Polysomnography findings and respiratory muscle function in infants with early onset spinal muscular atrophy after gene replacement as monotherapy: A prospective study.

BACKGROUND: Gene replacement therapy (onasemnogene abeparvovec) is associated with an improvement of the prognosis of children with spinal muscular atrophy, but information on long-term respiratory outcome is scarce. The aim of this study was to report the polysomnography findings and respiratory muscle function of infants with treatment-naive spinal muscular atrophy type 1 and 2 up to 24 months after onasemnogene abeparvovec monotherapy. METHODS: A clinical and motor evaluation, respiratory muscle function testing, and polysomnography were performed repeatedly. RESULTS: Fifteen spinal muscular atrophy patients (1 presymptomatic, 7 type 1b, 6 type 1c, and 1 type 2) were included at a median age of 8.6 months (range 3.8-12.6) and followed for 24 months. The thoracic over head circumference ratio was close to normal at baseline (median 1.00 (range 0.90-1.05)) and increased significantly over time. All polysomnography and nocturnal gas exchange parameters were within normal ranges at baseline (median apnea-hypopnea index 2.5 events/hour (range 0.4-5.3)) and follow-up. The inspiratory muscle strength was normal at baseline but tended to slightly decrease over time and the expiratory muscle strength was low at any time especially for patients with recurrent respiratory infections (median (range) at baseline in cmH2O: crying esophageal pressure 54 (30-110), crying transdiaphragmatic pressure 65 (35-107), gastric pressure during maximal cough 26 (10-130), esophageal pressure during maximal cough 61 (38-150)). Only 3 patients required noninvasive ventilation. CONCLUSION: A continuous respiratory monitoring of spinal muscular atrophy patients during the first years of life following onasemnogene abeparvovec monotherapy seems recommended despite the normality of polysomnography parameters.

Mask interfaces and devices for home noninvasive ventilation in children.

Home noninvasive ventilation (NIV), including continuous (CPAP) and bilevel (BPAP) positive airway pressure, is increasingly used in children worldwide. In this narrative review, we present a comprehensive summary of the equipment available for home NIV in pediatrics, excluding neonates. NIV may be challenging in young children, as the majority of the equipment has been developed for adults. Regarding the interfaces, only a few masks have been specifically developed for young children in recent years, while older children may benefit from a large variety of interfaces. Even though much progress has been made, skin injuries are still present, and need to be managed rapidly. Several studies addressed the management of the side effects, but recent studies are lacking regarding orofacial anomalies. No recent study reported the available interfaces for young children and the strategies for an optimal mask fit. Regarding the devices, an adapted NIV device to pediatrics that allows an adequate patient's breathing detection should guarantee optimal ventilatory efficiency and monitoring of NIV. A close follow-up and regular monitoring should be mandatory to rule out the potential issues, optimize NIV therapy and ascertain the efficacy of NIV. However, studies are lacking to guide the choice of devices in young children and the optimal management of home NIV in pediatrics. We summarized the characteristics of the different interfaces available for young children and the limitations of NIV devices. We finally addressed potential areas for future research on long-term home NIV in children.

Invasive versus non-invasive paediatric home mechanical ventilation: review of the international evolution over the past 24 years.

BACKGROUND: Home mechanical ventilation (HMV) is the treatment for chronic hypercapnic alveolar hypoventilation. The proportion and evolution of paediatric invasive (IMV) and non-invasive (NIV) HMV across the world is unknown, as well as the disorders and age of children using HMV. METHODS: Search of Medline/PubMed for publications of paediatric surveys on HMV from 2000 to 2023. RESULTS: Data from 32 international reports, representing 8815 children (59% boys) using HMV, were analysed. A substantial number of children had neuromuscular disorders (NMD; 37%), followed by cardiorespiratory (Cardio-Resp; 16%), central nervous system (CNS; 16%), upper airway (UA; 13%), other disorders (Others; 10%), central hypoventilation (4%), thoracic (3%) and genetic/congenital disorders (Gen/Cong; 1%). Mean age±SD (range) at HMV initiation was 6.7±3.7 (0.5-14.7) years. Age distribution was bimodal, with two peaks around 1-2 and 14-15 years. The number and proportion of children using NIV was significantly greater than that of children using IMV (n=6362 vs 2453, p=0.03; 72% vs 28%, p=0.048), with wide variations among countries, studies and disorders. NIV was used preferentially in the preponderance of children affected by UA, Gen/Cong, Thoracic, NMD and Cardio-Resp disorders. Children with NMD still receiving primary invasive HMV were mainly type I spinal muscular atrophy (SMA). Mean age±SD at initiation of IMV and NIV was 3.3±3.3 and 8.2±4.4 years (p<0.01), respectively. The rate of children receiving additional daytime HMV was higher with IMV as compared with NIV (69% vs 10%, p<0.001). The evolution of paediatric HMV over the last two decades consists of a growing number of children using HMV, in parallel to an increasing use of NIV in recent years (2020-2023). There is no clear trend in the profile of children over time (age at HMV). However, an increasing number of patients requiring HMV were observed in the Gen/Cong, CNS and Others groups. Finally, the estimated prevalence of paediatric HMV was calculated at 7.4/100 000 children. CONCLUSIONS: Patients with NMD represent the largest group of children using HMV. NIV is increasingly favoured in recent years, but IMV is still a prevalent intervention in young children, particularly in countries indicating less experience with NIV.

Accuracy of tidal volume delivery by paediatric intensive care ventilators: A bench-model study.

BACKGROUND: Tidal volume (Vt) delivery during mechanical ventilation is influenced by gas compression, humidity, and temperature. OBJECTIVES: This bench study aimed at assessing the accuracy of Vt delivery by paediatric intensive care ventilators according to the humidification system. Secondary objectives were to assess the following: (i) the accuracy of Vt delivery in ventilators with an integrated Y-piece pneumotachograph and (ii) the ability of ventilators to deliver and maintain a preset positive end-expiratory pressure. METHODS: Six latest-generation intensive care ventilators equipped with a paediatric mode were tested on the ASL5000 test lung in four simulated paediatric bench models (full-term neonate, infant, preschool-age chile, and school-age child), under volume-controlled mode with a heated humidifier (HH) or a heat moisture exchanger, with various loading conditions. Three ventilators equipped with a Y-piece pneumotachograph were tested with or without the pneumotachograph in the neonatal and infant models. "Accurate Vt" delivery was defined as a volume error (percentage of the preset Vt under body temperature and pressure and saturated water vapour conditions) being ≤10 % of the absolute preset value. RESULTS: Vt accuracy varied significantly across ventilators but was acceptable in almost all the ventilators and all the models, except the neonatal model. The humidification system had an impact on Vt delivery in the majority of the tested conditions (p < 0.05). The use of an HH was associated with a better Vt accuracy in four ventilators (V500, V800, R860, and ServoU) and allowed to achieve an acceptable level of volume error in the neonatal model as compared to the use of heat moisture exchanger. The use of an integrated pneumotachograph was associated with lower volume error in only one ventilator (p < 0.01). All the tested ventilators were able to maintain adequate positive end-expiratory pressure levels. CONCLUSION: The humidification system affects Vt accuracy of paediatric intensive care ventilators, especially in the youngest patients for whom the HH should be preferred.

Pediatric long-term noninvasive respiratory support in children with central nervous system disorders.

RATIONALE: The use of long-term noninvasive respiratory support is increasing in children along with an extension of indications, in particular in children with central nervous system (CNS) disorders. OBJECTIVE: The aim of this study was to describe the characteristics of children with CNS disorders treated with long-term noninvasive respiratory support in France. METHODS: Data were collected from 27 French pediatric university centers through an anonymous questionnaire filled for every child treated with noninvasive ventilatory support ≥3 months on 1st June 2019. MAIN RESULTS: The data of 182 patients (55% boys, median age: 10.2 [5.4;14.8] years old [range: 0.3-25]) were collected: 35 (19%) patients had nontumoral spinal cord injury, 22 (12%) CNS tumors, 63 (35%) multiple disabilities, 26 (14%) central alveolar hypoventilation and 36 (20%) other CNS disorders. Seventy five percent of the patients were treated with noninvasive ventilation (NIV) and 25% with continuous positive airway pressure (CPAP). The main investigations performed before CPAP/NIV initiation were nocturnal gas exchange recordings, alone or coupled with poly(somno)graphy (in 29% and 34% of the patients, respectively). CPAP/NIV was started in an acute setting in 10% of the patients. Median adherence was 8 [6;10] hours/night, with 12% of patients using treatment <4 h/day. Nasal mask was the most common interface (70%). Airway clearance techniques were used by 31% of patients. CONCLUSION: CPAP/NIV may be a therapeutic option in children with CNS disorders. Future studies should assess treatment efficacy and patient reported outcome measures.

Effect of long term noninvasive ventilation in children on parent's quality of life.

OBJECTIVE: Improving or maintaining the quality of life of the family of children treated with long term continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) is a major concern; but studies are scarce. The aim of the study was to evaluate the impact of long term CPAP or NIV in children on anxiety, depression, quality of sleep, and quality of life of their parents. METHODS: Validated questionnaires evaluating anxiety and depression (hospital anxiety and depression scale), sleep quality (Pittsburgh sleep quality index), daytime sleepiness (Epworth sleepiness scale), and parents' quality of life (PedsQL family impact module) were completed by parents of children who were started on CPAP/NIV before (M0) and after 6-9 months (M6) of treatment. RESULTS: The questionnaires of 36 parents (30 mothers, 6 fathers) of 31 children were analyzed. For the entire group, no significant change was observed in anxiety, depression, sleep quality, daytime sleepiness, and quality of life between M0 and M6. When analyzing questionnaire class changes between M0 and M6: anxiety was relieved in 23% of parents and worsened in 29%, depression was relieved in 14% and worsened in 20%, sleep quality improved in 43% and worsened in 27%, sleepiness improved in 26% and worsened in 17%, with no change in the other parents. CONCLUSION: Long term CPAP/NIV in children had no significant effect on parents' anxiety, depression, sleep quality, and quality of life.

Limitations of the apnea-hypopnea index in children and young adults with neuromuscular disorders.

There are no validated criteria to initiate noninvasive ventilation (NIV) in children and young adults with neuromuscular disease (NMD). In order to analyze NIV initiation criteria, we reviewed the polysomnography (PSG) criteria that led to the initiation of NIV in 61 consecutive patients with NMD, median age 4.1 (0.8-21) years, who had a PSG during their routine care. NIV was initiated on abnormal PSG data (apnea-hypopnea index (AHI) > 10 events/h and/or a transcutaneous carbon dioxide pressure > 50 mmHg and/or a pulse oximetry 〈 90%, both during at least 2% sleep time or 〉 5 consecutive minutes) in 11 (18%) patients. Six of these 11 patients had an AHI ≤ 10 events/h and would not have been ventilated if only AHI was retained. However, one of these 6 patients had isolated nocturnal hypoxemia, 3 isolated nocturnal hypercapnia and 2 abnormal respiratory events. Six (10%) patients with a normal PSG were started on NIV on clinical criteria. Our results show the limitation of the AHI when taken as the unique PSG criterion for NIV initiation in young patients with NMD and underline the need to include also abnormalities of overnight gas exchange into the NIV decision-making process.

Detection of Simulated Pediatric Breathing by CPAP/Noninvasive Ventilation Devices.

BACKGROUND: Home CPAP and noninvasive ventilation (NIV) are increasingly used in children. An appropriate choice of the CPAP/NIV device, according to the manufacturer recommendations, should guarantee accurate data collection software. However, not all devices display accurate patient data. We hypothesized that the detection of patient breathing may be expressed as a minimal tidal volume (VTmin ) rather than a minimal weight. The aim of the study was to estimate the VTmin detected by home ventilators when set on CPAP. METHODS: Twelve level I-III devices were analyzed using a bench test. Pediatric profiles were simulated with increasing VT values to determine the VTmin that the ventilator may detect. The duration of CPAP use and the presence/absence of waveform tracings on the built-in software were also gathered. RESULTS: VTmin varied according to the device, ranging from 16-84 mL, independent of level category. The duration of CPAP use was underestimated in all level I devices, which were either not able to display any waveform or only intermittently, until VTmin was reached. The duration of CPAP use was overestimated for the level II and III devices, with the display of different waveforms according to the device as soon as the device was switched on. CONCLUSIONS: Based on the VTmin detected, some level I and II devices may be suitable for infants. A careful testing of the device should be done at CPAP initiation, with a review of data generated from ventilator software.

Respiratory effort during noninvasive positive pressure ventilation and continuous positive airway pressure in severe acute viral bronchiolitis.

OBJECTIVES: To assess if noninvasive positive pressure ventilation (NIPPV) is associated with a greater reduction in respiratory effort as compared to continuous positive airway pressure (CPAP) during severe acute bronchiolitis, with both supports set either clinically or physiologically. METHODS: Twenty infants (median [IQR] age 1.2 [0.9; 3.2] months) treated <24 h with noninvasive respiratory support (CPAP Clin, set at 7 cmH2 O, or NIPPV Clin) for bronchiolitis were included in a prospective single-center crossover study. Esogastric pressures were measured first with the baseline support, then with the other support. For each support, recordings were performed with the clinical setting and a physiological setting (CPAP Phys and NIPPV Phys), aiming at normalising respiratory effort. Patients were then treated with the optimal support. The primary outcome was the greatest reduction in esophageal pressure-time product (PTPES /min). Other outcomes included improvement of the other components of the respiratory effort. RESULTS: NIPPV Clin and Phys were associated with a lower PTPES /min (164 [105; 202] and 106 [78; 161] cmH2 O s/min, respectively) than CPAP Clin (178 [145; 236] cmH2 O s/min; p = 0.01 and 2 × 10-4 , respectively). NIPPV Clin and Phys were also associated with a significant reduction of all other markers of respiratory effort as compared to CPAP Clin. PTPES /min with NIPPV (Clin or Phys) was not different from PTPES /min with CPAP Phys. There was no significant difference between physiological and clinical settings. CONCLUSION: NIPPV is associated with a significant reduction in respiratory effort as compared to CPAP set at +7 cmH2 O in infants with severe acute bronchiolitis. CPAP Phys performs as well as NIPPV Clin.

Pleural and transpulmonary pressures to tailor protective ventilation in children.

This review aims to: (1) describe the rationale of pleural (PPL) and transpulmonary (PL) pressure measurements in children during mechanical ventilation (MV); (2) discuss its usefulness and limitations as a guide for protective MV; (3) propose future directions for paediatric research. We conducted a scoping review on PL in critically ill children using PubMed and Embase search engines. We included peer-reviewed studies using oesophageal (PES) and PL measurements in the paediatric intensive care unit (PICU) published until September 2021, and excluded studies in neonates and patients treated with non-invasive ventilation. PL corresponds to the difference between airway pressure and PPL Oesophageal manometry allows measurement of PES, a good surrogate of PPL, to estimate PL directly at the bedside. Lung stress is the PL, while strain corresponds to the lung deformation induced by the changing volume during insufflation. Lung stress and strain are the main determinants of MV-related injuries with PL and PPL being key components. PL-targeted therapies allow tailoring of MV: (1) Positive end-expiratory pressure (PEEP) titration based on end-expiratory PL (direct measurement) may be used to avoid lung collapse in the lung surrounding the oesophagus. The clinical benefit of such strategy has not been demonstrated yet. This approach should consider the degree of recruitable lung, and may be limited to patients in which PEEP is set to achieve an end-expiratory PL value close to zero; (2) Protective ventilation based on end-inspiratory PL (derived from the ratio of lung and respiratory system elastances), might be used to limit overdistention and volutrauma by targeting lung stress values < 20-25 cmH2O; (3) PPL may be set to target a physiological respiratory effort in order to avoid both self-induced lung injury and ventilator-induced diaphragm dysfunction; (4) PPL or PL measurements may contribute to a better understanding of cardiopulmonary interactions. The growing cardiorespiratory system makes children theoretically more susceptible to atelectrauma, myotrauma and right ventricle failure. In children with acute respiratory distress, PPL and PL measurements may help to characterise how changes in PEEP affect PPL and potentially haemodynamics. In the PICU, PPL measurement to estimate respiratory effort is useful during weaning and ventilator liberation. Finally, the use of PPL tracings may improve the detection of patient ventilator asynchronies, which are frequent in children. Despite these numerous theoritcal benefits in children, PES measurement is rarely performed in routine paediatric practice. While the lack of robust clincal data partially explains this observation, important limitations of the existing methods to estimate PPL in children, such as their invasiveness and technical limitations, associated with the lack of reference values for lung and chest wall elastances may also play a role. PPL and PL monitoring have numerous potential clinical applications in the PICU to tailor protective MV, but its usefulness is counterbalanced by technical limitations. Paediatric evidence seems currently too weak to consider oesophageal manometry as a routine respiratory monitoring. The development and validation of a noninvasive estimation of PL and multimodal respiratory monitoring may be worth to be evaluated in the future.

Long term noninvasive ventilation and continuous positive airway pressure in children with neuromuscular diseases in France.

The aim of the study was to describe the characteristics of children with neuromuscular diseases treated with long term noninvasive ventilation or continuous positive airway pressure in France. On June 1st 2019, 387 patients (63% boys, mean age 11.2 ± 5.5 years) were treated with long term noninvasive ventilation/continuous positive airway pressure. Thirty three percent of patients had spinal muscular atrophy, 30% congenital myopathy/dystrophy, 20% Duchenne muscular dystrophy, 7% Steinert myotonic dystrophy, and 9% other neuromuscular diseases. Ninety-four percent of patients were treated with long term noninvasive ventilation and 6% with continuous positive airway pressure. Treatment was initiated electively for 85% of patients, mainly on an abnormal overnight gas exchange recording (38% of patients). Noninvasive ventilation/continuous positive airway pressure was initiated during a respiratory exacerbation in 15% of patients. Mean duration of noninvasive ventilation/continuous positive airway pressure was 3.3 ± 3.1 years. Mean objective long term noninvasive ventilation/continuous positive airway pressure use was 8.0 ± 3.1 h/24. Spinal muscular atrophy, congenital myopathy/dystrophy, and Duchenne muscular dystrophy represented 83% of children with neuromuscular diseases treated with long term noninvasive ventilation in France. Screening for nocturnal hypoventilation was satisfactory as noninvasive ventilation /continuous positive airway pressure was predominantly initiated electively.

Impact of sleep-disordered breathing on the management of children with Chiari malformation type I.

OBJECTIVES: Children with Chiari malformation type I (CM-I) have an increased risk of sleep apnea. The aim of the study was to describe the management of CM-I patients in relation to symptoms, magnetic resonance imaging (MRI) findings and sleep apnea syndrome (SAS). METHODS: We performed a retrospective analysis of clinical charts of all 57 CM-I patients seen between September 2013 and April 2017. RESULTS: A total of 45 patients had isolated CM-I or associated co-morbidity (CM-Iia), 5 had craniosynostosis (CM-Ics), and 7 a polymalformative syndrome (CM-Ipm). The prevalence of SAS, defined as an apnea-hypopnea index >1 event/h, was high in CM-I ranging from 50% to 80% according to the CM-I group. The prevalence of central sleep apnea (CSA) was low, with 5 (9%) patients having CSA and only 3 patients with CM-Iia having isolated CSA. A total of 17 patients (30%) had foramen magnum decompression (FMD). Neither positive symptoms of CM-I nor MRI findings alone, nor both combined were good indicators for FMD. No correlation was observed between the cerebellar tonsil descent and SAS in CM-I. But all 5 patients with CSA had a FMD. The combination of MRI findings and/or symptoms of CM-I together with moderate-to-severe SAS best discriminated patients who needed a FMD. CONCLUSION: Our findings highlight the importance of a combined evaluation of symptoms, MRI and polygraphy results in the management of CM-I patients.

Infliximab for anoperineal lesions in Crohn's disease: remission appears to be based on rapid combination therapy at high doses

Study Aim: The aim of the present study was to compare in real life the characteristics of treatment with infliximab according to the presence or absence of anoperineal involvement in Crohn's disease. Methods: We performed a single-center, prospective, non-interventional study, on patients with Crohn's disease in remission who had been treated with infliximab for at least 1 year. Patients with poor treatment compliance, on antibiotics, or those with a stoma were excluded. Results: We included 52 patients in this study: 34 with anoperineal lesions with or without luminal lesions, and 18 with luminal lesions only. Patients with anoperineal lesions were more likely to have undergone surgery (70.6% versus 38.9%, p = 0.027), had a shorter median time to infliximab treatment initiation (0.5 versus 5.5 years, p = 0.005), a higher mean dose of infliximab (6.6 versus 5.1 mg/kg, p = 0.015), and were more likely to receive combination treatments including infliximab (52.9% versus 11.1%, p = 0.008) than patients with luminal involvement only. Conclusions In our study, infliximab treatment was initiated more quickly, at higher doses, and more in combination therapy for anoperineal Crohn's disease than for luminal damage alone. Additional studies are required to confirm this finding and to assess the tolerance of this treatment throughout patient management. (AU)

Sleep-disordered breathing in pediatric neurofibromatosis type 1.

The relationship between neurofibromatosis type 1 (NF1) and sleep-disordered breathing (SDB) has not been widely studied. The aim of the study was to analyze SDB in children with NF1 of the respiratory system. All children with NF1 followed between September 2008 and July 2020 who had a respiratory polygraphy (RP) were included. The clinical charts, cerebral and cervical magnetic resonance imaging (MRI), and RP were analyzed. Twenty-two patients (11 girls, median age at RP 8.3 [0.2-18.2] years) were included in the study. Nine patients (41%) had a NF1 involvement of the upper airways, 13 (59%) patients of the central nervous system (CNS), the cranial nerves (CN) and/or medulla, and 17 (77%) patients had a hypertrophy of the adenoids and/or tonsils. Five patients were treated with Continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) before their first evaluation because of severe obstructive sleep apnea (OSA). Accordingly, 10 (45%) patients had no OSA, one (5%) mild OSA, 2 (9%) moderate OSA, and nine (41%) severe OSA. None of the patients had central sleep apnea. Despite upper airway surgery, three patients required CPAP, two could be weaned and one died after a switch to tracheostomy. None of the patients treated with CPAP/NIV could be weaned, one patient required tracheostomy. Neither the clinical nor the MRI findings were able to predict OSA on a RP. The prevalence of OSA in NF1 is high, regardless of the nature of airway obstruction and the clinical and MRI findings, underlining the value of a systematic RP. CPAP may reduce the need of tracheostomy.

Incidence of New-Onset Obstructive Sleep Apnea After Posterior Flap Pharyngoplasty in Children.

INTRODUCTION: Obstructive sleep apnea (OSA) is a well-recognized complication of velopharyngeal insufficiency (VPI) surgery, but studies assessing OSA by means of a respiratory polygraphy (PG) are scarce. The aim of the study was to evaluate the incidence of new-onset OSA after posterior flap pharyngoplasty (PFP). MATERIALS: The postoperative PG of children with VPI who had a normal preoperative PG were analyzed. RESULTS: Eighteen patients (mean age, 9.8 ± 4.8 years; Pierre Robin sequence [n = 5], isolated cleft palate [n = 7], 22q11 deletion [n = 3], and 3 other diagnoses) were included in the study. Mean delay between surgery and the postoperative PG was 11.5 ± 13.5 months. Two patients (11%) developed severe OSA after PFP. One patient with 22q11 deletion developed overt OSA symptoms immediately after surgery with an apnea-hypopnea index (AHI) of 39 events per hour, requiring continuous positive airway pressure (CPAP) therapy. Obstructive sleep apnea improved spontaneously after 10 months, with an AHI of 2 events/h after CPAP weaning. The second patient had a cleft palate associated with a fetal alcohol syndrome and developed OSA symptoms after surgery with an AHI of 18 events/h requiring CPAP therapy. He could be weaned from CPAP 6 months later after a complete section of the pharyngeal flap with an AHI of 6 events/h during spontaneous breathing. CONCLUSIONS: New-onset OSA after PFP in children with VPI who had a normal preoperative PG was uncommon (11%) in the present cohort.