Structural and functional development in airways throughout childhood: Children are not small adults.

Children are not small adults and this fact is particularly true when we consider the respiratory tract. The anatomic peculiarities of the upper airway make infants preferential nasal breathers between 2 and 6 months of life. The pediatric larynx has a more complex shape than previously believed, with the narrowest point located anatomically at the subglottic level and functionally at the cricoid cartilage. Alveolarization of the distal airways starts conventionally at 36-37 weeks of gestation, but occurs mainly after birth, continuing until adolescence. The pediatric chest wall has unique features that are particularly pronounced in infants. Neonates, infants, and toddlers have a higher metabolic rate, and consequently, their oxygen consumption at rest is more than double that of adults. The main anatomical and functional differences between pediatric and adult airways contribute to the understanding of various respiratory symptoms and disease conditions in childhood. Knowing the peculiarities of pediatric airways is helpful in the prevention, management, and treatment of acute and chronic diseases of the respiratory tract. Developmental modifications in the structure of the respiratory tract, in addition to immunological and neurological maturation, should be taken into consideration during childhood.

Mechanisms of larynx and vocal fold development and pathogenesis.

The larynx and vocal folds sit at the crossroad between digestive and respiratory tracts and fulfill multiple functions related to breathing, protection and phonation. They develop at the head and trunk interface through a sequence of morphogenetic events that require precise temporo-spatial coordination. We are beginning to understand some of the molecular and cellular mechanisms that underlie critical processes such as specification of the laryngeal field, epithelial lamina formation and recanalization as well as the development and differentiation of mesenchymal cell populations. Nevertheless, many gaps remain in our knowledge, the filling of which is essential for understanding congenital laryngeal disorders and the evaluation and treatment approaches in human patients. This review highlights recent advances in our understanding of the laryngeal embryogenesis. Proposed genes and signaling pathways that are critical for the laryngeal development have a potential to be harnessed in the field of regenerative medicine.

The development of the cricoid cartilage and its implications for the use of endotracheal tubes in the pediatric population.

BACKGROUND: The rigid cricoid cartilage is functionally the narrowest portion of the larynx. There is some controversy over the shape of the pediatric cricoid cartilage in the transverse plane. It is important to understand the development of the cricoid cartilage so that endo-traceheal tubes can be used more safely. AIM: To determine changes in the internal diameter and shape of the cricoid cartilage during development and explore the implications of those changes for the selection of ETT type and size for children. METHODS: The cervical computed tomography scans were reviewed in patients aged 1-20 years. After performing the multiplanar reconstruction and correcting the slant, the transverse and anteroposterior internal diameters of the inlet and outlet of the cricoid cartilage were measured, respectively. The angle between the arch and the lamina of the cricoid cartilage in the middle sagittal plane was measured. The ratios of transverse to anteroposterior diameter for the inlet and outlet of the cricoid cartilage were calculated, respectively. RESULTS: In females, the internal diameters of the cricoid cartilage increased linearly with age. In males, the internal diameters of the cricoid cartilage exhibited a growth spurt during adolescence. The transverse diameter of the inlet was the smallest diameter of the cricoid cartilage, and the predicting formula of the transverse diameter of the inlet for children aged 1-12 was 0.4 × age (year) + 5.1, R2  = .758. The angle between the arch and lamina of the cricoid cartilage and the ratios of transverse to anteroposterior diameter correlated weakly with age. CONCLUSION: The transverse inner diameter of the inlet is the smallest diameter of the cricoid cartilage. The "funnel shape" of the cricoid cartilage remains unchanged during development. The outer diameter should be considered when selecting an endotracheal tube.

Development of Excised Larynx.

The larynx is a complex organ which has a role in a variety of functions such as phonation, breathing, and swallowing. To research these functions, it is widely accepted that in vivo studies provide more anatomically and physiologically relevant findings. However, invasive procedures are generally needed to measure variables such a subglottal pressure, vocal fold tension and stiffness, and cricothyroid muscle stretch. Performing studies using excised larynges is a useful technique which makes it possible to not only measure phonation parameters but control them as well. Early studies using excised larynges mainly focused on controlling specific parameters and mathematical modeling simulations. The use of these studies has helped further research in laryngeal anatomy, imaging techniques, as well as aerodynamic, acoustic, and biomechanical properties. Here, we describe the progress of this research over the past 5 years. The number of accepted animal models has increased and ideas from excised larynx studies are starting to be applied to treatment methods for laryngeal disorders. These experiments are only valid for an excised situation and must continue to be combined with animal experimentation and clinical observations.

Consideration of Cough Reflex Development When Ordering Modified Barium Swallow Studies in Infants.

Infants < 51 weeks post-menstrual age (< 51 PMA) are often referred for modified barium swallow (MBS) studies for suspected silent aspiration (SA) given a possible association between SA and aspiration pneumonia. Infants this young are unlikely to have developed a mature laryngeal cough reflex, most likely rendering SA an expected finding in those who aspirate. The aims of this retrospective review were to (1) determine if SA resolves in a significant proportion of infants around the expected emergence of the laryngeal cough reflex, (2) determine which factors or characteristics are associated with and without SA resolution in these infants, and (3) determine if SA, or any aspiration, is associated with increased rates of lower respiratory infection (including aspiration pneumonia) in these infants. Results from the chart review revealed that 79/148 (53.4%) infants had SA on MBS < 51 PMA. 16/48 (33.3%) infants assessed for SA by the time of the expected emergence of the cough reflex had resolution. SA resolution was less common in infants with obstructive sleep apnea (p = 0.037). A total of 50/70 (71.4%) infants with a follow-up MBS had eventual SA resolution. Aspiration was not significantly associated with LRI, including aspiration pneumonia. The results suggested that the laryngeal cough reflex might develop later than reported in the literature and there is no association between aspiration and LRI. These findings may indicate that age should be considered before ordering an MBS solely to assess for SA in this population. The study provides preliminary evidence for future prospective research regarding SA resolution.

Vocal state change through laryngeal development.

Across vertebrates, progressive changes in vocal behavior during postnatal development are typically attributed solely to developing neural circuits. How the changing body influences vocal development remains unknown. Here we show that state changes in the contact vocalizations of infant marmoset monkeys, which transition from noisy, low frequency cries to tonal, higher pitched vocalizations in adults, are caused partially by laryngeal development. Combining analyses of natural vocalizations, motorized excised larynx experiments, tensile material tests and high-speed imaging, we show that vocal state transition occurs via a sound source switch from vocal folds to apical vocal membranes, producing louder vocalizations with higher efficiency. We show with an empirically based model of descending motor control how neural circuits could interact with changing laryngeal dynamics, leading to adaptive vocal development. Our results emphasize the importance of embodied approaches to vocal development, where exploiting biomechanical consequences of changing material properties can simplify motor control, reducing the computational load on the developing brain.

The influence of premature birth on laryngeal development for phonation.

INTRODUCTION: Dysphonia is a known consequence of premature birth, and is usually associated with endotracheal intubation in the neonatal period or surgical ligation of persistent patent ductus arteriosus. Recently, cases of dysphonia, in the absence of these causative factors, have been reported. OBJECTIVES: This review seeks to identify literature pertaining to those aspects of laryngeal development that may potentially be disrupted by premature birth. The purpose of the review is to determine whether there is any possible anatomical or physiological explanation for dysphonia to arose solely from premature birth. METHODS: This scoping review was conducted in accordance with the guidelines prescribed by Arskey and O'Malley (2005). Fifteen relevant papers were identified. Results were categorized into age-related categories, to identify changes in the developmental trajectory. Based on the results of the literature search, a further category of unphonated larynges was added. RESULTS: Potential differences in the laryngeal framework (e.g., the development of the cricoid cartilage and the shape of the glottis) and vocal fold histology, depending on gestational age and post-natal phonation were identified. Much literature focused on the macula flavae, however, the layers of the lamina propria were also discussed. DISCUSSION: It is unclear whether the process of differentiation of the layers of the lamina propria, which commences in the second to third months of life in term-born infants, is disrupted by prematurity. Further, development of the macula flavae continues until at least 28 weeks' gestation. Preterm children may not phonate immediately after birth, which may also affect laryngeal development.

A Tutorial of the Effects of Sex Hormones on Laryngeal Senescence and Neuromuscular Response to Exercise.

Purpose The purpose of this tutorial is to summarize how sex hormones affect both laryngeal senescence and neuromuscular response to exercise, highlighting the importance of considering sex differences in developing treatment for the senescent voice. Conclusion Men and women's voices are sexually dimorphic throughout the life span, including during the laryngeal adaptations observed during senescence. Therefore, presbyphonia (age-related dysphonia) likely clinically manifests differently for men and women due to differences in how the male and the female larynx change in response to aging. Because sexual dimorphism is evident in both laryngeal aging and response to exercise, voice therapy programs aimed at treating the typical and disordered aged voice should consider sex differences in their design.

Experimental validation of laryngotracheal growth and recurrent laryngeal nerve preservation after partial cricotracheal resection in a growing rabbit model.

PURPOSE: The aim of this study was to confirm laryngotracheal growth and recurrent laryngeal nerve (RLN) preservation after partial cricotracheal resection (PCTR) in a growing rabbit model by performing the procedure in pediatric animals. METHODS: Six female Japanese white rabbits, 12 weeks of age, underwent PCTR. The course of the RLN was evaluated during surgery (n = 3). Endoscopic and histologic examinations were performed at 22 weeks of age (n = 6). Four non-operated rabbits, 22 weeks of age, underwent endoscopic and histologic examinations as controls. RESULTS: The RLN was preserved at the esophageal side and entered the larynx behind the cricothyroid joint after PCTR. Endoscopic examination showed normal vocal cord movements and the large reconstructed subglottis. Histologically, sufficient submucosal vessels and cartilage growth were identified at the reconstructed larynx. The median inside luminal area at the anastomotic site in the PCTR group was 24.8 mm2 (range 21.8-29.0 mm2), and that at the cricoid cartilage and trachea in the control group was 23.4 mm2 (range 20.0-26.6 mm2) and 25.6 mm2 (range 22.9-28.8 mm2), respectively. CONCLUSION: No interference with laryngotracheal growth was seen, and RLN preservation was confirmed after PCTR. Use of PCTR in the pediatric age group seems appropriate.

The anatomy of the pediatric airway: Has our knowledge changed in 120 years? A review of historic and recent investigations of the anatomy of the pediatric larynx.

BACKGROUND: There is disagreement regarding the anatomy of the pediatric airway, particularly regarding the shape of the cricoid cartilage and the location of the narrowest portion of the larynx. AIMS: The aim of this review is to clarify the origin and the science behind these differing views. METHODS: We undertook a review of published literature, University Libraries, and authoritative textbooks with key search words and phrases. RESULTS: In vivo observations suggest that the narrowest portion of the airway is more proximal than the cricoid cartilage. However, in vitro studies of autopsy specimens measured with rods or calipers, confirm that the nondistensible and circular or near circular cricoid outlet is the narrowest level. These anatomic studies confirmed the classic "funnel" shape of the pediatric larynx. In vivo studies are potentially misleading as the aryepiglottic, vestibular, and true vocal folds are in constant motion with respiration. These studies also do not consider the effects of normal sleep, inhalation agents, and comorbidities such as adenoid or tonsil hypertrophy that cause some degree of pharyngeal collapse and alter the normal movement of the laryngeal tissues. Thus, the radiologic studies suggesting that the narrowest portion of the airway is not the cricoid cartilage may be the result of an artifact depending upon which phase of respiration was imaged. CONCLUSION: In vivo studies do not take into account the motion of the highly pliable laryngeal upper airway structures (aryepiglottic, vestibular, and vocal folds). Maximal abduction of these structures with tracheal tubes or bronchoscopes always demonstrates a larger opening of the glottis compared to the outlet of the cricoid ring. Injury to the larynx depends upon ease of tracheal tube or endoscope passage past the cricoid cartilage and not passage through the readily distensible more proximal structures. The infant larynx is funnel shaped with the narrowest portion the circular or near circular cricoid cartilage confirmed by multiple in vitro autopsy specimens carried out over the past century.

Ontogeny of the larynx and flight ability in Jamaican fruit bats (Phyllostomidae) with considerations for the evolution of echolocation.

Echolocating bats have adaptations of the larynx such as hypertrophied intrinsic musculature and calcified or ossified cartilages to support sonar emission. We examined growth and development of the larynx relative to developing flight ability in Jamaican fruit bats to assess how changes in sonar production are coordinated with the onset of flight during ontogeny as a window for understanding the evolutionary relationships between these systems. In addition, we compare the extent of laryngeal calcification in an echolocating shrew species (Sorex vagrans) and the house mouse (Mus musculus), to assess what laryngeal chiropteran adaptations are associated with flight versus echolocation. Individuals were categorized into one of five developmental flight stages (flop, flutter, flap, flight, and adult) determined by drop-tests. Larynges were cleared and stained with alcian blue and alizarin red, or sectioned and stained with hematoxylin and eosin. Our results showed calcification of the cricoid cartilage in bats, represented during the flap stage and this increased significantly in individuals at the flight stage. Thyroid and arytenoid cartilages showed no evidence of calcification and neither cricoid nor thyroid showed significant increases in rate of growth relative to the larynx as a whole. The physiological cross-sectional area of the cricothyroid muscles increased significantly at the flap stage. Shrew larynges showed signs of calcification along the margins of the cricoid and thyroid cartilages, while the mouse larynx did not. These data suggest the larynx of echolocating bats becomes stronger and sturdier in tandem with flight development, indicating possible developmental integration between flight and echolocation.

Growth of nasal and laryngeal airways in children: implications in breathing and inhaled aerosol dynamics.

BACKGROUND: The human respiratory airway undergoes dramatic growth during infancy and childhood, which induces substantial variability in air flow pattern and particle deposition. However, deposition studies have typically focused on adult subjects, the results of which cannot be readily extrapolated to children. We developed models to quantify the growth of human nasal-laryngeal airways at early ages, and to evaluate the impact of that growth on breathing resistance and aerosol deposition. METHODS: Four image-based nasal-laryngeal models were developed from 4 children, ages 10 days, 7 months, 3 years, and 5 years, and were compared to a nasal-laryngeal model of a 53-year-old adult. The airway dimensions were quantified in terms of different parameters (volume, cross-section area, and hydraulic diameter) and of different anatomies (nose, pharynx, and larynx). Breathing resistance and aerosol deposition were computed using a high-fidelity fluid-particle transport model, and were validated against the measurements made with the 3-dimensional models fabricated from the same airway computed tomography images. RESULTS: Significant differences in nasal morphology were observed among the 5 subjects, in both morphology and dimension. The turbinate region appeared to experience the most noticeable growth during the first 5 years of life. The nasal airway volume ratios of the 10-day, 7-month, 3-year, and 5-year-old subjects were 6.4%, 18.8%, 24.2%, and 40.3% that of the adult, respectively. Remarkable inter-group variability was observed in air flow, pressure drop, deposition fraction, and particle accumulation. The computational fluid dynamics predicted pressure drops and deposition fractions were in close agreement with in vitro measurements. CONCLUSIONS: Age effects are significant in both breathing resistance and micrometer particle deposition. The image/computational-fluid-dynamics coupled method provides an efficient and effective approach in understanding patient-specific air flows and particle deposition, which have important implications in pediatric inhalation drug delivery and respiratory disorder diagnosis.

Age-related changes of the larynx and trachea assessed by three-dimensional computed tomography in children: Application to endotracheal intubation and bronchoscopy.

The purpose of this study was to establish normative data of laryngotracheal dimensions and shape and to evaluate differences associated with age and sex using three-dimensional (3D) imaging. A total of 120 patients (64 boys and 56 girls) were included. Subjects were divided into four groups: Group 1 (0-2 years), Group 2 (3-7 years), Group 3 (8-13 years), and Group 4 (14-20 years). Using 3D image processing software, the laryngeal volume (LV), tracheal volume (TV), anteroposterior diameter at the glottis, cross-sectional area (CSA) at the subglottis, and laryngeal angle (LA) of the thyroid laminae were measured. Parameters of laryngotracheal volume and size were positively correlated with age, whereas the LA was inversely correlated with age. The LV, TV, CSA-3 mm, and CSA-5 mm exhibited a growth spurt in Groups 2 and 3. The LA decreased at a faster rate in Group 1 (P = 0.012). In Groups 1 and 2, there were no differences between genders for each laryngotracheal segmentation or plane. However, gender differences in the TV of Group 3 were statistically significant (P = 0.030). In Group 4, gender differences of all airway parameters were evident. Volume and other dimensions of the laryngotracheal airway increase with age. There was a significant increase in the LV, TV, CSA-3 mm, and CSA-5 mm in Groups 2 and 3. The LA correlated negatively with age in the Group 1. Significant sex dimorphisms are evident in Group 4.

Development of the rat larynx: a histological study.

OBJECTIVES/HYPOTHESIS: To evaluate and describe the cartilaginous and muscular development of the rat larynx. STUDY DESIGN: Histologic evaluation. METHODS: The larynges of Sprague Dawley rats of embryonic day (E) 13, 15, 17, 19, 21, postnatal day 0, 14, and adult of 250 gm were collected. Four larynges of each age were harvested, cut into 15-µm serial sections, stained with hematoxylin and eosin, and evaluated under light microscopy. Representative digital images were recorded and evaluated at the preglottic (supraglottic in humans), glottic, and postglottic (subglottic in humans) levels. RESULTS: Brachial arches were observed at E13. At E17, immature structures of the larynx, including skeletal muscle, cartilage, and the lumen were identifiable. Chondrification and muscle formation were clearly seen by E19. The muscular and cartilagenous components of the larynx were well established by E21. During the span between birth and adult maturation, the size of the larynx increased from a height of 1.10 mm to 2.90 mm, and from a width of 1.80 mm to 5.40 mm, and from a length of 1.38 mm to 4.77 mm in the stained section. Although developed at E21, the laryngeal structures continued to grow by approximately 30%. CONCLUSION: Rat laryngeal development parallels that in mice and humans. In the rat, at E17 immature structures of the larynx are identifiable, they are well developed at birth and grow by approximately 30% into adulthood. Understanding the chronology and morphology of the embryogenesis of the rat laryngeal musculature is essential and will allow for further evaluation of the embryologic innervation of these muscles.

Voice disorders in children.

This article reviews the management of voice disorders in children. We describe the relevant anatomy and development of the larynx throughout childhood, which affects voice. We consider the epidemiologic data to establish the size of the problem. The assessment of the patient in the clinic is described stepwise through the history, examination, laryngoscopy, and extra tests. We then review the common voice disorders encountered and their management, concluding with discussion of future directions, which may herald advances in this field.

Type IIB thyroplasty for phonic tics in a pediatric patient with autism spectrum disorder: a case report.

OBJECTIVES/HYPOTHESIS: Autism spectrum disorders (ASDs) are commonly associated with Tourette syndrome (TS). TS is classically associated with tic production. A tic is defined as sudden, brief, involuntary production of movement (motor tics) or sound (phonic tics). STUDY DESIGN: Case report. METHODS: We present a case report of a 14-year-old boy with ASD and vocal tics. Vocal tic frequency was nearly 2000 per day and 90 dB in volume. He presented to our laryngology clinic after multiple failed attempts of pharmacologic management of vocal fold botulinum toxin injection. After evaluation in our clinic, we recommended a lateralization (type IIB) thyroplasty. An autologous cartilage graft from the superior thyroid ala was used and held in place with a bioresorbable mesh. Using 4-0 prolene sutures, the mesh was secured in place. The operation was well tolerated with minimal signs of aspiration, and he was discharged to his home within 48 hours. RESULTS: Six months postoperatively, there was 90% reduction in tic frequency and 50% reduction in intensity. Additionally, he has shown improved ability to converse with his peers, participate in school activities, and even has improved nutritional status. CONCLUSIONS: Alteration of laryngeal geometry could serve as an effective site of intervention for intractable phonic tics. Reduction of phonic tic frequency and intensity may also stimulate language development in patients ASD. We also demonstrate additional use of bioresorbable plates in pediatric laryngeal framework surgery. Additional neurophysiologic studies are needed to explore the mechanism by which midline lateralization thyroplasty influences phonic tic generation.

Age-dependent structural and radiological changes in the larynx.

AIM: To define radiological physiological changes in the larynx by establishing an age-related scale. MATERIALS AND METHODS: The present retrospective study used radiological records of patients that had undergone lateral cervical imaging. Three hundred patients were included. Thyroid cartilage was divided into anatomical regions. The hyoid bone was evaluated as the body and greater horns. Cases were compared by grouping by age and gender. RESULTS: Thyroid tissue and cricoid cartilage only became visible after the second decade. Ossification in the thyroid cartilage began in the posterior inferior horn and progressed to the superior horn and central lamina. It also began in the posterior part of the cricoid cartilage and moved forward with age. In the first decade, the body and greater horn parts of the hyoid bone could be seen more distinctly, and after the third decade the hyoid bone appeared as a single bone. The hyoid bone was the only structure ossified in the laryngeal region below the age of 20 and formed an image on direct imaging. CONCLUSIONS: Age-related changes to the laryngeal tissues are evident on radiographs. Clinicians should bear this in mind when evaluating neck radiographs.

Laryngeal development and anatomy.

Knowledge of laryngeal and tracheobronchial development and anatomy is essential to the pediatric airway endoscopist. Normal and pathologic airway anatomy is discussed in this chapter.

Close relationship between the frequency of 22-kHz calls and vocal tract length in male rats.

It is known that the size of the components of the sound production apparatus in mammals may affect the acoustic structure of vocalizations. Therefore, some acoustic variables such as voice frequency may change with age in association with body size and body weight increases. However, whether this relationship also applies to ultrasonic vocalizations emitted by laboratory rats has not been investigated. Thus, in the present study, we first recorded changes in three acoustic variables (mean frequency, duration, and bandwidth) of air puff-induced 22-kHz calls in male rats during their growth period and assessed the relationship between these changes and body weight gain (Experiment 1). Then we directly recorded several body size measures including components of the sound production apparatus in 6- and 12-week-old male rats and examined the correlation between these values and the acoustic variables of 22-kHz calls (Experiment 2). In Experiment 1, the mean frequency of 22-kHz calls in male rats during the growth period showed negative correlations with body weight gain, while the duration of 22-kHz calls showed positive correlations. In Experiment 2, only a close negative correlation between the mean frequency of 22-kHz calls and vocal tract length in male rats was found. These results suggest that the age-related decrease in the mean frequency of 22-kHz calls may be ascribed to anatomical elongation of the vocal tract length in association with the growth of male rats. These acoustic differences could inform the receivers about the age of the signaler.

Ephrin-B reverse signaling controls septation events at the embryonic midline through separate tyrosine phosphorylation-independent signaling avenues.

We report that the disruption of bidirectional signaling between ephrin-B2 and EphB receptors impairs morphogenetic cell-cell septation and closure events during development of the embryonic midline. A novel role for reverse signaling is identified in tracheoesophageal foregut septation, as animals lacking the cytoplasmic domain of ephrin-B2 present with laryngotracheoesophageal cleft (LTEC), while both EphB2/EphB3 forward signaling and ephrin-B2 reverse signaling are shown to be required for midline fusion of the palate. In a third midline event, EphB2/EphB3 are shown to mediate ventral abdominal wall closure by acting principally as ligands to stimulate ephrin-B reverse signaling. Analysis of new ephrin-B2(6YFΔV) and ephrin-B2(ΔV) mutants that specifically ablate ephrin-B2 tyrosine phosphorylation- and/or PDZ domain-mediated signaling indicates there are at least two distinct phosphorylation-independent components of reverse signaling. These involve both PDZ domain interactions and a non-canonical SH2/PDZ-independent form of reverse signaling that may utilize associations with claudin family tetraspan molecules, as EphB2 and activated ephrin-B2 molecules are specifically co-localized with claudins in epithelia at the point of septation. Finally, the developmental phenotypes described here mirror common human midline birth defects found with the VACTERL association, suggesting a molecular link to bidirectional signaling through B-subclass Ephs and ephrins.