study group is shown. Upon midesophageal stimulation, a decrease in the occurrence of (A) UES contractile reflex (UESCR) and (B) LES relaxation response (LESRR) was more frequent in the study group (both P < 0.05).

Comparison of Responses at a Fixed Stimulus Volume

The most common peristaltic response was secondary peristalsis (Fig. 3), and the threshold volumes were similar (0.8 ± 0.2 mL vs 0.8 ± 0.1 mL, control vs study group). To determine whether the reduced frequency of responses was due to the sensory or the motor defects, we further analyzed the data by comparing the response characteristics evoked upon infusion of a fixed stimulus volume (1 mL of air, water, or apple juice). In control versus gastroschisis, the response latency to evoke deglutition response were similar with air stimulus (4.6 ± 1.6 vs 5.1 ± 1.6 seconds, control vs study group), water stimulus (2.9 ± 1.4 vs 3.3 ± 2.3 seconds), and apple juice stimulus (4.0 ± 2.2 vs 2.6 ± 2.1 seconds).

In control versus gastroschisis, the response latency to evoke secondary peristalsis response were similar with air stimulus (4.2 ± 1.5 vs. 4.2 ± 1.4 seconds, control vs study group), water stimulus (2.7 ± 1.7 vs 3.3 ± 1.4 seconds), and apple juice stimulus (3.7 ± 2.7 vs 2.8 ± 2.6 seconds).

The frequency recruitment of responses is summarized in Fig. 5. Comparison of responses within the control group for air vs both water and apple juice were different (P < 0.001) and water versus apple juice were similar. In the study group, air also was found to be handled differently than water or apple juice (both P < 0.001), but the distribution of reflex responses to water versus apple juice also was significantly different (P = 0.001).

FIG. 5.

Distribution of peristaltic responses to 1.0-mL infusions of esophageal (A) air, (B) water, and (C) apple juice is shown. At a constant physical or chemical stimulus, the frequency recruitment of peristaltic reflexes is different in the study group (with all media, P < 0.001). NR = no response; SP = secondary peristalsis; PP = primary peristalsis; C = control; S = study; AJ = apple juice.

DISCUSSION

In this study, we describe the sensory-motor aspects of esophageal motor function abnormalities in infants with gastroschisis. In contrast to control characteristics, the esophageal dysmotility mechanisms in the study infants include basal pharyngoesophageal peristaltic failure, impaired recruitment frequency of peristaltic reflexes and sphincteric reflexes upon esophageal provocation, and differences in the frequency of peristaltic responses upon mechano-, osmo-, or chemosensitive stimulation at a fixed stimulus volume. Furthermore, the markers of morbidity related to feeding and airway problems in the study group also were significant. The study group needed longer duration of gavage feeds and also needed longer duration of respiratory support. Prolonged gavage feeds in the study group generally were attributed to dysmotility and feeding intolerance. The esophageal dysmotility mechanisms characterized in this study may be the manometric correlates for the aerodigestive problems in infants with gastroschisis.

In general, neonates with gastroschisis are born earlier than term gestation, as was the case in the present study. The study and control groups were similar in gestational age at birth and postmenstrual age at study. However, esophageal motility advances with postmenstrual age in healthy premature infants (8,9,12). The postmenstrual age difference is unlikely to be a confounding factor for the differences in the neuromotor markers of esophageal motility because the characteristics of swallowing were different. Under normal circumstances, the characteristics of swallowing improve with maturation; such was not the case in the gastroschisis patients. Specifically, the study group had reduced swallow frequency and increased failed propagation rates. It is likely that the central control mechanisms that regulate initiation and propagation of swallowing are defective in gastroschisis. The amplitude of distal esophagus and the resting tone of LES were lower in the study group (compared with controls), but this did not achieve significance given the sample size. We speculate that a role is played by inflammation, a frequent factor in gastroschisis, which may have resulted in impaired motility characteristics.

Generally, infants with gastroschisis have feeding problems despite surgical repair. The potential confounding conditions may include intestinal atresia, gestational age, postmenstrual age at surgery, birth weight, postoperative complications, pharmacological management, and gastrointestinal dysmotility. Although intestinal abnormalities are well recognized in gastroschisis, the role of enteric neuromotor mechanisms pertinent to esophageal function is not understood. In this study, pharyngoesophageal motility studies were performed when the study patients were receiving full enteral gavage feeds and were having feeding difficulties. By the time of evaluation, the role of potential confounders in the study group is limited in that gavage feeds were incremental and postoperative concerns were not a question. However, the presence of comorbid conditions can influence feeding milestones. The study lacks sufficient statistical power to test the significance of any of these potential confounders, and such a study will require a larger sample size.

We noted significant differences in birth weight between the groups. In a retrospective study on postnatal outcome in gastroschisis, Charlesworth et al (13) observed that birth weight is a better outcome variable than gestational age. It is possible that somatic and organ growth may have been compromised in the gastroschisis patients, and therefore may have contributed to our study findings related to swallowing and airway concerns.

Swallowing is a complex act and involves integration of several aerodigestive reflexes, possibly mediated by the central pattern generator and the vagal nuclei (12). The adaptive responses require coordination of reflex sequences. Such responses evoked upon esophageal stimulation were impaired in the study group. The slower frequency of swallows and impaired propagation of waveforms in the study group are suggestive of central inhibition of the swallowing process, which may have origins in the distal foregut. Alternatively, persistence of feeding difficulties may be due to both central and enteric nervous system functional abnormalities, manifesting as weakened aerodigestive defenses and impaired esophageal clearance mechanisms. Significantly, the recruitment frequency, distribution of peristaltic responses, UES contractile response, and LES relaxation response frequency were different.

The rationale for testing the effects of air, water, and apple juice was to evaluate the effects of mechanostimulation, osmostimulation, and chemosensitive stimulation, respectively (9). At identical stimulus volumes (1.0 mL), the frequency and distribution of peristaltic and sphincteric responses in the study group was significantly different. The role played by postnatal maturation, chronic inflammation, or chronic noxious stimulation received during intensive care cannot be assessed in this study, albeit these may have contributed to the study findings. Larger studies controlling these variables may be required to clarify pathogenesis.

We recognize the following clinical implications: First, the study findings support and provide physiological explanation for the observation of higher incidence of GERD in infants with esophageal and abdominal wall defects after repair (2,3,6,7,14). In the event of esophageal provocation, such as may happen in gastroesophageal reflux, impairment in the aerodigestive defenses will provide less protection against retrograde movement of the refluxate, resulting in delayed clearance of the refluxate that may perpetuate inflammation. Second, the importance of esophageal dysmotility as defined in the study subjects may have contributed to the feeding and respiratory morbidities. Therefore, evaluation of pharyngoesophageal peristaltic failure and stimulus-response relationships, and characterization of esophageal motor abnormalities. may be of diagnostic and prognostic value in study infants. Proximal foregut abnormalities may be responsible in part for the aerodigestive symptoms, although more distal small bowel pathophysiology also can be contributory. Third, in counseling parents during antenatal and postnatal consultations, an expectation of foregut motor abnormalities, delayed acquisition of feeding milestones, and the need for chronic tube feeding should be considered. Fourth and finally, the compelling findings of this study have statistical and clinical significance despite limitations. The methodology described may provide valuable data for future investigations related to intestinal anomalies. Further studies are needed to evaluate the factors that may delay or accentuate recovery.