Telemonitoring-guided ambulatory fixed CPAP titration versus ambulatory APAP titration in moderate obstructive sleep apnea: A non-inferiority randomized controlled trial.

The present study aimed to evaluate whether titration of fixed continuous positive airway pressure at home using telemonitoring produces patient outcomes equal to auto-adjusting positive airway pressure titration at home for patients with moderate obstructive sleep apnea. Patients were randomized with a 1:1 allocation ratio to receive either auto-adjusting positive airway pressure titration based on the median of the 95th percentile pressure across seven nights or fixed continuous positive airway pressure titration based on a fixed calculated pressure and specific adaptations after telemonitoring of device data after 3 and 7 nights. The results of the ambulatory titration were evaluated with in-laboratory polysomnography after 2 weeks. We hypothesized that fixed continuous positive airway pressure titration would be non-inferior to auto-adjusting positive airway pressure titration in respect to continuous positive airway pressure adherence at a 3-month follow-up. A non-inferiority margin of -0.75 hr was prespecified. One-hundred and four patients were randomly allocated to fixed continuous positive airway pressure (n = 52) and auto-adjusting positive airway pressure (n = 52) titration. The mean difference and the 95% confidence intervals in continuous positive airway pressure adherence after 3 months between the two arms were 0.80 (-0.08, 1.69) hr. The non-inferiority hypothesis was confirmed as the lower one-sided 97.5% confidence interval for the mean difference was above the prespecified margin. Patients in the fixed continuous positive airway pressure titration arm were titrated at significantly lower pressure level and had a significantly lower amount of average leaks compared with auto-adjusting positive airway pressure-titrated patients, while there was no difference in residual obstructive apnea-hypopnea index on polysomnography. Telemonitoring enables ambulatory continuous positive airway pressure titration with fixed pressure that is non-inferior to ambulatory titration with auto-adjusting pressure in patients with moderate obstructive sleep apnea.

Comorbidity clusters in patients with moderate-to-severe OSA.

PURPOSE: Obstructive sleep apnea (OSA) is a prevalent and multifaceted disease. To date, the presence and severity of objectively identified comorbidities and their association with specific OSA phenotypes, CPAP adherence, and survival remain to be elucidated. The aim of this study is to cluster patients with OSA based on 10 clinically important objectively identified comorbidities, and to characterize the comorbidity clusters in terms of clinical and polysomnographic characteristics, CPAP adherence, and survival. STUDY DESIGN AND METHODS: Seven hundred ten consecutive patients starting CPAP for moderate-to-severe OSA were included. Comorbidities were based on generally accepted cutoffs identified in the peer-reviewed literature. Self-organizing maps were used to order patients based on presence and severity of their comorbidities and to generate clusters. RESULTS: The majority of patients were men (80%). They were generally middle-aged (52 years) and obese (BMI: 31.5 kg/m2). Mean apnea-hypopnea index (AHI) was 41 ± 20 per h of sleep. More than 94% of the patients had one or more comorbidities with arterial hypertension, dyslipidemia, and obesity being the most prevalent. Nine comorbidity clusters were identified. The clinical relevance of these comorbidity clusters was highlighted by the difference in symptoms, PSG parameters, and cardiovascular risk. Also, differences in CPAP adherence, improvements in ESS, and long-term survival were present between the clusters. CONCLUSION: Comorbidity prevalence in patients with OSA is high, and different comorbidity clusters, demonstrating differences in cardiovascular risk, CPAP adherence, and survival, can be identified. These results further substantiate the need for a comprehensive assessment of patients with OSA beyond the AHI.

Late-onset Pompe disease (LOPD) in Belgium: clinical characteristics and outcome measures.

BACKGROUND: Late-onset Pompe disease (LOPD) is a rare, hereditary, progressive disorder that is usually characterized by limb-girdle muscle weakness and/or respiratory insufficiency. LOPD is caused by mutations in the acid alpha-glucosidase (GAA) gene and treated with enzyme replacement therapy (ERT). METHODS: We studied the clinical, brain imaging, and genetic features of the Belgian cohort of late-onset Pompe disease patients (N = 52), and explored the sensitivity of different outcome measures, during a longitudinal period of 7 years (2010-2017), including the activity limitations ActivLim score, 6 min walking distance (6MWD), 10 m walk test (10MWT), MRC sum score, and forced vital capacity (FVC) sitting/supine. RESULTS: In Belgium, we calculated an LOPD prevalence of 3.9 per million. Mean age at onset of 52 LOPD patients was 28.9 years (SD: 15.8 y), ranging from 7 months to 68 years. Seventy-five percent (N = 39) of the patients initially presented with limb-girdle weakness, whereas in 13% (N = 7) respiratory symptoms were the only initial symptom. Non-invasive ventilation (NIV) was started in 37% (N = 19), at a mean age of 49.5 years (SD: 11.9 y), with a mean duration of 15 years (SD: 10.2 y) after symptom onset. Brain imaging revealed abnormalities in 25% (N = 8) of the patients, with the presence of small cerebral aneurysm(s) in two patients and a vertebrobasilar dolichoectasia in another two. Mean diagnostic delay was 12.9 years. All patients were compound heterozygotes with the most prevalent mutation being c.-32-13 T > G in 96%. We identified two novel mutations in GAA: c.1610_1611delA and c.186dup11. For the 6MWD, MRC sum score, FVC sitting and FVC supine, we measured a significant decrease over time (p = 0.0002, p = 0.0001, p = 0.0077, p = 0.0151), which was not revealed with the ActivLim score and 10MWT (p > 0.05). CONCLUSIONS: Awareness on LOPD should even be further increased because of the long diagnostic delay. The 6MWD, but not the ActivLim score, is a sensitive outcome measure to follow up LOPD patients.

Diaphragm plication for unilateral diaphragm paralysis: a case report and review of the literature.

Unilateral diaphragm paralysis is an often not recognised cause of dyspnoea. We present a patient with a unilateral phrenic nerve paralysis treated with diaphragmatic plication. Patient presented with life-style limiting dyspnoea and pulmonary function showed a decrease in FVC when lying down. Since there was no improvement after respiratory muscle training, plication of the hemidiaphragm was performed by a small thoracotomy. The patient improved with regard to respiratory complaints and lung function. Furthermore, we also demonstrate for the first time a significant improvement in exercise capacity with accompanying striking amelioration of quality of life. The patient is now in follow up up for more than 2 years and the impressive improvement in exercise capacity remains present. Surgical treatment of unilateral diaphragm paralysis has been described in case reports and in small series since 1985. Although comparison of the available data is difficult a diaphragm plication seems an effective and safe procedure for patients with symptomatic, acquired unilateral diaphragm paralysis. Improvement of dyspnoea is present in the majority of patients and we even observed an impressive amelioration in exercise capacity. Consequently, it seems appropriate to propose plication to patients with clear symptoms from the moment spontaneous recovery seems unlikely; yet, prospective randomised controlled studies are needed to prove this.

Treating primary insomnia: clinical effectiveness and predictors of outcomes on sleep, daytime function and health-related quality of life.

Primary insomnia, as defined by DSM-IV-TR, refers to a persistent sleep disturbance which is not connected to a current psychiatric or physical condition, but significantly impairs social and occupational functioning. This study explored the impact of Cognitive Behavioral Therapy for Insomnia (CBT-i) on sleep, daytime functioning and health-related quality of life (HRQoL). Next, we investigated which factors predicted positive treatment outcome by examining demographics, insomnia characteristics, baseline levels of daytime function, HRQoL, sleep-disruptive beliefs and psychological health on post-treatment sleep quality, daytime function and HRQoL. 138 consecutive primary insomnia patients completed questionnaires pre- and post-treatment and at 6 months follow-up. After CBT-i, robust clinical improvements were observed in sleep, daytime function and HRQoL, regardless of age, gender, type or duration of the complaint. Patients with pre-treatment severe insomnia, pronounced daytime impairment and low psychological well-being benefited most.

[Cognitive-behavioural therapy for primary insomnia: effectiveness in a clinical setting]. / Cognitieve gedragstherapie voor primaire insomnia: effectiviteit in een klinische setting.

BACKGROUND: The effectiveness of cognitive behavioural therapy for insomnia (cbt-i) has been demonstrated in randomised controlled trials (rct's) with primary insomnia patients and, more recently, with comorbid insomnia patients. The clinical impact of the treatment is mainly on sleep quality and the use of medication and to a lesser extent on daytime functioning. So far there have been very few studies of the effectiveness of cbt-i in clinical settings. AIM: To examine the effectiveness of cbt-i for primary insomnia via an uncontrolled prospective study in a clinical tertiary care setting. METHOD: We included 76 patients with primary insomnia, most of whom having been referred by their gp or medical specialist to the Leuven University Centre of Sleep, who followed a 6-week course of cbt-i as a group. Effects of cbt-i on primary and secondary outcome measures were studied. results cbt-i resulted in a significant improvement in all primary sleep variables such as sleep onset, sleep efficiency and sleep quality. The increase in total sleep time was less substantial, probably as a result of the specific sleep restriction guidelines. There was also a significant improvement on several secondary parameters, in particular dysfunctional cognitions, affective state, general health and use of medication. CONCLUSIONS: cbt-i has a significant impact on sleep quality, medication use and daytime functioning in primary insomniacs in a clinical tertiary care setting.

N150 in amygdalar ERPs in the rat: is there modulation by anticipatory fear?

The hypothesis was tested whether the amygdalar N150 of rats, a slow, negative component in the event-related potential from the lateral amygdala, is sensitive to a state of anxious anticipation. A conditioning procedure was applied in which a series of six auditory stimuli was followed by a shock when presented alone, but not when the auditory stimuli were preceded by a visual stimulus. Heart rate recordings confirmed that the auditory stimulus train induced a state of increasing anticipatory fear and that this condition was modulated by the visual stimulus. During behavioral training, a N150 appeared in the amygdalar event-related potential evoked by the auditory stimuli, replicating previous findings. However, the amplitude of the N150 was not affected by whether or not the visual stimulus had been presented before. These results failed to support the idea that the N150 is related to the expectancy of an aversive event. An alternative interpretation, emphasizing the increase in arousal and attention that is inherent to aversive learning, is discussed.

Treatment of chronic respiratory failure in kyphoscoliosis: oxygen or ventilation?

Patients with kyposcoliosis and chronic respiratory insufficiency are treated either with home oxygen therapy or ventilation. Kyphoscoliotic patients demonstrate impaired ventilatory mechanics, consequently ventilation seems to be the treatment of choice. Yet, no randomised controlled trials (CRT) exist to prove it. Most investigators find it difficult to ethically justify a CRT. Therefore, the current authors performed the following retrospective study: survival and pulmonary function were analysed in all consecutive kyphoscoliotic patients who started long-term oxygen therapy (LTO group; n=15, aged 62+/-11 yrs (mean+/-SD)) or LTO plus nocturnal nasal intermittent positive pressure ventilation (nNIPPV group; n=18, aged 61+/-7 yrs) in the Dept of Pulmonology (University Hospital Gasthuisberg, Leuven) between 1990-2002. Prior to treatment partial pressure of oxygen (PO2) was lower, partial pressure of carbon dioxide (PCO2) tended to be higher and vital capacity (VC) tended to be lower in the nNIPPV group than in the LTO group (PO2 5.9+/-1 versus 6.7+/-0.9 kPa (44+/-8 versus 50+/-7 mmHg), PCO2 8+/-1 versus 7.3+/-0.9 kPa (60+/-8 versus 55+/-7 mmHg), VC 32+/-12 versus 40+/-16% predicted, or 645+/-244 versus 970+/-387 mL). In the nNIPPV group the 1-yr survival was higher (100% versus 66%). nNIPPV patients demonstrated an improvement in PO2 (breathing air) +54%, PCO2 (breathing air) -21%, VC +47% and maximal static inspiratory mouth pressure +33%; these improvements were absent in the LTO group. In conclusion, nocturnal nasal intermittent positive pressure ventilation, plus long-term oxygen therapy results in more favourable survival and changes in blood gases and respiratory function than long-term oxygen therapy alone.

Cyclophosphamide rescue therapy for chronic rejection after lung transplantation.

BACKGROUND: Obliterative bronchiolitis remains the leading cause of late mortality after heart-lung and lung transplantation. Although several treatment options have been advocated, none has proven to be very successful. Cyclophosphamide is effective in the treatment of idiopathic pulmonary fibrosis, and chronic rejection after lung transplantation is also a fibroproliferative process. We therefore conducted an open, uncontrolled study to look at the effect of cyclophosphamide rescue therapy in the treatment of chronic rejection in lung transplant recipients. METHODS: Between October 1996 and March 1998 cyclophosphamide was prescribed to 7 patients with chronic and persistent rejection who failed to respond to conventional therapy (pulse steroids or antilymphocyte products or both). RESULTS: Cyclophosphamide therapy was initiated on postoperative day 478+/-366. At that time 2 patients were in bronchiolitis obliterans syndrome stage 0, 3 patients in stage 1, and 2 patients in stage 2. Their best postoperative forced expiratory volume in one second (FEV1) was 2.19+/-0.75 L. Three months before the start of cyclophosphamide the FEV1 had declined to 1.90+/-0.83 L, with a further decline to 1.63+/-0.64 L at the time of initiating cyclophosphamide. In 6 of the 7 patients the FEV1 stabilized or increased after cyclophosphamide had been started (mean FEV1 3 and 6 months after cyclophosphamide of 1.77+/-0.58 L and 1.79+/-0.48 L, respectively). One patient died 18 months after the introduction of cyclophosphamide due to progressive obliterative bronchiolitis. In one patient cyclophosphamide had to be stopped because of persistent leucopenia. CONCLUSIONS: Cyclophosphamide might be a promising therapeutic alternative for the treatment of chronic persistent rejection after lung transplantation.

Relief of sleep apnoea after treatment of acromegaly: report of three cases and review of the literature.

Sleep apnoea syndrome (SAS) is common in acromegalic patients. Occasionally, the relief of apnoeas after treatment of the acromegaly has been documented. We report the cases of three patients with acromegaly and severe obstructive sleep apnoea, who demonstrated a manifest improvement (respiratory disturbance index (RDI) <20) after treatment with octreotide, indicating that this drug may be effective in this disturbance. In one case, SAS disappeared although the growth hormone level was not fully normalized. This raises the intriguing hypothesis that octreotide has an effect on respiratory control or on the upper airway, that is not directly related to its action on production of growth hormone.

Respiratory dysfunction in multiple sclerosis: a prospective analysis of 60 patients.

This study aimed to determine the relationship between pulmonary function, respiratory muscle function and neurological function in multiple sclerosis (MS). Sixty patients (27 males and 33 females) aged 27-75 yrs (mean +/- SD 48 +/- 12 yrs) were prospectively studied. The Kurtzke Expanded Disability Status Scale (EDSS; range 0-10) score was 6.5 +/- 1.5; and the different Functional Systems Scores (FSS; ranges 0-5 and 0-6) were: pyramidal 3.4 +/- 1.1; brain stem 1.9 +/- 1.2; mental 1.3 +/- 0.9; cerebellar 2.2 +/- 1.0; sphincter 1.8 +/- 1.5; visual 1.4 +/- 1.4; and sensory 2.0 +/- 1.5. Results of lung function tests were: vital capacity (VC) 80 +/- 23% of predicted; single-breath transfer factor of the lung for carbon monoxide (TL, CO, sb) 83 +/- 17% pred; maximal static expiratory mouth pressure (MEP) 30 +/- 16% pred; and maximal static inspiratory mouth pressure (MIP) 47 +/- 23% pred, indicating a marked respiratory muscle dysfunction, with a minor restrictive defect. In 70% of the patients, a transcutaneous oxygen saturation (Stc, O2) of less than 92% at night was found. Comparison of lung function and disability scores showed that the abnormalities in both tended to be correlated to each other, and that this was significant for EDSS versus lung volumes, for most FSS with VC, and also for some FSS with MEP and/or MIP. Duration of disease was significantly correlated with the EDSS, but not with the different FSS scores (with the exception of mental status) and not with lung function. Multiple sclerosis leads to lung function abnormalities attributable to respiratory pump dysfunction.

Correlation between functional, radiological and anatomical abnormalities in upper airway obstruction (UAO) due to tracheal stenosis.

Few data are available on the relative sensitivity of different lung function tests in upper airway obstruction (UAO) and on the correlation of these tests with radiological estimations of tracheal stenosis. This paper is based on patients with a goiter or tracheal tumor and in healthy subjects breathing through rigid resistors, as well as on literature data. Lung function abnormalities present a specific pattern in UAO: this is characterised by a typical shape of the maximal flow-volume curve, a marked reduction in peakflow (PEF) and only minor changes in routine spirometry (e.g. FEV1, which thus tends to underestimate the stenosis). The clinical relevance of the lung function abnormalities in UAO can be estimated from their relationship with the exercise limitation: a moderate exercise limitation to about 60% pred is found if PEF is reduced to about 40% pred, and Raw is increased to about 600% pred (in which instance FEV1 is still 75% pred). This limitation grossly corresponds to a UAO of about 6 mm diameter. No good correlation is found between lung function abnormalities and the radiological stenosis (CT-scan or X-ray): CT-scan or X-ray are only moderately correlated with each other. Moreover, stenosis can be visualised through X-ray in only about 60% of the cases.

Long-term oxygen therapy with concentrators and liquid oxygen.

The National Institute for Insurance of Disease and Disablement (RIZIV/INAMI) in Belgium reimburses the costs of long term oxygen therapy (LTOT) by concentrators since 1984 and by liquid oxygen since 1988 for specific categories of patients supervised by approved medical centers. Since then we prescribed these therapies for 83 patients (49 with COPD, 12 with lung fibrosis, 22 with miscellaneous diseases). Since 1984 40 concentrators were prescribed of which 34 have been installed and 11 were still operating in July 1992 at the end of the study: 12 patients died, 2 stopped LTOT and 10 switched to liquid oxygen. Since 1989 43 patients started with liquid oxygen systems, together with the 10 patients who switched from concentrators to liquid oxygen, thus 53 liquid oxygen systems had been described and 46 were still in use in July 1992: 5 patients died and 2 stopped LTOT. Patient characteristics at entry were: age 62 +/- 11 years (mean +/- 1SD), PaO2 50 +/- 6 mmHg, PaCO2 47 +/- 10 mmHg, polycythemia in 12%, clinical right heart failure in 47% and ECG signs of right ventricle hypertrophy in 70%. Two year survival was 75% for the whole group and 60% for the COPD patients. In patients with COPD improvement of PaO2 (on air) after 1 year of LTOT (+ 10 +/- 8 mmHg in survivors versus 0 +/- 6 mmHg in non-survivors) was significantly related to survival (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Isolated lung transplantation; initial experience at the University Hospitals Leuven. Leuven Lung Transplant Group.

Lung transplantation nowadays has become a therapeutic modality in the treatment of patients with a variety of end-stage lung diseases. Between July 1991 and December 1992, twelve patients received an isolated lung transplant (eight single lungs and four double lungs) at the University Hospitals of Leuven. The indication for transplantation was emphysema in five patients, pulmonary fibrosis in three, cystic fibrosis in three and primary pulmonary hypertension in one. There were four early, in-hospital deaths (30%): two from sepsis and multi-organ failure, one from anoxia following a bronchial dehiscence and another patient exsanguinated following stent insertion for a partial bronchial dehiscence. Three more patients have died during follow-up: two from chronic respiratory failure secondary to the development of obliterative bronchiolitis (one at 8 months and one at 17 months), and one from a late bronchovascular fistula 4 months following transplantation. The overall actuarial one and two year-survival was 50.0% and 41.6% respectively. All patients discharged from hospital were oxygen free with an improved lung function and exercise capacity. We conclude that lung transplantation is a viable therapeutic option for selected patients with end-stage, irreversible lung disease. In our experience, the bronchial anastomosis remains an important keystone in the early success. Lung transplantation provides a good quality of life in patients free from infection and rejection. Nevertheless, chronic rejection resulting in obliterative bronchiolitis is a major problem in long-term survivors.