Periodic breathing in patients with NALCN mutations.

Biallelic mutations in NALCN are responsible for infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1). Common features of this condition include severe neonatal-onset hypotonia and profound global developmental delay. Given the rarity of this condition, long-term natural history studies are limited. Here, we present a 9-year-old male with a homozygous nonsense mutation in NALCN (c.3910C>T, p.Arg1304X) leading to profound intellectual disability, seizures, feeding difficulties, and significant periodic breathing. Breathing irregularity was also reported in three previous patients; similar to our patient, those children demonstrated periodic breathing that was characterized by alternating apneic periods with deep, rapid breathing. As the phenotype associated with NALCN mutations continues to be delineated, attention should be given to abnormal respiratory patterns, which may be an important distinguishing feature of this condition.

An Official American Thoracic Society Clinical Practice Guideline: Pediatric Chronic Home Invasive Ventilation.

BACKGROUND: Children with chronic invasive ventilator dependence living at home are a diverse group of children with special health care needs. Medical oversight, equipment management, and community resources vary widely. There are no clinical practice guidelines available to health care professionals for the safe hospital discharge and home management of these complex children. PURPOSE: To develop evidence-based clinical practice guidelines for the hospital discharge and home/community management of children requiring chronic invasive ventilation. METHODS: The Pediatric Assembly of the American Thoracic Society assembled an interdisciplinary workgroup with expertise in the care of children requiring chronic invasive ventilation. The experts developed four questions of clinical importance and used an evidence-based strategy to identify relevant medical evidence. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to formulate and grade recommendations. RESULTS: Clinical practice recommendations for the management of children with chronic ventilator dependence at home are provided, and the evidence supporting each recommendation is discussed. CONCLUSIONS: Collaborative generalist and subspecialist comanagement is the Medical Home model most likely to be successful for the care of children requiring chronic invasive ventilation. Standardized hospital discharge criteria are suggested. An awake, trained caregiver should be present at all times, and at least two family caregivers should be trained specifically for the child's care. Standardized equipment for monitoring, emergency preparedness, and airway clearance are outlined. The recommendations presented are based on the current evidence and expert opinion and will require an update as new evidence and/or technologies become available.

Respiratory syncytial virus infections in pediatric transplant recipients: A Canadian Paediatric Surveillance Program study.

The incidence and spectrum of severity of RSV infections in SOT or HSCT recipients is not known. From September 2010 through August 2013, pediatricians were surveyed monthly by the CPSP for SOT or HSCT recipients with RSV infection within two yr post-transplant. There were 24 completed case report forms that fit the inclusion criteria (10 HSCT and 14 SOT recipients). Six of 24 cases (25%) remained outpatients, and 11 (46%) were managed on an inpatient ward, while seven (29%) required intensive care of which five required mechanical ventilation and two died of RSV infection. Ten of 23 cases (43%) were nosocomial with these data not recorded for one case. Many transplant recipients recover uneventfully from RSV infection in the first two yr post-transplant. However, severe disease and death also occur. Larger studies are required to establish risk factors for poor outcomes. Prevention of nosocomial RSV should be a priority in transplant recipients.

Chronic tracheostomy care of ventilator-dependent and -independent children: Clinical practice patterns of pediatric respirologists in a publicly funded (Canadian) healthcare system.

OBJECTIVES: To describe the current clinical practice patterns of Canadian pediatric respirologists at pediatric tertiary care institutions regarding chronic tracheostomy tube care and management of home invasive ventilation. METHODS: A pediatric respirologist/pediatrician with expertise in tracheostomy tube care and home ventilation was identified at each Canadian pediatric tertiary care center to complete a 59-item survey of multiple choice and short answer questions. Domains assessed included tracheostomy tube care, caregiver competency and home monitoring, speaking valves, medical management of tracheostomy complications, decannulation, and long-term follow-up. RESULTS: The response rate was 100% (17/17) with all Canadian tertiary care pediatric centers represented and heterogeneity of practice was observed in all domains assessed. For example, though most centers employ Bivona™ (17/17) and Shiley™ (15/17) tracheostomy tubes, variability was observed around tube change, re-use, and cleaning practices. Most centers require two trained caregivers (14/17) and recommend 24/7 eyes on care and oxygen saturation monitoring. Discharge with an emergency tracheostomy kit was universal (17/17). Considerable heterogeneity was observed in the timing and use of speaking valves and speech-language assessment. Inhaled anti-pseudomonal antibiotics are employed by most centers (16/17) though the indication, agent, and protocol varied by center. Though decannulation practices varied considerably, the requirement of upper airway patency was universally required to proceed with decannulation (17/17) independent of ongoing ventilatory support requirements. CONCLUSION: Considerable variability in pediatric tracheostomy tube care practice exists across Canada. These results will serve as a starting point to standardize and evaluate tracheostomy tube care nationally.

Utility of contrast echocardiography for pulmonary arteriovenous malformation screening in pediatric hereditary hemorrhagic telangiectasia.

OBJECTIVE: To evaluate the utility of transthoracic contrast echocardiography (TTCE) as a screening tool for pulmonary arteriovenous malformations (PAVMs) in children with hereditary hemorrhagic telangiectasia (HHT). STUDY DESIGN: This was a single-center study of children who underwent baseline screening for PAVMs using both TTCE and chest computed tomography (CT) for evaluation of HHT. The CT and TTCE results were prospectively reviewed independently by 2 radiologists and 2 cardiologists blinded to the study results. RESULTS: Both intraobserver and interobserver agreement for interpreting TTCE results were excellent (κ = 0.97 and 0.92, respectively) and higher than the interobserver agreement for CT interpretation (κ = 0.75). The sensitivity and specificity of TTCE to predict PAVMs were 1 and 0.82, respectively, and the positive predictive and negative predictive values were 0.39 and 1, respectively. CONCLUSION: TTCE is a sensitive test for PAVMs in children with suspected HHT and can be a useful initial screening tool in pediatric HHT.

Associations between polysomnography measurements and postoperative adverse respiratory events in children with neuromuscular disease.

STUDY OBJECTIVES: To determine if polysomnographic cardiorespiratory outcomes are associated with and could have the potential to predict the presence of postoperative adverse respiratory events in children with neuromuscular disease undergoing any surgical procedure. METHODS: A retrospective cohort study was conducted at a tertiary pediatric institution. The study population included individuals with neuromuscular disease admitted for a surgical intervention under general anesthetic who had undergone a polysomnogram within 1 year before surgical intervention. Polysomnographic indices and postoperative adverse respiratory events were collected through chart review. Multivariable logistic regression was used to model postoperative adverse respiratory events, where PSG results were considered primary predictors. RESULTS: Postoperative adverse respiratory events occurred in 25/61 (41%) of individuals and consisted mainly of desaturations requiring intervention 33 (73%), airway obstruction 15 (33%), and atelectasis (22%). Results from the unadjusted and adjusted logistic regression models indicated that saturation nadir and bulbar dysfunction individually were independent risk factors for postoperative adverse respiratory events with the highest areas under the receiver operating characteristic curve. A multivariable prediction model using these 2 risk factors provided an area under the receiver operating characteristic curve of 0.74 (95% confidence interval, 0.65-0.83). CONCLUSIONS: Knowing that nocturnal oxygen saturation nadir and the presence of bulbar dysfunction are potential predictors of postoperative adverse respiratory events is useful for future counseling of families and surgical planning, in an effort to improve perioperative management and reduce adverse events.

Effectiveness of Intrapleural Tissue Plasminogen Activator and Dornase Alfa vs Tissue Plasminogen Activator Alone in Children with Pleural Empyema: A Randomized Clinical Trial.

Importance: Clinical guidelines recommend that children with pleural empyema be treated with chest tube insertion and intrapleural fibrinolytics. The addition of dornase alfa (DNase) has been reported to improve outcomes in adults but remains unproven in children. Objective: To determine if intrapleural tissue plasminogen activator (tPA) and DNase is more effective than tPA and placebo at reducing hospital length of stay in children with pleural empyema. Design, Setting, and Participants: This multicenter, parallel-group, placebo-controlled, superiority randomized clinical trial included children diagnosed as having pleural empyema requiring drainage aged 6 months to 18 years treated at 6 tertiary Canadian children's hospitals. A total of 379 children were assessed for eligibility; 281 were excluded and 98 were randomized. One child was excluded after randomization for not meeting the inclusion criteria. Data were collected from March 4, 2013, to December 13, 2017. Interventions: Participants underwent chest tube insertion and 3 daily administrations of intrapleural tPA, 4 mg, followed by DNase, 5 mg (intervention group), or 5 mL of normal saline (placebo; control group). Participants, families, clinical staff, and members of the study team were blinded to allocation. Main Outcomes and Measures: The primary outcome was hospital length of stay from chest tube insertion to discharge. Secondary outcomes included time to meeting discharge criteria, time to chest tube removal, mean fever duration, additional pleural drainage procedures, hospital readmissions, and total health care cost. Results: Of the 97 analyzed children with pleural empyema, 52 (54%) were male, and the mean (SD) age was 5.1 (3.6) years. A total of 49 children were randomized to tPA and DNase and 48 were randomized to tPA and placebo. Treatment with tPA and DNase was not associated with decreased hospital length of stay compared with tPA and placebo (mean [SD] length of stay, 9.0 [4.9] vs 9.1 [5.3] days; mean difference, -0.1 days; 95% CI, -2.0 to 2.1; P = .96). Similarly, no significant differences were observed for any of the secondary outcomes. Of the 14 adverse events in the tPA and DNase group, 6 (43%) were serious; of the 21 adverse events in the tPA and placebo group, 8 (38%) were serious. There were no deaths. Conclusions and Relevance: The addition of DNase to intrapleural tPA for children with pleural empyema had no effect on hospital length of stay or other outcomes compared with tPA with placebo. Clinical practice guidelines should continue to support the use of chest tube insertion and intrapleural fibrinolytics alone as first-line treatment for pediatric empyema. Trial Registration: ClinicalTrials.gov identifier: NCT01717742.

Longitudinal decline in lung volume in a population of children with sickle cell disease.

RATIONALE: Sickle cell disease (SCD) results in significant morbidity and mortality attributable to pulmonary complications. The pattern of lung function change across childhood in SCD is not well delineated. OBJECTIVES: To determine if the pattern of lung function in SCD differs from race-matched, predicted values across childhood, to describe that pattern of change, and to examine the effect of clinical covariates on lung function. METHODS: Lung function measurements for children with SCD, aged 8-18 years, from a single center were examined for inclusion. Mixed-model analysis was used to retrospectively review lung function in these children in comparison with those predicted by race-matched reference equations. The contribution of age, sex, Hb level, and beta-globin genotype on longitudinal changes in lung function was examined. MEASUREMENTS AND MAIN RESULTS: Children with SCD show significant decline in spirometric lung volumes across childhood that are concordant with the pattern of change in other measures of lung volume. The average decline for FEV(1) and total lung capacity is 2.93 and 2.15% predicted/year for males and 2.95 and 2.43% predicted/year for females. beta-Globin genotypes known to be associated with more severe disease showed a faster decline in lung function, whereas sex showed an inconsistent effect on lung function. CONCLUSIONS: Lung volumes in children with SCD decline with age. The pattern of decline begins in childhood, and supports a predominately restrictive defect.

Cardiac findings in children with juvenile Dermatomyositis at disease presentation.

BACKGROUND: Juvenile Dermatomyositis (JDM) is a pediatric vasculopathy characterized primarily by skin and muscle involvement. Cardiac findings have been reported in children with JDM but have rarely been investigated in detail. METHODS: We aimed to describe the relevant clinical and laboratory cardiac findings of a cohort of patients with JDM, followed at one centre, at disease diagnosis. RESULTS: We performed a retrospective review of 105 patients with JDM, followed from 1991 to 2007. Six of 70 patients (9%, 6% of the entire cohort) had abnormal electrocardiographic (ECG) findings, while 26 of 54 patients (48%, 25% of the entire cohort) had abnormal echocardiographic (echo) findings. Many of these findings were either mild or unlikely to be a result of JDM. CONCLUSIONS: Our findings suggest that cardiac abnormalities at JDM disease onset are frequently seen, but are rarely significant findings due to disease; however, JDM patients should be considered for screening for cardiac disease as late cardiac complications are well recognized.

Intrapleural Dornase and Tissue Plasminogen Activator in pediatric empyema (DTPA): a study protocol for a randomized controlled trial.

BACKGROUND: A randomized controlled trial of adults with empyema recently demonstrated decreased length of stay in hospital in patients treated with intrapleurally administered dornase alfa and fibrinolytics compared to fibrinolytics alone. Whether this treatment strategy is safe and effective in children remains unknown. METHODS/DESIGN: This study protocol is for a superiority, placebo-controlled, parallel-design, multicenter randomized controlled trial. The participants are previously well children admitted to a children's hospital with a diagnosis of empyema requiring chest tube insertion and fibrinolytics administered intrapleurally. Children will be randomized after the treating physician has decided that pleural drainage is required but prior to chest tube insertion. After chest tube insertion, participants in the treatment group will receive intrapleurally administered tissue plasminogen activator (tPA) 4 mg followed by dornase alfa 5 mg. Participants in the placebo group will receive tPA 4 mg followed by normal saline. Study treatments will be administered once daily for 3 days. All participants, parents or caregivers, clinicians, and research personnel will remain blinded. The primary outcome is length of stay from chest tube insertion to discharge from hospital. Secondary outcomes include time to meeting discharge criteria, chest tube duration, fever duration, need for additional procedures, adverse events, hospital readmission, cost of hospitalization, and mortality. DISCUSSION: This multicenter randomized controlled trial will assess the safety, effectiveness, and cost-effectiveness of combined treatment with dornase alfa and fibrinolytics compared to fibrinolytics alone for the treatment of empyema in children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01717742 . Registered on 8 October 2012.

Symptomatic children with hereditary hemorrhagic telangiectasia: a pediatric center experience.

OBJECTIVE: To assess the clinical and genetic characteristics of symptomatic children with hereditary hemorrhagic telangiectasia (HHT). DESIGN: Cross-sectional study. SETTING: The HHT clinics in Toronto. PARTICIPANTS: All children with symptomatic HHT treated from April 1, 1996, through December 31, 2002. INTERVENTIONS: Participants were screened for visceral arteriovenous malformations (AVMs). Molecular testing was performed in the children or their affected family members. MAIN OUTCOME MEASURES: Prevalence of epistaxis, telangiectases, pulmonary and cerebral AVMs, and genetic characteristics. RESULTS: Fourteen children presented with manifestations of HHT. Seven had cardiorespiratory symptoms related to pulmonary AVMs. Three had neurological symptoms secondary to bleeding from spinal or cerebral AVMs. Two were referred because of skin telangiectases and 2, because of multiple episodes of epistaxis. Screening results revealed a cerebral AVM in 1 of 11 neurologically asymptomatic children. Of the children without respiratory symptoms, 1 was diagnosed as having definite and 1, suspected pulmonary AVMs. Four children with pulmonary AVMs carried an endoglin gene mutation (HHT type 1), and 1 carried an activin receptor-like kinase 1 gene mutation (HHT type 2). The 2 children with spinal AVMs belong to the same HHT type 2 family. No mutation was found in 1 child with pulmonary and 1 with cerebral AVMs. CONCLUSIONS: Visceral AVMs and mucosal telangiectases are present in children with HHT and can lead to life-threatening events. Failure to identify a disease-associated mutation for each child suggests complex mutations or novel HHT genes.

Pediatric long-term home mechanical ventilation: twenty years of follow-up from one Canadian center.

BACKGROUND: Canadian longitudinal data from a pediatric domiciliary long-term mechanical ventilation (LTMV) program is lacking. OBJECTIVE: Our aim was to report on the clinical characteristics and trends of children followed in one of Canada's pediatric home ventilation programs over the past 20 years. METHODS: A retrospective chart review was conducted on patients receiving long-term domociliary mechanical ventilation between January 1, 1991 and December 31, 2011 in a single center. Domiciliary long-term mechanical ventilation was defined as the daily use of invasive mechanical ventilation (IMV) or noninvasive positive pressure ventilation (NiPPV) for at least 3 months, in the users' home or in a long-term residential facility. RESULTS: Between 1991 and 2011, a total of 379 children were identified (313 [83%] with noninvasive ventilation). The median age at initiation was 9.6 years (interquartile range [IQR] 2.9-13.9), the median duration of ventilation was 2.2 years (IQR 0.8-4.9) and 53% were male. Ninety-nine percent of children were cared for at home. The reason for ventilation was "musculoskeletal" in origin for the majority of children. The number of children receiving long-term mechanical ventilation at home increased from 2 in 1991 to 156 children as of December 2011. There was a twofold increase in the number of invasive ventilation initiations in the second 10 years, n = 45 (2001-2011) as compared to the first 10 years, n = 21 (1991-2000). However, there was more than a fivefold increase in the number of noninvasive initiations in the first 10 years, n = 50 (1991-2000) as compared to the second 10 years, n = 263 (2001-2011). The largest growth was in the 13-18 years age group. There were 55 (15%) mortalities over the study period. CONCLUSIONS: In summary, our 20-year retrospective study has shown that there has been an exponential growth in the number of children receiving domiciliary LTMV with the majority of children having favorable outcomes. Our study represents a step towards developing a Canadian registry to design and implement programmatic change for this medically complex population to ensure best practice for these children as well as their families.

Bronchial artery-pulmonary artery malformation as a cause of cryptogenic hemoptysis.

A 12-year-old girl with two episodes of massive hemoptysis was found to have a localized pulmonary hemorrhage on bronchoscopy. Multiple investigations including a computed tomography (CT) angiogram failed to identify the cause. Catheterization of the pulmonary and bronchial vessels uncovered a bronchial artery to pulmonary artery fistula, which was embolized by interventional radiology. This is the first pediatric case of this type of anomaly and it illustrates the importance of angiography in the investigation of cryptogenic hemoptysis.

Respiratory management strategies for Duchenne muscular dystrophy: practice variation amongst Canadian sub-specialists.

PURPOSE: Respiratory management of Duchenne muscular dystrophy (DMD) is not well studied and may vary across centers and practitioners. Our objective was to describe and compare the respiratory management practices of Canadian Pediatric Respirologists and Neuromuscular specialists for children with DMD. METHODS: A web-based survey was sent to all 56 practicing Canadian Pediatric Respirologists and to all 24 members of the Canadian Pediatric Neuromuscular Group (CPNG) who follow children with neuromuscular diseases. The survey included 28 questions about timing and indications for respiratory consultation, sleep disordered breathing (SDB) assessments, and treatments. RESULTS: Thirty eight (68%) pediatric respirologists and 17 (71%) CPNG members responded. Respirologists provide initial consultation after a patient's first admission to hospital with respiratory complications (14/38, 37%) and when symptoms of SDB are present (14/38, 37%). Half of the CPNG members request initial Respirology consultation at the time of DMD diagnosis. Both groups request routine pulmonary function tests. Ninety-six percent of respirologists use maximal inspiratory (MIP) and expiratory pressures (MEP) to assess respiratory muscle strength, whereas 82% of CPNG members additionally use peak cough flow. Assessment for SDB is requested by both groups when pulmonary function is abnormal or patients are symptomatic. Respirologists favor polysomnography, whereas CPNG members use overnight pulse oximetry. Nocturnal non-invasive ventilation and lung volume recruitment (LVR) are used in a minority of patients. CONCLUSIONS: Respirologists and CPNG members provide similar respiratory management of DMD patients, but differ in timing of consultation and choice of tests for pulmonary function and SDB. Canadian practices differ from the American Thoracic Society and Centre for Disease Control guidelines.

Presentation and treatment of monozygotic twins with congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation during sleep secondary to a blunted response to hypercapnia and hypoxia. The current case report describes developmentally normal four-year-old monozygotic twin boys who presented in infancy with variable presentations and clinical severity of congenital central hypoventilation syndrome. Both were managed with noninvasive positive pressure ventilation.

Nocturnal hypoventilation: predictors and outcomes in childhood progressive neuromuscular disease.

OBJECTIVES: To determine: (a) prevalence of clinically unsuspected nocturnal hypoventilation (NH) in a clinic population of children with progressive neuromuscular disease; (b) whether NH can be predicted from clinical/laboratory parameters; and (c) change over 1 year in pulmonary function decline, quality of life and attention in children with NH treated with non-invasive positive pressure ventilation (NPPV) compared with children without NH. DESIGN: Prospective cohort study. SETTING: Two tertiary-care paediatric neuromuscular clinics. PATIENTS: 46 children (6-17 years) with progressive neuromuscular disease without neurocognitive impairment or dystrophinopathy. INTERVENTIONS: Polysomnography, pulmonary function, manual muscle strength, quality of life (CHQ-PF50) and Conners questionnaires. OUTCOME MEASURES: (a) Prevalence of NH; (b) predictive value of surrogate clinical measures for NH; and (c) differences in change over 1 year in pulmonary function, muscle strength, quality of life and attention between children with and without NH. RESULTS: Prevalence of NH was 14.8%, 95% CI 8.0% to 25.7%. Maximal sensitivity and specificity for NH were achieved with thresholds of forced vital capacity <70% and forced expiratory volume in 1 s <65% predicted (sensitivities: 71.4, 71.4; specificities: 64.1, 79.5). Scoliosis also predicted NH (sensitivity 88.9; specificity 80.4). Over 1 year, those with NH had a greater increase in residual volume/total lung capacity (0.075 (-0.003 to 0.168) vs -0.03 (-0.065 to 0.028)), decline in muscle strength (-0.67 (-0.90 to 0.10) vs 0.53 (-0.05 to 0.90)) and worsened perception of health status. CONCLUSIONS: 15% of subjects had clinically unsuspected NH, predicted by moderate pulmonary function test impairment and scoliosis. Over 1 year those with NH had increased gas trapping, decline of muscle strength and worse perception of health status, despite NPPV.