Effects of Non-Nutritive Sucking on Gastroesophageal Reflux and Related Apneas in Symptomatic Preterm Infants
Condition: Gastroesophageal Reflux; Apneas; Bradycardia
MeSH terms: Gastroesophageal Reflux; Esophagitis, Peptic; Apnea; Bradycardia
Study type: Observational

Summary: 
      Gastro-esophageal reflux (GER) is a common condition among preterm infants, due to several
      physiological promoting factors. To limit the potentially harmful widespread of
      pharmacological treatment, a step-wise approach, which firstly applies conservative
      strategies, is currently considered the best choice to manage GER in the preterm population.
      Among the most common conservative strategies, postural measures seem to represent an
      effective measure to reduce GER features in symptomatic preterm babies, whereas feed
      thickening is almost ineffective. Non-nutritive sucking (NNS) is a care strategy largely
      applied in the Neonatal Intensive Care Unit (NICU) settings. The act of swallowing is both
      reported to trigger the onset of transient lower esophageal sphincter relaxations (TLESRs),
      thereby eliciting to GER episodes, and to promote the esophageal clearance of refluxate.
      Hence, a possible effect of NNS on GER features might be hypothesized.

      This observational, prospective and explorative study primarily aims to explore the effect of
      NNS, applied by means of a pacifier, on acid and non-acid GER features, evaluated in
      symptomatic preterm infants (gestational age ≤32 weeks) undergoing a diagnostic combined pH
      and multiple intraluminal impedance (pH-MII). The secondary aim of this study is to evaluate,
      in the subgroup of patients with recurrent GER-related apneas, the effect of NNS on
      cardiorespiratory events, defined as bradycardias and total, central, obstructive, mixed
      apneas and detected by a simultaneous polysomnographic monitoring.
    

Detailed description: 
      Due to several promoting factors related to the physiological immaturity of the
      gastro-intestinal tract, gastro-esophageal reflux (GER) is a frequent condition among preterm
      infants.

      GER clinical presentation may vary within a wide range of symptoms, being vomiting,
      regurgitations and cardiorespiratory events, such as apnoeas or bradycardia, the most common
      in the preterm population. Particularly, apneic episodes are inversely related to the
      gestational age (GA) and might be associated with such pathological events as hypoxia,
      hypercapnia or pressure variability, which seem to negatively affect the long-term
      neurological development of preterm babies.

      Combined pH and multiple intraluminal impedance (pH-MII) is currently considered the best
      choice for GER diagnosis in preterm infants. While pH monitoring is limited to the detection
      of acid reflux, combined pH-MII effectively identifies both acid and non-acid GER, which is
      predominant in preterm babies. Moreover, thanks to its multichannel probe, combined pH-MII
      allows to evaluate the height reached by the refluxate within the esophageal lumen and to
      distinguish retrograde fluid bolus movements (reflux) from the anterograde ones (swallows).

      In the last decade, GER pharmacological treatment has increasingly widespread in NICUs. The
      provision of anti-histamine2 (H2) blockers and proton pump inhibitors (PPI) in the preterm
      population, however, might lead to such adverse effects as an increased incidence of
      necrotizing enterocolitis and infections. Hence, to avoid a useless and potentially harmful
      pharmacological overtreatment, a step-wise approach, firstly promoting conservative
      strategies, is currently considered the most advisable choice for GER management in
      symptomatic preterm infants.

      Postural and dietetic interventions represent the most common conservative strategies and
      their efficacy in improving GER symptoms and features has been largely investigated.

      As we assessed in a previous pH-MII study, both prone and left-side positions were more
      effective than the right-side or the supine ones to determine a significant improvement in
      both acid and non-acid GER features.

      Feed thickening is widely employed to reducing vomiting and regurgitations in symptomatic
      term infants; with regard to the preterm population, however, little data is currently
      available. We have previously investigated the efficacy of thickened fortified human milk on
      preterm infants suffering from GER symptoms (frequent regurgitations, desaturations,
      bradycardia), observing no benefits. Furthermore, standard human milk fortification itself
      has been shown to increase GER frequency in preterm infants.

      With regard to anti-regurgitation (AR) formulas, we have recently evaluated the effectiveness
      of a specific AR formula, thickened with amylopectin and specifically tailored for preterm
      infants' nutritional needs; the tested thickened formula effectively reduced the number of
      acid GERs, but no difference was observed in the frequency of non-acid GERs and in the mean
      esophageal acid exposure, which is known to be the main determinant for the development of
      gastro-esophageal reflux disease (GERD). Thus, according to these preliminary data, feed
      thickening seem to be almost ineffective in improving GER symptoms and features in preterm
      infants.

      Non-nutritive sucking (NNS) is part of the routine neonatal care, being widely applied in
      NICU settings. NNS has been showed to positively influence gastric secretion, gut motility
      and to improve the digestive process. NICU hospitalization and the need for respiratory
      support, however, might delay the transition from tube feeding to full oral feeding, thereby
      increasing the length of hospital stay and negatively affecting the mother-neonate
      relationship. Over two decades ago, in their meta-analysis Schwartz et al. showed beneficial
      effects of NNS in reducing time to attain full oral feeding as well as the length of
      hospitalization. These results have been further confirmed in a recent review by Harding.

      The role of NNS on GER, however, has not been yet clarified. It has been previously shown
      that the swallowing enhances the occurrence of lower oesophageal sphincter relaxations, which
      are known to represent a trigger stimulus for reflux episodes. On the other hand, the act of
      swallowing appears to promote the esophageal clearance of refluxate; hence, a possible
      influence of NNS on GER might be hypothesized. In a pH-metric study, performed by Orenstein
      et al. on infants younger than 6 months, NNS seemed to have a worsening effect on GER when
      applied in the prone posture, whereas in the seated position was associated with an
      ameliorative outcome; this controversial result, however, cannot be extended to the preterm
      population. To date, the efficacy of NNS by means of a pacifier on preterm infants
      symptomatic for GER has been preliminary evaluated only by Zhao et al., reporting an
      improvement of overall GER features (number of refluxes, reflux index, total time at pH<4)
      and a faster time of gastric emptying in the NNS group. However, this study was performed by
      pH monitoring, so that the effect of NNS on non-acid GER has not been evaluated yet.

      Due to the buffering effect of milk feeding on gastric pH, and being the acidity of gastric
      juice GA-dependent, non-acid GERs represent a major percentage (70%) of the overall reflux
      episodes in the preterm population. Moreover, as we have recently observed, non-acid reflux
      is the main responsible for the occurrence of GER-related apneas. Hence, a beneficial effect
      on GER-related apneas and subsequent hypoxic episodes, potentially harmful for preterm
      infants, could be supplied by conservative strategies effective in decreasing non-acid GERs
      features.

      The primary aim of this observational, prospective, exploratory study is to evaluate the
      effect of NNS on GER pH-MII features in preterm infants (GA ≤32 weeks) symptomatic for GER
      (i.e. suffering from frequent regurgitations, feeding difficulties, failure to thrive and/or
      post-prandial desaturations) for which a 24-hour pH-MII monitoring for GER diagnostic
      evaluation has been scheduled.

      The secondary aim of this study is to assess, by means of a simultaneous non-invasive 6-hour
      polysomnographic recording, the effect of NNS on total, central, obstructive, mixed apneas
      and on cardiorespiratory events within the subgroup of patients with recurrent desaturations.

      Overall thirty preterm infants (GA ≤32 weeks) will be enrolled if suffering from
      moderate/severe GER symptoms and if a diagnostic 24-hour pH-MII monitoring has been scheduled
      to evaluate GER features, according to our clinical practice.

      During the 24-h pH-MII monitoring each infant will receive eight meals, four of which will be
      followed by NNS treatment with a pacifier. The sequence of NNS application will be
      consecutively alternated in study participants. For each evaluation, a minimum of 2 hours of
      NNS post-prandial treatment is required. The healthcare assistants (i.e. medical staff and
      nurses) will inspect the correct application of NNS, recording the effective time of pacifier
      usage and regularly checking the pacifier position in relation to the pH-MII probe and
      polysomnographic flow sensor, to avoid possible interferences. Due to their immaturity, the
      enrolled patients might show an ineffective sucking, potentially losing the pacifier. In this
      case, the healthcare assistants will offer the pacifier to the babies up to a maximum of four
      times for each postprandial period; measures to fix the pacifier will be avoided.

      The pH-MII device in use for this study (Comfortec pH-MII Sandhill Scientific) is a
      nasogastric probe with seven rings, composed by six dipolar impedance channels and one
      antimony electrode responsible for pH detection and placed in the middle of the distal
      impedance dipole. Due to these characteristics, pH-MII is able to measure the esophageal
      height reached by refluxate and to identify the direction of esophageal bolus movements,
      thereby distinguish between a retrograde flow (reflux) and an anti-retrograde flow (swallow).
      Esophageal probe length will be determined using Strobel's formula: [baby length (cm) x 0.252
      + 5)] - 13%.

      Impedance monitoring detects a GER episode (MII-GER) if there is a sequential drop in
      impedance values to less than 50% of the baseline, starting distally and propagating
      retrogradely to at least the next two more proximal measuring segments (about 4.5 cm above
      the lower esophageal sphincter (LES)). A GER episode is then defined as acid or non-acid
      according to its pH: the MII episodes with a pH lower than 4 are defined as acid MII-GERs,
      whereas the MII episodes with a pH≥4 are defined as non-acid MII-GERs. GERs migration height
      is the maximum distance from the LES reached by the esophageal refluxate. An acid GER episode
      is recorded by pH monitoring as a pH drop to less than 4; to be detected by the pH sensor,
      the pH drop has to last at least 5 s. The total percent time of esophageal exposure to a pH
      <4 is named Reflux Index (RIpH).

      Data from the pH-MII recording will be automatically acquired on a portable Sleuth Sandhill
      Scientific system and then stored in a personal computer containing a specific software
      (BioVIEW Analysis Sandhill Scientific, version 5.0.9). Data analysis will be performed by the
      aforementioned software and confirmed by direct visual evaluation.

      In the subgroup of patients with recurrent desaturations, a simultaneous non-invasive 6-hour
      polysomnographic monitoring, comprehensive of two meals (one followed by NNS and the other
      not), will be performed to evaluate a possible effect of NNS on apneic episodes (total,
      central, obstructive, mixed) and cardiorespiratory events.

      The polysomnographic device in use for this study (System Plus, Micromed, Mogliano Veneto,
      Italy) measures the oral/nasal airflow by a flow transducer placed below the nostrils,
      whereas abdominal movements are detected by a band placed around the abdomen which is
      connected to a respiratory inductance plethysmography. Each oral/nasal flow cessation ≥5
      seconds will be considered an apneic episode; apneas are then classified as central (CA:
      absence of both oral/nasal flow and movements of the abdominal wall), obstructive (OA:
      abdominal movements with an inadequate oral/nasal flow) and mixed (MA: components of both CA
      and OA). Apneas included in periodic breathing patters will be ruled out from the analysis.
      Systemic oxygen saturation is recorded by means of a pulse oximeter sensor, placed on the
      infant's foot. Cardiorespiratory events will be characterized as hypoxic episodes, defined as
      the occurrence of SatO2 <80%, and/or bradycardia, defined as pulse rate <100 bpm. The
      polysomnographic recording is automatically acquired in a computer connected to the
      polysomnographic device. The number of total apneas, CA, OA, MA and cardiorespiratory events
      will be traced down and visually analyzed by the sub-investigators.

      Statistical analysis will be performed by SPSS 20 (Statistical Package for the Social
      Sciences, SPSS Inc., Chicago, IL, USA) for Windows. Differences between NNS and control
      periods in terms of GER frequency and features, number of apneic and bradycardic episodes
      will be tested by Wilcoxon Signed Ranks Test. The level of significance is set at 0.05.
    

Intervention name(s): Pacifier
Intervention type(s): Device
Intervention description(s): The effect of NNS on GER features will be evaluated in preterm infants suffering from GER symptoms, for which a 24-hour pH-MII monitoring has been scheduled. During the monitoring period each infant will receive 8 meals: 4 meals will be followed by NNS, applied by pacifier, while the other 4 not. The sequence of NNS application will be consecutively alternated in study participants. At least 2 hours of NNS are required for the validity of each post-prandial evaluation; measures to fix the pacifier will be strictly forbidden. In the subgroup of babies with recurrent desaturations a simultaneous non-invasive 6-hour PSG monitoring comprehensive of 2 meals (one followed by NNS, the other not), will be performed to evaluate the effect of NNS on apneas, bradycardias and hypoxic episodes.
Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Due to the exploratory nature of this study, at least 30 preterm infants admitted to the
        Neonatal Intensive Care Unit of Sant'Orsola-Malpighi Universitary Hospital and fulfilling
        the inclusion criteria will be enrolled.
      
Keywords: Preterm infants; Non-nutritive sucking; Pacifier; Gastro-esophageal reflux; pH-multiple intraluminal impedance; Apneas; Bradycardias; Hypoxic episodes; Polysomnographic monitoring