Characteristics and outcomes in children with congenital central hypoventilation syndrome on long-term mechanical ventilation in the Netherlands.

Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by central hypoventilation, leading to the majority of patients being dependent on ventilatory support during sleep. This condition is often accompanied by various associated symptoms, due to a PHOX2B gene variant involved in neuronal crest cell migration. This study is the first to review the characteristics and outcomes in children with CCHS on long-term mechanical ventilation in the Netherlands. We performed a retrospective study of all CCHS patients treated in the 4 Centers of Home Mechanical Ventilation of the University Medical Centers in the Netherlands from 2000 till 2022 by collecting information from the electronic medical records, documented during follow-up. We included 31 patients, out of which 27 exhibited a known genetic profile associated with CCHS, while no PHOX2B variant was identified in the remaining patients. Among the 27 patients with known genetic profiles, 10 patients had a non-polyalanine repeat expansion mutation (NPARM), followed by 20/27, 20/25, and 20/26 polyalanine repeat expansion mutations (PARMs) in descending order. The most common presentation involved respiratory failure or apneas during the neonatal period with an inability to wean off ventilation. The majority of patients required ventilatory support during sleep, with four patients experiencing life-threatening events related to this dependency. Daily use of ventilatory support varied among different genetic profiles. All genotypes reported comorbidities, with Hirschsprung's disease and cardiac arrhythmias being the most reported comorbidities. Notably, Hirschprung's disease was exclusively observed in patients with a 20/27 PHOX2B variant. CONCLUSION: Our study results suggest that in our cohort, the genotype is not easily associated to the phenotype in CCHS. Consistent with these findings and international literature, we recommend a thorough annual evaluation for all patients with CCHS to ensure optimal management and follow-up. WHAT IS KNOWN: • The majority of CCHS patients are dependent on ventilatory support. • Variants in the PHOX2B gene are responsible for the characteristics of CCHS. WHAT IS NEW: • This study provides insight into the clinical course and long-term outcomes of CCHS patients in the Netherlands. • In CCHS, the genotype is not easily associated with the phenotype, requiring a thorough life-long follow-up for all patients.

Starting HMV at home: a reasonable option for many patients?

BACKGROUND AND OBJECTIVE: In the current study, we undertook a more detailed exploration of the reasons why patients undergoing HMV were screened out of a recently published study in order to better understand how applicable home initiation of HMV is under real life conditions. METHODS: All referred patients who had an indication for starting HMV were screened to participate in the Homerun study. In this trial 512 patients were screened out of the study. Those patients not enrolled in the trial were divided into the following 3 groups: (1) those not fulfilling the inclusion criteria; 2) those meeting the exclusion criteria and 3) those excluded on the basis of medical or organisation reasons. Each group was then further divided into those who would likely have been suitable for initiation of HMV at home in real world practice and those who were unsuitable. RESULTS: Based on inclusion criteria (group 1) 116 patients could not start HMV in real life, while this was 245 patients in the study. Based on the exclusion criteria (group 2) 11 patients could not start in real life while this was 79 in the study. One hundred and eighty-eight could not be enrolled in the study due to medical and organisational reasons ( group 3), while in real life this was only 95. CONCLUSION: This study indicates that more than 55% of patients who did not participate in the Homerun study could have started HMV at home in real life.

Nocturnal non-invasive ventilation in COPD patients with prolonged hypercapnia after ventilatory support for acute respiratory failure: a randomised, controlled, parallel-group study.

INTRODUCTION: The effectiveness of non-invasive positive pressure ventilation (NIV) in COPD patients with prolonged hypercapnia after ventilatory support for acute respiratory failure (ARF) remains unclear. We investigated if nocturnal NIV in these patients prolongs the time to readmission for respiratory causes or death (primary endpoint) in the following 12 months. METHODS: 201 COPD patients admitted to hospital with ARF and prolonged hypercapnia >48 h after termination of ventilatory support were randomised to NIV or standard treatment. Secondary outcomes were daytime arterial blood gasses, transcutaneous PCO2 during the night, lung function, health-related quality-of-life (HRQL), mood state, daily activities and dyspnoea. RESULTS: 1 year after discharge, 65% versus 64% of patients (NIV vs standard treatment) were readmitted to hospital for respiratory causes or had died; time to event was not different (p=0.85). Daytime PaCO2 was significantly improved in NIV versus standard treatment (PaCO2 0.5 kPa (95% CI 0.04 to 0.90, p=0.03)) as was transcutaneous PCO2 during the night. HRQL showed a trend (p=0.054, Severe Respiratory Insufficiency questionnaire) in favour of NIV. Number of exacerbations, lung function, mood state, daily activity levels or dyspnoea was not significantly different. DISCUSSIONS: We could not demonstrate an improvement in time to readmission or death by adding NIV for 1 year in patients with prolonged hypercapnia after an episode of NIV for ARF. There is no reason to believe the NIV was not effective since daytime PaCO2 and night-time PCO2 improved. The trend for improvement in HRQL favouring NIV we believe nevertheless should be explored further. TRIAL REGISTRATION NUMBER: NTR1100.

Continuous and bilevel positive airway pressure may improve radiotherapy delivery in patients with intra-thoracic tumors.

Background: Minimizing tumor motion in radiotherapy for intra-thoracic tumors reduces side-effects by limiting radiation exposure to healthy tissue. Continuous or Bilevel Positive Airway Pressure (CPAP/BiPAP) could achieve this, since it could increase lung inflation and decrease tidal volume variability. We aim to identify the better CPAP/BiPAP setting for minimizing tumor motion. Methods: In 10 patients (5 with lung cancer, 5 with other intra-thoracic tumors), CPAP/BiPAP was tested with the following settings for 10 min each: CPAP 5, 10 and 15 cmH2O and BiPAP 14/10 cmH2O with a lower (7 breaths/min) and higher back-up respiratory rate (BURR initially 1 breath/min above the spontaneous breathing frequency, with the option to adjust if the patient continued to initiate breaths). Electrical impedance tomography was used to analyse end-expiratory lung impedance (EELI) as an estimate of end-expiratory lung volume and tidal impedance variation (TIV) as an estimate of tidal volume. Results: Nine out of ten patients tolerated all settings; one patient could not sustain CPAP-15. A significant difference in EELI was observed between settings (χ2 22.960, p < 0.001), with most increase during CPAP-15 (median (IQR) 1.03 (1.00 - 1.06), normalized to the EELI during spontaneous breathing). No significant differences in TIV and breathing variability were found between settings. Conclusions: This study shows that the application of different settings of CPAP/BiPAP in patients with intra-thoracic tumors is feasible and tolerable. BiPAP with a higher BURR may offer the greatest potential for mitigating tumor motion among the applied settings, although further research investigating tumor motion should be conducted.

Long-term oral appliance therapy in obstructive sleep apnea syndrome: a controlled study on dental side effects.

OBJECTIVES: This study aimed to assess possible dental side effects associated with long-term use of an adjustable oral appliance compared with continuous positive airway pressure (CPAP) in patients with the obstructive sleep apnea syndrome and to study the relationship between these possible side effects and the degree of mandibular protrusion associated with oral appliance therapy. MATERIALS AND METHODS: As part of a previously conducted RCT, 51 patients were randomized to oral appliance therapy and 52 patients to CPAP therapy. At baseline and after a 2-year follow-up, dental plaster study models in full occlusion were obtained which were thereupon analyzed with respect to relevant variables. RESULTS: Long-term use of an oral appliance resulted in small but significant dental changes compared with CPAP. In the oral appliance group, overbite and overjet decreased 1.2 (±1.1) mm and 1.5 (±1.5) mm, respectively. Furthermore, we found a significantly larger anterior-posterior change in the occlusion (-1.3 ± 1.5 mm) in the oral appliance group compared to the CPAP group (-0.1 ± 0.6 mm). Moreover, both groups showed a significant decrease in number of occlusal contact points in the (pre)molar region. Linear regression analysis revealed that the decrease in overbite was associated with the mean mandibular protrusion during follow-up [regression coefficient (ß) = -0.02, 95 % confidence interval (-0.04 to -0.00)]. CONCLUSIONS: Oral appliance therapy should be considered as a lifelong treatment, and there is a risk of dental side effects to occur. CLINICAL RELEVANCE: Patients treated with the oral appliance need a thorough follow-up by a dentist or dental-specialist experienced in the field of dental sleep medicine.

Long-term oral appliance therapy in obstructive sleep apnea syndrome: a controlled study on temporomandibular side effects.

The objective of this study was to assess variations in the occurrence of temporomandibular disorders (TMDs) and the risk of developing pain and function impairment of the temporomandibular complex in obstructive sleep apnea syndrome (OSAS) patients treated with either an oral appliance (mandibular advancement device) or continuous positive airway pressure (CPAP) in a 2-year follow-up study. In addition, we assessed the relationship between the mean mandibular protrusion and the frequency of wearing the appliance during follow-up with the occurrence of pain and function impairment of the temporomandibular complex. Fifty-one patients were randomized to oral appliance therapy and 52 patients to CPAP therapy. TMDs (diagnosed according to the Axis I Research Diagnostic Criteria for TMD), pain intensity and disability and mandibular function impairment were recorded at baseline, after 2 months, 1 year and 2 years of therapy. Only in the initial period of treatment the occurrence of pain-related TMDs was considerably higher (24%) in the oral appliance group compared to CPAP (6%). Oral appliance therapy furthermore resulted in more temporomandibular pain compared to CPAP (odds ratio 2.33, 95% confidence interval (1.22-4.43)). However, there were no limitations in mandibular function in both groups during the (entire) follow-up period. Although generally not serious and of transient nature, oral appliance therapy results in more pain-related TMDs in the initial period of use compared with CPAP therapy. Oral appliance therapy is associated with increased pain in the temporomandibular complex in the initial period of use. Because of the transient nature, this pain is not a reason to contra-indicate an oral appliance in OSAS patients. Moreover, TMDs and the risk of developing pain and function impairment of the temporomandibular complex appear limited with long-term oral appliance use.

Home mechanical ventilation: the Dutch approach.

In the Netherlands we have an unique organisation of only 4 centres being responsible for all patients who need Home Mechanical ventilation(HMV). Nationwide criteria for referral and initiation of HMV are stated in our national guideline and recently a unique national learning management system (LMS) for all caregivers and professionals was developed. A nationwide multi-centric research program is running and every centre is participating. In this paper we provide information about the evolution of HMV in the Netherlands during the last 30 years, including details about the number of patients, different diagnose groups, residence and the type of ventilators.

New tools in pulmonary rehabilitation.

In patients with more severe chronic obstructive pulmonary disease (COPD), the benefits of rehabilitation might not be clear and, therefore, new treatment options have been developed to increase the benefits of rehabilitation. This review provides an overview of new approaches being developed as an addition to exercise training. In turn, the benefits of adding ventilatory support, oxygen, anabolics or neuromuscular stimulation to a rehabilitation programme will be discussed. While positive benefits for a number of these approaches have been found, many questions remain unsolved. Therefore, at present, we cannot recommend these new tools as part of the routine management of patients with COPD who start a rehabilitation programme.

Validation of a transcutaneous CO(2) monitor in adult patients with chronic respiratory failure.

BACKGROUND: Home mechanical ventilation is usually started in hospital as arterial blood gas sampling is deemed necessary to monitor CO(2) and O(2) adequately during institution of ventilatory support. A non-invasive device to reliably measure CO(2) transcutaneously would alleviate the need for high care settings for measurement and open the possibility for home registration. OBJECTIVES: In this study we investigated whether the TOSCA® transcutaneous CO(2) (PtcCO(2)) measurements, performed continuously during the night, reliably reflect arterial CO(2) (PaCO(2)) measurements in adults with chronic respiratory failure. METHODS: Paired measurements were taken in 15 patients hospitalised to evaluate their blood gas exchange. Outcomes were compared 30 min, 2, 4, 6 and 8 h after attaching the sensor to the earlobe. A maximum difference of 1.0 kPa and 95% limits of agreement (LOA) of 1 kPa between CO(2) pressure measurements, following the analysis by Bland and Altman, were determined as acceptable. RESULTS: Mean PtcCO(2) was 0.4 kPa higher (LOA -0.48 to 1.27 kPa) than mean PaCO(2) after 30 min. These figures were 0.6 kPa higher (LOA -0.60 to 1.80 kPa) after 4 h, with a maximum of 0.72 kPa (LOA 0.35 to 1.79 kPa) after 8 h. The corresponding values for changes in PtcCO(2) versus PaCO(2) were not significant (ANOVA). CONCLUSIONS: PtcCO(2) measurement, using TOSCA, is a valid method showing an acceptable agreement with PaCO(2) during 8 h of continuous measurement. Therefore, this device can be used to monitor CO(2) adequately during chronic ventilatory support.

[Home oxygen therapy; indications are still limited]. / Zuurstoftherapie thuis.

Prescription of long term oxygen treatment ( LTOT),based on old studies, is only indicated if there is severe hypoxaemia at rest (PaO2 < 8,0 kPa) and should be used atleast 15 hours per day.However as newer treatments like nocturnal non-invasive ventilatory support showed to be beneficial, LTOT stands not on its own but should be part of a multidimensional approach in individual patients with COPD.

Cardiac assessment of patients with late stage Duchenne muscular dystrophy.

Background. Duchenne muscular dystrophy (DMD) patients used to die mainly from pulmonary problems. However, as advances in respiratory care increase life expectancy, mortality due to cardiomyopathy rises. Echocardiography remains the standard diagnostic modality for cardiomyopathy in DMD patients, but is hampered by scoliosis and poor echocardiographic acoustic windows in adult DMD patients. Multigated cardiac radionuclide ventriculography (MUGA) does not suffer from these limitations. N-terminal proBNP (NTproBNP) has shown to be a diagnostic factor for heart failure. We present our initial experience with plasma NT-proBNP measurement in the routine screening and diagnosis of cardiomyopathy in adult mechanically ventilated DMD patients.Methods. Retrospective study, 13 patients. Echocardiography classified left ventricular (LV) function as preserved or depressed. NT-proBNP was determined using immunoassay. LV ejection fraction (LVEF) was determined using MUGA.Results. Median (range) NT-proBNP was 73 (25 to 463) ng/l. Six patients had an NT-proBNP >125 ng/l. Seven patients showed an LVEF <45% on MUGA. DMD patients with depressed LV function (n=4) as assessed by echocardiography had significantly higher median NT-proBNP than those (n=9) with preserved LV function: 346 (266 to 463) ng/l versus 69 (25 to 257) ng/l (p=0.003). NT-proBNP significantly correlated with depressed LV function on echocardiogram and with LVEF determined by MUGA.Conclusion. Although image quality of MUGA is superior to echocardiography, the combination of echocardiography and NT-proBNP achieves similar results in the evaluation of left ventricular function and is less time consuming and burdensome for our patients. We advise to add NT-proBNP to echocardiography in the routine cardiac assessment of DMD patients. (Neth Heart J 2009;17:232-7.).

Nocturnal non-invasive ventilation in addition to rehabilitation in hypercapnic patients with COPD.

BACKGROUND: Long-term non-invasive positive pressure ventilation (NIPPV) might improve the outcomes of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) with chronic respiratory failure. A study was undertaken to investigate whether nocturnal NIPPV in addition to pulmonary rehabilitation improves health-related quality of life, functional status and gas exchange compared with pulmonary rehabilitation alone in patients with COPD with chronic hypercapnic respiratory failure. METHODS: 72 patients with COPD were randomly assigned to nocturnal NIPPV in addition to rehabilitation (n = 37) or rehabilitation alone (n = 35). Outcome measures were assessed before and after the 3-month intervention period. RESULTS: The Chronic Respiratory Questionnaire total score improved 15.1 points with NIPPV + rehabilitation compared with 8.7 points with rehabilitation alone. The difference of 7.5 points was not significant (p = 0.08). However, compared with rehabilitation alone, the difference in the fatigue domain was greater with NIPPV + rehabilitation (mean difference 3.3 points, p<0.01), as was the improvement in the Maugeri Respiratory Failure questionnaire total score (mean difference -10%, p<0.03) and its cognition domain (mean difference -22%, p<0.01). Furthermore, the addition of NIPPV improved daytime arterial carbon dioxide pressure (mean difference -0.3 kPa; p<0.01) and daily step count (mean difference 1269 steps/day, p<0.01). This was accompanied by an increased daytime minute ventilation (mean difference 1.4 l; p<0.001). CONCLUSION: Non-invasive ventilation augments the benefits of pulmonary rehabilitation in patients with COPD with chronic hypercapnic respiratory failure as it improves several measures of health-related quality of life, functional status and gas exchange.

Health-related quality of life in COPD patients with chronic respiratory failure.

The Maugeri Respiratory Failure (MRF-28) and Severe Respiratory Insufficiency (SRI) questionnaires were recently developed to assess health-related quality of life (HRQoL) in patients with chronic respiratory failure, although not exclusively in chronic obstructive pulmonary disease (COPD) patients. The aim of the present study was to investigate whether the MRF-28 and SRI are reliable and valid HRQoL questionnaires in COPD patients with chronic hypercapnic respiratory failure (CHRF). In total, 72 COPD patients with CHRF underwent pulmonary function and exercise testing, and completed the MRF-28, the SRI, the Chronic Respiratory Questionnaire (CRQ), the Hospital Anxiety and Depression Scale, the Groningen Activity and Restriction Scale and two dyspnoea indexes. Physical domain scores of the questionnaires correlated with exercise tolerance, dyspnoea and daily activities, while psychological domains correlated strongly with anxiety and depression. Anxiety scores accounted for 51 and 56% of the total explained variance in total CRQ and SRI scores, respectively. The emphasis of the MRF-28 was restrictions in activities of daily living (52% of total variance). In conclusion, the present study showed that the Maugeri Respiratory Failure and Severe Respiratory Insufficiency questionnaires were reliable and valid questionnaires in chronic obstructive pulmonary disease patients with chronic hypercapnic respiratory failure. While the emphasis in the Maugeri Respiratory Failure questionnaire is on activities of daily living, the Severe Respiratory Insufficiency questionnaire, like the Chronic Respiratory Questionnaire, is more related to anxiety and depression.

Obstructive sleep apnea therapy.

In clinical practice, oral appliances are used primarily for obstructive sleep apnea patients who do not respond to continuous positive airway pressure (CPAP) therapy. We hypothesized that an oral appliance is not inferior to CPAP in treating obstructive sleep apnea effectively. We randomly assigned 103 individuals to oral-appliance or CPAP therapy. Polysomnography after 8-12 weeks indicated that treatment was effective for 39 of 51 persons using the oral appliance (76.5%) and for 43 of 52 persons using CPAP (82.7%). For the difference in effectiveness, a 95% two-sided confidence interval was calculated. Non-inferiority of oral-appliance therapy was considered to be established when the lower boundary of this interval exceeded -25%. The lower boundary of the confidence interval was -21.7%, indicating that oral-appliance therapy was not inferior to CPAP for effective treatment of obstructive sleep apnea. However, subgroup analysis revealed that oral-appliance therapy was less effective in individuals with severe disease (apnea-hypopnea index > 30). Since these people could be at particular cardiovascular risk, primary oral-appliance therapy appears to be supported only for those with non-severe apnea.

Developing concepts in the pulmonary rehabilitation of COPD.

Randomised trials have demonstrated that pulmonary rehabilitation (PR) can improve dyspnoea, exercise tolerance and health related quality of life. Rehabilitation has traditionally been provided in secondary care to patients with moderate to severe disease. Current concepts are however recommending that it should be delivered in a primary and community care setting for patients with milder disease. There are several opportunities for spreading the word for PR in primary care. One of these is to improve access to PR for all those disabled by their disease by the increase of community schemes and one such scheme being utilised in Canada is reviewed. The essential components of PR include behavior change, patient self-management and prescriptive exercise. In the last decade new strategies have been developed to enhance the effects of exercise training. An overview of these new approaches being an adjunct to exercise training is reviewed. Although the role of exercise training is well established, we are only just beginning to appreciate the importance of behavior change and patient self-management in contributing to improved health and diminished healthcare resource utilisation.

Predictors of obstructive sleep apnea-hypopnea treatment outcome.

Oral appliance therapy is an alternative to continuous positive airway pressure (CPAP) for treating the obstructive sleep apnea-hypopnea syndrome. However, the ability to pre-select suitable candidates for either treatment is limited. The aim of this study was to assess the value of relevant variables that can predict the outcome of oral appliance and CPAP therapy. Fifty-one patients treated with oral appliance therapy and 52 patients treated with CPAP were included. Relevant clinical, polysomnographic, and cephalometric variables were determined at baseline. The predictive value of variables for treatment outcome was evaluated in univariate and multivariate analyses. The outcome of oral appliance therapy was favorable, especially in less obese patients with milder sleep apnea and with certain craniofacial characteristics (mandibular retrognathism in particular). Neither univariate nor multivariate analyses yielded variables that reliably predicted the outcome of CPAP. We conclude that the variables found in this study are valuable for pre-selecting suitable candidates for oral-appliance therapy.

[Respiratory insufficiency in patients with progressive neuromuscular disease can sometimes be treated effectively with ventilatory support]. / Respiratoire insufficiëntie bij patiënten met progressieve neuromusculaire ziekte soms goed te behandelen door ademhalingsondersteuning.

Three patients with myotonic dystrophy (MD) developed respiratory failure. The first was a 55-year-old man with MD who had been admitted elsewhere with pneumonia and respiratory failure. After discharge he was re-admitted with respiratory failure due to respiratory pump failure. Ultimately, he was given a tracheostomy and was ventilated during the night. The second patient was a 38-year-old man who was admitted to the intensive care unit when he could not be weaned off the ventilator following cholecystectomy for symptomatic gall stones. It appeared that he had partial respiratory failure due to MD and overweight. Ultimately he was able to be weaned during the day with nightly non-invasive ventilation. The third patient was a 55-year-old woman who was admitted with recurrent pneumonia and respiratory failure. She appeared to have chronic respiratory failure due to MD. She was ventilated at night via a tracheostomy. All three patients reported a gradual decline in physical and mental performance in the years preceding this acute episode. All three experienced a remarkable recovery of performance after the institution of mechanical ventilatory support. Respiratory failure that develops over a number of years can be easily missed in aging patients with slowly progressing neuromuscular disease. Timely recognition may lead to improved survival and quality of life by the application of non-invasive ventilatory support.

[18 years experience with mechanical ventilation in patients with Duchenne muscular dystrophy]. / 18 jaar ervaring met chronische beademing bij patiënten met spierdystrofie van Duchenne.

OBJECTIVE: To find out which patients with Duchenne muscular dystrophy are eligible for starting home mechanical ventilation and what the survival rate is. DESIGN: Retrospective. METHOD: In 48 patients with Duchenne muscular dystrophy who were treated with home ventilation from 1987, the results were assessed in the follow-up visit in February 2005. Initially, ventilation was only given through a tracheotomy (TPPV), but after starting up a multidisciplinary neuromuscular consultation, non-invasive ventilation (NIPPV) was offered in an earlier stage of the disease. The following data were derived from the outpatient medical record: indication for ventilation, vital capacity (VC), arterial blood gas values, duration of ventilation up to February 2005, survival and causes of death. RESULTS: 15 patients died. The 5-year survival rate was 75% from the start of mechanical ventilation and 67% (18/27) of the patients were still living at home at the time of the follow-up visit. The most important causes of death were cardiomyopathy (5/15) and tracheal bleeding (3/15). The group of patients who started ventilation before 1995 (n = 17) had a significantly smaller VC than the group (n = 31) who started after the neuromuscular consultation was set up. The PaCO2 during daytime was significantly higher in the group that started ventilation before 1995 compared to the group that started later. CONCLUSION: Home mechanical ventilation can be implemented effectively in patients with Duchenne dystrophy, with a 5-year survival of 75%.