The Awake Resting Breathing and Thoraco-Abdominal Pattern In Children With Achondroplasia: A Pilot Cross-Sectional Study

Abstract

Achondroplasia is the most common skeletal dysplasia with an estimated prevalence of 1 in 20–30 thousand live births [1]. Acute brainstem compression, due to a small foramen magnum, is the most common cause of mortality in children younger than 4 years, while cardiovascular deaths are more prevalent in adults [1]. Respiratory complications occur mainly during childhood. Breathing was exclusively investigated during sleep, while the awake respiratory function in children with achondroplasia was not previously evaluated [2]. Testing the respiratory function in young children is difficult because it often requires a high degree of collaboration. The use of techniques requiring only passive collaboration, like opto-electronic plethysmography, can overcome this limitation.

Opto-electronic plethysmography is a motion analysis system that measures the movement of passive reflective markers put on the chest wall according to anatomical points. Starting from the coordinates of the markers, the thoraco-abdominal volume variations are computed and the complete ventilatory pattern is derived. Opto-electronic plethysmography was previously validated [3] and proved to be suited also for infants and young children [4].

We tested the feasibility of opto-electronic plethysmography to assess the thoraco-abdominal volumes at rest for the first time in a small sample of children with achondroplasia. We aimed to verify whether these children were characterized by particular ventilatory and/or thoraco-abdominal patterns during awake breathing.

We installed an opto-electronic plethysmography during the 2023 annual National Meeting of the Italian Association of Achondroplasia (AISAC) and 15 children (six girls), whose parents signed a written informed consent following the Declaration of Helsinki, were analyzed. The protocol was non-volitional and approved by the Research Ethics Board of Politecnico di Milano (registration code no. 13/2023): the child was asked to undress for reflective markers placement and then to choose and watch a cartoon in seated and supine positions for at least 5 min (Figure 1). The awake complete ventilatory pattern at rest was then computed. An age-matched group of 15 healthy children (four girls) followed the same protocol and served as control.

As shown in Table 1, age was similar between the two groups, with the youngest children acquired being 3 years old. As expected, the height and weight of children with achondroplasia were smaller, with a BMI higher than the control group. Indeed, BMI in children with achondroplasia remains substantially higher through 16 years of age in both sexes [5]. The thoracic lateral flexion, lumbar flexion, lumbar extension and lumbar lateral flexion were smaller in children with achondroplasia than age- and sex-matched healthy peers. The thoracic extension was greater in children with achondroplasia [6].

In both postures, children with achondroplasia breathed with lower tidal volume and minute ventilation. However, these two parameters became similar to healthy peers when normalized according to weight. Only in the seated position, the thoracic expansion was significantly restricted in children with achondroplasia, as indicated by the significantly reduced thoracic contribution to tidal volume (Table 1).

As far as we know, this was the first attempt to assess the awake breathing pattern in children with achondroplasia. The incidence of respiratory complications in these children is ~10%, and they include recurrent pulmonary infiltrates, chronic hypoxemia, cor pulmonale, and sudden death [7]. In addition, children with achondroplasia often have sleep disorder breathing with a reported prevalence between 22% and 93% [8]. The specific developmental abnormalities predisposing these children to sleep disorder breathing follow two patterns: upper obstruction (due to craniofacial structure) and/or neurological patterns (due to brainstem compression secondary to foramen magnum stenosis).

While there is a relatively high number of prospective evaluations of respiratory events during sleep in children with achondroplasia, no study during awakening is available. It is important to study also the awake condition because we spend the majority of the day in this status and because breathing is connected to health status, functionality, activity, quality of life and unmet needs. Tasker and colleagues firstly measured infant respiratory tidal breathing parameters, but they used sedation [9]. The lungs and the airways of children with achondroplasia were proved to be functionally normal [10]. However, no data on children with achondroplasia younger than 7 years old were shown [11]. Lung volume assessment in young children has been neglected because of the difficulty of performing forced maneuvers. Opto-electronic plethysmography was helpful in this regard, as the child was only requested to choose and watch a cartoon. When the child became comfortable with the condition, we “observed” their breathing spontaneously while watching the cartoon. The absence of instrumentation at the airways (namely, nose clip and mouthpiece) should minimize the white coat “stress” therefore allowing more physiological and spontaneous measurements also in very young children. (Figure 1).

In addition, opto-electronic plethysmography also allowed for compartmentalization of the breathing volume distribution to localize possible altered expansion. In this way, through the analysis of thoraco-abdominal volumes, it was possible to study the pathophysiology of achondroplasia with a non-volitional protocol suited also for young children. Despite a normal ventilatory pattern, we observed children with achondroplasia being characterized by a slight thoracic restriction at rest in the seated position.

Sleep disorder breathing was reported in two children with achondroplasia. These disorders were based on medical history and investigation by physicians. These children did not use a ventilator during the night.

The breathing pattern of these two children with achondroplasia with sleep disorder breathing presented frequent end-inspiratory pauses. We have computed the ventilatory and thoraco-addominal pattern considering the breaths where the end-inspiratory pauses were present and absent. The first child was an 8-year-old girl, with a diagnosis of mild OSAS (according to AHI). In the tract with the end-inspiratory pauses, her tidal volume was 161 mL (9.5 mL/Kg) versus 150 mL (8.8 mL/Kg) in the absence of end-inspiratory pauses. The respiratory rate was 19.8 breaths/min vs 20.2 breaths/min, the duty cycle was 66.1% versus 41.4%, the minute ventilation was 3.0 L/min versus 3.0 L/min, the ribcage contribution to tidal volume was 29.9% versus 28.3%. The second child was a 3-year-old boy, with a diagnosis of mild OSAS (according to AHI), but with mean oxygen saturation < 95%. In the tract with the end-inspiratory pauses, his tidal volume was 111 mL (7.4 mL/Kg) vs. 82 mL (5.5 mL/Kg) in the absence of end-inspiratory pauses. The respiratory rate was 33.3 breaths/min versus 41.4 breaths/min, the duty cycle was 72.3% versus 44.4%, the minute ventilation was 4.0 L/min versus 3.4 L/min, the ribcage contribution to tidal volume was 18% versus 4.4%.

Interestingly, frequent end-inspiratory pauses were identified only in the supine position in the breathing pattern of the two children with achondroplasia with reported sleep disorder breathing (Figure 1, bottom right panel). End-inspiratory pauses prolonged the inspiratory duty cycle. Indeed, the breaths with the end-inspiratory pauses of both children were characterized by a higher duty cycle and a higher tidal volume than the other children with achondroplasia and controls (Table 1). The inspiratory duty cycle was suggested to determine the individual's ability to compensate for inspiratory airflow limitation during sleep [12].

The relatively small number of children with achondroplasia (in particular those affected by sleep disorder breathing) is the main limitation of this study. An ideal convenience sample would be to have the same numerosity of children with obstructive sleep apnea as those without.

However, the results encourage more research in awake status aimed at (1) understanding the mechanisms of the thoracic restriction (i.e.: abnormal chest wall compliance or mechanical disadvantage of the thoracic muscles) and (2) verifying the systematic presence of end-inspiratory pauses in children affected by sleep disorder breathing.

If confirmed on a larger scale, the end-inspiratory pause can be an awake index of sleep disorder breathing, as the inspiratory duty cycle was speculated to represent a quantitative phenotype for obstructive sleep apnea susceptibility [12]. The analysis of awake end-inspiratory pauses in the supine position should be extended to children without achondroplasia affected by sleep disorder breathing to understand if the pause can be an awake surrogate index of sleep respiratory problems. For this reason, our result may have an impact on the breathing quality and quality of life in children, without and with achondroplasia.

In addition, it would be important to investigate what causes these pauses (i.e.: obstructive or central apneas), because they can indicate altered architecture of breathing control even in awake status. This would be important because breathing disorders are thought to underlie the increased risk for sudden infant death and neuropsychological deficits seen in achondroplasia.

These preliminary results also indicate the importance of considering both supine and seated positions, as some features may emerge only in one posture. In our small population, end-inspiratory pauses were present only in the supine position while thoracic restriction emerged only in the seated position. Possible causes (to be investigated) of this restriction can be the combination of abnormal lung growth with anatomical abnormalities of the ribcage and the spine leading to reduced chest wall/lung compliance.

To conclude, the awake breathing pattern was tested on children with achondroplasia for the first time. These preliminary results suggest how informative can be the analysis of quiet breathing in terms of timing and/or thoraco-abdominal volumes. Despite a normal ventilatory pattern, a slight thoracic restriction was observed at rest in the seated position. Sleep disorder breathing was reported in two children whose awake breathing was characterized by frequent end-inspiratory pauses in the supine position.

Antonella LoMauro: conceptualization, data curation, formal analysis, investigation, methodology, software, writing – original draft, writing – original draft. Gabriella Tringali: investigation, software, writing – original draft. Alessandro Sartorio: conceptualization, funding acquisition and resources, writing – original draft. Marco Sessa: conceptualization, funding acquisition and resources, project administration, writing – original draft. Andrea Aliverti: conceptualization, funding acquisition and resources, investigation, methodology, writing – original draft.

The authors declare no conflicts of interest.

The lead author Antonella LoMauro affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.