Loutfi S. Aboussouan

α1-antitrypsin deficiency

Summary α1-antitrypsin deficiency is a genetic disorder that affects about one in 2000–5000 individuals. It is clinically characterised by liver disease and early-onset emphysema. Although α1 antitrypsin is mainly produced in the liver, its main function is to protect the lung against proteolytic damage from neutrophil elastase. The most frequent mutation that causes severe α1-antitrypsin deficiency arises in the SERPINA 1 gene and gives rise to the Z allele. This mutation reduces concentrations in serum of α1 antitrypsin by retaining polymerised molecules within hepatocytes: an amount below the serum protective threshold of 11 μmol/L increases risk for emphysema. In addition to the usual treatments for emphysema, infusion of purified α1 antitrypsin from pooled human plasma represents a specific treatment and raises the concentrations in serum and epithelial-lining fluid above the protective threshold. Evidence suggests that this approach is safe, slows the decline of lung function, could reduce infection rates, and might enhance survival. However, uncertainty about the cost-effectiveness of this expensive treatment remains.

Determinants of hypercapnia in obese patients with obstructive sleep apnea: a systematic review and metaanalysis of cohort studies.

BACKGROUND Inconsistent information exists about factors associated with daytime hypercapnia in obese patients with obstructive sleep apnea (OSA). We systematically evaluated these factors in this population. METHODS We included studies evaluating the association between clinical and physiologic variables and daytime hypercapnia (Paco(2), >or= 45 mm Hg) in obese patients (body mass index [BMI], >or= 30 kg/m(2)) with OSA (apnea-hypopnea index [AHI], >or= 5) and with a < 15% prevalence of COPD. Two investigators conducted independent literature searches using Medline, Web of Science, and Scopus until July 31, 2008. The association between individual factors and hypercapnia was expressed as the mean difference (MD). Random effects models were used to account for heterogeneity. RESULTS Fifteen studies (n = 4,250) fulfilled the selection criteria. Daytime hypercapnia was present in 788 patients (19%). Age and gender were not associated with hypercapnia. Patients with hypercapnia had higher BMI (MD, 3.1 kg/m(2); 95% confidence interval [CI], 1.9 to 4.4) and AHI (MD, 12.5; 95% CI, 6.6 to 18.4) than eucapnic patients. Patients with hypercapnia had lower percent predicted FEV(1) (MD, -11.2; 95% CI, -15.7 to -6.8), lower percent predicted vital capacity (MD, -8.1; 95% CI, -11.3 to -4.9), and lower percent predicted total lung capacity (MD, -6.4; 95% CI, -10.0 to -2.7). FEV(1)/FVC percent predicted was not different between hypercapnic and eucapnic patients (MD, -1.7; 95% CI, -4.1 to 0.8), but mean overnight pulse oximetric saturation was significantly lower in hypercapnic patients (MD, -4.9; 95% CI, -7.0 to -2.7). CONCLUSIONS In obese patients with OSA and mostly without COPD, daytime hypercapnia was associated with severity of OSA, higher BMI levels, and degree of restrictive chest wall mechanics. A high index of suspicion should be maintained in patients with these factors, as early recognition and appropriate treatment can improve outcomes.

Disorders of Pulmonary Function, Sleep, and the Upper Airway in Charcot-Marie-Tooth Disease

Charcot-Marie Tooth disease (CMT) encompasses several inherited peripheral motor-sensory neuropathies and is one of the most common inherited neuromuscular diseases. Charcot–Marie–Tooth disease can be associated with several disorders that may be encountered by the pulmonary physician, including restrictive pulmonary impairment, sleep apnea, restless legs, and vocal cord dysfunction. Restrictive pulmonary impairment has been described in association with phrenic nerve dysfunction, diaphragm dysfunction, or thoracic cage abnormalities. Central sleep apnea may be associated with diaphragm dysfunction and hypercapnia, whereas obstructive sleep apnea has been reported as possibly due to a pharyngeal neuropathy. Restless legs and periodic limb movement during sleep are found in a large proportion of patients with CMT2, a type of CMT associated with prominent axonal atrophy. Vocal cord dysfunction, possibly due to laryngeal nerve involvement, is found in association with several CMT types and can often mimic asthma. There may be special therapeutic considerations for the treatment of those conditions in individuals with CMT. For instance, bilevel positive airway pressure may be more appropriate than continuous positive airway pressure (CPAP) for the treatment of sleep apnea in the individual with concomitant restrictive pulmonary impairment. The prominence of peripheral neuropathy as a cause of the restless legs syndrome in CMT may justify treatment with neuropathic medications as opposed to the more commonly recommended dopaminergic agents. The risk of progression to bilateral vocal cord dysfunction in CMT and the risk of aspiration with laryngeal neuropathy may limit the therapeutic options available for vocal cord paralysis.

Detection of alpha-1 antitrypsin deficiency: A review

Screening studies reveal a much larger number of individuals expected to have alpha-1 antitrypsin deficiency than is clinically recognized, with estimates that only about 2-10% of such individuals have been diagnosed. In the context that recognition of alpha-1 antitrypsin may prompt specific interventions (e.g., smoking avoidance, testing of family members, genetic counseling, and consideration of augmentation therapy), diagnosis is important, inviting much attention for efforts to identify affected individuals. Strategies to identify affected individuals include both population-based screening and targeted detection, and available studies have employed both approaches, though large-scale population-based screening is challenging. As reviewed in this paper, targeted-detection studies have generally produced a higher rate of detecting disease, and tend to be more successful with easier sampling techniques. Strategies to enhance detection in targeted studies have included awareness campaigns, easy testing techniques (such as evaluation of dried blood spots and home, confidential testing), and inclusive criteria for testing which span the full spectrum of clinical manifestations of alpha-1 antitrypsin deficiency.

Sleep-disordered Breathing in Neuromuscular Disease

Sleep-disordered breathing in neuromuscular diseases is due to an exaggerated reduction in lung volumes during supine sleep, a compromised physiologic adaptation to sleep, and specific features of the diseases that may promote upper airway collapse or heart failure. The normal decrease in the rib cage contribution to the tidal volume during phasic REM sleep becomes a critical vulnerability, resulting in saw-tooth oxygen desaturation possibly representing the earliest manifestation of respiratory muscle weakness. Hypoventilation can occur in REM sleep and progress into non-REM sleep, with continuous desaturation and hypercarbia. Specific characteristics of neuromuscular disorders, such as pharyngeal neuropathy or weakness, macroglossia, bulbar manifestations, or low lung volumes, predispose patients to the development of obstructive events. Central sleep-disordered breathing can occur with associated cardiomyopathy (e.g., dystrophies) or from instability in the control of breathing due to diaphragm weakness. Mitigating factors such as recruitment of accessory respiratory muscles, reduction in REM sleep, and loss of normal REM atonia in some individuals may partially protect against sleep-disordered breathing. Noninvasive ventilation, a standard-of-care management option for sleep-disordered breathing, can itself trigger specific sleep-disordered breathing events including air leaks, patient-ventilator asynchrony, central sleep apnea, and glottic closure. These events increase arousals, reduce adherence, and impair sleep architecture. Polysomnography plays an important role in addressing pitfalls in the diagnosis of sleep-disordered breathing in neuromuscular diseases, identifying sleep-disordered breathing triggered by noninvasive ventilation, and optimizing noninvasive ventilation settings.

Noninvasive positive pressure ventilation for stable outpatients: CPAP and beyond.

Noninvasive positive pressure ventilation (NIPPV) has been used in outpatients with sleep apnea, sleep disorders associated with heart failure, restrictive pulmonary diseases (subsuming neuromuscular diseases and thoracic cage deformities), severe stable chronic obstructive pulmonary disease, and the obesity-hypoventilation syndrome. NIPPV in these settings has resulted in significant physiologic benefits, improved quality of life, and in some cases longer survival. We discuss the modes of NIPPV, current indications, and potential benefits. We discuss the different types of noninvasive positive pressure ventilation, the specific conditions in which they can be used, and the evidence supporting their efficacy in outpatients.

Noninvasive positive pressure ventilation: Increasing use in acute care

In the past 2 decades, noninvasive positive pressure ventilation (NIPPV) has been increasingly used in acute respiratory failure to avoid the risks associated with intubation. It is now considered standard first-line therapy in several situations. In this review, we summarize how NIPPV has evolved, the current level of evidence that supports its use in various clinical situations, its potential contraindications, and its limitations in acute respiratory failure. How this mode has evolved, and its indications and contraindications in specific acute care conditions.

Long-Term Continuous Positive Airway Pressure Therapy Normalizes High Exhaled Nitric Oxide Levels in Obstructive Sleep Apnea

STUDY OBJECTIVES Upper airway inflammation and oxidative stress have been implicated in the pathogenesis of obstructive sleep apnea (OSA) and may be linked to cardiovascular consequences. We prospectively examined fraction of exhaled nitric oxide (FENO), a surrogate marker of upper airway inflammation using a portable nitric oxide analyzer (NIOX MINO). DESIGN In consecutive adult nonsmokers with suspected OSA, FENO was measured immediately before and after polysomnographic studies, and within 1-3 months following continuous positive airway pressure (CPAP) therapy. MEASUREMENT AND RESULTS FENO levels were increased in the 75 patients with OSA compared to the 29 controls, both before sleep (13.4 ± 6.5 ppb vs. 6.5 ± 3.5; p < 0.001) and after sleep (19.0 ± 7.7 ppb vs. 6.9 ± 3.7; p < 0.001). Furthermore, in patients with OSA, FENO levels were significantly higher post-sleep than pre-sleep (19.0 ± 7.7 ppb vs. 13.4 ± 6.5; p < 0.001), while there was no significant overnight change in patients without OSA. The rise in FENO correlated with the apnea-hypopnea index (r = 0.65, p < 0.001), nadir oxygen saturation (r = 0.54, p < 0.001), and arousal index (r = 0.52, p < 0.001). Thirty-seven of these patients underwent CPAP titration and treatment. Successful titration was associated with a lower overnight increase in FENO (7.2 ± 3.3 vs. 11.0 ± 4.3, p = 0.02). FENO levels declined after 1-3 months of CPAP therapy (11.7 ± 4.4 ppb, p < 0.001). CONCLUSIONS FENO levels are elevated in OSA, correlate with severity, and decrease after positive pressure therapy. This study supports the role of upper airway inflammation in OSA pathogenesis and a possible role for FENO in monitoring CPAP therapy.

Polysomnographic determinants of nocturnal hypercapnia in patients with sleep apnea.

STUDY OBJECTIVES Identify polysomnographic and demographic factors associated with elevation of nocturnal end-tidal CO2 in patients with obstructive sleep apnea. METHODS Forty-four adult patients with obstructive sleep apnea were selected such that the maximal nocturnal end-tidal CO2 was below 45 mm Hg in 15 studies, between 45 and 50 mm Hg in 14, and above 50 mm Hg in 15. Measurements included mean event (i.e., apneas or hypopneas) and mean inter-event duration, ratio of mean post- to mean pre-event amplitude, and percentage of total sleep time spent at an end-tidal CO2 < 45, 45-50, and > 50 mm Hg. An integrated nocturnal CO2 was calculated as the sum of the products of average end-tidal CO2 at each time interval by percent of total sleep time spent at the corresponding time interval. RESULTS The integrated nocturnal CO2 was inversely correlated with mean post-apnea duration, with lesser contributions from mean apnea duration and age (R (2) = 0.56), but did not correlate with the apnea-hypopnea index, or the body mass index. Mean post-event to mean pre-event amplitude correlated with mean post-apnea duration (r = 0.88, p < 0.001). Mean apnea duration did not correlate with mean post-apnea duration. CONCLUSIONS Nocturnal capnometry reflects pathophysiologic features of sleep apnea, such as the balance of apnea and post-apnea duration, which are not captured by the apnea-hypopnea index. This study expands the indications of capnometry beyond apnea detection and quantification of hypoventilation syndromes.

Sleep-Disordered Breathing in Neuromuscular Disease: Diagnostic and Therapeutic Challenges

&NA; Normal sleep‐related rapid eye movement sleep atonia, reduced lung volumes, reduced chemosensitivity, and impaired airway dilator activity become significant vulnerabilities in the setting of neuromuscular disease. In that context, the compounding effects of respiratory muscle weakness and disease‐specific features that promote upper airway collapse or cause dilated cardiomyopathy contribute to various sleep‐disordered breathing events. The reduction in lung volumes with neuromuscular disease is further compromised by sleep and the supine position, exaggerating the tendency for upper airway collapse and desaturation with sleep‐disordered breathing events. The most commonly identified events are diaphragmatic/pseudo‐central, due to a decrease in the rib cage contribution to the tidal volume during phasic rapid eye movement sleep. Obstructive and central sleep apneas are also common. Noninvasive ventilation can improve survival and quality of sleep but should be used with caution in the context of dilated cardiomyopathy or significant bulbar symptoms. Noninvasive ventilation can also trigger sleep‐disordered breathing events, including ineffective triggering, autotriggering, central sleep apnea, and glottic closure, which compromise the potential benefits of the intervention by increasing arousals, reducing adherence, and impairing sleep architecture. Polysomnography plays an important diagnostic and therapeutic role by correctly categorizing sleep‐disordered events, identifying sleep‐disordered breathing triggered by noninvasive ventilation, and improving noninvasive ventilation settings. Optimal management may require dedicated hypoventilation protocols and a technical staff well versed in the identification and troubleshooting of respiratory events.