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a cluster of neurons adjacent to pFRG&#44; plays a crucial role in carbon dioxide sensitivity<a class="elsevierStyleCrossRefs" href="#bib0004"><span class="elsevierStyleSup">4&#8211;6</span></a> and is involved in adapting alveolar ventilation to increased carbon dioxide expiration during exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> Experimentally reducing RTN activity decreases the tidal volume &#40;V<span class="elsevierStyleInf">T</span>&#41; responses to both hypercapnia and exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> Of major pathophysiological significance&#44; the RTN is almost or completely absent in rodents bearing mutations of the paired-like homeobox 2B &#40;<span class="elsevierStyleItalic">PHOX2B&#41;</span> gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0004"><span class="elsevierStyleSup">4&#8211;6</span></a></p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><p id="para0009" class="elsevierStylePara elsevierViewall">In humans&#44; such mutations are responsible for congenital central hypoventilation syndrome &#40;CCHS&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> formerly referred to as Ondine&#39;s curse syndrome&#46; CCHS patients suffer from defective breathing control&#44; with life-threatening sleep-related alveolar hypoventilation requiring ventilatory assistance at night and during naps&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> These patients have absent or blunted responses to hypercapnia and hypoxia&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">10&#8211;13</span></a> They also have diminished ventilatory response to exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> Although a possible human homologue of the RTN has recently been identified&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> it is currently impossible to link human <span class="elsevierStyleItalic">PHOX2B</span> mutations and functional respiratory perturbations to RTN abnormalities&#46;</p><p id="para0010" class="elsevierStylePara elsevierViewall">Bearing in mind that in the human ventilatory response to exercise V<span class="elsevierStyleInf">T</span> increases through the recruitment of both inspiratory muscle to take advantage of the inspiratory reserve volume &#40;IRV&#41; and expiratory muscle to exploit the expiratory reserve volume &#40;ERV&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a><span class="elsevierStyleBold">C</span>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> and assuming that the human organisation of respiratory control is similar to that described in rodents&#44; we reasoned that <span class="elsevierStyleItalic">PHOX2B</span>-related RTN dysfunction in CCHS patients would result in defective exercise-induced expiratory recruitment&#46; To test this hypothesis &#40;summarised in <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>&#41;&#44; we conducted a detailed analysis of the ventilatory response to exercise in adult CCHS patients and compared it to the corresponding response in healthy controls&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Setting and participants</span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">CCHS patients</span><p id="para0011" class="elsevierStylePara elsevierViewall">We studied 13 non-smoking&#44; clinically stable adult patients with CCHS &#40;<a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#41;&#46; The study was conducted at the adult branch of the French national reference center for CCHS&#44; located in a 1600-bed tertiary university hospital &#40;Piti&#233;-Salp&#234;tri&#232;re&#44; Paris&#44; France&#41;&#46; Inclusion criteria were&#58; CCHS diagnosis with documented <span class="elsevierStyleItalic">PHOX2B</span> mutations&#59; age above 18 years&#59; being routinely followed-up at the Piti&#233;-Salp&#234;tri&#232;re national adult CCHS reference center &#40;yearly complete workup performed over a single week&#41;&#46; Non-inclusion criteria were&#58; pregnancy&#59; body mass index &#40;BMI&#41; &#62;35 kg&#46;m<span class="elsevierStyleSup">2</span>&#41;&#59; restrictive or obstructive ventilatory defects on lung function testing&#59; any contra-indication to exercise testing&#46; Data were obtained prospectively as part of the routine follow-up of the patients at the reference center&#46; The research was carried out in accordance with the principles of the Declaration of Helsinki&#46; The study received the approval of the Institutional Review Board of the French society for respiratory medicine &#40;<span class="elsevierStyleItalic">Comit&#233; d&#39;&#233;valuation des protocoles de recherche observationnelle&#44; Soci&#233;t&#233; de pneumologie de langue fran&#231;aise&#44; CEPRO 2018&#8211;016</span>&#41; and patients consented to the use of their clinical data for research purposes&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Healthy control participants</span><p id="para0012" class="elsevierStylePara elsevierViewall">A control dataset was constituted by selecting healthy subjects from a database used in previous publications<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> using the exact same cardiopulmonary exercise testing &#40;CPET&#44; see below&#41; methodology as in the CCHS patients&#46; The resulting cohort comprised 13 lifelong non-smoking&#44; healthy individuals with normal pulmonary function&#44; matched with the CCHS cohort for age&#44; sex&#44; and BMI&#46;</p></span></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Descriptive data</span><p id="para0013" class="elsevierStylePara elsevierViewall">In the CCHS patients&#44; anthropometric data were collated from patients&#8217; medical charts&#44; together with genetic data&#44; the complete description of CCHS-related manifestations and treatments&#44; and medical history&#46; Lung function tests were performed using Medisoft &#40;Belgium&#41; and SentrySuite &#40;Germany&#41; according to the current recommendations of the European Respiratory Society&#44;<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a> and expressed as absolute value and as percentage of predicted value&#46;<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> Blood gases while breathing room air at rest were analysed using Radiometer ABL and Siemens Rapidlab blood gas analysers&#46; The ventilatory response to CO<span class="elsevierStyleInf">2</span> was assessed using Read&#39;s re-breathing method&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> In the controls&#44; only resting lung function tests and exercise variables &#40;see below&#41; were available&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Exercise testing</span><p id="para0014" class="elsevierStylePara elsevierViewall">Symptom-limited incremental CPET was conducted on an electrically braked cycle ergometer &#40;COSMED Bike&#44; Cosmed&#44; for CCHS patients and Ergometrics 800S&#44; SensorMedics for controls&#41; with a CPET system &#40;Cosmed&#44; Rome&#44; Italy for CCHS patients and Vmax29c&#44; SensorMedics for controls&#41; as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> All exercise tests consisted of a steady-state resting period of 6 min and a 3-minute warm-up of unloaded pedaling followed by an incremental test in which the work rate &#40;WR&#41; was increased in 1-minute intervals by increments of 5&#8211;15 W for CCHS patients and 20 W for controls until the point of symptom-limitation &#40;peak exercise&#41;&#46; Participants were instructed to maintain the pedaling rate between 50 and 70 rpm&#46;</p><p id="para0015" class="elsevierStylePara elsevierViewall">Inspiratory capacity &#40;IC&#41; maneuvers &#40;maximum inhalations starting from end expiration&#41; were performed at rest&#44; at every second minute during exercise&#44; and at peak exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> Inspiratory reserve volume &#40;IRV&#41; was calculated as the difference between IC and V<span class="elsevierStyleInf">T</span> &#40;IRV&#61;IC-V<span class="elsevierStyleInf">T</span>&#41;&#46; Expiratory reserve volume &#40;ERV&#41; was calculated as the difference between the resting forced vital capacity &#40;FVC&#41; measured immediately before starting CPET and IC &#40;ERV&#61;FVC-IC&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>A and <a class="elsevierStyleCrossRef" href="#fig0002">2</a>B&#41;&#44; based on total lung capacity &#40;TLC&#41; and FVC not changing significantly during exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> Tidal flow-volume curves were constructed at rest&#44; every 2 min during exercise and at peak exercise&#44; and plotted within their respective maximal flow-volume envelopes according to coinciding IC measurements&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia><p id="para0016" class="elsevierStylePara elsevierViewall">Breath-by-breath data were collected while subjects breathed through a facemask with attached low-resistance flow transducer&#58; oxygen consumption &#40;V&#39;O<span class="elsevierStyleInf">2</span>&#41;&#44; carbon dioxide production &#40;V&#39;CO<span class="elsevierStyleInf">2</span>&#41;&#44; ventilation &#40;V&#39;<span class="elsevierStyleInf">E</span>&#41;&#44; tidal volume &#40;V<span class="elsevierStyleInf">T</span>&#41;&#44; breathing frequency &#40;<span class="elsevierStyleItalic">f</span>B&#41;&#44; end-tidal oxygen and carbon dioxide partial pressure &#40;P<span class="elsevierStyleInf">ET</span>O<span class="elsevierStyleInf">2</span> and P<span class="elsevierStyleInf">ET</span>CO<span class="elsevierStyleInf">2</span>&#44; respectively&#41; were measured or calculated&#46; Electrocardiographic monitoring of heart rate &#40;HR&#41;&#44; rhythm&#44; ST-segment changes&#44; blood pressure &#40;by indirect sphygmomanometry&#41; and oxygen saturation &#40;by ear lobe sensor pulse oximetry &#91;SpO<span class="elsevierStyleInf">2</span>&#93;&#41;&#44; were carried out continuously at rest and throughout exercise testing&#46; In CCHS patients only&#44; measurements of arterial partial pressure of oxygen and carbon dioxide &#40;PaO<span class="elsevierStyleInf">2</span> and PaCO<span class="elsevierStyleInf">2</span>&#44; Torr&#41; were obtained at rest and at peak exercise&#46; Exercise variables were measured continuously and averaged over the last 20 s of each minute and at peak exercise&#46; Verbal encouragement was given during the tests&#44; which could be interrupted either by the patient in the presence of intolerable symptoms or by the operator in the presence of indications to stop exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a></p><p id="para0017" class="elsevierStylePara elsevierViewall">Peak work rate &#40;WR peak&#41;&#44; peak V&#39;O<span class="elsevierStyleInf">2</span> &#40;V&#39;O<span class="elsevierStyleInf">2</span> peak&#41; and peak V&#8217;<span class="elsevierStyleInf">E</span> &#40;V&#8217;<span class="elsevierStyleInf">E</span> peak&#41; were defined&#44; respectively&#44; as the highest level of exercise and the highest V&#39;O<span class="elsevierStyleInf">2</span> and V&#8217;<span class="elsevierStyleInf">E</span> that could be sustained for at least 30 s during the last stage of exercise&#46; V&#39;O<span class="elsevierStyleInf">2</span> peak was reported in absolute units&#44; after correction for body weight&#44; and as a percentage of predicted normal values accounting for age&#44; weight&#44; and sex&#46;<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> Breathing pattern during exercise was evaluated by individually plotting V<span class="elsevierStyleInf">T</span> as a function of V&#8217;<span class="elsevierStyleInf">E</span> &#40;V<span class="elsevierStyleInf">T</span>&#47;V&#8217;<span class="elsevierStyleInf">E</span> relations or Hey plots&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a> Inspiratory flow reserve&#44; defined as the distance between tidal inspiratory flows produced during exercise and those obtained during maximal volitional effort at rest during an FVC maneuver &#40;an indirect index of inspiratory muscle constraint&#47;fatigue&#41;&#44; was assessed using the technique described by Johnson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a> The presence or absence of expiratory flow limitation was determined by comparing tidal expiratory flows with those of the maximal envelope at isovolume&#46;<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a> The highest equivalent and common WR and V&#8217;<span class="elsevierStyleInf">E</span> achieved by each participant &#40;healthy controls and CCHS subjects&#41; during all the tests was used as iso-WR and iso-V&#8217;<span class="elsevierStyleInf">E</span> respectively to compare responses at identical physiological stimuli during standard CPET&#46; Metabolic and ventilatory responses at iso-V&#39;<span class="elsevierStyleInf">E</span> and at iso-WR were calculated by linear interpolation between adjacent measurement points for each subject&#46; Iso-WR and iso-V&#8217;<span class="elsevierStyleInf">E</span> points were calculated to counteract the effect that interindividual WR and V&#8217;<span class="elsevierStyleInf">E</span> may have on the variability of the ventilatory breathing pattern and respiratory mechanics &#40;IRV and ERV&#41; response to a standardized stimulus &#40;WR or V&#8217;<span class="elsevierStyleInf">E</span>&#41; during exercise&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Statistical analyses</span><p id="para0018" class="elsevierStylePara elsevierViewall">Data were expressed as median and 25th-75th quartile range&#46; Comparisons were performed using the Mann-Whitney <span class="elsevierStyleItalic">U</span> test&#46; CCHS patients and controls were compared at rest&#44; at common standardized exercise WR &#40;40 W&#58; iso-WR&#41;&#44; at common standardized V&#8217;<span class="elsevierStyleInf">E</span> &#40;15 L&#183;min<span class="elsevierStyleSup">&#8722;1</span>&#58; iso-V&#8217;<span class="elsevierStyleInf">E</span>&#41; and at peak exercise&#46; All statistical procedures were carried out using Intercooled Stata 8&#46;0 for Windows &#40;Stata&#44; College Station&#44; TX&#44; USA&#41; and SPSS 18&#46;0 for Windows &#40;SPSS Inc&#44; Chicago&#44; IL&#44; USA&#41;&#46; Differences were considered significant when the probability P of a type I error was &#60;0&#46;05&#46;</p></span></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">Results</span><p id="para0019" class="elsevierStylePara elsevierViewall">Participants&#8217; characteristics and resting lung function testing are summarised in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#46; There were no statistical differences between CCHS subjects and healthy controls in terms of sex&#44; age&#44; height&#44; weight&#44; BMI and lung function test variables &#40;<a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#41;&#46; Blood gases while breathing room air at rest and the ventilatory response to CO<span class="elsevierStyleInf">2</span> were not available for healthy controls as they were selected from a healthy-control database used in previous publications<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> in which blood gases and the ventilatory response to CO<span class="elsevierStyleInf">2</span> were not performed&#46; For the same reasons described above&#44; the PHOX2B testing was not available in historical healthy subject cohort&#46;</p><p id="para0020" class="elsevierStylePara elsevierViewall">Our study included a genotypically and phenotypically homogeneous set of CCHS patients&#58; twelve CCHS patients presented with PHOX2B polyalanine repeat expansion mutation &#40;PARM&#41; while only one CCHS patient presented with non-polyalanine repeat expansion mutation &#40;NPARM&#41;&#46; Among patients with PARM &#40;<span class="elsevierStyleItalic">n</span> &#61; 12&#41;&#58; four presented with 5 additional Alanine expansion &#40;20&#47;25&#44; 2 males vs 2 females&#41;&#44; four presented with 6 additional Alanine expansion &#40;20&#47;26&#44; 2 males vs 2 females&#41;&#44; three presented with 7 additional Alanine expansion &#40;20&#47;27&#44; 1 male vs 2 females&#41;&#44; only one presented with 9 additional Alanine expansion &#40;20&#47;29&#44; 1 female&#41;&#46; None had tumors of the neural crest&#46; One 23 years old male patient had Hirschsprung disease &#40;PARM 20&#47;26&#41;&#44; a cardiac pace-maker but not a diaphragm pacing at the time of the study&#46; All of them required ventilatory support only during sleep&#44; while none required full-time assisted ventilation at the time of the study&#46; None had assisted ventilation during the day&#44; such as diaphragm pacing&#44; at the time of the study&#46; None had tracheostomy at the time of the study&#58; nevertheless&#44; one female patient had tracheostomy and had required daytime artificial ventilation until age of 8&#44; one female patient had tracheostomy and had required daytime artificial ventilation until age of 10&#44; one female patient had tracheostomy and had required daytime artificial ventilation until age of 15&#44; one male patient had tracheostomy and had required daytime artificial ventilation until age of 16&#44; one female patient had tracheostomy and had required daytime artificial ventilation until age of 17&#46;</p><p id="para0021" class="elsevierStylePara elsevierViewall">All patients were in fact ventilated overnight&#46; All patients were ventilated using life support ventilator &#40;Astral ventilator&#41; with a pressure support mode and in approximately a third of cases with a targeted volume&#46; All patients had a high backup rate &#40;generally at least a minimum of 16 breaths&#47;min&#41;&#46; The level of expiratory pressure was usually set at 4 cmH<span class="elsevierStyleInf">2</span>O and the inspiratory pressure at 18 cmH<span class="elsevierStyleInf">2</span>O&#46; Most of our cohort was ventilated using oronasal mask and none of them had oxygen entrained in their ventilator&#46; All patients that underwent CPET had satisfactory control of overnight breathing&#46; All patients were rigorously adherent to non-invasive ventilation use &#40;approximately 8 hrs&#47;day of use&#41;&#46;</p><p id="para0022" class="elsevierStylePara elsevierViewall">In addition&#44; all CCHS patients were lifelong non-smokers&#46; None had asthma&#44; one had pulmonary arterial hypertension&#44; two had arterial hypertension&#44; three had cardiac pace-makers&#46; None of these abnormalities contra-indicated CPET <a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a>&#46; Pulmonary function tests and room air arterial blood gases were normal &#40;<a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#41;&#58; none had elevated P<span class="elsevierStyleInf">ET</span>CO<span class="elsevierStyleInf">2</span> or PaCO<span class="elsevierStyleInf">2</span> at rest before exercise or low oxygen saturations &#40;SpO<span class="elsevierStyleInf">2</span> or PaO<span class="elsevierStyleInf">2</span>&#41;&#46; The CO<span class="elsevierStyleInf">2</span> response was reduced compared with normal values published in the literature&#46;</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Ventilatory&#44; breathing pattern and respiratory mechanics response to CPET</span><p id="para0023" class="elsevierStylePara elsevierViewall">The physiological responses to CPET are detailed in <a class="elsevierStyleCrossRef" href="#tbl0002">Tables 2</a> and <a class="elsevierStyleCrossRef" href="#tbl0003">3</a>&#46;</p><elsevierMultimedia ident="tbl0002"></elsevierMultimedia><elsevierMultimedia ident="tbl0003"></elsevierMultimedia><p id="para0024" class="elsevierStylePara elsevierViewall">In the CCHS patients&#44; the criteria for CPET interruption <a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> were SpO<span class="elsevierStyleInf">2</span> falling below 90 &#37; in 5 patients&#44; P<span class="elsevierStyleInf">ET</span>CO<span class="elsevierStyleInf">2</span> &#62; 50 mmHg in 8 patients&#44; visual blur&#44; headache or eyes tingling in 4 patients&#44; leg fatigue in 2 patients&#44; and dyspnoea in 2 patients&#46; Healthy subjects had normal exercise capacity and consistently stopped exercising due to intolerable exertional leg discomfort&#46;</p><p id="para0025" class="elsevierStylePara elsevierViewall">Peak V&#39;O<span class="elsevierStyleInf">2</span> and WR were significantly lower in CCHS patients than controls&#46; V&#8217;<span class="elsevierStyleInf">E</span> and V<span class="elsevierStyleInf">T</span> increased in both CCHS and controls up to 40 W&#59; thereafter V&#8217;<span class="elsevierStyleInf">E</span> and V<span class="elsevierStyleInf">T</span> decreased consistently in CCHS patients but continued to increase in controls&#46; P<span class="elsevierStyleInf">ET</span>CO<span class="elsevierStyleInf">2</span> was comparable between CCHS and healthy subjects up to 40 W&#59; thereafter it increased significantly in CCHS patients until peak exercise and remained stable in controls&#46;</p><p id="para0026" class="elsevierStylePara elsevierViewall">Inspiratory capacity &#40;IC&#41; increased throughout exercise in controls &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>A&#41;&#44; but decreased by 0&#46;59 L in 5 CCHS patients&#44; increased by 0&#46;23 L in 2 CCHS patients&#44; and stayed the same as at rest in 6 CCHS patients&#46; Expiratory reserve volume &#40;ERV&#41; decreased consistently throughout exercise in controls &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>A&#41; &#40;tidal expiratory recruitment&#41;&#46; In contrast&#44; in CCHS patients&#44; ERV increased between rest and 40 W and then stabilised until peak exercise &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>B&#41; &#40;defective or absent expiratory recruitment&#41;&#46; IRV decreased consistently in both CCHS and controls from rest to peak &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>A and B&#41; &#40;tidal inspiratory recruitment&#41; and was more marked in CCHS patients than controls &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>&#41;&#46; Of note&#44; 2&#47;13 CCHS patients did not show oxygen desaturation or hypercapnia during exercise&#58; nonetheless&#44; the behavior of their ERV was the same as the remaining CCHS patients who showed significant oxygen desaturation or hypercapnia on exertion&#46; Last but not least&#44; in CCHS patients there were no differences between the sexes in terms of ventilatory&#44; V<span class="elsevierStyleInf">T</span> and IRV-ERV recruitment profile response to exercise&#46;</p><p id="para0027" class="elsevierStylePara elsevierViewall">Inspiratory reserve flow at peak exercise was not statistically different between CCHS and healthy subjects &#40;1&#46;8 vs 2&#46;0 L&#47;s&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;7&#41;&#46; Finally&#44; there was no evidence of expiratory flow limitation at rest or during exercise in CCHS patients or healthy controls&#46;</p></span></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Discussion</span><p id="para0028" class="elsevierStylePara elsevierViewall">During exercise under standard CPET conditions&#44; CCHS patients showed subnormal maximal oxygen uptake and reduced exercise tolerance&#46; In most patients &#40;11&#47;13&#41; the occurrence of hypercapnia during CPET indicated ventilatory limitation to exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a> In comparison to normal subjects who increased ventilation in response to exercise through both inspiratory and expiratory reserves&#44; CCHS patients showed an abnormal ventilatory response without any indication of expiratory muscle recruitment&#46;</p><p id="para0029" class="elsevierStylePara elsevierViewall">In healthy individuals&#44; alveolar ventilation &#40;and thus V&#39;<span class="elsevierStyleInf">E</span>&#41; rises linearly as a function of V&#39;CO<span class="elsevierStyleInf">2</span> so that alveolar carbon dioxide and oxygen partial pressures &#40;PACO<span class="elsevierStyleInf">2</span> and PAO<span class="elsevierStyleInf">2</span>&#41; and their arterial counterparts &#40;PaCO<span class="elsevierStyleInf">2</span> and PaO<span class="elsevierStyleInf">2</span>&#41; are maintained near resting values throughout exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> This involves&#58; &#40;i&#41; mechanical and chemical feedback to medullary respiratory pattern generators adjusting respiratory muscle activity&#44; and &#40;ii&#41; feed-forward mechanisms from higher neural centers driving the medullary generators and increasing locomotor muscle activity&#46;<a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a> In animals&#44; two medullary generators drive inspiration &#40;the preB&#246;tC&#41; and expiration &#40;the pFRG&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0033"><span class="elsevierStyleSup">33</span></a> Animal data show that&#44; during exercise&#44; the RTN&#44; adjacent to the pFRG&#44; is involved in adapting V&#8217;<span class="elsevierStyleInf">E</span> in response to increased V&#39;CO<span class="elsevierStyleInf">2</span> by augmenting expiratory activity&#44;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> possibly via PHOX2B-positive neuronal projections to the pFRG&#46;<a class="elsevierStyleCrossRef" href="#bib0034"><span class="elsevierStyleSup">34</span></a> In healthy humans&#44; V&#8217;<span class="elsevierStyleInf">E</span> initially increases during exercise through increases in V<span class="elsevierStyleInf">T</span> that normally expands to 50&#8211;60 &#37; of vital capacity by encroaching on the IRV and ERV&#46; The latter involves the early activation of expiratory muscles and results in reductions in ERV that vary with the type and intensity of exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">35</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0036"><span class="elsevierStyleSup">36</span></a> This was observed in our control cohort&#46; The recruitment of expiratory muscles directly increases V&#8217;<span class="elsevierStyleInf">E</span> and lengthens respiratory muscles&#44; optimizing their action and placing them at mechanical advantage&#44; as well as storing chest wall elastic recoil energy to be released at the beginning of inspiration&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> This IRV-ERV recruitment pattern&#44; clearly visible in our control group&#44; was lacking in our CCHS patients in whom ERV increased &#40;rather than decreased&#41; from rest to 40 W&#46; From 40 W to peak exercise ERV continued to decrease in controls but remained stable in CCHS patients&#46; In contrast&#44; inspiratory recruitment was higher in CCHS patients than controls&#46; These differences were best seen when comparing CCHS and healthy controls at the same ventilatory stimulus&#44; i&#46;e&#46; at iso-V&#8217;<span class="elsevierStyleInf">E</span>&#44; &#40;<a class="elsevierStyleCrossRef" href="#tbl0003">Table 3</a> and <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>&#41;&#46; The same profile was observed with regards to V&#39;<span class="elsevierStyleInf">E</span> and V<span class="elsevierStyleInf">T</span> response to exercise&#58; V&#39;<span class="elsevierStyleInf">E</span> and V<span class="elsevierStyleInf">T</span> increased in CCHS patients until 40 W&#44; this being in line with previous published literature&#44;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> and then decreased&#44; which was not observed in the healthy participants &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41;&#46;</p><p id="para0030" class="elsevierStylePara elsevierViewall">Several mechanisms can impede exercise-induced expiratory reserve recruitment&#46; Expiratory flow limitation &#40;forced or exercise-induced expiratory flows equal to or lower than tidal expiratory flow&#41;<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a> results from the bronchi closing prematurely in response to the expiratory driving pressure and is typically seen in chronic obstructive pulmonary disease &#40;COPD&#41;<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a> and in obesity&#46;<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a> This was not observed in our study and has not been described in the literature for CCHS patients&#46; In addition&#44; the shape of the maximal flow-volume loop at rest was completely normal in CCHS patients&#44; so that no expiratory flow limitation was observed at rest&#46; During exercise V<span class="elsevierStyleInf">T</span> increased only by encroaching on the IRV and not on the ERV&#44; so that a flow reserve was still available on the expiratory portion of the maximal flow-volume loop&#44; indicating that no expiratory flow limitation was noted in CCHS&#46; Expiratory muscle weakness or fatigue can also limit expiratory reserve recruitment&#44; as seen in patients with paraplegia&#46;<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a> This mechanism does not seem likely in CCHS patients&#44; who have normal lung function at rest&#46; Inspiratory muscle weakness or fatigue reducing IC can give a false impression of impeded recruitment of expiratory reserve when&#44; during CPET&#44; ERV is calculated as resting FVC minus IC&#46; Inspiratory muscle fatigue during exercise in our patients is made unlikely by the absence of any alteration of inspiratory reserve flow at peak exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a></p><p id="para0031" class="elsevierStylePara elsevierViewall">Central neurological mechanisms can also be invoked&#46; Although medullary sites have been identified in humans that could be homologous to the preB&#246;tC<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a> and RTN&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> the organisation and functioning of the respiratory network in humans is not necessarily similar to that described in rodents nor are the consequences of <span class="elsevierStyleItalic">PHOX2B</span> mutations necessarily the same in humans as in rodents&#46; However&#44; blunted CO<span class="elsevierStyleInf">2</span> chemosensitivity and a blunted ventilatory response to exercise characterized by defective expiratory recruitment that we have shown would be fully compatible with RTN dysfunction&#46; In our study&#44; CCHS patients showed a residual CO<span class="elsevierStyleInf">2</span> ventilatory response and responded to exercise with a progressive increase in V<span class="elsevierStyleInf">T</span> encroaching on IRV&#44; although all required ventilatory support during sleep&#46; This indicates the persistence of wakefulness-related automatic rhythmogenesis&#46; This may appear contradictory to the hypothesis of RTN dysfunction&#44; with interactions between the RTN and the preB&#246;tC complex being necessary for the latter to produce inspiration&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> However&#44; CCHS patients are known to activate respiratory-related cortical networks during wakefulness&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">40</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0041"><span class="elsevierStyleSup">41</span></a> a mechanism that is believed to maintain breathing through cortico-subcortical cooperation&#46; In the hypothesis of RTN deficiency&#44; the function of the cortical networks would be to allow the RTN-preB&#246;tC interaction to function despite the RTN defect&#44; a possibility that could depend on the existence of some residual PHOX2B-positive cells&#44; as has been observed in animals&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a></p><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Limitations</span><p id="para0032" class="elsevierStylePara elsevierViewall">Our study has some limitations&#46; The relatively small sample size means that we must be circumspect about generalising our findings to the wider CCHS population&#46; However&#44; we have performed a phenomenological study exploring a unique series of 13 adult patients &#40;which is not inconsiderable with this disease&#41; which represented a &#8220;genotypically and phenotypically homogeneous set of patients&#8221;&#46;</p><p id="para0033" class="elsevierStylePara elsevierViewall">Respiratory muscle function was not assessed in our study to formally rule out respiratory muscle weakness or fatigue&#44; but our choice was justified by the exploratory nature of the study and our concern to keep it as close to observational as possible&#46; Expiratory muscle weakness or fatigue can limit expiratory reserve recruitment&#46; This mechanism does not seem likely in CCHS patients&#44; who have normal lung function at rest&#46; In addition&#44; maximal expiratory pressure &#40;MEP&#41; was measured only in 3 CCHS patients &#40;data not shown&#41; and found normal&#46; Further studies should include MEP measures&#46; Inspiratory muscle weakness or fatigue reducing IC can give a false impression of impeded recruitment of expiratory reserve when&#44; during CPET&#44; ERV is calculated as resting FVC minus IC&#46; Inspiratory muscle fatigue during exercise in our CCHS patients is made unlikely by the absence of any alteration of inspiratory reserve flow at peak exercise&#46; In addition&#44; maximal inspiratory pressure &#40;MIP&#41; and Sniff Nasal Inspiratory Pressure &#40;SNIP&#41; were measured in 7 CCHS patients &#40;data not shown&#41; and found normal&#46; Further studies should include MIP and SNIP measures&#46;</p><p id="para0034" class="elsevierStylePara elsevierViewall">Blood gases at rest and the ventilatory response to CO<span class="elsevierStyleInf">2</span> were not available for healthy controls as they were selected from a healthy-control database used in previous publications<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> in which blood gases and the ventilatory response to CO<span class="elsevierStyleInf">2</span> were not performed&#46; Further studies containing this information are needed&#46;</p><p id="para0035" class="elsevierStylePara elsevierViewall">Further studies with a larger sample size and engaging more detailed esophageal&#44; gastric and transdiaphragmatic pressure measurements during exercise will be required to definitively elucidate the physiological mechanisms of the altered ventilatory mechanics seen in CCHS patients&#46;</p></span></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Conclusions</span><p id="para0036" class="elsevierStylePara elsevierViewall">In conclusion&#44; while our study is phenomenological and does not provide formal proof of the hypothesised mechanism&#44; we have shown defective exercise-induced expiratory recruitment in CCHS patients&#46; The consistency of the observations made across a genotypically and phenotypically homogeneous set of patients&#44; and their coherence with animal data&#44; are of heuristic interest&#46; For example&#44; the possibility of improving breathing control pharmacologically was raised by observations of restored CO<span class="elsevierStyleInf">2</span> responses under contraceptive treatment by desogestrel&#46;<a class="elsevierStyleCrossRef" href="#bib0042"><span class="elsevierStyleSup">42</span></a> This has prompted various projects investigating pharmacological interventions to improve respiratory rhythmogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0043"><span class="elsevierStyleSup">43&#8211;45</span></a> Our data&#44; by refining the phenotypic description of breathing control in CCHS patients&#44; suggest the use of the ERV response to exercise as a possible novel outcome for such investigations&#46;</p></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Author&#39;s contributions to the study</span><p id="para0037" class="elsevierStylePara elsevierViewall">PL&#58; Conceptualization&#44; Data curation&#44; Formal analysis&#44; Investigation&#44; Methodology&#44; Project administration&#44; Resources&#44; Software&#44; Supervision&#44; Validation&#44; Visualization&#44; Writing - original draft&#44; Writing - review &#38; editing&#46; QF&#58; Data curation&#44; Formal analysis&#44; Investigation&#44; Writing - review &#38; editing&#46; MB&#58; Data curation&#44; Formal analysis&#44; Writing - review &#38; editing&#46; MP&#58; Investigation&#44; Project administration&#44; Writing - review &#38; editing&#46; BD&#58; Investigation&#44; Writing - review &#38; editing&#46; CL&#58; Project administration&#44; Writing - review &#38; editing&#46; CMP&#58; Project administration&#44; Writing - review &#38; editing&#46; FC&#58; Methodology&#44; Writing - review &#38; editing&#46; LB&#58; Methodology&#44; Writing - review &#38; editing&#46; CS&#58; Conceptualization&#44; Methodology&#44; Writing - original draft&#44; Writing - review &#38; editing&#46; TS&#58; Conceptualization&#44; Methodology&#44; Writing - original draft&#44; Writing - review &#38; editing&#46;</p><p id="para00137" class="elsevierStylePara elsevierViewall">We declare that Artificial Intelligence program has not been used in writing this article&#46;</p></span></span>"
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              "titulo" => "Setting and participants"
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                  "titulo" => "CCHS patients"
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                  "titulo" => "Healthy control participants"
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              "titulo" => "Descriptive data"
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              "titulo" => "Exercise testing"
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              "titulo" => "Statistical analyses"
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          "titulo" => "Results"
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              "titulo" => "Ventilatory&#44; breathing pattern and respiratory mechanics response to CPET"
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    "fechaRecibido" => "2023-08-02"
    "fechaAceptado" => "2024-01-25"
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          "palabras" => array:6 [
            0 => "Central congenital hypoventilation syndrome"
            1 => "Alveolar hypoventilation"
            2 => "Cardiopulmonary exercise testing"
            3 => "Ventilation"
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            5 => "PHOX2B"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0002">Introduction and objectives</span><p id="spara013" class="elsevierStyleSimplePara elsevierViewall">The human congenital central hypoventilation syndrome &#40;CCHS&#41; is caused by mutations in the PHOX2B &#40;paired-like homeobox 2B&#41; gene&#46; Genetically engineered PHOX2B rodents exhibit defective development of the brainstem retrotrapezoid nucleus &#40;RTN&#41;&#44; a carbon dioxide sensitive structure that critically controls expiratory muscle recruitment&#46; This has been linked to a blunted exercise ventilatory response&#46; Whether this can be extrapolated to human CCHS is unknown and represents the objective of this study&#46;</p></span> <span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Materials and methods</span><p id="spara014" class="elsevierStyleSimplePara elsevierViewall">Thirteen adult CCHS patients and 13 healthy participants performed an incremental symptom-limited cycle cardiopulmonary exercise test&#46; Responses were analyzed using guideline approaches &#40;ventilation V&#39;<span class="elsevierStyleInf">E</span>&#44; tidal volume V<span class="elsevierStyleInf">T</span>&#44; breathing frequency&#44; oxygen consumption&#44; carbon dioxide production&#41; complemented by a breathing pattern analysis &#40;i&#46;e&#46; expiratory and inspiratory reserve volume&#44; ERV and IRV&#41;&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Results</span><p id="spara015" class="elsevierStyleSimplePara elsevierViewall">A ventilatory response occurred in both study groups&#44; as follows&#58; V&#39;<span class="elsevierStyleInf">E</span> and V<span class="elsevierStyleInf">T</span> increased in CCHS patients until 40 W and then decreased&#44; which was not observed in the healthy participants &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41;&#46; In the latter&#44; exercise-related ERV and IRV decreases attested to concomitant expiratory and inspiratory recruitment&#46; In the CCHS patients&#44; inspiratory recruitment occurred but there was no evidence of expiratory recruitment &#40;absence of any ERV decrease&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41;&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Conclusions</span><p id="spara016" class="elsevierStyleSimplePara elsevierViewall">Assuming a similar organization of respiratory rhythmogenesis in humans and rodents&#44; the lack of exercise-related expiratory recruitment observed in our CCHS patients is compatible with a PHOX2B-related defect of a neural structure that would be analogous to the rodents&#39; RTN&#46; Provided corroboration&#44; ERV recruitment could serve as a physiological outcome in studies aiming at correcting breathing control in CCHS&#46;</p></span>"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Summary of the study hypothesis&#46; <span class="elsevierStyleBold">Panel A&#46;</span> Anatomical organization of the brainstem respiratory network in humans &#40;left and top&#41;&#44; inferred from analogies with rodent data and human data &#40;see Schwarzacher&#44; S&#46; W&#46;&#44; U&#46; Rub and T&#46; Deller 2011&#44; reference 39 in the manuscript for the putative localization of the human pre-B&#246;tzinger complex &#40;preB&#246;tC&#41;&#59; see Levy&#44; J&#46;&#44; F&#46; Droz-Bartholet&#44; M&#46; Achour&#44; P&#46; Facchinetti&#44; B&#46; Parratte and F&#46; Giuliano 2021&#44; reference 15 in the manuscript for the putative location of the retrotrapezoid nucleus &#91;RTN&#93;&#41;&#46; The image shows the localisation of the hypoglossal motor nucleus &#40;XII&#41;&#44; the nucleus ambiguus&#44; the facial motor nucleus &#40;VII&#41;&#44; the inferior olive &#40;IO&#41;&#44; the lateral reticular nucleus &#40;LRN&#41;&#44; the parafacial respiratory group &#40;pFRG&#41; which contains the ventral parafacial nucleus &#40;pF<span class="elsevierStyleInf">V</span>&#44; originally and still most often referred to as the RTN&#41; and the lateral parafacial nucleus &#40;pF<span class="elsevierStyleInf">L</span>&#41;&#44; and the ventral respiratory column &#40;VRC&#41; which contains the preB&#246;tC&#46; The Fig&#46; follows the hypothesis that the preB&#246;tC mostly drives inspiratory muscles &#40;diaphragm and external intercostal muscles&#44; shown in red&#41; and that the pFRG mostly drives expiratory muscles &#40;internal intercostal and abdominal muscles&#44; shown in blue&#41;&#46; <span class="elsevierStyleBold">Panel B&#46;</span> Conceptual representation of the organisation of respiratory central pattern generators&#44; with inspiratory-related circuits shown in red and expiratory-related circuits shown in blue&#46; The rostral ventral respiratory group &#40;rVRG&#41; contains inspiratory neurons and premotor neurons&#46; The caudal ventral respiratory group &#40;cVRG&#41; contains expiratory premotor neurons&#46; This organisation mainly involves three essential components&#58; 1&#41; an &#40;inexorable&#41; inspiratory oscillator in preB&#246;tC that drives inspiration by exciting inspiratory premotor neuronal populations&#44; e&#46;g&#46;&#44; rVRG and parahypoglossal region &#40;XII&#41;&#44; and inhibits pF<span class="elsevierStyleInf">L</span>&#59; 2&#41; a &#40;conditional&#41; expiratory oscillator in pF<span class="elsevierStyleInf">L</span> that gates and drives expiration by exciting expiratory premotor neuronal populations&#44; such as cVRG and XII&#44; and assures alteration of phases by exciting neurons that inhibit preB&#246;tC&#44; e&#46;g&#46;&#44; inhibitory neurons in either the preB&#246;tC or B&#246;tC&#59; and 3&#41; a source of tonic drive in pF<span class="elsevierStyleInf">V</span> &#40;RTN&#41; which derives from dorsal progenitor cells that express paired-like homeobox 2B &#40;PHOX2B&#41; that are able to detect signals related to CO<span class="elsevierStyleInf">2</span> and&#47;or pH levels &#40;possibly with the involvement of glia&#41; and integrates other sensory afferents affecting respiratory drive&#44; via excitatory connections to preB&#246;tC&#44; B&#246;tC&#44; and respiratory premotor neurons&#44; such as rVRG&#44; cVRG&#44; and XII&#46; Respiratory muscles are activated at a certain frequency &#40;F<span class="elsevierStyleInf">B</span>&#41; and intensity to generate tidal volume &#40;V<span class="elsevierStyleInf">T</span>&#41;&#46; The excitation of rVRG activates inspiratory muscles that produce the inspired component of tidal volume &#40;V<span class="elsevierStyleInf">T</span>i&#41;&#44; at rest and its exercise-related increases&#46; The excitation of cVRG activates expiratory muscles that produce the expired component of tidal volume &#40;V<span class="elsevierStyleInf">T</span>e&#41;&#44; particularly during exercise&#46; <span class="elsevierStyleBold">Panel C&#46;</span> Tidal volume &#40;V<span class="elsevierStyleInf">T</span>&#41; dynamics at rest and during exercise in healthy humans &#40;&#8220;controls&#8221;&#44; top&#41; and patients with congenital central hypoventilation syndrome &#40;&#8220;CCHS&#8221;&#44; bottom&#41;&#46; At rest&#44; inspiration is active and expiration is passive&#44; breathing therefore occurring above functional residual capacity &#40;FRC&#41; defined as the respiratory system relaxation volume &#40;dotted horizontal line&#41;&#46; An inspiratory reserve volume &#40;IRV&#41; separates the end of tidal inspiration from full inspiration&#44; and an expiratory reserve volume &#40;ERV&#41; separates the end of tidal expiration &#40;i&#46;e&#46; FRC&#41; from full expiration&#46; The human ventilatory response to exercise is primarily achieved through an increase in tidal volume &#40;V<span class="elsevierStyleInf">T</span>&#41; that encroaches on both IRV and ERV through the recruitment of inspiratory and expiratory muscles&#44; as depicted on the top trace&#46; Assuming that the human organisation of respiratory rhythmogenesis is similar to that described in rodents&#44; we reasoned that PHOX2B-related RTN&#47;pFRG dysfunction in CCHS patients would result in defective exercise-induced expiratory recruitment&#46; The figure is original and based on a drawing commissioned to and contributed by artist Pierre Bourcier &#40;Paris&#44; France&#41;&#46;</p>"
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          "en" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">Operating lung volume &#40;in liters&#44; L&#41; plot versus cycle work rate &#40;WR&#44; in watts&#41;&#46; Inspiratory capacity maneuvers &#40;dotted grey lines&#41; and tidal volume evolution &#40;dotted gray lines&#41; are shown at rest &#40;0 W&#41;&#44; iso-ventilation &#40;iso-V&#39;<span class="elsevierStyleInf">E</span>&#41;&#44; iso-work rate &#40;iso-WR&#41; and at peak exercise&#46; TLC &#61; total lung capacity&#59; IRV &#61; inspiratory reserve volume &#40;shown in red&#41;&#59; ERV &#61; expiratory reserve volume &#40;shown in blue&#41;&#59; V<span class="elsevierStyleInf">T</span> &#61; tidal volume&#59; IC &#61; inspiratory capacity&#46; Data are presented as means of the whole group in healthy controls &#40;<span class="elsevierStyleBold">2A</span>&#41; vs means of the whole group in congenital central hypoventilation syndrome &#40;CCHS&#41; patients &#40;<span class="elsevierStyleBold">2B</span>&#41;&#46; In the controls&#44; V<span class="elsevierStyleInf">T</span> increases with work rate by encroaching on both IRV and ERV&#44; whereas in CCHS patients ERV is not recruited so that V<span class="elsevierStyleInf">T</span> increases by encroaching on IRV&#46; Dot points indicating IC show the IC manoeuver performed at rest&#44; at iso-WR and at peak during the exercise testing&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0001"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0003"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spara008" class="elsevierStyleSimplePara elsevierViewall">Results are presented as median &#40;IQR 25 &#37;&#8722;75 &#37;&#41; and as percentage &#40;&#37;&#41; of predicted normal values&#46; CCHS&#58; congenital central hypoventilation syndrome&#59; BMI&#58; body mass index&#59; PARM &#58; polyalanine repeat expansion mutation&#59; NPARM &#58; non polyalanine repeat expansion mutation&#59; FEV<span class="elsevierStyleInf">1</span>&#58; forced expiratory volume in one second&#59; VC max&#58; maximal vital capacity&#59; TLC&#58; total lung capacity&#59; FRC&#58; functional residual capacity&#59; RV&#58; residual volume&#59; IC&#58; inspiratory capacity&#59; ERV&#58; expiratory reserve volume&#59; PaO<span class="elsevierStyleInf">2</span>&#44; PaCO<span class="elsevierStyleInf">2</span>&#58; partial pressure of oxygen&#47;carbon dioxide in arterial blood&#44; respectively&#59; SaO<span class="elsevierStyleInf">2</span>&#58; arterial oxygen saturation&#59; &#47;&#58; not performed&#46; Please note that there were no statistical differences between CCHS subjects and healthy controls in terms of sex&#44; age&#44; height&#44; weight&#44; BMI and lung function test variables&#46; Blood gases while breathing room air at rest and the ventilatory response to CO<span class="elsevierStyleInf">2</span> were not available for healthy controls as they were selected from a healthy-control database used in previous publications &#40;references 17 and 18 in the main manuscript&#41; in which blood gases and the ventilatory response to CO<span class="elsevierStyleInf">2</span> were not performed&#46; Please also consider that PHOX2B testing was only available in CCHS patients&#44; for the same reasons described above&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">CCHS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0003"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0004"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Sex Female&#47;Male<span class="elsevierStyleItalic">&#44; n</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0005"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&#47;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0006"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#47;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0007"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Age&#44; <span class="elsevierStyleItalic">years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">24 &#40;19 &#8211; 32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0009"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">27 &#40;25 &#8211; 39&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0010"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Height&#44; <span class="elsevierStyleItalic">cm</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0011"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">172 &#40;164 &#8211; 176&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">172 &#40;167 &#8211; 176&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0013"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Weight&#44; <span class="elsevierStyleItalic">kg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">65 &#40;55 &#8211; 82&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">67 &#40;62 &#8211; 75&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0016"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">BMI<span class="elsevierStyleItalic">&#44; kg&#47;m<span class="elsevierStyleSup">2</span></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0017"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">22 &#40;19 &#8211; 26&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0018"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">23 &#40;20 &#8211; 26&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0019"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">PHOX2B mutation &#8211; n&#176; subjects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0020"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0021"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0022"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">PARM &#8211; n&#176; subjects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0024"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0025"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">NPARM &#8211; n&#176; subjects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0028"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Lung function tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0029"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0030"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0031"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">FEV<span class="elsevierStyleInf">1</span>&#44; <span class="elsevierStyleItalic">L</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3&#46;54 &#40;3&#46;32 &#8211; 4&#46;29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0033"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&#46;06 &#40;3&#46;76 &#8211; 4&#46;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0034"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">FEV<span class="elsevierStyleInf">1</span>&#44; <span class="elsevierStyleItalic">&#37; predicted</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">98 &#40;84 &#8211; 110&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">106 &#40;104 &#8211; 116&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0037"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">VC max&#44; <span class="elsevierStyleItalic">L</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&#46;35 &#40;3&#46;56 &#8211; 5&#46;07&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&#46;96 &#40;4&#46;61 &#8211; 5&#46;29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0040"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">VC max&#44; <span class="elsevierStyleItalic">&#37; predicted</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0041"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">91 &#40;85 &#8211; 110&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0042"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">106 &#40;101 &#8211; 116&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0043"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">FEV<span class="elsevierStyleInf">1</span>&#47;VC max&#44; <span class="elsevierStyleItalic">&#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">81 &#40;75 &#8211; 92&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0045"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">81 &#40;80 &#8211; 87&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0046"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">TLC<span class="elsevierStyleItalic">&#44; L</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0047"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#46;95 &#40;4&#46;99 &#8211;7&#46;01&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6&#46;33 &#40;5&#46;79 &#8211; 7&#46;58&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0049"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">TLC<span class="elsevierStyleItalic">&#44; &#37; predicted</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0050"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">96 &#40;89 &#8211; 104&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">106 &#40;98 &#8211; 111&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0052"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">FRC<span class="elsevierStyleItalic">&#44; L</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0053"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2&#46;85 &#40;2&#46;35 &#8211; 3&#46;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3&#46;23 &#40;2&#46;97 &#8211; 4&#46;07&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0055"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">FRC<span class="elsevierStyleItalic">&#44; &#37; predicted</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0056"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">103 &#40;86 &#8211; 113&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0057"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">111 &#40;97 &#8211; 116&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0058"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">RV<span class="elsevierStyleItalic">&#44; L</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0059"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;51 &#40;1&#46;26 &#8211; 1&#46;93&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;47 &#40;1&#46;37 &#8211; 2&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0061"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">RV<span class="elsevierStyleItalic">&#44; &#37; predicted</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0062"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">103 &#40;79 &#8211; 119&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0063"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">93 &#40;88 &#8211; 107&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0064"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">IC&#44; <span class="elsevierStyleItalic">L</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0065"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2&#46;71 &#40;2&#46;13 &#8211; 3&#46;31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3&#46;20 &#40;2&#46;76 &#8211; 3&#46;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0067"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">ERV&#44; <span class="elsevierStyleItalic">L</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0068"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;43 &#40;1&#46;15 &#8211; 1&#46;59&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0069"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;53 &#40;1&#46;45 &#8211; 1&#46;78&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0070"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">pH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0071"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&#46;43 &#40;7&#46;41 &#8211; 7&#46;48&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0072"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0073"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">PaO<span class="elsevierStyleInf">2</span><span class="elsevierStyleItalic">&#44; mmHg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">105 &#40;94 &#8211; 115&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0075"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0076"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">PaCO<span class="elsevierStyleInf">2</span><span class="elsevierStyleItalic">&#44; mmHg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0077"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">36 &#40;29 &#8211; 40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0079"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">SaO<span class="elsevierStyleInf">2</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0080"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">99 &#40;97 &#8211; 99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0081"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0082"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Ventilatory response to CO<span class="elsevierStyleInf">2</span> &#40;re-breathing method&#41;&#44; <span class="elsevierStyleItalic">L&#47;</span>min<span class="elsevierStyleItalic">&#47;mmHg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0083"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;37 &#40;0&#46;26 &#8211; 0&#46;58&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0084"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3469725.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara007" class="elsevierStyleSimplePara elsevierViewall">CCHS and healthy subjects&#8217; characteristics and resting lung function&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0002"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0004"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spara010" class="elsevierStyleSimplePara elsevierViewall">Results are presented as median &#40;IQR 25 &#37;&#8722;75 &#37;&#41;&#46; CCHS&#58; congenital central hypoventilation syndrome&#59; V&#39;O<span class="elsevierStyleInf">2</span>&#58; oxygen uptake&#59; SpO<span class="elsevierStyleInf">2</span>&#58; pulse oximetry oxygen saturation&#59; P<span class="elsevierStyleInf">ET</span>CO<span class="elsevierStyleInf">2</span>&#58; end-tidal carbon dioxide partial pressure&#59; PaO<span class="elsevierStyleInf">2</span>&#44; PaCO<span class="elsevierStyleInf">2</span>&#58; partial pressure of oxygen&#47;carbon dioxide in arterial blood&#44; respectively&#59; V&#8217;<span class="elsevierStyleInf">E</span>&#58; ventilation&#59; B<span class="elsevierStyleInf">f</span>&#58; breathing frequency&#59; V<span class="elsevierStyleInf">T</span>&#58; tidal volume&#59; IRV&#58; inspiratory reserve volume&#59; ERV&#58; expiratory reserve volume&#59; IC&#58; inspiratory capacity&#59; &#8710;&#58; the change or difference from rest&#59; pred&#58; predicted&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0085"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0086"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Rest</th><a name="en0087"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Peak</th></tr><tr title="table-row"><a name="en0088"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Variables&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0089"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">CCHS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0090"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0091"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">CCHS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0092"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0093"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Work rate&#44; watts&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0094"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 &#40;0 &#8211; 0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0095"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 &#40;0 &#8211; 0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0096"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">90 &#40;80 &#8211; 130&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0097"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">190 &#40;155 &#8211; 240&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0098"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">V&#39;O<span class="elsevierStyleInf">2</span>&#44; L&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0099"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;321 &#40;0&#46;296 &#8211; 0&#46;352&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0100"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;282 &#40;0&#46;273 &#8211; 0&#46;303&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0101"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;472 &#40;1&#46;160 &#8722; 1&#46;790&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0102"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2&#46;555 &#40;2&#46;070 &#8722; 2&#46;890&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0103"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">V&#39;O<span class="elsevierStyleInf">2</span>&#44; &#37; pred&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0104"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">15 &#40;13 &#8211; 16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0105"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">12 &#40;11 &#8211; 14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0106"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">68 &#40;44 &#8722; 80&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0107"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">99 &#40;98 &#8722; 102&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0108"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">SpO<span class="elsevierStyleInf">2</span>&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0109"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">98 &#40;96 &#8211; 99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0110"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">99 &#40;99 &#8211; 99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0111"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">91 &#40;86 &#8722; 95&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0112"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">99 &#40;98 &#8722; 99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0113"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">PaO<span class="elsevierStyleInf">2</span>&#44; mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0114"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">105 &#40;94 &#8211; 115&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0115"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0116"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">78 &#40;71 &#8722; 91&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0117"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0118"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">PaCO<span class="elsevierStyleInf">2</span>&#44; mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0119"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">36 &#40;29 &#8211; 40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0120"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0121"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">54 &#40;48 &#8722; 60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0122"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#47;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0123"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">P<span class="elsevierStyleInf">ET</span>CO<span class="elsevierStyleInf">2</span>&#44; mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0124"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">33 &#40;28 &#8211; 36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0125"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">39 &#40;38 &#8211; 40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0126"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">59 &#40;50 &#8722; 65&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0127"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">40 &#40;37 &#8722; 42&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0128"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">V&#8217;<span class="elsevierStyleInf">E</span>&#44; L&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0129"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">9&#46;8 &#40;9&#46;2 &#8211; 11&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0130"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">9&#46;9 &#40;9&#46;0 &#8211; 10&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0131"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">26&#46;3 &#40;20&#46;6 &#8722; 40&#46;9&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0132"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">106&#46;5 &#40;97&#46;2 &#8722; 110&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0133"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">V<span class="elsevierStyleInf">T</span>&#44; L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0134"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;58 &#40;0&#46;48 &#8211; 0&#46;71&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0135"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;60 &#40;0&#46;58 &#8211; 0&#46;68&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0136"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;21 &#40;0&#46;92 &#8722; 1&#46;40&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0137"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2&#46;94 &#40;2&#46;73 &#8722; 3&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0138"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">B<span class="elsevierStyleInf">f</span>&#44; breaths&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0139"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">17 &#40;15 &#8211; 22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0140"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">15 &#40;15 &#8211; 17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0141"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">27 &#40;19 &#8722; 30&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0142"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">37 &#40;32 &#8722; 40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0143"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">IRV&#44; L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0144"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;89 &#40;1&#46;69 &#8211; 2&#46;77&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0145"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2&#46;59 &#40;2&#46;31 &#8211; 2&#46;78&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0146"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;36 &#40;0&#46;84 &#8722; 1&#46;94&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0147"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;59 &#40;0&#46;40 &#8722; 0&#46;77&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0148"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">&#8710; IRV&#44; L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0149"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 &#40;0 &#8211; 0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0150"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 &#40;0 &#8211; 0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0151"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#8722;0&#46;95 &#40;&#8722;1&#46;06 &#8722; &#8722;0&#46;39&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0152"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#8722;1&#46;85 &#40;&#8722;2&#46;16 &#8722; &#8722;1&#46;44&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0153"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">ERV&#44; L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0154"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;40 &#40;1&#46;03 &#8211; 1&#46;63&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0155"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;83 &#40;1&#46;34 &#8211; 2&#46;08&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0156"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;86 &#40;1&#46;04 &#8722; 2&#46;09&#41;<a class="elsevierStyleCrossRef" href="#tb2fn1">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0157"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;44 &#40;0&#46;89 &#8722; 1&#46;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0158"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">&#8710; ERV&#44; L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0159"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 &#40;0 &#8211; 0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0160"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 &#40;0 &#8211; 0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0161"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;06 &#40;&#8722;0&#46;06 &#8722; 0&#46;53&#41;<a class="elsevierStyleCrossRef" href="#tb2fn1">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0162"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#8722;0&#46;45 &#40;&#8722;0&#46;60 &#8722; &#8722;0&#46;39&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0163"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">IC&#44; L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0164"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2&#46;51 &#40;2&#46;13 &#8211; 3&#46;44&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0165"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3&#46;20 &#40;2&#46;90 &#8211; 3&#46;36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0166"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2&#46;50 &#40;2&#46;02 &#8722; 3&#46;29&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0167"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3&#46;62 &#40;3&#46;42 &#8722; 3&#46;83&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0168"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">&#8710; IC&#44; L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0169"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 &#40;0 &#8211; 0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0170"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 &#40;0 &#8211; 0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0171"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#8722;0&#46;06 &#40;&#8722;0&#46;53 &#8722; 0&#46;06&#41;<a class="elsevierStyleCrossRef" href="#tb2fn3"><span class="elsevierStyleSup">&#8270;&#8270;&#8270;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0172"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;45 &#40;0&#46;39 &#8722; 0&#46;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spara012" class="elsevierStyleSimplePara elsevierViewall">Results are presented as median &#40;IQR 25 &#37;&#8722;75 &#37;&#41;&#46; CCHS&#58; congenital central hypoventilation syndrome&#59; iso-V&#8217;<span class="elsevierStyleInf">E</span>&#58; common standardized ventilation &#40;V&#8217;<span class="elsevierStyleInf">E</span>&#41; of 15 L&#47;min&#59; iso-WR&#58; common standardized exercise work-rate &#40;WR&#41; of 40 W&#59; V&#39;O<span class="elsevierStyleInf">2</span>&#58; oxygen uptake&#59; SpO<span class="elsevierStyleInf">2</span>&#58; pulse oximetry oxygen saturation&#59; P<span class="elsevierStyleInf">ET</span>CO<span class="elsevierStyleInf">2</span>&#58; end-tidal carbon dioxide partial pressure&#59; V&#8217;<span class="elsevierStyleInf">E</span>&#58; ventilation&#59; B<span class="elsevierStyleInf">f</span>&#58; breathing frequency&#59; V<span class="elsevierStyleInf">T</span>&#58; tidal volume&#59; IRV&#58; inspiratory reserve volume&#59; ERV&#58; expiratory reserve volume&#59; IC&#58; inspiratory capacity&#59; &#8710;&#58; the change or difference from rest&#59; pred&#58; predicted&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0173"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0174"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">iso-V&#8217;<span class="elsevierStyleInf">E</span> &#40;15 L&#47;min&#41;</th><a name="en0175"></a><th class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">iso-WR &#40;40 W&#41;</th></tr><tr title="table-row"><a name="en0176"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Variables&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">CCHS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">CCHS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0181"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Work rate&#44; watts&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0182"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">16 &#40;14 &#8211; 30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0183"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">26 &#40;19 &#8211; 29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0184"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0185"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0186"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">V&#39;O<span class="elsevierStyleInf">2</span>&#44; L&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0187"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;613 &#40;0&#46;491 &#8722; 0&#46;670&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0188"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;499 &#40;0&#46;443 &#8722; 0&#46;545&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0189"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;841 &#40;0&#46;750 &#8211; 0&#46;912&#41;<a class="elsevierStyleCrossRef" href="#tb3fn1">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">0&#46;660 &#40;0&#46;603 &#8211; 0&#46;785&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0191"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">V&#39;O<span class="elsevierStyleInf">2</span>&#44; &#37; pred&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0192"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">28 &#40;20 &#8722; 33&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0193"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">21 &#40;20 &#8722; 23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0194"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">35 &#40;26 &#8211; 42&#41;<a class="elsevierStyleCrossRef" href="#tb3fn1">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0195"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">27 &#40;25 &#8211; 31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0196"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">SpO<span class="elsevierStyleInf">2</span>&#44;&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0197"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">96 &#40;92 &#8722; 98&#41;<a class="elsevierStyleCrossRef" href="#tb3fn1">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0198"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">99 &#40;99 &#8722; 99&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">99 &#40;99 &#8211; 99&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">P<span class="elsevierStyleInf">ET</span>CO<span class="elsevierStyleInf">2</span>&#44; mmHg&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">41 &#40;40 &#8722; 42&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">45 &#40;38 &#8211; 51&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">41 &#40;40 &#8211; 42&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">V<span class="elsevierStyleInf">T</span>&#44; L&nbsp;\t\t\t\t\t\t\n
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