Daytime predictors of sleep disordered breathing in children and adolescents with neuromuscular disorders

Abstract

Sleep disordered breathing with or without nocturnal hypercapnic hypoventilation is a common complication of respiratory muscle weakness in childhood neuromuscular disorders. Nocturnal hypercapnic hypoventilation as a sign of respiratory muscle fatigue, portends a particularly poor prognosis. We aimed at identifying daytime predictors of sleep disordered breathing at its onset and sleep disordered breathing with nocturnal hypercapnic hypoventilation. Forty-nine children and adolescents (11.3±4.4 years) with progressive neuromuscular disorders were studied with inspiratory vital capacity, peak inspiratory pressure, arterial blood gases, polysomnography, and a ten-item symptoms questionnaire. Daytime respiratory function was prospectively compared with polysomnographic variables. Sleep disordered breathing was found in 35/49 patients (71%). Twenty-four (49%) had sleep disordered breathing with nocturnal hypercapnic hypoventilation. Inspiratory vital capacity and peak inspiratory pressure, but not symptom score, correlated with sleep disordered breathing and severity of nocturnal hypercapnic hypoventilation. Sleep disordered breathing-onset was predicted by inspiratory vital capacity<60% (sens. 97%, spec. 87%). Sleep disordered breathing with nocturnal hypercapnic hypoventilation was predicted by inspiratory vital capacity<40% (sens. 96%, spec. 88%) and PaCO₂>40 mmHg (sens. 92%, spec. 72%,). Sleep disordered breathing can reliably be predicted from simple daytime respiratory function tests, which, if applied systematically, will improve recognition of nocturnal respiratory failure.

Introduction

Sleep disordered breathing (SDB) is common in neuromuscular diseases [1], [2]. The principle cause is disease-related loss of respiratory muscle function, which in the context of sleep-induced reduction of respiratory muscle tone and drop of central drive results in limited capacity to compensate for sleep-related drop of alveolar ventilation. SDB is particularly prevalent in rapid eye movement (REM) sleep [3], [4], [5], a period of maximal muscle atonia, and in the presence of diaphragm dysfunction [6]. It can manifest in different ways, depending on the relative contribution of upper airway or diaphragm dysfunction. Hypopneas with desaturations in REM sleep are most common, particularly at early disease stages. As disease progresses, hypercapnic alveolar hypoventilation, first in REM, then in non-REM sleep prevails as the predominant marker of waning respiratory muscle force.

We have recently shown in adults with myopathic diseases that the degree of ventilatory restriction impacts directly on pattern and severity of SDB, and that nocturnal hypercapnic hypoventilation (NHHV) was prevalent at vital capacities below 40% predicted [7]. Because NHHV is likely to advance the development of cor pulmonale and daytime respiratory failure and may impact unfavorably on survival, timely recognition is important. Furthermore, as therapy in way of non-invasive ventilation may effectively normalize gas exchange and improve prognosis [8], [9], [10], [11].

Unfortunately, SDB and NHHV are rarely apparent on daytime presentation. Symptoms may be subtle and non-specific. In children, failure to thrive may be the only indicator. High index of suspicion and polysomnographic evaluation, therefore, are required for a diagnosis [12].

We investigated lung and respiratory muscle function and respiration during sleep in children with neuromuscular diseases with the intent of identifying daytime predictors of SDB at its onset and for SDB with NHHV. We were particularly interested in establishing the predictive values of readily available function tests such as vital capacity, peak inspiratory muscle pressure, daytime blood gas analysis, and symptoms.

Sixty-one children and adolescents (22 girls and 27 boys, aged 11.3±4.4 (range 5–18 years)) were referred and prospectively evaluated between January 1997 to December 2000. Reasons for referral were assessment of respiratory function prior to corrective spinal surgery (n=6), failure to thrive/suspected SDB (n=32), or advanced clinical disease (n=23). Twelve children were excluded from the study, five under the age of 6 years because reliable lung function test could not be obtained, seven because of acute respiratory failure necessitating emergent non-invasive ventilation. Eighteen patients had congenital muscular dystrophy (10.4±4.1 years), seven had Duchenne muscular dystrophy (DMD, 14.6±4.0 years), five had intermediate spinal muscular atrophy type I–II (SMA, 8.4±1.1 years), seven had SMA type II (8.9±2.5 years), four had limb girdle dystrophy (14.0±3.7 years), three had juvenile type of acid maltase deficiency (11.7±6.2 years), two had nemaline myopathy (6 and 14 years), two had hereditary motor and sensor neuropathy type I (11 and 12 years), and one subject had centronuclear myopathy (8 years). A pediatric neurologist had assessed all patients and the diagnosis had been confirmed at the histopathological, and where possible at the molecular level. Twenty-eight patients were wheelchair-bound. No patient was using ventilatory support before entering the study.

Inspiratory vital capacity (IVC), forced expiratory lung volumes (FEV₁), forced vital capacity (FVC), and respiratory muscle function were measured with a hand-held spirometer/manometer (ZAN Meßgeräte, Obertulba, Germany). The best of three consistent efforts (<5% variability) was used. Predicted values were derived from published data [13]. Respiratory muscle function was assessed as peak inspiratory pressure (PIP). Arterial blood gas tensions were determined from the arterialized ear lobe blood in an automated blood gas analyzer (AVL 500, AVL LIST GmbH Medizintechnik, Graz, Austria) on the evening prior to polysomnography.

PSG was performed according to the standards of the American Thoracic Society [14]. Signals were recorded onto a computerized workstation (Compumedics, Melbourne, Australia). Transcutaneous carbon dioxide tension (PtcCO₂) was recorded simultaneously (Radiometer, Copenhagen, Denmark). No oxygen was supplemented. Sleep stages and respiratory parameters were scored manually. Apnoeas were defined as >10 s cessation of airflow and respiratory effort (central) or >10 s cessation of airflow with persisting effort (obstructive). Hypopneas were defined as >10 s reduction of airflow or thoracoabdominal effort accompanied by >3% oxyhemoglobin desaturation or electroencephalographic (EEG) arousal of >3 s [15]. SDB was considered present if respiratory disturbance index (RDI) was above five events per hour of total sleep or above ten per hour of REM sleep. NHHV was defined as PtcCO₂>50 mmHg for >50% of total sleep time (TST) [16]. Respiratory failure (RF) was defined as daytime hypercapnia (PaCO₂≥45 mmHg), repeatedly measured over a period of respiratory stability.

Subjects were asked to complete a ten-item questionnaire on quality of sleep, nocturnal breathing problems, nocturnal sweating, morning headaches, appetite, concentration, mood, daytime function and general well-being, frequency of chest infections, and dyspnea. The questions had to be answered along a ten point scoring scale, the high end indicating intense and the low end a few complaints. Maximal total score was 100 points.

Analysis was performed with Statistica 5.1 software package (StatSoft, Inc., Tulsa, OK). Correlations between parameters of daytime function and nocturnal gas exchange were analyzed using the Spearman's rank test. Group comparison was performed with the Mann–Whitney U-test. All results are presented as mean±standard deviation. P<0.05 was considered as significant. Multiple regression analysis was used to identify the major determinant of SDB, the dependent variable being percentage of TST spend with PtcCO₂>50 mmHg, the independent variables being age, IVC, and PIP. Receiver operator curves (ROCs) were constructed for each independent variable, cut-off points separating patients with and without SDB were calculated by bi-dimensional analysis and with equal sensitivity/specificity (ratio 1:1). The variable with the largest area under the curve (AUC) was considered the strongest predictor of SDB.