Octavian C. Ioachimescu

Pharmacotherapy of insomnia

Introduction: Insomnia is one of the most prevalent sleep disorders in developed countries, being surpassed only by chronic sleep deprivation. Patients with insomnia tend to have an altered quality of life, impaired daytime functioning and an increased risk of work accidents and motor vehicle crashes. Insomnia is commonly associated with chronic medical conditions, metabolic illnesses and mental disorders (such as depression and anxiety), with which there is a dual, reciprocal relationship. Areas covered: This paper focuses on current pharmacotherapy options for the treatment of insomnia, particularly benzodiazepine receptor agonists, which nowadays represent the mainstay of hypnotic therapy. The melatonin receptor antagonist, ramelteon, is reviewed (an alternative for some patients with only sleep-onset difficulty), as are sedating antidepressants, which are commonly used ‘off-label’ to treat insomnia, despite limited efficacy data and potential significant safety concerns. Orexin (OX) antagonists are also discussed, especially those that block OX2 or both OX1 and OX2 receptors, as these are the most promising new agents for the treatment of insomnia, with encouraging results in preliminary clinical trials. Expert opinion: Research to evaluate and formulate treatments for insomnia is often complicated by the fact that insomnia is usually of multifactorial etiology. Understanding the molecular and receptor mechanisms involved in promoting sleep in varied disorders could provide future approaches in new drug development. In the long term, more randomized controlled trials are needed to assess both short-term and long-term effects of these medications and their efficacy in comorbid diseases that affect sleep quality or quantity.

Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome

Obstructive lung diseases (OLD) such as asthma and chronic obstructive pulmonary disease (COPD) are very prevalent conditions. Disease phenotypes (e.g. chronic bronchitis, emphysema, etc.) often overlap, and significant confusion exists about their optimal nosologic characterization. Obstructive sleep apnoea (OSA) is also a common condition that features bidirectional interactions with OLD. OSA appears to be more commonly seen in patients with OLD, perhaps as a result of shared risk factors, for example obesity, smoking, increased airway resistance, local and systemic inflammation, anti‐inflammatory therapy. Conversely, OSA is associated with worse clinical outcomes in patients with OLD, and continuous positive airway pressure therapy has potential beneficial effects on this vicious pathophysiological interaction. Possible shared mechanistic links include increased parasympathetic tone, hypoxaemia‐related reflex bronchoconstriction/vasoconstriction, irritation of upper airway neural receptors, altered nocturnal neurohormonal secretion, pro‐inflammatory mediators, within and inter‐breath interactions between upper and lower airways, lung volume‐airway dependence, etc. While the term overlap syndrome has been defined as the comorbid association of COPD and OSA, the interaction between asthma and OSA has not been integrated yet nosologically; in this review, the latter will be called alternative overlap syndrome. In an effort to bolster further investigations in this area, an integrated, lumping nomenclature for OSA in the setting of OLD is proposed here—OLDOSA (obstructive lung disease and obstructive sleep apnoea) syndrome.

The utility of spirometry in diagnosing pulmonary restriction

The aim of this retrospective study was to determine the utility of the spirometric measurements FVC, FEV1, and FEV1/FVC in diagnosing pulmonary restriction. Spirometry and lung volume measurements performed on the same patient visit were analyzed. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of (1) FVC < lower limit of normal (LLN) (NHANES III reference values) and (2) FVC < LLN and FEV1/FVC ≥ LLN were compared to diagnose restriction based on lung volume measurements. In all, 18,282 pulmonary function tests from 8,315 patients were analyzed. Twenty-six percent of the patients (n = 2,213) had restriction based on lung volume measurements. The sensitivity, specificity, PPV, and NPV of FVC < LLN to diagnose restriction based on lung volume measurement criteria were 88.6%, 56.8%, 39.9%, and 93.9%, respectively. The sensitivity, specificity, PPV, and NPV of FVC < LLN and FEV1/FVC ≥ normal to diagnose restriction based on lung volume criteria were 72.4%, 87.1%, 64.4%, and 90.7%, respectively. Analysis of ROC curves showed that spirometric criteria based on FVC alone performed better (area under the curve = 0.817) than those based on the combined criteria of FVC and FEV1/FVC (area under the curve = 0.584). Consistent with earlier findings, the negative predictive value for a normal FVC (≥ LLN) to exclude pulmonary restriction was high in this series (up to 95.7%). Also, a spirometric diagnosis of “restriction” (FVC < LLN and FEV1/FVC ≥ LLN) had a positive predictive value of 26.3–73.9%. On this basis, normal FVC can be regarded as excluding restriction with high reliability.

Sleep-Disordered Breathing

Obesity is a critical factor in the development of sleep-disordered breathing (SDB). Snoring is the most frequent nocturnal symptom suggesting a diagnosis of SDB. Other common nighttime symptoms include snorting, gasping, choking, coughing, and witnessed apneas. The most frequent diurnal symptom in SDB is excessive daytime sleepiness. Patients suspected of having SDB should undergo a full night of in-laboratory polysomnography or in-home oligosomnography. SDB includes a spectrum of disorders; the most common are obstructive sleep apnea and central sleep apnea.

Asthma and obstructive sleep apnea: clinical and pathogenic interactions.

Asthma and obstructive sleep apnea (OSA) are among the most prevalent chronic human diseases of the 21st century. They share several risk and aggravating factors such as obesity, smoking, gastroesophageal reflux, sinonasal disease or upper airway involvement, systemic inflammation, etc. Although the association between OSA and chronic obstructive pulmonary disease or “overlap syndrome” is better known and characterized, the association of asthma and OSA or “alternative overlap syndrome” is less clearly defined and understood. Nevertheless, their coexistence has synergistic effects on patient symptoms, response to therapy, and general outcomes. Taxonomically, asthma and OSA are syndromically defined entities that are quite heterogeneous, being characterized by a plethora of clinical phenotypes. The complex interactions between these conditions should take into account more specific etiopathogenic mechanisms or distinct disease endotypes. The potential clinical, pathogenic, and therapeutic significance of the disease endotypes is still emerging and needs further evaluation. We present here a review on the bidirectional relationships between asthma and OSA, including their clinical, pathophysiologic, and therapeutic connections. Furthermore, we propose here to look at these interactions beyond the development of comprehensive inventories of genotypes, clinical and pathophysiologic phenotypes, but in the larger context of obstructive lung and airway disorders, with the goal to reassess meaningful syndromes based on natural history and predictable patient outcomes, which will help us better stratify therapy in an era of personalized medicine.

VAMONOS (Veterans Affairs' Metabolism, Obstructed and Non-Obstructed Sleep) Study: Effects of CPAP Therapy on Glucose Metabolism in Patients with Obstructive Sleep Apnea.

STUDY OBJECTIVES Obstructive sleep apnea (OSA) and type 2 diabetes mellitus (T2DM) are prevalent disorders that pose increased risk of cardiovascular disease and death. The objective of this study was to clarify if continuous positive airway pressure (CPAP) therapy for OSA affects T2DM control and emergence. METHODS Point-of-care, comparative effectiveness study; cross-sectional and longitudinal analyses. RESULTS Our cohort included 928 consecutive patients; 13% were women; 36% were Caucasians and 61% African-Americans. OSA was diagnosed in approximately 738 patients and CPAP was initiated in 718 patients; median duration of therapy was 5 mo (25% to 75% interquartile range [IQR] 3-14). Patients with OSA used CPAP therapy for a median duration of 4.8 h, 34.5% of the nights. Adherence to CPAP was prespecified as follows: good (≥ 70% nights and ≥ 4 h/night), excellent (≥ 80% nights and ≥ 6 h/night) or outstanding (≥ 90% of nights and 8 h/night). Based on objective data, good, excellent, and outstanding compliance were found in only 30%, 20%, and 6%, respectively. Three percent of subjects without CPAP follow-up and less than 4% of those nonadherent to CPAP therapy (based on the established criteria) developed incident T2DM. Incident T2DM developed in only 0.8% of those with good compliance and in none (0%) of those in the excellent and outstanding groups. During follow-up, median weight change was +0.3 kg (IQR -1.8 to 2.7). CONCLUSIONS We found that an outstanding compliance to CPAP reduced fasting blood glucose in patients with OSA. Longitudinally, higher levels of therapeutic adherence may affect the rate of incident impaired fasting glucose, prediabetes, and T2DM, despite the observed weight gains. COMMENTARY A commentary on this article appears in this issue on page 365.

Restless Legs Syndrome

Restless legs syndrome is a common sensorimotor disorder characterized by an urge to move, and associated with uncomfortable sensations in the legs (limbs). Restless legs syndrome can lead to sleep-onset or sleep-maintenance insomnia, and occasionally excessive daytime sleepiness, all leading to significant morbidity. Brain iron deficiency and dopaminergic neurotransmission abnormalities play a central role in the pathogenesis of this disorder, along with other nondopaminergic systems, although the exact mechanisms are still. Intensive care unit patients are especially vulnerable to have unmasking or exacerbation of restless legs syndrome because of sleep deprivation, circadian rhythm disturbance, immobilization, iron deficiency, and use of multiple medications that can antagonize dopamine.

Calcium and Bone Turnover Markers in Acromegaly: A Prospective, Controlled Study.

Context Acromegaly has been associated with calcium-phosphate and bone turnover alterations. Controlled studies of these interactions are sparse. Objective To evaluate calcium and bone metabolism in active and treated acromegaly. Design/Setting/Patients We conducted a controlled, prospective study at a tertiary referral center. We studied 22 patients with acromegaly referred for surgical or medical therapy (ACM) and 22 with nonfunctioning pituitary adenomas referred for surgery (control). Main Outcome Measures Calcium (serum and urine), phosphorus, parathyroid hormone (PTH), 25-hydroxy- and 1,25-dihydroxy-vitamin D, bone turnover markers [serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP)], and cytokines [receptor activator of nuclear factor κB ligand (RANK-L) and osteoprotegerin (OPG)] at baseline and 3 to 6 months after treatment. Results At baseline, the ACM group had lower PTH levels than controls (36.3 ± 13.9 pg/mL vs 56.0 ± 19.9 pg/mL) and higher phosphorus (4.34 ± 0.71 mg/dL vs 3.55 ± 0.50 mg/dL) (P < 0.01). Groups had similar levels of serum and urine calcium and 25-hydroxy- and 1,25-dihydroxy-vitamin D. The ACM group had higher bone turnover markers than control; P1NP and CTX were strongly correlated (r2 = 0.82, P < 0.05). CTX was dependent on age and disease group but not on sex or gonadal status. After treatment of acromegaly, serum calcium (9.52 ± 0.43 mg/dL to 9.26 ± 0.28 mg/dL), phosphorus (4.34 ± 0.71 mg/dL to 3.90 ± 0.80 mg/dL), and CTX (0.91 ± 0.75 ng/mL to 0.63 ± 0.68 ng/mL) decreased, while PTH increased (36.3 ± 13.9 pg/mL to 48.9 ± 16.7 pg/mL) (P < 0.01). 25-hydroxy-vitamin D, P1NP, and RANK-L/OPG ratio did not change significantly. Conclusion Acromegaly patients exhibited PTH-independent calcium-phosphate alterations and enhanced coupled bone formation and resorption. Within 6 months of treatment, bone resorption decreased, whereas RANK-L/OPG changes were inconsistent.

Interpretation of pulmonary function tests: beyond the basics

Although the general framework described in the joint American Thoracic Society/European Respiratory Society guidelines provides a useful and practical method for the interpretation of pulmonary function tests, several other measurements and functional indices, if understood correctly, may help in diagnosis and management of patients with respiratory diseases and in design of research protocols. This review provides information on the underlying physiology, interpretative caveats, and the evidence supporting the use of a number of these indices. Some of these measurements, such as the inspiratory fraction, inspiratory capacity/total lung capacity (IC/TLC), may offer additional prognostic information, while others, such as residual volume (RV)/TLC and forced expiratory volume in 3 s/forced vital capacity (FEV3/FVC), may help fill in the gaps between patient symptoms and more traditional indices of pulmonary function. Although most studies of non-traditional indices focus on airflow-limiting disorders, many can be fruitfully applied in other settings. Understanding the physiology that catalyzed these investigations will undoubtedly enrich the functional assessment armamentarium of the practicing clinician and researcher.

Sleep disorders in COPD

In patients with chronic obstructive pulmonary disease (COPD, defined as a combination of emphysema and chronic bronchitis), sleep quality and architecture are often altered. The very common nocturnal symptoms of cough, dyspnea, chest tightness, and wheezing disturb sleep and lead to daytime dissatisfaction and additional symptoms in these patients. Sleep is often fragmented, while rapid eye movement sleep is generally diminished in duration. Due to nocturnal symptoms and possibly the use of certain medications, some patients with COPD experience difficulty initiating or maintaining sleep, symptoms that define insomnia. The known physiological changes that occur during sleep may have more profound consequences in COPD, such as persistent hypoxia and hypercapnia. The comorbid association of obstructive sleep apnea (OSA) and COPD (the “overlap syndrome”) may lead to more severe and persistent nocturnal hypoxemia and development of pulmonary hypertension, cor pulmonale, cardiac arrhythmia, and even sudden cardiac death. Diagnosing sleep abnormalities in patients with COPD is important, as it should address not only poorer sleep quality, but also co-existent sleep disordered breathing or other sleep conditions.