From Buds to Branches to Tubes!

: Respiratory and Ingestive Consequences of Premature Birth 2007 ASHA KAYPentax Lecture Session 1260 JL Miller, Ph.D. National Institutes of Health jmiller@cc.nih.gov From buds to branches to tubes, the developing human aerodigestive and pulmonary systems are truly incredible! The human upper aerodigestive and pulmonary systems develop in a series of tightly regulated prenatal events influenced by genetic, developmental and environmental factors. Birth prior to functional maturity can result in numerous aerodigestive and respiratory challenges. What is the role of the upper airway in aerodigestive and pulmonary development? Why do swallowing and respiration occur prior to birth? This lecture presents research on the morphogenesis of key aerodigestive systems and the clinical relevance of such knowledge in assessing and treating the unique needs of the premature infant. The lecture will focus on research in the following topics: 1. How new techniques using ultrasonography are dramatically pushing how we can detect and quantify processes of ingestion, respiration and motor activity in the living developing human. 2. Using these technologies, we will discuss relations between how aerodigestive and pulmonary structures grow and how these organs begin to function. 3. How new techniques in utero may map neuromaturation of these functions within critical windows of growth and development. The ultimate goal of this research is to identify across a prenatal-neonatal continuum those factors that may be predictive of both normal and abnormal developmental outcome. Key Points From Slides: Is it important to understand prenatal development? The premature infant is in many ways a prenatal being forced to exist outside of the womb. In both structure and function, these premature infants represent a unique biological system at each stage of development thus, the marked contrasts between term - preterm structures and functions necessitate we examine each group differently. Because of the early prenatal appearance of respiration and ingestion, developmental analyses are a powerful approach to understand emerging functions and may reveal the assembly of various systems as they pass through successive developmental stages of emergent complexity. Ultrasonography is non-invasive, safe, and cost-effective. In this research we use ultrasound to enhance identification and quantification of morphology and emerging behavioral organization within specific systems. We have developed new applications to identify the interplay of factors driving development of aerodigestivepulmonary and motor systems within the prenatal environment. 1

Part 1: Growth The aerodigestive system (e.g., nasal passageway, tongue, pharynx and larynx) continue to develop throughout gestation. Males tend to be slightly larger than females along growth curves of some aerodigestive system organs. Lungs: Studying human lung growth in vivo is now feasible through various prenatal ultrasound procedures. Human lung development starts at 4 weeks in the developing embryo and ends in early childhood---up to the 3rd year of postnatal life. Stages: Pseudoglandular (6-16 wks): Rapid growth. Epithelial cells line future airways, begin to differentiate. Terminal bronchioles form. Canalicular (16-26 wks): Airways widen-lengthen leading to potential air space for lungs. Terminal sacs - respiratory bronchioles connect. Terminal Saccular (26 -term) and Alveolar (32 weeks 8 yrs): Alveoli develop from terminal saccules. Surface area increases. Capillary growth. 95% of alveoli develop after birth! embryology.ch/images Problems can occur at any stage of lung development: Embryonic Period Problems: pulmonary agenesis, tracheal stenosis, laryngeal stenosis, ectopic lobes Psedoglandular and Canalicular Period Problems: pulmonary sequestration, lung hypoplasia, lung cysts, congenital diaphragmatic hernia (CDH), respiratory distress syndrome (RDS) Saccular and Alveolar Period Problems: Pulmonary hypoplasia, respiratory distress syndrome (RDS), acinar dysplasia, alveolar capillary dysplasia Ultrasound data indicates that the lungs grow in a steady manner with advancing gestational age. It should be noted that even at 30-34 weeks, the lung volumes present may represent only a fraction of term size. Premature birth when the lungs are 2

not fully mature presents problems. There is more smooth muscle, goblet cells and smaller airway diameters. Fewer large alveoli are present to support the airways with less surface area for gas exchange. Surfactant may not be fully present. The chest wall is more compliant. Respiratory distress syndrome develops within the first few hours after preterm birth. It manifests as deficient gas exchange and progressive respiratory failure, unless effective treatment is instituted. Clinical signs include tachypnea, grunting, retractions and cyanosis accompanied by increasing oxygen requirements. Physical findings include rales, poor gas exchange, use of diaphragmatic and other accessory muscles of breathing, nasal flaring, and abnormal patterns of respiration that may be complicated by apnea. Chest radiographs are characterized by diffuse reticulogranular infiltrates, atelectasis and air bronchograms often progressing to severe bilateral opacity. The clinical course depends on the severity of RDS and the maturity of the infant at birth. In uncomplicated RDS, typically seen in more mature infants, recovery is rapid during the first two weeks of life. In most cases, the surfactant content increases and reaches the normal level by one week of postnatal age (Hallman et al 1994). Source: herkules.oulu.fi/isbn9514272145/html Preterm infants are also at risk of developing chronic lung disease/bronchopulmonary dysplasia (BPD). The lungs of infants dying from BPD are inflamed and have fewer, larger alveoli than normal and abnormal pulmonary vascular development. There now is a growing appreciation of the contribution of intrauterine inflammation to the etiology of BPD. Source: T.J. Ross, AUPS Proceedings Part 2: Function: Aerodigestive: The many behaviors of the aerodigestive system, including oral motor movements and laryngeal-pharyngeal contraction patterns, develop in a progression of simple to complex movements. These patterns reflect changes to anatomic foundations and neuromaturation. The patterns follow a timeline of development that may be useful in pin-pointing developmental maturation. There is a trend that females display many complex aerodigestive behaviors earlier than males at very early stages of development. Left to mature to term; however, males and females display similar skills. Lungs: Several factors are important for prenatal lung growth and function. Some of these factors include: loss of the epithelial plug in the nares, an adequate intrathoracic space, adequate amniotic and pulmonary fluids; fetal breathing movements of normal incidence and amplitude; and, an upper airway such to maintain tracheal pressure > amniotic pressure > pleural pressure. A normal balance of volumes - pressures within airways and airspaces is important. Internal lung volumes exert a hydrostatic pressure at ~20 mm Hg on the developing pulmonary airways and saccules. The volume - rate fluid secreted in and out of the lungs is important to keep the lungs distended to simulate growth. During clinical prenatal examination, fetal respiration is traditionally evaluated via excursions of the chest wall - diaphragm echoes as seen on B-mode ultrasound images. However, using spectral based fluid flow estimates we can learn about the 3

timing/duration /pause times, (inspiratory, expiratory, cycle durations), peak velocity amplitudes, estimated fluid-flow volume displacements and sinusoidal patterns of developing fetal breath patterns. Trends in the data suggest: Duration of breaths increase across gestation p <.01 The amplitude of breaths increase 16-27.6 weeks GA p <.01; Fairly stable by 27.6 w GA- Term Birth The volume of breaths increase across gestation p <.01; By near term inspiratory and expiratory volume ~ 3 cc Breath cycle increase while pauses between breaths decrease across gestation p <.01 There is less variability in breath patterns We are also learning that, like fetuses, like newborns are obligate nasal breathers due to the configuration of upper airway (tongue occupies oral region, epiglottis large floppy and high position in pharynx contacting the soft palate). We are learning that respiratory rates in fetuses change across development. Respiratory rate at 32-39.6 wga I trending to be ~ 27-30 breaths per minute compared to: Adolescent 13-18 yrs: 12-20 bpm Toddler 1-3 yrs: 24-40 bpm Term Infant< 1 yr: 30-60 bpm Premature Infant < 5.5 lbs: 34-39 bpm (Cross and Oppe, 1952 J Physiol 116) Insults during early respiratory maturation may alter the developmental programming of neuronal respiratory networks leading to respiratory control abnormalities that may persist in infancy and adulthood (Gaultier and Gallego, 2005). In utero exposure to drugs of abuse may affect neuronal development and brainstem organization resulting in abnormal respiratory responses (Chen et al., 1991). Neonates with cocaine exposure in utero have been shown to exhibit abnormal ventilatory responses and respiratory pauses. Smoking, maternal drug use, heavy caffeine consumption and malnutrition during pregnancy lead to increased postnatal breathing instability. In cases with prenatal exposure to polysubstance abuse, fetal breath patterns are altered. Intrauterine Growth Restriction (IUGR) often results in LBW/ELBW neonates. Programming of organ development before birth has long-lasting consequences for later health. IUGR associated with increased risk for neonatal respiratory distress and/or ventilatory support (Harding et al, 2000). IUGR increases the risk of perinatal mortality, sudden infant death syndrome (Buck et al, 1989), lung hypoplasia and possible long term postnatal consequences. In early prenatal development, we are finding that lung volumes and some aspects of respiratory kinematics are different than healthy controls. IUGR cases show signs of prenatal apnea, irregular breath patterns and asymmetries between inspiration and expiration. Breaths can have long, shallow inspirations and expirations perhaps as an energy sparing mechanism. For lungs to function, the regulation of fluids via breathing patterns is essential. The lungs produce fluid (not same as amniotic fluid) rich in chloride and proteins. During fetal breathing the upper airways relax and diaphragmatic contractions assist to expand the lungs. Fluid also flows out of the lung into the upper airway where it is swallowed or effluxed back out into the placenta. The functional mechanism maintaining fluid flow (in and out of lungs) is fetal breathing. 4

When there is too much fluid in the placenta (polyhydramnios) or too little (oligohydramnios), fetal breathing patterns seem to change. These changes in prenatal respiratory patterns may hold clues for detecting normal or abnormal development. Data suggest that the fetus exhibits at specific periods of development, patterns of periodic breathing and apnea. Repeated hypoxemia due to severe apnea can induce major neurological disabilities (Back and Rivkees, 2004). Apnea of prematurity (AoP) is one of the most frequent problems of respiration in very premature infants. Is represented by a pause in breathing of at least 2 missed breaths (+ 20s) or if for a shorter time, accompanied by bradycardia, desaturation cyanosis or pallor (Com of Foetus and Newborn 2002. Pediatrics 11(1): 2000). There are different types: Pure Central is seen in about 95% of preemies (Marlier et al., 2005) and is associated with hypoxia or bradycardia. The frequency decreases with advancing age (Galutier, 1999). Central Obstructive occurs with cessation of breathing, but thoracic movements persist. Has been found in future SIDS victims Kato et al, 2001). Mixed (Central + Obstructive) is the most common-- is mixed when longer than 10 seconds duration and appears in the absence of thoracic movements. Human fetuses also demonstrate deep inspiratory efforts such as found in gasps and possible sighs (Harris et al., 1977, De Vries et al., 1986; Pillai and James, 1990). Gasps cause intense activation of inspiratory muscles. Thought to be induced by severe asphyxia (e.g., umbilical cord occlusion). Regardless of apnea duration, regarded as pathological and of clinical importance; usually indicates impending fetal death. Fetal airway contractility is likely one of the important physical factors influencing lung growth and development; however, little known (AM J. Respir. Cell Mol. Biol., 23(1) July 2000 3-6). Pathological conditions resulting in anatomical abnormality or central neurological immaturity due to preterm birth can lead to upper airway dysfunction and altered neonatal breathing. The Larynx Development: 4th week outgrowth of ventral wall of foregut (respiratory diverticulum) Diverticulum elongates in the caudal direction; becomes separated from the foregut; Ventral portion forms trachea Initially wide communication between the respiratory diverticulum and foregut is transformed into a T-shaped slit Cartilaginous (thyroid, cricoid, arytenoid cartilages) and muscular components of the larynx are derived from the mesoderm of the fourth and sixth branchial arches. Appearance of vocal ligaments at 9 weeks signals the onset of vocal cord development. The Pharynx: Magriples and Laitman, Am J Phys Anthro (1987): 15 wks epiglottic cartilage present 21 wks epiglottis well developed; in close palatal apposition 23-25 wks, full contact epiglottis - soft palate Various forces operate to collapse the pharynx or maintain its patency during normal respiration. Passive collapse during inspiration is a mechanism of mixed/obstructive apnea (Milner and Greenough, 2004). Fetal pharyngeal collapse? due to less connective tissue stiffness or flexed position in womb may influence collapsibility and resistance of the pharyngeal airway wall. Seems to be a marker of possible pathology. 5

In RDS infant attempts to avoid alveolar collapse by prolonging and increasing expiratory pressures by breathing against partially closed glottis, which causes the grunting noise characteristic of RDS, but also seen in other respiratory disorders. Also seen before birth. Source: Moore, Human Embryo 6